Fatal hepatic failure following accidental tramadol overdose

A case of fatal overdose of tramadol is described, occurring in a 67-year-old man with painful rib fractures who accidentally ingested more than the recommended daily dose. The mode of death was acute liver failure due to fulminant hepatic necrosis. Post-mortem toxicology was negative apart from revealing a blood tramadol concentration well above the normal therapeutic range. This is the first report of fatal tramadol ingestion occurring in a therapeutic setting and also the first tramadol-related death where the mechanism was liver failure.     

Fatal acetaminophen poisoning with evidence of subendocardial necrosis of the heart.

The authors describe a case of fatal acetaminophen overdose which occurred in a 16-year-old female. Her serum acetaminophen concentration 11.5 h postingestion was 154 mg/L. Antidotal therapy was unsuccessful, and after 9 days she died. Autopsy findings included centrilobular zonal liver necrosis, acute proximal renal tubular necrosis, and diffuse alveolar pulmonary damage. Her heart was transplanted into a young woman with congenital heart disease. The recipient expired 14 days after the transplant as a result of sepsis complicating bowel ischemia. The transplanted heart showed extensive subendocardial myocyte necrosis related to acetaminophen toxicity and not rejection.     

Fulminant liver failure in a young child following repeated acetaminophen overdosing

Acetaminophen (paracetamol), a widely used analgetic drug, is well tolerated at therapeutic doses, but may cause severe hepatotoxicity when ingested in large overdose. Self-poisoning is still very popular in adults and accidental ingestion of one single overdose occurs occasionally in children. In contrast, lethal intoxication in children after repeated administration of therapeutic doses is a very rare event. This case report describes an iatrogenic acetaminophen overdosing in a 5-year-old child receiving 8.5 g acetaminophen in 48 h. Fulminant liver failure developed within 60 h. Autopsy findings included panlobular liver cell necrosis. Acetaminophen serum levels were rather low compared to cases with ingestion of one single overdose. Postmortem diagnosis of chronic acetaminophen intoxication as cause of death should include the clinical history as well as, if available, the calculated drug serum half-life.     

Fatal intoxication involving 2-methyl AP-237

Novel synthetic opioids contribute considerably to the opioid epidemic, especially with the frequent emergence of structurally similar compounds. This case report describes a fatal intoxication involving 2-methyl AP-237. A 54-year-old Caucasian male was found deceased from an apparent drug overdose. A plastic container labeled “2MAP” and a cut straw were found in the decedent's backpack at the scene. A white substance found in the container tested positive for fentanyl by field testing. According to his medical history, the decedent was treated for a drug overdose 3 years prior to his death. With no diagnostic findings at autopsy, the case was submitted for toxicological analysis. An unknown substance was detected in peripheral blood and urine using gas chromatography with nitrogen phosphorous detection (GC-NPD). Further testing was conducted using gas chromatography–mass spectrometry (GC–MS) and liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) which confirmed the presence of 2-methyl AP-237 and potential metabolites in blood and urine. Quantitation by GC-NPD revealed concentrations of 2-methyl AP-237 in blood and urine at 480 ng/mL and 4200 ng/mL, respectively. The toxicological analysis also identified and quantitated alprazolam in the blood at 55 ng/mL. Additionally, the metabolism of 2-methyl AP-237 was investigated and three hydroxylated metabolites were identified in peripheral blood and urine. Limited literature is available for the detection and quantitation of 2-methyl AP-237 in postmortem specimens. Given the toxicological findings with unremarkable autopsy findings, this case is an example of a fatal intoxication involving 2-methyl AP-237.     

Acute fatal acetaminophen overdose without liver necrosis

Two unusual cases of suicidal overdose of acetaminophen (paracetamol) without the usual extensive centrilobular necrosis of the liver are reported. Both cases were subjected to comprehensive drug screening by immunoassay, and a combination of gas chromatography with mass spectrometry, nitrogen detection, and electron capture detection. Acetaminophen was detected in both cases. No other drugs were detected in case #1, and only a small amount of olanzapine (<0.1 mg/L) was detected in case #2. No anatomical cause of death was identified in either case. If untreated, the normal outcome of a large acetaminophen overdose would be massive hepatic necrosis with delayed death and low blood and tissue acetaminophen concentrations. In contrast, particularly high postmortem acetaminophen concentrations were measured in both our cases with little hepatic tissue damage. For case #1, femoral blood acetaminophen 1280 mg/L, vitreous 878 mg/L, and liver 729 mg/kg; in case #2, cardiac blood 1220 mg/L, vitreous 779 mg/L, liver 3260 mg/kg, and gastric 11,500 mg/500 g. Acetaminophen was measured using high performance liquid chromatography with UV detection (254 nm) using 3-hydroxyacetanilide as the internal standard. The very high concentrations of acetaminophen is these cases but relatively little hepatic damage suggests an alternative, possibly cardiac, mechanism of death.     

Possible Fatal Acetaminophen Intoxication with Atypical Clinical Presentation

Acetaminophen or paracetamol, a commonly used over‐the‐counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 μg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria.     

Delayed elimination in humans after ingestion of colchicine: Two fatal cases of colchicine poisoning

Colchicine has been widely used in the treatment of acute gout over the years, but it has a narrow therapeutic index, and overdose can be life threatening. A method using ultra-high-performance liquid chromatography–tandem mass spectrometry system was applied in two fatal cases of colchicine poisoning in this study to the determination of colchicine in blood. In case 1, a 19-year-old man suffered from depression and ingested 160 colchicine tablets (each 0.5 mg). The concentration of colchicine in his blood samples showed a fluctuating trend and kept above the therapeutic steady-state concentration for 5 days. In case 2, a 70-year-old female patient with a history of gout and chronic colchicine intake ingested five times the usual dose of colchicine (5 mg) and died after 12 days of medical care, with 5 ng/mL of colchicine in her blood sample. Our findings suggest that the delayed elimination and accumulation in humans after colchicine overdose could keep the concentration of colchicine maintaining above the therapeutic steady-state concentration for many days before dying, probably along with a fluctuating trend.     

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 microg/ml, 3.6 microg/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 fatal poisoning involving Bromo-Dragonfly

This paper reports a fatal overdose case involving the potent hallucinogenic drug Bromo-Dragonfly (1-(8-bromobenzo[1,2-b; 4,5-b′]difuran-4-yl)-2-aminopropane). In the present case, an 18-year-old woman was found dead after ingestion of a hallucinogenic liquid. A medico-legal autopsy was performed on the deceased, during which liver, blood, urine and vitreous humour were submitted for toxicological examination. Bromo-Dragonfly was identified in the liver blood using UPLC–TOFMS, and was subsequently quantified in femoral blood (0.0047 mg/kg), urine (0.033 mg/kg) and vitreous humour (0.0005 mg/kg) using LC–MS/MS. Calibration standards were prepared from Bromo-Dragonfly isolated from a bottle found next to the deceased. The structure and purity of the isolated compound were unambiguously determined from analysis of UPLC–TOFMS, GC–MS, HPLC–DAD, ¹H and ¹³C NMR data and by comparison to literature data.The autopsy findings were non-specific for acute poisoning. However, based on the toxicological findings, the cause of death was determined to be a fatal overdose of Bromo-Dragonfly, as no ethanol and no therapeutics or other drugs of abuse besides Bromo-Dragonfly were detected in the liver, blood or urine samples from the deceased. To our knowledge, this is the first report of quantification of Bromo-Dragonfly in a biological specimen from a deceased person. This case caused the drug to be classified as an illegal drug in Denmark on 5th December 2007.     

Accidental sharp force fatalities--beware of architectural glass, not knives.

In a retrospective evaluation of 799 consecutive autopsies of victims of sharp force performed between 1967 and 1996 in Münster and Berlin, only 18 cases (2.3%) were classified as accidents. A typical pattern was present in 15 cases: inebriated adults (1.4-3.6g/l BAC) fell into an architectural glass surface in the form of a door or window (12 cases), an aquarium, a mirrored wardrobe or a telephone cell. Another man fell into a large drinking glass. Many victims in this group showed multiple scratches, abrasions and superficial incisions as well as one or more deep tear/cut/puncture injury. The wound margins can be clean-cut or irregular and abraded. Death was mostly caused by exsanguination except for one case of air embolism and one case of cerebral injury. The fatal injuries were produced by large and dagger-like slivers of glass, by sharp-edged fragments of glass remaining inside the frame or by a portion of glass which fell down and acted in a way similar to a guillotine. Ordinary types of flat glass were involved in all cases and it is not until the impact that sharp fragments or cutting edges are produced. So the motion of the person commonly provides the force necessary for a fatal injury. This was also true for the remaining two cases not involving architectural glass. A farmer suffered cerebral injury from a fall into the long prong of a pitch fork, and the wounding agent was a knife in only one case. A man who stated that he had fallen into the knife in his hand died from pneumonia after inadequate therapy following a single stab injury to the periphery of the left lung and liver. Accidents where the victim is killed by his own knife therefore appear to be extremely rare.     

胰岛素中毒法医学研究进展

胰岛素作为一种临床上常见的降血糖药物,可以有效控制糖尿病患者血糖,使之维持在正常范围。但过量胰岛素可导致死亡,其中以意外中毒最多见,其次为自杀,胰岛素他杀虽极为罕见,但值得高度重视。胰岛素中毒致死的法医学鉴定极为困难,虽然相关研究已取得一定的进展,但在法医学实践中,这类案件仍然是一大难题。本文从法医病理学的角度,对胰岛素中毒的死亡机制、病理学改变、检测手段、注意要点及诊断要点进行综述,为法医学实践提供帮助。     

Accidental insulin overdose

Exogenous insulin has been used for many years to treat diabetes mellitus. Due to the complex nature of insulin therapy, there have been numerous accidental overdoses by these patients. Unfortunately, in other instances, insulin has been used as an agent for suicide and homicide in diabetics as well as nondiabetics. Presented here is a fatal case of accidental insulin overdose in a nondiabetic. Following the case presentation, we review insulin pharmacology and the methods of diagnosing insulin overdose postmortem. In any case of insulin overdose, a comprehensive scene investigation to document the amount and type of insulin used, along with information revealing the source of the insulin is critical. In addition, a complete autopsy, including appropriate laboratory studies, is needed to make a diagnosis in these cases. Proper attention should be given to collection and storage of blood samples, as these specimens often yield the strongest evidence of insulin overdose.     

Immunohistochemical quantification of pulmonary mast-cells and post-mortem blood dosages of tryptase and eosinophil cationic protein in 48 heroin-related deaths

Recent studies suggest that many fatal heroin overdoses are caused by anaphylactoid reaction. In the present study we measured tryptase and eosinophil cationic protein in post-mortem blood of 48 deaths after heroin injection. We also investigated the presence and pulmonary distribution of mast-cells using specific immunohistochemical antibody for tryptase and morphometric evaluation in those cases of heroin-related deaths. The data were compared with 44 subjects who died following head trauma and to 32 cases of fatal anaphylactic shock. In the heroin-related death cases, the measurements of serum tryptase levels and eosinophil cationic protein dosages resulted in particularly elevated concentrations compared with the trauma cases. Nevertheless, the data that our study supplies by immunohistochemical techniques indicate that when mast-cells count in the lung was determined, no definite pattern was obtained between fatal heroin overdose cases and the control groups. Furthermore, the wide range of morphine concentrations found in post-mortem blood samples suggest that the term 'overdose' is relative and does not sufficiently characterize death associated with heroin addiction. Our study confirms that elevated concentrations of serum tryptase are associated with many heroin-related deaths. At this moment to attribute the cause of these deaths to 'heroin overdose' ignores the likely causal contribution of other possible systemic reactions to the mechanism of death.     

Fatal intoxication due to tramadol alone: case report and review of the literature

Poisoning may also lead to both coma and multiple organ failure, also in youngsters without a known major medical history. As not all toxic agents are routinely screened when a poisoning is suspected, it is useful to consider less frequently encountered poisons in certain cases. We describe the occurrence of asystole and multiple organ failure which occurred in a young man after a suspected tramadol overdose. The tramadol concentration on admission in the ICU was indeed 8 microg/ml (mg/l), far above the therapeutic range. Subsequently, the patient developed severe acute liver failure, finally leading to death. Post-mortem toxicology did not reveal any other poison responsible for this unfavourable course as only very high serum and tissue tramadol and desmethyltramadol concentrations were found. Only a few fatal poisonings attributable to tramadol alone, as observed in our case, have been reported. An overview of these cases is presented.     

Polydrug fatality involving metaxalone

A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.     

Detection of Acetaminophen–Protein Adducts in Decedents with Suspected Opioid–Acetaminophen Combination Product Overdose

Acetaminophen overdose is a leading cause of drug‐induced liver failure in the United States. Acetaminophen–protein adducts have been suggested as a biomarker of hepatotoxicity. The purpose of this study was to determine whether protein‐derived acetaminophen–protein adducts are quantifiable in postmortem samples. Heart blood, femoral blood, and liver tissue were collected at autopsy from 22 decedents suspected of opioid–acetaminophen overdose. Samples were assayed for protein‐derived acetaminophen–protein adducts, acetaminophen, and selected opioids found in combination products containing acetaminophen. Protein‐derived APAP‐CYS was detected in 17 of 22 decedents and was measurable in blood that was not degraded or hemolyzed. Heart blood concentrations ranged from 11 ng/mL (0.1 μM) to 7817 ng/mL (28.9 μM). Protein‐derived acetaminophen–protein adducts were detectable in liver tissue for 20 of 22 decedents. Liver histology was also performed for all decedents, and no evidence of centrilobular hepatic necrosis was observed.     

Immunohistochemical quantification of pulmonary mast-cells and post-mortem blood dosages of tryptase and eosinophil cationic protein in 48 heroin-related deaths

Recent studies suggest that many fatal heroin overdoses are caused by anaphylactoid reaction. In the present study we measured tryptase and eosinophil cationic protein in post-mortem blood of 48 deaths after heroin injection. We also investigated the presence and pulmonary distribution of mast-cells using specific immunohistochemical antibody for tryptase and morphometric evaluation in those cases of heroin-related deaths. The data were compared with 44 subjects who died following head trauma and to 32 cases of fatal anaphylactic shock. In the heroin-related death cases, the measurements of serum tryptase levels and eosinophil cationic protein dosages resulted in particularly elevated concentrations compared with the trauma cases. Nevertheless, the data that our study supplies by immunohistochemical techniques indicate that when mast-cells count in the lung was determined, no definite pattern was obtained between fatal heroin overdose cases and the control groups. Furthermore, the wide range of morphine concentrations found in post-mortem blood samples suggest that the term ‘overdose’ is relative and does not sufficiently characterize death associated with heroin addiction. Our study confirms that elevated concentrations of serum tryptase are associated with many heroin-related deaths. At this moment to attribute the cause of these deaths to ‘heroin overdose’ ignores the likely causal contribution of other possible systemic reactions to the mechanism of death.     

Black Esophagus: Acute Esophageal Necrosis in Fatal Haloperidol Intoxication

Herein, we present a case of 53‐year‐old psychotic woman with acute esophageal necrosis (black esophagus), who was found lying on the floor in the living room of her flat. Pillboxes of antipsychotic drugs were located in the bin. External examination of the body was unremarkable. On internal examination, we found acute esophageal necrosis. Histologically, there was complete epithelial necrosis with focal involvement of muscularis mucosae, dense infiltrate of leukocytes, and ulcerations without any viable cells. There was no evidence of underlying organic diseases or trauma. Toxicological analysis revealed a fatal blood level of antipsychotics (haloperidol, zotepine, and chlorprothixene). Death of the deceased was attributed to fatal intoxication with three various types of antipsychotics. As far we know, this is the first described association between so‐called black esophagus and fatal blood level of neuroleptics.