Serum Phenobarbital Concentrations Research Articles

A retrospective evaluation of phenobarbital-induced hematologic changes in 69 cats.

Phenobarbital (PB) is used as a first-line treatment for recurrent epileptic seizures in cats. While hematologic abnormalities are well-known side effects of antiepileptic therapy with PB in humans and dogs, little is known about such alterations in cats. The aim of this retrospective study was to investigate the prevalence and clinical relevance of cytopenia during PB treatment in cats. In this single-center, retrospective clinical study, 69 cats-with suspected idiopathic epilepsy admitted to the Small Animal Clinic of the University of Veterinary Medicine in Vienna (VMU)-were included. A complete blood count for each patient was performed, and changes in hematocrit, leukocytes, neutrophils, and thrombocytes were documented and graded. Fifty-three out of 69 cats (76.8%) showed cytopenias with a reduction of at least one cell fraction during PB treatment. The most frequent change was neutropenia (60%), followed by leukopenia (49.3%), thrombocytopenia (24.1%), and anemia (20.3%). Most of the changes were mild or moderate; only one patient (1.5%) showed severe leukopenia and neutropenia, and one was a life-threatening neutropenia (1.5%) with a serum PB concentration within or even below the therapeutic range. These patients did not present with clinical symptoms other than those related to epileptic episodes. Cats who received combination therapy showed lower hematocrits than those who received monotherapy. A tendency for leukocytes and neutrophils to decrease during PB treatment was also seen. Blood cytopenias may frequently occur in cats on chronic PB therapy, even when serum drug levels are within the therapeutic range. However, clinical signs are typically mild to moderate and rarely severe.

Does switching brands matter? Complications associated with switching between phenobarbital brands in two dogs with idiopathic epilepsy

AbstractSwitching between brands of the same antiseizure medication has been associated with a loss of epileptic seizure control in people. No such reports are available in the veterinary literature. Here, we describe two cases in which client‐owned dogs with idiopathic epilepsy experienced complications following phenobarbital brand switch, despite no change in the administered dosage. Both dogs had been on treatment with oral phenobarbital for at least 23 months without complications. Following brand switching, one dog became markedly sedated, ataxic and anorexic, and the other dog experienced severe cluster seizures. The measured serum phenobarbital concentrations were significantly altered from the previously measured pre‐brand switching concentrations. Echoing what has been described in human medicine, these cases suggest that therapeutic complications can occur when switching phenobarbital brand in chronically treated dogs with idiopathic epilepsy. Such complications should be considered when modulating antiseizure treatment in dogs. The exact cause for the resulting complications is unclear.

Telmisartan as an add-on treatment for dogs with refractory idiopathic epilepsy: a nonrandomized, uncontrolled, open-label clinical trial.

To evaluate the effect on seizure frequency of add-on telmisartan treatment in dogs with refractory idiopathic epilepsy. 11 client-owned dogs with idiopathic epilepsy and ≥ 2 generalized seizures/mon that were currently being treated with ≥ 2 antiepileptic drugs. Telmisartan was administered at a dosage of 0.25 to 1 mg/kg, PO, every 12 hours for 4 to 16 months. Seizure frequencies before and during telmisartan treatment were recorded. 10 dogs completed the 4-month treatment protocol. One dog was excluded owing to a transient increase in serum creatinine concentration; no adverse effects of telmisartan were observed in the remaining 10 dogs. A reduction in seizure frequency greater than an estimated expected placebo effect of 30% was evident in 7 of the 10 dogs. Long-term (12 to 16 months) follow-up information was available for 6 dogs, of which 4 had a further reduction in seizure frequency. Differences in seizure frequency were not statistically significant. No significant difference was found in serum phenobarbital concentration throughout the treatment period in the 7 dogs that were tested. Telmisartan has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy. A randomized, double-blind, placebo-controlled trial is needed to determine the true efficacy of telmisartan. On the basis of our results, a sample size of 54 dogs with refractory idiopathic epilepsy would be needed.

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

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.

Serum NMR metabolomics uncovers multiple metabolic changes in phenobarbital-treated dogs

IntroductionPhenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized.ObjectivesTo identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels.MethodsLeftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific 1H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression.ResultsIncreasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value < .0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed.ConclusionThe identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.

Factors affecting serum phenobarbital concentration changes in pediatric patients receiving elixir and powder formulations

BackgroundPhenobarbital (PB) is commonly used as elixir and powder formulations in pediatric care. Its dose adjustment is performed based on individual drug concentration monitoring. Few studies have comprehensively analyzed the variation factors for serum PB concentration. In this study, we retrospectively investigated the factors that influence serum PB concentration and assessed the impacts of dosage formulation and administration route.MethodsThis retrospective cohort study covered clinical data from January 2007 to September 2019 at Mie University Hospital. The present study included 60 pediatric patients administered the elixir and powder of PB through oral route and enteral tube. Simple and multiple linear regression analyses were performed to identify the risk factors that affect the weight-corrected PB serum concentration/dose (C/D) ratio in pediatric patients. Six subgroups were also established according to the concomitant use of drugs that potentially inhibit PB metabolism, dosage formulation, and administration route to investigate the difference in the PB C/D ratio among the subgroups.ResultsA significant regression equation to predict the PB C/D ratio was found through simple and multiple linear regression analyses, with an adjusted coefficient of determination of 0.53 (p < 0.001). Further, the concomitant uses of valproic acid (VPA) or amiodarone, which were the only two drugs seen in this study as potential inhibitors of PB, was found to have the greatest effect on the PB C/D ratio (standardized partial regression coefficient (β) = 0.543, p < 0.001). Furthermore, a significant difference in the PB C/D ratio was found between the subgroups classified by the concomitant use of VPA or amiodarone (p = 0.002). However, there were no significant correlations between the PB C/D ratio, dosage formulation, and administration route.ConclusionsThe most influential factor on the PB C/D ratio was the concomitant use of VPA or amiodarone with PB. This result could provide an important perspective in pediatric drug therapy where elixir and powder formulations are administered via the oral route and enteral tube.

Population pharmacokinetics of phenobarbital in Caucasian patients with epilepsy

The present study aimed to establish a population pharmacokinetic (PopPK) model of Phenobarbital (PB) in Caucasian patients with epilepsy included in a Therapeutic Drug Monitoring program. In total, 855 PB serum concentrations (steady-state trough concentrations) were retrospectively collected during routine clinical monitoring of 395 patients over 15 years of age with epilepsy. The PopPK analysis was performed with NONMEM using a non-linear mixed-effect modelling approach. The influence of demographic, anthropometric, treatment, and comedication variables on the apparent clearance (CL/F) of PB were analysed. Goodness of fit plots and the bootstrap method were performed to evaluate the final model. External validation was carried out using an independent group of patients (107 patients, 178 blood samples). A one-compartment model with first-order absorption and elimination successfully described the data. In the final model, CL/F included body surface area (BSA) and comedication with phenytoin (PHT) and valproic acid (VPA), resulting in the following equation:CL/F[L/h]=(0.236+(0.115×(BSA−1.7)))×(0.822PHT)×(0.711VPA)The model presents acceptable estimation errors in the parameters of fixed (<12%) and random effects (<13%), and of the shrinkage values (<21%). Internal and external validations demonstrated the good predictability of the final model. A PopPK model of PB in Caucasian patients over 15 years of age was successfully established, which can be used to estimate phenobarbital CL/F. BSA and drug–drug interactions with PHT and VPA should be incorporated into dosing decisions. This PopPK, using Bayesian algorithms, could help establish an optimal dosage regimen in routine patient care.

Laboratory Evaluation and Serum Level of Phenobarbital Administered by Different Pathways in Dogs

Background: Anticonvulsants are widely used in the treatment of small animals for the remission of isolated seizures and recurrent seizures in epilepsy, including tonic-clonic seizures and in status epileticus. Phenobarbital is the drug of choice for the management of epileptic seizures, it is considered very effective, safe, low cost and with few side effects. Several routes of administration may be used, with the oral, intravenous and intramuscular routes being the most common, with rectal and nasal routes being the least common. Materials, Methods &amp; Results: Twenty mongrel dogs were used in the present study (aged 1 to 6-year-old, males and females, weighing 6.0 to 17.0 kg). The patients were previously evaluated via physical examination, temperature, respiratory and heart rate, laboratory tests (erythrogram and leukogram), and serum biochemistry by analyzing the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (FA), and gamma-glutamyltransferase (GGT). Four experimental groups were established with five animals in each group: animals receiving intramuscular injections of phenobarbital (VIM), animals receiving nasal administration of phenobarbital (VN), animals receiving rectal administration of phenobarbital (VR), and animals receiving oral administration of phenobarbital (VO). Phenobarbital was administered every 12 h for 15 days. To determine the serum level of phenobarbital, 5 mL of jugular vein blood was collected in vacuum tubes for evaluation via hemogram. The serum level was determined after 15 days of continuous administration of phenobarbital, as stable phenobarbital serum levels can only be achieved from 10 to 15 days after the first administration. For the serum biochemistry evaluation, 10 mL of blood from the jugular vein was collected using vacuum syringes for assessing ALT, AST, GGT, and FA levels. Statistical analyses were performed with contrasted variation analysis using the Tukey method and paired t-test for comparison of time points. The level of significance was determined to be 5%. There was a significant difference (P &lt; 0.05) among drug administration routes, and among the levels of AST and AF enzymes after the first administration of phenobarbital via the nasal and intramuscular routes. Based on the results, it was concluded that hepatic alterations secondary to the use of phenobarbital for 15 days may occur with a low incidence. The phenobarbital serum concentration in dogs varied when administered via nasal, rectal, and intramuscular routes, but was stable when administered orally.Discussion: The current results are consistent with those of previous studies, indicating that the chronic use of phenobarbital causes an increase in the serum levels of ALT and FA enzymes. It was found that phenobarbital serum levels varied greatly, particularly following nasal, rectal, and intramuscular administration. In the present study, serum phenobarbital levels were within the normal range when administered via the intramuscular, nasal, rectal, and oral routes. This result is inconsistent with that of previous studies where the serum levels were below the normal range following oral administration of phenobarbital. The serum concentration, rather than clinical criteria, should be used as a guide for treatment modification, as the distribution of this drug varies greatly among animals.

Pharmacokinetics and Optimal Dosing of Phenobarbital.

Researchers from the Baylor College of Medicine in Houston, TX, USA, conducted a retrospective population pharmacokinetic analysis of 355 patients ages less than 19 years of age in the inpatient setting who were initiated on intravenous or oral phenobarbital therapy and had one or more serum phenobarbital concentrations sampled.

Phenobarbital population pharmacokinetics across the pediatric age spectrum.

Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12hours, phenobarbital doses and serum concentrations, and potential drug-drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40mgkg-1 dose-1 , iv, followed by enteral doses of 3, 4, 5, and 6mgkg-1 d-1 . A total of 355 patients (50.3% male, median gestational age 39weeks (interquartile range [IQR] 35, 40), median age 0.28years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mgkg-1 dose-1 ; intravenous = 2.6 (IQR 2.2, 4.9) mgkg-1 dose-1 ) and mean serum concentration was 41.1±23.9mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one-compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat-free mass. Significant covariates included serum creatinine, postmenstrual age, and drug-drug interactions on clearance, and age in years on volume of distribution. Phenobarbital dosing of 30mgkg-1 dose-1 ,iv, followed by 4mgkg-1 d-1 had the highest probability of attaining a therapeutic concentration at 7days. Postmenstrual age and drug-drug interactions should be incorporated into dosing decisions.

Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation.

The disposition of drugs is potentially changed due to extracorporeal membrane oxygenation (ECMO) in neonates and infants. The aim of the study was to evaluate the individual pharmacokinetics (PK) of phenobarbital and the effect of PK covariates in neonates and infants undergoing ECMO. Sixteen patients (7 neonates, 9 infants) treated with phenobarbital during ECMO (centrifugal-flow pump circuits) were enrolled in the PK study. Phenobarbital serum concentrations were measured using a fluorescence polarization immunoassay. Individual PK parameters - volume of distribution (Vd) and clearance (CL) were calculated in a one-compartmental pharmacokinetic model. The mean (SD) Vd and CL values in neonates were 0.46 (0.24) L/kg and 8.0 (4.5) mL/h/kg, respectively. Respective values in infants were 0.56 (0.23) L/kg and 8.5 (3.1) mL/h/kg. PK parameters in neonates and infants were not significantly different. We observed high inter-individual variability in PK parameters (coefficients of variation [CV] were 52% and 53% for CL and Vd, respectively). Doses were adjusted based on therapeutic drug monitoring (TDM) in 87.5% patients. Only 50% of the first measured phenobarbital serum concentrations in each patient were within the therapeutic range of 10-40 mg/L, in comparison with 88.6% concentration measured after TDM implementation. Linear regression models showed that both Vd and CL are significantly related with body weight (BW) and length. Median optimal phenobarbital loading dose (LD) and maintenance dose (MD), calculated from pharmacokinetic data, were 15 mg/kg and 4 mg/kg/day, respectively. Body weight was shown to be the main PK covariate of phenobarbital disposition. Subsequent dosing nomograms are provided for phenobarbital dosing during ECMO.

Serum Phenobarbital Concentrations and Timing of Blood Collection in Epileptic Dogs on Chronic Treatment

Serum Phenobarbital Concentrations and Timing of Blood Collection in Epileptic Dogs on Chronic Treatment

Standardized Treatment of Neonatal Status Epilepticus Improves Outcome.

We aimed to decrease practice variation in treatment of neonatal status epilepticus by implementing a standardized protocol. Our primary goal was to achieve 80% adherence to the algorithm within 12 months. Secondary outcome measures included serum phenobarbital concentrations, number of patients progressing from seizures to status epilepticus, and length of hospital stay. Data collection occurred for 6 months prior and 12 months following protocol implementation. Adherence of 80% within 12 months was partially achieved in patients diagnosed in our hospital; in pretreated patients, adherence was not achieved. Maximum phenobarbital concentrations were decreased (56.8 vs 41.0 µg/mL), fewer patients progressed from seizures to status epilepticus (46% vs 36%), and hospital length of stay decreased by 9.7 days in survivors. In conclusion, standardized, protocol-driven treatment of neonatal status epilepticus improves consistency and short-term outcome.

Levetiracetam in the management of feline audiogenic reflex seizures: a randomised, controlled, open-label study

Objectives Currently, there are no published randomised, controlled veterinary trials evaluating the efficacy of antiepileptic medication in the treatment of myoclonic seizures. Myoclonic seizures are a hallmark of feline audiogenic seizures (FARS). Methods This prospective, randomised, open-label trial compared the efficacy and tolerability of levetiracetam (20-25 mg/kg q8h) with phenobarbital (3-5 mg/kg q12h) in cats with suspected FARS that experienced myoclonic seizures. Cats were included that had ⩾12 myoclonic seizure days during a prospective 12 week baseline period. This was followed by a 4 week titration phase (until a therapeutic serum concentration of phenobarbital was achieved) and a 12 week treatment phase. Results Fifty-seven cats completed the study: 28 in the levetiracetam group and 29 in the phenobarbital group. A reduction of ⩾50% in the number of myoclonic seizure days was seen in 100% of patients in the levetiracetam group and in 3% of patients in the phenobarbital group ( P <0.001) during the treatment period. Levetiracetam-treated cats had higher freedom from myoclonic seizures (50.0% vs 0%; P <0.001) during the treatment period. The most common adverse events were lethargy, inappetence and ataxia, with no difference in incidence between levetiracetam and phenobarbital. Adverse events were mild and transient with levetiracetam but persistent with phenobarbital. Conclusions and relevance These results suggest that levetiracetam is an effective and well tolerated treatment for cats with myoclonic seizures and is more effective than phenobarbital. Whether it will prevent the occurrence of generalised tonic-clonic seizures and other forebrain signs if used early in the course of FARS is not yet clear.

Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.

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.

Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004–2013)

To determine the percentage of cats with a phenobarbital (PB) concentration between 15 and 45 μg/mL that had a ≥ 50% reduction in the number of seizures and to investigate applicability of the 2011 International League Against Epilepsy (ILAE) classification system in cats. Retrospective case series. 30 cats with suspected or confirmed epilepsy. Medical records for 2004 to 2013 at 3 veterinary hospitals were searched. Information collected included signalment, duration of observation before treatment, frequency of seizures before PB administration, seizure phenotype, dose of PB, serum PB concentration, number of seizures after PB administration, duration of follow-up monitoring, and survival time. A modified 2011 ILAE classification system was applied to all cats. Seizure control was achieved in 28 of 30 (93%) cats with a serum PB concentration of 15 to 45 μg/mL. This comprised 10 of 11 cats with structural epilepsy, 14 of 15 cats with unknown epilepsy, and 4 of 4 cats with presumptive unknown epilepsy. Thirteen cats had no additional seizures after initiation of PB treatment. Seizure control was achieved in most cats with a serum PB concentration between 15 and 45 μg/mL, regardless of the cause of the seizures. A modified 2011 ILAE classification was applied to cats with seizures and enabled classification of cats without specific genetic testing and without identified structural or inflammatory disease. This classification system should be incorporated into veterinary neurology nomenclature to standardize communication between veterinarians and improve comparisons among species.

Phenobarbital use in an infant requiring extracorporeal membrane life support

Over the past two decades, there has been an increased use of extracorporeal membrane life support (ECLS) for critically ill neonates and infants. Approximately 20% of these children will experience seizures as a complication of ECLS or the comorbid condition which necessitated extracorporeal support. While phenobarbital is one of the most common drugs used to treat seizures in children, little is known about its dosing while on ECLS. We present a 3-month-old girl who required ECLS after cardiac arrest in the postoperative period following surgery for complex congenital heart disease. The patient subsequently developed seizure activity, which was treated with phenobarbital. Following an initial loading dose of 30 mg/kg, the serum concentration was 47.9 mcg/ml. A supplementary loading dose of 10 mg/kg was administered 8 h later with an increase of the maintenance dose to 8 mg/kg/day. The phenobarbital serum concentrations were 65.9 and 72.8 mcg/ml on the subsequent days. Despite therapeutic levels of phenobarbital, the patient continued to exhibit clinical and electroencephalographic evidence of seizure activity and a midazolam infusion was started at 0.3 mg/kg/h. Because of continued seizure activity, the patient ultimately required titration of midazolam to 1.2 mg/kg/h by day 7 of ECLS to control seizure activity. Due to severe intracerebral bleeding on day 9, ECLS was withdrawn and the patient expired. Our experience demonstrates some of the challenges of medication titration during ECLS. Previous reports of phenobarbital dosing during ECLS are reviewed and considerations for the dosing of anticonvulsant medications during extracorporeal support are discussed.

Association betweenABCB1 Genotype and Seizure Outcome in Collies with Epilepsy

Medically refractory seizures are an important problem in both humans and dogs with epilepsy. Altered expression of ABCB1, the gene encoding for p-glycoprotein (PGP), has been proposed to play a role in drug-resistant epilepsy. Heterogeneity of the ABCB1 gene is associated with seizure outcome in dogs with epilepsy. Twenty-nine Collies with epilepsy being treated with antiepileptic drugs (AEDs). Prospective and retrospective cohort study. Dogs were classified as having a good outcome (≤ 1 seizure/month, no cluster seizures) or a poor outcome (>1 seizure/month, with or without cluster seizures) based on owner-completed questionnaire. Serum AED concentrations were measured, and ABCB1 genotyping was performed on buccal tissue samples. Association analyses were performed for genotype and seizure outcome, number of AEDs administered, serum AED concentrations, and incidence of adverse effects. Fourteen dogs of 29 (48%) were homozygous for the ABCB1-1∆ mutation (M/M), 11 dogs (38%) were heterozygous (M/N), and 4 dogs (14%) had the wild-type genotype (N/N). Dogs with the M/M genotype were significantly more likely to have fewer seizures and have less AED-related sedation than M/N or N/N dogs (P = .003 and P = .001, respectively). Serum phenobarbital and bromide concentrations did not differ between groups, but the M/N and N/N groups received a larger number of AEDs than the M/M group (P = .014). ABCB1 genotype is associated with seizure outcome in Collies with epilepsy. This cannot be attributed to differences in PGP function, but might be because of intrinsic variations in seizure severity among phenotypes.

Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs

To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs. Double-blinded, randomized, parallel, clinical trial. 46 AED-naïve dogs with naturally occurring epilepsy. Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs. Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 μg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], p.o., q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], p.o., q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end. Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment.