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.

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.

[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.

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.

Zolpidem misuse with other medications or alcohol frequently results in intensive care unit admission.

Zolpidem (trade name Ambien ®) is commonly prescribed. Case reports and popular media suggest potential dangers exist and may result in unanticipated complications. The primary aim was to determine how commonly zolpidem ingestion results in hospital evaluation and admission. The secondary aim of this study was to determine what patient and clinical characteristics are associated with complications from zolpidem use. A retrospective review of all cases involving zolpidem reported to the Illinois Poison Center between January 1, 2004 and December 31, 2005 was conducted. Data were prospectively entered into a structured clinical database in real time at the Illinois Poison Center. Demographic, co-ingestant, and outcome data for all zolpidem cases was abstracted into a research database and analyzed using descriptive, univariate and multivariate analyses. Six-hundred ninety-two cases met inclusion criteria. Mean age was 34.7 years. Four-hundred sixty three cases (67%) resulted in Emergency Department (ED) evaluation. Only 17% (81/463) of ED patients were discharged home: 44% (203/463) required Intensive Care Unit (ICU) admit, 17% (79/463) medical floor admit, 16% (72/463) psychiatry admit. Associated with ICU admission were co-ingestion of over-the-counter medicines (OR 3.33, 95% CI, 1.93 to 5.76), other prescribed psychotropics (antidepressants or mood stabilizers) (OR 3.11, 95% CI, 2.21 to 4.39), or ethanol (OR 2.12, 95% CI, 1.36 to 3.32). When zolpidem is ingested with other medications or ethanol, admission to the ICU was common in our series. Despite its reported safely, zolpidem overdose often requires ICU admission from the ED, which is associated with ingestion of other pharmaceutical products or alcohol.

Coma with absent brainstem reflexes resulting from zolpidem overdose.

Zolpidem is a nonbenzodiazepine hypnotic with a favorable adverse effect profile. There are single reports of respiratory decompensation associated with zolpidem overdose. We report a case ofa young woman with depression who developed deep coma with respiratory failure and a loss of brainstem reflexes as a result of zolpidem overdose. Supportive management led to a complete recovery of neurologic function. Acute zolpidem overdose should be considered in the differential diagnosis of coma with absent brainstem reflexes.

Protracted deep coma after bromazepam poisoning.

BACKGROUND: Bromazepam intoxication is very common but surprisingly rarely reported. CASE DESCRIPTION: We describe the case of a 73-year-old woman who suffered from a prolonged coma after acute self poisoning with bromazepam (serum concentration of 2,000 ng/ml at admission, 2 - 10 hours after ingestion of up to 180 mg) and zolpidem (900 ng/ml at admission). Only the former lasted at toxic concentrations. Recovery of consciousness allowed extubation on Day 16. Repeat-dose activated charcoal (25 g every 6 h from Day 14 to 16) resulted in minimal effects on bromazepam grossly estimated kinetics. CONCLUSION: Despite its relatively low theoretic half-life, bromazepam may induce a prolonged life-threatening coma, even in the absence of renal or hepatic failure.

Pattern of pediatric zolpidem ingestions reported to Texas poison control centers, 2000 to 2006.

OBJECTIVES: The purpose of this study was to describe the pattern of zolpidem ingestions by young children reported to poison control centers. METHODS: Cases were all zolpidem ingestions by children 0 to 5 year old reported to Texas poison control centers during 2000 to 2006. Multiple substance ingestions were excluded. The distribution of cases was described with respect to such demographic and clinical factors as patient gender, ingestion reason, ingestion site, management site, and medical outcome. RESULTS: There were a total of 463 cases, all unintentional exposures. The patient was male in 52.2% of the cases, and the exposure occurred at the patient's own home in 92.8% of the cases. The patient was managed on-site in 54.4% cases, already at or en route to a health care facility in 29.6% cases, and referred to a health care facility in 16.0% cases. Of the 322 cases with a known final medical outcome, 59.0% had no effect, 35.1% had minor effects, and 5.9% had moderate effects. CONCLUSIONS: Pediatric ingestions of zolpidem alone reported to Texas poison control centers most frequently resulted in at most minor effects and were often managed at home.

[Acute poisoning with neonicotinoid insecticide acetamiprid].

Acetamiprid belongs to a new class of insecticides called neonicotinoids, which have different effects from other insecticides. Neonicotinoids act as selective agonists at the nicotinic acetylcholine receptors, therefore their toxicity is higher to insect pests than to humans. Cases of acetamiprid poisoning are still rare, because neonicotinoids have been released in the market only within the last decade. We experienced a case of acute acetamiprid poisoning and measured the blood concentration of acetamiprid. A 79-year-old man had ingested acetamiprid and got medical attention two hours after ingestion. On arrival, he had consciousness disturbance (GCS-8), hypotension, nausea, vomiting and hyperglycemia, but had no constricted pupils nor mucous supersecretion which are characteristic in organophosphate poisoning. Gastric lavage was performed and activated charcoal and laxative were administered. Paroxysmal atrial fibrillation persisted until 11 hours after ingestion. The next day, his symptoms with regards to the effects of acetamiprid improved and he was discharged from the hospital without complication. Blood concentration of acetamiprid on arrival, approximately 2 hours after the ingestion, was 21.1 microg/ml.

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.

Comparison of zolpidem and zaleplon exposures in Texas, 1998-2004.

Zolpidem and zaleplon are used for the treatment of insomnia. The objective of this study was to compare the patterns of zolpidem and zaleplon exposures reported to Texas poison control centers during 1998-2004. There were 5842 total reported zolpidem exposures, of which 2918 (50%) were isolated exposures, and 467 total reported zaleplon exposures, of which 201 (43%) were isolated exposures. Zolpidem patients were 62% male and 67% adult. Zaleplon patients were 67% male and 34% adult. The exposure was intentional in 62% of zolpidem and 58% of zaleplon exposures. The exposure occurred at the patient's own residence in 94% of zolpidem and 97% of zaleplon exposures. Management occurred outside of a health care facility for 29% of zolpidem and 32% of zaleplon exposures. The medical outcome involved no symptoms due to exposure for 29% of zolpidem and 44% of zaleplon exposures, a statistically significant difference. Although many of the most frequently reported adverse clinical effects for the two drugs were similar (drowsiness, slurred speech, hallucinations, ataxia, tachycardia, dizziness, confusion, vomiting), the proportion of exposures with a given adverse clinical effect was generally lower for zaleplon. Thus, although zolpidem and zaleplon exposures were generally similar with respect to patient gender and age, exposure reason and site, and management site, zaleplon exposures were less likely to result in minor medical outcomes or manifest as adverse clinical effects.

Medication sleuth: an important role for pharmacists in determining the etiology of delirium.

Delirium is characterized by disturbances of consciousness, attention, cognition, and perception and is the most common reason for acute cognitive dysfunction in hospitalized elderly patients. Causes of delirium can be multifactorial, and a careful medical and medication history can help determine the underlying cause of behavioral disturbances. A 65-year-old patient with a history of chronic pain, insomnia, and multiple medical problems, who presented with altered mental status and aggressive behavior, is described. The patient had taken an overdose of zolpidem prior to admission, and she required chemical and physical restraints and one-on-one care for safety. With time and washout of the zolpidem, the patient's behavior did not improve. On the second day of admission, medication reconciliation of this patient's medication profile helped to reveal a medication cause for this patient's delirium. A pharmacist should be included early in the process of obtaining a medication history. Recommendations for the management of chronic pain and insomnia in the elderly are presented.

Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure.

An 18-year-old woman with no prior history of renal or hematologic dysfunction developed severe, acute methemoglobinemia after an overdose of phenazopyridine hydrochloride (Pyridium). The methemoglobinemia was reversed acutely with methylene blue, and during the course of ten days, the patient developed a hemolytic anemia with "bite cells" and acute renal failure. The patient recovered fully with conservative management. Several putative pathophysiologic explanations for the development of methemoglobinemia, hemolytic anemia, and renal failure following oxidative stress are considered and include a direct toxic effect on the renal tubules or methemoglobin-caused damage. Renal failure as a complication of phenazopyridine-related methemoglobinemia and hemolytic anemia should be borne in mind in cases of overdosage with this common drug.

Cardiac consequences and treatment of disopyramide intoxication: experimental evaluation in dogs.

A slow (1.18 mumol.kg-1.mm-1) intravenous infusion of disopyramide (mol.wt 339) was given to 8 adult Beagle dogs. An initial phase of slow decline in cardiac output and broadening of the QRS complex on the ECG, with systolic blood pressure maintained above 13.5 kPa (100 mmHg), was followed by a phase of rapid circulatory failure without a correspondingly dramatic change in ECG appearances. Underventilation and cardiac arrhythmias were observed only in the agonal phase after several minutes of circulatory arrest. They were not therefore the primary cause of death, which was due to failure of myocardial contractility. Three positively inotropic drugs (isoprenaline, dopamine, and glucagon) are shown to be capable of restoring the failing circulation, provided they are given before the phase of complete circulatory standstill. In this respect isoprenaline appears superior to dopamine and glucagon.

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.

MPTP-induced parkinsonism in human and non-human primates--clinical and experimental aspects.

In this review, we describe the discovery of a new neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP, which appears to be highly selective for the substantia nigra of human and non-human primates. This compound appears to produce a "pure" parkinsonian state more consistently than most, if not all previously described neurotoxins. Identification of its unique properties has already led to the development of an animal model for Parkinson's disease in the monkey. In this paper we review the history of the compound, and describe its clinical effects in man and monkeys. Experiments are reviewed which suggest that the "4-5" double bond in the nitrogen-containing ring is key for this compound to exert its toxic effects, probably serving as a starting point for oxidation of MPTP to its quaternary amine, 1-methyl-4-phenylpyridinium ion (MPP+). MPTP appears to be rapidly converted to the latter compound in all tissues studied to date, including brain. We believe that this newly recognized nigrotoxin holds promise as a tool for the study of Parkinson's disease and the nigrostriatal dopaminergic system of the brain.