Administration Of Phenobarbital Research Articles

Decompensated MASH-Cirrhosis Model by Acute and Toxic Effects of Phenobarbital.

Metabolic dysfunction-associated Steatohepatitis (MASH), is a prominent cause for liver cirrhosis. MASH-cirrhosis is responsible for liver complications and there is no specific treatment. To develop new therapeutic approaches, animal models are needed. The aim of this study was to develop a fast animal model of MASH-cirrhosis in rats reflecting the human disease. Carbon tetrachloride (CCl4) injections in combination with a high-fat Western diet (WD) were used to induce MASH-cirrhosis. To accelerate liver injury, animals received phenobarbital (PB) in their drinking water using two different regimens. Rats developed advanced MASH-cirrhosis characterized by portal hypertension, blood biochemistry, hepatic ballooning, steatosis, inflammation and fibrosis. Importantly, rats receiving low-dose PB for the long term (LT) showed ascites after 6 weeks, whereas rats with high-dose short-term (ST) PB developed ascites after 8 weeks. ST- and LT-treated rats showed increased portal pressure (PP) and decreased mean arterial pressure (MAP). Of note, hepatocyte ballooning was only observed in the LT group. The LT administration of low-dose PB with CCl4 intoxication and WD represents a fast and reproducible rat model mimicking decompensated MASH-cirrhosis in humans. Thus, CCl4 + WD with LT low-dose phenobarbital treatment might be the preferred rat animal model for drug development in MASH-cirrhosis.

Safety of Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal in Critically Ill Patients With Primary Neurologic Injuries.

Alcohol withdrawal syndrome (AWS) is a complication of alcohol use disorder that manifests as a range of symptoms. Symptom-triggered benzodiazepines (BZDs) are often used as first-line treatment of AWS. However, recent literature suggests phenobarbital (PHB) may be safer and more efficacious, but studies are limited by exclusion of patients with neurological injuries. We aimed to evaluate the safety of PHB compared to BZDs for the management of AWS among patients with primary neurologic injuries. Retrospective cohort study of patients with primary neurologic injuries admitted to an ICU who received PHB or symptom-triggered BZD for AWS between December 2013 and February 2020. The primary outcome was incidence of oversedation, defined as Richmond Agitation Sedation Scale (RASS) scores from -5 to -3 within 24 hours of initial PHB or BZD dose. Secondary outcomes included largest decrease in RASS, need for mechanical ventilation, and additional sedative use within 24 hours of initial PHB or BZD dose. A multivariable analysis was performed to evaluate the association of PHB administration with the primary outcome. Among 600 patients treated for AWS, 84 patients were included in our analysis (PHB, n = 56; BZD, n = 28). In the unadjusted analysis, there were no differences between the PHB and BZD groups for the primary outcome of oversedation (21.4 vs. 7.1%, P = 0.13), or secondary outcomes of decrease in RASS (P = 0.34), or new ventilator requirement (P = 0.55). Patients who received PHB had higher rates of additional sedative use (P < 0.01). Multivariable regression revealed an increase in oversedation among intubated patients (P = 0.014), while PHB administration was not independently associated with oversedation (P = 0.516). Phenobarbital did not independently increase the risk of oversedation compared to BZD for AWS in patients with primary neurologic injuries. Future studies should determine optimal dosing of PHB in this population.

Load and go: Assessing safety outcomes of patients discharged from the emergency department after receiving phenobarbital for alcohol withdrawal.

Phenobarbital (PB) is a long-acting GABA A-agonist with favorable pharmacokinetics (long half-life and duration of effect) that allows effective treatment of alcohol withdrawal (AW) after administration of a single loading dose. Current evidence suggests that in the setting of AW, PB administration may be associated with decreased hospital admissions and hospital length of stay. The aim of this study was to evaluate the safety outcomes of AW patients who were treated and discharged from the emergency department (ED) after receiving PB for AW. This retrospective chart review included a convenience sample of 33 AW patients who presented to four EDs within an 18-month span. Descriptive statistics (frequencies and percentages) were used to describe demographics, distribution of resources and referrals, and the safety outcomes of PB administration for low-risk AW patients. Patients were selected for inclusion in consultation with a medical toxicologist, treated with PB, and discharged from the ED. Electronic medical records were utilized to gather information on the patient cohort. All patients were treated with at least a single loading dose of 5‒10mg/kg (ideal body weight) of intravenous or per os PB during their ED stay. Only one patient had an unanticipated event after discharge, which was related to driving against advice. Two additional patients had ED revisits for recurrent alcohol use within 72h, and 16 patients had recurrent alcohol use within 30 days. All 33 patients were provided with resources for linkage to treatment. None required hospital admission. ED PB "load and go" may be a safe, effective AW treatment that could help treat AW, facilitate linkage to specific rehabilitation treatments, and decrease hospital admissions.

Phenobarbital Dosing for the Treatment of Alcohol Withdrawal Syndrome: A Review of the Literature.

Objective: To determine the most appropriate phenobarbital dosing regimen by evaluating the safety and efficacy of the drug when specifically used in alcohol withdrawal syndrome (AWS). Data sources: A comprehensive literary search was conducted using PubMed and bibliographic mining in October 2023. Study selection and data extraction: An established monotherapy phenobarbital regimen needed to be established within the article to be included in analysis. Location of implementation was not a deterrent to evaluation, nor was the route of phenobarbital administration. Data synthesis: Six publications were evaluated in this review, and two main phenobarbital dosing regimens emerged. While fix-based dosing strategies and weight-based dosing strategies resulted, the dosing within the regimens resulted in the same or relatively similar doses employed, respectively. Each of the studies had a statistically significant decrease in their primary outcome being studied, and the use of phenobarbital as monotherapy was proven to improve AWS symptoms, significantly decrease intensive care unit and hospital length of stay, decrease the use of adjunctive medications, decrease the use of a ventilator, and prevent seizures. Conclusions: Despite benzodiazepines having been the clinical first-line therapy for AWS, research shows that the pharmacokinetic stability and clinical benefits of phenobarbital are in support creation of phenobarbital protocols, as monotherapy, in hospitals or institutions for patients with AWS.

Analysis of Adverse Events Following Phenobarbital Administration for Pediatric Patients Categorized by One-Year Age Increments Using the U.S. Food and Drug Administration Adverse Event Reporting System.

Background Organ and body development greatly varies in pediatric patients from year to year. Therefore, the incidence of each adverse event following phenobarbital (PB) administration would vary with age. However, in clinical trials, increasing the sample size of pediatric patients in each age group has been challenging. Therefore, previous studies were conducted by dividing pediatric patients into three or four age groups based on the development stage. Although these results were useful in clinical settings, information on adverse events that occurred at one-year age increments in pediatric patients could further enhance treatment and care. Objectives This study investigated in one-year age increments the occurrence tendency of each adverse event following PB administration in pediatric patients. Methods This study used data obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Two inclusion criteria were set: (1) treatment with PB between January 2004 and June 2023 and (2) age 0-15 years. Using the cutoff value obtained using the Wilcoxon-Mann-Whitney test by the minimum p-value approach, this study explored changes in the occurrence tendency of each adverse event in one-year age increments. At the minimum p-value of <0.05, the age corresponding to this p-value was determined as the cutoff value. Conversely, at the minimum p-value of ≥0.05, the cutoff value was considered nonexistent. Results This study investigated all types of adverse events and explored the cutoff value for each adverse event. We identified 34, 16, 15, nine, five, five, eight, three, and eight types of adverse events for the cutoff values of ≤3/>3, ≤4/>4, ≤5/>5, ≤6/>6, ≤7/>7, ≤8/>8, ≤9/>9, ≤10/>10, and ≤11/>11 years, respectively. Conclusions This study demonstrated that adverse events requiring attention in pediatric patients varied with age. The findings help in the improvement of treatment and care in the pediatric clinical settings.

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 μg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Pentylenetetrazole Induced Kindling Model of Refractory Epilepsy: A Proof-of-concept Study to Explore Dose and Time Range of Phenobarbital in Rats.

Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods. Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed. The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14. The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.

Once-a-day oral treatment with phenobarbital in cats with presumptive idiopathic epilepsy.

Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in decreased quality of life for both cat and owner. The aim of this retrospective study was to evaluate treatment with oral PB q24h in cats with presumptive idiopathic epilepsy. Nine cats with presumptive idiopathic epilepsy, receiving oral PB q24h, were included in a retrospective descriptive study. Seizure remission was achieved in 88% (8/9) of the cats and good seizure control in 12% (1/9) of the cats, treated with a mean dose of oral PB of 2.6 mg/kg q24h (range 1.4-3.8 mg/kg). No cats required an increase of their PB frequency at any time during a mean follow-up period of 3.5 years (range 1.1-8.0 years). No cats displayed side effects or issues with compliance at the last recorded follow-up. Once-a-day administration of PB for feline epilepsy was safe and resulted in satisfactory seizure control for the nine cats included in this study. The results of this study justify exploring this topic further in larger prospective studies.

Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress.

We investigated the role of endoplasmic reticulum (ER)-phagy in NAFLD-related hepatocarcinogenesis in high-fat diet (HFD)-fed and/or phenobarbital (PB)-treated rats by clustering the expression levels of the selective autophagy receptor p62 and the ER-phagy-specific receptor FAM134B in preneoplastic hepatic lesions. We obtained four clusters with variable expression levels of p62 and FAM134B in preneoplastic lesions, and a variable population of clusters in each group. PB administration increased the clusters with high expression levels of p62 while HFD feeding increased the clusters with high expression levels of both p62 and FAM134B. The areas of preneoplastic lesions of these clusters were significantly increased than those of other clusters with low expression levels of p62 and FAM134B. The combination of HFD feeding with PB counteracted the effects of each other, and the cluster composition was similar to that in the control group. The results were associated with decreased gene expression of ER stress, inflammatory cytokine, autophagy, and increased expression of antioxidant enzyme. The present study demonstrated that clustering analysis is useful for understanding the role of autophagy in each preneoplastic lesion, and that HFD feeding increased preneoplastic lesions through the inhibition of ER-phagy, which was cancelled with PB administration through the induction of ER-phagy.

Evaluation of Dexmedetomidine as an Adjunct to Phenobarbital for Alcohol Withdrawal in Critically Ill Patients.

Dexmedetomidine (DEX) is commonly used with benzodiazepines for the management of alcohol withdrawal syndrome (AWS), but limited data exist regarding its use with phenobarbital (PHB). This analysis evaluated the utility of DEX in addition to PHB for AWS in adult patients admitted to the intensive care unit (ICU). This was a single-center, retrospective cohort analysis of critically ill adult patients who received PHB plus either DEX or different adjunctive therapies (NO-DEX) for AWS between 2018 and 2021. Patients were excluded if they had underlying altered mental status or seizure disorder unrelated to AWS or received PHB at outside hospitals. Coarsened exact matching (CEM) was performed to match patients on baseline characteristics in a 1:1 ratio. The primary outcome was ICU length of stay (LOS). A multivariate linear regression analysis was performed to assess the effects of DEX on ICU LOS when accounting for confounders. Secondary outcomes included days with delirium and incidence of mechanical ventilation after PHB administration. Of the 606 encounters evaluated, 197 met criteria for inclusion. After CEM, 56 encounters remained in each group for analysis. The median ICU LOS was 97.2 [50.1:139.5] hours for the DEX group and 47.5 [28.8:88.1] hours for the NO-DEX group (P = .002). The multivariate linear regression analysis showed the use of DEX (P = .008) was independently associated with an increased ICU LOS by 49.8 h. The DEX group had higher rates of total delirium days (208 vs 143 days, P < .001) and a higher incidence of mechanical ventilation after PHB administration (32% vs 9%, P < .001). This analysis suggests the use of adjunctive DEX with PHB for AWS was associated with a prolonged ICU LOS. Additional studies are needed to further understand the role of adjunctive DEX in the treatment of AWS in critically ill patients.

787: STANDARDIZING PHENOBARBITAL USE IN ALCOHOL WITHDRAWAL SYNDROME FOR A MULTIHOSPITAL SYSTEM

Introduction: Phenobarbital (PHB) use in the treatment of alcohol withdrawal syndrome (AWS) has become common in clinical practice despite the lack of dosing standardization and when to initiate PHB. Recently, clinical trials have evaluated PHB as a safe and effective alternative to benzodiazepines (BZD). The ASAM Guidelines on Alcohol Withdrawal Management recommend the use of PHB only by clinicians experienced in its use and where extensive monitoring may occur. PHB is listed as an alternative to BZDs for severe AWS, but otherwise is only recommended in patients with a contraindication to BZDs. The objective of this project is to assess PHB use to determine a standardized dosing recommendation for patients experiencing AWS, leading to an improved understanding of PHB resulting in improved outcomes. Methods: This retrospective, multicenter, observational cohort included patients ≥18 years of age admitted to 16 AAH hospitals in WI and IL between June 4, 2021 to August 30, 2021 who received PHB for the treatment of AWS. Clinical data was extracted from the electronic medical record by chart review including comorbid conditions, PHB form and dose, CIWA scores before and 24 hours after PHB administration, and total concomitant BZD use. The primary outcome was improvement in median CIWA score after PHB administration while secondary outcomes included admission to the ICU, intubation, and death. Results: 100 patients were included. Improvement in median CIWA score after PHB occurred in both moderate and severe initial CIWA scores. Median severe initial CIWA scores decreased from 23 to 7 about 24 hours after PHB and median moderate initial CIWA scores decreased from 12 to 4 about 24 hours after PHB. Looking at where PHB orders were placed, 56 orders were in the ICU, 15 orders were in the ED, and the remaining placed on a general medicine floor. Prior to PHB, 18 patients were intubated with only 3 patients needing intubation after PHB. Only 4 patients who received PHB died with 2 related to a cancer diagnosis and the remaining 2 unrelated to AWS. Conclusions: The project concluded there was a decrease in CIWA scores after PHB in both moderate and severe AWS with the largest reduction in CIWA scores seen in patients with severe AWS. Earlier phenobarbital was associated with lower BZD use.

1146: EARLY VERSUS LATE ADMINISTRATION OF PHENOBARBITAL IN ACUTE ALCOHOL WITHDRAWAL

Introduction: Alcohol withdrawal syndrome (AWS) is the leading cause of mortality in patients with alcohol use disorder due to complications like seizures and delirium tremens. The current standard of care for management is Clinical Institute Withdrawal Assessment (CIWA)-guided benzodiazepine administration. Phenobarbital in addition to a CIWA protocol is shown to be a safe adjuvant in patients with AWS but optimal timing has not been established. The purpose of this study is to evaluate the effects of early vs. late vs. no administration of phenobarbital for the management of AWS. Methods: A retrospective chart review of adult patients in the emergency department (ED) for AWS who received a benzodiazepine or phenobarbital. Exclusion criteria included: pregnancy, study drug use for an indication other than AWS, left against medical advice/discharged within 48 hours, and primary seizure disorder. Study groups were as follows: early (phenobarbital before receiving >30mg of lorazepam equivalents), late (phenobarbital after receiving >30mg of lorazepam equivalents), and none. The primary outcome was cumulative dose of benzodiazepine per day. Secondary outcomes included ICU admissions, reduction of CIWA score from baseline, need for adjuvant agents, and safety outcomes. Results: Seventy-five patients were included in this study (29 early group, 20 late group, 26 none group). Early phenobarbital patients received less benzodiazepines compared to the late and none groups (11.88 mg vs. 36.21 mg vs. 21.29 mg). Average change from baseline CIWA was greater in the early group than in the late and none groups (12.94 vs. 7.89 vs. 5.25). Early phenobarbital compared to late resulted in lower ICU admissions (67.7% vs. 88.0%) and less need for adjuvant therapy (34.3% vs. 64%). More intubations were seen in the early and late groups compared to the no phenobarbital group, but all intubations were due to severe AWS requiring continuous sedation. Conclusions: Phenobarbital led to decreased benzodiazepine requirements, greater change from baseline CIWA score, and less need for adjuvant therapy without an increased risk of adverse effects. Early phenobarbital administration was associated with decreased benzodiazepine requirements, greater change from baseline CIWA score, less ICU admissions, and less need for adjuvant therapy.

Human targeted phenobarbital presents a poor substrate of gut microbiome deciphering new drug targets beyond pharmacokinetic curbs

BackgroundThe gut microbiome, a new organ of the body, can potentially alter the pharmacokinetics of orally administered drugs through microbial enzymes. However, absorption of orally administered non-antibiotic drugs by the gut microbiome, during drug-microbiome interaction, is barely addressed. Structural homology studies confirm similar membrane transport proteins in gut epithelial cells and the gut microbiome of the host that may compete for drug substrates with the host itself for its absorbance. Therefore, it is hypothesized that orally administered human targeted phenobarbital may interact and/or be uptake by the gut microbiome during its transit through the small intestine.MethodsIn the current in vivo study, thirty-six male Wistar albino rats were divided into six groups including one control and 5 treatment groups, each having an equal number of rats (n = 6). Phenobarbital was administered orally (single dose of 15 mg/kg bw) to treatment groups. Animals were subsequently sacrificed to harvest microbial mass pallets residing in the small intestine after 2, 3, 4, 5, and 6 h of phenobarbital administration. Phenobarbital absorbance by the microbiome in the microbial lysate was estimated through RP-HPLC–UV at a wavelength of 207 nm.ResultsMaximum phenobarbital absorbance (149.0 ± 5.93 µg) and drug absorbance per milligram of microbial mass (1.19 ± 0.05 µg) were found significantly higher at 4 h of post-administration in comparison to other groups. Percent dose recovery of phenobarbital was 5.73 ± 0.19% at 4 h while the maximum intestinal transit time was 5 h till the drug was absorbed by the microbes. Such results pronounce the idea of the existence of structural homology between membrane transporters of the gut microbiome and intestinal enterocytes of the host that may competitively absorb orally administered phenobarbital during transit in the small intestine. The docking studies revealed that the phenobarbital is a poor substrate for the gut microbiome.ConclusionGut microbiome may competitively absorb the non-antibiotics such as phenobarbital as novel substrates due to the presence of structurally homologous transporting proteins as in enterocytes. This phenomenon suggests the microbiome as a potential candidate that can significantly alter the pharmacokinetics of drugs.

Phenobarbital and/or benzodiazepines for recurrent alcohol withdrawal: A self-controlled, retrospective cohort study

BackgroundWhile there is ample data supporting the use of barbiturates and benzodiazepines (BZDs) for the treatment of alcohol withdrawal, there is a paucity of information on treating recurrent withdrawal among high healthcare utilizing patients. The purpose of this study was to assess the efficacy and safety of phenobarbital (PB), with or without adjuvant BZDs, for treatment of acute alcohol withdrawal in the emergency department (ED) in patients with high rates of recurrent withdrawal. MethodsThis non-matched, self-controlled, retrospective cohort study evaluated patients seen in the ED of an urban trauma center and safety-net teaching hospital between July 1st, 2018, and July 31st, 2019. Patients treated for alcohol withdrawal were included if they had at least one visit where they received intravenous PB with or without BZDs, then during a separate encounter received BZD only. Each encounter was then assigned to a treatment group based on administration of PB only, BZD only, or the combination of PB and BZD. The primary outcomes were admission to hospital or discharge and return to the ED for any reason within 48 h of disposition. ResultsA total of 137 unique patients were included, with 642 encounters composed of 245 PB only, 293 BZD only, and 104 combination visitations. No significant difference was found between the PB, BZD, or combination treatment groups for rates of admission (36.7%, 38.9%, and 46.1% respectively) or for return within 48 h (17.1%, 15.0%, and 13.5%). There was a significantly longer ED length of stay for the combination group (8.6 h) compared to either the PB or BZD only groups (6.4 and 7.0 h, respectively, p < 0.05) but not between the monotherapy groups. There were significantly higher rates of ICU admission and hypotension when PB and BZDs were used together (8.6% and 15.4%) versus either agent alone (PB 2.9% and 5.7%, BZD 3.8% and 4.5%, p < 0.05). ConclusionAmong patients with multiple visits presenting with alcohol withdrawal, treatment with PB, BZDs, or both did not result in significantly different rates of admission or readmission within 48 h. Receiving a combination of PB and BZDs was associated with significantly longer ED length of stay, more ICU care, and increased incidence of hypotension as compared to either PB or a BZD alone.

Correlation between Level of Serum Transaminases and Duration of Antiepileptic Drugs in Epilepsy Children in Sanglah Hospital

BACKGROUND: Some antiepileptic drugs (AEDs), particularly sodium valproate, phenytoin, phenobarbital, and carbamazepine induce and increase production of hepatic enzymes. The adverse metabolic effects of AEDs treatments have become main concern, however data about evaluation of serum transaminases and duration of AEDs in Indonesia still limited. AIM: The aim of the study was to investigate correlation of AEDs and serum transaminases in children with epilepsy. METHODS: This cross-sectional research was conducted in pediatric neurology outpatient clinic in Sanglah Hospital. The target was children with epilepsy who had taken AEDs for at least 6 months. Data were collected from January 2020 to the number of samples were achieved. The exclusion criteria were concomitant liver disease, taking drugs which induce elevated serum transaminase or alcohol abuse. Data including age, gender, nutritional status, type, and duration of AEDs were obtained from medical record. Correlation was analyzed by Pearson’s or Spearman’s correlation, p &lt; 0.05 was considered significant. RESULTS: Total 148 epileptic children enrolled in this study. Aspartate transaminase (AST) and alanine aminotransferase (ALT) level were highest in the group receiving combination therapy (34.37 ± 24.9 U/L and 35.96 ± 23.3 U/L). There was a significant negative correlation between duration of carbamazepine and AST (r = –0.723, p = 0.0001) and ALT (r = –0.457, p = 0.009), as well as duration of valproic acid with AST and ALT (r = –0.689 and –0.677, p = 0.0001). Duration of phenobarbital administration was positively correlated with AST and ALT (r = 0.546 and 0.425, p = 0.0001). Combination therapy also had positive correlation with AST and ALT (r = 0.815 and 0.781, p = 0.0001, respectively). CONCLUSION: Duration administration of carbamazepine and valproic acid had negative correlation with AST and ALT; however, phenobarbital and combination therapy were positively correlated with AST and ALT.

Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs.

To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. 9 healthy, purpose bred Beagles. A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.

RETROSPECTIVE EVALUATION OF PHENOBARBITAL COMPARED TO STANDARD BENZODIAZEPINE THERAPY FOR ALCOHOL WITHDRAWAL PATIENTS IN THE ICU AT AN ACADEMIC MEDICAL CENTER

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Phenobarbital has long been studied in the setting of acute Alcohol Withdrawal Syndrome (AWS), yet data is lacking for practical protocol utilization in hospitals. The purpose of this study was to determine if the use of phenobarbital decreases benzodiazepine requirement in alcohol withdrawal patients requiring ICU care. We evaluated patients ages 19 and older with AWS who were admitted to the ICU with CIWA scores over 20. Patients who received phenobarbital with benzodiazepines were compared to those who received benzodiazepines alone. METHODS: This study was approved by the Institutional Review Board. A retrospective chart review was conducted of 134 patients being treated for AWS between June 1, 2017 to October 31, 2020 who received a dose of phenobarbital with benzodiazepines (n = 69) or benzodiazepines alone (n = 65) for AWS. The primary outcome assessed is benzodiazepine utilization, measured as benzodiazepine equivalents by converting non-lorazepam doses to an equal dose of lorazepam. Secondary outcomes included hospital length of stay (LOS), ICU LOS, CIWA scores, use of ventilator, delirium (CAM-ICU days), and hours on dexmedetomidine. RESULTS: There was no statistically significant difference in benzodiazepine equivalents in the phenobarbital group vs the benzodiazepine group (64.1 vs. 62.5, p = 0.365 in Spearman’s Correlation and 0.379 in Mann Whitney U Test). Statistical significance was found in hospital LOS (10.0 days vs 14.4 days, p = 0.012) and positive CAM-ICU days (1.6 days vs. 3.0 days, p = 0.005) in favor of the phenobarbital group. The study population was mostly male (85.5% in phenobarbital group and 84.6% in control group). Baseline characteristics were not significant between the two groups with the exception of age. Patients who received phenobarbital were younger in median age (47 years vs. 61 years; p < 0.05). When controlled for age, hospital LOS was no longer statistically significant. Differences in favor of the phenobarbital group were found in ICU LOS (7.3 days vs 8.0 days), time on dexmedetomidine (42.0 days vs. 45.5 days), and need for mechanical ventilation (13% vs. 21.5%), however these differences were not statistically significant. Average CIWA scores were higher in the phenobarbital group compared to the control group (16.4 vs 15.6), however this also did not meet statistical significance. CONCLUSIONS: The present retrospective analysis suggests that phenobarbital administration does not decrease the utilization of benzodiazepines in AWS. However, a significant decrease in delirium was shown in the phenobarbital group. Given the evidence that favorable outcomes are shown and safety outcomes are similar, phenobarbital should be explored further for incorporation into institutions' standard AWS protocol. CLINICAL IMPLICATIONS: A quality improvement project with a goal of incorporating phenobarbital use early in AWS hospital stay should be considered. DISCLOSURES: No relevant relationships by Jared Alberts, source=Web Response No relevant relationships by Carolina Landeen, source=Web Response No relevant relationships by Mark Malesker, source=Web Response No relevant relationships by Robert Plambeck, source=Web Response No relevant relationships by Yongyue Qi, source=Web Response No relevant relationships by Cassandra Walters, source=Web Response

SEVERE LACTIC ACIDOSIS SECONDARY TO ACUTE ALCOHOL INTOXICATION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. Alcoholic ketoacidosis is one of the several etiologies where serum lactate level rarely exceeds 3 mmol/L. We present to you an interesting case of severe lactic acidosis (24 mmol/L) in a patient with acute alcohol intoxication. CASE PRESENTATION: Patient is a 62-year male who presented with intractable abdominal pain for 2 days. Past medical history was significant for alcohol use disorder. On presentation, patient had tachycardia, tachypnea, was restless with slurred speech with mild abdominal tenderness. Laboratory findings were remarkable for leukocytosis of 22.7, serum bicarbonate of 4 mmol/L, serum glucose 104 mg/dL, serum lactate 24 mmol/L. ABG showed pH of < 7.00, pCO2 12 mmHg, HC03 4.6 mmol/L. Anion gap was 41.0. Serum ethanol level was elevated at 0.185 g/dl. Patient was started on bicarbonate infusion, IV thiamine with 5% dextrose fluid and CIWA protocol. Serum beta hydroxybutyrate was elevated at 2.9, serum osmolality was elevated at 344 with osmolar gap of 13. LFT was deranged with unremarkable liver ultrasound. Patient was admitted to the ICU. Serum isopropanol, methanol, and ethylene glycol were negative. Infectious workup including blood culture, urine culture, pneumonia workup were negative. Acetaminophen and salicylate levels were normal. Urine drug screen was unremarkable. No history of GI malabsorption (short-bowel syndrome), renal failure or recent phenobarbital administration. Lactic acidosis was therefore attributed to alcoholic ketoacidosis in a setting of alcoholic hepatitis. Patient gradually improved with final pH 7.38, lactate 1.80 and serum HC03 24.6 by day 2. DISCUSSION: Lactate level of > 4 mmol/L with arterial pH < 7.35 suggests lactic acidosis. Lactic acidosis is broadly classified into type A which occurs due to impaired systemic tissue oxygenation and type B due to toxin induced cellular metabolism impairment and regional ischemia, commonly in alcoholism, HIV, antiretroviral medications, beta adrenergic medications, D lactic acidosis (short-bowel syndrome), diabetes mellitus, metformin, malignancy. Alcoholic ketoacidosis remains important etiology as if missed may result in fatal consequences including sudden death. Occasionally, alcoholic ketoacidosis can be misdiagnosed as diabetic ketoacidosis with subsequent mismanagement resulting in increased morbidity and mortality. CONCLUSIONS: Alcoholic ketoacidosis typically presents with metabolic acidosis but rarely with lactate > 3mmol/L in absence of other contributing factors. Oftentimes, the diagnosis is missed or misdiagnosed as diabetic ketoacidosis resulting in mismanagement contributing to increased morbidity and mortality. REFERENCE #1: Adeva-Andany, M., et al. 'Comprehensive Review on Lactate Metabolism in Human Health'. Mitochondrion, vol. 17, July 2014, pp. 76–100. PubMed, doi:10.1016/j.mito.2014.05.007. REFERENCE #2: Kreisberg, R. A. 'Lactate Homeostasis and Lactic Acidosis'. Annals of Internal Medicine, vol. 92, no. 2 Pt 1, Feb. 1980, pp. 227–37. PubMed, doi:10.7326/0003-4819-92-2-227 REFERENCE #3: Madias, N. E. 'Lactic Acidosis'. Kidney International, vol. 29, no. 3, Mar. 1986, pp. 752–74. PubMed, doi:10.1038/ki.1986.62 DISCLOSURES: No relevant relationships by Luna Khanal, source=Web Response No relevant relationships by Adarsha Ojha, source=Web Response

Assessment of Phenobarbital Administration to Reduce Opioid and Benzodiazepine Use in the Immediate Postoperative Period Following Stage 2 Single-Ventricle Palliation

OBJECTIVE The Glenn procedure may lead to the development of elevated cerebral venous pressures, which is believed to result in “Glenn headaches.” This manifests as excessive irritability, often requiring significant use of opioids and benzodiazepines. This study was designed to report our experience with the use of phenobarbital in the postoperative phase after the Glenn procedure. METHODS We performed a retrospective chart review to compare Glenn patients before and after implementation of a sedation protocol using phenobarbital. The 2 groups were compared for demographics, surgical characteristics, and cumulative sedation usage. Correlation coefficients between the preoperative catheterization variables and sedation usage were also calculated. RESULTS Groups A (pre-phenobarbital; n = 8) and B (post-phenobarbital; n = 11) were comparable in terms of demographics, cardiac anatomy, preoperative catheterization data, and hemodynamics. Patients in Group B received a median dose of 21.8 mg/kg of phenobarbital during their ICU stay. Although there was a decreased administration of morphine equivalents (2.60 mg/kg vs 2.25 mg/kg, p = 0.38), benzodiazepine (0.1 mg/kg vs 0.074 mg/kg, p = 0.43), and dexmedetomidine (47 mcg/kg vs 37.2 mcg/kg, p = 0.53) in Group B, the differences were not statistically significant. There was also no strong correlation between preoperative hemodynamic variables and the postoperative sedation requirement, and there was no statistically significant difference in overall outcomes between the 2 groups. CONCLUSIONS While phenobarbital may have mitigated the use of opioids, benzodiazepines, and alpha-agonist agents in some postoperative Glenn patients, the overall findings for all patients were not statistically significant. Further prospective studies are needed to ascertain the role of phenobarbital in these patients.

Evaluation of the effect of phenobarbital administration on the biochemistry profile, with a focus on serum liver values, in epileptic cats.

Phenobarbital (PB) is the most common antiseizure drug (ASD) used for the management of feline epilepsy. In dogs, PB is known to cause serum liver enzyme induction and hepatotoxicity, especially after administration long term or in high concentrations. In cats, insufficient evidence is available to draw similar conclusions. The aim of this study was to evaluate the effect of PB administration on the serum biochemistry profile of epileptic cats. As an additional objective, other adverse effects arising, related to PB treatment, were recorded. Medical records of four veterinary centres were retrospectively reviewed for epileptic cats receiving PB treatment. Cats were included if they had a diagnosis of idiopathic epilepsy or structural epilepsy; a normal baseline serum biochemistry profile; at least one follow-up serum biochemistry profile; no concurrent disease or had not received medication that could possibly influence liver function or lead to serum liver enzyme induction. Alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase and gamma-glutamyl transferase activities, and total bilirubin, bile acids, glucose, albumin, total protein, urea and creatinine concentrations before and during PB administration were recorded. PB serum concentration was also recorded, when available. Thirty-three cats (24 males, nine females) with a median age of 3 years (range 2 months to 12 years) met the inclusion criteria. Idiopathic or structural epilepsy was diagnosed in 25 (76%) and eight (24%) cats, respectively. The follow-up period ranged from 9 to 62 months. This study found an increase in ALT in three cats, possibly related to a PB serum concentration >30 µg/ml. No statistically significant increase in serum liver enzymes or other evaluated biochemistry parameters was found by comparing pre- and post-treatment parameters. PB administration did not result in hepatic enzyme induction or other biochemical abnormalities in cats. This strengthens the safety profile of PB as an ASD in cats.