Phenytoin Loading Research Articles

Comparison of cubosomes and hexosomes for the delivery of phenytoin to the brain

The ability to formulate cubosomes and hexosomes with a single lipid by changing only the colloidal stabiliser presents a unique opportunity to directly compare the biological performance of these uniquely structured nanoparticles. This was explored here via the encapsulation and brain delivery of a model anti-seizure drug, phenytoin, in selachyl alcohol cubosomes and hexosomes. Nanoparticles were prepared with Pluronic® F127 or Tween 80® as the stabiliser and characterised. The internal nanostructure of nanoparticles shifted from hexosomes when using Pluronic® F127 as the stabiliser to cubosomes when using Tween 80® and was conserved following loading of phenytoin, with high encapsulation efficiencies (>97%) in both particle type. Cytotoxicity towards brain endothelial cells using the hCMEC/D3 line was comparable regardless of stabiliser type. Finally, in vivo brain delivery of phenytoin encapsulated in cubosomes and hexosomes after intravenous administration to rats was studied over a period of 60 min, showing cubosomes to be superior to hexosomes, both in terms of brain concentrations and brain to plasma ratio. While the role of stabiliser and/or internal nanostructure remains to be conclusively determined, this study is the first in vivo comparison of cubosomes and hexosomes for the delivery of a therapeutic drug molecule across the BBB and into the brain.

Psychiatric manifestations of anti-N-methyl-D-aspartate receptor encephalitis: A case report.

Psychiatric manifestations of anti-N-methyl-D-aspartate receptor encephalitis: A case report.

Aneurysmal Subarachnoid Hemorrhage: Impact on Phenytoin Permeability across the Blood-Brain Barrier.

Phenytoin (PHT) is a routinely prescribed prophylactic antiepileptic following aneurysmal subarachnoid hemorrhage (aSAH). However, its prophylactic use in aSAH is controversial as emerging evidence suggests worsening of the neurological and functional outcomes. In addition, there is profound damage to the blood-brain barrier (BBB) in aSAH, posing uncertainty about the permeability of PHT across BBB in these patients. This pilot study was designed to evaluate the alteration in PHT permeability across BBB in aSAH patients. For conducting the study, 20 patients (control n = 10; aSAH (grade 3 or 4) n = 10) were recruited from a tertiary care hospital. The patients undergoing cranial surgery for pathology with intracerebral mass lesions on MRI were chosen as control for aSAH group. Both groups were administered PHT loading dose (20 mg/kg), infused in 5% dextrose, at a rate not more than 50 mg/min, followed by a maintenance dose (5 mg/kg). Quantification of PHT concentration was performed in brain tissue, plasma, and cerebrospinal fluid (CSF) by LC-MS/MS. The median PHT concentration in brain was found to be significantly decreased (64.8%) in aSAH group (3.78 μg/g) as compared to control (10.73 μg/g), P = 0.010. Similarly, median PHT brain concentration as fraction of plasma was significantly decreased in aSAH group (36.72%) compared to that of control (89.55%), P = 0.003. There was no significant difference in PHT concentration in plasma, CSF, and CSF as a fraction of plasma between both the groups. There is a definite decrease in the penetration of PHT to the brain in patients with grade 3 and 4 aSAH.

Critical Care Management of Status Epilepticus at a Tertiary Care University Hospital.

Status epilepticus (SE) is a neurological emergency associated with significant morbidity and mortality. The objective of this study was to review the critical care management of patients with SE focusing on antiepileptic drugs (AEDs) as well as to determine the optimal dosing strategies of phenytoin (PHT) and predictors of its effectiveness. A retrospective chart review of adult patients with SE admitted to the University of Alberta Hospital, Canada, was conducted. Fifty-six admissions were included. Benzodiazepines (BDZs) were initially given in 89% of our patients. Following BDZs, PHT and levetiracetam were the most commonly initiated AEDs as first- and second-line agents and were deemed effective in 30/44 and 5/11 patients, respectively. Patients who received a PHT loading dose (LD) of 1000 mg were less likely to reach target levels compared with a weight-based LD ≥15 mg/kg (29% vs. 60%). Likewise, patients who received a maintenance dose (MD) of 300 mg/day were less likely to reach target compared with 400 mg/day or >5 mg/kg per day; however, this did not reach statistical significance. Three variables were found to be associated with PHT effectiveness: tonic-clonic SE (OR 5.01, 95% CI 1.02-24.7, p = 0.048), history of seizures and BMI <30 kg/m2 (OR 0.16, 95% CI 0.03-1.07, p = 0.059). Further studies of the predictors of PHT effectiveness, specifically obesity, are necessary to help individualize care. Finally, we suggest that PHT should be loaded according to the guidelines as 20 mg/kg followed by an MD of at least 400 mg/day or >5 mg/kg per day.

Assessment of dose capping in phenytoin loading practices in the emergency department and the impact of an emergency medicine pharmacist

ObjectivesPhenytoin is a common anticonvulsant used for the acute treatment of seizures in the emergency department (ED). Certain patient populations, such as the obese, have been shown to present dosing challenges. Often doses are arbitrarily “capped” for fear of overdosing. Emergency medicine pharmacists (EPhs) have been shown to optimize the care of patients receiving phenytoin therapy in other settings, demonstrating reductions in seizure activity, duration of therapy, and cost.MethodsRecords of patients presenting to the ED that were at least 18 years old and were prescribed intravenous phenytoin were reviewed. Patients weighing 100 kg or more were compared with those less than 100 kg. To evaluate the impact of an EPh, intravenous phenytoin orders placed during the EPh's hours were compared with those placed outside of those hours.ResultsA total of 117 patients were included, 42 (36%) weighed 100 kg or more. No significant difference was found in the achievement of target (10‐20 μg/mL) postload concentrations between the two groups (P = 0.795). Patients weighing 100 kg or more received significantly lower weight‐based phenytoin doses (16.0 vs 18.6 mg/kg, P = 0.0001). Those 100 kg or more who received less than 15 mg/kg were found to have significantly lower postload concentrations than those that received 15 mg/kg or more regardless of total dose (11.5 vs 16.5 μg/mL; P = 0.003). The presence of an EPh was found to result in significantly higher rates of postload concentrations within the therapeutic range across all groups (72.4% vs 53.7%; P = 0.04).ConclusionsThe available data suggest that artificial total dose limitations in patients yield significantly lower postload concentrations, potentially delaying seizure control in the acute setting. The presence of EPhs at the bedside increases the success of initial phenytoin dosing strategies in this population.

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

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. To examine the influence of obesity and sex on phenytoin LDs. 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. 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.

Painful Proximal Weakness and HyperCKemia Related to Intravenous Loading of Phenytoin

Painful Proximal Weakness and HyperCKemia Related to Intravenous Loading of Phenytoin

Camphor induced status epilepticus: a case report

Camphor is very toxic compound, which can be fatal for infants and children even if ingested in very small doses. Around 3-5 ml of 20% camphor oil or &gt;30mg/Kg is a potentially lethal dose. Camphor is used very frequently for house hold purposes. The chances of accidental ingestion by children are high particularly in toddlers. Here author report 2 years old previously well child brought with status epilepticus with no apparent trigger. Child required benzodiazipine, phenytoin and levetiracetam loading for seizure control and was ventilated. Complete evaluation for seizure cause was planned post stabilization, but during intubation camphor odour was noticed and parents accepted a possibility of camphor ingestion. Hence seizure was attributed to camphor toxicity. Further evaluation was withheld. Child had no seizure recurrence and AED was stopped prior to discharge after documenting normal neurological examination and EEG. This case highlights the need for considering camphor poisoning as a cause of status epilepticus in the toddler age group and importance of proper enquiry about possible exposure and complete examination including odour in all cases of unprovoked seizures in children which can help us avoid unnecessary investigations searching for the cause of status epilepticus.

Why we prefer levetiracetam over phenytoin for treatment of status epilepticus.

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment.

IV fosphenytoin in obese patients: Dosing strategies, safety, and efficacy.

Previous studies evaluated the disposition of IV phenytoin loading doses and found that obese patients had increased drug distribution into excess body weight, larger volumes of distribution, and longer half-lives when compared to their nonobese counterparts. We assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs). A retrospective chart review was conducted in 410 patients who received fosphenytoin. Patients were divided into 2 groups: BMI <30 (nonobese) and BMI ≥30 (obese). Patient demographics, fosphenytoin dose administered in mg/kg body weight, renal and liver function tests, fosphenytoin drug levels, and pre- and post-fosphenytoin administration vital signs were collected to assess for adverse events. Necessity of additional antiepileptic loading doses was used as a surrogate for clinical efficacy. The median dose of fosphenytoin administered was 19 mg/kg (interquartile range 15-20). The most frequently encountered adverse event was hypotension, which occurred in 39% of the cohort. Using a Bonferroni adjustment for multiple comparisons, there were no differences in adverse events between the 2 groups. The need for additional antiepileptic loading doses was not different between the 2 groups (p = 0.07). The incidence of adverse events and the need for repeat loading antiepileptic medications was similar between the 2 groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.

Alpha 3 ganglionic acetylcholine receptor antibody associated refractory status epilepticus

Autoimmune encephalitides are a group of syndromes that may present with subacute onset of disorientation, personality changes, memory loss and most prominently seizures. Earlier reports of this entity were from patients with paraneoplastic limbic encephalitis, however autoimmune etiologies have also been described in patients with non-paraneoplastic encephalitis [1]. The Alpha 3 ganglionic acetylcholine receptor autoantibody (a3-AChR Ab) mainly causes autoimmune dysautonomia that is either subacute or insidious in onset. A direct relationship betweenantibody titer and severity of dysautonomia occurs in both experimental animals and patients [2]. Most of these cases have been paraneoplastic (mainly adenocarcinomas) however a few cases have been linked to other autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome. Patients who are seropositive for a3-AChR Ab may present with less common neurological manifestations such as peripheral neuropathies, encephalopathy and subacute neuropsychiatric presentations. This report presents a unique case of refractory new-onset status epilepticus associated with a3-AChR antibody which responded to immunotherapy.

Misdiagnosis of Bupropion Intoxication

Bupropion inhibits catecholamine’s neuronal reuptake selectively but has a minimal effect on indolamine reuptake. It can be used in the treatment of major depressive disorder. A 3.5-year-old 15 kg girl had vomiting and disorders in her speech. After a time, she did not take breath and stared at one point and had a seizure. She was diagnosed with epilepsy and diazepam and then phenytoin was given intravenously. Midazolam infusion was performed. Although phenytoin loading and midazolam infusion, she had seizures intermittently. Her anamnesis in terms of drug story was rechecked but her family did not give any important data. Due to atypical process in clinical picture, multi-drug survey, stomach irrigation and activated charcoal were performed. The parent found bupropion which patient’s mother had used. During 14 days follow-up, she was intubated and mechanical ventilation was performed. She had resuscitation for three times due to cardiopulmonary arrest. Fortunately, after successful conservative treatment, she was discharged without any neurological sequel. Neurologic effects are tremor, pain, hallucinations, coma and seizures. Cardiovascular effects are tachycardia and widening in QRS and lengthened QT interval. Gastrointestinal effects are nausea and vomiting. Deaths were reported rarely. In our case, the patient had most of the findings stated above. So that wide QRS tachycardia firstly, then bradycardia and asystole finally had developed. When child is admitted to emergency service with seizures, their parents must be asked about intoxication. J Med Cases. 2015;6(7):322-324 doi: https://doi.org/10.14740/jmc2180w

Impact of a phenytoin loading dose program in the emergency department.

The use of a combined physician-and pharmacist-directed phenytoin loading dose program in an emergency department (ED) was evaluated. This single-center, observational, preimplementation-postimplementation study evaluated adult patients who received a phenytoin loading dose in the ED. The primary outcome compared the proportion of optimal phenytoin loading doses in the preimplementation and postimplementation groups. The postimplementation group was further stratified into pharmacist- and prescriber-dosing groups. Other outcomes evaluated included the numbers of appropriate serum phenytoin concentrations measured, adverse drug reactions (ADRs), and recurrence of seizures within 24 hours of loading dose administration in the preimplementation and postimplementation groups. There was no difference in the proportion of optimal phenytoin loading doses between the preimplementation and postimplementation groups (50% versus 62%, respectively; p=0.19). When stratified by individual groups, the rate of optimal phenytoin loading doses increased by 64% in the postimplementation pharmacist group (50% versus 82%, p=0.007), while the rate in the prescriber-dosing group remained relatively unchanged (50% versus 49%, p=0.91). The number of appropriate serum phenytoin concentrations significantly improved in the postimplementation versus preimplementation group (65% versus 40%, p=0.025). Rates of ADRs and recurrence of seizures did not differ across the study groups. No change in the percentage of optimal phenytoin loading doses in the ED was observed after implementation of a combined pharmacist- and physician- dosing program. When stratified into pharmacist or prescriber dosing, the pharmacist-led dosing program significantly improved the proportion of patients who received optimal phenytoin loading doses.

Use of Levetiracetam in Prophylaxis of Early Post-Traumatic Seizures.

Traumatic brain injury is one of the leading causes of mortality and morbidity worldwide. The role of prophylactic anti-epileptic drugs has been established. Phenytoin used traditionally for this purpose carries a burden of adverse reactions and cumbersome need of monitoring and maintaining levels in serum. Therefore, as the evidence on levetiracetam, emerged part of neurosurgery section started using this drug for seizure prophylaxis after early loading with phenytoin. So we decided to assess the use of enteral levetiracetam in prophylaxis of early post-traumatic seizures. This was a retrospective cohort study done at the department of neurosurgery of Aga Khan University in Karachi from July 2010 to March 2011. Charts of patients who were started on levetiracetam enterally were reviewed and followed for occurrence of clinical seizures within one week of trauma. The results were then compared to the group of patients treated prophylactically with phenytoin alone over the same time period. The study included 50 patients in each group. Both groups were comparable in terms of demographics and baseline characteristics. However, 2 patients in each group suffered from clinical seizures with a non-significant p value. Enteral levetiracetam after initial phenytoin loading is a viable option in the armamentarium of anti-epileptic drugs. Further larger prospective studies are required to improve the evidence.

Fixed Drug Eruption in an Epileptic Patient Previously Receiving Treatment With Phenytoin for Seven Years.

A 52-year-old African American female presented with severe left thigh pain of unknown etiology. She had a past medical history of generalized seizure disorder treated with phenytoin for 7 years without incident. During admission a nurse witnessed a seizure, and consequently loading and maintenance doses of phenytoin were administered to obtain a therapeutic serum concentration. The patient had a history of noncompliance with multiple subtherapeutic phenytoin levels. Subsequently, unifocal blue discolored spots appeared, progressing to a bullous component that was positive for skin sloughing. Drug-induced fixed drug eruption was diagnosed and attributed to phenytoin. Clinicians should be cognizant of drug-induced fixed drug eruption in patients just initiated and those receiving long-term treatment with phenytoin. The administration rate of phenytoin may be associated with the development of fixed drug eruption.

Phenytoin Loading Doses in Adult Critical Care Patients: Does Current Practice Achieve Adequate Drug Levels?

Phenytoin is regularly employed in the critically ill for prophylaxis against or treatment of seizure disorders. No prior studies have examined current dosing practices in an Australasian intensive care unit (ICU) setting. The aims of this study were to: a) describe the adequacy of contemporary dosing in respect to free and total serum phenytoin concentrations; b) identify factors associated with therapeutic drug concentrations; and c) examine the accuracy of predictive equations that estimate free concentrations in this setting. All patients receiving a loading dose of phenytoin in a tertiary-level ICU were eligible for enrolment; 53 patients were enrolled in the study. Serum samples to determine free and total phenytoin concentrations (measured by high performance liquid chromatography) were then drawn prior to the following dose. Free concentrations below the recommended target (<1 mg/l) were considered as suboptimal. The most common indication for phenytoin loading was traumatic brain injury (49%) and the mean administered dose was 14.5 (3.66) mg/kg. Twenty-six patients (49%) had suboptimal trough free concentrations, although this subgroup was significantly heavier and therefore received a lower per kilogram dose (12.8 [3.1] vs 16.3 [3.4] mg/kg, P=0.001). In multivariate analysis, larger weight adjusted doses (P=0.018), higher albumin concentration (P=0.034) and receiving phenytoin for an indication other than seizure (P=0.035), were associated with a greater likelihood of adequate concentrations. In conclusion, phenytoin dosing remains complex in critically ill patients, although lower per kilogram loading doses are strongly associated with free concentrations below the desired target.

Intravenous phenytoin: a retrospective analysis of Bayesian forecasting versus conventional dosing in patients

In the hospital, medication management for effective antiepileptic therapy with phenytoin (PHT) often needs rapid IV loading and subsequent dose adjustment according to therapeutic drug monitoring (TDM). To investigate PHT performance in reaching therapeutic target serum concentration rapidly and sustainably, a Bayesian forecasting (BF) regimen was compared to conventional dosing (CD), according to the official summary of product characteristics. A 500-600 bed acute care teaching hospital in Switzerland, serving as a referral centre for neurology and neurosurgery. In a retrospective, single centre, long-term analysis of hospitalized in- and out-patients, all PHT serum tests from the central hospital laboratory from 1997 to 2007 were assessed. The BF regimen consisted of a guided, body weight-adapted rapid IV PHT loading over 5 days with pre-defined TDM time points. The conventional dosage was performed without written guidance. Assuming non-normally distributed data, non-parametric statistical methods for analysis were applied. The extent of target therapeutic PHT serum levels (40-80 μmol/L) was measured and compared between the two regimens. Also, the influence of gender and age was analysed. A total of 6,120 PHT serum levels (2,819 BF and 3,301 conventionally dosed) from 2,589 patients (869 BF and 1,720 conventionally dosed) were evaluated and compared. 63.6 % of the PHT serum levels from the BF group were within the therapeutic range, compared with only 34.0 % in the conventional group (p < 0.0001). The mean BF serum level was 52.0 ± 22.1 μmol/L (within target range) (n = 2,819), whereas the mean serum level of the CD was 39.8 ± 28.2 μmol/L (sub-target range) (n = 3,301). In the BF group, men had small but significantly lower PHT serum levels compared to women (p < 0.0001). The conventionally dosed group showed no significant gender differences (p = 0.187). A comparative sub-analysis of age-related groups (children, adolescents, adults, seniors, and elderly) showed significantly lower target levels (p < 0.0001) for each group in the conventional dosed group, compared to BF. Comparing the two cohorts, BF with the well-defined dose regimen showed significantly better performance in reaching therapeutic PHT serum levels rapidly and for longer duration.

Nonconvulsive Status Epilepticus

SUMMARY Status epilepticus (SE) can be divided into two subgroups, convul- sive status epilepticus (CSE) and nonconvulsive status epilepticus (NCSE). NCSE is clinically characterized by recurrence or persistence of absence or complex partial seizures which unconsciousness per- sists. Seizures are lasted more than 30 minutes, and accompanied by mental and behavioral changes. Although the main feature is the change of level of consciousness, affective, memory, cognitive, speech, motor systems, behavioral and psychiatric disorders can be also seen. Electroencephalography (EEG) is the single diagnos- tic method in this situation. NCSE constitutes approximately 25% of all SE, however it is thought that sometimes it is misdiagnosed and the incidence of NCSE may be higher. The causes are disorders of central nervous system (stroke, infection, trauma, tumor), and metabolic factors (hypoxia, renal diseases, drugs, failure to use an- tiepileptic drug). The treatment contains the standard therapy of SE. Short-acting benzodiazepines are preferred in initial treatment. For more resistant cases, loading of phenytoin is applied. If there is no response to treatment, midazolam and propofol additionally to barbiturates can be used. We aimed to present a case admitted to our ED with altered mental status and diagnosed as NCSE that is under-diagnosed.

Do we need sick-day guidelines for hypoparathyroidism?

Do we need sick-day guidelines for hypoparathyroidism?

Management of Acute Seizure and Status Epilepticus in Pediatric Emergency

Acute seizure and status epilepticus constitute one of the major medical emergencies in children. Among children, the incidence ranges from 4-38/100,000 children per year respectively. The incidence in developing countries is somewhat higher because of infections. Although, the definition of status epilepticus is based on duration of seizures, the operational definition is to treat any child who is brought seizing to the emergency room, as status epilepticus. An urgent time bound approach is of paramount importance when managing a child in status epilepticus. Benzodiazepines remain the first line antiepileptic drugs in the emergency room; a long acting drug (Lorazepam) is preferred when available. This is followed by Phenytoin (20 mg/kg) loading. In patients refractory to above drugs, valproate (30 mg/kg) loading is commonly used and if effective, followed by an infusion (5 mg/kg/h) for seizure free period of 6 h. In non-responders, a trial of Levetiracetam (40 mg/kg infused at 5 mg/kg/min) can be used before starting benzodiazepine or thiopental coma (3-4 mg/kg loading dose, followed by 2 mg/kg/min infusion). When pharmacological coma is initiated, the child needs to be shifted to pediatric intensive care unit for proper monitoring and titration of medications.