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Phenobarbital for Alcohol Withdrawal Masterclass

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  1. Pathophysiology and Assessment of Acute Alcohol Withdrawal Syndrome
    Background
  2. Pathophysiology
  3. Pharmacology and Pharmacokinetics of Common Medications
    Benzodiazepines
  4. Phenobarbital Pharmacology
  5. Clinical Literature
    Studies
Lesson 5 of 5
In Progress

Studies

Riszel January 14, 2022

Phenobarbital for Acute Alcohol Withdrawal: Prospective Randomized Double-blind Placebo-controlled Study.

Rosenson et al. J Emerg Med. 2013 Mar;44(3):592-598

ObjectiveTo investigate if a single dose of intravenous (i.v.) phenobarbital combined with a standardized lorazepam-based alcohol withdrawal protocol decreases intensive care unit (ICU) admission in ED patients with acute alcohol withdrawal
DesignProspective, randomized, double blind, placebo-controlled study.
Population198 patients with suspected acute alcohol withdrawal syndrome

Design

Inclusion/ExclusionI: > 18 year old with suspected acute alcohol withdrawal syndrome
E: Allergy to study drugs, hepatic impairment, no IV access, and other primary diagnosis
InterventionIV phenobarbital (10 mg/kg) in 100 mL normal saline over 30 mins
OutcomesPrimary: Initial level of hospital admission from the ED
Secondary: Use of continuous lorazepam infusion, hospital length of stay, total amount of lorazepam used, and incidence of adverse events

Baseline Characteristics

 Phenobarbital (n = 51)Placebo (n = 51)
Male46 (90)45 (88)
Age, years: median (IQR)46 (40–52)48 (37–54)
Initial AWCA score: median (IQR)6 (4–10)7 (4–10)
Initial heart rate: median (IQR)106 (100–123)112 (108–120)
Initial tremor: n (%)48 (95)48 (95)
Initial sweats: n (%)25 (49)32 (63)
Initial agitation: n (%)20 (40)21 (41)
Initial anxiety: n (%)35 (68)43 (84)
Altered level of consciousness: n (%)30 (58)35 (68)
Auditory/visual disturbances: n (%)20 (40)21 (41)
Time to initial lorazepam administration, minutes: median (IQR)84 (48–146)84 (40–312)
Time to study medication administration, minutes: median (IQR)144 (103–263)150 (100–26
Patients with prior alcohol withdrawal admissions to study institution: n (%)21 (41)25 (49)

Results

Primary OutcomeICU admission rate: Phenobarbital vs Placebo8% vs. 25% Difference 17% [95% confidence interval (CI) 4–32%])
Secondary OutcomesUse of continuous lorazepam infusion4% vs. 31%Difference 27% [95% CI 14–41%]Total lorazepam required26 vs. 49 mg Difference 23 mg [95% CI 7–40]
There were no differences in telemetry admission or floor ward admissionTrend toward lower median ICU or total hospitalHospital LOS: 76 hr (54–114) vs 118 hr (47–190) ICU LOS: 34 hr (30-276) vs 94 hr (43–134)
Adverse EffectsNo differences in incidence of intubation, seizure, mechanical restraints, and bedside sitter.There were no falls or mortality reported in either group.

Discussion

Strengths

  • Randomized 
  • Prospective
  • Clinical relevant study outcomes

Limitations

  • Formal sample size analysis was not done
  • Small sample
  • Single Center
  • Delirium, respiratory depression, EtOH level, and hypotension were missing from analysis

Takeaways

  • Phenobarbital is an option as adjunct to benzodiazepine for AAWS 
  • 10 mg/kg did not lead to significant increase in adverse effects compared to standard of care 


Alcohol withdrawal syndrome in critically ill patients: Protocolized versus Nonprotocolized management.

Duby JJ et al. J Trauma Acute Care Surg. 2014 Dec;77(6):938-43

Objectiveto compare patient outcomes in critically ill patients with AWS, regardless of their admission ICU diagnosis, that were treated with this protocolized approach versus a non-protocolized approach.
DesignRetrospective pre-post study.
Population135 patients with suspected acute alcohol withdrawal syndrome admitted to the ICU

Design

Inclusion/ExclusionI: > 18 year old with suspected acute alcohol withdrawal syndrome admitted to ICU
E: Patients with severe brain injury—defined as persistent Glasgow Coma Score < 8
InterventionPre-Protocol:Typically received continuous infusions or scheduled doses of BZDs per physician preference
Post-ProtocolEscalating doses of diazepam and phenobarbital according to an AWS protocol
OutcomesPrimary: ICU length of stay
Secondary: Mean and median BZD use, mean and median phenobarbital use, duration of sedation, requirement for mechanical ventilation (MV), ventilator-free days, and requirement for MV due to AWS

Baseline Characteristics

 Pre  (n = 60)Post (n = 75)P Value
Age55.7 ± 8.7 50.7 ± 13.80.03
Male81.6%81.3%1.0
History of Alcohol Withdrawal40%30.6%0.28
History of Psychosis10%12%0.78
History of Delirium Tremens10%4%0.19
History of Seizure18.3%21%0.83
Mean SOFA score on admit6.1 ± 3.73.9 ± 2.90.0004
Mean blood alcohol level on admit (mg/dL)135 ± 156134 ± 1400.56

Results

Primary OutcomeICU LOS: Pre vs Post Protocol9.6 ± 10.5 vs 5.2 ± 6.4   (P-value 0.0004)
Secondary OutcomesTime on Ventilator (days)5.6 ± 13.9   vs 1.31 ± 5.6    (P-value < 0.0001)
Ventilator-free days21.3 ± 9.5  vs  26.3 ± 5.6   (P-value 0.0004)
Intubation due to AWS 13 (22%)  vs 4 (5%) (P-value < 0.001)
Need for continuous sedation33 (55%) vs 18 (24%)    (P-value < 0.001)
Duration of sedation (days)10.8 ± 8.9  vs 3.5 ± 3.5    (P-value < 0.001)
Adverse EffectsDeath7 (12%)  vs 2 (3%) (P-value 0.07)

Discussion

Strengths

  • Clinical relevant study outcomes
  • Provided protocol

Limitations

  • Retrospective
  • Small sample
  • Single Center
  • Delirium, respiratory depression, and hypotension were missing from analysis

Takeaways

  • Phenobarbital is an option as adjunct to benzodiazepine for AAWS 
  • Protocol utilizing adjunct phenobarbital may reduce ICU LOS


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;27(6):454-460.

  • Objective
    • To compare a symptom-triggered benzodiazepine protocol to a phenobarbital protocol for the treatment of alcohol withdrawal
  • Design
    • Retrospective cohort study of a 42-bed medical ICU in a private teaching hospital in Nashville Tennessee
    • Inclusion: Medical ICU patients admitted from January 1, 2016 through June 30, 2017 and treated for the onset or prevention of AWS 
    • Exclusion: Received CIWA-Ar-based treatment for >24 hours before starting phenobarbital protocol; received no doses of either protocol; pregnant;  had phenobarbital as a documented outpatient maintenance medication
  • Intervention and Comparator
    • Phenobarbital taper protocol including lorazepam prn for agitation – initial phenobarbital dose 64.8 mg PO TID-260 mg IV based on history of delirium tremens, n=60
    • CIWA-Ar-based lorazepam protocol, n=60
  • Outcomes (Phenobarbital protocol vs CIWA-Ar protocol)
    • Use of phenobarbital protocol was associated with a statistically significant in ICU LOS (2.5 vs 4.4, p <0.001)
    • Use of phenobarbital protocol was associated with a significantly total hospital LOS (4.3 vs 6.9, p=0.004)
    • Use of phenobarbital significantly the total lorazepam equivalents (11.3 mg vs 35.2 mg, p <0.001)
    • Use of adjunctive medications, specifically dexmedetomidine, was much lower in the phenobarbital group (7% vs 17%, p=0.002)
  • Limitations
    • Small sample size, single-center, retrospective design
    • High incidence of comorbid conditions may have affected need for mechanical ventilation
  • Conclusions
    • Phenobarbital-based treatment of AWS seems to provide comparable benefit to traditional benzodiazepine-based treatment

Overview of Evidence

Studies evaluating the use of Phenobarbital in Benzodiazepine in alcohol withdrawal

Author and YearResearch Design and Sample sizeInterventionResults
Nisavic, 2019Retrospective observational/ n=562Benzodiazepine only fixed dosingPhenobarbital- Based Protocol (IM load + PO taper)No difference in AWS-related seizures, ICU admission, over-sedation, LOS, and hallucinations ↑ Delirium in BZD group In BZD→PB crossover pts, PB led to rapid improvement of BZD resistant AWS symptoms
Sullivan, 2018Retrospective observational/ n=209Benzodiazepine only CIWA- Protocol PB + Benzodiazepine CIWA ProtocolNo difference in ICU admission, intubation, hypotension, ED LOS, CIWA score at ED discharge PB group had ↓ hospital LOS and Max CIWA score at 24 hrs
Rosenson, 2013Retrospective cohort analysisn=102PB 10 mg/kg IV x1 + PRN benzodiazepines Placebo + PRN benzodiazepinesPB had ↓ ICU admission PB had ↓continuous infusion lorazepam PB had ↓ total lorazepam requirements No difference in ICU or hospital LOS
Duby et al (2014)Retrospective,
pre-post
studyn = 135
Nonprotocolized BZD
versus symptom-
triggered, protocolized
dose escalation
of diazepam and
phenobarbital
ICU LOS was significantly lower with
protocolized delivery (5.2 ± 6.4 days vs  9.6 ± 10.5 days, P = 0.0004); significantly  fewer intubations for AWS with protocolized delivery (5% vs 22%, P < 0.001). Protocolized delivery resulted in significantly less time on the ventilator, more ventilator free days, less need for continuous sedation, and shorter duration of sedation
Ibarra, 2019Retrospective observational/ n=78Lorazepam protocol only (LZP)
 
PB x 1 + LZP protocol (PB+LZP)
No difference in daily lorazepam requirements or hospital LOS
 
PB+LZP group had ↑ pts d/c within 72 hrs
 
No patient in PB group experienced intubation or hypotension
Nelson, 2019Pre-post observational/ n=300IV diazepam alone (DZP)
 
IV LZP + IV PB (LZP + PB)
 
IV PB alone (PB)
No difference in ICU admission, ICU LOS, and need for intubation.
 
PB associated with ↑ ED LOS but ↓ BZD requirements
Sullivan, 2018Retrospective observational/ n=209BZD only CIWA- Protocol
 
PB + BZD CIWA Protocol
No difference in ICU admission, intubation, hypotension, ED LOS, CIWA score at ED discharge
 
PB group had ↓ hospital LOS and Max CIWA score at 24 hrs
Hendey, 2011Prospective, randomized,
double-blind trial

n=44
PB 260 mg IV ×1, 130 mg IV PRN
 
Lorazepam 2 mg IV PRN + PRN chlordiazepoxide
PB and LZ both reduced the average CIWA-Ar score from baseline to discharge
 
No difference in  ED LOS and hospital LOS
Young, 1987Prospective, uncontrolled
trial

n=62
260 mg IV ×1 then
130 mg IV until clinical end point of light sedation
Safe discharge from ED was achieved in 92% of patients
 
Average ED LOS was 3 h, 47 min
 
No discharged patients returned to ED during the following week
 
Adverse effect in 6% of patients (none were admitted to hospital): 1 hypotension, 1
ataxia, 2 lethargy after final bolus doses

Phenobarbital Protocols

Duby JJ et al. J Trauma Acute Care Surg. 2014 Dec;77(6):938-43
Nelson AC et al. Am J Emerg Med. 2018 Mar 21. pii: S0735-6757(18)30241-9.