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 beta-adrenergic blocker toxicity are discussed; clinical data are currently lacking.

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.