Meropenem as an antidote for intentional valproic acid overdose.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug indicated for monotherapy and adjunctive therapy of seizures, and complex manic episodes associated with bipolar disorder [1]. While uncommon due to monitoring, VPA can cause toxicity at supratherapeutic levels [1, 2]. Traditional treatment for VPA toxicity is primarily supportive care, however activated charcoal, l-carnitine, and hemodialysis have been successful in removing free VPA [2]. An interaction between carbapenem antibiotics and VPA is well-established and listed in respective package inserts as a combination to be avoided due to decreased VPA efficacy [1, 3]. Recent literature suggests co-administration of meropenem with VPA reduces mean plasma VPA levels by 50-80% [4, 6]. This case report describes the successful use of carbapenems to intentionally lower toxic VPA levels in a 42 year old female that presented to the emergency department with VPA toxicity from an overdose with divalproex sodium.

Levocarnitine for the Treatment of Valproic Acid-Induced Hyperammonemic Encephalopathy in Children: The Experience of a Large, Tertiary Care Pediatric Hospital and a Poison Center.

BACKGROUND: Although rare, symptomatic hyperammonemia is sometimes associated with valproic acid (VPA), especially in children. L-carnitine (levocarnitine), sometimes classified as an essential amino acid, is vital to mitochondrial utilization of fatty acids and can be helpful in treating this condition. The data supporting this, however, are limited. STUDY QUESTION: The aim of the study was to illustrate the role of L-carnitine in the treatment of patients with VPA-induced hyperammonemic encephalopathy (VPE) at 2 different institutions. METHODS: Medical records of affected patients were reviewed; data collected included exposure history, clinical manifestations, physical examination, and laboratory values. RESULTS: There were 13 cases of VPE; 12 were associated with therapeutic dosing and 1 with an overdose. The maximum ammonia concentration was 557 µmol/L, and blood concentrations of VPA ranged from 68 to 600 µg/mL (therapeutic range 50-100 µg/mL). In all cases, liver function tests were normal or only mildly increased. In this study, 12 patients received a daily dose of L-carnitine 100 mg/kg, and 1 received 200 mg/kg (intravenous infusion over 30 minutes) divided every 8 hours until clinical improvement. All patients made a full recovery. None developed adverse effects or reactions, and no cases of toxicity were reported. CONCLUSION: Our series suggests that intravenous L-carnitine, at a dose of 100 mg·kg·d in 3 divided doses each over 30 minutes until clinical improvement occurs, is a safe and effective treatment in the management of VPE in children.

Valproic Acid Overdose Review of a Case With Electrocardiographic Changes.

BACKGROUND: Valproic 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. OBJECTIVES: A case is presented in an adolescent with ischemic electrocardiographic changes after an acute overdose with VPA. DISCUSSION: Major 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. CONCLUSIONS: Valproic 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.

Severe Acute Valproic Acid Intoxication Successfully Treated with Liver Support Therapy.

Valproic acid (VPA) is widely used for the treatment of epilepsy. However, its overdose can cause intoxication and could be life-threatening. Due to the lack of specific antidote and poorness of endogenous clearance, extracorporeal treatment for severe intoxication cases is indicated. Here, we report a case of severe intoxication of VPA which was successfully treated with liver support therapy. A previously healthy woman was admitted due to coma and hypotension after intentional ingestion of 20 g of sodium valproate. Her serum concentration of VPA measured on admission was 420.84 mg/L. In addition to standard therapy, she received two sessions of extracorporeal blood purification using a system based on fractionated plasma separation and adsorption mode integrated with continuous veno-venous haemofiltration (FPSA-CVVH), which is usually used for liver support therapy at our hospital. Her serum concentration of VPA decreased dramatically to 40.18 mg/L and her consciousness recovered completely within 24 hr after admission. Therefore, although haemodialysis has been reported to be effective in the treatment for VPA poisoning, FPSA-CVVH may provide an option for patients who require bedside therapy but have an unstable haemodynamic status or other conditions that result in inability to endure haemodialysis.

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.

Psychoactive pharmaceuticals at environmental concentrations induce in vitro gene expression associated with neurological disorders.

BACKGROUND: A number of researchers have speculated that neurological disorders are mostly due to the interaction of common susceptibility genes with environmental, epigenetic and stochastic factors. Genetic factors such as mutations, insertions, deletions and copy number variations (CNVs) are responsible for only a small subset of cases, suggesting unknown environmental contaminants play a role in triggering neurological disorders like idiopathic autism. Psychoactive pharmaceuticals have been considered as potential environmental contaminants as they are detected in the drinking water at very low concentrations. Preliminary studies in our laboratory identified gene sets associated with neuronal systems and human neurological disorders that were significantly enriched after treating fish brains with psychoactive pharmaceuticals at environmental concentrations. These gene expression inductions were associated with changes in fish behavior. Here, we tested the hypothesis that similar treatments would alter in vitro gene expression associated with neurological disorders (including autism) in human neuronal cells. We differentiated and treated human SK-N-SH neuroblastoma cells with a mixture (fluoxetine, carbamazepine and venlafaxine) and valproate (used as a positive control to induce autism-associated profiles), followed by transcriptome analysis with RNA-Seq approach. RESULTS: We found that psychoactive pharmaceuticals and valproate significantly altered neuronal gene sets associated with human neurological disorders (including autism-associated sets). Moreover, we observed that altered expression profiles in human cells were similar to gene expression profiles previously identified in fish brains. CONCLUSIONS: Psychoactive pharmaceuticals at environmental concentrations altered in vitro gene expression profiles of neuronal growth, development and regulation. These expression patterns were associated with potential neurological disorders including autism, suggested psychoactive pharmaceuticals at environmental concentrations might mimic, aggravate, or induce neurological disorders.

Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup.

BACKGROUND: The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup presents its systematic review and clinical recommendations on the use of extracorporeal treatment (ECTR) in valproic acid (VPA) poisoning. METHODS: The lead authors reviewed all of the articles from a systematic literature search, extracted the data, summarized the key findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote was conducted to determine the final workgroup recommendations. RESULTS: The latest literature search conducted in November 2014 retrieved a total of 79 articles for final qualitative analysis, including one observational study, one uncontrolled cohort study with aggregate analysis, 70 case reports and case series, and 7 pharmacokinetic studies, yielding a very low quality of evidence for all recommendations. Clinical data were reported for 82 overdose patients while pharmaco/toxicokinetic grading was performed in 55 patients. The workgroup concluded that VPA is moderately dialyzable (level of evidence = B) and made the following recommendations: ECTR is recommended in severe VPA poisoning (1D); recommendations for ECTR include a VPA concentration > 1300 mg/L (9000 µmol/L)(1D), the presence of cerebral edema (1D) or shock (1D); suggestions for ECTR include a VPA concentration > 900 mg/L (6250 µmol/L)(2D), coma or respiratory depression requiring mechanical ventilation (2D), acute hyperammonemia (2D), or pH ≤ 7.10 (2D). Cessation of ECTR is indicated when clinical improvement is apparent (1D) or the serum VPA concentration is between 50 and 100 mg/L (350-700 µmol/L)(2D). Intermittent hemodialysis is the preferred ECTR in VPA poisoning (1D). If hemodialysis is not available, then intermittent hemoperfusion (1D) or continuous renal replacement therapy (2D) is an acceptable alternative. CONCLUSIONS: VPA is moderately dialyzable in the setting of overdose. ECTR is indicated for VPA poisoning if at least one of the above criteria is present. Intermittent hemodialysis is the preferred ECTR modality in VPA poisoning.

Overdose with antiepileptic drugs: the efficacy of extracorporeal removal techniques.

Drug overdose is a growing problem among adolescents. Clinical severity depends on the drug and ingested amount, which in some cases may be life-threatening. We present a clinical case of a previously healthy teenage girl who ingested 16.4 g of carbamazepine and 14.5 g of valproic acid. She presented with profound disturbance of consciousness and toxic levels of both drugs, raised in the first hours after the ingestion. She was successfully treated with charcoal haemoperfusion followed by continuous venovenous hemodiafiltration. Overdose with the two drugs separately is common, but there are no reports of intoxication by simultaneous ingestion. High levels of carbamazepine and valproic acid can lead to severe systemic effects and management is made difficult by the absence of specific antidotes. Extracorporeal removal techniques are a good therapeutic option in these cases as they enhance the clearance by reducing the half-life of both drugs thereby preventing serious complications.

Peripheral mononeuropathy associated with valproic acid poisoning in an adult patient.

OBJECTIVE: To present the case of axillary nerve neuropathy associated with valproic acid (VPA) poisoning. CASE REPORT: A 26-year-old man was hospitalized because of a suicide attempt with VPA overdose. Toxicology analysis revealed high serum VPA level (2,896 µmol/L; therapeutic range: 350 - 690 µmol/L). Three days after admission, the patient complained of weakness in his right arm. Neurological examination revealed weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. A nerve conduction velocity test was normal in the ulnar, radial, median, musculocutaneous, and suprascapular nerves. Compound muscle action potential showed reduced amplitude and prolonged latencies in the right axillary nerve taken from Erb's point and absent taken from distal stimulation point. Right axillary nerve paresis was diagnosed and the patient underwent a physical therapy program, which resulted in gradual recovery. DISCUSSION: In the presented case, other possible causes of neuropathy were excluded by medical history, laboratory and radiological tests, and clinical course of the disease.The temporal relationship between the VPA poisoning and the occurrence of neuropathy supports the hypothesis of a VPA-caused axillary neuropathy. According to the Naranjo's Adverse Drug Reaction (ADR) Probability Scale, VPA-induced neuropathy was rated "probable". CONCLUSION: VPA-induced neuropathy may be a serious ADR, but it is potentially preventable and reversible. Thus, clinicians should be aware of this rare ADR.

Ameliorating effect of piperine on behavioral abnormalities and oxidative markers in sodium valproate induced autism in BALB/C mice.

Post natal exposure to VPA (valproic acid) in mice induces behavioral deficits, abnormal sensitivity to sensory stimuli and self-injurious behavior, observed in autism. Piperine has been reported to have protective effect on brain. The present study aimed at evaluating effect of piperine on VPA induced neurobehavioral and biochemical alterations in BALB/c mice. Young BALB/c mice 13 days old were procured from five different litters and segregated into five groups (n=6; 3 male, 3 female) i.e., Group I served as control group, received physiological saline on PND (Post natal day) 14 & Tween 80 p.o. from PND13-40. Group II served as normal treated group and received piperine (20mg/kg p.o.) from PND 13-40 and saline s.c. on PND 14. Group III served as valproate treated group received VPA (400mg/kg s.c.) on PND 14 and Tween 80 p.o. from PND 13-40. Group IV & V served as disease treated group received VPA (400mg/kg s.c.) on PND 14 & piperine (5 & 20mg/kg p.o.) from PND 13-40 respectively. BALB/c mice pups were subjected to behavioral testing to assess motor skill development, nociceptive response, locomotion, anxiety, and cognition on various postnatal days up to PND 40. At the end of behavioral evaluation, mice were sacrificed; brain was isolated for biochemical estimations (serotonin, glutathione, MDA and nitric oxide) and histopathological examination. Our study revealed that treatment with piperine significantly improved behavioral alterations, lowered oxidative stress markers, and restored histoarchitecture of cerebellum. This ameliorating effect of piperine is attributed to its anti-oxidant activity, cognition enhancing and neuroprotective activity.

The toxic trio: valproic acid, lithium, and carbamazepine.

Patients with altered mental status and seizure or psychiatric disease often present with an unclear medication history. Commonly prescribed medications include valproic acid (VPA), lithium (Li), or carbamazepine (CZN) of which the regional poison center (RPC) often recommends obtaining these serum concentrations. Regularly ruling out supratherapeutic concentrations without a known history of ingestion may help direct care. Cases from the RPC coded as VPA, Li, and CZN, from January 1, 2006 to December 31, 2008, were searched. All patients with supratherapeutic concentrations (VPA >100 µg/mL, Li >1.2 mEq/L, and CZN >12 µg/mL) were evaluated for the following criteria: (1) those with altered mental status and an unclear history of seizure or psychiatric disorder and (2) a mediation profile not including VPA, Li, or CZN. Twenty-six patients met the inclusion criteria: 8 patients in the VPA group (113-247 µg/mL; mean, 158), 9 patients in the Li group (1.9-5.2 mEq/L; mean, 2.9), and 9 patients in the CZN group (13.4-38.8 µg/mL; mean, 23.2). All patients survived and were treated with supportive care; however, 1 patient had a Li level of 5.2 mEq/L and received hemodialysis. In altered patients potentially being treated for seizure or psychiatric disorders and unknown ingestions or medication lists, obtaining concentrations of VPA, Li, and CZN may help direct care and provide clinically relevant information. The RPC detected 26 patients with supratherapeutic VPA, Li, or CZN concentrations in patients with potential indications for the agent but no available history of drug ingested or medication list. A prospective study is warranted to evaluate the usefulness of obtaining these concentrations in this patient population.

Analysis of variability of concentrations of valproic acid (VPA) and its selected metabolites in the blood serum of patients treated with VPA and patients hospitalized because of VPA poisoning.

AIM OF THE STUDY: To compare the metabolic profile of valproic acid (VPA) in the studied groups of cases through an analysis of variability of concentrations of VPA with its selected metabolites (2-ene-VPA, 4-ene-VPA, 3-keto-VPA). STUDY MATERIAL: Blood serum samples collected from 27 patients treated with VPA drugs in the Psychiatry Unit and in the Neurology and Cerebral Strokes Unit at the Ludwik Rydygier Provincial Specialist Hospital in Krakow, and blood serum samples collected from 26 patients hospitalized because of suspected acute VPA poisoning at the Toxicology Department, Chair of Toxicology and Environmental Diseases, Jagiellonian University Medical College in Krakow. RESULTS AND CONCLUSIONS: The analysis of concentrations of VPA and its selected metabolites has shown that the metabolic profile of VPA determined in cases of acute poisoning is different from cases of VPA therapy. One of VPA's metabolic pathways - the process of desaturation - is unchanged in acute poisoning and prevails over the process of ß-oxidation. The ingestion of toxic VPA doses results in an increased formation of 4-ene-VPA, proportional to an increase in VPA concentration. Acute VPA poisoning involves the saturation of VPA's metabolic transformations at the stage of ß-oxidation. The process of oxidation of 2-ene-VPA to 3-keto-VPA is slowed down after the ingestion of toxic doses.

Methylene blue used in the treatment of refractory shock resulting from drug poisoning.

BACKGROUND: Methylene blue inhibits the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, decreasing vasodilation and increasing responsiveness to vasopressors. It is reported to improve haemodynamics in distributive shock from various causes including septicaemia and post-cardiac surgery. Reports of use in overdose are limited. We describe the use of methylene blue to treat a case of refractory distributive shock following a mixed drug poisoning. CASE DETAILS: A 41-year-old male presented following reported ingestion of 18 g extended-release quetiapine, 10 g controlled-release carbamazepine, 240 mg fluoxetine, 35 g enteric-coated sodium valproate and 375 mg oxazepam. He was comatose and intubated on presentation. Progressive hypotension developed. Echocardiogram revealed a hyperdynamic left ventricle, suggesting distributive shock. The patient remained hypotensive despite intravenous fluid boluses, escalating vasopressor infusions. Arterial blood gas revealed metabolic acidaemia and high lactate. Methylene blue was administered as loading-dose of 1.5 mg/kg and continuous infusion (1.5 mg/kg/h for 12 h, then 0.75 mg/kg/h for 12 h) resulting in rapid improvement in haemodynamic parameters and weaning of vasopressors. Serum quetiapine concentration was 18600 ng/mL (30-160 ng/mL), collected at the time of peak toxicity. CONCLUSION: Severe quetiapine poisoning produces hypotension primarily from alpha-adrenoreceptor antagonism. Methylene blue may have utility in the treatment of distributive shock resulting from poisoning refractory to standard vasopressor therapy.

Chronic valproic acid intoxication.

Valproic acid intoxication may be associated with cerebral, cardiovascular, respiratory, gastrointestinal, and hematologic complications. We report a case of a 7-year-old girl, epilepsy-treated chronically with valproic acid, sulthiame, and clonazepam, who presented to the emergency room because of a global deterioration during the preceding 2 months, including poorer feeding and worsened general responsiveness. The girl was later diagnosed to have chronic valproic acid intoxication.