Jason Hoppe, D.O. Department of Emergency Medicine University of Colorado

Transcription

1 Jason Hoppe, D.O. Department of Emergency Medicine University of Colorado

2 Remember that patient you admitted 56 yo M broken hip and mild alcohol withdrawal, no other complaints, non-focal exam and workup 30 mg clorazepate, 40 mg lorazepam Ripped out his IV, hallucinating and being restrained HR 120 s, BP 160/90, RR 20, T 101, Glucose 110 What happened?

3 Objectives Why didn t the benzo s alone work? Should we have seen this coming? What medications should we use next?

4 Why do we care? Alcohol withdrawal sx 2-4% US population 5% pts with AWS go on to DTs or severe AWS 8-15% admissions 16% surgery admits 31% trauma admits Delirium Tremens Mortality 20-35% 1-5%

5 Goals of treatment Control symptoms Agitation, HR, AMS Decrease morbidity related to AWS Decrease ICU admissions and LOS Decrease intubations and mechanical ventilation

6 GABA is your friend Primary inhibitory CNS transmitter Gated ion channel with 5 subunits Open hyperpolarization neuronal inhibition QuickTime and a decompressor are needed to see this picture.

7 Physiology Glutamate Glutamate Glutamate GABA GABA GABA Alcoh Health Res World 1997; 21:

8 Benzodiazepines Advantages: Predictable Excellent safety profile Anticonvulsant Symptom triggered bolus therapy Ease of administration, rapid onset & titratable Max dose determined by clinical effect

9 Benzodiazepines Disadvantages: Resistance/high doses may be necessary Shortages Over-sedation (rare) Diluent: propylene glycol

10 Resistant Alcohol Withdrawal Refractory to typical doses of IV BDZ Deficiency of GABA activity Insufficient to overcome glutamate Changes of GABA receptor subtypes: sensitivity to BDZ Genetics

11 >50 mg of diazepam w/i 1 st hour 4/19 = Non-RAW normalized vitals within 3 hours 15/19 = RAW Additional sedatives and/or Persistent abnl 24 hrs J Med Tox 2006; 2:55 60

12 Median dose of diazepam (mg)

13 Should I have seen this coming? Benefits Early identification Avoid ineffective doses Break the cycle Difficult population Morbidity Visit fatigue Scoring systems flawed

14 Risk factors for RAW Historical Prior severe withdrawal (DTs/ICU) Kindling Repeated AWS episodes = severity of subsequent AWS Older Sicker (co-morbidities)

15 Risk factors for RAW Historical Racial variations Chan G et al. JMT 2009

16 Risk factors for RAW Acute Difficult to control autonomic activity temp, HR, BP Complicating condition (infection/trauma) Lack of response to BDZ High doses, need for restraints, 3 hrs? AWS BAL >100 mg/dl

17 What should I do now? Second line agents: Barbiturates Propofol Dexmedetomidine IV EtOH Antipsychotics Clonidine/β blockers Anticonvulsants

18 Barbiturates Advantages Cross tolerance with ethanol Potentiate effect of GABA Separate binding site from BDZ High dose anesthetic barbiturates directly open Cl- channel Disadvantages Hypotension Respiratory depression

19 Prospective, uncontrolled 62 pts IV phenobarb for mod AWS 60% SZ 57/62 (92%) d/c d (avg ED stay 3 hrs 47 min) 4 (6%) ADE (1 hypotension, 1 ataxia, 2 lethargy) Annals Emerg Med 1987; 16:

20 Pre vs. post-intervention ICU AWS patients total diazepam 562 vs. 248 mg (p=.001) use phenobarb 58 vs. 17% (p=.01) intubation 22 vs 47% (p=.008) Trend ICU stay and nosocomial pna Crit Care Med 2007; 35(3)

21 Propofol (2,6 diisopropylphenol) Dose dependent hypnotic Activates GABAA receptor complex and antagonizes excitatory NMDA receptors Highly lipophilic, large Vd ( L) Rapid uptake, elimination from CNS No active metabolites

22 RAW 2 nd line agents: Propofol Advantages: Less cross tolerance vs. BDZ Predictable effects Quick on/quick off= Easily titratable Disadvantages: Respiratory depression intubation Triglyceride load Propofol Infusion Syndrome

23 . Dexmedetomidine Central α2 receptor agonist α2 1600:1 α1 (7-8x clonidine) Sympathetic response neurotransmitter release (not GABA) tachycardia, hypertension, tremors Sedative, analgesic, antihistamine

24 RAW 2 nd line agents: Dexmedetomidine Advantages: Short duration of action (6 min) ø resp depression, ø CV rebound dosage of sedative hypnotics Disadvantages Cost Side effects: hypotn (30%), htn (12%), nausea (11%), bradycardia (9%) Ann Pharmacother 2008;42:1703-5

25 What would I do? More benzodiazepines Frequent re-evaluations Consider second line agent barbs/propofol

26 Conclusions Be aware of RAW Not all patients respond to the same treatment Have an idea of risk factors that may predict severe withdrawal/bdz resistance Have a plan for escalating treatment to a secondary agent

27 Bibliography McCowan C, Marik P. Refractory delirium tremens treated with propofol: A case series. Critical Care Medicine 2000; 28: Sellers EM, Spies CD, Otter HE, et al. Alcohol withdrawal severity is decreased by symptom-orientated adjusted bolus therapy in the ICU. Intensive Care Medicine 2003; 29: Chan GM, Hoffman RS, Gold JA, et al. Racial Variations in the Incidence of Severe Alcohol Withdrawal. Journal of Medical Toxicology 2009; 5: 8-14 Becker HC. Kindling in Alcohol Withdrawal. Alcohol Health & Research World 1998; 22: Coomes TR, Smith SW. Successful Use of Propofol in Refractory Delirium Tremens. Annals of Emergency Medicine 1997; 30: Khan A, Levy P, DeHorn S, et al. Predictors of Morality in Patients with Delirium Tremens. Society for Academic Emergency Medicine 2008; 15: Lee JH, Jang MK, Lee JY, et al. Clinical predictors for delirium tremens in alcohol dependence. Journal of Gatroenteroloty and Hepatology 2005; 20: DeCarolis DD, Pharm D, Rice KL, et al. Sympton-Driven Lorazepam Protocol for Treatment of Severe Alcohol Withdrawal Delirium in the Intensive Care Unit. Pharmacotherapy 2007; 27: Palmstierna T. A Model for Predicting Alcohol Withdrawal Delirium. Psychiatric Services 2001; 52: Young GP, Rores C, Murphy C, et al. Intravenous Phenobarbital for Alcohol Withdrawal and Convulsions. Annals of Emergency Medicine 1987; 16: Lukan JK, Reed DN, Looney SW, et al. Risk Factors for Delirium Tremens in Trauma Patients. The Journal of Trauma Injury, Infection, and Critical Care 2002; 53: Fiellin DA, O Connor PG, Holmboe ES, et al. Risk for Delirium Tremens in Patients with Alcohol Withdrawal Syndrome. Association for Medical Education and Research in Substance Abuse 2002; 23: Pictures: The virtual absinth museum.

28 Bibliography Gold JA, Rimal B, Nolan A, et al. A strategy of escalating doses of benzodiazepines and Phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Critical Care Medicine 2007; 35: Cuculi F, Kobza R, Ebmann T, et al. ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens. Swiss Medical Weekly 2006; 136: Skrobik Y. Protocols, practice, and patients The case of alcohol withdrawal. Critical Care Medicine 2007; 25: 955 Hodges B, Pharm D, Mazur J. Intravenous Ethanol for the Treatment of Alcohol Withdrawal Syndrome in Critically Ill Patients. Pharmacotherapy 2004; 24: Darrouj J, Puri N, Prince E, et al. Dexmedetomidine Infusion as Adjunctive Therapy to Benzodiazepines for Acute Alcohol Withdrawal. The Annals of Pharmacotherapy 2008; 42: Rovasalo A, Tohma H, Aantaa R, et al. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. General Hospital Psychiatry 2006; 28: Ulrichsen J, Haugbol S, Brandt C, et al. Irreversibility of Kindled Alcohol-Withdrawal Behaviour in Rats. Medical Council on Alcoholism 1998; 33: Van Munster B, Korevaar J, Rooij S, et al. Genetic Polymorphisms Related to Delirium Tremens: A Systematic Review. Alcohol Clinical and Experimental Research 2007; 31: Hack JB, Hoffman RS, Nelson LS. Resistant Alcohol Withdrawal: Does an Unexpectedly Large Sedative Requirement Identify These Patients Early? Journal Of Medical Toxicology 2006; 2: 55-60