Phenobarbital vs CIWA-Ar Protocol
Treatment of Alcohol Withdrawal Syndrome: Phenobarbital vs CIWA-Ar Protocol
Tidwell WP, Thomas TL, Pouliot JD, Canonico AE, Webber AJ.
Am J Crit Care. 2018 Nov;27(6):454-460. [Full text]
The clinical institute withdrawal assessment for alcohol scale (CIWA-Ar, revised scale) [1] is a standardized alcohol withdrawal tool that, when used to determine if benzodiazepine should be administered, decreased the duration and the amount of benzodiazepine used for the prevention and treatment of acute withdrawal syndrome (AWS) [2].
Implementing CIWA-Ar is operationally labor intensive, requiring frequent reassessment, and there are multiple components of the score that are subjectively rated. In severe AWS, patients may still receive large doses of benzodiazepines despite the standardized protocol, increasing the risk of respiratory depression and delirium [3].
Phenobarbital has some theoretical advantages for AWS management when compared to benzodiazepines. Its phamacokinetics and pharmakodynamics may be more predictable, it has a wider therapeutic index [4], and its mechanisms of action (activity on GABA, NMDA and AMPA receptors) may be better targeted to the physiology of AWS.
Up to the point of this retrospective 2018 study, phenobarbital had been shown in a randomized trial to be superior to placebo for AWS [5]. Here the authors aimed to compared it directly to CIWA-Ar based dosing of lorazepam.
Patient population and Design
This was a retrospective cohort study at a 42-bed medical ICU in a private teaching hospital in Nashville, Tennessee. Patients with suspected AWS or diagnosed AWS, identified by the attending or admitting physician, were included.
Those that had received CIWA-Ar–based treatment for >24 hours before starting the phenobarbital protocol, had received no doses of either protocol, were currently pregnant, left against medical advice within 24 hours of presentation, died within 24 hours of presentation, or had phenobarbital as a documented outpatient maintenance medication, were excluded.
The phenobarbital protocol fixed dosing was based on the initial risk of delerium tremens (DT). For active DT a loading dose was followed by a tapering oral phenobarbital TID dosing schedule for a total . The CIWA-Ar symptom based dosing used lorazepam.
Outcomes
The primary outcome was the ICU length of stay between the standard treatment protocol and the phenobarbital protocol. Secondary outcomes included hospital LOS, use of invasive mechanical ventilation, and use of adjunctive and sedating agents to control AWS symptoms (i.e. haloperidol, quetiapine, olanzapine, and dexmedetomidine).
Results
A total of 120 patients met inclusion criteria , with 60 receiving the phenobarbital protocol and 60 receiving the CIWA-Ar protocol. Baseline demographics were similar with regard to sex and ethnicity though the mean age was lower in the phenobarbital group (45 vs 52 years).
The phenobarbital protocol had a statistically significant shorter ICU LOS of 2 days (mean [SD], 2.4 [1.5] vs 4.4 [3.9] days; P < 0.001). The phenobarbital protocol was had a statistically shorter hospital LOS by 2.6 days (4.3 [3.4] vs 6.9 [6.6] days; P = 0.004).
The incidence of mechanical ventilation was lower in patients treated with the phenobarbital (1 [2%] vs 14 [23%] patients). Additionally, use of adjunctive medications to control AWS was markedly lower in patients treated with phenobarbital. Specifically, dexmedetomidine use was much lower with phenobarbital (4 [7%] vs 17 [28%]; P = 0.002). Haloperidol and quetiapine use was also lower but olanzapine use was similar.
Discussion
In this small, retrospective cohort study, a fixed dosing phenobarbital protocol for AWS was associated with a significant reduction in ICU LOS when compared to CIWA-Ar symptom based lorazepam dosing. The total hospital stay was also shorter and there was less use of adjunctive medications like dexmedetomidine.
This was retrospective and a relatively small trial. The benzodiazepine used was lorazepam, though diazepam may have been a better choice with faster onset and longer duration of action [4]. There is not yet a large prospective randomized trial but other retrospective studies have confirmed these findings.
Phenobarbital is a safe and viable alternative to benzodiazepines for AWS. Phenobarbital levels can be monitored and the total dose should be kept < 30 mg/kg [4]. Given its dosing is weight based, phenobarbital dosing in obesity, should be done with caution. Still, its theoretical advantages (listed above), along with fixed dosing that is independent of the somewhat subjective and staff intensive CIWA-Ar and that IV, IM, and PO dosing can be used nearly interchangeably are logistical advantages for phenobarbital. It currently does not replace benzodiazepines in guidelines, though it should be considered, especially during benzodiazepine shortages!
| F: Follow up | N/A |
| R: Randomization | No, retrospective |
| I: Intention to treat | N/A |
| S: Similar at baseline | No: Mean age – 45 yr phenobarbital vs 52 yr CIWA-Ar |
| B: Blinding | N/A |
| E: Equal treatment | N/A |
| S: Source (funding) | Not discussed |
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