Efficacy of second-line anticonvulsant agents with adult status epilepticus: A systematic review and network meta-analysis.

BACKGROUND: Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs. OBJECTIVE: We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing multiple second-line AEDs for SE to investigate the efficacy of AEDs. METHODS: We searched MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal and included RCTs for patients aged ≥15 years with SE on December 31, 2023. We compared multiple second-line AEDs for SE including fosphenytoin (fPHT), lacosamide (LCM), levetiracetam (LEV), phenytoin (PHT), phenobarbital (PHB), and valproate (VPA). The primary and secondly outcomes were termination of seizures integrating the absence of seizure recurrence at 30 min and 60 min, and adverse events associated with AEDs, respectively, with expressing as relative risk (RR) with a 95% confidence interval (CI). We conducted a NMA using frequentist-based approach with multivariate random effects, and assessed the certainty based on the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: Seven RCTs (n = 780) were included, and statistically significant difference was detected between VPA vs. PHB (RR, 0.67; 95% CI, 0.53-0.85; very low certainty), fPHT vs. PHB (RR, 0.66; 95% CI, 0.48-0.90; very low certainty), LCM vs. PHB (RR, 0.62; 95% CI, 0.41-0.93; very low certainty), and LEV vs. PHB (RR, 0.69; 95% CI, 0.51-0.94; very low certainty). Moreover, PHB was the highest in the ranking for termination of seizures. For adverse events, no significant reduction was observed owing to the selection of AEDs, although the ranking of PHB was the lowest. CONCLUSIONS: PHB may have been the most effective for seizure termination as second-line AEDs in adult patients with SE. However, the certainty of almost all comparisons was "very low", and careful interpretation is essential.

Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate-Severe Traumatic Brain Injury: A Clinical Practice Guideline for Health Care Professionals from the Neurocritical Care Society.

BACKGROUND: There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI). METHODS: We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS: The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use. CONCLUSIONS: Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

BACKGROUND: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

Intravenous fosphenytoin as treatment for acute exacerbation of trigeminal neuralgia: A prospective systematic study of 15 patients.

INTRODUCTION: Intravenous fosphenytoin is widely used for acute exacerbation of trigeminal neuralgia, however, few studies have investigated this treatment. We aimed to examine the efficacy and side effects of initial intravenous fosphenytoin plus oral tapering of phenytoin for exacerbation of trigeminal neuralgia. METHODS: Consecutive patients with primary trigeminal neuralgia were included in this prospective observational 90-days follow-up study. Data were collected using standardized interviews before, at 24 hours, day 7, 30 and 90 post loading dose. The primary outcome was the proportion of responders defined as a 50% reduction in pain intensity 24 hours post loading dose. RESULTS: We included 15 patients. Nine patients (60%) were responders. Pain intensity 24 hours post loading dose was reduced by 5.00 points on the numerical rating scale (p < 0.001), and at day 7 by 5.5 points (p < 0.001). The most common side effects were hypotension and dizziness. CONCLUSION: Intravenous fosphenytoin relieves trigeminal neuralgia pain in most patients and provides a window for titrating prophylactic trigeminal neuralgia medications or planning neurosurgery. The decision to administer intravenous fosphenytoin should be taken with support from trigeminal neuralgia experts and involves considerations of co-morbidities and other treatment options for acute exacerbation of trigeminal neuralgia.Clinical Trial: Preregistered (ClinicalTrials.gov Identifier: NCT03712254.

Treatment of Toxin-Related Status Epilepticus With Levetiracetam, Fosphenytoin, or Valproate in Patients Enrolled in the Established Status Epilepticus Treatment Trial.

STUDY OBJECTIVE: We describe a subset of patients with toxin-related precipitants of seizures/status epilepticus enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: The ESETT was a prospective, double-blinded, adaptive trial evaluating levetiracetam, valproate, and fosphenytoin as second-line agents in benzodiazepine-refractory status epilepticus in adults and children. The primary outcome was the absence of seizures and improvement in the level of consciousness 1 hour after study drug administration. In this post hoc analysis, the safety and efficacy of second-line agents in a subset of patients with toxin-related seizures are described. RESULTS: A total of 249 adults and 229 children were enrolled in the ESETT. Toxin-related seizures occurred in 29 (11.6%) adults and 1 child (0.4%). In adults, men were more likely to have toxin-related seizures than women (25 of 145, 17.2% versus 4 of 104, 3.9%). The most common toxin-related precipitants were alcohol withdrawal and cocaine, 11(37%) of 30 patients each. Cocaine was used with other substances by most patients 10 (91%) of 11, most commonly with an opioid 7 (64%) of 11. For alcohol withdrawal-related seizures, treatment successes with levetiracetam, valproate, and fosphenytoin were 3 (100%) of 3, 3 (50%) of 6, and 1 (50%) of 2, respectively. For cocaine-related seizures, treatment success was 1 (14%) of 7 for levetiracetam, 0 (0%) of 1 for valproate, and 1 (33%) of 3 for fosphenytoin. One patient who used cocaine and an opioid received fosphenytoin and developed life-threatening hypotension. CONCLUSION: In the ESETT, approximately 1 in 10 adult patients with status epilepticus presented with a toxin-related seizure. Alcohol withdrawal and cocaine/opioid use were the most common toxin-related precipitants. Toxin-related benzodiazepine-refractory status epilepticus was successfully treated with a single dose of second-line antiseizure medication in 42% of the patients.

Fosphenytoin Alleviates Herpes Simplex Virus Infection-Induced Provoked and Spontaneous Pain-Like Behaviors in Mice.

In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

OBJECTIVE: To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. DATA SOURCES: We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. DATA EXTRACTION AND SYNTHESIS: Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. RESULTS: We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). CONCLUSIONS: The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus.

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Antiepileptic combination therapy with Stevens-Johnson syndrome and toxic epidermal necrolysis: Analysis of a Japanese pharmacovigilance database.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated diseases characterized by an extensive loss of the epidermal skin layer, often resulting in death. SJS and TEN are often triggered by certain drugs, including antiepileptic drugs (AEDs). Epilepsy is very difficult to treat and often involves the combination of two or more AEDs. In this study, we quantified not only the risk of SJS or TEN associated with single-AED therapy but also the risk related to concomitant AED treatment using reporting-derived signals. METHODS: An analysis of the Japanese Adverse Drug Event Report (JADER) database was performed from the first quarter of 2004 to the fourth quarter of 2018. The single-AED signals were evaluated using the proportional reporting ratio (PRR), and the combination therapy signals were evaluated using Ω shrinkage measure and combination risk ratio (CRR). RESULTS: SJS signals were associated with 11 AEDs, and TEN signals were related to 12 AEDs. Moreover, the following AED combinations were associated with SJS signals: carbamazepine-lorazepam (Ω025 : 0.33, CRR: 2.18) and fosphenytoin-lorazepam (Ω025 : 0.99, CRR: 39.20). The TEN signals were related to the following combinations: clobazam-gabapentin (Ω025 : 0.35, CRR: 3.14), phenytoin-gabapentin (Ω025 : 0.03, CRR: 2.18), valproic acid-gabapentin (Ω025 : 0.15, CRR: 2.25), clobazam-clonazepam (Ω025 : 0.03, CRR: 2.93), clobazam-valproic acid (Ω025 : 0.29, CRR: 1.55), fosphenytoin-lamotrigine (Ω025 : 0.05, CRR: 7.37), and lacosamide-levetiracetam (Ω025 : 0.74, CRR: 1.85). SIGNIFICANCE: This study identified two AED combinations that increased the SJS signals and seven combinations that increased the TEN signals. Although AED monotherapies require attention for SJS and TEN, some AED combinations require extra caution.

Effect of therapeutic plasma exchange on phenytoin plasma concentration in patients receiving intravenous fosphenytoin therapy.

We report for patients with encephalitis treated with plasma exchange (PE) and fosphenytoin. In patient 1, phenytoin levels decreased on the maintenance dose, and the phenytoin concentration was <10 µg/mL on day 12 of administration. In patient 2, the phenytoin levels was <10 µg/mL on day 4. Increasing the fosphenytoin dose pushed the phenytoin level into therapeutic range. There were no differences between the areas under the concentration-time curve of phenytoin with and without PE. We previously reported a decline in phenytoin levels after prolonged use of fosphenytoin. Therefore, dose adjustment of fosphenytoin in patients undergoing PE may be unnecessary.

Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.

OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS: Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION: LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.

European Academy of Neurology guideline on trigeminal neuralgia.

BACKGROUND AND PURPOSE: Trigeminal neuralgia (TN) is an extremely painful condition which can be difficult to diagnose and treat. In Europe, TN patients are managed by many different specialities. Therefore, there is a great need for comprehensive European guidelines for the management of TN. The European Academy of Neurology asked an expert panel to develop recommendations for a series of questions that are essential for daily clinical management of patients with TN. METHODS: A systematic review of the literature was performed and recommendations was developed based on GRADE, where feasible; if not, a good practice statement was given. RESULTS: The use of the most recent classification system is recommended, which diagnoses TN as primary TN, either classical or idiopathic depending on the degree of neurovascular contact, or as secondary TN caused by pathology other than neurovascular contact. Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN. If MRI is not possible, trigeminal reflexes can be used. Neurovascular contact plays an important role in primary TN, but demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression. In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used. For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice. Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy. It is recommended that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated. Microvascular decompression is recommended as first-line surgery in patients with classical TN. No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN. Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact. Treatment for patients with secondary TN should in general follow the same principles as for primary TN. In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support. CONCLUSIONS: Compared with previous TN guidelines, there are important changes regarding diagnosis and imaging. These allow better characterization of patients and help in decision making regarding the planning of medical and surgical management. Recommendations on pharmacological and surgical management have been updated. There is a great need for future research on all aspects of TN, including pathophysiology and management.

Population Pharmacokinetic Analysis of Phenytoin After Intravenous Administration of Fosphenytoin in Adult and Elderly Epileptic Patients.

BACKGROUND: Fosphenytoin, the diphosphate ester salt of phenytoin, is widely used to treat status epilepticus. The aim of this study was to develop a population pharmacokinetic (PPK) model to describe serum phenytoin concentrations after the intravenous administration of fosphenytoin in adult and elderly epileptic patients. METHODS: Patient backgrounds, laboratory tests, and prescribed drugs were retrospectively collected from electronic medical records. Patients who received fosphenytoin were enrolled. The PPK analysis was performed using NONMEM 7.3.0 with the first-order conditional estimation method with interaction. Age, sex, laboratory tests, and coadministered drugs were selected as candidates for covariates. Significance levels for forward inclusion and backward elimination were set at 0.05 and 0.01, respectively. The study protocol was approved by the Fukuoka Tokushukai Ethics Committee. RESULTS: A total of 340 serum phenytoin concentrations from 200 patients treated with fosphenytoin were available. The median age and body weight of the population were 71 years and 53.4 kg, respectively. A linear 1-compartment model with the conversion rate of fosphenytoin to phenytoin clearly described the pharmacokinetics of phenytoin after the intravenous administration of fosphenytoin. Age was detected as a covariate of clearance (CL): CL (L/h) = 1.99 × (body weight/53.4) × (age/71). Goodness-of-fit plots revealed the high-predictive performance of the final PPK model, and systematic deviations were not observed. The final model was validated by a prediction-corrected visual predictive check and bootstrap analysis. CONCLUSIONS: We herein developed a PPK model to describe phenytoin concentrations after the intravenous administration of fosphenytoin. Age was identified as a significant covariate for CL.

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex.

BACKGROUND: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. OBJECTIVES: To examine the influence of obesity and sex on phenytoin LDs. METHODS: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. RESULTS: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.

Time-Dependent Decline in Serum Phenytoin Concentration With Heightened Convulsive Seizure Risk by Prolonged Administration of Fosphenytoin in Japanese: A Retrospective Study.

BACKGROUND: Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. METHODS: Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 mcg/mL) was calculated from the parameters. RESULTS: Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/d, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/d). CONCLUSIONS: Prolonged use of fosphenytoin, for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus, time dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

Fosphenytoin for control of electrical storm in acute myocardial infarction and Purkinje fiber-mediated arrhythmias.

BACKGROUND: Purkinje fiber-mediated arrhythmias in the setting of acute myocardial infarction are poorly responsive to conventional antiarrhythmic therapy, increases overall mortality and often requires radiofrequency ablation (RFA) for control. In this study, we report the use of intravenous Fosphenytoin for the control of arrhythmic storm in patients with acute myocardial infarction. METHODS AND RESULTS: Six patients with acute myocardial infarction (5 AW/1 LW) and Purkinje-triggered ventricular arrhythmias refractory to conventional antiarrhythmics were treated with intravenous Fosphenytoin before considering RFA. Arrhythmia control was obtained in all patients after the initial bolus dose. Breakthrough episodes were seen in 5/6 within 24-36 hours of the initial bolus, necessitating a second bolus. Complete arrhythmia control was obtained in all patients within 72 hours and 5/6 patients were successfully discharged from the hospital. One patient succumbed to sepsis in hospital while another patient succumbed to Sub Dural Hematoma after 3 months. CONCLUSIONS: Intravenous Fosphenytoin should be considered before RFA for control of Purkinje fiber-mediated refractory arrhythmias in acute myocardial infarction patients.

Fosphenytoin Population Pharmacokinetics in the Acutely Ill Pediatric Population.

OBJECTIVE: The purpose of this study is to describe the pharmacokinetics of phenytoin in pediatric patients receiving fosphenytoin. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: Emergency department or PICU of a large tertiary care children's hospital. PATIENTS: Patients less than 19 years old who received fosphenytoin in the PICU or emergency center for treatment of seizures from January 2011 to June 2017 were included. INTERVENTIONS: Population pharmacokinetic analysis was performed with NONMEM v7.3 (Icon Plc, Dublin, Ireland). Simulation was performed to determine optimal loading dose and maintenance dosing regimens. MEASUREMENTS AND MAIN RESULTS: A total of 536 patients (55.4% male; median age, 3.4 yr [interquartile range, 0.92-8.5 yr]) met study criteria. Fosphenytoin was administered at median 15.1 mg/kg/dose (interquartile range, 6.3-20.7 mg/kg/dose). Mean serum concentrations of 17.5 ± 7.8 mg/L were at a median 4.2 hours (interquartile range, 2.5-7.8 hr) after a dose. A pharmacokinetic model with two compartments, allometrically scaled fat-free mass on all parameters, and serum creatinine and concomitant phenobarbital use on clearance had the best fit. Simulation demonstrated that a 20 mg/kg loading dose followed by 6 mg/kg/dose every 8 hours had the greatest percentage of concentrations in the 10-20 mg/L range, with reduced doses to achieve therapeutic in patients with reduced kidney function. CONCLUSIONS: A loading dose of 20 mg/kg followed by 6 mg/kg/dose every 8 hours based on fat-free mass is a reasonable empiric strategy for attainment and maintenance of therapeutic trough concentrations. Concomitant phenobarbital use may increase clearance of phenytoin and fosphenytoin dose reductions should occur in patients with reduced kidney function.

A cool side effect of valproic acid administration: Single dose-induced hypothermia.

Thermoregulatory derangements secondary to valproic acid (VPA) administration, specifically hypothermia, have been reported throughout the literature, but a handful of times. This case report describes a 28-year-old male presenting status-post multiple tonic-clonic seizures, treated for persistent seizure activity refractory to benzodiazepines with valproic acid (VPA), levetiracetam, and fosphenytoin. After just over an hour, the patient's core temperature fell from 36.8 °C to 34.9 °C. Temperatures were repeated for confirmation, no further doses of VPA were administered, and the patient's temperature returned to normal over the next 7 h with the use of warming blankets. Levetiracetam and fosphenytoin were continued with no further reported development of hypothermia during the patient's admission. After reviewing other potential causes, a thorough drug database review was performed that found VPA to be the only medication administered with published reports of inducing hypothermia. The mechanism of thermoregulatory derangement associated with VPA is not clearly defined and much of the evidence surrounds alterations in gamma-aminobutyric acid (GABA) activity in animal studies. To our knowledge, this case report is the first reported case of VPA-induced hypothermia following a single dose in the emergency department and offers the potential that prompt return to normothermia is likely following discontinuation of the offending agent.