User login
Getting Warmer
The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.
A 3-month-old otherwise healthy, immunized female presented to clinic with 2 days of intermittent low-grade fevers (maximum, 100º F), decreased oral intake, and sleepiness. Her pediatrician noted a faint, maculopapular rash on her trunk and extremities with mild conjunctival injection bilaterally that appeared that day, according to her mother. The infant otherwise appeared alert, well-hydrated, and without respiratory distress. She had no history of sick contacts or recent travel. She was prescribed amoxicillin for empiric treatment of a possible bacterial sinusitis or pharyngitis, despite a negative rapid strep antigen test.
At this age, multiple conditions can cause rashes. Given that this is early in the course of illness, without focal symptoms but with low-grade fevers, the initial differential diagnosis is broad and would include infectious, rheumatologic, and hematologic-oncologic etiologies, although the latter would be less likely. While the patient’s mother reports decreased oral intake, the fact that the patient is alert and appears hydrated is encouraging, suggesting time to observe and see if other symptoms present that may assist in elucidating the cause. The history of increased sleepiness warrants further investigation of meningeal signs, which would point to a central nervous system infection.
While streptococcal infection is possible, it would be uncommon at this age. The patient would have a higher fever and focal infection, and the rash does not appear consistent unless it was described as “sandpaper” in feel and appearance. A negative rapid strep test, while not sensitive, further supports this impression. A low-grade fever and rash would be consistent with a viral syndrome and, given the conjunctival injection, adenovirus, cytomegalovirus, rhinovirus, and Epstein Barr virus (EBV) are possibilities. Without ocular discharge, bacterial conjunctivitis would be unlikely. Another consideration would be Kawasaki disease, though it would be too early to diagnose this condition since at least 5 days of fever are required. Next steps include a detailed physical examination, looking for other focal signs such as swelling or desquamation of hands and feet, lymphadenopathy, strawberry tongue, and mucositis. Rather than empirically starting antibiotics, it would be more reasonable to observe her with close outpatient follow-up. The patient’s family should be instructed to monitor for additional and/or worsening symptoms, further decreased oral intake, signs of dehydration, or changes in alertness.
At home, the patient completed 5 doses of amoxicillin but continued to be febrile (maximum, 102.6º F). She was taken to a local emergency department on day 6 of her illness. She had worsening conjunctival injection and progression of the rash, involving the palms and soles. She was noted to have edema of hands and feet without desquamation (Figure 1). She had no oral mucous membrane changes and no cervical lymphadenopathy. Cerebrospinal fluid (CSF) was unremarkable, and empiric treatment with intravenous (IV) ceftriaxone was initiated. Complete blood count was notable for a white blood cell (WBC) count of 18.9 k/μL (normal range, 6.0-17.0); hemoglobin, 7.6 g/dL (normal range, 10-13); mean corpuscular volume, 84 (normal range, 74-108); and platelet count, 105 k/μL (normal range, 150-400). A peripheral blood smear revealed no abnormal cells. C-reactive protein (CRP) was elevated at 6.5 mg/dL (normal range, 0.0-0.6). She was admitted for further management.
Infection remains on the differential diagnosis given the elevated WBC count. Since the patient has completed a reasonable course of antibiotics, a bacterial infection would be less likely but not fully excluded. The cultures obtained would be helpful if they become positive, but given that the patient has been on antibiotics, a negative culture may represent partial sterilization and would not rule out infection. A viral infection continues to be high on the differential, but one would expect that symptoms and fever would have begun to abate. The normal peripheral blood smear makes a hematologic disorder less likely.
Kawasaki disease has risen on the differential with 5 days of fever surpassing 102º F. She has 3 of 5 primary clinical criteria, including conjunctival injection, rash, and edema of the hands and feet. Desquamation of the peripheral extremities would not be expected until the convalescent phase. A diagnosis of typical Kawasaki disease would require a fourth criterion, either oral mucous membrane changes or cervical lymphadenopathy. She meets the criteria for atypical or incomplete Kawasaki disease, which requires only fever for at least 5 days, elevated CRP, and 2 or 3 additional clinical criteria. She also meets supplemental laboratory criteria with an elevated WBC count greater than 15,000/μL, normocytic and normochromic anemia for age, and elevated CRP. Urinalysis positive for pyuria or serum albumin less than 3 g/dL would lend further support but is not necessary. Fever of 7 or more days in a child less than 6 months old without other explanation would also increase the likelihood of incomplete Kawasaki disease. Admission to the hospital, treatment with IV immunoglobulin (IVIg), and echocardiography to evaluate for typical cardiac involvement (eg, aneurysms, coronary arteritis, and pericardial effusion) are the appropriate next steps.
The patient was diagnosed with atypical Kawasaki disease. A transthoracic echocardiogram was normal on admission. On day 7 of her illness, she was treated with 1 dose of IVIg at 2 g/kg and high-dose aspirin at 100 mg/kg per day in divided doses. Despite this treatment, she continued to be febrile and was given a second dose of IVIg on day 9. Her fevers persisted.
In Kawasaki disease, persistent fever is concerning for long-term sequelae, including coronary artery aneurysms. Continued treatment is reasonable. After 2 doses of IVIg with a cumulative dose of 4 g/kg, it is prudent to switch therapy to IV methylprednisolone 30mg/kg with repeated doses as needed for up to 3 days should her fevers persist.
Her blood culture was negative. EBV serology, enterovirus polymerase chain reaction, and viral cultures were negative. Chest radiography on day 9 was normal. Abdominal ultrasonography on day 10 showed hydrops of the gallbladder.
The patient was started on IV corticosteroids on day 11 with resolution of her fevers and improvement in her rash. A repeat echocardiogram revealed new findings of dilated left main, left anterior descending, and right coronary arteries. On day 13, a steroid wean was attempted because she had remained afebrile for more than 48 hours, but the wean was halted due to recurrence of fevers and rash. Her high-dose aspirin was reduced to 81 mg PO daily on day 14, and she was started on enoxaparin injections.
It is unusual for Kawasaki disease not to respond to 2 doses of IVIg, followed by corticosteroids. As such, the differential diagnosis must be revisited. The findings of coronary artery dilation, prolonged fever, and rash corroborate the diagnosis of Kawasaki disease, although this could be an atypical presentation of another vasculitis. Systemic onset juvenile idiopathic arthritis usually affects children at 2 to 5 years old and is, therefore, less likely. Henoch-Schönlein purpura manifests with a rash but is often associated with diarrhea. There does not appear to be objective evidence of polyarteritis nodosa, although biopsy or angiography would be required to make this diagnosis. Hydrops of the gallbladder is an over-distention of the organ filled with watery or mucoid content. While hydrops can be noninflammatory and seen in gallstone disease, it can also occur in vasculitides. Despite the reassuring serologies, false negative results are possible. Thus, these viral infections are not eliminated, but they are less likely. Given the echocardiogram findings and continued concern for atypical Kawasaki disease, high-dose aspirin should be continued. It is reasonable to consider rheumatology consultation for assessment and recommendations as to length of steroid treatment and/or alternative interventions.
Pediatric cardiology was consulted. Repeat echocardiogram on day 16 showed an increase in the size of her coronary artery aneurysms, and her fevers persisted. Computed tomography scan of the abdomen and pelvis with contrast, obtained to further evaluate for a source of infection, was unremarkable.
The patient was transferred to a tertiary care institution on day 19, at which time she remained on aspirin, enoxaparin, and oral corticosteroids. On arrival, her temperature was 101.3º F, heart rate 225 beats per minute, and respiratory rate 57 breaths per minute. She was fussy with bilateral conjunctivitis and a maculopapular rash involving palms, soles, and right infraorbital region. Laboratory studies were significant for a WBC count of 30.3 k/μL; hemoglobin, 10.9 g/dL; platelets, 106 k/μL; and CRP, 8.3 mg/dL.
Pediatric rheumatology was consulted on day 20. The patient was treated with 3 days IV pulse-dose methylprednisolone at 30 mg/kg daily. Her fevers resolved, although her CRP level remained elevated. She was treated with 1 dose of infliximab 10 mg/kg IV on day 24, followed by 1 dose of anakinra 15 mg subcutaneously on day 27 due to persistently elevated CRP.
The symptoms and diagnostic evaluation remain most consistent with atypical Kawasaki disease. Her tachycardia and tachypnea are likely driven by her fever and fussiness, and should be followed closely. The elevated WBC is likely a consequence of the steroids and demargination of neutrophils. The elevated and increasing CRP is a marker of acute inflammation. The adage “treat the patient, not the numbers” comes to mind, because it is reassuring that the patient’s overall clinical picture seems to be improving with resolution of her fevers. However, further discussion with the pediatric rheumatology consultant is prudent, specifically regarding the significance of the persistently elevated CRP, refinement of the differential diagnosis including the potential for other vasculitides and appropriate evaluation of such, as well as recommendations for further treatment.
The patient was noted to have ongoing fevers. Based on reports of success with cyclophosphamide in refractory Kawasaki disease, she was treated with 2 doses at 60 mg IV per dose starting on day 28. Her CRP level decreased. Cardiology and rheumatology consultants recommended magnetic resonance imaging/magnetic resonance angiography of the chest, abdomen, and pelvis with and without contrast. These studies revealed dilation of the axillary and brachial arteries (Figure 2).
The response to cyclophosphamide confirms an autoimmune/inflammatory process. The imaging results and pattern are most consistent with either Kawasaki disease or polyarteritis nodosa. Therefore, rheumatology’s input will be invaluable with regard to which diagnosis is most likely, additional diagnostic testing, and appropriate medical regimen and follow-up plans.
Systemic extracoronary vascular inflammation on imaging and the refractory nature of the patient’s disease process, despite appropriate treatment for Kawasaki disease, led to the diagnosis of childhood polyarteritis nodosa (PAN). The patient was discharged home and closely followed in rheumatology clinic. Her most recent outpatient visit 1 year after the initial onset of her illness showed no further fevers or rashes, normal inflammatory markers, and stabilization of her coronary aneurysms on daily maintenance azathioprine.
DISCUSSION
Fever with an accompanying rash is a common issue in children. The extensive differential diagnosis includes infectious diseases, rheumatologic disorders, and medication reactions (Table 1). A thorough history and physical examination are essential in guiding the physician toward the proper diagnosis and management. Important information includes patient age, season, associated symptoms, exposure to sick contacts, travel history, host immune status, and immunization history. Fever duration and pattern must be elicited, as should features of the rash, including temporal relationship to the fever, distribution, progression, and morphology.1
When unexplained fever persists for 5 days or more in the pediatric patient, the diagnosis of KD must be suspected. KD is an acute, febrile, primary systemic vasculitis affecting small- and medium-sized vessels, with a predilection for coronary arteries.2 KD affects younger children, with approximately 85% of cases occurring in children under 5 years old. KD has a higher incidence in Asian populations, suggesting a possible genetic predisposition.3 The etiology of KD is not well understood, but infection and immune dysregulation have been proposed as contributing factors. KD is the leading cause of acquired heart disease in developed countries.2
The diagnosis of KD is made clinically (Table 2). Atypical KD is considered in patients with at least 5 days of fever but only 2 or 3 clinical criteria. Supportive laboratory findings include elevated inflammatory markers, anemia, neutrophilia, abnormal plasma lipids, low albumin, sterile pyuria, CSF pleocytosis, and elevated serum transaminases. Two-dimensional echocardiography should be performed in all children with definite or suspected KD at the time of diagnosis, 1 to 2 weeks later, and 6 weeks following discharge for evaluation of the coronary arteries, left ventricular function, and valve function. The American Heart Association recommends follow-up echocardiography at 1 year in children without coronary vessel involvement.4
Treatment is aimed at minimizing inflammation and coronary artery involvement, and should be initiated promptly.5 Therapy includes a single infusion of high-dose IVIg and aspirin;6,7 the latter is initially provided at high anti-inflammatory doses, followed by lower antithrombotic doses once fever and laboratory markers have resolved.2 Aspirin can be discontinued if there is no evidence of coronary involvement at the 6-week follow-up echocardiogram.5 A second dose of IVIg is given within 48 hours for refractory cases, defined as persistent fever following the first dose of IVIg.4 Fifteen percent of children have refractory illness, and refractory KD is associated with a higher risk of coronary artery lesions.5 Additional agents that suppress immune activation and cytokine secretion contributing to KD pathogenesis have been studied. Corticosteroids inhibit phospholipase A, an enzyme required for production of inflammatory markers.8 Infliximab, a tumor necrosis factor-alpha inhibitor, has been shown to reduce duration of fever and length of hospital stay.8,9 Anakinra, an interleukin-1 receptor antagonist, has been shown to decrease fever duration and prevent progression of vascular injury in cases of refractory KD.10 There is, however, a lack of sufficient evidence and consensus on best practice.8-10
If inflammation, evidenced by fever, elevated inflammatory markers (such as erythrocyte sedimentation rate, CRP), or vessel involvement on imaging, persists or worsens despite standard therapy, physicians should seek alternative diagnoses. This patient’s extracoronary vascular inflammation and favorable response only to cyclophosphamide led to the diagnosis of systemic PAN. Like KD, PAN is a multi-system vasculitis affecting small- and medium-sized vessels. Unlike KD, PAN is rarely seen in children.11 Historically, PAN was thought to represent an extreme fatal end of the KD spectrum. Today, PAN is accepted as a separate entity. Clinical features and histological findings often overlap with KD, creating a diagnostic dilemma for providers.12
At the onset of illness, clinical features of systemic PAN may include recurrent fever, weight loss, and myalgia, with gradual progression to multi-organ system involvement. Laboratory assessment reveals elevated inflammatory markers and leukocytosis. Thrombocytosis, anemia, proteinuria, and hematuria may be present. A positive antineutrophil cytoplasmic antibody is rare in PAN and should raise suspicion for a microscopic polyangiitis, which is distinguished from PAN by small vessel involvement only. When compared to KD, cardiac vessel involvement in PAN is more variable.11 Diagnostic criteria for childhood PAN are listed in Table 2.13
Treatment of PAN is aimed at inducing remission with high-dose steroids and cyclophosphamide. Maintenance of remission is achieved using low-dose steroids and azathioprine.11 Total duration of treatment averages 2 to 3 years, with a minimum of 18 months.14 Plasma exchange has been used in severe, life-threatening cases.11 Prognosis for children with PAN is more favorable compared to adults with PAN, in whom the mortality rate is as high as 20% to 30%, even with aggressive treatment. In 1 multicenter study of childhood and adolescent PAN, overall mortality was 1.1%.15
This patient initially presented with findings consistent with KD. As her inflammatory markers remained elevated and fevers persisted, her physicians appropriately reconsidered the etiology of her symptoms, thereby “getting warmer” in the search for the correct diagnosis of systemic PAN, a rare disease and a separate entity from KD. Recognizing the overlapping and distinct clinical features of each entity can promote more timely and appropriate selection of therapy, thereby minimizing clinical manifestations and complications associated with each vasculitis.
KEY TEACHING POINTS
- KD and childhood PAN are disseminated vasculitides affecting small- and medium-sized vessels. Although they are distinct entities, KD and PAN exhibit overlapping clinical and pathological features that make appropriate diagnosis and treatment challenging.
- In cases of refractory KD, alternative diagnoses should be considered.
- Recognizing the individual features of both entities is imperative because treatment differs: KD is treated with high-dose aspirin and IVIg; corticosteroids and immunosuppressive agents are used to treat PAN.
Disclosure
Nothing to report.
1. McKinnon HD Jr, Howard T. Evaluating the febrile patient with a rash. Am Fam Physician. 2000;62:804-816. PubMed
2. Dimitriades V, Brown AG, Gedalia A. Kawasaki disease: pathophysiology, clinical manifestations, and management. Curr Rheumatol Rep. 2014;16:423. PubMed
3. Callinan L, Holman RC, Vugia DJ, Schonberger LB, Belay ED. Kawasaki disease hospitalization rate among children younger than 5 years of age in California, 2003-2010. Pediatr Infect Dis J. 2014;33:781-783. PubMed
4. Newburger JW, Takahashi M, Gerber MA, Gewirtz MH, Tani LY, Burns JC, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771. PubMed
5. Son M, Newburger JW. Kawasaki disease. Pediatr Rev. 2013;34:151-61. PubMed
6. Newberger JW, Takahasi M, Beiser AS, et al. A single intravenous infusion of gammaglobulin as compared with four infusions in treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324:1633-1639. PubMed
7. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87:1776-1780. PubMed
8. Saneeymehri S, Baker K, So TY. Overview of pharmacological treatment options for pediatric patients with refractory Kawasaki disease. J Pediatr Pharmacol Ther. 2015;20:163-177. PubMed
9. Brogan R, Eleftheriou D, Gnanapragasam J, Klein NJ, Brogan PA. Infliximab for the treatment of intravenous immunoglobulin resistant Kawasaki disease complicated by coronary artery aneurysms: a case report. Pediatr Rheumatol Online J. 2009;7:3. PubMed
10. Cohen S, Tacke CE, Straver B, Meijer N, Kuipers IM, Kuijpers TW. A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation. Ann Rheum Dis. 2012;71:2059-2061. PubMed
11. Kelly A, Tizard E. Vasculitis in children. Paediatrics and Child Health. 2010;20:65-72.
12. Yamazaki-Nakashimada MA, Espinosa-Lopez M, Hernandez-Bautista V, Espinosa-Padilla S, Espinosa-Rosales F. Catastrophic Kawasaki disease or juvenile polyarteritis nodosa? Semin Arthritis Rheum. 2006;35:349-354. PubMed
13. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69:798-806. PubMed
14. Eleftheriou D, Brogan PA. Vasculitis in children. Best Pract Res Clin Rheumatol. 2009;23:309-323. PubMed
15. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr. 2004;145:517-522. PubMed
The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.
A 3-month-old otherwise healthy, immunized female presented to clinic with 2 days of intermittent low-grade fevers (maximum, 100º F), decreased oral intake, and sleepiness. Her pediatrician noted a faint, maculopapular rash on her trunk and extremities with mild conjunctival injection bilaterally that appeared that day, according to her mother. The infant otherwise appeared alert, well-hydrated, and without respiratory distress. She had no history of sick contacts or recent travel. She was prescribed amoxicillin for empiric treatment of a possible bacterial sinusitis or pharyngitis, despite a negative rapid strep antigen test.
At this age, multiple conditions can cause rashes. Given that this is early in the course of illness, without focal symptoms but with low-grade fevers, the initial differential diagnosis is broad and would include infectious, rheumatologic, and hematologic-oncologic etiologies, although the latter would be less likely. While the patient’s mother reports decreased oral intake, the fact that the patient is alert and appears hydrated is encouraging, suggesting time to observe and see if other symptoms present that may assist in elucidating the cause. The history of increased sleepiness warrants further investigation of meningeal signs, which would point to a central nervous system infection.
While streptococcal infection is possible, it would be uncommon at this age. The patient would have a higher fever and focal infection, and the rash does not appear consistent unless it was described as “sandpaper” in feel and appearance. A negative rapid strep test, while not sensitive, further supports this impression. A low-grade fever and rash would be consistent with a viral syndrome and, given the conjunctival injection, adenovirus, cytomegalovirus, rhinovirus, and Epstein Barr virus (EBV) are possibilities. Without ocular discharge, bacterial conjunctivitis would be unlikely. Another consideration would be Kawasaki disease, though it would be too early to diagnose this condition since at least 5 days of fever are required. Next steps include a detailed physical examination, looking for other focal signs such as swelling or desquamation of hands and feet, lymphadenopathy, strawberry tongue, and mucositis. Rather than empirically starting antibiotics, it would be more reasonable to observe her with close outpatient follow-up. The patient’s family should be instructed to monitor for additional and/or worsening symptoms, further decreased oral intake, signs of dehydration, or changes in alertness.
At home, the patient completed 5 doses of amoxicillin but continued to be febrile (maximum, 102.6º F). She was taken to a local emergency department on day 6 of her illness. She had worsening conjunctival injection and progression of the rash, involving the palms and soles. She was noted to have edema of hands and feet without desquamation (Figure 1). She had no oral mucous membrane changes and no cervical lymphadenopathy. Cerebrospinal fluid (CSF) was unremarkable, and empiric treatment with intravenous (IV) ceftriaxone was initiated. Complete blood count was notable for a white blood cell (WBC) count of 18.9 k/μL (normal range, 6.0-17.0); hemoglobin, 7.6 g/dL (normal range, 10-13); mean corpuscular volume, 84 (normal range, 74-108); and platelet count, 105 k/μL (normal range, 150-400). A peripheral blood smear revealed no abnormal cells. C-reactive protein (CRP) was elevated at 6.5 mg/dL (normal range, 0.0-0.6). She was admitted for further management.
Infection remains on the differential diagnosis given the elevated WBC count. Since the patient has completed a reasonable course of antibiotics, a bacterial infection would be less likely but not fully excluded. The cultures obtained would be helpful if they become positive, but given that the patient has been on antibiotics, a negative culture may represent partial sterilization and would not rule out infection. A viral infection continues to be high on the differential, but one would expect that symptoms and fever would have begun to abate. The normal peripheral blood smear makes a hematologic disorder less likely.
Kawasaki disease has risen on the differential with 5 days of fever surpassing 102º F. She has 3 of 5 primary clinical criteria, including conjunctival injection, rash, and edema of the hands and feet. Desquamation of the peripheral extremities would not be expected until the convalescent phase. A diagnosis of typical Kawasaki disease would require a fourth criterion, either oral mucous membrane changes or cervical lymphadenopathy. She meets the criteria for atypical or incomplete Kawasaki disease, which requires only fever for at least 5 days, elevated CRP, and 2 or 3 additional clinical criteria. She also meets supplemental laboratory criteria with an elevated WBC count greater than 15,000/μL, normocytic and normochromic anemia for age, and elevated CRP. Urinalysis positive for pyuria or serum albumin less than 3 g/dL would lend further support but is not necessary. Fever of 7 or more days in a child less than 6 months old without other explanation would also increase the likelihood of incomplete Kawasaki disease. Admission to the hospital, treatment with IV immunoglobulin (IVIg), and echocardiography to evaluate for typical cardiac involvement (eg, aneurysms, coronary arteritis, and pericardial effusion) are the appropriate next steps.
The patient was diagnosed with atypical Kawasaki disease. A transthoracic echocardiogram was normal on admission. On day 7 of her illness, she was treated with 1 dose of IVIg at 2 g/kg and high-dose aspirin at 100 mg/kg per day in divided doses. Despite this treatment, she continued to be febrile and was given a second dose of IVIg on day 9. Her fevers persisted.
In Kawasaki disease, persistent fever is concerning for long-term sequelae, including coronary artery aneurysms. Continued treatment is reasonable. After 2 doses of IVIg with a cumulative dose of 4 g/kg, it is prudent to switch therapy to IV methylprednisolone 30mg/kg with repeated doses as needed for up to 3 days should her fevers persist.
Her blood culture was negative. EBV serology, enterovirus polymerase chain reaction, and viral cultures were negative. Chest radiography on day 9 was normal. Abdominal ultrasonography on day 10 showed hydrops of the gallbladder.
The patient was started on IV corticosteroids on day 11 with resolution of her fevers and improvement in her rash. A repeat echocardiogram revealed new findings of dilated left main, left anterior descending, and right coronary arteries. On day 13, a steroid wean was attempted because she had remained afebrile for more than 48 hours, but the wean was halted due to recurrence of fevers and rash. Her high-dose aspirin was reduced to 81 mg PO daily on day 14, and she was started on enoxaparin injections.
It is unusual for Kawasaki disease not to respond to 2 doses of IVIg, followed by corticosteroids. As such, the differential diagnosis must be revisited. The findings of coronary artery dilation, prolonged fever, and rash corroborate the diagnosis of Kawasaki disease, although this could be an atypical presentation of another vasculitis. Systemic onset juvenile idiopathic arthritis usually affects children at 2 to 5 years old and is, therefore, less likely. Henoch-Schönlein purpura manifests with a rash but is often associated with diarrhea. There does not appear to be objective evidence of polyarteritis nodosa, although biopsy or angiography would be required to make this diagnosis. Hydrops of the gallbladder is an over-distention of the organ filled with watery or mucoid content. While hydrops can be noninflammatory and seen in gallstone disease, it can also occur in vasculitides. Despite the reassuring serologies, false negative results are possible. Thus, these viral infections are not eliminated, but they are less likely. Given the echocardiogram findings and continued concern for atypical Kawasaki disease, high-dose aspirin should be continued. It is reasonable to consider rheumatology consultation for assessment and recommendations as to length of steroid treatment and/or alternative interventions.
Pediatric cardiology was consulted. Repeat echocardiogram on day 16 showed an increase in the size of her coronary artery aneurysms, and her fevers persisted. Computed tomography scan of the abdomen and pelvis with contrast, obtained to further evaluate for a source of infection, was unremarkable.
The patient was transferred to a tertiary care institution on day 19, at which time she remained on aspirin, enoxaparin, and oral corticosteroids. On arrival, her temperature was 101.3º F, heart rate 225 beats per minute, and respiratory rate 57 breaths per minute. She was fussy with bilateral conjunctivitis and a maculopapular rash involving palms, soles, and right infraorbital region. Laboratory studies were significant for a WBC count of 30.3 k/μL; hemoglobin, 10.9 g/dL; platelets, 106 k/μL; and CRP, 8.3 mg/dL.
Pediatric rheumatology was consulted on day 20. The patient was treated with 3 days IV pulse-dose methylprednisolone at 30 mg/kg daily. Her fevers resolved, although her CRP level remained elevated. She was treated with 1 dose of infliximab 10 mg/kg IV on day 24, followed by 1 dose of anakinra 15 mg subcutaneously on day 27 due to persistently elevated CRP.
The symptoms and diagnostic evaluation remain most consistent with atypical Kawasaki disease. Her tachycardia and tachypnea are likely driven by her fever and fussiness, and should be followed closely. The elevated WBC is likely a consequence of the steroids and demargination of neutrophils. The elevated and increasing CRP is a marker of acute inflammation. The adage “treat the patient, not the numbers” comes to mind, because it is reassuring that the patient’s overall clinical picture seems to be improving with resolution of her fevers. However, further discussion with the pediatric rheumatology consultant is prudent, specifically regarding the significance of the persistently elevated CRP, refinement of the differential diagnosis including the potential for other vasculitides and appropriate evaluation of such, as well as recommendations for further treatment.
The patient was noted to have ongoing fevers. Based on reports of success with cyclophosphamide in refractory Kawasaki disease, she was treated with 2 doses at 60 mg IV per dose starting on day 28. Her CRP level decreased. Cardiology and rheumatology consultants recommended magnetic resonance imaging/magnetic resonance angiography of the chest, abdomen, and pelvis with and without contrast. These studies revealed dilation of the axillary and brachial arteries (Figure 2).
The response to cyclophosphamide confirms an autoimmune/inflammatory process. The imaging results and pattern are most consistent with either Kawasaki disease or polyarteritis nodosa. Therefore, rheumatology’s input will be invaluable with regard to which diagnosis is most likely, additional diagnostic testing, and appropriate medical regimen and follow-up plans.
Systemic extracoronary vascular inflammation on imaging and the refractory nature of the patient’s disease process, despite appropriate treatment for Kawasaki disease, led to the diagnosis of childhood polyarteritis nodosa (PAN). The patient was discharged home and closely followed in rheumatology clinic. Her most recent outpatient visit 1 year after the initial onset of her illness showed no further fevers or rashes, normal inflammatory markers, and stabilization of her coronary aneurysms on daily maintenance azathioprine.
DISCUSSION
Fever with an accompanying rash is a common issue in children. The extensive differential diagnosis includes infectious diseases, rheumatologic disorders, and medication reactions (Table 1). A thorough history and physical examination are essential in guiding the physician toward the proper diagnosis and management. Important information includes patient age, season, associated symptoms, exposure to sick contacts, travel history, host immune status, and immunization history. Fever duration and pattern must be elicited, as should features of the rash, including temporal relationship to the fever, distribution, progression, and morphology.1
When unexplained fever persists for 5 days or more in the pediatric patient, the diagnosis of KD must be suspected. KD is an acute, febrile, primary systemic vasculitis affecting small- and medium-sized vessels, with a predilection for coronary arteries.2 KD affects younger children, with approximately 85% of cases occurring in children under 5 years old. KD has a higher incidence in Asian populations, suggesting a possible genetic predisposition.3 The etiology of KD is not well understood, but infection and immune dysregulation have been proposed as contributing factors. KD is the leading cause of acquired heart disease in developed countries.2
The diagnosis of KD is made clinically (Table 2). Atypical KD is considered in patients with at least 5 days of fever but only 2 or 3 clinical criteria. Supportive laboratory findings include elevated inflammatory markers, anemia, neutrophilia, abnormal plasma lipids, low albumin, sterile pyuria, CSF pleocytosis, and elevated serum transaminases. Two-dimensional echocardiography should be performed in all children with definite or suspected KD at the time of diagnosis, 1 to 2 weeks later, and 6 weeks following discharge for evaluation of the coronary arteries, left ventricular function, and valve function. The American Heart Association recommends follow-up echocardiography at 1 year in children without coronary vessel involvement.4
Treatment is aimed at minimizing inflammation and coronary artery involvement, and should be initiated promptly.5 Therapy includes a single infusion of high-dose IVIg and aspirin;6,7 the latter is initially provided at high anti-inflammatory doses, followed by lower antithrombotic doses once fever and laboratory markers have resolved.2 Aspirin can be discontinued if there is no evidence of coronary involvement at the 6-week follow-up echocardiogram.5 A second dose of IVIg is given within 48 hours for refractory cases, defined as persistent fever following the first dose of IVIg.4 Fifteen percent of children have refractory illness, and refractory KD is associated with a higher risk of coronary artery lesions.5 Additional agents that suppress immune activation and cytokine secretion contributing to KD pathogenesis have been studied. Corticosteroids inhibit phospholipase A, an enzyme required for production of inflammatory markers.8 Infliximab, a tumor necrosis factor-alpha inhibitor, has been shown to reduce duration of fever and length of hospital stay.8,9 Anakinra, an interleukin-1 receptor antagonist, has been shown to decrease fever duration and prevent progression of vascular injury in cases of refractory KD.10 There is, however, a lack of sufficient evidence and consensus on best practice.8-10
If inflammation, evidenced by fever, elevated inflammatory markers (such as erythrocyte sedimentation rate, CRP), or vessel involvement on imaging, persists or worsens despite standard therapy, physicians should seek alternative diagnoses. This patient’s extracoronary vascular inflammation and favorable response only to cyclophosphamide led to the diagnosis of systemic PAN. Like KD, PAN is a multi-system vasculitis affecting small- and medium-sized vessels. Unlike KD, PAN is rarely seen in children.11 Historically, PAN was thought to represent an extreme fatal end of the KD spectrum. Today, PAN is accepted as a separate entity. Clinical features and histological findings often overlap with KD, creating a diagnostic dilemma for providers.12
At the onset of illness, clinical features of systemic PAN may include recurrent fever, weight loss, and myalgia, with gradual progression to multi-organ system involvement. Laboratory assessment reveals elevated inflammatory markers and leukocytosis. Thrombocytosis, anemia, proteinuria, and hematuria may be present. A positive antineutrophil cytoplasmic antibody is rare in PAN and should raise suspicion for a microscopic polyangiitis, which is distinguished from PAN by small vessel involvement only. When compared to KD, cardiac vessel involvement in PAN is more variable.11 Diagnostic criteria for childhood PAN are listed in Table 2.13
Treatment of PAN is aimed at inducing remission with high-dose steroids and cyclophosphamide. Maintenance of remission is achieved using low-dose steroids and azathioprine.11 Total duration of treatment averages 2 to 3 years, with a minimum of 18 months.14 Plasma exchange has been used in severe, life-threatening cases.11 Prognosis for children with PAN is more favorable compared to adults with PAN, in whom the mortality rate is as high as 20% to 30%, even with aggressive treatment. In 1 multicenter study of childhood and adolescent PAN, overall mortality was 1.1%.15
This patient initially presented with findings consistent with KD. As her inflammatory markers remained elevated and fevers persisted, her physicians appropriately reconsidered the etiology of her symptoms, thereby “getting warmer” in the search for the correct diagnosis of systemic PAN, a rare disease and a separate entity from KD. Recognizing the overlapping and distinct clinical features of each entity can promote more timely and appropriate selection of therapy, thereby minimizing clinical manifestations and complications associated with each vasculitis.
KEY TEACHING POINTS
- KD and childhood PAN are disseminated vasculitides affecting small- and medium-sized vessels. Although they are distinct entities, KD and PAN exhibit overlapping clinical and pathological features that make appropriate diagnosis and treatment challenging.
- In cases of refractory KD, alternative diagnoses should be considered.
- Recognizing the individual features of both entities is imperative because treatment differs: KD is treated with high-dose aspirin and IVIg; corticosteroids and immunosuppressive agents are used to treat PAN.
Disclosure
Nothing to report.
The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.
A 3-month-old otherwise healthy, immunized female presented to clinic with 2 days of intermittent low-grade fevers (maximum, 100º F), decreased oral intake, and sleepiness. Her pediatrician noted a faint, maculopapular rash on her trunk and extremities with mild conjunctival injection bilaterally that appeared that day, according to her mother. The infant otherwise appeared alert, well-hydrated, and without respiratory distress. She had no history of sick contacts or recent travel. She was prescribed amoxicillin for empiric treatment of a possible bacterial sinusitis or pharyngitis, despite a negative rapid strep antigen test.
At this age, multiple conditions can cause rashes. Given that this is early in the course of illness, without focal symptoms but with low-grade fevers, the initial differential diagnosis is broad and would include infectious, rheumatologic, and hematologic-oncologic etiologies, although the latter would be less likely. While the patient’s mother reports decreased oral intake, the fact that the patient is alert and appears hydrated is encouraging, suggesting time to observe and see if other symptoms present that may assist in elucidating the cause. The history of increased sleepiness warrants further investigation of meningeal signs, which would point to a central nervous system infection.
While streptococcal infection is possible, it would be uncommon at this age. The patient would have a higher fever and focal infection, and the rash does not appear consistent unless it was described as “sandpaper” in feel and appearance. A negative rapid strep test, while not sensitive, further supports this impression. A low-grade fever and rash would be consistent with a viral syndrome and, given the conjunctival injection, adenovirus, cytomegalovirus, rhinovirus, and Epstein Barr virus (EBV) are possibilities. Without ocular discharge, bacterial conjunctivitis would be unlikely. Another consideration would be Kawasaki disease, though it would be too early to diagnose this condition since at least 5 days of fever are required. Next steps include a detailed physical examination, looking for other focal signs such as swelling or desquamation of hands and feet, lymphadenopathy, strawberry tongue, and mucositis. Rather than empirically starting antibiotics, it would be more reasonable to observe her with close outpatient follow-up. The patient’s family should be instructed to monitor for additional and/or worsening symptoms, further decreased oral intake, signs of dehydration, or changes in alertness.
At home, the patient completed 5 doses of amoxicillin but continued to be febrile (maximum, 102.6º F). She was taken to a local emergency department on day 6 of her illness. She had worsening conjunctival injection and progression of the rash, involving the palms and soles. She was noted to have edema of hands and feet without desquamation (Figure 1). She had no oral mucous membrane changes and no cervical lymphadenopathy. Cerebrospinal fluid (CSF) was unremarkable, and empiric treatment with intravenous (IV) ceftriaxone was initiated. Complete blood count was notable for a white blood cell (WBC) count of 18.9 k/μL (normal range, 6.0-17.0); hemoglobin, 7.6 g/dL (normal range, 10-13); mean corpuscular volume, 84 (normal range, 74-108); and platelet count, 105 k/μL (normal range, 150-400). A peripheral blood smear revealed no abnormal cells. C-reactive protein (CRP) was elevated at 6.5 mg/dL (normal range, 0.0-0.6). She was admitted for further management.
Infection remains on the differential diagnosis given the elevated WBC count. Since the patient has completed a reasonable course of antibiotics, a bacterial infection would be less likely but not fully excluded. The cultures obtained would be helpful if they become positive, but given that the patient has been on antibiotics, a negative culture may represent partial sterilization and would not rule out infection. A viral infection continues to be high on the differential, but one would expect that symptoms and fever would have begun to abate. The normal peripheral blood smear makes a hematologic disorder less likely.
Kawasaki disease has risen on the differential with 5 days of fever surpassing 102º F. She has 3 of 5 primary clinical criteria, including conjunctival injection, rash, and edema of the hands and feet. Desquamation of the peripheral extremities would not be expected until the convalescent phase. A diagnosis of typical Kawasaki disease would require a fourth criterion, either oral mucous membrane changes or cervical lymphadenopathy. She meets the criteria for atypical or incomplete Kawasaki disease, which requires only fever for at least 5 days, elevated CRP, and 2 or 3 additional clinical criteria. She also meets supplemental laboratory criteria with an elevated WBC count greater than 15,000/μL, normocytic and normochromic anemia for age, and elevated CRP. Urinalysis positive for pyuria or serum albumin less than 3 g/dL would lend further support but is not necessary. Fever of 7 or more days in a child less than 6 months old without other explanation would also increase the likelihood of incomplete Kawasaki disease. Admission to the hospital, treatment with IV immunoglobulin (IVIg), and echocardiography to evaluate for typical cardiac involvement (eg, aneurysms, coronary arteritis, and pericardial effusion) are the appropriate next steps.
The patient was diagnosed with atypical Kawasaki disease. A transthoracic echocardiogram was normal on admission. On day 7 of her illness, she was treated with 1 dose of IVIg at 2 g/kg and high-dose aspirin at 100 mg/kg per day in divided doses. Despite this treatment, she continued to be febrile and was given a second dose of IVIg on day 9. Her fevers persisted.
In Kawasaki disease, persistent fever is concerning for long-term sequelae, including coronary artery aneurysms. Continued treatment is reasonable. After 2 doses of IVIg with a cumulative dose of 4 g/kg, it is prudent to switch therapy to IV methylprednisolone 30mg/kg with repeated doses as needed for up to 3 days should her fevers persist.
Her blood culture was negative. EBV serology, enterovirus polymerase chain reaction, and viral cultures were negative. Chest radiography on day 9 was normal. Abdominal ultrasonography on day 10 showed hydrops of the gallbladder.
The patient was started on IV corticosteroids on day 11 with resolution of her fevers and improvement in her rash. A repeat echocardiogram revealed new findings of dilated left main, left anterior descending, and right coronary arteries. On day 13, a steroid wean was attempted because she had remained afebrile for more than 48 hours, but the wean was halted due to recurrence of fevers and rash. Her high-dose aspirin was reduced to 81 mg PO daily on day 14, and she was started on enoxaparin injections.
It is unusual for Kawasaki disease not to respond to 2 doses of IVIg, followed by corticosteroids. As such, the differential diagnosis must be revisited. The findings of coronary artery dilation, prolonged fever, and rash corroborate the diagnosis of Kawasaki disease, although this could be an atypical presentation of another vasculitis. Systemic onset juvenile idiopathic arthritis usually affects children at 2 to 5 years old and is, therefore, less likely. Henoch-Schönlein purpura manifests with a rash but is often associated with diarrhea. There does not appear to be objective evidence of polyarteritis nodosa, although biopsy or angiography would be required to make this diagnosis. Hydrops of the gallbladder is an over-distention of the organ filled with watery or mucoid content. While hydrops can be noninflammatory and seen in gallstone disease, it can also occur in vasculitides. Despite the reassuring serologies, false negative results are possible. Thus, these viral infections are not eliminated, but they are less likely. Given the echocardiogram findings and continued concern for atypical Kawasaki disease, high-dose aspirin should be continued. It is reasonable to consider rheumatology consultation for assessment and recommendations as to length of steroid treatment and/or alternative interventions.
Pediatric cardiology was consulted. Repeat echocardiogram on day 16 showed an increase in the size of her coronary artery aneurysms, and her fevers persisted. Computed tomography scan of the abdomen and pelvis with contrast, obtained to further evaluate for a source of infection, was unremarkable.
The patient was transferred to a tertiary care institution on day 19, at which time she remained on aspirin, enoxaparin, and oral corticosteroids. On arrival, her temperature was 101.3º F, heart rate 225 beats per minute, and respiratory rate 57 breaths per minute. She was fussy with bilateral conjunctivitis and a maculopapular rash involving palms, soles, and right infraorbital region. Laboratory studies were significant for a WBC count of 30.3 k/μL; hemoglobin, 10.9 g/dL; platelets, 106 k/μL; and CRP, 8.3 mg/dL.
Pediatric rheumatology was consulted on day 20. The patient was treated with 3 days IV pulse-dose methylprednisolone at 30 mg/kg daily. Her fevers resolved, although her CRP level remained elevated. She was treated with 1 dose of infliximab 10 mg/kg IV on day 24, followed by 1 dose of anakinra 15 mg subcutaneously on day 27 due to persistently elevated CRP.
The symptoms and diagnostic evaluation remain most consistent with atypical Kawasaki disease. Her tachycardia and tachypnea are likely driven by her fever and fussiness, and should be followed closely. The elevated WBC is likely a consequence of the steroids and demargination of neutrophils. The elevated and increasing CRP is a marker of acute inflammation. The adage “treat the patient, not the numbers” comes to mind, because it is reassuring that the patient’s overall clinical picture seems to be improving with resolution of her fevers. However, further discussion with the pediatric rheumatology consultant is prudent, specifically regarding the significance of the persistently elevated CRP, refinement of the differential diagnosis including the potential for other vasculitides and appropriate evaluation of such, as well as recommendations for further treatment.
The patient was noted to have ongoing fevers. Based on reports of success with cyclophosphamide in refractory Kawasaki disease, she was treated with 2 doses at 60 mg IV per dose starting on day 28. Her CRP level decreased. Cardiology and rheumatology consultants recommended magnetic resonance imaging/magnetic resonance angiography of the chest, abdomen, and pelvis with and without contrast. These studies revealed dilation of the axillary and brachial arteries (Figure 2).
The response to cyclophosphamide confirms an autoimmune/inflammatory process. The imaging results and pattern are most consistent with either Kawasaki disease or polyarteritis nodosa. Therefore, rheumatology’s input will be invaluable with regard to which diagnosis is most likely, additional diagnostic testing, and appropriate medical regimen and follow-up plans.
Systemic extracoronary vascular inflammation on imaging and the refractory nature of the patient’s disease process, despite appropriate treatment for Kawasaki disease, led to the diagnosis of childhood polyarteritis nodosa (PAN). The patient was discharged home and closely followed in rheumatology clinic. Her most recent outpatient visit 1 year after the initial onset of her illness showed no further fevers or rashes, normal inflammatory markers, and stabilization of her coronary aneurysms on daily maintenance azathioprine.
DISCUSSION
Fever with an accompanying rash is a common issue in children. The extensive differential diagnosis includes infectious diseases, rheumatologic disorders, and medication reactions (Table 1). A thorough history and physical examination are essential in guiding the physician toward the proper diagnosis and management. Important information includes patient age, season, associated symptoms, exposure to sick contacts, travel history, host immune status, and immunization history. Fever duration and pattern must be elicited, as should features of the rash, including temporal relationship to the fever, distribution, progression, and morphology.1
When unexplained fever persists for 5 days or more in the pediatric patient, the diagnosis of KD must be suspected. KD is an acute, febrile, primary systemic vasculitis affecting small- and medium-sized vessels, with a predilection for coronary arteries.2 KD affects younger children, with approximately 85% of cases occurring in children under 5 years old. KD has a higher incidence in Asian populations, suggesting a possible genetic predisposition.3 The etiology of KD is not well understood, but infection and immune dysregulation have been proposed as contributing factors. KD is the leading cause of acquired heart disease in developed countries.2
The diagnosis of KD is made clinically (Table 2). Atypical KD is considered in patients with at least 5 days of fever but only 2 or 3 clinical criteria. Supportive laboratory findings include elevated inflammatory markers, anemia, neutrophilia, abnormal plasma lipids, low albumin, sterile pyuria, CSF pleocytosis, and elevated serum transaminases. Two-dimensional echocardiography should be performed in all children with definite or suspected KD at the time of diagnosis, 1 to 2 weeks later, and 6 weeks following discharge for evaluation of the coronary arteries, left ventricular function, and valve function. The American Heart Association recommends follow-up echocardiography at 1 year in children without coronary vessel involvement.4
Treatment is aimed at minimizing inflammation and coronary artery involvement, and should be initiated promptly.5 Therapy includes a single infusion of high-dose IVIg and aspirin;6,7 the latter is initially provided at high anti-inflammatory doses, followed by lower antithrombotic doses once fever and laboratory markers have resolved.2 Aspirin can be discontinued if there is no evidence of coronary involvement at the 6-week follow-up echocardiogram.5 A second dose of IVIg is given within 48 hours for refractory cases, defined as persistent fever following the first dose of IVIg.4 Fifteen percent of children have refractory illness, and refractory KD is associated with a higher risk of coronary artery lesions.5 Additional agents that suppress immune activation and cytokine secretion contributing to KD pathogenesis have been studied. Corticosteroids inhibit phospholipase A, an enzyme required for production of inflammatory markers.8 Infliximab, a tumor necrosis factor-alpha inhibitor, has been shown to reduce duration of fever and length of hospital stay.8,9 Anakinra, an interleukin-1 receptor antagonist, has been shown to decrease fever duration and prevent progression of vascular injury in cases of refractory KD.10 There is, however, a lack of sufficient evidence and consensus on best practice.8-10
If inflammation, evidenced by fever, elevated inflammatory markers (such as erythrocyte sedimentation rate, CRP), or vessel involvement on imaging, persists or worsens despite standard therapy, physicians should seek alternative diagnoses. This patient’s extracoronary vascular inflammation and favorable response only to cyclophosphamide led to the diagnosis of systemic PAN. Like KD, PAN is a multi-system vasculitis affecting small- and medium-sized vessels. Unlike KD, PAN is rarely seen in children.11 Historically, PAN was thought to represent an extreme fatal end of the KD spectrum. Today, PAN is accepted as a separate entity. Clinical features and histological findings often overlap with KD, creating a diagnostic dilemma for providers.12
At the onset of illness, clinical features of systemic PAN may include recurrent fever, weight loss, and myalgia, with gradual progression to multi-organ system involvement. Laboratory assessment reveals elevated inflammatory markers and leukocytosis. Thrombocytosis, anemia, proteinuria, and hematuria may be present. A positive antineutrophil cytoplasmic antibody is rare in PAN and should raise suspicion for a microscopic polyangiitis, which is distinguished from PAN by small vessel involvement only. When compared to KD, cardiac vessel involvement in PAN is more variable.11 Diagnostic criteria for childhood PAN are listed in Table 2.13
Treatment of PAN is aimed at inducing remission with high-dose steroids and cyclophosphamide. Maintenance of remission is achieved using low-dose steroids and azathioprine.11 Total duration of treatment averages 2 to 3 years, with a minimum of 18 months.14 Plasma exchange has been used in severe, life-threatening cases.11 Prognosis for children with PAN is more favorable compared to adults with PAN, in whom the mortality rate is as high as 20% to 30%, even with aggressive treatment. In 1 multicenter study of childhood and adolescent PAN, overall mortality was 1.1%.15
This patient initially presented with findings consistent with KD. As her inflammatory markers remained elevated and fevers persisted, her physicians appropriately reconsidered the etiology of her symptoms, thereby “getting warmer” in the search for the correct diagnosis of systemic PAN, a rare disease and a separate entity from KD. Recognizing the overlapping and distinct clinical features of each entity can promote more timely and appropriate selection of therapy, thereby minimizing clinical manifestations and complications associated with each vasculitis.
KEY TEACHING POINTS
- KD and childhood PAN are disseminated vasculitides affecting small- and medium-sized vessels. Although they are distinct entities, KD and PAN exhibit overlapping clinical and pathological features that make appropriate diagnosis and treatment challenging.
- In cases of refractory KD, alternative diagnoses should be considered.
- Recognizing the individual features of both entities is imperative because treatment differs: KD is treated with high-dose aspirin and IVIg; corticosteroids and immunosuppressive agents are used to treat PAN.
Disclosure
Nothing to report.
1. McKinnon HD Jr, Howard T. Evaluating the febrile patient with a rash. Am Fam Physician. 2000;62:804-816. PubMed
2. Dimitriades V, Brown AG, Gedalia A. Kawasaki disease: pathophysiology, clinical manifestations, and management. Curr Rheumatol Rep. 2014;16:423. PubMed
3. Callinan L, Holman RC, Vugia DJ, Schonberger LB, Belay ED. Kawasaki disease hospitalization rate among children younger than 5 years of age in California, 2003-2010. Pediatr Infect Dis J. 2014;33:781-783. PubMed
4. Newburger JW, Takahashi M, Gerber MA, Gewirtz MH, Tani LY, Burns JC, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771. PubMed
5. Son M, Newburger JW. Kawasaki disease. Pediatr Rev. 2013;34:151-61. PubMed
6. Newberger JW, Takahasi M, Beiser AS, et al. A single intravenous infusion of gammaglobulin as compared with four infusions in treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324:1633-1639. PubMed
7. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87:1776-1780. PubMed
8. Saneeymehri S, Baker K, So TY. Overview of pharmacological treatment options for pediatric patients with refractory Kawasaki disease. J Pediatr Pharmacol Ther. 2015;20:163-177. PubMed
9. Brogan R, Eleftheriou D, Gnanapragasam J, Klein NJ, Brogan PA. Infliximab for the treatment of intravenous immunoglobulin resistant Kawasaki disease complicated by coronary artery aneurysms: a case report. Pediatr Rheumatol Online J. 2009;7:3. PubMed
10. Cohen S, Tacke CE, Straver B, Meijer N, Kuipers IM, Kuijpers TW. A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation. Ann Rheum Dis. 2012;71:2059-2061. PubMed
11. Kelly A, Tizard E. Vasculitis in children. Paediatrics and Child Health. 2010;20:65-72.
12. Yamazaki-Nakashimada MA, Espinosa-Lopez M, Hernandez-Bautista V, Espinosa-Padilla S, Espinosa-Rosales F. Catastrophic Kawasaki disease or juvenile polyarteritis nodosa? Semin Arthritis Rheum. 2006;35:349-354. PubMed
13. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69:798-806. PubMed
14. Eleftheriou D, Brogan PA. Vasculitis in children. Best Pract Res Clin Rheumatol. 2009;23:309-323. PubMed
15. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr. 2004;145:517-522. PubMed
1. McKinnon HD Jr, Howard T. Evaluating the febrile patient with a rash. Am Fam Physician. 2000;62:804-816. PubMed
2. Dimitriades V, Brown AG, Gedalia A. Kawasaki disease: pathophysiology, clinical manifestations, and management. Curr Rheumatol Rep. 2014;16:423. PubMed
3. Callinan L, Holman RC, Vugia DJ, Schonberger LB, Belay ED. Kawasaki disease hospitalization rate among children younger than 5 years of age in California, 2003-2010. Pediatr Infect Dis J. 2014;33:781-783. PubMed
4. Newburger JW, Takahashi M, Gerber MA, Gewirtz MH, Tani LY, Burns JC, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771. PubMed
5. Son M, Newburger JW. Kawasaki disease. Pediatr Rev. 2013;34:151-61. PubMed
6. Newberger JW, Takahasi M, Beiser AS, et al. A single intravenous infusion of gammaglobulin as compared with four infusions in treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324:1633-1639. PubMed
7. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87:1776-1780. PubMed
8. Saneeymehri S, Baker K, So TY. Overview of pharmacological treatment options for pediatric patients with refractory Kawasaki disease. J Pediatr Pharmacol Ther. 2015;20:163-177. PubMed
9. Brogan R, Eleftheriou D, Gnanapragasam J, Klein NJ, Brogan PA. Infliximab for the treatment of intravenous immunoglobulin resistant Kawasaki disease complicated by coronary artery aneurysms: a case report. Pediatr Rheumatol Online J. 2009;7:3. PubMed
10. Cohen S, Tacke CE, Straver B, Meijer N, Kuipers IM, Kuijpers TW. A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation. Ann Rheum Dis. 2012;71:2059-2061. PubMed
11. Kelly A, Tizard E. Vasculitis in children. Paediatrics and Child Health. 2010;20:65-72.
12. Yamazaki-Nakashimada MA, Espinosa-Lopez M, Hernandez-Bautista V, Espinosa-Padilla S, Espinosa-Rosales F. Catastrophic Kawasaki disease or juvenile polyarteritis nodosa? Semin Arthritis Rheum. 2006;35:349-354. PubMed
13. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69:798-806. PubMed
14. Eleftheriou D, Brogan PA. Vasculitis in children. Best Pract Res Clin Rheumatol. 2009;23:309-323. PubMed
15. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr. 2004;145:517-522. PubMed
© 2017 Society of Hospital Medicine
A Problem of Capacity
For a number of years, those challenged with improving discharge transitions and preventing readmissions have suggested more—more case managers, more checklists and systems, more discharge pharmacists; and better—better communication, better medication reconciliation, better discharge documentation, better follow-up. In a study by Chan Carusone et al.,1 high-need, high-complexity patients receiving treatment at Casey House, a specialized urban hospital providing inpatient and community programs, were afforded a full complement of discharge planning and posthospitalization services. Despite these services, the patients achieved little success in maintaining their health and following their discharge plans after hospitalization.
This longitudinal qualitative study detailing the lived experience of discharge extends our knowledge of challenges faced by patients during the posthospital transition,2 and further elucidates the differences between patients’ expectations and assessments of their resources and goals, and their actual abilities and priorities on discharge. Despite substantial assistance, including housing, food assistance, and case management, Chan Carusone et al. found that the exigencies of day-to-day existence exceeded the patients’ capacities to sustain themselves outside the hospital. This failure implies a question: If the interventions alluded to in this study were not enough, then how much more, and how much better, is needed?
Attention to this question of how to best serve high-need patients continues to increase,3 and success in intervening to improve care transitions for this population is limited,4 in part because providing more care and more coordination requires more resources. Observing the challenges that remain for patients treated in the highly-resourced setting that is Casey House, the authors propose a previously described theoretical construct, minimally disruptive medicine (MDM),5 as a framework to guide patients and providers in creating a discharge plan that relies on the patient’s capacity to integrate disease self-management into his or her daily circumstances. MDM hinges on the concept of balancing workload and capacity: the burden of managing disease with the resources and abilities to do so. On first consideration, this seems an attractive approach to operationalizing patient-centered care by tailoring a discharge plan to a patient’s goals and capacities. On closer examination, however, MDM, applied to a single transition episode, raises some important concerns.
As Chan Carusone et al. describe, patients may poorly judge their future resources and capacity when making decisions in the hospital setting. Likewise, physicians and other team members may lack insight, perspective, and detailed knowledge of resources and barriers in the outpatient setting. From their vantage point, they may not see the fragile contingencies of the discharge plan that is reflected in the patients’ spoken words. At any moment, a well-meant, seemingly well-crafted discharge plan could fall apart.
Within the walls of the hospital, we tend to perform what might be termed maximally disruptive medicine—the treatments provided are exactly those that can’t be delivered in a nonhospital setting. For many patients, these interventions are not curative, but rather stabilizing;6 we assuage chronic conditions that had become exacerbated by new illness, disease progression, or conditions outside the hospital. To return the patient to his or her home situation, especially one that is under-resourced, with minimized workload can feel counterproductive and demoralizing at best. What prevents one from worrying that, where capacity can’t be improved, planning for MDM is, in essence, planning for minimal care?
Viewed in the broader context of a life course health development framework,7 which integrates biological, psychological, cultural, and historical experience to explain the development of health trajectories over an individual’s lifetime, a minimally disruptive approach might be viewed as amplifying disparities. The patients contributing to the study by Chan Carusone et al. may have arrived in their respective situations through a life course marked by poverty, violence, inadequate housing, poor nutrition, discrimination, and other disadvantages that may have resulted from accident, malfeasance, or choice. Their limited personal capacity and the ongoing chaos that is reflected in many of their comments requires that discharge planning uses imagination and dialogue, with careful, compassionate listening by providers, and close partnering and decision-making by patient and providers. Approaches to building the capacity for such compassion, as well as structural interventions to provide care that is necessary and just for these most vulnerable patients by considering their experiences and beliefs,8 remain to be articulated.
In a sense, the narrative unfolded by Chan Carusone et al. appropriately emphasizes that care transitions contain both complex problems and “wicked” problems.9 While aspects of transitions are complex and can be reasonably addressed with complex solutions, these same complex solutions are inadequate to mitigate the seemingly intractable socioeconomic challenges that drive hospital dependence for many high-need patients. Addressing these likely requires a reexamination of what we expect from hospitals, what systems we are able to design and are willing to support to keep people from returning to them, and what it means that for some people returning is the best, and sometimes only, thing to do.
As we continue to seek new models for healthcare in high-need, high-risk populations, we may do well to focus further longitudinal qualitative study on building a deep understanding of when and how patients achieve success following discharge. What characterizes patients, caregivers, service networks, and communities in healthcare settings with the highest rates of effective transitions? Maintaining equilibrium outside an institutional setting is convoluted, time-consuming, nuanced, and taxing; that those who have not experienced doing so as a patient or caregiver might struggle to help others should not surprise us. The concepts of capacity and workload lend themselves to structuring discovery of the resources that patients, not providers and policy-makers, have found through their lived experience to be most crucial to their enduring well-being. Learning from these experiences may shift the balance by increasing our own capacity to understand what constitutes success.
Disclosures
The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors report no conflicts of interest.
References
1. Chan Carusone S, O’Leary B, McWatt S, Stewart S, Craig S, Brennan D. The lived experience of the hospital discharge “plan”: a longitudinal qualitative study of complex patients. J Hosp Med. 2017;12(1):5-10. PubMed
2. Kangovi S, Barg FK, Carter T, et al. Challenges faced by patients with low socioeconomic status during the post-hospital transition. J Gen Intern Med. 2014;29:283-289. PubMed
3. Blumenthal D, Chernof B, Fulmer T, Lumpkin J, Selberg J. Caring for high-need, high-cost patients - an urgent priority. N Engl J Med. 2016;375:909-911. PubMed
4. Powers BW, Milstein A, Jain SH. Delivery models for high-risk older patients: back to the future? JAMA. 2016;315:23-24. PubMed
5. Abu Dabrh AM, Gallacher K, Boehmer KR, Hargraves IG, Mair FS. Minimally disruptive medicine: the evidence and conceptual progress supporting a new era of healthcare. J R Coll Physicians Edinb. 2015;45:114-117. PubMed
6. Pannick S, Wachter RM, Vincent C, Sevdalis N. Rethinking medical ward quality. BMJ. 2016;355:i5417. PubMed
7. Kressin NR, Chapman SE, Magnani JW. A tale of two patients: patient-centered approaches to adherence as a gateway to reducing disparities. Circulation. 2016;133:2583-2592. PubMed
8. Thiel de Bocanegra H, Gany F. Good provider, good patient: changing behaviors to eliminate disparities in healthcare. Am J Manag Care. 2004;10:SP20-28. PubMed
9. Churchman CW. Wicked problems. Manage Sci. 1967;14(4):B141-B142.
For a number of years, those challenged with improving discharge transitions and preventing readmissions have suggested more—more case managers, more checklists and systems, more discharge pharmacists; and better—better communication, better medication reconciliation, better discharge documentation, better follow-up. In a study by Chan Carusone et al.,1 high-need, high-complexity patients receiving treatment at Casey House, a specialized urban hospital providing inpatient and community programs, were afforded a full complement of discharge planning and posthospitalization services. Despite these services, the patients achieved little success in maintaining their health and following their discharge plans after hospitalization.
This longitudinal qualitative study detailing the lived experience of discharge extends our knowledge of challenges faced by patients during the posthospital transition,2 and further elucidates the differences between patients’ expectations and assessments of their resources and goals, and their actual abilities and priorities on discharge. Despite substantial assistance, including housing, food assistance, and case management, Chan Carusone et al. found that the exigencies of day-to-day existence exceeded the patients’ capacities to sustain themselves outside the hospital. This failure implies a question: If the interventions alluded to in this study were not enough, then how much more, and how much better, is needed?
Attention to this question of how to best serve high-need patients continues to increase,3 and success in intervening to improve care transitions for this population is limited,4 in part because providing more care and more coordination requires more resources. Observing the challenges that remain for patients treated in the highly-resourced setting that is Casey House, the authors propose a previously described theoretical construct, minimally disruptive medicine (MDM),5 as a framework to guide patients and providers in creating a discharge plan that relies on the patient’s capacity to integrate disease self-management into his or her daily circumstances. MDM hinges on the concept of balancing workload and capacity: the burden of managing disease with the resources and abilities to do so. On first consideration, this seems an attractive approach to operationalizing patient-centered care by tailoring a discharge plan to a patient’s goals and capacities. On closer examination, however, MDM, applied to a single transition episode, raises some important concerns.
As Chan Carusone et al. describe, patients may poorly judge their future resources and capacity when making decisions in the hospital setting. Likewise, physicians and other team members may lack insight, perspective, and detailed knowledge of resources and barriers in the outpatient setting. From their vantage point, they may not see the fragile contingencies of the discharge plan that is reflected in the patients’ spoken words. At any moment, a well-meant, seemingly well-crafted discharge plan could fall apart.
Within the walls of the hospital, we tend to perform what might be termed maximally disruptive medicine—the treatments provided are exactly those that can’t be delivered in a nonhospital setting. For many patients, these interventions are not curative, but rather stabilizing;6 we assuage chronic conditions that had become exacerbated by new illness, disease progression, or conditions outside the hospital. To return the patient to his or her home situation, especially one that is under-resourced, with minimized workload can feel counterproductive and demoralizing at best. What prevents one from worrying that, where capacity can’t be improved, planning for MDM is, in essence, planning for minimal care?
Viewed in the broader context of a life course health development framework,7 which integrates biological, psychological, cultural, and historical experience to explain the development of health trajectories over an individual’s lifetime, a minimally disruptive approach might be viewed as amplifying disparities. The patients contributing to the study by Chan Carusone et al. may have arrived in their respective situations through a life course marked by poverty, violence, inadequate housing, poor nutrition, discrimination, and other disadvantages that may have resulted from accident, malfeasance, or choice. Their limited personal capacity and the ongoing chaos that is reflected in many of their comments requires that discharge planning uses imagination and dialogue, with careful, compassionate listening by providers, and close partnering and decision-making by patient and providers. Approaches to building the capacity for such compassion, as well as structural interventions to provide care that is necessary and just for these most vulnerable patients by considering their experiences and beliefs,8 remain to be articulated.
In a sense, the narrative unfolded by Chan Carusone et al. appropriately emphasizes that care transitions contain both complex problems and “wicked” problems.9 While aspects of transitions are complex and can be reasonably addressed with complex solutions, these same complex solutions are inadequate to mitigate the seemingly intractable socioeconomic challenges that drive hospital dependence for many high-need patients. Addressing these likely requires a reexamination of what we expect from hospitals, what systems we are able to design and are willing to support to keep people from returning to them, and what it means that for some people returning is the best, and sometimes only, thing to do.
As we continue to seek new models for healthcare in high-need, high-risk populations, we may do well to focus further longitudinal qualitative study on building a deep understanding of when and how patients achieve success following discharge. What characterizes patients, caregivers, service networks, and communities in healthcare settings with the highest rates of effective transitions? Maintaining equilibrium outside an institutional setting is convoluted, time-consuming, nuanced, and taxing; that those who have not experienced doing so as a patient or caregiver might struggle to help others should not surprise us. The concepts of capacity and workload lend themselves to structuring discovery of the resources that patients, not providers and policy-makers, have found through their lived experience to be most crucial to their enduring well-being. Learning from these experiences may shift the balance by increasing our own capacity to understand what constitutes success.
Disclosures
The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors report no conflicts of interest.
For a number of years, those challenged with improving discharge transitions and preventing readmissions have suggested more—more case managers, more checklists and systems, more discharge pharmacists; and better—better communication, better medication reconciliation, better discharge documentation, better follow-up. In a study by Chan Carusone et al.,1 high-need, high-complexity patients receiving treatment at Casey House, a specialized urban hospital providing inpatient and community programs, were afforded a full complement of discharge planning and posthospitalization services. Despite these services, the patients achieved little success in maintaining their health and following their discharge plans after hospitalization.
This longitudinal qualitative study detailing the lived experience of discharge extends our knowledge of challenges faced by patients during the posthospital transition,2 and further elucidates the differences between patients’ expectations and assessments of their resources and goals, and their actual abilities and priorities on discharge. Despite substantial assistance, including housing, food assistance, and case management, Chan Carusone et al. found that the exigencies of day-to-day existence exceeded the patients’ capacities to sustain themselves outside the hospital. This failure implies a question: If the interventions alluded to in this study were not enough, then how much more, and how much better, is needed?
Attention to this question of how to best serve high-need patients continues to increase,3 and success in intervening to improve care transitions for this population is limited,4 in part because providing more care and more coordination requires more resources. Observing the challenges that remain for patients treated in the highly-resourced setting that is Casey House, the authors propose a previously described theoretical construct, minimally disruptive medicine (MDM),5 as a framework to guide patients and providers in creating a discharge plan that relies on the patient’s capacity to integrate disease self-management into his or her daily circumstances. MDM hinges on the concept of balancing workload and capacity: the burden of managing disease with the resources and abilities to do so. On first consideration, this seems an attractive approach to operationalizing patient-centered care by tailoring a discharge plan to a patient’s goals and capacities. On closer examination, however, MDM, applied to a single transition episode, raises some important concerns.
As Chan Carusone et al. describe, patients may poorly judge their future resources and capacity when making decisions in the hospital setting. Likewise, physicians and other team members may lack insight, perspective, and detailed knowledge of resources and barriers in the outpatient setting. From their vantage point, they may not see the fragile contingencies of the discharge plan that is reflected in the patients’ spoken words. At any moment, a well-meant, seemingly well-crafted discharge plan could fall apart.
Within the walls of the hospital, we tend to perform what might be termed maximally disruptive medicine—the treatments provided are exactly those that can’t be delivered in a nonhospital setting. For many patients, these interventions are not curative, but rather stabilizing;6 we assuage chronic conditions that had become exacerbated by new illness, disease progression, or conditions outside the hospital. To return the patient to his or her home situation, especially one that is under-resourced, with minimized workload can feel counterproductive and demoralizing at best. What prevents one from worrying that, where capacity can’t be improved, planning for MDM is, in essence, planning for minimal care?
Viewed in the broader context of a life course health development framework,7 which integrates biological, psychological, cultural, and historical experience to explain the development of health trajectories over an individual’s lifetime, a minimally disruptive approach might be viewed as amplifying disparities. The patients contributing to the study by Chan Carusone et al. may have arrived in their respective situations through a life course marked by poverty, violence, inadequate housing, poor nutrition, discrimination, and other disadvantages that may have resulted from accident, malfeasance, or choice. Their limited personal capacity and the ongoing chaos that is reflected in many of their comments requires that discharge planning uses imagination and dialogue, with careful, compassionate listening by providers, and close partnering and decision-making by patient and providers. Approaches to building the capacity for such compassion, as well as structural interventions to provide care that is necessary and just for these most vulnerable patients by considering their experiences and beliefs,8 remain to be articulated.
In a sense, the narrative unfolded by Chan Carusone et al. appropriately emphasizes that care transitions contain both complex problems and “wicked” problems.9 While aspects of transitions are complex and can be reasonably addressed with complex solutions, these same complex solutions are inadequate to mitigate the seemingly intractable socioeconomic challenges that drive hospital dependence for many high-need patients. Addressing these likely requires a reexamination of what we expect from hospitals, what systems we are able to design and are willing to support to keep people from returning to them, and what it means that for some people returning is the best, and sometimes only, thing to do.
As we continue to seek new models for healthcare in high-need, high-risk populations, we may do well to focus further longitudinal qualitative study on building a deep understanding of when and how patients achieve success following discharge. What characterizes patients, caregivers, service networks, and communities in healthcare settings with the highest rates of effective transitions? Maintaining equilibrium outside an institutional setting is convoluted, time-consuming, nuanced, and taxing; that those who have not experienced doing so as a patient or caregiver might struggle to help others should not surprise us. The concepts of capacity and workload lend themselves to structuring discovery of the resources that patients, not providers and policy-makers, have found through their lived experience to be most crucial to their enduring well-being. Learning from these experiences may shift the balance by increasing our own capacity to understand what constitutes success.
Disclosures
The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors report no conflicts of interest.
References
1. Chan Carusone S, O’Leary B, McWatt S, Stewart S, Craig S, Brennan D. The lived experience of the hospital discharge “plan”: a longitudinal qualitative study of complex patients. J Hosp Med. 2017;12(1):5-10. PubMed
2. Kangovi S, Barg FK, Carter T, et al. Challenges faced by patients with low socioeconomic status during the post-hospital transition. J Gen Intern Med. 2014;29:283-289. PubMed
3. Blumenthal D, Chernof B, Fulmer T, Lumpkin J, Selberg J. Caring for high-need, high-cost patients - an urgent priority. N Engl J Med. 2016;375:909-911. PubMed
4. Powers BW, Milstein A, Jain SH. Delivery models for high-risk older patients: back to the future? JAMA. 2016;315:23-24. PubMed
5. Abu Dabrh AM, Gallacher K, Boehmer KR, Hargraves IG, Mair FS. Minimally disruptive medicine: the evidence and conceptual progress supporting a new era of healthcare. J R Coll Physicians Edinb. 2015;45:114-117. PubMed
6. Pannick S, Wachter RM, Vincent C, Sevdalis N. Rethinking medical ward quality. BMJ. 2016;355:i5417. PubMed
7. Kressin NR, Chapman SE, Magnani JW. A tale of two patients: patient-centered approaches to adherence as a gateway to reducing disparities. Circulation. 2016;133:2583-2592. PubMed
8. Thiel de Bocanegra H, Gany F. Good provider, good patient: changing behaviors to eliminate disparities in healthcare. Am J Manag Care. 2004;10:SP20-28. PubMed
9. Churchman CW. Wicked problems. Manage Sci. 1967;14(4):B141-B142.
References
1. Chan Carusone S, O’Leary B, McWatt S, Stewart S, Craig S, Brennan D. The lived experience of the hospital discharge “plan”: a longitudinal qualitative study of complex patients. J Hosp Med. 2017;12(1):5-10. PubMed
2. Kangovi S, Barg FK, Carter T, et al. Challenges faced by patients with low socioeconomic status during the post-hospital transition. J Gen Intern Med. 2014;29:283-289. PubMed
3. Blumenthal D, Chernof B, Fulmer T, Lumpkin J, Selberg J. Caring for high-need, high-cost patients - an urgent priority. N Engl J Med. 2016;375:909-911. PubMed
4. Powers BW, Milstein A, Jain SH. Delivery models for high-risk older patients: back to the future? JAMA. 2016;315:23-24. PubMed
5. Abu Dabrh AM, Gallacher K, Boehmer KR, Hargraves IG, Mair FS. Minimally disruptive medicine: the evidence and conceptual progress supporting a new era of healthcare. J R Coll Physicians Edinb. 2015;45:114-117. PubMed
6. Pannick S, Wachter RM, Vincent C, Sevdalis N. Rethinking medical ward quality. BMJ. 2016;355:i5417. PubMed
7. Kressin NR, Chapman SE, Magnani JW. A tale of two patients: patient-centered approaches to adherence as a gateway to reducing disparities. Circulation. 2016;133:2583-2592. PubMed
8. Thiel de Bocanegra H, Gany F. Good provider, good patient: changing behaviors to eliminate disparities in healthcare. Am J Manag Care. 2004;10:SP20-28. PubMed
9. Churchman CW. Wicked problems. Manage Sci. 1967;14(4):B141-B142.
© 2017 Society of Hospital Medicine
Improving Quality in Against Medical Advice Discharges
Against Medical Advice (AMA) discharges, when a patient chooses to leave the hospital prior to a clinically specified and physician recommended endpoint, remain a healthcare quality problem. Patients who leave the hospital AMA challenge the healthcare professionals entrusted to care for them as well as the institutions that work to promote continuity and improved quality. AMA discharges account for up to 2% of all hospital discharges and, compared with conventional discharges, are associated with worse health and health services outcomes. Patients discharged AMA have higher rates of 30-day readmission, morbidity, and 30-day mortality.1,2 Additionally, the burden of worse health outcomes is disproportionate among disadvantaged patient populations. Patients with human immunodeficiency virus,3 substance use disorders,4 and psychiatric illness5 are more likely to be discharged AMA, as are patients with low socioeconomic status, without insurance, or with Medicaid insurance.
In this issue of the Journal of Hospital Medicine, Stearns and colleagues6 provide an important contribution to this area of medicine in need of more high quality empiric studies. The study reviewed all AMA discharges from a single year in an urban community hospital in order to assess provider perceptions and knowledge about AMA discharges. The study reconfirmed both the patient-level predictors of AMA discharges that have been demonstrated consistently (ie, male gender, younger age, Medicare or no insurance, and injection drug use) as well as the low rates of documentation of patient capacity, medication prescribed, and follow-up plans in AMA discharges.7
The authors’ investigation has also advanced the study of AMA discharges in two important directions. First, by characterizing patients with multiple AMA discharges, the authors focus on a more vulnerable population. These patients, who may have particular difficulty in consistently engaging in care, could help provide insight into the general phenomenon of AMA discharges. Second, the authors broadened their attention to include the study of nurses, a group of healthcare professionals who may play an important but not well recognized role in the AMA discharge process. In further characterizing nurses’ attitudes toward AMA discharges, medication prescriptions, and outpatient follow-up, the authors highlight nurses’ role in gathering critical patient information and promoting ethical practices in discharge planning. To better understand this dynamic and its potential role in mediating adverse health outcomes, further studies should also examine the attitudes of other central members of the treatment team (eg, pharmacists, social workers, etc.) who participate in discharge planning.
Inadequate documentation of AMA discharges remains a problem. In an attempt to address this, some institutions use AMA discharge forms to facilitate documentation of the informed consent process, the patient’s signed declination of care, medico-legal considerations, and the resulting treatment plan. Although systematic efforts to improve documentation should be encouraged, significant uncertainty about the optimal use of AMA discharge forms remains. Specifically, the use of a patient-signed AMA discharge form has not been demonstrated to advance patient care and may promote harm by stigmatizing patients8 and reducing the likelihood that they will pursue follow-up care.9 Furthermore, given that these forms may be written using institution-centered legalistic language or at an inappropriate reading level, this common hospital practice should be evaluated to assess whether patients comprehend and benefit from the forms, and how the forms influence healthcare decision making.10
Finally, the authors’ finding that 38% of nurses, 22% of physician trainees, and 6% of attendings believe patients discharged AMA lose the “right” to follow-up is noteworthy. The practice would suggest a significant lapse in understanding the professional obligation to acknowledge and communicate that the informed consent process is voluntary and patients have the right to decline recommended treatment without forfeiting future access to care. Harm reduction principles indicate that simply choosing to decline an episode of inpatient care does not make a patient ineligible for other medically indicated treatments and services. Previous studies have demonstrated that physicians may incorrectly inform patients that insurance will not pay for their care if they leave AMA, in order to persuade them to remain hospitalized.11 The current study suggests similar and potentially well-meaning but coercive attitudes about AMA discharge that can undermine a patient’s voluntary choice to accept medical care.
Stearns and colleagues6 rightly point to educational and policy interventions to improve the quality of care for patients discharged AMA. Additionally, setting patients’ expectations early in the hospitalization,12 empathically addressing their concerns,13 and sharing clinical decisions with patients by providing a medically reasonable range of clinical options rather than a single choice14 are practical bedside interventions that all clinicians can implement. System changes like developing clear policies and electronic medical records templates are particularly important, as they are more likely to lead to durable institutional change that is systematic, transparent, and fair. Moreover, research that expands the object of study beyond the physician-patient relationship could significantly improve outcomes in this vulnerable population of patients. Recent studies have begun to elucidate the deficiencies that may underlie communication failures with patients before they choose to leave AMA,15 how providers decide to designate a discharge as AMA,16 and how changing the structure and environment of care for patients who use injection drugs can reduce AMA discharges and improve health outcomes.17
AMA discharges are a persistent, complicated healthcare quality problem that defies an easy solution. Improving the quality of care for these patients will require building upon the empirical research base, providing enhanced education and guidance to healthcare professionals in the ethical and clinical management of AMA discharges, and making systems changes that promote enduring institutional change. We are moving in the right direction, but we have further to go.
Disclosures
The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the US Department of Veterans Affairs or the National Center for Ethics in Health Care. The author has no conflicts of interest to disclose.
References
1. Alfandre DJ. “I’m going home”: discharges against medical advice. Mayo Clin Proc. 2009;84(3):255-260. PubMed
2. Southern WN, Nahvi S, Arnsten JH. Increased risk of mortality and readmission among patients discharged against medical advice. Am J Med. 2012;125(6):
594-602. PubMed
3. Anis AH, Sun H, Guh DP, Palepu A, Schechter MT, O’Shaughnessy MV. Leaving hospital against medical advice among HIV-positive patients. CMAJ. 2002;167(6):633-637. PubMed
4. Chan AC, Palepu A, Guh DP, et al. HIV-positive injection drug users who leave the hospital against medical advice: the mitigating role of methadone and social support. J Acquir Immune Defic Syndr. 2004;35(1):56-59. PubMed
5. Kuo CJ, Tsai SY, Liao YT, Lee WC, Sung XW, Chen CC. Psychiatric discharge against medical advice is a risk factor for suicide but not for other causes of death. J Clin Psychiatry. 2010;71(6):808-809. PubMed
6. Edwards J, Markert R, Bricker D. Discharge against medical advice: how often do we intervene? J Hosp Med. 2013;8(10):574-577. PubMed
7. Stearns CR, Bakamjian A, Sattar S, Ritterman Weintraub M. Discharges against medical advice at a county hospital: provider perceptions and practice. J Hosp Med. 2017;12(1):11-17. PubMed
8. Windish DM, Ratanawongsa N. Providers’ perceptions of relationships and professional roles when caring for patients who leave the hospital against medical advice. J Gen Intern Med. 2008;23(10):1698-1707. PubMed
9. Jerrard DA, Chasm RM. Patients leaving against medical advice (AMA) from the emergency department—disease prevalence and willingness to return. J Emerg Med. 2011;41(4):412-417. PubMed
10. Alfandre D. Reconsidering against medical advice discharges: embracing patient-centeredness to promote high quality care and a renewed research agenda.
J Gen Intern Med. 2013;28(12):1657-1662. PubMed
11. Schaefer GR, Matus H, Schumann JH, et al. Financial responsibility of hospitalized patients who left against medical advice: Medical urban legend? J Gen Intern Med. 2012;27(7):825-830. PubMed
12. Steinglass P, Grantham CE, Hertzman M. Predicting which patients will be discharged against medical advice: a pilot study. Am J Psychiatry. 1980;137(11):
1385-1389. PubMed
13. Clark MA, Abbott JT, Adyanthaya T. Ethics seminars: a best-practice approach to navigating the against-medical-advice discharge. Acad Emerg Med. 2014;21(9):1050-1057. PubMed
14. Alfandre D. Clinical recommendations in medical practice: a proposed framework to reduce bias and improve the quality of medical decisions. J Clin Ethics. 2016;27(1):21-27. PubMed
15. Lekas HM, Alfandre D, Gordon P, Harwood K, Yin MT. The role of patient-provider interactions: Using an accounts framework to explain hospital discharges against medical advice. Soc Sci Med. 2016;156:106-113. PubMed
16. Brenner J, Joslin J, Goulette A, Grant WD, Wojcik SM. Against medical advice: A survey of ED clinicians’ rationale for use. J Emerg Nurs. 2016;42(5):408-411. PubMed
17. McNeil R, Small W, Wood E, Kerr T. Hospitals as a ‘risk environment’: an ethno-epidemiological study of voluntary and involuntary discharge from hospital against medical advice among people who inject drugs. Soc Sci Med. 2014;105:59-66. PubMed
Against Medical Advice (AMA) discharges, when a patient chooses to leave the hospital prior to a clinically specified and physician recommended endpoint, remain a healthcare quality problem. Patients who leave the hospital AMA challenge the healthcare professionals entrusted to care for them as well as the institutions that work to promote continuity and improved quality. AMA discharges account for up to 2% of all hospital discharges and, compared with conventional discharges, are associated with worse health and health services outcomes. Patients discharged AMA have higher rates of 30-day readmission, morbidity, and 30-day mortality.1,2 Additionally, the burden of worse health outcomes is disproportionate among disadvantaged patient populations. Patients with human immunodeficiency virus,3 substance use disorders,4 and psychiatric illness5 are more likely to be discharged AMA, as are patients with low socioeconomic status, without insurance, or with Medicaid insurance.
In this issue of the Journal of Hospital Medicine, Stearns and colleagues6 provide an important contribution to this area of medicine in need of more high quality empiric studies. The study reviewed all AMA discharges from a single year in an urban community hospital in order to assess provider perceptions and knowledge about AMA discharges. The study reconfirmed both the patient-level predictors of AMA discharges that have been demonstrated consistently (ie, male gender, younger age, Medicare or no insurance, and injection drug use) as well as the low rates of documentation of patient capacity, medication prescribed, and follow-up plans in AMA discharges.7
The authors’ investigation has also advanced the study of AMA discharges in two important directions. First, by characterizing patients with multiple AMA discharges, the authors focus on a more vulnerable population. These patients, who may have particular difficulty in consistently engaging in care, could help provide insight into the general phenomenon of AMA discharges. Second, the authors broadened their attention to include the study of nurses, a group of healthcare professionals who may play an important but not well recognized role in the AMA discharge process. In further characterizing nurses’ attitudes toward AMA discharges, medication prescriptions, and outpatient follow-up, the authors highlight nurses’ role in gathering critical patient information and promoting ethical practices in discharge planning. To better understand this dynamic and its potential role in mediating adverse health outcomes, further studies should also examine the attitudes of other central members of the treatment team (eg, pharmacists, social workers, etc.) who participate in discharge planning.
Inadequate documentation of AMA discharges remains a problem. In an attempt to address this, some institutions use AMA discharge forms to facilitate documentation of the informed consent process, the patient’s signed declination of care, medico-legal considerations, and the resulting treatment plan. Although systematic efforts to improve documentation should be encouraged, significant uncertainty about the optimal use of AMA discharge forms remains. Specifically, the use of a patient-signed AMA discharge form has not been demonstrated to advance patient care and may promote harm by stigmatizing patients8 and reducing the likelihood that they will pursue follow-up care.9 Furthermore, given that these forms may be written using institution-centered legalistic language or at an inappropriate reading level, this common hospital practice should be evaluated to assess whether patients comprehend and benefit from the forms, and how the forms influence healthcare decision making.10
Finally, the authors’ finding that 38% of nurses, 22% of physician trainees, and 6% of attendings believe patients discharged AMA lose the “right” to follow-up is noteworthy. The practice would suggest a significant lapse in understanding the professional obligation to acknowledge and communicate that the informed consent process is voluntary and patients have the right to decline recommended treatment without forfeiting future access to care. Harm reduction principles indicate that simply choosing to decline an episode of inpatient care does not make a patient ineligible for other medically indicated treatments and services. Previous studies have demonstrated that physicians may incorrectly inform patients that insurance will not pay for their care if they leave AMA, in order to persuade them to remain hospitalized.11 The current study suggests similar and potentially well-meaning but coercive attitudes about AMA discharge that can undermine a patient’s voluntary choice to accept medical care.
Stearns and colleagues6 rightly point to educational and policy interventions to improve the quality of care for patients discharged AMA. Additionally, setting patients’ expectations early in the hospitalization,12 empathically addressing their concerns,13 and sharing clinical decisions with patients by providing a medically reasonable range of clinical options rather than a single choice14 are practical bedside interventions that all clinicians can implement. System changes like developing clear policies and electronic medical records templates are particularly important, as they are more likely to lead to durable institutional change that is systematic, transparent, and fair. Moreover, research that expands the object of study beyond the physician-patient relationship could significantly improve outcomes in this vulnerable population of patients. Recent studies have begun to elucidate the deficiencies that may underlie communication failures with patients before they choose to leave AMA,15 how providers decide to designate a discharge as AMA,16 and how changing the structure and environment of care for patients who use injection drugs can reduce AMA discharges and improve health outcomes.17
AMA discharges are a persistent, complicated healthcare quality problem that defies an easy solution. Improving the quality of care for these patients will require building upon the empirical research base, providing enhanced education and guidance to healthcare professionals in the ethical and clinical management of AMA discharges, and making systems changes that promote enduring institutional change. We are moving in the right direction, but we have further to go.
Disclosures
The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the US Department of Veterans Affairs or the National Center for Ethics in Health Care. The author has no conflicts of interest to disclose.
Against Medical Advice (AMA) discharges, when a patient chooses to leave the hospital prior to a clinically specified and physician recommended endpoint, remain a healthcare quality problem. Patients who leave the hospital AMA challenge the healthcare professionals entrusted to care for them as well as the institutions that work to promote continuity and improved quality. AMA discharges account for up to 2% of all hospital discharges and, compared with conventional discharges, are associated with worse health and health services outcomes. Patients discharged AMA have higher rates of 30-day readmission, morbidity, and 30-day mortality.1,2 Additionally, the burden of worse health outcomes is disproportionate among disadvantaged patient populations. Patients with human immunodeficiency virus,3 substance use disorders,4 and psychiatric illness5 are more likely to be discharged AMA, as are patients with low socioeconomic status, without insurance, or with Medicaid insurance.
In this issue of the Journal of Hospital Medicine, Stearns and colleagues6 provide an important contribution to this area of medicine in need of more high quality empiric studies. The study reviewed all AMA discharges from a single year in an urban community hospital in order to assess provider perceptions and knowledge about AMA discharges. The study reconfirmed both the patient-level predictors of AMA discharges that have been demonstrated consistently (ie, male gender, younger age, Medicare or no insurance, and injection drug use) as well as the low rates of documentation of patient capacity, medication prescribed, and follow-up plans in AMA discharges.7
The authors’ investigation has also advanced the study of AMA discharges in two important directions. First, by characterizing patients with multiple AMA discharges, the authors focus on a more vulnerable population. These patients, who may have particular difficulty in consistently engaging in care, could help provide insight into the general phenomenon of AMA discharges. Second, the authors broadened their attention to include the study of nurses, a group of healthcare professionals who may play an important but not well recognized role in the AMA discharge process. In further characterizing nurses’ attitudes toward AMA discharges, medication prescriptions, and outpatient follow-up, the authors highlight nurses’ role in gathering critical patient information and promoting ethical practices in discharge planning. To better understand this dynamic and its potential role in mediating adverse health outcomes, further studies should also examine the attitudes of other central members of the treatment team (eg, pharmacists, social workers, etc.) who participate in discharge planning.
Inadequate documentation of AMA discharges remains a problem. In an attempt to address this, some institutions use AMA discharge forms to facilitate documentation of the informed consent process, the patient’s signed declination of care, medico-legal considerations, and the resulting treatment plan. Although systematic efforts to improve documentation should be encouraged, significant uncertainty about the optimal use of AMA discharge forms remains. Specifically, the use of a patient-signed AMA discharge form has not been demonstrated to advance patient care and may promote harm by stigmatizing patients8 and reducing the likelihood that they will pursue follow-up care.9 Furthermore, given that these forms may be written using institution-centered legalistic language or at an inappropriate reading level, this common hospital practice should be evaluated to assess whether patients comprehend and benefit from the forms, and how the forms influence healthcare decision making.10
Finally, the authors’ finding that 38% of nurses, 22% of physician trainees, and 6% of attendings believe patients discharged AMA lose the “right” to follow-up is noteworthy. The practice would suggest a significant lapse in understanding the professional obligation to acknowledge and communicate that the informed consent process is voluntary and patients have the right to decline recommended treatment without forfeiting future access to care. Harm reduction principles indicate that simply choosing to decline an episode of inpatient care does not make a patient ineligible for other medically indicated treatments and services. Previous studies have demonstrated that physicians may incorrectly inform patients that insurance will not pay for their care if they leave AMA, in order to persuade them to remain hospitalized.11 The current study suggests similar and potentially well-meaning but coercive attitudes about AMA discharge that can undermine a patient’s voluntary choice to accept medical care.
Stearns and colleagues6 rightly point to educational and policy interventions to improve the quality of care for patients discharged AMA. Additionally, setting patients’ expectations early in the hospitalization,12 empathically addressing their concerns,13 and sharing clinical decisions with patients by providing a medically reasonable range of clinical options rather than a single choice14 are practical bedside interventions that all clinicians can implement. System changes like developing clear policies and electronic medical records templates are particularly important, as they are more likely to lead to durable institutional change that is systematic, transparent, and fair. Moreover, research that expands the object of study beyond the physician-patient relationship could significantly improve outcomes in this vulnerable population of patients. Recent studies have begun to elucidate the deficiencies that may underlie communication failures with patients before they choose to leave AMA,15 how providers decide to designate a discharge as AMA,16 and how changing the structure and environment of care for patients who use injection drugs can reduce AMA discharges and improve health outcomes.17
AMA discharges are a persistent, complicated healthcare quality problem that defies an easy solution. Improving the quality of care for these patients will require building upon the empirical research base, providing enhanced education and guidance to healthcare professionals in the ethical and clinical management of AMA discharges, and making systems changes that promote enduring institutional change. We are moving in the right direction, but we have further to go.
Disclosures
The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the US Department of Veterans Affairs or the National Center for Ethics in Health Care. The author has no conflicts of interest to disclose.
References
1. Alfandre DJ. “I’m going home”: discharges against medical advice. Mayo Clin Proc. 2009;84(3):255-260. PubMed
2. Southern WN, Nahvi S, Arnsten JH. Increased risk of mortality and readmission among patients discharged against medical advice. Am J Med. 2012;125(6):
594-602. PubMed
3. Anis AH, Sun H, Guh DP, Palepu A, Schechter MT, O’Shaughnessy MV. Leaving hospital against medical advice among HIV-positive patients. CMAJ. 2002;167(6):633-637. PubMed
4. Chan AC, Palepu A, Guh DP, et al. HIV-positive injection drug users who leave the hospital against medical advice: the mitigating role of methadone and social support. J Acquir Immune Defic Syndr. 2004;35(1):56-59. PubMed
5. Kuo CJ, Tsai SY, Liao YT, Lee WC, Sung XW, Chen CC. Psychiatric discharge against medical advice is a risk factor for suicide but not for other causes of death. J Clin Psychiatry. 2010;71(6):808-809. PubMed
6. Edwards J, Markert R, Bricker D. Discharge against medical advice: how often do we intervene? J Hosp Med. 2013;8(10):574-577. PubMed
7. Stearns CR, Bakamjian A, Sattar S, Ritterman Weintraub M. Discharges against medical advice at a county hospital: provider perceptions and practice. J Hosp Med. 2017;12(1):11-17. PubMed
8. Windish DM, Ratanawongsa N. Providers’ perceptions of relationships and professional roles when caring for patients who leave the hospital against medical advice. J Gen Intern Med. 2008;23(10):1698-1707. PubMed
9. Jerrard DA, Chasm RM. Patients leaving against medical advice (AMA) from the emergency department—disease prevalence and willingness to return. J Emerg Med. 2011;41(4):412-417. PubMed
10. Alfandre D. Reconsidering against medical advice discharges: embracing patient-centeredness to promote high quality care and a renewed research agenda.
J Gen Intern Med. 2013;28(12):1657-1662. PubMed
11. Schaefer GR, Matus H, Schumann JH, et al. Financial responsibility of hospitalized patients who left against medical advice: Medical urban legend? J Gen Intern Med. 2012;27(7):825-830. PubMed
12. Steinglass P, Grantham CE, Hertzman M. Predicting which patients will be discharged against medical advice: a pilot study. Am J Psychiatry. 1980;137(11):
1385-1389. PubMed
13. Clark MA, Abbott JT, Adyanthaya T. Ethics seminars: a best-practice approach to navigating the against-medical-advice discharge. Acad Emerg Med. 2014;21(9):1050-1057. PubMed
14. Alfandre D. Clinical recommendations in medical practice: a proposed framework to reduce bias and improve the quality of medical decisions. J Clin Ethics. 2016;27(1):21-27. PubMed
15. Lekas HM, Alfandre D, Gordon P, Harwood K, Yin MT. The role of patient-provider interactions: Using an accounts framework to explain hospital discharges against medical advice. Soc Sci Med. 2016;156:106-113. PubMed
16. Brenner J, Joslin J, Goulette A, Grant WD, Wojcik SM. Against medical advice: A survey of ED clinicians’ rationale for use. J Emerg Nurs. 2016;42(5):408-411. PubMed
17. McNeil R, Small W, Wood E, Kerr T. Hospitals as a ‘risk environment’: an ethno-epidemiological study of voluntary and involuntary discharge from hospital against medical advice among people who inject drugs. Soc Sci Med. 2014;105:59-66. PubMed
References
1. Alfandre DJ. “I’m going home”: discharges against medical advice. Mayo Clin Proc. 2009;84(3):255-260. PubMed
2. Southern WN, Nahvi S, Arnsten JH. Increased risk of mortality and readmission among patients discharged against medical advice. Am J Med. 2012;125(6):
594-602. PubMed
3. Anis AH, Sun H, Guh DP, Palepu A, Schechter MT, O’Shaughnessy MV. Leaving hospital against medical advice among HIV-positive patients. CMAJ. 2002;167(6):633-637. PubMed
4. Chan AC, Palepu A, Guh DP, et al. HIV-positive injection drug users who leave the hospital against medical advice: the mitigating role of methadone and social support. J Acquir Immune Defic Syndr. 2004;35(1):56-59. PubMed
5. Kuo CJ, Tsai SY, Liao YT, Lee WC, Sung XW, Chen CC. Psychiatric discharge against medical advice is a risk factor for suicide but not for other causes of death. J Clin Psychiatry. 2010;71(6):808-809. PubMed
6. Edwards J, Markert R, Bricker D. Discharge against medical advice: how often do we intervene? J Hosp Med. 2013;8(10):574-577. PubMed
7. Stearns CR, Bakamjian A, Sattar S, Ritterman Weintraub M. Discharges against medical advice at a county hospital: provider perceptions and practice. J Hosp Med. 2017;12(1):11-17. PubMed
8. Windish DM, Ratanawongsa N. Providers’ perceptions of relationships and professional roles when caring for patients who leave the hospital against medical advice. J Gen Intern Med. 2008;23(10):1698-1707. PubMed
9. Jerrard DA, Chasm RM. Patients leaving against medical advice (AMA) from the emergency department—disease prevalence and willingness to return. J Emerg Med. 2011;41(4):412-417. PubMed
10. Alfandre D. Reconsidering against medical advice discharges: embracing patient-centeredness to promote high quality care and a renewed research agenda.
J Gen Intern Med. 2013;28(12):1657-1662. PubMed
11. Schaefer GR, Matus H, Schumann JH, et al. Financial responsibility of hospitalized patients who left against medical advice: Medical urban legend? J Gen Intern Med. 2012;27(7):825-830. PubMed
12. Steinglass P, Grantham CE, Hertzman M. Predicting which patients will be discharged against medical advice: a pilot study. Am J Psychiatry. 1980;137(11):
1385-1389. PubMed
13. Clark MA, Abbott JT, Adyanthaya T. Ethics seminars: a best-practice approach to navigating the against-medical-advice discharge. Acad Emerg Med. 2014;21(9):1050-1057. PubMed
14. Alfandre D. Clinical recommendations in medical practice: a proposed framework to reduce bias and improve the quality of medical decisions. J Clin Ethics. 2016;27(1):21-27. PubMed
15. Lekas HM, Alfandre D, Gordon P, Harwood K, Yin MT. The role of patient-provider interactions: Using an accounts framework to explain hospital discharges against medical advice. Soc Sci Med. 2016;156:106-113. PubMed
16. Brenner J, Joslin J, Goulette A, Grant WD, Wojcik SM. Against medical advice: A survey of ED clinicians’ rationale for use. J Emerg Nurs. 2016;42(5):408-411. PubMed
17. McNeil R, Small W, Wood E, Kerr T. Hospitals as a ‘risk environment’: an ethno-epidemiological study of voluntary and involuntary discharge from hospital against medical advice among people who inject drugs. Soc Sci Med. 2014;105:59-66. PubMed
© 2017 Society of Hospital Medicine
In Reference to “Pilot Study Aiming to Support Sleep Quality and Duration During Hospitalizations”
We commend Gathecha et al.1 on the implementation of a well-formed, multicomponent sleep intervention to improve sleep in hospitalized patients. While they were unable to show objective improvement in sleep outcomes, they found improvements in patient-reported sleep outcomes across hospital days, implying that multiple hospital nights are needed to realize the benefits. We wish to propose an alternative strategy. To produce a more observable and immediate improvement in patient sleep outcomes, the behavioral economics principle of nudges2 could be an effective way to influence hospital staff toward sleep-promoting practices.
In focus groups at the University of Chicago Medicine, nurses, hospitalists, and residents reported unnecessary nocturnal disruptions were the “default” option hardwired in electronic medical records admission order sets. It was time-consuming to enter orders that minimized unnecessary nocturnal disruptions, such as forgo overnight vitals for stable patients. Given that changing default settings of order sets have been shown to effectively nudge physicians in other areas,3-5 altering default settings in admission orders could facilitate physicians’ adherence to sleep-promoting practices. An intervention combining these nudges with educational initiatives may be more effective in sustained reductions in nocturnal disruptions and improved inpatient sleep from the start of a hospital stay.
References
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395. PubMed
4. Halpern SD, Ubel PA, Asch DA. Harnessing the power of default options to improve health care. N Engl J Med. 2007;357(13):1340-1344. doi:10.1056/NEJMsb071595. PubMed
5. Ansher C, Ariely D, Nagler A, Rudd M, Schwartz J, Shah A. Better medicine by default. Med Decis Making. 2014;34(2):147-158. doi:10.1177/0272989X13507339. PubMed
We commend Gathecha et al.1 on the implementation of a well-formed, multicomponent sleep intervention to improve sleep in hospitalized patients. While they were unable to show objective improvement in sleep outcomes, they found improvements in patient-reported sleep outcomes across hospital days, implying that multiple hospital nights are needed to realize the benefits. We wish to propose an alternative strategy. To produce a more observable and immediate improvement in patient sleep outcomes, the behavioral economics principle of nudges2 could be an effective way to influence hospital staff toward sleep-promoting practices.
In focus groups at the University of Chicago Medicine, nurses, hospitalists, and residents reported unnecessary nocturnal disruptions were the “default” option hardwired in electronic medical records admission order sets. It was time-consuming to enter orders that minimized unnecessary nocturnal disruptions, such as forgo overnight vitals for stable patients. Given that changing default settings of order sets have been shown to effectively nudge physicians in other areas,3-5 altering default settings in admission orders could facilitate physicians’ adherence to sleep-promoting practices. An intervention combining these nudges with educational initiatives may be more effective in sustained reductions in nocturnal disruptions and improved inpatient sleep from the start of a hospital stay.
We commend Gathecha et al.1 on the implementation of a well-formed, multicomponent sleep intervention to improve sleep in hospitalized patients. While they were unable to show objective improvement in sleep outcomes, they found improvements in patient-reported sleep outcomes across hospital days, implying that multiple hospital nights are needed to realize the benefits. We wish to propose an alternative strategy. To produce a more observable and immediate improvement in patient sleep outcomes, the behavioral economics principle of nudges2 could be an effective way to influence hospital staff toward sleep-promoting practices.
In focus groups at the University of Chicago Medicine, nurses, hospitalists, and residents reported unnecessary nocturnal disruptions were the “default” option hardwired in electronic medical records admission order sets. It was time-consuming to enter orders that minimized unnecessary nocturnal disruptions, such as forgo overnight vitals for stable patients. Given that changing default settings of order sets have been shown to effectively nudge physicians in other areas,3-5 altering default settings in admission orders could facilitate physicians’ adherence to sleep-promoting practices. An intervention combining these nudges with educational initiatives may be more effective in sustained reductions in nocturnal disruptions and improved inpatient sleep from the start of a hospital stay.
References
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395. PubMed
4. Halpern SD, Ubel PA, Asch DA. Harnessing the power of default options to improve health care. N Engl J Med. 2007;357(13):1340-1344. doi:10.1056/NEJMsb071595. PubMed
5. Ansher C, Ariely D, Nagler A, Rudd M, Schwartz J, Shah A. Better medicine by default. Med Decis Making. 2014;34(2):147-158. doi:10.1177/0272989X13507339. PubMed
References
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395. PubMed
4. Halpern SD, Ubel PA, Asch DA. Harnessing the power of default options to improve health care. N Engl J Med. 2007;357(13):1340-1344. doi:10.1056/NEJMsb071595. PubMed
5. Ansher C, Ariely D, Nagler A, Rudd M, Schwartz J, Shah A. Better medicine by default. Med Decis Making. 2014;34(2):147-158. doi:10.1177/0272989X13507339. PubMed
© 2017 Society of Hospital Medicine
The Authors Reply, “Pilot Study Aiming to Support Sleep Quality and Duration During Hospitalizations”
We thank the authors for their comments and thoughts about our recent publication.1 Their suggestion that the incorporation of principles from the “Nudge Theory” might enhance the impact of our sleep intervention and shorten the lag time until patients appreciate the benefits is interesting.2 Our study aimed to assess the effect of a sleep-promoting intervention on sleep quality and duration among hospitalized patients within a quasi-experimental prospective study design. As is the case at the University of Chicago hospital described in Machado’s letter, nocturnal disruptions are also the “default” in order sets in our electronic medical records (EMR). Because the EMR team at our hospital is stretched thin with more requests than it can fulfill, it was not feasible or possible to incorporate any sleep supporting changes when designing the pilot.
Complementing sleep-promoting procedures for hospitalized patients with “nudge” principles, such as the use of choice architecture with appropriate EMR defaults or even incentives and mappings, seems like a wise recommendation.3 Regular nudges may be helpful for sustaining any multicomponent interventions in healthcare delivery that rely on cooperation by multiple parties. It appears as if evidence is growing that “nudge principles” can augment behavior change attributable to interventions.4,5 Sleep-promoting nudges, namely “anti-nudges” by members of the healthcare team, should help patients to sleep better during their hospitalizations, when sleep is critically important to recovery and health restitution.
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395 PubMed
4. Hollands GJ, Shemilt I, Marteau TM, et al. Altering micro-environments to change population health behaviour: towards an evidence base for choice architecture interventions. BMC Public Health. 2013;13:1218. doi:10.1186/1471-2458-13-1218. PubMed
5. Arno A, Thomas S. The efficacy of nudge theory strategies in influencing adult dietary behavior: a systematic review and meta-analysis. BMC Public Health. 2016;16:676. doi:10.1186/s12889-016-3272-x. PubMed
We thank the authors for their comments and thoughts about our recent publication.1 Their suggestion that the incorporation of principles from the “Nudge Theory” might enhance the impact of our sleep intervention and shorten the lag time until patients appreciate the benefits is interesting.2 Our study aimed to assess the effect of a sleep-promoting intervention on sleep quality and duration among hospitalized patients within a quasi-experimental prospective study design. As is the case at the University of Chicago hospital described in Machado’s letter, nocturnal disruptions are also the “default” in order sets in our electronic medical records (EMR). Because the EMR team at our hospital is stretched thin with more requests than it can fulfill, it was not feasible or possible to incorporate any sleep supporting changes when designing the pilot.
Complementing sleep-promoting procedures for hospitalized patients with “nudge” principles, such as the use of choice architecture with appropriate EMR defaults or even incentives and mappings, seems like a wise recommendation.3 Regular nudges may be helpful for sustaining any multicomponent interventions in healthcare delivery that rely on cooperation by multiple parties. It appears as if evidence is growing that “nudge principles” can augment behavior change attributable to interventions.4,5 Sleep-promoting nudges, namely “anti-nudges” by members of the healthcare team, should help patients to sleep better during their hospitalizations, when sleep is critically important to recovery and health restitution.
We thank the authors for their comments and thoughts about our recent publication.1 Their suggestion that the incorporation of principles from the “Nudge Theory” might enhance the impact of our sleep intervention and shorten the lag time until patients appreciate the benefits is interesting.2 Our study aimed to assess the effect of a sleep-promoting intervention on sleep quality and duration among hospitalized patients within a quasi-experimental prospective study design. As is the case at the University of Chicago hospital described in Machado’s letter, nocturnal disruptions are also the “default” in order sets in our electronic medical records (EMR). Because the EMR team at our hospital is stretched thin with more requests than it can fulfill, it was not feasible or possible to incorporate any sleep supporting changes when designing the pilot.
Complementing sleep-promoting procedures for hospitalized patients with “nudge” principles, such as the use of choice architecture with appropriate EMR defaults or even incentives and mappings, seems like a wise recommendation.3 Regular nudges may be helpful for sustaining any multicomponent interventions in healthcare delivery that rely on cooperation by multiple parties. It appears as if evidence is growing that “nudge principles” can augment behavior change attributable to interventions.4,5 Sleep-promoting nudges, namely “anti-nudges” by members of the healthcare team, should help patients to sleep better during their hospitalizations, when sleep is critically important to recovery and health restitution.
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395 PubMed
4. Hollands GJ, Shemilt I, Marteau TM, et al. Altering micro-environments to change population health behaviour: towards an evidence base for choice architecture interventions. BMC Public Health. 2013;13:1218. doi:10.1186/1471-2458-13-1218. PubMed
5. Arno A, Thomas S. The efficacy of nudge theory strategies in influencing adult dietary behavior: a systematic review and meta-analysis. BMC Public Health. 2016;16:676. doi:10.1186/s12889-016-3272-x. PubMed
1. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to support sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467-472. doi:10.1002/jhm.2578. PubMed
2. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, CT: Yale University Press; 2008.
3. Bourdeaux CP, Davies KJ, Thomas MJC, Bewley JS, Gould TH. Using “nudge” principles for order set design: a before and after evaluation of an electronic prescribing template in critical care. BMJ Qual Saf. 2014;23(5):382-388. doi:10.1136/bmjqs-2013-002395 PubMed
4. Hollands GJ, Shemilt I, Marteau TM, et al. Altering micro-environments to change population health behaviour: towards an evidence base for choice architecture interventions. BMC Public Health. 2013;13:1218. doi:10.1186/1471-2458-13-1218. PubMed
5. Arno A, Thomas S. The efficacy of nudge theory strategies in influencing adult dietary behavior: a systematic review and meta-analysis. BMC Public Health. 2016;16:676. doi:10.1186/s12889-016-3272-x. PubMed
© 2017 Society of Hospital Medicine
Postexposure management of infectious diseases
People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,1 patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.1,2 Some may need postexposure prophylaxis.
ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT
Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.1,2
Postexposure management should include the following elements:
- Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.1–6
- Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
- Initiating prophylaxis as soon as possible.
- Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
- Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
- Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
- Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.1,2
IS POSTEXPOSURE PROPHYLAXIS INDICATED?
Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.1,2
Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.1,2
HOW GREAT IS THE RISK OF INFECTION?
Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:
- Type and extent of exposure (see below)
- Characteristics of the infectious agent (eg, virulence, infectious dose)
- Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis7–10
- Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis2
- Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.1
WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?
Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.1,2,7,9–15
Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.
The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.
BLOOD-BORNE INFECTIONS
Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.16)
Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.17
When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.3,4,16,18
Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.3,4,16,18
Hepatitis B
Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).1,2,4,16
Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.4,16,19
Hepatitis C
The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.16 The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.16,18
Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.
Human immunodeficiency virus
The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.20
If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.3,18
The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.3,16,18
SEXUALLY TRANSMITTED INFECTIONS
In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.22 People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.23–25
Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.22 Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.
Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.22
Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).22
Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.3,18,26
Chlamydia
Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.22,29
Gonorrhea
Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.22 When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.22
Human immunodeficiency virus
Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.30
Syphilis
The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.22
After sexual assault
In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.22
Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.22 The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).22,26
Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.22
Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.
Emergency contraception should be given if there is a risk of pregnancy.22,26
In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center.
Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).
INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE
Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.1
Measles
Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.11
Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).31,32
Tuberculosis
Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.1,7
Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.7,33
Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.7,33,34
A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.7,33
All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .7,33,35–37
Varicella and disseminated herpes zoster
Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.12 Herpes zoster is less contagious than varicella.38
Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.12
Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).12,38–40
Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.12,39
Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.12,38
INFECTIONS TRANSMITTED BY THE DROPLET ROUTE
Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.1
Group A streptococcal infection
Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.9,41,42
Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).9,41,42
Influenza
Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.13,43
Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.13,44,45
Meningococcal disease
N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.8
Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).46 Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.
Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).8,46
Pertussis
Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.10
Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).10,47
Rubella
Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.11
INFECTIONS TRANSMITTED BY DIRECT CONTACT
Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).1
There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.1
Hepatitis A
Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.1,15
Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.15,48
Scabies
Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.
All potentially infested persons should be treated concomitantly (Table 5).14,49
INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES
Bites and injury wounds account for approximately 1% of all visits to emergency departments.50 Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.50
Rabies
Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.6 Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.51
High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.
Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.6
Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.6 If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.
The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).6
Tetanus
Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).5
Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).2,5,52
- Siegel JD, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007; 35(suppl 2): S65–S164.
- Advisory Committee on Immunization Practices; Centers for Disease Control and Prevention. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1–45.
- Kuhar DT, Henderson DK, Struble KA, et al; US Public Health Service Working Group. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013; 34: 875–892.
- Schille S, Murphy TV, Sawyer M, et al; Centers for Disease Control and Prevention (CDC). CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013; 62:1–19.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:13–15.
- Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57:1–28.
- Jensen PA, Lambert LA, Iademarco MF, Ridzon R, Centers for Disease Control and Prevention (CDC). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Morb Mortal Wkly Rep 2005; 54:1–141.
- Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–28.
- Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for Disease Control and Prevention. Clin Infect Dis 2002; 35:950–959.
- Tiwari T, Murphy TV, Moran J; National Immunization Program, Centers for Disease Control and Prevention (CDC). Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Morb Mortal Wkly Rep 2005; 54:1–16.
- McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention (CDC). Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–34.
- Marin M, Guris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1–40.
- Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1003–1032.
- Centers for Disease Control and Prevention (CDC). Scabies. www.cdc.gov/parasites/scabies/. Accessed November 4, 2016.
- Advisory Committee on Immunization Practices (ACIP); Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2006; 55:1–23.
- US Public Health Service. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2001; 50:1–52.
- Treakle AM, Schultz M, Giannakos GP, Joyce PC, Gordin FM. Evaluating a decade of exposures to blood and body fluids in an inner-city teaching hospital. Infect Control Hosp Epidemiol 2011; 32:903–907.
- New York State Department of Health AIDS Institute. Update: HIV prophylaxis following non-occupational exposure. www.hivguidelines.org/clinical-guidelines/post-exposure-prophylaxis/hiv-prophylaxis-following-non-occupational-exposure/. Accessed November 4, 2016.
- Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983; 2:1099–1102.
- Baggaley RF, Boily MC, White RG, Alary M. Risk of HIV-1 transmission for parenteral exposure and blood transfusion: a systematic review and meta-analysis. AIDS 2006; 20:805–812.
- McAllister J, Read P, McNulty A, Tong WW, Ingersoll A, Carr A. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med 2014; 15:13–22.
- Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1–137.
- US Preventive Services Task Force (USPSTF). Final recommendation statement: chlamydia and gonorrhea: screening. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/chlamydia-and-gonorrhea-screening. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Human immunodeficiency virus (HIV) infection: screening. www.uspreventiveservicestaskforce.org/uspstf/uspshivi.htm. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Screening for syphilis. www.uspreventiveservicestaskforce.org/uspstf/uspssyph.htm#update. Accessed November 4, 2016.
- Smith DK, Grohskopf LA, Black RJ, et al; US Department of Health and Human Services. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the US Department of Health and Human Services. MMWR Recomm Rep 2005; 54:1–20.
- Lin JS, Donegan SP, Heeren TC, et al. Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among men with urethritis and their female sex partners. J Infect Dis 1998; 178:1707–1712.
- Varghese B, Maher JE, Peterman TA, Branson BM, Steketee RW. Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use. Sex Transm Dis 2002; 29:38–43.
- Gülmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy. Cochrane Database Syst Rev 2011; (5):CD000220.
- Forna F, Gülmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003; (2):CD000218.
- Rice P, Young Y, Cohen B, Ramsay M. MMR immunization after contact with measles virus. Lancet 2004; 363:569–570.
- Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunization for preventing measles. Cochrane Database Syst Rev 2014; 4:CD010056.
- National Tuberculosis Controllers Association; Centers for Disease Control and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005; 54:1–47.
- Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1–25.
- Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Morb Mortal Wkly Rep 2000; 49:1–51.
- Stagg HR, Zenner D, Harris RJ, Munoz L, Lipman MC, Abubakar I. Treatment of latent tuberculosis infection: a network meta-analysis. Ann Intern Med 2014; 161:419–428.
- Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011; 60:1650–1653.
- Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008; 57:1–30.
- Macartney K, Heywood A, McIntyre P. Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults. Cochrane Database Syst Rev 2014; 6:CD001833.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of VariZIG—United States, 2013. MMWR Morb Mortal Wkly Rep 2013; 62: 574–576.
- Public Health Agency of Canada. Guidelines for the prevention and control of invasive group A streptococcal disease. Can Commun Dis Rep 2006; 32(suppl 2):1–26.
- Steer JA, Lamagni T, Healy B, et al. Guidelines for prevention and control of group A streptococcal infection in acute healthcare and maternity settings in the UK. J Infect 2012; 64:1–18.
- Grohskopf LA, Olsen SJ, Sokolow LZ, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014–15 influenza season. MMWR Morb Mortal Wkly Rep 2014; 63: 691–697.
- Fiore AE, Fry A, Shay D, et al; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011; 60:1–24.
- Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4:CD008965.
- Zalmanovici Trestioreanu A, Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Antibiotics for preventing meningococcal infections. Cochrane Database Syst Rev 2013; 10:CD004785.
- Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev 2007: CD004404.
- Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Update: prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1080–1084.
- FitzGerald D, Grainger RJ, Reid A. Interventions for preventing the spread of infestation in close contacts of people with scabies. Cochrane Database Syst Rev 2014; 2:CD009943.
- Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014; 59:e10–e52.
- Rupprecht CE, Briggs D, Brown CM, et al; Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies—recommendations of the Advisory Committee on Immunization Practice. MMWR Recomm Rep 2010; 59:1–9.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2012; 61:468–470.
People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,1 patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.1,2 Some may need postexposure prophylaxis.
ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT
Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.1,2
Postexposure management should include the following elements:
- Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.1–6
- Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
- Initiating prophylaxis as soon as possible.
- Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
- Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
- Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
- Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.1,2
IS POSTEXPOSURE PROPHYLAXIS INDICATED?
Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.1,2
Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.1,2
HOW GREAT IS THE RISK OF INFECTION?
Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:
- Type and extent of exposure (see below)
- Characteristics of the infectious agent (eg, virulence, infectious dose)
- Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis7–10
- Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis2
- Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.1
WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?
Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.1,2,7,9–15
Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.
The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.
BLOOD-BORNE INFECTIONS
Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.16)
Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.17
When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.3,4,16,18
Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.3,4,16,18
Hepatitis B
Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).1,2,4,16
Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.4,16,19
Hepatitis C
The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.16 The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.16,18
Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.
Human immunodeficiency virus
The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.20
If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.3,18
The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.3,16,18
SEXUALLY TRANSMITTED INFECTIONS
In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.22 People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.23–25
Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.22 Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.
Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.22
Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).22
Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.3,18,26
Chlamydia
Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.22,29
Gonorrhea
Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.22 When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.22
Human immunodeficiency virus
Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.30
Syphilis
The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.22
After sexual assault
In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.22
Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.22 The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).22,26
Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.22
Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.
Emergency contraception should be given if there is a risk of pregnancy.22,26
In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center.
Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).
INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE
Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.1
Measles
Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.11
Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).31,32
Tuberculosis
Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.1,7
Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.7,33
Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.7,33,34
A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.7,33
All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .7,33,35–37
Varicella and disseminated herpes zoster
Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.12 Herpes zoster is less contagious than varicella.38
Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.12
Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).12,38–40
Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.12,39
Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.12,38
INFECTIONS TRANSMITTED BY THE DROPLET ROUTE
Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.1
Group A streptococcal infection
Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.9,41,42
Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).9,41,42
Influenza
Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.13,43
Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.13,44,45
Meningococcal disease
N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.8
Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).46 Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.
Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).8,46
Pertussis
Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.10
Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).10,47
Rubella
Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.11
INFECTIONS TRANSMITTED BY DIRECT CONTACT
Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).1
There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.1
Hepatitis A
Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.1,15
Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.15,48
Scabies
Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.
All potentially infested persons should be treated concomitantly (Table 5).14,49
INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES
Bites and injury wounds account for approximately 1% of all visits to emergency departments.50 Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.50
Rabies
Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.6 Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.51
High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.
Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.6
Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.6 If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.
The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).6
Tetanus
Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).5
Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).2,5,52
People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,1 patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.1,2 Some may need postexposure prophylaxis.
ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT
Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.1,2
Postexposure management should include the following elements:
- Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.1–6
- Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
- Initiating prophylaxis as soon as possible.
- Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
- Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
- Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
- Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.1,2
IS POSTEXPOSURE PROPHYLAXIS INDICATED?
Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.1,2
Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.1,2
HOW GREAT IS THE RISK OF INFECTION?
Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:
- Type and extent of exposure (see below)
- Characteristics of the infectious agent (eg, virulence, infectious dose)
- Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis7–10
- Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis2
- Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.1
WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?
Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.1,2,7,9–15
Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.
The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.
BLOOD-BORNE INFECTIONS
Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.16)
Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.17
When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.3,4,16,18
Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.3,4,16,18
Hepatitis B
Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).1,2,4,16
Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.4,16,19
Hepatitis C
The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.16 The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.16,18
Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.
Human immunodeficiency virus
The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.20
If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.3,18
The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.3,16,18
SEXUALLY TRANSMITTED INFECTIONS
In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.22 People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.23–25
Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.22 Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.
Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.22
Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).22
Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.3,18,26
Chlamydia
Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.22,29
Gonorrhea
Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.22 When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.22
Human immunodeficiency virus
Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.30
Syphilis
The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.22
After sexual assault
In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.22
Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.22 The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).22,26
Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.22
Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.
Emergency contraception should be given if there is a risk of pregnancy.22,26
In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center.
Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).
INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE
Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.1
Measles
Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.11
Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).31,32
Tuberculosis
Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.1,7
Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.7,33
Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.7,33,34
A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.7,33
All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .7,33,35–37
Varicella and disseminated herpes zoster
Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.12 Herpes zoster is less contagious than varicella.38
Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.12
Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).12,38–40
Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.12,39
Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.12,38
INFECTIONS TRANSMITTED BY THE DROPLET ROUTE
Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.1
Group A streptococcal infection
Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.9,41,42
Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).9,41,42
Influenza
Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.13,43
Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.13,44,45
Meningococcal disease
N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.8
Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).46 Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.
Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).8,46
Pertussis
Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.10
Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).10,47
Rubella
Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.11
INFECTIONS TRANSMITTED BY DIRECT CONTACT
Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).1
There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.1
Hepatitis A
Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.1,15
Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.15,48
Scabies
Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.
All potentially infested persons should be treated concomitantly (Table 5).14,49
INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES
Bites and injury wounds account for approximately 1% of all visits to emergency departments.50 Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.50
Rabies
Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.6 Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.51
High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.
Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.6
Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.6 If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.
The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).6
Tetanus
Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).5
Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).2,5,52
- Siegel JD, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007; 35(suppl 2): S65–S164.
- Advisory Committee on Immunization Practices; Centers for Disease Control and Prevention. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1–45.
- Kuhar DT, Henderson DK, Struble KA, et al; US Public Health Service Working Group. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013; 34: 875–892.
- Schille S, Murphy TV, Sawyer M, et al; Centers for Disease Control and Prevention (CDC). CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013; 62:1–19.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:13–15.
- Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57:1–28.
- Jensen PA, Lambert LA, Iademarco MF, Ridzon R, Centers for Disease Control and Prevention (CDC). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Morb Mortal Wkly Rep 2005; 54:1–141.
- Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–28.
- Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for Disease Control and Prevention. Clin Infect Dis 2002; 35:950–959.
- Tiwari T, Murphy TV, Moran J; National Immunization Program, Centers for Disease Control and Prevention (CDC). Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Morb Mortal Wkly Rep 2005; 54:1–16.
- McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention (CDC). Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–34.
- Marin M, Guris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1–40.
- Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1003–1032.
- Centers for Disease Control and Prevention (CDC). Scabies. www.cdc.gov/parasites/scabies/. Accessed November 4, 2016.
- Advisory Committee on Immunization Practices (ACIP); Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2006; 55:1–23.
- US Public Health Service. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2001; 50:1–52.
- Treakle AM, Schultz M, Giannakos GP, Joyce PC, Gordin FM. Evaluating a decade of exposures to blood and body fluids in an inner-city teaching hospital. Infect Control Hosp Epidemiol 2011; 32:903–907.
- New York State Department of Health AIDS Institute. Update: HIV prophylaxis following non-occupational exposure. www.hivguidelines.org/clinical-guidelines/post-exposure-prophylaxis/hiv-prophylaxis-following-non-occupational-exposure/. Accessed November 4, 2016.
- Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983; 2:1099–1102.
- Baggaley RF, Boily MC, White RG, Alary M. Risk of HIV-1 transmission for parenteral exposure and blood transfusion: a systematic review and meta-analysis. AIDS 2006; 20:805–812.
- McAllister J, Read P, McNulty A, Tong WW, Ingersoll A, Carr A. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med 2014; 15:13–22.
- Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1–137.
- US Preventive Services Task Force (USPSTF). Final recommendation statement: chlamydia and gonorrhea: screening. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/chlamydia-and-gonorrhea-screening. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Human immunodeficiency virus (HIV) infection: screening. www.uspreventiveservicestaskforce.org/uspstf/uspshivi.htm. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Screening for syphilis. www.uspreventiveservicestaskforce.org/uspstf/uspssyph.htm#update. Accessed November 4, 2016.
- Smith DK, Grohskopf LA, Black RJ, et al; US Department of Health and Human Services. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the US Department of Health and Human Services. MMWR Recomm Rep 2005; 54:1–20.
- Lin JS, Donegan SP, Heeren TC, et al. Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among men with urethritis and their female sex partners. J Infect Dis 1998; 178:1707–1712.
- Varghese B, Maher JE, Peterman TA, Branson BM, Steketee RW. Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use. Sex Transm Dis 2002; 29:38–43.
- Gülmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy. Cochrane Database Syst Rev 2011; (5):CD000220.
- Forna F, Gülmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003; (2):CD000218.
- Rice P, Young Y, Cohen B, Ramsay M. MMR immunization after contact with measles virus. Lancet 2004; 363:569–570.
- Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunization for preventing measles. Cochrane Database Syst Rev 2014; 4:CD010056.
- National Tuberculosis Controllers Association; Centers for Disease Control and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005; 54:1–47.
- Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1–25.
- Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Morb Mortal Wkly Rep 2000; 49:1–51.
- Stagg HR, Zenner D, Harris RJ, Munoz L, Lipman MC, Abubakar I. Treatment of latent tuberculosis infection: a network meta-analysis. Ann Intern Med 2014; 161:419–428.
- Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011; 60:1650–1653.
- Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008; 57:1–30.
- Macartney K, Heywood A, McIntyre P. Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults. Cochrane Database Syst Rev 2014; 6:CD001833.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of VariZIG—United States, 2013. MMWR Morb Mortal Wkly Rep 2013; 62: 574–576.
- Public Health Agency of Canada. Guidelines for the prevention and control of invasive group A streptococcal disease. Can Commun Dis Rep 2006; 32(suppl 2):1–26.
- Steer JA, Lamagni T, Healy B, et al. Guidelines for prevention and control of group A streptococcal infection in acute healthcare and maternity settings in the UK. J Infect 2012; 64:1–18.
- Grohskopf LA, Olsen SJ, Sokolow LZ, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014–15 influenza season. MMWR Morb Mortal Wkly Rep 2014; 63: 691–697.
- Fiore AE, Fry A, Shay D, et al; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011; 60:1–24.
- Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4:CD008965.
- Zalmanovici Trestioreanu A, Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Antibiotics for preventing meningococcal infections. Cochrane Database Syst Rev 2013; 10:CD004785.
- Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev 2007: CD004404.
- Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Update: prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1080–1084.
- FitzGerald D, Grainger RJ, Reid A. Interventions for preventing the spread of infestation in close contacts of people with scabies. Cochrane Database Syst Rev 2014; 2:CD009943.
- Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014; 59:e10–e52.
- Rupprecht CE, Briggs D, Brown CM, et al; Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies—recommendations of the Advisory Committee on Immunization Practice. MMWR Recomm Rep 2010; 59:1–9.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2012; 61:468–470.
- Siegel JD, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007; 35(suppl 2): S65–S164.
- Advisory Committee on Immunization Practices; Centers for Disease Control and Prevention. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1–45.
- Kuhar DT, Henderson DK, Struble KA, et al; US Public Health Service Working Group. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013; 34: 875–892.
- Schille S, Murphy TV, Sawyer M, et al; Centers for Disease Control and Prevention (CDC). CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep 2013; 62:1–19.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:13–15.
- Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57:1–28.
- Jensen PA, Lambert LA, Iademarco MF, Ridzon R, Centers for Disease Control and Prevention (CDC). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Morb Mortal Wkly Rep 2005; 54:1–141.
- Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–28.
- Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for Disease Control and Prevention. Clin Infect Dis 2002; 35:950–959.
- Tiwari T, Murphy TV, Moran J; National Immunization Program, Centers for Disease Control and Prevention (CDC). Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Morb Mortal Wkly Rep 2005; 54:1–16.
- McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention (CDC). Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013; 62:1–34.
- Marin M, Guris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1–40.
- Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1003–1032.
- Centers for Disease Control and Prevention (CDC). Scabies. www.cdc.gov/parasites/scabies/. Accessed November 4, 2016.
- Advisory Committee on Immunization Practices (ACIP); Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2006; 55:1–23.
- US Public Health Service. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2001; 50:1–52.
- Treakle AM, Schultz M, Giannakos GP, Joyce PC, Gordin FM. Evaluating a decade of exposures to blood and body fluids in an inner-city teaching hospital. Infect Control Hosp Epidemiol 2011; 32:903–907.
- New York State Department of Health AIDS Institute. Update: HIV prophylaxis following non-occupational exposure. www.hivguidelines.org/clinical-guidelines/post-exposure-prophylaxis/hiv-prophylaxis-following-non-occupational-exposure/. Accessed November 4, 2016.
- Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983; 2:1099–1102.
- Baggaley RF, Boily MC, White RG, Alary M. Risk of HIV-1 transmission for parenteral exposure and blood transfusion: a systematic review and meta-analysis. AIDS 2006; 20:805–812.
- McAllister J, Read P, McNulty A, Tong WW, Ingersoll A, Carr A. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med 2014; 15:13–22.
- Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1–137.
- US Preventive Services Task Force (USPSTF). Final recommendation statement: chlamydia and gonorrhea: screening. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/chlamydia-and-gonorrhea-screening. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Human immunodeficiency virus (HIV) infection: screening. www.uspreventiveservicestaskforce.org/uspstf/uspshivi.htm. Accessed November 4, 2016.
- US Preventive Services Task Force (USPSTF). Screening for syphilis. www.uspreventiveservicestaskforce.org/uspstf/uspssyph.htm#update. Accessed November 4, 2016.
- Smith DK, Grohskopf LA, Black RJ, et al; US Department of Health and Human Services. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the US Department of Health and Human Services. MMWR Recomm Rep 2005; 54:1–20.
- Lin JS, Donegan SP, Heeren TC, et al. Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among men with urethritis and their female sex partners. J Infect Dis 1998; 178:1707–1712.
- Varghese B, Maher JE, Peterman TA, Branson BM, Steketee RW. Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use. Sex Transm Dis 2002; 29:38–43.
- Gülmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy. Cochrane Database Syst Rev 2011; (5):CD000220.
- Forna F, Gülmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003; (2):CD000218.
- Rice P, Young Y, Cohen B, Ramsay M. MMR immunization after contact with measles virus. Lancet 2004; 363:569–570.
- Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunization for preventing measles. Cochrane Database Syst Rev 2014; 4:CD010056.
- National Tuberculosis Controllers Association; Centers for Disease Control and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005; 54:1–47.
- Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1–25.
- Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Morb Mortal Wkly Rep 2000; 49:1–51.
- Stagg HR, Zenner D, Harris RJ, Munoz L, Lipman MC, Abubakar I. Treatment of latent tuberculosis infection: a network meta-analysis. Ann Intern Med 2014; 161:419–428.
- Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011; 60:1650–1653.
- Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008; 57:1–30.
- Macartney K, Heywood A, McIntyre P. Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults. Cochrane Database Syst Rev 2014; 6:CD001833.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of VariZIG—United States, 2013. MMWR Morb Mortal Wkly Rep 2013; 62: 574–576.
- Public Health Agency of Canada. Guidelines for the prevention and control of invasive group A streptococcal disease. Can Commun Dis Rep 2006; 32(suppl 2):1–26.
- Steer JA, Lamagni T, Healy B, et al. Guidelines for prevention and control of group A streptococcal infection in acute healthcare and maternity settings in the UK. J Infect 2012; 64:1–18.
- Grohskopf LA, Olsen SJ, Sokolow LZ, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014–15 influenza season. MMWR Morb Mortal Wkly Rep 2014; 63: 691–697.
- Fiore AE, Fry A, Shay D, et al; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011; 60:1–24.
- Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4:CD008965.
- Zalmanovici Trestioreanu A, Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Antibiotics for preventing meningococcal infections. Cochrane Database Syst Rev 2013; 10:CD004785.
- Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev 2007: CD004404.
- Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Update: prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1080–1084.
- FitzGerald D, Grainger RJ, Reid A. Interventions for preventing the spread of infestation in close contacts of people with scabies. Cochrane Database Syst Rev 2014; 2:CD009943.
- Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014; 59:e10–e52.
- Rupprecht CE, Briggs D, Brown CM, et al; Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies—recommendations of the Advisory Committee on Immunization Practice. MMWR Recomm Rep 2010; 59:1–9.
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2012; 61:468–470.
KEY POINTS
- Whether to give prophylactic therapy depends on the transmissibility of the infection, the susceptibility of the exposed individual, and the risk of infection-related complications.
- Postexposure prophylactic therapy should begin as soon as possible, while awaiting results of further diagnostic tests, to maximize the chances of preventing or ameliorating the infection.
- Keeping up-to-date with current institutional policies and national guidelines is essential. Sources include US Public Health Service guidelines and reports from the US Centers for Disease Control and Prevention, as well as consultation with an expert healthcare provider (eg, infectious diseases physician, infection control provider, public health officer).
Parsimonious blood use and lower transfusion triggers: What is the evidence?
For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.
However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.
This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.
EVIDENCE FROM HEMODILUTION STUDIES
Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:
- Increasing cardiac output
- Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
- Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.
Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.
Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.6
Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.6–8
Studies in healthy patients
Weiskopf et al9 assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.
Leung et al10 addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.
Hemodilution in healthy elderly patients
Spahn et al11 performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.
The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.
Hemodilution in coronary artery disease
Spahn et al12 performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.
There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.
Licker et al13 studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.
Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).
Hemodilution in mitral regurgitation
Spahn et al14 performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.
Effect of hemodilution on cognition
Weiskopf et al15 assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.
There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.15
Weiskopf et al16 subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao2) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study15 and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.
When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao2 to 406 mm Hg and normalized neurocognitive performance.
Hemodilution studies in surgical patients
A 2015 meta-analysis17 of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.
However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.
STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES
Studies in critical care and high-risk patients
Hébert et al18 randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:
- Overall at 30 days 18.7% vs 23.3%, P = .11
- In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
- In the subgroup under age 55, 5.7% vs 13%, P = .02
- In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
- In the hospital, 22.2% vs 28.1%; P = .05.
This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.
Carson et al19 evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.
There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.
Rao et al20 analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.
At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.
This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.
Carson et al,21 however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).
Murphy et al22 similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):
- Transfusion rates 53.4% vs 92.2%
- Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30) - Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
- Total costs did not differ significantly between the groups.
These studies21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.
Holst et al23 randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.
This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.
Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.
Villanueva et al24 randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:
- Freedom from transfusion 51% vs 14% (P < .001)
- Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
- Rebleeding 10% vs 16% (P = .01).
Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.
The RELIEVE trial25 compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.
Meta-analyses and observational studies
Rohde et al26 performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.
The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).
Salpeter et al27 performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:
- In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
- Total mortality (RR 0.80, 95% CI 0.65–0.98)
- Rebleeding (RR 0.64, 95% CI 0.45–0.90)
- Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
- Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
- Bacterial infections (RR 0.86, 95% CI 0.73–1.00).
Wang et al28 performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:
- A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
- A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
- Shorter hospitalizations (P = .009)
- Less blood transfused (P = .0005).
Vincent et al,29 in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).
Dunne et al30 performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.
These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.
Brunskill et al,31 in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.
Weinberg et al32 found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).
Studies in sickle cell disease
Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).33,34
In trials in surgical patients,35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.35
In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.34
Is hemoglobin the most relevant marker?
Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.
We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.37 Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.
Is fresh blood better than old blood?
Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.38,39
The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.40 Similar poor outcomes have been seen in trauma patients.32
Lacroix et al,41 in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).
The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.
RISKS ASSOCIATED WITH TRANSFUSION
Infections
The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.42
Noninfectious complications
Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.42
Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.
Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.
Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.43
Surgery and condition-specific complications of red blood cell transfusion
Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.44
Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.44–47
Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.44
ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.44
COST OF RED BLOOD CELL TRANSFUSION
Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.42 At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.
The Premier Healthcare Alliance48 analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.
In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.49,50
RECOMMENDATIONS FROM THE AABB
In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.51 Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),42 which are similar to the national clinical guideline on blood transfusion in the United Kingdom,52 and have recently been updated, confirming the initial recommendations.53
In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.
In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.
In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.
Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,54 which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.
The Society of Hospital Medicine55 and the American Society of Hematology56 concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).57
New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.52
CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL
The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.
However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).
Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.
Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.
- Shander A, Gross I, Hill S, Javidroozi M, Sledge S; College of American Pathologists; American Society of Anesthesiologists; Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists; Society of Critical Care Medicine; Italian Society of Transfusion Medicine and Immunohaematology; American Association of Blood Banks. A new perspective on best transfusion practices. Blood Transfus 2013; 11:193–202.
- Madjdpour C, Spahn DR. Allogeneic red blood cell transfusion: physiology of oxygen transport. Best Pract Res Clin Anaesthesiol 2007; 21:163–171.
- Tánczos K, Molnár Z. The oxygen supply-demand balance: a monitoring challenge. Best Pract Res Clin Anaesthesiol 2013; 27:201–207.
- Hebert PC, Van der Linden P, Biro G, Hu LQ. Physiologic aspects of anemia. Crit Care Clin 2004; 20:187–212.
- Spinelli E, Bartlett RH. Anemia and transfusion in critical care: physiology and management. J Intensive Care Med 2016; 31:295–306.
- Jamnicki M, Kocian R, Van Der Linden P, Zaugg M, Spahn DR. Acute normovolemic hemodilution: physiology, limitations, and clinical use. J Cardiothorac Vasc Anesth 2003; 17:747–754.
- Monk TG. Acute normovolemic hemodilution. Anesthesiol Clin North America 2005; 23:271–281.
- Shander A, Rijhwani TS. Acute normovolemic hemodilution. Transfusion 2004; 44(suppl 2):26S–34S.
- Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279:217–221.
- Leung JM, Weiskopf RB, Feiner J, et al. Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans. Anesthesiology 2000; 93:1004–1010.
- Spahn DR, Zollinger A, Schlumpf RB, et al. Hemodilution tolerance in elderly patients without known cardiac disease. Anesth Analg 1996; 82:681–686.
- Spahn DR, Schmid ER, Seifert B, Pasch T. Hemodilution tolerance in patients with coronary artery disease who are receiving chronic beta-adrenergic blocker therapy. Anesth Analg 1996; 82:687–694.
- Licker M, Ellenberger C, Sierra J, Christenson J, Diaper J, Morel D. Cardiovascular response to acute normovolemic hemodilution in patients with coronary artery diseases: assessment with transesophageal echocardiography. Crit Care Med 2005; 33:591–597.
- Spahn DR, Seifert B, Pasch T, Schmid ER. Haemodilution tolerance in patients with mitral regurgitation. Anaesthesia 1998; 53:20–24.
- Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646–1652.
- Weiskopf RB, Feiner J, Hopf HW, et al. Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002; 96:871–877.
- Zhou X, Zhang C, Wang Y, Yu L, Yan M. Preoperative acute normovolemic hemodilution for minimizing allogeneic blood transfusion: a meta-analysis. Anesth Analg 2015; 121:1443–1455.
- Hébert P, Wells G, Blajchman M, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999: 340:409–417.
- Carson JL, Terrin ML, Noveck H, et al; FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011; 365:2453–2462.
- Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562.
- Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:964.e1–971.e1.
- Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015; 372:997–1008.
- Holst LB, Haase N, Wetterslev J, et al; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381–1391.
- Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11–21.
- Walsh TS, Boyd JA, Watson D, et al; RELIEVE Investigators. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med 2013; 41:2354–2363.
- Rohde JM, Dimcheff DE, Blumberg N, et al. Health care–associated infection after red blood cell transfusion. JAMA 2014; 311:1317–1326.
- Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med 2014; 127:124.e3–131.e3.
- Wang J, Bao YX, Bai M, Zhang YG, Xu WD, Qi XS. Restrictive vs liberal transfusion for upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. World J Gastroenterol 2013; 19:6919–6927.
- Vincent JL, Baron JF, Reinhart K, et al; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288:1499–1507.
- Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002; 102:237–244.
- Brunskill SJ, Millette SL, Shokoohi A, et al. Red blood cell transfusion for people undergoing hip fracture surgery. Cochrane Database Syst Rev 2015; 4:CD009699.
- Weinberg JA, McGwin G Jr, Griffin RL, et al. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma 2008; 65:279–284.
- Steinberg M. Management of sickle cell disease. N Engl J Med 1999; 340:1021–1030.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease. JAMA 2014; 312:1033–1048.
- Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995; 333:206–213.
- Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013; 381:930–938.
- Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet 2013; 381:1845–1854.
- Holme S. Current issues related to the quality of stored RBCs. Transfus Apher Sci 2005; 33:55–61.
- Hovav T, Yedgar S, Manny N, Barshtein G. Alteration of red cell aggregability and shape during blood storage. Transfusion 1999; 39:277–281.
- Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358:1229–1239.
- Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med 2015; 372:1410–1418.
- Carson JL, Grossman BJ, Kleinman S, et al; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012; 157:49–58.
- Bolton-Maggs P, Watt A, Poles D, et al, on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2015 Annual SHOT Report. www.shotuk.org/wp-content/uploads/SHOT-2015-Annual-Report-Web-Edition-Final-bookmarked.pdf. Accessed November 30, 2016.
- Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107(suppl 1):i41–i59.
- Reeh M, Ghadban T, Dedow J, et al. Allogenic blood transfusion is associated with poor perioperative and long-term outcome in esophageal cancer. World J Surg 2016 Oct 11. [Epub ahead of print]
- Elmi M, Mahar A, Kagedan D, et al. The impact of blood transfusion on perioperative outcomes following gastric cancer resection: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database. Can J Surg 2016; 59:322–329.
- Aquina CT, Blumberg N, Becerra AZ, et al. Association among blood transfusion, sepsis, and decreased long-term survival after colon cancer resection. Ann Surg 2016; Sep 14. [Epub ahead of print] PubMed PMID: 27631770.
- Premiere Analysis. Standardization of blood utilization practices could provide opportunity for improved outcomes, reduced costs. A Premiere Healthcare Alliance Analysis. 2012.
- Simeone F, Franchi F, Cevenini G, et al. A simple clinical model for planning transfusion quantities in heart surgery. BMC Med Inform Decis Mak 2011; 11:44.
- Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet 2013; 381:1855–1865.
- Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ 2015; 350:h1354.
- National Institute for Health and Care Excellence: Clinical Guidelines. London: National Institute for Health and Care Excellence (UK). www.ncbi.nlm.nih.gov/books/NBK11822/.
- Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 2016 Oct 12. doi: 10.1001/jama.2016.9185. [Epub ahead of print]
- Consensus conference. Perioperative red blood cell transfusion. JAMA 1988; 260:2700–2703.
- Bulger J, Nickel W, Messler J, et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med 2013; 8:486–492.
- Hicks LK, Bering H, Carson KR, et al. The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question. Blood 2013; 122:3879–3883.
- Haemonetics IMPACT Online. The Blood Management Company. www.haemonetics.com/Products/Services/Consulting Services/IMPACT Online.aspx. Accessed November 30, 2016.
For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.
However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.
This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.
EVIDENCE FROM HEMODILUTION STUDIES
Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:
- Increasing cardiac output
- Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
- Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.
Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.
Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.6
Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.6–8
Studies in healthy patients
Weiskopf et al9 assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.
Leung et al10 addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.
Hemodilution in healthy elderly patients
Spahn et al11 performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.
The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.
Hemodilution in coronary artery disease
Spahn et al12 performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.
There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.
Licker et al13 studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.
Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).
Hemodilution in mitral regurgitation
Spahn et al14 performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.
Effect of hemodilution on cognition
Weiskopf et al15 assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.
There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.15
Weiskopf et al16 subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao2) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study15 and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.
When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao2 to 406 mm Hg and normalized neurocognitive performance.
Hemodilution studies in surgical patients
A 2015 meta-analysis17 of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.
However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.
STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES
Studies in critical care and high-risk patients
Hébert et al18 randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:
- Overall at 30 days 18.7% vs 23.3%, P = .11
- In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
- In the subgroup under age 55, 5.7% vs 13%, P = .02
- In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
- In the hospital, 22.2% vs 28.1%; P = .05.
This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.
Carson et al19 evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.
There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.
Rao et al20 analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.
At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.
This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.
Carson et al,21 however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).
Murphy et al22 similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):
- Transfusion rates 53.4% vs 92.2%
- Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30) - Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
- Total costs did not differ significantly between the groups.
These studies21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.
Holst et al23 randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.
This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.
Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.
Villanueva et al24 randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:
- Freedom from transfusion 51% vs 14% (P < .001)
- Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
- Rebleeding 10% vs 16% (P = .01).
Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.
The RELIEVE trial25 compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.
Meta-analyses and observational studies
Rohde et al26 performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.
The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).
Salpeter et al27 performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:
- In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
- Total mortality (RR 0.80, 95% CI 0.65–0.98)
- Rebleeding (RR 0.64, 95% CI 0.45–0.90)
- Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
- Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
- Bacterial infections (RR 0.86, 95% CI 0.73–1.00).
Wang et al28 performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:
- A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
- A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
- Shorter hospitalizations (P = .009)
- Less blood transfused (P = .0005).
Vincent et al,29 in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).
Dunne et al30 performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.
These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.
Brunskill et al,31 in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.
Weinberg et al32 found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).
Studies in sickle cell disease
Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).33,34
In trials in surgical patients,35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.35
In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.34
Is hemoglobin the most relevant marker?
Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.
We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.37 Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.
Is fresh blood better than old blood?
Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.38,39
The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.40 Similar poor outcomes have been seen in trauma patients.32
Lacroix et al,41 in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).
The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.
RISKS ASSOCIATED WITH TRANSFUSION
Infections
The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.42
Noninfectious complications
Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.42
Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.
Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.
Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.43
Surgery and condition-specific complications of red blood cell transfusion
Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.44
Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.44–47
Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.44
ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.44
COST OF RED BLOOD CELL TRANSFUSION
Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.42 At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.
The Premier Healthcare Alliance48 analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.
In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.49,50
RECOMMENDATIONS FROM THE AABB
In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.51 Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),42 which are similar to the national clinical guideline on blood transfusion in the United Kingdom,52 and have recently been updated, confirming the initial recommendations.53
In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.
In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.
In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.
Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,54 which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.
The Society of Hospital Medicine55 and the American Society of Hematology56 concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).57
New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.52
CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL
The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.
However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).
Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.
Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.
For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.
However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.
This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.
EVIDENCE FROM HEMODILUTION STUDIES
Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:
- Increasing cardiac output
- Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
- Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.
Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.
Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.6
Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.6–8
Studies in healthy patients
Weiskopf et al9 assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.
Leung et al10 addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.
Hemodilution in healthy elderly patients
Spahn et al11 performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.
The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.
Hemodilution in coronary artery disease
Spahn et al12 performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.
There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.
Licker et al13 studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.
Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).
Hemodilution in mitral regurgitation
Spahn et al14 performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.
Effect of hemodilution on cognition
Weiskopf et al15 assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.
There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.15
Weiskopf et al16 subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao2) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study15 and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.
When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao2 to 406 mm Hg and normalized neurocognitive performance.
Hemodilution studies in surgical patients
A 2015 meta-analysis17 of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.
However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.
STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES
Studies in critical care and high-risk patients
Hébert et al18 randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:
- Overall at 30 days 18.7% vs 23.3%, P = .11
- In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
- In the subgroup under age 55, 5.7% vs 13%, P = .02
- In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
- In the hospital, 22.2% vs 28.1%; P = .05.
This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.
Carson et al19 evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.
There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.
Rao et al20 analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.
At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.
This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.
Carson et al,21 however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).
Murphy et al22 similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):
- Transfusion rates 53.4% vs 92.2%
- Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30) - Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
- Total costs did not differ significantly between the groups.
These studies21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.
Holst et al23 randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.
This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.
Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.
Villanueva et al24 randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:
- Freedom from transfusion 51% vs 14% (P < .001)
- Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
- Rebleeding 10% vs 16% (P = .01).
Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.
The RELIEVE trial25 compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.
Meta-analyses and observational studies
Rohde et al26 performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.
The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).
Salpeter et al27 performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:
- In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
- Total mortality (RR 0.80, 95% CI 0.65–0.98)
- Rebleeding (RR 0.64, 95% CI 0.45–0.90)
- Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
- Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
- Bacterial infections (RR 0.86, 95% CI 0.73–1.00).
Wang et al28 performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:
- A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
- A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
- Shorter hospitalizations (P = .009)
- Less blood transfused (P = .0005).
Vincent et al,29 in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).
Dunne et al30 performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.
These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.
Brunskill et al,31 in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.
Weinberg et al32 found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).
Studies in sickle cell disease
Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).33,34
In trials in surgical patients,35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.35
In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.34
Is hemoglobin the most relevant marker?
Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.
We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.37 Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.
Is fresh blood better than old blood?
Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.38,39
The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.40 Similar poor outcomes have been seen in trauma patients.32
Lacroix et al,41 in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).
The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.
RISKS ASSOCIATED WITH TRANSFUSION
Infections
The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.42
Noninfectious complications
Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.42
Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.
Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.
Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.43
Surgery and condition-specific complications of red blood cell transfusion
Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.44
Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.44–47
Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.44
ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.44
COST OF RED BLOOD CELL TRANSFUSION
Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.42 At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.
The Premier Healthcare Alliance48 analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.
In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.49,50
RECOMMENDATIONS FROM THE AABB
In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.51 Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),42 which are similar to the national clinical guideline on blood transfusion in the United Kingdom,52 and have recently been updated, confirming the initial recommendations.53
In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.
In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.
In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.
Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,54 which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.
The Society of Hospital Medicine55 and the American Society of Hematology56 concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).57
New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.52
CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL
The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.
However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).
Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.
Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.
- Shander A, Gross I, Hill S, Javidroozi M, Sledge S; College of American Pathologists; American Society of Anesthesiologists; Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists; Society of Critical Care Medicine; Italian Society of Transfusion Medicine and Immunohaematology; American Association of Blood Banks. A new perspective on best transfusion practices. Blood Transfus 2013; 11:193–202.
- Madjdpour C, Spahn DR. Allogeneic red blood cell transfusion: physiology of oxygen transport. Best Pract Res Clin Anaesthesiol 2007; 21:163–171.
- Tánczos K, Molnár Z. The oxygen supply-demand balance: a monitoring challenge. Best Pract Res Clin Anaesthesiol 2013; 27:201–207.
- Hebert PC, Van der Linden P, Biro G, Hu LQ. Physiologic aspects of anemia. Crit Care Clin 2004; 20:187–212.
- Spinelli E, Bartlett RH. Anemia and transfusion in critical care: physiology and management. J Intensive Care Med 2016; 31:295–306.
- Jamnicki M, Kocian R, Van Der Linden P, Zaugg M, Spahn DR. Acute normovolemic hemodilution: physiology, limitations, and clinical use. J Cardiothorac Vasc Anesth 2003; 17:747–754.
- Monk TG. Acute normovolemic hemodilution. Anesthesiol Clin North America 2005; 23:271–281.
- Shander A, Rijhwani TS. Acute normovolemic hemodilution. Transfusion 2004; 44(suppl 2):26S–34S.
- Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279:217–221.
- Leung JM, Weiskopf RB, Feiner J, et al. Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans. Anesthesiology 2000; 93:1004–1010.
- Spahn DR, Zollinger A, Schlumpf RB, et al. Hemodilution tolerance in elderly patients without known cardiac disease. Anesth Analg 1996; 82:681–686.
- Spahn DR, Schmid ER, Seifert B, Pasch T. Hemodilution tolerance in patients with coronary artery disease who are receiving chronic beta-adrenergic blocker therapy. Anesth Analg 1996; 82:687–694.
- Licker M, Ellenberger C, Sierra J, Christenson J, Diaper J, Morel D. Cardiovascular response to acute normovolemic hemodilution in patients with coronary artery diseases: assessment with transesophageal echocardiography. Crit Care Med 2005; 33:591–597.
- Spahn DR, Seifert B, Pasch T, Schmid ER. Haemodilution tolerance in patients with mitral regurgitation. Anaesthesia 1998; 53:20–24.
- Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646–1652.
- Weiskopf RB, Feiner J, Hopf HW, et al. Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002; 96:871–877.
- Zhou X, Zhang C, Wang Y, Yu L, Yan M. Preoperative acute normovolemic hemodilution for minimizing allogeneic blood transfusion: a meta-analysis. Anesth Analg 2015; 121:1443–1455.
- Hébert P, Wells G, Blajchman M, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999: 340:409–417.
- Carson JL, Terrin ML, Noveck H, et al; FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011; 365:2453–2462.
- Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562.
- Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:964.e1–971.e1.
- Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015; 372:997–1008.
- Holst LB, Haase N, Wetterslev J, et al; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381–1391.
- Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11–21.
- Walsh TS, Boyd JA, Watson D, et al; RELIEVE Investigators. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med 2013; 41:2354–2363.
- Rohde JM, Dimcheff DE, Blumberg N, et al. Health care–associated infection after red blood cell transfusion. JAMA 2014; 311:1317–1326.
- Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med 2014; 127:124.e3–131.e3.
- Wang J, Bao YX, Bai M, Zhang YG, Xu WD, Qi XS. Restrictive vs liberal transfusion for upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. World J Gastroenterol 2013; 19:6919–6927.
- Vincent JL, Baron JF, Reinhart K, et al; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288:1499–1507.
- Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002; 102:237–244.
- Brunskill SJ, Millette SL, Shokoohi A, et al. Red blood cell transfusion for people undergoing hip fracture surgery. Cochrane Database Syst Rev 2015; 4:CD009699.
- Weinberg JA, McGwin G Jr, Griffin RL, et al. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma 2008; 65:279–284.
- Steinberg M. Management of sickle cell disease. N Engl J Med 1999; 340:1021–1030.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease. JAMA 2014; 312:1033–1048.
- Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995; 333:206–213.
- Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013; 381:930–938.
- Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet 2013; 381:1845–1854.
- Holme S. Current issues related to the quality of stored RBCs. Transfus Apher Sci 2005; 33:55–61.
- Hovav T, Yedgar S, Manny N, Barshtein G. Alteration of red cell aggregability and shape during blood storage. Transfusion 1999; 39:277–281.
- Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358:1229–1239.
- Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med 2015; 372:1410–1418.
- Carson JL, Grossman BJ, Kleinman S, et al; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012; 157:49–58.
- Bolton-Maggs P, Watt A, Poles D, et al, on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2015 Annual SHOT Report. www.shotuk.org/wp-content/uploads/SHOT-2015-Annual-Report-Web-Edition-Final-bookmarked.pdf. Accessed November 30, 2016.
- Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107(suppl 1):i41–i59.
- Reeh M, Ghadban T, Dedow J, et al. Allogenic blood transfusion is associated with poor perioperative and long-term outcome in esophageal cancer. World J Surg 2016 Oct 11. [Epub ahead of print]
- Elmi M, Mahar A, Kagedan D, et al. The impact of blood transfusion on perioperative outcomes following gastric cancer resection: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database. Can J Surg 2016; 59:322–329.
- Aquina CT, Blumberg N, Becerra AZ, et al. Association among blood transfusion, sepsis, and decreased long-term survival after colon cancer resection. Ann Surg 2016; Sep 14. [Epub ahead of print] PubMed PMID: 27631770.
- Premiere Analysis. Standardization of blood utilization practices could provide opportunity for improved outcomes, reduced costs. A Premiere Healthcare Alliance Analysis. 2012.
- Simeone F, Franchi F, Cevenini G, et al. A simple clinical model for planning transfusion quantities in heart surgery. BMC Med Inform Decis Mak 2011; 11:44.
- Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet 2013; 381:1855–1865.
- Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ 2015; 350:h1354.
- National Institute for Health and Care Excellence: Clinical Guidelines. London: National Institute for Health and Care Excellence (UK). www.ncbi.nlm.nih.gov/books/NBK11822/.
- Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 2016 Oct 12. doi: 10.1001/jama.2016.9185. [Epub ahead of print]
- Consensus conference. Perioperative red blood cell transfusion. JAMA 1988; 260:2700–2703.
- Bulger J, Nickel W, Messler J, et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med 2013; 8:486–492.
- Hicks LK, Bering H, Carson KR, et al. The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question. Blood 2013; 122:3879–3883.
- Haemonetics IMPACT Online. The Blood Management Company. www.haemonetics.com/Products/Services/Consulting Services/IMPACT Online.aspx. Accessed November 30, 2016.
- Shander A, Gross I, Hill S, Javidroozi M, Sledge S; College of American Pathologists; American Society of Anesthesiologists; Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists; Society of Critical Care Medicine; Italian Society of Transfusion Medicine and Immunohaematology; American Association of Blood Banks. A new perspective on best transfusion practices. Blood Transfus 2013; 11:193–202.
- Madjdpour C, Spahn DR. Allogeneic red blood cell transfusion: physiology of oxygen transport. Best Pract Res Clin Anaesthesiol 2007; 21:163–171.
- Tánczos K, Molnár Z. The oxygen supply-demand balance: a monitoring challenge. Best Pract Res Clin Anaesthesiol 2013; 27:201–207.
- Hebert PC, Van der Linden P, Biro G, Hu LQ. Physiologic aspects of anemia. Crit Care Clin 2004; 20:187–212.
- Spinelli E, Bartlett RH. Anemia and transfusion in critical care: physiology and management. J Intensive Care Med 2016; 31:295–306.
- Jamnicki M, Kocian R, Van Der Linden P, Zaugg M, Spahn DR. Acute normovolemic hemodilution: physiology, limitations, and clinical use. J Cardiothorac Vasc Anesth 2003; 17:747–754.
- Monk TG. Acute normovolemic hemodilution. Anesthesiol Clin North America 2005; 23:271–281.
- Shander A, Rijhwani TS. Acute normovolemic hemodilution. Transfusion 2004; 44(suppl 2):26S–34S.
- Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279:217–221.
- Leung JM, Weiskopf RB, Feiner J, et al. Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans. Anesthesiology 2000; 93:1004–1010.
- Spahn DR, Zollinger A, Schlumpf RB, et al. Hemodilution tolerance in elderly patients without known cardiac disease. Anesth Analg 1996; 82:681–686.
- Spahn DR, Schmid ER, Seifert B, Pasch T. Hemodilution tolerance in patients with coronary artery disease who are receiving chronic beta-adrenergic blocker therapy. Anesth Analg 1996; 82:687–694.
- Licker M, Ellenberger C, Sierra J, Christenson J, Diaper J, Morel D. Cardiovascular response to acute normovolemic hemodilution in patients with coronary artery diseases: assessment with transesophageal echocardiography. Crit Care Med 2005; 33:591–597.
- Spahn DR, Seifert B, Pasch T, Schmid ER. Haemodilution tolerance in patients with mitral regurgitation. Anaesthesia 1998; 53:20–24.
- Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646–1652.
- Weiskopf RB, Feiner J, Hopf HW, et al. Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. Anesthesiology 2002; 96:871–877.
- Zhou X, Zhang C, Wang Y, Yu L, Yan M. Preoperative acute normovolemic hemodilution for minimizing allogeneic blood transfusion: a meta-analysis. Anesth Analg 2015; 121:1443–1455.
- Hébert P, Wells G, Blajchman M, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999: 340:409–417.
- Carson JL, Terrin ML, Noveck H, et al; FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011; 365:2453–2462.
- Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562.
- Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:964.e1–971.e1.
- Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015; 372:997–1008.
- Holst LB, Haase N, Wetterslev J, et al; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381–1391.
- Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11–21.
- Walsh TS, Boyd JA, Watson D, et al; RELIEVE Investigators. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med 2013; 41:2354–2363.
- Rohde JM, Dimcheff DE, Blumberg N, et al. Health care–associated infection after red blood cell transfusion. JAMA 2014; 311:1317–1326.
- Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med 2014; 127:124.e3–131.e3.
- Wang J, Bao YX, Bai M, Zhang YG, Xu WD, Qi XS. Restrictive vs liberal transfusion for upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. World J Gastroenterol 2013; 19:6919–6927.
- Vincent JL, Baron JF, Reinhart K, et al; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288:1499–1507.
- Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002; 102:237–244.
- Brunskill SJ, Millette SL, Shokoohi A, et al. Red blood cell transfusion for people undergoing hip fracture surgery. Cochrane Database Syst Rev 2015; 4:CD009699.
- Weinberg JA, McGwin G Jr, Griffin RL, et al. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma 2008; 65:279–284.
- Steinberg M. Management of sickle cell disease. N Engl J Med 1999; 340:1021–1030.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease. JAMA 2014; 312:1033–1048.
- Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995; 333:206–213.
- Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013; 381:930–938.
- Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet 2013; 381:1845–1854.
- Holme S. Current issues related to the quality of stored RBCs. Transfus Apher Sci 2005; 33:55–61.
- Hovav T, Yedgar S, Manny N, Barshtein G. Alteration of red cell aggregability and shape during blood storage. Transfusion 1999; 39:277–281.
- Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358:1229–1239.
- Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med 2015; 372:1410–1418.
- Carson JL, Grossman BJ, Kleinman S, et al; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012; 157:49–58.
- Bolton-Maggs P, Watt A, Poles D, et al, on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2015 Annual SHOT Report. www.shotuk.org/wp-content/uploads/SHOT-2015-Annual-Report-Web-Edition-Final-bookmarked.pdf. Accessed November 30, 2016.
- Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107(suppl 1):i41–i59.
- Reeh M, Ghadban T, Dedow J, et al. Allogenic blood transfusion is associated with poor perioperative and long-term outcome in esophageal cancer. World J Surg 2016 Oct 11. [Epub ahead of print]
- Elmi M, Mahar A, Kagedan D, et al. The impact of blood transfusion on perioperative outcomes following gastric cancer resection: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database. Can J Surg 2016; 59:322–329.
- Aquina CT, Blumberg N, Becerra AZ, et al. Association among blood transfusion, sepsis, and decreased long-term survival after colon cancer resection. Ann Surg 2016; Sep 14. [Epub ahead of print] PubMed PMID: 27631770.
- Premiere Analysis. Standardization of blood utilization practices could provide opportunity for improved outcomes, reduced costs. A Premiere Healthcare Alliance Analysis. 2012.
- Simeone F, Franchi F, Cevenini G, et al. A simple clinical model for planning transfusion quantities in heart surgery. BMC Med Inform Decis Mak 2011; 11:44.
- Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet 2013; 381:1855–1865.
- Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ 2015; 350:h1354.
- National Institute for Health and Care Excellence: Clinical Guidelines. London: National Institute for Health and Care Excellence (UK). www.ncbi.nlm.nih.gov/books/NBK11822/.
- Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 2016 Oct 12. doi: 10.1001/jama.2016.9185. [Epub ahead of print]
- Consensus conference. Perioperative red blood cell transfusion. JAMA 1988; 260:2700–2703.
- Bulger J, Nickel W, Messler J, et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med 2013; 8:486–492.
- Hicks LK, Bering H, Carson KR, et al. The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question. Blood 2013; 122:3879–3883.
- Haemonetics IMPACT Online. The Blood Management Company. www.haemonetics.com/Products/Services/Consulting Services/IMPACT Online.aspx. Accessed November 30, 2016.
KEY POINTS
- In critical care patients, transfusion should be considered when the hemoglobin concentration reaches 7 g/dL or less.
- In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered at a hemoglobin concentration of 8 g/dL or less or for symptoms such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.
- Consider both the hemoglobin concentration and the symptoms when deciding whether to give a patient a transfusion.
A patient with altered mental status and an acid-base disturbance
A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.
In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.
Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”
The patient’s laboratory values are shown in Table 1.
WHICH ACID-BASE DISORDER DOES SHE HAVE?
1. Which acid-base disorder does this patient have?
- Metabolic acidosis and respiratory alkalosis
- Metabolic acidosis and respiratory acidosis
- Metabolic acidosis with an elevated anion gap
- A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis
A 5-step approach
Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)1:
1. Determine the arterial pH status.
2. Determine whether the primary process is respiratory, metabolic, or both.
3. Calculate the anion gap.
4. Check the degree of compensation (respiratory or metabolic).
5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).
Let us apply this approach to the patient described above.
1. What is her pH status?
An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)
Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco2), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.
Our patient’s pH is 7.25, which is in the acidemic range.
2. Is her acidosis respiratory, metabolic, or both?
Respiratory acidosis and alkalosis affect the Pco2. The Pco2 is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).
Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.
Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco2 can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco2 can be low (Table 2).
Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco2 is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.
3. What is her anion gap?
Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.
Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.
Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.2
Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.
4. Is the degree of compensation appropriate for the primary acid-base disturbance?
The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco2 (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).
In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco2 should decrease by 1.3 mm Hg.
Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.
Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco2 should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco2 is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.
If we use Winter’s formula instead (Pco2 = [1.5 × the bicarbonate level] + 8 ± 2),3 the lowest calculated Pco2 would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.3
This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.
5. Is there a delta gap?
Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap.
In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.
Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.
So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).
‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS
The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).
Methanol and ethylene glycol
We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time.
In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.
In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).4,5 Therefore, her osmol gap is elevated.
Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.6 A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.7 Liquid chromatography identifies these two toxins, but results are not available emergently.
Diethylene glycol ingestion should also be considered.8 Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.
Uremia
Renal failure can lead to metabolic acidosis.9 Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m2—low, but not uremic.
Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.
Diabetes
The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).10
There is another, less common cause of ketoacidosis: alcohol.11 Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.11 Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.11
This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.
THE NEW MUD PILES
2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:
- The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
- There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
- Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
- Salicylates can paradoxically be associated both with elevated and low anion gaps.
Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.
Paraldehyde, isoniazid, lactate
The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.
UPDATING THE ‘P’ IN MUD PILES
Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).12–20
Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.
5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen
Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).21,22
Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.
Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,23 the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.
No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.
Propylene glycol, a component of parenteral lorazepam
Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.24,25
Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.23
Isoniazid
Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,26 either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.
The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.27 A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.28
Lactic acidosis
Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.29 However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.29
d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).30 With short bowel syndrome, the neurologic manifestations occur after eating and clear later.30
Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.
Salicylates
Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.
Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.
Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.31 Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.
WHAT ELSE MUST BE CONSIDERED?
3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)
- Methanol, ethylene, or diethylene glycol
- Excessive, chronic acetaminophen ingestion
- Salicylate toxicity
- Alcoholic ketoacidosis
All of the above can potentially contribute to metabolic acidosis.
A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.
Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.
The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.
GOLD MARK: ANOTHER WAY TO REMEMBER
Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).32
ACID-BASE DISORDERS IN DIFFERENT DISEASES
Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:
Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.33
Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.34
Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.35,36
Cancer37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.
An expanding array of toxic ingestions
Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.
As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.
- Whittier WL, Rutecki GW. Primer on clinical acid-base problem solving. Dis Mon 2004; 50:122–162.
- Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162–174.
- Adrogué HJ, Madias NE. Secondary responses to altered acid-base status: the rules of engagement. J Am Soc Nephrol 2010; 21:920–923.
- Krasowski MD, Wilcoxon RM, Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012;12:1.
- Latus J, Kimmel M, Alscher MD, Braun N. Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis—a single-centre experience. Clin Kidney J 2012; 5:120–123.
- Kraut JA. Diagnosis of toxic alcohols: limitations of present methods. Clin Toxicol (Phila) 2015; 53:589–595.
- Ghannoum M, Hoffman RS, Mowry JB, Lavergne V. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial 2014; 27:395–401.
- Schep LJ, Slaughter RJ, Temple WA, Beasley DM. Diethylene glycol poisoning. Clin Toxicol (Phila) 2009; 47:525–535.
- Kraut JA, Madias NE. Metabolic acidosis of CKD: an update. Am J Kidney Dis 2016; 67:307–317.
- Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849–2852.
- Yokoyama A, Yokoyama T, Mizukami T, et al. Alcoholic ketosis: prevalence, determinants, and ketohepatitis in Japanese alcoholic men. Alcohol Alcohol 2014; 49:618–625.
- Hayward JN, Boshell BR. Paraldehyde intoxication with metabolic acidosis; report of two cases, experimental data and a critical review of the literature. Am J Med 1957; 23:965–976.
- Elkinton JR, Huth EJ, Clark JK, Barker ES, Seligson D. Renal tubular acidosis with organic aciduria during paraldehyde ingestion; six year study of an unusual case. Am J Med 1957; 23:977–986.
- Waterhouse C, Stern EA. Metabolic acidosis occurring during administration of paraldehyde. Am J Med 1957; 23:987–989.
- Beier LS, Pitts WH, Gonick HC. Metabolic acidosis occurring during paraldehyde intoxication. Ann Intern Med 1963; 58:155–158.
- Hiemcke T. Metabolic acidosis due to paraldehyde. Ned Tijdschr Geneeskd 1964; 108:2165–2167. Dutch.
- Gailitis RJ. Paraldehyde acidosis syndrome. IMJ III Med J 1966; 129:258–262.
- Gutman RA, Burnell JM. Paraldehyde acidosis. Am J Med 1967; 42:435–440.
- Hadden JW, Metzner RJ. Pseudoketosis and hyperacetaldehydemia in paraldehyde acidosis. Am J Med 1969; 47:642–647.
- Linter CM, Linter SP. Severe lactic acidosis following paraldehyde administration. Br J Psychiatry 1986; 149:650–651.
- Zand L, Muriithi A, Nelsen E, et al. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation. Am J Med Sci 2012; 344:501–504.
- Abkur TM, Mohammed W, Ali M, Casserly L. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report. J Med Case Rep 2014; 8:409.
- Tan EM, Kalimullah E, Sohail MR, Ramar K. Diagnostic challenge in a patient with severe anion gap metabolic acidosis. Case Rep Crit Care 2015; 2015:272914.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acid acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Barnes BJ, Gerst C, Smith JR, Terrell AR, Mullins ME. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy 2006; 26:23–33.
- Gokhale YA, Vaidya MS, Mehta AD, Rathod NN. Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J Assoc Physicians India 2009; 57:70–71.
- Ben-Abraham R, Szold O, Rudick V, Weinbroum AA. ‘Ecstasy’ intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. Eur J Emerg Med 2003; 10:309–313.
- German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci 2014; 97:2–8.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Kang KP, Le S, Kang SK. d-Lactic acidosis in humans: review and update. Electrolyte Blood Press 2006; 4:53–56.
- Emmett M. Approach to the patient with a negative anion gap. Am J Kidney Dis 2016; 67:143–150.
- Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st Century. Lancet 2008; 372:892.
- Palmer BF, Clegg DJ. Electrolyte and acid-base disturbances in patients with diabetes mellitus. N Engl J Med 2015; 373:548–559.
- Park JJ, Choi DJ, Yoon CH, et al; KorHF Registry. The prognostic value of arterial blood gas analysis in high-risk acute heart failure patients: an analysis of the Korean Heart Failure (KorHF) registry. Eur J Heart Fail 2015; 17:601–611.
- Musso CG, Belloso WH, Glassock RJ. Water, electrolytes, and acid-base alterations in human immunodeficiency virus infected patients. World J Nephrol 2016; 5:33–42.
- Camara-Lemarroy CR, Flores-Cantu H, Calderon-Hernandez HJ, Diaz-Torres MA, Villareal-Velazquez HJ. Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge. Int J STD AIDS 2015; 26:1052–1054.
- Miltiadous G, Christidis D, Kalogirou M, Elisaf M. Causes and mechanisms of acid-base and electrolyte abnormalities in cancer. Eur J Intern Med 2008; 19:1–7.
- Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark 2015; 15:725–734.
A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.
In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.
Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”
The patient’s laboratory values are shown in Table 1.
WHICH ACID-BASE DISORDER DOES SHE HAVE?
1. Which acid-base disorder does this patient have?
- Metabolic acidosis and respiratory alkalosis
- Metabolic acidosis and respiratory acidosis
- Metabolic acidosis with an elevated anion gap
- A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis
A 5-step approach
Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)1:
1. Determine the arterial pH status.
2. Determine whether the primary process is respiratory, metabolic, or both.
3. Calculate the anion gap.
4. Check the degree of compensation (respiratory or metabolic).
5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).
Let us apply this approach to the patient described above.
1. What is her pH status?
An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)
Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco2), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.
Our patient’s pH is 7.25, which is in the acidemic range.
2. Is her acidosis respiratory, metabolic, or both?
Respiratory acidosis and alkalosis affect the Pco2. The Pco2 is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).
Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.
Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco2 can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco2 can be low (Table 2).
Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco2 is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.
3. What is her anion gap?
Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.
Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.
Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.2
Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.
4. Is the degree of compensation appropriate for the primary acid-base disturbance?
The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco2 (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).
In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco2 should decrease by 1.3 mm Hg.
Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.
Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco2 should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco2 is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.
If we use Winter’s formula instead (Pco2 = [1.5 × the bicarbonate level] + 8 ± 2),3 the lowest calculated Pco2 would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.3
This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.
5. Is there a delta gap?
Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap.
In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.
Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.
So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).
‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS
The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).
Methanol and ethylene glycol
We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time.
In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.
In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).4,5 Therefore, her osmol gap is elevated.
Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.6 A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.7 Liquid chromatography identifies these two toxins, but results are not available emergently.
Diethylene glycol ingestion should also be considered.8 Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.
Uremia
Renal failure can lead to metabolic acidosis.9 Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m2—low, but not uremic.
Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.
Diabetes
The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).10
There is another, less common cause of ketoacidosis: alcohol.11 Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.11 Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.11
This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.
THE NEW MUD PILES
2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:
- The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
- There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
- Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
- Salicylates can paradoxically be associated both with elevated and low anion gaps.
Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.
Paraldehyde, isoniazid, lactate
The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.
UPDATING THE ‘P’ IN MUD PILES
Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).12–20
Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.
5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen
Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).21,22
Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.
Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,23 the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.
No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.
Propylene glycol, a component of parenteral lorazepam
Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.24,25
Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.23
Isoniazid
Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,26 either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.
The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.27 A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.28
Lactic acidosis
Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.29 However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.29
d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).30 With short bowel syndrome, the neurologic manifestations occur after eating and clear later.30
Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.
Salicylates
Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.
Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.
Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.31 Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.
WHAT ELSE MUST BE CONSIDERED?
3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)
- Methanol, ethylene, or diethylene glycol
- Excessive, chronic acetaminophen ingestion
- Salicylate toxicity
- Alcoholic ketoacidosis
All of the above can potentially contribute to metabolic acidosis.
A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.
Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.
The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.
GOLD MARK: ANOTHER WAY TO REMEMBER
Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).32
ACID-BASE DISORDERS IN DIFFERENT DISEASES
Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:
Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.33
Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.34
Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.35,36
Cancer37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.
An expanding array of toxic ingestions
Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.
As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.
A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.
In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.
Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”
The patient’s laboratory values are shown in Table 1.
WHICH ACID-BASE DISORDER DOES SHE HAVE?
1. Which acid-base disorder does this patient have?
- Metabolic acidosis and respiratory alkalosis
- Metabolic acidosis and respiratory acidosis
- Metabolic acidosis with an elevated anion gap
- A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis
A 5-step approach
Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)1:
1. Determine the arterial pH status.
2. Determine whether the primary process is respiratory, metabolic, or both.
3. Calculate the anion gap.
4. Check the degree of compensation (respiratory or metabolic).
5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).
Let us apply this approach to the patient described above.
1. What is her pH status?
An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)
Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco2), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.
Our patient’s pH is 7.25, which is in the acidemic range.
2. Is her acidosis respiratory, metabolic, or both?
Respiratory acidosis and alkalosis affect the Pco2. The Pco2 is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).
Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.
Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco2 can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco2 can be low (Table 2).
Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco2 is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.
3. What is her anion gap?
Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.
Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.
Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.2
Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.
4. Is the degree of compensation appropriate for the primary acid-base disturbance?
The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco2 (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).
In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco2 should decrease by 1.3 mm Hg.
Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.
Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco2 should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco2 is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.
If we use Winter’s formula instead (Pco2 = [1.5 × the bicarbonate level] + 8 ± 2),3 the lowest calculated Pco2 would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.3
This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.
5. Is there a delta gap?
Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap.
In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.
Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.
So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).
‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS
The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).
Methanol and ethylene glycol
We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time.
In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.
In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).4,5 Therefore, her osmol gap is elevated.
Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.6 A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.7 Liquid chromatography identifies these two toxins, but results are not available emergently.
Diethylene glycol ingestion should also be considered.8 Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.
Uremia
Renal failure can lead to metabolic acidosis.9 Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m2—low, but not uremic.
Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.
Diabetes
The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).10
There is another, less common cause of ketoacidosis: alcohol.11 Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.11 Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.11
This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.
THE NEW MUD PILES
2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:
- The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
- There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
- Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
- Salicylates can paradoxically be associated both with elevated and low anion gaps.
Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.
Paraldehyde, isoniazid, lactate
The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.
UPDATING THE ‘P’ IN MUD PILES
Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).12–20
Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.
5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen
Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).21,22
Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.
Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,23 the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.
No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.
Propylene glycol, a component of parenteral lorazepam
Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.24,25
Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.23
Isoniazid
Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,26 either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.
The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.27 A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.28
Lactic acidosis
Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.29 However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.29
d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).30 With short bowel syndrome, the neurologic manifestations occur after eating and clear later.30
Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.
Salicylates
Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.
Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.
Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.31 Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.
WHAT ELSE MUST BE CONSIDERED?
3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)
- Methanol, ethylene, or diethylene glycol
- Excessive, chronic acetaminophen ingestion
- Salicylate toxicity
- Alcoholic ketoacidosis
All of the above can potentially contribute to metabolic acidosis.
A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.
Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.
The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.
GOLD MARK: ANOTHER WAY TO REMEMBER
Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).32
ACID-BASE DISORDERS IN DIFFERENT DISEASES
Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:
Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.33
Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.34
Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.35,36
Cancer37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.
An expanding array of toxic ingestions
Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.
As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.
- Whittier WL, Rutecki GW. Primer on clinical acid-base problem solving. Dis Mon 2004; 50:122–162.
- Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162–174.
- Adrogué HJ, Madias NE. Secondary responses to altered acid-base status: the rules of engagement. J Am Soc Nephrol 2010; 21:920–923.
- Krasowski MD, Wilcoxon RM, Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012;12:1.
- Latus J, Kimmel M, Alscher MD, Braun N. Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis—a single-centre experience. Clin Kidney J 2012; 5:120–123.
- Kraut JA. Diagnosis of toxic alcohols: limitations of present methods. Clin Toxicol (Phila) 2015; 53:589–595.
- Ghannoum M, Hoffman RS, Mowry JB, Lavergne V. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial 2014; 27:395–401.
- Schep LJ, Slaughter RJ, Temple WA, Beasley DM. Diethylene glycol poisoning. Clin Toxicol (Phila) 2009; 47:525–535.
- Kraut JA, Madias NE. Metabolic acidosis of CKD: an update. Am J Kidney Dis 2016; 67:307–317.
- Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849–2852.
- Yokoyama A, Yokoyama T, Mizukami T, et al. Alcoholic ketosis: prevalence, determinants, and ketohepatitis in Japanese alcoholic men. Alcohol Alcohol 2014; 49:618–625.
- Hayward JN, Boshell BR. Paraldehyde intoxication with metabolic acidosis; report of two cases, experimental data and a critical review of the literature. Am J Med 1957; 23:965–976.
- Elkinton JR, Huth EJ, Clark JK, Barker ES, Seligson D. Renal tubular acidosis with organic aciduria during paraldehyde ingestion; six year study of an unusual case. Am J Med 1957; 23:977–986.
- Waterhouse C, Stern EA. Metabolic acidosis occurring during administration of paraldehyde. Am J Med 1957; 23:987–989.
- Beier LS, Pitts WH, Gonick HC. Metabolic acidosis occurring during paraldehyde intoxication. Ann Intern Med 1963; 58:155–158.
- Hiemcke T. Metabolic acidosis due to paraldehyde. Ned Tijdschr Geneeskd 1964; 108:2165–2167. Dutch.
- Gailitis RJ. Paraldehyde acidosis syndrome. IMJ III Med J 1966; 129:258–262.
- Gutman RA, Burnell JM. Paraldehyde acidosis. Am J Med 1967; 42:435–440.
- Hadden JW, Metzner RJ. Pseudoketosis and hyperacetaldehydemia in paraldehyde acidosis. Am J Med 1969; 47:642–647.
- Linter CM, Linter SP. Severe lactic acidosis following paraldehyde administration. Br J Psychiatry 1986; 149:650–651.
- Zand L, Muriithi A, Nelsen E, et al. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation. Am J Med Sci 2012; 344:501–504.
- Abkur TM, Mohammed W, Ali M, Casserly L. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report. J Med Case Rep 2014; 8:409.
- Tan EM, Kalimullah E, Sohail MR, Ramar K. Diagnostic challenge in a patient with severe anion gap metabolic acidosis. Case Rep Crit Care 2015; 2015:272914.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acid acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Barnes BJ, Gerst C, Smith JR, Terrell AR, Mullins ME. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy 2006; 26:23–33.
- Gokhale YA, Vaidya MS, Mehta AD, Rathod NN. Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J Assoc Physicians India 2009; 57:70–71.
- Ben-Abraham R, Szold O, Rudick V, Weinbroum AA. ‘Ecstasy’ intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. Eur J Emerg Med 2003; 10:309–313.
- German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci 2014; 97:2–8.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Kang KP, Le S, Kang SK. d-Lactic acidosis in humans: review and update. Electrolyte Blood Press 2006; 4:53–56.
- Emmett M. Approach to the patient with a negative anion gap. Am J Kidney Dis 2016; 67:143–150.
- Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st Century. Lancet 2008; 372:892.
- Palmer BF, Clegg DJ. Electrolyte and acid-base disturbances in patients with diabetes mellitus. N Engl J Med 2015; 373:548–559.
- Park JJ, Choi DJ, Yoon CH, et al; KorHF Registry. The prognostic value of arterial blood gas analysis in high-risk acute heart failure patients: an analysis of the Korean Heart Failure (KorHF) registry. Eur J Heart Fail 2015; 17:601–611.
- Musso CG, Belloso WH, Glassock RJ. Water, electrolytes, and acid-base alterations in human immunodeficiency virus infected patients. World J Nephrol 2016; 5:33–42.
- Camara-Lemarroy CR, Flores-Cantu H, Calderon-Hernandez HJ, Diaz-Torres MA, Villareal-Velazquez HJ. Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge. Int J STD AIDS 2015; 26:1052–1054.
- Miltiadous G, Christidis D, Kalogirou M, Elisaf M. Causes and mechanisms of acid-base and electrolyte abnormalities in cancer. Eur J Intern Med 2008; 19:1–7.
- Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark 2015; 15:725–734.
- Whittier WL, Rutecki GW. Primer on clinical acid-base problem solving. Dis Mon 2004; 50:122–162.
- Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162–174.
- Adrogué HJ, Madias NE. Secondary responses to altered acid-base status: the rules of engagement. J Am Soc Nephrol 2010; 21:920–923.
- Krasowski MD, Wilcoxon RM, Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012;12:1.
- Latus J, Kimmel M, Alscher MD, Braun N. Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis—a single-centre experience. Clin Kidney J 2012; 5:120–123.
- Kraut JA. Diagnosis of toxic alcohols: limitations of present methods. Clin Toxicol (Phila) 2015; 53:589–595.
- Ghannoum M, Hoffman RS, Mowry JB, Lavergne V. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial 2014; 27:395–401.
- Schep LJ, Slaughter RJ, Temple WA, Beasley DM. Diethylene glycol poisoning. Clin Toxicol (Phila) 2009; 47:525–535.
- Kraut JA, Madias NE. Metabolic acidosis of CKD: an update. Am J Kidney Dis 2016; 67:307–317.
- Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849–2852.
- Yokoyama A, Yokoyama T, Mizukami T, et al. Alcoholic ketosis: prevalence, determinants, and ketohepatitis in Japanese alcoholic men. Alcohol Alcohol 2014; 49:618–625.
- Hayward JN, Boshell BR. Paraldehyde intoxication with metabolic acidosis; report of two cases, experimental data and a critical review of the literature. Am J Med 1957; 23:965–976.
- Elkinton JR, Huth EJ, Clark JK, Barker ES, Seligson D. Renal tubular acidosis with organic aciduria during paraldehyde ingestion; six year study of an unusual case. Am J Med 1957; 23:977–986.
- Waterhouse C, Stern EA. Metabolic acidosis occurring during administration of paraldehyde. Am J Med 1957; 23:987–989.
- Beier LS, Pitts WH, Gonick HC. Metabolic acidosis occurring during paraldehyde intoxication. Ann Intern Med 1963; 58:155–158.
- Hiemcke T. Metabolic acidosis due to paraldehyde. Ned Tijdschr Geneeskd 1964; 108:2165–2167. Dutch.
- Gailitis RJ. Paraldehyde acidosis syndrome. IMJ III Med J 1966; 129:258–262.
- Gutman RA, Burnell JM. Paraldehyde acidosis. Am J Med 1967; 42:435–440.
- Hadden JW, Metzner RJ. Pseudoketosis and hyperacetaldehydemia in paraldehyde acidosis. Am J Med 1969; 47:642–647.
- Linter CM, Linter SP. Severe lactic acidosis following paraldehyde administration. Br J Psychiatry 1986; 149:650–651.
- Zand L, Muriithi A, Nelsen E, et al. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation. Am J Med Sci 2012; 344:501–504.
- Abkur TM, Mohammed W, Ali M, Casserly L. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report. J Med Case Rep 2014; 8:409.
- Tan EM, Kalimullah E, Sohail MR, Ramar K. Diagnostic challenge in a patient with severe anion gap metabolic acidosis. Case Rep Crit Care 2015; 2015:272914.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acid acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Barnes BJ, Gerst C, Smith JR, Terrell AR, Mullins ME. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy 2006; 26:23–33.
- Gokhale YA, Vaidya MS, Mehta AD, Rathod NN. Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J Assoc Physicians India 2009; 57:70–71.
- Ben-Abraham R, Szold O, Rudick V, Weinbroum AA. ‘Ecstasy’ intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. Eur J Emerg Med 2003; 10:309–313.
- German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci 2014; 97:2–8.
- Jorens PG, Demey HE, Schepens PJ, et al. Unusual d-lactic acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004; 42:163–169.
- Kang KP, Le S, Kang SK. d-Lactic acidosis in humans: review and update. Electrolyte Blood Press 2006; 4:53–56.
- Emmett M. Approach to the patient with a negative anion gap. Am J Kidney Dis 2016; 67:143–150.
- Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st Century. Lancet 2008; 372:892.
- Palmer BF, Clegg DJ. Electrolyte and acid-base disturbances in patients with diabetes mellitus. N Engl J Med 2015; 373:548–559.
- Park JJ, Choi DJ, Yoon CH, et al; KorHF Registry. The prognostic value of arterial blood gas analysis in high-risk acute heart failure patients: an analysis of the Korean Heart Failure (KorHF) registry. Eur J Heart Fail 2015; 17:601–611.
- Musso CG, Belloso WH, Glassock RJ. Water, electrolytes, and acid-base alterations in human immunodeficiency virus infected patients. World J Nephrol 2016; 5:33–42.
- Camara-Lemarroy CR, Flores-Cantu H, Calderon-Hernandez HJ, Diaz-Torres MA, Villareal-Velazquez HJ. Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge. Int J STD AIDS 2015; 26:1052–1054.
- Miltiadous G, Christidis D, Kalogirou M, Elisaf M. Causes and mechanisms of acid-base and electrolyte abnormalities in cancer. Eur J Intern Med 2008; 19:1–7.
- Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark 2015; 15:725–734.
January 2017 Digital Edition
Click here to access the January 2017 Digital Edition
Table of Contents
- What’s New for Federal Practitioner in 2017?
- Addressing Sexual Health With Patients
- Leadership Initiatives in Patient-Centered Transgender Care
- Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
- Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
- The Importance of Subclavian Angiography in the Evaluation of Chest Pain
- Diabetes: Health Literacy Education Improves Veteran Outcomes
- Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
- Dementia Evaluation, Management, and Outreach
Click here to access the January 2017 Digital Edition
Table of Contents
- What’s New for Federal Practitioner in 2017?
- Addressing Sexual Health With Patients
- Leadership Initiatives in Patient-Centered Transgender Care
- Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
- Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
- The Importance of Subclavian Angiography in the Evaluation of Chest Pain
- Diabetes: Health Literacy Education Improves Veteran Outcomes
- Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
- Dementia Evaluation, Management, and Outreach
Click here to access the January 2017 Digital Edition
Table of Contents
- What’s New for Federal Practitioner in 2017?
- Addressing Sexual Health With Patients
- Leadership Initiatives in Patient-Centered Transgender Care
- Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
- Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
- The Importance of Subclavian Angiography in the Evaluation of Chest Pain
- Diabetes: Health Literacy Education Improves Veteran Outcomes
- Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
- Dementia Evaluation, Management, and Outreach
What stool testing is appropriate when diarrhea develops in a hospitalized patient?
A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?
Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.
CAUSES OF DIARRHEA IN THE HOSPITAL
Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.
Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.1
Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.2 Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,3 and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.1
RECOMMENDED TESTING
The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).
In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.4
In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.
Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.5
Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.
In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.
TESTING FOR C DIFFICILE INFECTION
A number of diagnostic tests for C difficile infection are available.
Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.2,6
Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.6
Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.6
Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.7 Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,7 but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.
In a prospective, observational, cohort study,7 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.
In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).7 Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.8 However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.
Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.9–11
The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.
Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.2,8
RETURNING TO OUR PATIENT
Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.
- Polage CR, Solnick JV, Cohen SH. Nosocomial diarrhea: evaluation and treatment of causes other than Clostridum difficile. Clin Infect Dis 2012; 55:982–989.
- Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–455.
- Greig JD, Lee MB. A review of nosocomial norovirus outbreaks: infection control interventions found effective. Epidemiol Infect 2012; 140:1151–1160.
- Guerrant RL, Van Gilder T, Steiner TS, et al; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001; 32:331–351.
- Savola KL, Baron EJ, Tompkins LS, Passaro DJ. Fecal leukocyte stain has diagnostic value for outpatients but not inpatients. Clin Microbiol 2001; 39:266–269.
- Bagdasarian N, Rao, K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015; 313:398–408.
- Polage CR, Gyorke CE, Kennedy MA, et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern Med 2015; 175:1792–1801.
- Surawica CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108:478–498.
- Staneck JL, Weckbah LS, Allen SD, et al. Multicenter evaluation of four methods for Clostridium difficile detection: immunocard C. difficile, cytotoxin assay, culture, and latex agglutination. J Clin Microbiol 1996; 34:2718–2721.
- Novak-Weekley SM, Marlow EM, Miller JM, et al. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 2010; 48:889–893.
- Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficle infection. J Clin Microbiol 2014; 52:489–496.
A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?
Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.
CAUSES OF DIARRHEA IN THE HOSPITAL
Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.
Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.1
Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.2 Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,3 and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.1
RECOMMENDED TESTING
The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).
In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.4
In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.
Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.5
Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.
In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.
TESTING FOR C DIFFICILE INFECTION
A number of diagnostic tests for C difficile infection are available.
Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.2,6
Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.6
Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.6
Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.7 Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,7 but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.
In a prospective, observational, cohort study,7 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.
In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).7 Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.8 However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.
Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.9–11
The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.
Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.2,8
RETURNING TO OUR PATIENT
Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.
A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?
Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.
CAUSES OF DIARRHEA IN THE HOSPITAL
Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.
Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.1
Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.2 Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,3 and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.1
RECOMMENDED TESTING
The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).
In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.4
In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.
Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.5
Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.
In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.
TESTING FOR C DIFFICILE INFECTION
A number of diagnostic tests for C difficile infection are available.
Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.2,6
Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.6
Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.6
Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.7 Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,7 but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.
In a prospective, observational, cohort study,7 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.
In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).7 Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.8 However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.
Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.9–11
The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.
Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.2,8
RETURNING TO OUR PATIENT
Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.
- Polage CR, Solnick JV, Cohen SH. Nosocomial diarrhea: evaluation and treatment of causes other than Clostridum difficile. Clin Infect Dis 2012; 55:982–989.
- Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–455.
- Greig JD, Lee MB. A review of nosocomial norovirus outbreaks: infection control interventions found effective. Epidemiol Infect 2012; 140:1151–1160.
- Guerrant RL, Van Gilder T, Steiner TS, et al; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001; 32:331–351.
- Savola KL, Baron EJ, Tompkins LS, Passaro DJ. Fecal leukocyte stain has diagnostic value for outpatients but not inpatients. Clin Microbiol 2001; 39:266–269.
- Bagdasarian N, Rao, K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015; 313:398–408.
- Polage CR, Gyorke CE, Kennedy MA, et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern Med 2015; 175:1792–1801.
- Surawica CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108:478–498.
- Staneck JL, Weckbah LS, Allen SD, et al. Multicenter evaluation of four methods for Clostridium difficile detection: immunocard C. difficile, cytotoxin assay, culture, and latex agglutination. J Clin Microbiol 1996; 34:2718–2721.
- Novak-Weekley SM, Marlow EM, Miller JM, et al. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 2010; 48:889–893.
- Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficle infection. J Clin Microbiol 2014; 52:489–496.
- Polage CR, Solnick JV, Cohen SH. Nosocomial diarrhea: evaluation and treatment of causes other than Clostridum difficile. Clin Infect Dis 2012; 55:982–989.
- Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–455.
- Greig JD, Lee MB. A review of nosocomial norovirus outbreaks: infection control interventions found effective. Epidemiol Infect 2012; 140:1151–1160.
- Guerrant RL, Van Gilder T, Steiner TS, et al; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001; 32:331–351.
- Savola KL, Baron EJ, Tompkins LS, Passaro DJ. Fecal leukocyte stain has diagnostic value for outpatients but not inpatients. Clin Microbiol 2001; 39:266–269.
- Bagdasarian N, Rao, K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015; 313:398–408.
- Polage CR, Gyorke CE, Kennedy MA, et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern Med 2015; 175:1792–1801.
- Surawica CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108:478–498.
- Staneck JL, Weckbah LS, Allen SD, et al. Multicenter evaluation of four methods for Clostridium difficile detection: immunocard C. difficile, cytotoxin assay, culture, and latex agglutination. J Clin Microbiol 1996; 34:2718–2721.
- Novak-Weekley SM, Marlow EM, Miller JM, et al. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 2010; 48:889–893.
- Schroeder LF, Robilotti E, Peterson LR, Banaei N, Dowdy DW. Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficle infection. J Clin Microbiol 2014; 52:489–496.
