Editor: Frederick L. Kiechle, MD, PhD
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Q. If a person died from an overdose, would the toxicology screen always show which drugs were in their system?
A. August 2020—In a drug` intoxication death, toxicology testing typically will detect the drugs in a person’s system. However, there are instances of fatal drug intoxications in which testing does not detect the drug.
Laboratories that are accredited to perform forensic toxicology testing typically test for more than 100 different medications, illicit drugs, and alcohols. Most routine hospital toxicology testing involves a rapid urine screening test for a handful of common drugs or classes of drugs—for example, opiates, cocaine, methamphetamine, and benzodiazepines. These are simple screening tests and do not meet the more rigorous standards for forensic testing, which are broader and require additional definitive testing. In the forensic setting, definitive testing usually involves blood specimens (peripheral sample preferred) as detection in blood may equate to an acute intoxication.
Yet a person could die from a drug intoxication without the testing detecting the drug for numerous reasons. This may occur because the drug is not included in the scope of testing, the drug concentration is below the laboratory’s reporting limit, or there was a prolonged survival interval. Some people may survive for hours or longer in a comatose state following the initial pathological effects of a drug. During this period, the drug continues to metabolize, so it may not be detected in autopsy samples. In such cases, forensic pathologists may attempt to obtain remaining hospital admission blood samples for further testing. Admission specimens retained by the hospital can be a valuable resource for a medical examiner. Postmortem changes, such as decomposition, and the postmortem interval also may affect the concentration of a substance, but most drugs or their metabolites can still be detected.
The recent increase in illicit use of fentanyl, which some hospitals do not include in their urine screen, provides a relevant example. A young person may be admitted to the hospital for a suspected intoxication based on being found with a needle and drug packet. But if fentanyl is not included in the urine screen, the hospital may miss the diagnosis. In such an instance, the medical examiner or coroner may test the blood drawn at admission and detect fentanyl. New fentanyl analogs, such as butyryl fentanyl, are also being used illicitly and may not be detected by a laboratory until new toxicology standards are formulated and implemented.
Cina SJ, Collins KA, Goldberger BA. Toxicology: what is routine for medicolegal death investigation purposes? Acad Forensic Pathol. 2011;1(1):28–31.
Davis GG. National Association of Medical Examiners position paper: recommendations for the investigation, diagnosis, and certification of deaths related to opioid drugs. Acad Forensic Pathol. 2013;3(1):77–83.
James R. Gill, MD
Chief Medical Examiner
Office of the Chief Medical Examiner
State of Connecticut
Farmington, Conn.
Former Member
CAP Forensic Pathology Committee
Q. We are looking into using a scale to measure 24-hour urine samples, but we can’t find much literature about it. Is the variation between the measurement from a scale and actual volume clinically significant? What kind of validation is recommended?
A. Accurate collection and measurement of 24-hour urine samples is important for normalizing downstream testing. Volumetric measurement of such samples is burdensome, while gravimetric measurement may be more straightforward, reproducible, and streamlined for many laboratories. However, this process typically does not include measuring an aliquot of the patient’s urine to determine specific gravity, which affects the sample’s weight and, therefore, the calculated volume of the sample. But, does this matter?
Donald Young, PhD, determined volume, specific gravity, and weight of 24-hour urine specimens in a classic study.1 The average specific gravity was 1.011, ranging from 1.0 to 1.037. The specific gravity tended to be higher for smaller volumes, although the range was broad. The maximum error in calculated volume that would arise from using the mean specific gravity in this study would be less than two percent for any specimen, which is less than the coefficient of variation for common chemical analyses. Although error theoretically can be reduced by measuring the sample’s specific gravity, this would also reduce the speed and efficiency of specimen processing and testing and increase risk for exposure to potential pathogens.
In Dr. Young’s study, when an average specific gravity was applied to the weight calculation, the average difference between that measurement and the volumetric measurements was 0.2 percent for more than 150 specimens, whereas the average difference between volume from measured weight and measured specific gravity for each sample was 0.9 percent. When comparing the weight to the volume (1 g urine = 1 mL urine), the average difference was 1.1 percent. The study did not report standard deviations of differences.
These errors associated with gravimetric measurements are quite small. In Dr. Young’s study, repeated volumetric measures of urine in graduated cylinders had CVs of 0.3 to 0.7 percent (standard deviation, 1.8–13.9 mL) between different technologists. The range for repeated gravimetric measurement was similar at 0.3 to 0.5 percent (standard deviation, 2.4–9.4 mL).
Other sources of variability in the diagnostic cascade outweigh the error that may be introduced by gravimetric measurement. Foremost, 24-hour urine collections rarely represent 24 hours of collection. In studies that have examined compliant collection determined by urinary creatinine excretion or recovery of ingested para-aminobenzoic acid (PABA), the rate of noncompliant collections may approach or exceed 50 percent.2 In addition, the analytic variation of downstream tests will contribute further error. Biological variation offers a benchmark for allowable error, and estimates suggest a total allowable error of 15 percent for 24-hour urine creatinine and 40 percent for total protein.3 It is reasonable to presume that the variation associated with weighing a specimen falls below the sum of the above sources of variability—well within total allowable error as defined by biological variation (though studies defining such variation may have been affected by variable duration of urine collection).
From a practical standpoint, we recommend standardizing as much of the process as possible, including using standard urine collection containers that are manufactured with consistent weight and standard balances that are calibrated. One can either tare a scale with a clean, empty container or subtract a measured or standardized mass. Validating volume calculations by weight against measured volumes in graduated cylinders over a range of volumes reflecting the collections in your laboratory would be sufficient for showing equivalence. It is acceptable to use an average specific gravity, as measured for your patient population by your laboratory, or the specific gravity of water (1 g = 1 mL).
- Young DS. Automatic determination of urine volume from weight of sample. Clin Chim Acta. 1969;25(3):429–433.
- John KA, Cogswell ME, Campbell NR, et al. Accuracy and usefulness of select methods for assessing complete collection of 24-hour urine: a systematic review. J Clin Hypertens. 2016;18(5):456–467.
- Desirable biological variation database specifications. Westgard QC. Updated 2014. www.westgard.com/biodatabase1.htm.
David Manthei, MD, PhD
Assistant Professor, Chemical Pathology and Molecular Pathology
Michigan Medicine
University of Michigan, Ann Arbor
Lee Schroeder, MD, PhD
Associate Professor, Chemical Pathology
Director of Point of Care Testing
Associate Director of Chemical Pathology
Michigan Medicine
University of Michigan, Ann Arbor
Member, CAP Clinical Chemistry Committee