Distribution of Eight QT-Prolonging Drugs and Their Main Metabolites Between Postmortem Cardiac Tissue and Blood Reveals Potential Pitfalls in Toxicological Interpretation.

Femoral blood concentrations are usually used in postmortem toxicology to assess possible toxic effects of drugs. This includes QT-prolongation and other cardiac dysrhythmia, which could have been the cause of death. However, blood concentration is only a surrogate for the active site concentration, and therefore cardiac tissue concentration may provide a more accurate toxicological interpretation. Thus, cardiac tissue and femoral and cardiac blood concentrations were examined for eight frequently used QT-prolonging drugs (QTD) and their metabolites in a mentally ill population. In total, 180 cases were included from the Danish autopsy-based forensic study SURVIVE. The concentrations were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry utilizing stable isotopically labeled internal standards. The results showed that the cardiac tissue concentrations were significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood/cardiac tissue concentrations. Within this dataset, citalopram displayed a wide overlap in cardiac tissue concentrations (~50%) between non-toxic and toxic citalopram cases, as estimated from femoral blood concentrations. In contrast, quetiapine displayed no overlap in cardiac tissue concentrations between non-toxic and toxic quetiapine cases based on femoral blood concentrations. The implication of the citalopram finding is that possible intoxications can be overlooked when only considering femoral blood concentrations. Based on the present findings, non-toxic cardiac tissue 10th-90th percentile concentration ranges were estimated for citalopram (0.93-4.4 mg/kg) and quetiapine (0.0073-0.60 mg/kg).

Quantification of 16 QT-prolonging Drugs and Metabolites in Human Postmortem Blood and Cardiac Tissue Using UPLC-MS-MS.

QT-prolonging compounds present a treatment risk in mentally ill patients. Knowledge of the concentration in the heart compared with blood is necessary to assess the cardiac toxicity of QT-prolonging compounds. To address this issue, this article presents a validated analytical method for the quantification of 16 QT-prolonging drugs (QTD) and metabolites in postmortem whole blood and postmortem cardiac tissue. Samples were prepared by protein precipitation and quantified using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Deuterated internal standards were used. Validation results showed that the bias was ±15% and precision was ≤15% for all compounds in both matrices. The recovery ranged from 78.8 to 127.4%, and the matrix effect ranged from 61.0 to 128.7% across both matrices. The limit of detection and the lower limit of quantification were below the therapeutic concentrations of the prescription drugs. No noteworthy degradation during storage of the extracts was detected. The method was applied in five authentic cases of mentally ill patients. In conclusion, an analytical method was successfully developed and validated for the quantification of QTD in postmortem whole blood and cardiac tissue. To the best of the authors' knowledge, this article presents the first fully validated method for quantification of QTD in cardiac tissue.

Fatal poisoning among patients with drug addiction.

INTRODUCTION: Fatal poisonings among drug addicts in Denmark in 2012 were examined. Cause of death, abuse pattern and geographic differences are discussed and data are compared with previous studies. METHODS: All fatal poisonings examined at the three institutes of forensic medicine in Denmark in 2012 were included in the study. RESULTS: A total of 188 fatal intoxications were recorded. The median age increased from 37.5 in 2007 to 41.5 in 2012. The majority were men (77%). Methadone (59%) was the main intoxicant. The decrease in the frequency of heroin/morphine deaths since 1997 (71%) continued, declining to 44% in 2002, 33% in 2007 and finally to 27% in 2012. Few deaths from central stimulants (amphetamine and cocaine) occurred. Multiple drug use was common and consisted mainly of opioids, cocaine, amphetamine, cannabis, benzodiazepines and alcohol. Heroin/morphine use was most frequent on Funen and in South Jutland. Cocaine was most frequently detected in East Denmark, while amphetamine was more frequent in West Denmark. CONCLUSIONS: The number of fatal poisonings among drug addicts has stabilised around 200. The increase in methadone deaths continued and, as in 2007, methadone was the main intoxicant. The increase in methadone deaths seems to be associated with use of methadone in substitution treatment. Nevertheless, methadone treatment also seems to save lives, as indicated by the increasing median age. Use of antidepressants and antipsychotics increased to a high level compared with 2007, indicating that a considerable number of drug addicts also have psychiatric illness. FUNDING: none. TRIAL REGISTRATION: not relevant.

Completeness and positive predictive value of registration of upper limb embolectomy in the Danish National Vascular Registry.

OBJECTIVE: TO EVALUATE COMPLETENESS AND POSITIVE PREDICTIVE VALUE OF THE DANISH NATIONAL VASCULAR REGISTRY REGARDING REGISTRATION OF THE SURGICAL PROCEDURES: embolectomy of brachial, ulnar, or radial artery. STUDY DESIGN AND SETTINGS: The study was based on first-time embolectomies in the brachial, ulnar, or radial artery performed in Denmark from January 1, 1990 to December 31, 2002. The data were primarily retrieved from the Danish National Vascular Registry and secondarily from the Danish National Registry of Patients. Medical records were retrieved using a standardized form. RESULTS: In total, 1433 incident cases of first-time embolectomy were found in both registries. The positive predictive value of the registration was 97.5% (95% confidence interval [CI]; 96.4-98.4). The degree of completeness was 86.5% (95% CI; 84.3-88.5). For the registration period from 1990 till 1996 the degree of completeness was 78.2% (95% CI; 74.4-81.7), and from 1997 till 2002 it was 93.8% (95% CI; 91.6-95.7). CONCLUSION: The completeness and positive predictive value of registration of embolectomy in the upper limb in the Danish National Vascular Registry was 86.5% and 97.5%, respectively. This registry can be a valuable tool for epidemiological research and quality-monitoring.