lacosamide and Critical-Illness

The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT).. With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016.. Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known.. Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible.. Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents.

Topics: Acetamides; Acute Kidney Injury; Amines; Anticonvulsants; Carbamates; Critical Illness; Cyclohexanecarboxylic Acids; Dibenzazepines; Dose-Response Relationship, Drug; Ethosuximide; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lacosamide; Lamotrigine; Levetiracetam; Phenobarbital; Phenylcarbamates; Phenylenediamines; Phenytoin; Piracetam; Propylene Glycols; Renal Dialysis; Renal Replacement Therapy; Seizures; Topiramate; Triazines; Valproic Acid; Zonisamide

Many patients with critical illness have been noted to have nonconvulsive seizures (NCSs) and nonconvulsive status epilepticus (NCSE). How aggressively these seizures should be treated is unclear. Many investigators feel that the morbidity of NCSs and NCSE is different from that of generalized convulsive status epilepticus (GCSE), so treatment should be less urgent. Consequently, many nonsedating AEDs have been used to treat NCSs and NCSE in patients with critical illness. Randomized, controlled trials demonstrating the efficacy of AEDs in NCSs and NCSE are lacking. The Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) study compared lacosamide to fosphenytoin in the treatment of NCSs. An update of the study is presented. This article is part of a Special Issue entitled "Status Epilepticus".

Topics: Acetamides; Anticonvulsants; Critical Illness; Humans; Lacosamide; Phenytoin; Recurrence; Seizures; Status Epilepticus

Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations.. Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination.. The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities.. The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.

Topics: Albumins; Anticonvulsants; Continuous Renal Replacement Therapy; Critical Illness; Drug Elimination Routes; Humans; Lacosamide; Levetiracetam; Phenytoin

Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH).. Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide.. The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics.. CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.

Topics: Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Hemofiltration; Humans; Lacosamide; Prospective Studies; Ultraviolet Rays

The objective of this study is to describe the pharmacokinetics of lacosamide in a critically ill adult during continuous venovenous hemofiltration (CVVH). A 78-year-old male developed sepsis and acute kidney injury following cardiac surgery. He was initially treated with intermittent hemodialysis but developed nonconvulsive status epilepticus at the end of the first session and was subsequently initiated on CVVH. In addition to lorazepam boluses, levetiracetam, and midazolam infusion, he was loaded with lacosamide 400 mg intravenously and started on 200 mg intravenously twice daily as maintenance therapy. Noncompartmental modeling of lacosamide pharmacokinetics revealed significant extracorporeal removal, a volume of distribution of 0.69 L/kg, elimination half-life of 13.6 hours, and peak and trough concentrations of 7.4 and 3.7 mg/L, respectively (goal trough, 5-10 mg/L). We found significant extracorporeal removal of serum lacosamide during CVVH, which was higher than previously reported. This led to subtherapeutic concentrations and decreased overall antiepileptic drug exposure. The relationship between serum lacosamide concentrations and clinical efficacy is not well understood; thus, therapeutic drug monitoring is not routinely recommended. Yet, we demonstrated that measuring serum lacosamide concentrations in the critically ill population during continuous renal replacement therapy may be useful to individualize dosing programs. Further pharmacokinetic studies of lacosamide may be necessary to generate widespread dosing recommendations.

Topics: Aged; Continuous Renal Replacement Therapy; Critical Illness; Hemofiltration; Humans; Lacosamide; Levetiracetam; Male

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH.

Topics: Anticonvulsants; Critical Illness; Hemofiltration; Humans; Lacosamide; Male; Middle Aged; Status Epilepticus

Acute seizures are common in critically ill children. These patients would benefit from intravenous anti-seizure medications with few adverse effects. We reviewed the usage and effects of intravenous lacosamide in critically ill children with seizures or status epilepticus.. This retrospective series included consecutive patients who received at least one dose of intravenous lacosamide from April 2011 to February 2016 in the pediatric intensive care unit of a quaternary care children's hospital, including patients with new lacosamide initiation and continuation of outpatient oral lacosamide. Dosing and prescribing practices were reviewed. Adverse effects were defined by predefined criteria, and most were evaluated during the full admission.. We identified 51 intensive care unit admissions (47 unique patients) with intravenous lacosamide administration. Lacosamide was utilized as a third or fourth-line anti-seizure medication for acute seizures or status epilepticus in the lacosamide-naïve cohort. One patient experienced bradycardia and one patient experienced a rash that were considered potentially related to lacosamide. No other adverse effects were identified, including no evidence of PR interval prolongation.. Lacosamide was well tolerated in critically ill children. Further study is warranted to evaluate the effectiveness of earlier lacosamide use for pediatric status epilepticus and acute seizures.

Topics: Acetamides; Adolescent; Anticonvulsants; Child; Child, Preschool; Cohort Studies; Critical Illness; Electroencephalography; Epilepsy; Female; Humans; Infant; Infant, Newborn; Injections, Intravenous; Lacosamide; Male; Retrospective Studies

Status epilepticus (SE) often does not respond to initial treatment. A second-line agent with a less established safety and efficacy profile is then required. This study examined the safety of intravenous (IV) lacosamide (LCM) in a critically ill population and obtained an estimate of effectiveness in patients with refractory SE on continuous video EEG monitoring (cEEG).. Retrospective review of critically ill patients in SE on cEEG treated with IV LCM from June 2009 to April 2011.. Eighty-four patients in SE (43 F/41 M), mean age 59.6 years, were identified; and 59.5 % had nonconvulsive SE. The most common etiologies were ischemic and hemorrhagic strokes. There were no significant changes in serial blood pressure monitoring, PR prolongation, aspartate aminotransferase (AST), or creatinine pre- and post-LCM. There was a significant increase in alanine aminotransferase (ALT) from days 1-7 (p = 0.031). Fifty-one patients were LCM-naïve. In these patients, cessation of SE on cEEG after LCM occurred in 15.7, 25.5, 58.8, and 82.4 % by 4, 12, 24, and 48 h, respectively.. IV LCM appears safe short term in critically ill patients with SE. The retrospective estimate of effectiveness for LCM appears promising for management in SE. Prospective, randomized controlled studies are needed to better determine the role of LCM in treating SE.

Topics: Acetamides; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Critical Illness; Drug Resistant Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Outcome Assessment, Health Care; Retrospective Studies; Status Epilepticus; Young Adult

Seizures are common in critically ill patients and can impact morbidity and mortality. Traditional anti-epileptic drugs (AEDs) in this setting are not always effective and are associated with adverse events and drug interactions. Lacosamide (LCM) is a new AED which is available in parental form although few studies have evaluated the safety and efficacy of LCM in critically ill patients.. Critically ill patients at Emory University Hospital who received LCM from April 1, 2009 to February 1, 2010 were retrospectively reviewed. Primary outcome measure was incidence and time to seizure cessation. Adverse effects were also recorded.. LCM was administered in 24 patients including 13 episodes of refractory status epilepticus (RSE) occurring in 10 patients and for treatment of isolated seizures or following resolution of RSE in an additional 14 patients. Seizure cessation was achieved in 5/13 (38%) episodes of RSE (mean 11.2 h) while there was at least a 50% decrease in seizure frequency in 7/13 (54%). 11/14 patients (76%) who received LCM for treatment of isolated seizures or prevention of seizure recurrence remained seizure free. Three patients experienced a decline in systolic blood pressure (> 20 mmHg) while one patient experienced unexplained fever and one patient had elevation of liver function tests.. This preliminary data suggests that LCM may be a safe and effective alternative for treatment of seizures in critically ill patients. Further prospective, randomized controlled trials are needed to confirm these findings and further explore the incidence of adverse effects.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Critical Illness; Female; Humans; Hypotension; Intensive Care Units; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

We investigated the safety, tolerability, and effectiveness of lacosamide (LCM) in patients with acute recurrent seizures or with periodic epileptiform activity captured during continuous EEG monitoring. A total of 17 patients received LCM; 12 patients received LCM as a second or third antiepileptic drug (AED), one patient as a fourth AED, and one patient as a fifth AED. No additional AEDs were introduced after LCM in 15 patients. Twelve patients responded to LCM with improvement in the seizures or periodic epileptiform activity. Two patients required further AED management or burst suppression. No adverse effects, including symptomatic bradycardia and allergic reactions, were seen for intravenous infusion dosages up to 300 mg. Eleven patients were eventually discharged on LCM. LCM is an important new AED in the add-on treatment of acute recurrent seizures and periodic epileptiform activity in critically ill patients.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain; Critical Illness; Electroencephalography; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome