Svetlana Chernyavsky, DO

Case

A 57-year-old man with a history of alcohol abuse (no history of seizures) presents to the ED “feeling awful.” He claims his last drink was 1 day prior. Initial vital signs are: T = 99.1°F, HR 102 bpm, BP 162/85 mm Hg, respirations 18/minute, and 99% oxygen saturation. He is tremulous, diaphoretic, and has an unsteady gait. What is the best way to manage his symptoms while hospitalized?

Brief overview of the issue

With over 15 million people with alcohol use disorder (AUD) in the United States alone, alcohol dependence and misuse remain significant issues among hospitalized patients.¹ It is estimated that over 20% of admitted patients meet DSM-5 criteria for AUD and that over 2 million will withdraw each year.^2,3 Acute withdrawal includes a spectrum of symptoms ranging from mild anxiety and diaphoresis to hallucinations, seizures, and delirium tremens. Onset of these symptoms ranges from 24 hours up to 5 days.

Severe alcohol withdrawal syndrome (SAWS) attributable to abrupt discontinuation of alcohol leads to increased morbidity and mortality; therefore, early detection and prevention in the acute care setting is critical. Several factors can help predict who may withdraw, and once detected, pharmacological treatment is necessary.⁴ Thorough evaluation and treatment can help reduce mortality from the most severe forms of alcohol withdrawal including delirium tremens, which has up to 40% mortality if left untreated.⁵

Overview of the data

How do we use benzodiazepines to treat alcohol withdrawal?

Benzodiazepines are the mainstay of alcohol withdrawal treatment. Benzodiazepines work by stimulating the gamma-aminobutyric acid (GABA) receptor resulting in a reduction of neuronal activity. This leads to a sedative effect and thus slows the progression of withdrawal symptoms.

Long-acting benzodiazepines, such as chlordiazepoxide and diazepam, are the preferred choices for most patients. Their active metabolites have a rapid onset of action and their long half-lives allow for a lower incidence of breakthrough symptoms and rebound phenomena such as seizures.⁶ Benzodiazepines with shorter half-lives, such as lorazepam and oxazepam, are preferred in patients with liver dysfunction and those prone to respiratory depression.

Intravenous administration has a rapid onset of action and is the standard administration route of choice in patients with acute severe withdrawal, delirium tremens, and seizure activity. In patients with mild withdrawal symptoms or those in the outpatient setting, oral administration is generally effective.⁶

The Clinical Institute Withdrawal Assessment (CIWA) is one commonly used titration model that requires calculation of a symptom-based withdrawal score. Data have consistently demonstrated that a symptom-triggered method results in administration of less total benzodiazepines over a significantly shorter duration, thereby reducing cost and duration of treatment and minimizing side effects. This regimen may also reduce the risk of undermedicating or overmedicating a patient since the dosing is based upon an individual’s symptoms.^7,8

The efficacy of symptom-triggered regimens however, depends on the reliability and accuracy of the patient assessment. A fixed-interval benzodiazepine-dosing approach where benzodiazepines are administered regardless of symptoms is useful when frequent monitoring and reassessment are not feasible or are unreliable.
 

What about phenobarbital?

Phenobarbital has similar pharmacokinetics to the benzodiazepines frequently used for alcohol withdrawal, including simultaneous effects on gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors, and has been proposed as a treatment option for delirium tremens.

In 2019, as reported in the American Journal of Emergency Medicine, Nelson et al. found that incorporating phenobarbital into a benzodiazepine-based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department.⁹ The authors concluded that “phenobarbital (was) a safe and effective treatment alternative for alcohol withdrawal.” The systematic review by Hammond et al. in 2017 found that phenobarbital, either as monotherapy or in conjunction with benzodiazepines, could have comparable or superior results in comparison to other treatments, including benzodiazepines monotherapy.¹⁰ Further studies are needed to determine dosing and the most effective way to incorporate the use of phenobarbital in treatment of Alcohol Withdrawal Syndrome (AWS).
 

Should gabapentin or any other medications be added to his treatment regimen?

Chronic alcohol use induces a reduction in GABA activity (the major inhibitory neurotransmitter in the brain) and alcohol cessation results in decreased inhibitory tone. This physiologic imbalance contributes to the syndrome of alcohol withdrawal. As such, gabapentin has emerged as a promising treatment option in AWS and may help reduce the need for benzodiazepines.

Gabapentin has few drug-drug interactions and is safe for use in patients with impaired liver function; however, dosage adjustment is required for renal dysfunction (CrCl less than 60 mL/min). Gabapentin’s neuroprotective effects may also help decrease the neurotoxic effects associated with AWS. Common side effects of gabapentin include dizziness, drowsiness, ataxia, diarrhea, nausea, and vomiting. The potential for misuse has been reported.

In several small studies, gabapentin monotherapy was found to be comparable to benzodiazepines in the treatment of mild to moderate AWS. Gabapentin is efficacious in reducing cravings as well as improving mood, anxiety, and sleep, and showed an advantage over benzodiazepines in preventing relapse with no difference in length of hospital stay.^6,11 Given the small sample sizes of these studies and the differing methods, settings, and inclusion/ exclusion criteria used, the generalizability of these findings to patients with significant medical and/or psychiatric comorbidities remains limited. Additional studies are needed to standardize dosing protocols and treatment strategies for both inpatients and outpatients.

Alternative agents such as antipsychotics (e.g., haloperidol), centrally acting alpha-2 agonists (e.g., clonidine), beta-blockers, and an agonist of the GABA-B receptor (e.g., baclofen) may also attenuate the symptoms of withdrawal. Since these all have limited evidence of their efficacy and have potential for harm, such as masking symptoms of progressive withdrawal and lowering seizure threshold, these agents are not routinely recommended for use. Valproic acid/divalproex, levetiracetam, topiramate, and zonisamide have also showed some efficacy in reducing symptoms of alcohol withdrawal in limited studies. The data on prevention of withdrawal seizures or delirium tremens when used as monotherapy is less robust.¹²

A daily multivitamin and folate are ordered. What about thiamine? Does the route matter?

Alarmingly, 80% of people who chronically abuse alcohol are thiamine deficient.¹³ This deficiency is attributable to several factors including inadequate oral intake, malabsorption, and decreased cellular utilization. Thiamine is a crucial factor in multiple enzymatic and metabolic pathways. Its deficiency can lead to free radical production, neurotoxicity, impaired glucose metabolism, and ultimately, cell death.¹⁴ A clinical concern stemming from thiamine deficiency is the development of Wernicke’s encephalopathy (WE), which is potentially reversible with prompt recognition and treatment, in comparison to its irreversible amnestic sequela, Korsakoff’s syndrome.

Wernicke’s encephalopathy had been defined as a triad of ataxia, ophthalmoplegia, and global confusion. However, Harper et al. discovered that only 16% of patients presented with the classic triad and 19% had none of these signs.¹⁵ Diagnosis is clinical since thiamine serology results do not accurately represent brain storage.

Currently, there are no consistent guidelines regarding repletion of thiamine administration in the treatment or prevention of WE attributable to alcohol overuse. Thiamine has a safe toxicity profile as excess thiamine is excreted in the urine. Outside of rare reports of anaphylactoid reactions involving large parenteral doses, there is no concern for overtreatment. As Wernicke-Korsakoff syndrome is associated with significant morbidity and mortality, high doses such as 200 to 500 mg are recommended to ensure blood-brain barrier passage. The intravenous route is optimal over oral administration to bypass concerns of gastrointestinal malabsorption. Thiamine 100 mg by mouth daily for ongoing supplementation can be considered for patients who are at risk for WE. It is also important to recognize that magnesium and thiamine are intertwined in several key enzymatic pathways. To optimize the responsiveness of thiamine repletion, magnesium levels should be tested and repleted if low.
 

Application of the data to our patient

Nurses are able to frequently monitor the patient so he is started on symptom-triggered treatment with chlordiazepoxide using the CIWA protocol. This strategy will help limit the amount of benzodiazepines he receives and shorten his treatment duration. Given the ataxia, the patient is also started on high-dose IV thiamine three times a day to treat possible Wernicke’s encephalopathy. Gabapentin is added to his regimen to help manage his moderate alcohol withdrawal syndrome.

Bottom line

Long-acting benzodiazepines using symptom-triggered administration when feasible are the mainstay of treating alcohol withdrawal. Other medications such as gabapentin, carbamazepine, and phenobarbital can be considered as adjunctive agents. Given the high rate of thiamine deficiency and the low risk of overreplacement, intravenous thiamine can be considered for inpatients with AWS.

Dr. Agrawal, Dr. Chernyavsky, Dr. Dharapak, Dr. Grabscheid, Dr. Merrill, Dr. Pillay, and Dr. Rizk are hospitalists at Mount Sinai Beth Israel in New York.

References

1. CDC - Fact Sheets: “Alcohol Use And Health – Alcohol.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 3 Jan. 2018.

2. Rawlani V et al. Treatment of the hospitalized alcohol-dependent patient with alcohol withdrawal syndrome. Internet J Intern Med. 2008;8(1).

3. Grant BF et al. Epidemiology of DSM-5 alcohol use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72:757.

4. Wood E et al. Will this hospitalized patient develop severe alcohol withdrawal syndrome?: The Rational Clinical Examination Systematic Review. JAMA. 2018;320:825.

5. Sarkar S et al. Risk factors for the development of delirium in alcohol dependence syndrome: Clinical and neurobiological implications. Indian J Psychiatry. 2017 Jul-Sep;59(3):300-5.

6. Sachdeva A et al. Alcohol withdrawal syndrome: Benzodiazepines and beyond. J Clinical Diagn Res. 2015 Sep 9(9).

7. Sullivan JT et al. Benzodiazepine requirements during alcohol withdrawal syndrome: Clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol. 1991;11:291-5.

8. Saitz R et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994;272(7):519.

9. Nelson AC et al. Benzodiazepines vs. barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019 Jan 3.

10. Hammond DA et al. Patient outcomes associated with phenobarbital use with or without benzodiazepines for alcohol withdrawal syndrome: A systematic review. Hosp Pharm. 2017 Oct;52(9):607-16.

11. Mo Y et al. Current practice patterns in the management of alcohol withdrawal syndrome. P T. 2018 Mar;43(3):158-62.

12. Leung JG et al. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015 Aug;49(8):897-906.

13. Martin P et al. The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health. 2003:27(2):134-42.

14. Flannery A et al. Unpeeling the evidence for the banana bag: Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. Crit Care Med. 2016 Aug:44(8):1545-52.

15. Harper CG et al. Clinical signs in Wernicke Korsakoff complex: A retrospective analysis of 131 cases diagnosed at autopsy. J Neurol Neurosurg Psychiatry. 1986;49(4):341-5.
 

Key points

• Alcohol use disorder and alcohol withdrawal are significant problems in hospitalized patients; early detection and treatment are crucial in preventing high morbidity and mortality.
• Long acting benzodiazepines with active metabolites such as chlordiazepoxide and diazepam are the preferred treatment for alcohol withdrawal except for patients with advanced liver disease or those prone to respiratory depression.
• Symptom-triggered therapy decreases the amount of medication, shortens treatment duration, and decreases inpatient length of stay, compared with fixed schedule dosing.
• Gabapentin may be effective in the treatment of mild to moderate AWS but cannot yet be routinely recommended as monotherapy in severe withdrawal, in patients with seizure history, or in patients who are at high risk for progression to delirium tremens.
• Thiamine deficiency is common in chronic alcohol use disorders; thiamine repletion should be considered for patients at risk or when Wernicke’s encephalopathy and Korsakoff’s syndrome are suspected.

Additional reading

1. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5):401-10.

2. Mayo-Smith MF. Pharmacological management of alcohol withdrawal: A meta-analysis and evidence-based practice guideline. JAMA. 1997;278(2):144-51.

3. Michael F. Mayo-Smith, MD, MPH et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-12.
 

Quiz

A 51-year-old female with a history of hypertension and continuous alcohol abuse presents to the hospital with fever and cough. She is found to have community-acquired pneumonia and is admitted for treatment. How else would you manage this patient?

A. Start scheduled benzodiazepines and oral thiamine.

B. Start CIWA protocol using a long-acting benzodiazepine and oral thiamine.

C. Start scheduled benzodiazepines and IV thiamine.

D. Start CIWA protocol using a long-acting benzodiazepine and consider IV or oral thiamine.

Answer: D. Symptom-triggered benzodiazepine therapy is favored as is consideration for thiamine repletion in the treatment of AWS.

Case

A 57-year-old man with a history of alcohol abuse (no history of seizures) presents to the ED “feeling awful.” He claims his last drink was 1 day prior. Initial vital signs are: T = 99.1°F, HR 102 bpm, BP 162/85 mm Hg, respirations 18/minute, and 99% oxygen saturation. He is tremulous, diaphoretic, and has an unsteady gait. What is the best way to manage his symptoms while hospitalized?

Brief overview of the issue

With over 15 million people with alcohol use disorder (AUD) in the United States alone, alcohol dependence and misuse remain significant issues among hospitalized patients.¹ It is estimated that over 20% of admitted patients meet DSM-5 criteria for AUD and that over 2 million will withdraw each year.^2,3 Acute withdrawal includes a spectrum of symptoms ranging from mild anxiety and diaphoresis to hallucinations, seizures, and delirium tremens. Onset of these symptoms ranges from 24 hours up to 5 days.

Severe alcohol withdrawal syndrome (SAWS) attributable to abrupt discontinuation of alcohol leads to increased morbidity and mortality; therefore, early detection and prevention in the acute care setting is critical. Several factors can help predict who may withdraw, and once detected, pharmacological treatment is necessary.⁴ Thorough evaluation and treatment can help reduce mortality from the most severe forms of alcohol withdrawal including delirium tremens, which has up to 40% mortality if left untreated.⁵

Overview of the data

How do we use benzodiazepines to treat alcohol withdrawal?

Benzodiazepines are the mainstay of alcohol withdrawal treatment. Benzodiazepines work by stimulating the gamma-aminobutyric acid (GABA) receptor resulting in a reduction of neuronal activity. This leads to a sedative effect and thus slows the progression of withdrawal symptoms.

Long-acting benzodiazepines, such as chlordiazepoxide and diazepam, are the preferred choices for most patients. Their active metabolites have a rapid onset of action and their long half-lives allow for a lower incidence of breakthrough symptoms and rebound phenomena such as seizures.⁶ Benzodiazepines with shorter half-lives, such as lorazepam and oxazepam, are preferred in patients with liver dysfunction and those prone to respiratory depression.

Intravenous administration has a rapid onset of action and is the standard administration route of choice in patients with acute severe withdrawal, delirium tremens, and seizure activity. In patients with mild withdrawal symptoms or those in the outpatient setting, oral administration is generally effective.⁶

The Clinical Institute Withdrawal Assessment (CIWA) is one commonly used titration model that requires calculation of a symptom-based withdrawal score. Data have consistently demonstrated that a symptom-triggered method results in administration of less total benzodiazepines over a significantly shorter duration, thereby reducing cost and duration of treatment and minimizing side effects. This regimen may also reduce the risk of undermedicating or overmedicating a patient since the dosing is based upon an individual’s symptoms.^7,8

The efficacy of symptom-triggered regimens however, depends on the reliability and accuracy of the patient assessment. A fixed-interval benzodiazepine-dosing approach where benzodiazepines are administered regardless of symptoms is useful when frequent monitoring and reassessment are not feasible or are unreliable.
 

What about phenobarbital?

Phenobarbital has similar pharmacokinetics to the benzodiazepines frequently used for alcohol withdrawal, including simultaneous effects on gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors, and has been proposed as a treatment option for delirium tremens.

In 2019, as reported in the American Journal of Emergency Medicine, Nelson et al. found that incorporating phenobarbital into a benzodiazepine-based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department.⁹ The authors concluded that “phenobarbital (was) a safe and effective treatment alternative for alcohol withdrawal.” The systematic review by Hammond et al. in 2017 found that phenobarbital, either as monotherapy or in conjunction with benzodiazepines, could have comparable or superior results in comparison to other treatments, including benzodiazepines monotherapy.¹⁰ Further studies are needed to determine dosing and the most effective way to incorporate the use of phenobarbital in treatment of Alcohol Withdrawal Syndrome (AWS).
 

Should gabapentin or any other medications be added to his treatment regimen?

Chronic alcohol use induces a reduction in GABA activity (the major inhibitory neurotransmitter in the brain) and alcohol cessation results in decreased inhibitory tone. This physiologic imbalance contributes to the syndrome of alcohol withdrawal. As such, gabapentin has emerged as a promising treatment option in AWS and may help reduce the need for benzodiazepines.

Gabapentin has few drug-drug interactions and is safe for use in patients with impaired liver function; however, dosage adjustment is required for renal dysfunction (CrCl less than 60 mL/min). Gabapentin’s neuroprotective effects may also help decrease the neurotoxic effects associated with AWS. Common side effects of gabapentin include dizziness, drowsiness, ataxia, diarrhea, nausea, and vomiting. The potential for misuse has been reported.

In several small studies, gabapentin monotherapy was found to be comparable to benzodiazepines in the treatment of mild to moderate AWS. Gabapentin is efficacious in reducing cravings as well as improving mood, anxiety, and sleep, and showed an advantage over benzodiazepines in preventing relapse with no difference in length of hospital stay.^6,11 Given the small sample sizes of these studies and the differing methods, settings, and inclusion/ exclusion criteria used, the generalizability of these findings to patients with significant medical and/or psychiatric comorbidities remains limited. Additional studies are needed to standardize dosing protocols and treatment strategies for both inpatients and outpatients.

Alternative agents such as antipsychotics (e.g., haloperidol), centrally acting alpha-2 agonists (e.g., clonidine), beta-blockers, and an agonist of the GABA-B receptor (e.g., baclofen) may also attenuate the symptoms of withdrawal. Since these all have limited evidence of their efficacy and have potential for harm, such as masking symptoms of progressive withdrawal and lowering seizure threshold, these agents are not routinely recommended for use. Valproic acid/divalproex, levetiracetam, topiramate, and zonisamide have also showed some efficacy in reducing symptoms of alcohol withdrawal in limited studies. The data on prevention of withdrawal seizures or delirium tremens when used as monotherapy is less robust.¹²

A daily multivitamin and folate are ordered. What about thiamine? Does the route matter?

Alarmingly, 80% of people who chronically abuse alcohol are thiamine deficient.¹³ This deficiency is attributable to several factors including inadequate oral intake, malabsorption, and decreased cellular utilization. Thiamine is a crucial factor in multiple enzymatic and metabolic pathways. Its deficiency can lead to free radical production, neurotoxicity, impaired glucose metabolism, and ultimately, cell death.¹⁴ A clinical concern stemming from thiamine deficiency is the development of Wernicke’s encephalopathy (WE), which is potentially reversible with prompt recognition and treatment, in comparison to its irreversible amnestic sequela, Korsakoff’s syndrome.

Wernicke’s encephalopathy had been defined as a triad of ataxia, ophthalmoplegia, and global confusion. However, Harper et al. discovered that only 16% of patients presented with the classic triad and 19% had none of these signs.¹⁵ Diagnosis is clinical since thiamine serology results do not accurately represent brain storage.

Currently, there are no consistent guidelines regarding repletion of thiamine administration in the treatment or prevention of WE attributable to alcohol overuse. Thiamine has a safe toxicity profile as excess thiamine is excreted in the urine. Outside of rare reports of anaphylactoid reactions involving large parenteral doses, there is no concern for overtreatment. As Wernicke-Korsakoff syndrome is associated with significant morbidity and mortality, high doses such as 200 to 500 mg are recommended to ensure blood-brain barrier passage. The intravenous route is optimal over oral administration to bypass concerns of gastrointestinal malabsorption. Thiamine 100 mg by mouth daily for ongoing supplementation can be considered for patients who are at risk for WE. It is also important to recognize that magnesium and thiamine are intertwined in several key enzymatic pathways. To optimize the responsiveness of thiamine repletion, magnesium levels should be tested and repleted if low.
 

Application of the data to our patient

Nurses are able to frequently monitor the patient so he is started on symptom-triggered treatment with chlordiazepoxide using the CIWA protocol. This strategy will help limit the amount of benzodiazepines he receives and shorten his treatment duration. Given the ataxia, the patient is also started on high-dose IV thiamine three times a day to treat possible Wernicke’s encephalopathy. Gabapentin is added to his regimen to help manage his moderate alcohol withdrawal syndrome.

Bottom line

Long-acting benzodiazepines using symptom-triggered administration when feasible are the mainstay of treating alcohol withdrawal. Other medications such as gabapentin, carbamazepine, and phenobarbital can be considered as adjunctive agents. Given the high rate of thiamine deficiency and the low risk of overreplacement, intravenous thiamine can be considered for inpatients with AWS.

Dr. Agrawal, Dr. Chernyavsky, Dr. Dharapak, Dr. Grabscheid, Dr. Merrill, Dr. Pillay, and Dr. Rizk are hospitalists at Mount Sinai Beth Israel in New York.

References

1. CDC - Fact Sheets: “Alcohol Use And Health – Alcohol.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 3 Jan. 2018.

2. Rawlani V et al. Treatment of the hospitalized alcohol-dependent patient with alcohol withdrawal syndrome. Internet J Intern Med. 2008;8(1).

3. Grant BF et al. Epidemiology of DSM-5 alcohol use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72:757.

4. Wood E et al. Will this hospitalized patient develop severe alcohol withdrawal syndrome?: The Rational Clinical Examination Systematic Review. JAMA. 2018;320:825.

5. Sarkar S et al. Risk factors for the development of delirium in alcohol dependence syndrome: Clinical and neurobiological implications. Indian J Psychiatry. 2017 Jul-Sep;59(3):300-5.

6. Sachdeva A et al. Alcohol withdrawal syndrome: Benzodiazepines and beyond. J Clinical Diagn Res. 2015 Sep 9(9).

7. Sullivan JT et al. Benzodiazepine requirements during alcohol withdrawal syndrome: Clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol. 1991;11:291-5.

8. Saitz R et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994;272(7):519.

9. Nelson AC et al. Benzodiazepines vs. barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019 Jan 3.

10. Hammond DA et al. Patient outcomes associated with phenobarbital use with or without benzodiazepines for alcohol withdrawal syndrome: A systematic review. Hosp Pharm. 2017 Oct;52(9):607-16.

11. Mo Y et al. Current practice patterns in the management of alcohol withdrawal syndrome. P T. 2018 Mar;43(3):158-62.

12. Leung JG et al. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015 Aug;49(8):897-906.

13. Martin P et al. The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health. 2003:27(2):134-42.

14. Flannery A et al. Unpeeling the evidence for the banana bag: Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. Crit Care Med. 2016 Aug:44(8):1545-52.

15. Harper CG et al. Clinical signs in Wernicke Korsakoff complex: A retrospective analysis of 131 cases diagnosed at autopsy. J Neurol Neurosurg Psychiatry. 1986;49(4):341-5.
 

Key points

• Alcohol use disorder and alcohol withdrawal are significant problems in hospitalized patients; early detection and treatment are crucial in preventing high morbidity and mortality.
• Long acting benzodiazepines with active metabolites such as chlordiazepoxide and diazepam are the preferred treatment for alcohol withdrawal except for patients with advanced liver disease or those prone to respiratory depression.
• Symptom-triggered therapy decreases the amount of medication, shortens treatment duration, and decreases inpatient length of stay, compared with fixed schedule dosing.
• Gabapentin may be effective in the treatment of mild to moderate AWS but cannot yet be routinely recommended as monotherapy in severe withdrawal, in patients with seizure history, or in patients who are at high risk for progression to delirium tremens.
• Thiamine deficiency is common in chronic alcohol use disorders; thiamine repletion should be considered for patients at risk or when Wernicke’s encephalopathy and Korsakoff’s syndrome are suspected.

Additional reading

1. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5):401-10.

2. Mayo-Smith MF. Pharmacological management of alcohol withdrawal: A meta-analysis and evidence-based practice guideline. JAMA. 1997;278(2):144-51.

3. Michael F. Mayo-Smith, MD, MPH et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-12.
 

Quiz

A 51-year-old female with a history of hypertension and continuous alcohol abuse presents to the hospital with fever and cough. She is found to have community-acquired pneumonia and is admitted for treatment. How else would you manage this patient?

A. Start scheduled benzodiazepines and oral thiamine.

B. Start CIWA protocol using a long-acting benzodiazepine and oral thiamine.

C. Start scheduled benzodiazepines and IV thiamine.

D. Start CIWA protocol using a long-acting benzodiazepine and consider IV or oral thiamine.

Answer: D. Symptom-triggered benzodiazepine therapy is favored as is consideration for thiamine repletion in the treatment of AWS.

Case

A 57-year-old man with a history of alcohol abuse (no history of seizures) presents to the ED “feeling awful.” He claims his last drink was 1 day prior. Initial vital signs are: T = 99.1°F, HR 102 bpm, BP 162/85 mm Hg, respirations 18/minute, and 99% oxygen saturation. He is tremulous, diaphoretic, and has an unsteady gait. What is the best way to manage his symptoms while hospitalized?

Brief overview of the issue

With over 15 million people with alcohol use disorder (AUD) in the United States alone, alcohol dependence and misuse remain significant issues among hospitalized patients.¹ It is estimated that over 20% of admitted patients meet DSM-5 criteria for AUD and that over 2 million will withdraw each year.^2,3 Acute withdrawal includes a spectrum of symptoms ranging from mild anxiety and diaphoresis to hallucinations, seizures, and delirium tremens. Onset of these symptoms ranges from 24 hours up to 5 days.

Severe alcohol withdrawal syndrome (SAWS) attributable to abrupt discontinuation of alcohol leads to increased morbidity and mortality; therefore, early detection and prevention in the acute care setting is critical. Several factors can help predict who may withdraw, and once detected, pharmacological treatment is necessary.⁴ Thorough evaluation and treatment can help reduce mortality from the most severe forms of alcohol withdrawal including delirium tremens, which has up to 40% mortality if left untreated.⁵

Overview of the data

How do we use benzodiazepines to treat alcohol withdrawal?

Benzodiazepines are the mainstay of alcohol withdrawal treatment. Benzodiazepines work by stimulating the gamma-aminobutyric acid (GABA) receptor resulting in a reduction of neuronal activity. This leads to a sedative effect and thus slows the progression of withdrawal symptoms.

Long-acting benzodiazepines, such as chlordiazepoxide and diazepam, are the preferred choices for most patients. Their active metabolites have a rapid onset of action and their long half-lives allow for a lower incidence of breakthrough symptoms and rebound phenomena such as seizures.⁶ Benzodiazepines with shorter half-lives, such as lorazepam and oxazepam, are preferred in patients with liver dysfunction and those prone to respiratory depression.

Intravenous administration has a rapid onset of action and is the standard administration route of choice in patients with acute severe withdrawal, delirium tremens, and seizure activity. In patients with mild withdrawal symptoms or those in the outpatient setting, oral administration is generally effective.⁶

The Clinical Institute Withdrawal Assessment (CIWA) is one commonly used titration model that requires calculation of a symptom-based withdrawal score. Data have consistently demonstrated that a symptom-triggered method results in administration of less total benzodiazepines over a significantly shorter duration, thereby reducing cost and duration of treatment and minimizing side effects. This regimen may also reduce the risk of undermedicating or overmedicating a patient since the dosing is based upon an individual’s symptoms.^7,8

The efficacy of symptom-triggered regimens however, depends on the reliability and accuracy of the patient assessment. A fixed-interval benzodiazepine-dosing approach where benzodiazepines are administered regardless of symptoms is useful when frequent monitoring and reassessment are not feasible or are unreliable.
 

What about phenobarbital?

Phenobarbital has similar pharmacokinetics to the benzodiazepines frequently used for alcohol withdrawal, including simultaneous effects on gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors, and has been proposed as a treatment option for delirium tremens.

In 2019, as reported in the American Journal of Emergency Medicine, Nelson et al. found that incorporating phenobarbital into a benzodiazepine-based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department.⁹ The authors concluded that “phenobarbital (was) a safe and effective treatment alternative for alcohol withdrawal.” The systematic review by Hammond et al. in 2017 found that phenobarbital, either as monotherapy or in conjunction with benzodiazepines, could have comparable or superior results in comparison to other treatments, including benzodiazepines monotherapy.¹⁰ Further studies are needed to determine dosing and the most effective way to incorporate the use of phenobarbital in treatment of Alcohol Withdrawal Syndrome (AWS).
 

Should gabapentin or any other medications be added to his treatment regimen?

Chronic alcohol use induces a reduction in GABA activity (the major inhibitory neurotransmitter in the brain) and alcohol cessation results in decreased inhibitory tone. This physiologic imbalance contributes to the syndrome of alcohol withdrawal. As such, gabapentin has emerged as a promising treatment option in AWS and may help reduce the need for benzodiazepines.

Gabapentin has few drug-drug interactions and is safe for use in patients with impaired liver function; however, dosage adjustment is required for renal dysfunction (CrCl less than 60 mL/min). Gabapentin’s neuroprotective effects may also help decrease the neurotoxic effects associated with AWS. Common side effects of gabapentin include dizziness, drowsiness, ataxia, diarrhea, nausea, and vomiting. The potential for misuse has been reported.

In several small studies, gabapentin monotherapy was found to be comparable to benzodiazepines in the treatment of mild to moderate AWS. Gabapentin is efficacious in reducing cravings as well as improving mood, anxiety, and sleep, and showed an advantage over benzodiazepines in preventing relapse with no difference in length of hospital stay.^6,11 Given the small sample sizes of these studies and the differing methods, settings, and inclusion/ exclusion criteria used, the generalizability of these findings to patients with significant medical and/or psychiatric comorbidities remains limited. Additional studies are needed to standardize dosing protocols and treatment strategies for both inpatients and outpatients.

Alternative agents such as antipsychotics (e.g., haloperidol), centrally acting alpha-2 agonists (e.g., clonidine), beta-blockers, and an agonist of the GABA-B receptor (e.g., baclofen) may also attenuate the symptoms of withdrawal. Since these all have limited evidence of their efficacy and have potential for harm, such as masking symptoms of progressive withdrawal and lowering seizure threshold, these agents are not routinely recommended for use. Valproic acid/divalproex, levetiracetam, topiramate, and zonisamide have also showed some efficacy in reducing symptoms of alcohol withdrawal in limited studies. The data on prevention of withdrawal seizures or delirium tremens when used as monotherapy is less robust.¹²

A daily multivitamin and folate are ordered. What about thiamine? Does the route matter?

Alarmingly, 80% of people who chronically abuse alcohol are thiamine deficient.¹³ This deficiency is attributable to several factors including inadequate oral intake, malabsorption, and decreased cellular utilization. Thiamine is a crucial factor in multiple enzymatic and metabolic pathways. Its deficiency can lead to free radical production, neurotoxicity, impaired glucose metabolism, and ultimately, cell death.¹⁴ A clinical concern stemming from thiamine deficiency is the development of Wernicke’s encephalopathy (WE), which is potentially reversible with prompt recognition and treatment, in comparison to its irreversible amnestic sequela, Korsakoff’s syndrome.

Wernicke’s encephalopathy had been defined as a triad of ataxia, ophthalmoplegia, and global confusion. However, Harper et al. discovered that only 16% of patients presented with the classic triad and 19% had none of these signs.¹⁵ Diagnosis is clinical since thiamine serology results do not accurately represent brain storage.

Currently, there are no consistent guidelines regarding repletion of thiamine administration in the treatment or prevention of WE attributable to alcohol overuse. Thiamine has a safe toxicity profile as excess thiamine is excreted in the urine. Outside of rare reports of anaphylactoid reactions involving large parenteral doses, there is no concern for overtreatment. As Wernicke-Korsakoff syndrome is associated with significant morbidity and mortality, high doses such as 200 to 500 mg are recommended to ensure blood-brain barrier passage. The intravenous route is optimal over oral administration to bypass concerns of gastrointestinal malabsorption. Thiamine 100 mg by mouth daily for ongoing supplementation can be considered for patients who are at risk for WE. It is also important to recognize that magnesium and thiamine are intertwined in several key enzymatic pathways. To optimize the responsiveness of thiamine repletion, magnesium levels should be tested and repleted if low.
 

Application of the data to our patient

Nurses are able to frequently monitor the patient so he is started on symptom-triggered treatment with chlordiazepoxide using the CIWA protocol. This strategy will help limit the amount of benzodiazepines he receives and shorten his treatment duration. Given the ataxia, the patient is also started on high-dose IV thiamine three times a day to treat possible Wernicke’s encephalopathy. Gabapentin is added to his regimen to help manage his moderate alcohol withdrawal syndrome.

Bottom line

Long-acting benzodiazepines using symptom-triggered administration when feasible are the mainstay of treating alcohol withdrawal. Other medications such as gabapentin, carbamazepine, and phenobarbital can be considered as adjunctive agents. Given the high rate of thiamine deficiency and the low risk of overreplacement, intravenous thiamine can be considered for inpatients with AWS.

Dr. Agrawal, Dr. Chernyavsky, Dr. Dharapak, Dr. Grabscheid, Dr. Merrill, Dr. Pillay, and Dr. Rizk are hospitalists at Mount Sinai Beth Israel in New York.

References

1. CDC - Fact Sheets: “Alcohol Use And Health – Alcohol.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 3 Jan. 2018.

2. Rawlani V et al. Treatment of the hospitalized alcohol-dependent patient with alcohol withdrawal syndrome. Internet J Intern Med. 2008;8(1).

3. Grant BF et al. Epidemiology of DSM-5 alcohol use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72:757.

4. Wood E et al. Will this hospitalized patient develop severe alcohol withdrawal syndrome?: The Rational Clinical Examination Systematic Review. JAMA. 2018;320:825.

5. Sarkar S et al. Risk factors for the development of delirium in alcohol dependence syndrome: Clinical and neurobiological implications. Indian J Psychiatry. 2017 Jul-Sep;59(3):300-5.

6. Sachdeva A et al. Alcohol withdrawal syndrome: Benzodiazepines and beyond. J Clinical Diagn Res. 2015 Sep 9(9).

7. Sullivan JT et al. Benzodiazepine requirements during alcohol withdrawal syndrome: Clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol. 1991;11:291-5.

8. Saitz R et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994;272(7):519.

9. Nelson AC et al. Benzodiazepines vs. barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019 Jan 3.

10. Hammond DA et al. Patient outcomes associated with phenobarbital use with or without benzodiazepines for alcohol withdrawal syndrome: A systematic review. Hosp Pharm. 2017 Oct;52(9):607-16.

11. Mo Y et al. Current practice patterns in the management of alcohol withdrawal syndrome. P T. 2018 Mar;43(3):158-62.

12. Leung JG et al. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015 Aug;49(8):897-906.

13. Martin P et al. The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health. 2003:27(2):134-42.

14. Flannery A et al. Unpeeling the evidence for the banana bag: Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. Crit Care Med. 2016 Aug:44(8):1545-52.

15. Harper CG et al. Clinical signs in Wernicke Korsakoff complex: A retrospective analysis of 131 cases diagnosed at autopsy. J Neurol Neurosurg Psychiatry. 1986;49(4):341-5.
 

Key points

• Alcohol use disorder and alcohol withdrawal are significant problems in hospitalized patients; early detection and treatment are crucial in preventing high morbidity and mortality.
• Long acting benzodiazepines with active metabolites such as chlordiazepoxide and diazepam are the preferred treatment for alcohol withdrawal except for patients with advanced liver disease or those prone to respiratory depression.
• Symptom-triggered therapy decreases the amount of medication, shortens treatment duration, and decreases inpatient length of stay, compared with fixed schedule dosing.
• Gabapentin may be effective in the treatment of mild to moderate AWS but cannot yet be routinely recommended as monotherapy in severe withdrawal, in patients with seizure history, or in patients who are at high risk for progression to delirium tremens.
• Thiamine deficiency is common in chronic alcohol use disorders; thiamine repletion should be considered for patients at risk or when Wernicke’s encephalopathy and Korsakoff’s syndrome are suspected.

Additional reading

1. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5):401-10.

2. Mayo-Smith MF. Pharmacological management of alcohol withdrawal: A meta-analysis and evidence-based practice guideline. JAMA. 1997;278(2):144-51.

3. Michael F. Mayo-Smith, MD, MPH et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-12.
 

Quiz

A 51-year-old female with a history of hypertension and continuous alcohol abuse presents to the hospital with fever and cough. She is found to have community-acquired pneumonia and is admitted for treatment. How else would you manage this patient?

A. Start scheduled benzodiazepines and oral thiamine.

B. Start CIWA protocol using a long-acting benzodiazepine and oral thiamine.

C. Start scheduled benzodiazepines and IV thiamine.

D. Start CIWA protocol using a long-acting benzodiazepine and consider IV or oral thiamine.

Answer: D. Symptom-triggered benzodiazepine therapy is favored as is consideration for thiamine repletion in the treatment of AWS.

Clinical question: Does low-dose dopamine or low-dose nesiritide added to diuretic therapy enhance pulmonary volume reduction and preserve renal function in patients with acute heart failure and renal dysfunction, compared to placebo?

Background: Small studies have suggested that low-dose dopamine or low-dose nesiritide may be beneficial in enhancing decongestion and improving renal dysfunction; however, there is ambiguity in overall benefit. Some observational studies suggest that dopamine and nesiritide are associated with higher length of stay, higher costs, and greater mortality.

Study Design: RCT.

Setting: Twenty-six hospital sites in the U.S. and Canada.

Synopsis: Three hundred sixty patients with acute heart failure and renal dysfunction were randomized to receive either nesiritide or dopamine within 24 hours of admission. Within each of these arms, patients were then randomized, in a double-blinded 2:1 fashion, into active treatment versus placebo groups. Treatment groups were compared to the pooled placebo groups.

Two main endpoints were urine output and change in serum cystatin C, from enrollment to 72 hours. Compared with placebo, low-dose dopamine had no significant effect on urine output or serum cystatin C level. Similarly, low-dose nesiritide had no significant effect on 72-hour urine output or serum cystatin C level.

Other studies have shown these drugs to be potentially harmful. Hospitalists should use caution and carefully interpret the relevant evidence when considering their use.

Bottom line: Neither low-dose nesiritide nor low-dose dopamine improved urine output or serum cystatin C levels at 72 hours in patients with acute heart failure and renal dysfunction.

Citation: Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543.

Clinical question: Does low-dose dopamine or low-dose nesiritide added to diuretic therapy enhance pulmonary volume reduction and preserve renal function in patients with acute heart failure and renal dysfunction, compared to placebo?

Background: Small studies have suggested that low-dose dopamine or low-dose nesiritide may be beneficial in enhancing decongestion and improving renal dysfunction; however, there is ambiguity in overall benefit. Some observational studies suggest that dopamine and nesiritide are associated with higher length of stay, higher costs, and greater mortality.

Study Design: RCT.

Setting: Twenty-six hospital sites in the U.S. and Canada.

Synopsis: Three hundred sixty patients with acute heart failure and renal dysfunction were randomized to receive either nesiritide or dopamine within 24 hours of admission. Within each of these arms, patients were then randomized, in a double-blinded 2:1 fashion, into active treatment versus placebo groups. Treatment groups were compared to the pooled placebo groups.

Two main endpoints were urine output and change in serum cystatin C, from enrollment to 72 hours. Compared with placebo, low-dose dopamine had no significant effect on urine output or serum cystatin C level. Similarly, low-dose nesiritide had no significant effect on 72-hour urine output or serum cystatin C level.

Other studies have shown these drugs to be potentially harmful. Hospitalists should use caution and carefully interpret the relevant evidence when considering their use.

Bottom line: Neither low-dose nesiritide nor low-dose dopamine improved urine output or serum cystatin C levels at 72 hours in patients with acute heart failure and renal dysfunction.

Citation: Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543.

Clinical question: Does low-dose dopamine or low-dose nesiritide added to diuretic therapy enhance pulmonary volume reduction and preserve renal function in patients with acute heart failure and renal dysfunction, compared to placebo?

Background: Small studies have suggested that low-dose dopamine or low-dose nesiritide may be beneficial in enhancing decongestion and improving renal dysfunction; however, there is ambiguity in overall benefit. Some observational studies suggest that dopamine and nesiritide are associated with higher length of stay, higher costs, and greater mortality.

Study Design: RCT.

Setting: Twenty-six hospital sites in the U.S. and Canada.

Synopsis: Three hundred sixty patients with acute heart failure and renal dysfunction were randomized to receive either nesiritide or dopamine within 24 hours of admission. Within each of these arms, patients were then randomized, in a double-blinded 2:1 fashion, into active treatment versus placebo groups. Treatment groups were compared to the pooled placebo groups.

Two main endpoints were urine output and change in serum cystatin C, from enrollment to 72 hours. Compared with placebo, low-dose dopamine had no significant effect on urine output or serum cystatin C level. Similarly, low-dose nesiritide had no significant effect on 72-hour urine output or serum cystatin C level.

Other studies have shown these drugs to be potentially harmful. Hospitalists should use caution and carefully interpret the relevant evidence when considering their use.

Bottom line: Neither low-dose nesiritide nor low-dose dopamine improved urine output or serum cystatin C levels at 72 hours in patients with acute heart failure and renal dysfunction.

Citation: Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543.

Clinical question: Does the use and timing of beta blockers in COPD patients experiencing a first myocardial infarction (MI) affect survival after the event?

Background: Beta blockers are effective in reducing mortality and reinfarction after an MI; however, concerns regarding the side effects of beta blockers, such as bronchospasm, continue to limit their use in patients with COPD.

Study design: Population-based cohort study.

Setting: The Myocardial Ischemia National Audit Project, linked to the General Practice Research Database, in the United Kingdom.

Synopsis: Researchers identified 1,063 patients over the age of 18 with COPD admitted to the hospital with a first acute MI. Use of beta blockers during hospitalization was associated with increased overall and one-year survival. Initiation of beta blockers during an MI had a mortality-adjusted hazard ratio of 0.50 (95% CI 0.36 to 0.69; P<0.001; median follow-up time=2.9 years).

Patients already on beta blockers prior to the MI had overall survival-adjusted hazard ratio of 0.59 (95% CI 0.44 to 0.79; P<0.001). Both scenarios showed survival benefits compared to COPD patients who were not prescribed beta blockers. Patients given beta blockers with COPD either during the MI hospitalization or before the event were younger and had fewer comorbidities. This may have accounted for some of the survival bias.

Bottom line: The use of beta blockers in patients with COPD started prior to, or at the time of, hospital admission for a first MI is associated with improved survival.

Citation: Quint JK, Herret E, Bhaskaran K, et al. Effect of ß blockers on mortality after myocardial infarction in adults with COPD: population-based cohort study of UK electronic healthcare records. BMJ. 2013;347:f6650.

Clinical question: Does the use and timing of beta blockers in COPD patients experiencing a first myocardial infarction (MI) affect survival after the event?

Background: Beta blockers are effective in reducing mortality and reinfarction after an MI; however, concerns regarding the side effects of beta blockers, such as bronchospasm, continue to limit their use in patients with COPD.

Study design: Population-based cohort study.

Setting: The Myocardial Ischemia National Audit Project, linked to the General Practice Research Database, in the United Kingdom.

Synopsis: Researchers identified 1,063 patients over the age of 18 with COPD admitted to the hospital with a first acute MI. Use of beta blockers during hospitalization was associated with increased overall and one-year survival. Initiation of beta blockers during an MI had a mortality-adjusted hazard ratio of 0.50 (95% CI 0.36 to 0.69; P<0.001; median follow-up time=2.9 years).

Patients already on beta blockers prior to the MI had overall survival-adjusted hazard ratio of 0.59 (95% CI 0.44 to 0.79; P<0.001). Both scenarios showed survival benefits compared to COPD patients who were not prescribed beta blockers. Patients given beta blockers with COPD either during the MI hospitalization or before the event were younger and had fewer comorbidities. This may have accounted for some of the survival bias.

Bottom line: The use of beta blockers in patients with COPD started prior to, or at the time of, hospital admission for a first MI is associated with improved survival.

Citation: Quint JK, Herret E, Bhaskaran K, et al. Effect of ß blockers on mortality after myocardial infarction in adults with COPD: population-based cohort study of UK electronic healthcare records. BMJ. 2013;347:f6650.

Clinical question: Does the use and timing of beta blockers in COPD patients experiencing a first myocardial infarction (MI) affect survival after the event?

Background: Beta blockers are effective in reducing mortality and reinfarction after an MI; however, concerns regarding the side effects of beta blockers, such as bronchospasm, continue to limit their use in patients with COPD.

Study design: Population-based cohort study.

Setting: The Myocardial Ischemia National Audit Project, linked to the General Practice Research Database, in the United Kingdom.

Synopsis: Researchers identified 1,063 patients over the age of 18 with COPD admitted to the hospital with a first acute MI. Use of beta blockers during hospitalization was associated with increased overall and one-year survival. Initiation of beta blockers during an MI had a mortality-adjusted hazard ratio of 0.50 (95% CI 0.36 to 0.69; P<0.001; median follow-up time=2.9 years).

Patients already on beta blockers prior to the MI had overall survival-adjusted hazard ratio of 0.59 (95% CI 0.44 to 0.79; P<0.001). Both scenarios showed survival benefits compared to COPD patients who were not prescribed beta blockers. Patients given beta blockers with COPD either during the MI hospitalization or before the event were younger and had fewer comorbidities. This may have accounted for some of the survival bias.

Bottom line: The use of beta blockers in patients with COPD started prior to, or at the time of, hospital admission for a first MI is associated with improved survival.

Citation: Quint JK, Herret E, Bhaskaran K, et al. Effect of ß blockers on mortality after myocardial infarction in adults with COPD: population-based cohort study of UK electronic healthcare records. BMJ. 2013;347:f6650.

Clinical question: What is the long-term efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation (Afib)?

Background: Edoxaban is an oral factor Xa inhibitor approved for use in Japan for the prevention of venous thromboembolism after orthopedic surgery. No specific antidote for edoxaban exists, but hemostatic agents can reverse its anticoagulation effect.

Study design: RCT.

Setting: More than 1,300 centers in 46 countries.

Synopsis: Researchers randomized 21,105 patients in a 1:1:1 ratio to receive warfarin (goal INR of 2-3), low-dose edoxaban, or high-dose edoxoban. All patients received two sets of drugs, either active warfarin with placebo edoxaban or active edoxaban (high- or low-dose) and placebo warfarin (with sham INRs drawn), and were followed for a median of 2.8 years.

The annualized rate of stroke or systemic embolic event was 1.5% in the warfarin group, compared with 1.18% in the high-dose edoxaban group (hazard ratio 0.79; P<0.001) and 1.61% in the low-dose edoxaban group (hazard ratio 1.07; P=0.005). Annualized rate of major bleeding was 3.43% with warfarin, 2.75% with high-dose edoxoban (hazard ratio 0.80; P<0.001), and 1.61% with low-dose edoxaban (hazard ratio 0.47; P<0.001).

Both edoxaban regimens were noninferior to warfarin for the prevention of stroke or systemic emboli. The rates of cardiovascular events, bleeding, or death from any cause was lower with both doses of edoxaban as compared with warfarin.

Bottom line: Once-daily edoxaban is noninferior to warfarin for the prevention of stroke or systemic emboli and is associated with lower rates of bleeding and death.

Citation: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med. 2013;369(22):2093-2104.

Clinical question: What is the long-term efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation (Afib)?

Background: Edoxaban is an oral factor Xa inhibitor approved for use in Japan for the prevention of venous thromboembolism after orthopedic surgery. No specific antidote for edoxaban exists, but hemostatic agents can reverse its anticoagulation effect.

Study design: RCT.

Setting: More than 1,300 centers in 46 countries.

Synopsis: Researchers randomized 21,105 patients in a 1:1:1 ratio to receive warfarin (goal INR of 2-3), low-dose edoxaban, or high-dose edoxoban. All patients received two sets of drugs, either active warfarin with placebo edoxaban or active edoxaban (high- or low-dose) and placebo warfarin (with sham INRs drawn), and were followed for a median of 2.8 years.

The annualized rate of stroke or systemic embolic event was 1.5% in the warfarin group, compared with 1.18% in the high-dose edoxaban group (hazard ratio 0.79; P<0.001) and 1.61% in the low-dose edoxaban group (hazard ratio 1.07; P=0.005). Annualized rate of major bleeding was 3.43% with warfarin, 2.75% with high-dose edoxoban (hazard ratio 0.80; P<0.001), and 1.61% with low-dose edoxaban (hazard ratio 0.47; P<0.001).

Both edoxaban regimens were noninferior to warfarin for the prevention of stroke or systemic emboli. The rates of cardiovascular events, bleeding, or death from any cause was lower with both doses of edoxaban as compared with warfarin.

Bottom line: Once-daily edoxaban is noninferior to warfarin for the prevention of stroke or systemic emboli and is associated with lower rates of bleeding and death.

Citation: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med. 2013;369(22):2093-2104.

Clinical question: What is the long-term efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation (Afib)?

Background: Edoxaban is an oral factor Xa inhibitor approved for use in Japan for the prevention of venous thromboembolism after orthopedic surgery. No specific antidote for edoxaban exists, but hemostatic agents can reverse its anticoagulation effect.

Study design: RCT.

Setting: More than 1,300 centers in 46 countries.

Synopsis: Researchers randomized 21,105 patients in a 1:1:1 ratio to receive warfarin (goal INR of 2-3), low-dose edoxaban, or high-dose edoxoban. All patients received two sets of drugs, either active warfarin with placebo edoxaban or active edoxaban (high- or low-dose) and placebo warfarin (with sham INRs drawn), and were followed for a median of 2.8 years.

The annualized rate of stroke or systemic embolic event was 1.5% in the warfarin group, compared with 1.18% in the high-dose edoxaban group (hazard ratio 0.79; P<0.001) and 1.61% in the low-dose edoxaban group (hazard ratio 1.07; P=0.005). Annualized rate of major bleeding was 3.43% with warfarin, 2.75% with high-dose edoxoban (hazard ratio 0.80; P<0.001), and 1.61% with low-dose edoxaban (hazard ratio 0.47; P<0.001).

Both edoxaban regimens were noninferior to warfarin for the prevention of stroke or systemic emboli. The rates of cardiovascular events, bleeding, or death from any cause was lower with both doses of edoxaban as compared with warfarin.

Bottom line: Once-daily edoxaban is noninferior to warfarin for the prevention of stroke or systemic emboli and is associated with lower rates of bleeding and death.

Citation: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med. 2013;369(22):2093-2104.

Clinical question: Can intervention by pharmacists and physicians improve compliance to cardio-protective medications?

Background: Adherence to cardio-protective medications in the year after hospitalization for acute coronary syndrome is poor.

Study design: RCT.

Setting: Four Department of Veterans Affairs medical centers.

Synopsis: The intervention consisted of pharmacist-led medication reconciliation, patient education, pharmacist and PCP +/- cardiologist collaboration, and voice messaging. The outcome measured was the proportion of patients adherent to medication regimens based on a mean proportion of days covered (PDC) >0.80 in the year after discharge, using pharmacy refill data for clopidogrel, beta blockers, statins, and ACEI/ARBs.

Two hundred forty-one patients (95.3%) completed the study. In the intervention group, 89.3% of patients were adherent vs. 73.9% in the usual care group (P=0.003). Mean PDC was higher in the intervention group (0.94 vs. 0.87; P<0.001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs. 70.7%; P=0.03), statins (93.2% vs. 71.3%; P<0.001), and ACEI/ARBs (93.1% vs. 81.7%; P=0.03), but not beta blockers (88.1% vs. 84.8%; P=0.59). There were no statistically significant differences in the proportion of patients who achieved blood pressure and LDL-C level goals.

Bottom line: An interdisciplinary, multi-faceted intervention increased medication compliance in the year after discharge for ACS but did not improve blood pressure or LDL-C levels.

Citation: Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge. JAMA Intern Med. 2014;174(2):186-193.

Clinical question: Can intervention by pharmacists and physicians improve compliance to cardio-protective medications?

Background: Adherence to cardio-protective medications in the year after hospitalization for acute coronary syndrome is poor.

Study design: RCT.

Setting: Four Department of Veterans Affairs medical centers.

Synopsis: The intervention consisted of pharmacist-led medication reconciliation, patient education, pharmacist and PCP +/- cardiologist collaboration, and voice messaging. The outcome measured was the proportion of patients adherent to medication regimens based on a mean proportion of days covered (PDC) >0.80 in the year after discharge, using pharmacy refill data for clopidogrel, beta blockers, statins, and ACEI/ARBs.

Two hundred forty-one patients (95.3%) completed the study. In the intervention group, 89.3% of patients were adherent vs. 73.9% in the usual care group (P=0.003). Mean PDC was higher in the intervention group (0.94 vs. 0.87; P<0.001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs. 70.7%; P=0.03), statins (93.2% vs. 71.3%; P<0.001), and ACEI/ARBs (93.1% vs. 81.7%; P=0.03), but not beta blockers (88.1% vs. 84.8%; P=0.59). There were no statistically significant differences in the proportion of patients who achieved blood pressure and LDL-C level goals.

Bottom line: An interdisciplinary, multi-faceted intervention increased medication compliance in the year after discharge for ACS but did not improve blood pressure or LDL-C levels.

Citation: Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge. JAMA Intern Med. 2014;174(2):186-193.

Clinical question: Can intervention by pharmacists and physicians improve compliance to cardio-protective medications?

Background: Adherence to cardio-protective medications in the year after hospitalization for acute coronary syndrome is poor.

Study design: RCT.

Setting: Four Department of Veterans Affairs medical centers.

Synopsis: The intervention consisted of pharmacist-led medication reconciliation, patient education, pharmacist and PCP +/- cardiologist collaboration, and voice messaging. The outcome measured was the proportion of patients adherent to medication regimens based on a mean proportion of days covered (PDC) >0.80 in the year after discharge, using pharmacy refill data for clopidogrel, beta blockers, statins, and ACEI/ARBs.

Two hundred forty-one patients (95.3%) completed the study. In the intervention group, 89.3% of patients were adherent vs. 73.9% in the usual care group (P=0.003). Mean PDC was higher in the intervention group (0.94 vs. 0.87; P<0.001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs. 70.7%; P=0.03), statins (93.2% vs. 71.3%; P<0.001), and ACEI/ARBs (93.1% vs. 81.7%; P=0.03), but not beta blockers (88.1% vs. 84.8%; P=0.59). There were no statistically significant differences in the proportion of patients who achieved blood pressure and LDL-C level goals.

Bottom line: An interdisciplinary, multi-faceted intervention increased medication compliance in the year after discharge for ACS but did not improve blood pressure or LDL-C levels.

Citation: Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge. JAMA Intern Med. 2014;174(2):186-193.

Clinical question: In critically ill patients admitted to the ICU with hypovolemic shock, does the use of colloid for fluid resuscitation, compared with crystalloid, improve mortality?

Background: The current Surviving Sepsis Campaign guidelines recommend crystalloids as the preferred fluid for resuscitation of patients with hypovolemic shock; however, evidence supporting the choice of intravenous colloid vs. crystalloid solutions for management of hypovolemic shock is weak.

Study design: RCT.

Setting: International, multi-center study.

Synopsis: Researchers randomized 2,857 adult patients who were admitted to an ICU and required fluid resuscitation for acute hypovolemia to receive either crystalloids or colloids.

At 28 days, there were 359 deaths (25.4%) in the colloids group vs. 390 deaths (27.0%) in the crystalloids group (P=0.26). At 90 days, there were 434 deaths (30.7%) in the colloids group vs. 493 deaths (34.2%) in the crystalloids group (P=0.03).

Renal replacement therapy was used in 11.0% of the colloids group vs. 12.5% of the crystalloids group (P=0.19). There were more days alive without mechanical ventilation in the colloids group vs. the crystalloids group at seven days (P=0.01) and at 28 days (P=0.01), and there were more days alive without vasopressor therapy in the colloids group vs. the crystalloids group at seven days (P=0.04) and at 28 days (P=0.03).

Major limitations of the study included the use of open-labeled fluids during allocation, so the initial investigators were not blinded to the type of fluid. Moreover, the study compared two therapeutic strategies (colloid vs. crystalloids) rather than two types of molecules.

Bottom line: In ICU patients with hypovolemia requiring resuscitation, the use of colloids vs. crystalloids did not result in a significant difference in 28-day mortality; however, 90-day mortality was lower among patients receiving colloids.

Citation: Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality of critically ill patients presenting with hypovolemic shock: the CRISTAL randomization trial. JAMA. 2013;310(17):1809-1817

Clinical question: In critically ill patients admitted to the ICU with hypovolemic shock, does the use of colloid for fluid resuscitation, compared with crystalloid, improve mortality?

Background: The current Surviving Sepsis Campaign guidelines recommend crystalloids as the preferred fluid for resuscitation of patients with hypovolemic shock; however, evidence supporting the choice of intravenous colloid vs. crystalloid solutions for management of hypovolemic shock is weak.

Study design: RCT.

Setting: International, multi-center study.

Synopsis: Researchers randomized 2,857 adult patients who were admitted to an ICU and required fluid resuscitation for acute hypovolemia to receive either crystalloids or colloids.

At 28 days, there were 359 deaths (25.4%) in the colloids group vs. 390 deaths (27.0%) in the crystalloids group (P=0.26). At 90 days, there were 434 deaths (30.7%) in the colloids group vs. 493 deaths (34.2%) in the crystalloids group (P=0.03).

Renal replacement therapy was used in 11.0% of the colloids group vs. 12.5% of the crystalloids group (P=0.19). There were more days alive without mechanical ventilation in the colloids group vs. the crystalloids group at seven days (P=0.01) and at 28 days (P=0.01), and there were more days alive without vasopressor therapy in the colloids group vs. the crystalloids group at seven days (P=0.04) and at 28 days (P=0.03).

Major limitations of the study included the use of open-labeled fluids during allocation, so the initial investigators were not blinded to the type of fluid. Moreover, the study compared two therapeutic strategies (colloid vs. crystalloids) rather than two types of molecules.

Bottom line: In ICU patients with hypovolemia requiring resuscitation, the use of colloids vs. crystalloids did not result in a significant difference in 28-day mortality; however, 90-day mortality was lower among patients receiving colloids.

Citation: Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality of critically ill patients presenting with hypovolemic shock: the CRISTAL randomization trial. JAMA. 2013;310(17):1809-1817

Clinical question: In critically ill patients admitted to the ICU with hypovolemic shock, does the use of colloid for fluid resuscitation, compared with crystalloid, improve mortality?

Background: The current Surviving Sepsis Campaign guidelines recommend crystalloids as the preferred fluid for resuscitation of patients with hypovolemic shock; however, evidence supporting the choice of intravenous colloid vs. crystalloid solutions for management of hypovolemic shock is weak.

Study design: RCT.

Setting: International, multi-center study.

Synopsis: Researchers randomized 2,857 adult patients who were admitted to an ICU and required fluid resuscitation for acute hypovolemia to receive either crystalloids or colloids.

At 28 days, there were 359 deaths (25.4%) in the colloids group vs. 390 deaths (27.0%) in the crystalloids group (P=0.26). At 90 days, there were 434 deaths (30.7%) in the colloids group vs. 493 deaths (34.2%) in the crystalloids group (P=0.03).

Renal replacement therapy was used in 11.0% of the colloids group vs. 12.5% of the crystalloids group (P=0.19). There were more days alive without mechanical ventilation in the colloids group vs. the crystalloids group at seven days (P=0.01) and at 28 days (P=0.01), and there were more days alive without vasopressor therapy in the colloids group vs. the crystalloids group at seven days (P=0.04) and at 28 days (P=0.03).

Major limitations of the study included the use of open-labeled fluids during allocation, so the initial investigators were not blinded to the type of fluid. Moreover, the study compared two therapeutic strategies (colloid vs. crystalloids) rather than two types of molecules.

Bottom line: In ICU patients with hypovolemia requiring resuscitation, the use of colloids vs. crystalloids did not result in a significant difference in 28-day mortality; however, 90-day mortality was lower among patients receiving colloids.

Citation: Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality of critically ill patients presenting with hypovolemic shock: the CRISTAL randomization trial. JAMA. 2013;310(17):1809-1817

Clinical question: How does “triple rule out” (TRO) computed tomographic (CT) angiography compare to other imaging modalities in evaluating coronary and other life-threatening etiologies of chest pain, such as pulmonary embolism (PE) and aortic dissection?

Background: TRO CT angiography is a noninvasive technology that evaluates the coronary arteries, thoracic aorta, and pulmonary vasculature simultaneously. Comparison with other tests in the diagnosis of common clinical conditions is useful information for clinical practice.

Study design: Systematic review and meta-analysis.

Setting: Systematic review of 11 studies (one randomized, 10 observational).

Synopsis: Using an enrolled population of 3,539 patients, TRO CT was compared to other imaging modalities on the basis of image quality, diagnostic accuracy, radiation, and contrast volume. When TRO CT was compared to dedicated CT scans, no significant imaging difference was discovered. TRO CT detected CAD with a sensitivity of 94.3% (95% CI, 89.1% to 97.5%, I2=58.2%) and specificity of 97.4% (95% CI, 96.1% to 98.5%, I2=91.2%).

An insufficient number of patients with PE or aortic dissection were studied to generate diagnostic accuracy for these conditions. TRO CT involved greater radiation exposure and contrast exposure than non-TRO CT.

This study reports high accuracy of TRO CT in the diagnosis of coronary artery disease. Due to the low prevalence of patients with PE or aortic dissection (<1%), the data cannot be extrapolated to these conditions.

Bottom line: Although TRO CT is highly accurate for detecting coronary artery disease, there is insufficient data to recommend its use for the diagnosis of PE or aortic dissection.

Citation: Ayaram D, Bellolio MF, Murad MH, et al. Triple rule-out computed tomographic angiography for chest pain: a diagnostic systematic review and meta-analysis. Acad Emerg Med. 2013;20(9):861-871.

Clinical question: How does “triple rule out” (TRO) computed tomographic (CT) angiography compare to other imaging modalities in evaluating coronary and other life-threatening etiologies of chest pain, such as pulmonary embolism (PE) and aortic dissection?

Background: TRO CT angiography is a noninvasive technology that evaluates the coronary arteries, thoracic aorta, and pulmonary vasculature simultaneously. Comparison with other tests in the diagnosis of common clinical conditions is useful information for clinical practice.

Study design: Systematic review and meta-analysis.

Setting: Systematic review of 11 studies (one randomized, 10 observational).

Synopsis: Using an enrolled population of 3,539 patients, TRO CT was compared to other imaging modalities on the basis of image quality, diagnostic accuracy, radiation, and contrast volume. When TRO CT was compared to dedicated CT scans, no significant imaging difference was discovered. TRO CT detected CAD with a sensitivity of 94.3% (95% CI, 89.1% to 97.5%, I2=58.2%) and specificity of 97.4% (95% CI, 96.1% to 98.5%, I2=91.2%).

An insufficient number of patients with PE or aortic dissection were studied to generate diagnostic accuracy for these conditions. TRO CT involved greater radiation exposure and contrast exposure than non-TRO CT.

This study reports high accuracy of TRO CT in the diagnosis of coronary artery disease. Due to the low prevalence of patients with PE or aortic dissection (<1%), the data cannot be extrapolated to these conditions.

Bottom line: Although TRO CT is highly accurate for detecting coronary artery disease, there is insufficient data to recommend its use for the diagnosis of PE or aortic dissection.

Citation: Ayaram D, Bellolio MF, Murad MH, et al. Triple rule-out computed tomographic angiography for chest pain: a diagnostic systematic review and meta-analysis. Acad Emerg Med. 2013;20(9):861-871.

Clinical question: How does “triple rule out” (TRO) computed tomographic (CT) angiography compare to other imaging modalities in evaluating coronary and other life-threatening etiologies of chest pain, such as pulmonary embolism (PE) and aortic dissection?

Background: TRO CT angiography is a noninvasive technology that evaluates the coronary arteries, thoracic aorta, and pulmonary vasculature simultaneously. Comparison with other tests in the diagnosis of common clinical conditions is useful information for clinical practice.

Study design: Systematic review and meta-analysis.

Setting: Systematic review of 11 studies (one randomized, 10 observational).

Synopsis: Using an enrolled population of 3,539 patients, TRO CT was compared to other imaging modalities on the basis of image quality, diagnostic accuracy, radiation, and contrast volume. When TRO CT was compared to dedicated CT scans, no significant imaging difference was discovered. TRO CT detected CAD with a sensitivity of 94.3% (95% CI, 89.1% to 97.5%, I2=58.2%) and specificity of 97.4% (95% CI, 96.1% to 98.5%, I2=91.2%).

An insufficient number of patients with PE or aortic dissection were studied to generate diagnostic accuracy for these conditions. TRO CT involved greater radiation exposure and contrast exposure than non-TRO CT.

This study reports high accuracy of TRO CT in the diagnosis of coronary artery disease. Due to the low prevalence of patients with PE or aortic dissection (<1%), the data cannot be extrapolated to these conditions.

Bottom line: Although TRO CT is highly accurate for detecting coronary artery disease, there is insufficient data to recommend its use for the diagnosis of PE or aortic dissection.

Citation: Ayaram D, Bellolio MF, Murad MH, et al. Triple rule-out computed tomographic angiography for chest pain: a diagnostic systematic review and meta-analysis. Acad Emerg Med. 2013;20(9):861-871.

Clinical question: Do patients who experience overcrowding and long waits in the emergency department (ED) prefer boarding within ED hallways or within inpatient medical unit hallways?

Background: Boarding of admitted patients in EDs can be problematic, especially with regard to patient safety and patient satisfaction. Patient satisfaction data comparing boarding in the ED versus boarding in an inpatient unit hallway is limited.

Study design: Post-discharge, structured, telephone satisfaction survey.

Setting: Suburban, university-based teaching hospital.

Synopsis: A group of patients who experienced hallway boarding in the ED and then hallway boarding on the inpatient medical unit were identified. They were contacted by phone and asked to take a survey on their experience; 105 of 110 patients identified agreed. Patients were asked to rate their location preference with regard to various aspects of care. A five-point Likert scale consisting of the following answers was used: ED hallway much better, ED hallway better, no preference, inpatient hallway better, and inpatient hallway much better.

The inpatient hallway was the overall preferred location in 85% of respondents. Respondents preferred inpatient boarding with regard to multiple other parameters: rest, 85%; safety, 83%; confidentiality, 82%; treatment, 78%; comfort, 79%; quiet, 84%; staff availability, 84%; and privacy, 84%. For no item was there a preference for boarding in the ED.

Patient demographics in this hospital may differ from other settings and should be considered when applying the results. With Hospital Consumer Assessment of Healthcare Providers and Systems scores and ED throughput being publicly reported, further studies in this area would be valuable.

Bottom line: In a post-discharge telephone survey, patients preferred boarding in inpatient unit hallways rather than boarding in the ED.

Citation: Viccellio P, Zito JA, Sayage V, et al. Patients overwhelmingly prefer inpatient boarding to emergency department boarding. J Emerg Med. 2013;45(6):942-946.

Clinical question: Do patients who experience overcrowding and long waits in the emergency department (ED) prefer boarding within ED hallways or within inpatient medical unit hallways?

Background: Boarding of admitted patients in EDs can be problematic, especially with regard to patient safety and patient satisfaction. Patient satisfaction data comparing boarding in the ED versus boarding in an inpatient unit hallway is limited.

Study design: Post-discharge, structured, telephone satisfaction survey.

Setting: Suburban, university-based teaching hospital.

Synopsis: A group of patients who experienced hallway boarding in the ED and then hallway boarding on the inpatient medical unit were identified. They were contacted by phone and asked to take a survey on their experience; 105 of 110 patients identified agreed. Patients were asked to rate their location preference with regard to various aspects of care. A five-point Likert scale consisting of the following answers was used: ED hallway much better, ED hallway better, no preference, inpatient hallway better, and inpatient hallway much better.

The inpatient hallway was the overall preferred location in 85% of respondents. Respondents preferred inpatient boarding with regard to multiple other parameters: rest, 85%; safety, 83%; confidentiality, 82%; treatment, 78%; comfort, 79%; quiet, 84%; staff availability, 84%; and privacy, 84%. For no item was there a preference for boarding in the ED.

Patient demographics in this hospital may differ from other settings and should be considered when applying the results. With Hospital Consumer Assessment of Healthcare Providers and Systems scores and ED throughput being publicly reported, further studies in this area would be valuable.

Bottom line: In a post-discharge telephone survey, patients preferred boarding in inpatient unit hallways rather than boarding in the ED.

Citation: Viccellio P, Zito JA, Sayage V, et al. Patients overwhelmingly prefer inpatient boarding to emergency department boarding. J Emerg Med. 2013;45(6):942-946.

Clinical question: Do patients who experience overcrowding and long waits in the emergency department (ED) prefer boarding within ED hallways or within inpatient medical unit hallways?

Background: Boarding of admitted patients in EDs can be problematic, especially with regard to patient safety and patient satisfaction. Patient satisfaction data comparing boarding in the ED versus boarding in an inpatient unit hallway is limited.

Study design: Post-discharge, structured, telephone satisfaction survey.

Setting: Suburban, university-based teaching hospital.

Synopsis: A group of patients who experienced hallway boarding in the ED and then hallway boarding on the inpatient medical unit were identified. They were contacted by phone and asked to take a survey on their experience; 105 of 110 patients identified agreed. Patients were asked to rate their location preference with regard to various aspects of care. A five-point Likert scale consisting of the following answers was used: ED hallway much better, ED hallway better, no preference, inpatient hallway better, and inpatient hallway much better.

The inpatient hallway was the overall preferred location in 85% of respondents. Respondents preferred inpatient boarding with regard to multiple other parameters: rest, 85%; safety, 83%; confidentiality, 82%; treatment, 78%; comfort, 79%; quiet, 84%; staff availability, 84%; and privacy, 84%. For no item was there a preference for boarding in the ED.

Patient demographics in this hospital may differ from other settings and should be considered when applying the results. With Hospital Consumer Assessment of Healthcare Providers and Systems scores and ED throughput being publicly reported, further studies in this area would be valuable.

Bottom line: In a post-discharge telephone survey, patients preferred boarding in inpatient unit hallways rather than boarding in the ED.

Citation: Viccellio P, Zito JA, Sayage V, et al. Patients overwhelmingly prefer inpatient boarding to emergency department boarding. J Emerg Med. 2013;45(6):942-946.

Clinical question: Does targeted hypothermia (33°C) after cardiac arrest confer benefits compared with targeted temperature management at 36°C?

Background: Therapeutic hypothermia is a current recommendation in resuscitation guidelines after cardiac arrest. Fever develops in many patients after arrest, and it is unclear if the treatment benefit is due to hypothermia or due to the prevention of fever.

Study design: RCT.

Setting: ICUs in Europe and Australia.

Synopsis: The study authors randomized 950 patients who experienced out-of-hospital cardiac arrest to targeted temperature management at either 36°C or 33°C. The goal of this trial was to prevent fever in both groups during the first 36 hours after cardiac arrest. No statistically significant difference in outcomes between these two approaches was found. In the 33°C group, 54% died or had poor neurologic function, compared with 52% in the 36°C group (risk ratio 1.02; 95% CI 0.88 to 1.16; P=0.78).

Given the wide confidence interval, a trial with either more participants or more events might be able to determine whether a true difference in these management approaches exists.

Bottom line: Therapeutic hypothermia at 33°C after out-of-hospital cardiac arrest did not confer a benefit compared with targeted temperature management at 36°C.

Citation: Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.

Clinical question: Does targeted hypothermia (33°C) after cardiac arrest confer benefits compared with targeted temperature management at 36°C?

Background: Therapeutic hypothermia is a current recommendation in resuscitation guidelines after cardiac arrest. Fever develops in many patients after arrest, and it is unclear if the treatment benefit is due to hypothermia or due to the prevention of fever.

Study design: RCT.

Setting: ICUs in Europe and Australia.

Synopsis: The study authors randomized 950 patients who experienced out-of-hospital cardiac arrest to targeted temperature management at either 36°C or 33°C. The goal of this trial was to prevent fever in both groups during the first 36 hours after cardiac arrest. No statistically significant difference in outcomes between these two approaches was found. In the 33°C group, 54% died or had poor neurologic function, compared with 52% in the 36°C group (risk ratio 1.02; 95% CI 0.88 to 1.16; P=0.78).

Given the wide confidence interval, a trial with either more participants or more events might be able to determine whether a true difference in these management approaches exists.

Bottom line: Therapeutic hypothermia at 33°C after out-of-hospital cardiac arrest did not confer a benefit compared with targeted temperature management at 36°C.

Citation: Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.

Clinical question: Does targeted hypothermia (33°C) after cardiac arrest confer benefits compared with targeted temperature management at 36°C?

Background: Therapeutic hypothermia is a current recommendation in resuscitation guidelines after cardiac arrest. Fever develops in many patients after arrest, and it is unclear if the treatment benefit is due to hypothermia or due to the prevention of fever.

Study design: RCT.

Setting: ICUs in Europe and Australia.

Synopsis: The study authors randomized 950 patients who experienced out-of-hospital cardiac arrest to targeted temperature management at either 36°C or 33°C. The goal of this trial was to prevent fever in both groups during the first 36 hours after cardiac arrest. No statistically significant difference in outcomes between these two approaches was found. In the 33°C group, 54% died or had poor neurologic function, compared with 52% in the 36°C group (risk ratio 1.02; 95% CI 0.88 to 1.16; P=0.78).

Given the wide confidence interval, a trial with either more participants or more events might be able to determine whether a true difference in these management approaches exists.

Bottom line: Therapeutic hypothermia at 33°C after out-of-hospital cardiac arrest did not confer a benefit compared with targeted temperature management at 36°C.

Citation: Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Peri-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from peri-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality.

Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear.

This study supports the concept that higher-risk patients benefit more from peri-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: a Danish nationwide cohort study. JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Peri-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from peri-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality.

Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear.

This study supports the concept that higher-risk patients benefit more from peri-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: a Danish nationwide cohort study. JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Peri-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from peri-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality.

Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear.

This study supports the concept that higher-risk patients benefit more from peri-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: a Danish nationwide cohort study. JAMA Intern Med. 2014;174(3):336-344.