SCCM Resource Library-47-Comparison of Two Dosing Strategies of Phenobarbital for Alcohol Withdrawal Syndrome

Video Transcription

Hello, my name is Pansy El-Samadisi, I'm a critical care clinical pharmacist at Beth Israel Deaconess Medical Center in Boston, and today I will be presenting the results  of our study titled Comparison of Two Dosing Strategies of Phenobarbital for Alcohol Withdrawal Syndrome. My co-authors, including myself, declare no potential conflict of interest  to disclose. Alcohol Withdrawal Syndrome is common in ICU patients, and the mainstay of therapy for this syndrome involves augmentation of GABA using various pharmacological agents,  such as benzodiazepines. Phenobarbital, a barbiturate exhibiting both GABA receptor agonism and NMDA receptor antagonism, has been used to manage Alcohol Withdrawal Syndrome  decades ago. It has recently been reintroduced into practice and studied more robustly. Recent data suggests that phenobarbital use has been associated with a decrease in CO-scores  made for ICU admission, ICU, and hospital length of stay. In these studies, the doses of phenobarbital has varied, and despite the long half-life and auto-tapering effects of  phenobarb, some studies have employed the use of loading doses while other studies have  employed the use of a taper. Given the paucity of data on optimal phenobarbital dosing regimen, we sought to compare the effectiveness of two dosing strategies of phenobarbital for  the management of Alcohol Withdrawal Syndrome. Our study was a retrospective cohort study conducted at Beth Israel Deaconess Medical Center from October of 2017 to May of 2019.  The dates chosen here was because initially our hospital had a guideline which recommended the use of a loading dose of phenobarbital followed by a seven-day weight-based tapered  regimen in patients with Alcohol Withdrawal Syndrome. In November of 2018, our hospital guideline was modified to remove that taper. For our study, we included patients who are  18 years or older received phenobarbital for Alcohol Withdrawal Syndrome during our study  period. We excluded patients who did not receive phenobarbital dosing for our hospital protocol  or they received phenobarbital prior to admission, whether it was a home medication or they received  it at an outside hospital. In both of our dosing strategies, a phenobarbital loading dose of 10 milligrams per kilo was recommended. The 10 milligrams per kilo were dosed based  on ideal body weight, but in patients whose actual body weight was less than their ideal  body weight, the actual body weight was used. In the taper group, the loading dose was followed  by a maintenance dose that was weight-based from days two through seven. Patients could receive rescue doses of phenobarbital in 2.5 to 5 milligrams per kilo increments at  any time for a max cumulative dose of 15 milligrams per kilo, including the loading dose. Adjunctive  medications were used when needed for symptomatic management in both of our treatment groups.  For our primary outcome, we wanted to evaluate the proportion of patients requiring adjunctive  medications after receiving the initial phenobarbital loading dose. Secondary outcomes included  the total dose of phenobarbital administered, proportion of patients requiring rescue doses  of phenobarbital, number of adjunctive medication used, as well as their cumulative doses, ICU  and hospital length of stay, and the frequency of clinically significant drug interactions given that phenobarbital is a cytochrome P450 potent inducer.  Of the 136 patients screened, 103 patients were included. The most common reason for exclusion was patients did not receive the full 10 milligram per kilogram loading dose  of phenobarbital. For our baseline characteristics, patients in the no taper group were significantly  older, had higher SEWA scores and higher RASC scores. In terms of our primary outcomes, there was no significant difference noted between the proportion of patients requiring  adjunctive medication in both of our treatment strategies. For our secondary outcomes, the  cumulative dose of phenobarbital was significantly higher in the taper group versus the no taper  group. Given that the use of rescue phenobarb doses were similar between both treatment groups, the higher cumulative dose seen in the taper group was most likely a reflection  of additional phenobarbital received as part of the taper and not necessarily due to poorly  controlled symptoms. Patients in both treatment groups received a median of two adjunctive medications, and it did not differ between any of the medications listed here, with the  exception of hydroxyzine, which was most commonly used in the no taper group than in  the tapered regimen. The reason for this trend is unclear and may have been physician's discretion  during our study period. There was no significant difference noted in our ICU length of stay or our hospital length of stay. When taking a closer look at our taper group, 23 of our  patients in the taper group did not complete the seven day taper. Seven of those patients had documented reason for why the taper was not completed, and the two most common reasons  were altered mental status and clinical stability. No patients who did not complete the taper  were discharged home on orthophenobarbital prescription. We also evaluated the cumulative doses of adjunctive medications per patient from the time the loading dose was given up  until seven days, and there was no significant difference in the doses received between both  of our treatment strategies. Again, with the exception of hydroxyzine, which was most commonly given in the no taper group versus the taper group. When looking at drug interaction,  clinically significant drug interactions were identified in nine patients in the taper group  and eight patients in the no taper group. Of the nine patients that were identified in the taper  group, two patients had it documented in the medical chart, and a change in therapy occurred.  While in all the other patients, it was not documented in the medical chart and no changes occurred. One patient in each of the groups who was receiving phenytoin had subtherapeutic  phenytoin levels when phenobarbital was added. Although our study findings were informative, we did have several limitations. First, our study was a retrospective cohort study  with a small sample size. Our patient population was not matched at baseline, and our CEWA scores were only available for about half of our study population,  and CEWA scores in general are susceptible to inter-rater variability and have not been validated in critically ill patients. Lastly, our primary outcome was an indirect measure of  clinical symptoms such as seizures and delirium tremens, and given that we did look at adjunctive  medications, that could have been compounded by other factors in the ICU. To try to mitigate that  situation, we only reported adjunctive medications used specifically for alcohol withdrawal syndrome if that was documented as the reason for these medications.  In conclusion, there's emerging evidence to support the use of phenobarbital for the treatment of alcohol withdrawal syndrome. Based on our study finding, there was no  significant difference in the percentage of patients requiring adjunctive medication between both of our treatment strategies. The use of phenobarbital 10 mg per kilo loading dose  with up to an additional 5 mg per kilo rescue dose without a taper was effective in controlling  symptoms of alcohol withdrawal syndrome. Given that phenobarbital results in clinically significant drug interactions, tapered regimen may increase the duration of this induction  compared to the use of a single loading dose and can therefore make these drug interactions even more impactful. Thank you so much for listening. Goodbye.  you

Video Summary

The study compared two dosing strategies of phenobarbital for the management of Alcohol Withdrawal Syndrome. The first strategy involved a loading dose followed by a weight-based tapered regimen, while the second strategy used only a loading dose without a taper. The study found that there was no significant difference in the proportion of patients requiring adjunctive medication between the two strategies. However, the cumulative dose of phenobarbital was significantly higher in the taper group. There were also no significant differences in ICU or hospital length of stay. The study suggests that the use of a loading dose without a taper may be effective in controlling symptoms of alcohol withdrawal syndrome without the risk of drug interactions associated with a tapered regimen.

Asset Subtitle

Pharmacology, Behavioral Health and Well Being, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Pansy Elsamadisi

Introduction/Hypothesis: Phenobarbital (PHB) has been studied for the management of alcohol withdrawal syndrome (AWS), but the optimal dosing regimen for AWS is unknown. Given the long half-life of PHB, it auto-tapers, suggesting that a single loading dose of PHB may provide AWS symptom control for several days. The purpose of this study is to compare two different dosing strategies (loading dose only vs. loading dose followed by a 7 day taper) with respect to the need for rescue medications.

Methods: This was a retrospective pre-post analysis performed at a tertiary-care academic medical center to evaluate patients admitted to the intensive care unit (ICU) who received PHB for AWS. Patients who were ordered a loading dose (10 mg/kg) and taper (7 days) were in the PRE group. Following implementation of a hospital protocol, patients who were ordered for only a loading dose consisted of the POST group. Patients in both groups were able to receive rescue PHB up to a total cumulative dose of 15 mg/kg, along with adjunctive medications for AWS. The primary outcome was the proportion of patients requiring adjunctive medications after the initial PHB dose. Secondary outcomes included type of adjunctive medications used, ICU and hospital length of stay (LOS).

Results: A total of 122 patients were included in this study (PRE: n=60; POST: n=62). Patients in the PRE group were significantly older than in those in the POST group (56 vs. 48, p=0.0004). The median cumulative PHB dose in the PRE group was 908 mg (IQR 585-880), compared to 715 mg (IQR 689-1081) in the POST group (p<0.001). There was no difference in the need for rescue adjunctive medications between the PRE and POST groups (55 vs. 61%, p=0.71). There was also no difference in types of adjunctive medications used between the two groups for AWS, except for a significantly higher use of hydroxyzine in the POST group (p=0.006). There were no significant differences in ICU or hospital LOS.

Conclusions: The use of a PHB taper, in addition to a loading dose, did not result in decreased use of adjunctive medications for AWS, compared to a no-taper regimen. The results of this study support the use of only a loading dose of phenobarbital to manage AWS.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Behavioral Health and Well Being

Knowledge Level Advanced

Membership Level Select

Tag Alcohol and Substance Abuse

Year 2021

Keywords

phenobarbital

dosing strategies

Alcohol Withdrawal Syndrome

loading dose

weight-based tapered regimen

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