Drug. Alcohol is one of the most frequently abused drugs in American society. Update

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1 AACN Advanced Critical Care Volume 28, Number 3, pp AACN Drug Update Earnest Alexander, PharmD, and Gregory M. Susla, PharmD Department Editors Pharmacologic Management of Alcohol Withdrawal Syndrome in Intensive Care Units Beatrice Adams, PharmD, BCPS, BCCCP Kevin Ferguson, PharmD, BCPS, BCCCP Alcohol is one of the most frequently abused drugs in American society. In 2014, there were 17 million people aged 12 years or older (6.4% of the population) who had an alcohol use disorder (AUD). 1 According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), risky alcohol use can place people at increased risk of health consequences. 2 Risky alcohol consumption is defined as alcohol intake of 14 drinks per week or more than 4 drinks per day for men younger than 65 years and 7 drinks per week or greater than 3 drinks per day for women younger than 65 years. 2 Risky alcohol use usually is not severe enough to constitute AUD, but people who have risky alcohol use may develop AUD. Alcohol use disorder may be classified as mild, moderate, or severe depending on the number of diagnostic criteria present (mild, 2-3 symptoms; moderate, 4-5 symptoms; severe, 6 or more symptoms) (see Table). 3,4 The NIAAA defines binge drinking as drinking enough alcohol within 2 hours to raise the blood alcohol concentration to 0.08 g/dl or greater. The amount of alcohol to reach binge drinking level correlates to approximately 5 drinks in men and 4 drinks in women. Alcohol withdrawal syndrome (AWS) symptoms occur when a person stops using alcohol after a period of heavy drinking or chronic use. Patients who have moderate to severe AUD may develop AWS, and up to 30% of patients who have AWS may be admitted to intensive care units (ICUs). 5 Patients who are at risk of developing AWS and being admitted to ICUs are susceptible to longer ICU stays, longer time using mechanical ventilation, increased medical costs, and increased mortality rates compared with other patients. Although AWS is not uncommon in critically ill patients, guidelines and standards of care for critically ill patients with AWS are unclear. In this article, we review AWS and discuss the available treatments for critically ill patients with AWS. Pathogenesis The effects of alcohol on the central nervous system are mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and excitatory neurotransmitter N-methyl-D-aspartate (NMDA). 6 The normal balance between these neurotransmitters is disrupted upon exposure to alcohol (Figure 1). Shortterm alcohol use causes stimulation of GABA receptors and suppression of Beatrice Adams is Critical Care Clinical Pharmacist, Medical and Burn Intensive Care Unit, Department of Pharmacy Services, Tampa General Hospital, PO Box 1289, Tampa, FL (badams@tgh.org). Kevin Ferguson is Critical Care Clinical Pharmacist, Medical Intensive Care Unit, Department of Pharmacy Services, Tampa General Hospital, Tampa, Florida. The authors declare no conflicts of interest. DOI: 233

2 Table: Diagnostic Criteria for Alcohol Withdrawal a A. Cessation or reduction of heavy and prolonged alcohol use. B. At least 2 of the following symptoms develop within several hours to a few days after criterion A is met: Autonomic hyperactivity (eg, sweating, heart rate > 100 beats per minute) Hand tremor Insomnia Nausea or vomiting Transient visual, tactile, or auditory hallucinations or illusions Psychomotor agitation Anxiety Generalized tonic-clonic seizures C. Symptoms in criterion B cause clinically major distress or impairment in social, occupational, or other important areas of functioning. D. Signs or symptoms cannot be attributed to another medical condition nor be explained by another mental disorder such as intoxication or withdrawal from another substance. a Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association. 4 Normal state Short-term alcohol use Chronic alcohol use Cessation of alcohol use Figure 1: Effect of alcohol on neurotransmitters. Abbreviations: GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate. NMDA receptors, increasing inhibitory neurotransmission and decreasing excitatory neurotransmission (ie, alcohol intoxication). Chronic exposure to alcohol causes a compensatory decrease in GABA activity that results in downregulation of GABA receptors and upregulation of NMDA receptors, thus maintaining an equilibrium between the 2 receptors. With chronic alcohol exposure, the patient develops increased tolerance to alcohol and may function normally despite higher alcohol intake. Abrupt cessation of alcohol exposure causes increased NMDA activity because the NMDA receptors are no longer inhibited by alcohol, resulting in brain hyperexcitability, psychomotor agitation, and AWS (Figure 1). 7 Alcohol Withdrawal Syndrome Patients with AUD who are admitted to the hospital may be underdiagnosed because it can be difficult for clinicians to recognize the presence of AUD. Screening tools used during patient admission assessment may help clinicians identify patients who are at risk for developing AWS. These question-based screening tools including the CAGE (Cut 234

3 VOLUME 28 NUMBER 3 FALL 2017 down, Annoyed, Guilty, Eye-opener) questionnaire, 8 the Alcohol Use Disorders Identification Test, 9 and the Short Michigan Alcoholism Screening Test 10 used with clinical biomarkers such as blood alcohol concentration may help clinicians identify patients who may develop AWS. Patients who have AWS can have diverse symptoms and signs that vary depending on the length of time after alcohol cessation. 4 The 4 stages of AWS are characterized by different levels of clinical severity: (1) stage 1 occurs 6 to 8 hours after the most recent alcoholic drink and is associated with symptoms of anxiety, tremor, nausea, and tachycardia; (2) stage 2 occurs 10 to 30 hours after the most recent alcoholic drink with symptoms of hyperactivity, insomnia, and hallucinations; (3) stage 3 occurs 12 to 48 hours after the most recent alcoholic drink and adds tonic-clonic seizures to the stage 2 symptoms; and (4) stage 4 occurs 3 to 5 days after the most recent alcoholic drink with symptoms of delirium tremens (DTs). 11 Complications Patients with AWS may have major complications including seizures, DTs, and Wernicke encephalopathy. Hyperexcitability observed after alcohol cessation and increased glutamate may lead to seizures. Alcohol withdrawal seizures occur in more than 5% of untreated patients 12 and typically are observed 6 to 48 hours after cessation of alcohol intake (Figure 2). Although tonic-clonic seizures are the most common seizures with alcohol withdrawal, partial seizures and status epilepticus may occur. Most seizures (90%) occur within the first 48 hours (Figure 2), but some patients may have seizures 5 days after alcohol cessation The risk of developing seizures and seizure severity may increase with the number of previous episodes of withdrawal. 13 Clinicians should consider the previous history of alcohol withdrawal when treating patients who are at risk of developing alcohol withdrawal, especially when recommending duration of therapy and treatment options. Delirium tremens are a serious complication that may occur in 5% patients who have alcohol withdrawal and typically occur at 48 to 96 hours after alcohol cessation (Figure 2) The signs of DTs include extreme hyperactivity of the central nervous system, manifested by disorientation, agitation, Figure 2: Timing of alcohol withdrawal symptoms and signs after cessation of alcohol intake. hallucinations, diaphoresis, tachycardia, hypertension, and hyperthermia. These symptoms may persist for 7 days. Risk factors for the development of DTs include history of sustained drinking, previous history of DTs, aged 30 years or older, concomitant illness, and longer time since the most recent drink and start of AWS Although mortality from DTs has decreased because of early identification and treatment, death occurs in 5% of patients, mostly because of arrhythmias. 13 Clinicians need to identify AWS early and be aware of the risk factors for severe complications caused by AWS. Alcoholic hallucinosis is a syndrome that is manifested by hallucinations and may occur 12 to 24 hours after alcohol cessation. The hallucinations typically persist for 2 hours. Alcoholic hallucinosis is distinct from DTs and usually resolves before the typical onset of DTs. Furthermore, patients who have alcoholic hallucinosis have stable vital signs and report visual hallucinations without global clouding of the sensorium Alcohol Withdrawal Treatment Supportive Care The goals of therapy for AWS include alleviation of withdrawal symptoms, prevention of symptom progression, and treatment of underlying comorbidities. Patients with AWS may require intravenous drugs and endotracheal intubation for airway protection. Patients who have moderate to severe symptoms should have laboratory tests performed, including a complete blood count to assess for anemia, serum glucose and electrolyte levels including magnesium, blood alcohol concentration, liver function tests, and toxicology studies. In addition, patients with AWS usually have intravascular volume depletion and require fluid resuscitation and correction of electrolyte and glucose level abnormalities. Thiamine should be administered to prevent Wernicke encephalopathy. Many patients who have AWS are 235

4 nutritionally depleted and benefit from folate and multivitamin supplements. Assessment The revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) 14 and the Riker Sedation-Agitation Scale (SAS) 15 are the most commonly used tools for the assessment of alcohol withdrawal. Some institutions replace the SAS with the Richmond Agitation-Sedation Scale (RASS) 16 ; both are validated sedation scales for use in critically ill patients. The CIWA-Ar relies on patients to answer questions related to nausea, vomiting, headaches, tactile and auditory disturbances, and anxiety it is neither validated for use in the ICU nor reliable for patients who are intubated and on mechanical ventilation. Pharmacologic Therapy Benzodiazepines are the cornerstone of pharmacologic therapy for AWS. They bind to GABA A receptors in the central nervous system and replace the inhibitory effect of alcohol, helping control agitation and preventing progression to more severe withdrawal symptoms. Benzodiazepines can be given with a fixed tapering dose regimen (FTDR), a fixed schedule of doses and gradual drug taper over 4 to 7 days. Alternatively, benzodiazepines may be given with a symptom triggered regimen (STR), in which the patient receives benzodiazepine doses as needed based on symptom scores. The FTDR and STR are well tolerated and have similar efficacy, but in some studies STRs were shown to use a lower cumulative benzodiazepine dosage and shorter treatment duration than FTDRs The most commonly used benzodiazepines in treating AWS include lorazepam, chlordiazepoxide, and diazepam. Lorazepam or oxazepam are recommended for patients who have advanced cirrhosis or alcoholic hepatitis because lorazepam and oxazepam have shorter half-lives and fewer active metabolites than do diazepam or chlordiazepoxide. Lorazepam and diazepam are available in oral and parenteral formulations, but chlordiazepoxide is available only as an oral formulation. Most patients who have moderate to severe withdrawal symptoms are given intravenous benzodiazepines because of rapid onset and guaranteed absorption. All benzodiazepines have adverse events including respiratory depression, excessive sedation, ataxia, confusion, memory impairment, and delirium that may be confused with the signs of DTs Propofol is an intravenous drug that has sedative and anesthetic properties and has been used as an alternative or adjunct therapy for AWS patients who have endotracheal intubation. Propofol may cause central nervous system depression by activating GABA A receptors and blocking NMDA receptors. It is unknown whether propofol may improve time to AWS resolution, mechanical ventilation duration, or ICU and hospital length of stay compared with benzodiazepines. 6 Propofol is used in AWS patients who have advanced liver disease and are being treated with endotracheal intubation and mechanical ventilation. Treating Refractory Alcohol Withdrawal Syndrome Dexmedetomidine Dexmedetomidine is a selective alpha-2 agonist that has anesthetic and sedative properties and commonly is used in the ICU. 25 In patients who have AWS, dexmedetomidine may reduce autonomic hyperactivity and help control tremor, hypertension, and tachycardia without causing respiratory depression. 26 Dexmedetomidine, however, does not prevent seizures because it has no effect on GABA receptors. Therefore, dexmedetomidine should not be used as monotherapy or a first-line drug and is recommended only as an adjunct to other treatment. Adverse events with dexmedetomidine include bradycardia and hypotension. 25 Dexmedetomidine may be used as an adjunct in patients who require high doses of benzodiazepines and are susceptible to benzodiazepine-induced adverse effects. In a few studies, dexmedetomidine was found to decrease benzodiazepine use and improve hemodynamics, but more research is needed to determine whether dexmedetomidine may affect clinical outcomes. 26,27 Clonidine Clonidine is an oral selective alpha-2 agonist that may provide the same effect as intravenous dexmedetomidine. Clonidine may decrease symptoms such as hypertension and tachycardia in mild to moderate AWS but does not prevent seizures or DTs. 28 Clonidine has been used to help transition the patient from dexmedetomidine to an oral agent, but is often less effective because 236

5 VOLUME 28 NUMBER 3 FALL 2017 dexmedetomidine is 8 times more selective toward the alpha-2 receptor than clonidine. 25 Moreover, clonidine has not been adequately studied for AWS treatment; thus, it is not recommended as an adjunct therapy for ICU patients with AWS. Barbiturates Barbiturates typically are not used as a first-line treatment of AWS. However, when used for treatment of AWS, phenobarbital is the barbiturate of choice because it has long duration of action and low abuse potential. 29 Phenobarbital when given in conjunction with benzodiazepines may decrease the need for ICU admission or mechanical ventilation in patients who have AWS symptoms that are refractory to benzodiazepines. 30 Early use of phenobarbital in AWS may provide favorable response, but further studies are needed before early use may be recommended. 30 Baclofen Baclofen is a GABA B receptor agonist evaluated for use in AWS. 31 Baclofen may decrease alcohol craving in chronic alcohol users and may reduce benzodiazepine use in AWS. However, 2 randomized trials that evaluated the use of oral baclofen in outpatients and patients who were not critically ill did not show improvement in CIWA-Ar scores. 32,33 Furthermore, neither of these trials evaluated safety. Therefore, baclofen is not indicated in critically ill patients, and more studies are needed. Inappropriate and Contraindicated Therapies Several other therapies have been evaluated for use in patients with AWS, including beta blockers, anticonvulsants, and antipsychotics, but these agents are poorly studied and may mask the symptoms and signs of AWS. Although these drugs may help mitigate minor withdrawal symptoms, they do not act on GABA neurotransmitters and therefore do not prevent seizures. Thus, these agents are not recommended for treatment of AWS, especially in critically ill patients. 6,11,14 Conclusion Alcohol withdrawal syndrome is a multifactorial syndrome that requires rapid identification and treatment to prevent complications. Benzodiazepines are the primary therapy for AWS and may be used in an FTDR or STR. Treatment adjuncts may be considered for patients who have refractory symptoms or signs of AWS despite high doses of benzodiazepines. REFERENCES 1. Center for Behavioral Health Statistics and Quality. Behavioral health trends in the United States: results from the 2014 national survey on drug use and health (HHS Publication No. SMA , NSDUH Series H-50). Substance Abuse and Mental Health Services Administration web site FRR pdf. Accessed May 30, National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. National Institutes of Health web site. Accessed May 30, Grant BF, Goldstein RB, Saha TD, 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(8): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; de Wit M, Jones DG, Sessler CN, Zilberberg MD, Weaver MF. Alcohol-use disorders in the critically ill patient. Chest. 2010;138(4): Dixit D, Endicott J, Burry L, et al. Management of acute alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy. 2016;36(7): Cagetti E, Liang J, Spigelman I, Olsen RW. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol. 2003; 63(1): doi.org/ /mol Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA. 1984;252(14): Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings. J Stud Alcohol. 1995;56(4): Selzer ML. The Michigan alcoholism screening test: the quest for a new diagnostic instrument. Am J Psychiatry. 1971;127(12): Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5): doi: /s Trevisan LA, Boutros N, Petrakis IL, Krystal JH. Complications of alcohol withdrawal: pathophysiological insights. Alcohol Health Res World. 1998;22(1): Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician. 2004;69(6): Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict. 1989;84(11): Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27(7): Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10): doi: /rccm Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994;272(7): Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc. 2001;76(7): doi: /

6 19. Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002;162(10): Cassidy EM, O Sullivan I, Bradshaw P, Islam T, Onovo C. Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen. Emerg Med J. 2012;29(10): Valium (diazepam) injection [package insert]. Lake Forest, IL: Hospira; Ativan (lorazepam) injection [package insert]. Corona, CA: Watson Laboratories; Librium (chlordiazepoxide) [package insert]. Corona, CA: Watson Laboratories; Serax (oxazepam) [package insert]. Princeton, NJ: Sandoz; Precedex (dexmedetomidine) [package insert]. Lake Forest, IL: Hospira; Linn DD, Loeser KC. Dexmedetomidine for alcohol withdrawal syndrome. Ann Pharmacother. 2015;49(12): doi: / Bielka K, Kuchyn I, Glumcher F. Addition of dexmedeto- midine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study. Ann Intensive Care. 2015; 5(1): Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of α2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011;45(5): Phenobarbital [package insert]. Boca Raton, FL: E5 Pharma; Mo Y, Thomas MC, Karras GE Jr. Barbiturates for the treatment of alcohol withdrawal syndrome: a systematic review of clinical trials. J Crit Care. April 2016;32: doi: /j.jcrc Baclofen [package insert]. North Wales, PA; Teva Pharmaceuticals; Liu J, Wang LN. Baclofen for alcohol withdrawal. Cochrane Database of Systematic Reviews. Hoboken, NJ: John Wiley & Sons; doi: / cd pub Vourc h M, Feuillet F, Mahe PJ, Sebille V, Asehnoune K; BACLOREA Trial Group. Baclofen to prevent agitation in alcohol-addicted patients in the ICU: study protocol for a randomised controlled trial. Trials. 2016;17(1):415. doi: /s CE Evaluation Instructions This article has been designated for CE contact hour(s). The evaluation demonstrates your knowledge of the following objectives: 1. Describe pathogenesis and complications associated with alcohol withdrawal in the intensive care unit. 2. Identify critically ill patients at risk for alcohol withdrawal. 3. Discuss available treatment options for alcohol withdrawal in critically ill patients. Contact hour: 1.0 Pharmacology contact hour: 1.0 Synergy CERP Category: A To complete evaluation for CE contact hour(s) for this article #ACC7331, visit and click the CE Articles button. No CE evaluatin fee for AACN members. This expires on July 1, American Association of Critical-Care Nurses is an accredited provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. AACN has been approved as a provider of continuing education in nursing by the State Boards of Registered Nursing of California (#01036) and Louisiana (#LSBN12). 238