Mixed Drug Toxicity Research Articles

Accidental drug deaths in Fulton County, Georgia, 2002: characteristics, case management and certification issues.

Historically, the duty of the medical examiner in assigning cause and manner of death in drug-related death cases has been fraught with controversial challenges. The lack of standardization in certifying drug-related deaths may involve differences among practicing forensic pathologists in their approach to such cases. The central objectives of the present study include characterization of current drug death patterns and the variability among medical examiners with respect to autopsy performance and death certification practices in one county medical examiner's office. Death certificates, scene information/investigative reports, autopsy reports, and toxicological laboratory results for each of the 100 cases of drug-related death occurring in 2002 in Fulton County, Georgia were reviewed. Comparison of overall autopsy rates and autopsy rates in drug-related death cases for each medical examiner individually and for the group collectively was performed. In examining cocaine-related deaths (most common), statistical analysis was performed for comparison of drug concentrations (cocaine and benzoylecgonine) between deaths certified as cocaine toxicity (poisoning) versus cocaine-complicating disease or causing an adverse event such as cerebral hemorrhage. Causes of accidental drug deaths included cocaine 40%, mixed drug intoxication 37%, opioids 10%, ethanol 7%, and prescription medication (nonopioid) 5%. Overall total autopsy rates in 2002 for each of the 6 independent medical examiners ranged from 51% to 69% (mean 64%), whereas autopsy rates in drug-related death ranged from 55% to 91% (mean 81%). In review of the subset of 40 cocaine-related deaths, 25% were certified as cocaine toxicity (poisoning), with the remaining 75% certified as cocaine-complicating disease or causing and adverse event. Autopsy rates in cocaine-related deaths were as follows: cocaine toxicity 80%, cocaine-complicating disease 77.3%, and cocaine causing adverse event 62.5%. Thirty-eight percent of cocaine-related deaths were considered to be of "low suspicion" for drug involvement at the time the death was reported to the medical examiner with the remaining 62% being of "high suspicion". Autopsy rates were somewhat lower in the low suspicion group (67%) versus the high suspicion group (72%). Comparison of drug levels between cocaine-related death certification groups was performed. No statistically significant difference was shown in drug levels (cocaine, P > 0.3; benzoylecgonine, P > 0.2) between deaths certified as cocaine toxicity versus those certified as cocaine-complicating disease or causing adverse event. In Fulton County, accidental drug deaths in 2002 most often involved cocaine either alone or in combination with opiates and/or alcohol. Cocaine, opiates, or both were involved in greater than three-fourths (77%) of all drug-related deaths. The majority of all decedents were black (57%) and male (76%) with an average age of 42.2 years. Cocaine and ethanol were more frequently detected in black decedents, whereas opiates and polydrug abuse were more common in white decedents throughout the period studied. Preliminary investigation showed a high index of suspicion for the specific drug involved in virtually all opiate and alcohol cases, and in 62% of cocaine-related cases. Overall, the 100 accidental drug deaths in 2002 accounted for 7.5% of all deaths investigated and certified by the Fulton County Medical Examiner's Office. Our study provides further evidence to support the lack of correlation between serum drug levels and the mechanism of drug toxicity in cocaine-related deaths. No statistically significant differences were shown in parent cocaine or benzoylecgonine concentrations between those cases certified as toxicities or poisonings versus those cases certified as aggravating underlying disease or causing an adverse event. In addition, 62% of the cocaine-related death cases were considered initially to be of high suspicion for drug-related death, thus emphasizing the strong importance of scene information/investigative reports in evaluating drug-death cases and in formulating plans of action to handle each individual case. Among the drug-death cases handled by 6 staff medical examiners at the Fulton County Medical Examiner's Office, variation existed in autopsy performance and death certification practices. These issues are discussed in the context of the National Association of Medical Examiners' (NAME) Position Paper on Cocaine, NAME Forensic Autopsy Performance Standards, and other relevant literature. Most variations relate to completeness of the cause-of-death statement (whether or not comorbid conditions are included) rather than classification of manner of death within the office. However, specific wording in the cause of death may have significant ramifications regarding drug-related mortality statistics processed by the vital statistics system, with possible under-representation of drug-related deaths in single-cause mortality data.

Accuracy of current clinical diagnosis in recreational drug‐related attendance to the emergency department

To determine the accuracy of current clinical diagnosis in recreational drug-related attendances to emergency by blood analysis. A prospective convenience sample of 103 patients who attended hospital with suspected recreational drug-related presentations was collected. Doctors' clinical impression of drugs responsible for presentation was compared with a detailed forensic blood analysis for recreational drugs. Among 103 samples, 80 (78%, 95% confidence intervals [CI] 70-86%) were found to have correct clinical suspicion of the recreational drug responsible for clinical presentation confirmed by laboratory analysis. Clinical diagnosis was most accurate for gamma-hydroxy butyrate (GHB) (sensitivity 97%, specificity 91%) and less accurate for amphetamines (sensitivity 61%, specificity 79%), alcohol (sensitivity 42%, specificity 84%) and opiates (sensitivity 46%, specificity 100%). Multiple drug ingestion was found in 70% (95% CI 61-79%) of samples. Sensitivity and specificity of clinical impression for prediction of multiple drug ingestion presence is 75% (95% CI 66-83%) and 85% (95% CI 78-92%), respectively. Clinical diagnosis in recreational drug-related attendances to the ED was correct in most cases. Drugs, such as GHB, were the most accurately diagnosed. Inaccuracy in recognizing other drugs, like amphetamines, opiates and alcohol, occurs where a coingestant produces a more profound clinical picture. Multiple drug ingestion is a common scenario in recreational drug presentations to emergency.

A 30-year survey of drug use in the 1914 birth cohort in Glostrup County, Denmark: 1964–1994

Use of drugs increases with age. Several drugs as well as multiple drug intake are recognized risk factors for symptoms, disability, hospitalizations, and even mortality, due to side effects and problems with compliance. Yet, little is known about the long-term effects. As a first step, this longitudinal study of a general population gives insight into consumption patterns including multiple drug intake ("polypharmacy") and individual adherence to drug use over a 30-year period. This is a study based on the first large longitudinal population study of the health of adult Danes. Examinations were performed at 50, 60, 70 and 80 years of age. The Statistical Package for the Social Sciences (SPSS) was used to check participants' individual adherence to each of six main drug categories, calculated stepwise. 802 persons were included at 50 years of age in 1964. Of these, 213 were still participating in the study in 1994. The general use of drugs increased for all drug categories with age. Women used statistically significantly more drugs than men and showed a higher degree of polypharmacy. The individual adherence to antihypertensives was greater than the corresponding adherences to analgesics, psychoactive drugs, or hypnotics. At least two-thirds of all remaining initial users of antihypertensives still took them at 80 years of age. For other drug categories, the corresponding values were half or less. For the initial population studied over a period of 30 years, the use of drugs increased with age, but the drugs were not prescribed for the same people over time. During the 30-year period, individual patients' drug adherence habits were in accordance with scientific evidence: patients adhered to long-term use of antihypertensive drugs, but used analgesics, psychoactive drugs and hypnotics for only shorter periods.

Oral Abuse of Fentanyl Patches (Duragesic®): Seven Case Reports

In order to increase the understanding regarding the oral abuse and potential toxicity of fentanyl patches seven cases were identified over a 3-year period where fentanyl, either alone or in combination with other factors, contributed to death following the oral abuse of Duragesic patches. The decedents comprised three females and four males with ages ranging from 20 to 51 years. Postmortem blood fentanyl concentrations were determined in all cases and ranged from 7 to 97 ng/mL. Two deaths were classified as a fentanyl overdose, three deaths were classified as a fentanyl and ethanol overdose, one death was considered a mixed drug intoxication and the remaining death was determined to be a combination of fentanyl and medical causes. These cases represent the largest reported series of deaths following the oral administration of transdermal fentanyl patches and provide detailed information on the potential for the abuse of transdermal Duragesic patches via this route. The postmortem blood fentanyl concentrations detected for each of the decedents demonstrate the potentially fatal blood concentrations that can arise after this relatively rare route of administration.

Problems in three Japanese drug users with Human Immunodeficiency Virus infection

Numbers of individuals infected with Human Immunodeficiency Virus (HIV) are increasing in Japan. The majority of them are Men who have sex with men and a part of them take drugs as 'Sex drug' at their sexual intercourse. Especially, Amyl nitrite, Methamphetamine, 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT; Foxy), and 3, 4-methylenedioxy- methamphetamine (MDMA; Ecstasy) are used, and they sometimes cause the physical and mental disorders. However, the actual drug inducing troubles among Japanese HIV-infected drug users had not yet been discussed enough. In this report, we describe three cases with HIV infection; a case developed severe neuroleptic malignant syndrome (NMS) after taking 5-MeO-DIPT, a case with persistent convulsion due to multiple drug intake and a case with rhabdomyolysis due to the non-subjective methamphetamine intake. Through these cases, we raise and discuss several underlying problems associated with drug use among HIV-infected individuals.

Two Cases of Fatal Amlodipine Overdose

Two fatal overdoses of the calcium channel blocker amlodipine are described. Postmortem samples were screened for volatiles and therapeutic and abused drugs. Amlodipine was measured by liquid chromatography-atmospheric pressure photoionization-mass spectrometry. The heart blood amlodipine concentrations for the two cases were 2.4 and 0.95 mg/L, and amlodipine was quantified in all other tissues. In the first case, venlafaxine and norvenlafaxine were also found, and the angiotensin receptor antagonist olmesartan was tentatively identified. The concentrations of amlodipine are compared with previously reported fatal and nonfatal overdoses. The medical examiners ruled in both cases that the manner of death was suicide and the causes of death were mixed drug intoxication and amlodipine intoxication.

Diabetic Ketoacidosis – A possible Complicating Factor in Deaths associated with Drug Overdose

Two cases are described where diabetic ketoacidosis was found in conjunction with significant levels of prescription drugs. Case 1: A 45-year-old woman with a history of insulin-dependent diabetes mellitus was found to have Armanni-Ebstein nephropathy characteristic of hyperglycaemia with a vitreous humour glucose level of 63.1 mmol/L and a beta-hydroxybutyrate level of 14.25 mmol/L. Ancillary toxicological evaluation revealed a lethal level of sertraline (2.5 mg/L), with an elevated level of methadone (0.23mg/L). Death was due to diabetic ketoacidosis complicating mixed drug toxicity. Case 2: A 27-year-old man with a history of insulin-dependent diabetes mellitus was found to have Armanni-Ebstein nephropathy with a vitreous humour glucose level of 51.7 mmol/L and a beta-hydroxybutyrate level of 18.6mmol/L. Ancillary toxicological evaluation revealed a potentially lethal level of methadone of 0.39mg/L. Death was attributed to diabetic ketoacidosis complicating methadone toxicity. These cases demonstrate a situation where drug toxicity led to diabetic ketoacidosis resulting in death most likely from a combination of factors. Measuring vitreous humour glucose and beta-hydroxybutyrate levels is important in individuals with histories, or scene evidence, of insulin-dependent diabetes mellitus, in addition to toxicological screening when there is evidence of possible drug taking. It appears that drug intoxication in both cases had impaired the ability to administer insulin, resulting in the development over time of diabetic ketoacidotic states. Lethal mechanisms were, therefore, more complex than simple drug toxicity or diabetic ketoacidosis in isolation.

Acute medical problems due to Ecstasy use. Case-series of emergency department visits.

To describe the clinical characteristics of Ecstasy (3,4-Methylenedioxymethamphetamine, MDMA) toxicity. Retrospective case-study of 52 self-reported Ecstasy intoxications presenting to our Emergency Department (ED) between January 2001 and December 2003. Most patients ingested Ecstasy together with other substances, including alcohol (51.9%) or other illicit drugs (71.1%). Medical problems leading to ED presentation were collapse or loss of consciousness (36.5%), palpitations (19.2%), dizziness or weakness (15.4%), and anxiety (13.5%). When other drugs were used in combination with Ecstasy the clinical presentation significantly changed. Panic reactions were observed in 4 of 13 patients with cocaine co-use (30.7%), compared to 3 of 39 patients without cocaine use (7.7%). Deep coma was found in 11 of 16 patients with co-use of gamma-hydroxybutyrate (GHB) or opiates (68.8%) but in none of the 36 patients who took Ecstasy without these drugs. Most patients were monitored in the ED. Six patients (11.5%) were transferred to an intensive care unit. Medical complications were severe in five patients and included cardiac arrest, hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, renal insufficiency and liver failure, seizures, and one fatal outcome. The clinical picture of Ecstasy related problems is complicated by multiple drug ingestion. Co-use of cocaine induces panic reactions. Co-use of GHB or opiates results in depressed levels of consciousness.

Amitriptyline Abuse and Misuse

Deaths related to amitriptyline toxicity are relatively common and are typically related to suicidal overdose. A less well-recognized situation of amitriptyline intoxication occurs when the drug is abused for its euphorigenic effects. An amitriptyline-related death due to a mixed drug intoxication is presented. Death investigation revealed that the death was accidental rather than suicidal. The case serves to remind forensic investigators that not all amitriptyline overdose deaths represent suicides. A segment of the population is known to abuse amitriptyline.

Retrospective Evaluation of Tiagabine Overdose

Background. Tiagabine is an anticonvulsant that blocks reuptake of the inhibitory neurotransmitter GABA. There are no published studies or case series of tiagabine overdoses. Methods. The records of six poison centers and one statewide poison center network were searched for all exposures to tiagabine for the years 2000–2002. Inclusion criterion was a human tiagabine exposure with follow-up to a known outcome; exclusion criterion was multiple drug ingestion. Results. 57 cases met the inclusion criterion. Thirty-seven patients were female (67%). Mean and median ages were 30.5 years (S.D. ± 18.5) and 31 years, respectively, with a range of 2 to 80 years. Seven patients were ≤ 6 years. Neurologic symptoms were common: lethargy, seizures (multiple), status epilepticus, seizure (single), coma, confusion, agitation, tremors, dizziness, dystonias/abnormal posturing, and hallucinations. Other symptoms included respiratory depression, tachycardia, hypertension, and hypotension. Therapies included benzodiazepines, mechanical ventilation, phenytoin, phenobarbital, diphenhydramine, and dopamine. The mean onset and duration of symptoms were 1.3 hours (± 0.5, range 1–2 hours) and 9.1 hours (± 3.8, range 4–24 hours), respectively. Dose ingested by history was known for 38 patients (67%). The lowest dose with the development of multiple seizures and coma was 96 mg. This occurred in a 36-year-old female with a history of epilepsy. The lowest dose with symptoms in a child was 8 mg, in a 6-year-old with drowsiness. Mean dose of those with and without symptoms was 102 mg and 10 mg, respectively. The mean dose for patients experiencing seizures was 224 mg (± 172, range 96 to 680 mg). The mean dose for patients experiencing coma and respiratory depression was 270 mg (± 204, range 96 to 680 mg). Fifty-two patients (91%) were evaluated in the ED of whom 43 were admitted for medical care. Conclusion. Seizures and altered mental status were common with tiagabine overdose, with rapid onset and resolution of symptoms. In this series, seizures did not occur until the ingestion was greater than three times the maximum recommended daily dose.

The Safety Profile of Sustained Release Paracetamol During Therapeutic Use and Following Overdose

Sustained release (SR) formulations of paracetamol (acetaminophen) have been introduced in several countries to provide lasting pain relief and reduced risk of rebound pain. However, few studies have evaluated the safety of paracetamol SR formulations. To assess the available published safety data regarding SR formulations of paracetamol, the EMBASE and MEDLINE databases were searched from 1980 to June 2003 for published worldwide human experience with paracetamol SR formulations. All publications that included any information about ingestion of any paracetamol SR formulation were systematically reviewed and abstracted by trained staff. The literature searches returned a total of 14 references containing safety data on paracetamol SR. In addition, the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers (AAPCC) database was searched for human exposure cases. The TESS database yielded 3003 cases from 1994 to 2002 that involved a paracetamol SR product. The available information indicates that the adverse event and safety profile of paracetamol SR is very similar to immediate release (IR) formulations of paracetamol. During therapeutic use, minor effects such as gastrointestinal upset and headache may occur. The rate of these effects varies substantially among studies but overall does not appear to be different between the SR and IR formulations of paracetamol. Overdose with paracetamol SR is expected to cause liver injury similar to overdose with IR formulations. The number of human exposure cases has increased since introduction of the SR formulation; however, sales of the SR formulation amounted to 7.5% of all paracetamol sales but accounted for 2.5% of the cases reported to poison centres. There were two deaths recorded in the TESS database: both were the result of multiple drug ingestion. No cases of death or unusual types of toxicity have been described from an overdose of paracetamol SR alone.

Alcohol and drugs in drivers fatally injured in traffic accidents in Sweden during the years 2000–2002

During the years 2000–2002, alcohol, pharmaceuticals and illicit drugs were analysed in blood samples from fatally injured drivers in Sweden. The total number of drivers was 920 and in 855 of these, corresponding to 93%, a toxicological investigation was performed. About 85% of the drivers were men and 15% were women. All but three women (96%) were car drivers while the corresponding figure for men was about 78% and about 13% were motorcyclists. The number of positive cases increased from 38.9% in year 2000 to 45.9% in year 2002 and alcohol was the most common drug with frequencies of 19.8%, 25.0% and 21.8% for the studied years 2000, 2001 and 2002, respectively. The median blood alcohol concentration ranged from 1.6 to 2.0 mg/mL for men and from 1.2 to 1.8 mg/mL for women. There was a decrease in cases where alcohol was the only drug detected, from 52 out of 58 cases (90%) in year 2000 to 41 out of 61 cases (67%) in 2002. At the same time there was an increase, from 5.4% to 10.0% of illicit drugs, mainly amphetamine, and the cases with multiple drug intake increased from 10% to 26%. The prevalence of pharmaceuticals as the only drug or drugs detected decreased from 14.0% to 10.4% and in the majority of these cases the drug concentrations were within the therapeutic range.

An autopsy case of combined drug intoxication involving verapamil, metoprolol and digoxin

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 μg/ml, 3.6 μg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.

A Mixed-Drug Intoxication Involving Venlafaxine and Verapamil

This case report describes the suicide of a 52-year-old woman whose cause of death was attributed to a mixed-drug intoxication involving venlafaxine and verapamil. Venlafaxine is prescribed for the treatment of depression and should be used with caution in patients with cardiovascular disease. Verapamil is a calcium channel blocker primarily used for treatment of cardiovascular disorders. The following drug concentrations were determined in postmortem fluids: verapamil--3.5 mg/L (femoral blood), 9.4 mg/L (subclavian blood), and 1.0 mg/L (vitreous fluid); norverapamil--1.0 mg/L (femoral blood), 2.1 mg/L (subclavian blood), and 0.20 mg/L (vitreous fluid); verapamil and norverapamil could not be detected in bile or urine due to the high levels of erythromycin present; venlafaxine--6.2 mg/L (femoral blood), 8.6 mg/L (subclavian blood), 5.3 mg/L (vitreous fluid), 54.0 mg/L (bile), and 72.3 mg/L (urine); and O-desmethylvenlafaxine--5.4 mg/L (femoral blood), 8.3 mg/L (subclavian blood), positive (vitreous fluid), 29.2 mg/L (bile), and 9.5 mg/L (urine). The cause of death was determined to be a mixed-drug intoxication resulting from an overdose of verapamil and venlafaxine. The manner of death was determined to be suicide.

Postmortem Forensic Toxicology of Selective Serotonin Reuptake Inhibitors: A Review of Pharmacology and Report of 168 Cases

This paper reviews the complex pharmacology of the new class of antidepressant medications exhibiting selective inhibition of serotonin reuptake. The four selective serotonin reuptake inhibitors (SSRIs) considered--fluoxetine, fluvoxamine, sertraline and paroxetine--can result in toxicity and death through contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, leading to accumulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern in patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extraction at alkaline pH into n-butyl chloride, and analysis by gas chromatography/mass spectrometry (GC/MS) is described, together with some of its limitations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved. The potential for drug interactions between members of this class of drugs is discussed as well as their metabolites and a variety of other therapeutic and abused drugs which can contribute to their toxicity. In the absence of other risk factors, the lowest concentrations determined to have resulted in death were 0.63 mg/L for fluoxetine, 0.4 mg/L for paroxetine, and 1.5 mg/L for sertraline. We had insufficient data to make even this crude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atherosclerotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be carefully considered before determining the appropriate cause and manner of death in these cases.

Anileridine Fatalities: An Update

ABSTRACTAnileridine is a synthetic narcotic available in Canada by prescription as Leritine® (Frosst). An earlier review of 20 cases found that although blood concentrations greater than 1.5 mg/L and liver concentrations greater than 5 mg/kg were consistent with fatality, virtually all the cases surveyed involved multiple drug ingestion. Since that review, however, we have received four fatalities involving anileridine as the sole drug, one of which also contained ethanol. Three case histories are presented with blood concentrations ranging from 1.4 to 2.1 mg/L and liver 4.7 to 27 mg/kg, where anileridine is the cause of death. A fourth case, involving a natural death, is included as a comparison.

Use of flumazenil in the treatment of drug overdose

To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. An 800-bed, teaching, university-affiliated hospital. Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant "waking" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.

Acute zolpidem poisoning--analysis of 344 cases.

Zolpidem is a new short acting hypnotic agent, first launched in France in 1988. Three hundred forty-four cases of intentional acute overdoses are reviewed retrospectively. Patients were predominantly female (70%) in their third or fourth decade. Ingested doses of zolpidem ranged between 10 and 1400 mg (one pack or less in 80%). Half of the patients ingested other substances (psychotropic drugs and alcohol) concomitantly. Signs of intoxication were observed in two thirds of the population but could be attributed to zolpidem in only 105 cases: drowsiness (N = 89) occurred at doses of 140 to 440 mg; coma (N = 4) or respiratory failure (N = 1). Other symptoms were rare (excepted vomiting, N = 7). Of the rare electrocardiographic or biological abnormalities, none appeared to be directly related to zolpidem. Therapy for intoxication was usually limited to supportive measures and/or gastric lavage. Symptoms of intoxication rapidly remitted in 91% of cases. Three percent of patients with multiple drug ingestion recovered despite severe complications during intensive care. Fatalities were reported for 6% but could not be directly linked to zolpidem. Previous published reports are confirmed: zolpidem acute overdose is generally benign and requires no specific therapeutic measures.

Application of a computer-assisted high-performance liquid chromatographic multi-wavelength ultraviolet detection system to simultaneous toxicological drug analyses

An emergency drug screening system for the separation and identification of toxic drugs, MULTI-HPLC, is presented. Chromatographic peaks, which were impossible to identify with a conventional high-performance liquid chromatographic UV detection system, became distinguishable by the spectral search and retention prediction of the data-processing program MCASYST. Sixty-five toxic drugs, frequently identified in drug poisonings in Japan, were selected as references in the drug library. Retention time, optimum detection wavelength, detection limit and recoveries from serum and urine were listed. Possible applications of the system are demonstrated, using gastric contents, sera and urines in cases of multiple drug ingestion. Quantitative analysis was sufficiently sensitive and precise to permit clinical diagnosis with increased accuracy.

The use of flumazenil in the treatment of 34 intoxicated patients

The efficacy and safety of the newly available benzodiazepine (BDZ) antagonist flumazenil (Ro 15-1788, Anexate®) was prospectively evaluated in the treatment of 34 intoxicated patients. Twenty-three patients had attempted suicide with various drugs, and 11 suffered iatrogenic BDZ overdose. Following 0.2 mg i.v. flumazenil (Flu) injection, 22 patients intoxicated mainly with BDZ (11 iatrogenic and 11 intentional) regained full consciousness within two minutes, enabling even extubation of two. Eight patients required repeated boluses or continuous infusion of Flu to maintain alertness. Five patients with mixed drug intoxication awakened only briefly and relapsed into unconsciousness. In spite of Flu doses of up to 20 mg, no effect on consciousness was observed in 7 patients, intoxicated mainly with non-BDZ drugs. No significant side effects were noted attributable to Flu which has proved to be a safe and effective drug. It may be employed to achieve complete reversal of pure BDZ overdose, or for ‘unmasking’ the relative action of BDZ in mixed drug overdose. The danger of complications from drug overdose may thus be lessened, obviating the need for invasive interventions such as mechanical ventilation and invasive hemodynamic monitoring, at the same time decreasing risk and expense.