Postmortem concentrations of citalopram

The postmortem concentrations of citalopram in blood, bile, liver, and vitreous humour were investigated in 14 cases using a specially developed high performance liquid chromatography assay. Concentrations from drug and non-drug related deaths were categorized to determine a postmortem therapeutic and toxic range. Therapeutic citalopram concentrations for blood, bile, liver, and vitreous humour ranged to 0.4 mg/L, 2.1 mg/l, 6.6 mg/kg, and 0.2 mg/L, respectively. In one potentially fatal response to citalopram, concentrations were 0.8 mg/L, 6.0 mg/L, 0.3 mg/L for blood, bile and vitreous humour, respectively.     

Postmortem oxycodone and hydrocodone blood concentrations

There is limited data on postmortem oxycodone concentrations, consisting of three published reports with a total of 11 cases, many of which were polypharmacy cases. This report presents the results of a review of autopsy and coroner's reports from 10 counties for the years 2000 and 2001 to locate cases with oxycodone or hydrocodone exposure as a leading cause of death. Eighty-eight cases were located. Twenty-four deaths were attributed to oxycodone alone. Mean and median postmortem oxycodone blood concentrations were 1.23 mg/L and 0.43 mg/L, respectively. The range was 0.12 to 8.0 mg/L, with 13 cases (54%) < or = 0.5 mg/L. Seventeen deaths were attributed to hydrocodone alone. Mean and median postmortem hydrocodone blood concentrations were 0.53 mg/L and 0.40 mg/L, respectively. The range was 0.12 to 1.6 mg/L, with 11 cases (65%) < or = 0.5 mg/L. There were seven cases where the cause of death was attributed to the effects of a combination of hydrocodone and oxycodone. Mean oxycodone and hydrocodone blood concentrations were 0.34 mg/L and 0.14 mg/L, respectively. Forty cases involved polysubstance overdoses with significant involvement of other drugs and ethanol. Mean oxycodone and hydrocodone blood concentrations were 0.18 mg/L and 0.29 mg/L, respectively. The list of other substances involved was extensive but included ethanol, amitriptyline, methadone, codeine, propoxyphene, and acetaminophen. The findings of this study report oxycodone values associated with a fatality at blood concentrations lower than previously reported. This may represent enhanced information because of the larger sample group. Hydrocodone values associated with a fatality were similar to previously published values.     

Postmortem tissue concentrations of venlafaxine

Venlafaxine is a phenethylamine antidepressant which inhibits both serotonin and norepinephrine reuptake and is structurally unrelated to the serotonin reuptake inhibitors (SSRIs). Its major metabolite, O-desmethylvenlafaxine (ODV), also inhibits serotonin reuptake. Although metabolized by the cytochrome P-450 (CYP) system, venlafaxine inhibits CYP 2D6 and 3A4 to a far lesser extent than do the SSRIs. Mechanisms of drug action are reviewed and evaluated in the investigation of 12 fatalities occurring over a 6-month-period where venlafaxine was detected.Venlafaxine and ODV were identified by liquid chromatography-mass spectrometry (LC-MS) using atmospheric pressure ionization (API) electrospray in positive mode following an n-butyl chloride extraction. Postmortem tissue concentrations studied in each of 12 postmortem cases for venlafaxine and ODV, were 0.1-36 and <0.05-3.5mg/l (peripheral blood), <0.05-22 and <0.05-9.9mg/kg (liver), <0.05-10 and <0.05-1.5mg/l (vitreous), <0.05-53 and <0.05-6.8mg/l (bile), <0.05-55 and <0.05-21mg/l (urine), respectively, and 0.1-200mg of venlafaxine in the gastric contents. Venlafaxine was typically present with other drugs, including other antidepressants, alcohol, and benzodiazepines. The potential for interaction with each drug is discussed. Over the 6-month-period of this study, there were no deaths ascribed solely to venlafaxine intoxication.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.     

Postmortem hydroxychloroquine concentrations in nontoxic cases

Hydroxychloroquine (HCQ) is a 4-aminoquinoline compound used to treat malaria and chronic autoimmune disorders and is not uncommonly found in the medical examiner setting. Studies have shown HCQ to have a long half-life (32-56 days in blood), high volume of distribution (580-815 L/kg), and therapeutic concentrations ranging from 0.03 to 15 mg/L, depending on the chronicity of treatment. Previous reports have shown that the toxic concentration of HCQ ranges from 3 to 26 mg/L, whereas the lethal concentration ranges from 20 to 104 mg/L. A report addressing nontoxic postmortem concentrations of HCQ in individuals known to be taking the medication, and in whom there is no evidence of toxicity, has not been previously undertaken. This study found that postmortem concentrations in nontoxic cases can range from 0.3 to 39 mg/L, which is well within the reported range of both lethal and toxic concentrations. It is recommended that all investigative and autopsy data be considered and that the cause of death not be certified based purely on blood HCQ concentrations.     

Postmortem atropine concentrations in resuscitation cases

The medications used during resuscitation are often in and of themselves toxic. Several reports have been published regarding toxicities of these drugs, including lidocaine, procainamide, and atropine. But how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitory use especially given that the concentrations of such drugs, when used in the setting of resuscitation, have not been studied? Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during attempted resuscitation in an effort to address this deficiency. A review of deaths occurring in 2009 was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. Eighty-nine cases were identified in which atropine was given before death during attempted resuscitation and was detected in the blood on postmortem toxicological screening; 11 cases were identified in which atropine was administered before death yet was not detected on the postmortem toxicological screening. Mean age was 41 years, and there were 65 males and 35 females. The overall median dose of atropine given was 3 mg, the median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, and the median atropine concentration was 0.1 mg/L. Analysis failed to reveal significant differences in the atropine concentration based on the route of administration (intravenous or intraosseus), the cause of death, or the time since administration (within the first 2 hours). Analysis did reveal a difference between the atropine concentrations in peripheral versus central blood sources and with prolonged postmortem interval (>24 hours) suggesting postmortem redistribution.     

Postmortem evaluation of serum and urine neopterin concentrations

Cellular immune response is accompanied by the release of neopterin. Increased neopterin levels in urine and serum are observed in patients during viral infections, autoimmune diseases, and allograft rejections and certain malignant diseases. We investigated postmortem neopterin concentrations in urine and serum samples taken from 32 corpses 3 to 69 h (mean 19.3 h) after death. Urine neopterin concentrations in corpses are similar to those of healthy live controls and are independent of the time after death. In contrast, serum neopterin concentrations are frequently greatly increased in corpses, and the levels are higher in sera collected more than 10 h after death in comparison with samples obtained earlier. Neopterin measurement in urine and serum samples of corpses is feasible. It appears likely that urine neopterin concentrations could aid the diagnosis of inflammatory diseases in corpses.     

Postmortem serum selenium concentrations and their possible etiological role in Sudden Infant Death (SID)

The importance of selenium (Se) deficiency in the pathogenesis of human diseases such as Keshan Disease has been extensively studied. It is possible that low Se-levels could cause immunosuppression and be an etiological factor in Sudden Infant Death (SID). We investigated 50 serum samples (40 SID and 10 non-SID victims) by atomic absorption spectrometry. The results show that there is no evidence of a serum selenium deficiency in SID-victims in the region of Aachen. A relationship between selenium concentration and the infant immune system still remains speculative and 21 samples even showed increased serum levels. It could be necessary to define a ‘local’ normal range by examining a greater number of healthy infants.     

Postmortem stability and interpretation of beta 2-agonist concentrations.

This paper describes a series of stability and redistribution studies aimed at understanding the presence and significance of beta 2-agonists in asthma deaths. Salbutamol and terbutaline were shown to be stable in postmortem blood at 23 degrees C for 1 week, 4 degrees C for 6 months and -20 degrees C for 1 to 2 years. However, fenoterol was shown to degrade at 23 degrees C (83% loss), 4 degrees C (93% loss) and -20 degrees C (66% loss) over the same time. Salbutamol concentrations detected in blood taken at the time of body admission to the mortuary were not significantly different from the concentrations detected in blood taken from the same cases at the time of autopsy (45 h later). This suggests that significant postmortem redistribution of salbutamol is unlikely to occur during this period. Postmortem blood concentrations of at least salbutamol are likely to reflect the concentration of these drugs in the body at the time of death.     

Postmortem tricyclic antidepressant concentrations. Lethal versus nonlethal levels

Evidence has accumulated that postmortem release of tissue-bound tricyclic antidepressants (TCAs) may cause falsely elevated postmortem blood levels, thus rendering it more difficult to determine if the cause of death was an overdose. This study, a review of 24 TCA-related deaths, is aimed at defining the practical significance of such a problem and providing a workable approach to interpreting postmortem TCA levels. Deaths clearly due to TCA drugs were compared with deaths that were not caused by TCA drugs, but in which the decedent's postmortem blood tested positive for TCA medications. There is little evidence that postmortem elevations in blood TCA levels cause frequent problems in differentiating lethal from nonlethal levels (overdose from nonoverdose cases). The data suggest that using a heart blood level of 0.100 mg/dl as an indicator of lethality is practical at the present time and poses little likelihood of error. Isolated cases suggest that postmortem TCA increases can occur; further work is needed in this area to clarify more fully the significance and frequency of such cases. At present, it seems prudent to utilize peripheral blood samples for TCA testing on autopsy material, if a conservative estimate of TCA concentration is desired, possibly augmented by liver TCA levels and parent-metabolite ratios if money, facilities, and time permit.     

Postmortem blood free and total morphine concentrations in medical examiner cases

This purpose of this study was to determine the relationships between postmortem free morphine and total morphine levels in a large series of medical examiner morphine and heroin related deaths. Free morphine, total morphine, and 6-monoacetylmorphine (6-MAM) concentrations were measured by gas chromatography-mass spectrometry (GC-MS) in 87 medical examiner cases over 20 months. The mean total morphine concentration, mean free morphine concentration, and mean percent free morphine for all cases were: 2.3 mg/L (SD 5.2 mg/L), 0.5 mg/L (SD 1.6 mg/L), and 19.4% (SD 22.8%); respectively. Regression analyses showed weak correlations between total and free morphine concentrations over the entire concentration range (0 to 36.6 m/L, r = 0.603, n = 91) and over a subset concentration range of 0 to 1.0 mg/L (r = 0.369, n = 54). Twenty-three out of 56 (41%) tested positive for 6-MAM, indicative heroin abuse cases. Lower total and free morphine concentrations and a higher percent free morphine were found in individuals with detectable 6-MAM. Comparing blood concentrations for cases with and without detectable 6-MAM demonstrated mean total morphine concentrations of 0.9 mg/L versus 2.1 mg/L (p = 0.05), mean free morphine concentrations of 0.3 mg/L versus 0.4 mg/L (p = 0.21), and mean percent free morphine of 34.7% versus 13.7% (p < 0.003), respectively. Our findings demonstrate higher free to total morphine ratios in individuals with detectable 6-MAM than in individuals without 6-MAM. The database established in this study may assist medical examiners in the evaluation of postmortem blood opiates regarding the cause of death in opiate related ingestion cases.     

Postmortem citalopram concentrations: alone or along with other compounds

Citalopram, an antidepressant whose use has become more widespread in Spain in recent years participates directly and indirectly in the lethal mechanism in voluntary and involuntary poisonings. There were 30 cases of autopsies in the Madrid region where citalopram and other psychoactive substances (psychotropic drugs, alcohol, opiates) were detected in the corpses. The postmortem citalopram levels in relation to the manner and mechanism of death were evaluated, and a significant difference between the toxic and nontoxic cases (p < 0.01) was found. We studied the citalopram blood levels alone and along with other psychoactive products, and these cases were then further divided into those where the compounds were at deadly levels and those which were not. We found a range of citalopram levels between 0.37 and 0.83 microg/mL in which some cases were associated with citalopram toxicity and others were not. Citalopram blood levels of less than 0.35 microg/mL did not lead to fatal poisoning when it was the sole substance detected.     

Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance

We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths.     

Postmortem serotonin (5-HT) concentrations in the cerebrospinal fluid of medicolegal cases

In a medicolegal study the postmortem serotonin (5-HT) cerebrospinal fluid (CSF) concentrations were determined in routine autopsies using a high performance liquid chromatographic procedure with electrochemical detection. There was no correlation between 5-HT concentrations and age, sex or blood alcohol concentration using a postmortem delay < or = 3 days. In suicides the suboccipital CSF concentrations were significantly decreased compared to the levels measured in the control group (8.55+/-5.99 ng/ml versus 20.15+/-13.56 ng/ml). Additionally, a decrease of 5-HT was found in the suboccipital CSF of opiate fatalities (15.56+/-13.52 ng/ml). The results support the hypothesis that decreased 5-HT concentrations in the CSF are characteristic in suicides. However, due to a rather broad overlapping of values between suicides and controls the results failed to define a possible cut-off level in the 5-HT CSF concentration to distinguish between a suicidal and a non-suicidal incident.     

Postmortem blood and vitreous humor ethanol concentrations in a victim of a fatal motor vehicle crash

A 20-year-old male was found on the passenger side of a small car after a collision with a semi-trailer truck. Postmortem blood, collected from the chest cavity, and vitreous humor samples were collected following harvesting of the heart and bones. Gas chromatographic analysis revealed a blood ethanol concentration of 0.32 g/dL and a vitreous humor ethanol concentration of 0.09 g/dL. The stomach was intact and full of fluid and food, but its contents were not collected. Possible explanations for the large difference between the two results include diffusion of ethanol from the stomach into the chest cavity, contamination of the blood sample prior to collection, and ingestion of a large quantity of ethanol shortly before death. This case demonstrates the importance of proper quality assurance procedures in collecting postmortem specimens and of collecting a vitreous humor sample for ethanol analysis in postmortem toxicology cases.     

Postmortem biochemistry

Postmortem biochemistry may provide significant information in determining the cause of death. Due to the rapid postmortem breakdown of metabolism and active membrane transport only analytes which are stable in blood can be determined on this fluid compartment, other parameters have to be analysed on other fluid compartments like vitreous humor (VH). However, using another fluid compartment as a mirror of blood at the moment of death involves severe methodical problems. The conceptual problems of reference values in vitreous humor as a mirror of blood are addressed. Additionally, the necessary steps to be taken before calculating the discriminating values between "normal" and "diseased" are described. For all chemical determinations, a clear definition of the site of sample acquisition is necessary. Up to now chemical determinations on alternative fluids have mainly been carried out using instruments calibrated for urine or serum. Developing calibrated methods for analysis of alternative fluids is a further task for the future.     

Postmortem skeletal lesions

Postmortem bone alterations are very frequent and can raise the issue of their nature (antemortem, perimortem or postmortem defects). The aim of this work is to study various aspects of defects which were not assessed as perimortem trauma, from a series of 50 defects examined, resulting from 24 forensic cases. This study emphasizes the variability of size, shape and number of postmortem defects. Usually the diagnosis of antemortem defects is helped by a careful examination of some characteristics as the edges of the defects, the areas of discoloration of the edges and of the whole bone. Elsewhere it appears very difficult to know the true nature (antemortem, postmortem, or perimortem alterations) of the bone.