Frédéric J. Baud

Elevated Blood Cyanide Concentrations in Victims of Smoke Inhalation

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 patients hospital admission, an elevated plasma lactate concentration is a useful indicator of cyanide toxicity in fire victims who do not have severe burns.

Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole

THE toxic effects of ethylene glycol result from its metabolic conversion by alcohol dehydrogenase into glycolic acid — a process that causes metabolic acidosis. Glycolate is then metabolized to ox...

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 (t ½ α) of 5 h and a mean elimination half-life (t ½ β) 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.

4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man

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.

Clinical review: Aggressive management and extracorporeal support for drug-induced cardiotoxicity

Poisoning may induce failure in multiple organs, leading to death. Supportive treatments and supplementation of failing organs are usually efficient. In contrast, the usefulness of cardiopulmonary bypass in drug-induced shock remains a matter of debate. The majority of deaths results from poisoning with membrane stabilising agents and calcium channel blockers. There is a need for more aggressive treatment in patients not responding to conventional treatments. The development of new antidotes is limited. In contrast, experimental studies support the hypothesis that cardiopulmonary bypass is life-saving. A review of the literature shows that cardiopulmonary bypass of the poisoned heart is feasible. The largest experience has resulted from the use of peripheral cardiopulmonary bypass. However, a literature review does not allow any conclusions regarding the efficiency and indications for this invasive method. Indeed, the majority of reports are single cases, with only one series of seven patients. Appealing results suggest that further studies are needed. Determination of prognostic factors predictive of refractoriness to conventional treatment for cardiotoxic poisonings is mandatory. These prognostic factors are specific for a toxicant or a class of toxicants. Knowledge of them will result in clarification of the indications for cardiopulmonary bypass in poisonings.

Fomepizole in treatment of uncomplicated ethylene glycol poisoning.

Fomepizole is an effective alternative to ethanol in the treatment of ethylene glycol poisoning. In a series of 38 acute poisonings without renal failure, fomepizole obviated the need for haemodialysis.

Acute Digitalis Intoxication — Is Pacing Still Appropriate?

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.

The Role of Insulin and Glucose (Hyperinsulinaemia/Euglycaemia) Therapy in Acute Calcium Channel Antagonist and β-Blocker Poisoning

The inotropic effect of insulin has been long established. High-dose (0.5–1 IU/kg/hour) insulin, in combination with a glucose infusion to maintain euglycaemia (hyperinsulinaemia/euglycaemia therapy), has been proposed as a treatment for calcium channel antagonist (CCA) and β-adrenoceptor antagonist (β-blocker) poisonings. However, the basis for its beneficial effect is poorly understood.CCAs inhibit insulin secretion, resulting in hyperglycaemia and alteration of myocardial fatty acid oxidation. Similarly, blockade of β2-adrenoceptors in β-blocker poisoning results in impaired lipolysis, glycogenolysis and insulin release. Insulin administration switches cell metabolism from fatty acids to carbohydrates and restores calcium fluxes, resulting in improvement in cardiac contractility.Experimental studies in verapamil poisoning have shown that high-dose insulin significantly improved survival compared with calcium salts, epinephrine or glucagon. In several life-threatening poisonings in humans, the administration of high-dose insulin produced cardiovascular stabilisation, decreased the catecholamine vasopressor infusion rate and improved the survival rate.In a canine model of propranolol intoxication, high-dose insulin provided a sustained increase in systemic blood pressure, cardiac performance and survival rate compared with glucagon or epinephrine. In contrast, insulin had no effect on heart rate and electrical conduction in the myocardium. In another study, high-dose insulin reversed the negative inotropic effect of propranolol to 80% of control function and normalised heart rate. High-dose insulin produced a significant decrease in the left ventricular end-diastolic pressure and a significant increase in the stroke volume and cardiac output. The vasodilator effect was explained by an enhanced cardiac output leading to withdrawal of compensatory vasoconstriction. No clinical studies have yet been performed.Although not effective in all cases, we recommend hyperinsulinaemia/euglycaemia therapy in patients with severe CCA poisoning who present with hypotension and respond poorly to fluid, calcium salts, glucagon and catecholamine infusion. However, careful monitoring of blood glucose and serum potassium concentrations is required to avoid serious adverse effects. More clinical data are needed before this therapy can be recommended in β-blocker poisoning. There is a need for large prospective clinical trials to confirm safety and efficacy of hyperinsulinaemia/euglycaemia therapy in both CCA and β-blocker poisoning.

Impaired plasma B-type natriuretic peptide clearance in human septic shock.

Introduction:High B-type natriuretic peptide (BNP) levels are reported in the context of septic shock. We hypothesized that high BNP levels might be related to an alteration in BNP clearance pathway, namely neutral endopeptidase (NEP) 24.11. NEP 24.11 activity was measured in septic shock and in cardiogenic shock patients. We further evaluated whether baseline plasma BNP can predict fluid responsiveness and whether BNP can still be released in plasma despite high initial BNP levels, in response to overloading. Material and Methods:Prospective observational study. Patients in severe sepsis (S) or in septic shock (SS) needing a fluid challenge were included. Stroke volume (SV) and BNP were measured before (SV1, BNP1) and 45 mins after (SV2, BNP2) a standardized fluid challenge. DeltaBNP was defined as the difference between BNP2 and BNP1. NEP 24.11 activity was determined by fluorometry in 12 SS and 4 S patients before fluid challenge and in 5 cardiogenic shock patients. Results:Twenty-three patients (61 ± 18 years old, Simplified Acute Physiology Score II: 54 ± 21; 19 SS, 4 S; BNP1: 1371 ± 1434 pg/mL) were studied. BNP1 concentrations were significantly higher in SS than in S (1643 ± 1437 vs. 80 ± 35 pg/mL; p = 0.002). There was no correlation between baseline BNP and fluid responsiveness. Nine of the 11 patients with BNP1 >1000 pg/mL were fluid responders. DeltaBNP was greater in fluid nonresponders than in fluid responders (22 ± 27% vs. 6 ± 11%, p = 0.028). Plasma BNP was higher in SS than in cardiogenic shock patients (1367 ± 1438 vs. 750 ± 346 respectively; p = 0.027). NEP 24.11 activity was lower in SS than in S patients (0.10 ± 0.06 nmole/mL/min vs. 0.50 ± 0.22 nmole/mL/min, p <0.0001) cardiogenic shock patients (0.10 ± 0.06 nmole/mL/min vs. 0.58 ± 0.19 nmole/mL/min; p = 0.002). Conclusion:High levels of BNP might be related to an alteration in BNP clearance. During sepsis, high BNP levels are not predictive of fluid nonresponsiveness. Nevertheless, in fluid nonresponders, acute ventricular stretching can result in further BNP release.

Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat:

Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague–Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam–opioid drug–drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam–opioid lethal interactions are needed.