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Pediatrics Jun 2020There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.
METHODS
The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists.
RESULTS
Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam ( < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant).
CONCLUSIONS
In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.
Topics: Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy, Benign Neonatal; Female; Humans; Infant, Newborn; Levetiracetam; Male; Phenobarbital; Seizures
PubMed: 32385134
DOI: 10.1542/peds.2019-3182 -
Psychosomatics 2019Benzodiazepine-based protocols offer a standard of care for management of alcohol withdrawal, though they may not be safe or appropriate for all patients. Phenobarbital,... (Comparative Study)
Comparative Study
Use of Phenobarbital in Alcohol Withdrawal Management - A Retrospective Comparison Study of Phenobarbital and Benzodiazepines for Acute Alcohol Withdrawal Management in General Medical Patients.
BACKGROUND
Benzodiazepine-based protocols offer a standard of care for management of alcohol withdrawal, though they may not be safe or appropriate for all patients. Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment, though existing research offers only modest guidance to the safety and effectiveness of phenobarbital in managing alcohol withdrawal syndrome (AWS) in general hospital settings.
METHODS
To compare clinical effectiveness of phenobarbital versus benzodiazepines in managing symptoms of alcohol withdrawal, we conducted a retrospective chart review of 562 patients admitted over a 2-year period to a general hospital and treated for AWS. The development of AWS-related complications (seizures, alcoholic hallucinosis, and alcohol withdrawal delirium) post-treatment initiation was the primary outcome examined in both treatment groups. Additional outcomes measured included hospital length of stay, intensive care unit (ICU) admission rates/length of stay, medication-related adverse events, and discharge against medical advice.
RESULTS
Despite being significantly more likely to have a history of prior complications related to AWS (including seizures and delirium), patients initiated on phenobarbital (n = 143) had overall similar primary and secondary treatment outcomes to those in the benzodiazepine treatment protocol (n = 419). Additionally, a subset of patients (n = 16) initially treated with benzodiazepines displayed signs of treatment nonresponse, including significantly higher rates of AWS-related delirium and ICU admission rates, but were well-managed following transition to the phenobarbital protocol.
CONCLUSION
The data from this retrospective chart review lend further support to effectiveness and safety of phenobarbital for the treatment and management of AWS. Further randomized controlled trials are warranted.
Topics: Acute Disease; Alcohol Withdrawal Delirium; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Length of Stay; Male; Middle Aged; Phenobarbital; Retrospective Studies; Treatment Outcome
PubMed: 30876654
DOI: 10.1016/j.psym.2019.02.002 -
Pharmacotherapy Jul 2016Approximately 16-31% of patients in the intensive care unit (ICU) have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (AWS). Patients... (Review)
Review
Approximately 16-31% of patients in the intensive care unit (ICU) have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (AWS). Patients admitted to the ICU with AWS have an increased hospital and ICU length of stay, longer duration of mechanical ventilation, higher costs, and increased mortality compared with those admitted without an alcohol-related disorder. Despite the high prevalence of AWS among ICU patients, no guidelines for the recognition or management of AWS or delirium tremens in the critically ill currently exist, leading to tremendous variability in clinical practice. Goals of care should include immediate management of dehydration, nutritional deficits, and electrolyte derangements; relief of withdrawal symptoms; prevention of progression of symptoms; and treatment of comorbid illnesses. Symptom-triggered treatment of AWS with γ-aminobutyric acid receptor agonists is the cornerstone of therapy. Benzodiazepines (BZDs) are most studied and are often the preferred first-line agents due to their efficacy and safety profile. However, controversy still exists as to who should receive treatment, how to administer BZDs, and which BZD to use. Although most patients with AWS respond to usual doses of BZDs, ICU clinicians are challenged with managing BZD-resistant patients. Recent literature has shown that using an early multimodal approach to managing BZD-resistant patients appears beneficial in rapidly improving symptoms. This review highlights the results of recent promising studies published between 2011 and 2015 evaluating adjunctive therapies for BZD-resistant alcohol withdrawal such as antiepileptics, baclofen, dexmedetomidine, ethanol, ketamine, phenobarbital, propofol, and ketamine. We provide guidance on the places in therapy for select agents for management of critically ill patients in the presence of AWS.
Topics: Baclofen; Benzodiazepines; Critical Illness; Dexmedetomidine; Ethanol; Humans; Length of Stay; Phenobarbital; Substance Withdrawal Syndrome
PubMed: 27196747
DOI: 10.1002/phar.1770 -
Current Pediatric Reviews 2016Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on... (Review)
Review
Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on GABAA. The loading dose of phenobarbital is 20 mg/kg intravenously and the maintenance dose is 3 to 4 mg/kg by mouth. The serum concentration of phenobarbital is up to 40 µg/ml. Nonresponders should receive additional doses of 5 to 10 mg/kg until seizures stop. Infants with refractory seizures may have a serum concentration of phenobarbital of 100 µg/ml. Phenobarbital is metabolized in the liver by CYP2C9 with minor metabolism by CYP2C19 and CYP2E1. A quarter of the dose of phenobarbital is excreted unchanged in the urine. In adults, the half-life of phenobarbital is 100 hours and in term and preterm infants is 103 and 141 hours, respectively. The half-life of phenobarbital decreases 4.6 hours per day and it is 67 hours in infants 4 week old.
Topics: Anticonvulsants; Dose-Response Relationship, Drug; Female; Humans; Infant, Newborn; Male; Pharmacology, Clinical; Phenobarbital; Seizures
PubMed: 26496779
DOI: 10.2174/1573397111666151026223914 -
American Journal of Critical Care : An... Nov 2018Benzodiazepine-based therapy for alcohol withdrawal is associated with agitation and respiratory depression. Treatment can be complicated by a need for adjunctive...
BACKGROUND
Benzodiazepine-based therapy for alcohol withdrawal is associated with agitation and respiratory depression. Treatment can be complicated by a need for adjunctive therapy to control these symptoms and in patients requiring mechanical ventilation. Strong evidence for the effectiveness of alternative treatment modalities is lacking, despite the availability of promising pharmacological agents such as phenobarbital.
OBJECTIVE
To compare the standard of care for the treatment of alcohol withdrawal-a symptom-triggered benzodiazepine protocol used in conjunction with the revised Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scale-with a phenobarbital protocol.
METHODS
Retrospective cohort study conducted from January 2016 through June 2017 at a 42-bed medical intensive care unit in a private teaching hospital in Nashville, Tennessee. The primary outcome was intensive care unit length of stay. Secondary outcomes included hospital length of stay, incidence of invasive mechanical ventilation, and use of adjunctive pharmacotherapy.
RESULTS
Patients who received phenobarbital had significantly shorter stays in the intensive care unit than did those who received therapy based on the CIWA-Ar scale (mean [SD], 2.4 [1.5] vs 4.4 [3.9] days; < .001). Those who received phenobarbital also had significantly shorter hospital stays (4.3 [3.4] vs 6.9 [6.6] days; = .004). The incidence of invasive mechanical ventilation was lower in the phenobarbital group (1 [2%] vs 14 [23%] patients; < .001), as was use of adjunctive agents for symptom control, including dexmedetomidine (4 [7%] vs 17 [28%] patients; = .002).
CONCLUSION
A phenobarbital protocol for the treatment of alcohol withdrawal is an effective alternative to the standard-of-care protocol of symptom-triggered benzodiazepine therapy.
Topics: Adult; Aged; Alcohol Withdrawal Delirium; Benzodiazepines; Clinical Protocols; Drug Therapy, Combination; Female; Hospitals, Teaching; Humans; Hypnotics and Sedatives; Intensive Care Units; Length of Stay; Male; Middle Aged; Phenobarbital; Retrospective Studies
PubMed: 30385536
DOI: 10.4037/ajcc2018745 -
Neuropsychopharmacology Reports Dec 2023Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing...
AIM
Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing research offers only modest guidance on the safety and effectiveness of phenobarbital in managing AWS in hospital settings. The study objective was to assess if a phenobarbital protocol for the treatment of AWS reduces respiratory complications when compared to a more traditionally used benzodiazepine protocol.
METHODS
A retrospective cohort study analyzing adults who received either phenobarbital or benzodiazepine-based treatment for AWS over a 4-year period, 2015-2019, in a community teaching hospital in a large academic medical system.
RESULTS
A total of 147 patient encounters were included (76 phenobarbital and 71 benzodiazepine). Phenobarbital was associated with a significantly decreased risk of respiratory complications, defined by the occurrence of intubation (15/76 phenobarbital [20%] vs. 36/71 benzodiazepine [51%]) and decreased incidence of the requirement of six or greater liters of oxygen when compared with benzodiazepines (10/76 [13%] vs. 28/71 [39%]). There was a significantly higher incidence of pneumonia in benzodiazepine patients (15/76 [20%] vs. 33/71 [47%]). Mode Richmond Agitation Sedation Scale (RASS) scores were more frequently at goal (0 to -1) between 9 and 48 h after the loading dose of study medication for phenobarbital patients. Median hospital and ICU length of stay were significantly shorter for phenobarbital patients when compared with benzodiazepine patients (5 vs. 10 days and 2 vs. 4 days, respectively).
CONCLUSION
Parenteral phenobarbital loading doses with an oral phenobarbital tapered protocol for AWS resulted in decreased risk of respiratory complications when compared to standard treatment with benzodiazepines.
Topics: Adult; Humans; Benzodiazepines; Substance Withdrawal Syndrome; Alcoholism; Hypnotics and Sedatives; Retrospective Studies; Phenobarbital
PubMed: 37368937
DOI: 10.1002/npr2.12347 -
Journal of Addiction MedicineXylazine is an alpha-2 adrenergic agonist commonly used as a large animal anesthetic. It is used as an adulterant in illicit opioids, and it is now well established that...
BACKGROUND
Xylazine is an alpha-2 adrenergic agonist commonly used as a large animal anesthetic. It is used as an adulterant in illicit opioids, and it is now well established that its synergistic effect with opioids increases lethality. The amount of xylazine adulterating illicit opioids is growing at an alarming rate, present in almost one-third of opioid overdose deaths reported in Philadelphia in 2019. Despite this, there are no reports considering the management of patients using xylazine chronically. In particular, there are no reported cases detailing the management of xylazine withdrawal or exploring the potential for ongoing treatment for those in recovery from xylazine use.
CASE SUMMARY
We present the case of a 29 year old female with opioid use disorder and chronic xylazine use, admitted to the intensive care unit for treatment of chronic lower extremity wounds thought to be due to xylazine injection. Her xylazine withdrawal was managed with a combination of dexmedetomidine infusion, phenobarbital and tizanidine, later transitioned to clonidine. By hospital day 4 she was no longer experiencing withdrawal symptoms. She was transitioned from full-agonist opioids for pain to buprenorphine via a buprenorphine "micro-induction" and was ultimately discharged on buprenorphine, clonidine, and gabapentin on day 19 of admission.
CLINICAL SIGNIFICANCE
This case illustrates a potential treatment pathway that allows for safe and comfortable xylazine withdrawal in hospitalized patients. It also provides an introduction into several medical concerns affecting this patient population specifically, including xylazine-mediated soft tissue wounds.
Topics: Adrenergic Agonists; Analgesics, Opioid; Animals; Buprenorphine; Clonidine; Dexmedetomidine; Female; Gabapentin; Humans; Opioid-Related Disorders; Phenobarbital; Substance Withdrawal Syndrome; Xylazine
PubMed: 35020700
DOI: 10.1097/ADM.0000000000000955 -
Journal of Medical Toxicology :... Jul 2022Phenobarbital is frequently used to manage severe alcohol withdrawal. The purpose of this study was to compare the incidence of mechanical ventilation in patients with...
INTRODUCTION
Phenobarbital is frequently used to manage severe alcohol withdrawal. The purpose of this study was to compare the incidence of mechanical ventilation in patients with benzodiazepine-resistant alcohol withdrawal between front-loaded and low-intermittent phenobarbital dosing strategies.
METHODS
In this retrospective before-after study, we analyzed patients that received phenobarbital for severe alcohol withdrawal syndrome in a tertiary medical ICU. Patients received low-intermittent phenobarbital doses (260 mg intravenous push × 1 followed by 130 mg intravenous push every 15 min as needed) from January 2013 to July 2015, and front-loaded phenobarbital doses (10 mg/kg intravenous infusion over 30 min) from July 2015 to January 2017.
RESULTS
In total, 87 patients met inclusion criteria for this study: 41 received low-intermittent phenobarbital and 46 received front-loaded phenobarbital). The incidence of mechanical ventilation was 13 (28%) in the front-loaded dosing group vs. 26 (63%) in the low-intermittent dosing group (odds ratio 4.4 [95% CI 1.8-10.9]). The cumulative dose of phenobarbital administered and serum phenobarbital levels were similar between both groups, although the front-loaded group had significantly lower benzodiazepine requirements than the low-intermittent group (median 86 mg [IQR 24-197] vs. 228 mg [115-298], P < 0.01) and reduced need for any continuous sedative infusion (OR 7.7 [95% CI 1.6-27], P < 0.01). There was no difference in respiratory failure or hypotension.
CONCLUSIONS
Front-loaded phenobarbital dosing, when compared to low-intermittent phenobarbital dosing, for benzodiazepine-resistant alcohol withdrawal was associated with significantly lower mechanical ventilation incidence and continuous sedative use.
Topics: Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Ethanol; Humans; Hypnotics and Sedatives; Length of Stay; Phenobarbital; Retrospective Studies; Substance Withdrawal Syndrome
PubMed: 35668289
DOI: 10.1007/s13181-022-00900-8 -
Seizure Nov 2022Multiple interventions have been studied for benzodiazepine-resistant status epilepticus (SE) in children and adults. This review aimed to summarize the available... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Multiple interventions have been studied for benzodiazepine-resistant status epilepticus (SE) in children and adults. This review aimed to summarize the available evidence and provide estimates of comparative effectiveness and ranking of treatment effects.
METHODS
All randomized controlled trials studying patients (>1 month of age) with benzodiazepine-resistant SE were included. Outcomes including seizure cessation within 60 min, seizure freedom for 24 h, death, respiratory depression warranting intubation and cardiovascular instability were studied. Conventional and network meta-analyses (NMA) were done.
RESULTS
Seventeen studies were included (16 in NMA). Phenobarbital and high-dose levetiracetam were significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking demonstrated that phenobarbital had the highest probability of being the best among the studied interventions followed by high-dose levetiracetam and high-dose valproate. Network meta-analysis was limited by predominant indirect evidence and high heterogeneity.On pairwise comparisons, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability. Levetiracetam had a better safety profile than fosphenytoin.
CONCLUSIONS
Based on low quality evidence, phenobarbital appears to be the most effective agent for seizure cessation within 60 min of administration in patients with benzodiazepine resistant status epilepticus. High-dose levetiracetam, high-dose valproate and fosphenytoin are probably equally effective. Choice of medication may be guided by effectiveness, safety concerns, availability, cost and systemic co-morbidities.
Topics: Adult; Child; Humans; Anticonvulsants; Benzodiazepines; Levetiracetam; Network Meta-Analysis; Phenobarbital; Phenytoin; Seizures; Status Epilepticus; Valproic Acid; Drug Resistance; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 36209676
DOI: 10.1016/j.seizure.2022.09.017 -
The Annals of Pharmacotherapy Mar 2021Benzodiazepine is first-line therapy for alcohol withdrawal syndrome (AWS), and phenobarbital is an alternative therapy. However, its use has not been well validated in...
BACKGROUND
Benzodiazepine is first-line therapy for alcohol withdrawal syndrome (AWS), and phenobarbital is an alternative therapy. However, its use has not been well validated in the surgical-trauma patient population.
OBJECTIVE
To describe the use of fixed-dose phenobarbital monotherapy for the management of patients at risk for AWS in the surgical-trauma intensive care unit.
METHODS
Surgical-trauma critically ill patients who received phenobarbital monotherapy, loading dose followed by a taper regimen, for the management of AWS were included in this evaluation. The effectiveness of phenobarbital monotherapy to treat AWS and prevent development of AWS-related complications were evaluated. Safety end points assessed included significant hypotension, bradycardia, respiratory depression, and need for invasive mechanical ventilation.
RESULTS
A total of 31 patients received phenobarbital monotherapy; the majority of patients were at moderate risk for developing AWS (n = 20; 65%) versus high risk (n = 11; 35%). None of the patients developed AWS-related complications; all patients were successfully managed for their AWS. Nine patients (29%) received nonbenzodiazepine adjunct therapy for agitation post-phenobarbital initiation. Three patients (10%) experienced hypotension, and 3 (10%) were intubated. None of the patients had clinically significant bradycardia or respiratory depression.
CONCLUSION AND RELEVANCE
Fixed-dose phenobarbital monotherapy appears to be well tolerated and effective in the management of AWS. Further evaluation is needed to determine the extent of benefit with the use of phenobarbital monotherapy for management of AWS.
Topics: Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Male; Phenobarbital; Retrospective Studies; Substance Withdrawal Syndrome; Wounds and Injuries
PubMed: 32830517
DOI: 10.1177/1060028020949137