Hospital Medicine

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 62-year-old woman with type 2 diabetes mellitus, systemic hypertension, coronary artery disease, and obesity is admitted for AKI found on routine laboratory testing. She has been taking amoxicillin and doxycycline for left leg cellulitis the past 5 days, but improvement has been minimal. On admission, blood pressure is 120/74 mm Hg, and heart rate is 89 beats per minute. Serum creatinine level is increased, from 0.7 mg/dL at baseline to 3.6 mg/dL on admission. Complete urinalysis reveals 1+ protein and presence of white blood cells and isormorphic red blood cells. No casts or crystals are seen. Given the possibility of AIN, UE testing is ordered. UEs are positive at 25%. Does this result significantly increase the patient’s posttest probability of having AIN?

WHY YOU MIGHT THINK ORDERING URINE EOSINOPHILS IN THE EVALUATION OF AIN IS HELPFUL

AKI occurs in more than 1 in 5 hospitalizations and is associated with a more than 4-fold increased likelihood of in-hospital mortality at 21 days.¹ AIN is an important cause of AKI and has been found in 6% to 30% of AKI patients who had biopsies performed.^2-4 AIN is characterized by infiltration of inflammatory cells in the kidney interstitium and is more commonly caused by drugs, especially beta-lactam antibiotics, and less commonly by autoimmune or systemic diseases and infections. As the signs and symptoms of AIN are nonspecific, and the gold-standard test is renal biopsy, diagnosticians have sought a noninvasive test, such as UEs.

In 1978, Galpin et al.⁵ found that UEs comprised 10% to 60% of urine white blood cells in 9 of 9 patients with methicillin-induced interstitial nephritis; 6 of the 9 had biopsy-proven AIN. In 1980, Linton et al.⁶ found UEs in 6 of 9 patients with drug-induced AIN; 8 of the 9 had biopsy-proven AIN. In 1986, Nolan et al.⁷ reported that, compared with Wright stain, Hansel stain was more sensitive in visualizing UEs; they did not use biopsy for confirmation. Wright-stain detection of UEs is limited by the variable staining characteristics of “eosinophilic” granules in body fluids other than blood. With Hansel stain, UEs are readily identified by their brilliant red-pink granules. These 3 small studies helped make UEs the go-to noninvasive test for assessing for AIN.⁸

WHY THERE IS LITTLE REASON TO ORDER URINE EOSINOPHILS IN PATIENTS WITH SUSPICION FOR AIN

While initial studies indicated UEs might be diagnostically helpful, subsequent studies did not. In 1985, Corwin et al.⁹ used Wright stain and found UEs in 65 of 470 adults with AKI. Only 9 (14%) of the 65 had a diagnosis of AIN, which was made mostly on clinical grounds. These findings showed that UEs were produced by other renal or urinary tract abnormalities, such as urinary tract infections, acute tubular necrosis, and glomerulonephritis. In a second study, Corwin et al.¹⁰ found that Hansel stain (vs Wright stain) improved the sensitivity of UEs for AIN diagnosis, from 25% to 62.5%. Sensitivity was improved at the expense of specificity, as Hansel stain was positive in other diagnoses as well. The AIN diagnosis was not confirmed by kidney biopsy in the large majority of patients in this study. Lack of confirmation by biopsy, the gold-standard diagnostic test, was a methodologic flaw of this study and others.

Sutton¹¹ reviewed data from 10 studies and found AIN could not be reliably excluded in the absence of UEs (only 19 of 32 biopsy-confirmed AIN cases had UEs present). In addition, Ruffing et al.¹² used Hansel stain and concluded that the positive predictive value of UEs was inadequate in diagnosing AIN. Only 6 of their 15 patients with AIN had positive UEs. Urine eosinophils were also present in patients with other diagnoses (glomerulonephritis, chronic kidney disease, acute pyelonephritis, prerenal azotemia). Like many other investigators, Ruffing et al. made the AIN diagnosis on clinical grounds in the large majority of cases.

Muriithi et al.¹³ reported similarly negative results in their retrospective AKI study involving 566 Mayo Clinic patients and spanning almost 2 decades. The study included patients who underwent both Hansel-stain UE testing and kidney biopsy within a week of each other. Only 28 (30%) of 91 biopsy-proven AIN cases were positive for UEs. Using the 1% cutoff for a positive UE test yielded only 30.8% sensitivity and 68.2% specificity. Using the 5% cutoff increased specificity to 91.2%, at the expense of sensitivity (19.2%); positive predictive value improved to only 30%, and negative predictive value remained relatively unchanged, at 85.6%. In short, Muriithi et al. found that UE testing had no utility in AIN diagnosis.

In summary, initial studies, such as those by Corwin et al,^9,10 supported the conclusion that UEs are useful in AIN diagnosis but had questionable validity owing to methodologic issues, including small sample size and lack of biopsy confirmation of AIN. On the other hand, more recent studies, such as the one conducted by Muriithi et al.,¹³ had larger sample sizes and biopsy-proven diagnoses and confirmed the poor diagnostic value of UEs in AIN.

The poor sensitivity and specificity of UE tests can have important consequences. A false positive test may cause the clinician to incorrectly diagnose the patient with AIN and prompt the clinician to remove medications that may be vitally important. The clinician may also consider treating the patient with steroids empirically. A false negative test may inappropriately reassure the clinician that the patient does not have AIN and does not need cessation of the culprit drug. This may also lead the clinician to forego a necessary kidney biopsy.

WHAT YOU SHOULD DO INSTEAD

A history of recent exposure to a classic offending drug (eg, beta-lactam, proton pump inhibitor, nonsteroidal anti-inflammatory drug) in combination with the classic triad of fever, rash, and peripheral eosinophilia suggests an AIN diagnosis. However, less than 5% to 10% of patients present with this triad.^14,15 Regardless of the triad’s presence, if other causes of AKI have been excluded, stopping a potential offending agent and monitoring for improvement are recommended. If a culprit drug cannot be safely discontinued, renal biopsy may be necessary for confirmation of the diagnosis. Moreover, if kidney function continues to deteriorate, a nephrology consultation may be warranted for guidance on the risks and benefits of performing a kidney biopsy to confirm the diagnosis and/or the use of corticosteroids.

• Urine eosinophils should not be used in the diagnosis of AIN.
• The clinical diagnosis of drug-associated AIN should be based on excluding other possible likely etiologies of AKI and confirming the history of drug exposure. This is reinforced when kidney function improves upon discontinuation of offending agent.
• Kidney biopsy is the gold standard for AIN and should be performed if the clinical picture is unclear or the renal function is not improving upon discontinuation of offending agent.

Since the mid-1980s, studies have found that UEs are too insensitive and nonspecific to confirm or exclude the diagnosis of AIN in patients with AKI (Table). UEs are seen in other AKI etiologies, such as pyelonephritis, acute tubular necrosis, atheroembolic renal disease, and glomerulonephritis. Current evidence-based medicine does not support use of UEs as a biomarker for AIN. False-positive and false-negative results confuse the overall picture and result either in discontinuation of important medications and unnecessary steroid treatment or in delayed removal of a culprit medication.¹⁶

Our case’s positive UE test does not affect the posttest probability that our patient has AIN. Presence of a culprit drug and absence of clinical data suggesting an alternative diagnosis would lead most clinicians to change antibiotic therapy and observe for improvement in renal function.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 62-year-old woman with type 2 diabetes mellitus, systemic hypertension, coronary artery disease, and obesity is admitted for AKI found on routine laboratory testing. She has been taking amoxicillin and doxycycline for left leg cellulitis the past 5 days, but improvement has been minimal. On admission, blood pressure is 120/74 mm Hg, and heart rate is 89 beats per minute. Serum creatinine level is increased, from 0.7 mg/dL at baseline to 3.6 mg/dL on admission. Complete urinalysis reveals 1+ protein and presence of white blood cells and isormorphic red blood cells. No casts or crystals are seen. Given the possibility of AIN, UE testing is ordered. UEs are positive at 25%. Does this result significantly increase the patient’s posttest probability of having AIN?

WHY YOU MIGHT THINK ORDERING URINE EOSINOPHILS IN THE EVALUATION OF AIN IS HELPFUL

AKI occurs in more than 1 in 5 hospitalizations and is associated with a more than 4-fold increased likelihood of in-hospital mortality at 21 days.¹ AIN is an important cause of AKI and has been found in 6% to 30% of AKI patients who had biopsies performed.^2-4 AIN is characterized by infiltration of inflammatory cells in the kidney interstitium and is more commonly caused by drugs, especially beta-lactam antibiotics, and less commonly by autoimmune or systemic diseases and infections. As the signs and symptoms of AIN are nonspecific, and the gold-standard test is renal biopsy, diagnosticians have sought a noninvasive test, such as UEs.

In 1978, Galpin et al.⁵ found that UEs comprised 10% to 60% of urine white blood cells in 9 of 9 patients with methicillin-induced interstitial nephritis; 6 of the 9 had biopsy-proven AIN. In 1980, Linton et al.⁶ found UEs in 6 of 9 patients with drug-induced AIN; 8 of the 9 had biopsy-proven AIN. In 1986, Nolan et al.⁷ reported that, compared with Wright stain, Hansel stain was more sensitive in visualizing UEs; they did not use biopsy for confirmation. Wright-stain detection of UEs is limited by the variable staining characteristics of “eosinophilic” granules in body fluids other than blood. With Hansel stain, UEs are readily identified by their brilliant red-pink granules. These 3 small studies helped make UEs the go-to noninvasive test for assessing for AIN.⁸

WHY THERE IS LITTLE REASON TO ORDER URINE EOSINOPHILS IN PATIENTS WITH SUSPICION FOR AIN

While initial studies indicated UEs might be diagnostically helpful, subsequent studies did not. In 1985, Corwin et al.⁹ used Wright stain and found UEs in 65 of 470 adults with AKI. Only 9 (14%) of the 65 had a diagnosis of AIN, which was made mostly on clinical grounds. These findings showed that UEs were produced by other renal or urinary tract abnormalities, such as urinary tract infections, acute tubular necrosis, and glomerulonephritis. In a second study, Corwin et al.¹⁰ found that Hansel stain (vs Wright stain) improved the sensitivity of UEs for AIN diagnosis, from 25% to 62.5%. Sensitivity was improved at the expense of specificity, as Hansel stain was positive in other diagnoses as well. The AIN diagnosis was not confirmed by kidney biopsy in the large majority of patients in this study. Lack of confirmation by biopsy, the gold-standard diagnostic test, was a methodologic flaw of this study and others.

Sutton¹¹ reviewed data from 10 studies and found AIN could not be reliably excluded in the absence of UEs (only 19 of 32 biopsy-confirmed AIN cases had UEs present). In addition, Ruffing et al.¹² used Hansel stain and concluded that the positive predictive value of UEs was inadequate in diagnosing AIN. Only 6 of their 15 patients with AIN had positive UEs. Urine eosinophils were also present in patients with other diagnoses (glomerulonephritis, chronic kidney disease, acute pyelonephritis, prerenal azotemia). Like many other investigators, Ruffing et al. made the AIN diagnosis on clinical grounds in the large majority of cases.

Muriithi et al.¹³ reported similarly negative results in their retrospective AKI study involving 566 Mayo Clinic patients and spanning almost 2 decades. The study included patients who underwent both Hansel-stain UE testing and kidney biopsy within a week of each other. Only 28 (30%) of 91 biopsy-proven AIN cases were positive for UEs. Using the 1% cutoff for a positive UE test yielded only 30.8% sensitivity and 68.2% specificity. Using the 5% cutoff increased specificity to 91.2%, at the expense of sensitivity (19.2%); positive predictive value improved to only 30%, and negative predictive value remained relatively unchanged, at 85.6%. In short, Muriithi et al. found that UE testing had no utility in AIN diagnosis.

In summary, initial studies, such as those by Corwin et al,^9,10 supported the conclusion that UEs are useful in AIN diagnosis but had questionable validity owing to methodologic issues, including small sample size and lack of biopsy confirmation of AIN. On the other hand, more recent studies, such as the one conducted by Muriithi et al.,¹³ had larger sample sizes and biopsy-proven diagnoses and confirmed the poor diagnostic value of UEs in AIN.

The poor sensitivity and specificity of UE tests can have important consequences. A false positive test may cause the clinician to incorrectly diagnose the patient with AIN and prompt the clinician to remove medications that may be vitally important. The clinician may also consider treating the patient with steroids empirically. A false negative test may inappropriately reassure the clinician that the patient does not have AIN and does not need cessation of the culprit drug. This may also lead the clinician to forego a necessary kidney biopsy.

WHAT YOU SHOULD DO INSTEAD

A history of recent exposure to a classic offending drug (eg, beta-lactam, proton pump inhibitor, nonsteroidal anti-inflammatory drug) in combination with the classic triad of fever, rash, and peripheral eosinophilia suggests an AIN diagnosis. However, less than 5% to 10% of patients present with this triad.^14,15 Regardless of the triad’s presence, if other causes of AKI have been excluded, stopping a potential offending agent and monitoring for improvement are recommended. If a culprit drug cannot be safely discontinued, renal biopsy may be necessary for confirmation of the diagnosis. Moreover, if kidney function continues to deteriorate, a nephrology consultation may be warranted for guidance on the risks and benefits of performing a kidney biopsy to confirm the diagnosis and/or the use of corticosteroids.

• Urine eosinophils should not be used in the diagnosis of AIN.
• The clinical diagnosis of drug-associated AIN should be based on excluding other possible likely etiologies of AKI and confirming the history of drug exposure. This is reinforced when kidney function improves upon discontinuation of offending agent.
• Kidney biopsy is the gold standard for AIN and should be performed if the clinical picture is unclear or the renal function is not improving upon discontinuation of offending agent.

Since the mid-1980s, studies have found that UEs are too insensitive and nonspecific to confirm or exclude the diagnosis of AIN in patients with AKI (Table). UEs are seen in other AKI etiologies, such as pyelonephritis, acute tubular necrosis, atheroembolic renal disease, and glomerulonephritis. Current evidence-based medicine does not support use of UEs as a biomarker for AIN. False-positive and false-negative results confuse the overall picture and result either in discontinuation of important medications and unnecessary steroid treatment or in delayed removal of a culprit medication.¹⁶

Our case’s positive UE test does not affect the posttest probability that our patient has AIN. Presence of a culprit drug and absence of clinical data suggesting an alternative diagnosis would lead most clinicians to change antibiotic therapy and observe for improvement in renal function.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 62-year-old woman with type 2 diabetes mellitus, systemic hypertension, coronary artery disease, and obesity is admitted for AKI found on routine laboratory testing. She has been taking amoxicillin and doxycycline for left leg cellulitis the past 5 days, but improvement has been minimal. On admission, blood pressure is 120/74 mm Hg, and heart rate is 89 beats per minute. Serum creatinine level is increased, from 0.7 mg/dL at baseline to 3.6 mg/dL on admission. Complete urinalysis reveals 1+ protein and presence of white blood cells and isormorphic red blood cells. No casts or crystals are seen. Given the possibility of AIN, UE testing is ordered. UEs are positive at 25%. Does this result significantly increase the patient’s posttest probability of having AIN?

WHY YOU MIGHT THINK ORDERING URINE EOSINOPHILS IN THE EVALUATION OF AIN IS HELPFUL

AKI occurs in more than 1 in 5 hospitalizations and is associated with a more than 4-fold increased likelihood of in-hospital mortality at 21 days.¹ AIN is an important cause of AKI and has been found in 6% to 30% of AKI patients who had biopsies performed.^2-4 AIN is characterized by infiltration of inflammatory cells in the kidney interstitium and is more commonly caused by drugs, especially beta-lactam antibiotics, and less commonly by autoimmune or systemic diseases and infections. As the signs and symptoms of AIN are nonspecific, and the gold-standard test is renal biopsy, diagnosticians have sought a noninvasive test, such as UEs.

In 1978, Galpin et al.⁵ found that UEs comprised 10% to 60% of urine white blood cells in 9 of 9 patients with methicillin-induced interstitial nephritis; 6 of the 9 had biopsy-proven AIN. In 1980, Linton et al.⁶ found UEs in 6 of 9 patients with drug-induced AIN; 8 of the 9 had biopsy-proven AIN. In 1986, Nolan et al.⁷ reported that, compared with Wright stain, Hansel stain was more sensitive in visualizing UEs; they did not use biopsy for confirmation. Wright-stain detection of UEs is limited by the variable staining characteristics of “eosinophilic” granules in body fluids other than blood. With Hansel stain, UEs are readily identified by their brilliant red-pink granules. These 3 small studies helped make UEs the go-to noninvasive test for assessing for AIN.⁸

WHY THERE IS LITTLE REASON TO ORDER URINE EOSINOPHILS IN PATIENTS WITH SUSPICION FOR AIN

While initial studies indicated UEs might be diagnostically helpful, subsequent studies did not. In 1985, Corwin et al.⁹ used Wright stain and found UEs in 65 of 470 adults with AKI. Only 9 (14%) of the 65 had a diagnosis of AIN, which was made mostly on clinical grounds. These findings showed that UEs were produced by other renal or urinary tract abnormalities, such as urinary tract infections, acute tubular necrosis, and glomerulonephritis. In a second study, Corwin et al.¹⁰ found that Hansel stain (vs Wright stain) improved the sensitivity of UEs for AIN diagnosis, from 25% to 62.5%. Sensitivity was improved at the expense of specificity, as Hansel stain was positive in other diagnoses as well. The AIN diagnosis was not confirmed by kidney biopsy in the large majority of patients in this study. Lack of confirmation by biopsy, the gold-standard diagnostic test, was a methodologic flaw of this study and others.

Sutton¹¹ reviewed data from 10 studies and found AIN could not be reliably excluded in the absence of UEs (only 19 of 32 biopsy-confirmed AIN cases had UEs present). In addition, Ruffing et al.¹² used Hansel stain and concluded that the positive predictive value of UEs was inadequate in diagnosing AIN. Only 6 of their 15 patients with AIN had positive UEs. Urine eosinophils were also present in patients with other diagnoses (glomerulonephritis, chronic kidney disease, acute pyelonephritis, prerenal azotemia). Like many other investigators, Ruffing et al. made the AIN diagnosis on clinical grounds in the large majority of cases.

Muriithi et al.¹³ reported similarly negative results in their retrospective AKI study involving 566 Mayo Clinic patients and spanning almost 2 decades. The study included patients who underwent both Hansel-stain UE testing and kidney biopsy within a week of each other. Only 28 (30%) of 91 biopsy-proven AIN cases were positive for UEs. Using the 1% cutoff for a positive UE test yielded only 30.8% sensitivity and 68.2% specificity. Using the 5% cutoff increased specificity to 91.2%, at the expense of sensitivity (19.2%); positive predictive value improved to only 30%, and negative predictive value remained relatively unchanged, at 85.6%. In short, Muriithi et al. found that UE testing had no utility in AIN diagnosis.

In summary, initial studies, such as those by Corwin et al,^9,10 supported the conclusion that UEs are useful in AIN diagnosis but had questionable validity owing to methodologic issues, including small sample size and lack of biopsy confirmation of AIN. On the other hand, more recent studies, such as the one conducted by Muriithi et al.,¹³ had larger sample sizes and biopsy-proven diagnoses and confirmed the poor diagnostic value of UEs in AIN.

The poor sensitivity and specificity of UE tests can have important consequences. A false positive test may cause the clinician to incorrectly diagnose the patient with AIN and prompt the clinician to remove medications that may be vitally important. The clinician may also consider treating the patient with steroids empirically. A false negative test may inappropriately reassure the clinician that the patient does not have AIN and does not need cessation of the culprit drug. This may also lead the clinician to forego a necessary kidney biopsy.

WHAT YOU SHOULD DO INSTEAD

A history of recent exposure to a classic offending drug (eg, beta-lactam, proton pump inhibitor, nonsteroidal anti-inflammatory drug) in combination with the classic triad of fever, rash, and peripheral eosinophilia suggests an AIN diagnosis. However, less than 5% to 10% of patients present with this triad.^14,15 Regardless of the triad’s presence, if other causes of AKI have been excluded, stopping a potential offending agent and monitoring for improvement are recommended. If a culprit drug cannot be safely discontinued, renal biopsy may be necessary for confirmation of the diagnosis. Moreover, if kidney function continues to deteriorate, a nephrology consultation may be warranted for guidance on the risks and benefits of performing a kidney biopsy to confirm the diagnosis and/or the use of corticosteroids.

• Urine eosinophils should not be used in the diagnosis of AIN.
• The clinical diagnosis of drug-associated AIN should be based on excluding other possible likely etiologies of AKI and confirming the history of drug exposure. This is reinforced when kidney function improves upon discontinuation of offending agent.
• Kidney biopsy is the gold standard for AIN and should be performed if the clinical picture is unclear or the renal function is not improving upon discontinuation of offending agent.

Since the mid-1980s, studies have found that UEs are too insensitive and nonspecific to confirm or exclude the diagnosis of AIN in patients with AKI (Table). UEs are seen in other AKI etiologies, such as pyelonephritis, acute tubular necrosis, atheroembolic renal disease, and glomerulonephritis. Current evidence-based medicine does not support use of UEs as a biomarker for AIN. False-positive and false-negative results confuse the overall picture and result either in discontinuation of important medications and unnecessary steroid treatment or in delayed removal of a culprit medication.¹⁶

Our case’s positive UE test does not affect the posttest probability that our patient has AIN. Presence of a culprit drug and absence of clinical data suggesting an alternative diagnosis would lead most clinicians to change antibiotic therapy and observe for improvement in renal function.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

In this issue of the Journal of Hospital Medicine, Lusica et al.¹ discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.² Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.² In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.³ There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?

As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.⁴ A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.⁵ The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.³ Small studies in highly select patients supported its use for this purpose.⁶ Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,⁶ likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.

It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.⁷ Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.⁷ The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.⁷

The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.⁸ Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.⁸ But we may be moving in the right direction. An early urine biomarker publication from a small, single center study⁹ revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.¹⁰ These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck^®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.¹¹ In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).¹¹ A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predicting dialysis requirement or death.¹¹ And while this test has yet to find its clinical niche, its operating characteristics are well-studied and likely valid. While predicting AKI earlier does not currently result in effective therapy, it may allow more timely discontinuation or avoidance of potentially nephrotoxic medications, ultimately reducing the severity of AKI and its consequences.

In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.

Disclosure

Nothing to report.

In this issue of the Journal of Hospital Medicine, Lusica et al.¹ discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.² Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.² In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.³ There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?

As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.⁴ A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.⁵ The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.³ Small studies in highly select patients supported its use for this purpose.⁶ Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,⁶ likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.

It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.⁷ Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.⁷ The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.⁷

The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.⁸ Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.⁸ But we may be moving in the right direction. An early urine biomarker publication from a small, single center study⁹ revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.¹⁰ These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck^®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.¹¹ In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).¹¹ A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predicting dialysis requirement or death.¹¹ And while this test has yet to find its clinical niche, its operating characteristics are well-studied and likely valid. While predicting AKI earlier does not currently result in effective therapy, it may allow more timely discontinuation or avoidance of potentially nephrotoxic medications, ultimately reducing the severity of AKI and its consequences.

In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.

Disclosure

Nothing to report.

In this issue of the Journal of Hospital Medicine, Lusica et al.¹ discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.² Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.² In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.³ There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?

As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.⁴ A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.⁵ The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.³ Small studies in highly select patients supported its use for this purpose.⁶ Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,⁶ likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.

It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.⁷ Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.⁷ The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.⁷

The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.⁸ Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.⁸ But we may be moving in the right direction. An early urine biomarker publication from a small, single center study⁹ revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.¹⁰ These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck^®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.¹¹ In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).¹¹ A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predicting dialysis requirement or death.¹¹ And while this test has yet to find its clinical niche, its operating characteristics are well-studied and likely valid. While predicting AKI earlier does not currently result in effective therapy, it may allow more timely discontinuation or avoidance of potentially nephrotoxic medications, ultimately reducing the severity of AKI and its consequences.

In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.

Disclosure

Nothing to report.

We both attend on the Infectious Disease consult team in Veterans Affairs (VA) Hospitals, and predictably the conversation on afternoon rounds often revolves around antibiotics. When we have those discussions, our focus is not on a need to “preserve antibiotics” so they might be available to some unknown patient in the future. Rather, we are working with the primary team to provide the very best treatment for the patient entrusted to our care in the bed right in front of us. We believe it is in this context—providing optimal patient care—that the current efforts in the United States to improve antibiotic use should be viewed.

The growing challenges posed by antibiotic-resistant infections and the related threat of Clostridium difficile infection combine to sicken more than 2 million people each year and contribute to the deaths of more than 25,000 patients.¹ Improving antibiotic use through antibiotic stewardship is often proposed to hospitalists as an important part of stemming this tide. While this is true, even as infectious disease specialists with strong interests in antimicrobial stewardship we do not find that pitch compelling when we are on clinical service.

What motivates us to optimize antibiotic use for our patients is the evidence that doing so will have direct and immediate benefits to the patients under our care. Improving antibiotic use has been proven to decrease a patient’s risk of acquiring C. difficile infection or an antibiotic-resistant infection not at some ill-defined time in the future, but during their current hospital stay.^2,3 Even more important, support from antibiotic stewardship programs has been proven to improve infection cure rates and reduce the risk of treatment failure for hospitalized patients.⁴ The bottom line of antibiotic stewardship is better patient care. Sometimes that means narrowing or stopping antibiotics to reduce the risks of adverse events. In other cases, like in the treatment of suspected sepsis, it means ensuring patients get broad spectrum antibiotics quickly.

The patient care benefits of improving antibiotic use led the Centers for Disease Control and Prevention (CDC) to issue a call in 2014 for all hospitals to have antibiotic stewardship programs, and to the development of The Core Elements of Hospital Antibiotic Stewardship Programs to support that effort. As of January 1, 2017, antibiotic stewardship programs that incorporate all the CDC core elements became an accreditation requirement of The Joint Commission, and the Centers for Medicare and Medicaid Services has proposed making the same requirement of all hospitals that participate in their payment programs.

This means the question is no longer whether we should have antibiotic stewardship efforts in hospitals, but how we can do this most effectively. As the physicians who provide the most care in hospitals, hospitalists are best positioned to turn stewardship theories into practice. The article from Graber et al.⁵ in this issue of the Journal of Hospital Medicine provides some important information that can help busy hospitalists incorporate stewardship into daily practice. The authors reviewed their experience with implementing stewardship efforts in VA hospitals to see which specific interventions were most likely to translate into improved antibiotic use. Based on their findings, we offer some suggestions for three conditions: pneumonia, urinary tract infection (UTI), and skin and soft tissue infection (SSTI). Together, these conditions drive roughly two-thirds of all antibiotic use in US hospitals.⁶

The literature on treatment of pneumonia is increasingly demonstrating that shorter use of antibiotics is often better.⁷ Even though current guidelines recommend 5 to 7 days of antibiotics for uncomplicated community-acquired pneumonia, average durations of therapy are often longer.⁸ Previous work published in the Journal of Hospital Medicine focused on improving antimicrobial documentation as well as access to local clinical guidelines and implementing a 72-hour antimicrobial “time out” by hospitalists.⁹ When these multimodal interventions tailored for hospitalists were in place, utilization of antibiotics improved. Graber et al.⁵ also found that facility educational programs for prudent antimicrobial use and frequency of de-escalation review were associated with decreased overall antimicrobial use. Providing vague recommendations on antibiotic course, or none at all, at discharge or sign-out can lead to unnecessary antibiotics or an extended course of them. Pneumonia-specific interventions could target duration by outlining antibiotic course in hospitalist progress notes and at hand-off.

Misuse of antibiotics in UTI often stems from overtreatment of asymptomatic bacteriuria or unneeded diagnostic testing. Often, the pivotal step in avoiding unnecessary treatment lies in the ordering of the urine culture.¹⁰ Graber et al.⁵ showed that order sets were associated with decreased antimicrobial use. In the case of UTI, hospitalists could work with the stewardship team to design order sets that guide providers to appropriate reasons for ordering a urine culture. Order sets could also help providers recognize important patient-specific risks for certain antibiotics, such as the risk of C. difficile with fluoroquinolones in an elderly patient. Targeting different steps in overutilization of antibiotics would encompass more prescribers and could lead to reducing other unnecessary testing, which is a current focus for many hospitalists.

Skin and soft tissue infections (SSTI) also offer a specific disease state to use order sets and education to improve duration of antibiotics, decrease overuse of broad spectrum antibiotics, and reduce unnecessary diagnostic studies. For example, gram negative and/or anaerobic coverage are rarely indicated in treating SSTIs but are often used. SSTI-specific order sets and guidelines have already been shown to improve both diagnostic work-up and antibiotic treatment.¹¹ As the providers who manage most of these infections in hospitals, hospitalists are ideally positioned to inform the development of SSTI order sets and pathways. The work by Graber et al.⁵ provides some important insights into how we can effectively implement interventions to improve antibiotic use. These insights have never been more important as more hospitals move toward starting or expanding antibiotic stewardship programs. As leaders in patient safety and quality, and as the most important antibiotic prescribers in hospitals, hospitalists must play a central role in stewardship if we are to make meaningful progress.

Disclosure

Nothing to report.

We both attend on the Infectious Disease consult team in Veterans Affairs (VA) Hospitals, and predictably the conversation on afternoon rounds often revolves around antibiotics. When we have those discussions, our focus is not on a need to “preserve antibiotics” so they might be available to some unknown patient in the future. Rather, we are working with the primary team to provide the very best treatment for the patient entrusted to our care in the bed right in front of us. We believe it is in this context—providing optimal patient care—that the current efforts in the United States to improve antibiotic use should be viewed.

The growing challenges posed by antibiotic-resistant infections and the related threat of Clostridium difficile infection combine to sicken more than 2 million people each year and contribute to the deaths of more than 25,000 patients.¹ Improving antibiotic use through antibiotic stewardship is often proposed to hospitalists as an important part of stemming this tide. While this is true, even as infectious disease specialists with strong interests in antimicrobial stewardship we do not find that pitch compelling when we are on clinical service.

What motivates us to optimize antibiotic use for our patients is the evidence that doing so will have direct and immediate benefits to the patients under our care. Improving antibiotic use has been proven to decrease a patient’s risk of acquiring C. difficile infection or an antibiotic-resistant infection not at some ill-defined time in the future, but during their current hospital stay.^2,3 Even more important, support from antibiotic stewardship programs has been proven to improve infection cure rates and reduce the risk of treatment failure for hospitalized patients.⁴ The bottom line of antibiotic stewardship is better patient care. Sometimes that means narrowing or stopping antibiotics to reduce the risks of adverse events. In other cases, like in the treatment of suspected sepsis, it means ensuring patients get broad spectrum antibiotics quickly.

The patient care benefits of improving antibiotic use led the Centers for Disease Control and Prevention (CDC) to issue a call in 2014 for all hospitals to have antibiotic stewardship programs, and to the development of The Core Elements of Hospital Antibiotic Stewardship Programs to support that effort. As of January 1, 2017, antibiotic stewardship programs that incorporate all the CDC core elements became an accreditation requirement of The Joint Commission, and the Centers for Medicare and Medicaid Services has proposed making the same requirement of all hospitals that participate in their payment programs.

This means the question is no longer whether we should have antibiotic stewardship efforts in hospitals, but how we can do this most effectively. As the physicians who provide the most care in hospitals, hospitalists are best positioned to turn stewardship theories into practice. The article from Graber et al.⁵ in this issue of the Journal of Hospital Medicine provides some important information that can help busy hospitalists incorporate stewardship into daily practice. The authors reviewed their experience with implementing stewardship efforts in VA hospitals to see which specific interventions were most likely to translate into improved antibiotic use. Based on their findings, we offer some suggestions for three conditions: pneumonia, urinary tract infection (UTI), and skin and soft tissue infection (SSTI). Together, these conditions drive roughly two-thirds of all antibiotic use in US hospitals.⁶

The literature on treatment of pneumonia is increasingly demonstrating that shorter use of antibiotics is often better.⁷ Even though current guidelines recommend 5 to 7 days of antibiotics for uncomplicated community-acquired pneumonia, average durations of therapy are often longer.⁸ Previous work published in the Journal of Hospital Medicine focused on improving antimicrobial documentation as well as access to local clinical guidelines and implementing a 72-hour antimicrobial “time out” by hospitalists.⁹ When these multimodal interventions tailored for hospitalists were in place, utilization of antibiotics improved. Graber et al.⁵ also found that facility educational programs for prudent antimicrobial use and frequency of de-escalation review were associated with decreased overall antimicrobial use. Providing vague recommendations on antibiotic course, or none at all, at discharge or sign-out can lead to unnecessary antibiotics or an extended course of them. Pneumonia-specific interventions could target duration by outlining antibiotic course in hospitalist progress notes and at hand-off.

Misuse of antibiotics in UTI often stems from overtreatment of asymptomatic bacteriuria or unneeded diagnostic testing. Often, the pivotal step in avoiding unnecessary treatment lies in the ordering of the urine culture.¹⁰ Graber et al.⁵ showed that order sets were associated with decreased antimicrobial use. In the case of UTI, hospitalists could work with the stewardship team to design order sets that guide providers to appropriate reasons for ordering a urine culture. Order sets could also help providers recognize important patient-specific risks for certain antibiotics, such as the risk of C. difficile with fluoroquinolones in an elderly patient. Targeting different steps in overutilization of antibiotics would encompass more prescribers and could lead to reducing other unnecessary testing, which is a current focus for many hospitalists.

Skin and soft tissue infections (SSTI) also offer a specific disease state to use order sets and education to improve duration of antibiotics, decrease overuse of broad spectrum antibiotics, and reduce unnecessary diagnostic studies. For example, gram negative and/or anaerobic coverage are rarely indicated in treating SSTIs but are often used. SSTI-specific order sets and guidelines have already been shown to improve both diagnostic work-up and antibiotic treatment.¹¹ As the providers who manage most of these infections in hospitals, hospitalists are ideally positioned to inform the development of SSTI order sets and pathways. The work by Graber et al.⁵ provides some important insights into how we can effectively implement interventions to improve antibiotic use. These insights have never been more important as more hospitals move toward starting or expanding antibiotic stewardship programs. As leaders in patient safety and quality, and as the most important antibiotic prescribers in hospitals, hospitalists must play a central role in stewardship if we are to make meaningful progress.

Disclosure

Nothing to report.

We both attend on the Infectious Disease consult team in Veterans Affairs (VA) Hospitals, and predictably the conversation on afternoon rounds often revolves around antibiotics. When we have those discussions, our focus is not on a need to “preserve antibiotics” so they might be available to some unknown patient in the future. Rather, we are working with the primary team to provide the very best treatment for the patient entrusted to our care in the bed right in front of us. We believe it is in this context—providing optimal patient care—that the current efforts in the United States to improve antibiotic use should be viewed.

The growing challenges posed by antibiotic-resistant infections and the related threat of Clostridium difficile infection combine to sicken more than 2 million people each year and contribute to the deaths of more than 25,000 patients.¹ Improving antibiotic use through antibiotic stewardship is often proposed to hospitalists as an important part of stemming this tide. While this is true, even as infectious disease specialists with strong interests in antimicrobial stewardship we do not find that pitch compelling when we are on clinical service.

What motivates us to optimize antibiotic use for our patients is the evidence that doing so will have direct and immediate benefits to the patients under our care. Improving antibiotic use has been proven to decrease a patient’s risk of acquiring C. difficile infection or an antibiotic-resistant infection not at some ill-defined time in the future, but during their current hospital stay.^2,3 Even more important, support from antibiotic stewardship programs has been proven to improve infection cure rates and reduce the risk of treatment failure for hospitalized patients.⁴ The bottom line of antibiotic stewardship is better patient care. Sometimes that means narrowing or stopping antibiotics to reduce the risks of adverse events. In other cases, like in the treatment of suspected sepsis, it means ensuring patients get broad spectrum antibiotics quickly.

The patient care benefits of improving antibiotic use led the Centers for Disease Control and Prevention (CDC) to issue a call in 2014 for all hospitals to have antibiotic stewardship programs, and to the development of The Core Elements of Hospital Antibiotic Stewardship Programs to support that effort. As of January 1, 2017, antibiotic stewardship programs that incorporate all the CDC core elements became an accreditation requirement of The Joint Commission, and the Centers for Medicare and Medicaid Services has proposed making the same requirement of all hospitals that participate in their payment programs.

This means the question is no longer whether we should have antibiotic stewardship efforts in hospitals, but how we can do this most effectively. As the physicians who provide the most care in hospitals, hospitalists are best positioned to turn stewardship theories into practice. The article from Graber et al.⁵ in this issue of the Journal of Hospital Medicine provides some important information that can help busy hospitalists incorporate stewardship into daily practice. The authors reviewed their experience with implementing stewardship efforts in VA hospitals to see which specific interventions were most likely to translate into improved antibiotic use. Based on their findings, we offer some suggestions for three conditions: pneumonia, urinary tract infection (UTI), and skin and soft tissue infection (SSTI). Together, these conditions drive roughly two-thirds of all antibiotic use in US hospitals.⁶

The literature on treatment of pneumonia is increasingly demonstrating that shorter use of antibiotics is often better.⁷ Even though current guidelines recommend 5 to 7 days of antibiotics for uncomplicated community-acquired pneumonia, average durations of therapy are often longer.⁸ Previous work published in the Journal of Hospital Medicine focused on improving antimicrobial documentation as well as access to local clinical guidelines and implementing a 72-hour antimicrobial “time out” by hospitalists.⁹ When these multimodal interventions tailored for hospitalists were in place, utilization of antibiotics improved. Graber et al.⁵ also found that facility educational programs for prudent antimicrobial use and frequency of de-escalation review were associated with decreased overall antimicrobial use. Providing vague recommendations on antibiotic course, or none at all, at discharge or sign-out can lead to unnecessary antibiotics or an extended course of them. Pneumonia-specific interventions could target duration by outlining antibiotic course in hospitalist progress notes and at hand-off.

Misuse of antibiotics in UTI often stems from overtreatment of asymptomatic bacteriuria or unneeded diagnostic testing. Often, the pivotal step in avoiding unnecessary treatment lies in the ordering of the urine culture.¹⁰ Graber et al.⁵ showed that order sets were associated with decreased antimicrobial use. In the case of UTI, hospitalists could work with the stewardship team to design order sets that guide providers to appropriate reasons for ordering a urine culture. Order sets could also help providers recognize important patient-specific risks for certain antibiotics, such as the risk of C. difficile with fluoroquinolones in an elderly patient. Targeting different steps in overutilization of antibiotics would encompass more prescribers and could lead to reducing other unnecessary testing, which is a current focus for many hospitalists.

Skin and soft tissue infections (SSTI) also offer a specific disease state to use order sets and education to improve duration of antibiotics, decrease overuse of broad spectrum antibiotics, and reduce unnecessary diagnostic studies. For example, gram negative and/or anaerobic coverage are rarely indicated in treating SSTIs but are often used. SSTI-specific order sets and guidelines have already been shown to improve both diagnostic work-up and antibiotic treatment.¹¹ As the providers who manage most of these infections in hospitals, hospitalists are ideally positioned to inform the development of SSTI order sets and pathways. The work by Graber et al.⁵ provides some important insights into how we can effectively implement interventions to improve antibiotic use. These insights have never been more important as more hospitals move toward starting or expanding antibiotic stewardship programs. As leaders in patient safety and quality, and as the most important antibiotic prescribers in hospitals, hospitalists must play a central role in stewardship if we are to make meaningful progress.

Disclosure

Nothing to report.

Medical services overuse is the provision of healthcare services for which there is no medical basis or for which harms equal or exceed benefits.¹ This overuse drives poor-quality care and unnecessary cost.^2,3 The high prevalence of overuse is recognized by patients,⁴ clinicians,⁵ and policymakers.⁶ Initiatives to reduce overuse have targeted physicians,⁷ the public,⁸ and medical educators^9,10 but have had limited impact.^11,12 Few studies have addressed methods for reducing overuse, and de-implementation of nonbeneficial practices has proved challenging.^1,13,14 Models for reducing overuse are only theoretical¹⁵ or are focused on administrative decisions.^16,17 We think a practical framework is needed. We used an iterative process, informed by expert opinion and discussion, to design such a framework.

The authors, who have expertise in overuse, value, medical education, evidence-based medicine, and implementation science, reviewed related conceptual frameworks¹⁸ and evidence regarding drivers of overuse. We organized these drivers into domains to create a draft framework, which we presented at Preventing Overdiagnosis 2015, a meeting of clinicians, patients, and policymakers interested in overuse. We incorporated feedback from meeting attendees to modify framework domains, and we performed structured searches (using key words in Pubmed) to explore, and estimate the strength of, evidence supporting items within each domain. We rated supporting evidence as strong (studies found a clear correlation between a factor and overuse), moderate (evidence suggests such a correlation or demonstrates a correlation between a particular factor and utilization but not overuse per se), weak (only indirect evidence exists), or absent (no studies identified evaluating a particular factor). All authors reached consensus on ratings.

Framework Principles and Evidence

Patient-centered definition of overuse. During framework development, defining clinical appropriateness emerged as the primary challenge to identifying and reducing overuse. Although some care generally is appropriate based on strong evidence of benefit, and some is inappropriate given a clear lack of benefit or harm, much care is of unclear or variable benefit. Practice guidelines can help identify overuse, but their utility may be limited by lack of evidence in specific clinical situations,¹⁹ and their recommendations may apply poorly to an individual patient. This presents challenges to using guidelines to identify and reduce overuse.

Despite limitations, the scope of overuse has been estimated by applying broad, often guideline-based, criteria for care appropriateness to administrative data.²⁰ Unfortunately, these estimates provide little direction to clinicians and patients partnering to make usage decisions. During framework development, we identified the importance of a patient-level, patient-specific definition of overuse. This approach reinforces the importance of meeting patient needs while standardizing treatments to reduce overuse. A patient-centered approach may also assist professional societies and advocacy groups in developing actionable campaigns and may uncover evidence gaps.

Centrality of patient-clinician interaction. During framework development, the patient–clinician interaction emerged as the nexus through which drivers of overuse exert influence. The centrality of this interaction has been demonstrated in studies of the relationship between care continuity and overuse²¹ or utilization,^22,23 by evidence that communication and patient–clinician relationships affect utilization,²⁴ and by the observation that clinician training in shared decision-making reduces overuse.²⁵ A patient-centered framework assumes that, at least in the weighing of clinically reasonable options, a patient-centered approach optimizes outcomes for that patient.

Incorporating drivers of overuse. We incorporated drivers of overuse into domains and related them to the patient–clinician interaction.²⁶ Domains included the culture of healthcare consumption, patient factors and experiences, the practice environment, the culture of professional medicine, and clinician attitudes and beliefs.

We characterized the evidence illustrating how drivers within each domain influence healthcare use. The evidence for each domain is listed in Table 1.

The final framework is shown in the Figure. Within the healthcare system, patients are influenced by the culture of healthcare consumption, which varies within and among countries.²⁷ Clinicians are influenced by the culture of medical care, which varies by practice setting,²⁸ and by their training environment.²⁹ Both clinicians and patients are influenced by the practice environment and by personal experiences. Ultimately, clinical decisions occur within the specific patient–clinician interaction.²⁴ Table 1 lists each domain’s components, likely impact on overuse, and estimated strength of supporting evidence. Interventions can be conceptualized within appropriate domains or through the interaction between patient and clinician.

We developed a novel and practical conceptual framework for characterizing drivers of overuse and potential intervention points. To our knowledge, this is the first framework incorporating a patient-specific approach to overuse and emphasizing the patient–clinician interaction. Key strengths of framework development are inclusion of a range of perspectives and characterization of the evidence within each domain. Limitations include lack of a formal systematic review and broad, qualitative assessments of evidence strength. However, we believe this framework provides an important conceptual foundation for the study of overuse and interventions to reduce overuse.

Framework Applications

This framework, which highlights the many drivers of overuse, can facilitate understanding of overuse and help conceptualize change, prioritize research goals, and inform specific interventions. For policymakers, the framework can inform efforts to reduce overuse by emphasizing the need for complex interventions and by clarifying the likely impact of interventions targeting specific domains. Similarly, for clinicians and quality improvement professionals, the framework can ground root cause analyses of overuse-related problems and inform allocation of limited resources. Finally, the relatively weak evidence on the role of most acknowledged drivers of overuse suggests an important research agenda. Specifically, several pressing needs have been identified: defining relevant physician and patient cultural factors, investigating interventions to impact culture, defining practice environment features that optimize care appropriateness, and describing specific patient–clinician interaction practices that minimize overuse while providing needed care.

Targeting Interventions

Domains within the framework are influenced by different types of interventions, and different stakeholders may target different domains. For example:
 

• The culture of healthcare consumption may be influenced through public education (eg, Choosing Wisely^® patient resources)^30-32 and public health campaigns.
• The practice environment may be influenced by initiatives to align clinician incentives,³³ team care,³⁴ electronic health record interventions,³⁵ and improved access.³⁶
• Clinician attitudes and beliefs may be influenced by audit and feedback,^37-40 reflection,⁴¹ role modeling,⁴² and education.^43-45
• Patient attitudes and beliefs may be influenced by education, access to price and quality information, and increased engagement in care.^46,47
• For clinicians, the patient–clinician interaction can be improved through training in communication and shared decision-making,25 through access to information (eg, costs) that can be easily shared with patients,^48,49 and through novel visit structures (eg, scribes).⁵⁰
• On the patient side, this interaction can be optimized with improved access (eg, through telemedicine)^51,52 or with patient empowerment during hospitalization.
• The culture of medicine is difficult to influence. Change likely will occur through:

○ Regulatory interventions (eg, Transforming Clinical Practice Initiative of Center for Medicare & Medicaid Innovation).

○ Educational initiatives (eg, high-value care curricula of Alliance for Academic Internal Medicine/American College of Physicians⁵³).

○ Medical journal features (eg, “Less Is More” in JAMA Internal Medicine⁵⁴ and “Things We Do for No Reason” in Journal of Hospital Medicine).

○ Professional organizations (eg, Choosing Wisely^®).

As organizations implement quality improvement initiatives to reduce overuse of services, the framework can be used to target interventions to relevant domains. For example, a hospital leader who wants to reduce opioid prescribing may use the framework to identify the factors that encourage prescribing in each domain—poor understanding of pain treatment (a clinician factor), desire for early discharge encouraging overly aggressive pain management (an environmental factor), patient demand for opioids combined with poor understanding of harms (patient factors), and poor communication regarding pain (a patient–clinician interaction factor). Although not all relevant factors can be addressed, their classification by domain facilitates intervention, in this case perhaps leading to a focus on clinician and patient education on opioids and development of a practical communication tool that targets 3 domains. Table 2 lists ways in which the framework informs approaches to this and other overused services in the hospital setting. Note that some drivers can be acknowledged without identifying targeted interventions.

Moving Forward

Through a multi-stakeholder iterative process, we developed a practical framework for understanding medical overuse and interventions to reduce it. Centered on the patient–clinician interaction, this framework explains overuse as the product of medical and patient culture, the practice environment and incentives, and other clinician and patient factors. Ultimately, care is implemented during the patient–clinician interaction, though few interventions to reduce overuse have focused on that domain.

Conceptualizing overuse through the patient–clinician interaction maintains focus on patients while promoting population health that is both better and lower in cost. This framework can guide interventions to reduce overuse in important parts of the healthcare system while ensuring the final goal of high-quality individualized patient care.

Acknowledgments

The authors thank Valerie Pocus for helping with the artistic design of Framework. An early version of Framework was presented at the 2015 Preventing Overdiagnosis meeting in Bethesda, Maryland.

Disclosures

Dr. Morgan received research support from the VA Health Services Research (CRE 12-307), Agency for Healthcare Research and Quality (AHRQ) (K08- HS18111). Dr. Leppin’s work was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). Dr. Korenstein’s work on this paper was supported by a Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center (award number P30 CA008748). Dr. Morgan provided a self-developed lecture in a 3M-sponsored series on hospital epidemiology and has received honoraria for serving as a book and journal editor for Springer Publishing. Dr. Smith is employed by the American College of Physicians and owns stock in Merck, where her husband is employed. The other authors report no potential conflicts of interest.

Medical services overuse is the provision of healthcare services for which there is no medical basis or for which harms equal or exceed benefits.¹ This overuse drives poor-quality care and unnecessary cost.^2,3 The high prevalence of overuse is recognized by patients,⁴ clinicians,⁵ and policymakers.⁶ Initiatives to reduce overuse have targeted physicians,⁷ the public,⁸ and medical educators^9,10 but have had limited impact.^11,12 Few studies have addressed methods for reducing overuse, and de-implementation of nonbeneficial practices has proved challenging.^1,13,14 Models for reducing overuse are only theoretical¹⁵ or are focused on administrative decisions.^16,17 We think a practical framework is needed. We used an iterative process, informed by expert opinion and discussion, to design such a framework.

The authors, who have expertise in overuse, value, medical education, evidence-based medicine, and implementation science, reviewed related conceptual frameworks¹⁸ and evidence regarding drivers of overuse. We organized these drivers into domains to create a draft framework, which we presented at Preventing Overdiagnosis 2015, a meeting of clinicians, patients, and policymakers interested in overuse. We incorporated feedback from meeting attendees to modify framework domains, and we performed structured searches (using key words in Pubmed) to explore, and estimate the strength of, evidence supporting items within each domain. We rated supporting evidence as strong (studies found a clear correlation between a factor and overuse), moderate (evidence suggests such a correlation or demonstrates a correlation between a particular factor and utilization but not overuse per se), weak (only indirect evidence exists), or absent (no studies identified evaluating a particular factor). All authors reached consensus on ratings.

Framework Principles and Evidence

Patient-centered definition of overuse. During framework development, defining clinical appropriateness emerged as the primary challenge to identifying and reducing overuse. Although some care generally is appropriate based on strong evidence of benefit, and some is inappropriate given a clear lack of benefit or harm, much care is of unclear or variable benefit. Practice guidelines can help identify overuse, but their utility may be limited by lack of evidence in specific clinical situations,¹⁹ and their recommendations may apply poorly to an individual patient. This presents challenges to using guidelines to identify and reduce overuse.

Despite limitations, the scope of overuse has been estimated by applying broad, often guideline-based, criteria for care appropriateness to administrative data.²⁰ Unfortunately, these estimates provide little direction to clinicians and patients partnering to make usage decisions. During framework development, we identified the importance of a patient-level, patient-specific definition of overuse. This approach reinforces the importance of meeting patient needs while standardizing treatments to reduce overuse. A patient-centered approach may also assist professional societies and advocacy groups in developing actionable campaigns and may uncover evidence gaps.

Centrality of patient-clinician interaction. During framework development, the patient–clinician interaction emerged as the nexus through which drivers of overuse exert influence. The centrality of this interaction has been demonstrated in studies of the relationship between care continuity and overuse²¹ or utilization,^22,23 by evidence that communication and patient–clinician relationships affect utilization,²⁴ and by the observation that clinician training in shared decision-making reduces overuse.²⁵ A patient-centered framework assumes that, at least in the weighing of clinically reasonable options, a patient-centered approach optimizes outcomes for that patient.

Incorporating drivers of overuse. We incorporated drivers of overuse into domains and related them to the patient–clinician interaction.²⁶ Domains included the culture of healthcare consumption, patient factors and experiences, the practice environment, the culture of professional medicine, and clinician attitudes and beliefs.

We characterized the evidence illustrating how drivers within each domain influence healthcare use. The evidence for each domain is listed in Table 1.

The final framework is shown in the Figure. Within the healthcare system, patients are influenced by the culture of healthcare consumption, which varies within and among countries.²⁷ Clinicians are influenced by the culture of medical care, which varies by practice setting,²⁸ and by their training environment.²⁹ Both clinicians and patients are influenced by the practice environment and by personal experiences. Ultimately, clinical decisions occur within the specific patient–clinician interaction.²⁴ Table 1 lists each domain’s components, likely impact on overuse, and estimated strength of supporting evidence. Interventions can be conceptualized within appropriate domains or through the interaction between patient and clinician.

We developed a novel and practical conceptual framework for characterizing drivers of overuse and potential intervention points. To our knowledge, this is the first framework incorporating a patient-specific approach to overuse and emphasizing the patient–clinician interaction. Key strengths of framework development are inclusion of a range of perspectives and characterization of the evidence within each domain. Limitations include lack of a formal systematic review and broad, qualitative assessments of evidence strength. However, we believe this framework provides an important conceptual foundation for the study of overuse and interventions to reduce overuse.

Framework Applications

This framework, which highlights the many drivers of overuse, can facilitate understanding of overuse and help conceptualize change, prioritize research goals, and inform specific interventions. For policymakers, the framework can inform efforts to reduce overuse by emphasizing the need for complex interventions and by clarifying the likely impact of interventions targeting specific domains. Similarly, for clinicians and quality improvement professionals, the framework can ground root cause analyses of overuse-related problems and inform allocation of limited resources. Finally, the relatively weak evidence on the role of most acknowledged drivers of overuse suggests an important research agenda. Specifically, several pressing needs have been identified: defining relevant physician and patient cultural factors, investigating interventions to impact culture, defining practice environment features that optimize care appropriateness, and describing specific patient–clinician interaction practices that minimize overuse while providing needed care.

Targeting Interventions

Domains within the framework are influenced by different types of interventions, and different stakeholders may target different domains. For example:
 

• The culture of healthcare consumption may be influenced through public education (eg, Choosing Wisely^® patient resources)^30-32 and public health campaigns.
• The practice environment may be influenced by initiatives to align clinician incentives,³³ team care,³⁴ electronic health record interventions,³⁵ and improved access.³⁶
• Clinician attitudes and beliefs may be influenced by audit and feedback,^37-40 reflection,⁴¹ role modeling,⁴² and education.^43-45
• Patient attitudes and beliefs may be influenced by education, access to price and quality information, and increased engagement in care.^46,47
• For clinicians, the patient–clinician interaction can be improved through training in communication and shared decision-making,25 through access to information (eg, costs) that can be easily shared with patients,^48,49 and through novel visit structures (eg, scribes).⁵⁰
• On the patient side, this interaction can be optimized with improved access (eg, through telemedicine)^51,52 or with patient empowerment during hospitalization.
• The culture of medicine is difficult to influence. Change likely will occur through:

○ Regulatory interventions (eg, Transforming Clinical Practice Initiative of Center for Medicare & Medicaid Innovation).

○ Educational initiatives (eg, high-value care curricula of Alliance for Academic Internal Medicine/American College of Physicians⁵³).

○ Medical journal features (eg, “Less Is More” in JAMA Internal Medicine⁵⁴ and “Things We Do for No Reason” in Journal of Hospital Medicine).

○ Professional organizations (eg, Choosing Wisely^®).

As organizations implement quality improvement initiatives to reduce overuse of services, the framework can be used to target interventions to relevant domains. For example, a hospital leader who wants to reduce opioid prescribing may use the framework to identify the factors that encourage prescribing in each domain—poor understanding of pain treatment (a clinician factor), desire for early discharge encouraging overly aggressive pain management (an environmental factor), patient demand for opioids combined with poor understanding of harms (patient factors), and poor communication regarding pain (a patient–clinician interaction factor). Although not all relevant factors can be addressed, their classification by domain facilitates intervention, in this case perhaps leading to a focus on clinician and patient education on opioids and development of a practical communication tool that targets 3 domains. Table 2 lists ways in which the framework informs approaches to this and other overused services in the hospital setting. Note that some drivers can be acknowledged without identifying targeted interventions.

Moving Forward

Through a multi-stakeholder iterative process, we developed a practical framework for understanding medical overuse and interventions to reduce it. Centered on the patient–clinician interaction, this framework explains overuse as the product of medical and patient culture, the practice environment and incentives, and other clinician and patient factors. Ultimately, care is implemented during the patient–clinician interaction, though few interventions to reduce overuse have focused on that domain.

Conceptualizing overuse through the patient–clinician interaction maintains focus on patients while promoting population health that is both better and lower in cost. This framework can guide interventions to reduce overuse in important parts of the healthcare system while ensuring the final goal of high-quality individualized patient care.

Acknowledgments

The authors thank Valerie Pocus for helping with the artistic design of Framework. An early version of Framework was presented at the 2015 Preventing Overdiagnosis meeting in Bethesda, Maryland.

Disclosures

Dr. Morgan received research support from the VA Health Services Research (CRE 12-307), Agency for Healthcare Research and Quality (AHRQ) (K08- HS18111). Dr. Leppin’s work was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). Dr. Korenstein’s work on this paper was supported by a Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center (award number P30 CA008748). Dr. Morgan provided a self-developed lecture in a 3M-sponsored series on hospital epidemiology and has received honoraria for serving as a book and journal editor for Springer Publishing. Dr. Smith is employed by the American College of Physicians and owns stock in Merck, where her husband is employed. The other authors report no potential conflicts of interest.

Medical services overuse is the provision of healthcare services for which there is no medical basis or for which harms equal or exceed benefits.¹ This overuse drives poor-quality care and unnecessary cost.^2,3 The high prevalence of overuse is recognized by patients,⁴ clinicians,⁵ and policymakers.⁶ Initiatives to reduce overuse have targeted physicians,⁷ the public,⁸ and medical educators^9,10 but have had limited impact.^11,12 Few studies have addressed methods for reducing overuse, and de-implementation of nonbeneficial practices has proved challenging.^1,13,14 Models for reducing overuse are only theoretical¹⁵ or are focused on administrative decisions.^16,17 We think a practical framework is needed. We used an iterative process, informed by expert opinion and discussion, to design such a framework.

The authors, who have expertise in overuse, value, medical education, evidence-based medicine, and implementation science, reviewed related conceptual frameworks¹⁸ and evidence regarding drivers of overuse. We organized these drivers into domains to create a draft framework, which we presented at Preventing Overdiagnosis 2015, a meeting of clinicians, patients, and policymakers interested in overuse. We incorporated feedback from meeting attendees to modify framework domains, and we performed structured searches (using key words in Pubmed) to explore, and estimate the strength of, evidence supporting items within each domain. We rated supporting evidence as strong (studies found a clear correlation between a factor and overuse), moderate (evidence suggests such a correlation or demonstrates a correlation between a particular factor and utilization but not overuse per se), weak (only indirect evidence exists), or absent (no studies identified evaluating a particular factor). All authors reached consensus on ratings.

Framework Principles and Evidence

Patient-centered definition of overuse. During framework development, defining clinical appropriateness emerged as the primary challenge to identifying and reducing overuse. Although some care generally is appropriate based on strong evidence of benefit, and some is inappropriate given a clear lack of benefit or harm, much care is of unclear or variable benefit. Practice guidelines can help identify overuse, but their utility may be limited by lack of evidence in specific clinical situations,¹⁹ and their recommendations may apply poorly to an individual patient. This presents challenges to using guidelines to identify and reduce overuse.

Despite limitations, the scope of overuse has been estimated by applying broad, often guideline-based, criteria for care appropriateness to administrative data.²⁰ Unfortunately, these estimates provide little direction to clinicians and patients partnering to make usage decisions. During framework development, we identified the importance of a patient-level, patient-specific definition of overuse. This approach reinforces the importance of meeting patient needs while standardizing treatments to reduce overuse. A patient-centered approach may also assist professional societies and advocacy groups in developing actionable campaigns and may uncover evidence gaps.

Centrality of patient-clinician interaction. During framework development, the patient–clinician interaction emerged as the nexus through which drivers of overuse exert influence. The centrality of this interaction has been demonstrated in studies of the relationship between care continuity and overuse²¹ or utilization,^22,23 by evidence that communication and patient–clinician relationships affect utilization,²⁴ and by the observation that clinician training in shared decision-making reduces overuse.²⁵ A patient-centered framework assumes that, at least in the weighing of clinically reasonable options, a patient-centered approach optimizes outcomes for that patient.

Incorporating drivers of overuse. We incorporated drivers of overuse into domains and related them to the patient–clinician interaction.²⁶ Domains included the culture of healthcare consumption, patient factors and experiences, the practice environment, the culture of professional medicine, and clinician attitudes and beliefs.

We characterized the evidence illustrating how drivers within each domain influence healthcare use. The evidence for each domain is listed in Table 1.

The final framework is shown in the Figure. Within the healthcare system, patients are influenced by the culture of healthcare consumption, which varies within and among countries.²⁷ Clinicians are influenced by the culture of medical care, which varies by practice setting,²⁸ and by their training environment.²⁹ Both clinicians and patients are influenced by the practice environment and by personal experiences. Ultimately, clinical decisions occur within the specific patient–clinician interaction.²⁴ Table 1 lists each domain’s components, likely impact on overuse, and estimated strength of supporting evidence. Interventions can be conceptualized within appropriate domains or through the interaction between patient and clinician.

We developed a novel and practical conceptual framework for characterizing drivers of overuse and potential intervention points. To our knowledge, this is the first framework incorporating a patient-specific approach to overuse and emphasizing the patient–clinician interaction. Key strengths of framework development are inclusion of a range of perspectives and characterization of the evidence within each domain. Limitations include lack of a formal systematic review and broad, qualitative assessments of evidence strength. However, we believe this framework provides an important conceptual foundation for the study of overuse and interventions to reduce overuse.

Framework Applications

This framework, which highlights the many drivers of overuse, can facilitate understanding of overuse and help conceptualize change, prioritize research goals, and inform specific interventions. For policymakers, the framework can inform efforts to reduce overuse by emphasizing the need for complex interventions and by clarifying the likely impact of interventions targeting specific domains. Similarly, for clinicians and quality improvement professionals, the framework can ground root cause analyses of overuse-related problems and inform allocation of limited resources. Finally, the relatively weak evidence on the role of most acknowledged drivers of overuse suggests an important research agenda. Specifically, several pressing needs have been identified: defining relevant physician and patient cultural factors, investigating interventions to impact culture, defining practice environment features that optimize care appropriateness, and describing specific patient–clinician interaction practices that minimize overuse while providing needed care.

Targeting Interventions

Domains within the framework are influenced by different types of interventions, and different stakeholders may target different domains. For example:
 

• The culture of healthcare consumption may be influenced through public education (eg, Choosing Wisely^® patient resources)^30-32 and public health campaigns.
• The practice environment may be influenced by initiatives to align clinician incentives,³³ team care,³⁴ electronic health record interventions,³⁵ and improved access.³⁶
• Clinician attitudes and beliefs may be influenced by audit and feedback,^37-40 reflection,⁴¹ role modeling,⁴² and education.^43-45
• Patient attitudes and beliefs may be influenced by education, access to price and quality information, and increased engagement in care.^46,47
• For clinicians, the patient–clinician interaction can be improved through training in communication and shared decision-making,25 through access to information (eg, costs) that can be easily shared with patients,^48,49 and through novel visit structures (eg, scribes).⁵⁰
• On the patient side, this interaction can be optimized with improved access (eg, through telemedicine)^51,52 or with patient empowerment during hospitalization.
• The culture of medicine is difficult to influence. Change likely will occur through:

○ Regulatory interventions (eg, Transforming Clinical Practice Initiative of Center for Medicare & Medicaid Innovation).

○ Educational initiatives (eg, high-value care curricula of Alliance for Academic Internal Medicine/American College of Physicians⁵³).

○ Medical journal features (eg, “Less Is More” in JAMA Internal Medicine⁵⁴ and “Things We Do for No Reason” in Journal of Hospital Medicine).

○ Professional organizations (eg, Choosing Wisely^®).

As organizations implement quality improvement initiatives to reduce overuse of services, the framework can be used to target interventions to relevant domains. For example, a hospital leader who wants to reduce opioid prescribing may use the framework to identify the factors that encourage prescribing in each domain—poor understanding of pain treatment (a clinician factor), desire for early discharge encouraging overly aggressive pain management (an environmental factor), patient demand for opioids combined with poor understanding of harms (patient factors), and poor communication regarding pain (a patient–clinician interaction factor). Although not all relevant factors can be addressed, their classification by domain facilitates intervention, in this case perhaps leading to a focus on clinician and patient education on opioids and development of a practical communication tool that targets 3 domains. Table 2 lists ways in which the framework informs approaches to this and other overused services in the hospital setting. Note that some drivers can be acknowledged without identifying targeted interventions.

Moving Forward

Through a multi-stakeholder iterative process, we developed a practical framework for understanding medical overuse and interventions to reduce it. Centered on the patient–clinician interaction, this framework explains overuse as the product of medical and patient culture, the practice environment and incentives, and other clinician and patient factors. Ultimately, care is implemented during the patient–clinician interaction, though few interventions to reduce overuse have focused on that domain.

Conceptualizing overuse through the patient–clinician interaction maintains focus on patients while promoting population health that is both better and lower in cost. This framework can guide interventions to reduce overuse in important parts of the healthcare system while ensuring the final goal of high-quality individualized patient care.

Acknowledgments

The authors thank Valerie Pocus for helping with the artistic design of Framework. An early version of Framework was presented at the 2015 Preventing Overdiagnosis meeting in Bethesda, Maryland.

Disclosures

Dr. Morgan received research support from the VA Health Services Research (CRE 12-307), Agency for Healthcare Research and Quality (AHRQ) (K08- HS18111). Dr. Leppin’s work was supported by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). Dr. Korenstein’s work on this paper was supported by a Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center (award number P30 CA008748). Dr. Morgan provided a self-developed lecture in a 3M-sponsored series on hospital epidemiology and has received honoraria for serving as a book and journal editor for Springer Publishing. Dr. Smith is employed by the American College of Physicians and owns stock in Merck, where her husband is employed. The other authors report no potential conflicts of interest.

Reacting quickly to complaints of caregivers who had their eligibility for Program of Comprehensive Assistance for Family Caregivers (PCAFC) funding revoked, the VA has announced that it will pause revocations while reviewing the program’s implementation. “VA is taking immediate action to review the National Caregiver Support Program to ensure we honor our commitment to enhance the health and well-being of veterans,” said Secretary of Veterans Affairs David J. Shulkin, MD, in a prepared statement. “I have instructed an internal review to evaluate consistency of revocations in the program and standardize communication with veterans and caregivers nationwide.”

An NPR report documented a number of cases of PCAFC support that had been changed recently despite little evidence for change in the veterans’ need for care. According to the NPR analysis, some VA facilities saw significant drops in the number of caregivers who received support; whereas others saw equally significant increases.

According to the VA, veterans who need a VA designated family caregiver to assist with the management of personal care functions that are required for everyday living and are in conjunction with standard care provided by the VA are eligible for the program. A clinical support team evaluates the veteran for eligibility, and the caregiver receives training. The program provides a monthly stipend based on the veterans’ “level of need and required assistance.”

During the review, the VA will continue accepting PCAFC applications, approving applicants based on current eligibility criteria, processing appeals, and monitoring eligible veterans’ well-being at least every 90 days unless otherwise clinically indicated.

 “Caregivers play a critically important role in the health and well-being of veterans, and caring for an injured veteran is a labor of love,” said Dr. Poonam Alaigh, acting VA Under Secretary for Health. “We remain focused on process improvements and support services for our family caregivers so they can take care of our veterans.” 

Reacting quickly to complaints of caregivers who had their eligibility for Program of Comprehensive Assistance for Family Caregivers (PCAFC) funding revoked, the VA has announced that it will pause revocations while reviewing the program’s implementation. “VA is taking immediate action to review the National Caregiver Support Program to ensure we honor our commitment to enhance the health and well-being of veterans,” said Secretary of Veterans Affairs David J. Shulkin, MD, in a prepared statement. “I have instructed an internal review to evaluate consistency of revocations in the program and standardize communication with veterans and caregivers nationwide.”

An NPR report documented a number of cases of PCAFC support that had been changed recently despite little evidence for change in the veterans’ need for care. According to the NPR analysis, some VA facilities saw significant drops in the number of caregivers who received support; whereas others saw equally significant increases.

According to the VA, veterans who need a VA designated family caregiver to assist with the management of personal care functions that are required for everyday living and are in conjunction with standard care provided by the VA are eligible for the program. A clinical support team evaluates the veteran for eligibility, and the caregiver receives training. The program provides a monthly stipend based on the veterans’ “level of need and required assistance.”

During the review, the VA will continue accepting PCAFC applications, approving applicants based on current eligibility criteria, processing appeals, and monitoring eligible veterans’ well-being at least every 90 days unless otherwise clinically indicated.

 “Caregivers play a critically important role in the health and well-being of veterans, and caring for an injured veteran is a labor of love,” said Dr. Poonam Alaigh, acting VA Under Secretary for Health. “We remain focused on process improvements and support services for our family caregivers so they can take care of our veterans.” 

Reacting quickly to complaints of caregivers who had their eligibility for Program of Comprehensive Assistance for Family Caregivers (PCAFC) funding revoked, the VA has announced that it will pause revocations while reviewing the program’s implementation. “VA is taking immediate action to review the National Caregiver Support Program to ensure we honor our commitment to enhance the health and well-being of veterans,” said Secretary of Veterans Affairs David J. Shulkin, MD, in a prepared statement. “I have instructed an internal review to evaluate consistency of revocations in the program and standardize communication with veterans and caregivers nationwide.”

An NPR report documented a number of cases of PCAFC support that had been changed recently despite little evidence for change in the veterans’ need for care. According to the NPR analysis, some VA facilities saw significant drops in the number of caregivers who received support; whereas others saw equally significant increases.

According to the VA, veterans who need a VA designated family caregiver to assist with the management of personal care functions that are required for everyday living and are in conjunction with standard care provided by the VA are eligible for the program. A clinical support team evaluates the veteran for eligibility, and the caregiver receives training. The program provides a monthly stipend based on the veterans’ “level of need and required assistance.”

During the review, the VA will continue accepting PCAFC applications, approving applicants based on current eligibility criteria, processing appeals, and monitoring eligible veterans’ well-being at least every 90 days unless otherwise clinically indicated.

 “Caregivers play a critically important role in the health and well-being of veterans, and caring for an injured veteran is a labor of love,” said Dr. Poonam Alaigh, acting VA Under Secretary for Health. “We remain focused on process improvements and support services for our family caregivers so they can take care of our veterans.”