Henry Ford Hospital Medical Journal

Volume 34 Number 2 Article 4

6-1986

Management of Withdrawal in the Critically Ill Patient: A Selected Review

Rebecca B. Kantz

H. Mathilda Horst

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Recommended Citation Kantz, Rebecca B. and Horst, H. Mathilda (1986) "Management of Alcohol Withdrawal in the Critically Ill Patient: A Selected Review," Henry Ford Hospital Medical Journal : Vol. 34 : No. 2 , 87-89. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol34/iss2/4

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. IVIanagement of Alcohol Withdrawal in the Critically 111 Patient: X Selected Review

I Rebecca B. Kantz, RPh,* and H. Mathilda Horst, MD*

roper management of alcohol withdrawal represents a the critically ill patient) (1). Although withdrawal is thought to therapeutic challenge in the critically ill patient. The sever­ be a dose-dependent phenomenon, there is considerable indi­ Pity ofthe withdrawal syndrome varies with both the intensity and vidual variation in the amount of alcohol consumption necessary duration of the preceding alcohol exposure and may be compli­ to produce withdrawal. Furthermore, alcoholics are generally cated by other diseases such as traumatic injury, alcoholic gas­ unreliable in reporting their tme alcohol intake. Blood alcohol tritis, pancreatitis, liver failure, respiratory insufficiency, and/or concentrations may be used to detect tolerance; heavy imbibers malnutrition. These patients often cannot use the oral route for may show no symptoms of intoxication with blood alcohol lev­ therapy, and demonstrate considerable variability in response to els which would render a nontolerant person intoxicated (100 to treatment modalities. 250 mg%) or unconscious (350 to 500 mg%). Since tolerance to other CNS dmgs (, Diagnosis , and other ) occurs concurrently with Alcohol withdrawal may present a wide variety of clinical pat­ tolerance to alcohol (3), administration of a normally sedating terns ranging from mild self-limiting hyperadrenergic state, dose of medication (50 mg or ) to tenned the common abstinence syndrome (CAS), to full-blown a tolerant individual may produce no sedation whatsoever This hallucinosis, grand mal seizures, and (DT's). method may provide the clinician with another clue as to which CAS is characterized by tremor, anxiety, and diaphoresis and patient is at risk for withdrawal. may occur as soon as six to eight hours after cessation of drink­ The theory behind pharmacologic treatment of alcohol with­ ing. Symptoms may occur alone or with auditory hallucinations drawal syndrome is that of substituting a agent which is and/or convulsions. Peak symptoms are seen within ten to 30 cross-tolerant with alcohol, and then slowly weaning the patient hours and generally subside in 40 to 50 hours (1,2). Progression from that agent to prevent precipitation of symptoms. Numerous to DT's occurs in 1% to 10% of patients (1). Some authors feel pharmacologic agents have been used to treat alcohol with­ that aggressive treatment of early symptoms will minimize pro­ drawal syndrome, including phenothiazines, paraldehyde, ben­ gression to DT's; however, occasionally a patient will develop zodiazepines, barbiturates, , butyrophenones, T's despite every preventive effort. beta-blockers, and (Table). Several studies have com­ DT's consist of profound disorientation associated with visual pared the efficacy of the first four dmgs in this list (5-10). In hallucinations and motor hyperactivity. The onset of DT's is 60 combining the results of five of these studies, Thompson (3) to 80 hours after the last drink. The average duration of DT's is found that patients treated with paraldehyde or benzodiaze­ two and one-half days, but symptoms may persist for a week or pines had the lowest incidence of DT's and seizures, while the more (1-3). use of phenothiazines was associated with a greater incidence of seizures. (Often deaths reported in the entire study popu­ Overlap in symptomatology may preclude a precise diagnosis lation of 978 patients, nine patients had been treated with in the critically ill patient (CAS versus DT's), although most au­ phenothiazines.) thors concur that symptoms are more easily controlled when agressively treated in the early stages (1). These studies were not controlled, and the dmg dosages em­ ployed varied widely. As there is no conclusive evidence as to which regimen is best, the choice of agent to control alcohol Tolerance withdrawal syndrome must therefore be based on efficacy, avail­ Alcohol, unlike other central nervous system (CNS) depres- ability, and lowest incidence of toxicity. Furthermore, the most santSj is metabolized primarily by the cytosolic liver enzyme appropriate regimen in the critically ill patient may be different alcohol dehydrogenase. Increased activity of this enzyme con- from that used to treat a patient with uncomplicated withdrawal tnbutes to the "tolerance" to alcohol displayed by heavy drink­ symptoms. ers (2). In theory, tolerance and physical dependence on ethanol 's a manifestation of compensatory neurophysiologic changes which offset the depressant effect of alcohol on neuronal excit­ ability, impulse conduction, and neurotransmitter release (4). Submitted for publication: May 9. 1986. Two methods have been suggested to aid the clinician in iden­ Accepted for publication: June 20, 1986. *Division of Trauma Surgery. Henry Ford Hospital. tifying the patient at risk of withdrawal (in addition to a positive Address correspondence to Ms Kantz, Division of Trauma Surgery, Henry Ford Hospital, history forwithdrawa l or DT's, which may not be elicited from 2799 W Grand Blvd. Detroit. Ml 48202.

'^"ry Ford Hosp Med J- -Vol -'i4. No 2, 1986 Alcohol Withdrawal in Critically 111—Kantz et al 87 Table TVeatment of Alcohol Withdrawal in the Critically III

Maximal Recommended Dose Reported Drug Route* Dose Frequency Dose Reference Chlordiazepoxide PO,lM,IVP 50 to 100 mg Every 6 hrs 1600 mg/day 1 Diazapam PO,lM,lVP Sto 10 mg IV Every 5 min until calm then 5 to 15 mg every 2 to 6 hrs l536 mg/48 hrs li PO,lM,lVP 2 to 8 mg Every 2 to 4 hrs Not available quire less i Haloperidol PO,lM,lVP 0.5 to 5 mg Every 2 to 6 hrs Not available 4,9,11,12 Paraldehyde P0,1V, 10 to 170 mL Every 6 hrs 436 mU24 hrs 13 Metabolisi rectal rectally Clinical Secobarbital IM 200 mg initially Every 6 hrs Not available 4,18,19 torydepres then 100 to 200 mg Propranolol PO 40 mg Every 6 hrs Not available 16,17 accumulati IV 0.5 mg Every 6 hrs tensive wi •PO = orally, IM = intramuscular, IV = intravenous, and IVP = intravenous pu.sh. half-life ol to diazepa to active i glucuronic Phenothiazines are not widely recommended in the treatment with bronchospastic disease, heart failure, and insulin-depen­ Further of alcohol withdrawal syndrome since they have not been shown dent diabetes. Efficacy studies of these agents in critically ill pa­ influencec to be superior to other agents. In addition, phenothiazines lower tients are lacking. biotransfo seizure threshold, cause sedation, and may potentiate the hyper­ Barbiturates are effective, inexpensive agents for alcohol ide may b thermia seen in withdrawal (4,5,7-9). Antihistamines are con­ withdrawal, provide sedation and activity, and by coadm traindicated for this purpose and have anticholinergic effects can be given intravenously (4,18,19). and secobar­ the half-l that can cause tachycardia, somnolence, and hallucinations bital have been used in doses of 200 mg IM initially, then 100 to these san (4,9,11). 200 mg IM every six hours. Despite favorable effects in control­ enced by Haloperidol, a butyrophenone and major tranquilizer, has ling withdrawal, barbiturates have largely been replaced by In dosi been shown to be effective in controlling agitation, hallucina­ newer agents. (normal half-life two to five days) severaln tions, and DT's with minimal side-effects (12). However, the metabolism may be impaired in hepatic disease. Furthermore, diazepox ability ofthis dmg to lower seizure threshold is worrisome. For combining phenobarbital with narcotic analgesics can poten­ six hours the treatment of withdrawal, haloperidol is recommended in in­ tially cause oversedation in the critically ill patient (20,21). employei tramuscular (IM) doses of 0.5 to 2 mg every one to two hours The administration of intravenous ethanol has been used as a Thorn until satisfactory response is achieved, then 2 to 5 mg IM every 5% solution in 5% dextrose at 150 mL/hr to prevent withdrawal required four to six hours (4,9,11,12). symptoms (22). The drug has a narrow therapeutic index, a short than pat Paraldehyde is one of the classic dmgs used for alcohol with­ half-life, and may perpetuate metabolic disturbances. Its use is creatitis. drawal. Paraldehyde is a short-acting sedative- that has not widely recommended (4). tially ca employe cross-tolerance with alcohol. It also has anticonvulsant activity Many clinicians consider the benzodiazepines to be the Thomps which prevents progression to seizures or DT's when used early agents of choice for the treatment of withdrawal due to their IV push in withdrawal (3,5,8). Paraldehyde is not without its attendant efficacy as well as their safety. These dmgs produce adequate (If agit;i problems, such as being erratically absorbed from the oral and sedation, anticonvulsant activity, and fewer side-effects than bled.) N rectal routes and causing sterile abscess formation with repeated other agents. While control of withdrawal symptoms may be two to s IM injections. In a controlled comparison of rectally admin­ achieved with any , only three agents are avail­ then tht istered paraldehyde and intravenous to treat DT's, the able in the parenteral form, lending themselves to treatment of Appr diazepam-treated patients were calmed in one-half the time the critically ill patient; diazepam, chlordiazepoxide, and criticall needed to calm the paraldehyde-treated patients. No adverse ef­ lorazepam. Rapid onset of action is achieved using the IV route, 2mgo1 fects were noted with diazepam. One-half of the paraldehyde- while IM injections may be absorbed erratically or incom­ lieving treated patients suffered adverse effects (13). Intravenous (IV) pletely. Of these three agents, differences in pharmaco­ Man administration of paraldehyde has been associated with hy­ kinetic parameters may predispose one agent to be superior in ill patit potension, pulmonary edema, metabolic acidosis, and liver treating alcohol withdrawal syndrome. toxicity (13-15). Paraldehyde is contraindicated in broncho­ dieting of prev pulmonary disease and hepatic insufficiency and would be of Distribution limited value in the critically ill. Popula The capacity of dmgs to cross the blood-brain barrier is deter­ chlord Alcohol withdrawal is associated with an increase in urine and mined in part by their inherent lipophilicity. While all ben­ in the plasma catecholamines, and clinical features suggest a hyper­ zodiazepines are lipophilic, diazepam is more so than either ferenc' adrenergic state. Beta-blockers such as propranolol have been chlordiazepoxide or lorazepam. Presumably owing to its inoutf effective in reducing tremor, blood pressure, heart rate, and cat­ lipophilic nature, diazepam also has a greater propensity fof als are echolamine levels in doses of 40 mg every six hours or 0.5 mg peripheral distribution to nonblood compartments (adipose slow IV push (16,17). Propranolol is contraindicated in patients tissue). Following IV administration, diazepam has a rapid

He, Henry Ford Hosp Med J—Vol 34. No 2, 1986 Alcohol Withdrawal in Critically 111- ^ Kantz etal nryR onset of action, but CNS levels of the dmg fall rapidly, coincid­ in clinical efficacy among the benzodiazepines and to further de­ ing with peripheral redistribution of the dmg. Lorazepam, how­ lineate optimal dosing regimens. ever, is less lipophilic and has less propensity for peripheral redistribution. Thus, paradoxically, the "shorter acting" benzodiazepine (lorazepam T Vi = 10 hours) may have a longer References acting clinical effect in the treatment of alcohol withdrawal than 1. Lewis DC, Femino J. Management of alcohol withdrawal. Drug Ther the "longer acting" diazepam (T Vi = 36 hours) and may re­ 1982;16:1-5. quire less frequent dosing (23-25). 2. West LJ, Maxwell DS, Noble EP, Solomon DH. Alcoholism. Ann Intern Med 1984;100:405-16. Metabolism 3. Thompson WL. Management of alcohol withdrawal syndromes. Arch In­ tem Med 1978;138:278-83. Clinical side-effects of benzodiazepines (including respira­ 4. Sellers EM, Kalant H. Alcohol intoxication and withdrawal. N Engl J Med tory depression) during chronic dosing may be the result of dmg 1976;294:757-62. accumulation. The longer the half-life of the dmg, the more ex­ 5. Thomas DW, Freedman DX. Treatment of the alcohol withdrawal syn­ tensive will be its accumulation. Lorazepam has the shortest drome: Comparison of promazine and paraldehyde. JAMA 1964;188:316-18. half-life of the injectable benzodiazepines. This is due in part 6. Muller DJ. A comparison of three approaches to alcohol withdrawal states. South Med J 1969;62:495-6. to diazepam and chlordiazepoxide being hepatically oxidized 7. Sereny G, Kalant H. Comparative clinical evaluation of chlordiazepoxide to active metabolites, whereas lorazepam forms an inactive and promazine in treatment of alcohol withdrawal syndrome. Br Med J glucuronide conjugate (23). 1965;1:92-7. Furthermore, these two metabolic pathways are differently 8. Goldbert TM, Sanz CJ, Rose HE, et al. Comparative evaluations of treat­ influenced by factors altering the individual capacity for dmg ments of alcohol withdrawal syndromes. JAMA 1967;201:99-102. 9. Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal biotransformation. Oxidation of diazepam and chlordiazepox­ state: A comparison of four drugs. Am J Psychiatry 1969;125:1640-6. ide may be impaired by liver disease (ie, cirrhosis), old age, or 10. Kaim SC, Klett CJ. Treatment of delirium tremens: A comparative evalua­ by coadministration of drugs (ie, cimetidine), further extending tion of four drugs. Q J Stud Ale 1972;33:1065-72. the half-life ofthese agents. Conjugation is not impaired by 11. Dilts SL, Keleher DL, HogeG, Haglund B. in the treatment these same factors; thus inactivation of lorazepam is not influ­ of alcohol withdrawal. AmJ Psychiatry 1977;134:92-3. 12. Palestine ML. Drug treatment of the alcohol withdrawal syndrome and enced by alcoholic cirrhosis (23,24). delirium tremens: A comparison of haloperidol with mesoridazine and hydrox­ In dosing the benzodiazepines to treat alcohol withdrawal, yzine. QJStud Ale 1973;43:185-93. several regimens have been reported to be successful. Chlor­ 13. Thompson WL, Johnson AD, Maddrey WL, and Osier Medical House diazepoxide may be used in initial doses of 50 to 100 mg every Staff. Diazepam and paraldehyde for treatment of severe delirium tremens: A six hours (IM or IV push). Doses of up to 1600 mg/day have been controlled trial. Ann Intem Med 1975;82:175-80. 14. Burstein CL. The hazard of paraldehyde administration. JAMA employed (1). 1943;121:187-9. Thompson et al (13) reported that patients with simple DT's 15. Hayward JN, Boschell BR. Paraldehyde intoxication with metabolic aci­ required less than half the sedative dose required for calming dosis. Am J Med 1957;23:965. than patients with associated pneumonia, hepatitis, or pan­ 16. Zilm DH, Sellers EM, MacLeod SM, Degani N. Propranolol effect on creatitis. Diazepam doses of 15 to 215 mg were required to ini­ tremor in alcoholic withdrawal. Ann Intem Med 1975;83:234-36. 17. Sellers EM, Zilm DH, Degani N. Comparative efficacy of propranolol tially calm patients, and total doses of 525 to 1355 mg were and chlordiazepoxide in alcohol withdrawal. Q J Stud Ale 1977;38:2096-108. employed over six to 52 hours without excessive sedation (13). 18. Leroy JB. Recognition and treatment of the alcohol withdrawal syn­ Thompson et al advocate initial treatment with 5 mg diazepam drome. Primary Care 1979;6:529-39. IV push every five minutes until the patient is calm but awake. 19. Kramp P, Rafaelsen OJ. Delirium tremens: A double-blind comparison of (If agitation persi.sts after 30 minutes, the dosage can be dou­ diazepam and treatment. Acta Psychiatr Scand 1978;58:174-90. 20. Alvin J, McHorse T, Hoyuma A, et al. The effect of liver disease in man bled.) Maintenance doses of 5 to 15 mg should be given every on the disposition of phenobarbital. J Pharmacol Exp Ther 1975;192:224-35. two to six hours until the patient has remained calm for 48 hours; 21. Hridberg EF, Dam M. Clinical pharmacokinetics of . Clin then the doses can be tapered. Pharmacokinet 1976;1:161-88. Appropriate doses of lorazepam for alcohol withdrawal in the 22. Gower WE, Kersten H. Prevention of alcohol withdrawal symptoms in surgical patients. Surg Gynecol Obstet 1980;151:382-4. critically ill have not been identified. Conner et al (26) found that 23. Greenblatt DJ. Clinical pharmacokinetics of and lorazepam. com- I 2 mg of lorazepam was as effective as 10 mg of diazepam in re­ Clin Pharmacokinet 1981;6:89-105. laco- I lieving anxiety and providing preoperative sedation. 24. Greenblatt DJ, Shader RI, Abernethy DR. Current status of ben­ iorin Many therapeutic problems still exist in treating the critically zodiazepines. Part 1. N Engl J Med 1983;309:354-8. '11 patient having alcohol withdrawal. Definitive means of pre- 25. Greenblatt DJ, Shader RI, Abernethy DR. Current status of ben­ tlicting progression to delirium tremens, as well as specific ways zodiazepines. Part II. N Engl J Med 1983;309:410-6. 26. Conner JT, Katz RL, Belville JW, Graham C, Pagano R, Dorey F Di­ ''f preventing this progression, are unavailable for this patient azepam and lorazepam for intravenous surgical premedication. J Clin Pharmacol population. Studies comparing clinical efficacy of lorazepam, 1978:18:285-92. 'Chlordiazepoxide, and diazepam in treating alcohol withdrawal 27. Solomon JS, Rouck LA, Koepke HH. Double blind comparison of "tthe critically til are lacking. No statistically significant dif­ lorazepam and chlordiazepoxide in the treatment of acute alcohol absrinence ferences in efficacy among these agents have been demonstrated syndrome. Clin Ther 1983;6:52-8. 28. O'Brien JE, Meyer RE, Thoms DC. Double blind comparison of outpatients treated for alcohol withdrawal (27,28). Further tri­ lorazepam and diazepam in the treatment of the acute alcohol abstinence syn­ als are needed in the critically ill to detect potential differences drome. Curr Ther Res 1983;34:825-31.

-Kantz et^ *y Ford Hosp Med J—Vol 34, No 2, 1986 Alcohol Withdrawal in Critically 111—Kantz et al 89