Fatal zolpidem poisoning due to its intravenous self-injection: Postmortem distribution/redistribution of zolpidem and its predominant metabolite zolpidem phenyl-4-carboxylic acid in body fluids and solid tissues in an autopsy case.

We experienced a curious fatal case, in which a male in his 20s self-administered zolpidem intravenously. The victim was found dead lying on floor of his apartment room, with a tourniquet band and new injection marks on his right forearm. Nearby the body, a medical disposal syringe containing small-volume solution dissolving crushed zolpidem tablets was found. The postmortem interval was estimated at about two days. The direct cause of his death was judged as asphyxia due to the aspiration of stomach contents into the trachea and bronchi. The specimens dealt with were body fluids and solid tissues including femoral vein blood, right and left heart blood, pericardial fluid, urine, bile, stomach contents, the brain, lung, heart muscle, liver, spleen, kidney, pancreas and skeletal muscle. For the extractions of zolpidem, zolpidem phenyl-4-carboxylic acid, deuterated internal standards zolpidem-d7 and zolpidem phenyl-4-carboxylic acid-d4, a modified QuEChERS method was used, followed by the analysis by liquid chromatography-tandem mass spectrometry. Because this study included various kinds of human matrices with quite different properties, the standard addition method was most preferable to overcome the matrix effects and recovery rates, and also did not need to use blank human matrices for validation experiments. The concentration of zolpidem and its phenyl-4-carboxylic acid metabolite in various specimens tested were generally extreme higher than those of reported fatal cases, supporting that the victim had died of intravenous zolpidem injection. The concentrations of zolpidem in femoral vein blood and right and left heart blood specimens in the present case were 9.55, 28.5 and 46.9µg/mL, respectively, which far exceeded estimated fatal levels. The present study also showed the postmortem distribution/redistribution of zolpidem and its phenyl-4-carboxylic acid metabolite in 15 body fluid and solid tissue specimens including stomach contents. Although a number of published literatures dealt with zolpidem poisoning cases due to oral ingestion of the drug, this is the first report on fatal intravenous zolpidem injection case and postmortem distribution of zolpidem and its predominant metabolite.

Zolpidem Overdose: A Medical and Ethical Dilemma.

Acute altered mental status can be caused by a broad range of etiologies, including cerebrovascular, neurologic, traumatic, metabolic, infectious, psychiatric, medications, etc. We present a case of a 53-year-old healthcare professional with an acute altered mental status after a trip to Africa. The patient was extensively worked up for infectious, cardiovascular, and neurologic etiologies, and all results were within normal limits. Further history revealed an overdose of a self-medicated hypnotic (zolpidem) for insomnia. The patient was conservatively managed and discharged on trazadone for insomnia.

[Research Progress on Forensic Toxicology of Z-drugs].

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

Myocardial Injury without Electrocardiographic Changes after a Suicide Attempt by an Overdose of Glimepiride and Zolpidem: A Case Report and Literature Review.

A 40-year-old diabetic man was admitted to our hospital for poor glycemic control. During hospitalization, he took 42 mg glimepiride and 50 mg zolpidem as a suicide attempt. The following day, the creatine kinase-MB fraction and troponin I levels were elevated to 112 IU/L and 8.77 ng/mL, respectively, without any electrocardiographic abnormalities. The patient recovered completely without any complications. Four weeks later, coronary computed tomography angiography and myocardial perfusion scintigraphy revealed moderate one-vessel coronary disease without the evidence of myocardial ischemia or old infarction. Cardiac-specific markers must be considered in sulfonylurea-induced hypoglycemic patients, particularly when the patient is unconscious and does not exhibit any clinical manifestations.

A fatal case of thiacloprid poisoning.

Neonicotinoid insecticides are considered to be less toxic to humans compared to older insecticides such as organophosphates, carbamates, pyrethroids, and organochlorine compounds. However,reports of severe human toxicity with neonicotinoids are emerging. Acute human thiacloprid poisoning and death as a result have not been reported in the literature so far. Here we report a case of thiacloprid poisoning resulting from deliberate ingestion in a 23-year-old man, manifesting with status epilepticus, respiratory paralysis,rhabdomyolysis, metabolic acidosis, and acute kidney injury (AKI), and ultimately giving rise to refractory shock and death. Thiacloprid can cause fatal human toxicity when ingested heavily, and absence of an effective antidote raises concern in this regard.

Use of continuous veno-venous haemodiafiltration therapy in dabigatran overdose.

CONTEXT: Dabigatran etexilate is one of the newer oral anticoagulants and a direct thrombin inhibitor. Concerns regarding dabigatran's use include its lack of validated laboratory markers for measuring its anticoagulation effect, the impact of renal impairment on its clearance, and the lack of effective strategies for reversal of anticoagulation. Hemodialysis has been utilized to reverse the anticoagulant effects of dabigatran in therapeutic doses. However, hemodialysis may not be feasible in hemodynamically unstable patients. There is little data on clearance rates of dabigatran by continuous renal replacement therapies. CASE DETAILS: A 66-year-old male presented following a poly-pharmacy overdose of 9 g of dabigatran in combination with metoprolol, amlodipine, olmesartan, and moxonidine. Eleven hours post overdose extracorporeal elimination was implemented as the patient developed worsening coagulopathy with an elevated international normalized ratio of 11 IU, an activated partial thromboplastin time of 115 s, and had renal impairment with a creatinine of 158 µmol/L. As the patient was hemodynamically unstable, continuous veno-venous hemodiafiltration was preferred over intermittent hemodialysis. Renal replacement therapy was performed for 32 h in total and the patient made a full recovery with no hemorrhagic complications or end organ injury. This patient developed a peak serum dabigatran level of 1560 ng/ml, 11 h postoverdose. Clearance of dabigatran via continuous veno-venous hemodiafiltration was calculated, using both the recovery and A-V pair methods, with a mean clearance of 58.1 and 31.9 ml/h, respectively, and a calculated mean extraction ratio of 0.2. CONCLUSION: There are few case reports and little experience when dabigatran is taken in overdose. This is a case report of a large dabigatran overdose presenting data on the extraction ratio and clearance of dabigatran using continuous veno-venous hemodiafiltration.

Determination of acetamiprid and IM-1-2 in postmortem human blood, liver, stomach contents by HPLC-DAD.

An HPLC-DAD method was developed to detect and quantify a neonicotinoid insecticide acetamiprid (ATP) and its metabolite IM-1-2 in autopsy samples of a fatal intoxication case. The postmortem blood and tissue distribution of ATP and IM-1-2 was determined for the first time. The method showed acceptable precisions and recoveries with relative standard deviations of <10% for ATP level and 1.38 % for IM-1-2. The detection and quantification limits for ATP were 0.015 µg/mL and 0.030 µg/mL for blood and were 0.035 µg/g and 0.050 µg/g for liver samples, respectively. The mean contents of ATP were 0.79 µg/g in the liver, 47.35 µg/g in the stomach contents and 2.7 µg/mL in the blood. IM-1-2 content was 17.0 µg/g in the stomach contents. ATP and IM-1-2 were not detected in the urine. The presence of ATP and IM-1-2 in the samples was confirmed by GC-MS. The method can be exploited in future forensic casework.

Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil.

Zolpidem is a widely prescribed anti-insomnia agent. Although most pediatric zolpidem ingestions are benign, large ingestions can cause significant central nervous system (CNS) depression. Flumazenil has been reported to reverse the CNS effects of zolpidem. We describe a case of a large pediatric zolpidem ingestion resulting in profound CNS depression that responded to flumazenil administration. Serial zolpidem serum levels confirmed the ingestion. A 10-year-old boy with trisomy 21 presented to the emergency department 1 hour after he was found sedate with several zolpidem 5-mg tablets in his mouth. Seventeen tables (85 mg) were unaccounted for from a prescription bottle. He became unarousable approximately 2 hours after his ingestion. Flumazenil 0.2 mg intravenously was given with rapid return to his baseline mental status. He became resedate 1 hour later but was arousable. Sixteen hours after his presentation, he was asymptomatic. Serial zolpidem serum levels were obtained, showed an initial level of 310 ng/mL, and demonstrated zero-order kinetics. Zolpidem is an imidazopyridine, which binds to the benzodiazepine receptor. It is rapidly absorbed and has a short-half life. Unintentional pediatric ingestions of zolpidem are typically well tolerated. However, this case demonstrates that large ingestions may cause significant and prolonged CNS depression. Flumazenil, a benzodiazepine receptor antagonist, has been described to reverse the effects of zolpidem in adult ingestions. There are few published reports describing flumazenil use in pediatric ingestion patients. This case suggests that flumazenil may be an effective treatment for zolpidem-induced CNS depression in the pediatric patient.

Suicide by self-administration of a drug mixture (propofol, midazolam, and zolpidem) in an anesthesiologist: the first case report in Italy.

The authors report an unusual case of suicide of an anesthesiologist, in which the suicide manner and means depend upon the victim's occupation. This is the first case report published in Italy of a death involving propofol and other drugs. The anesthesiologist was found dead with an empty drip still inserted in the hand and another one near his body. Forensic and toxicological findings suggested that the cause of death was a respiratory depression due to a self-administration of a rapidly infused lethal drug mixture. Analytical drug quantification was performed by gas chromatography-mass spectrometry. Blood analysis revealed: zolpidem (0.86 µg/mL), propofol (0.30 µg/mL), midazolam (0.08 µg/mL), thiopental (0.03 µg/mL), and amitriptyline (0.07 µg/mL). Adipose tissue and hair analysis suggested a previous and repeated use of these drugs verifying the fact that in Italy recreational abuse of anesthetic and sedative agents in health care practitioners is becoming an increasing problem.

The clinical and forensic toxicology of Z-drugs.

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1-7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

Reversal of thienopyridine-induced platelet dysfunction following desmopressin administration.

Adenosine diphosphate (ADP)-receptor antagonists are widely used for thrombus prevention, although reversing their platelet dysfunction is difficult. This study evaluated the ability of desmopressin to reverse clopidogrel-induced platelet dysfunction. Sprague-Dawley rats received either clopidogrel (30 mg/kg) or placebo, followed 4 h later by saline or desmopressin (0.15, 0.3, or 0.6 µg/kg). Bleeding times and platelet aggregation studies were subsequently performed. A bleeding time >25 min was considered "prolonged." The median bleeding time for clopidogrel-exposed rats was 21 min, vs. 6 min for controls (p < 0.01). Progressively higher doses of 1-deamino-8-D-arginine vasopressin (DDAVP) were associated with a reduced number of rats with prolonged bleeding time (p = 0.001). Higher doses of DDAVP were also associated with a reduction in the median (IQR) bleeding time; 29 (13.5-30) min in rats receiving clopidogrel without DDAVP vs. 19 (12-28) min in rats receiving clopidogrel and 0.6 µg/kg DDAVP. The step-wise dosing of DDAVP resulted in a 54 % reduction in meeting the endpoint of prolonged bleeding time (OR 0.46; p = 0.025; 95 % CI 0.23-0.91). Platelet aggregation was observed in all control rats, but only some of those clopidogrel-treated rats who received 0.6 µg/kg DDAVP. In this model of an ADP-receptor antagonist, DDAVP results in partial reversal of clopidogrel-induced platelet dysfunction.

Simultaneous determination of 5 psychotropic drugs of various types in an autopsy case of acute multiple drug poisoning.

We attempted the simultaneous determination of 5 drugs, mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem, detected in a gas chromatography-mass spectrometry screening test in an autopsy case. The solid-phase extraction of the analytes from biological samples was achieved using Oasis(®)HLB cartridges (Waters, Milford, MA, USA). Gas chromatography was performed on a HP-5MS fused silica capillary column (30 m × 0.25 mm i.d., 0.25 µm film thickness, Agilent Technologies). The mass spectrometer was operated with an electron energy of 70 eV in electron impact mode. The qualitative and quantitative analyses were performed in full-scan mode and the selected ion monitoring mode, respectively. The total ion chromatogram showed good separation of these drugs. Linear graphs were obtained with good correlation coefficients for these drugs from 0.001 to 2.0 µg/mL (r(2)=0.9909-0.9986) using imipramine-d6 as an internal standard. The recoveries of these drugs were found to be 62.8-88.0% in spiked whole blood. Mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem were found in post-mortem samples of the deceased at concentrations of 2.67, 0.07, 0.25, 0.32 and 0.68 µg/mL, respectively. The concentration of mirtazapine was within the lethal level and those of amoxapine and zolpidem were within the toxic level. We diagnosed that the cause of death was acute multiple drug poisoning. The simple and practical procedure used in this study is useful for the simultaneous determination of psychotropic drugs of various types in post-mortem biological samples.

Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies.

The concentrations of zolpidem and zopiclone were determined in peripheral blood samples in two forensic materials collected over a 10-year period (2001-2010). The z-hypnotics were determined in venous blood from living subjects (impaired drivers) and in femoral blood from deceased persons (forensic autopsies), with the latter classified as intoxication or other causes of death. The z-hypnotics were determined in blood by capillary column gas chromatography (GC) with a nitrogen-phosphorous (N-P) detector after solvent extraction with n-butyl acetate. The analytical limit of quantitation (LOQ) was 0.02 mg/L for zopiclone and 0.05 mg/L for zolpidem and these have remained unchanged throughout the study. When death was attributed to drug intoxication (N=918), the median concentration of zopiclone in blood was 0.20 mg/L compared with 0.06 mg/L for other causes of death (N=1215) and 0.07 mg/L in traffic offenders (N=691) (p<0.001). Likewise, a higher median concentration (0.30 mg/L) was found in intoxication deaths involving zolpidem (N=357) compared with 0.13 mg/L for other causes of death (N=397) or 0.19 mg/L in impaired drivers (N=837) (p<0.001). Median concentration in blood of both z-hypnotics were appreciably higher in intoxication deaths when no other substances were identified; 0 70 mg/L (N=12) for zopiclone and 1.35 mg/L (N=12) for zolpidem. The median concentrations of z-hypnotics in blood decreased as the number of co-ingested substances increased for intoxication deaths but not other causes of death. The most prevalent co-ingested substances were ethanol in autopsy cases and diazepam in the motorists. This large compilation of forensic cases should prove useful when toxicologists are required to interpret concentrations of z-hypnotics in blood samples in relation to cause of death.

Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001-2010.

All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05-3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide.

Detoxification of high-dose zolpidem using cross-titration with an adequate equivalent dose of diazepam.

BACKGROUND: There have been numerous case reports of zolpidem abuse and dependence in the recent decade, giving rise to a focus on adverse withdrawal events such as seizure. No standard detoxification regimen has been proposed to date, despite the similarity of effects of zolpidem and benzodiazepines at high doses. CASE DESCRIPTIONS: We describe the results, in a 53-year-old female patient, of undergoing three different zolpidem detoxification programs. CONCLUSIONS: Because of her experiences, we recommend using the cross-titration strategy with an adequate equivalent dose of diazepam.

Sleep aid toxicosis in dogs: 317 cases (2004-2010).

OBJECTIVE: To summarize the signalment, clinical signs observed, time to onset of clinical signs, duration of clinical signs, and the outcome in a large case series of nonbenzodiazepine sleep aid ingestions in dogs, including 2 sleep aids that have not been previously described in the veterinary literature. DESIGN: Retrospective study conducted between 2004 and 2010. SETTING: An animal poison control center based out of Bloomington, MN. ANIMALS: During this time frame, 453 cases were identified involving 467 dogs. Of these cases, 150 cases were excluded due to incomplete medical records, multipet households, or the inability to calculate a dose exposure. A total of 317 dogs with presumed sleep aid medication toxicosis were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Records of dogs with sleep aid medication toxicosis identified by a review of an animal poison control center electronic database were evaluated. The most common sleep aid medications ingested were zolpidem (240/317 [75.7%]), eszopiclone (62/317 [19.5%]), and zaleplon (15/317 [4.7%]). Overall, clinical signs developed in 36% of patients (115/317), while 64% (202/317) remained asymptomatic. The most common organ systems affected and clinical signs seen involved the central nervous system (eg, agitation, sedation) and gastrointestinal tract (eg, anorexia, hypersalivation, vomiting). CONCLUSIONS: Overall, the prognosis for dogs with sleep aid medication toxicosis was excellent, and no fatalities were reported in this clinical population. As significant clinical signs can still be seen with ingestion, appropriate decontamination is warranted in asymptomatic patients via emesis or gastric lavage, followed by activated charcoal administration. Symptomatic patients should be hospitalized for monitoring and supportive care for a minimum of 12 hours or until clinical signs resolve.