Postmortem Redistribution of Fentanyl in Blood

Clinical Chemistry / Postmortem Redistribution of Fentanyl Postmortem Redistribution of Fentanyl in Blood Kalen N. Olson, PhD,1 Kristin Luckenbill, PhD, JD,1 Jonathan Thompson, MD,2 Owen Middleton, MD,2 Roberta Geiselhart, RN,2 Kelly M. Mills, MD,3 Julie Kloss, CLS, MBA,1 and Fred S. Apple, PhD1,4 Key Words: Fentanyl; Postmortem redistribution; Forensic; Toxicology DOI: 10.1309/AJCP4X5VHFSOERFT Abstract Fentanyl concentrations were measured in postmortem specimens collected in 20 medical examiner cases from femoral blood (FB), heart blood (HB), heart tissue, liver tissue, and skeletal muscle. Unique was a subset of 7 cases in which FB was obtained at 2 postmortem intervals, shortly after death (FB1) and at autopsy (FB2). The mean collection times of FB1 and FB2 after death were 4.0 and 21.6 hours, respectively. Fentanyl concentrations for FB1 and FB2 ranged from undetectable to 14.6 μg/L (mean, 4.6 μg/L) and 2.0 to 52.5 μg/L (mean, 17.3 μg/L), respectively. Corresponding mean HB, liver tissue, and heart tissue fentanyl concentrations were 29.8 μg/L, 109.7 mg/kg, and 103.4 mg/kg, respectively. The fentanyl HB/FB1 ratio (mean, 8.39) was higher compared with the corresponding HB/FB2 ratio (mean, 3.48). These results suggest that postmortem redistribution of fentanyl can occur in FB. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 511. Exam is located at www.ascp.org/ajcpcme. The cause and manner of death established by forensic authorities in cases involving single or mixed drug ingestion must take into consideration postmortem redistribution (PMR). PMR is defined as the variation of drug concentration in blood samples taken from different sites (heart blood [HB] and femoral blood [FB]) and can be affected by the postmortem interval, or the time of death to specimen collection. As the interval between death and collection of blood becomes longer, drugs from tissues and organs that contain high drug concentrations redistribute owing to cadaver decomposition, leading to increased drug concentration in the blood. During the postmortem interval, drugs from the gastrointestinal tract, lungs, heart, or liver may travel via diffusion through blood vessels or via direct diffusion into other organs or vessels.1-3 Drugs that are highly concentrated in the liver, lungs, or myocardium redistribute quickly into HB, causing concentrations to increase. Examples of these drugs include tricyclic antidepressants, morphine, and flecainide.4-9 Other factors, such as blood coagulation and hypostasis or movement of the cadaver before sampling, may cause PMR.2,3 Mechanisms of PMR may also be affected by a particular drug’s characteristics, such as lipophilicity, volume of distribution, and pH status (acidic, basic, or neutral). For example, basic, highly lipophilic drugs with a volume of distribution greater than 3 L/kg (fentanyl, 3-8 L/kg) are particularly susceptible to PMR.3 The most common postmortem samples used for forensic toxicologic analysis include FB (peripheral), HB (central), urine, liver tissue, gastric contents, and vitreous humor. For most drugs, peripheral blood is regarded as the optimal sample for interpretation based on its greater distance from organs that may be influenced by PMR mechanisms.3,4 However, studies have emerged that demonstrate alternative samples as © American Society for Clinical Pathology Am J Clin Pathol 2010;133:447-453 447 DOI: 10.1309/AJCP4X5VHFSOERFT 447 447 CME/SAM Upon completion of this activity you will be able to: • describe the mechanisms that influence postmortem redistribution of drugs and the most common characteristics of a drug that cause it to redistribute after death. • state the specimen types that may be most accurate for determination of fentanyl concentration in forensic toxicology. • describe why interpretation of blood fentanyl concentrations in cause of death determinations can be difficult. Olson et al / Postmortem Redistribution of Fentanyl more accurate in reflecting perimortem drug concentrations for particular drugs. For example, it has been shown that liver concentrations better represent true body burden of tricyclic antidepressants, which are highly concentrated in tissues that may break down after death and cause falsely increased concentrations of the drug in blood.5,6 In the same way, the unique PMR patterns of each type of drug must be taken into account in creating a complete picture of the perimortem conditions. Fentanyl is a high-potency, rapid-onset synthetic opioid drug prescribed for the treatment of chronic pain and used as a surgical anesthetic.10 In the past decade, fentanyl misuse and abuse have steadily been on the rise.11-16 Fentanyl toxicity causes decreased respiratory rate and depth, delirium, hypotension, bradycardia, and decreased body temperature, leading to death if untreated. As with all opioids, long-term fentanyl use often leads to tolerance, and increasing amounts of the drug are required to maintain its effects, putting its users at risk for developing a dangerous dependence. Because of these tendencies, fentanyl contribution to the cause and manner of death in medical examiner cases is complicated by the high amounts of the drug present in long-term users. This makes the decision of the medical examiner or coroner more difficult when determining whether increased fentanyl blood concentrations beyond what was expected from a patient’s clinical history contributed to the patient’s death. Considerable overlap exists between blood fentanyl concentrations in deaths attributed to fentanyl alone and those attributed to mixed drug overdose, along with the concentrations found in fentanyl-related overdose deaths compared with hospitalized patients being treated for chronic pain.14 The possibility of a drug concentration falsely increasing in a blood sample owing to the lengthening of a postmortem interval makes defining therapeutic, toxic, and lethal ranges more difficult. A study of 25 cases by Anderson and Muto15 on the postmortem distribution of fentanyl led to their conclusion that liver concentrations less than 31 μg/kg appear to represent therapeutic use, and liver concentrations greater than 69 μg/kg seem to indicate overdose situations. The primary purpose of the present study was to determine whether PMR of fentanyl occurs in FB. Materials and Methods Specimens The experimental design used in this study was approved by the institutional review board for human subjects research. FB (FB2), HB, heart (...truncated)