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Bruno Mégarbane

Publications and source records attributed to Bruno Mégarbane.

At least 19 recordsLinked to original sources
PubMed2007

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships.

INTRODUCTION: Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations. METHODS: We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay. RESULTS: Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects. CONCLUSION: After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.

Adult↗
PubMed2006

Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression.

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg(-1) was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg(-1) buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N=24) and arterial blood gases (N=12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3]+buprenorphine [day 4]), (dexamethasone solvent [days 1-3]+buprenorphine [day 4]), (dexamethasone [days 1-3]+buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3]+buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P<0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg(-1) buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.

Animals↗
PubMed2006

Extracorporeal life support in a case of acute carbamazepine poisoning with life-threatening refractory myocardial failure.

OBJECTIVE: To report the efficacy of extracorporeal life support (ECLS) in acute carbamazepine poisoning with sustained refractory myocardial failure and a high degree of conductance disturbances. DESIGN AND SETTING: Case report from the toxicological and medical intensive care unit in a university hospital. PATIENT: A 26-year-old man with severe myocardial failure unresponsive to 1.7 microg kg(-1) min(-1) epinephrine and 1.9 microg kg(-1) min(-1) norepinephrine (SvO2, 17.8% and cardiac index, 0.8 l min(-1) m(-2)) following a suicidal ingestion of 32 g slow-release carbamazepine. INTERVENTIONS: ECLS (Jostra-Maquet centrifugal pump (Rotaflow) connected to a hollow-fiber membrane oxygenator). MEASUREMENTS AND RESULTS: ECLS device allowed inotropic drug weaning while maintaining end-organ function and supported the patient until myocardial recovery. The plasma carbamazepine level was 224 micromol/l on admission and peaked at 338 micromol/l 101 h after admission with a prolonged gastrointestinal absorption phase despite multiple doses of activated charcoal. The patient survived and was successfully explanted on day 6. An extensive and regressive thrombosis of the inferior vena cava was noted. Cardiac function totally recovered and at 2-year follow-up. There were no significant sequelae. CONCLUSIONS: We report a case of life-threatening myocardial failure with conductance disturbances secondary to an acute carbamazepine poisoning, demonstrating the efficacy of ECLS to assist recovery.

Adult↗
PubMed2006

Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences.

Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.

Analgesics, Opioid↗
PubMed2005

Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation.

High dose buprenorphine is used as substitution treatment in heroin addiction. However, deaths have been reported in addicts using buprenorphine. The role of norbuprenorphine, an N-dealkyl metabolite of buprenorphine, was hypothesized to explain these fatal cases. We determined the median intravenous lethal dose (LD(50)) of norbuprenorphine in male Sprague-Dawley rats. The effects of a single intravenous dose of 3 or 9 mg/kg norbuprenorphine alone on arterial blood gases were studied. Finally, the effect of pre- and post-administrations of buprenorphine on norbuprenorphine-induced changes on arterial blood gases were analyzed. Norbuprenorphine's LD(50) was 10 mg kg(-1). Norbuprenorphine 3 mg kg(-1) produces the rapid onset of sustained respiratory depression, as demonstrated at 20 min by a maximal significant increase in PaCO(2) (8.4+/-0.9 versus 5.7+/-0.1 kPa), decrease in arterial pH (7.25+/-0.06 versus 7.44+/-0.01), and hypoxia (8.3+/-0.6 versus 11.1+/-0.2 kPa). Buprenorphine not only protected against the effects of 3 mg kg(-1) norbuprenorphine in a dose-dependent manner but also reversed the effects when given afterward. Binding experiments suggest a role for micro- and to a lesser extent for delta-opioid receptors in buprenorphine protective effect against norbuprenorphine-induced respiratory depression. In conclusion, our data clearly show that norbuprenorphine alone causes important deleterious effects on ventilation in rats. However, buprenorphine protective effect calls into question the role for norbuprenorphine in respiratory toxicity associated with buprenorphine use.

Animals↗
PubMed2005

[Acute hydroxychloroquine poisoning. The danger of rapid or excessive correction of initial hypokalemia].

INTRODUCTION: Toxic effects of hydroxychloroquine, like chloroquine, include membrane stabilization and hypokalemia, which is correlated with the severity of the overdose. Correction of hypokalemia can expose patients to the risk of ventricular arrhythmia. CASE: A 19-year-old woman who had ingested 6 grams of hydroxychloroquine was admitted to intensive care with severe hypokalemia (1.5 mmol/L on admission). Thirty-six hours after correction of the hypokalemia, circulatory arrest followed ventricular fibrillation. Her potassium level at that time was 5.8 mmol/L. Outcome was favorable after it returned to normal. DISCUSSION: Because its pathogenesis remains debatable, the hypokalemia following hydroxychloroquine poisoning must be corrected with care, even when severe. This correction is difficult, and extracellular transfer of the excess potassium after elimination of the toxin exposes the patient to the risk of ventricular arrhythmia.

Adult↗
PubMed2005

Difficulties in assessing cytomegalovirus-associated gastric perforation in an HIV-infected patient.

BACKGROUND: Active Cytomegalovirus (CMV) infection is a common complication in advanced symptomatic Human Immunodeficiency Virus (HIV) infection. CMV-induced intestinal perforations are hard to diagnose and may be observed throughout the gastrointestinal tract. Isolated stomach perforation is exceptional. CASE PRESENTATION: A 47-year-old man was admitted to our intensive care unit with multiorgan failure. Gastrointestinal endoscopic examination showed erythematous gastritis but normal duodenum and colon. CMV blood culture was positive. Histologic examination of a gastric biopsy showed inflammatory infiltrate and immunostaining typical intranuclear CMV inclusion bodies. Concomitant abdominal CT scan disclosed large peripancreatic hypodensities without pneumoperitoneum. The patient died despite supportive therapies and ganciclovir infusion. Postmortem examination showed a 4-cm gastric perforation adhering to the transverse colon and liver, with a thick necrotic inflammatory coating around the pancreas. The whole GI tract, except the stomach, was normal. As other causes, especially Helicobacter pylori infection could be ruled out, a causal relationship between CMV and gastric disease was assumed. CONCLUSION: CMV may be responsible for gastric perforations, with difficulties in assessing the diagnosis. Early diagnosis based on cautious endoscopy and histopathologic examination is needed to make a favorable outcome possible.

Antiviral Agents↗
PubMed2004

Current recommendations for treatment of severe toxic alcohol poisonings.

BACKGROUND: Ethylene glycol (EG) and methanol are responsible for accidental, suicidal, and epidemic poisonings, resulting in death or permanent sequelae. Toxicity is due to the metabolic products of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. Conventional management of these intoxications consists of ethanol and hemodialysis. Fomepizole, a potent ADH inhibitor, has largely replaced antidotal ethanol use in France and two recent prospective U.S. trials definitively established its efficacy. Fomepizole appears safer than ethanol and while no comparative study of efficacy exists, fomepizole is recommended as the first-line antidote. FOCUS: Fomepizole, administered early in EG intoxication, prevents renal injury. In the absence of renal failure, EG clearance is rapid, avoiding the need for prolonged fomepizole administration. The long elimination half-life of methanol poisonings, with absent hemodialysis, necessitates prolonged administration of fomepizole. In the U.S. trials, patients were dialyzed when plasma EG or methanol concentrations were >/=0.5 g/l. However, EG-poisoned patients treated with fomepizole prior to the onset of significant acidosis may not require hemodialysis. Indeed, fomepizole may also obviate the need for hemodialysis in selected methanol-poisoned patients, in the absence of neurological and ocular impairment or severe acidosis. When dialysis is indicated, 1 mg.kg.h continuous infusion of fomepizole should be provided to compensate for its elimination. CONCLUSIONS: Fomepizole is an effective and safe first-line recommended antidote for EG and methanol intoxication. In selected patients, fomepizole may obviate the need for hemodialysis.

Alcohol Dehydrogenase↗
PubMed2004

Increased diffusion of soluble adhesion molecules in meningitis, severe sepsis and systemic inflammatory response without neurological infection is associated with intrathecal shedding in cases of meningitis.

OBJECTIVE: Sepsis and systemic inflammatory response syndrome (SIRS) result in the release in plasma of inflammatory cytokines and soluble forms of adhesion molecules in relation to endothelial activation. This study was designed to compare cerebrospinal fluid (CSF) concentrations of adhesion molecules in meningitis and SIRS without neurological infection and to evaluate in meningitis whether they originate from passive diffusion through damaged blood-CSF barrier or from local production. DESIGN: Prospective observational study. SETTING: University hospital medical intensive care unit. PATIENTS: Nineteen patients with meningitis and 41 patients with sepsis or SIRS without cerebrospinal infection consecutively admitted to the critical care unit over an 18-month period. INTERVENTIONS: Soluble forms of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (interleukin (IL)-1beta and TNF-alpha) were measured in paired CSF and blood samples. RESULTS: Serum concentrations of soluble adhesion molecules and cytokines were increased in the two groups, without significant differences. The CSF concentrations were elevated in both cases, whereas patients with meningitis demonstrated significantly higher CSF concentrations of soluble ICAM-1, VCAM-1, E-selectin, and TNF-alpha ( p<0.001), with higher corresponding CSF/serum ratios. Correlations between CSF and serum concentrations were found only in meningitis. These correlations were strong for soluble ICAM-1 (r(2)=0.7, p<0.001) and E-selectin (r(2)=0.9, p<0.001), but weaker for VCAM-1. VCAM-1 CSF/serum ratios were increased, in comparison with ICAM-1 and E-selectin CSF/serum ratios, despite similar molecular weights. Serum and CSF levels of cytokines and adhesion molecules were not predictive of death for the whole population, except concentrations of ICAM-1 significantly increased in non-surviving patients ( p<0.05). CONCLUSIONS: The CSF soluble adhesion molecules are increased in sepsis, SIRS and meningitis. In meningitis, the correlation between CSF and serum concentrations of adhesion molecules and the presence of a discrepancy of CSF/serum ratios for molecules of the same molecular weight may suggest intrathecal shedding in addition to diffusion through blood-CSF barrier.

Adult↗
PubMed2004

Difficulties in assessing brain death in a case of benzodiazepine poisoning with persistent cerebral blood flow.

Assessing brain death may sometimes be difficult, with isoelectric EEG following psychotrope overdoses or normal cerebral blood flow (CBF) persisting despite brain death in the case of ventricular drainage or craniotomy. A 42-year-old man, resuscitated after cardiac arrest following a suicidal ingestion of ethanol, bromazepam and zopiclone, was admitted in deep coma. On day 4, his brainstem reflexes and EEG activity disappeared. On day 5, his serum bromazepam concentration was 817 ng/ml (therapeutic: 80-150). The patient was unresponsive to 1 mg of flumazenil. MRI showed diffuse cerebral swelling. CBF assessed by angiography and Doppler remained normal and EEG isoelectric until he died on day 8 with multiorgan failure. There was a discrepancy between the clinically and EEG-assessed brain death, and CBF persistence. We hypothesized that brain death, resulting from diffuse anoxic injury, may lead, in the absence of major intracranial hypertension, to angiographic misdiagnoses. Therefore, EEG remains useful to assess diagnosis in such unusual cases.

Adult↗
PubMed2004

The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-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 beta-adrenoceptor antagonist (beta-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 beta(2)-adrenoceptors in beta-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 beta-blocker poisoning. There is a need for large prospective clinical trials to confirm safety and efficacy of hyperinsulinaemia/euglycaemia therapy in both CCA and beta-blocker poisoning.

Adrenergic beta-Antagonists↗
PubMed2003

Is elevated plasma lactate a useful marker in the evaluation of pure carbon monoxide poisoning?

OBJECTIVE: To examine whether CO poisoning induces a significant increase in plasma lactate concentration. DESIGN AND SETTING: Prospective observational clinical study in the emergency department and intensive care unit in a university-affiliated teaching hospital. PATIENTS: 146 pure CO poisonings resulting from dysfunction of gas cookers or water heaters. MEASUREMENTS AND RESULTS: Patients were classified into four neurological impairment groups: 37% were severely, 8% moderately, and 45% mildly intoxicated, while 1% were asymptomatic. We found only very mild increases in plasma lactate concentration (median 2.30 mmol/l) which, however, was significantly correlated with the severity of neurological impairment and blood CO concentration (1.41 mmol/l, Spearman's test r=0.3). CONCLUSIONS: Plasma lactate is mildly elevated in pure CO-exposed patients. This mild increase and the extensive overlap between the groups of neurological impairment severity do not suggest the usefulness of systematic plasma lactate measurement in pure CO poisoning.

Adult↗
PubMed2003

Antidotal treatment of cyanide poisoning.

Cyanide poisoning may result from different exposures: residential fires, industrial accidents, drug and plant intoxication. Clinical features include coma, respiratory arrest and cardiovascular collapse. The biological hallmark is lactic acidosis. A plasma lactate concentration > or = 10 mmol/L in fire victims without severe burns and > or = 8 mmol/L in pure cyanide poisoned patients is a sensitive and specific indicator of cyanide intoxication. Many antidotes are available and efficient. However, therapeutic strategies are still debated. Our objective was to compare conventional treatments to hydroxocobalamin. This article reviews the literature on cyanide poisoning treatment. Conventional treatment of cyanide poisoning includes decontamination, supportive and specific treatment. Decontamination should be adapted to the route of poisoning and never postpone supportive treatment. Basic life support includes immediate administration of high flow of oxygen, airway protection and cardiopulmonary resuscitation. Advanced life support includes mechanical ventilation, catecholamine and sodium bicarbonate infusion. Supportive treatment is efficient but does not modify the time course or the body burden of cyanide. Numerous antidotes are available. Oxygen counteracts efficiently cyanide action at the mitochondrial level. Sodium thiosulfate, methemoglobin forming agents and cobalt compounds act efficiently by complexing or transforming cyanide into non-toxic stable derivatives. However, regarding the main clinical condition of cyanide poisoning, i.e. smoke inhalation, we should take into account not only the efficiency of antidotes but also their safety. Sodium thiosulfate is both efficient and safe, but acts with delay. Methemoglobin-forming agents are potent, but due to the transformation of hemoglobin into methemoglobin, they impair tissue delivery of oxygen. Experimental data showed increased mortality in carbon monoxide- and cyanide-poisoned rats treated with these agents. Cobalt EDTA and hydroxocobalamin are efficient and act immediately. Cobalt EDTA is more potent on a molar basis; however, numerous side effects limit its use to evidenced cyanide poisoning. In a prospective study, hydroxocobalamin appeared safe in fire victims with or without cyanide poisoning. The only reported side effect was a red coloration of skin and urine. In conclusion, antidotes are beneficial in cyanide poisoning. In suspected cyanide-poisoned patients, we recommend the use of hydroxocobalamin as first-line antidote, owing to its safety. In massive cyanide poisoning, due to the limited potency of hydroxocobalamin, continuous infusion of sodium thiosulfate should be associated.

Antidotes↗