Drug overdose deaths and toxicology tests: Let’s talk

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Joseph A. Prahlow, MD
Erin G. Brooks, MD
Prentiss Jones Jr., PhD

December 2018—Drug overdose deaths in the United States continue to rise, and recently many of these deaths have been attributed to opioids, including fentanyl, fentanyl analogs, and other opioid receptor agonists. The rise in drug overdoses and drug-related deaths, and the devastating effects of the opioid crisis, highlight the need for communication and coordination among forensic pathologists, hospital clinicians, and laboratorians.

Typically, coordinated efforts between these groups in death investigations are few or nonexistent. In fact, non-forensic health care providers are often unaware of the challenges their forensic pathology colleagues face and may not fully understand how their collaboration with forensic pathologists might have an impact on public health. The lack of a coordinated effort to foster communication among these groups results in a lost opportunity to collectively raise the level of awareness of the emergent public health crisis, obscures the extent and prevalence of the various types of drugs being used, and diminishes efforts to reduce the overall rate of drug overdose deaths.

Hospital-based pathologists, laboratory professionals, emergency department physicians, and hospital administrative personnel should work with local medicolegal death investigation offices to establish protocols for collecting and retaining appropriate blood samples for eventual toxicologic analysis in cases in which patients are admitted for a suspected drug overdose and eventually die. We will present five cases that illustrate the importance of quantitative toxicologic testing and collaboration between medical examiner/coroner (ME/C) and hospital staff.

Drug overdose deaths fall under ME/C jurisdiction and require unbiased and scientifically sound cause of death determinations. Fundamental and often pivotal components of those determinations are the decedent’s medical history, circumstances involving the death, collection of appropriate specimens, postmortem examination, integration of comprehensive laboratory tests, and a recognition of the unique requirements for the interpretation of postmortem results. Despite a thorough investigation and the attention given to these components, questions about the cause of death may persist in some cases. A collaborative effort among the ME/C community, clinicians, hospital pathologists, and laboratories—especially when there is suspicion of drug-related involvement—is critical in ensuring that these deaths are categorized accurately and the certification of death is appropriate.

Postmortem and antemortem specimens. Biological specimens collected during an autopsy and submitted for toxicological analysis are typically considered the gold standard for providing information to assist in determining the cause of death in cases of suspected drug overdose. Without question, the reliability of toxicology results relies heavily on the fidelity of the specimen collection process. Forensic pathologists are trained in multiple aspects of specimen collection protocol, including the selection of a suitable specimen container, collection of an appropriate volume of specimen, proper specimen labelling, and storage in a manner that best preserves endogenous and xenobiotic constituents until the specimen can be delivered to the testing location. In certain cases, however, it may not be possible to establish the cause of death by analyzing postmortem specimens, and the availability of blood collected prior to death becomes critical.

Patients who have overdosed may be hospitalized for hours, days, or even weeks prior to death. This interval provides time for the body to significantly metabolize drugs and alcohol, leading to lower or undetectable drug levels in postmortem specimens. Additionally, resuscitative efforts such as high-volume fluid restoration may have a diluting effect on drug or alcohol concentrations in postmortem specimens. In such cases, blood samples procured soon after hospital admission can be essential in ascertaining which drugs were present and to what degree they likely contributed to death. These antemortem blood samples generally reflect the substances circulating throughout the body prior to death, have the potential to provide information about the likelihood that a toxic effect was produced, and have the advantage of eliminating potential interpretive issues associated with changes in the concentration of drugs or other substances in the blood due to their movement from one area of the body to another after death (postmortem redistribution).

Antemortem specimens also make it possible to perform a quantitative and comprehensive array of toxicologic testing. Unfortunately, in many hospitals, unused antemortem specimens such as blood, plasma, or serum are discarded relatively rapidly, often triggered by the results of urine drug screen results. Urine drug screens are used extensively in the clinical setting to corroborate a clinical suspicion of drug overdose; however, while urine drug screens may be adequate in the hospital setting, they do not provide the quantitative blood levels necessary to determine whether a drug contributed to death. Also, many designer drugs such as fentanyl analogs are not currently detected by standard urine drug screen panels, and urine drug screening immunoassays are subject to many false-positive and -negative results. As such, for the purposes of identifying potentially lethal substances in the setting of clinically suspected overdose, urine testing is inadequate.

If the overdose results in death, only quantitative blood testing provides sufficient information to confidently certify overdose deaths. Testing of antemortem blood samples collected in the hospital setting is of paramount importance in these cases. Unfortunately, even in instances where unused antemortem specimens are successfully requisitioned by the ME/C prior to disposal, sample quantity or a compromise in specimen quality due to handling or storage conditions may result in a specimen that is suboptimal for toxicological analysis. Thus, collaboration among forensic and hospital pathologists, other hospital clinicians, and laboratorians is key to ensuring that necessary samples are collected, procured, and retained prior to death in suspected drug overdose cases.

Specimen collection and death certification. Given the importance of the type of specimen needed for analysis, the required specimen type should be defined clearly in preanalytical protocols. Numerous collection tube additives exist (typically identified by the tube closure/stopper) and must be considered because not all additives are interchangeable and suitable for all testing. The antemortem collection of blood in a collection tube that contains an anticoagulant and preservative additive should be a requisite component of any care set designated for suspected drug overdose cases. The conventional gray stopper tube, which contains the anticoagulant potassium oxalate and the preservative sodium fluoride, is ideal for this purpose. Immediately after specimen collection, the gray stoppered tube should be gently inverted several times to ensure proper mixing of the anticoagulant and preservative with the blood. This mixing results in a specimen that is not clotted and affords a degree of protection from degradation. Upon centrifugation the mixed specimen yields plasma; without centrifugation the specimen is considered sodium fluoride-enriched whole blood. For some testing scenarios, the distinction between the use of plasma versus whole blood or the use of serum is important and may have a bearing on test results. The specific additive required depends on the laboratory’s testing method. For example, if an analytical method employs the use of plasma in the analysis of ethanol (alcohol) rather than whole blood, the plasma alcohol result is expected to be approximately 15 percent higher than in a concomitantly collected whole blood specimen. Despite some testing limitations, the ubiquitous gray stoppered tube is the preferred specimen collection tube for toxicology analysis. Arrangements for proper storage of specimens is required before, during, and upon completion of testing.

Specimens not meeting these criteria are generally deemed unacceptable but should not be discarded without consultation with the toxicologist, forensic pathologist, or both. Occasionally, a specimen deemed unacceptable for one test might be acceptable for another test or be acceptable for the requested test provided the laboratory has an ancillary method in its armamentarium. When decisions are being made about analytical testing, heed should be given to the adage coined during the early years of computer science: “Garbage in, garbage out.” The integrity of analytical testing results relies not only on the quality of the specimen collected but also on adherence to documented and well-purposed preanalytical, analytical, and postanalytical practices.

Particularly when deaths are related to drugs/toxins, the ME/C community is strongly advised to be as specific as possible on death certificates about the drugs involved in a given death. As such, the use of nondescript, general terms or phrases, such as “mixed drug intoxication” or “opiate overdose,” is discouraged. The use of such terms does not allow for adequate tracking of individual drugs related to death. Without knowledge of the specific drug types involved in death, devising appropriate preventive strategies is more difficult. To determine which drugs are involved in a particular death, forensic pathologists rely on the performance of toxicology testing on blood samples collected at or shortly after the drug-related event/death.

Here are the five cases that illustrate the importance of quantitative toxicologic testing and collaboration between ME/C and hospital staff.