An acute gabapentin fatality: a case report with postmortem concentrations.

Gabapentin (GBP) (Neurontin®, Horizant®, Gralise®) is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. GBP has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional GBP self-poisonings, serious effects are rare. A 47-year-old female was found dead at work with her daughter's bottle of GBP 600 mg. There were 26 tablets missing and the decedent's only known medication was hydrocodone/acetaminophen. Following initial detection by an alkaline drug screen (GC-MS), analysis utilizing specific liquid chromatography-mass spectrometry revealed an elevated postmortem GBP peripheral blood concentration of 37 mg/L, central blood 32 mg/L, liver 26 mg/kg, vitreous 32 mg/L, and gastric contents 6 mg. Screening for volatiles, drugs of abuse, alkaline compounds, and acid/neutral compounds was negative with the exception of ibuprofen (<2 mg/L) detected in peripheral blood. This report presents a fatality that appears to be associated with an isolated and acute GBP ingestion.

Liver and peripheral blood concentration ratio (L/P) as a marker of postmortem drug redistribution: a literature review.

The liver to peripheral blood (L/P) ratio, based upon review of previously published works, was evaluated as a marker of postmortem redistribution (PMR). Literature supported the proposed model that drugs exhibiting an L/P ratio of less than 5 are prone to little or no PMR, while those with an L/P ratio greater than 20-30 have propensity for significant redistribution. Many antidepressants, including both tricyclic antidepressants and selective serotonin re-uptake inhibitors, were markedly differentiated from drugs previously verified to be free from, or exhibit little, PMR. The magnitude of the liver to blood concentrations also appeared to provide an advantage over the conventional central to peripheral blood ratio model of PMR by demonstrating a wide range of values (1.6-97) for interpretation of drugs' potential for, and variations in, redistribution.

Acidic Drug Concentrations in Postmortem Vitreous Humor and Peripheral Blood.

Vitreous humor is a potential alternative matrix for postmortem toxicology drug screens when peripheral blood is unavailable. It is easily and reliably collected and may not suffer from the same postmortem redistribution as seen in blood. Here, we compared the concentrations of 7 acidic drugs (acetaminophen, ibuprofen, naproxen, salicylic acid, carbamazepine, phenobarbital and phenytoin) in peripheral blood and vitreous fluid collected in 89 autopsy cases. Analysis was done by high-performance liquid chromatography with diode-array detection. Overall, we found that vitreous drug concentrations were significantly lower than peripheral blood with median vitreous to peripheral blood (V/PB) ratios ranging from 0.0 to 0.6 (mean, 0.1-0.6). The correlations between the concentrations of over-the-counter analgesics in peripheral blood versus vitreous fluid were poor, with acetaminophen exhibiting the best linearity (R2 = 0.72). The antiepileptic drugs (carbamazepine, phenytoin and phenobarbital) exhibited good correlations between peripheral blood and vitreous humor, with all exhibiting an R2 ≥ 0.95. Overall, we have demonstrated the potential of vitreous fluid as an alternative matrix for the detection of select acidic drugs.

An evaluation of postmortem concentrations of Δ9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH).

Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, leads to impaired cognitive and psychomotor function resulting in an increased risk of fatal motor vehicle collisions and other traumas resulting in death. It is important to measure cannabinoids in postmortem cases to improve understanding of this growing public safety issue. However, postmortem concentrations of THC and its primary inactive metabolite, 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH), have not been extensively studied. We aim to further characterize postmortem concentrations of THC and THCCOOH in peripheral blood with and without preservation, central blood, and central "serum" to support improved forensic interpretation. Cannabinoids were extracted from blood and "serum" from twenty-five decedents using solid phase extraction followed by quantification using gas chromatography - mass spectrometry. We evaluated the impact of sample preservation, reported central blood-to-peripheral blood (CB:PB) ratios and blood-to-"serum" ratios, and assessed the relationship of CB:PB and postmortem interval for THC and THCCOOH. Correlations of preserved compared to unpreserved blood were strong with r2 > 0.97. The median CB:PB ratios were 1.1 and 1.3 for THC and THCCOOH, respectively. THCCOOH CB:PB was significantly higher than 1.0 (p-value < 0.001). The CB:PB ratio was only weakly correlated with PMI for both compounds. The median blood-to-"serum" ratio was 1.0 for THC and 0.8 for THCCOOH. The blood-to-"serum" ratio of THCCOOH was significantly lower than 1.0 (p-value < 0.001). Results demonstrated minimal potential for postmortem redistribution of THC and THCCOOH and that the ratio of blood-to-"serum" in postmortem samples differs from the blood-to-plasma ratio established in living humans. Based on these results, it is not recommended to apply a correction factor to THC and THCCOOH concentrations from postmortem blood samples. Our study improves the understanding of postmortem cannabinoid concentrations to support forensic interpretation in cases of fatal motor vehicle accidents.

Postmortem tissue concentrations of olanzapine.

Twenty-eight cases from 2004-2007 involving olanzapine were analyzed at the San Diego County Medical Examiner's Office. Olanzapine was initially detected by gas chromatography coupled with mass spectrometry (GC-MS), and then confirmed by GC with a nitrogen-phosphorus detector. In cases where olanzapine was detected, concentrations in peripheral blood (PB), central blood (CB), liver, and vitreous were determined if available. In the six olanzapine-only deaths, average olanzapine concentrations (mean+/-standard deviation) were 3.2+/-2.0 mg/L (PB), 4.5+/-2.6 mg/L (CB), 40+/-29 mg/kg (liver), and 1.6+/-0.50 mg/L (vitreous). This was compared to the 10 non-olanzapine-related deaths, which showed average olanzapine concentrations of 0.26+/-0.13 mg/L (PB), 0.29+/-0.17 mg/L (CB), 5.6+/-5.6 mg/kg (liver), and 0.24+/-0.38 mg/L (vitreous). The remaining 10 multi-drug deaths had average concentrations of 0.59+/-0.33 mg/L (PB), 0.64+/-0.60 mg/L (CB), 5.9+/-4.3 mg/kg (liver), and 0.78+/-0.91 mg/L (vitreous). Concentrations of olanzapine associated with toxicity were found to be in the range of 1.4-6.2 mg/L (PB), 1.1-7.4 mg/L (CB), 14-88 mg/kg (liver), and 1.1-2.1 mg/L (vitreous). Concentrations associated with therapeutic use were found to be in the range of 0.11-0.43 mg/L (PB), 0-0.53 mg/L (CB), 0-8.6 mg/kg (liver), and 0-0.98 mg/L (vitreous). Deaths attributed solely to olanzapine were distinguished by a 10-fold or more increase in tissue concentrations over those found in the non-olanzapine-related deaths.

A fluvoxamine-related fatality: Case report with postmortem concentrations.

Fluvoxamine is a selective serotonin reuptake inhibitor that has been considered relatively safe in overdose. At therapeutic and supratherapeutic concentrations, fluvoxamine affects cardiac conduction, prolongs QTc interval, causes hypotension, obtundation, and can increase propensity for seizures. A man in his 60s was found dead at his home with a postmortem fluvoxamine peripheral blood concentration of 4.9 mg/L, and a liver concentration of 440 mg/kg. His cause of death was determined to be acute fluvoxamine toxicity.

A pediatric fatality due to accidental hydromorphone ingestion.

BACKGROUND: Death due to prescription opioid exposure has increased dramatically in North America. Currently, there is a lack of literature detailing potentially lethal doses as well as postmortem tissue analysis concentrations from prescription opioid fatalities in children. We report a pediatric hydromorphone fatality with postmortem peripheral blood, central blood, liver, and gastric concentrations. CASE REPORT: A 3-year-old male was found unresponsive on a couch. Emergency services were contacted and responders found him pulseless, apneic, and asystolic. Resuscitative measures were unsuccessful and he was pronounced dead at a local hospital soon after arrival. Postmortem investigations revealed that two hydromorphone tablets (2 mg each) were missing. There was no demonstrable natural disease or traumatic injury to which to attribute his death upon autopsy; while postmortem concentrations of hydromorphone were confirmed and quantitated in peripheral blood at 0.03 mg/L, central blood 0.06 mg/L, and liver 0.10 mg/kg. CONCLUSION: Given the paucity of reported pediatric opioid-related fatalities, we describe a hydromorphonep-related death in a child, which includes postmortem hydromorphone concentrations.

A Fatality Related to the Synthetic Opioid U-47700: Postmortem Concentration Distribution.

In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. A man who had a history of drug abuse was found unresponsive and not breathing on his bed. Drug paraphernalia, indicating drug insufflation, was located in the decedent's room. Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid-liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). Other drugs detected in peripheral blood were alprazolam (0.12 mg/L), nordiazepam (<0.05 mg/L), doxylamine (0.30 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L), salicylic acid (<20 mg/L) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (2.4 ng/mL). The cause of death was certified as acute U-47700 and alprazolam abuse, and the manner of death was certified as accident.

Brain distribution of selected antipsychotics in schizophrenia.

The brain distribution of phenothiazine antipsychotics in 22 confirmed schizophrenic and 11 control subjects were collected at autopsy. Specimens were homogenized, extracted with n-butyl chloride, and analyzed via liquid chromatography-mass spectrometry, using atmospheric pressure electrospray ionization operating in the positive mode. Drug concentrations normalized for those observed in cerebellum showed three distinct patterns of distribution corresponding to different structural features of each type of phenothiazine. Those drugs with high affinity for dopamine receptors were detected in the highest concentrations in regions with high concentrations of such receptors. However, those associated with relatively lower dopaminergic activity were found in the highest concentration in the occipital cortex, a region with a relatively low concentration of dopamine receptors. The regional brain distribution of thioridazine and its metabolites was concentration dependent. These results have implications for determining the role of these drugs in the sudden and unexpected deaths of schizophrenics.

Therapeutic and toxic concentrations of mirtazapine.

Six cases involving the antidepressant mirtazapine were analyzed in detail at the San Diego County Medical Examiner's Office from 2004 to 2005. Mirtazapine was initially detected and confirmed in each of these cases by a liquid-liquid gas chromatography (GC)-MS basic drug screen. Following another liquid-liquid basic extraction, mirtazapine was quantitated by GC with nitrogen-phosphorus detection. For each case, mirtazapine concentrations in peripheral blood (pb), central blood (cb), vitreous (vit), and liver were determined against matrix specific calibration curves (limit of detection 0.01 mg/L; linear range 0.025-1.0 mg/L). In contrast with earlier studies of postmortem distribution of mirtazapine, we found concentrations in liver that were significantly higher. Mirtazapine was identified in the cause of death by the pathologist in three cases. In the drug-related deaths, mirtazapine concentrations (mean +/- S.D.) were 2.0 +/- 1.5 mg/L (pb), 1.6 +/- 1.0 mg/L (cb), 0.78 +/- 0.56 mg/L (vit), and 10 +/- 7.4 mg/kg (liver). Alternatively, concentrations considered therapeutic (three non-drug-related deaths) were (mean +/- S.D.) 0.18 +/- 0.22 mg/L (pb), 0.16 +/- 0.17 mg/L (cb), 0.12 +/- 0.16 mg/L (vit), and 0.73 +/- 0.68 mg/kg (liver). Although mirtazapine concentrations were elevated in blood and liver in three cases, it should be noted that other drugs were also found in toxic concentrations in each case. These data may further support the fact that mirtazapine is a relatively safe drug with respect to overdose.

Two deaths attributed to the use of 2,4-dinitrophenol.

We report the cases of two individuals, one in Tacoma, WA, and the second in San Diego, CA, whose deaths were attributed to ingestion of 2,4-dinitrophenol (2,4-DNP). 2,4-DNP has historically been used as a herbicide and fungicide. By uncoupling mitochondrial oxidative phosphorylation, the drug causes a marked increase in fat metabolism that has led to its use to aid weight loss. Both cases reported here involved its use for this purpose. Features common to both cases included markedly elevated body temperature, rapid pulse and respiration, yellow coloring of the viscera at autopsy, history of use of weight loss or body building supplements, and presence of a yellow powder at the decedent's residence. Because of its acidic nature, the drug is not detected in the basic drug fraction of most analytical protocols, but it is recovered in the acid/neutral fraction of biological extracts and can be measured by high-performance liquid chromatography or gas chromatography-mass spectrometry. The concentration of 2,4-DNP in the admission blood samples of the two deaths reported here were 36.1 and 28 mg/L, respectively. Death in both cases was attributed to 2,4-DNP toxicity. Review of information available on the internet suggests that, although banned, 2,4-DNP is still illicitly promoted for weight loss.

Analytical data supporting the "theoretical" postmortem redistribution factor (Ft ): a new model to evaluate postmortem redistribution.

The concepts of postmortem redistribution (PMR, F) factor, and "theoretical" PMR (Ft ) - based upon a drug's characteristic L/P ratio - have been defined to express the direct relationship between postmortem peripheral blood and the corresponding antemortem whole-blood concentration. This paper applies recent data describing liver/peripheral blood (L/P) ratios for many commonly detected drugs to assess these models, and provide a ranking of drugs' propensity for (and degree of) PMR.

Assessment and Comparison of Vitreous Humor as an Alternative Matrix for Forensic Toxicology Screening by GC-MS.

Alternative specimens have been occasionally considered as substitutes for whole blood for postmortem toxicology testing. We studied the applicability of vitreous humor, and evaluated whether it would be suitable to replace (or augment) whole blood for routine drug screening. Results showed that from 51 autopsy cases, we were able to identify an aggregate of 209 findings in whole blood compared with 169 in vitreous. The total number of compounds identified was 71 for whole blood and 60 for vitreous humor. Quantitative analysis showed that whole-blood concentrations of trazodone were several fold higher than vitreous humor concentrations (1.42 ± 0.57 vs. 0.15 ± 0.05 mg/L, respectively) and similar results were also obtained for diazepam (0.37 ± 0.06 vs. 0.13 ± 0.01, respectively). For other drugs such as oxycodone, hydrocodone and doxylamine, a trend suggesting higher concentrations in vitreous humor vs. whole blood was observed; however, this was not significant. Our results are consistent with the limited work of other investigators, and suggest that vitreous humor could be an appropriate matrix for drug screening in postmortem toxicology.

Gabapentin concentrations and postmortem distribution.

Gabapentin is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. Gabapentin has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional self-poisonings, serious effects are generally rare. In this report, gabapentin analyses were performed on 30 postmortem cases that had peripheral blood, central blood and liver tissue. Overall the central to peripheral blood (C/P) ratio mean was 0.90±0.24 (mean±standard deviation), and a median of 0.97. The liver to peripheral blood (L/P) ratio mean was 0.68±0.26L/kg (mean±standard deviation), and a median of 0.65L/kg. An additional case, where both antemortem blood and postmortem peripheral blood specimens were available, revealed the same gabapentin concentration in both specimens. Taken together, the data presented suggests that gabapentin is unlikely to show postmortem redistribution.

An Acute Butyr-Fentanyl Fatality: A Case Report with Postmortem Concentrations.

In this case report, we present an evaluation of the distribution of postmortem concentrations of butyr-fentanyl in a fatality attributed principally to the drug. A man who had a history of intravenous drug abuse was found unresponsive on the bathroom floor of his home. Drug paraphernalia was located on the bathroom counter. Toxicology testing, which initially screened positive for fentanyl by enzyme-linked immunosorbent assay, subsequently confirmed butyr-fentanyl, which was then quantitated by gas chromatography-mass spectrometry-specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. The butyr-fentanyl peripheral blood concentration was quantitated at 58 ng/mL compared with the central blood concentration of 97 ng/mL. The liver concentration was 320 ng/g, the vitreous was 40 ng/mL, the urine was 670 ng/mL and the gastric contained 170 mg. Acetyl-fentanyl was also detected in all biological specimens tested. Peripheral blood concentration was quantitated at 38 ng/mL compared with the central blood concentration of 32 ng/mL. The liver concentration was 110 ng/g, the vitreous was 38 ng/mL, the urine was 540 ng/mL and the gastric contained <70 mg. The only other drug detected was a relatively low concentration of benzoylecgonine. The cause of death was certified as acute butyr-fentanyl, acetyl-fentanyl and cocaine intoxication, and the manner of death was certified as accident.

A tapentadol related fatality: Case report with postmortem concentrations.

Tapentadol (TAP) is an analgesic agent indicated for the management of different types of pain. It has a novel mechanism of action in that it induces analgesia via both µ-opioid receptor agonism and norepinephrine reuptake inhibition. Although deaths associated with TAP use have been reported, there is a paucity of published literature regarding TAP concentrations in biological samples obtained from TAP-associated fatalities. We report a case of TAP toxicity resulting in death with postmortem peripheral and central blood concentrations, liver, vitreous, urine, and gastric contents. A 41-year-old female was found slumped over a sink at home following a welfare check by police. She was transported to a local hospital where she was pronounced dead despite all resuscitative measures. The autopsy was remarkable only for pulmonary edema and signs of aspiration pneumonia. Postmortem concentrations of TAP were confirmed in peripheral blood at 1.1mg/L, central blood 1.3mg/L, liver 9.9mg/kg, vitreous humor 0.94mg/L, urine 88mg/L, and the gastric contained 2mg. Also of note, oxycodone was found in the decedent's blood at a concentration of 0.58mg/L. We report a death related to an intentional ingestion of TAP and oxycodone-the cause and manner of death were determined to be mixed drug intoxication; suicide. We hope that the variety of TAP concentrations identified in this case provide valuable points of reference for future cases of TAP intoxication.

Synthetic cannabinoid drug use as a cause or contributory cause of death.

Adverse effects associated with synthetic cannabinoid use include agitation, psychosis, seizures and cardiovascular effects, all which may result in a lethal outcome. We report the collection of data from 25 medical examiner and coroner cases where the presence of synthetic cannabinoids was analytically determined. Participating offices provided case history, investigative and relevant autopsy findings and toxicology results along with the cause and manner of death determination. This information, with the agency and cause and manner of death determinations blinded, was sent to participants. Participants offered their opinions regarding the likely contribution of the toxicology findings to cause and manner of death. The results show that some deaths are being attributed to synthetic cannabinoids, with the highest risk areas being behavioral toxicity resulting in excited delirium, trauma or accidents and as contributing factors in subjects with pre-existing cardiopulmonary disease. While insufficient information exists to correlate blood synthetic cannabinoid concentrations to effect, in the absence of other reasonable causes, the drugs should be considered as a cause or contributory cause of death based on history and circumstances with supporting toxicological data.

Case studies of postmortem quetiapine: therapeutic or toxic concentrations?

The focus of this study was to determine if the analysis of a variety of postmortem biological specimens would aid in the toxicological interpretation of quetiapine in the cause and manner of death determinations. Postmortem quetiapine concentrations were examined in 21 medical examiner cases using liquid-liquid extraction and high-performance liquid chromatography analysis. Specimens analyzed were peripheral blood, central blood, liver, vitreous humor, and gastric contents, when available. Findings from this study suggest that therapeutic postmortem quetiapine concentrations may be less than 1 mg/L in both peripheral and central blood, less than 0.5 mg/L in vitreous, and less than 5 mg/kg in liver. Quetiapine concentrations indicative of toxicity were estimated at greater than 1 mg/L in peripheral and central blood, greater than 0.5 mg/L in vitreous, and greater than 5 mg/kg in the liver. Liver concentrations appeared to be particularly helpful in determining the potential for toxicity when compared with blood concentrations. Cases in which quetiapine was determined to play a significant role in the death indicated postmortem liver concentrations greater than 5 mg/kg. Cases in which quetiapine concentrations were considered incidental or noncontributory in the death had liver concentrations 2 mg/kg or less.

Postmortem distribution of trazodone concentrations.

Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Re-analyses showed that there may be degradation of trazodone in postmortem blood stored at 4°C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0mg/L with liver concentrations to at least 2.2mg/kg. Overall, trazodone concentrations ranged from 0.08-6.1mg/L in peripheral blood, 0.07-7.1mg/L in central blood, and 0.39-26mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N=19). The liver to peripheral blood ratios showed a median value of 2.8L/kg (N=18). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution.