Phenobarbital for the Management of Acute Alcohol Withdrawal (AAW) - PowerPoint Presentation

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Phenobarbital for the Management of Acute Alcohol Withdrawal (AAW)

Samantha Tracy, PharmDPGY1 Pharmacy Resident Providence St Patrick Hospital Missoula, Montana MPA Spring Seminar 2022 April 22, 2022

Disclosure Statement

IRB Status:

Approved

Co-Investigators:

-

Carla Federici, PharmD, BCPS

- Jayme Hartzell, PharmD, BCPS

Conflicts of Interest:

None

Project Sponsorship:

None

Learning Objectives

Background

First-Line therapy: Benzodiazepines

High risk of “adaptation response”

Severe withdrawal (delirium tremens)

Increased risk of overall harm

More recent use of barbiturates (phenobarbital):

Adaptation response

Severe alcohol withdrawal

Phenobarbital Advantages

Mechanism of action

Pharmacokinetics

Promising evidence

No statistically significant difference in intubation rates

Lower hospital length of stay, lower CIWA scores

Withdrawal Timeline

Adaptation Response:

Benzodiazepines

for AAW

MOA:

Increases frequency of GABA channel opening.

Pharmacokinetic Parameters:

Agent-Dependent

Dosing:

Formulation-Dependent

Front-Loading Dosing

:

Those with increased harm from extended periods of high blood pressure and heart rate

Older patients

Those with severe CIWA scores (

>

19)

Those with CAD

Delirium tremens

Common Benzodiazepines for AAW

Agent

Onset of Action

Symptom-Triggered Dosing for Withdrawal

Half-Life

Metabolism

Lorazepam (Ativan)

15-20 minutes (IV)

20-30 minute (PO)

2-4 mg

(IV or PO)

~14 hours (IV)

~12 hours (PO)

Conjugation (Inactive)

Chlordiazepoxide (Librium)

Several hours

25-125 mg (PO)

24-48 hours

Conjugation (Active)

Diazepam (Valium)

4-5 minutes (IV)

1-1.5 hours (PO)

5-10 mg (IV)

5-20 mg (PO)

60-72 hours

CYP3A4/2C19 (Active)

Phenobarbital for AAW

MOA:

NMDA receptor antagonist (inhibits glutamate)

Increases duration of GABA channel opening at a different binding site

Homeostasis at both ends.

Pharmacokinetic Profile:

Onset of Action (IV):

~5 minutes

Onset of Ation (PO):

~30 minutes

Half-Life (range):

~79 hours (53-118 hours)

Metabolism:

CYP2C9/2C19/2E1

Clinical Significance

Fast onset

Duration approximates typical length of withdrawal (~2-3 days)

Clinical Considerations for Phenobarbital

Pharmacokinetics: - Advanced age

- Liver disease Induced Metabolism: - Contraceptives - Anticoagulants - Anti-epileptics - Antimicrobials - Immunosuppressants

Study

Results

Phenobarbital Dose Range

Nisavic

M, et al.

Retrospective.

Compared protocols with and without phenobarbital

- No statistically significant differences of AWS or hospital length of stay seen between phenobarbital and BZD

- No significant differences in adverse outcomes (seizures, hallucinations, high sedation)

6-8 mg/kg to 12-15 mg/kg

(depending on risk of AW)

Ibarra F.

Retrospective.

Single IV dose phenobarbital vs lorazepam

- No statistically significant difference of

lorazepam dosing

seen between groups.

- More patients receiving single dose of phenobarbital alongside CIWA lorazepam were discharged within 3 days

- No difference between groups with respect to hospital length of stay, intubations, and seizures

130 – 260 mg

Nelson A, et al.

Retrospective.

Comparison of 3 alcohol withdrawal protocols

- Lorazepam + phenobarbital resulted in lower benzodiazepine dose needed

- No differences in ICU admissions between groups

- Shorter hospital length of stay in the phenobarbital + lorazepam group

65 mg x1

260 mg x1, followed by 130 mg IV

260 mg x3, followed by 130 mg IV

(depending on risk of alcohol withdrawal)

Sullivan, et al.

Retrospective.

Adjunct-phenobarbital vs benzodiazepine monotherapy

- Similar ICU admissions with

both phenobarbital-adjunct vs benzodiazepine-only symptom management

260 mg (IQR 130-500)

Median weight was 81 kg

(~3.2 mg/kg)

Oks, et al.

Retrospective.

130 mg phenobarbital Q15 minutes until RASS 0 to -1

- 19.8% patients using phenobarbital required mechanical ventilation, but likely not solely due to treatment (likely due to high BZD dose prior to medical ICU admission).

1977 mg

+

1531 mg

(25

+

17 mg/kg)

Rosenson

, et al.

Prospective, randomized, double-blind, placebo-controlled.

10 mg/kg loading dose phenobarbital vs placebo

- Decreased ICU admission rate in the phenobarbital group

- Lower lorazepam requirements in the phenobarbital group

- No differences in intubation or hospital length of stay

10 mg/kg LD

Nguyen, et al.

Prospective review.

Phenobarbital + lorazepam vs BZD monotherapy

- Phenobarbital group had shorter hospital length of stay

- No difference in ICU length of stay

- 3 intubations needed with phenobarbital use

909.4

+

785.4 mg

Hawa

, et al.

Retrospective.

Phenobarbital vs lorazepam-based treatment

- Significantly lower length of stay in the phenobarbital group vs lorazepam group

- Significantly lower all-cause 30-day readmission rate in phenobarbital group

- Significantly lower 30-day ED visits post-discharge

------

Hendey

, et al.

Prospective, randomized, double-blind.

Phenobarbital loading dose + Placebo vs lorazepam + chlordiazepoxide

- No statistically significant differences between phenobarbital and lorazepam CIWA score or ED discharge score.

509 mg (ranged from 260-910)

* Mean number of doses 2.9 (ranged from 1-6)

Purpose

To determine if phenobarbital use for acute alcohol withdrawal results in fewer ICU admissions and lessens the amount of lorazepam a patient uses during their hospital stay.

Project

Single-Center, retrospective chart review

Outcomes Measured:

Total amount of lorazepam used

Total amount of phenobarbital used

Hospital length of stay

ICU admissions

Intubations

Inclusion Criteria:

18 years or older

No allergies or contraindications to use

Exclusion Criteria:

On phenobarbital for other indications

Less than 18 years old

Cumulative Patient Demographics:

/

Separated Demographics/Outcomes:

Phenobarbital (n = 9)Benzodiazepine Monotherapy (n = 198)

Age Range

[Average]

32 – 50

[41.8]

24 – 82

[48]

Gender

7 Male, 2 Female

110 Male, 88 Female

Cumulative lorazepam Dose Range (mg)

[Average]

0 – 91.4

[34.5]

0 – 288.2

[16.2]

Average Daily lorazepam Dose Range (mg)

[Average]

3.5-16.8

[10.12]

3.5 – 25

[9.55]

Average Mg lorazepam Before phenobarbital

21

N/A

Average Mg lorazepam After Phenobarbital

13.5

N/A

Cumulative Phenobarbital Range (mg/kg)

[Average]

1 – 8.9

[3.34]

N/A

Average Phenobarbital Duration (days)

1.1

N/A

Phenobarbital Regimens Used

5 mg/kg x1

65 – 520 mg x1

N/A

Range of Days Hospitalized

[Average]

1 – 9

[3.7]

1 – 16

[2.3]

30-Day Readmissions

4 (0 alcohol-related)

62 (32 alcohol-related)

Intubations

0

2 (non-benzodiazepine related)

Strengths

Long time period for data collection (~ 2 years)

All patients within that time period were included

Large number of patients included in data collection

Limitations

Small sample size in the phenobarbital group (n = 9)

Retrospective data collection

Chart review, may not be comprehensive

Non-standardized phenobarbital doses given

Conclusions

Future Directions/

Follow-Up

What is Left?

Standardized phenobarbital order set use

Continued education to nursing staff and providers

Overall Impact?

Patients staying out of the ICU for withdrawal management

Potentially less benzodiazepine use and duration of stay

QUESTIONS?Samantha.tracy@providence.org

References

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Kleinshmidt

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Kmiec

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Accessed October 18, 20201. Available at https://www.asam.org/docs/default-source/quality-science/the_asam_clinical_practice_guideline_on_alcohol-1.pdf?sfvrsn=ba255c2_2