Alcoholism

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CAEP 09 (Sunday, June 7, 2009 at 1030AM)
Alcohol Withdrawal
Lewis R. Goldfrank, MD Professor and Chairman,
Emergency Medicine New York University School of
Medicine Director, Emergency Medicine Bellevue
Hospital/NYU Hospitals/VA Hospital Medical
Director, New York City Poison Center
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Disclosure
I do not have an affiliation (financial or
otherwise) with any commercial organization that
may have a direct or indirect connection to the
content of my presentation.
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Learning Objectives

• Master the toxicology of alcohol dependency
• Master the characteristics of alcohol withdrawal
• Master the clinical management of alcohol
  withdrawal
• Master the clinical pharmacology of
  benzodiazepines for alcohol withdrawal

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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

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History of Alcoholism at Bellevue

• 256,755 admission from 1902-1935
• Peak admissions 4.99/1000 population/year
• Malefemale about 41
• Jolliffe Science 193683306-309
• Currently, 25 of patients brought to the ED by
  ambulance are alcoholics
• Whiteman Acad Emerg Med 2000714-20

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Ethanol and the CNS

• Changes fluid properties of lipid membranes (?)
• Augments GABA mediated inhibition
• Chronic use of ethanol results in down-regulation
  of the number and sensitivity at the GABA
  receptor chloride channel complex

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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

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Ethanol and Excitatory Amino Acids

• Ethanol inhibits NMDA. (N-methyl-d-aspartate)
• 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 199265452.
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Hamilton RJ Withdrawal Principles. In
Flomenbaum NA, Goldfrank LR, Hoffman RS, et al.,
eds Goldfranks Toxicologic Emergencies, 8th ed.
New York, McGraw-Hill, 2006, pp. 249-254.
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Ethanol Withdrawal

• Down-regulation of GABA
• Decreased ability to inhibit
• Up-regulation of NMDA
• Increased ability to excite
• Net result Hyperadrenergic condition

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What Does Alcoholism, Long Term Treatment of
Alcoholism and Repetitive Treatment of Delirium
Tremans do to the CNS?

• Repetitive Agonism at GABA receptor chloride
  channel complex.
• Subunit shift from a1 ? a4 results in reduced
  sensitivity to the sedating effects of ethanol.
• Long Antagonism of the N-methyl-D-aspartate
  glutamate receptor (NMDA) results in upregulation
  of number and enhanced wakefulness.
• CNS plasticity and therapy?? Example
  benzodiazepines.

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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
195332526.
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Victor and Adams Res Pub Assoc Res Nerv Ment Dis
195332526.
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Decreasing Alcohol Concentration Alcoholic
Tremulousness Hypertension Tachycardia Hyperthermi
a Tremor Diaphoresis Delirium Tremens
Withdrawal Seizure
Alcoholic Hallucinosis
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Alcoholic HallucinosisKrapelins Hallucinatory
Insanity

• Hallucinations
• Often auditory
• Often persecutory
• Orientation intact
• Transient in nature
• Not necessarily associated with tremulousness

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Rum Fits

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

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Onset of Seizures
Number of Seizures
Hours from last drink
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Number of Seizures
Number of Patients
of seizures
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Time Between First and Last Seizure
Number of Patients
Time in hours
n77
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Delirium Tremens
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• All manifestations of
• alcoholic tremulousness
• Autonomic instability
• Disorientation
• High case fatality rate
• Osler, 1916 14
• Philadelphia General, 1950 5.4
• Today?

0
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Onset of DTs
Percentage of Patients
Time in hours
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Duration of DTs
Percentage of Patients
Time in hours
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Causes of Death

• Hyperthermia
• Fluid and electrolyte abnormalities
• Infection
• Occult cause of withdrawal
• Aspiration secondary to seizures or over-sedation
• Cardiovascular (especially in the elderly)

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

• General Supportive care
• Intravenous fluids
• Dextrose, thiamine 100mg IV
• Other water soluble vitamins
• ECG
• Combined with blood tests to r/o Ca, Mg, K
  abnormalities
• Ethanol level
• Exclude occult infections and trauma

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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

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Table 1. Pharmacologic properties of
benzodiazepines
Hoffman RS, Nelson LS, Howland MA Antidotes in
Depth Benzodiazepines. In Nelson LS, Lewin NA,
Howland MA, et al., eds Goldfranks Toxicologic
Emergencies, 9th ed. New York, McGraw-Hill, in
press.
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Table 2. Selected pharmacokinetic and
pharmacodynamic properties of benzodiazepines
Adapted from Arendt RM, Greenblatt DJ, deJong
RH, et al In vitro correlates of benzodiazepine
cerebrospinal fluid uptake, pharmacodynamic
action and peripheral distribution. J Pharmacol
Exp Ther 198322798-106.
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Table A24-3 Relative Pharmacodynamic Properties
of Benzodiazepines in Humans
Hoffman RS, Nelson LS, Howland MA Antidotes in
Depth Benzodiazepines. In Nelson LS, Lewin NA,
Howland MA, et al., eds Goldfranks Toxicologic
Emergencies, 9th ed. New York, McGraw-Hill, in
press.
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Chlordiazepoxide
Blum J Toxicol 19763427
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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 199398170
• Very high doses may be required (2640 mg in 48h)
• Nolop Crit Care Med 198513246
• Follow with PRN dosing only

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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 197839673 Greenland
Am J Psych 19781351234
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Haloperidol
Blum J Toxicol 19763427
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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 1994272519.
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Results

• Duration of treatment
• 9 hours in PRN group vs 68 hours in fixed dose
  group (plt0.01)
• Total benzodiazepine dose
• 100 mg in the PRN group vs 425 mg in the fixed
  dose group (Plt0.01)
• Similar withdrawal severity, seizure incidence,
  and DTs
• Trends favor PRN group

Saitz JAMA 1994272519.
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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 200176695-701.
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Sullivan JT, et al. Br J Addict
1989841353-1357.
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Goal of Management

• A dose of IV diazepam that controls behavior for
  1 hr.
• Attains calm or drowsy state arousable to voice
  or light touch.
• Example
• Richmond agitation scale RASS 0 to -2

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Richmond Agitation Sedation Scale
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Role of Magnesium

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

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Role of Magnesium in Withdrawal

• Randomized double-blind study in 100 alcoholics
• 4 IM injections of 2g of MgSO4 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 19848542.
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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

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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 19891491089.
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Clonidine for Acute Withdrawal

• 61 men admitted to inpatient detoxification
• Double-blind comparison of clonidine 0.2 mg TID
  vs. chlordiazepoxide 50 mg TID
• Alcohol withdrawal scores compared over 4 day
  study period.
• Clonidine favorable BP, pulse, RR, tremor,
  diaphoresis, and restlessness

Baumgartner GR, et al Arch Intern Med
19871471223-1226.
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Benzodiazepine Failures

• Failure of or insufficient cross tolerance
• Large doses in short periods of time
• No accepted definition of large or short
• gt 400 mg of diazepam in 24 hours?

Hack JB. J Toxicol Clin Toxicol
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Benzodiazepine Failures

• Barbiturates
• Advantage Work well
• Disadvantage Respiratory depression

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Benzodiazepine Failures

• Phenobarbital
• IV start 65 130mg 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

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Propofol

• GABA agonist
• NMDA antagonist
• Rapidly acting
• Ease to titrate start 25µg/Kg/min IV
• Supported by case reports
• But majority of patients require intubation

McCowan Crit Care Med 2000281781-1784. Coomes
Ann Emerg Med 199730825-828. Olmedo J Toxicol
Clin Toxicol 200038537.
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McCowan Crit Care Med 2000281781-1784.
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Chan GM, Hoffman RS, Gold JA, Whiteman PJ,
Goldfrank LR, Nelson LS. Racial Variations in
the Incidence of Severe Alcohol Withdrawal. J Med
Toxicol 20095.
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Chan GM, Hoffman RS, Gold JA, Whiteman PJ,
Goldfrank LR, Nelson LS. Racial Variations in
the Incidence of Severe Alcohol Withdrawal. J Med
Toxicol 20095.
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Chan GM, Hoffman RS, Gold JA, Whiteman PJ,
Goldfrank LR, Nelson LS. Racial Variations in
the Incidence of Severe Alcohol Withdrawal. J Med
Toxicol 20095.
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Chan GM, Hoffman RS, Gold JA, Whiteman PJ,
Goldfrank LR, Nelson LS. Racial Variations in
the Incidence of Severe Alcohol Withdrawal. J Med
Toxicol 20095.
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Chan GM, Hoffman RS, Gold JA, Whiteman PJ,
Goldfrank LR, Nelson LS. Racial Variations in
the Incidence of Severe Alcohol Withdrawal. J Med
Toxicol 20095.
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Summary

• Dont 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

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