Bio: Bruno Mégarbane is Professor of intensive care medicine at the University Paris Cité. He is the head of the Department of Medical and Toxicological Critical Care at Lariboisière Hospital. He leads a research team at INSERM dedicated to the study of the mechanisms of toxicity of psychotropic and recreational drugs. He has conducted multiple clinical and experimental studies in toxicology and participated in several multicentric studies. He is a past President of the European Association of Poison Centres and Clinical Toxicologists (EAPCCT). He is associate editor of Clinical Toxicology and Annals of Intensive Care. 

Abstract: A major crisis of opioid overdose-related fatalities is ongoing in the occidental countries since the end of the 90s. The crisis has progressed in three successive waves, attributed to the neuro-respiratory toxicity of prescription opioid analgesics (1st wave), heroin (2nd wave), and more recently fentanyl and analogues (3rd wave). In 2023, about 120,000 opioid users died in the US, mainly due to fentanyl abuse or misuse. Despite the massive decrease in opioid prescription, deaths related to the recreational use of non-medical opioids have exponentially progressed. Modification of the route of fentanyl abuse/misuse and co-exposures to stimulant drugs have highly contributed to the progression of the number of overdose-related fatalities. Additional factors explain that the crisis may not rapidly stop. Use of various new potent synthetic opioids is spreading including 2-benzylbenzimidazoles (e.g., nitazenes), cyclohexylbenzamides (e.g., AH-7921) diphenylethylpiperazines (e.g., MT-45), benzimidazolones (e.g., brorphine), and U-drugs (e.g., U47700). Combination of fentanyl and xylazine, a veterinary alfa2-adrenergic receptor agonist drug is also spreading; however, its exact contribution to the overall neuro-respiratory toxicity remains questioned. This talk will give an overview of the pharmacology, epidemiology of use and acute/chronic harms associated with the use of fentanyloids and non-fentanyl synthetic opioids.

Abstract: Opioids represent the first cause of drug-induced fatalities in the US, with ~1000 Americans dying each week from opioid abuse or misuse. Several factors explain the increase in opioid abuse including availability of multiple molecules and formulations, facilitated prescriptions to combat pain, underestimation risk of dependence development and spread of new synthetic opioids on the recreational scene. Opioid overdose is mainly responsible for central nervous system depression resulting in an almost pathognomonic triad combining consciousness impairment, miosis and bradypnea, at risk of leading to asphyxial death. Onset and duration of toxicity are variable, depending on the opioid properties, formulation and route of exposure. The dose is not the unique factor that influences the risk of overdose. Gene polymorphisms, drug–drug interactions, additional toxicity mechanisms of the new opioids also contribute to explaining the individual vulnerability. Other features of respiratory depression have been observed, such as the wooden chest wall syndrome with possible non-opioidergic pathways. Naloxone, a competitive antagonist at the opioid receptors, is the first-line antidote to reverse life-threatening opioid-related neuro-respiratory toxicity. Maintenance treatments are the cornerstone for opiate dependence management. Recently, take-home intranasal or intramuscular naloxone programs with education of the populations at risk were developed with success.

Abstract: Organophosphorus pesticides (OP) are responsible for approximately 3,000,000 severe poisonings and 200,000 deaths worldwide, mainly in developing countries. Cholinergic syndrome (muscarinic + nicotinic + central) following OP exposure is characteristic. Therefore, the emergent administration of high-dose atropine in combination with supportive care, appropriate decontamination, and protection personnel use If applicable, is based on the exposure circumstances and clinical approach. Plasma butyrylcholinesterase activity is a readily available but not specific biomarker while erythrocyte acetylcholinesterase activity is more specific but with limited availability. The exact contribution of oximes in OP poisoning treatment is still debated. In a randomized controlled trial comparing pralidoxime versus placebo, no significant benefit in survival or mechanical ventilation requirement was found, despite the correction of acetylcholinesterase activities in diethyl-OP-poisoned patients receiving pralidoxime. By contrast, in an Indian randomized controlled trial, high versus conventional dose pralidoxime significantly improved clinical presentation and reduced mortality. To date, optimal management of OP poisoning should include a rational (evidence-based) administration of an oxime to improve outcome. We recommend that oximes should be limited to severe OP poisonings with nicotinic syndrome or requiring high-dose atropine. Once indicated, oximes should be infused rapidly (before enzyme aging) and monitored by measuring acetylcholinesterase reactivation and serum concentration.

Abstract: Lithium-related toxicity results in seizures, myoclonic encephalopathy, and coma. Three different poisoning presentations exist, including acute poisoning in non-previously treated patients, acute-on-chronic poisoning, and therapeutic overdose. The reasons why severity and features are different between these presentations are unknown. Prolonged rat exposure results in brain lithium accumulation, which is more marked in the presence of renal failure. Differences in plasma and brain kinetics at least partially explain the observed variability between intoxication patterns. Severity of lithium-induced encephalopathy measured based on EEG is dependent on the poisoning pattern. Poisoning severity if related to the duration of exposure and to the brain accumulation of lithium. EXTRIP workgroup recommended hemodialysis if kidney function is impaired and serum lithium >4.0 mmol/L in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmia, irrespective of serum lithium. EXTRIP workgroup suggested hemodialysis if serum lithium is >5.0 mmol/L; if confusion is present; and if expected time to obtain a lithium < 1.0 mmol/L with optimal management is >36 h. Although debated, simple Paris criteria (serum lithium ≥5.2 mmol/L or serum creatinine ≥200 µmol/L) may be better. This lecture will present experimental data to clarify determinants of inter-individual variability in lithium poisoning and discuss guidelines to improve indications of hemodialysis.