Fentanyl Postmortem Redistribution: Preliminary Findings Regarding the Relationship Among Femoral Blood and Liver and Heart Tissue Concentrations

Journal of Analytical Toxicology, Vol. 32, October 2008 Fentanyl Postmortem Redistribution: Preliminary Findings Regarding the Relationship Among Femoral Blood and Liver and Heart Tissue Concentrations Kristin Luckenbill1,2, Jonathan Thompson3, Owen Middleton3, Julie Kloss1, and Fred Apple1,2,* 1Hennepin County Medical Center, 2University of Minnesota School of Medicine, and 3Hennepin County Medical Examiner’s Office, Minneapolis, Minnesota 55415 Abstract Postmortem redistribution refers to the process of drugs diffusing from tissues into blood along a concentration gradient between death and time of specimen collection at autopsy. Anatomical site-to-site variation can exist for drug concentrations. The purpose of this study was twofold. First femoral blood, liver, and heart fentanyl concentrations were compared in medical examiner cases to assist in determining which specimen most appropriately should be used for interpretation. Nine fentanylpositive cases were identified by history of drug use over a 15-month period (2007–2008). Femoral blood fentanyl concentrations (n = 9) ranged from 2.7 to 52.5 µg/L, liver fentanyl tissue (n = 9) ranged from 37.0 to 179 µg/kg, and heart fentanyl tissue (n = 3) ranged from 52.8 to 179 µg/kg. Liver tissue to femoral blood ratios ranged from 0.85 to 35.8, and heart tissue to femoral blood ratios ranged from 1.9 to 5.4. Second, utilizing a published compendium of multiple postmortem drugs, liver and heart tissues to femoral blood drug ratios were compared to known volumes of distribution, solubilities, and pKa. No significant relationships were observed. In conclusion, establishing a larger evidence-based database using liver fentanyl concentrations may be more optimal than blood concentrations for interpretation of postmortem fentanyl concentrations in medical examiner and coroner cases. Introduction Postmortem redistribution (PMR) is the process of drugs diffusing from solid organs into blood and surrounding tissues along a concentration gradient in the time between death and sample collection at autopsy. Many factors can influence postmortem redistribution, such as the characteristics and pharmacokinetics of drugs, incomplete drug distribution at the time of death, the interval between death and sampling, * Author to whom correspondence should be addressed: Dr. Apple, Hennepin County Medical Center, Clinical Labs P4, 701 Park Ave., Minneapolis, MN 55415. E-mail: . anatomical collection site, the amount of sample drawn, the effects of cell death, putrefaction, and body position and movement after death (1). These factors may cloud the ability to accurately interpret postmortem toxicology results as they pertain to cause of death. Historically, heart blood and femoral blood concentrations reported in the 1960s for barbituates showed differences in central versus femoral blood concentrations (2,3). These studies concluded that peripheral blood should be the specimen of choice for postmortem toxicology quantitation. Additional studies conducted with other drugs agreed with this observation and found that, in general, heart blood concentrations tended to be higher than those of femoral blood (2,3). The ratio of heart blood to femoral blood drug concentrations has been discussed as an indicator of postmortem redistribution (4), but this concept is not universally accepted. In general few studies have accurately addressed whether 1. there is a correlation between the heart blood to femoral blood drug concentrations at the time of death and 2. whether there is a relationship between the heart blood to femoral blood drug ratio and the postmortem interval (4). Furthermore, large series of cases are not available to accurately assess postmortem relationships between tissue (heart or liver) and blood (heart or peripheral) drug concentration and what changes occur postmortem. Fentanyl is a synthetic opioid used as a surgical anesthetic and for chronic pain control (5). The effects of fentanyl include analgesia, euphoria, tolerance, physiological dependence, and respiratory depression (6). Fentanyl is highly lipophilic, with an n-octanol/water coefficient of 860:1 (7). Fentanyl is also 80–86% protein-bound and has a moderate to large volume of distribution (Vd) of 3–8 L/kg (8,9). The majority of fentanyl accumulates in muscle and adipose tissue, and it is slowly released into blood (10). Because of the high potency and short duration of action of fentanyl, it has become a therapeutically misused and recreationally abused drug and is viewed as a suitable replacement for heroin (11,12). However, because low concentrations of fentanyl can cause respiratory depression, Downloaded from https://academic.oup.com/jat/article-abstract/32/8/639/829909 Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission. by guest on 21 May 2018 639 Journal of Analytical Toxicology, Vol. 32, October 2008 abuse of fentanyl can be dangerous (12). Because there is no standardized guideline for what type or types of specimen should be collected, medical examiner and coroner offices vary in what they collect, including femoral and heart blood, heart tissue, liver tissue, and/or vitreous humor fluid (as well as other tissues) to help establish whether drugs found during toxicological analysis were at therapeutic or toxic levels. The forensic toxicologist often assists in medicolegal death investigations through interpretation of drug concentrations in the deceased based on what blood or tissue results are provided. It was hypothesized by the authors that heart blood may not be the ideal specimen for quantitating postmortem fentanyl concentrations because of the potential of postmortem redistribution of fentanyl from both heart and liver tissues into heart blood, falsely increasing the heart blood fentanyl level. To partially address this concept, comparisons were made for fentanyl concentrations from femoral blood, and liver and heart tissue in nine fentanyl-related deaths and heart tissue and liver tissue to femoral blood ratios. In addition, reanalysis of a published compendium (4) of numerous drugs, heart blood to femoral blood ratios were compared to their corresponding volumes of distribution, water solubilities, and pKas to investigate their potential relationships with PMR. Experimental Specimens Nine cases over a 15-month period in 2007 and 2008 from the Hennepin County Medical Examiner’s Office where fentanyl was suspected as a potential contributor to the investigation by history were examined. At autopsy, femoral blood samples were collected in EDTA or sodium fluoride tubes, and liver (right lobe) tissue and heart (left ventricle) tissue were stored without preservative in plastic vials. Samples were stored at 4°C and analyzed by gas chromatography–mass spectrometry (GC–MS) within 24 to 72 h of collection. Materials Fentanyl standards and deuterated fentanyl internal standards were obtained from Ce (...truncated)