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Case Studies In Toxicology: Withdrawal: Another Danger of Diversion
Case
A 34-year-old man with a history of polysubstance abuse presented to the ED after he had a seizure during his regular methadone-treatment program meeting. While at the clinic, attendees witnessed the patient experience a loss of consciousness accompanied by generalized shaking movements of his extremities, which lasted for several minutes.
Upon arrival in the ED, the patient stated that he had a mild headache; he was otherwise asymptomatic. Initial vital signs were: blood pressure, 126/80 mm Hg; heart rate, 82 beats/minute; respiratory rate, 16 breaths/minute; and temperature, 97.3°F. Oxygen saturation was 98% on room air, and a finger-stick glucose test was 140 mg/dL.
Physical examination revealed a small right-sided parietal hematoma. The patient had no tremors and his neurological examination, including mental status, was normal. When reviewing the patient’s medical history and medications in the health record, it was noted that the patient had a prescription for alprazolam for an anxiety disorder. On further questioning, the patient admitted that he had sold his last alprazolam prescription and had not been taking the drug for the past week.
What characterizes the benzodiazepine withdrawal syndrome?
Although introduced into clinical practice in the 1960s, the potential for dependence and a withdrawal syndrome was not appreciated until the early 1980s. This clinical syndrome can manifest with a wide variety of findings, most commonly with what are termed “rebound effects” or “rebound hyperexcitability.” These effects include anxiety, insomnia or sleep disturbance, tremulousness, irritability, sweating, psychomotor agitation, difficulty in concentration, nausea, weight loss, palpitations, headache, muscular pain and stiffness, or generalized weakness.2 More severe manifestations include delirium, seizures, or psychosis. Often, these symptoms and signs may be confused with the very manifestations that prompted the initial use of the BZD, a reemergence of which can exacerbate the withdrawal syndrome.
When does benzodiazepine withdrawal occur?
The exact time course of BZD withdrawal can vary considerably and, unlike alcohol withdrawal (which occurs from a single compound, ethanol), can be difficult to characterize. The onset of withdrawal symptoms is dependent on a number of factors, including the half-life of the BZD involved. For example, delayed onset withdrawal symptoms of up to 3 weeks after cessation of the medication are described with long-acting BZDs such as chlordiazepoxide and diazepam. Conversely, symptoms may present as early as 24 to 48 hours after abrupt termination of BZDs with shorter half-lives, alprazolam and lorazepam. This variable time of onset differs considerably from other withdrawal syndromes, notably ethanol withdrawal. While both syndromes correlate to the individual patient’s severity of dependence, alcohol withdrawal follows a more predictable time course.
Some authors distinguish a rebound syndrome from a true withdrawal syndrome, the former of which is self-limited in nature and the result of cessation of treatment for the primary disease process. In this model, rebound symptoms begin 1 to 4 days after the abrupt cessation or dose reduction of the BZD, and are relatively short-lived, lasting 2 to 3 days.2
What is the appropriate treatment for benzodiazepine withdrawal?
The standard therapy for almost all withdrawal syndromes is reinstitution of the causal agent. A number of non-BZD-based treatment strategies have been investigated, and all have met with limited success. Of these, anticonvulsant drugs such as carbamazepine and valproic acid were initially considered promising based on case reports and small case series.4 These medications ultimately proved ineffective in randomized, placebo-controlled studies.5 β-Adrenergic antagonists, such as propranolol, have been studied as a method to normalize a patient’s vital signs but also proved nonbeneficial in managing withdrawal.5,6
The safest and most effective management approach for patients with BZD withdrawal is reinstitution of the BZD followed by a prolonged and gradual tapering until cessation, if that is desired.1,2,5,6 While all BZDs share structural and mechanistic similarities, there are subtle variations within this class that can affect their pharmacologic effects. These structural differences may result in incomplete cross-tolerance, which may lead to inadequate mitigation of the withdrawal syndrome. For example, previous reports suggest that alprazolam and clonazepam are structurally unique and bind to the BZD receptor with higher affinity than other BZDs. Therefore, while in general any BZD can be used to treat withdrawal from another BZD, it is recommended to treat withdrawal from these two agents with the implicated BZD.
There are, however, limitations to this approach. Namely, some BZDs are only available in oral formulations (eg, alprazolam and clonazepam) or the BZD of choice may not be readily available or on formulary within a given institution. In a patient with a severe withdrawal syndrome where it is not feasible or potentially harmful to administer an oral medication, it is reasonable to provide parenteral (preferably intravenous [IV]) BZD therapy. The optimal approach is to start with a small “standard” dose and titrate to effect while monitoring for adverse effects (eg, oversedation, ventilatory depression). Redosing should be triggered by symptoms or signs, and not performed in a timed or standing-order fashion. If this approach proves ineffective and withdrawal symptoms persist despite adequate BZD therapy, a direct GABA agonist such as propofol is a sensible alternative or adjuvant treatment. This may sound similar to the management of patients with ethanol withdrawal; indeed, this approach is essentially the same, with the exception of the more drawn-out time course.
Case Conclusion
After arrival in the ED, the patient received diazepam 10 mg IV and was subsequently admitted to the hospital for further evaluation. During his hospitalization, the patient was re-started on his usual dose of oral alprazolam. No further withdrawal syndrome was observed, and he was discharged on hospital day 2 with a plan to slowly taper his alprazolam dose with his outpatient psychiatrist.
Dr Repplinger is a senior medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
- Withdrawal: Another Danger of Diversion
- Marriott S, Tyrer P. Benzodiazepine dependence. Avoidance and withdrawal. Drug Saf. 1993;9(2):93-103.
- Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-1459.
- Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408-413.
- Pages KP, Ries RK. Use of anticonvulsants in benzodiazepine withdrawal. Am J Addict. 1998;7(3):198-204.
- Ashton H. The treatment of benzodiazepine dependence. Addiction. 1994;89(11):1535-1541.
- Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24.
Case
A 34-year-old man with a history of polysubstance abuse presented to the ED after he had a seizure during his regular methadone-treatment program meeting. While at the clinic, attendees witnessed the patient experience a loss of consciousness accompanied by generalized shaking movements of his extremities, which lasted for several minutes.
Upon arrival in the ED, the patient stated that he had a mild headache; he was otherwise asymptomatic. Initial vital signs were: blood pressure, 126/80 mm Hg; heart rate, 82 beats/minute; respiratory rate, 16 breaths/minute; and temperature, 97.3°F. Oxygen saturation was 98% on room air, and a finger-stick glucose test was 140 mg/dL.
Physical examination revealed a small right-sided parietal hematoma. The patient had no tremors and his neurological examination, including mental status, was normal. When reviewing the patient’s medical history and medications in the health record, it was noted that the patient had a prescription for alprazolam for an anxiety disorder. On further questioning, the patient admitted that he had sold his last alprazolam prescription and had not been taking the drug for the past week.
What characterizes the benzodiazepine withdrawal syndrome?
Although introduced into clinical practice in the 1960s, the potential for dependence and a withdrawal syndrome was not appreciated until the early 1980s. This clinical syndrome can manifest with a wide variety of findings, most commonly with what are termed “rebound effects” or “rebound hyperexcitability.” These effects include anxiety, insomnia or sleep disturbance, tremulousness, irritability, sweating, psychomotor agitation, difficulty in concentration, nausea, weight loss, palpitations, headache, muscular pain and stiffness, or generalized weakness.2 More severe manifestations include delirium, seizures, or psychosis. Often, these symptoms and signs may be confused with the very manifestations that prompted the initial use of the BZD, a reemergence of which can exacerbate the withdrawal syndrome.
When does benzodiazepine withdrawal occur?
The exact time course of BZD withdrawal can vary considerably and, unlike alcohol withdrawal (which occurs from a single compound, ethanol), can be difficult to characterize. The onset of withdrawal symptoms is dependent on a number of factors, including the half-life of the BZD involved. For example, delayed onset withdrawal symptoms of up to 3 weeks after cessation of the medication are described with long-acting BZDs such as chlordiazepoxide and diazepam. Conversely, symptoms may present as early as 24 to 48 hours after abrupt termination of BZDs with shorter half-lives, alprazolam and lorazepam. This variable time of onset differs considerably from other withdrawal syndromes, notably ethanol withdrawal. While both syndromes correlate to the individual patient’s severity of dependence, alcohol withdrawal follows a more predictable time course.
Some authors distinguish a rebound syndrome from a true withdrawal syndrome, the former of which is self-limited in nature and the result of cessation of treatment for the primary disease process. In this model, rebound symptoms begin 1 to 4 days after the abrupt cessation or dose reduction of the BZD, and are relatively short-lived, lasting 2 to 3 days.2
What is the appropriate treatment for benzodiazepine withdrawal?
The standard therapy for almost all withdrawal syndromes is reinstitution of the causal agent. A number of non-BZD-based treatment strategies have been investigated, and all have met with limited success. Of these, anticonvulsant drugs such as carbamazepine and valproic acid were initially considered promising based on case reports and small case series.4 These medications ultimately proved ineffective in randomized, placebo-controlled studies.5 β-Adrenergic antagonists, such as propranolol, have been studied as a method to normalize a patient’s vital signs but also proved nonbeneficial in managing withdrawal.5,6
The safest and most effective management approach for patients with BZD withdrawal is reinstitution of the BZD followed by a prolonged and gradual tapering until cessation, if that is desired.1,2,5,6 While all BZDs share structural and mechanistic similarities, there are subtle variations within this class that can affect their pharmacologic effects. These structural differences may result in incomplete cross-tolerance, which may lead to inadequate mitigation of the withdrawal syndrome. For example, previous reports suggest that alprazolam and clonazepam are structurally unique and bind to the BZD receptor with higher affinity than other BZDs. Therefore, while in general any BZD can be used to treat withdrawal from another BZD, it is recommended to treat withdrawal from these two agents with the implicated BZD.
There are, however, limitations to this approach. Namely, some BZDs are only available in oral formulations (eg, alprazolam and clonazepam) or the BZD of choice may not be readily available or on formulary within a given institution. In a patient with a severe withdrawal syndrome where it is not feasible or potentially harmful to administer an oral medication, it is reasonable to provide parenteral (preferably intravenous [IV]) BZD therapy. The optimal approach is to start with a small “standard” dose and titrate to effect while monitoring for adverse effects (eg, oversedation, ventilatory depression). Redosing should be triggered by symptoms or signs, and not performed in a timed or standing-order fashion. If this approach proves ineffective and withdrawal symptoms persist despite adequate BZD therapy, a direct GABA agonist such as propofol is a sensible alternative or adjuvant treatment. This may sound similar to the management of patients with ethanol withdrawal; indeed, this approach is essentially the same, with the exception of the more drawn-out time course.
Case Conclusion
After arrival in the ED, the patient received diazepam 10 mg IV and was subsequently admitted to the hospital for further evaluation. During his hospitalization, the patient was re-started on his usual dose of oral alprazolam. No further withdrawal syndrome was observed, and he was discharged on hospital day 2 with a plan to slowly taper his alprazolam dose with his outpatient psychiatrist.
Dr Repplinger is a senior medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
Case
A 34-year-old man with a history of polysubstance abuse presented to the ED after he had a seizure during his regular methadone-treatment program meeting. While at the clinic, attendees witnessed the patient experience a loss of consciousness accompanied by generalized shaking movements of his extremities, which lasted for several minutes.
Upon arrival in the ED, the patient stated that he had a mild headache; he was otherwise asymptomatic. Initial vital signs were: blood pressure, 126/80 mm Hg; heart rate, 82 beats/minute; respiratory rate, 16 breaths/minute; and temperature, 97.3°F. Oxygen saturation was 98% on room air, and a finger-stick glucose test was 140 mg/dL.
Physical examination revealed a small right-sided parietal hematoma. The patient had no tremors and his neurological examination, including mental status, was normal. When reviewing the patient’s medical history and medications in the health record, it was noted that the patient had a prescription for alprazolam for an anxiety disorder. On further questioning, the patient admitted that he had sold his last alprazolam prescription and had not been taking the drug for the past week.
What characterizes the benzodiazepine withdrawal syndrome?
Although introduced into clinical practice in the 1960s, the potential for dependence and a withdrawal syndrome was not appreciated until the early 1980s. This clinical syndrome can manifest with a wide variety of findings, most commonly with what are termed “rebound effects” or “rebound hyperexcitability.” These effects include anxiety, insomnia or sleep disturbance, tremulousness, irritability, sweating, psychomotor agitation, difficulty in concentration, nausea, weight loss, palpitations, headache, muscular pain and stiffness, or generalized weakness.2 More severe manifestations include delirium, seizures, or psychosis. Often, these symptoms and signs may be confused with the very manifestations that prompted the initial use of the BZD, a reemergence of which can exacerbate the withdrawal syndrome.
When does benzodiazepine withdrawal occur?
The exact time course of BZD withdrawal can vary considerably and, unlike alcohol withdrawal (which occurs from a single compound, ethanol), can be difficult to characterize. The onset of withdrawal symptoms is dependent on a number of factors, including the half-life of the BZD involved. For example, delayed onset withdrawal symptoms of up to 3 weeks after cessation of the medication are described with long-acting BZDs such as chlordiazepoxide and diazepam. Conversely, symptoms may present as early as 24 to 48 hours after abrupt termination of BZDs with shorter half-lives, alprazolam and lorazepam. This variable time of onset differs considerably from other withdrawal syndromes, notably ethanol withdrawal. While both syndromes correlate to the individual patient’s severity of dependence, alcohol withdrawal follows a more predictable time course.
Some authors distinguish a rebound syndrome from a true withdrawal syndrome, the former of which is self-limited in nature and the result of cessation of treatment for the primary disease process. In this model, rebound symptoms begin 1 to 4 days after the abrupt cessation or dose reduction of the BZD, and are relatively short-lived, lasting 2 to 3 days.2
What is the appropriate treatment for benzodiazepine withdrawal?
The standard therapy for almost all withdrawal syndromes is reinstitution of the causal agent. A number of non-BZD-based treatment strategies have been investigated, and all have met with limited success. Of these, anticonvulsant drugs such as carbamazepine and valproic acid were initially considered promising based on case reports and small case series.4 These medications ultimately proved ineffective in randomized, placebo-controlled studies.5 β-Adrenergic antagonists, such as propranolol, have been studied as a method to normalize a patient’s vital signs but also proved nonbeneficial in managing withdrawal.5,6
The safest and most effective management approach for patients with BZD withdrawal is reinstitution of the BZD followed by a prolonged and gradual tapering until cessation, if that is desired.1,2,5,6 While all BZDs share structural and mechanistic similarities, there are subtle variations within this class that can affect their pharmacologic effects. These structural differences may result in incomplete cross-tolerance, which may lead to inadequate mitigation of the withdrawal syndrome. For example, previous reports suggest that alprazolam and clonazepam are structurally unique and bind to the BZD receptor with higher affinity than other BZDs. Therefore, while in general any BZD can be used to treat withdrawal from another BZD, it is recommended to treat withdrawal from these two agents with the implicated BZD.
There are, however, limitations to this approach. Namely, some BZDs are only available in oral formulations (eg, alprazolam and clonazepam) or the BZD of choice may not be readily available or on formulary within a given institution. In a patient with a severe withdrawal syndrome where it is not feasible or potentially harmful to administer an oral medication, it is reasonable to provide parenteral (preferably intravenous [IV]) BZD therapy. The optimal approach is to start with a small “standard” dose and titrate to effect while monitoring for adverse effects (eg, oversedation, ventilatory depression). Redosing should be triggered by symptoms or signs, and not performed in a timed or standing-order fashion. If this approach proves ineffective and withdrawal symptoms persist despite adequate BZD therapy, a direct GABA agonist such as propofol is a sensible alternative or adjuvant treatment. This may sound similar to the management of patients with ethanol withdrawal; indeed, this approach is essentially the same, with the exception of the more drawn-out time course.
Case Conclusion
After arrival in the ED, the patient received diazepam 10 mg IV and was subsequently admitted to the hospital for further evaluation. During his hospitalization, the patient was re-started on his usual dose of oral alprazolam. No further withdrawal syndrome was observed, and he was discharged on hospital day 2 with a plan to slowly taper his alprazolam dose with his outpatient psychiatrist.
Dr Repplinger is a senior medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
- Withdrawal: Another Danger of Diversion
- Marriott S, Tyrer P. Benzodiazepine dependence. Avoidance and withdrawal. Drug Saf. 1993;9(2):93-103.
- Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-1459.
- Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408-413.
- Pages KP, Ries RK. Use of anticonvulsants in benzodiazepine withdrawal. Am J Addict. 1998;7(3):198-204.
- Ashton H. The treatment of benzodiazepine dependence. Addiction. 1994;89(11):1535-1541.
- Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24.
- Withdrawal: Another Danger of Diversion
- Marriott S, Tyrer P. Benzodiazepine dependence. Avoidance and withdrawal. Drug Saf. 1993;9(2):93-103.
- Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-1459.
- Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408-413.
- Pages KP, Ries RK. Use of anticonvulsants in benzodiazepine withdrawal. Am J Addict. 1998;7(3):198-204.
- Ashton H. The treatment of benzodiazepine dependence. Addiction. 1994;89(11):1535-1541.
- Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24.
Betting the Farm
A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.
The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.
He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.
The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.
On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.
The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.
Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm3 (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm3. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.
Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.
His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H20 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.
Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.
The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.
The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.
His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.
A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.
The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.
Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.
DISCUSSION
Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.
Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.
C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]
Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]
This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.
There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.
The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.
TEACHING POINTS
- Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
- Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
- Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.
Disclosure: Nothing to report.
- . “Q” fever, a new fever entity: clinical features, diagnosis, and laboratory investigation. Rev Infect Dis. 1983;5(4):790–800.
- , , , . Q fever: a biological weapon in your backyard. Lancet Infect Dis. 2003;3(11):709–721.
- , , , . Role of sex, age, previous valve lesion, and pregnancy in the clinical expression and outcome of Q fever after a large outbreak. Clin Infect Dis. 2007;15:44(2):232–237.
- , , , , . Unusual manifestations of acute Q fever: autoimmune hemolytic anemia and tubulointerstitial nephritis. Ann of Clin Microbiol Antimicrob. 2012;11:14.
- , , . Q fever. Lancet. 2006;367(9511):679–688.
- , , , , , . Transitory monoclonal gammopathy and acute Q fever. Enferm Infecc Microbiol Clin. 1995;13(7):442.
- , . Q fever. Clin Microbiol Rev. 1999;12(4):518–553.
- , , , et al. Diagnosis and management of Q fever—United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62(RR‐03):1–30.
- , , , et al. Hepatic fibrin‐ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol. 1991;22(6):607–613.
- , , . Travel‐associated zoonotic bacterial diseases. Curr Opin Infect Dis. 2011;24(5):457–463.
A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.
The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.
He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.
The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.
On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.
The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.
Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm3 (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm3. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.
Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.
His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H20 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.
Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.
The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.
The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.
His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.
A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.
The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.
Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.
DISCUSSION
Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.
Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.
C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]
Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]
This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.
There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.
The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.
TEACHING POINTS
- Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
- Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
- Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.
Disclosure: Nothing to report.
A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.
The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.
He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.
The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.
On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.
The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.
Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm3 (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm3. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.
Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.
His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H20 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.
Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.
The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.
The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.
His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.
A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.
The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.
Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.
DISCUSSION
Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.
Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.
C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]
Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]
This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.
There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.
The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.
TEACHING POINTS
- Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
- Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
- Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.
Disclosure: Nothing to report.
- . “Q” fever, a new fever entity: clinical features, diagnosis, and laboratory investigation. Rev Infect Dis. 1983;5(4):790–800.
- , , , . Q fever: a biological weapon in your backyard. Lancet Infect Dis. 2003;3(11):709–721.
- , , , . Role of sex, age, previous valve lesion, and pregnancy in the clinical expression and outcome of Q fever after a large outbreak. Clin Infect Dis. 2007;15:44(2):232–237.
- , , , , . Unusual manifestations of acute Q fever: autoimmune hemolytic anemia and tubulointerstitial nephritis. Ann of Clin Microbiol Antimicrob. 2012;11:14.
- , , . Q fever. Lancet. 2006;367(9511):679–688.
- , , , , , . Transitory monoclonal gammopathy and acute Q fever. Enferm Infecc Microbiol Clin. 1995;13(7):442.
- , . Q fever. Clin Microbiol Rev. 1999;12(4):518–553.
- , , , et al. Diagnosis and management of Q fever—United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62(RR‐03):1–30.
- , , , et al. Hepatic fibrin‐ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol. 1991;22(6):607–613.
- , , . Travel‐associated zoonotic bacterial diseases. Curr Opin Infect Dis. 2011;24(5):457–463.
- . “Q” fever, a new fever entity: clinical features, diagnosis, and laboratory investigation. Rev Infect Dis. 1983;5(4):790–800.
- , , , . Q fever: a biological weapon in your backyard. Lancet Infect Dis. 2003;3(11):709–721.
- , , , . Role of sex, age, previous valve lesion, and pregnancy in the clinical expression and outcome of Q fever after a large outbreak. Clin Infect Dis. 2007;15:44(2):232–237.
- , , , , . Unusual manifestations of acute Q fever: autoimmune hemolytic anemia and tubulointerstitial nephritis. Ann of Clin Microbiol Antimicrob. 2012;11:14.
- , , . Q fever. Lancet. 2006;367(9511):679–688.
- , , , , , . Transitory monoclonal gammopathy and acute Q fever. Enferm Infecc Microbiol Clin. 1995;13(7):442.
- , . Q fever. Clin Microbiol Rev. 1999;12(4):518–553.
- , , , et al. Diagnosis and management of Q fever—United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62(RR‐03):1–30.
- , , , et al. Hepatic fibrin‐ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol. 1991;22(6):607–613.
- , , . Travel‐associated zoonotic bacterial diseases. Curr Opin Infect Dis. 2011;24(5):457–463.
Management and Outcomes After SVTE
Superficial thrombophlebitis (SVTE), inflammation of superficial veins associated with thrombosis, is a painful condition, and 3% to 11% of the population will develop SVTE during their lifetime. Although generally considered a benign, self‐limited disease, it can cause considerable discomfort, impact mobility, and lead to further complications. Recent and accumulating evidence suggests that it is often associated with more serious forms of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE),[1] and SVTE is a strong risk factor for subsequent DVT or PE.[2, 3]
There is no clear consensus on the optimal treatment of SVTE. Although antithrombotic medications such as fondaparinux may be more effective than placebo in reducing the risk of subsequent DVT,[4] the evidence is generally of low grade, and the costs and inconveniences of anticoagulant therapy are not inconsequential.[1, 5, 6] Surveys suggest that physician opinions on the appropriate management of SVTE vary significantly, and management includes nonsteroidal anti‐inflammatory drugs (NSAIDs), topical therapies, or watchful waiting.[7] The objective of our study was to describe the initial management of SVTE in a community‐based population and examine subsequent rates of diagnosed DVT or PE in the following year.
MATERIALS AND METHODS
This was a retrospective, observational study seeking to describe the initial treatment for patients diagnosed with isolated SVTE.
Cohort Assembly
Data for this study were obtained from the Cardiovascular Research Network Venous Thromboembolism cohort study. The source population was based in Kaiser Permanente Northern California (KPNC), a large, integrated healthcare delivery system currently providing comprehensive care for >3.84 million members, and comprised of all adults aged 21 years or older with continuous enrollment in the KPNC health plan for 1 year and with a primary or secondary International Classification of Diseases, 9th RevisionClinical Modification (ICD‐9‐CM) diagnosis code of venous thrombosis (415.1x, 451.1x, 451.2, 451.81, 453.4x, 453.5x, 451.83, 451.84, 451.89, 453.72, 453.73, 453.74, 453.75, 453.76, 453.77, 453.82, 453.83, 453.84, 453.85, 453.86, 453.87, 451, 451.9, 452, 453, 453.0, 453.1, 453.2, 453.3, 453.79, 453.8, 453.89, 453.9) between January 1, 2004 and December 31, 2010. Of the 31,967 individuals meeting these criteria, 930 patients were selected by a random number generator for manual chart abstraction and review. Trained physician reviewers reviewed available emergency department, admission and discharge notes, outpatient clinic notes, and relevant radiology reports to determine whether or not the encounter represented a DVT, a SVTE, or other event.
Episodes were considered isolated SVTE if there was no evidence of a DVT or PE, and if there was medical chart documentation of either a diagnosis of SVTE, ultrasound evidence of a superficial vein clot, or a clinical description of SVTE as determined by the reviewing physician. All SVTE episodes in the study underwent a confirmatory review by second physician reviewer to confirm the diagnosis of SVTE.
Predictors and Outcomes
The primary outcome was documentation in the medical chart of a treatment recommendation for an antithrombotic agent, specifically, antiplatelet agents (aspirin, clopidogrel, ticlopidine), NSAIDs, and anticoagulants (low‐molecular‐weight heparin, fondaparinux, or warfarin). The secondary outcome was a subsequent diagnosis of VTE, which we defined as a subsequent encounter with an ICD‐9‐CM code for DVT or PE within 12 months after the initial episode, accompanied by a prescription for an anticoagulant within 7 days.
Data on patient age, sex, self‐reported race/ethnicity, and treatment setting (inpatient, emergency department, or outpatient) were obtained from health plan databases. Clinical risk factors for SVTE and the clinical presentation and treatment were obtained from physician chart review. Assessed risk factors included clinical conditions that have been associated with mildly increased SVTE risk (history of tobacco smoking, high body mass index), strongly increased risk (surgery or hospitalization within 30 days, active malignancy, hormonal therapy/pregnant or postpartum), provoking events (local trauma, central or peripheral intravenous catheter placement), and medical conditions that raise the risk for DVT (such as prior history of thrombosis or ischemic stroke).[8, 9] Data were abstracted by a single author (B.T.S.) using a standardized abstraction form. The study was approved by the institutional review boards of the collaborating institutions and informed consent was waived due to the nature of the study.
Statistical Methods
Analyses were conducted using SAS statistical software version 9.3 (SAS Institute Inc., Cary, NC), with a 2‐sided P < 0.05 considered significant. We used 2 tests and Student t tests for categorical and continuous variables, respectively, to test the bivariate association of risk factors with receipt of antithrombotic therapy after SVTE. Multivariable models were not developed due to the limited sample size.
RESULTS
Out of 930 patients with a diagnosis code for venous thrombosis and who underwent chart review, we identified 329 individuals who were considered by reviewers to have isolated SVTE events. Most SVTEs were of the lower extremity (60.8%) and diagnosed in an outpatient or emergency department setting (91.8%). Risk factors for SVTE were common, including documented varicose veins, recent peripheral venous catheterization or injection, or antecedent hospitalization (Table 1).
| Clinical Characteristic | Value, n = 329 |
|---|---|
| Age, y, mean (standard deviation) | 59.4 (15.8) |
| Female, n (%) | 199 (60.5) |
| Race, n (%) | |
| White | 236 (71.7) |
| Black | 23 (7.0) |
| Asian/Pacific Islander | 22 (6.7) |
| Unknown | 48 (14.6) |
| Location of thrombophlebitis, n (%) | |
| Lower extremity | 200 (60.8) |
| Upper extremity | 108 (32.8) |
| Other/unknown | 21 (6.3) |
| Clinical risk factors, n (%) | |
| Varicose veins | 85 (25.8) |
| History of recent peripheral intravenous catheters | 71 (21.6) |
| History of recent local trauma | 22 (6.7) |
| History of thrombosis | 12 (3.7) |
| History of stroke | 7 (2.1) |
| Sepsis/acute infection | 18 (5.5) |
| Heart failure | 7 (2.1) |
| Chronic lung disease | 24 (7.3) |
| Malignant neoplasm | 29 (8.8) |
| Hospitalization or surgery within 30 days | 48 (14.6) |
| Hormone therapy | 12 (3.6) |
| Pregnant/postpartum | 3 (0.9) |
| Current smoker | 13 (4.0) |
| Body mass index available | 184 (55.9) |
| <25 | 48 (14.6) |
| >2530 | 64 (19.5) |
| >30 | 72 (21.9) |
Initial treatment strategies for the 329 patients are presented in Table 2. Few patients with SVTE received anticoagulants for initial treatment, although patients with lower extremity SVTE were more likely to receive antithrombotic therapy compared to patients with SVTE of other locations (P < 0.001). None of the identified risk factors for thrombosis were statistically significantly associated with a greater likelihood of receiving anticoagulants (P > 0.05 for all).
| VTE Risk* | Initial Management, % (No.) | Total | |||
|---|---|---|---|---|---|
| NSAIDs | LMWH | Warfarin | No Documented Antithrombotic Therapy | ||
| |||||
| Low | 52% (128) | 1% (3) | 2% (5) | 45% (112) | 248 |
| High | 25% (20) | 4% (3) | 4% (3) | 68% (55) | 81 |
| Total | 45% (148) | 2% (6) | 2% (8) | 51% (167) | 329 |
In the 12 months after SVTE, 19 (5.8%) patients had a diagnosis encounter for VTE associated with a prescription for either warfarin or parenteral anticoagulant. Of the 200 patients in our study with lower extremity SVTE, 15 (7.5%) had a subsequent VTE diagnosis associated with anticoagulation prescription in the following year.
DISCUSSION
Clinically significant VTE within a year after SVTE diagnosis was uncommon in our study despite infrequent use of antithrombotic therapy. Although recommendations for the initial treatment of SVTE have evolved in more recent years to support the use of fondaparinux in selected patients, there are significant costs and inconveniences associated with anticoagulation therapy and debate among physicians about the preferred treatment.[7] The low rate of anticoagulant use in our study may be related to the years studied (before guidelines supported fondaparinux), as well as being largely comprised of outpatients, and also because we included types of SVTE that are unlikely to progress to DVT, such as small vein phlebitis or upper extremity SVTE.[4, 10]
Limitations of our analysis include the heterogeneous types of SVTE included in our study and our reliance on available chart documentation to ascertain SVTE diagnosis, risk factors, and treatment. Because of the observational nature of our study, SVTE in the hospital setting may have been less well documented in medical records, leading to a sample of mostly outpatients. Hence, our observed subsequent VTE rate may not be generalizable to a more inclusive population. Finally, the low rate of anticoagulant treatment and VTE diagnoses limited our ability to conduct multivariable modeling.
In conclusion, clinically significant VTE within a year after SVTE was uncommon in our study despite infrequent use of antithrombotic therapy. Although our data are observational, they suggest that not all patients may require anticoagulation for the management of SVTE, and that further investigation into defining which populations would most benefit from treatment with fondaparinux or other agents is warranted.
Disclosures
This study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01HL103820 and U19HL91179). The sponsor was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Go received research grant funding from CSL Behring. None of the other authors have financial conflicts of interest.
- , , . Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev. 2013;4:CD004982.
- , , , et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152:218–224.
- , , , et al. Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study. Blood. 2015;125:229–235.
- , , , et al. Fondaparinux for the treatment of superficial‐vein thrombosis in the legs. N Engl J Med. 2010;363:1222–1232.
- , , , . Fondaparinux for isolated superficial vein thrombosis of the legs: a cost‐effectiveness analysis. Chest. 2012;141:321–329.
- , , , et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S–e494S.
- , , , , . The disparate management of superficial venous thrombosis in primary and secondary care. Phlebology. 2015;30:172–179.
- , , , , , . The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood. 2013;122:4264–4269.
- , , , et al. Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum). Thromb Res. 2014;133:196–202.
- , , , et al. Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies. J Thromb Haemost. 2012;10:1004–1011.
Superficial thrombophlebitis (SVTE), inflammation of superficial veins associated with thrombosis, is a painful condition, and 3% to 11% of the population will develop SVTE during their lifetime. Although generally considered a benign, self‐limited disease, it can cause considerable discomfort, impact mobility, and lead to further complications. Recent and accumulating evidence suggests that it is often associated with more serious forms of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE),[1] and SVTE is a strong risk factor for subsequent DVT or PE.[2, 3]
There is no clear consensus on the optimal treatment of SVTE. Although antithrombotic medications such as fondaparinux may be more effective than placebo in reducing the risk of subsequent DVT,[4] the evidence is generally of low grade, and the costs and inconveniences of anticoagulant therapy are not inconsequential.[1, 5, 6] Surveys suggest that physician opinions on the appropriate management of SVTE vary significantly, and management includes nonsteroidal anti‐inflammatory drugs (NSAIDs), topical therapies, or watchful waiting.[7] The objective of our study was to describe the initial management of SVTE in a community‐based population and examine subsequent rates of diagnosed DVT or PE in the following year.
MATERIALS AND METHODS
This was a retrospective, observational study seeking to describe the initial treatment for patients diagnosed with isolated SVTE.
Cohort Assembly
Data for this study were obtained from the Cardiovascular Research Network Venous Thromboembolism cohort study. The source population was based in Kaiser Permanente Northern California (KPNC), a large, integrated healthcare delivery system currently providing comprehensive care for >3.84 million members, and comprised of all adults aged 21 years or older with continuous enrollment in the KPNC health plan for 1 year and with a primary or secondary International Classification of Diseases, 9th RevisionClinical Modification (ICD‐9‐CM) diagnosis code of venous thrombosis (415.1x, 451.1x, 451.2, 451.81, 453.4x, 453.5x, 451.83, 451.84, 451.89, 453.72, 453.73, 453.74, 453.75, 453.76, 453.77, 453.82, 453.83, 453.84, 453.85, 453.86, 453.87, 451, 451.9, 452, 453, 453.0, 453.1, 453.2, 453.3, 453.79, 453.8, 453.89, 453.9) between January 1, 2004 and December 31, 2010. Of the 31,967 individuals meeting these criteria, 930 patients were selected by a random number generator for manual chart abstraction and review. Trained physician reviewers reviewed available emergency department, admission and discharge notes, outpatient clinic notes, and relevant radiology reports to determine whether or not the encounter represented a DVT, a SVTE, or other event.
Episodes were considered isolated SVTE if there was no evidence of a DVT or PE, and if there was medical chart documentation of either a diagnosis of SVTE, ultrasound evidence of a superficial vein clot, or a clinical description of SVTE as determined by the reviewing physician. All SVTE episodes in the study underwent a confirmatory review by second physician reviewer to confirm the diagnosis of SVTE.
Predictors and Outcomes
The primary outcome was documentation in the medical chart of a treatment recommendation for an antithrombotic agent, specifically, antiplatelet agents (aspirin, clopidogrel, ticlopidine), NSAIDs, and anticoagulants (low‐molecular‐weight heparin, fondaparinux, or warfarin). The secondary outcome was a subsequent diagnosis of VTE, which we defined as a subsequent encounter with an ICD‐9‐CM code for DVT or PE within 12 months after the initial episode, accompanied by a prescription for an anticoagulant within 7 days.
Data on patient age, sex, self‐reported race/ethnicity, and treatment setting (inpatient, emergency department, or outpatient) were obtained from health plan databases. Clinical risk factors for SVTE and the clinical presentation and treatment were obtained from physician chart review. Assessed risk factors included clinical conditions that have been associated with mildly increased SVTE risk (history of tobacco smoking, high body mass index), strongly increased risk (surgery or hospitalization within 30 days, active malignancy, hormonal therapy/pregnant or postpartum), provoking events (local trauma, central or peripheral intravenous catheter placement), and medical conditions that raise the risk for DVT (such as prior history of thrombosis or ischemic stroke).[8, 9] Data were abstracted by a single author (B.T.S.) using a standardized abstraction form. The study was approved by the institutional review boards of the collaborating institutions and informed consent was waived due to the nature of the study.
Statistical Methods
Analyses were conducted using SAS statistical software version 9.3 (SAS Institute Inc., Cary, NC), with a 2‐sided P < 0.05 considered significant. We used 2 tests and Student t tests for categorical and continuous variables, respectively, to test the bivariate association of risk factors with receipt of antithrombotic therapy after SVTE. Multivariable models were not developed due to the limited sample size.
RESULTS
Out of 930 patients with a diagnosis code for venous thrombosis and who underwent chart review, we identified 329 individuals who were considered by reviewers to have isolated SVTE events. Most SVTEs were of the lower extremity (60.8%) and diagnosed in an outpatient or emergency department setting (91.8%). Risk factors for SVTE were common, including documented varicose veins, recent peripheral venous catheterization or injection, or antecedent hospitalization (Table 1).
| Clinical Characteristic | Value, n = 329 |
|---|---|
| Age, y, mean (standard deviation) | 59.4 (15.8) |
| Female, n (%) | 199 (60.5) |
| Race, n (%) | |
| White | 236 (71.7) |
| Black | 23 (7.0) |
| Asian/Pacific Islander | 22 (6.7) |
| Unknown | 48 (14.6) |
| Location of thrombophlebitis, n (%) | |
| Lower extremity | 200 (60.8) |
| Upper extremity | 108 (32.8) |
| Other/unknown | 21 (6.3) |
| Clinical risk factors, n (%) | |
| Varicose veins | 85 (25.8) |
| History of recent peripheral intravenous catheters | 71 (21.6) |
| History of recent local trauma | 22 (6.7) |
| History of thrombosis | 12 (3.7) |
| History of stroke | 7 (2.1) |
| Sepsis/acute infection | 18 (5.5) |
| Heart failure | 7 (2.1) |
| Chronic lung disease | 24 (7.3) |
| Malignant neoplasm | 29 (8.8) |
| Hospitalization or surgery within 30 days | 48 (14.6) |
| Hormone therapy | 12 (3.6) |
| Pregnant/postpartum | 3 (0.9) |
| Current smoker | 13 (4.0) |
| Body mass index available | 184 (55.9) |
| <25 | 48 (14.6) |
| >2530 | 64 (19.5) |
| >30 | 72 (21.9) |
Initial treatment strategies for the 329 patients are presented in Table 2. Few patients with SVTE received anticoagulants for initial treatment, although patients with lower extremity SVTE were more likely to receive antithrombotic therapy compared to patients with SVTE of other locations (P < 0.001). None of the identified risk factors for thrombosis were statistically significantly associated with a greater likelihood of receiving anticoagulants (P > 0.05 for all).
| VTE Risk* | Initial Management, % (No.) | Total | |||
|---|---|---|---|---|---|
| NSAIDs | LMWH | Warfarin | No Documented Antithrombotic Therapy | ||
| |||||
| Low | 52% (128) | 1% (3) | 2% (5) | 45% (112) | 248 |
| High | 25% (20) | 4% (3) | 4% (3) | 68% (55) | 81 |
| Total | 45% (148) | 2% (6) | 2% (8) | 51% (167) | 329 |
In the 12 months after SVTE, 19 (5.8%) patients had a diagnosis encounter for VTE associated with a prescription for either warfarin or parenteral anticoagulant. Of the 200 patients in our study with lower extremity SVTE, 15 (7.5%) had a subsequent VTE diagnosis associated with anticoagulation prescription in the following year.
DISCUSSION
Clinically significant VTE within a year after SVTE diagnosis was uncommon in our study despite infrequent use of antithrombotic therapy. Although recommendations for the initial treatment of SVTE have evolved in more recent years to support the use of fondaparinux in selected patients, there are significant costs and inconveniences associated with anticoagulation therapy and debate among physicians about the preferred treatment.[7] The low rate of anticoagulant use in our study may be related to the years studied (before guidelines supported fondaparinux), as well as being largely comprised of outpatients, and also because we included types of SVTE that are unlikely to progress to DVT, such as small vein phlebitis or upper extremity SVTE.[4, 10]
Limitations of our analysis include the heterogeneous types of SVTE included in our study and our reliance on available chart documentation to ascertain SVTE diagnosis, risk factors, and treatment. Because of the observational nature of our study, SVTE in the hospital setting may have been less well documented in medical records, leading to a sample of mostly outpatients. Hence, our observed subsequent VTE rate may not be generalizable to a more inclusive population. Finally, the low rate of anticoagulant treatment and VTE diagnoses limited our ability to conduct multivariable modeling.
In conclusion, clinically significant VTE within a year after SVTE was uncommon in our study despite infrequent use of antithrombotic therapy. Although our data are observational, they suggest that not all patients may require anticoagulation for the management of SVTE, and that further investigation into defining which populations would most benefit from treatment with fondaparinux or other agents is warranted.
Disclosures
This study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01HL103820 and U19HL91179). The sponsor was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Go received research grant funding from CSL Behring. None of the other authors have financial conflicts of interest.
Superficial thrombophlebitis (SVTE), inflammation of superficial veins associated with thrombosis, is a painful condition, and 3% to 11% of the population will develop SVTE during their lifetime. Although generally considered a benign, self‐limited disease, it can cause considerable discomfort, impact mobility, and lead to further complications. Recent and accumulating evidence suggests that it is often associated with more serious forms of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE),[1] and SVTE is a strong risk factor for subsequent DVT or PE.[2, 3]
There is no clear consensus on the optimal treatment of SVTE. Although antithrombotic medications such as fondaparinux may be more effective than placebo in reducing the risk of subsequent DVT,[4] the evidence is generally of low grade, and the costs and inconveniences of anticoagulant therapy are not inconsequential.[1, 5, 6] Surveys suggest that physician opinions on the appropriate management of SVTE vary significantly, and management includes nonsteroidal anti‐inflammatory drugs (NSAIDs), topical therapies, or watchful waiting.[7] The objective of our study was to describe the initial management of SVTE in a community‐based population and examine subsequent rates of diagnosed DVT or PE in the following year.
MATERIALS AND METHODS
This was a retrospective, observational study seeking to describe the initial treatment for patients diagnosed with isolated SVTE.
Cohort Assembly
Data for this study were obtained from the Cardiovascular Research Network Venous Thromboembolism cohort study. The source population was based in Kaiser Permanente Northern California (KPNC), a large, integrated healthcare delivery system currently providing comprehensive care for >3.84 million members, and comprised of all adults aged 21 years or older with continuous enrollment in the KPNC health plan for 1 year and with a primary or secondary International Classification of Diseases, 9th RevisionClinical Modification (ICD‐9‐CM) diagnosis code of venous thrombosis (415.1x, 451.1x, 451.2, 451.81, 453.4x, 453.5x, 451.83, 451.84, 451.89, 453.72, 453.73, 453.74, 453.75, 453.76, 453.77, 453.82, 453.83, 453.84, 453.85, 453.86, 453.87, 451, 451.9, 452, 453, 453.0, 453.1, 453.2, 453.3, 453.79, 453.8, 453.89, 453.9) between January 1, 2004 and December 31, 2010. Of the 31,967 individuals meeting these criteria, 930 patients were selected by a random number generator for manual chart abstraction and review. Trained physician reviewers reviewed available emergency department, admission and discharge notes, outpatient clinic notes, and relevant radiology reports to determine whether or not the encounter represented a DVT, a SVTE, or other event.
Episodes were considered isolated SVTE if there was no evidence of a DVT or PE, and if there was medical chart documentation of either a diagnosis of SVTE, ultrasound evidence of a superficial vein clot, or a clinical description of SVTE as determined by the reviewing physician. All SVTE episodes in the study underwent a confirmatory review by second physician reviewer to confirm the diagnosis of SVTE.
Predictors and Outcomes
The primary outcome was documentation in the medical chart of a treatment recommendation for an antithrombotic agent, specifically, antiplatelet agents (aspirin, clopidogrel, ticlopidine), NSAIDs, and anticoagulants (low‐molecular‐weight heparin, fondaparinux, or warfarin). The secondary outcome was a subsequent diagnosis of VTE, which we defined as a subsequent encounter with an ICD‐9‐CM code for DVT or PE within 12 months after the initial episode, accompanied by a prescription for an anticoagulant within 7 days.
Data on patient age, sex, self‐reported race/ethnicity, and treatment setting (inpatient, emergency department, or outpatient) were obtained from health plan databases. Clinical risk factors for SVTE and the clinical presentation and treatment were obtained from physician chart review. Assessed risk factors included clinical conditions that have been associated with mildly increased SVTE risk (history of tobacco smoking, high body mass index), strongly increased risk (surgery or hospitalization within 30 days, active malignancy, hormonal therapy/pregnant or postpartum), provoking events (local trauma, central or peripheral intravenous catheter placement), and medical conditions that raise the risk for DVT (such as prior history of thrombosis or ischemic stroke).[8, 9] Data were abstracted by a single author (B.T.S.) using a standardized abstraction form. The study was approved by the institutional review boards of the collaborating institutions and informed consent was waived due to the nature of the study.
Statistical Methods
Analyses were conducted using SAS statistical software version 9.3 (SAS Institute Inc., Cary, NC), with a 2‐sided P < 0.05 considered significant. We used 2 tests and Student t tests for categorical and continuous variables, respectively, to test the bivariate association of risk factors with receipt of antithrombotic therapy after SVTE. Multivariable models were not developed due to the limited sample size.
RESULTS
Out of 930 patients with a diagnosis code for venous thrombosis and who underwent chart review, we identified 329 individuals who were considered by reviewers to have isolated SVTE events. Most SVTEs were of the lower extremity (60.8%) and diagnosed in an outpatient or emergency department setting (91.8%). Risk factors for SVTE were common, including documented varicose veins, recent peripheral venous catheterization or injection, or antecedent hospitalization (Table 1).
| Clinical Characteristic | Value, n = 329 |
|---|---|
| Age, y, mean (standard deviation) | 59.4 (15.8) |
| Female, n (%) | 199 (60.5) |
| Race, n (%) | |
| White | 236 (71.7) |
| Black | 23 (7.0) |
| Asian/Pacific Islander | 22 (6.7) |
| Unknown | 48 (14.6) |
| Location of thrombophlebitis, n (%) | |
| Lower extremity | 200 (60.8) |
| Upper extremity | 108 (32.8) |
| Other/unknown | 21 (6.3) |
| Clinical risk factors, n (%) | |
| Varicose veins | 85 (25.8) |
| History of recent peripheral intravenous catheters | 71 (21.6) |
| History of recent local trauma | 22 (6.7) |
| History of thrombosis | 12 (3.7) |
| History of stroke | 7 (2.1) |
| Sepsis/acute infection | 18 (5.5) |
| Heart failure | 7 (2.1) |
| Chronic lung disease | 24 (7.3) |
| Malignant neoplasm | 29 (8.8) |
| Hospitalization or surgery within 30 days | 48 (14.6) |
| Hormone therapy | 12 (3.6) |
| Pregnant/postpartum | 3 (0.9) |
| Current smoker | 13 (4.0) |
| Body mass index available | 184 (55.9) |
| <25 | 48 (14.6) |
| >2530 | 64 (19.5) |
| >30 | 72 (21.9) |
Initial treatment strategies for the 329 patients are presented in Table 2. Few patients with SVTE received anticoagulants for initial treatment, although patients with lower extremity SVTE were more likely to receive antithrombotic therapy compared to patients with SVTE of other locations (P < 0.001). None of the identified risk factors for thrombosis were statistically significantly associated with a greater likelihood of receiving anticoagulants (P > 0.05 for all).
| VTE Risk* | Initial Management, % (No.) | Total | |||
|---|---|---|---|---|---|
| NSAIDs | LMWH | Warfarin | No Documented Antithrombotic Therapy | ||
| |||||
| Low | 52% (128) | 1% (3) | 2% (5) | 45% (112) | 248 |
| High | 25% (20) | 4% (3) | 4% (3) | 68% (55) | 81 |
| Total | 45% (148) | 2% (6) | 2% (8) | 51% (167) | 329 |
In the 12 months after SVTE, 19 (5.8%) patients had a diagnosis encounter for VTE associated with a prescription for either warfarin or parenteral anticoagulant. Of the 200 patients in our study with lower extremity SVTE, 15 (7.5%) had a subsequent VTE diagnosis associated with anticoagulation prescription in the following year.
DISCUSSION
Clinically significant VTE within a year after SVTE diagnosis was uncommon in our study despite infrequent use of antithrombotic therapy. Although recommendations for the initial treatment of SVTE have evolved in more recent years to support the use of fondaparinux in selected patients, there are significant costs and inconveniences associated with anticoagulation therapy and debate among physicians about the preferred treatment.[7] The low rate of anticoagulant use in our study may be related to the years studied (before guidelines supported fondaparinux), as well as being largely comprised of outpatients, and also because we included types of SVTE that are unlikely to progress to DVT, such as small vein phlebitis or upper extremity SVTE.[4, 10]
Limitations of our analysis include the heterogeneous types of SVTE included in our study and our reliance on available chart documentation to ascertain SVTE diagnosis, risk factors, and treatment. Because of the observational nature of our study, SVTE in the hospital setting may have been less well documented in medical records, leading to a sample of mostly outpatients. Hence, our observed subsequent VTE rate may not be generalizable to a more inclusive population. Finally, the low rate of anticoagulant treatment and VTE diagnoses limited our ability to conduct multivariable modeling.
In conclusion, clinically significant VTE within a year after SVTE was uncommon in our study despite infrequent use of antithrombotic therapy. Although our data are observational, they suggest that not all patients may require anticoagulation for the management of SVTE, and that further investigation into defining which populations would most benefit from treatment with fondaparinux or other agents is warranted.
Disclosures
This study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01HL103820 and U19HL91179). The sponsor was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Go received research grant funding from CSL Behring. None of the other authors have financial conflicts of interest.
- , , . Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev. 2013;4:CD004982.
- , , , et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152:218–224.
- , , , et al. Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study. Blood. 2015;125:229–235.
- , , , et al. Fondaparinux for the treatment of superficial‐vein thrombosis in the legs. N Engl J Med. 2010;363:1222–1232.
- , , , . Fondaparinux for isolated superficial vein thrombosis of the legs: a cost‐effectiveness analysis. Chest. 2012;141:321–329.
- , , , et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S–e494S.
- , , , , . The disparate management of superficial venous thrombosis in primary and secondary care. Phlebology. 2015;30:172–179.
- , , , , , . The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood. 2013;122:4264–4269.
- , , , et al. Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum). Thromb Res. 2014;133:196–202.
- , , , et al. Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies. J Thromb Haemost. 2012;10:1004–1011.
- , , . Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev. 2013;4:CD004982.
- , , , et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152:218–224.
- , , , et al. Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study. Blood. 2015;125:229–235.
- , , , et al. Fondaparinux for the treatment of superficial‐vein thrombosis in the legs. N Engl J Med. 2010;363:1222–1232.
- , , , . Fondaparinux for isolated superficial vein thrombosis of the legs: a cost‐effectiveness analysis. Chest. 2012;141:321–329.
- , , , et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S–e494S.
- , , , , . The disparate management of superficial venous thrombosis in primary and secondary care. Phlebology. 2015;30:172–179.
- , , , , , . The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood. 2013;122:4264–4269.
- , , , et al. Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum). Thromb Res. 2014;133:196–202.
- , , , et al. Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies. J Thromb Haemost. 2012;10:1004–1011.
Rapid Response Team Meta‐analysis
In 2004, the Institute for Healthcare Improvement (IHI) launched its 100,000 Lives Campaign, a national initiative with a goal of saving 100,000 lives among hospitalized patients through improvements in the safety and effectiveness of healthcare.[1] One of their recommended strategies to reduce preventable inpatient deaths was for hospitals to establish rapid response teams (RRTs).[2, 3] The goal of RRTs, also termed medical emergency teams (METs), is to identify patients at risk for rapid decline in condition and intervene prior to a catastrophic event such as cardiopulmonary arrest.[4] The basis for recommending RRT/METs was evidence of predictable warning signs occurring in patients prior to cardiopulmonary arrest that could alert physicians.[5] A pilot study by the IHI, including 8 hospitals in the United States and the United Kingdom, found reductions in code calls after implementing RRTs, with 2 hospitals also showing a reduction in mortality.[3]
In response to the IHI report, many hospitals established RRT/METs.[6] Proponents for RRT/METs argued that the potential benefit justified immediate implementation, whereas others advocated for further research.[6] Despite the rapid, widespread adoption of RRT/METs, questions remain regarding their effectiveness in reducing hospital mortality and nonintensive care unit (ICU) cardiopulmonary arrests.[6, 7] In 2010, Chan et al. reported the results of a meta‐analysis of studies published through 2008 that demonstrated a reduction in cardiac arrests, but not mortality, following the implementation of RRTs.[8] An updated systematic review, including studies published through 2012, suggested that RRTs are associated with reduced non‐ICU cardiac arrest and reduced mortality.[9]
Since the publication of the Winters et al. systematic review, several new studies have been published.[9, 10, 11, 12] We performed a systematic review and meta‐analysis including studies published through 2014 to examine the impact of RRT/METs on hospital mortality and in‐hospital cardiopulmonary arrest (IHCA).
METHODS
Search Methods
We conducted a systematic search of publications on RRTs using PubMed (19462014), Cumulative Index to Nursing and Allied Health Literature (19372014), and the Cochrane Library (issue 10 of 12, 2014). The search used no language restrictions and no limits. Medical Subject Headings with keywords in a Boolean search strategy were employed. The major themes used were cardiopulmonary arrest and rapid response teams.
Study Eligibility Criteria
Prespecified criteria for determining study eligibility included: before‐after studies, cohort studies, nonrandomized control studies, or cluster randomized controlled trials (RCTs); implementation of an RRT and/or a MET as the intervention; adults (based on individual study definition) hospitalized in a non‐ICU setting; reported 1 or both prespecified outcomes, hospital mortality, or IHCA. There were no exclusion criteria or language restrictions.
Data Extraction
We prospectively outlined a standard protocol that included the research question, inclusion/exclusion criteria, as well as our outcomes and search approaches. We used standard methodology for analysis in accordance with the guidelines in Cochrane Handbook for Systematic Reviews of Interventions.[13] The protocol can be obtained by request to the authors. All changes to our original protocol were recorded in a protocol amendments table.
The studies identified underwent title and abstract screening by 1 of 2 reviewers (G.S.C., R.S.S.). After irrelevant studies were removed, reviewers independently assessed the remaining studies for eligibility based on full‐text review. All disagreements were resolved with consensus and the help of a third reviewer (D.C.B.).
Prior to extracting data, a piloted standardized data‐collection form was created. Eligible studies were independently reviewed by each of the 2 reviewers, and the relevant data extracted. Conflicts between the reviewers regarding the data collected for a given study were resolved by a third reviewer. The essential data were total events (hospital deaths and IHCA) and total hospital admissions.
Assessment of Methodological Quality
We utilized design‐specific tools to assess the methodological quality of included studies. For nonrandomized control and cohort studies, we used the Newcastle Ottawa Scale. This allowed us to evaluate the representativeness of the intervention cohort, selection of the nonintervention cohort, ascertainment of the intervention, whether or not the outcome was present at the start of the study, comparability of cohorts, assessment of the outcome, and whether there was adequate follow‐up.[14] We assigned stars as a measure of rating for each category and tallied the number of stars to assess the methodological quality. The maximum score was 9.[14]
For before‐after studies, an assessment scale developed by the ECRI (Emergency Care Research Institute) to test the internal validity of each study was utilized.[15] The ECRI Before‐After Scale allowed us to evaluate if the study was prospective, inclusion and exclusion criteria were established a priori, consecutive patients were enrolled, the same initial/subsequent treatment was administered, outcomes were objectively measured, follow‐up was complete, cohorts were comparable, there were no conflicts of interest, and conclusions were supported by data.[15] We ascertained whether each criterion was met and converted answers to numerical scores. A yes was scored 1, a no was scored 1, and no response was scored 0.5. The sum of these scores was then added to 11, divided by 22, and multiplied by 10 to yield the total quality score. The summary score can range from 0 to 10. A total score <5 was considered unacceptable quality. A score 5 but <7.5 was considered low quality, and a total 7.5 was considered moderate quality.[15]
To assess the methodological quality of RCTs, we used the Cochrane Risk of Bias Tool.[13] The tool involves determining whether a study has a high, low, or unclear risk of bias for specific criteria.[13]
Two independent reviewers evaluated the studies using these scales, and discrepancies were resolved by discussion.
Data Analysis
Measure of Treatment Effect
We used relative risk (RR) to summarize outcome data for our prespecified outcomes: hospital mortality and IHCA.
Dealing With Missing Data
If essential data were missing, study authors were contacted. If we did not receive a response, we calculated total events (deaths and IHCAs) using total admissions and event rates per admissions. If total admissions and/or event rates were missing, studies were not included in the analysis.
Data Synthesis
We used Review Manager 5.3 to calculate pooled summary estimates.[16] Meta‐analyses for each outcome were conducted by means of a random effects model.
Assessment of Heterogeneity
To assess for heterogeneity, we calculated I2 and P values. If the I2< 0.50 or the P > 0.10, then the test for heterogeneity was passed. If heterogeneity was present, we evaluated each study in an effort to identify outliers. If an outlier was identified, the study was removed from the analysis.
Assessment of Reporting Bias
To assess publication bias, we used a funnel plot of the primary outcome. The findings were arranged by study size and effect size, and the plot was assessed for symmetry.
Subgroup Analyses
Subgroup analyses were performed for study type, RRT/MET composition, and publication year. Study type was grouped by cluster RCT and nonrandomized studies versus cohort/before‐after studies. Team composition was grouped by whether or not there was a physician on the RRT/MET. Publication year was grouped by studies published before or after 2010.
Sensitivity Analysis
We conducted sensitivity analyses to evaluate the impact of methodological quality on summary estimates. We compared overall summary estimates to summary estimates based only on before‐after studies judged to be low risk for bias. We also conducted an analysis to evaluate the inclusion of studies in which total events were calculated from rates and total admissions. We compared the overall summary estimates to summary estimates based on studies in which we were able to obtain essential data.
RESULTS
Description of Studies
Our search identified 691 studies, of which 90 were duplicates. The remaining studies were screened by title and abstract, identifying 82 potentially eligible studies, of which 30 studies were identified as eligible for inclusion in the meta‐analysis (Figure 1).
Of the 30 eligible studies, 10 were excluded from pooled estimates for hospital mortality,[7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28] and 10 were excluded from pooled estimates for IHCA due to missing data.[17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30] For the analysis, 20 studies were included for the hospital mortality analysis and 20 studies were included for the IHCA analysis. The 22 studies included in either or both analyses spanned the years 2000 to 2014. The characteristics of the included studies are summarized in Table 1.
| Author/Year | Study Design | Setting/Location | Subjects (No.) | Age, y | Description of Intervention | Description of Control | Duration of Study | Outcome(s) of Interest |
|---|---|---|---|---|---|---|---|---|
| ||||||||
| Al‐Qahtani, 2013[10] | Before‐after | Saudi Arabia (tertiary care academic center) | Before: 157,804; after: 98,391 | Before: 59.2 19.2; after: 59 19.0 | RRT Implementation | Before RRT implementation | 5 years (January 2006December 2010) | IH mortality, IHCA, ward mortality |
| Bader, 2009[37] | Before‐after | USA (community acute care hospital) | Before: 15,949; after: 16,907 | N/R | RRT Implementation | Before RRT implementation | 3 years (October 2005June 2008) | IHCA, code mortality, ICU transfer |
| Beitler, 2011[31] | Before‐after | USA (tertiary referral public teaching hospital) | Before: 77,021; after: 79,013 | Pre‐RRT: 40.9 (22.3); post‐RRT: 42.0 (22.2) | RRT implementation | Before RRT implementation | 5 years (20032008) | IHCA mortality, IHCA, out‐of‐ICU mortality, IH mortality |
| Bellomo, 2003[32] | Before‐after | Australia (tertiary referral hospital) | Before: 21,090; after: 20,921 | Before: 60.7; after: 60.2 | MET implementation | Before MET implementation | 8 months (before: May 1999August 1999; after: November 2000February 2001) | IHCA, CA‐related mortality, IH mortality |
| Bristow, 2000[33] | Nonrandomized controlled | Australia (3 public hospitals) | 50,942 | NR | Hospitals with MET | Hospitals without MET (with conventional CA teams) | 5 months (2006) | IHCA, IH mortality |
| Buist, 2002[38] | Before‐after | Australia (tertiary referral teaching hospital) | Before: 25,254; after: 28,801 | Before: 36.6 (26.0); after: 36.4 (26.0) | MET implementation | Before MET implementation | 3 years (19961999) | Incidence and outcome of unexpected IHCA |
| Chan, 2008[39] | Prospective cohort | USA (tertiary care academic hospital) | Before: 24,193; after: 24,978 | Before: 56.8 (13.6) in 2004; 56.5 (13.8) in 2005; after: 57.0 (13.9) in 2006; 57.1 (13.8) in 2007 | RRT implementation | Standard care | 3.5 years (20042007) | IHCA, IH mortality |
| Chen, 2014[11] | Nonrandomized controlled | Australia (teaching hospital) | Before: 1,088,491; after: 479,194 | NR | Teaching hospital with a mature RRS | Three teaching hospitals without RRS | 8 years (20022009) | IHCA, IHCA mortality, IH mortality |
| Goncales, 2012[34] | Before‐after | Brazil (high complexity general hospital) | Before: 40,033; after: 42,796 | Before: 73; after: 68 | Implementation of RRT called Code Yellow | Before Implementation of RRTCode Blue | 3 years (20052008) | IHCA, IHCA mortality, IH mortality |
| Hatler, 2009[19] | Before‐after | USA (tertiary care hospital) | Before: 24,739; after: 25,470 | N/R | RRT implementation | Before RRT implementation | 2 years (20052007) | IHCA |
| Hillman, 2005[20] | Cluster RCT | Australia (23 hospitals) | Control hospitals: 56.756; MET hospitals: 68,376 | Control hospitals: 56.9; MET hospitals: 55.4 | MET implementation | Care as usual | 6 months | IH Mortality, IHCA |
| Jones, 2005[7] | Before‐after | Australia (tertiary care teaching hospital) | Before: 16,246; after: 104,001 | Before: 73.4; after: 70.8 | MET implementation | Before MET implementation | 5 years (19992004) | IHCA, death following cardiac arrest |
| Jones, 2007[29] | Before‐after | Australia (teaching hospital) | Before: 25,334; after: 100,243 | N/R | MET implementation | Before MET implementation | 6 years (19982004) | Surgical and medical mortality |
| Kenward, 2004[22] | Before‐after | UK (general hospital) | Before: 53,500; after: 53,500 | Before: N/R; after: 73 | MET implementation | Before MET implementation | 1 year (20002001) | IH mortality, IHCA |
| Konrad, 2010[36] | Before‐after | Sweden (tertiary care center) | Before: 203,892; after 73,825 | Before: 53.1; after: 52.4 | MET implementation | Before MET implementation | 6 years (20002006) | IH mortality, IHCA |
| Lighthall, 2010[40] | Before‐after | USA (university affiliated VA hospital) | Before: 2,975; after: 9,077 | Before: 65.26; after: 65.56 | RRT implementation | Before RRT implementation | 3 years (20042007) | IH mortality, IHCA |
| Lim, 2011[41] | Before‐after | South Korea (Samsung Medical Center) | Before: 33,360; after: 34,699 | Before: 64; after: 59 | MET implementation | Before MET implementation | 1 year (20082009) | IH mortality, IHCA, unexpected ICU transfers |
| Moroseos, 2014[12] | Before‐after | USA (teaching hospital) | Before: 7,092; after: 9,357 | Before: 30.1; after: 30.9 | Teaching hospital after RRT implementation | Teaching hospital before RRT implementation | 10 years (before: January 2000December 2004; after: January 2007December 2011) | IH mortality, IHCA, unexpected ICU transfers |
| Salvatierra, 2014[30] | Observational cohort | USA (10 tertiary care hospitals) | Before: 235,718; after: 235,344 | N/R | RRT implementation | Before RRT implementation | 62 months (September 2001December 2009) | IH mortality |
| Santamaria, 2010[35] | Before‐after | Australia (teaching hospital) | Before (IH mortality): 22,698; before (IHCA): 8,190 after (IH mortality): 74,616; after (IHCA): 81,628 | Median: 5860 (19932007) | RRT implementation | Before RRT implementation | 14 years (19932007) | IH mortality, IHCA |
| Segon, 2014[42] | Before‐after | USA (teaching hospital) | Before: 14,013; after: 14,333 | N/R | RRT implementation | Before RRT implementation | 2 years (January 2004April 2006) | IH mortality, unexpected ICU transfer, IHCA, ICU length of stay |
| Shah, 2011[28] | Retrospective cohort | USA (teaching hospital) | Before: 16,244; after: 45,145 | N/R | RRT implementation | Before RRT implementation | 3 years (20052008) | IHCA, IH mortality, unplanned ICU transfers |
Methodological Quality
The methodological quality of the 4 cohort studies, based on the New Castle Ottawa Scale, was either 8 or 9 stars. Using the ECRI Before‐After Scale, the average quality score of the 17 included before‐after studies was 8.41 (range, 7.279.32). Included before‐after studies were of moderate quality, with the exception of 1 of lower quality. The cluster RCT had low risk of bias for random sequence generation, allocation concealment, blinding of participants/personnel, and incomplete outcome data; however, it had unclear risk of bias for blinding of outcome assessment, selective reporting, and sources of bias due to lack of reporting.[20] Overall, the 22 studies included ranged from moderate to good quality.
Effect of RRT on Hospital Mortality
Of the 20 studies that reported hospital mortality, 9 favored RRT/METs,[10, 11, 30, 31, 32, 33, 34, 35, 36] 10 found no difference with RRT/METs,[12, 20, 22, 28, 37, 38, 39, 40, 41, 42] and 1 favored RRT/METs for surgical patients while favoring usual care (no RRT/MET) for medical patients[29] (Figure 2a). The pooled analysis demonstrated that implementation of RRT/METs was associated with a significant reduction in hospital mortality (RR = 0.88, 95% confidence interval [CI]: 0.83‐0.93). There was heterogeneity among the contributing studies (I2 = 86%).
Effect of RRT on IHCA
Of the 20 studies that reported rates of IHCA, 12 favored RRT/METs [7, 10, 11, 12, 31, 32, 34, 35, 36, 37, 38, 39] and 8 found no difference with RRT/METs[16, 19, 20, 22, 28, 33, 40, 41, 42] (Figure 2b). In the pooled analysis, RRT/METs were associated with a significant reduction in IHCA (RR = 0.62, 95% CI: 0.55‐0.69). There was moderate heterogeneity among the studies (I2 = 71%).
Subgroup Analysis
Study Type
For hospital mortality, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.83, 95% CI: 0.80‐0.87) and 17 cohort/before‐after studies[10, 12, 22, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.89, 95% CI: 0.83‐0.96). The cluster RCT and non‐randomized studies had minimal heterogeneity (I2 = 7%), and the cohort/before‐after studies exhibited substantial heterogeneity (I2 = 88%). The test for subgroup differences (I2 = 54.7%) indicates that study type may have an impact on hospital mortality.
For IHCA, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.68, 95% CI: 0.52‐0.88) and 17 before‐after studies[7, 10, 12, 19, 22, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.60, 95% CI: 0.52‐0.69). The cluster RCT and nonrandomized studies had substantial heterogeneity (I2 = 79%), whereas the cohort/before‐after studies had moderate heterogeneity (I2 = 69%). The test for subgroup differences (I2 = 0%) indicates that study type had no impact on IHCA.
RRT/MET Team Composition
For hospital mortality, there were 14 studies[10, 20, 29, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.88, 95% CI: 0.82‐0.95) and 4 studies[12, 28, 30, 39] without physicians (RR = 0.85, 95% CI: 0.74‐0.99). Both groups exhibited substantial heterogeneity (I2 = 85% for both). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on hospital mortality.
Similarly, for IHCA there were 14 studies[7, 10, 20, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.61, 95% CI: 0.54‐0.69) and 4 studies[12, 19, 28, 39] without (RR = 0.60, 95% CI: 0.39‐0.92). The studies with physicians on the RRT had moderate heterogeneity (I2 = 55%), whereas studies without a physician on the RRT had substantial heterogeneity (I2 = 81%). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on IHCA.
Publication Year
Publication year had no impact on hospital mortality. Studies published 2010 or earlier had an RR of 0.88 (95% CI: 0.80‐0.97), whereas studies published after 2010 had an RR of 0.87 (95% CI: 0.83‐0.92). Both groups had substantial heterogeneity (I2 of 88% and 75%, respectively). The test for subgroup differences (I2 = 0%) indicates publication year had no impact on hospital mortality.
Publication year had no impact on IHCA. Studies published in 2010 or earlier had an RR of 0.63 (95% CI: 0.54‐0.73), whereas studies published after 2010 had an RR of 0.60 (95% CI: 0.50‐0.72). The 2010 or earlier group had moderate heterogeneity (I2 = 60%), whereas the post‐2010 group had substantial heterogeneity (I2 = 77%). The test for subgroup differences (I2 = 0%) indicates that publication year had no impact on IHCA.
Sensitivity Analysis
A sensitivity analysis was performed excluding studies with low methodological quality from the analysis. For hospital mortality there were no studies of low methodological quality. For IHCA there was no major change in the summary estimate or the heterogeneity (RR = 0.59, 95% CI: 0.53‐0.67, I2 = 66%).
A sensitivity analysis was performed excluding studies only reporting rates and/or average annual admissions from the analysis. For hospital mortality, there was no major change in the summary estimate or the heterogeneity (RR = 0.87, 95% CI: 0.82‐0.93, I2 = 87%). For IHCA there was no major change in the summary estimate, but there was a decrease in heterogeneity (RR = 0.59, 95% CI: 0.53‐0.66, I2 = 63%).
Publication Bias
Funnel plots generated for the effect of RRTs on hospital mortality and on IHCA did not indicate publication bias. Our search of
DISCUSSION
We found implementation of RRT/METs was associated with reductions in hospital mortality and IHCA. Our analysis extends the meta‐analysis of Chan et al. and is consistent with the recent systematic review by Winters et al.[8, 9] These findings provide support for the IHI recommendation that hospitals implement RRT/METs.[1]
Following the 2004 IHI recommendations, RRT/METs were widely implemented, with over 50% of hospitals having some form of RRT by 2010.[6] The adoption of RRT/METs occurred despite limited evidence on the effectiveness of RRT/METs. A meta‐analysis of studies published through 2008 demonstrated a reduction in cardiac arrests, but no reduction in mortality after implementation of RRT/METs.[8] More recently a systematic review that included studies through 2012 suggested that RRT/METs are associated with reduced IHCA and reduced mortality.[9] Our analysis addressed the conflicting results of the prior reviews and included 13 studies published after the Chan et al. meta‐analysis and several studies published after the Winters et al. systemic review.[8, 9] The studies included in our analysis were completed in hospitals across multiple countries and settings, increasing the generalizability of the results. Most studies were performed in teaching hospitals; thus, the results may not be as applicable to community hospitals.
We found publication year did not impact either outcome. However, this may reflect our use of 2 broad publication periods rather than smaller periods, as 5 of the 6 newly included studies favor RRT interventions. Additionally, if the studies missing data had been included in our analysis, they may have shown that publication year impacts the outcomes. We noted that a physician on a RRT/MET did not affect outcomes, contrary to suggestions by Winters et al.[9] This may reflect the skill of nonphysician providers and/or the collaboration of the RRT/MET with critical care teams. However, very few RRTs did not include a physician, limiting the conclusion that can be drawn regarding team composition.
Many patients exhibit observable clinical deterioration or measurable changes that could identify them prior to an event such as cardiac arrest.[5, 43] Measurable physiologic parameters, in fact, are the basis of medical early warning systems and recent automated systems.[44, 45] Similarly, delayed transfer to the ICU has been shown to be associated with increased mortality.[46] Therefore, RRTs, either by identifying patients at risk for clinical deterioration and/or facilitating transfer of patients to the ICU earlier, could result in improved clinical outcomes. We did not specifically look at ICU transfer or ICU codes in our analysis. However, in a recent single‐center before‐after study, RRT implementation increased ICU admission rates and the transfer of less severely ill patients to the ICU without improvement in severity of illness‐adjusted outcomes.[47] This finding may reflect the ICU organization of the particular institution; however, given limited ICU resources, admitting an increased number of less severely ill patients without clear clinical benefit is a potential concern. More studies are needed to better understand the mechanism of benefit as well as potential trade‐offs associated with RRT implementation. It is possible that institutional factors determine the benefit that can be achieved through RRTs.
Our study has several limitations. Although the methodological quality of the included studies was moderate to good, confounding and biases can be an issue with before‐after trials and cohort studies. Most studies were before‐after observational trials, lacking a concurrent control group making it difficult to draw causal relationships. This is particularly the case for hospital mortality, which has been independently falling since 2000.[48] Thus, changes in observed hospital mortality may simply reflect the general trend independent of the RRT intervention. However, this does not appear the case for cardiopulmonary arrest, which has been increasing in incidence since 2000.[49] There were several studies eligible for inclusion in our analysis, but could not be included because of insufficient data. It is possible that the inclusion of these studies could influence the results of our analysis. Finally, there was heterogeneity among the studies for both outcomes, particularly in‐hospital mortality. This likely reflects variations in hospital characteristics and case‐mix indices. There may also be other factors impacting teams such as how hospitals handled deteriorating patients before RRT implementation, education periods, and differing mechanisms and criteria for RRT activation.
In conclusion, RRT/METs are effective in decreasing both IHCA and hospital mortality. Our findings support the 2004 IHI recommendations for the implementation of RRTs in hospitals. Additional studies are still required to explore team composition, activation criteria, activation mechanism, and implementation strategies.
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In 2004, the Institute for Healthcare Improvement (IHI) launched its 100,000 Lives Campaign, a national initiative with a goal of saving 100,000 lives among hospitalized patients through improvements in the safety and effectiveness of healthcare.[1] One of their recommended strategies to reduce preventable inpatient deaths was for hospitals to establish rapid response teams (RRTs).[2, 3] The goal of RRTs, also termed medical emergency teams (METs), is to identify patients at risk for rapid decline in condition and intervene prior to a catastrophic event such as cardiopulmonary arrest.[4] The basis for recommending RRT/METs was evidence of predictable warning signs occurring in patients prior to cardiopulmonary arrest that could alert physicians.[5] A pilot study by the IHI, including 8 hospitals in the United States and the United Kingdom, found reductions in code calls after implementing RRTs, with 2 hospitals also showing a reduction in mortality.[3]
In response to the IHI report, many hospitals established RRT/METs.[6] Proponents for RRT/METs argued that the potential benefit justified immediate implementation, whereas others advocated for further research.[6] Despite the rapid, widespread adoption of RRT/METs, questions remain regarding their effectiveness in reducing hospital mortality and nonintensive care unit (ICU) cardiopulmonary arrests.[6, 7] In 2010, Chan et al. reported the results of a meta‐analysis of studies published through 2008 that demonstrated a reduction in cardiac arrests, but not mortality, following the implementation of RRTs.[8] An updated systematic review, including studies published through 2012, suggested that RRTs are associated with reduced non‐ICU cardiac arrest and reduced mortality.[9]
Since the publication of the Winters et al. systematic review, several new studies have been published.[9, 10, 11, 12] We performed a systematic review and meta‐analysis including studies published through 2014 to examine the impact of RRT/METs on hospital mortality and in‐hospital cardiopulmonary arrest (IHCA).
METHODS
Search Methods
We conducted a systematic search of publications on RRTs using PubMed (19462014), Cumulative Index to Nursing and Allied Health Literature (19372014), and the Cochrane Library (issue 10 of 12, 2014). The search used no language restrictions and no limits. Medical Subject Headings with keywords in a Boolean search strategy were employed. The major themes used were cardiopulmonary arrest and rapid response teams.
Study Eligibility Criteria
Prespecified criteria for determining study eligibility included: before‐after studies, cohort studies, nonrandomized control studies, or cluster randomized controlled trials (RCTs); implementation of an RRT and/or a MET as the intervention; adults (based on individual study definition) hospitalized in a non‐ICU setting; reported 1 or both prespecified outcomes, hospital mortality, or IHCA. There were no exclusion criteria or language restrictions.
Data Extraction
We prospectively outlined a standard protocol that included the research question, inclusion/exclusion criteria, as well as our outcomes and search approaches. We used standard methodology for analysis in accordance with the guidelines in Cochrane Handbook for Systematic Reviews of Interventions.[13] The protocol can be obtained by request to the authors. All changes to our original protocol were recorded in a protocol amendments table.
The studies identified underwent title and abstract screening by 1 of 2 reviewers (G.S.C., R.S.S.). After irrelevant studies were removed, reviewers independently assessed the remaining studies for eligibility based on full‐text review. All disagreements were resolved with consensus and the help of a third reviewer (D.C.B.).
Prior to extracting data, a piloted standardized data‐collection form was created. Eligible studies were independently reviewed by each of the 2 reviewers, and the relevant data extracted. Conflicts between the reviewers regarding the data collected for a given study were resolved by a third reviewer. The essential data were total events (hospital deaths and IHCA) and total hospital admissions.
Assessment of Methodological Quality
We utilized design‐specific tools to assess the methodological quality of included studies. For nonrandomized control and cohort studies, we used the Newcastle Ottawa Scale. This allowed us to evaluate the representativeness of the intervention cohort, selection of the nonintervention cohort, ascertainment of the intervention, whether or not the outcome was present at the start of the study, comparability of cohorts, assessment of the outcome, and whether there was adequate follow‐up.[14] We assigned stars as a measure of rating for each category and tallied the number of stars to assess the methodological quality. The maximum score was 9.[14]
For before‐after studies, an assessment scale developed by the ECRI (Emergency Care Research Institute) to test the internal validity of each study was utilized.[15] The ECRI Before‐After Scale allowed us to evaluate if the study was prospective, inclusion and exclusion criteria were established a priori, consecutive patients were enrolled, the same initial/subsequent treatment was administered, outcomes were objectively measured, follow‐up was complete, cohorts were comparable, there were no conflicts of interest, and conclusions were supported by data.[15] We ascertained whether each criterion was met and converted answers to numerical scores. A yes was scored 1, a no was scored 1, and no response was scored 0.5. The sum of these scores was then added to 11, divided by 22, and multiplied by 10 to yield the total quality score. The summary score can range from 0 to 10. A total score <5 was considered unacceptable quality. A score 5 but <7.5 was considered low quality, and a total 7.5 was considered moderate quality.[15]
To assess the methodological quality of RCTs, we used the Cochrane Risk of Bias Tool.[13] The tool involves determining whether a study has a high, low, or unclear risk of bias for specific criteria.[13]
Two independent reviewers evaluated the studies using these scales, and discrepancies were resolved by discussion.
Data Analysis
Measure of Treatment Effect
We used relative risk (RR) to summarize outcome data for our prespecified outcomes: hospital mortality and IHCA.
Dealing With Missing Data
If essential data were missing, study authors were contacted. If we did not receive a response, we calculated total events (deaths and IHCAs) using total admissions and event rates per admissions. If total admissions and/or event rates were missing, studies were not included in the analysis.
Data Synthesis
We used Review Manager 5.3 to calculate pooled summary estimates.[16] Meta‐analyses for each outcome were conducted by means of a random effects model.
Assessment of Heterogeneity
To assess for heterogeneity, we calculated I2 and P values. If the I2< 0.50 or the P > 0.10, then the test for heterogeneity was passed. If heterogeneity was present, we evaluated each study in an effort to identify outliers. If an outlier was identified, the study was removed from the analysis.
Assessment of Reporting Bias
To assess publication bias, we used a funnel plot of the primary outcome. The findings were arranged by study size and effect size, and the plot was assessed for symmetry.
Subgroup Analyses
Subgroup analyses were performed for study type, RRT/MET composition, and publication year. Study type was grouped by cluster RCT and nonrandomized studies versus cohort/before‐after studies. Team composition was grouped by whether or not there was a physician on the RRT/MET. Publication year was grouped by studies published before or after 2010.
Sensitivity Analysis
We conducted sensitivity analyses to evaluate the impact of methodological quality on summary estimates. We compared overall summary estimates to summary estimates based only on before‐after studies judged to be low risk for bias. We also conducted an analysis to evaluate the inclusion of studies in which total events were calculated from rates and total admissions. We compared the overall summary estimates to summary estimates based on studies in which we were able to obtain essential data.
RESULTS
Description of Studies
Our search identified 691 studies, of which 90 were duplicates. The remaining studies were screened by title and abstract, identifying 82 potentially eligible studies, of which 30 studies were identified as eligible for inclusion in the meta‐analysis (Figure 1).
Of the 30 eligible studies, 10 were excluded from pooled estimates for hospital mortality,[7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28] and 10 were excluded from pooled estimates for IHCA due to missing data.[17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30] For the analysis, 20 studies were included for the hospital mortality analysis and 20 studies were included for the IHCA analysis. The 22 studies included in either or both analyses spanned the years 2000 to 2014. The characteristics of the included studies are summarized in Table 1.
| Author/Year | Study Design | Setting/Location | Subjects (No.) | Age, y | Description of Intervention | Description of Control | Duration of Study | Outcome(s) of Interest |
|---|---|---|---|---|---|---|---|---|
| ||||||||
| Al‐Qahtani, 2013[10] | Before‐after | Saudi Arabia (tertiary care academic center) | Before: 157,804; after: 98,391 | Before: 59.2 19.2; after: 59 19.0 | RRT Implementation | Before RRT implementation | 5 years (January 2006December 2010) | IH mortality, IHCA, ward mortality |
| Bader, 2009[37] | Before‐after | USA (community acute care hospital) | Before: 15,949; after: 16,907 | N/R | RRT Implementation | Before RRT implementation | 3 years (October 2005June 2008) | IHCA, code mortality, ICU transfer |
| Beitler, 2011[31] | Before‐after | USA (tertiary referral public teaching hospital) | Before: 77,021; after: 79,013 | Pre‐RRT: 40.9 (22.3); post‐RRT: 42.0 (22.2) | RRT implementation | Before RRT implementation | 5 years (20032008) | IHCA mortality, IHCA, out‐of‐ICU mortality, IH mortality |
| Bellomo, 2003[32] | Before‐after | Australia (tertiary referral hospital) | Before: 21,090; after: 20,921 | Before: 60.7; after: 60.2 | MET implementation | Before MET implementation | 8 months (before: May 1999August 1999; after: November 2000February 2001) | IHCA, CA‐related mortality, IH mortality |
| Bristow, 2000[33] | Nonrandomized controlled | Australia (3 public hospitals) | 50,942 | NR | Hospitals with MET | Hospitals without MET (with conventional CA teams) | 5 months (2006) | IHCA, IH mortality |
| Buist, 2002[38] | Before‐after | Australia (tertiary referral teaching hospital) | Before: 25,254; after: 28,801 | Before: 36.6 (26.0); after: 36.4 (26.0) | MET implementation | Before MET implementation | 3 years (19961999) | Incidence and outcome of unexpected IHCA |
| Chan, 2008[39] | Prospective cohort | USA (tertiary care academic hospital) | Before: 24,193; after: 24,978 | Before: 56.8 (13.6) in 2004; 56.5 (13.8) in 2005; after: 57.0 (13.9) in 2006; 57.1 (13.8) in 2007 | RRT implementation | Standard care | 3.5 years (20042007) | IHCA, IH mortality |
| Chen, 2014[11] | Nonrandomized controlled | Australia (teaching hospital) | Before: 1,088,491; after: 479,194 | NR | Teaching hospital with a mature RRS | Three teaching hospitals without RRS | 8 years (20022009) | IHCA, IHCA mortality, IH mortality |
| Goncales, 2012[34] | Before‐after | Brazil (high complexity general hospital) | Before: 40,033; after: 42,796 | Before: 73; after: 68 | Implementation of RRT called Code Yellow | Before Implementation of RRTCode Blue | 3 years (20052008) | IHCA, IHCA mortality, IH mortality |
| Hatler, 2009[19] | Before‐after | USA (tertiary care hospital) | Before: 24,739; after: 25,470 | N/R | RRT implementation | Before RRT implementation | 2 years (20052007) | IHCA |
| Hillman, 2005[20] | Cluster RCT | Australia (23 hospitals) | Control hospitals: 56.756; MET hospitals: 68,376 | Control hospitals: 56.9; MET hospitals: 55.4 | MET implementation | Care as usual | 6 months | IH Mortality, IHCA |
| Jones, 2005[7] | Before‐after | Australia (tertiary care teaching hospital) | Before: 16,246; after: 104,001 | Before: 73.4; after: 70.8 | MET implementation | Before MET implementation | 5 years (19992004) | IHCA, death following cardiac arrest |
| Jones, 2007[29] | Before‐after | Australia (teaching hospital) | Before: 25,334; after: 100,243 | N/R | MET implementation | Before MET implementation | 6 years (19982004) | Surgical and medical mortality |
| Kenward, 2004[22] | Before‐after | UK (general hospital) | Before: 53,500; after: 53,500 | Before: N/R; after: 73 | MET implementation | Before MET implementation | 1 year (20002001) | IH mortality, IHCA |
| Konrad, 2010[36] | Before‐after | Sweden (tertiary care center) | Before: 203,892; after 73,825 | Before: 53.1; after: 52.4 | MET implementation | Before MET implementation | 6 years (20002006) | IH mortality, IHCA |
| Lighthall, 2010[40] | Before‐after | USA (university affiliated VA hospital) | Before: 2,975; after: 9,077 | Before: 65.26; after: 65.56 | RRT implementation | Before RRT implementation | 3 years (20042007) | IH mortality, IHCA |
| Lim, 2011[41] | Before‐after | South Korea (Samsung Medical Center) | Before: 33,360; after: 34,699 | Before: 64; after: 59 | MET implementation | Before MET implementation | 1 year (20082009) | IH mortality, IHCA, unexpected ICU transfers |
| Moroseos, 2014[12] | Before‐after | USA (teaching hospital) | Before: 7,092; after: 9,357 | Before: 30.1; after: 30.9 | Teaching hospital after RRT implementation | Teaching hospital before RRT implementation | 10 years (before: January 2000December 2004; after: January 2007December 2011) | IH mortality, IHCA, unexpected ICU transfers |
| Salvatierra, 2014[30] | Observational cohort | USA (10 tertiary care hospitals) | Before: 235,718; after: 235,344 | N/R | RRT implementation | Before RRT implementation | 62 months (September 2001December 2009) | IH mortality |
| Santamaria, 2010[35] | Before‐after | Australia (teaching hospital) | Before (IH mortality): 22,698; before (IHCA): 8,190 after (IH mortality): 74,616; after (IHCA): 81,628 | Median: 5860 (19932007) | RRT implementation | Before RRT implementation | 14 years (19932007) | IH mortality, IHCA |
| Segon, 2014[42] | Before‐after | USA (teaching hospital) | Before: 14,013; after: 14,333 | N/R | RRT implementation | Before RRT implementation | 2 years (January 2004April 2006) | IH mortality, unexpected ICU transfer, IHCA, ICU length of stay |
| Shah, 2011[28] | Retrospective cohort | USA (teaching hospital) | Before: 16,244; after: 45,145 | N/R | RRT implementation | Before RRT implementation | 3 years (20052008) | IHCA, IH mortality, unplanned ICU transfers |
Methodological Quality
The methodological quality of the 4 cohort studies, based on the New Castle Ottawa Scale, was either 8 or 9 stars. Using the ECRI Before‐After Scale, the average quality score of the 17 included before‐after studies was 8.41 (range, 7.279.32). Included before‐after studies were of moderate quality, with the exception of 1 of lower quality. The cluster RCT had low risk of bias for random sequence generation, allocation concealment, blinding of participants/personnel, and incomplete outcome data; however, it had unclear risk of bias for blinding of outcome assessment, selective reporting, and sources of bias due to lack of reporting.[20] Overall, the 22 studies included ranged from moderate to good quality.
Effect of RRT on Hospital Mortality
Of the 20 studies that reported hospital mortality, 9 favored RRT/METs,[10, 11, 30, 31, 32, 33, 34, 35, 36] 10 found no difference with RRT/METs,[12, 20, 22, 28, 37, 38, 39, 40, 41, 42] and 1 favored RRT/METs for surgical patients while favoring usual care (no RRT/MET) for medical patients[29] (Figure 2a). The pooled analysis demonstrated that implementation of RRT/METs was associated with a significant reduction in hospital mortality (RR = 0.88, 95% confidence interval [CI]: 0.83‐0.93). There was heterogeneity among the contributing studies (I2 = 86%).
Effect of RRT on IHCA
Of the 20 studies that reported rates of IHCA, 12 favored RRT/METs [7, 10, 11, 12, 31, 32, 34, 35, 36, 37, 38, 39] and 8 found no difference with RRT/METs[16, 19, 20, 22, 28, 33, 40, 41, 42] (Figure 2b). In the pooled analysis, RRT/METs were associated with a significant reduction in IHCA (RR = 0.62, 95% CI: 0.55‐0.69). There was moderate heterogeneity among the studies (I2 = 71%).
Subgroup Analysis
Study Type
For hospital mortality, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.83, 95% CI: 0.80‐0.87) and 17 cohort/before‐after studies[10, 12, 22, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.89, 95% CI: 0.83‐0.96). The cluster RCT and non‐randomized studies had minimal heterogeneity (I2 = 7%), and the cohort/before‐after studies exhibited substantial heterogeneity (I2 = 88%). The test for subgroup differences (I2 = 54.7%) indicates that study type may have an impact on hospital mortality.
For IHCA, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.68, 95% CI: 0.52‐0.88) and 17 before‐after studies[7, 10, 12, 19, 22, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.60, 95% CI: 0.52‐0.69). The cluster RCT and nonrandomized studies had substantial heterogeneity (I2 = 79%), whereas the cohort/before‐after studies had moderate heterogeneity (I2 = 69%). The test for subgroup differences (I2 = 0%) indicates that study type had no impact on IHCA.
RRT/MET Team Composition
For hospital mortality, there were 14 studies[10, 20, 29, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.88, 95% CI: 0.82‐0.95) and 4 studies[12, 28, 30, 39] without physicians (RR = 0.85, 95% CI: 0.74‐0.99). Both groups exhibited substantial heterogeneity (I2 = 85% for both). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on hospital mortality.
Similarly, for IHCA there were 14 studies[7, 10, 20, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.61, 95% CI: 0.54‐0.69) and 4 studies[12, 19, 28, 39] without (RR = 0.60, 95% CI: 0.39‐0.92). The studies with physicians on the RRT had moderate heterogeneity (I2 = 55%), whereas studies without a physician on the RRT had substantial heterogeneity (I2 = 81%). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on IHCA.
Publication Year
Publication year had no impact on hospital mortality. Studies published 2010 or earlier had an RR of 0.88 (95% CI: 0.80‐0.97), whereas studies published after 2010 had an RR of 0.87 (95% CI: 0.83‐0.92). Both groups had substantial heterogeneity (I2 of 88% and 75%, respectively). The test for subgroup differences (I2 = 0%) indicates publication year had no impact on hospital mortality.
Publication year had no impact on IHCA. Studies published in 2010 or earlier had an RR of 0.63 (95% CI: 0.54‐0.73), whereas studies published after 2010 had an RR of 0.60 (95% CI: 0.50‐0.72). The 2010 or earlier group had moderate heterogeneity (I2 = 60%), whereas the post‐2010 group had substantial heterogeneity (I2 = 77%). The test for subgroup differences (I2 = 0%) indicates that publication year had no impact on IHCA.
Sensitivity Analysis
A sensitivity analysis was performed excluding studies with low methodological quality from the analysis. For hospital mortality there were no studies of low methodological quality. For IHCA there was no major change in the summary estimate or the heterogeneity (RR = 0.59, 95% CI: 0.53‐0.67, I2 = 66%).
A sensitivity analysis was performed excluding studies only reporting rates and/or average annual admissions from the analysis. For hospital mortality, there was no major change in the summary estimate or the heterogeneity (RR = 0.87, 95% CI: 0.82‐0.93, I2 = 87%). For IHCA there was no major change in the summary estimate, but there was a decrease in heterogeneity (RR = 0.59, 95% CI: 0.53‐0.66, I2 = 63%).
Publication Bias
Funnel plots generated for the effect of RRTs on hospital mortality and on IHCA did not indicate publication bias. Our search of
DISCUSSION
We found implementation of RRT/METs was associated with reductions in hospital mortality and IHCA. Our analysis extends the meta‐analysis of Chan et al. and is consistent with the recent systematic review by Winters et al.[8, 9] These findings provide support for the IHI recommendation that hospitals implement RRT/METs.[1]
Following the 2004 IHI recommendations, RRT/METs were widely implemented, with over 50% of hospitals having some form of RRT by 2010.[6] The adoption of RRT/METs occurred despite limited evidence on the effectiveness of RRT/METs. A meta‐analysis of studies published through 2008 demonstrated a reduction in cardiac arrests, but no reduction in mortality after implementation of RRT/METs.[8] More recently a systematic review that included studies through 2012 suggested that RRT/METs are associated with reduced IHCA and reduced mortality.[9] Our analysis addressed the conflicting results of the prior reviews and included 13 studies published after the Chan et al. meta‐analysis and several studies published after the Winters et al. systemic review.[8, 9] The studies included in our analysis were completed in hospitals across multiple countries and settings, increasing the generalizability of the results. Most studies were performed in teaching hospitals; thus, the results may not be as applicable to community hospitals.
We found publication year did not impact either outcome. However, this may reflect our use of 2 broad publication periods rather than smaller periods, as 5 of the 6 newly included studies favor RRT interventions. Additionally, if the studies missing data had been included in our analysis, they may have shown that publication year impacts the outcomes. We noted that a physician on a RRT/MET did not affect outcomes, contrary to suggestions by Winters et al.[9] This may reflect the skill of nonphysician providers and/or the collaboration of the RRT/MET with critical care teams. However, very few RRTs did not include a physician, limiting the conclusion that can be drawn regarding team composition.
Many patients exhibit observable clinical deterioration or measurable changes that could identify them prior to an event such as cardiac arrest.[5, 43] Measurable physiologic parameters, in fact, are the basis of medical early warning systems and recent automated systems.[44, 45] Similarly, delayed transfer to the ICU has been shown to be associated with increased mortality.[46] Therefore, RRTs, either by identifying patients at risk for clinical deterioration and/or facilitating transfer of patients to the ICU earlier, could result in improved clinical outcomes. We did not specifically look at ICU transfer or ICU codes in our analysis. However, in a recent single‐center before‐after study, RRT implementation increased ICU admission rates and the transfer of less severely ill patients to the ICU without improvement in severity of illness‐adjusted outcomes.[47] This finding may reflect the ICU organization of the particular institution; however, given limited ICU resources, admitting an increased number of less severely ill patients without clear clinical benefit is a potential concern. More studies are needed to better understand the mechanism of benefit as well as potential trade‐offs associated with RRT implementation. It is possible that institutional factors determine the benefit that can be achieved through RRTs.
Our study has several limitations. Although the methodological quality of the included studies was moderate to good, confounding and biases can be an issue with before‐after trials and cohort studies. Most studies were before‐after observational trials, lacking a concurrent control group making it difficult to draw causal relationships. This is particularly the case for hospital mortality, which has been independently falling since 2000.[48] Thus, changes in observed hospital mortality may simply reflect the general trend independent of the RRT intervention. However, this does not appear the case for cardiopulmonary arrest, which has been increasing in incidence since 2000.[49] There were several studies eligible for inclusion in our analysis, but could not be included because of insufficient data. It is possible that the inclusion of these studies could influence the results of our analysis. Finally, there was heterogeneity among the studies for both outcomes, particularly in‐hospital mortality. This likely reflects variations in hospital characteristics and case‐mix indices. There may also be other factors impacting teams such as how hospitals handled deteriorating patients before RRT implementation, education periods, and differing mechanisms and criteria for RRT activation.
In conclusion, RRT/METs are effective in decreasing both IHCA and hospital mortality. Our findings support the 2004 IHI recommendations for the implementation of RRTs in hospitals. Additional studies are still required to explore team composition, activation criteria, activation mechanism, and implementation strategies.
In 2004, the Institute for Healthcare Improvement (IHI) launched its 100,000 Lives Campaign, a national initiative with a goal of saving 100,000 lives among hospitalized patients through improvements in the safety and effectiveness of healthcare.[1] One of their recommended strategies to reduce preventable inpatient deaths was for hospitals to establish rapid response teams (RRTs).[2, 3] The goal of RRTs, also termed medical emergency teams (METs), is to identify patients at risk for rapid decline in condition and intervene prior to a catastrophic event such as cardiopulmonary arrest.[4] The basis for recommending RRT/METs was evidence of predictable warning signs occurring in patients prior to cardiopulmonary arrest that could alert physicians.[5] A pilot study by the IHI, including 8 hospitals in the United States and the United Kingdom, found reductions in code calls after implementing RRTs, with 2 hospitals also showing a reduction in mortality.[3]
In response to the IHI report, many hospitals established RRT/METs.[6] Proponents for RRT/METs argued that the potential benefit justified immediate implementation, whereas others advocated for further research.[6] Despite the rapid, widespread adoption of RRT/METs, questions remain regarding their effectiveness in reducing hospital mortality and nonintensive care unit (ICU) cardiopulmonary arrests.[6, 7] In 2010, Chan et al. reported the results of a meta‐analysis of studies published through 2008 that demonstrated a reduction in cardiac arrests, but not mortality, following the implementation of RRTs.[8] An updated systematic review, including studies published through 2012, suggested that RRTs are associated with reduced non‐ICU cardiac arrest and reduced mortality.[9]
Since the publication of the Winters et al. systematic review, several new studies have been published.[9, 10, 11, 12] We performed a systematic review and meta‐analysis including studies published through 2014 to examine the impact of RRT/METs on hospital mortality and in‐hospital cardiopulmonary arrest (IHCA).
METHODS
Search Methods
We conducted a systematic search of publications on RRTs using PubMed (19462014), Cumulative Index to Nursing and Allied Health Literature (19372014), and the Cochrane Library (issue 10 of 12, 2014). The search used no language restrictions and no limits. Medical Subject Headings with keywords in a Boolean search strategy were employed. The major themes used were cardiopulmonary arrest and rapid response teams.
Study Eligibility Criteria
Prespecified criteria for determining study eligibility included: before‐after studies, cohort studies, nonrandomized control studies, or cluster randomized controlled trials (RCTs); implementation of an RRT and/or a MET as the intervention; adults (based on individual study definition) hospitalized in a non‐ICU setting; reported 1 or both prespecified outcomes, hospital mortality, or IHCA. There were no exclusion criteria or language restrictions.
Data Extraction
We prospectively outlined a standard protocol that included the research question, inclusion/exclusion criteria, as well as our outcomes and search approaches. We used standard methodology for analysis in accordance with the guidelines in Cochrane Handbook for Systematic Reviews of Interventions.[13] The protocol can be obtained by request to the authors. All changes to our original protocol were recorded in a protocol amendments table.
The studies identified underwent title and abstract screening by 1 of 2 reviewers (G.S.C., R.S.S.). After irrelevant studies were removed, reviewers independently assessed the remaining studies for eligibility based on full‐text review. All disagreements were resolved with consensus and the help of a third reviewer (D.C.B.).
Prior to extracting data, a piloted standardized data‐collection form was created. Eligible studies were independently reviewed by each of the 2 reviewers, and the relevant data extracted. Conflicts between the reviewers regarding the data collected for a given study were resolved by a third reviewer. The essential data were total events (hospital deaths and IHCA) and total hospital admissions.
Assessment of Methodological Quality
We utilized design‐specific tools to assess the methodological quality of included studies. For nonrandomized control and cohort studies, we used the Newcastle Ottawa Scale. This allowed us to evaluate the representativeness of the intervention cohort, selection of the nonintervention cohort, ascertainment of the intervention, whether or not the outcome was present at the start of the study, comparability of cohorts, assessment of the outcome, and whether there was adequate follow‐up.[14] We assigned stars as a measure of rating for each category and tallied the number of stars to assess the methodological quality. The maximum score was 9.[14]
For before‐after studies, an assessment scale developed by the ECRI (Emergency Care Research Institute) to test the internal validity of each study was utilized.[15] The ECRI Before‐After Scale allowed us to evaluate if the study was prospective, inclusion and exclusion criteria were established a priori, consecutive patients were enrolled, the same initial/subsequent treatment was administered, outcomes were objectively measured, follow‐up was complete, cohorts were comparable, there were no conflicts of interest, and conclusions were supported by data.[15] We ascertained whether each criterion was met and converted answers to numerical scores. A yes was scored 1, a no was scored 1, and no response was scored 0.5. The sum of these scores was then added to 11, divided by 22, and multiplied by 10 to yield the total quality score. The summary score can range from 0 to 10. A total score <5 was considered unacceptable quality. A score 5 but <7.5 was considered low quality, and a total 7.5 was considered moderate quality.[15]
To assess the methodological quality of RCTs, we used the Cochrane Risk of Bias Tool.[13] The tool involves determining whether a study has a high, low, or unclear risk of bias for specific criteria.[13]
Two independent reviewers evaluated the studies using these scales, and discrepancies were resolved by discussion.
Data Analysis
Measure of Treatment Effect
We used relative risk (RR) to summarize outcome data for our prespecified outcomes: hospital mortality and IHCA.
Dealing With Missing Data
If essential data were missing, study authors were contacted. If we did not receive a response, we calculated total events (deaths and IHCAs) using total admissions and event rates per admissions. If total admissions and/or event rates were missing, studies were not included in the analysis.
Data Synthesis
We used Review Manager 5.3 to calculate pooled summary estimates.[16] Meta‐analyses for each outcome were conducted by means of a random effects model.
Assessment of Heterogeneity
To assess for heterogeneity, we calculated I2 and P values. If the I2< 0.50 or the P > 0.10, then the test for heterogeneity was passed. If heterogeneity was present, we evaluated each study in an effort to identify outliers. If an outlier was identified, the study was removed from the analysis.
Assessment of Reporting Bias
To assess publication bias, we used a funnel plot of the primary outcome. The findings were arranged by study size and effect size, and the plot was assessed for symmetry.
Subgroup Analyses
Subgroup analyses were performed for study type, RRT/MET composition, and publication year. Study type was grouped by cluster RCT and nonrandomized studies versus cohort/before‐after studies. Team composition was grouped by whether or not there was a physician on the RRT/MET. Publication year was grouped by studies published before or after 2010.
Sensitivity Analysis
We conducted sensitivity analyses to evaluate the impact of methodological quality on summary estimates. We compared overall summary estimates to summary estimates based only on before‐after studies judged to be low risk for bias. We also conducted an analysis to evaluate the inclusion of studies in which total events were calculated from rates and total admissions. We compared the overall summary estimates to summary estimates based on studies in which we were able to obtain essential data.
RESULTS
Description of Studies
Our search identified 691 studies, of which 90 were duplicates. The remaining studies were screened by title and abstract, identifying 82 potentially eligible studies, of which 30 studies were identified as eligible for inclusion in the meta‐analysis (Figure 1).
Of the 30 eligible studies, 10 were excluded from pooled estimates for hospital mortality,[7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28] and 10 were excluded from pooled estimates for IHCA due to missing data.[17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30] For the analysis, 20 studies were included for the hospital mortality analysis and 20 studies were included for the IHCA analysis. The 22 studies included in either or both analyses spanned the years 2000 to 2014. The characteristics of the included studies are summarized in Table 1.
| Author/Year | Study Design | Setting/Location | Subjects (No.) | Age, y | Description of Intervention | Description of Control | Duration of Study | Outcome(s) of Interest |
|---|---|---|---|---|---|---|---|---|
| ||||||||
| Al‐Qahtani, 2013[10] | Before‐after | Saudi Arabia (tertiary care academic center) | Before: 157,804; after: 98,391 | Before: 59.2 19.2; after: 59 19.0 | RRT Implementation | Before RRT implementation | 5 years (January 2006December 2010) | IH mortality, IHCA, ward mortality |
| Bader, 2009[37] | Before‐after | USA (community acute care hospital) | Before: 15,949; after: 16,907 | N/R | RRT Implementation | Before RRT implementation | 3 years (October 2005June 2008) | IHCA, code mortality, ICU transfer |
| Beitler, 2011[31] | Before‐after | USA (tertiary referral public teaching hospital) | Before: 77,021; after: 79,013 | Pre‐RRT: 40.9 (22.3); post‐RRT: 42.0 (22.2) | RRT implementation | Before RRT implementation | 5 years (20032008) | IHCA mortality, IHCA, out‐of‐ICU mortality, IH mortality |
| Bellomo, 2003[32] | Before‐after | Australia (tertiary referral hospital) | Before: 21,090; after: 20,921 | Before: 60.7; after: 60.2 | MET implementation | Before MET implementation | 8 months (before: May 1999August 1999; after: November 2000February 2001) | IHCA, CA‐related mortality, IH mortality |
| Bristow, 2000[33] | Nonrandomized controlled | Australia (3 public hospitals) | 50,942 | NR | Hospitals with MET | Hospitals without MET (with conventional CA teams) | 5 months (2006) | IHCA, IH mortality |
| Buist, 2002[38] | Before‐after | Australia (tertiary referral teaching hospital) | Before: 25,254; after: 28,801 | Before: 36.6 (26.0); after: 36.4 (26.0) | MET implementation | Before MET implementation | 3 years (19961999) | Incidence and outcome of unexpected IHCA |
| Chan, 2008[39] | Prospective cohort | USA (tertiary care academic hospital) | Before: 24,193; after: 24,978 | Before: 56.8 (13.6) in 2004; 56.5 (13.8) in 2005; after: 57.0 (13.9) in 2006; 57.1 (13.8) in 2007 | RRT implementation | Standard care | 3.5 years (20042007) | IHCA, IH mortality |
| Chen, 2014[11] | Nonrandomized controlled | Australia (teaching hospital) | Before: 1,088,491; after: 479,194 | NR | Teaching hospital with a mature RRS | Three teaching hospitals without RRS | 8 years (20022009) | IHCA, IHCA mortality, IH mortality |
| Goncales, 2012[34] | Before‐after | Brazil (high complexity general hospital) | Before: 40,033; after: 42,796 | Before: 73; after: 68 | Implementation of RRT called Code Yellow | Before Implementation of RRTCode Blue | 3 years (20052008) | IHCA, IHCA mortality, IH mortality |
| Hatler, 2009[19] | Before‐after | USA (tertiary care hospital) | Before: 24,739; after: 25,470 | N/R | RRT implementation | Before RRT implementation | 2 years (20052007) | IHCA |
| Hillman, 2005[20] | Cluster RCT | Australia (23 hospitals) | Control hospitals: 56.756; MET hospitals: 68,376 | Control hospitals: 56.9; MET hospitals: 55.4 | MET implementation | Care as usual | 6 months | IH Mortality, IHCA |
| Jones, 2005[7] | Before‐after | Australia (tertiary care teaching hospital) | Before: 16,246; after: 104,001 | Before: 73.4; after: 70.8 | MET implementation | Before MET implementation | 5 years (19992004) | IHCA, death following cardiac arrest |
| Jones, 2007[29] | Before‐after | Australia (teaching hospital) | Before: 25,334; after: 100,243 | N/R | MET implementation | Before MET implementation | 6 years (19982004) | Surgical and medical mortality |
| Kenward, 2004[22] | Before‐after | UK (general hospital) | Before: 53,500; after: 53,500 | Before: N/R; after: 73 | MET implementation | Before MET implementation | 1 year (20002001) | IH mortality, IHCA |
| Konrad, 2010[36] | Before‐after | Sweden (tertiary care center) | Before: 203,892; after 73,825 | Before: 53.1; after: 52.4 | MET implementation | Before MET implementation | 6 years (20002006) | IH mortality, IHCA |
| Lighthall, 2010[40] | Before‐after | USA (university affiliated VA hospital) | Before: 2,975; after: 9,077 | Before: 65.26; after: 65.56 | RRT implementation | Before RRT implementation | 3 years (20042007) | IH mortality, IHCA |
| Lim, 2011[41] | Before‐after | South Korea (Samsung Medical Center) | Before: 33,360; after: 34,699 | Before: 64; after: 59 | MET implementation | Before MET implementation | 1 year (20082009) | IH mortality, IHCA, unexpected ICU transfers |
| Moroseos, 2014[12] | Before‐after | USA (teaching hospital) | Before: 7,092; after: 9,357 | Before: 30.1; after: 30.9 | Teaching hospital after RRT implementation | Teaching hospital before RRT implementation | 10 years (before: January 2000December 2004; after: January 2007December 2011) | IH mortality, IHCA, unexpected ICU transfers |
| Salvatierra, 2014[30] | Observational cohort | USA (10 tertiary care hospitals) | Before: 235,718; after: 235,344 | N/R | RRT implementation | Before RRT implementation | 62 months (September 2001December 2009) | IH mortality |
| Santamaria, 2010[35] | Before‐after | Australia (teaching hospital) | Before (IH mortality): 22,698; before (IHCA): 8,190 after (IH mortality): 74,616; after (IHCA): 81,628 | Median: 5860 (19932007) | RRT implementation | Before RRT implementation | 14 years (19932007) | IH mortality, IHCA |
| Segon, 2014[42] | Before‐after | USA (teaching hospital) | Before: 14,013; after: 14,333 | N/R | RRT implementation | Before RRT implementation | 2 years (January 2004April 2006) | IH mortality, unexpected ICU transfer, IHCA, ICU length of stay |
| Shah, 2011[28] | Retrospective cohort | USA (teaching hospital) | Before: 16,244; after: 45,145 | N/R | RRT implementation | Before RRT implementation | 3 years (20052008) | IHCA, IH mortality, unplanned ICU transfers |
Methodological Quality
The methodological quality of the 4 cohort studies, based on the New Castle Ottawa Scale, was either 8 or 9 stars. Using the ECRI Before‐After Scale, the average quality score of the 17 included before‐after studies was 8.41 (range, 7.279.32). Included before‐after studies were of moderate quality, with the exception of 1 of lower quality. The cluster RCT had low risk of bias for random sequence generation, allocation concealment, blinding of participants/personnel, and incomplete outcome data; however, it had unclear risk of bias for blinding of outcome assessment, selective reporting, and sources of bias due to lack of reporting.[20] Overall, the 22 studies included ranged from moderate to good quality.
Effect of RRT on Hospital Mortality
Of the 20 studies that reported hospital mortality, 9 favored RRT/METs,[10, 11, 30, 31, 32, 33, 34, 35, 36] 10 found no difference with RRT/METs,[12, 20, 22, 28, 37, 38, 39, 40, 41, 42] and 1 favored RRT/METs for surgical patients while favoring usual care (no RRT/MET) for medical patients[29] (Figure 2a). The pooled analysis demonstrated that implementation of RRT/METs was associated with a significant reduction in hospital mortality (RR = 0.88, 95% confidence interval [CI]: 0.83‐0.93). There was heterogeneity among the contributing studies (I2 = 86%).
Effect of RRT on IHCA
Of the 20 studies that reported rates of IHCA, 12 favored RRT/METs [7, 10, 11, 12, 31, 32, 34, 35, 36, 37, 38, 39] and 8 found no difference with RRT/METs[16, 19, 20, 22, 28, 33, 40, 41, 42] (Figure 2b). In the pooled analysis, RRT/METs were associated with a significant reduction in IHCA (RR = 0.62, 95% CI: 0.55‐0.69). There was moderate heterogeneity among the studies (I2 = 71%).
Subgroup Analysis
Study Type
For hospital mortality, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.83, 95% CI: 0.80‐0.87) and 17 cohort/before‐after studies[10, 12, 22, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.89, 95% CI: 0.83‐0.96). The cluster RCT and non‐randomized studies had minimal heterogeneity (I2 = 7%), and the cohort/before‐after studies exhibited substantial heterogeneity (I2 = 88%). The test for subgroup differences (I2 = 54.7%) indicates that study type may have an impact on hospital mortality.
For IHCA, there was 1 cluster RCT and 2 nonrandomized studies[11, 20, 33] (RR = 0.68, 95% CI: 0.52‐0.88) and 17 before‐after studies[7, 10, 12, 19, 22, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42] (RR = 0.60, 95% CI: 0.52‐0.69). The cluster RCT and nonrandomized studies had substantial heterogeneity (I2 = 79%), whereas the cohort/before‐after studies had moderate heterogeneity (I2 = 69%). The test for subgroup differences (I2 = 0%) indicates that study type had no impact on IHCA.
RRT/MET Team Composition
For hospital mortality, there were 14 studies[10, 20, 29, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.88, 95% CI: 0.82‐0.95) and 4 studies[12, 28, 30, 39] without physicians (RR = 0.85, 95% CI: 0.74‐0.99). Both groups exhibited substantial heterogeneity (I2 = 85% for both). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on hospital mortality.
Similarly, for IHCA there were 14 studies[7, 10, 20, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42] of RRTs with physicians (RR = 0.61, 95% CI: 0.54‐0.69) and 4 studies[12, 19, 28, 39] without (RR = 0.60, 95% CI: 0.39‐0.92). The studies with physicians on the RRT had moderate heterogeneity (I2 = 55%), whereas studies without a physician on the RRT had substantial heterogeneity (I2 = 81%). The test for subgroup differences (I2 = 0%) indicates that team composition had no impact on IHCA.
Publication Year
Publication year had no impact on hospital mortality. Studies published 2010 or earlier had an RR of 0.88 (95% CI: 0.80‐0.97), whereas studies published after 2010 had an RR of 0.87 (95% CI: 0.83‐0.92). Both groups had substantial heterogeneity (I2 of 88% and 75%, respectively). The test for subgroup differences (I2 = 0%) indicates publication year had no impact on hospital mortality.
Publication year had no impact on IHCA. Studies published in 2010 or earlier had an RR of 0.63 (95% CI: 0.54‐0.73), whereas studies published after 2010 had an RR of 0.60 (95% CI: 0.50‐0.72). The 2010 or earlier group had moderate heterogeneity (I2 = 60%), whereas the post‐2010 group had substantial heterogeneity (I2 = 77%). The test for subgroup differences (I2 = 0%) indicates that publication year had no impact on IHCA.
Sensitivity Analysis
A sensitivity analysis was performed excluding studies with low methodological quality from the analysis. For hospital mortality there were no studies of low methodological quality. For IHCA there was no major change in the summary estimate or the heterogeneity (RR = 0.59, 95% CI: 0.53‐0.67, I2 = 66%).
A sensitivity analysis was performed excluding studies only reporting rates and/or average annual admissions from the analysis. For hospital mortality, there was no major change in the summary estimate or the heterogeneity (RR = 0.87, 95% CI: 0.82‐0.93, I2 = 87%). For IHCA there was no major change in the summary estimate, but there was a decrease in heterogeneity (RR = 0.59, 95% CI: 0.53‐0.66, I2 = 63%).
Publication Bias
Funnel plots generated for the effect of RRTs on hospital mortality and on IHCA did not indicate publication bias. Our search of
DISCUSSION
We found implementation of RRT/METs was associated with reductions in hospital mortality and IHCA. Our analysis extends the meta‐analysis of Chan et al. and is consistent with the recent systematic review by Winters et al.[8, 9] These findings provide support for the IHI recommendation that hospitals implement RRT/METs.[1]
Following the 2004 IHI recommendations, RRT/METs were widely implemented, with over 50% of hospitals having some form of RRT by 2010.[6] The adoption of RRT/METs occurred despite limited evidence on the effectiveness of RRT/METs. A meta‐analysis of studies published through 2008 demonstrated a reduction in cardiac arrests, but no reduction in mortality after implementation of RRT/METs.[8] More recently a systematic review that included studies through 2012 suggested that RRT/METs are associated with reduced IHCA and reduced mortality.[9] Our analysis addressed the conflicting results of the prior reviews and included 13 studies published after the Chan et al. meta‐analysis and several studies published after the Winters et al. systemic review.[8, 9] The studies included in our analysis were completed in hospitals across multiple countries and settings, increasing the generalizability of the results. Most studies were performed in teaching hospitals; thus, the results may not be as applicable to community hospitals.
We found publication year did not impact either outcome. However, this may reflect our use of 2 broad publication periods rather than smaller periods, as 5 of the 6 newly included studies favor RRT interventions. Additionally, if the studies missing data had been included in our analysis, they may have shown that publication year impacts the outcomes. We noted that a physician on a RRT/MET did not affect outcomes, contrary to suggestions by Winters et al.[9] This may reflect the skill of nonphysician providers and/or the collaboration of the RRT/MET with critical care teams. However, very few RRTs did not include a physician, limiting the conclusion that can be drawn regarding team composition.
Many patients exhibit observable clinical deterioration or measurable changes that could identify them prior to an event such as cardiac arrest.[5, 43] Measurable physiologic parameters, in fact, are the basis of medical early warning systems and recent automated systems.[44, 45] Similarly, delayed transfer to the ICU has been shown to be associated with increased mortality.[46] Therefore, RRTs, either by identifying patients at risk for clinical deterioration and/or facilitating transfer of patients to the ICU earlier, could result in improved clinical outcomes. We did not specifically look at ICU transfer or ICU codes in our analysis. However, in a recent single‐center before‐after study, RRT implementation increased ICU admission rates and the transfer of less severely ill patients to the ICU without improvement in severity of illness‐adjusted outcomes.[47] This finding may reflect the ICU organization of the particular institution; however, given limited ICU resources, admitting an increased number of less severely ill patients without clear clinical benefit is a potential concern. More studies are needed to better understand the mechanism of benefit as well as potential trade‐offs associated with RRT implementation. It is possible that institutional factors determine the benefit that can be achieved through RRTs.
Our study has several limitations. Although the methodological quality of the included studies was moderate to good, confounding and biases can be an issue with before‐after trials and cohort studies. Most studies were before‐after observational trials, lacking a concurrent control group making it difficult to draw causal relationships. This is particularly the case for hospital mortality, which has been independently falling since 2000.[48] Thus, changes in observed hospital mortality may simply reflect the general trend independent of the RRT intervention. However, this does not appear the case for cardiopulmonary arrest, which has been increasing in incidence since 2000.[49] There were several studies eligible for inclusion in our analysis, but could not be included because of insufficient data. It is possible that the inclusion of these studies could influence the results of our analysis. Finally, there was heterogeneity among the studies for both outcomes, particularly in‐hospital mortality. This likely reflects variations in hospital characteristics and case‐mix indices. There may also be other factors impacting teams such as how hospitals handled deteriorating patients before RRT implementation, education periods, and differing mechanisms and criteria for RRT activation.
In conclusion, RRT/METs are effective in decreasing both IHCA and hospital mortality. Our findings support the 2004 IHI recommendations for the implementation of RRTs in hospitals. Additional studies are still required to explore team composition, activation criteria, activation mechanism, and implementation strategies.
- , , , . The 100,000 lives campaign: setting a goal and a deadline for improving health care quality. JAMA. 2006;295(3):324–327.
- Institute for Healthcare Improvement. Overview of the 100,000 Lives Campaign. Available at: https://www.ihi.org/Engage/Initiatives/Completed/5MillionLivesCampaign/Documents/Overview%20of%20 the%20100K%20Campaign.pdf. Accessed September 18, 2014.
- , , . Reducing Hospital Mortality Rates (Part 2). IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2005.
- , . Developing strategies to prevent inhospital cardiac arrest: analyzing responses of physicians and nurses in the hours before the event. Crit Care Med. 1994;22(2):244–247.
- , , , et al. Duration of life‐threatening antecedents prior to intensive care admission. Intensive Care Med. 2002;28(11):1629–1634.
- , , . The tension between needing to improve care and knowing how to do it. N Engl J Med. 2007;357(6):608–613.
- , , , et al. Long term effect of a medical emergency team on cardiac arrests in a teaching hospital. Crit Care. 2005;9(6):R808–R815.
- , , , , . Rapid response teams: a systematic review and meta‐analysis. Arch Intern Med. 2010;170(1):18–26.
- , , , , , . Rapid‐response systems as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 pt 2):417–425.
- , , , et al. Impact of an intensivist‐led multidisciplinary extended rapid response team on hospital‐wide cardiopulmonary arrests and mortality. Crit Care Med. 2013;41(2):506–517.
- , , , et al. The impact of implementing a rapid response system: a comparison of cardiopulmonary arrests and mortality among four teaching hospitals in Australia. Resuscitation. 2014;85(9):1275–1281.
- , , , et al. Rapid response team implementation on a burn surgery/acute care ward. J Burn Care Res. 2014;35(1):21–27.
- Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Oxford, United Kingdom: The Cochrane Collaboration; 2011: Available at: http://www.cochrane‐handbook.org. Accessed October 9, 2014.
- , , , et al. The Newcastle‐Ottawa Scale (NOS) for Assessing The Quality of Nonrandomised Studies in Meta‐analyses. Ottawa, Canada: Ottawa Hospital Research Institute; 2014.
- Agency for Healthcare Research and Quality. Remote cardiac monitoring: a systematic review. Available at: http://www.cms.gov/determinationprocess/downloads/id51ta.pdf. Published December 12, 2007.
- Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen, the Netherlands: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
- , , . Implementing a rapid‐response team using a nurse‐to‐nurse consult approach. J Vasc Nurs. 2008;26(2):37–42.
- , , , et al. The effect of a rapid response team on major clinical outcome measures in a community hospital. Crit Care Med. 2007;35(9):2076–2082.
- , , , et al. Implementing a rapid response team to decrease emergencies outside the ICU: one hospital's experience. Medsurg Nurs. 2009;18(2):84–90, 126.
- , , , et al. Introduction of the medical emergency team (MET) system: a cluster‐randomised controlled trial. Lancet. 2005;365(9477):2091–2097.
- , , , , . Rapid response teams: do they make a difference? Dimens Crit Care Nurs. 2007;26(6):253–260; quiz 261–262.
- , , , . Evaluation of a medical emergency team one year after implementation. Resuscitation. 2004;61(3):257–263.
- , , , . Improving patient safety to reduce preventable deaths: the case of a California safety net hospital. J Healthc Qual. 2012;34(2):64–76.
- , . Implementation and outcomes of a rapid response team. J Nurs Care Qual. 2007;22(4):307–313, quiz 314–315.
- , , . Implementation of a rapid response team decreases cardiac arrest outside of the intensive care unit. J Trauma. 2007;62(5):1223–1227; discussion 1227–1228.
- , , , et al. Introducing Critical Care Outreach: a ward‐randomised trial of phased introduction in a general hospital. Intensive Care Med. 2004;30(7):1398–1404.
- , , , , . Four years' experience with a hospitalist‐led medical emergency team: an interrupted time series. J Hosp Med. 2012;7(2):98–103.
- , , , . Rapid response team in an academic institution: does it make a difference? Chest. 2011;139(6):1361–1367.
- , , , et al. Long‐term effect of a medical emergency team on mortality in a teaching hospital. Resuscitation. 2007;74(2):235–241.
- , , , , . Rapid response team implementation and in‐hospital mortality*. Crit Care Med. 2014;42(9):2001–2006.
- , , , , . Reduction in hospital‐wide mortality after implementation of a rapid response team: a long‐term cohort study. Crit Care. 2011;15(6):R269.
- , , , et al. A prospective before‐and‐after trial of a medical emergency team. Med J Aust. 2003;179(6):283–287.
- , , , et al. Rates of in‐hospital arrests, deaths and intensive care admissions: the effect of a medical emergency team. Med J Aust. 2000;173(5):236–240.
- , , , et al. Reduced frequency of cardiopulmonary arrests by rapid response teams. Einstein (Sao Paulo). 2012;10(4):442–448.
- , , . Changing cardiac arrest and hospital mortality rates through a medical emergency team takes time and constant review. Crit Care Med. 2010;38(2):445–450.
- , , , , , . Reducing in‐hospital cardiac arrests and hospital mortality by introducing a medical emergency team. Intensive Care Med. 2010;36(1):100–106.
- , , , et al. Rescue me: saving the vulnerable non‐ICU patient population. Jt Comm J Qual Patient Saf. 2009;35(4):199–205.
- , , , , , . Effects of a medical emergency team on reduction of incidence of and mortality from unexpected cardiac arrests in hospital: preliminary study. BMJ. 2002;324(7334):387–390.
- , , , , , . Hospital‐wide code rates and mortality before and after implementation of a rapid response team. JAMA. 2008;300(21):2506–2513.
- , , , . Introduction of a rapid response system at a United States veterans affairs hospital reduced cardiac arrests. Anesth Analg. 2010;111(3):679–686.
- , , , et al. Early impact of medical emergency team implementation in a country with limited medical resources: a before‐and‐after study. J Crit Care. 2011;26(4):373–378.
- , , , , , . Effect of a rapid response team on patient outcomes in a community‐based teaching hospital. J Grad Med Educ. 2014;6(1):61–64.
- , , . Abnormal vital signs are associated with an increased risk for critical events in US veteran inpatients. Resuscitation. 2009;80(11):1264–1269.
- , , , et al. A randomized trial of real‐time automated clinical deterioration alerts sent to a rapid response team. J Hosp Med. 2014;9(7):424–429.
- , , , , , . Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. J Hosp Med. 2012;7(5):388–395.
- , , , . Adverse outcomes associated with delayed intensive care unit transfers in an integrated healthcare system. J Hosp Med. 2012;7(3):224–230.
- , , , , , . The impact of rapid response team on outcome of patients transferred from the ward to the ICU: a single‐center study. Crit Care Med. 2013;41(10):2284–2291.
- , , . Trends in inpatient hospital deaths: National Hospital Discharge Survey, 2000–2010. NCHS Data Brief. 2013(118):1–8.
- , , . Epidemiology and outcomes of in‐hospital cardiopulmonary resuscitation in the United States, 2000–2009. Resuscitation. 2013;84(9):1255–1260.
- , , , . The 100,000 lives campaign: setting a goal and a deadline for improving health care quality. JAMA. 2006;295(3):324–327.
- Institute for Healthcare Improvement. Overview of the 100,000 Lives Campaign. Available at: https://www.ihi.org/Engage/Initiatives/Completed/5MillionLivesCampaign/Documents/Overview%20of%20 the%20100K%20Campaign.pdf. Accessed September 18, 2014.
- , , . Reducing Hospital Mortality Rates (Part 2). IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2005.
- , . Developing strategies to prevent inhospital cardiac arrest: analyzing responses of physicians and nurses in the hours before the event. Crit Care Med. 1994;22(2):244–247.
- , , , et al. Duration of life‐threatening antecedents prior to intensive care admission. Intensive Care Med. 2002;28(11):1629–1634.
- , , . The tension between needing to improve care and knowing how to do it. N Engl J Med. 2007;357(6):608–613.
- , , , et al. Long term effect of a medical emergency team on cardiac arrests in a teaching hospital. Crit Care. 2005;9(6):R808–R815.
- , , , , . Rapid response teams: a systematic review and meta‐analysis. Arch Intern Med. 2010;170(1):18–26.
- , , , , , . Rapid‐response systems as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 pt 2):417–425.
- , , , et al. Impact of an intensivist‐led multidisciplinary extended rapid response team on hospital‐wide cardiopulmonary arrests and mortality. Crit Care Med. 2013;41(2):506–517.
- , , , et al. The impact of implementing a rapid response system: a comparison of cardiopulmonary arrests and mortality among four teaching hospitals in Australia. Resuscitation. 2014;85(9):1275–1281.
- , , , et al. Rapid response team implementation on a burn surgery/acute care ward. J Burn Care Res. 2014;35(1):21–27.
- Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Oxford, United Kingdom: The Cochrane Collaboration; 2011: Available at: http://www.cochrane‐handbook.org. Accessed October 9, 2014.
- , , , et al. The Newcastle‐Ottawa Scale (NOS) for Assessing The Quality of Nonrandomised Studies in Meta‐analyses. Ottawa, Canada: Ottawa Hospital Research Institute; 2014.
- Agency for Healthcare Research and Quality. Remote cardiac monitoring: a systematic review. Available at: http://www.cms.gov/determinationprocess/downloads/id51ta.pdf. Published December 12, 2007.
- Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen, the Netherlands: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
- , , . Implementing a rapid‐response team using a nurse‐to‐nurse consult approach. J Vasc Nurs. 2008;26(2):37–42.
- , , , et al. The effect of a rapid response team on major clinical outcome measures in a community hospital. Crit Care Med. 2007;35(9):2076–2082.
- , , , et al. Implementing a rapid response team to decrease emergencies outside the ICU: one hospital's experience. Medsurg Nurs. 2009;18(2):84–90, 126.
- , , , et al. Introduction of the medical emergency team (MET) system: a cluster‐randomised controlled trial. Lancet. 2005;365(9477):2091–2097.
- , , , , . Rapid response teams: do they make a difference? Dimens Crit Care Nurs. 2007;26(6):253–260; quiz 261–262.
- , , , . Evaluation of a medical emergency team one year after implementation. Resuscitation. 2004;61(3):257–263.
- , , , . Improving patient safety to reduce preventable deaths: the case of a California safety net hospital. J Healthc Qual. 2012;34(2):64–76.
- , . Implementation and outcomes of a rapid response team. J Nurs Care Qual. 2007;22(4):307–313, quiz 314–315.
- , , . Implementation of a rapid response team decreases cardiac arrest outside of the intensive care unit. J Trauma. 2007;62(5):1223–1227; discussion 1227–1228.
- , , , et al. Introducing Critical Care Outreach: a ward‐randomised trial of phased introduction in a general hospital. Intensive Care Med. 2004;30(7):1398–1404.
- , , , , . Four years' experience with a hospitalist‐led medical emergency team: an interrupted time series. J Hosp Med. 2012;7(2):98–103.
- , , , . Rapid response team in an academic institution: does it make a difference? Chest. 2011;139(6):1361–1367.
- , , , et al. Long‐term effect of a medical emergency team on mortality in a teaching hospital. Resuscitation. 2007;74(2):235–241.
- , , , , . Rapid response team implementation and in‐hospital mortality*. Crit Care Med. 2014;42(9):2001–2006.
- , , , , . Reduction in hospital‐wide mortality after implementation of a rapid response team: a long‐term cohort study. Crit Care. 2011;15(6):R269.
- , , , et al. A prospective before‐and‐after trial of a medical emergency team. Med J Aust. 2003;179(6):283–287.
- , , , et al. Rates of in‐hospital arrests, deaths and intensive care admissions: the effect of a medical emergency team. Med J Aust. 2000;173(5):236–240.
- , , , et al. Reduced frequency of cardiopulmonary arrests by rapid response teams. Einstein (Sao Paulo). 2012;10(4):442–448.
- , , . Changing cardiac arrest and hospital mortality rates through a medical emergency team takes time and constant review. Crit Care Med. 2010;38(2):445–450.
- , , , , , . Reducing in‐hospital cardiac arrests and hospital mortality by introducing a medical emergency team. Intensive Care Med. 2010;36(1):100–106.
- , , , et al. Rescue me: saving the vulnerable non‐ICU patient population. Jt Comm J Qual Patient Saf. 2009;35(4):199–205.
- , , , , , . Effects of a medical emergency team on reduction of incidence of and mortality from unexpected cardiac arrests in hospital: preliminary study. BMJ. 2002;324(7334):387–390.
- , , , , , . Hospital‐wide code rates and mortality before and after implementation of a rapid response team. JAMA. 2008;300(21):2506–2513.
- , , , . Introduction of a rapid response system at a United States veterans affairs hospital reduced cardiac arrests. Anesth Analg. 2010;111(3):679–686.
- , , , et al. Early impact of medical emergency team implementation in a country with limited medical resources: a before‐and‐after study. J Crit Care. 2011;26(4):373–378.
- , , , , , . Effect of a rapid response team on patient outcomes in a community‐based teaching hospital. J Grad Med Educ. 2014;6(1):61–64.
- , , . Abnormal vital signs are associated with an increased risk for critical events in US veteran inpatients. Resuscitation. 2009;80(11):1264–1269.
- , , , et al. A randomized trial of real‐time automated clinical deterioration alerts sent to a rapid response team. J Hosp Med. 2014;9(7):424–429.
- , , , , , . Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. J Hosp Med. 2012;7(5):388–395.
- , , , . Adverse outcomes associated with delayed intensive care unit transfers in an integrated healthcare system. J Hosp Med. 2012;7(3):224–230.
- , , , , , . The impact of rapid response team on outcome of patients transferred from the ward to the ICU: a single‐center study. Crit Care Med. 2013;41(10):2284–2291.
- , , . Trends in inpatient hospital deaths: National Hospital Discharge Survey, 2000–2010. NCHS Data Brief. 2013(118):1–8.
- , , . Epidemiology and outcomes of in‐hospital cardiopulmonary resuscitation in the United States, 2000–2009. Resuscitation. 2013;84(9):1255–1260.
Knee pain • no popping • no previous trauma • Dx?
THE CASE
A 36-year-old man sought care at our family medicine clinic for knee pain that he’d had for the past year. He denied any previous injury or trauma to the knee. The pain affected the posterolateral left knee and was aggravated by squatting and deep flexion. Daily activities did not bother him, but skiing, golfing, mountain biking, and lifting weights worsened the pain. His pain had gradually become more severe and frequent. He denied any mechanical symptoms such as catching, popping, or locking.
Examination of his left knee demonstrated range of motion from 0 to 120 degrees; further flexion caused significant pain. McMurray and Thessaly tests were positive for posterolateral pain, particularly with knee flexion >120 degrees. Physical examination was otherwise unremarkable. Standard x-rays of the left knee were normal. Our patient completed a month of physical therapy, but his symptoms did not improve.
THE DIAGNOSIS
After the patient completed physical therapy, magnetic resonance imaging (MRI) was performed. The MRI did not reveal any left knee effusion, and the menisci, collateral ligaments, and cartilage surfaces were normal. And, while the cruciate ligaments were intact, a large pericruciate ganglion cyst was noted (FIGURES 1 AND 2).
DISCUSSION
Ganglion cysts are dense, encapsulated structures filled with clear viscous fluid that often arise adjacent to tendon sheaths or joint capsules, most commonly over the dorsum of the hand.1 Intra-articular ganglia involving the cruciate ligaments of the knee are relatively uncommon.2 The estimated prevalence of cruciate ligament ganglion cysts at arthroscopy is 0.2% to 1.9%; similar rates have been demonstrated with MRI.3-6 There are more reported cases of these cysts involving the anterior cruciate ligament (ACL) compared to those affecting the posterior cruciate ligament (PCL).2,6
Classification of these cysts is based on relative location with respect to the ligaments. Type 1 cysts originate anterior to the ACL; type 2, between the ACL and PCL; and type 3, posterior to the PCL.6,7 Cruciate ligament ganglion cysts are more common in men, are typically discovered between age 20 and 40, and are usually incidental findings.8
The pathogenesis of ganglion cyst formation is unknown.1,6,7 The most widely accepted theory is that ganglion cysts result from mucinous degeneration of connective tissue in areas of repetitive stress.1,6,7 Other theories suggest hyaluronic acid production secondary to mesenchymal stem cell proliferation within the ligaments, synovial tissue herniation, or congenital translocation of synovial tissue as possible etiologies.2,6,7
Concurrent pathologies such as meniscal tears or chondral lesions may also be present; however, there is some disagreement as to what role, if any, antecedent trauma has in the pathogenesis of cyst formation.1,6 Several investigators have suggested that prior knee trauma is a likely risk factor.2,8,9
In most patients, cruciate ligament ganglion cysts are asymptomatic.7 The most common presenting symptom is nonspecific pain that is exacerbated by activity, such as stair climbing, squatting, or other activities that require extreme flexion or extension of the knee.6,9 Other possible symptoms include limited range of motion (extension block with ACL involvement, limited flexion with PCL lesions), a catching or locking sensation, instability, or joint line tenderness.5,6 A palpable mass on physical exam is not usually present.6 Some investigators suggest that larger lesions and those closer to the femoral ligamentous attachments are more likely to cause symptoms.5
Cruciate ligament ganglion cysts can be an easily overlooked source of a patient’s symptoms because they often mimic more common pathologies.2 The differential diagnosis of cruciate ligament ganglion cysts and posterior knee pain includes any other intra-articular cysts (eg, meniscal cysts), posterior meniscal tear, popliteus tendinopathy, or neoplasms (eg, hemangioma and synovial sarcoma).2,6
MRI is the best method of diagnosis
Because the symptoms of cruciate ligament ganglion cysts are variable and nonspecific, the diagnosis is rarely made on clinical grounds alone.1 The best method of evaluating suspected intra-articular pathologies such as cruciate ligament ganglion cysts is MRI.5,10
Cruciate ligament ganglion cysts typically follow fluid signal on all sequences, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.1,2,5,6 A pericruciate location with a multilocular appearance is usually sufficient evidence to make a diagnosis. However, solid or semi-solid pathologies (such as synovial cell sarcoma, synovial hemangioma, or synovial chondromatosis) can have similar signal intensity.
If necessary, intravenous contrast can be helpful; a lack of central contrast enhancement can differentiate ganglion cysts from other solid, enhancing, or partially enhancing lesions. Other diagnostic modalities, such as ultrasound, computed tomography (CT), and diagnostic arthroscopy, are less practical and have a wide range of sensitivity and specificity.5,6,10
Arthroscopic excision is the treatment of choice
Asymptomatic cruciate ligament ganglion cysts are usually managed with clinical follow-up. For patients with symptomatic cysts, ultrasound- or CT-guided percutaneous cyst aspiration may temporarily improve symptoms, but recurrence rates have not been well studied.2,6,9,10 Additionally, accessibility to cysts in this location via these approaches is limited. Arthroscopic excision of the cyst is the treatment of choice for symptomatic cases.1,2,5,6,10
Our patient underwent arthroscopic cyst resection, which resulted in complete resolution of his symptoms. In 3 months, he returned to his regular physical activities with no pain or discomfort. One year later, he remained asymptomatic.
THE TAKEAWAY
Cruciate ligament ganglion cysts are a rare cause of posterior knee pain. An MRI is the best diagnostic modality to evaluate and confirm the diagnosis, as well as rule out other pathologies. The treatment of choice for symptomatic cases is arthroscopic excision of the cyst.
1. Mao Y, Dong Q, Wang Y. Ganglion cysts of the cruciate ligaments: a series of 31 cases and review of the literature. BMC Musculoskelet Disord. 2012;13:137.
2. Krudwig WK, Schulte KK, Heinemann C. Intra-articular ganglion cysts of the knee joint: a report of 85 cases and review of the literature. Knee Surg Sports Traumatol Arthrosc. 2004;12:123-129.
3. Bergin D, Morrison WB, Carrino JA, et al. Anterior cruciate ligament ganglia and mucoid degeneration: coexistence and clinical correlation. AJR Am J Roentgenol. 2004;182:1283-1287.
4. Bui-Mansfield LT, Youngberg RA. Intraarticular ganglia of the knee: prevalence, presentation, etiology, and management. AJR Am J Roentgenol. 1997;168:123-127.
5. Lunhao B, Yu S, Jiashi W. Diagnosis and treatment of ganglion cysts of the cruciate ligaments. Arch Orthop Trauma Surg. 2011;131:1053-1057.
6. Stein D, Cantlon M, Mackay B, et al. Cysts about the knee: evaluation and management. J Am Acad Orthop Surg. 2013;21:469-479.
7. Zantop T, Rusch A, Hassenpflug J, et al. Intra-articular ganglion cysts of the cruciate ligaments: case report and review of the literature. Arch Orthop Trauma Surg. 2003;123:195-198.
8. Tsai TY, Yang YS, Tseng FJ, et al. Arthroscopic excision of ganglion cysts of the posterior cruciate ligaments using posterior trans-septal portal. Arthroscopy. 2012;28:95-99.
9. Huang GS, Lee CH, Chan WP, et al. Ganglion cysts of the cruciate ligaments. Acta Radiol. 2002;43:419-424.
10. Tyrrell PN, Cassar-Pullicino VN, McCall IW. Intra-articular ganglion cysts of the cruciate ligaments. Eur Radiol. 2000;10:1233-1238.
THE CASE
A 36-year-old man sought care at our family medicine clinic for knee pain that he’d had for the past year. He denied any previous injury or trauma to the knee. The pain affected the posterolateral left knee and was aggravated by squatting and deep flexion. Daily activities did not bother him, but skiing, golfing, mountain biking, and lifting weights worsened the pain. His pain had gradually become more severe and frequent. He denied any mechanical symptoms such as catching, popping, or locking.
Examination of his left knee demonstrated range of motion from 0 to 120 degrees; further flexion caused significant pain. McMurray and Thessaly tests were positive for posterolateral pain, particularly with knee flexion >120 degrees. Physical examination was otherwise unremarkable. Standard x-rays of the left knee were normal. Our patient completed a month of physical therapy, but his symptoms did not improve.
THE DIAGNOSIS
After the patient completed physical therapy, magnetic resonance imaging (MRI) was performed. The MRI did not reveal any left knee effusion, and the menisci, collateral ligaments, and cartilage surfaces were normal. And, while the cruciate ligaments were intact, a large pericruciate ganglion cyst was noted (FIGURES 1 AND 2).
DISCUSSION
Ganglion cysts are dense, encapsulated structures filled with clear viscous fluid that often arise adjacent to tendon sheaths or joint capsules, most commonly over the dorsum of the hand.1 Intra-articular ganglia involving the cruciate ligaments of the knee are relatively uncommon.2 The estimated prevalence of cruciate ligament ganglion cysts at arthroscopy is 0.2% to 1.9%; similar rates have been demonstrated with MRI.3-6 There are more reported cases of these cysts involving the anterior cruciate ligament (ACL) compared to those affecting the posterior cruciate ligament (PCL).2,6
Classification of these cysts is based on relative location with respect to the ligaments. Type 1 cysts originate anterior to the ACL; type 2, between the ACL and PCL; and type 3, posterior to the PCL.6,7 Cruciate ligament ganglion cysts are more common in men, are typically discovered between age 20 and 40, and are usually incidental findings.8
The pathogenesis of ganglion cyst formation is unknown.1,6,7 The most widely accepted theory is that ganglion cysts result from mucinous degeneration of connective tissue in areas of repetitive stress.1,6,7 Other theories suggest hyaluronic acid production secondary to mesenchymal stem cell proliferation within the ligaments, synovial tissue herniation, or congenital translocation of synovial tissue as possible etiologies.2,6,7
Concurrent pathologies such as meniscal tears or chondral lesions may also be present; however, there is some disagreement as to what role, if any, antecedent trauma has in the pathogenesis of cyst formation.1,6 Several investigators have suggested that prior knee trauma is a likely risk factor.2,8,9
In most patients, cruciate ligament ganglion cysts are asymptomatic.7 The most common presenting symptom is nonspecific pain that is exacerbated by activity, such as stair climbing, squatting, or other activities that require extreme flexion or extension of the knee.6,9 Other possible symptoms include limited range of motion (extension block with ACL involvement, limited flexion with PCL lesions), a catching or locking sensation, instability, or joint line tenderness.5,6 A palpable mass on physical exam is not usually present.6 Some investigators suggest that larger lesions and those closer to the femoral ligamentous attachments are more likely to cause symptoms.5
Cruciate ligament ganglion cysts can be an easily overlooked source of a patient’s symptoms because they often mimic more common pathologies.2 The differential diagnosis of cruciate ligament ganglion cysts and posterior knee pain includes any other intra-articular cysts (eg, meniscal cysts), posterior meniscal tear, popliteus tendinopathy, or neoplasms (eg, hemangioma and synovial sarcoma).2,6
MRI is the best method of diagnosis
Because the symptoms of cruciate ligament ganglion cysts are variable and nonspecific, the diagnosis is rarely made on clinical grounds alone.1 The best method of evaluating suspected intra-articular pathologies such as cruciate ligament ganglion cysts is MRI.5,10
Cruciate ligament ganglion cysts typically follow fluid signal on all sequences, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.1,2,5,6 A pericruciate location with a multilocular appearance is usually sufficient evidence to make a diagnosis. However, solid or semi-solid pathologies (such as synovial cell sarcoma, synovial hemangioma, or synovial chondromatosis) can have similar signal intensity.
If necessary, intravenous contrast can be helpful; a lack of central contrast enhancement can differentiate ganglion cysts from other solid, enhancing, or partially enhancing lesions. Other diagnostic modalities, such as ultrasound, computed tomography (CT), and diagnostic arthroscopy, are less practical and have a wide range of sensitivity and specificity.5,6,10
Arthroscopic excision is the treatment of choice
Asymptomatic cruciate ligament ganglion cysts are usually managed with clinical follow-up. For patients with symptomatic cysts, ultrasound- or CT-guided percutaneous cyst aspiration may temporarily improve symptoms, but recurrence rates have not been well studied.2,6,9,10 Additionally, accessibility to cysts in this location via these approaches is limited. Arthroscopic excision of the cyst is the treatment of choice for symptomatic cases.1,2,5,6,10
Our patient underwent arthroscopic cyst resection, which resulted in complete resolution of his symptoms. In 3 months, he returned to his regular physical activities with no pain or discomfort. One year later, he remained asymptomatic.
THE TAKEAWAY
Cruciate ligament ganglion cysts are a rare cause of posterior knee pain. An MRI is the best diagnostic modality to evaluate and confirm the diagnosis, as well as rule out other pathologies. The treatment of choice for symptomatic cases is arthroscopic excision of the cyst.
THE CASE
A 36-year-old man sought care at our family medicine clinic for knee pain that he’d had for the past year. He denied any previous injury or trauma to the knee. The pain affected the posterolateral left knee and was aggravated by squatting and deep flexion. Daily activities did not bother him, but skiing, golfing, mountain biking, and lifting weights worsened the pain. His pain had gradually become more severe and frequent. He denied any mechanical symptoms such as catching, popping, or locking.
Examination of his left knee demonstrated range of motion from 0 to 120 degrees; further flexion caused significant pain. McMurray and Thessaly tests were positive for posterolateral pain, particularly with knee flexion >120 degrees. Physical examination was otherwise unremarkable. Standard x-rays of the left knee were normal. Our patient completed a month of physical therapy, but his symptoms did not improve.
THE DIAGNOSIS
After the patient completed physical therapy, magnetic resonance imaging (MRI) was performed. The MRI did not reveal any left knee effusion, and the menisci, collateral ligaments, and cartilage surfaces were normal. And, while the cruciate ligaments were intact, a large pericruciate ganglion cyst was noted (FIGURES 1 AND 2).
DISCUSSION
Ganglion cysts are dense, encapsulated structures filled with clear viscous fluid that often arise adjacent to tendon sheaths or joint capsules, most commonly over the dorsum of the hand.1 Intra-articular ganglia involving the cruciate ligaments of the knee are relatively uncommon.2 The estimated prevalence of cruciate ligament ganglion cysts at arthroscopy is 0.2% to 1.9%; similar rates have been demonstrated with MRI.3-6 There are more reported cases of these cysts involving the anterior cruciate ligament (ACL) compared to those affecting the posterior cruciate ligament (PCL).2,6
Classification of these cysts is based on relative location with respect to the ligaments. Type 1 cysts originate anterior to the ACL; type 2, between the ACL and PCL; and type 3, posterior to the PCL.6,7 Cruciate ligament ganglion cysts are more common in men, are typically discovered between age 20 and 40, and are usually incidental findings.8
The pathogenesis of ganglion cyst formation is unknown.1,6,7 The most widely accepted theory is that ganglion cysts result from mucinous degeneration of connective tissue in areas of repetitive stress.1,6,7 Other theories suggest hyaluronic acid production secondary to mesenchymal stem cell proliferation within the ligaments, synovial tissue herniation, or congenital translocation of synovial tissue as possible etiologies.2,6,7
Concurrent pathologies such as meniscal tears or chondral lesions may also be present; however, there is some disagreement as to what role, if any, antecedent trauma has in the pathogenesis of cyst formation.1,6 Several investigators have suggested that prior knee trauma is a likely risk factor.2,8,9
In most patients, cruciate ligament ganglion cysts are asymptomatic.7 The most common presenting symptom is nonspecific pain that is exacerbated by activity, such as stair climbing, squatting, or other activities that require extreme flexion or extension of the knee.6,9 Other possible symptoms include limited range of motion (extension block with ACL involvement, limited flexion with PCL lesions), a catching or locking sensation, instability, or joint line tenderness.5,6 A palpable mass on physical exam is not usually present.6 Some investigators suggest that larger lesions and those closer to the femoral ligamentous attachments are more likely to cause symptoms.5
Cruciate ligament ganglion cysts can be an easily overlooked source of a patient’s symptoms because they often mimic more common pathologies.2 The differential diagnosis of cruciate ligament ganglion cysts and posterior knee pain includes any other intra-articular cysts (eg, meniscal cysts), posterior meniscal tear, popliteus tendinopathy, or neoplasms (eg, hemangioma and synovial sarcoma).2,6
MRI is the best method of diagnosis
Because the symptoms of cruciate ligament ganglion cysts are variable and nonspecific, the diagnosis is rarely made on clinical grounds alone.1 The best method of evaluating suspected intra-articular pathologies such as cruciate ligament ganglion cysts is MRI.5,10
Cruciate ligament ganglion cysts typically follow fluid signal on all sequences, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.1,2,5,6 A pericruciate location with a multilocular appearance is usually sufficient evidence to make a diagnosis. However, solid or semi-solid pathologies (such as synovial cell sarcoma, synovial hemangioma, or synovial chondromatosis) can have similar signal intensity.
If necessary, intravenous contrast can be helpful; a lack of central contrast enhancement can differentiate ganglion cysts from other solid, enhancing, or partially enhancing lesions. Other diagnostic modalities, such as ultrasound, computed tomography (CT), and diagnostic arthroscopy, are less practical and have a wide range of sensitivity and specificity.5,6,10
Arthroscopic excision is the treatment of choice
Asymptomatic cruciate ligament ganglion cysts are usually managed with clinical follow-up. For patients with symptomatic cysts, ultrasound- or CT-guided percutaneous cyst aspiration may temporarily improve symptoms, but recurrence rates have not been well studied.2,6,9,10 Additionally, accessibility to cysts in this location via these approaches is limited. Arthroscopic excision of the cyst is the treatment of choice for symptomatic cases.1,2,5,6,10
Our patient underwent arthroscopic cyst resection, which resulted in complete resolution of his symptoms. In 3 months, he returned to his regular physical activities with no pain or discomfort. One year later, he remained asymptomatic.
THE TAKEAWAY
Cruciate ligament ganglion cysts are a rare cause of posterior knee pain. An MRI is the best diagnostic modality to evaluate and confirm the diagnosis, as well as rule out other pathologies. The treatment of choice for symptomatic cases is arthroscopic excision of the cyst.
1. Mao Y, Dong Q, Wang Y. Ganglion cysts of the cruciate ligaments: a series of 31 cases and review of the literature. BMC Musculoskelet Disord. 2012;13:137.
2. Krudwig WK, Schulte KK, Heinemann C. Intra-articular ganglion cysts of the knee joint: a report of 85 cases and review of the literature. Knee Surg Sports Traumatol Arthrosc. 2004;12:123-129.
3. Bergin D, Morrison WB, Carrino JA, et al. Anterior cruciate ligament ganglia and mucoid degeneration: coexistence and clinical correlation. AJR Am J Roentgenol. 2004;182:1283-1287.
4. Bui-Mansfield LT, Youngberg RA. Intraarticular ganglia of the knee: prevalence, presentation, etiology, and management. AJR Am J Roentgenol. 1997;168:123-127.
5. Lunhao B, Yu S, Jiashi W. Diagnosis and treatment of ganglion cysts of the cruciate ligaments. Arch Orthop Trauma Surg. 2011;131:1053-1057.
6. Stein D, Cantlon M, Mackay B, et al. Cysts about the knee: evaluation and management. J Am Acad Orthop Surg. 2013;21:469-479.
7. Zantop T, Rusch A, Hassenpflug J, et al. Intra-articular ganglion cysts of the cruciate ligaments: case report and review of the literature. Arch Orthop Trauma Surg. 2003;123:195-198.
8. Tsai TY, Yang YS, Tseng FJ, et al. Arthroscopic excision of ganglion cysts of the posterior cruciate ligaments using posterior trans-septal portal. Arthroscopy. 2012;28:95-99.
9. Huang GS, Lee CH, Chan WP, et al. Ganglion cysts of the cruciate ligaments. Acta Radiol. 2002;43:419-424.
10. Tyrrell PN, Cassar-Pullicino VN, McCall IW. Intra-articular ganglion cysts of the cruciate ligaments. Eur Radiol. 2000;10:1233-1238.
1. Mao Y, Dong Q, Wang Y. Ganglion cysts of the cruciate ligaments: a series of 31 cases and review of the literature. BMC Musculoskelet Disord. 2012;13:137.
2. Krudwig WK, Schulte KK, Heinemann C. Intra-articular ganglion cysts of the knee joint: a report of 85 cases and review of the literature. Knee Surg Sports Traumatol Arthrosc. 2004;12:123-129.
3. Bergin D, Morrison WB, Carrino JA, et al. Anterior cruciate ligament ganglia and mucoid degeneration: coexistence and clinical correlation. AJR Am J Roentgenol. 2004;182:1283-1287.
4. Bui-Mansfield LT, Youngberg RA. Intraarticular ganglia of the knee: prevalence, presentation, etiology, and management. AJR Am J Roentgenol. 1997;168:123-127.
5. Lunhao B, Yu S, Jiashi W. Diagnosis and treatment of ganglion cysts of the cruciate ligaments. Arch Orthop Trauma Surg. 2011;131:1053-1057.
6. Stein D, Cantlon M, Mackay B, et al. Cysts about the knee: evaluation and management. J Am Acad Orthop Surg. 2013;21:469-479.
7. Zantop T, Rusch A, Hassenpflug J, et al. Intra-articular ganglion cysts of the cruciate ligaments: case report and review of the literature. Arch Orthop Trauma Surg. 2003;123:195-198.
8. Tsai TY, Yang YS, Tseng FJ, et al. Arthroscopic excision of ganglion cysts of the posterior cruciate ligaments using posterior trans-septal portal. Arthroscopy. 2012;28:95-99.
9. Huang GS, Lee CH, Chan WP, et al. Ganglion cysts of the cruciate ligaments. Acta Radiol. 2002;43:419-424.
10. Tyrrell PN, Cassar-Pullicino VN, McCall IW. Intra-articular ganglion cysts of the cruciate ligaments. Eur Radiol. 2000;10:1233-1238.
These umbilical lesions weren't granulomas after all
THE CASES
CASE 1 › A 15-month-old boy was brought to our center for plastic surgery after being referred by his general practitioner (GP). The patient had a non-healing lesion on his umbilicus that had been present since birth. It had remained the same size, but bled occasionally. The GP initially presumed the lesion was a granuloma and treated it with silver nitrate cautery, but this did not eradicate it.
After talking with the boy’s mother further, we learned that there had been a constant oozing from the area since birth and that the lesion protruded slightly from the abdomen when the child cried. The boy had congenital heart disease, but his bowel and genitourinary history were normal. A clinical examination revealed pink, moist tissue herniating from the umbilicus with surrounding abdominal fullness when the boy stood up (FIGURE 1A). An ultrasound showed a focal 19 x 7 mm complex area around the umbilicus with no definite track. The lesion was surgically removed. Histology revealed a completely excised vitellointestinal duct remnant.
CASE 2 › A 6-year-old boy with a history of attention-deficit/hyperactivity disorder was brought to our clinic with a non-healing umbilical lesion after being referred by his GP. The lesion had been present since birth and had failed to resolve despite several attempts to treat it with silver nitrate cautery. Clinically, the patient appeared to have a granulomatous umbilical polyp (FIGURE 1B). The patient underwent surgical excision of the lesion. Histological analysis revealed a completely excised vitellointestinal duct remnant (FIGURE 2).
DISCUSSION
The vitellointestinal duct (VID), also called the omphalomesenteric duct (OMD), connects the alimentary canal and the yolk sac in early embryogenesis. Failure of involution of the duct results in abnormalities such as Meckel’s diverticulum, cysts, and polyps.
VID anomalies occur in approximately 2% of newborns; a small percentage of these have patent connections to the intestine.1 Parents are often the first to notice the abnormality and will typically see a reddish protrusion around the umbilicus or a persistent serous discharge around the umbilicus soon after birth.
VID remnants are similar in presentation to benign granulomas or granulation tissue, which are benign lesions that present in the first few weeks of life. Granulomas are reddish in color, bleed minimally when irritated by trauma, and respond well to silver nitrate cautery.2 When the lesion fails to respond to treatment, an alternative diagnosis should be investigated further.
Ultrasonography is the best way to evaluate a suspected VID remnant
A suspected VID remnant should first be assessed with ultrasonography to determine the extent of the remnant and guide surgical treatment. Ultrasonography can also delineate the relationship of these congenital remnants with the umbilicus and bladder.3
Potential complications that can arise from these lesions include an intestinal hernia, intussusception, volvulus, abdominal pain, or a persistent discharge that can lead to infection.3 Mortality following complications is significantly high.4
Although the etiology of patent VIDs and their remnants remains unknown, the presence of such ducts is associated with other congenital anomalies, including Down Syndrome, structural cardiac malformation, conduction abnormalities, and cleft lip and palate.5-7 Therefore, additional history taking and examinations may be required to identify these associated pathologies. In Case 1, the 15-month-old boy had congenital heart disease.
Surgical excision will prevent complications
A simple surgical excision should be performed for VID remnants. The prognosis is excellent when such procedures are performed in the non-acute setting. Some debate exists as to whether all remnants require formal abdominal exploration.8,9
Treatment of patent VIDs requires surgical excision of the duct, with or without a segment of the small bowel, to obliterate the connection.10 Reconstruction of the umbilicus is then performed, depending on the surgical technique used.
Our patients both made complete recoveries following their surgeries with resolution of their symptoms.
THE TAKEAWAY
Consider a VID remnant as part of the differential diagnosis for any patient who has what appears to be a granulomatous umbilical lesion. Order ultrasonography to evaluate a suspected VID, especially for lesions that fail to respond to 2 or 3 silver nitrate treatments. Surgical excision of a VID remnant is usually curative.
1. Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies. Experience with 217 childhood cases. Arch Surg. 1987;122:542-547.
2. Piparsaliya S, Joshi M, Rajput N, et al. Patent vitellointestinal duct: A close differential diagnosis of umbilical granuloma: A case report and review of literature. Surgical Science. 2011;2:134-136.
3. Khati NJ, Enquist EG, Javitt MC. Imaging of the umbilicus and periumbilical region. Radiographics. 1998;18:413-431.
4. Yamada T, Seiki Y, Ueda M, et al. Patent omphalomesenteric duct: a case report and review of Japanese literature. Asia Oceania J Obstet Gynaecol. 1989;15:229-236.
5. Martin RH, Doublestein GL, Jarvis MR. Concurrent ectopic pregnancy, Meckel’s diverticulum with vitelline duct remnant, cecal volvulus, and congenital complete heart block: report of a case. J Am Osteopath Assoc. 1986;86:589-591.
6. Elebute EA, Ransome-Kuti O. Patent vitello-intestinal duct with ileal prolapse. Arch Surg. 1965;91:456-460.
7. Blair SP, Beasley SW. Intussusception of vitello-intestinal tract through an exomphalos in trisomy 13. Pediatric Surgery International. 1989;4:422-423.
8. Kutin ND, Allen JE, Jewett TC. The umbilical polyp. J Pediatr Surg. 1979;14:741-744.
9. Pacilli M, Sebire NJ, Maritsi D, et al. Umbilical polyp in infants and children. Eur J Pediatr Surg. 2007;17:397-399.
10. Storms P, Pexsters J, Vandekerkhof J. Small omphalocele with ileal prolapse through a patent omphalomesenteric duct. A case report and review of literature. Acta Chir Belg. 1988;88:392-394.
THE CASES
CASE 1 › A 15-month-old boy was brought to our center for plastic surgery after being referred by his general practitioner (GP). The patient had a non-healing lesion on his umbilicus that had been present since birth. It had remained the same size, but bled occasionally. The GP initially presumed the lesion was a granuloma and treated it with silver nitrate cautery, but this did not eradicate it.
After talking with the boy’s mother further, we learned that there had been a constant oozing from the area since birth and that the lesion protruded slightly from the abdomen when the child cried. The boy had congenital heart disease, but his bowel and genitourinary history were normal. A clinical examination revealed pink, moist tissue herniating from the umbilicus with surrounding abdominal fullness when the boy stood up (FIGURE 1A). An ultrasound showed a focal 19 x 7 mm complex area around the umbilicus with no definite track. The lesion was surgically removed. Histology revealed a completely excised vitellointestinal duct remnant.
CASE 2 › A 6-year-old boy with a history of attention-deficit/hyperactivity disorder was brought to our clinic with a non-healing umbilical lesion after being referred by his GP. The lesion had been present since birth and had failed to resolve despite several attempts to treat it with silver nitrate cautery. Clinically, the patient appeared to have a granulomatous umbilical polyp (FIGURE 1B). The patient underwent surgical excision of the lesion. Histological analysis revealed a completely excised vitellointestinal duct remnant (FIGURE 2).
DISCUSSION
The vitellointestinal duct (VID), also called the omphalomesenteric duct (OMD), connects the alimentary canal and the yolk sac in early embryogenesis. Failure of involution of the duct results in abnormalities such as Meckel’s diverticulum, cysts, and polyps.
VID anomalies occur in approximately 2% of newborns; a small percentage of these have patent connections to the intestine.1 Parents are often the first to notice the abnormality and will typically see a reddish protrusion around the umbilicus or a persistent serous discharge around the umbilicus soon after birth.
VID remnants are similar in presentation to benign granulomas or granulation tissue, which are benign lesions that present in the first few weeks of life. Granulomas are reddish in color, bleed minimally when irritated by trauma, and respond well to silver nitrate cautery.2 When the lesion fails to respond to treatment, an alternative diagnosis should be investigated further.
Ultrasonography is the best way to evaluate a suspected VID remnant
A suspected VID remnant should first be assessed with ultrasonography to determine the extent of the remnant and guide surgical treatment. Ultrasonography can also delineate the relationship of these congenital remnants with the umbilicus and bladder.3
Potential complications that can arise from these lesions include an intestinal hernia, intussusception, volvulus, abdominal pain, or a persistent discharge that can lead to infection.3 Mortality following complications is significantly high.4
Although the etiology of patent VIDs and their remnants remains unknown, the presence of such ducts is associated with other congenital anomalies, including Down Syndrome, structural cardiac malformation, conduction abnormalities, and cleft lip and palate.5-7 Therefore, additional history taking and examinations may be required to identify these associated pathologies. In Case 1, the 15-month-old boy had congenital heart disease.
Surgical excision will prevent complications
A simple surgical excision should be performed for VID remnants. The prognosis is excellent when such procedures are performed in the non-acute setting. Some debate exists as to whether all remnants require formal abdominal exploration.8,9
Treatment of patent VIDs requires surgical excision of the duct, with or without a segment of the small bowel, to obliterate the connection.10 Reconstruction of the umbilicus is then performed, depending on the surgical technique used.
Our patients both made complete recoveries following their surgeries with resolution of their symptoms.
THE TAKEAWAY
Consider a VID remnant as part of the differential diagnosis for any patient who has what appears to be a granulomatous umbilical lesion. Order ultrasonography to evaluate a suspected VID, especially for lesions that fail to respond to 2 or 3 silver nitrate treatments. Surgical excision of a VID remnant is usually curative.
THE CASES
CASE 1 › A 15-month-old boy was brought to our center for plastic surgery after being referred by his general practitioner (GP). The patient had a non-healing lesion on his umbilicus that had been present since birth. It had remained the same size, but bled occasionally. The GP initially presumed the lesion was a granuloma and treated it with silver nitrate cautery, but this did not eradicate it.
After talking with the boy’s mother further, we learned that there had been a constant oozing from the area since birth and that the lesion protruded slightly from the abdomen when the child cried. The boy had congenital heart disease, but his bowel and genitourinary history were normal. A clinical examination revealed pink, moist tissue herniating from the umbilicus with surrounding abdominal fullness when the boy stood up (FIGURE 1A). An ultrasound showed a focal 19 x 7 mm complex area around the umbilicus with no definite track. The lesion was surgically removed. Histology revealed a completely excised vitellointestinal duct remnant.
CASE 2 › A 6-year-old boy with a history of attention-deficit/hyperactivity disorder was brought to our clinic with a non-healing umbilical lesion after being referred by his GP. The lesion had been present since birth and had failed to resolve despite several attempts to treat it with silver nitrate cautery. Clinically, the patient appeared to have a granulomatous umbilical polyp (FIGURE 1B). The patient underwent surgical excision of the lesion. Histological analysis revealed a completely excised vitellointestinal duct remnant (FIGURE 2).
DISCUSSION
The vitellointestinal duct (VID), also called the omphalomesenteric duct (OMD), connects the alimentary canal and the yolk sac in early embryogenesis. Failure of involution of the duct results in abnormalities such as Meckel’s diverticulum, cysts, and polyps.
VID anomalies occur in approximately 2% of newborns; a small percentage of these have patent connections to the intestine.1 Parents are often the first to notice the abnormality and will typically see a reddish protrusion around the umbilicus or a persistent serous discharge around the umbilicus soon after birth.
VID remnants are similar in presentation to benign granulomas or granulation tissue, which are benign lesions that present in the first few weeks of life. Granulomas are reddish in color, bleed minimally when irritated by trauma, and respond well to silver nitrate cautery.2 When the lesion fails to respond to treatment, an alternative diagnosis should be investigated further.
Ultrasonography is the best way to evaluate a suspected VID remnant
A suspected VID remnant should first be assessed with ultrasonography to determine the extent of the remnant and guide surgical treatment. Ultrasonography can also delineate the relationship of these congenital remnants with the umbilicus and bladder.3
Potential complications that can arise from these lesions include an intestinal hernia, intussusception, volvulus, abdominal pain, or a persistent discharge that can lead to infection.3 Mortality following complications is significantly high.4
Although the etiology of patent VIDs and their remnants remains unknown, the presence of such ducts is associated with other congenital anomalies, including Down Syndrome, structural cardiac malformation, conduction abnormalities, and cleft lip and palate.5-7 Therefore, additional history taking and examinations may be required to identify these associated pathologies. In Case 1, the 15-month-old boy had congenital heart disease.
Surgical excision will prevent complications
A simple surgical excision should be performed for VID remnants. The prognosis is excellent when such procedures are performed in the non-acute setting. Some debate exists as to whether all remnants require formal abdominal exploration.8,9
Treatment of patent VIDs requires surgical excision of the duct, with or without a segment of the small bowel, to obliterate the connection.10 Reconstruction of the umbilicus is then performed, depending on the surgical technique used.
Our patients both made complete recoveries following their surgeries with resolution of their symptoms.
THE TAKEAWAY
Consider a VID remnant as part of the differential diagnosis for any patient who has what appears to be a granulomatous umbilical lesion. Order ultrasonography to evaluate a suspected VID, especially for lesions that fail to respond to 2 or 3 silver nitrate treatments. Surgical excision of a VID remnant is usually curative.
1. Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies. Experience with 217 childhood cases. Arch Surg. 1987;122:542-547.
2. Piparsaliya S, Joshi M, Rajput N, et al. Patent vitellointestinal duct: A close differential diagnosis of umbilical granuloma: A case report and review of literature. Surgical Science. 2011;2:134-136.
3. Khati NJ, Enquist EG, Javitt MC. Imaging of the umbilicus and periumbilical region. Radiographics. 1998;18:413-431.
4. Yamada T, Seiki Y, Ueda M, et al. Patent omphalomesenteric duct: a case report and review of Japanese literature. Asia Oceania J Obstet Gynaecol. 1989;15:229-236.
5. Martin RH, Doublestein GL, Jarvis MR. Concurrent ectopic pregnancy, Meckel’s diverticulum with vitelline duct remnant, cecal volvulus, and congenital complete heart block: report of a case. J Am Osteopath Assoc. 1986;86:589-591.
6. Elebute EA, Ransome-Kuti O. Patent vitello-intestinal duct with ileal prolapse. Arch Surg. 1965;91:456-460.
7. Blair SP, Beasley SW. Intussusception of vitello-intestinal tract through an exomphalos in trisomy 13. Pediatric Surgery International. 1989;4:422-423.
8. Kutin ND, Allen JE, Jewett TC. The umbilical polyp. J Pediatr Surg. 1979;14:741-744.
9. Pacilli M, Sebire NJ, Maritsi D, et al. Umbilical polyp in infants and children. Eur J Pediatr Surg. 2007;17:397-399.
10. Storms P, Pexsters J, Vandekerkhof J. Small omphalocele with ileal prolapse through a patent omphalomesenteric duct. A case report and review of literature. Acta Chir Belg. 1988;88:392-394.
1. Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies. Experience with 217 childhood cases. Arch Surg. 1987;122:542-547.
2. Piparsaliya S, Joshi M, Rajput N, et al. Patent vitellointestinal duct: A close differential diagnosis of umbilical granuloma: A case report and review of literature. Surgical Science. 2011;2:134-136.
3. Khati NJ, Enquist EG, Javitt MC. Imaging of the umbilicus and periumbilical region. Radiographics. 1998;18:413-431.
4. Yamada T, Seiki Y, Ueda M, et al. Patent omphalomesenteric duct: a case report and review of Japanese literature. Asia Oceania J Obstet Gynaecol. 1989;15:229-236.
5. Martin RH, Doublestein GL, Jarvis MR. Concurrent ectopic pregnancy, Meckel’s diverticulum with vitelline duct remnant, cecal volvulus, and congenital complete heart block: report of a case. J Am Osteopath Assoc. 1986;86:589-591.
6. Elebute EA, Ransome-Kuti O. Patent vitello-intestinal duct with ileal prolapse. Arch Surg. 1965;91:456-460.
7. Blair SP, Beasley SW. Intussusception of vitello-intestinal tract through an exomphalos in trisomy 13. Pediatric Surgery International. 1989;4:422-423.
8. Kutin ND, Allen JE, Jewett TC. The umbilical polyp. J Pediatr Surg. 1979;14:741-744.
9. Pacilli M, Sebire NJ, Maritsi D, et al. Umbilical polyp in infants and children. Eur J Pediatr Surg. 2007;17:397-399.
10. Storms P, Pexsters J, Vandekerkhof J. Small omphalocele with ileal prolapse through a patent omphalomesenteric duct. A case report and review of literature. Acta Chir Belg. 1988;88:392-394.
The solution to EHR woes: A team-based care model
For some time, electronic health records (EHRs) have been the focus of many articles (“EHR use and patient satisfaction: What we learned.” J Fam Pract. 2015;64:687-696) and the source of great debate (and frustration) in the health care community. But there’s a logical solution to the dilemmas created by EHRs: A team-based care model.1
A fundamental principle of team-based care is that all members of the team work at the top of their skill set. So, with that in mind, most of the duties of EHR management should be delegated to other team members, rather than to the physicians. In our system, every physician works with 2 other people—certified medical assistants or licensed practical nurses—who help with standing orders, protocols, templates, and many of the EHR duties, including a significant portion of team documentation. They do this while recognizing and respecting guidelines from the Centers for Medicare & Medicaid Services and other payers. That leaves the physicians and advanced practice clinicians the time they need to focus on the patient during the visit.
Not surprisingly, patient satisfaction, staff satisfaction, and quality measures are all improving with this model of care. It is proving financially viable, as well. This model may well be the future of health care delivery for office-based practices.2
Jim Jerzak, MD
Green Bay, Wis
1. Sinsky CA, Willard-Grace R, Schutzbank AM, et al. In search of joy in practice: a report of 23 high-functioning primary care practices. Ann Fam Med. 2013;11:272-278.
2. Ghorob A, Bodenheimer T. Building teams in primary care: A practical guide. Fam Syst Health. 2015;33:182-192.
For some time, electronic health records (EHRs) have been the focus of many articles (“EHR use and patient satisfaction: What we learned.” J Fam Pract. 2015;64:687-696) and the source of great debate (and frustration) in the health care community. But there’s a logical solution to the dilemmas created by EHRs: A team-based care model.1
A fundamental principle of team-based care is that all members of the team work at the top of their skill set. So, with that in mind, most of the duties of EHR management should be delegated to other team members, rather than to the physicians. In our system, every physician works with 2 other people—certified medical assistants or licensed practical nurses—who help with standing orders, protocols, templates, and many of the EHR duties, including a significant portion of team documentation. They do this while recognizing and respecting guidelines from the Centers for Medicare & Medicaid Services and other payers. That leaves the physicians and advanced practice clinicians the time they need to focus on the patient during the visit.
Not surprisingly, patient satisfaction, staff satisfaction, and quality measures are all improving with this model of care. It is proving financially viable, as well. This model may well be the future of health care delivery for office-based practices.2
Jim Jerzak, MD
Green Bay, Wis
1. Sinsky CA, Willard-Grace R, Schutzbank AM, et al. In search of joy in practice: a report of 23 high-functioning primary care practices. Ann Fam Med. 2013;11:272-278.
2. Ghorob A, Bodenheimer T. Building teams in primary care: A practical guide. Fam Syst Health. 2015;33:182-192.
For some time, electronic health records (EHRs) have been the focus of many articles (“EHR use and patient satisfaction: What we learned.” J Fam Pract. 2015;64:687-696) and the source of great debate (and frustration) in the health care community. But there’s a logical solution to the dilemmas created by EHRs: A team-based care model.1
A fundamental principle of team-based care is that all members of the team work at the top of their skill set. So, with that in mind, most of the duties of EHR management should be delegated to other team members, rather than to the physicians. In our system, every physician works with 2 other people—certified medical assistants or licensed practical nurses—who help with standing orders, protocols, templates, and many of the EHR duties, including a significant portion of team documentation. They do this while recognizing and respecting guidelines from the Centers for Medicare & Medicaid Services and other payers. That leaves the physicians and advanced practice clinicians the time they need to focus on the patient during the visit.
Not surprisingly, patient satisfaction, staff satisfaction, and quality measures are all improving with this model of care. It is proving financially viable, as well. This model may well be the future of health care delivery for office-based practices.2
Jim Jerzak, MD
Green Bay, Wis
1. Sinsky CA, Willard-Grace R, Schutzbank AM, et al. In search of joy in practice: a report of 23 high-functioning primary care practices. Ann Fam Med. 2013;11:272-278.
2. Ghorob A, Bodenheimer T. Building teams in primary care: A practical guide. Fam Syst Health. 2015;33:182-192.
Personality disorders: A measured response
› Maintain a high index of suspicion for personality disorders (PDs) in patients who appear to be “difficult,” and take care to distinguish these diagnoses from primary mood, anxiety, and psychotic disorders. C
› Refer patients with PDs for psychotherapy, as it is considered the mainstay of treatment—particularly for borderline PD. B
› Use pharmacotherapy judiciously as an adjunctive treatment for PD. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Personality disorders (PDs) are common, affecting up to 15% of US adults, and are associated with comorbid medical and psychiatric conditions and increased utilization of health care resources.1,2 Having a basic understanding of these patterns of thinking and behaving can help family physicians (FPs) identify specific PD diagnoses, ensure appropriate treatment, and reduce the frustration that arises when an individual is viewed as a “difficult patient.”
Here we describe the diagnostic features of the disorders in the 3 major clusters of PDs and review an effective approach to the management of the most common disorder in each cluster, using a case study patient.
Defense mechanisms offer clues that your patient may have a PD
Personality is an enduring pattern of inner experience and behaviors that is relatively stable across time and in different situations. Such traits comprise an individual’s inherent makeup.1 PDs are diagnosed when an individual’s personality traits create significant distress or impairment in daily functioning. Specifically, PDs have a negative impact on cognition, affect, interpersonal relationships, and/or impulse control.1
One of the ways people alleviate distress is by using defense mechanisms. Defense mechanisms are unconscious mental processes that individuals use to resolve conflicts, and thereby reduce anxiety and depression on a conscious level. Taken alone, defense mechanisms are not pathologic, but they may become maladaptive in certain stressful circumstances, such as when receiving medical treatment. Recognizing patterns of chronic use of certain defense mechanisms may be a clue that your patient has a PD. TABLE 13,4 and TABLE 23,4 provide an overview of common defense mechanisms used by patients with PDs.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) organizes PDs into 3 clusters based on similar and often overlapping symptoms.1TABLE 31 provides a brief summary of the characteristic features of each disorder in these clusters.
Cluster A: Odd, eccentric
Patients with one of these disorders are odd, eccentric, or bizarre in their behavior and thinking. There appears to be a genetic link between cluster A PDs (especially schizotypal) and schizophrenia.5 These patients rarely seek treatment for their disorder because they have limited insight into their maladaptive traits.5,6
CASE 1 › Daniel A, age 57, has hypertension and hyperlipidemia and comes in to see his FP for a 6-month follow-up appointment. He never misses appointments, but has a history of poor adherence with prescribed medications. He enjoys his discussions with you in the office, although he often perseverates on conspiracy theories. He lives alone and has never been married. He believes that some of the previously prescribed medications, including a statin and a thiazide diuretic, were interfering with the absorption of “positive nutrients” in his diet. He also refuses to take the generic form of a statin, which he believes was adulterated by the government to be sold at lower cost.
Mr. A demonstrates the odd and eccentric beliefs that characterize schizotypal personality disorder. How can his FP best help him adhere to his medication regimen? (For the answer, click here.)
Schizotypal personality disorder shares certain disturbances of thought with schizophrenia, and is believed to exist on a spectrum with other primary psychotic disorders. Support for this theory comes from the higher rates of schizotypal PD among family members of patients with schizophrenia. There is a genetic component to the disorder.3,5,6
Clinically, these patients appear odd and eccentric with unusual beliefs. They may have a fascination with magic, clairvoyance, telepathy, or other such notions.1,5 Although the perceptual disturbances are unusual and often bizarre, they are not frank delusions: patients with schizotypal PD are willing to consider alternative explanations for their beliefs and can engage in rational discussion. Cognitive deficits, particularly of memory and attention, are common and distressing to patients. Frequently, the presenting complaint is depression and anxiety due to the emotional discord and isolation from others.1,3,5,6
Continue to cluster B >>
Cluster B: Dramatic, erratic
Patients with cluster B PDs are dramatic, excessively emotional, confrontational, erratic, and impulsive in their behaviors.1 They often have comorbid mood and anxiety disorders, as well as a disproportionately high co-occurrence of functional disorders.3,7 Their rates of health care utilization can be substantial. Because individuals with one of these PDs sometimes exhibit reckless and impulsive behavior, physicians should be aware these patients have a high risk of physical injuries (fights, accidents, self-injurious behavior), suicide attempts, risky sexual behaviors, and unplanned pregnancy.8,9
CASE 2 › Sheryl B is a 34-year-old new patient with a history of irritable bowel syndrome, fibromyalgia, depression, and anxiety who shows up for her appointment an hour late. She is upset and blames the office scheduler for not reminding her of the appointment. She brings a list of medications from her previous physician that includes sertraline, clonazepam, gabapentin, oxycodone, and as-needed alprazolam. She insists that her physician increase the dose of the benzodiazepines.
A review of her medical history reveals diagnoses of anxiety, bipolar disorder, and posttraumatic stress disorder. Ms. B has also engaged in superficial cutting since adolescence, often triggered by arguments with her boyfriend. Currently, she attributes her anxiety and pain to not receiving the “correct medications” because of her transition from a previous physician who “knew her better than any other doctor.” After the FP explains to Ms. B that he would have to carefully review her case before continuing to prescribe benzodiazepines, she becomes tearful and argumentative, proclaiming, “You won’t give me the only thing that will help me because you want me to be miserable!”
Ms. B exhibits many cluster B personality traits consistent with borderline PD. How should the FP respond to her claims? (For the answer, click here.)
Borderline PD is the most studied of the PDs. It can be a stigmatizing diagnosis, and even experienced psychiatrists may hesitate to inform patients of this diagnosis.10 Patients with borderline PD may be erroneously diagnosed with bipolar disorder, treatment-resistant depression, or posttraumatic stress disorder because of a complicated clinical presentation, physician unfamiliarity with diagnostic criteria, or the presence of genuine comorbid conditions.3,11
The etiology of this disorder appears to be multifactorial, and includes genetic predisposition, disruptive parent-child relationships (especially separation), and, often, past sexual or physical trauma.9,12
Predominant clinical features include emotional lability, efforts to avoid abandonment, extremes of idealization and devaluation, unstable and intense interpersonal relationships, and impulsivity.1 Characteristically, these patients also engage in self-injurious behaviors.13,14 Common defense mechanisms used by patients with borderline PD include splitting (viewing others as either all good or all bad), acting out (yelling, agitation, or violence), and passive aggression (TABLE 13,4).
Cluster C: Anxious, fearful
Individuals with cluster C PDs appear anxious, fearful, and worried. They have features that overlap with anxiety disorders.15
CASE 3 › Judy C is a 40-year-old lawyer with a history of gastroesophageal reflux disorder, hypertension, and anxiety who presents for a 3-week follow-up visit after starting sertraline. The patient describes herself as a perfectionist who has increased work-related stress recently because she has to “do extra work for my colleagues who don’t know how to get things done right.” She recently fired her assistant for “not understanding my filing system.” She appears formal and serious, often looking at her watch during the evaluation.
Ms. C demonstrates a pattern of perfectionism, formality, and rigidity in thought and behavior characteristic of obsessive-compulsive PD. What treatment should her physician recommend? (For the answer, click here.)
Obsessive-compulsive PD. Although this disorder is associated with significant anxiety, patients often view the specific traits of obsessive-compulsive PD, such as perfectionism, as desirable. Neurotic defense mechanisms are common, especially rationalization, intellectualization, and isolation of affect (TABLE 23,4). These patients appear formal, rigid, and serious, and are preoccupied with rules and orderliness to achieve perfection.1 Significant anxiety often arises from fear of making mistakes and ruminating on decision-making.1,11,15
Although some overlap exists between obsessive-compulsive disorder (OCD) and obsessive-compulsive PD, patients with OCD exhibit distinct obsessions and associated compulsive behavior, whereas those with obsessive-compulsive PD do not.1
In terms of treatment, it is generally appropriate to recognize the 2 conditions as distinct entities.15 OCD responds well to cognitive behavioral therapies and high-dose selective serotonin reuptake inhibitors (SSRIs).16 In contrast, there is little data that suggests antidepressants are effective for obsessive-compulsive PD, and treatment is aimed at addressing comorbid anxiety with psychotherapy and pharmacotherapy, if needed.11,15
Continue to psychotherapy for PD is the first-line treatment >>
Psychotherapy for PD is the first-line treatment
Psychotherapy is the most effective treatment for PDs.11,17,18 Several psychotherapies are used to treat these disorders, including dialectical behavioral therapy, schema therapy, and cognitive behavioral therapy (CBT). A recent study demonstrated the superiority of several evidence-based psychotherapies for PD compared to treatment-as-usual.17 Even more promising is that certain benefits have been demonstrated when psychotherapy is provided by clinicians without advanced mental health training.19-21 However, the benefits of therapies for specific disorders are often limited by lack of available data, patient preference, and accessibility of resources.
Limited evidence supports pharmacotherapy
The use of pharmacotherapy for treating PDs is common, although there’s limited evidence to support the practice.11,22 Certain circumstances may allow for the judicious use of medication, although prescribing strategies are based largely on clinical experience and expert opinion.
Prescribers should emphasize a realistic perspective on treatment response, because research suggests at best a mild-moderate response of some personality traits to pharmacotherapy.11,22-25 There is no evidence for polypharmacy in treating PDs, and FPs should allow for sufficient treatment duration, switch medications rather than augment ineffective treatments, and resist the urge to prescribe for every psychological crisis.11,22,25,26
Patient safety should always be a consideration when prescribing medication. Because use of second-generation antipsychotics is associated with the metabolic syndrome, the patient’s baseline weight and fasting glucose, lipids, and hemoglobin A1c levels should be obtained and monitored regularly. Weight gain can be particularly distressing to patients, increase stress and anxiety, and hinder the doctor-patient relationship.25 Finally, medications with abuse potential or that can be lethal in overdose (eg, tricyclic antidepressants and benzodiazepines) are best avoided in patients with emotional lability and impulsivity.25,26
Tailor treatment to the specific PD
Tx for cluster A disorders. Few studies have examined the effectiveness of psychotherapies for cluster A disorders. Cognitive therapy may have benefit in addressing cognitive distortions and social impairment in schizotypal PD.11,12,22 There is little evidence supporting psychotherapy for paranoid PD, because challenging patients’ beliefs in this form is likely to exacerbate paranoia. Low-dose risperidone has demonstrated some beneficial effects on perceptual disturbances; however, the adverse metabolic effects of this medication may outweigh any potential benefit, as these symptoms are often not distressing to patients.6,27 In comparison, patients often find deficits in memory and attention to be more bothersome, and some data suggest that the alpha-2 agonist guanfacine may help treat these symptoms.28
Tx for cluster B disorders. Several forms of psychotherapy have proven effective in managing symptoms and improving overall functioning in patients with borderline PD, including dialectical behavioral therapy, mentalization-based therapy, transference-focused therapy, and schema therapy.29 Dialectical behavioral therapy is often the initial treatment because it emphasizes reducing self-harm behaviors and emotion regulation.11,17,26
Gunderson19 developed a more basic approach to treating borderline PD that is intended to be used by all clinicians who treat the disorder, and not just mental health professionals with advanced training in psychotherapy. A large, multisite randomized controlled trial found that the clinical efficacy of the technique, known as good psychiatric management, rivaled that of dialectical behavioral therapy.20,21
The general premise is that clinicians foster a therapeutic relationship that is supportive, engaging, and flexible. Physicians are encouraged to educate patients about the disorder and emphasize improvement in daily functioning. Clinicians should share the diagnosis with patients, which may give patients a sense of relief in having an accurate diagnosis and allow them to fully invest in diagnosis-specific treatments.19
Systematic reviews and meta-analyses of studies that evaluated pharmacotherapy for borderline PD often have had conflicting conclusions as a result of analyzing data from underpowered studies with varying study designs.23,24,26,30,31 In targeting specific symptoms of the disorder, the most consistent evidence has supported the use of antipsychotics for cognitive perceptual disturbances; patients commonly experience depersonalization or out-of-body experiences.25 Additionally, the use of antipsychotics and mood stabilizers (lamotrigine and topiramate) appears to be somewhat effective for managing emotional lability and impulsivity.26,32,33 Despite the widespread use of SSRIs, a recent systematic review found the least support for these and other antidepressants for management of borderline PD.25
Tx for cluster C disorders. Some evidence supports using cognitive and interpersonal psychotherapies to treat cluster C PDs.34 In contrast, there is little evidence to support the use of pharmacotherapy.35 However, given the significant overlap among these disorders (especially avoidant PD) and social phobia and generalized anxiety disorder, effective pharmacologic strategies can be inferred based on data for those conditions.11 SSRIs, serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine), and gabapentin have demonstrated efficacy in anxiety disorders and are reasonable and safe initial treatments for patients with a cluster C PD.11,34
Continue for the answers >>
CASE 1 › Mr. A’s schizotypal PD symptoms interfere with medication adherence because of his unusual belief system. Importantly, unlike patients with frank delusions, patients with schizotypal PD are willing to consider alternative explanations for their unusual beliefs. Mr. A’s intense suspiciousness may indicate some degree of overlap between paranoid and schizotypal PDs.
The FP is patient and willing to listen to Mr. A’s beliefs without devaluing them. To improve medication adherence, the FP offers him reasonable alternatives with clear explanations. (“I understand you have concerns about previous medications. At the same time, it seems that managing your blood pressure and cholesterol is important to you. Can we discuss alternative treatments?”)
CASE 2 › In response to Ms. B’s borderline PD, the FP must be cautious to avoid reacting out of frustration, which may upset the patient and validate her mistrust. The FP first reflects her anger (“I can tell you are upset because you don’t think I want to help you”), which may allow her to calmly engage in a discussion. He wants to recognize Ms. B’s dramatic behavior, but not reward it with added attention and unreasonable concessions. To help establish rapport, he provides a statement to legitimize Ms. B’s concerns (“Many patients would be frustrated during the process of changing physicians”).
The FP listens empathically to Ms. B, sets clear limits, and provides consistent and evidence-based treatments. He also provides early referral to psychotherapy, but to mitigate any perceived abandonment, he assures Ms. B he will remain involved with her treatment. (“It sounds like managing your anxiety is important to you, and often psychiatrists or therapists can help give additional options for treatment. I want you to know that I am still your doctor and we can review their recommendations together at our next visit.”)
CASE 3 › The FP recognizes that Ms. C’s pattern of perfectionism, formality, and rigidity in thought and behavior are likely a manifestation of obsessive-compulsive PD, and that the maladaptive psychological traits underlying her anxiety are distinct from a primary anxiety disorder.
An SSRI may be a reasonable option to treat Ms. B’s anxiety, and the FP also refers her for CBT. (“I can tell you are feeling really anxious and many people feel that way, especially with work. I think the medication is a good start, but I wonder if we could discuss other forms of therapy to maximize your symptom improvement.”) Because of their exacting nature, many patients with cluster C personality traits are willing to engage in treatments, especially if they are supported by data and recommended by a knowledgeable physician.
CORRESPONDENCE
Nicholas Morcos, Department of Psychiatry, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109; [email protected].
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
2. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
3. Cloninger C, Svrakie D. Personality disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry. 11th ed. Philadelphia, Pa: Wolters Kluwer; 2015:2197-2240.
4. Bowins B. Personality disorders: a dimensional defense mechanism approach. Am J Psychother. 2010;64:153-169.
5. Raine A. Schizotypal personality: neurodevelopmental and psychosocial trajectories. Annu Rev Clin Psychol. 2006;2:291-326.
6. Rosell DR, Futterman SE, McMaster A, et al. Schizotypal personality disorder: a current review. Curr Psychiatry Rep. 2014;16:452.
7. Gabbard GO, Simonsen E. Complex Case: The impact of personality and personality disorders on the treatment of depression. Personal Ment Health. 2007;1:161-175.
8. Caspi A, Begg D, Dickson N, et al. Personality differences predict health-risk behaviors in young adulthood: evidence from a longitudinal study. J Pers Soc Psychol. 1997;73:1052-1063.
9. Tomko RL, Trull TJ, Wood PK, et al. Characteristics of borderline personality disorder in a community sample: comorbidity, treatment utilization, and general functioning. J Pers Disord. 2014;28:734-750.
10. Vaillant GE. The beginning of wisdom is never calling a patient a borderline; or, the clinical management of immature defenses in the treatment of individuals with personality disorders. J Psychother Pract Res. 1992;1:117-134.
11. Bateman AW, Gunderson J, Mulder R. Treatment of personality disorder. Lancet. 2015;385:735-743.
12. Beck AT, Davis DD, Freeman A, eds. Cognitive therapy of personality disorders. 3rd ed. New York, NY: Guilford Press, 2015.
13. O’Connor RC, Nock MK. The psychology of suicidal behaviour. Lancet Psychiatry. 2014;1:73-85.
14. Paris J. Understanding self-mutilation in borderline personality disorder. Harv Rev Psychiatry. 2005;13:179-185.
15. Diedrich A, Voderholzer U. Obsessive-compulsive personality disorder: a current review. Curr Psychiatry Rep. 2015;17:2.
16. Pittenger C, Bloch MH. Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014;37:375-391.
17. Budge SL, Moore JT, Del Re AC, et al. The effectiveness of evidence-based treatments for personality disorders when comparing treatment-as-usual and bona fide treatments. Clin Psychol Rev. 2013;33:1057-1066.
18. Leichsenring F, Leibing E. The effectiveness of psychodynamic therapy and cognitive behavior therapy in the treatment of personality disorders: a meta-analysis. Am J Psychiatry. 2003;160:1223-1232.
19. Gunderson JG, Links PS. Handbook of good psychiatric management for borderline personality disorder. Washington, DC: American Psychiatric Publishing, 2014.
20. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
21. McMain SF, Guimond T, Streiner DL, et al. Dialectical behavior therapy compared with general psychiatric management for borderline personality disorder: clinical outcomes and functioning over a 2-year follow-up. Am J Psychiatry. 2012;169:650-661.
22. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
23. Coccaro EF. Clinical outcome of psychopharmacologic treatment of borderline and schizotypal personality disordered subjects. J Clin Psychiatry. 1998;59:30-35.
24. Soloff PH. Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation. Bull Menninger Clin. 1998;62:195-214.
25. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
26. Saunders EF, Silk KR. Personality trait dimensions and the pharmacological treatment of borderline personality disorder. J Clin Psychopharmacol. 2009;29:461-467.
27. Koenigsberg HW, Reynolds D, Goodman M, et al. Risperidone in the treatment of schizotypal personality disorder. J Clin Psychiatry. 2003;64:628-634.
28. McClure MM, Barch DM, Romero MJ, et al. The effects of guanfacine on context processing abnormalities in schizotypal personality disorder. Biol Psychiatry. 2007;61:1157-1160.
29. Stoffers JM, Vollm BA, Rucker G, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2012;8:CD005652.
30. Siever LJ, Davis KL. A psychobiological perspective on the personality disorders. Am J Psychiatry. 1991;148:1647-1658.
31. Binks CA, Fenton M, McCarthy L, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006:CD005653.
32. Nickel MK, Nickel C, Kaplan P, et al. Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study. Biol Psychiatry. 2005;57:495-499.
33. Tritt K, Nickel C, Lahmann C, et al. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo-controlled study. J Psychopharmacol. 2005;19:287-291.
34. Simon W. Follow-up psychotherapy outcome of patients with dependent, avoidant and obsessive-compulsive personality disorders: A meta-analytic review. Int J Psychiatry Clin Pract. 2009;13:153-165.
35. Ansseau M, Troisfontaines B, Papart P, et al. Compulsive personality as predictor of response to serotoninergic antidepressants. BMJ. 1991;303:760-761.
› Maintain a high index of suspicion for personality disorders (PDs) in patients who appear to be “difficult,” and take care to distinguish these diagnoses from primary mood, anxiety, and psychotic disorders. C
› Refer patients with PDs for psychotherapy, as it is considered the mainstay of treatment—particularly for borderline PD. B
› Use pharmacotherapy judiciously as an adjunctive treatment for PD. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Personality disorders (PDs) are common, affecting up to 15% of US adults, and are associated with comorbid medical and psychiatric conditions and increased utilization of health care resources.1,2 Having a basic understanding of these patterns of thinking and behaving can help family physicians (FPs) identify specific PD diagnoses, ensure appropriate treatment, and reduce the frustration that arises when an individual is viewed as a “difficult patient.”
Here we describe the diagnostic features of the disorders in the 3 major clusters of PDs and review an effective approach to the management of the most common disorder in each cluster, using a case study patient.
Defense mechanisms offer clues that your patient may have a PD
Personality is an enduring pattern of inner experience and behaviors that is relatively stable across time and in different situations. Such traits comprise an individual’s inherent makeup.1 PDs are diagnosed when an individual’s personality traits create significant distress or impairment in daily functioning. Specifically, PDs have a negative impact on cognition, affect, interpersonal relationships, and/or impulse control.1
One of the ways people alleviate distress is by using defense mechanisms. Defense mechanisms are unconscious mental processes that individuals use to resolve conflicts, and thereby reduce anxiety and depression on a conscious level. Taken alone, defense mechanisms are not pathologic, but they may become maladaptive in certain stressful circumstances, such as when receiving medical treatment. Recognizing patterns of chronic use of certain defense mechanisms may be a clue that your patient has a PD. TABLE 13,4 and TABLE 23,4 provide an overview of common defense mechanisms used by patients with PDs.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) organizes PDs into 3 clusters based on similar and often overlapping symptoms.1TABLE 31 provides a brief summary of the characteristic features of each disorder in these clusters.
Cluster A: Odd, eccentric
Patients with one of these disorders are odd, eccentric, or bizarre in their behavior and thinking. There appears to be a genetic link between cluster A PDs (especially schizotypal) and schizophrenia.5 These patients rarely seek treatment for their disorder because they have limited insight into their maladaptive traits.5,6
CASE 1 › Daniel A, age 57, has hypertension and hyperlipidemia and comes in to see his FP for a 6-month follow-up appointment. He never misses appointments, but has a history of poor adherence with prescribed medications. He enjoys his discussions with you in the office, although he often perseverates on conspiracy theories. He lives alone and has never been married. He believes that some of the previously prescribed medications, including a statin and a thiazide diuretic, were interfering with the absorption of “positive nutrients” in his diet. He also refuses to take the generic form of a statin, which he believes was adulterated by the government to be sold at lower cost.
Mr. A demonstrates the odd and eccentric beliefs that characterize schizotypal personality disorder. How can his FP best help him adhere to his medication regimen? (For the answer, click here.)
Schizotypal personality disorder shares certain disturbances of thought with schizophrenia, and is believed to exist on a spectrum with other primary psychotic disorders. Support for this theory comes from the higher rates of schizotypal PD among family members of patients with schizophrenia. There is a genetic component to the disorder.3,5,6
Clinically, these patients appear odd and eccentric with unusual beliefs. They may have a fascination with magic, clairvoyance, telepathy, or other such notions.1,5 Although the perceptual disturbances are unusual and often bizarre, they are not frank delusions: patients with schizotypal PD are willing to consider alternative explanations for their beliefs and can engage in rational discussion. Cognitive deficits, particularly of memory and attention, are common and distressing to patients. Frequently, the presenting complaint is depression and anxiety due to the emotional discord and isolation from others.1,3,5,6
Continue to cluster B >>
Cluster B: Dramatic, erratic
Patients with cluster B PDs are dramatic, excessively emotional, confrontational, erratic, and impulsive in their behaviors.1 They often have comorbid mood and anxiety disorders, as well as a disproportionately high co-occurrence of functional disorders.3,7 Their rates of health care utilization can be substantial. Because individuals with one of these PDs sometimes exhibit reckless and impulsive behavior, physicians should be aware these patients have a high risk of physical injuries (fights, accidents, self-injurious behavior), suicide attempts, risky sexual behaviors, and unplanned pregnancy.8,9
CASE 2 › Sheryl B is a 34-year-old new patient with a history of irritable bowel syndrome, fibromyalgia, depression, and anxiety who shows up for her appointment an hour late. She is upset and blames the office scheduler for not reminding her of the appointment. She brings a list of medications from her previous physician that includes sertraline, clonazepam, gabapentin, oxycodone, and as-needed alprazolam. She insists that her physician increase the dose of the benzodiazepines.
A review of her medical history reveals diagnoses of anxiety, bipolar disorder, and posttraumatic stress disorder. Ms. B has also engaged in superficial cutting since adolescence, often triggered by arguments with her boyfriend. Currently, she attributes her anxiety and pain to not receiving the “correct medications” because of her transition from a previous physician who “knew her better than any other doctor.” After the FP explains to Ms. B that he would have to carefully review her case before continuing to prescribe benzodiazepines, she becomes tearful and argumentative, proclaiming, “You won’t give me the only thing that will help me because you want me to be miserable!”
Ms. B exhibits many cluster B personality traits consistent with borderline PD. How should the FP respond to her claims? (For the answer, click here.)
Borderline PD is the most studied of the PDs. It can be a stigmatizing diagnosis, and even experienced psychiatrists may hesitate to inform patients of this diagnosis.10 Patients with borderline PD may be erroneously diagnosed with bipolar disorder, treatment-resistant depression, or posttraumatic stress disorder because of a complicated clinical presentation, physician unfamiliarity with diagnostic criteria, or the presence of genuine comorbid conditions.3,11
The etiology of this disorder appears to be multifactorial, and includes genetic predisposition, disruptive parent-child relationships (especially separation), and, often, past sexual or physical trauma.9,12
Predominant clinical features include emotional lability, efforts to avoid abandonment, extremes of idealization and devaluation, unstable and intense interpersonal relationships, and impulsivity.1 Characteristically, these patients also engage in self-injurious behaviors.13,14 Common defense mechanisms used by patients with borderline PD include splitting (viewing others as either all good or all bad), acting out (yelling, agitation, or violence), and passive aggression (TABLE 13,4).
Cluster C: Anxious, fearful
Individuals with cluster C PDs appear anxious, fearful, and worried. They have features that overlap with anxiety disorders.15
CASE 3 › Judy C is a 40-year-old lawyer with a history of gastroesophageal reflux disorder, hypertension, and anxiety who presents for a 3-week follow-up visit after starting sertraline. The patient describes herself as a perfectionist who has increased work-related stress recently because she has to “do extra work for my colleagues who don’t know how to get things done right.” She recently fired her assistant for “not understanding my filing system.” She appears formal and serious, often looking at her watch during the evaluation.
Ms. C demonstrates a pattern of perfectionism, formality, and rigidity in thought and behavior characteristic of obsessive-compulsive PD. What treatment should her physician recommend? (For the answer, click here.)
Obsessive-compulsive PD. Although this disorder is associated with significant anxiety, patients often view the specific traits of obsessive-compulsive PD, such as perfectionism, as desirable. Neurotic defense mechanisms are common, especially rationalization, intellectualization, and isolation of affect (TABLE 23,4). These patients appear formal, rigid, and serious, and are preoccupied with rules and orderliness to achieve perfection.1 Significant anxiety often arises from fear of making mistakes and ruminating on decision-making.1,11,15
Although some overlap exists between obsessive-compulsive disorder (OCD) and obsessive-compulsive PD, patients with OCD exhibit distinct obsessions and associated compulsive behavior, whereas those with obsessive-compulsive PD do not.1
In terms of treatment, it is generally appropriate to recognize the 2 conditions as distinct entities.15 OCD responds well to cognitive behavioral therapies and high-dose selective serotonin reuptake inhibitors (SSRIs).16 In contrast, there is little data that suggests antidepressants are effective for obsessive-compulsive PD, and treatment is aimed at addressing comorbid anxiety with psychotherapy and pharmacotherapy, if needed.11,15
Continue to psychotherapy for PD is the first-line treatment >>
Psychotherapy for PD is the first-line treatment
Psychotherapy is the most effective treatment for PDs.11,17,18 Several psychotherapies are used to treat these disorders, including dialectical behavioral therapy, schema therapy, and cognitive behavioral therapy (CBT). A recent study demonstrated the superiority of several evidence-based psychotherapies for PD compared to treatment-as-usual.17 Even more promising is that certain benefits have been demonstrated when psychotherapy is provided by clinicians without advanced mental health training.19-21 However, the benefits of therapies for specific disorders are often limited by lack of available data, patient preference, and accessibility of resources.
Limited evidence supports pharmacotherapy
The use of pharmacotherapy for treating PDs is common, although there’s limited evidence to support the practice.11,22 Certain circumstances may allow for the judicious use of medication, although prescribing strategies are based largely on clinical experience and expert opinion.
Prescribers should emphasize a realistic perspective on treatment response, because research suggests at best a mild-moderate response of some personality traits to pharmacotherapy.11,22-25 There is no evidence for polypharmacy in treating PDs, and FPs should allow for sufficient treatment duration, switch medications rather than augment ineffective treatments, and resist the urge to prescribe for every psychological crisis.11,22,25,26
Patient safety should always be a consideration when prescribing medication. Because use of second-generation antipsychotics is associated with the metabolic syndrome, the patient’s baseline weight and fasting glucose, lipids, and hemoglobin A1c levels should be obtained and monitored regularly. Weight gain can be particularly distressing to patients, increase stress and anxiety, and hinder the doctor-patient relationship.25 Finally, medications with abuse potential or that can be lethal in overdose (eg, tricyclic antidepressants and benzodiazepines) are best avoided in patients with emotional lability and impulsivity.25,26
Tailor treatment to the specific PD
Tx for cluster A disorders. Few studies have examined the effectiveness of psychotherapies for cluster A disorders. Cognitive therapy may have benefit in addressing cognitive distortions and social impairment in schizotypal PD.11,12,22 There is little evidence supporting psychotherapy for paranoid PD, because challenging patients’ beliefs in this form is likely to exacerbate paranoia. Low-dose risperidone has demonstrated some beneficial effects on perceptual disturbances; however, the adverse metabolic effects of this medication may outweigh any potential benefit, as these symptoms are often not distressing to patients.6,27 In comparison, patients often find deficits in memory and attention to be more bothersome, and some data suggest that the alpha-2 agonist guanfacine may help treat these symptoms.28
Tx for cluster B disorders. Several forms of psychotherapy have proven effective in managing symptoms and improving overall functioning in patients with borderline PD, including dialectical behavioral therapy, mentalization-based therapy, transference-focused therapy, and schema therapy.29 Dialectical behavioral therapy is often the initial treatment because it emphasizes reducing self-harm behaviors and emotion regulation.11,17,26
Gunderson19 developed a more basic approach to treating borderline PD that is intended to be used by all clinicians who treat the disorder, and not just mental health professionals with advanced training in psychotherapy. A large, multisite randomized controlled trial found that the clinical efficacy of the technique, known as good psychiatric management, rivaled that of dialectical behavioral therapy.20,21
The general premise is that clinicians foster a therapeutic relationship that is supportive, engaging, and flexible. Physicians are encouraged to educate patients about the disorder and emphasize improvement in daily functioning. Clinicians should share the diagnosis with patients, which may give patients a sense of relief in having an accurate diagnosis and allow them to fully invest in diagnosis-specific treatments.19
Systematic reviews and meta-analyses of studies that evaluated pharmacotherapy for borderline PD often have had conflicting conclusions as a result of analyzing data from underpowered studies with varying study designs.23,24,26,30,31 In targeting specific symptoms of the disorder, the most consistent evidence has supported the use of antipsychotics for cognitive perceptual disturbances; patients commonly experience depersonalization or out-of-body experiences.25 Additionally, the use of antipsychotics and mood stabilizers (lamotrigine and topiramate) appears to be somewhat effective for managing emotional lability and impulsivity.26,32,33 Despite the widespread use of SSRIs, a recent systematic review found the least support for these and other antidepressants for management of borderline PD.25
Tx for cluster C disorders. Some evidence supports using cognitive and interpersonal psychotherapies to treat cluster C PDs.34 In contrast, there is little evidence to support the use of pharmacotherapy.35 However, given the significant overlap among these disorders (especially avoidant PD) and social phobia and generalized anxiety disorder, effective pharmacologic strategies can be inferred based on data for those conditions.11 SSRIs, serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine), and gabapentin have demonstrated efficacy in anxiety disorders and are reasonable and safe initial treatments for patients with a cluster C PD.11,34
Continue for the answers >>
CASE 1 › Mr. A’s schizotypal PD symptoms interfere with medication adherence because of his unusual belief system. Importantly, unlike patients with frank delusions, patients with schizotypal PD are willing to consider alternative explanations for their unusual beliefs. Mr. A’s intense suspiciousness may indicate some degree of overlap between paranoid and schizotypal PDs.
The FP is patient and willing to listen to Mr. A’s beliefs without devaluing them. To improve medication adherence, the FP offers him reasonable alternatives with clear explanations. (“I understand you have concerns about previous medications. At the same time, it seems that managing your blood pressure and cholesterol is important to you. Can we discuss alternative treatments?”)
CASE 2 › In response to Ms. B’s borderline PD, the FP must be cautious to avoid reacting out of frustration, which may upset the patient and validate her mistrust. The FP first reflects her anger (“I can tell you are upset because you don’t think I want to help you”), which may allow her to calmly engage in a discussion. He wants to recognize Ms. B’s dramatic behavior, but not reward it with added attention and unreasonable concessions. To help establish rapport, he provides a statement to legitimize Ms. B’s concerns (“Many patients would be frustrated during the process of changing physicians”).
The FP listens empathically to Ms. B, sets clear limits, and provides consistent and evidence-based treatments. He also provides early referral to psychotherapy, but to mitigate any perceived abandonment, he assures Ms. B he will remain involved with her treatment. (“It sounds like managing your anxiety is important to you, and often psychiatrists or therapists can help give additional options for treatment. I want you to know that I am still your doctor and we can review their recommendations together at our next visit.”)
CASE 3 › The FP recognizes that Ms. C’s pattern of perfectionism, formality, and rigidity in thought and behavior are likely a manifestation of obsessive-compulsive PD, and that the maladaptive psychological traits underlying her anxiety are distinct from a primary anxiety disorder.
An SSRI may be a reasonable option to treat Ms. B’s anxiety, and the FP also refers her for CBT. (“I can tell you are feeling really anxious and many people feel that way, especially with work. I think the medication is a good start, but I wonder if we could discuss other forms of therapy to maximize your symptom improvement.”) Because of their exacting nature, many patients with cluster C personality traits are willing to engage in treatments, especially if they are supported by data and recommended by a knowledgeable physician.
CORRESPONDENCE
Nicholas Morcos, Department of Psychiatry, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109; [email protected].
› Maintain a high index of suspicion for personality disorders (PDs) in patients who appear to be “difficult,” and take care to distinguish these diagnoses from primary mood, anxiety, and psychotic disorders. C
› Refer patients with PDs for psychotherapy, as it is considered the mainstay of treatment—particularly for borderline PD. B
› Use pharmacotherapy judiciously as an adjunctive treatment for PD. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Personality disorders (PDs) are common, affecting up to 15% of US adults, and are associated with comorbid medical and psychiatric conditions and increased utilization of health care resources.1,2 Having a basic understanding of these patterns of thinking and behaving can help family physicians (FPs) identify specific PD diagnoses, ensure appropriate treatment, and reduce the frustration that arises when an individual is viewed as a “difficult patient.”
Here we describe the diagnostic features of the disorders in the 3 major clusters of PDs and review an effective approach to the management of the most common disorder in each cluster, using a case study patient.
Defense mechanisms offer clues that your patient may have a PD
Personality is an enduring pattern of inner experience and behaviors that is relatively stable across time and in different situations. Such traits comprise an individual’s inherent makeup.1 PDs are diagnosed when an individual’s personality traits create significant distress or impairment in daily functioning. Specifically, PDs have a negative impact on cognition, affect, interpersonal relationships, and/or impulse control.1
One of the ways people alleviate distress is by using defense mechanisms. Defense mechanisms are unconscious mental processes that individuals use to resolve conflicts, and thereby reduce anxiety and depression on a conscious level. Taken alone, defense mechanisms are not pathologic, but they may become maladaptive in certain stressful circumstances, such as when receiving medical treatment. Recognizing patterns of chronic use of certain defense mechanisms may be a clue that your patient has a PD. TABLE 13,4 and TABLE 23,4 provide an overview of common defense mechanisms used by patients with PDs.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) organizes PDs into 3 clusters based on similar and often overlapping symptoms.1TABLE 31 provides a brief summary of the characteristic features of each disorder in these clusters.
Cluster A: Odd, eccentric
Patients with one of these disorders are odd, eccentric, or bizarre in their behavior and thinking. There appears to be a genetic link between cluster A PDs (especially schizotypal) and schizophrenia.5 These patients rarely seek treatment for their disorder because they have limited insight into their maladaptive traits.5,6
CASE 1 › Daniel A, age 57, has hypertension and hyperlipidemia and comes in to see his FP for a 6-month follow-up appointment. He never misses appointments, but has a history of poor adherence with prescribed medications. He enjoys his discussions with you in the office, although he often perseverates on conspiracy theories. He lives alone and has never been married. He believes that some of the previously prescribed medications, including a statin and a thiazide diuretic, were interfering with the absorption of “positive nutrients” in his diet. He also refuses to take the generic form of a statin, which he believes was adulterated by the government to be sold at lower cost.
Mr. A demonstrates the odd and eccentric beliefs that characterize schizotypal personality disorder. How can his FP best help him adhere to his medication regimen? (For the answer, click here.)
Schizotypal personality disorder shares certain disturbances of thought with schizophrenia, and is believed to exist on a spectrum with other primary psychotic disorders. Support for this theory comes from the higher rates of schizotypal PD among family members of patients with schizophrenia. There is a genetic component to the disorder.3,5,6
Clinically, these patients appear odd and eccentric with unusual beliefs. They may have a fascination with magic, clairvoyance, telepathy, or other such notions.1,5 Although the perceptual disturbances are unusual and often bizarre, they are not frank delusions: patients with schizotypal PD are willing to consider alternative explanations for their beliefs and can engage in rational discussion. Cognitive deficits, particularly of memory and attention, are common and distressing to patients. Frequently, the presenting complaint is depression and anxiety due to the emotional discord and isolation from others.1,3,5,6
Continue to cluster B >>
Cluster B: Dramatic, erratic
Patients with cluster B PDs are dramatic, excessively emotional, confrontational, erratic, and impulsive in their behaviors.1 They often have comorbid mood and anxiety disorders, as well as a disproportionately high co-occurrence of functional disorders.3,7 Their rates of health care utilization can be substantial. Because individuals with one of these PDs sometimes exhibit reckless and impulsive behavior, physicians should be aware these patients have a high risk of physical injuries (fights, accidents, self-injurious behavior), suicide attempts, risky sexual behaviors, and unplanned pregnancy.8,9
CASE 2 › Sheryl B is a 34-year-old new patient with a history of irritable bowel syndrome, fibromyalgia, depression, and anxiety who shows up for her appointment an hour late. She is upset and blames the office scheduler for not reminding her of the appointment. She brings a list of medications from her previous physician that includes sertraline, clonazepam, gabapentin, oxycodone, and as-needed alprazolam. She insists that her physician increase the dose of the benzodiazepines.
A review of her medical history reveals diagnoses of anxiety, bipolar disorder, and posttraumatic stress disorder. Ms. B has also engaged in superficial cutting since adolescence, often triggered by arguments with her boyfriend. Currently, she attributes her anxiety and pain to not receiving the “correct medications” because of her transition from a previous physician who “knew her better than any other doctor.” After the FP explains to Ms. B that he would have to carefully review her case before continuing to prescribe benzodiazepines, she becomes tearful and argumentative, proclaiming, “You won’t give me the only thing that will help me because you want me to be miserable!”
Ms. B exhibits many cluster B personality traits consistent with borderline PD. How should the FP respond to her claims? (For the answer, click here.)
Borderline PD is the most studied of the PDs. It can be a stigmatizing diagnosis, and even experienced psychiatrists may hesitate to inform patients of this diagnosis.10 Patients with borderline PD may be erroneously diagnosed with bipolar disorder, treatment-resistant depression, or posttraumatic stress disorder because of a complicated clinical presentation, physician unfamiliarity with diagnostic criteria, or the presence of genuine comorbid conditions.3,11
The etiology of this disorder appears to be multifactorial, and includes genetic predisposition, disruptive parent-child relationships (especially separation), and, often, past sexual or physical trauma.9,12
Predominant clinical features include emotional lability, efforts to avoid abandonment, extremes of idealization and devaluation, unstable and intense interpersonal relationships, and impulsivity.1 Characteristically, these patients also engage in self-injurious behaviors.13,14 Common defense mechanisms used by patients with borderline PD include splitting (viewing others as either all good or all bad), acting out (yelling, agitation, or violence), and passive aggression (TABLE 13,4).
Cluster C: Anxious, fearful
Individuals with cluster C PDs appear anxious, fearful, and worried. They have features that overlap with anxiety disorders.15
CASE 3 › Judy C is a 40-year-old lawyer with a history of gastroesophageal reflux disorder, hypertension, and anxiety who presents for a 3-week follow-up visit after starting sertraline. The patient describes herself as a perfectionist who has increased work-related stress recently because she has to “do extra work for my colleagues who don’t know how to get things done right.” She recently fired her assistant for “not understanding my filing system.” She appears formal and serious, often looking at her watch during the evaluation.
Ms. C demonstrates a pattern of perfectionism, formality, and rigidity in thought and behavior characteristic of obsessive-compulsive PD. What treatment should her physician recommend? (For the answer, click here.)
Obsessive-compulsive PD. Although this disorder is associated with significant anxiety, patients often view the specific traits of obsessive-compulsive PD, such as perfectionism, as desirable. Neurotic defense mechanisms are common, especially rationalization, intellectualization, and isolation of affect (TABLE 23,4). These patients appear formal, rigid, and serious, and are preoccupied with rules and orderliness to achieve perfection.1 Significant anxiety often arises from fear of making mistakes and ruminating on decision-making.1,11,15
Although some overlap exists between obsessive-compulsive disorder (OCD) and obsessive-compulsive PD, patients with OCD exhibit distinct obsessions and associated compulsive behavior, whereas those with obsessive-compulsive PD do not.1
In terms of treatment, it is generally appropriate to recognize the 2 conditions as distinct entities.15 OCD responds well to cognitive behavioral therapies and high-dose selective serotonin reuptake inhibitors (SSRIs).16 In contrast, there is little data that suggests antidepressants are effective for obsessive-compulsive PD, and treatment is aimed at addressing comorbid anxiety with psychotherapy and pharmacotherapy, if needed.11,15
Continue to psychotherapy for PD is the first-line treatment >>
Psychotherapy for PD is the first-line treatment
Psychotherapy is the most effective treatment for PDs.11,17,18 Several psychotherapies are used to treat these disorders, including dialectical behavioral therapy, schema therapy, and cognitive behavioral therapy (CBT). A recent study demonstrated the superiority of several evidence-based psychotherapies for PD compared to treatment-as-usual.17 Even more promising is that certain benefits have been demonstrated when psychotherapy is provided by clinicians without advanced mental health training.19-21 However, the benefits of therapies for specific disorders are often limited by lack of available data, patient preference, and accessibility of resources.
Limited evidence supports pharmacotherapy
The use of pharmacotherapy for treating PDs is common, although there’s limited evidence to support the practice.11,22 Certain circumstances may allow for the judicious use of medication, although prescribing strategies are based largely on clinical experience and expert opinion.
Prescribers should emphasize a realistic perspective on treatment response, because research suggests at best a mild-moderate response of some personality traits to pharmacotherapy.11,22-25 There is no evidence for polypharmacy in treating PDs, and FPs should allow for sufficient treatment duration, switch medications rather than augment ineffective treatments, and resist the urge to prescribe for every psychological crisis.11,22,25,26
Patient safety should always be a consideration when prescribing medication. Because use of second-generation antipsychotics is associated with the metabolic syndrome, the patient’s baseline weight and fasting glucose, lipids, and hemoglobin A1c levels should be obtained and monitored regularly. Weight gain can be particularly distressing to patients, increase stress and anxiety, and hinder the doctor-patient relationship.25 Finally, medications with abuse potential or that can be lethal in overdose (eg, tricyclic antidepressants and benzodiazepines) are best avoided in patients with emotional lability and impulsivity.25,26
Tailor treatment to the specific PD
Tx for cluster A disorders. Few studies have examined the effectiveness of psychotherapies for cluster A disorders. Cognitive therapy may have benefit in addressing cognitive distortions and social impairment in schizotypal PD.11,12,22 There is little evidence supporting psychotherapy for paranoid PD, because challenging patients’ beliefs in this form is likely to exacerbate paranoia. Low-dose risperidone has demonstrated some beneficial effects on perceptual disturbances; however, the adverse metabolic effects of this medication may outweigh any potential benefit, as these symptoms are often not distressing to patients.6,27 In comparison, patients often find deficits in memory and attention to be more bothersome, and some data suggest that the alpha-2 agonist guanfacine may help treat these symptoms.28
Tx for cluster B disorders. Several forms of psychotherapy have proven effective in managing symptoms and improving overall functioning in patients with borderline PD, including dialectical behavioral therapy, mentalization-based therapy, transference-focused therapy, and schema therapy.29 Dialectical behavioral therapy is often the initial treatment because it emphasizes reducing self-harm behaviors and emotion regulation.11,17,26
Gunderson19 developed a more basic approach to treating borderline PD that is intended to be used by all clinicians who treat the disorder, and not just mental health professionals with advanced training in psychotherapy. A large, multisite randomized controlled trial found that the clinical efficacy of the technique, known as good psychiatric management, rivaled that of dialectical behavioral therapy.20,21
The general premise is that clinicians foster a therapeutic relationship that is supportive, engaging, and flexible. Physicians are encouraged to educate patients about the disorder and emphasize improvement in daily functioning. Clinicians should share the diagnosis with patients, which may give patients a sense of relief in having an accurate diagnosis and allow them to fully invest in diagnosis-specific treatments.19
Systematic reviews and meta-analyses of studies that evaluated pharmacotherapy for borderline PD often have had conflicting conclusions as a result of analyzing data from underpowered studies with varying study designs.23,24,26,30,31 In targeting specific symptoms of the disorder, the most consistent evidence has supported the use of antipsychotics for cognitive perceptual disturbances; patients commonly experience depersonalization or out-of-body experiences.25 Additionally, the use of antipsychotics and mood stabilizers (lamotrigine and topiramate) appears to be somewhat effective for managing emotional lability and impulsivity.26,32,33 Despite the widespread use of SSRIs, a recent systematic review found the least support for these and other antidepressants for management of borderline PD.25
Tx for cluster C disorders. Some evidence supports using cognitive and interpersonal psychotherapies to treat cluster C PDs.34 In contrast, there is little evidence to support the use of pharmacotherapy.35 However, given the significant overlap among these disorders (especially avoidant PD) and social phobia and generalized anxiety disorder, effective pharmacologic strategies can be inferred based on data for those conditions.11 SSRIs, serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine), and gabapentin have demonstrated efficacy in anxiety disorders and are reasonable and safe initial treatments for patients with a cluster C PD.11,34
Continue for the answers >>
CASE 1 › Mr. A’s schizotypal PD symptoms interfere with medication adherence because of his unusual belief system. Importantly, unlike patients with frank delusions, patients with schizotypal PD are willing to consider alternative explanations for their unusual beliefs. Mr. A’s intense suspiciousness may indicate some degree of overlap between paranoid and schizotypal PDs.
The FP is patient and willing to listen to Mr. A’s beliefs without devaluing them. To improve medication adherence, the FP offers him reasonable alternatives with clear explanations. (“I understand you have concerns about previous medications. At the same time, it seems that managing your blood pressure and cholesterol is important to you. Can we discuss alternative treatments?”)
CASE 2 › In response to Ms. B’s borderline PD, the FP must be cautious to avoid reacting out of frustration, which may upset the patient and validate her mistrust. The FP first reflects her anger (“I can tell you are upset because you don’t think I want to help you”), which may allow her to calmly engage in a discussion. He wants to recognize Ms. B’s dramatic behavior, but not reward it with added attention and unreasonable concessions. To help establish rapport, he provides a statement to legitimize Ms. B’s concerns (“Many patients would be frustrated during the process of changing physicians”).
The FP listens empathically to Ms. B, sets clear limits, and provides consistent and evidence-based treatments. He also provides early referral to psychotherapy, but to mitigate any perceived abandonment, he assures Ms. B he will remain involved with her treatment. (“It sounds like managing your anxiety is important to you, and often psychiatrists or therapists can help give additional options for treatment. I want you to know that I am still your doctor and we can review their recommendations together at our next visit.”)
CASE 3 › The FP recognizes that Ms. C’s pattern of perfectionism, formality, and rigidity in thought and behavior are likely a manifestation of obsessive-compulsive PD, and that the maladaptive psychological traits underlying her anxiety are distinct from a primary anxiety disorder.
An SSRI may be a reasonable option to treat Ms. B’s anxiety, and the FP also refers her for CBT. (“I can tell you are feeling really anxious and many people feel that way, especially with work. I think the medication is a good start, but I wonder if we could discuss other forms of therapy to maximize your symptom improvement.”) Because of their exacting nature, many patients with cluster C personality traits are willing to engage in treatments, especially if they are supported by data and recommended by a knowledgeable physician.
CORRESPONDENCE
Nicholas Morcos, Department of Psychiatry, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109; [email protected].
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
2. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
3. Cloninger C, Svrakie D. Personality disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry. 11th ed. Philadelphia, Pa: Wolters Kluwer; 2015:2197-2240.
4. Bowins B. Personality disorders: a dimensional defense mechanism approach. Am J Psychother. 2010;64:153-169.
5. Raine A. Schizotypal personality: neurodevelopmental and psychosocial trajectories. Annu Rev Clin Psychol. 2006;2:291-326.
6. Rosell DR, Futterman SE, McMaster A, et al. Schizotypal personality disorder: a current review. Curr Psychiatry Rep. 2014;16:452.
7. Gabbard GO, Simonsen E. Complex Case: The impact of personality and personality disorders on the treatment of depression. Personal Ment Health. 2007;1:161-175.
8. Caspi A, Begg D, Dickson N, et al. Personality differences predict health-risk behaviors in young adulthood: evidence from a longitudinal study. J Pers Soc Psychol. 1997;73:1052-1063.
9. Tomko RL, Trull TJ, Wood PK, et al. Characteristics of borderline personality disorder in a community sample: comorbidity, treatment utilization, and general functioning. J Pers Disord. 2014;28:734-750.
10. Vaillant GE. The beginning of wisdom is never calling a patient a borderline; or, the clinical management of immature defenses in the treatment of individuals with personality disorders. J Psychother Pract Res. 1992;1:117-134.
11. Bateman AW, Gunderson J, Mulder R. Treatment of personality disorder. Lancet. 2015;385:735-743.
12. Beck AT, Davis DD, Freeman A, eds. Cognitive therapy of personality disorders. 3rd ed. New York, NY: Guilford Press, 2015.
13. O’Connor RC, Nock MK. The psychology of suicidal behaviour. Lancet Psychiatry. 2014;1:73-85.
14. Paris J. Understanding self-mutilation in borderline personality disorder. Harv Rev Psychiatry. 2005;13:179-185.
15. Diedrich A, Voderholzer U. Obsessive-compulsive personality disorder: a current review. Curr Psychiatry Rep. 2015;17:2.
16. Pittenger C, Bloch MH. Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014;37:375-391.
17. Budge SL, Moore JT, Del Re AC, et al. The effectiveness of evidence-based treatments for personality disorders when comparing treatment-as-usual and bona fide treatments. Clin Psychol Rev. 2013;33:1057-1066.
18. Leichsenring F, Leibing E. The effectiveness of psychodynamic therapy and cognitive behavior therapy in the treatment of personality disorders: a meta-analysis. Am J Psychiatry. 2003;160:1223-1232.
19. Gunderson JG, Links PS. Handbook of good psychiatric management for borderline personality disorder. Washington, DC: American Psychiatric Publishing, 2014.
20. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
21. McMain SF, Guimond T, Streiner DL, et al. Dialectical behavior therapy compared with general psychiatric management for borderline personality disorder: clinical outcomes and functioning over a 2-year follow-up. Am J Psychiatry. 2012;169:650-661.
22. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
23. Coccaro EF. Clinical outcome of psychopharmacologic treatment of borderline and schizotypal personality disordered subjects. J Clin Psychiatry. 1998;59:30-35.
24. Soloff PH. Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation. Bull Menninger Clin. 1998;62:195-214.
25. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
26. Saunders EF, Silk KR. Personality trait dimensions and the pharmacological treatment of borderline personality disorder. J Clin Psychopharmacol. 2009;29:461-467.
27. Koenigsberg HW, Reynolds D, Goodman M, et al. Risperidone in the treatment of schizotypal personality disorder. J Clin Psychiatry. 2003;64:628-634.
28. McClure MM, Barch DM, Romero MJ, et al. The effects of guanfacine on context processing abnormalities in schizotypal personality disorder. Biol Psychiatry. 2007;61:1157-1160.
29. Stoffers JM, Vollm BA, Rucker G, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2012;8:CD005652.
30. Siever LJ, Davis KL. A psychobiological perspective on the personality disorders. Am J Psychiatry. 1991;148:1647-1658.
31. Binks CA, Fenton M, McCarthy L, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006:CD005653.
32. Nickel MK, Nickel C, Kaplan P, et al. Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study. Biol Psychiatry. 2005;57:495-499.
33. Tritt K, Nickel C, Lahmann C, et al. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo-controlled study. J Psychopharmacol. 2005;19:287-291.
34. Simon W. Follow-up psychotherapy outcome of patients with dependent, avoidant and obsessive-compulsive personality disorders: A meta-analytic review. Int J Psychiatry Clin Pract. 2009;13:153-165.
35. Ansseau M, Troisfontaines B, Papart P, et al. Compulsive personality as predictor of response to serotoninergic antidepressants. BMJ. 1991;303:760-761.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
2. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
3. Cloninger C, Svrakie D. Personality disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry. 11th ed. Philadelphia, Pa: Wolters Kluwer; 2015:2197-2240.
4. Bowins B. Personality disorders: a dimensional defense mechanism approach. Am J Psychother. 2010;64:153-169.
5. Raine A. Schizotypal personality: neurodevelopmental and psychosocial trajectories. Annu Rev Clin Psychol. 2006;2:291-326.
6. Rosell DR, Futterman SE, McMaster A, et al. Schizotypal personality disorder: a current review. Curr Psychiatry Rep. 2014;16:452.
7. Gabbard GO, Simonsen E. Complex Case: The impact of personality and personality disorders on the treatment of depression. Personal Ment Health. 2007;1:161-175.
8. Caspi A, Begg D, Dickson N, et al. Personality differences predict health-risk behaviors in young adulthood: evidence from a longitudinal study. J Pers Soc Psychol. 1997;73:1052-1063.
9. Tomko RL, Trull TJ, Wood PK, et al. Characteristics of borderline personality disorder in a community sample: comorbidity, treatment utilization, and general functioning. J Pers Disord. 2014;28:734-750.
10. Vaillant GE. The beginning of wisdom is never calling a patient a borderline; or, the clinical management of immature defenses in the treatment of individuals with personality disorders. J Psychother Pract Res. 1992;1:117-134.
11. Bateman AW, Gunderson J, Mulder R. Treatment of personality disorder. Lancet. 2015;385:735-743.
12. Beck AT, Davis DD, Freeman A, eds. Cognitive therapy of personality disorders. 3rd ed. New York, NY: Guilford Press, 2015.
13. O’Connor RC, Nock MK. The psychology of suicidal behaviour. Lancet Psychiatry. 2014;1:73-85.
14. Paris J. Understanding self-mutilation in borderline personality disorder. Harv Rev Psychiatry. 2005;13:179-185.
15. Diedrich A, Voderholzer U. Obsessive-compulsive personality disorder: a current review. Curr Psychiatry Rep. 2015;17:2.
16. Pittenger C, Bloch MH. Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014;37:375-391.
17. Budge SL, Moore JT, Del Re AC, et al. The effectiveness of evidence-based treatments for personality disorders when comparing treatment-as-usual and bona fide treatments. Clin Psychol Rev. 2013;33:1057-1066.
18. Leichsenring F, Leibing E. The effectiveness of psychodynamic therapy and cognitive behavior therapy in the treatment of personality disorders: a meta-analysis. Am J Psychiatry. 2003;160:1223-1232.
19. Gunderson JG, Links PS. Handbook of good psychiatric management for borderline personality disorder. Washington, DC: American Psychiatric Publishing, 2014.
20. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
21. McMain SF, Guimond T, Streiner DL, et al. Dialectical behavior therapy compared with general psychiatric management for borderline personality disorder: clinical outcomes and functioning over a 2-year follow-up. Am J Psychiatry. 2012;169:650-661.
22. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
23. Coccaro EF. Clinical outcome of psychopharmacologic treatment of borderline and schizotypal personality disordered subjects. J Clin Psychiatry. 1998;59:30-35.
24. Soloff PH. Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation. Bull Menninger Clin. 1998;62:195-214.
25. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
26. Saunders EF, Silk KR. Personality trait dimensions and the pharmacological treatment of borderline personality disorder. J Clin Psychopharmacol. 2009;29:461-467.
27. Koenigsberg HW, Reynolds D, Goodman M, et al. Risperidone in the treatment of schizotypal personality disorder. J Clin Psychiatry. 2003;64:628-634.
28. McClure MM, Barch DM, Romero MJ, et al. The effects of guanfacine on context processing abnormalities in schizotypal personality disorder. Biol Psychiatry. 2007;61:1157-1160.
29. Stoffers JM, Vollm BA, Rucker G, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2012;8:CD005652.
30. Siever LJ, Davis KL. A psychobiological perspective on the personality disorders. Am J Psychiatry. 1991;148:1647-1658.
31. Binks CA, Fenton M, McCarthy L, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006:CD005653.
32. Nickel MK, Nickel C, Kaplan P, et al. Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study. Biol Psychiatry. 2005;57:495-499.
33. Tritt K, Nickel C, Lahmann C, et al. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo-controlled study. J Psychopharmacol. 2005;19:287-291.
34. Simon W. Follow-up psychotherapy outcome of patients with dependent, avoidant and obsessive-compulsive personality disorders: A meta-analytic review. Int J Psychiatry Clin Pract. 2009;13:153-165.
35. Ansseau M, Troisfontaines B, Papart P, et al. Compulsive personality as predictor of response to serotoninergic antidepressants. BMJ. 1991;303:760-761.
What next when metformin isn't enough for type 2 diabetes?
› Turn first to metformin for pharmacologic treatment of type 2 diabetes. A
› Add a second oral agent (such as a sulfonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, or dipeptidyl peptidase 4 inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin if metformin at a maximum tolerated dose does not achieve the HbA1c target over 3 months. A
› Progress to bolus mealtime insulin or a GLP-1 agonist to cover postprandial glycemic excursions if HbA1c remains above goal despite an adequate trial of basal insulin. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The "Standards of Medical Care in Diabetes" guidelines published in 2015 by the American Diabetes Association (ADA) state that metformin is the preferred initial pharmacotherapy for managing type 2 diabetes.1 Metformin, a biguanide, enhances insulin sensitivity in muscle and fat tissue and inhibits hepatic glucose production. Advantages of metformin include the longstanding research supporting its efficacy and safety, an expected decrease in the glycated hemoglobin (HbA1c) level of 1% to 1.5%, low cost, minimal hypoglycemic risk, and potential reductions in cardiovascular (CV) events due to decreased low-density lipoprotein (LDL) cholesterol.1,2
To minimize adverse gastrointestinal effects, start metformin at 500 mg once or twice a day and titrate upward every one to 2 weeks to the target dose.3 To help guide dosing decisions, use the estimated glomerular filtration rate (eGFR) instead of the serum creatinine (SCr) level, because the SCr can translate into a variable range of eGFRs (TABLE 1).4,5
What if metformin alone isn't enough?
CASE › Richard C, age 50, has type 2 diabetes, hypertension, hyperlipidemia, and obesity. He takes metformin 1 g twice a day for his diabetes. After 3 months on this regimen, his HbA1c is 8.8%. How would you manage Mr. C's diabetes going forward?
If metformin at a maximum tolerated dose does not achieve the HbA1c target after 3 months, add a second oral agent (a sulfonylurea [SU], thiazolidinedione [TZD], dipeptidyl peptidase 4 [DPP-4] inhibitor, or sodium-glucose cotransporter-2 [SGLT2] inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or a basal insulin (TABLE 2).1
Factors that will affect the choice of the second agent include patient preference, cost, potential adverse effects, impact on weight, efficacy, and risk of hypoglycemia.
Based on cost, familiarity, and longstanding safety data, you decide to give Mr. C an SU, while cautioning him about hypoglycemia.
CASE › Mr. C has now been taking metformin and an SU at maximum doses for 2 years and continues with lifestyle modifications. Though his HbA1c level dropped after adding the SU, over 2 years it has crept up to 8.6% and his mean blood glucose is 186 mg/dL. What are your treatment options now?
If the target HbA1c level is not achieved on dual therapy, consider triple therapy combinations (TABLE 3).1
In Mr. C's case, a third oral agent could be added, but DPP-4 and SGLT2 are unlikely to get his HbA1c below 7%. TZD may get his HbA1c into the desired range but is associated with adverse effects such as heart failure, edema, and weight gain. Mr. C agrees instead to start a basal insulin in conjunction with metformin. You could continue the SU, but you decide to stop it because the additive effect of these medications increases the risk of hypoglycemia.
CASE › Six months later Mr. C is taking metformin and insulin glargine, a basal insulin, adjusted to a fasting blood glucose of 80 to 130 mg/dL. His HbA1c is still above target at 8.4%, and the mean postprandial blood glucose is 232 mg/dL.
Mr. C is still above target for HbA1c and for postprandial blood glucose (goal: <180 mg/dL), so he needs pharmacotherapy that targets postprandial glucose elevations.1 His fasting blood glucose readings are at goal, so increasing his insulin glargine is not recommended because it could cause hypoglycemia. An oral agent other than SU could be added, but none is potent enough to lower the HbA1c to goal (TABLE 2).1 There are 3 other options:
- add a mealtime bolus of insulin
- add a GLP-1 receptor agonist
- switch to premixed (biphasic) insulin.
What to do when basal insulin isn’t enough—with or without oral medsFor type 2 diabetes poorly controlled on basal insulin with or without oral agents, the 2015 ADA treatment guidelines recommend adding a GLP-1 receptor agonist or mealtime insulin.1 A less desirable alternative is to switch from basal insulin to a twice-daily premixed (biphasic) insulin analog (70/30 aspart mix or 75/25 or 50/50 lispro mix). The human NPH-Regular premixed formulations (70/30) are less costly alternatives. The disadvantage with all premixed insulins is they only cover 2 postprandial glucose elevations a day.1,6,7
Insulin requires multiple daily injections, can lead to weight gain, and carries the risk of hypoglycemia, which causes significant morbidity.8,9 Daily or weekly administration of a GLP-1 receptor agonist combined with basal insulin can offer a more convenient alternative to mealtime boluses of insulin.
What are GLP-1 receptor agonists?
GLP-1 receptor agonists exert their maximum influence on blood glucose levels during the postprandial period by mimicking the body’s natural incretin hormonal response to oral glucose ingestion.10 They delay gastric emptying, promote satiety, decrease glucagon secretion, and increase insulin secretion.10,11 This mechanism blunts the spiking of postprandial blood glucose after a meal and improves blood glucose control and weight reduction.1,6,7
A systematic review and meta-analysis by Eng and colleagues compared the safety and efficacy of combined GLP-1 agonist and basal insulin with other treatment regimens.7 Fifteen randomized controlled trials were included involving 4348 participants with a mean trial duration of 25 weeks.
Compared with all other treatment regimens, the GLP-1 receptor agonist and basal insulin combination not only significantly reduced HbA1c by 0.44% (95% confidence interval [CI], -0.60 to -0.29) and increased the likelihood of attaining an HbA1c of <7.0% (relative risk [RR]=1.92; 95% CI, 1.43 to 2.56) but also reduced weight by 3.22 kg (-4.90 to -1.54) with no increased risk of hypoglycemia (RR=0.99; 0.76 to 1.29).7
GLP-1 agonist vs bolus insulin
Compared with basal-bolus insulin regimens, the combination of a GLP-1 receptor agonist with basal insulin has led to a significantly lowered risk of hypoglycemia (RR=0.67; 95% CI, 0.56 to 0.80), greater weight loss (-5.66 kg; 95% CI, -9.8 to -1.51) and an average reduction in HbA1c of 0.1% (95% CI, -0.17 to -0.02).7
There are 5 GLP-1 receptor agonists that have US Food and Drug Administration approval for the treatment of type 2 diabetes: albiglutide, dulaglutide, exenatide, exenatide XR, and liraglutide (TABLE 4).3,12
All 5 agents are administered subcutaneously and packaged in pen-injector form. Adverse effects include nausea, which is transient and diminishes within the first few weeks of therapy, and less commonly, pancreatitis.3,12
All of the GLP-1 receptor agonists, except short-acting exenatide, carry a warning about the risk of worsening renal function and a possible association with medullary thyroid carcinomas, which were identified in rats, but have not been observed in humans.3,12 Medications in this drug class have a low risk for precipitating hypoglycemia.11 Cost is their chief disadvantage, although copay reduction cards are available online for most of the products. Evaluate efficacy, ease of use, tolerability, and cost when selecting a GLP-1 receptor agonist.3,12
CASE › Mr. C prefers a more convenient option than adding another daily injection. Given his obesity, a GLP-1 receptor agonist can help with weight loss and lower his risk for hypoglycemia. To further increase the convenience in dosing, you lean toward either weekly exenatide XR or dulaglutide over basal-bolus combination insulin. Weekly albiglutide is less potent than exenatide XR and dulaglutide in decreasing HbA1c.12 Mr. C’s insurance plan provides preferred coverage for exenatide XR and he is eligible for a copay savings card, meaning he will pay no more than $25 per month for this new prescription. You prescribe exenatide XR and ask him to record his postprandial blood glucose levels. You follow up in one month to assess his response.
CORRESPONDENCE
Anne Mounsey, MD, University of North Carolina School of Medicine, Department of Family Medicine, 590 Manning Drive, Campus Box 7595, Chapel Hill, NC 27599; [email protected].
1. American Diabetes Association. Standards of medical care in diabetes - 2015. Diabetes Care. 2015;38 (Suppl):S1-S94.
2. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613.
3. Merck Manual. Metformin. Available at: http://www.merckmanuals.com/professional/appendixes/brand-names-of-some-commonly-used-drugs. Accessed April 18, 2015.
4. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34:1431-1437.
5. Philbrick AM, Ernst ME, McDanel DL, et al. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm. 2009;66:2017-2023.
6. Pharmacist’s Letter. Drugs for Type 2 Diabetes [detail document]. September 2015. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=2&segment=4407&dd=280601. Accessed December 28, 2015.
7. Eng C, Kramer CK, Zinman B, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228-2234.
8. Inzucchi SE, Burgenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.
9. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010:340:b4909.
10. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 (Suppl 2):S279-S284.
11. Young LA, Buse JB. GLP-1 receptor agonists and basal insulin in type 2 diabetes. Lancet. 2014;384:2180-2181.
12. Pharmacist’s Letter. Comparison of GLP-1 Agonists [detail document]. December 2014. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/Browse.aspx?cs=&s=PL&pt=6&fpt=31&dd=300804&pb=PL&cat=5718#dd. Accessed December 28, 2015.
› Turn first to metformin for pharmacologic treatment of type 2 diabetes. A
› Add a second oral agent (such as a sulfonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, or dipeptidyl peptidase 4 inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin if metformin at a maximum tolerated dose does not achieve the HbA1c target over 3 months. A
› Progress to bolus mealtime insulin or a GLP-1 agonist to cover postprandial glycemic excursions if HbA1c remains above goal despite an adequate trial of basal insulin. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The "Standards of Medical Care in Diabetes" guidelines published in 2015 by the American Diabetes Association (ADA) state that metformin is the preferred initial pharmacotherapy for managing type 2 diabetes.1 Metformin, a biguanide, enhances insulin sensitivity in muscle and fat tissue and inhibits hepatic glucose production. Advantages of metformin include the longstanding research supporting its efficacy and safety, an expected decrease in the glycated hemoglobin (HbA1c) level of 1% to 1.5%, low cost, minimal hypoglycemic risk, and potential reductions in cardiovascular (CV) events due to decreased low-density lipoprotein (LDL) cholesterol.1,2
To minimize adverse gastrointestinal effects, start metformin at 500 mg once or twice a day and titrate upward every one to 2 weeks to the target dose.3 To help guide dosing decisions, use the estimated glomerular filtration rate (eGFR) instead of the serum creatinine (SCr) level, because the SCr can translate into a variable range of eGFRs (TABLE 1).4,5
What if metformin alone isn't enough?
CASE › Richard C, age 50, has type 2 diabetes, hypertension, hyperlipidemia, and obesity. He takes metformin 1 g twice a day for his diabetes. After 3 months on this regimen, his HbA1c is 8.8%. How would you manage Mr. C's diabetes going forward?
If metformin at a maximum tolerated dose does not achieve the HbA1c target after 3 months, add a second oral agent (a sulfonylurea [SU], thiazolidinedione [TZD], dipeptidyl peptidase 4 [DPP-4] inhibitor, or sodium-glucose cotransporter-2 [SGLT2] inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or a basal insulin (TABLE 2).1
Factors that will affect the choice of the second agent include patient preference, cost, potential adverse effects, impact on weight, efficacy, and risk of hypoglycemia.
Based on cost, familiarity, and longstanding safety data, you decide to give Mr. C an SU, while cautioning him about hypoglycemia.
CASE › Mr. C has now been taking metformin and an SU at maximum doses for 2 years and continues with lifestyle modifications. Though his HbA1c level dropped after adding the SU, over 2 years it has crept up to 8.6% and his mean blood glucose is 186 mg/dL. What are your treatment options now?
If the target HbA1c level is not achieved on dual therapy, consider triple therapy combinations (TABLE 3).1
In Mr. C's case, a third oral agent could be added, but DPP-4 and SGLT2 are unlikely to get his HbA1c below 7%. TZD may get his HbA1c into the desired range but is associated with adverse effects such as heart failure, edema, and weight gain. Mr. C agrees instead to start a basal insulin in conjunction with metformin. You could continue the SU, but you decide to stop it because the additive effect of these medications increases the risk of hypoglycemia.
CASE › Six months later Mr. C is taking metformin and insulin glargine, a basal insulin, adjusted to a fasting blood glucose of 80 to 130 mg/dL. His HbA1c is still above target at 8.4%, and the mean postprandial blood glucose is 232 mg/dL.
Mr. C is still above target for HbA1c and for postprandial blood glucose (goal: <180 mg/dL), so he needs pharmacotherapy that targets postprandial glucose elevations.1 His fasting blood glucose readings are at goal, so increasing his insulin glargine is not recommended because it could cause hypoglycemia. An oral agent other than SU could be added, but none is potent enough to lower the HbA1c to goal (TABLE 2).1 There are 3 other options:
- add a mealtime bolus of insulin
- add a GLP-1 receptor agonist
- switch to premixed (biphasic) insulin.
What to do when basal insulin isn’t enough—with or without oral medsFor type 2 diabetes poorly controlled on basal insulin with or without oral agents, the 2015 ADA treatment guidelines recommend adding a GLP-1 receptor agonist or mealtime insulin.1 A less desirable alternative is to switch from basal insulin to a twice-daily premixed (biphasic) insulin analog (70/30 aspart mix or 75/25 or 50/50 lispro mix). The human NPH-Regular premixed formulations (70/30) are less costly alternatives. The disadvantage with all premixed insulins is they only cover 2 postprandial glucose elevations a day.1,6,7
Insulin requires multiple daily injections, can lead to weight gain, and carries the risk of hypoglycemia, which causes significant morbidity.8,9 Daily or weekly administration of a GLP-1 receptor agonist combined with basal insulin can offer a more convenient alternative to mealtime boluses of insulin.
What are GLP-1 receptor agonists?
GLP-1 receptor agonists exert their maximum influence on blood glucose levels during the postprandial period by mimicking the body’s natural incretin hormonal response to oral glucose ingestion.10 They delay gastric emptying, promote satiety, decrease glucagon secretion, and increase insulin secretion.10,11 This mechanism blunts the spiking of postprandial blood glucose after a meal and improves blood glucose control and weight reduction.1,6,7
A systematic review and meta-analysis by Eng and colleagues compared the safety and efficacy of combined GLP-1 agonist and basal insulin with other treatment regimens.7 Fifteen randomized controlled trials were included involving 4348 participants with a mean trial duration of 25 weeks.
Compared with all other treatment regimens, the GLP-1 receptor agonist and basal insulin combination not only significantly reduced HbA1c by 0.44% (95% confidence interval [CI], -0.60 to -0.29) and increased the likelihood of attaining an HbA1c of <7.0% (relative risk [RR]=1.92; 95% CI, 1.43 to 2.56) but also reduced weight by 3.22 kg (-4.90 to -1.54) with no increased risk of hypoglycemia (RR=0.99; 0.76 to 1.29).7
GLP-1 agonist vs bolus insulin
Compared with basal-bolus insulin regimens, the combination of a GLP-1 receptor agonist with basal insulin has led to a significantly lowered risk of hypoglycemia (RR=0.67; 95% CI, 0.56 to 0.80), greater weight loss (-5.66 kg; 95% CI, -9.8 to -1.51) and an average reduction in HbA1c of 0.1% (95% CI, -0.17 to -0.02).7
There are 5 GLP-1 receptor agonists that have US Food and Drug Administration approval for the treatment of type 2 diabetes: albiglutide, dulaglutide, exenatide, exenatide XR, and liraglutide (TABLE 4).3,12
All 5 agents are administered subcutaneously and packaged in pen-injector form. Adverse effects include nausea, which is transient and diminishes within the first few weeks of therapy, and less commonly, pancreatitis.3,12
All of the GLP-1 receptor agonists, except short-acting exenatide, carry a warning about the risk of worsening renal function and a possible association with medullary thyroid carcinomas, which were identified in rats, but have not been observed in humans.3,12 Medications in this drug class have a low risk for precipitating hypoglycemia.11 Cost is their chief disadvantage, although copay reduction cards are available online for most of the products. Evaluate efficacy, ease of use, tolerability, and cost when selecting a GLP-1 receptor agonist.3,12
CASE › Mr. C prefers a more convenient option than adding another daily injection. Given his obesity, a GLP-1 receptor agonist can help with weight loss and lower his risk for hypoglycemia. To further increase the convenience in dosing, you lean toward either weekly exenatide XR or dulaglutide over basal-bolus combination insulin. Weekly albiglutide is less potent than exenatide XR and dulaglutide in decreasing HbA1c.12 Mr. C’s insurance plan provides preferred coverage for exenatide XR and he is eligible for a copay savings card, meaning he will pay no more than $25 per month for this new prescription. You prescribe exenatide XR and ask him to record his postprandial blood glucose levels. You follow up in one month to assess his response.
CORRESPONDENCE
Anne Mounsey, MD, University of North Carolina School of Medicine, Department of Family Medicine, 590 Manning Drive, Campus Box 7595, Chapel Hill, NC 27599; [email protected].
› Turn first to metformin for pharmacologic treatment of type 2 diabetes. A
› Add a second oral agent (such as a sulfonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, or dipeptidyl peptidase 4 inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin if metformin at a maximum tolerated dose does not achieve the HbA1c target over 3 months. A
› Progress to bolus mealtime insulin or a GLP-1 agonist to cover postprandial glycemic excursions if HbA1c remains above goal despite an adequate trial of basal insulin. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The "Standards of Medical Care in Diabetes" guidelines published in 2015 by the American Diabetes Association (ADA) state that metformin is the preferred initial pharmacotherapy for managing type 2 diabetes.1 Metformin, a biguanide, enhances insulin sensitivity in muscle and fat tissue and inhibits hepatic glucose production. Advantages of metformin include the longstanding research supporting its efficacy and safety, an expected decrease in the glycated hemoglobin (HbA1c) level of 1% to 1.5%, low cost, minimal hypoglycemic risk, and potential reductions in cardiovascular (CV) events due to decreased low-density lipoprotein (LDL) cholesterol.1,2
To minimize adverse gastrointestinal effects, start metformin at 500 mg once or twice a day and titrate upward every one to 2 weeks to the target dose.3 To help guide dosing decisions, use the estimated glomerular filtration rate (eGFR) instead of the serum creatinine (SCr) level, because the SCr can translate into a variable range of eGFRs (TABLE 1).4,5
What if metformin alone isn't enough?
CASE › Richard C, age 50, has type 2 diabetes, hypertension, hyperlipidemia, and obesity. He takes metformin 1 g twice a day for his diabetes. After 3 months on this regimen, his HbA1c is 8.8%. How would you manage Mr. C's diabetes going forward?
If metformin at a maximum tolerated dose does not achieve the HbA1c target after 3 months, add a second oral agent (a sulfonylurea [SU], thiazolidinedione [TZD], dipeptidyl peptidase 4 [DPP-4] inhibitor, or sodium-glucose cotransporter-2 [SGLT2] inhibitor), a glucagon-like peptide-1 (GLP-1) receptor agonist, or a basal insulin (TABLE 2).1
Factors that will affect the choice of the second agent include patient preference, cost, potential adverse effects, impact on weight, efficacy, and risk of hypoglycemia.
Based on cost, familiarity, and longstanding safety data, you decide to give Mr. C an SU, while cautioning him about hypoglycemia.
CASE › Mr. C has now been taking metformin and an SU at maximum doses for 2 years and continues with lifestyle modifications. Though his HbA1c level dropped after adding the SU, over 2 years it has crept up to 8.6% and his mean blood glucose is 186 mg/dL. What are your treatment options now?
If the target HbA1c level is not achieved on dual therapy, consider triple therapy combinations (TABLE 3).1
In Mr. C's case, a third oral agent could be added, but DPP-4 and SGLT2 are unlikely to get his HbA1c below 7%. TZD may get his HbA1c into the desired range but is associated with adverse effects such as heart failure, edema, and weight gain. Mr. C agrees instead to start a basal insulin in conjunction with metformin. You could continue the SU, but you decide to stop it because the additive effect of these medications increases the risk of hypoglycemia.
CASE › Six months later Mr. C is taking metformin and insulin glargine, a basal insulin, adjusted to a fasting blood glucose of 80 to 130 mg/dL. His HbA1c is still above target at 8.4%, and the mean postprandial blood glucose is 232 mg/dL.
Mr. C is still above target for HbA1c and for postprandial blood glucose (goal: <180 mg/dL), so he needs pharmacotherapy that targets postprandial glucose elevations.1 His fasting blood glucose readings are at goal, so increasing his insulin glargine is not recommended because it could cause hypoglycemia. An oral agent other than SU could be added, but none is potent enough to lower the HbA1c to goal (TABLE 2).1 There are 3 other options:
- add a mealtime bolus of insulin
- add a GLP-1 receptor agonist
- switch to premixed (biphasic) insulin.
What to do when basal insulin isn’t enough—with or without oral medsFor type 2 diabetes poorly controlled on basal insulin with or without oral agents, the 2015 ADA treatment guidelines recommend adding a GLP-1 receptor agonist or mealtime insulin.1 A less desirable alternative is to switch from basal insulin to a twice-daily premixed (biphasic) insulin analog (70/30 aspart mix or 75/25 or 50/50 lispro mix). The human NPH-Regular premixed formulations (70/30) are less costly alternatives. The disadvantage with all premixed insulins is they only cover 2 postprandial glucose elevations a day.1,6,7
Insulin requires multiple daily injections, can lead to weight gain, and carries the risk of hypoglycemia, which causes significant morbidity.8,9 Daily or weekly administration of a GLP-1 receptor agonist combined with basal insulin can offer a more convenient alternative to mealtime boluses of insulin.
What are GLP-1 receptor agonists?
GLP-1 receptor agonists exert their maximum influence on blood glucose levels during the postprandial period by mimicking the body’s natural incretin hormonal response to oral glucose ingestion.10 They delay gastric emptying, promote satiety, decrease glucagon secretion, and increase insulin secretion.10,11 This mechanism blunts the spiking of postprandial blood glucose after a meal and improves blood glucose control and weight reduction.1,6,7
A systematic review and meta-analysis by Eng and colleagues compared the safety and efficacy of combined GLP-1 agonist and basal insulin with other treatment regimens.7 Fifteen randomized controlled trials were included involving 4348 participants with a mean trial duration of 25 weeks.
Compared with all other treatment regimens, the GLP-1 receptor agonist and basal insulin combination not only significantly reduced HbA1c by 0.44% (95% confidence interval [CI], -0.60 to -0.29) and increased the likelihood of attaining an HbA1c of <7.0% (relative risk [RR]=1.92; 95% CI, 1.43 to 2.56) but also reduced weight by 3.22 kg (-4.90 to -1.54) with no increased risk of hypoglycemia (RR=0.99; 0.76 to 1.29).7
GLP-1 agonist vs bolus insulin
Compared with basal-bolus insulin regimens, the combination of a GLP-1 receptor agonist with basal insulin has led to a significantly lowered risk of hypoglycemia (RR=0.67; 95% CI, 0.56 to 0.80), greater weight loss (-5.66 kg; 95% CI, -9.8 to -1.51) and an average reduction in HbA1c of 0.1% (95% CI, -0.17 to -0.02).7
There are 5 GLP-1 receptor agonists that have US Food and Drug Administration approval for the treatment of type 2 diabetes: albiglutide, dulaglutide, exenatide, exenatide XR, and liraglutide (TABLE 4).3,12
All 5 agents are administered subcutaneously and packaged in pen-injector form. Adverse effects include nausea, which is transient and diminishes within the first few weeks of therapy, and less commonly, pancreatitis.3,12
All of the GLP-1 receptor agonists, except short-acting exenatide, carry a warning about the risk of worsening renal function and a possible association with medullary thyroid carcinomas, which were identified in rats, but have not been observed in humans.3,12 Medications in this drug class have a low risk for precipitating hypoglycemia.11 Cost is their chief disadvantage, although copay reduction cards are available online for most of the products. Evaluate efficacy, ease of use, tolerability, and cost when selecting a GLP-1 receptor agonist.3,12
CASE › Mr. C prefers a more convenient option than adding another daily injection. Given his obesity, a GLP-1 receptor agonist can help with weight loss and lower his risk for hypoglycemia. To further increase the convenience in dosing, you lean toward either weekly exenatide XR or dulaglutide over basal-bolus combination insulin. Weekly albiglutide is less potent than exenatide XR and dulaglutide in decreasing HbA1c.12 Mr. C’s insurance plan provides preferred coverage for exenatide XR and he is eligible for a copay savings card, meaning he will pay no more than $25 per month for this new prescription. You prescribe exenatide XR and ask him to record his postprandial blood glucose levels. You follow up in one month to assess his response.
CORRESPONDENCE
Anne Mounsey, MD, University of North Carolina School of Medicine, Department of Family Medicine, 590 Manning Drive, Campus Box 7595, Chapel Hill, NC 27599; [email protected].
1. American Diabetes Association. Standards of medical care in diabetes - 2015. Diabetes Care. 2015;38 (Suppl):S1-S94.
2. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613.
3. Merck Manual. Metformin. Available at: http://www.merckmanuals.com/professional/appendixes/brand-names-of-some-commonly-used-drugs. Accessed April 18, 2015.
4. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34:1431-1437.
5. Philbrick AM, Ernst ME, McDanel DL, et al. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm. 2009;66:2017-2023.
6. Pharmacist’s Letter. Drugs for Type 2 Diabetes [detail document]. September 2015. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=2&segment=4407&dd=280601. Accessed December 28, 2015.
7. Eng C, Kramer CK, Zinman B, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228-2234.
8. Inzucchi SE, Burgenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.
9. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010:340:b4909.
10. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 (Suppl 2):S279-S284.
11. Young LA, Buse JB. GLP-1 receptor agonists and basal insulin in type 2 diabetes. Lancet. 2014;384:2180-2181.
12. Pharmacist’s Letter. Comparison of GLP-1 Agonists [detail document]. December 2014. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/Browse.aspx?cs=&s=PL&pt=6&fpt=31&dd=300804&pb=PL&cat=5718#dd. Accessed December 28, 2015.
1. American Diabetes Association. Standards of medical care in diabetes - 2015. Diabetes Care. 2015;38 (Suppl):S1-S94.
2. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613.
3. Merck Manual. Metformin. Available at: http://www.merckmanuals.com/professional/appendixes/brand-names-of-some-commonly-used-drugs. Accessed April 18, 2015.
4. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34:1431-1437.
5. Philbrick AM, Ernst ME, McDanel DL, et al. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm. 2009;66:2017-2023.
6. Pharmacist’s Letter. Drugs for Type 2 Diabetes [detail document]. September 2015. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=2&segment=4407&dd=280601. Accessed December 28, 2015.
7. Eng C, Kramer CK, Zinman B, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228-2234.
8. Inzucchi SE, Burgenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.
9. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010:340:b4909.
10. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 (Suppl 2):S279-S284.
11. Young LA, Buse JB. GLP-1 receptor agonists and basal insulin in type 2 diabetes. Lancet. 2014;384:2180-2181.
12. Pharmacist’s Letter. Comparison of GLP-1 Agonists [detail document]. December 2014. Available at: http://pharmacistsletter.therapeuticresearch.com/pl/Browse.aspx?cs=&s=PL&pt=6&fpt=31&dd=300804&pb=PL&cat=5718#dd. Accessed December 28, 2015.
Kidney stones? It’s time to rethink those meds
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones ≤10 mm.1
Strength of recommendation
A: Based on a high-quality randomized controlled trial.
Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
Illustrative case
Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?
The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4
The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.
STUDY SUMMARY: MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones >10 mm typically require surgery or lithotripsy.)
In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).
At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.
There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.
No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).
There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.
WHAT'S NEW: This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.9
CAVEATS: This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1
CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr., Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CU, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013;189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40:280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones ≤10 mm.1
Strength of recommendation
A: Based on a high-quality randomized controlled trial.
Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
Illustrative case
Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?
The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4
The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.
STUDY SUMMARY: MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones >10 mm typically require surgery or lithotripsy.)
In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).
At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.
There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.
No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).
There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.
WHAT'S NEW: This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.9
CAVEATS: This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1
CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones ≤10 mm.1
Strength of recommendation
A: Based on a high-quality randomized controlled trial.
Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
Illustrative case
Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?
The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.2 Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.3,4
The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.5 Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.
STUDY SUMMARY: MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial1 was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.8 (Stones >10 mm typically require surgery or lithotripsy.)
In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).
At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.
There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.
No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).
There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.
WHAT'S NEW: This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.9
CAVEATS: This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.1
CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr., Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CU, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013;189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40:280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr., Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CU, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013;189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40:280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.
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