Interpretation of postmortem digoxin levels: evaluating a "corrective factor" for postmortem blood digoxin concentration

Interpretation of postmortem serum digoxin levels is made difficult above all by a possible prefinal or postmortem rise in digoxin concentrations in the blood. To compensate for this postmortem increase, Eriksson et al. (1984) divided the level of postmortem digoxin in femoral venous blood by a factor of 1.5; in the opinion of these authors, postmortem digoxin levels still exceeding "therapeutic levels" after division by 1.5 are an index of digoxin overdose. The diagnostic value of this "correction factor" was investigated. In 56 cases with documented digoxin medication, samples of postmortem femoral venous blood were taken and the level of digoxin determined. In none of the cases had there been a clinical diagnosis of digoxin intoxication. Fifty percent of the measured values were above "therapeutic levels" (0.7 ng/ml to 2.2 ng/ml). Following division by 1.5, 20% of the cases still showed levels exceeding 2.2 ng/ml; the highest "corrected" value was 4.44 ng/ml. Taking into account the length of time between final dosage and death, individual differences in sensitivity to digitalis glycoside, and the complexity of ante- and postmortem dispersion processes, we concluded for the cases we studied that an (undetected) digoxin overdose was not even likely in those cases whose postmortem values after division by 1.5 lie above "therapeutic levels". The "correction factor" proposed by Eriksson et al. (1984) is only of limited diagnostic value; at best the "corrected" values can give an approximate indication of the corresponding antemortem serum digoxin concentrations. In particular, "corrected" values only a little above "therapeutic levels" could not confirm suspicion of an overdose with sufficient certainty.     

Suicide by sodium tetraoxoselenate(VI) poisoning

Selenium is one of the most toxic elements necessary for the life of mammals. Only a narrow range separates therapeutic (connected with a protective effect) and toxic doses. Selenium incorporated into animal or human tissues in larger amounts can exceed normal human levels and may be toxic (only elemental selenium and selenium sulphide are poorly absorbed). Acute poisonings with selenium or its compounds, especially fatal ones, occur extremely rarely in humans. Levels of selenium in four fatal cases are reviewed, and the levels in a fatal poisoning with sodium tetraoxoselenate(VI) are evaluated. Postmortem tissue selenium contents in the latter case were the following: brain, 1.45 and 1.60 microg/g; stomach, 6.12 and 6.37 microg/g; small intestine, 4.37 and 4.13 microg/g; large intestine, 4.53 and 4.43 microg/g; liver, 4.20 and 4.35 microg/g; kidney, 3.35 and 3.60 microg/g; lung, 1.80 and 1.60 microg/g; blood, 1.43 and 1.41 microg/ml measured by the use of ETA-AAS and fluorimetric methods, respectively.     

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.     

Fatal brodifacoum rodenticide poisoning: autopsy and toxicologic findings.

This report details the pathologic and toxicologic findings in the case of a 15-year-old girl who deliberately and fatally ingested brodifacoum, a commonly used rodenticide. The mechanism of death, massive pulmonary hemorrhage, has not been previously reported. Brodifacoum was quantitated in liver, spleen, lung, brain, bile, vitreous humor, heart blood, and femoral blood using HPLC with fluorescence detection. The highest brodifacoum concentrations were detected in bile (4276 ng/mL) and femoral blood (3919 ng/mL). No brodifacoum was detected in brain or vitreous humor. A brodifacoum concentration of 50 ng/g was observed in frozen liver while formalin fixed liver exhibited a concentration of 820 ng/g. A very high blood:liver brodifacoum concentration ratio suggested acute poisoning but the historical and pathologic findings suggested a longer period of anticoagulation. Though most cases of brodifacoum poisoning in humans are non-fatal, this compound can be deadly because of its very long half-life. Forensic pathologists and toxicologists should suspect superwarfarin rodenticides when confronted with cases of unexplained bleeding. Anticoagulant poisoning can mimic fatal leukemia or infectious diseases such as bacterial sepsis, rickettsioses, plague, and leptospirosis. A thorough death scene investigation may provide clues that a person has ingested these substances.     

Acute fatal poisoning with cyamemazine

A case of fatal poisoning with cyamemazine is presented. The cyamemazine was identified in post-mortem blood using a specific gas chromatographic/mass spectrometry method. The autopsy blood concentration of cyamemazine was 1800 ng/ml. Chronic use of cyamemazine was demonstrated by the presence of the drug in hair. Two other drugs were also detected (bromazepam and trimeprazine). We think that this current blood concentration (1800 ng/ml) is a fatal blood concentration because of the negativity of the other parameters, but careful interpretation of analytical findings are important, the possibility that this death was a consequence of the toxicity of combined drugs could not be excluded. Not many therapeutics and toxic levels were previously reported in overdosage cases in which cyamemazine was involved. We consider that this concentration is only of guidance value for a fatal cyamemazine poisoning.     

Distribution of digoxin, digitoxin and their cardioactive metabolites in human heart and kidney tissue. A postmortem study

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of six patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approximately 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.     

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.     

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.     

Postmortem redistribution of digoxin in rats

Adult male Wistar rats were treated with either 0.1 or 3 mg/kg body weight X day of digoxin for five days, then killed and stored at 4 degrees C for 12 h in an attempt to mimic the normal preautopsy procedures in our hospital. In rats treated with 0.1 mg/kg body weight X day, the antemortem serum digoxin concentrations (SDC) were 1.1 +/- 0.4 ng/mL while the 12-h postmortem concentration was markedly increased (16.3 +/- 5.9 ng/mL) (P less than 0.01). In rats treated with 3 mg/kg body weight X day, SDC was not changed significantly (11.2 +/- 4.8 ng/mL antemortem and 13.3 +/- 6 ng/mL postmortem). Postmortem redistribution of digoxin was assessed by injection of 125I-labelled digoxin with or without pretreatment with the unlabelled drug. The results indicate that after death passive redistribution of digoxin may take place. When the SDC are within the therapeutic or low toxic range, digoxin may reenter the blood. High antemortem serum concentrations of digoxin may prevent such passive redistribution. Therefore, antemortem digoxin intoxication cannot be reliably inferred on the basis of high postmortem levels of the drug. Digoxin intoxication can be ruled out when postmortem SDC remain within the therapeutic range. The above changes cast doubt on some of the forensic and cardiologic literature, which has in the past been based on incorrect assumptions concerning postmortem behavior of digoxin.     

Exhumation examination to confirm suspicion of fatal lead poisoning

Acute poisonings with inorganic lead compounds are exceptionally rare. In all cases of diagnosis, there are two possible sources of error: failing to recognise lead poisoning when it is present, and mistaking other diseases for lead poisoning. If exposure history is carefully taken and proper laboratory techniques are employed, the diagnosis of lead poisoning should not be difficult. In the described case of the death of a 41-year-old-man, no enzymatic disturbances characteristic of congenital erythropoietic porphyria were ascertained, and furthermore, a considerable concentration of lead was found in antemortem material, 5 months before death (blood: 1584 microg/l, urine: 531 microg/24 h). Postmortem tissue lead content in the biological material, exhumed 6 months after death, were as follows: liver, 47.6 microg/g; kidney, 4.75 microg/g; bone, 103 microg/g of sacral vertebra, 20.4 microg/g of femoral bone, 112 microg/g of pelvis; hair, 30.2 microg/g of scalp hair, 33.7 microg/g of pubic hair; nails, 13.6 microg/g. The results indicated a case of acute lead poisoning (with lead(II) oxide, as it later turned out), which manifested as acute intermittent porphyria.     

Fatal Intoxication with α‐PVP,a Synthetic Cathinone Derivative

This study presents the fatal case of a young man who was admitted to the ICAU due to sudden cardiac arrest. An interview revealed that the patient had taken some unspecified crystals. From the moment of admission, his condition deteriorated dramatically as a result of increasing circulatory insufficiency. After a few hours, sudden cardiac arrest occurred again and the patient was pronounced dead. In the course of a medicolegal autopsy, samples of biological material were preserved for toxicology tests and histopathological examination. The analysis of samples using the LC‐MS/MS technique revealed the presence of α‐PVP in the following concentrations: blood—174 ng/mL, urine—401 ng/mL, brain—292 ng/g, liver—190 ng/g, kidney—122 ng/g, gastric contents—606 ng/g. The study also presents findings from the parallel histopathological examination. Based on these findings, cardiac arrest secondary to intoxication with alpha‐PVP was determined as the direct cause of the patient's death.     

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.     

Histopathological Profile In Fatal Yellow Phosphorous Poisoning

Yellow phosphorous (YP) is the toxic form of elemental phosphorous and the chief constituent of firecrackers and rodenticides. In India, the rodenticide paste is frequently used for the suicidal purpose. This study is an autopsy‐based observational study which describes the histopathological features of heart, lungs, liver, and kidney of fatal cases of YP poisoning. The most common autopsy features in the viscera were congestion and petechial hemorrhage. The liver histopathology findings were microvesicular steatosis (68%), hepatic necrosis (62%), macrovesicular steatosis (50%), inflammatory cells (46%), sinusoidal congestion (40%), cholestasis (32%), and toxic hepatitis (18%). Hepatic necrosis ranged from being focal to centrizonal in distribution. Congestion was the most common feature observed in the lungs and the kidney. This is the largest autopsy‐based study on YP poisoning till date. The histopathological features of liver were consistent with YP poisoning whereas the findings of heart, lungs, and kidney were nonspecific in nature.     

Homicidal Paraquat Poisoning

Paraquat poisoning usually results from suicide, occupational, or accidental exposure. Herein, we report a rare fatal case of homicidal paraquat poisoning. A 58‐year‐old man was poisoned by taking paraquat‐mixed medicine and wearing paraquat‐soaked underwear. In the absence of a history of paraquat exposure, the patient was misdiagnosed with pulmonary infection and scrotal dermatitis and died of respiratory failure 24 days after the initial exposure to paraquat. Ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) was applied to detect and quantify paraquat in postmortem specimens. The concentration of paraquat in postmortem specimens from high to low is lung (0.49 μg/g), brain (0.32 μg/g), kidney (0.24 μg/g), liver (0.20 μg/g), cardiac blood (0.11 μg/mL), and stomach wall (<LOQ). Identification of homicidal paraquat poisoning is not easy for a clinician or a forensic pathologist, it is important to consider the possibility of paraquat poisoning when patients suffer from rapidly aggravating pneumonia of unknown origin.     

The PMMA epidemic in Norway: comparison of fatal and non-fatal intoxications

During a 6 month period (July 2010-January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as "Death", is occasionally found in street drugs offered as "ecstasy" or "amphetamine". The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non-fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15-50) with 67% males; in non-fatal cases 27 years (20-47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17-3.30), which is in the reported lethal range of 0.6-3.1 mg/L in peripheral blood and 1.2-15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01-0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58-3.30), 2.56 (1.52-3.23) and 0.52 mg/L (0.17-1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal "ecstasy" or "speed" drugs.     

Tissue disposition of cocaine in man: a report of five fatal poisonings

The disposition of cocaine in five cases of fatal poisoning are presented. The highest concentrations of cocaine were found in urine, kidney, spleen, brain, lung and skeletal muscle. Cocaine concentrations in these organs far exceeded those in blood. Cocaine was detected in all other specimens tested including: bile, heart, liver, vitreous and adipose tissue. These results are in agreement with limited, previously reported, tissue data, and indicate that when urine is not available, kidney, spleen, brain and/or lung should be the specimen of choice for cocaine detection.     

Cause of death in heroin users with low blood morphine concentration

The blood morphine concentrations in cases of heroin-associated fatalities can vary considerably. Currently, a free-morphine concentration of > or = 100 ng/ml in blood is generally considered as potentially fatal. Moreover, it is a common observation that fatal cases of heroin-intoxication with blood morphine concentrations lower than 100 ng/ml occur. This poses the question of how the fatal cases with low blood morphine concentrations can be explained. In the study described here, 62 cases of morphine only intoxications were examined. The fatal cases were divided into two groups according to the free morphine concentrations measured in the blood of the heart (group I: free morphine concentration < 100 ng/ml, n = 21 cases; group II: free morphine concentration > or = 100 ng/ml, n = 41 cases). The two groups were compared as to circumstances of death, as well as to autopsy findings and histopathologic alterations. Overall, infections of the respiratory tract occurred significantly more often in group I (lower morphine concentrations) than in group II. In a second step, the group I cases were analyzed individually to get detailed information on the cause of death. In 19 of the 21 cases the authors could find a plausible explanation for death in combination with low free morphine concentrations in the blood.     

Development and validation of a LC–MS/MS method for analysis of vortioxetine in postmortem specimens. First data from an authentic case

Vortioxetine is an antidepressant recently licensed in USA and EU for the treatment of major depressive disorder. Neither fatal case due to overdose nor data about postmortem concentrations on blood or other specimens have been reported. The aims of this study were the development and validation of a method for vortioxetine analysis by Liquid Chromatography Tandem Mass Spectrometry (LC–MS/MS) in postmortem samples and its application in an authentic case. The method was validated and applied on blood, vitreous humor, bile, brain, liver, kidney, and gastric content. After protein precipitation, the supernatant was directly injected into LC–MS/MS. Analysis was carried out by Multiple Reaction Monitoring (MRM) mode. The authentic case concerned a 38 years-old woman, affected by depression, who was found hanged at home. The method determined an acceptable sensitivity, selectivity, linearity, precision, and accuracy for all matrices. No interference was shown for all matrices. The matrices do not significantly reduce the peak intensity of vortioxetine. No carryover was shown. Toxicological analysis of the authentic case showed vortioxetine in blood (234 ng/ml), vitreous humor (10.5 ng/ml), brain (490 ng/g), lung (479 ng/g), liver (3751 ng/g), kidney (798 ng/g), bile (2267 ng/ml) and gastric content (253 ng/ml). Our case suggests that even at blood concentrations of vortioxetine equal to 234 ng/ml, the subject was able to stage and carry out the hanging. Vortioxetine concentrations found in the other cadaveric samples (biological fluids, organs, and gastric content) may be helpful to evaluate further similar comparable cases.     

Distribution of ∆9‐Tetrahydrocannabinol and 11‐Nor‐9‐Carboxy‐∆9‐Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents

Little is known of the postmortem distribution of ?⁹‐tetrahydrocannabinol (THC) and its major metabolite, 11‐nor‐9‐carboxy‐?⁹‐tetrahydrocannabinol (THCCOOH). Data from 55 pilots involved in fatal aviation accidents are presented in this study. Gas chromatography/mass spectrometry analysis obtained mean THC concentrations in blood from multiple sites, liver, lung, and kidney of 15.6 ng/mL, 92.4 ng/g, 766.0 ng/g, 44.1 ng/g and mean THCCOOH concentrations of 35.9 ng/mL, 322.4 ng/g, 42.6 ng/g, 138.5 ng/g, respectively. Heart THC concentrations (two cases) were 184.4 and 759.3 ng/g, and corresponding THCCOOH measured 11.0 and 95.9 ng/g, respectively. Muscle concentrations for THC (two cases) were 16.6 and 2.5 ng/g; corresponding THCCOOH, “confirmed positive” and 1.4 ng/g. The only brain tested in this study showed no THC detected and 2.9 ng/g THCCOOH, low concentrations that correlated with low values in other specimens from this case. This research emphasizes the need for postmortem cannabinoid testing and demonstrates the usefulness of a number of tissues, most notably lung, for these analyses.     

Using DNA-barcoding to make the necrobiont beetle family Cholevidae accessible for forensic entomology

Although many cases of fatal hydrogen sulfide poisoning have been reported, in most of these cases, it resulted from the accidental inhalation of hydrogen sulfide gas. In recent years, we experienced 17 autopsy cases of fatal hydrogen sulfide poisoning due to the inhalation of intentionally generated hydrogen sulfide gas. In this study, the concentrations of sulfide and thiosulfate in blood, urine, cerebrospinal fluid and pleural effusion were examined using GC/MS. The sulfide concentrations were blood: 0.11-31.84, urine: 0.01-1.28, cerebrospinal fluid: 0.02-1.59 and pleural effusion: 2.00-8.59 (μg/ml), while the thiosulfate concentrations were blood: 0-0.648, urine: 0-2.669, cerebrospinal fluid: 0.004-0.314 and pleural effusion: 0.019-0.140 (μmol/ml). In previous reports, the blood concentration of thiosulfate was said to be higher than that of sulfide in hydrogen sulfide poisoning cases, although the latter was higher than the former in 8 of the 14 cases examined in this study. These results are believed to be strongly influenced by the atmospheric concentration of hydrogen sulfide the victims were exposed to and the time interval between exposure and death.