Toxicodynetics in nordiazepam and oxazepam overdoses.

OBJECTIVES: Toxicodynetics aims at defining the time-course of major clinical events in drug overdose. We report the toxicodynetics in mono-intoxications with oxazepam and nordiazepam. METHODS: Cases of oxazepam or nordiazepam overdoses collected at the Paris poison control centre from 1999 to 2014 on the basis of self-report. A particular attention was paid to eliminate the concomitant alcohol or psychotropic co-ingestions. The toxicodynetic parameters were assessed as previously described. Results are expressed using 10-90 percentiles. In adults, the dose was normalized (TI, toxic Index) by dividing the supposed ingested dose by the maximal recommended dose. RESULTS: Two hundred and fifty-one and 74 cases of oxazepam and nordiazepam poisonings were included, respectively. The Emax for oxazepam and nordiazepam were sleepiness or obtundation in 106 and 36 cases, respectively. Coma was used to qualify only one oxazepam overdose. The median delay in onset of the Emax was 1.5h (0.33-15) in nordiazepam and 4h (0.5-15) in oxazepam overdose. In both overdoses, the onset of Emax occurred on an "on-off" mode. In adults, the greatest TIs in nordiazepam and oxazepam overdoses were 45 and 26.7, respectively. The TI in the oxazepam-induced coma was 26.7, the largest dose. CONCLUSION: Data collected in PCC allow determining a number of toxicodynetic parameters. Toxicodynetics showed that nordiazepam is not a cause of coma even in large overdose while oxazepam causes coma only at a very high dose. Deep coma in nordiazepam overdose whatever the dose and deep coma in overdose with oxazepam involving TI less than 20 result from unrecognized drug-drug interaction.

Toxicodynetics: A new discipline in clinical toxicology.

OBJECTIVES: Regarding the different disciplines that encompass the pharmacology and the toxicology, none is specifically dedicated to the description and analysis of the time-course of relevant toxic effects both in experimental and clinical studies. The lack of a discipline devoted to this major field in toxicology results in misconception and even in errors by clinicians. MATERIAL AND METHODS: Review of the basic different disciplines that encompass pharmacology toxicology and comparing with the description of the time-course of effects in conditions in which toxicological analysis was not performed or with limited analytical evidence. RESULTS: Review of the literature clearly shows how misleading is the current extrapolation of toxicokinetic data to the description of the time-course of toxic effects. CONCLUSION: A new discipline entitled toxicodynetics should be developed aiming at a more systematic description of the time-course of effects in acute human and experimental poisonings. Toxicodynetics might help emergency physicians in risk assessment when facing a poisoning and contribute to a better assessment of quality control of data collected by poison control centres. Toxicodynetics would also allow a quantitative approach to the clinical effects resulting from drug-drug interaction.

Predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae causing infection among intensive care unit patients with prior colonization.

We investigated the predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) causing infections among intensive care unit patients with prior documented ESBL-PE colonization. Using multivariate analysis, referral from medical ward, nursing home or rehabilitation center [Odds ratio (OR), 2.5; 95 % confidence interval (CI), [1.3-5.0]; p = 0.007], previous fluoroquinolone treatment (OR, 3.4; CI, [1.1-10.5]; p = 0.003), extracorporeal membrane oxygenation (OR, 4.6; CI, [1.3-15.9]; p = 0.02), and absence of prior positive ESBL-PE rectal swab culture (OR, 5.0; CI, [1.6-10.0]; p = 0.0009) were risk factors for ESBL-PE infection. Easily identifiable factors may help with targeting carbapenem prescriptions.

[Mechanisms of opioid-induced overdose: experimental approach to clinical concerns]. / Etude du mécanisme des overdoses aux opioïdes : apport de l'expérimental à la clinique.

The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO(2). However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO(2)). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO(2). This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO(2,) even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.

LC-MS/MS method for quantification of baclofen in hair: A useful tool to assess compliance in alcohol dependent patients?

To evaluate adherence to treatment, we developed and validated a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for baclofen quantification in hair.Twenty mg was washed twice with dichloromethane, incubated in phosphate buffer (pH 5) for 10 minutes at 95°C, then extracted by liquid-liquid extraction in alkaline condition. Baclofen-d4 was used as the internal standard. This method was applied to assess compliance in4 treated alcohol-dependent patients (3 dead and one living). Blood quantification of baclofen and ethanol were performed in the 4 cases. Hair ethylglucuronide (ethanol metabolite, EtG) measurement (2x3 cm) was associated in 1 patient. Baclofen quantification in hair was validated over the range 10-5000 pg/mg. The accuracy was within 96.0%-110.9% and the precision was less than 9.3%. Baclofen segmental (3x2cm) hair concentrations found in the living patient were 4420, 4260, and 4380 pg/mg, reflecting a regular exposure over the last 6 months and suggesting patient compliance. However, the high EtG level found in this patient in the analyzed segments (225 pg/mg and 215 pg/mg) showed excessive alcohol consumption during the same period, suggesting therapeutic failure. In the 3 deceased patients, the non-segmental analysis of hair showed baclofen concentrations of 15, 545, and 2475 pg/mg. The low concentrations in the 2 first cases are compatible either with a poor compliance or to a beginning of a treatment. This is the first measurement of baclofen in hair of alcohol dependent patients. It could be used as a monitoring biomarker to assess patient's compliance.

Acute lower limb ischemia is a frequent complication of severe diabetic hyperosmolarity.

AIM: To describe the outcome of intensive care unit (ICU) patients admitted with a hyperglycaemic hyperosmolar non-ketotic syndrome (HHNS), with a specific analysis of precipitating conditions and complications including lower limb ischemia. METHODS: Retrospective review of patients admitted in a university-hospital ICU for HHNS. RESULTS: Seventeen consecutive patients (9F/8M, age: 75 years [57-81] (median [25-75% percentiles], Glasgow Coma score: 13 [12-14]) were admitted for HHNS over an 8-year period (1998-2005). On admission, the blood glucose level was 40.0 mmol/l [26.3-60.8], the corrected serum sodium concentration 167 mmol/l [158-174], and the calculated plasma osmolarity 384 mosmol/l [365-405]. All the patients presented with renal failure due to severe dehydration. An infection was identified as the precipitating factor in 8/17 cases. Three (18%) patients died in the ICU. Non-survivors were significantly older than survivors (P=0.02). Using univariate analysis, no other parameter measured on admission was related to mortality. Four patients (24%) presented with lower limb ischemia. They had a significantly more elevated blood urea nitrogen (P=0.03), creatinine phosphokinase level (P=0.04), and leukocyte count (P=0.02). The bilateral, symmetrical, and distal extremity involvement suggested diminished blood flow due to hyperviscosity, hypotension, vasoconstrictors, or cholesterol emboli rather than a proximal arterial obstruction as causative mechanisms. No patient was treated surgically. Ischemia reversed with fluid loading and resulted in toe dry digital necrosis. CONCLUSION: HHNS is a rare but life-threatening cause of ICU admission. There is a high incidence of lower limb ischemia in HHNS patients, which may be related to dehydration and blood hyperviscosity.

Cyanide: critical issues in diagnosis and treatment.

The concern of a terrorist attack using cyanide, as well as the gradual awareness of cyanide poisoning in fire victims, has resulted in a renewed interest in the diagnosis and treatment of cyanide poisoning. The formerly academic presentation of cyanide poisoning must be replaced by more useful knowledge, which will allow emergency physicians and rescue workers to strongly suspect cyanide poisoning at the scene. Human cyanide poisonings may result from exposure to cyanide, its salts, or cyanogenic compounds, while residential fires are the most common condition of exposure. In fire victims, recognition of the cyanide toxidrome has been hampered by the short half-life in blood and poor stability of cyanide. In contrast, carboxyhemoglobin, as a marker of carbon monoxide poisoning, is easily measured and long-lasting. No evidence supports the assumption of the arbitrary fixed lethal thresholds of 50% for carboxyhemoglobin, and 3 mg/L for cyanide, in fire victims. Preliminary data, drawn when comparing pure carbon monoxide and pure cyanide poisonings, suggest that a cyanide toxidrome can be defined considering signs and symptoms induced by cyanide and carbon monoxide, respectively. Prospective studies in fire victims may provide value in clarifying signs and symptoms related to both toxicants. Cyanide can induce a life-threatening poisoning from which a full recovery is possible. A number of experimentally efficient antidotes to cyanide exist, whose clinical use has been hampered due to serious side effects. The availability of potentially safer antidotes unveils the possibility of their value as first-line treatment, even in a complex clinical situation, where diagnosis is rapid and presumptive.

Lingual angioedema after perindopril use.

We report a case of severe lingual edema and airway compromise associated with angiotensin-converting enzyme inhibitor use. Although angiotensin-converting enzyme inhibitors are generally considered as safe drugs, angioedema may induce severe respiratory distress and death.

Value of C-reactive protein in the detection of bacterial contamination at the time of presentation in drug-induced aspiration pneumonia.

STUDY OBJECTIVES: To compare the plasma concentration of C-reactive protein (CRP) with traditional markers for diagnosis of bacterial pneumonia in patients with suspected aspiration. DESIGN: Prospective, nonrandomized, controlled study of consecutive hospital admissions. SETTING: Toxicology ICU in a university hospital. PATIENTS OR PARTICIPANTS: Acutely poisoned comatose patients admitted to the hospital with suspicion of aspiration pneumonia. INTERVENTIONS: Distal protected catheter sampling per fiberoptic bronchoscopy and bacteriologic culture were employed as a standard to detect the bacterial component of suspected aspiration pneumonia. Plasma CRP concentrations, temperature, and WBC count were measured on hospital day 1. MEASUREMENTS AND RESULTS: Sixty-six patients were evaluated. Thirty-two had bacterial contamination by positive culture (> or =10(3) cfu/mL). Multiple receiver-operating characteristic (ROC) curves were used to compare each parameter for detection of infection secondary to aspiration. The ROC curve of CRP concentrations showed that a CRP >75 mg/L is associated with bacterial contamination with a sensitivity of 87%, specificity of 76%, positive predictive value of 78%, and negative predictive value of 87%. ROC curves of temperature and WBC count demonstrated poor diagnostic value of these markers in indicating the bacterial component of suspected aspiration pneumonia. CONCLUSIONS: Early measurement of CRP is useful for the diagnosis of aerobic bacterial content of aspiration pneumonia and perhaps in determining the need for invasive bacteriologic sampling. Temperature and WBC count are poor indicators of bacterial infection of aspiration pneumonia in poisoned patients.

Early complications and value of initial clinical and paraclinical observations in victims of smoke inhalation without burns.

OBJECTIVE: To evaluate the incidence of early pulmonary complications and the value of initial clinical signs and paraclinical investigations in victims of smoke inhalation not suffering from burns following structural fires. DESIGN: Retrospective chart review. SETTING: Thirteen-bed ICU. PATIENTS: Sixty-four victims of smoke inhalation following household fires were admitted to the ICU between January 1987 and December 1992. Exclusion criteria from the study were patients with cutaneous burns or multiple trauma or blast injury, and patients found in cardiac arrest. METHODS: Clinical, biological, and radiologic parameters were collected over a 5-day period. RESULTS: The mortality rate in relation to progressive respiratory failure was 3.1%. Mean ICU stay was 5.8 days (range, 1 to 33 days), and was longer in the patients presenting with soot deposits in the oropharynx (p = 0.02), dysphonia (D) (p = 0.05), or ronchi (R) (p = 0.0004) at the first examination, and in those having a positive sputum bacteriologic analysis (p = 0.003) or requiring parenteral bronchodilator agents for more than 24 h (p = 0.04). Thirty-five patients underwent mechanical ventilation (MV) for a mean of 101.2 h (range, 8 to 648 h). Mean MV duration was higher in the patients presenting initially with R (p = 0.003), high carbon monoxide (but not cyanide) levels (p = 0.02), or a positive bacteriologic sample (p = 0.0001). Positive bacteriologic sampling correlated with the presence of D (p = 0.02) or R (p = 0.04) and with immediate intubation (p = 0.0003). No correlation was found with chest radiograph. CONCLUSIONS: In this selected series of fire victims without cutaneous burns, respiratory injury was frequent. The initial clinical signs may be helpful to predict pulmonary complications.

A case of life-threatening lactic acidosis after smoke inhalation - interference between beta-adrenergic agents and ethanol?

A 49-year-old male developed bronchospasm and severe lactic acidosis after exposition to fire smoke. The correction of lactic acidosis following beta-adrenergic agents withdrawal, and the transitory increase in lactate after salbutamol reintroduction are consistent with hypersensitivity to salbutamol. However, the plasma lactate concentration (32.6 mmol/l) that we observed 9.5 h after admission is far above those currently seen after administration of beta-adrenergic agents. We searched for causes able to potentiate the adverse effects of these drugs and we noticed that our patient had a high plasma ethanol level (2.4 g/l). Alcohol metabolism in the liver results in generation of high NADH/NAD+ ratios, thus reducing lactate liver clearance. This observation suggests that plasma lactate levels should be monitored closely in alcoholic patients treated with beta-mimetic agents.

Mercury oxycyanide and mercuric cyanide poisoning: two cases.

BACKGROUND: Although cyanide poisoning can be serious or fatal, it is typically described as mild when the cyanide is ingested in the form of either mercuric cyanide or mercury oxycyanide. METHODS: We studied two patients with acute cyanide poisoning following ingestion of one of these two agents in each case. RESULTS: Both patients demonstrated features of life-threatening cyanide poisoning, including hemodynamic instability, severe lactic acidosis, and high blood cyanide concentration. One of the patients died, while the second demonstrated signs of mercury intoxication (acute renal failure and severe gastrointestinal symptoms), in addition to cyanide intoxication. CONCLUSION: Ingestion of either mercuric cyanide or mercury oxycyanide can result in life-threatening cyanide intoxication.

Hyperthermia complicating tricyclic antidepressant overdose.

We observed a 51-year-old woman who was admitted for severe amitriptyline overdose. Besides major cardiovascular complications, the patient developed severe hyperpyrexia with a central body temperature of more than 43 degrees C for 5 h. The patient died on day 3 from cardiocirculatory collapse and arrhythmias. Hyperthermia was unresponsive to cooling with ice water, gastric lavage, muscle relaxation, and dantrolene and bromocriptine administration. The possible mechanisms of refractory hyperthermia are discussed.

Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity.

OBJECTIVE: Acute chloroquine intoxication is responsible for a membrane-stabilising effect which results in electrocardiographic (ECG) and hemodynamic disturbances. Diazepam is used in acute chloroquine intoxication on the basis of clinical and experimental observations, but its utility alone, in man, remains unproven. The goal of this study was to verify whether diazepam alone has an effect on the membrane-stabilising effect observed in moderately severe chloroquine intoxications. DESIGN: Prospective, multi-center, double-blind, placebo-controlled study. SETTING: Prehospital mobile intensive care units (Paris) and hospital intensive care units (paris and Dakar). PATIENTS AND PARTICIPANTS: Adults with moderately severe intoxication defined as: a suspected ingested dose of 2 or more but less than 4 g, systolic blood pressure (SBP) higher than 80 mmHg, QRS duration less than 0.12 s and the absence of dysrhythmia at inclusion. INTERVENTIONS: Patients received either a loading dose of 0.5 mg/kg diazepam followed by an infusion of 1 mg/kg over 24 h or an equivalent volume of placebo. MEASUREMENTS AND RESULTS: Outcome was measured by serial assessments of SBP, ECG (QRS and QT segments) and clinical deterioration. There were no significant differences observed in the initial or serial ECG or SBP measurements. There were no deaths and no patient had to be removed from the study due to clinical deterioration. CONCLUSIONS: Diazepam, at the dose studied, does not appear to reverse the chloroquine-induced membrane-stabilising effect in acute moderately severe chloroquine intoxication. Supportive intensive care of these intoxications appears to be all that is necessary.

Treatment of acute methanol poisoning with fomepizole.

OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients. DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism. CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.

Paraquat poisoning. An overview of the current status.

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.

Effects of respiratory acidosis and alkalosis on the distribution of cyanide into the rat brain.

The aim of this study was to determine whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. The pharmacokinetics of a nontoxic dose of cyanide were first studied in a group of 7 rats in order to determine the distribution phase. The pharmacokinetics were found to best fit a 3-compartment model with very rapid distribution (whole blood T(1/2)alpha = 21.6 +/- 3.3 s). Then the effects of the modulation of arterial pH on the distribution of a nontoxic dose of intravenously administered cyanide into the brains of rats were studied by means of the determination of the permeability-area product (PA). The modulation of arterial blood pH was performed by variation of arterial carbon dioxide tension (PaCO2) in 3 groups of 8 anesthetized mechanically ventilated rats. The mean arterial pH measured 20 min after the start of mechanical ventilation in the acidotic, physiologic, and alkalotic groups were 7.07 +/- 0.03, 7.41 +/- 0.01, and 7.58 +/- 0.01, respectively. The mean PAs in the acidotic, physiologic, and alkalotic groups, determined 30 s after the intravenous administration of cyanide, were 0.015 +/- 0.002, 0.011 +/- 0.001, and 0.008 +/- 0.001 s(-1), respectively (one-way ANOVA; p < 0.0087). At alkalotic pH the mean permeability-area product was 43% of that measured at acidotic pH. This effect of pH on the rapidity of cyanide distribution does not appear to be limited to specific areas of the brain. We conclude that modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.

Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat.

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths.

AIMS: To assess the trends in the number, mortality and the nature of forensic cases involving toxicological detection of buprenorphine or methadone among toxicological investigations performed in Paris from June 1997 to June 2002. DESIGN: Retrospective, 5 year study with review of premortem data, autopsy, police reports, hospital data, and post-mortem toxicological analyses. SETTING AND PARTICIPANTS: 34 forensic cases of buprenorphine and 35 forensic cases of methadone detection among 1600 toxicological investigations performed at the Laboratory of Toxicology in the Medical Examiner's Office in Paris. MEASUREMENTS AND RESULTS: Therapeutic, toxic or lethal drug concentrations were defined based upon the results of blood analyses and the published literature. Drug concentrations were cross-referenced with other available ante- and post-mortem data. Subsequently, we classified a 'clear responsibility', 'possible responsibility' or 'not causative' role for buprenorphine or methadone in the death process, or 'no explanation of death'. Buprenorphine and methadone can be regarded as being directly implicated in, respectively, four of 34 death cases (12%) and three of 35 death cases (9%), and their participation in the lethal process is strongly plausible in eight (buprenorphine) and 11 (methadone) additional deaths. CONCLUSIONS: Analysis of causes of death reveals the difficulties in determining the role of substitution drugs in the death process, as many other factors may be involved, including circumstances surrounding death, past history, differential selection of subjects into either substitution modality and concomitant intake of other drugs (especially benzodiazepines and neuroleptics). The potential for synergistic or additive actions by other isolated molecules-particularly opioids, benzodiazepines, other psychotropes and alcohol-must be also considered.

Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995-99.

AIMS: (1). To assess the trends in the number, mortality and the nature of severe opiate/opioid poisonings from 1995 to 1999 in north-east Paris and adjacent suburbs and (2). to examine the effects of the introduction of high-dose buprenorphine on these parameters. DESIGN: Retrospective, 5-year study with review of pre-hospital, hospital and post-mortem data. SETTING AND PARTICIPANTS: Eighty patients from the toxicological intensive care unit (TICU) in north-east Paris, 421 patients from the pre-hospital emergency medical service in a north-east suburb of Paris (SAMU 93) and 40 deaths from the coroner's office in Paris. MEASUREMENTS AND RESULTS: We found that the number of pre-hospital opiate/opioid poisonings and deaths decreased over 5 years. During the same time frame, opiate/opioid poisoning admissions to our TICU remained steady, but the number of deaths declined. From 1995 to 1999, the detection of buprenorphine among opiate/opioid-poisoned TICU patients increased from two to eight occurrences per year while detection of opiates diminished from 17 to 10 occurrences per year. Increased buprenorphine detection correlated directly with increasing sales over this time period. In spite of the increased use of buprenorphine, the mortality associated with opiate/opioid poisonings has diminished in the pre-hospital environment from 9% in 1995 to 0% in 1999, and in the TICU from 12% in 1995 to 0% in 1997 and thereafter. We found a high frequency of multiple opiate/opioid use in severe poisonings, as well as the frequent association of other psychoactive drugs including ethanol. CONCLUSIONS: The number and the mortality of opiate/opioid poisonings appear to be stable or decreasing in our region. The association of multiple opiates/ opioids appears nearly as common as the association with other psychoactive drugs. The introduction of high-dose buprenorphine coincides with a decrease in opiate/opioid poisoning mortality. Further study will be necessary to clarify this observation.