Forensic toxicological implications of pleural effusion; an autopsy case of drug overdose

Overview

A fatal poisoning case involving multiple psychotropic drugs is presented. Quantitative toxicological analysis showed that the concentrations of phenobarbital, promethazine, chlorpromazine, alprazolam and bromazepam in the femoral blood were 69.51μg/ml, 32.73μg/ml 24.76μg/ml, 0.04μg/ml and 0.31μg/ml respectively, and large amounts of drugs were also detected in the stomach contents. We concluded that the cause of death was mainly due to overdose of phenobarbital, promethazine and chlorpromazine by massive ingestion, and we also discuss the value of pleural effusions as an alternative specimen for toxicological examination.

Keywords:
multiple drug – poisoning – liquid chromatography mass spectrometry – phenobarbital – pleural effusion

Toxicity in poisoning cases is usually evaluated from concentrations of the drugs in the blood, based on previous reports of fatal or non-fatal cases (17). Pleural effusions are occasionally collected in forensic practice as alternative specimens in toxicological examination, in cases where clean blood samples are not available (6). Here we report a case of death due to the toxicity of multiple psychotropic drugs, and we discuss the usefulness of pleural effusions as alternative specimens in toxicological examination.

CASE REPORT

A female in her twenties was found dead in her room. The subsequent police investigation revealed that the deceased had been receiving therapy for mental disorder and had been receiving prescribed drugs.

The deceased was 165 cm in height and 45 kg in weight. External examination revealed slight abrasion on her left lower leg. The heart weighed 173g, containing 30ml of blood without coagulum. The brain weighed 1380g and was slightly edematous. The left and right lungs weighed 485g and 504g, respectively, and were moderately congested. The stomach contained approximately 400 ml of brownish fluid with granules. There were no notable changes, other than congestion. Drug screening test using a Triage^TM (Biosite Diagnostic Inc, San Diego, USA) panel was positive for barbiturates. Postmortem samples such as femoral venous blood, urine, bilateral pleural effusions and the stomach contents were collected for toxicological examination.

Toxicological analysis was performed using a liquid chromatography-mass spectrometry (Quattro micro^® API mass spectrometer in combination with 2695 alliance system^®, Waters, Milford, MA, USA). Its operation and the preparation of the samples were in accordance with the manufacturer’s specifications (16). Quantitation of ethanol was performed using a head-space gas-chromatography.

RESULTS AND DISCUSSION

Toxicological analysis identified the presence of phenobarbital, promethazine, chlorpromazine, alprazolam and bromazepam. However, no ethanol was detected in the blood or urine. Table 1 shows the quantitation of each drug in the victim’s blood, urine, left/right pleural effusion and stomach contents, and also summarizes their fatal and therapeutic levels (13,14,15,17). The victim’s femoral blood concentrations of phenobarbital, promethazine, chlorpromazine, alprazolam and bromazepam were 69.51μg/ml, 32.73μg/ml 24.76μg/ml, 0.04μg/ml and 0.31μg/ml, respectively. The concentration of phenobarbital, promethazine and chlorpromazine exceeded fatal levels (15,17), and the victim died during the absorption phase of these drugs, as large amount of these drugs were detected in the stomach. The concentration of alprazolam and bromazepam are around the therapeutic levels (13,17), and were found in the elimination phase, as the concentration of each drug in stomach contents is similar to these in blood. From the autopsy findings and the results of the toxicological examination, we concluded that death was mainly due to the combined toxicity of phenobarbital, promethazine and chlorpromazine by massive ingestion, while alprazolam and bromazepam may also have made a small contribution to her death.

As shown in Table 1, the concentrations of promethazine and chlorpromazine in the pleural effusion were over 7.8 and about 10 times higher than those in the femoral blood, while the concentration of phenobarbital in the samples of the pleural effusion were about 1.5-2 times higher than in the femoral blood. These phenomena may have been due to the postmortem redistribution of the drugs from lung or liver, and postmortem diffusion of drugs from the stomach (3,5,9,11,12). On the other hand, the concentrations of alprazolam and bromazepam in pleural effusions were similar to those found in the femoral blood.

We should to pay attention to the pharmacokinetic properties of each drug. Drugs which have large distribution volume (Vd) value, are also distributed in surrounding tissue (1). The Vd values of drugs detected in the present case were as follows; phenobarbital (0.5L/kg), promethazine (13L/kg), chlorpromazine (21L/kg), alprazolam (0.7L/kg), bromazepam (0.9L/kg) (8). Pleural effusions are formed by exudation from the edematous and congestive lungs. Both promethazine and chlorpromazine are basic drugs with large Vd values, and the concentration of promethazine and chlorpromazine in the lungs were higher than in the blood, respectively (4,7). Diffusion of promethazine and chlorpromazine from the lungs to the pleural effusions may be observed during the postmortem period, as reported previously (9,10). On the other hand, as the Vd values of phenobarbital, alprazolam and bromazepam were relatively small, their concentrations in the pleural effusion may not have been highly increment. The apparent Vd of more than 3-4L/kg is a good predictor that a drug is liable to cause postmortem redistribution (2). These pharmacokinetic properties of each drug may cause significant postmortem redistribution to pleural effusions.

The concentration of phenobarbital, promethazine and chlorpromazine in the pleural effusion in the left thoracic cavity were higher than those in the right thoracic cavity. Since higher concentration of these drugs were detected in the stomach contents, and in consideration of the anatomical structure and relationship of the organs, postmortem diffusion from the stomach should also be considered (12).

The present case indicates that we have to consider the postmortem diffusion or redistribution of drugs when evaluating postmortem data. Since the pleural effusion is easily collected at the time of autopsy or inspection, and contains relatively high concentration of drugs, it would be a good predictor for the toxicological screening. As like alprazolam and bromazepam in this case, drugs with low Vd value and death during elimination phase, the drug concentrations in the pleural effusion may be applicable to estimate the blood levels at the time of death. However, it may not be suitable for quantitative analysis, especially in some basic drugs. Concentration of the pleural effusion is rarely related to the ranges of blood concentration (6). In the present case, concentration of phenobarbital, promethazine and chlorpromazine, in pleural effusion are inapplicable to the estimation of the concentration in femoral blood. The role of pharmacokinetic properties of drugs may be an interesting target for the study of postmortem redistribution. The usefulness of the pleural effusion in toxicological examination is not clear and additional studies and case report will be required.

Address for correspondence:

Dr. H. Kinoshita,

Department of Forensic Medicine, Faculty of Medicine,

Kagawa University

1750-1, Miki, Kita, Kagawa, 761-0793, Japan

tel: +81-87-891-2140 fax: +81-87-891-2141

e-mail: kinochin@med.kagawa-u.ac.jp