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The aim of this study was to determine: 1) the factors implicated in fire deaths in children, 2) the relevance of blood carbon monoxide (CO) and hydrogen cyanide (CN) concentrations in child fire victims. 34 child fire victims (17 males: 17 females) were studied. Mean age was 4.5 years. In 12 cases medico-legal autopsies were performed, but no toxicological analyses were done (group A). In 14 cases autopsies were not performed, but blood CO and CN concentrations were measured in the victims (group B). In the remaining 8 cases both toxicological analyses and medicolegal autopsies were done (group C). In 29 cases out of 34, children had been left alone by their parents. In 20 cases out of 34, children had 80% burns of their body surface. In groups A and C autopsies enabled violence or other criminal cause of deaths to be excluded. All victims had smoke inhalation. The mean blood CN concentration in the 22 fire victims (groups B and C) was 70.67 +/- 14.11 micromol/l (0-207). The mean blood CO concentration was 1.89 +/- 0.51 mmol/l (0.11-5.89). There was no significant correlation between CN and the CO blood concentrations. There was no significant correlation between the burn surface area and the blood concentration of either CN or CO. In 11 cases, one or both gases concentrations were in the potential toxic range (CN: 40-<100 micromol/l; CO: 1-<5.8 micromol/l) but below the lethal range. Therefore these deaths were considered to be due to the combined effect of gas toxicity. It is concluded that: 1) In case of fire death, a medico-legal autopsy should be performed to confirm that victims suffered smoke inhalation and to exclude violence or other criminal cause of deaths; 2) Blood CN and CO measurements identify the exact contribution of each to the death; 3) Immediate blood sampling at the scene of death should be done because CN may disappear rapidly from body tissue after death.

The use of routine nonspecific immunoassays to detect or quantitate opiates in biological fluids raises the question of the relevance of such immunoassays in the investigation of opiate overdose disposition. We investigated the plasma disposition of morphine in 13 patients intoxicated by the intravascular (i.v.) (n = 5) or oral routes (n = 8) using both a highly morphine-specific antibody radioimmunoassay (RIA) and a nonspecific morphine RIA. Both RIAs showed a first-order elimination rate after i.v. intoxication (apparent plasma terminal half-life ranged from 2.9 to 4.7 hours for unchanged morphine and from 3.2 to 4.9 hours for total opiates) and a persistent opiate concentration with rebound after oral ingestion, suggesting a slow release of opiates from the gastrointestinal tract, in dealers and bodypackers. Moreover, i.v. and oral kinetic data were similar for the two RIAs, except for the ratio between total and unchanged morphine concentrations. The nonspecific morphine assay gave a threefold to 16-fold higher concentration than the specific morphine assay but with parallel kinetics for all patients. We conclude that the current, routine nonspecific morphine immunoassays could be a valuable analytical tool for investigating opiate toxicokinetics.

Hydroxocobalamin (OHCo) and cyanocobalamin (CNCo) are determined directly in biological media, without extraction, by using first derivative spectrophotometry. We diluted 200 mL of plasma, urine, or standards with 1.8 mL of pH 6 buffer (boric acid, potassium dihydrogen orthophosphate, and potassium hydroxide). The first derivative spectra of the dilutions were plotted between 320 and 400 nm. At the exact zero-crossing point for hydroxocobalamin, the derivative values of cyanocobalamin concentration were determined. The same procedure was followed for hydroxocobalamin at the zero-crossing point for cyanocobalamin. The derivative values of the concentration curves are linear in the range 5-100 microM. The minimum detection limit is approximately 5 microM for hydroxocobalamin of cyanocobalamin on the determination of hydroxocobalamin or vice versa, although the spectra strongly overlap. The method is fast and simple to use, thus making it easy to assess the in vivo transformation of hydroxocobalamin into cyanocobalamin after the administration of high doses of hydrocobalamin in cyanide poisoning.

The intensity of gastrointestinal and visual symptoms together with hyperkalemia and the characteristic ECG features make diagnosis of acute digitalis intoxication relatively easy. Death results mainly from ventricular fibrillation or from ventricular asystole or pump failure. Mesenteric infarct may also occur in elderly patients. Previous assessment of outcome has shown that mortality increases in patients exhibiting five prognostic factors: 1) advanced age; 2) heart disease; 3) male sex; 4) high-degree atrioventricular block; 5) hyperkalemia. Conventional treatment includes gastric lavage, activated charcoal and supportive care. First-line antiarrhythmic therapy is usually atropine, because of bradycardia-induced arrhythmia. Ventricular pacing is a toxicodynamic treatment that may be helpful in both bradycardia-induced arrhythmia and high-degree atrioventricular block. Pacing is difficult to handle and can result in serious adverse effects. Immunotherapy has two advantages. First, a strong toxicodynamic effect due to quick reversal of digitalis-induced dysrhythmias, hyperkalemia, and myocardial depression, by reactivation of membrane ATPases. Second, a toxicokinetic effect due to accelerated renal excretion of Fab-digitalis complexes. Since this therapy is well tolerated and efficient, we recommend early administration of Fab fragments as soon as poor prognostic factors are identified.

Over a six year period, 92 patients intoxicated with either digitoxin or digoxin were admitted to our ICU. Fifty-one patients were treated with cardiac pacing and/or Fab fragments, and the mortality rate was 13% (14 were intoxications with digoxin, 36 with digitoxin, 1 was mixed). Forty-five cases were suicide attempts; six were accidental overdosages. Since cardiac pacing may trigger fatal arrhythmia or delay the administration of Fab fragments, we conducted a retrospective study to determine whether fatal outcomes could be related either to cardiac pacing or to unsatisfactory use of immunotherapy. In our study, prevention of life-threatening arrhythmia failed in 8% of cases with Fab and in 23% with pacing. Though Fab tended to be more effective, this difference was not significant. In our study, the main obstacles to the success of Fab were pacing-induced arrhythmias and delayed or insufficient administration of Fab. Iatrogenic accidents of cardiac pacing were frequent (14/39, 36%) and often fatal (5/39, 13%). In contrast, immunotherapy was not associated with any serious adverse effects (0/28, 0%) and was safer than cardiac pacing (p < 0.05). In conclusion, during digitalis intoxication, the pacemaker has limited preventive and curative effects, is difficult to handle, and exposes patients to severe iatrogenic accidents. Fab fragments act as a powerful antidote and are safer and much easier to use than pacing. These results encourage us to prescribe Fab fragments as first-line therapy during acute digitalis intoxication.

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.

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.

A method was developed for the separation and measurement of chloroquine and three metabolites (desethylchloroquine, bisdesethylchloroquine and 4-amino-7-chloroquinoline) in biological samples by ion-pair high-performance liquid chromatography with UV detection. The method uses 2,3-diaminoaphthalene as an internal standard and provides a limit of detection between 1 and 2 ng/ml for chloroquine and its metabolites. The assay was linear in the range 12.5-250 ng/ml and the analytical recovery and reproducibility were sufficient. The assay was applied to the analysis of biological samples from a patient undergoing chloroquine chemoprophylaxis and a patient who had ingested chloroquine in a suicide attempt.

The cardiac risk of cocaine body packing was studied by means of continuous ECG monitoring in 13 cocaine body-packers during spontaneous elimination. The packages were all well manufactured bundles (McCarron type 2) not susceptible to spontaneous breakage. At the beginning of the Holter study, packages were still present in the bowel of twelve patients (range: 2 to 196). The mean time of Holter recording was 46 h (range 16 h to 75 h). Ten patients eliminated all their packages during the time of Holter recording. No ECG modifications were recorded for all of the patients in regard to usually admitted standard requirements of the American Heart Association. While initial cardiac frequencies were within the normal range, a significant decrease of pulse rates was associated with the elimination of bundles. We conclude that the McCarron type 2 cocaine body-packers are not in impending danger of cardiac acute events allowing a non-surgical management of these individuals.

Background: The nature of the toxic gases that cause death from smoke inhalation is not known. In addition to carbon monoxide, hydrogen cyanide may be responsible, but its role is uncertain, because blood cyanide concentrations are often measured only long after exposure., Methods: We measured cyanide concentrations in blood samples obtained at the scene of residential fires from 109 fire victims before they received any treatment. We compared the results with those in 114 persons with drug intoxication (40 subjects), carbon monoxide intoxication (29 subjects), or trauma (45 subjects). The metabolic effect of smoke inhalation was assessed by measuring plasma lactate at the time of admission to the hospital in 39 patients who did not have severe burns., Results: The mean (+/-SD) blood cyanide concentrations in the 66 surviving fire victims (21.6 +/- 36.4 mumol per liter, P less than 0.001) and the 43 victims who died (116.4 +/- 89.6 mumol per liter, P less than 0.001) were significantly higher than those in the 114 control subjects (5.0 +/- 5.5 mumol per liter). Among the 43 victims who died, the blood cyanide concentrations were above 40 mumol per liter in 32 (74 percent), and above 100 mumol per liter in 20 of these (46 percent). There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (P less than 0.001). Plasma lactate concentrations at the time of hospital admission correlated more closely with blood cyanide concentrations than with blood carbon monoxide concentrations. Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter., Conclusions: Residential fires may cause cyanide poisoning. At the time of a patient's hospital admission, an elevated plasma lactate concentration is a useful indicator of cyanide toxicity in fire victims who do not have severe burns.

The effects of sodium cyanide (1 mM) and the antidotal action of hydroxocobalamin (1 mM) were studied on rat cardiac papillary muscle. A 10-min period of exposure to cyanide induced a marked decrease in inotropy as shown by a decrease in the maximum unloaded shortening velocity (Vmax: 64 +/- 11% of precyanide values, p <0.01) and active isometric force (AF/s: 35 +/- 13%, p <0.01). The impairment of contraction-relaxation coupling under low load and the nearly complete disappearance of the load sensitivity of relaxation suggested a decrease in sarcoplasmic reticulum function. The proportional acceleration in isometric relaxation suggested a decrease in myofilament calcium sensitivity. There was a nearly complete recovery from cyanide poisoning after 5 min of exposure to hydroxocobalamin, whereas in a control group receiving cyanide alone, the mechanical parameters remained unchanged or were further impaired. The effects of hydroxocobalamin developed very quickly, beat to beat. The main toxic target of cyanide is brain and heart cytochrome oxidase, and brain damage appears only a few minutes after the onset of anoxia. Because hydroxocobalamin is a rapid and powerful antidote, it may be useful in the treatment of acute cyanide poisoning.

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.

Toloxatone is a new monoamine oxidase inhibitor. One hundred and twenty two cases of poisoning with this drug are reported. In this series, the minimal toxic dose was 2 g. The first symptoms appeared about one hour after ingestion. In most cases, only drowsiness and mild adrenergic effects were observed. In a few cases of massive overdose, coma, pyramidal irritation, and myoclonic jerks occurred. In 3 cases of severe poisoning, toloxatone was associated with tricyclic antidepressants. Symptoms were similar to those reported in intoxications associating classical monoamine oxidase inhibitors and tricyclic antidepressants: muscular rigidity, hyperthermia and cardiovascular collapse. Two of these patients died.

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.

Toxicity of cardiac glycosides involves the inhibition of the Na(+)-K(+) ATPase pump. As a consequence, extracellular K(+) concentration rises and intracellular K(+) concentration strongly decreases. Red blood cell (RBC) K(+) is a practical marker of ATPase inhibition. In a group of 15 patients intoxicated by digitoxin and lanatoside C, correlations between the calculated digitoxin ingested dose or plasma digitoxin levels and the kinetics of plasma K(+) and RBC K(+) have been assessed using kinetic-effect modelling. A correlation between the calculated ingested dose of digitoxin with RBC K(+) was found (r = 0.64). A direct relation based on the linear model fitted the relation between extracellular K(+) and digitalis concentration. An indirect relation based on the Emax sigmoid model fitted the relation between RBC K(+) and digitoxin concentrations. Specific parameters were obtained from the linear model with a = 0.0196 +/- 0.0272 and b = 0.455 +/- 0.035. Specific parameters were derived from the Emax sigmoid model with k(eo) = 0.0139 +/- 0.0052/hr and EC(50) = 91.95 +/- 20.55 ng/ml, where k(eo) = first-order rate constant of the disappearance of the toxic effect and EC(50) = digitoxin concentration decreasing the RBC K(+) concentration by 50%. These data showed that the in vitro assays of plasma K(+) and RBC K(+) are convenient and predictive assays for evaluating the severity of human digitoxin poisoning.

There is a striking discrepancy between: the efficacy of the kidneys, haemodialysis (HD) and Haemoperfusion (HP) in removing paraquat from the body and the poor prognosis of paraquat poisoning even when the blood and urine levels (which are good indices of concentrations in lung and other tissues) are very low. Extra-corporeal elimination techniques have been used worldwide in paraquat poisoning. Do they remove paraquat effectively? Certainly. Do they increase the survival rate? Probably not. The reason being that when these techniques of elimination are initiated, potentially lethal concentrations of paraquat have already been attained in the highly vascular tissues of vital organs and in pneumocytes. The data presented suggest that the successful treatment of paraquat poisoning does not depend on modification of toxicokinetics.

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.

A technique is described in which the toxicokinetics of paraquat on passage through the heart and lung were studied by means of blood samples drawn simultaneously from the pulmonary and radial arteries in six cases of acute human life-threatening paraquat intoxications. There was a trend for the radial plasma concentrations of paraquat to be greater than or equal to the pulmonary concentrations. This data suggests that from a clinical point of view the distribution of paraquat into the lungs is not a slow process. There may also exist some efflux of the paraquat into the circulation. This efflux of paraquat may result from direct lung and/or heart injury induced by massive paraquat poisoning.

4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene glycol (EG) or methanol intoxication has been suggested in experimental studies about its efficacy and safety. We report three cases of accidental intoxication with ethylene glycol in man treated orally with 20 mg/kg/day of 4 MP. The treatment was maintained until plasma EG concentrations became unmeasurable. The patients were admitted early during the course of the poisoning. Their neurological status was good. A slight metabolic acidosis observed in two cases was easily corrected and did not recur. Renal function remained normal in all cases. No patient underwent hemodialysis. On admission plasma EG concentrations were 24.2 mmol/l, 13 mmol/l and 9.7 mmol/l respectively. Plasma EG half-lives were 14.5, 11.5 and 14.75 hours respectively. Plasma oxalate concentrations and the rate of urine oxalate elimination, determined in two patients, were high on admission but quickly returned to normal. Concerning possible side effects of 4 MP, a skin rash was observed in one patient and a possible eosinophilia in the others. These three cases suggest that 4 MP may decrease the metabolic consequences of EG poisoning in man and may be of therapeutic value when administered early during the course of the intoxication before coma, seizures and organic renal failure have occurred.

There is a striking discrepancy between the efficacy of the kidneys, haemodialysis and haemoperfusion in removing paraquat from the body and the poor prognosis of paraquat poisoning even when the blood and urine concentrations (which are good indices of concentrations in lung and other tissues) are very low. Extracorporeal elimination techniques have been used world-wide in paraquat poisoning. Do they remove paraquat effectively? Certainly. Do they increase the survival rate? Probably not. The reason being that when these techniques of elimination are initiated, potentially lethal concentrations of paraquat have already been attained in the highly vascular tissues of vital organs and in pneumocytes. The data presented here suggest that the successful treatment of paraquat poisoning will not be achieved by modification of toxicokinetics.

The presence of opiates and benzoylecgonine, the major metabolite of cocaine, in the urine was detected by means of enzyme immunoassay in a series of 120 smugglers who had either ingested or inserted into their rectum cocaine or heroin packaged for transportation. There was a striking relation between the presence of drugs in the urine and swallowing of drug-filled bundles (cocaine 49 of 50 cases, heroin 9 of 10). The proportion of positive results was also high in cases of rectal insertion (cocaine 2 of 2, heroin 35 of 58). In 30 cases of cocaine-packet ingestion, serial measurements showed that the accuracy of the test progressively decreased with respect to the detection of residual packets in the body. Drug detection in the urine of suspected body-packers seems to be a useful test, positive results justifying subsequent radiological investigations.

Arterial-venous plasma concentration differences of meprobamate were studied on admission of acute overdose in man. The patients were divided in two groups. In the control group (n = 25) two successive blood samples were collected from the same vessel. In the study group (n = 35) femoral arterial and venous blood samples were collected simultaneously. In the control group the differences were not significant. In the study group the differences were statistically significant (P less than 0.01). The present study suggests that the origin of blood samples should be stated for toxicological studies and that the toxicokinetics may be more complex than those recognized previously.

No therapy has been proved to be effective for patients with severe chloroquine poisoning, which is usually fatal. In a retrospective study of 51 cases, we found that ingestion of more than 5 g of chloroquine was an accurate predictor of a fatal outcome, and therefore chose this dose as the criterion for severe chloroquine poisoning. We selected as a control group 11 consecutive patients who had ingested more than 5 g of chloroquine between July 1983 and December 1985. We then undertook a prospective study to determine whether a better outcome could be obtained with immediate mechanical ventilation and the administration of diazepam and epinephrine. Eleven consecutive patients who ingested more than 5 g of chloroquine in 1986 received this combination therapy. Ten of these patients survived, whereas only one control had survived (P = 0.0003). There was no significant difference between the combination-therapy and control groups in age (29 +/- 3 vs. 27 +/- 2 years), amount of chloroquine ingested (7.5 +/- 0.5 vs. 8.5 +/- 0.8 g), systolic arterial pressure (74 +/- 2 vs. 74 +/- 3 mm Hg), or QRS duration (0.14 +/- 0.01 vs. 0.14 +/- 0.01 second). In our combination-therapy group, blood chloroquine levels ranged from 40 to 80 mumol per liter, whereas a literature search showed that no patient in whom blood levels were more than 25 mumol per liter had survived. These preliminary data suggest that combining early mechanical ventilation with the administration of diazepam and epinephrine may be effective in the treatment of severe chloroquine poisoning.

The anaphylactic shock is a life-threatening reaction produced by the release of pharmacologically active substances (histamine, leukotriene...) by most cells and basophils. The release of these mediators may be immunologically mediated (anaphylactic reaction a typical immediate hypersensitivity reaction mediated by IgE) or not (anaphylactic reaction when not mediated by an antigen-antibody process). These mediators in turn specific end-organ responses in the cardio-vascular system, (vasodilatation, change in inotropy, increased capillary permeability), the respiratory system (bronchospasm upper airway oedema) and the skin (urticaria). Because of its etiology (mainly drugs, contrast media and colloids) the treatment of anaphylactic or anaphylactic reactions must be prophylactic. When it occurs, its cure is based upon adrenaline and fluid loading and eventually bronchodilators.

The aim of this study was to determine whether femoral arterio-venous plasma concentration differences (AVD) of amitriptyline exist during acute intoxication in man. All patients studied were comatose and were divided into a control group who had two successive blood samples drawn from the same vessel and a study group who had samples drawn from the femoral artery and vein simultaneously. Serial plasma concentrations of amitriptyline were measured by gas liquid chromatography. In each group the differences were assessed by means of the Wilcoxon matched pairs test. In the control group (n = 13) there were no differences (T = 31, n = 12). In the study group (n = 24) the AVD were significantly different (T = 52, n = 23). For amitriptyline, the arterial or venous origin of blood samples for toxicological studies must be stated.

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.