Dantrolene--a new therapeutic approach to the neuroleptic malignant syndrome.

The Neuroleptic Malignant Syndrome (NMS) is a rare but severe affection (spontaneous mortality 30 to 50 per cent), associating fever, hypertonia with myolysis, and respiratory impairment. Its mechanism remains debatable: The origin of the hypertonia might be central (as phenothiazines and butyrophenones induce a blockade of dopaminergic receptors in the hypothalamus) or it might be muscular (with an impairment of the sarcoplasmic reticulum uptake of calcium in a genetically abnormal muscle, as is proven in malignant hyperthermia). Whatever the actual mechanism, the oral or intravenous administration of sodium dantrolene, a peripheral muscle relaxant agent which does not affect the neuromuscular transmission but prevents the calcium-dependent contraction of actin and myosine, has proved to be effective in three recent cases of NMS.

Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: a report of two cases.

Two schizophrenic patients developed muscular rigidity, stupor, and hyperpyrexia consistent with neuroleptic malignant syndrome, 8 to 10 days after starting haloperidol therapy. Muscle rigidity was not affected by etybenzatropine or diazepam, but dantrolene, a direct-acting skeletal muscle relaxant, provided muscle relaxation with a concomitant decrease of fever and serum creatine kinase. Neuroleptic malignant syndrome and malignant hyperthermia are clinically similar, and dantrolene is effective in both; suggesting a muscular origin of fever in these two diseases.

Mercury oxycyanide and mercuric cyanide poisoning: two cases.

BACKGROUND: Although cyanide poisoning can be serious or fatal, it is typically described as mild when the cyanide is ingested in the form of either mercuric cyanide or mercury oxycyanide. METHODS: We studied two patients with acute cyanide poisoning following ingestion of one of these two agents in each case. RESULTS: Both patients demonstrated features of life-threatening cyanide poisoning, including hemodynamic instability, severe lactic acidosis, and high blood cyanide concentration. One of the patients died, while the second demonstrated signs of mercury intoxication (acute renal failure and severe gastrointestinal symptoms), in addition to cyanide intoxication. CONCLUSION: Ingestion of either mercuric cyanide or mercury oxycyanide can result in life-threatening cyanide intoxication.

Treatment of acute methanol poisoning with fomepizole.

OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients. DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism. CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.

Paraquat poisoning. An overview of the current status.

Paraquat is a bipyridyl compound with no known chronic toxicity or teratogenicity. It is poorly absorbed when inhaled, but causes severe illness when ingested orally, death usually occurring within 2 days of ingestion of 50 mg/kg. At lower doses death may be delayed for several weeks. The toxic compound accumulates in lung tissue where free radicals are formed, lipid peroxidation is induced and nicotinamide adenine dinucleotide phosphate (NADPH) is depleted. This produces diffuse alveolitis followed by extensive pulmonary fibrosis. The most important prognostic indicator is the quantity of paraquat absorbed, as shown by the plasma paraquat concentration. While renal failure will develop in the majority of those patients who eventually die, it may not, if present alone, indicate a fatal outcome. The absence of caustic burns in the upper digestive tract indicates a good prognosis. Treatment of paraquat poisoning remains ineffective, but Fuller's earth, activated charcoal and resins may prevent some absorption of the toxin. When tubular necrosis occurs, renal excretion of the compound decreases rapidly. A 3-compartment pharmacokinetic model has been described following ingestion of tracer doses including a 'deep' compartment for active pulmonary accumulation. Haemodialysis, haemoperfusion and forced dialysis have been attempted, with no clear improvement in survival rates. Superoxide dismutase, glutathione peroxidase, N-acetylcysteine and other 'free radical scavengers' have failed to alter the outcome in poisoned patients. Other theoretical treatments, such as deferoxamine, immunotherapy, NADPH repletion and lung transplantation still require clinical validation.

Use of paracetamol for suicide and non-fatal poisoning in the UK and France: are restrictions on availability justified?

OBJECTIVE: To investigate the relationship between the availability of paracetamol and its use for overdose and suicide. DESIGN: Analysis of routinely collected information on time trends for paracetamol suicides, non-fatal overdoses, and sales. SETTING: England and Wales and France. RESULTS: There were strong correlations between trends in paracetamol sales in the UK and trends in non-fatal paracetamol overdose in Oxford between 1976 and 1993 (Spearman's r = 0.86; 95% confidence interval (CI) 0.54, 0.96) and between paracetamol sales and non-fatal overdoses in France between 1974 and 1990 (r = 0.99; 95% CI 0.97, 1.00). Sales figures were also correlated with paracetamol related suicides in both England and Wales, 1983-91 (r = 0.72; 95% CI 0.11, 0.94) and France, 1974-90 (r = 0.79; 95% CI 0.50, 0.92). Similarly strong relationships were observed between trends in non-fatal overdoses and suicide by paracetamol poisoning in England and Wales (r = 0.85; 95% CI 0.61, 0.95) and France (r = 0.79; 95% CI 0.50, 0.92). It is estimated that approximately 32,000 overdoses involving paracetamol occur annually in England and Wales. Fatality rates from paracetamol overdose were four times as high in England and Wales (0.4%, 95% CI 0.38, 0.46) as in France (0.1%, 95% CI 0.06, 0.17). CONCLUSION: Trends towards greater availability of paracetamol are paralleled by increases in its use for both non-fatal overdose and suicide. Paracetamol related morbidity and mortality seem to be less frequent in France where the quantity of paracetamol in a single purchase is limited. Although not conclusive, these data add to a body of evidence which suggests that restrictions in the quantity of paracetamol available as a single purchase in the UK may reduce suicide and liver failure related to paracetamol.

Advances in the management of digoxin toxicity in the older patient.

Digoxin intoxication is a common problem in the elderly. In its mildest forms it may go undiagnosed, but in severe cases it is often fatal. Altered digoxin pharmacokinetics, attributable to the physiological changes associated with aging, underlying illness, and drug-drug interactions all contribute to the occurrence of digoxin toxicity. Advanced age, male gender, initial hyperkalaemia, underlying heart disease, and advanced atrioventricular block at the time of admission are poor prognostic factors. Supportive care alone is often insufficient. Digoxin-specific Fab therapy may result in dramatic recovery from digoxin intoxication, but it must be administered early and in a an adequate dosage if reductions in mortality are to be achieved.

Modifying toxicokinetics with antidotes.

Five approaches may be described through which antidotes can modify toxicokinetics: (1) Decreased bioavailability of the toxins; (2) Cellular redistribution of the toxin in the organism; (3) Promotion of elimination in an unchanged form; (4) Slowing of metabolic activation pathways; (5) Acceleration of metabolic deactivation pathways. However, the ability to modify toxicokinetics with a new treatment, while demonstrating an understanding of the mechanism of action, must never be construed to be, in and of itself, the goal of therapy. The ultimate evaluation of an antidote modifying toxicokinetics is strictly clinical.

Pre-hospital strategy for therapeutic intervention of fire victims.

Fire victims are exposed to the triple threat of thermal injury (skin and lungs), smoke toxicity (toxic or irritant gases and soots) and even trauma whose occurrences are somewhat independent one from the other but whose addition does sharply increase the probability of death of the victims. As the different victims of the same fire may not suffer from the same injuries, this triple threat must be looked for in each fire victim.

Toxicokinetics of colchicine in humans: analysis of tissue, plasma and urine data in ten cases.

1. A specific and sensitive radioimmunoassay was used to study the toxicokinetics of colchicine in seven cases of acute human poisoning. Post-mortem tissue concentrations of colchicine were measured in three further cases. Depending on the time of patient admission, two disposition processes could be observed. The first, in three patients, admitted early, showed a bi-exponential plasma colchicine decrease, with distribution half-lives of 30, 45 and 90 min. The second, in four patients, admitted late, showed a mono-exponential decrease. Plasma terminal half-lives ranged from 10.6 to 31.7 h for both groups. 2. Pharmacokinetic analysis of urine colchicine data was performed for two patients. The fraction of unchanged colchicine excreted in urine was about 30%, renal clearance was about 13 l h-1 and three-fold less than total body clearance (39 l h-1). The apparent volume of distribution was 21 l kg-1. 3. Post-mortem tissue analysis showed an ubiquitous colchicine distribution. Colchicine accumulated at high concentrations in the bone marrow (more than 600 ng g-1), testicle (400 ng g-1), spleen (250 ng g-1), kidney (200 ng g-1), lung (200 ng g-1) and heart (95 ng g-1); it was also found in the brain (125 ng g-1). 4. This toxicokinetic study shows that after massive ingestion, the disposition parameters and kinetics of colchicine are not markedly modified from those occurring in healthy volunteers. The absorption process was not delayed and the distribution and elimination half-lives were in the range known to occur with therapeutic doses.

Toxicokinetics of paraquat in humans.

1. The toxicokinetics of paraquat were studied in 18 cases of acute human poisoning using a specific radioimmunoassay. Plasma paraquat concentration exhibited a mean distribution half-life (t1/2 alpha) of 5 h and a mean elimination half-life (t1/2 beta) of 84 h. Cardiovascular collapse supervened early during the course of the intoxication and was associated with the distribution phase. Death related to pulmonary fibrosis occurred late and was associated with the elimination phase. 2. Pharmacokinetic analysis of urine paraquat excretion confirmed the biphasic decline of paraquat. Moreover, renal paraquat and creatinine clearances were not correlated but renal paraquat clearance was never higher than the renal creatinine clearance. 3. Tissue paraquat distribution was ubiquitous with an apparent volume of distribution ranging from 1.2 to 1.6 l/kg. Muscle could represent an important reservoir explaining the long persistence of paraquat in plasma and urine for several weeks or months after poisoning.

Cyanide poisoning from propionitrile exposure.

A 55-year-old worker was exposed to propionitrile by both the inhalational and dermal routes. He rapidly lost consciousness and developed metabolic acidosis consistent with cyanide poisoning. Treatment with hydroxycobalamin and sodium thiosulfate produced complete symptom resolution within an hour. Serial blood cyanide and thiocyanate levels documented a rapid decrease in cyanide and concomitant increase in thiocyanate. Serious cyanide poisoning can occur from propionitrile exposure. Treatment with hydroxycobalamin and sodium thiosulfate can produce rapid clinical improvement.

The cocaine body-packer syndrome: evaluation of a method of contrast study of the bowel.

The questionable reliability of the conventional procedures for detection of ingested drug packages triggered us to evaluate the accuracy of a method of contrast study of the bowel in 23 nonsurgically managed cocaine body-packers. A single dose (60 mL) of a water-soluble contrast compound (amidotrizoate + meglumine) was given orally after initial clinical examination and drug detection in urine. Thereafter, roentgenograms were performed daily after spontaneous passage until obtaining two packet-free stools and negative views. Roentgenograms showed packages when performed at least 3 h after the ingestion of the contrast compound. Sensitivity and specificity of the method with respect to the detection of residual packets in the body, assessed by subsequent examination of stools, was good and did not diminish as the number of packages decreased during the time spent in ward. No side-effects were observed. We conclude that oral administration of a water-soluble contrast compound is an easily performed, efficient, and safe method for the nonsurgical management of cocaine body-packers.

[Cardiac toxicity of ajmaline. Comparison of acute voluntary poisoning with complications of the ajmaline test]. / Toxicité cardiaque de l'ajmaline. Comparaison des intoxications aiguës volontaires et des accidents du test à l'ajmaline.

A comparative and retrospective study of 59 cases of acute voluntary self-poisoning observed at the Toxicology Department of Fernand Widal Hospital, and 15 cases of complications of the Ajmaline test observed in the Cardiology Department of Bichat Hospital showed a similarity in the cardiac effects of high dosage regardless of the mode of administration of the antiarrhythmic. Acute suicidal poisoning in adults or accidental poisoning in children caused toxic effects at doses over more than Ig: they are characterised by their sudden onset after a latent period of 1 to 2 hours and their short duration (no effects after the 12th hour). The ECG changes included:--First degree atrioventricular block (15 p. 100).--Intraventricular conduction defects were observed in almost all cases. They were proportional to the dose taken and were of prognostic interes (no cardiac arrests when the QRS remained less then 0,2 sec).--ST-T wave changes were observed in all patients. They lasted longer and were of no prognostic importance.--Extrasystoles and ventricular tachycardia are nearly always associated with poor hemodynamic tolerance (70 p. 100 of cardiac arrests, compared to only 16 p. 100 in this absence). This intoxication is serious with a mortality of 24 p. 100 of the reported cases and of 9 p. 100 of cases admitted to an Intensive Care Unit.--The complications of the Ajmaline test were similar, the time of apparition being a few minutes instead of a few hours. There were no deaths or serious hemodynamic complications in this series. This is without doubt related to the observation of the contraindications and the fractional administration of the Ajmaline. We conclude that oral Ajmaline, though well tolerated at therapeutic does may cause severe toxic overdose effects. Although its use remains justified in the treatment of arrhythmias, it should not be used for the symptomatic treatment of palpitations and neurovegetative imbalance.

[The importance of software for the planning and adjusting of dosage. Application with aminoglycosides]. / Intérêt d'un logiciel informatique pour la prévision et l'adaptation des posologies. Application aux aminosides.

We are presenting a Mac Intosh--Apple computer program (Excel*) for the aminoglycosides (AG) drug monitoring useful in the following situations: --initiation of an AG's dosing regimen depending on the desired peak and through concentration (AG's pharmacokinetic parameters have been calculated according to the AG's literature values). --an adequate dosing regimen after revision of the patient's parameters (calculated with the observed concentrations). The technique has been validated comparing desired (des. C) and measured concentrations (mes. C). --either at the beginning of the treatment, --or after revision of the individual parameters. In the first case, the correlation coefficient obtained between 14 des C and 14 mes. C is equal to 0.91 and is improved when individual parameters are calculated (0.94).

[Visceral histologic lesions of lethal acute colchicine poisoning. Apropos of 12 cases]. / Lésions viscérales histologiques des intoxications aiguës mortelles par la colchicine. A propos de 12 observations.

The authors reported histological characteristics (on post-mortem examination) of 12 cases of lethal acute colchicine intoxication and compare these results with the 5 previous anatomical studies of such cases in the literature. Abnormal mitosis (stathmocinesis, "caryomerie", caryorrhexis and mitonecrosis) are constant and essentially seen in the bone marrow and digestive mucosae, especially in oesophagus which squamous epithelium is more resistant to autolysis than others digestive mucosae. Biological or histological symptoms or lesions of intravascular diffuse coagulation are present 7 cases but both biological and histological manifestations in only one case. Hematological disorders are constant when more than 0.5 mg/kg (of corporeal weight) of colchicine has been ingested. Granulocytic elements are most affected both by hypoplasia (essentially in the first four days) and maturation troubles. A microvacuolar non systematized and diffuse liver fatty change is found in 10 cases, probably related to alteration of lipoproteins synthesis and secretion by hepatocytes. Interstitial myocardial oedema is a constant feature; in addition true interstitial myocarditis (with infiltration by polymorphs) is seen in two cases. These cardiac lesions may be related to the cardiogenic shock which is often observed in these patients.

[Shock caused by poisoning. Use of cardiotropic agents]. / Collapsus par intoxication. Utilisation des agents cardiotropes.

At toxic doses, cardiotropic drugs may compromise cardiac output leading to circulatory shock. Specific treatment varies depending on the nature and the dose of the drugs ingested as well as causal mechanism including vasopegia, hypovolaemia, cardiogenic effects and sepsis. Progress in our understanding of the pharmacodynamic aspects of intoxication and the development of specific antidotes has led to reduced morbidity and mortality. In addition to the classical inotropes, mainly catecholamines and phosphodiesterase inhibitors, other therapeutic agents may have specific inotrope effects in such ad hoc situations. These include hypertonic alkaline saline solution, calcium, glucagon, hydroxocobalamine and other cobalt salts, oxygen and immunotoxicotherapy. Together with volum replacement, dobutamine at the dose of 7 to 20 micrograms/kg/min can usually restore cardiac performance in cases of carbamate-induced circulatory shock. In case of tricyclic antidepressant overdose, treatment should include respiratory assistance and infusion of alkaline sodium solutions to both reverse the extracellular acidosis and correct sodium balance. Catecholamines may be necessary in cases with severe hypotension. Major vasoplegia and impaired intraventricular conduction may be induced by overdoses of chloroquine and class I antiarrhythmic drugs. Signs of gravity are: ingested dose above 4 g, QRS > or = 0.12 s or systolic arterial pressure < or = 80 mmHg. Treatment with epinephrine, respiratory assistance and diazepam has been proven effective during the acute phase, but right catheterism is often required due to major haemodynamic instability during the first 72 first hours. Beta-blockers have both a bronchoconstrictor and respiratory depressor effects favouring cardiovascular failure by hypoemia. Symptoms occur in 30-40% of the cases of overdose. Shock results from the reduction in blood pressure and cardiac inotropism. Glucagon, isoprenaline and epinephrine, prescribed in that order, can considerably reduce mortality to less than 4%. Despite the development of specific molecules, the risk of mortality due to toxic shock caused by antiarrhythmics, chloroquine, colchicine, calcium inhibitors and paraquat remains high.

[Hypokalemia in massive chloroquine poisoning. 2 cases]. / Hypokaliémie au cours d'intoxications massives par la chloroquine. Deux cas.

Two cases of hypokalemia which was deep (1.1 mmol/l), symptomatic and protracted were observed during the early course of acute massive chloroquine intoxication. Biochemical data suggest that the mechanism of hypokalemia in such cases is intracellular transport.

[Pure defibrination after timber rattlesnake bite]. / Défibrination pure après morsure de crotale horridus.

The only disorder of coagulation observed after a timber rattlesnake (Crotalus horridus) bite was a total absence of fibrinogen which lasted 64 hours despite hourly administration of cryoprecipitates. The pure defibrination experimentally obtained with this particular species of crotalid snakes underlines the specificity of the coagulation disorder and the impossibility of identifying the coagulopathy induced by venom poisoning without laboratory examination.

[Cyanide poisoning. Priority to symptomatic treatment. 25 cases]. / Intoxication cyanhydrique. Primauté du traitement symptomatique. Vingt-cinq observations.

A retrospective study of 25 cases of cyanide poisoning has brought to light the following points: cardiorespiratory arrests are frequent (7/25) and often inaugural; in severe intoxications (7/25), deep metabolic acidosis is the rule, and cyanide poisoning should always be suspected in cases of coma with severe acidosis; mild intoxications are frequently symptomless. Anxiety and agitation should not be considered as evidence of cyanide poisoning; they are merely due to fear in most cases. The present treatment of acute cyanide poisoning relies basically on symptomatic measures: sodium bicarbonate, cardiac massage and, above all, assisted ventilation with 100% oxygen. Our experience does not support the concept of a lethal cyanide blood level when patients can rapidly be transferred by a medical team to an intensive care unit. Survival depends more on prompt medical care than on the accessibility to sophisticated antidotes.