Philippe Lheureux

Carnitine in the treatment of valproic acid-induced toxicity.

Introduction. Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. VPA is usually well tolerated, but serious complications, including hepatotoxicity and hyperammonemic encephalopathy, may occur. These complications may also arise following acute VPA overdose, the incidence of which is increasing. Intoxication usually only results in mild central nervous system depression, but serious toxicity and death have been reported. Valproic acid and carnitine. As a branched chain carboxylic acid, VPA is extensively metabolized by the liver via glucuronic acid conjugation, mitochondrial β- and cytosolic ω-oxidation to produce multiple metabolites, some of which may be involved in its toxicity. Carnitine is an amino acid derivative that is an essential cofactor in the β-oxidation of fatty acids. It is synthesized endogenously from the essential amino acids, methionine and lysine. VPA inhibits the biosynthesis of carnitine by decreasing the concentration of α-ketoglutarate and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the β-oxidation of VPA, thereby limiting cytosolic ω-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. Carnitine supplementation. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy although a correlation between ammonia concentrations and the clinical condition was not always observed. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children, although the clinical benefit in terms of liver protection or hastening of recovery from unconsciousness has not been established clearly. Prophylactic carnitine supplementation is also advocated during VPA therapy in high-risk pediatric patients. Conclusion. Further controlled, randomized, and probably multicenter trials are required to better delineate the therapeutic and prophylactic roles of l-carnitine and the optimal regimen of administration in the management of VPA toxicity.

Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions.

Pyridoxine in clinical toxicology: a review

Pyridoxine (vitamin B6) is a co-factor in many enzymatic pathways involved in amino acid metabolism: the main biologically active form is pyridoxal 5-phosphate. Pyridoxine has been used as an antidote in acute intoxications, including isoniazid overdose, Gyromitra mushroom or false morrel (monomethylhydrazine) poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid into glycine in ethylene glycol poisoning. Other indications are recommended by some sources (for example crimidine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant supporting data. The value of pyridoxine or its congener metadoxine as an agent for hastening ethanol metabolism or improving vigilance in acute alcohol intoxication is controversial. This paper reviews the various indications of pyridoxine in clinical toxicology and the supporting literature. The potential adverse effects of excessive pyridoxine dosage will also be summarized.

Acute and long term respiratory damage following inhalation of ammonia.

A lifelong non-smoker who was the victim of a massive accidental exposure to anhydrous ammonia gas was followed up for 10 years. In the acute phase the patient presented with severe tracheobronchitis and respiratory failure, caused by very severe burns of the respiratory mucosa. After some improvement he was left with severe and fixed airways obstruction. Isotope studies of mucociliary clearance, computed tomography, and bronchography showed mild bronchiectasis. It is concluded that acute exposure to high concentrations of ammonia may lead to acute respiratory injury but also to long term impairment of respiratory function.

Bench-to-bedside review: Hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers

Hyperinsulinaemia/euglycaemia therapy (HIET) consists of the infusion of high-dose regular insulin (usually 0.5 to 1 IU/kg per hour) combined with glucose to maintain euglycaemia. HIET has been proposed as an adjunctive approach in the management of overdose of calcium-channel blockers (CCBs). Indeed, experimental data and clinical experience, although limited, suggest that it could be superior to conventional pharmacological treatments including calcium salts, adrenaline (epinephrine) or glucagon. This paper reviews the patho-physiological principles underlying HIET. Insulin administration seems to allow the switch of the cell metabolism from fatty acids to carbohydrates that is required in stress conditions, especially in the myocardium and vascular smooth muscle, resulting in an improvement in cardiac contractility and restored peripheral resistances. Studies in experimental verapamil poisoning in dogs have shown that HIET significantly improves metabolism, haemodynamics and survival in comparison with conventional therapies. Clinical experience currently consists only of a few isolated cases or short series in which the administration of HIET substantially improved cardiovascular conditions in life-threatening CCB poisonings, allowing the progressive discontinuation of vasoactive agents. While we await further well-designed clinical trials, some rational recommendations are made about the use of HIET in severe CBB overdose. Although the mechanism of action is less well understood in this condition, some experimental data suggesting a potential benefit of HIET in β-adrenergic blocker toxicity are discussed; clinical data are currently lacking.

Flumazenil in mixed benzodiazepine/tricyclic antidepressant overdose: A placebo-controlled study in the dog☆

This study evaluates the cardiac and neurologic risks associated with the antagonization of the benzodiazepine component of mixed drug overdoses, when cyclic antidepressants are also implicated. Twenty-four mongrel dogs were anesthetized and ventilated. Electroencephalogram, electrocardiogram, and tidal carbon dioxide and arterial pressure were continuously recorded. Amitriptyline (1 mg/kg/min) associated with midazolam (1 mg/kg + 1 mg/kg/h) was infused in 12 of the dogs. Midazolam was replaced by saline in the other 12. Drug administration was continued until signs of cardiotoxicity (QRS prolongation greater than 120 milliseconds or sustained arrhythmias) occurred. At that moment, midazolam effects were suddenly reversed by administration of flumazenil 0.2 mg/kg in six dogs out of each group. Placebo was administered in the others. Reactions were observed for the next 120 minutes. Midazolam-induced sedation efficiently protects (P less than .02) against seizures due to amitriptyline toxicity. This protective effect is counteracted by flumazenil. Midazolam has limited influence on the cardiac toxic effects of amitriptyline. The bolus of flumazenil is, however, associated with a significant worsening of electrocardiogram disturbances, and two sudden deaths were recorded. The mechanism of this effect remains unclear, as it could be unrelated to the antagonization of midazolam sedation. Given the problem of extrapolating animal data to humans, these results suggest that bolus administration of high doses of flumazenil in mixed intoxication implicating benzodiazepine and cyclic antidepressants has the potential to precipitate convulsions and/or arrhythmias. A slowly titrated administration of the antidote, as usually recommended, could prevent these effects.

Zolpidem Intoxication Mimicking Narcotic Overdose: Response to Flumazenil

Zolpidem is a recently introduced sleep-inducer which is thought to act on the central-type benzodiazepine receptors. This observation is the first report of drug poisoning with this compound. The toxic response was characterized by the development of a profound but short-lasting coma, associated with pin-point pupils and respiratory depression, as observed in a narcotic overdose. These clinical signs were not influenced by the administration of naloxone, but responded dramatically to flumazenil. Some analytical data on zolpidem toxicokinetics are presented.

Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study.

Background: The choice of tetanus prophylaxis for patients with wounds depends on obtaining their vaccination history, which has been demonstrated to be unreliable. Use of a rapid immunoassay (Tétanos Quick Stick, the TQS), combined with knowledge of certain demographic characteristics, may improve the evaluation of tetanus immunity and thus help to avoid inadequate prophylactic measures and reduce costs. Objectives: To evaluate the contribution of the TQS in the choice of tetanus prophylaxis and to perform a cost-effectiveness analysis. The final aim was to define the place of the TQS in a modified algorithm for assessment of tetanus immunity in the emergency department. Method: In this Belgian prospective, double-blind, multicentre study, 611 adult patients with a wound were included; 498 (81.5%) records were valid. The TQS test was performed by a nurse before the vaccination history was taken and the choice of prophylaxis was made, using the official algorithm (Belgian Superior Health Council), by a doctor who was unaware of the TQS result. Results: The prevalence of protective anti-tetanus immunity was 74.1%. Immunity was lower in older patients and in female patients. The TQS was a cost-effective tool for patients presenting with a tetanus-prone wound and considered from the vaccination history to be unprotected. Use of the TQS would have improved management in 56.9% (95% CI 47.7% to 65.7%) of patients by avoiding unnecessary treatments, leading to a reduction in the mean cost per patient (€10.58/patient with the TQS versus €11.34/patient without). The benefits of the TQS use were significantly greater in patients <61 years old: unnecessary treatment would have been avoided in 76.9% (95% CI 65.8% to 85.4%) of cases and the mean cost per patient reduced to €8.31. Conclusion: In selected patients, the TQS is a cost-effective tool to evaluate tetanus immunity. An algorithm is proposed for ED assessment of tetanus immunity integrating age and the TQS result.

Survey of non-invasive ventilation for acute exacerbation of chronic obstructive pulmonary disease patients in emergency departments in Belgium.

A study was undertaken to assess the availability and use of non-invasive ventilation (NIV) for the treatment of acute exacerbation of chronic obstructive pulmonary disease (COPD) in emergency departments in Belgium. A questionnaire was sent to the head physicians of 145 emergency departments (EDs) found in the list of the Belgian College of Emergency Physicians (BeCEP). Ninety eight questionnaires were analysed (representing 68% of the questionnaires sent). NIV was used in 49% of the EDs. In the hospitals where NIV was not used, the most important reasons given were no available equipment in 71%, lack of experience with this form of treatment in 32.7%, and more time consuming for physicians and nursing staff in 22.8%. Only 3.8% of the physicians doubted the benefit of NIV treatment. In the hospitals where NIV was used, the patient was watched during the first hour by one nurse only in 19.6%, by one physician in 8.6% and by a nurse and a physician in 54.5%. NIV was used for more than 4 h in 33% of EDs. Pressure-controlled ventilation (with home respirators) was used more often than volume-controlled ventilation.

Specific treatment of benzodiazepine overdose

Intentional benzodiazepine (BZD) overdose is usually a benign condition frequently encountered in the emergency department of hospital. Twenty-one patients, who were suspected of BZD overdose, were treated with the antagonist of the central type BZD-receptors Ro 15-1788. Samples for toxicological analysis were taken before and after treatment. The patients were divided into three groups. In the first group (pure BZD overdose, n = 9), rapid and complete awakening was observed in all the patients (9/9) with 3.5 ± 1.5 mg Ro 15-1788. In the second group of patients with multiple drugs poisoning (including BZD, n = 6), CNS depression improved in all the patients despite incomplete awakening. In the last group (n = 6), where no BZD were detected in toxicological samples, none of the comatous patients improved significantly during Ro 15-1788 administration, except one patient with pure ethanol intoxication. No undesirable effects are reported, except mild transitory withdrawal syndrome in three cases following rapid injection. This study supports the introduction of Ro 15-1788 as a useful antidote in the diagnosis and the treatment of drug-induced coma.