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.     

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.     

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.     

The acetaminophen experience in south Florida

Toxicology records of the Dade County Medical Examiner Department were reviewed for the years 1972 to 1981. Any case in which acetaminophen was detected, regardless of the cause of death, was included in the study. Of 95 cases where acetaminophen was detected, no trends were observable in age, sex, or race. Acetaminophen deaths have increased in recent years, probably because of increased marketing of products containing this substance. Some two thirds of the cases involved suicides or accidental deaths, with 40 cases being directly attributable to overdose with a variety of drugs. It is suggested that acetaminophen may be a useful indicator of polydrug overdoses.     

Case report of a fatal intoxication by citalopram

Citalopram is an antidepressant drug within the group of the selective serotonin reuptake inhibitors (SSRI). It is widely prescribed both in Europe and in United States, and it has always been considered a "safe" drug as pure intoxication with lethal outcome is rare, and most cases of overdose, even with high doses of citalopram ingested, are reported to have an uneventful course.We report the case of a young woman found dead at home. She had been prescribed citalopram by her family doctor 3 weeks before her death for a depressive syndrome. Police found in her house 3 empty blister packages of 28 citalopram tablets (20 mg) and 2 bottles of citalopram oral solution (4%, 15 mL each). The autopsy findings were unremarkable. Nasal swabs, blood from femoral vein, urine, bile and tissue samples were collected for toxicologic investigation. Citalopram separation was performed by solid/liquid method, using Bond-Elute columns. The extracts were analyzed by GLC and GC/MS methods. The toxicologic analysis showed high levels of citalopram in all the examined fluids and tissue samples (blood concentration: 11.60 mg/L). No other drugs and alcohol were detected. Our data confirm that if no other drug is involved, fatal complications occur only after ingestion of very high doses. However, there is no predefined "toxic dose," and the conditions under which the overdose occurs can be very important. We report the exact concentrations of the citalopram in the organs, and wethink that this can be useful in the cases where the blood samples were not available (ie, carbonized or decomposed body).     

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.     

Fatal venlafaxine overdose with acinar zone 3 liver cell necrosis

We present a case of fatal venlafaxine overdose in a 34-year-old male with a history of depression and previous suicide attempts. He presented unwell, and his condition deteriorated with the development of rhabdomyocytolysis and renal failure. Although treatment was provided, this was unsuccessful, and he died within a day of his admission. A postmortem examination was performed, and the findings included an acinar zone 3 pattern of liver cell necrosis and a very high level of serum venlafaxine in the deceased. No other elevated drug levels were detected. From this case, it is clear that venlafaxine overdose was the primary cause of a fatal acinar zone 3 pattern of liver cell necrosis. As far as we are aware, this is the first reported case of fatal acinar zone 3 liver necrosis caused by venlafaxine overdose alone.     

Toxicological analysis of a fatal baclofen (Lioresal) ingestion

A fatality following ingestion of the drug baclofen (Lioresal) is described. Baclofen was identified in urine by gas chromatography/mass spectrometry. After derivatization with trinitrobenzene sulfonic acid, baclofen was quantitated in serum and urine by high-performance liquid chromatography. The concentration of baclofen was 17 mg/L in serum and 760 mg/L in urine collected approximately 12 h after the overdose. To our knowledge, this is only the second reported fatality involving a baclofen overdose. The previous case did not include quantitation of baclofen in any biological fluid.     

Acute flurazepam intoxication: a case report

A fatality due to ingestion of flurazepam is reported. Flurazepam is a benzodiazepine, a widely prescribed hypnotic drug for use in sleep disorders. There are only few documented reports of the disposition of flurazepam in deaths due to overdose. A 68-year-old woman was found deceased at home with no evidence of trauma or asphyxia. Toxicologic analyses were performed and drug levels measured by means of gas chromatography coupled to mass spectrometry. The flurazepam concentration in each specimen was as follows: heart blood 2.8 microg/mL, bile 323 microg/mL, and urine 172 microg/mL. Presence of flurazepam into gastric content was observed too. Based on the autopsy findings, patient history, and toxicologic results, the cause of death was determined to be acute intoxication of flurazepam and the manner, suicide.     

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.     

Fatality caused by a combined trimipramine-citalopram intoxication

A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.     

Doxepin and nordoxepin concentrations in body fluids and tissues in doxepin associated deaths

Body fluids and tissues in eight doxepin (Dox)-related deaths were investigated in order to prove whether the individual concentration of Dox, the concentration sum of parent drug and its active metabolite N-desmethyldoxepin (NDox) or the concentration ratio Dox/Ndox valuably contribute to making a cause of death determination. Individual case histories were shortly described. Dox and NDox concentrations were determined by LC–MS/MS. Dox concentration measured from two cases was well within a concentration range considered therapeutic, whereas subtherapeutic dosing may have occurred in another two cases. There were two cases of fatal Dox ingestion, as well as a case of high dosage and advanced putrefaction, respectively. The liver concentration sum may be more useful if a fatal ingestion cannot be clearly separated from a person's medication usage. High concentrations could be observed in lung tissue, and combined concentrations of Dox and NDox may also be helpful in making a cause of death determination. There was a trend to a higher concentration sum in the brain with increasing combined levels in blood. Overall, the sum of the absolute figures allows a more accurate interpretation in Dox-related deaths as compared to the molar concentration ratio which may be helpful in acute ingestion. Determination of the N-desmethyl metabolite along with its parent is recommended and analysis should include more than a single specimen.     

Toxicological findings in Federal Aviation Administration general aviation accidents

Blood, urine, and tissue specimens were received from 377 Federal Aviation Administration (FAA) aviation fatalities during fiscal year 1989. Carbon monoxide at less than 10% saturation was found in 94% of the cases, and cyanide at less than 0.5 mg/L was found in 96% of the cases. Ethanol at greater than 10 mg/dL was found in 14.8% of the cases, but only 4.5% were determined to be due to ethanol ingestion from toxicological findings. Excluding nicotine and ethanol, 12.6% of the cases were positive for one or more drugs. Acetaminophen and salicylate were the most frequently found drugs. Cannabinoids were found in 1.3% of the cases and benzoylecgonine in 1.6%. There was minimal use of therapeutic drugs that cause central nervous system depression or stimulation. These results show no consistent pattern of drug involvement in civilian aviation fatalities.     

Dispensing error causing fatal chlorpropamide intoxication in a nondiabetic

A 38-year-old nondiabetic female developed fatal hypoglycemia when chlorpropamide (Diabinese) was accidentally substituted for acetaminophen (Tylenol) with codeine no. 3 in a pharmacy dispensing error. When found, the patient's serum glucose was less than 20 mg/dL. The serum chlorpropamide level on hospital admission was 124 micrograms/mL. The possibility of dispensing error should be considered whenever unexpected drug effects are encountered. In cases of suspected drug overdose, labels and contents of medicine vials found at the scene should be checked for discrepancy.     

Postmortem distribution of sertraline and desmethylsertraline in a fatality

Sertraline (CAS 79617-96-2) is a relatively safe medication for patients suffering from depression. Data reporting the postmortal distribution of sertraline and desmethylsertraline remain rare as well as reports of risks of side effects following ingestion of the drug. In a case of a young woman found dead in her flat sertraline and desmethylsertraline were identified and quantified in body fluids and tissues by gas chromatography/mass spectrometry and high performance liquid chromatography with diode array detection after alkaline extraction. Sertraline and its desmethyl metabolite were found in the peripheral blood in levels of 0.15 mg/l and 0.20 mg/l, concentrations in liver and bile were markedly higher. By exclusion of other reasons for death a lethal sertraline intoxication was decided. Sertraline is suggested to possess a low inherent toxicity, however, a risk of side-effects which may occur in single cases even under moderate dosages should be considered.     

Digoxin-like immunoreactive substance in postmortem blood of infants and children

A digoxin-like immunoreactive substance (DLIS) has been reported in the serum of infants not receiving digoxin. This study was undertaken to determine if DLIS is present in the postmortem blood and tissues of infants or children and whether the endogenous substance could interfere with forensic toxicological analysis in suspected overdose. Ninety blood specimens taken from the heart at autopsy of children or infants were screened for DLIS using commercial radioimmunoassay kits. The average age at death in these cases was 8.6 months, the median age was 2 months. DLIS equivalent to 0.25 to 2.0 ng/mL digoxin was found in one third of the cases. The incidence of positive findings was 5/6 stillborns, 10/45 Sudden Infant Death Syndrome (SIDS), 10/15 deaths as a result of infection, 4/7 homicides, 1/8 deaths caused by congenital defects, and 0/9 accidental deaths. The body distribution of DLIS was investigated and highest levels were found in the liver. Findings of DLIS in blood were correlated with renal failure, (elevated vitreous urea nitrogen), electrolyte imbalance, and liver trauma. Apparent concentrations were in the equivalent therapeutic range of digoxin and would not be confused with accidental or intentional overdose with digoxin.     

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.