Alcohol Withdrawal. Medical Director, New York City Poison Center. Sorrento, Italy (September 19, 2007)

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1 Alcohol Withdrawal Sorrento, Italy (September 19, 2007) Lewis R. Goldfrank, MD Professor and Chairman, Emergency Medicine New York University School of Medicine Director, Emergency Medicine Bellevue Hospital/NYU Hospitals/VA Hospital 1 Medical Director, New York City Poison Center

2 Alcoholism Third largest health problem in the US After ASHD and cancer Affects at least 10 million people Causes 200,000 deaths annually Implicated in 50% of MVC and fires, 67% of homicides and 37% of suicides Annual cost at least $60 billion 2

3 History of Alcoholism at Bellevue 256,755 admission from Peak admissions 4.99/1000 population/year Male:female about 4:1 Jolliffe: Science 1936;83: Currently, 25% of patients brought to the ED by ambulance are alcoholics Whiteman: Acad Emerg Med 2000;7:

4 Ethanol and the CNS Changes fluid properties of lipid membranes (?) Augments GABA mediated inhibition Chronic use of ethanol results in downregulation of the number and sensitivity at the GABA receptor chloride channel complex 4

5 Problems With The GABA Model Cross tolerance between ethanol and GABA agonists is not perfect Administration of ethanol to patients in withdrawal results in normalization of mental status. Administration of GABA agonists to patients in withdrawal results in sedation This suggests other neurotransmitter system(s) are involved 5

6 Ethanol and Excitatory Amino Acids Ethanol inhibits NMDA. (N-methyl-daspartate) Chronic use of ethanol increases the number of NMDA receptors. (Family of glutamate receptors Ethanol withdrawal results in excess NMDA activity. Can be blocked by dizocilpine (MK-801). Hoffman: Ann NY Acad Sci 1992;654:52 6

7 Ethanol Withdrawal Down-regulation of GABA Decreased ability to inhibit Up-regulation of NMDA Increased ability to excite Net result: Hyperadrenergic condition 7

8 Alcohol Abstinence Syndromes Analyzed consecutive admissions to Boston City Hospital related to alcohol abuse. Collected 266 patients over 60 days. Characterized presentations Victor and Adams: Res Pub Assoc Res Nerv Ment Dis 1953;32:526. 8

9 Number Percent Acute alcoholic tremulousness Acute intoxication Intoxication Stupor or coma Combative Rum fits Tremor and transitory hallucinations Typical delirium tremens Atypical delirious-hallucinatory Wernicke-Korsakoff 8 3 Acute auditory hallucinosis Other Victor and Adams: Res Pub Assoc Res Nerv Ment Dis 1953;32:526. 9

10 Decreasing Alcohol Level Withdrawal Seizure Alcoholic Hallucinosis Alcoholic Tremulousness Hypertension Tachycardia Hyperthermia Tremor Diaphoresis Delirium Tremens 10

11 Alcoholic Hallucinosis Krapelin s Hallucinatory Insanity Hallucinations Often auditory Often persecutory Orientation intact Transient in nature Not necessarily associated with tremulousness 11

12 Rum Fits Tonic clonic seizure May be multiple Status epilepticus uncommon Short postictal period Not preceded by tremulousness May progress to DTs 12

13 Onset of Seizures Number of Seizures >65 Hours from last drink 13

14 Number of Seizures Number of Patients Status # of seizures 14

15 Time Between First and Last Seizure Number of Patients < Time in hours n=77 15

16 Delirium Tremens All manifestations of alcoholic tremulousness Autonomic instability Disorientation High case fatality rate Osler, 1916: 14% Philadelphia General, 1950: 5.4% Today? 16

17 Onset of DTs Percentage of Patients Last Drink Hospitalized 0 < >96 Time in hours 17

18 Duration of DTs Percentage of Patients < >96 Time in hours 18

19 Causes of Death Hyperthermia Fluid and electrolyte abnormalities Infection Occult cause of withdrawal Aspiration secondary to seizures or oversedation Cardiovascular (especially in the elderly) 19

20 Delirium Tremens Dogma No one should be given the diagnosis of DTs without first receiving a Head CT and an LP. 20

21 Treatment General Supportive care Intravenous fluids Glucose, thiamine Other water soluble vitamins ECG Combined with blood tests to r/o Ca ++, Mg ++, K + abnormalities Ethanol level Exclude occult infections and trauma 21

22 Benzodiazepine Dosing Choice of benzodiazepines Intravenous vs oral Active metabolites vs. inactive metabolites Rapidity of onset PRN vs. standing orders All decisions favor intravenous diazepam 22

23 Chlordiazepoxide Blum: J Toxicol 1976;3:427 23

24 Benzodiazepine Loading Give intravenous doses in rapid succession based on the pharmacokinetics of the agent until the patient becomes somnolent Manikant: Ind J Med Res 1993;98:170 Very high doses may be required (2640 mg in 48h) Nolop: Crit Care Med 1985;13:246 Follow with PRN dosing only 24

25 Neuroleptics Not cross tolerant with ethanol Interfere with the ability to dissipate heat Lower the seizure threshold Exacerbate autonomic instability Associated with bad outcomes when used in humans Greenblatt: J Clin Psych 1978;39:673 Greenland: Am J Psych 1978;135:

26 Haloperidol Blum: J Toxicol 1976;3:427 26

27 Individualized Treatment 101 withdrawal patients Randomized double-blind control Fixed dose of chlordiazepoxide vs PRN dosing Placebo given to maintain blinding Outcome measures Duration of treatment Total dose of benzodiazepine Saitz: JAMA 1994;272:519 27

28 Results Duration of treatment: 9 hours in PRN group vs 68 hours in fixed dose group (p<0.01) Total benzodiazepine dose: 100 mg in the PRN group vs 425 mg in the fixed dose group (P<0.01) Similar withdrawal severity, seizure incidence, and DTs Trends favor PRN group Saitz: JAMA 1994;272:519 28

29 Symptom Triggered Therapy 216 admissions for withdrawal Retrospective comparison of outcome before and after symptom triggered therapy Benzodiazepine dose Duration of therapy Progression to DTs Jaeger TM: Mayo Clin Proc 2001;76:

30 Outcome Before After Duration of therapy (h) Mean Median Total Bz Dose (mg) Mean Median Progression to DTs (%) Death (%) Any complication (%)

31 Sullivan JT, et al. Br J Addict 84: ,

32 Role of Magnesium Ethanol use results in hypomagnesemia Poor intake Malabsorption Renal tubular wasting syndrome Hypomagnesemia resembles ethanol withdrawal Magnesium is an NMDA antagonist 32

33 Role of Magnesium in Withdrawal Randomized double-blind study in 100 alcoholics 4 IM injections of 2g of MgSO 4 q6h or NS All got benzodiazepines as needed 3 observers rated withdrawal scores No difference between groups with regard to withdrawal score total benzodiazepine dose Wilson: Alcoholism 1984;8:542 33

34 Who Should Get Magnesium Patients with documented hypomagnesemia Patients with prolonged QT on ECG Patients with hypocalcemia Delirium Tremens? Other?? Check renal function before giving multiple doses 34

35 Beta Adrenergic Blockade Randomized double-blind trial in 88 patients with outpatient ethanol withdrawal Atenolol vs placebo Atenolol improved vital signs, decreased craving One seizure patient in atenolol group needing hospitalization, no seizures in placebo Suggest that the withdrawal was not very severe No comparison of atenolol with diazepam Horowitz: Arch Intern Med 1989;149:

36 Clonidine for Acute Withdrawal 61 men admitted to a detox unit Double-blind comparison of clonidine 0.2 mg TID vs chlordiazepoxide 50 mg TID Alcohol withdrawal scores compared over 4 day study period. Comprised of BP, pulse, RR, tremor, diaphoresis, and restlessness Baumgartner: Arch Intern Med 1987;147:

37 Benzodiazepine Failures Failure of or insufficient cross tolerance Large doses in short periods of time No accepted definition of large or short > 400 mg of diazepam in 24 hours? Hack JB. J Toxicol Clin Toxicol 37

38 Benzodiazepine Failures Barbiturates Advantage: Work well Disadvantage: Respiratory depression 38

39 Benzodiazepine Failures Phenobarbital IM or IV Long half-life, preferable But: too slow in onset for very ill patients Pentobarbital Rapid acting IV Easily titrated continuous infusion But: Respiratory depression common Bioaccumulates 39

40 Propofol GABA agonist NMDA antagonist Rapidly acting Ease to titrate Supported by case reports But: majority require intubation McCowan: Crit Care Med 2000;28: Coomes: Ann Emerg Med 1997;30: Olmedo: J Toxicol Clin Toxicol 2000;38:537 40

41 McCowan: Crit Care Med 2000;28:

42 Summary Don t forget the differential diagnosis Differentiate mild from severe withdrawal Be aggressive with benzodiazepines IV diazepam preferred No Librium tapers for more than mild withdrawal For benzodiazepine-resistent withdrawal Phenobarbital Propofol 42

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