Abstract
A 37-year-old, one-pack-per-day tobacco smoker collapsed and died at home. At autopsy, he had an occluded left anterior descending coronary artery. Δ9-Tetrahydrocannabinol-carboxylic acid was found in his urine but no cannabinoids were detected in his blood. Misadventure was the inquest verdict on the basis of the urinary cannabis, with acute myocardial infarction as the primary cause and cannabis as the secondary cause of death. Such a conclusion is a misinterpretation of the evidence when the time duration for cannabis as a trigger for myocardial infarction is at most two hours. The absence of cannabis in the blood likely places the time since inhalation at more than two hours. The role of tobacco smoking as a trigger was ignored. Cotinine, the biochemical marker of tobacco smoke, should be added to the standard toxicological screen in the guidelines on autopsy practice of the Royal College of Pathologists.
Introduction
In 2002, the Royal College of Pathologists published guidelines on autopsy practice and in 2005 published a best-practice Scenario 1: sudden death with likely cardiac pathology. This document lists marijuana in the drug toxicity listing causes of sudden cardiac death. The case-crossover study of Mittelman et al. 1 in which the subject becomes his/her own control is the evidential foundation for the inclusion of cannabis on the list. Smoking marijuana increased the risk of myocardial infarction by 4.8-fold in the first hour after commencing smoking compared with periods of non-use. In the second hour after smoking, the relative risk is 1.7 (95% confidence interval [CI] 0.6–5.1). If the confounders who had sex or cocaine in the first-hour period are omitted, the first-hour relative risk is 3.2 (95% CI 1.4–7.3). This is the key paper on marijuana as a precipitant of sudden cardiac death and is influential.
Tetrahydrocannabinol (THC) is the major active constituent of cannabis. After smoking, it rapidly reaches a peak in the blood and declines to about 10% of peak levels within 1–2 hours. THC is lipophilic and rapidly enters fat, muscle and brain. It slowly moves back to the plasma and is metabolized in the liver. THC can be detected in the blood for 4–12 hours after intake depending on the dose and analytical sensitivity. Whole blood levels one hour after smoking 20–25 mg THC are usually in the range of 5–10 µg/L. 2 The terminal elimination half-life is one day in casual marijuana users and three to five days in chronic users. In the urine, chronic smokers may test positive for three to four weeks after abstinence. Some heavy smokers may have positive urine tests for 46 days. 3
In a 1999 review, the mean plasma elimination half-life of cannabis and cannabinoid metabolites was 20 hours and 25–28 hours and the urine detectability based on common laboratory cut-offs for cannabinoids was three days for single use, four days for moderate use, 10 days for heavy daily use and up to 36 days for heavy long-term use. 4 It is possible to relate blood levels of THC and metabolites to the time of usage and to pharmacological effects. 5
Passive smoking is also a problem and cannabinoids in blood or urine is not unequivocal evidence of active cannabis smoking. THC levels in the urine of 30–50 ng/mL have been found from passive smoking. 6,7 A cut-off of 65 ng/mL has been suggested to distinguish between active and passive smoking. 7
It is clear that there is a wide tolerance around the figures for the kinetics of cannabinoids in the literature.
The coroner's court may have to determine the role and significance of cannabinoids found in blood and/or urine in a case of sudden cardiac death. There are published models for calculating the time of last cannabis use from plasma levels of Δ9-THC and 11-nor-9-carboxy-Δ9-THC concentrations. 8
Case report
A 37-year-old man complained of chest pains, dizziness and immediately collapsed and died at home. He smoked 20 cigarettes per day. One month earlier, he had been hospitalized with venous thrombosis in his leg. He was prescribed Tylex (paracetamol 500 mg and codeine 30 mg), diclofenac and tramadol for arthritic symptoms and back pain. Liver biochemistry revealed alanine transaminase of 104 and 111 IU/L on repeat. Gamma glutamyl transferase was normal. The C-reactive protein was 3.3 mg/dl (normal <0.5). It is unknown as to whether the prescription was taken but his wife reported that he smoked cannabis for relief of back pain. At autopsy, there was a fresh organizing thrombus in the left anterior descending coronary artery 2 cm distal to the origin. Histology showed a focus of mild chronic inflammation that was not an arteritis. Histology of the liver revealed mild-to-moderate steatohepatitis and mild chronic inactive gastritis was found in the stomach.
Toxicology analysis revealed Δ9-THC-carboxylic acid between 751 and 1000 ng/mL in the urine with no cannabis detected in the blood. The laboratory interpretation provided included: ‘a positive urine result means only that the person … used marijuana in the recent past which could be hours, days or weeks depending on the specific use pattern’. 9 Tramadol and one metabolite were also found on a urine screen using REMEDI HS (Bio-Rad, Munich, Germany) high-performance liquid chromatography with ultraviolet detection.
Coroner's inquest
On receiving the pathologist's report, the coroner determined that the primary cause of death was one of organizing coronary thrombosis and the secondary cause of death was cannabis use. The coroner then recorded a verdict of death by misadventure. The coroner defended the decision on the basis that the determination was fairly reached and was primarily reached on the basis of the medical evidence available from a competent, experienced, independent and impartial pathologist. Contrasting opinion from a chemical pathologist was discounted.
Discussion
Where there is a negative blood test for cannabis but a positive urine value in a patient who has died from a cardiac arrest due to myocardial infarction, it is reasonable to conclude that the patient did not smoke cannabis in the preceding two hours. The wide tolerance in the excretion rates of cannabinoids in the urine makes the time interpretation speculative in these cases. If the blood level is zero, then calculation of the time of cannabis usage is not possible. The potential triggering effect of cannabis on myocardial infarction is no longer operative or evidence-based after two hours according to the objective literature. 1 Thus, it seems perverse to conclude that cannabis was a contributory factor in this death. Why are the tobacco biomarkers nicotine and cotinine ignored in conventional postmortem practice? Smoking 20 cigarettes per day is a more likely trigger than cannabis.
The autopsy pathologist should report the limitations of interpretation of the finding of a positive result for urine cannabinoids. Best-practice guideline protocols for autopsy practice at the Royal College of Pathologists need revision to include tobacco biomarkers, especially cotinine. The coroner has the discretion in both jurisdictions in Ireland and in England and Wales to direct biochemical toxicological investigations. Cotinine should be central to that menu.
Tobacco smokers aged from 35 to 39 years old have ×5 times increased risk of heart attack than non-smokers of the same age. Data from the UK indicate that for diclofenac, there is one additional heart attack for every 521 treated patients. Diclofenac increased the rate ratio for vascular events by 1.63 (95% CI 1.12–2.37). 10 Diclofenac may have liver effects which could account for the cell damage. There was no information on alcohol consumption or on glucose tolerance as causes of fatty liver. Cannabinoids have been associated with beneficial effects on the cardiovascular system including a protective role in atherosclerotic progression and in cerebral and myocardial ischaemia. 11
Accuracy in medical evidence is essential to allow the coroner make the most appropriate decisions. Currently, legal drugs such as nicotine may be ignored as a proximate cause of cardiac death while the role of cannabinoids may be misinterpretated due to the strict time-limit of their role as triggers.
Under the Criminal Procedure Rules 2010, an expert must give an unbiased opinion on matters within his expertise. The Jones v Kaney 2011 UKSC 13 case held that there is no justification for holding expert witnesses immune from suit for breach of duty in relation to their evidence. 12 The European Court of Human Rights also expressed unease with the application of generalized immunity from suit for expert witnesses. 13 The way forward for coroners, where there is more than one expert witness, is to incorporate rule 33.6 (b) of the Criminal Procedure Rules and direct that the experts prepare a statement for court of the matters on which they agree and disagree, giving their reasons. That will limit the likelihood of bad decisions. In this case, the coroner's decision must be revisited.