Addressing Emergency Neuro- Pharmacologic Controversies Head-On. What dose of IV benzodiazepine makes you uncomfortable?

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1 Addressing Emergency Neuro- Pharmacologic Controversies Head-On 38 y/o 136 bpm Bryan D. Sz, tremor, hallucinations Which benzodiazepine would you administer first? Why? Diazepam Lorazepam Other What dose of IV benzodiazepine makes you uncomfortable? Diazepam 20 mg Diazepam 40 mg Lorazepam 10 mg Lorazepam 20 mg What additional medications would you use in refractory EtOH withdrawal? Phenobarbital Propofol Dexmedetomidine Other 1

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3 NMDA GABA excitatory inhibitory Benzodiazepines Barbiturates Propofol 3

4 Biggest Mistake We Make UNDERDOSING 24 Hours Mean: 234 mg Highest: 2600 mg Individual: 200 mg +/- phenobarbital GABA Range: mg Gold JA, et al. Crit Care Med 2007;35: Wojnar M, et al. Alcohol Clin Exp Res 1997;21: Spies CD, et al. Intensive Care Med 2003;29: Phenobarbital mg Onset min Avoid stacking Ives TJ, et al. South Med J 1991;84: Hill A, et al. J Subst Abuse Treat 1993;10: Rosenson J, et al. J Emerg Med 2013;44:

5 1. Less delirium 2. No paradoxical reactions 3. Linear dose to concentration 4. Supporting RCT data vs benzos Moore PW, et al. J Med Toxicol 2014;10(2): Ives TJ, et al. South Med J 1991;84(1): Tangmose K, et al. Dan Med Bull 2010;57(8):A4141. Kramp P, et al. Acta Psychiatr Scand 1978;58(2): Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. Rosenson J, et al. J Emerg Med 2013;44(3): patients 10 mg/kg + lorazepam symptom-triggered ICU admission (8% vs. 25%) No difference in adverse effects A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Gold JA, et al. Crit Care Med 2007;35(3): patients, pre/post-new guideline Indiv Diazepam Total Diazepam Phenobarb Use 32 mg 248 mg 17% 86 mg 562 mg 58% 50% reduction in MV (47% vs. 22%) GABA NMDA Use of propofol infusion in alcohol withdrawal-induced refractory delirium tremens. Lorentzen K, et al. Dan Med J 2014;61(5):A patients Diazepam 1,500 mg or Phenobarbital 1,200 mg Mean Propofol dose: 70 mcg/kg/min 12 patients treated successfully 5

6 Focus on GABA ICU pts Dexmedetomidine HR/BP Benzos 1.5 mcg/kg/hr A randomized, double-blind, placebo-controlled, dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Mueller SW, et al. Crit Care Med 2014;42(5): ICU pts Lorazepam requirements 209 excluded A randomized, double-blind, placebo-controlled, dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Mueller SW, et al. Crit Care Med 2014;42(5): Lorazepam 24 hrs prior to study initiation Placebo Low Dose High Dose 39 mg 94 mg 75 mg Lorazepam 24 hrs after study initiation Placebo Low Dose High Dose 77 mg 28 mg 15 mg 6

7 24 hrs before randomization 11 pts already intubated Endpoint selection 1. Adjunct only 2. Preserved respiratory drive 3. Future study outcomes No effect: Severity Seizures Wilson A, et al. Alcohol Clin Exp Res 1984;8: Baclofen Gabapentin Cochrane Database Syst Rev 2013;2:CD Bonnet U, et al. Alcohol Alcohol 2010;45(2):

8 NMDA Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Wong A, et al. Ann Pharmacother 2015;49(1): pts Median 0.2 mg/kg/hr BZD -40 & mg (12/24 hr) Reduction of BZD requirements Adjunctive ketamine us in the management of severe ethanol withdrawal. Pizon A, et al. Crit Care Med [Epub ahead of print] 63 pts Mean 0.2 mg/kg/hr (19 loading dose) ICU LOS 3 days intubation benzo (2,525 vs 1,508 mg) DTs Severe EtOH w/d Benzos, benzos, benzos Phenobarb & propofol Dexmedetomidine adjunctive Ketamine on horizon? 8

9 What s the Code- Dose of tpa? 9

10 Courtesy of Courtesy of Courtesy of Courtesy of 10

11 50 mg IV push, may repeat X 1 CPR not a contraindication; continue 15 min Evidence best for PE; NOT undifferentiated Migraine +/- anticoagulants Recommendation Conclusion About Efficacy Should offer (Level B) May offer (C) May avoid (C) No recs (U) Highly likely to be effective Possibly/likely effective Likely ineffective/ Possibly ineffective/ Insufficient evidence/ Possibly effective/ Insufficient evidence Orr SL, et al. Headache 2016;56: Metoclopramide mg IV Prochlorperazine 10 mg IV Sumatriptan 6 mg subcut Droperidol/haloperidol IM/IV Valproic Acid IV NSAIDS/APAP IV Dexamethasone should be offered to prevent recurrence in adults discharged from an ED Orr SL, et al. Headache 2016;56: Should Offer Orr SL, et al. Headache 2016;56: May Offer 11

12 Diphenhydramine * Lidocaine Opioids Adjunctive Metoclopramide 10 mg AVOID Metoclopramide 20 mg CONSIDER Prochlorperazine 10 mg GIVE Orr SL, et al. Headache 2016;56: May Avoid Magnesium Ketamine Propofol 1. tpa 50 mg for PE; CPR 15 min 2. Migraine: prochlorperazine or metoclopramide +/- diphenhydramine +/- dexamethasone Orr SL, et al. Headache 2016;56: Addressing Emergency Neuro- Pharmacologic Controversies Head-On Bryan D. Hayes, PharmD, FAACT, FASHP MGH/Harvard Medical School bryanhayes13@gmail.com 12