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.

Treating Seizures after Hypoxic-Ischemic Encephalopathy—Current Controversies and Future Directions

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

Prospective crossover clinical trial comparing transdermal with oral phenobarbital administration in epileptic cats

Objectives The aim of this study was to compare serum phenobarbital concentrations, adverse events and client satisfaction during 14 weeks of transdermal vs oral phenobarbital administration to epileptic cats. Methods This was a prospective, fixed-order, crossover pilot study. Nine client-owned cats with presumptive or diagnosed idiopathic epilepsy were enrolled. Oral phenobarbital (PO-PB) was administered for weeks 1–14 (median starting dosage of 3.8 mg/kg [2.0–5.4 mg/kg/day] q12h); transdermal phenobarbital (TD-PB) was administered for weeks 14–28 (median starting dosage 18.8 mg/kg/day [17.6–24.0 mg/kg/day] q12h). Serum phenobarbital concentrations (S-PB) were measured at weeks 2, 14, 16 and 28. Client satisfaction questionnaires and biochemistry were evaluated at 14 and 28 weeks. Results Median S-PB concentrations during oral administration were 21 µg/ml (observed range 11–40 µg/ml) at week 2 and 22 µg/ml (8–35 µg/ml) at week 14, and at the higher TD dosage were 18 µg/ml (0–42 µg/ml) at week 16 and 17 µg/ml (7–50 µg/ml) at week 28. Phenobarbital concentrations were significantly correlated with PO dosage at week 2 ( r = 0.75, P = 0.03) but not at weeks 16 and 28. Significantly more dose adjustments were needed during the TD phase ( P = 0.03), but 6/9 owners (67%) still preferred TD to PO administration. Adverse effects were mild and comparable in both groups. Conclusions and relevance Therapeutic S-PB concentrations were achievable in some cats using TD-PB at 18 mg/kg/day q12h. Poor correlation between TD dosage and S-PB concentrations was observed and more dosage adjustments were required during TD administration. These findings necessitate close therapeutic drug monitoring if TD-PB is prescribed.

Suspected phenobarbital-induced fever in a cat

Case summary A 3-year-old spayed female domestic shorthair cat developed a fever 1 week after starting the anticonvulsant phenobarbital. A diagnostic work-up for seizures and subsequent onset of fever of unknown origin, consisting of MRI of the brain, cerebrospinal fluid analysis and infectious disease testing, was unremarkable. The cat was switched from phenobarbital onto pregabalin with complete resolution of the fever within 24 h, consistent with a drug-induced fever following phenobarbital administration. Relevance and novel information While anticonvulsant hypersensitivities have been reported and studied in veterinary medicine, phenobarbital-induced fever outside of the context of systemic clinical signs has not been documented in the veterinary scientific literature. Drug-induced fever secondary to anticonvulsants should be considered in patients that develop a fever after starting anticonvulsant therapy with an unrewarding diagnostic work-up for fever of unknown origin.

Recurrent Admissions for Hypothermia From Concomitant Topiramate and Phenobarbital: A Case Report

Introduction: This article presents an additional case of concomitant topiramate and phenobarbital administration that resulted in 8 hospital admissions for hypothermia that resolved after discontinuation of phenobarbital. Case: A 56-year-old white female with cerebral palsy and quadriplegia, epilepsy, and hypothyroidism was admitted to a community teaching hospital multiple times with documented hypothermia. These admissions followed a subsequent dose increase of topiramate in December 2014. In February 2015, the patient was admitted with 35°C rectal temperature. Her 2 admissions in April were for hypothermia with temperatures of 34.6°C and 33.6°C, respectively. The patient had 5 other admissions with hypothermia through December 2015. All other causes of hypothermia were ruled out. The hypothermia resolved when phenobarbital was discontinued. Discussion: A recent case series noted an association between phenobarbital and topiramate causing hypothermia. The patient’s hypothermia developed while on concomitant phenobarbital and topiramate but only after an increase in topiramate. No other causes for hypothermia were found based upon physical examination or lab work. The Naranjo nomogram noted a probable causation. Conclusion: This case report points to an association of hypothermia with concomitant topiramate and phenobarbital with resolution after phenobarbital discontinuation. Improvement after discontinuation of phenobarbital seems to support a drug-effect relationship.