Phenobarbital vs Ativan for Alcohol Withdrawal in the Intensive Care Unit (PARTI)

Our aim is to compare outcomes of patients with benzodiazepine-refractory alcohol withdrawal syndrome who are treated with either a phenobarbital-based or a lorazepam based protocol.

This study is a prospective, open-label, randomized, controlled trial. The electronic medical record will be used to identify patients who have a diagnosis of alcohol withdrawal or are receiving alcohol withdrawal. Subjects who are anticipated to meet inclusion criteria will be pre-consented for the study using an informed consent process. see informed consent form. Subjects will not be enrolled and randomized until they have met inclusion criteria. If a patient meets criteria, but is deemed non-decisional or unable to give consent, the patient's medical decision maker will undergo the informed consent process. After enrollment, participants will be randomized to either the control group (lorazepam-based therapy) or the study group (phenobarbital-based therapy) Personnel unassociated with patient screening, enrollment, or follow up will create the allocation sequence and will use a random, computerized number generator. The allocation sequence will then be transferred to sequentially numbered, opaque envelopes for purposes of allocation concealment. These sequentially numbered envelopes, which are blinded to clinical trial coordinators/physicians, will be handed out in order as patients are enrolled. Clinical trial coordinators/physicians will verify treatment eligibility and informed consent before opening the envelope to obtain the treatment assignment. The study group will be placed on the phenobarbital-based protocol as described below in procedures. The control group will be placed on the lorazepam-based protocol, also listed below in procedures. All medications in the study are FDA approved. No investigational medicines will be used. Data will be collected on each participant as noted below in measurements. The data will be analyzed and published as noted above in the statistical analysis plan and data use and management section.

lorazepam, phenobarbital, ativan, alcohol withdrawal syndrome, alcohol withdrawal, intensive care unit, delirium tremens, refractory alcohol withdrawal, benzodiazepine

The phenobarbital group will undergo management with a phenobarbital based treatment protocol with additional symptom triggered therapies. On day 1, the phenobarbital group receive a loading dose of phenobarbital intravenous 10mg/kg (actual body weight) with a maximum dose of 1 g/100 mL On day 2 of study protocol, and no sooner than 12 hours after loading dose, phenobarbital 64.8 mg is administered every 12 hours for two doses. On day 3 of study protocol, patients will receive phenobarbital 32.4 mg every 12 hours for two doses. On day 4 of study protocol, patients will receive phenobarbital 32.4 mg once, to be given 24 hours after last scheduled dose. Throughout the 4 day protocol, the patient will have phenobarbital 65 mg every 6 hours as needed available either IM or IV, starting no sooner than 30 minutes after the loading dose.

The lorazepam group will undergo management with a lorazepam based treatment protocol with additional symptom triggered therapies. On Day 1, the lorazepam group will be started on scheduled lorazepam 4 mg every 6 hours After day 1, the scheduled lorazepam dose will be modified based on the total lorazepam requirements from the previous day and divided into 4-6 doses. A lorazepam infusion, at physician discretion, will be available at any point if the dose of scheduled and PRN lorazepam being given is too high or frequent to effectively be administered. Once symptoms are well controlled on lorazepam based therapy, the total dose given over the past 24 hours will be calculated and weaned by approximately 10-20% per day when clinically appropriate. Throughout the entire protocol, 2-4 mg lorazepam IV q 30 minutes PRN will be available for a goal CIWA <6 or RASS -1 to 0.

Phenobarbital loading dose followed by a taper will be given to control acute alcohol withdrawal syndrome

Ativan will be given according to our institutional alcohol withdrawal protocol to control acute alcohol withdrawal syndrome

Inclusion Criteria: Patients will be eligible for randomization if he/she has met one of the following three conditions: has required more than 10 mg of lorazepam within a one hour time period, has required more than 30 mg of lorazepam within a four hour time period, or requires admission/transfer to the intensive care unit for primarily uncontrolled alcohol withdrawal symptoms Exclusion Criteria: Patients will be excluded from the study if he/she: has a traumatic brain injury or other neurological condition requiring frequent neurological assessment (stroke, intracranial hemorrhage, active seizures on admission) has severe hypotension requiring vasopressor support is less than 18 years of age is actively pregnant has an allergy to either of the drugs being studied (phenobarbital or lorazepam) is already intubated at the time of randomization

Friedmann PD. Alcohol use in adults. N Engl J Med. 2013 Apr 25;368(17):1655-6. doi: 10.1056/NEJMc1302445. No abstract available.

Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995 Sep;10(9):479-87. doi: 10.1007/BF02602395.

Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003 May 1;348(18):1786-95. doi: 10.1056/NEJMra020617. No abstract available.

Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Diagnosis and management of acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):675-80.

Miller NS, Gold MS. Management of withdrawal syndromes and relapse prevention in drug and alcohol dependence. Am Fam Physician. 1998 Jul;58(1):139-46. Erratum In: Am Fam Physician 1998 Sep 15;58(4):866.

Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969 Jun;125(12):1640-6. doi: 10.1176/ajp.125.12.1640. No abstract available.

Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010 Sep;38(9 Suppl):S494-501. doi: 10.1097/CCM.0b013e3181ec5412.

Dixit D, Endicott J, Burry L, Ramos L, Yeung SY, Devabhakthuni S, Chan C, Tobia A, Bulloch MN. Management of Acute Alcohol Withdrawal Syndrome in Critically Ill Patients. Pharmacotherapy. 2016 Jul;36(7):797-822. doi: 10.1002/phar.1770. Epub 2016 Jun 30.

Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol. 2006 Jun;2(2):55-60. doi: 10.1007/BF03161171.

Wong A, Benedict NJ, Lohr BR, Pizon AF, Kane-Gill SL. Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: Benzodiazepine dose-escalation with or without propofol. Drug Alcohol Depend. 2015 Sep 1;154:296-9. doi: 10.1016/j.drugalcdep.2015.07.005. Epub 2015 Jul 16.

Duby JJ, Berry AJ, Ghayyem P, Wilson MD, Cocanour CS. Alcohol withdrawal syndrome in critically ill patients: protocolized versus nonprotocolized management. J Trauma Acute Care Surg. 2014 Dec;77(6):938-43. doi: 10.1097/TA.0000000000000352.

Crispo AL, Daley MJ, Pepin JL, Harford PH, Brown CV. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014 Sep;34(9):910-7. doi: 10.1002/phar.1448. Epub 2014 Jun 5.

Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, Ely EW. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. doi: 10.1001/jama.298.22.2644.

Ives TJ, Mooney AJ 3rd, Gwyther RE. Pharmacokinetic dosing of phenobarbital in the treatment of alcohol withdrawal syndrome. South Med J. 1991 Jan;84(1):18-21. doi: 10.1097/00007611-199101000-00006.

Tangmose K, Nielsen MK, Allerup P, Ulrichsen J. Linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients. Dan Med Bull. 2010 Aug;57(8):A4141.

Kramp P, Rafaelsen OJ. Delirium tremens: a double-blind comparison of diazepam and barbital treatment. Acta Psychiatr Scand. 1978 Aug;58(2):174-90. doi: 10.1111/j.1600-0447.1978.tb06930.x.

Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979 Aug;26(2):256-64. doi: 10.1002/cpt1979262256.

Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981 Jul;30(1):71-6. doi: 10.1038/clpt.1981.129.

Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987 Aug;16(8):847-50. doi: 10.1016/s0196-0644(87)80520-6.

Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011 May;29(4):382-5. doi: 10.1016/j.ajem.2009.10.010. Epub 2010 Mar 25.

Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F, Cisse B, Lam J, Alter H. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med. 2013 Mar;44(3):592-598.e2. doi: 10.1016/j.jemermed.2012.07.056. Epub 2012 Sep 19.

Ibarra F Jr. Single dose phenobarbital in addition to symptom-triggered lorazepam in alcohol withdrawal. Am J Emerg Med. 2020 Feb;38(2):178-181. doi: 10.1016/j.ajem.2019.01.053. Epub 2019 Jan 30.

Tidwell WP, Thomas TL, Pouliot JD, Canonico AE, Webber AJ. Treatment of Alcohol Withdrawal Syndrome: Phenobarbital vs CIWA-Ar Protocol. Am J Crit Care. 2018 Nov;27(6):454-460. doi: 10.4037/ajcc2018745.

Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007 Mar;35(3):724-30. doi: 10.1097/01.CCM.0000256841.28351.80.

Gashlin LZ, Groth CM, Wiegand TJ, et al. Comparison of alcohol withdrawal outcomes in patients treated with benzodiazepines alone versus adjunctive phenobarbital: a retrospective cohort study. Asia Pac J Med Toxicol 2015;4:31-6.

Hjermo I, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010 Aug;57(8):A4169.

Askgaard G, Hallas J, Fink-Jensen A, Molander AC, Madsen KG, Pottegard A. Phenobarbital compared to benzodiazepines in alcohol withdrawal treatment: A register-based cohort study of subsequent benzodiazepine use, alcohol recidivism and mortality. Drug Alcohol Depend. 2016 Apr 1;161:258-64. doi: 10.1016/j.drugalcdep.2016.02.016. Epub 2016 Feb 18.

Mo Y, Thomas MC, Karras GE Jr. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016 Apr;32:101-7. doi: 10.1016/j.jcrc.2015.11.022. Epub 2015 Dec 8.