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Background: Cyanide quickly binds to the ferric ion of cytochrome [aa.sub.3] inducing a noncompetitive inhibition of the mitochondrial cytochrome c oxidase activity. The inactivation of cytochrome c oxidase results in a shift of aerobic to anaerobic metabolism eventually leading to cellular ATP depletion and lactic acidosis. Due to the shift from aerobic to anaerobic metabolism, significant cyanide poisoning is invariably associated with lactic acidosis. Methods: Retrospective study in a university hospital ICU. Repeated blood samples were simultaneously collected for blood cyanide and plasma lactate determination in acute cyanide poisonings, excluding fire victims. The correlations were studied using the Spearman test. Results: Eleven patients were studied. Before antidotal treatment (hydroxocobalamin [+ or -] thiosulfate), the median plasma lactate concentration was 18.6 mmol/L, the median blood cyanide concentration was 156 [micro]mol/L (4.0 mg/L). There was a significant correlation between plasma lactate and blood cyanide concentrations (r = 0.745, p = 0.0174). There were significant inverse correlations between plasma lactate concentrations and systolic blood pressure (r = -0.875, p = 0.0016), spontaneous respiratory rate (r = -0.867, p = 0.0123), and arterial pH (r = -0.870, p = 0.0045). There was a significant positive correlation between plasma lactate concentrations and anion gap (r = 0.833, p = 0.0083). The correlation with blood glucose concentration did not reach the level of statistical significance (p = 0.0589). There was no significant correlation of plasma lactate concentrations with heart rate, Glasgow coma score, Pa[CO.sub.2] or Pa[O.sub.2]. Before antidotal treatment, there were significant inverse correlations of blood cyanide concentrations with systolic blood pressure (r = -0.717, p = 0.0234), and arterial pH (r = -0.912, p = 0.0013). There was a significant positive correlation with anion gap (r = 0.767, p = 0.0214), and blood glucose concentration (r = 0.783, p = 0.0172). There was no significant correlation of blood cyanide concentration with pulse rate, respiratory rate, Glasgow coma score, Pa[O.sub.2] or Pa[CO.sub.2]. During the course of cyanide poisonings, a plasma lactate concentration [is greater than or equal to] 8 mmol/L was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration ([is greater than or equal to] 40 [micro]mol/L or 1.0 mg/L). The specificity was substantially improved in patients not receiving catecholamines (85%). Interpretation: Several factors may contribute to the onset of lactic acidosis in cyanide poisoning including mitochondrial inhibition, cardiovascular collapse, respiratory depression, and catecholamine rush while seizures seems rare. The serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning., Baud FJ, Borron SW, Megarbane B, Bismuth C. Reanimation Medicale et Toxicologique, Universite Paris VII-INSERM U26, Hopital Lariboisiere, Paris, France; Department of Emergency Medicine, George Washington University, Washington, DC, [...]

Introduction: The value of PK-PD relationships in clinical pharmacology is now well recognized. However, the potential interest of Toxicodynamic-Toxicokinetic (TK-TD) relationships in medical toxicology has been poorly investigated. The aim of this study was to correlate the depth of coma with plasma meprobamate concentrations. Materials and Methods: Plasma meprobamate concentrations were measured using a colorimetric assay. The depth of coma was assessed using the Glasgow coma scale (GCS). Non-linear regression was used for modeling TK-TD relationships. Results: TK-TD relationships were studied in 7 acute meprobamate poisonings. Three patients were previously treated with meprobamate. Previous treatment was unknown in 2 patients. Mixed drug poisoning was noted in the 7 patients. The mean GCS at the time of hospital admission was 4 [+ or -] 1, the mean plasma meprobamate concentration was 1054 [+ or -] 318 [micro]mol/L. The mean plasma meprobamate concentration associated with a GCS of 3 was 714.6 [+ or -] 277.7 [micro]mol/L (95% CI: 546.8-882.4). The TK-TD relationship was well fitted with the sigmoidal Emax model. In the 7 patients, the mean Hill coefficient (m [+ or -] SD) was 6.9 [+ or -] 4.0 (95% CI: 3.2-10.7), the mean [C.sub.50] was 487.9 [+ or -] 318.8 [micro]mol/L (95% CI: 193.0-782.7). Two patients exhibited tolerance to the sedative effect of meprobamate. In the 5 non-tolerant patients, the mean Hill coefficient (m [+ or -] SD) was 8.0 [+ or -] 4.4 (95% CI: 2.5-13.4), the mean [C.sub.50] was 315.8 [+ or -] 148.9 [micro]mol/L (95% CI: 130.9-500.7). Discussion: A maximal toxic effect, i.e.: GCS of 3, was associated with a wide range of plasma concentrations. During the course of acute human meprobamate poisoning, the relationship between the depth of coma and the corresponding plasma concentrations is of a sigmoidal shape. The high value of the Hill coefficient in non-tolerant patients showed that a small decrease in plasma meprobamate concentrations near the [C.sub.50] was associated with a dramatic improvement in their level of consciousness. In non-tolerant patients, the mean [C.sub.50] was close to the upper limit of the therapeutic plasma concentration of meprobamate given by our toxicological laboratory ([is less than or equal to] 200 [micro]mol/L). Baud FJ, Galliot R, Borron SW, Debray M, Bismuth C. Reanimation Medicale et Toxicologique-INSERM U26--University Paris 7 Laboratoire de Biomathematiques, University Paris V, France, George Washington University, Washington DC, USA

Background: Acute toxicity is the expression of dose-effect relationships, toxicokinetics, toxicodynamics, and their interactions. Some compounds (benzodiazepines) appear to involve single mechanism toxicity. Others (paraquat, ethylene glycol) induce toxic effects through multistage mechanisms. We propose `dynetics' as a general term to describe the chronology of toxic effects, their individual duration and magnitude, and the dependence of one effect on another. In other words, dynetics represents the kinetics of dynamic events. Attention to dynetics may allow the refinement of our understanding of the contribution of individual mechanisms of toxicity demonstrated in experimental studies to the clinical presentation of poisoning in humans. The medical interests of such a concept are manifold. In acetaminophen poisoning, the diagnosis and prognosis within the first 24 h rest on serum acetaminophen concentrations, while late in the course of poisoning they depend on serum ASAT and ALAT. Obtaining the right diagnostic test depends on an understanding of dynetics. Specific treatments (antidotes, extracorporeal elimination) cannot be adequately evaluated without considering this concept. Experimental and clinical data show that fomepizole can prevent life threatening intoxication at a time when plasma ethylene glycol concentrations are high and glycolate concentrations are low. Fomepizole appears to be devoid of any therapeutic value, however, when plasma glycolate and oxalate concentrations are high and plasma ethylene glycol concentrations are low. The efficacy of many antidotes will be strongly dependent on the dynetic phase at which they are administered. Dynetics demands that we classify patients in clinical trials according to the dynetic phase of the poisoning in order to more precisely assess treatment efficiency. Conclusion: Dynetics belongs to the area of integrated physiological systems. Dynetics attempts to integrate the mechanisms of toxicity in order to explain the pathophysiology of a poisoning and the corresponding signs and symptoms observed throughout its course. The consequence of this approach is to assess more precisely the efficacy of specific treatments. Baud FJ, Borron SW, Bismuth C. Reanimation Medicale et Toxicologique, Hopital Lariboisiere, INSERM U26, Universite Paris VII, 75010 Paris, France

Digitalis poisoning is a rare life-threatening event with a mortality rate before the availability of specific treatment of about 15%. Digitalis poisoning may result from an overdose of either digoxin or digitoxin. The nature of the cardiac glycoside will dramatically modify the duration of life-threatening events, in the range of 36 hours for digoxin and of 5 days for digitoxin. Furthermore, digitalis poisoning may result either from the ingestion of a single high dose of digitalis or from a too high dose during a chronic treatment. This presentation will be focused on the prognosis and the management of acute digitalis poisoning resulting from the ingestion of a single high dose of cardiac glycoside. At the time of presentation several prognostic factors can be determined in order to assess the likelihood of life-threatening cardiac events. These prognostic factors include: the age, the sex, a past history of cardiac disease, an atrioventricular block whatever its degree, and hyperkalemia. According to these prognostic factors, the probability of death ranges from about 2% to 75%. In our experience a serum potassium level greater than or equal to 6.4 mmol/L, in a digitalis poisoning without any factors of potassium overload is associated with a mortality rate of about 90%. The death of acute digitalis poisoning is mainly related to the occurrence of cardiac events either conduction abnormalities or ventricular arrhythmias. Supportive treatment including atropine, endocardial pace-maker, and anti-arrhythmics are efficient. However, their use was not associated with an improvement in the prognosis of digitalis poisoning. Digoxin-specific Fab fragments have been shown efficient in digitalis poisoning regarding the reversal of conduction abnormalities, ventricular arrhythmias, and hyperkalemia. However, there are no prospective studies comparing the mortality rate of acute digitalis poisonings treated with or without Fab fragments. Furthermore, the mortality rate of digitalis poisonings treated with specific Fab fragments in previous large series appears quite similar to that observed without Fab fragments. In a retrospective study we observed an improvement in the prognosis of digitalis poisoning only when Fab fragments were used as first line antidote in patients without life-threatening cardiac disturbances. Fab fragments are expensive and the minimal efficient dose of Fab fragments remains a matter of debate. Our data suggest that a curative dose (equimolar neutralization) is recommended for patients with life threatening intoxication while a prophylactic dose (half-equimolar neutralization) should be recommended if the patient had poor prognosis factors without acute life-threatening toxicity. However, some patients may require an additional dose of Fab fragments more especially if digitalis poisoning results from the ingestion of digitoxin. Baud FJ, Lapostolle F, Borron SW, Bismuth C. Reanimation Medicale et Toxicologique-INSERM U26--University Paris 7, SAMU 93