Valproic Acid Overdose Research Articles

L-carnitine for valproic acid-induced toxicity.

Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.

Possible Efficacy of Agarose Powder Compared with Activated Charcoal in Treatment of Acute Valproic Acid Overdose in Rats.

Possible Efficacy of Agarose Powder Compared with Activated Charcoal in Treatment of Acute Valproic Acid Overdose in Rats.

Risk factors of hyperammonemia in epilepsy patients with valproic acid therapy

BackgroundHyperammonemia can occur after acute overdose or chronic use of valproic acid (VPA). Although VPA-related hyperammonemic encephalopathy (VHE) is a rare complication of VPA therapy, early recognition of VHE and identifying its risk factors are important because VHE can lead to loss of consciousness and increased seizure frequency. PurposeThe purpose of our study is to evaluate the risk factors of hyperammonemia in epilepsy patients during treatment with VPA therapy. MethodsWe reviewed the medical records of 1084 adult patients with epilepsy and enrolled 116 patients with VPA therapy who had results of blood levels of ammonia over a 3-year period. Hyperammonemia was defined as a blood ammonia level exceeding 80 µg/dL. Correlations of blood levels of ammonia with dosages and blood levels of VPA were evaluated. We further performed univariate and multivariate linear regression analyses to identify risk factors for hyperammonemia in epilepsy patients treated with VPA therapy. ResultsBlood levels of ammonia were well correlated with dosages of VPA (p = 0.036), but not with blood levels of VPA (p = 0.463). Hyperammonemia was more common in patients with higher VPA dosage and higher total drug loads of concurrent antiseizure medications (ASMs). Hyperammonemia was also associated with the use of topiramate and phenobarbital. In multivariate analysis, we identified total drug load of ASMs (p = 0.003) and use of topiramate (p = 0.007) as independent predictors of hyperammonemia. Four patients (4/116, 3.4 %) had clinical symptoms of VHE. Three of them had hyperammonemia while the other patient had normal blood level of ammonia with a high blood level of VPA. ConclusionOur study shows that higher total drug loads of concurrent ASMs and use of topiramate were independent risk factors of hyperammonemia in epilepsy patients with VPA therapy. Although the incidence of VHE was not high in our study, clinicians should be aware of this potential adverse effect of VPA therapy, especially in patients with polytherapy of ASMs including topiramate.

Combined Therapy in Severe Valproic Acid Intoxication

Valproic acid is frequently given to individuals who suffer from a variety of psychological and neurological conditions, including bipolar disorder, manic-depressive psychosis, major depressive disorder, post-traumatic stress disorder, and epilepsy. Because of its narrow therapeutic spectrum, it is one of agents that frequently cause toxicological emergencies. This case presents an adult patient who had valproic acid overdose, required intubation, hemodialysis, and concurrent treatment with carbapenem group antibiotics. Keywords: Valproic acid, intoxication, hemodialysis, carbapenem

Treatment of valproic acid overdose with meropenem in an epileptic patient

Valproic acid (VPA) and derivatives are effective anticonvulsants that are also used for numerous mood disorders. VPA toxicity can cause central nervous system (CNS) depression, dose related hyperammonemia, and eventually hepatotoxicity. While traditional treatment of VPA toxicity often includes l-carnitine, activated charcoal, and hemodialysis; an interaction with carbapenem class antibiotics has been well established in literature and may offer a different avenue of treatment. This case describes a 38year-old female with a past medical history of epilepsy effectively treated with meropenem to rapidly and safely lower toxic VPA levels after an acute ingestion. A review of four VPA poisoning case reports and the interaction with carbapenem class antibiotics is also included.

A case of valproic acid overdose with delayed hyperammonemia due to carnitine deficiency

A case of valproic acid overdose with delayed hyperammonemia due to carnitine deficiency

Late-stage sequela of an isolated optic neuropathy after acute magnesium valproate overdose: A case report.

Magnesium valproate is a valproic acid (VPA) derivative that is widely used for the treatment of epilepsy and bipolar disorders. Acute overdose of VPA may cause complicated systemic syndromes; however, the reports of ocular sequelae caused by toxic optic neuropathy (TON) are rare. We present a case of a 19-year-old female with bilateral damage to visual function after acute VPA overdose. She was comatose and received systemic treatments for 1 month, during which she suffered a substantial loss of visual function without any evident neurological sequelae. The first recorded visual acuity was no light perception in the right eye (OD) and hand motion in the left eye (OS). Her best-corrected visual acuity improved to 20/100 OS after 4 months of hyperbaric oxygen therapy and neurotrophic treatments. Her visual field was limited to an inferior nasal area OS. Therefore, a diagnosis of TON was made. Her visual function remained stable in the left eye, but did not recover in the right eye during the 5-month follow-up. We found damage to the optic nerve pathway during ophthalmic examinations. We report a rare case of TON caused by acute VPA overdose. Hyperbaric oxygen therapy, and neuroprotective and neurotrophic treatments might be effective at the early stage but cannot fully reverse the damage to the optic nerve. The present case indicates the potential neurotoxicity of VPA. It is crucial to determine the severity of an isolated optic nerve sequela caused by VPA overdose, though it might be rare as observed in previous reports. Further confirmation of the likelihood of its causation and its pathophysiology is needed in the future.

Two cases of L-carnitine replacement therapy for valproic acid overdose

Two cases of L-carnitine replacement therapy for valproic acid overdose

Valproic acid overdose. Review of the clinical cases in a third level hospital in Spain

The composite materials have a gained a tremendous usage in the areas of the aerospace, aeronautical and marine engineering areas. Due to such heavy usage of composites, many researchers are working on the topic of improving materials properties of the composites and tailoring their properties for a specific application. In the process of improving the composite materials, the researchers have identified hybridization as one of the decent methods for achieving better and tailored properties for the composite materials. In this paper, the effect of the stacking sequence arrangement on the mechanical and thermal properties of the hybrid laminates has been investigated. In this paper, two types of hybrid stacking arrangements namely sandwich and interlaced hybrid sequences has been investigated. Two different hybrid laminates namely kevlar49/S-glass laminas and IM7-carbon/boron lamina shave been developed and analyzed to know the generalized effectiveness of the hybrid stacking sequence. The modeling and analysis of the problem were performed using the MATLAB software. The properties of the individual lamina were found using finite element analysis implemented in ANSYS software.

Valproic Acid Overdose Review of a Case With Electrocardiographic Changes

BackgroundValproic acid (VPA) is increasingly used to treat a variety of medical disorders, such as seizures, psychiatric disorders, and headaches. Therefore, accidental and intentional ingestions with valproic acid are increasing. ObjectivesA case is presented in an adolescent with ischemic electrocardiographic changes after an acute overdose with VPA. DiscussionMajor features of a valproic acid overdose include respiratory depression, progressive coma, hepatotoxicity, thrombocytopenia, and hemodynamic instability. Electrocardiographic abnormalities usually consist of tachycardia and nonspecific changes. Supportive care is indicated in most overdoses and involves the monitoring and correction of electrolyte abnormalities, coagulopathies, and acid-base imbalances. Treatment may include activated charcoal, naloxone, l-carnitine, and extracorporeal detoxification. ConclusionsValproic acid overdose is a relatively rare and electrocardiographic changes usually consist of tachycardia and nonspecific changes, but ischemic changes may occur and usually transient and require only recognition.

L-Arginine in the treatment of valproate overdose – five clinical cases

Background: Valproic acid and its metabolites – particularly valproyl-CoA – are inhibitors of the enzyme N-acetylglutamate synthetase. The amino acid l-arginine can stimulate N-acetylglutamate synthetase activity and could be potentially used therapeutically to correct hyperammonemia caused by valproate therapy or overdose. Severely valproic-acid-poisoned patients are usually treated with l-carnitine or hemodialysis in order to decrease hyperammonemia. We herein report of five cases, in which l-arginine was administered. Methods: Observational study on five cases. Patients with hyperammonemia (i.e., ammonia 80 > μg/dL) and symptoms consistent with valproate overdose (i.e., drowsiness, coma) were selected for treatment with l-arginine. Data was collected retrospectively. Results: l-Arginine decreased ammonia levels in a close temporal relation (case I ammonia in EDTA-plasma [μg/dL] decreased from 381 to 39; case II from 281 to 50; case III from 669 to 74; case IV from 447 to 56; case V from 202 to 60). In cases I and II, hemodialysis was performed and l-carnitine was given before the administration of l-arginine. In case III, hemodialysis was performed after the administration of l-arginine was already started. In cases IV and V, treatment with l-arginine was the sole measure to decrease ammonia levels in plasma. Conclusion: The results suggest that l-arginine may be beneficial in selected cases of valproate overdose complicated by hyperammonemia. l-Arginine could extend our conventional treatment options for valproic acid overdose.

Favorable results after conservative management of 316 valproate intoxicated patients.

Background:Valproic acid (VPA) is an effective antiepileptic drug widely used worldwide. Despite several studies indicating the usefulness of intravenous L-carnitine in the treatment of VPA poisoning, this drug is not readily available in Iran. The aim of this study was to determine whether supportive care without antidote would result in acceptable outcomes in VPA poisoned patients.Materials and Methods:In an observational, retrospective, single-center case series, all patients >12-year-old with VPA overdose who had referred to a tertiary center between 2009 and 2013 were consecutively enrolled. Patients’ demographic and presenting features, physical examinations, clinical management, laboratory data, and outcomes were recorded.Results:A total of 316 patients were enrolled with pure VPA toxicity. The most common presenting signs/symptoms were drowsiness, nausea and vomiting, vertigo, and headache. In the course of the disease, 14 patients (4.4%) were intubated and three (0.9%) required hemodialysis with mean dialysis sessions of two. Fourteen patients were admitted to Intensive Care Unit, and seizures occurred in five. The initial level of consciousness was lower in patients with poor outcome. The median ingested dose of VPA in patients who required dialysis was significantly higher (20 vs. 6 g; P = 0.006). Multivariate analyses revealed that coma on presentation was associated with a worse outcome (P = 0.001; odds ratio = 61.5, 95% CI = 5.8-646.7).Conclusion:Prognosis of VPA poisoned patients appears to be good even with supportive care. According to our study, older age, ingestion of higher amounts of VPA and lower PCO2, HCO3, base excess, and CPK levels prone the patients to more severe toxicities in univariate analysis, but the main poor prognostic factor is coma on presentation in multivariate analysis.

Altered Mental Status and Hyperammonemia after Overdose of Valproic Acid with Therapeutic Valproic Acid Concentrations

Valproic acid is used in the treatment of multiple disorders. Adverse effects from valproic acid include hepatotoxicity, hypotension, metabolic acidosis, and decreased mental status. Valproic acid also causes hyperammonemia. Many physicians assume that this is due to a supratherapeutic valproic acid concentration; when in fact, it can occur with therapeutic valproic acid concentrations. This is because the hyperammonemia may be related to carnitine deficiency and disruption of the urea cycle, which can both occur with therapeutic valproic acid concentrations. We report a patient presented to the emergency department with alteration of mental status after ingesting valproic acid for recreational purposes, who developed hyperammonemia with a therapeutic valproic acid concentration.

Successful Treatment of Valproic Acid Intoxication with Hemodialysis and L-Carnitine

Valproic acid (VPA) is a conventional antiepileptic drug and, in parallel to its widespread prescription, it has been used in many cases of suicide attempts. VPA intoxication may cause electrolyte disturbances, hepatotoxicity, pancreatitis, bone marrow suppression, and brain edema. However, there is no specific antidote for treatment of VPA overdose. Case reports describe the efficacy of naloxone, L-carnitine and various extracorporeal elimination techniques in the treatment of VPA toxicity. We present the case of a 31 year old female with VPA intoxication who was successfully treated with hemodialysis and L-carnitine, and a review of the literature on the management of VPA overdose.

Presence of a volatile substance mistaken for diethylene glycole in plasma in a case of valproic acid overdose

Presence of a volatile substance mistaken for diethylene glycole in plasma in a case of valproic acid overdose

Levocarnitine-Induced Hypophosphatemia in a Hemodialysis Patient With Acute Valproic Acid Toxicity

To the Editor: Levocarnitine is utilized for valproic acid overdose to prevent the formation of hepatotoxic metabolites. Levocarnitine has been shown to reduce phosphorus levels. We present a case where levocarnitine was administered for valproic acid toxicity and may have contributed to hypophosphatemia. Levocarnitine (L-carnitine) may be utilized for acute toxicity in valproic acid (VPA) overdose. It is primarily metabolized in the liver via glucuronidation and also undergoes mitochondrial beta-oxidation and microsomal omega-oxidation. In overdose, a shift in metabolism to the omega-oxidative pathway occurs, yielding the hepatotoxic metabolite 2-propyl-4-pentanoic acid. L-carnitine acts as a cofactor for VPA metabolism, increasing beta-oxidation of VPA and limiting hepatotoxic metabolites. 1

Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy

The use of levocarnitine for the treatment of valproic-acid-induced hyperammonemic encephalopathy (VHE) is reviewed. VHE is generally characterized by an acute onset of impaired consciousness, focal neurologic symptoms, and increased seizure frequency. The exact mechanism of VHE is unclear but relates to the accumulation of toxic valproic acid metabolites and elevated ammonia levels. Carnitine is an essential cofactor in the proper metabolism of valproic acid and ammonia elimination. A lack of carnitine is thought to contribute to hyperammonemia. Valproic acid is thought to increase renal metabolism of glutamate and may contribute to ammonia production. Levocarnitine, the active isomer of carnitine, has been used to treat VHE resulting from valproic acid overdose as well as usual dosages of valproic acid. A literature search of PubMed was conducted for all English-language articles published from 1948 to May 2011 regarding the use of levocarnitine for VHE. Search terms included levocarnitine, l-carnitine, valproic acid, and hyperammonemia encephalopathy. Although large, randomized controlled trials of levocarnitine treatment in VHE are lacking, levocarnitine has been shown to be generally safe and effective in retrospective trials and case reports. Overall, there is more literature supporting the use of levocarnitine in VHE associated with acute overdose than with short- or long-term treatment with usual dosages of valproic acid. No adverse events related to levocarnitine therapy were reported in any of the literature reviewed. Prospective trials are needed to further support the efficacy and safety of levocarnitine in the treatment of VHE. Levocarnitine may be effective and appears to be safe in the treatment of VHE.

Image in toxicology: Pseudo-subarachnoid hemorrhage in a case of severe valproic acid poisoning

Pseudo-subarachnoid hemorrhage (PSAH) is a false-positive finding on cranial computed tomography (CT) in patients with cerebral edema. Its appearance on CT resembles subarachnoid hemorrhage despite the absence of subarachnoid blood. We report the finding of PSAH in a case of massive valproic acid overdose.

L-Carnitine for Acute Valproic Acid Overdose: A Systematic Review of Published Cases

To review the evidence supporting the efficacy and safety of l-carnitine in the management of acute valproic acid overdose. MEDLINE (1950-May 2010), EMBASE (1980-May 2010), and Google Scholar (to May 2010) were searched, using the terms carnitine, valproic acid, and carnitine for valproic acid overdose. Reference citations from identified publications were reviewed. Full-text publications evaluating the use of l-carnitine for management of valproic acid overdose in humans were sought. All studies, regardless of design, case series, and case reports reporting efficacy or safety endpoints were included. All languages were included. Two authors extracted primary data elements including patient demographics, presenting features, clinical management, and outcomes. Seven articles discussing 8 patients and 1 reporting safety data from records of 674 patients were reviewed. Reports covered both pediatric and adult patients with acute exposures to valproic acid mono- and polydrug overdose who were treated with various regimens of l-carnitine. All patients recovered clinically and no adverse effects were noted. Published evidence of the efficacy and safety of l-carnitine as an antidote for acute valproic acid overdose is limited. Based on the available evidence, it is reasonable to consider l-carnitine for patients with acute overdose of valproic acid who demonstrate decreased level of consciousness. We recommend intravenous administration of 100 mg/kg once, followed by infusions of 50 mg/kg (to a maximum of 3 g per dose) every 8 hours thereafter, continuing until ammonia levels are decreasing (if they were elevated initially) and the patient demonstrates signs of clinical improvement or until adverse events associated with l-carnitine occur.

A Case of Valproic Acid Overdose Treated with Continuous Veno-Venous Hemodiafiltration - A Case Report -

A Case of Valproic Acid Overdose Treated with Continuous Veno-Venous Hemodiafiltration - A Case Report -