Postmortem determination of the biological distribution of formic acid in methanol intoxication.

Two 25-year-old men were fatally intoxicated with methanol. The formic acid levels in their blood, urine, and organs were determined postmortem by headspace gas chromatography. The postmortem concentrations of formic acid in the two patients were the following: 0.32 and 0.23 mg/mL in blood, 2.27 and 0.47 mg/mL in urine, 0.11 and 1.17 mg/g in the brain, 0.54 and 0.51 mg/g in the liver, and 0.13 and 1.19 mg/g in the kidneys. The total amounts of formic acid in the gastric contents were 108 and 23.2 mg.     

The relationship of methanol and formate concentrations in fatalities where methanol is detected

An automated headspace gas chromatography method was developed for the determination of formate (formic acid) in postmortem specimens, based on the in situ sulfuric acid-methanol methylation of formic acid to methyl formate. Diisopropyl ether was used as an internal standard. The method was applied to over 150 postmortem cases where methanol was detected. Of the 153 cases presented, 107 deaths were attributed to acute methanol toxicity. In the vast majority of the remaining 46 deaths, the methanol was determined to be present as a postmortem or perimortem artifact, or was otherwise incidental to the cause of death. Of the 76 victims who were found dead and blood was collected by the medical examiner, all but one had a postmortem blood formate concentration greater than 0.50 g/L (mean 0.85 g/L; n = 74). The sole exception involved suicidal ingestion of methanol where the blood methanol concentration was 7.9 g/L (790 mg/100 mL) and blood formate 0.12 g/L. In 97% (72/74) of the cases where blood was available, the blood formate was between 0.60 and 1.40 g/L. In 31 of the 153 cases, the victim was hospitalized and blood obtained on admission or soon after was analyzed for methanol and formate during the subsequent death investigation; the vast majority (27/30) had antemortem blood formate concentrations greater than 0.50 g/L. Cases with samples taken prior to death with blood formate concentrations less than 0.5 g/L can readily be explained by active treatment such as dialysis. The blood formate method has also been useful in confirming probable perimortem or postmortem contamination of one of more fluids or tissues with methanol (e.g., windshield washer fluid or embalming fluid), where methanol ingestion was unlikely.     

Methanol Detected in a Subdural Hematoma as an Embalming Artifact

Analysis of subdural hematomata has been used to suggest antemortem drug concentrations, with the assumption that materials within the hematoma are less subject to metabolism or degradation during any survival period and postmortem interval. We report the case of an 87‐year‐old woman whose death had not been reported to the coroner's office until postembalming. Autopsy revealed a traumatic brain injury with subdural hematoma causing a mass effect. Testing of the clot indicated a methanol concentration of 51.8 mg%. No additional analyses were detected. These findings suggest that methanol can be present in a postmortem hematoma sample, yet not represent a poisoning. Our findings also suggest that while the interior of hematomata do not necessarily represent completely “protected space” from postmortem diffusion of some blood constituents, such diffusion is not facile, and analysis may still provide useful indications of antemortem drugs present, if not actual concentrations.     

Determination of formic acid tissue and fluid concentrations in three fatalities due to methanol poisoning

Three fatalities caused by methanol ingestion are reported. Admission blood methanol concentrations ranged from 0.28 to 4.6 g/L. Two patients had been admitted after a significant delay (>20 hours), and one patient was observed within 90 minutes following ingestion. Formic acid levels were determined in blood samples at admission and ranged from 302 to 680 mg/L. The patients died 44, 55, and 82 hours after poisoning. Formic acid determinations in postmortem tissues were performed by a gas chromatograph method. The authors found great variability in formic acid distribution among the patients and among organs.     

Death of an infant involving benzocaine

This report describes the death of a four-month-old Hispanic male which may be related to benzocaine toxicity. A toxicological evaluation revealed benzocaine at a concentration of 3.48 mg/L, and postmortem methemoglobin of 36% (normal 0.4-1.5). Methemoglobinemia is a complication of benzocaine toxicity. In light of the toxicology findings, the coroner investigated the source of the benzocaine and discovered that the child was treated with Zenith Goldline Allergen Ear Drops containing 0.25% w/v benzocaine and 5.4% w/v antipyrine. There was an admission by a caregiver that on the day prior to the child's death, he had been treated with three times the prescribed dose. Blood benzocaine concentrations in nine other unrelated cases were determined and concentrations ranged from <0.05-5.3 mg/L (mean 1.48 mg/L). Seven of the nine cases were positive for drugs of abuse, and one additional case was described as a known drug user. Methemoglobin in these benzocaine positive cases ranged from 6-69%; however, methemoglobin concentrations in postmortem cases are frequently elevated and should be interpreted with caution. The unknown significance of the benzocaine, and the circumstances of the case raise questions about the ultimate attribution of this death to SIDS.     

Post-mortem analysis of formic acid disposition in acute methanol intoxication

Fifteen cases of fatal massive methanol intoxication have been investigated. Victims received either no treatment or ethanol therapeutic treatment. Methanol poisoning cases were classified in three groups according to survival time: more than 3 days (group 1), up to 3 days (group 2) and few hours (group 3). Body distribution of methanol and formic acid, as the main metabolite, was analyzed in blood and in different organs (brain, kidney, lung and liver). Relationships between formic acid concentration in the different tissues, survival time and type of treatment applied to victims were studied. Formic acid in blood and tissues was analyzed by head space gas chromatography (head space-GC) with FID detector, previous transformation in methyl formate, essentially as described by Abolin. Formic acid concentration was between 0.03 and 1.10g/l in the samples under study. A good correlation between blood and brain, but poor between blood and the remaining tissues was found. Obtained data suggested that the use of blood and brain could help to improve the analysis of formic acid intoxication. The best correlation among organs was found between lung and kidney for all groups (r(2)=0.91, 0.84 and 0.87, corresponding to groups 1, 2 and 3, respectively). Lethality index was defined as LI = (concentration of formic acid in blood in (g/l)/0.5) x 100, taking into account that 0.5g/l is the concentration reported by Mahieu in severe methanol poisoning. LI parameter was used to estimate formic acid incidence on the lethality of methanol poisoning cases. LI showed a good correlation with total formic acid concentration of the different tissues analyzed (r(2)=0.80). Furthermore, LI allowed us to discriminate between individuals that received therapeutic treatment and survived different periods. LI>100 indicated a severe intoxication and short survival time if the victim was assisted with ethanol therapy and hemodialysis was not applied. With regard to victims who received no therapeutic treatment and died in few hours, LI was in the range 40-100. LI was below 40 for individuals that survived more than 3 days and hemodialysis was not performed. Results showed the importance of performing formic acid analysis to diagnose severe methanol intoxication in post-mortem cases.     

Brain amino acid abnormalities in kidney disease and diabetes mellitus

The present postmortem study examines whether specific amino acid abnormalities associated with renal diseases or diabetes mellitus in animal experiments and on clinical examination may also be found in human brain samples obtained at clinical autopsies. The material includes 12 deceased with renal insufficiency, 23 deceased with diabetes mellitus and 26 control cases with lethal cardiovascular diseases (without a history of hepatic, renal or metabolic disturbances). The autopsy and clinical records were retrospectively analyzed for age, sex, postmortem delay, cause of death, substantial preexisting diseases and histological findings. The analysis of free amino acid concentrations in human brain specimens was performed applying a Beckman amino acid analyzer. The results were evaluated using the U-test according to Mann, Willcox and Whitney. A P-value less than 0.05 was considered to be significantly different. Differences of amino acid concentrations attributable to sex, age and postmortem delay were not significant. The comparison of postmortem amino acid concentrations in the brains of patients with diabetes mellitus and controls did not reveal relevant changes. However, the patients with renal diseases, as compared to controls, showed a significant cerebral increase of urea, phenylethanolamine and gamma-aminobutyric acid. Thus, the postmortem amino acid analysis may contribute to the understanding of pathophysiological mechanisms of uremic encephalopathy and may supplement the conventional postmortem morphological diagnosis in kidney diseases by indication of functional impairment.     

Regional distribution of cocaine in postmortem brain of chronic human cocaine users

We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.     

The forensic science implications of site and temporal influences on postmortem blood-drug concentrations

The dependence of postmortem blood-drug concentrations on the collection site and on the postmortem interval before specimen collection has been studied. These studies consisted of both sequential sampling from the same collection site at defined time intervals and a comparison of the drug concentrations of postmortem blood simultaneously collected from various sites. A site and time dependence was observed for postmortem blood-drug concentrations. The heart blood-drug concentrations were, in general, significantly higher than those of peripheral specimens. As a result of this phenomenon, the analysis of peripheral blood specimens and solid tissues is often necessary before a definitive interpretation of postmortem toxicological analyses is possible.     

Elevated morphine concentrations determined during infant death investigations: artifacts of withdrawal of care

Abstract:  Three cases are reported of elevated postmortem blood morphine concentrations (189–3036 ng/mL) that were observed during the course of death investigations involving three children ranging in age from 1 week to 2 years, all of whom underwent withdrawal of life support. In all three cases, the presence of opiates in postmortem blood was indicated by immunoassay (ELISA) and quantitative confirmatory analysis of free morphine concentrations in postmortem blood was performed by solid-phase extraction followed by gas chromatography/mass spectrometry (GC/MS) in the selected ion monitoring mode. While the practice of withdrawing life support from terminally ill patients, with the accompanying administration of narcotics/analgesics has been reported in the medical literature, it has not been adequately described in the forensic literature. The implications of this practice on the forensic toxicological interpretation of morphine findings are discussed. To our knowledge, this is the first report of postmortem morphine concentrations arising directly from administration in conjunction with withdrawal of care in pediatric patients.     

Fatal Candida tropicalis infection in an 8-month-old infant with an aplasia of the thymus as a rare cause of death in infancy

Anomalies of the thymus can lead to immunodeficiencies that are often associated with complex syndromes. The clinical relevance of those anomalies varies a lot. Regarding mortality and morbidity, opportunistic infections play a major role in immunocompromised individuals. Case report: An 8-month-old infant died of a sepsis with multi-organ failure after 32 days in intensive care. At autopsy, no thymus gland could be found; toxicological examinations yielded high morphine concentrations. Autopsy findings and the results of further examinations performed postmortem are discussed in view of the clinical findings, the classification and the cause of death.     

阿维菌素在急性中毒死家兔体内的再分布研究

目的考察阿维菌素在急性中毒死家兔体内的再分布。方法按最小致死量一次性灌胃250mg/kg阿维菌素,HPLC法检测家兔死后0h、24h、48h和72h中阿维菌素的含量。结果给家兔一次性灌胃250mg/kg阿维菌素的临床死亡时间为120.6±9.2min(±s,n=10);测定了阿维菌素的致死血浓度和致死组织浓度;家兔死后0h~72h心血和各主要脏器组织中阿维菌素含量存在体内再分布现象;确定肝、肾、肺为最佳组织检材。结论阿维菌素在急性中毒死家兔体内的再分布数据,对法医办理此类案件具有重要参考价值。     

Blood versus bone marrow methanol concentrations in rabbits

Postmortem methanol levels in bone marrow and heart blood were determined in rabbits. The average ratio of heart blood concentration to observed bone marrow concentration in 36 rabbits was 2.6 ± 0.6 with a range of 1.5 to 4.2. Correcting for the lipid content of the bone marrow decreased the average ratio, reduced the ratio range and improved the correlation. The heart blood to corrected bone marrow ratio was 1.6 ± 0.3 with a range of 1.2 to 2.9. Direct injection gas chromatographic techniques were employed to quantitate methanol concentrations.     

Evaluation of the Role of Toxicological Data in Discriminating Between H2S Femoral Blood Concentration Secondary to Lethal poisoning and Endogenous H2S Putrefactive Production

Hydrogen sulfide is a colorless gas and has a strong odor of rotten eggs. It is absorbed by the upper respiratory tract mucosa, and it causes histotoxic hypoxemia and respiratory depression by exerting an inhibitory effect on cytochrome oxidase. To evaluate the role of toxicological data in distinguishing between the H₂S blood concentration secondary to lethal poisoning and the endogenous H₂S produced during putrefaction, we compared the postmortem H₂S concentrations of six fatal H₂S poisoning cases (8.7–28.6 mg/L) with the postmortem concentrations of endogenous H₂S of 12 subjects who died from other causes (traffic‐related deaths) (2.2–32.7 mg/L). These results will be of interest to the forensic community as it underlines the importance of considering circumstantial evidence along with the toxicological and pathological findings in the identification of H₂S lethal poisoning.     

Olanzapine‐Induced Fatal Ketoacidosis with Pneumomediastinum and Subcutaneous Emphysema

We report a case of fatal olanzapine‐induced ketoacidosis in which pneumomediastinum (PM) and subcutaneous emphysema (SE) were detected on postmortem computed tomographic (CT) images. A man in his forties was found in a state of cardiopulmonary arrest with profuse perspiration, and 50 empty capsules of olanzapine (10 mg) and flunitrazepam (1 mg) were found in his room. The major findings of postmortem CT prior to autopsy were PM and SE from the lower half of the face to the height of the first rib. The results of autopsy, biochemical tests, and toxicological analyses indicated the cause of death to be fatal ketoacidosis induced by olanzapine intoxication. No injuries, medical interventions, or particular diseases were evident, suggesting that PM and SE were caused by ketoacidosis. Our findings indicated that toxicological analyses should be performed when PM and SE are detected on CT images.     

Brain amino acid abnormalities in liver disease--a postmortem study

In a postmortem exploratory study, we examined whether specific amino acid abnormalities associated with liver diseases in vivo may also be detected in human brain samples obtained at clinical autopsies. The branched-chain amino acids (BCAA: valine, leucine, isoleucine) were decreased in the group of patients with liver diseases compared with the control group, whereas the aromatic amino acids (AAA: phenylalanine, tyrosine) were increased. However, the ranges overlapped significantly and were not statistically different. The molar ratio BCAA/AAA was determined to be 1.92 in the collection of patients with liver diseases compared with 2.27 in the control group. In patients with liver disease, ornithine concentrations in the brain appeared significantly decreased whereas glutamine was significantly increased. No significant difference was found in the brain concentrations of proline. Amino acid analysis may contribute to the understanding of pathophysiological mechanisms of liver disease, which are discussed, and may supplement the postmortem diagnosis.     

Interpretation of a 3,4-methylenedioxymethamphetamine (MDMA) blood level: discussion by means of a distribution study in two fatalities

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy" is a currently used or abused designer drug and fatalities are frequently encountered in forensic practice. However, the question remains open whether an MDMA blood level can be toxic or even potentially lethal. In order to provide insight in the interpretation of a detected MDMA concentration, the distribution of MDMA and its metabolite 3,4-methylenedioxyamphetamine (MDA) in various body fluids and tissues was studied and discussed in two different fatalities. Apart from peripheral blood samples (such as femoral and subclavian blood), various blood samples obtained centrally in the human body and several body fluids (such as vitreous humour) were examined. In addition, various tissues such as cardiac muscle, lungs, liver, kidneys, and brain lobes were analysed. In contrast to the peripheral blood levels, high MDMA and MDA levels were found in cardiac blood and the majority of the organs, except for the abdominal adipose tissue. The high concentrations observed in all lung lobes, the liver and stomach contents indicate that post-mortem redistribution of MDMA and MDA into cardiac blood can occur and, as a result, blood sampled centrally in the body should be avoided. Therefore, our data confirm that peripheral blood sampling remains "the golden standard". In addition, a distinct difference in peripheral blood MDMA concentrations in our two overdose cases was established (namely 0.271 and 13.508 microg/ml, respectively). Furthermore, our results suggest that, if a peripheral blood sample is not available and when putrefaction is not too pronounced, vitreous humour and iliopsoas muscle can be valuable specimens for toxicological analysis. Finally, referring to the various mechanisms of death following amphetamine intake, which can result in different survival times (e.g. cardiopulmonary complications versus hyperthermia), the anatomo-pathological findings and the toxicological results should be considered as a whole in arriving at a conclusion.     

Vitreous humor magnesium in alcoholics

Postmortem vitreous humor magnesium concentrations were determined in 27 alcoholics and in 27 nonalcoholics who died of various causes. No significant differences in magnesium values were present between these two groups. The concentrations in those dying with alcohol withdrawal syndrome or in those with postmortem findings limited to hepatic fatty change did not differ significantly from those in the nonalcoholic group or from those of the alcoholics dying of other causes. There was no correlation between vitreous humor magnesium concentrations and postmortem interval in any group. We conclude that vitreous humor magnesium determination is not helpful in the postmortem evaluation of suspected alcohol-related deaths or in determining postmortem interval.     

Comparative study of postmortem barbiturates, methadone, and morphine in vitreous humor, blood, and tissue

With the introduction of radioimmunoassay (RIA) techniques, it has become toxicologically possible to determine drug concentrations in postmortem vitreous humor. This study demonstrates and confirms this toxicological feasibility. In 49 medical examiner's drug related cases, postmortem tissue levels of morphine, barbiturates, and methadone were compared to the vitreous humor.     

Olanzapine concentrations in clinical serum and postmortem blood specimens--when does therapeutic become toxic?

The concentration of olanzapine (Zyprexa) was determined in 1653 clinical serum specimens during routine drug monitoring, and in 58 postmortem whole blood specimens as part of routine toxicological analysis. The analysis of olanzapine was performed by the solid-phase extraction of 1.0 mL of buffered serum or blood, followed by gas chromatography separation with nitrogen-phosphorus detection. The analysis of the clinical serum samples showed that 86% of positive serum values were within the range of 5 to 75 ng/mL, with a mean and median of 36 and 26 ng/mL, respectively. These data suggest that the concentrations of olanzapine expected during therapy may be higher than those previously reported. In 58 postmortem whole blood specimens the mean olanzapine concentration was 358 ng/mL with a range of 10 to 5200 ng/mL. Further, investigation of deaths involving olanzapine suggest that potential toxicity should be considered at concentrations above 100 ng/mL. Although the majority of the olanzapine-related deaths were associated with many other drugs, death primarily due to olanzapine toxicity was determined at concentrations in post-mortem blood as low as 160 ng/mL.