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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 CenterSorrento, Italy (September 19, 2007)

Alcoholism

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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

History of Alcoholism at Bellevue

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256,755 admission from 1902-1935Peak admissions 4.99/1000 population/yearMale:female about 4:1� Jolliffe: Science 1936;83:306-309

Currently, 25% of patients brought to the ED by ambulance are alcoholics� Whiteman: Acad Emerg Med

2000;7:14-20

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 1992;654:526

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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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

Number Percent

Acute alcoholic tremulousness 92 34.6

Acute intoxicationIntoxicationStupor or comaCombative

56 14 27 15

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Rum fits 32 12

Tremor and transitory hallucinations 30 11.1

Typical delirium tremens 14 5.3

Atypical delirious-hallucinatory 11 4.1

Wernicke-Korsakoff 8 3

Acute auditory hallucinosis 6 2.3

Other 42 18

Victor and Adams: Res Pub Assoc Res Nerv Ment Dis 1953;32:526.9

Decreasing Alcohol Level

Alcoholic TremulousnessHypertensionTachycardiaHyperthermia

TremorDiaphoresis

Delirium Tremens

Withdrawal Seizure Alcoholic Hallucinosis

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Alcoholic HallucinosisKrapelin’s 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

0

5

10

15

20

25

30

35

40

0-6 7-12 13-18 19-24 25-30 31-36 37-42 43-48 49-54 55-60 61-65 >65

Hours from last drink

Num

ber

of

Se

izur

es

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Number of Seizures

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7-12 Status

# of seizures

Num

ber

of

Pa

tient

s

14

Time Between First and Last Seizure

0

10

20

30

40

50

60

70

<6 8 9 10 12 20 96 120

Time in hours n=77

Num

ber

of

Pa

tient

s

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Delirium Tremens

All manifestations of alcoholic tremulousnessAutonomic instabilityDisorientationHigh case fatality rate� Osler, 1916: 14%� Philadelphia General, 1950: 5.4%� Today?

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Onset of DTs

0

2

4

6

8

10

12

14

16

18

<24 24-48 49-72 73-96 >96

Last DrinkHospitalized

Time in hours

Pe

rce

nta

ge

of P

atie

nts

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Duration of DTs

0

5

10

15

20

25

30

<24 25-48 49-72 73-96 >96

Time in hours

Pe

rce

nta

ge

of P

atie

nts

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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 DogmaNo one should be given the diagnosis of DTs

without first receiving a Head CT and an LP.

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

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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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Chlordiazepoxide

Blum: J Toxicol 1976;3:42723

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

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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 1978;39:673

Greenland: Am J Psych 1978;135:123425

Haloperidol

Blum: J Toxicol 1976;3:42726

Individualized Treatment

101 withdrawal patientsRandomized double-blind controlFixed dose of chlordiazepoxide vs PRN dosing� Placebo given to maintain blinding

Outcome measures� Duration of treatment� Total dose of benzodiazepine

Saitz: JAMA 1994;272:51927

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;272:51928

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;76:695-70129

Outcome Before AfterDuration of therapy (h)

Mean

Median

55.5

38.9

44.9

31.8

Total Bz Dose (mg)

Mean

Median

20.1

10.8

20.1

9.0

Progression to DTs (%) 20.5 6.9

Death (%) 2.4 0.0

Any complication (%) 32.5 17.630

Sullivan JT, et al. Br J Addict 84:1353-1357, 1989.

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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 1984;8:54233

Who Should Get Magnesium

Patients with documented hypomagnesemiaPatients with prolonged QT on ECGPatients with hypocalcemiaDelirium 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 1989;149:108935

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;147:122336

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 Toxicol37

Benzodiazepine Failures

Barbiturates� Advantage: Work well

� Disadvantage: Respiratory depression

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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

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Propofol

GABA agonist

NMDA antagonist

Rapidly acting

Ease to titrate

Supported by case reports

But: majority require intubationMcCowan: Crit Care Med 2000;28:1781-1784Coomes: Ann Emerg Med 1997;30:825-828Olmedo: J Toxicol Clin Toxicol 2000;38:537

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McCowan: Crit Care Med 2000;28:1781-1784

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Summary

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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