The Elephant in the Room: Outbreak of Carfentanil Deaths in Minnesota and the Importance of Multiagency Collaboration.

Over a three-month period in early 2017, the Hennepin County Medical Examiner's Office investigated nine apparent opioid toxicity deaths that occurred in three separate urban, suburban, and rural counties in our jurisdiction. All decedents were known substance abusers and had reportedly recently used heroin; most were found with drug paraphernalia. Complete autopsies variably showed classic stigmata of opioid overdose with no significant injury or natural disease to explain death. Initial toxicology screens failed to identify heroin or other narcotic substances. Several cases were presumptively positive for fentanyl by immunoassay, yet failed to confirm positive for fentanyl. Following American Board of Forensic Toxicology reporting standards, these cases were reported as negative for fentanyl by the laboratory. Due to the discrepant scene and toxicology findings suggestive of an opioid toxicity death, further discussion between the medical examiners and toxicologists prompted additional testing at a referral laboratory. This resulted in quantifiable blood carfentanil in all cases (mean 0.26 ng/mL, range 0.12 - 0.64 ng/mL). Cointoxicants included ethanol (n=2), methamphetamine (n=3), benzodiazepines (n=3), and cocaine (n=1). No case had definitive evidence of acute heroin intoxication, but two cases had low concentrations of morphine present (0.03 and 0.06 ng/mL), and two others had 6-monoacetyl morphine in the urine without morphine in the blood, suggesting recent use. All deaths were certified as accidental acute or mixed carfentanil toxicity. These cases present additional information about carfentanil-related deaths and highlight the importance of collaboration between forensic pathologists and toxicologists.

Heroin-related Deaths from the Hennepin County Medical Examiner's Office from 2004 Through 2015.

Over the past two decades, prescription and illicit opioid use has led to changes in public health policy to address the increasing number of opioid-related deaths. The purpose of this study was to review cases from Hennepin County Medical Examiner's Office between 2004 through 2015 where heroin was listed as a significant contributor or as the cause of death. We identified 322 heroin-related deaths, which were predominantly male (255; 79%). 6-Monoacetylmorphine (6-MAM) median (range) concentrations were as follows: blood (n = 7), 0.010 (0.006-0.078) mg/L; urine (n = 30), 0.359 (0.009-1.75) mg/L; and vitreous humor (n = 31), 0.034 (0.004-0.24) mg/L. Free morphine was measurable in 273 cases and the percent free morphine (range), when grouped by COD, was opioid (n = 124), 28% (2.2%-92%), and mixed drug toxicity (n = 135), 35.3% (1.5%-100%); (p < 0.01). Quantitation of 6-MAM in blood and vitreous humor, along with a free to total morphine ratio >26%, was useful in establishing heroin-related deaths.

Urine Creatinine Concentrations in Drug Monitoring Participants and Hospitalized Patients.

Urine drug testing is commonly performed in both clinical and forensic arenas for screening, monitoring and compliance purposes. We sought to determine if urine creatinine concentrations in monitoring program participants were significantly different from hospital in-patients and out-patients undergoing urine drug testing. We retrospectively reviewed urine creatinine submitted in June through December 2015 for all specimens undergoing urine drug testing. The 20,479 creatinine results were categorized as hospitalized patients (H) and monitoring/compliance groups for pain management (P), legal (L) or recovery (R). Median creatinine concentrations (interquartile range, mg/dL) were significantly different (P < 0.001) between groups: H 126 (122-136); P 138 (137-143); L 147 (144-154); R 95 (92-97). In the two groups subject to on-demand sampling time pressures, median creatinine concentrations were significantly lower in the R vs. L group (P<0.001). In conclusion, recovery (R) participants have more dilute specimens, reflected by significantly lower creatinine concentration and may indicate participants' attempts to tamper with their drug test results through dilution means.

Relationship between blood alcohol concentration and observable symptoms of intoxication in patients presenting to an emergency department.

AIMS: Clinical and medico-legal decisions often require knowledge of alcohol impairment that is not necessarily revealed by an individual's appearance, and in turn, may not necessarily reflect level of blood alcohol. This study compares clinical signs and symptoms with measured and estimated blood alcohol concentrations (BACs). METHOD: Individuals (n = 384) perceived to be under the influence of alcohol at presentation to an emergency department were assessed by physicians and nurses for clinical features of alcohol intoxication (alcohol symptom checklist, ASC), who were asked to estimate the patient's BAC. Relation to measured BACs was assessed by correlation. RESULTS: BACs ranged from 0 to 418 mg/100 ml. The correlation between the estimated BAC and measured BAC was r = 0.513. Measured BAC correlated with ASC r = 0.250. In subjects without a history of chronic drinking (n = 134) there was a better (P < 0.05) correlation with the ASC score (r = 0.363) versus measured BAC compared with that for chronic drinkers (r = 0.154). The positive predictive value of estimating BAC at or above a particular BAC cut-off decreased from 93.2% at 100 mg/100 ml to 37.7% at 300 mg/100 ml (P < 0.05). CONCLUSIONS: Measured BAC does not correlate well with the outward physical signs of intoxication, especially for chronic drinkers. There is a need for further education on how tolerance masks clinical signs of intoxication for the chronic drinker. BACs should be measured especially in the obtunded where no history (symptoms) can be given by the patient.

Superiority of postmortem liver fentanyl concentrations over peripheral blood influenced by postmortem interval for determination of fentanyl toxicity.

OBJECTIVE: The current study was undertaken to determine the relationship between postmortem (PM) peripheral blood (PB) and liver fentanyl concentrations and the role of measuring liver fentanyl concentrations in cause of death investigations in medical examiner cases in which fentanyl was identified. DESIGN AND METHODS: FB and liver tissue were routinely collected at autopsy from 4 Minnesota medical examiners' offices in 2010-2011. Samples were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: PB fentanyl ranged from <2-15µg/L in non-drug related deaths (n=5), <2-22µg/L from mixed drug toxicity (n=26) and 3.7-56µg/L from fentanyl toxicity (n=33). Liver fentanyl ranged from 11 to 104µg/kg, 6 to 235µg/kg, and 18 to 365µg/kg, respectively. PB and liver fentanyl showed a modest correlation (r=0.67). PM interval to the liver/blood ratio showed a decreasing ratio over increasing PM interval in cases from fentanyl and mixed drug toxicity. Liver fentanyl concentrations best define therapeutic use at <23µg/kg and fatal toxicity at >56µg/kg, without substantial overlap as found in blood fentanyl concentrations. CONCLUSION: Discriminatory liver fentanyl concentrations suggestive of therapeutic or toxic drug levels may better assist cause of death determination in cases of suspected fentanyl toxicity than postmortem PB concentrations. Peripheral blood fentanyl concentrations appear to undergo postmortem redistribution, associated with an increasing PM interval.

Postmortem redistribution of fentanyl in blood.

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 microg/L (mean, 4.6 microg/L) and 2.0 to 52.5 microg/L (mean, 17.3 microg/L), respectively. Corresponding mean HB, liver tissue, and heart tissue fentanyl concentrations were 29.8 microg/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.

Fentanyl postmortem redistribution: preliminary findings regarding the relationship among femoral blood and liver and heart tissue concentrations.

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 fentanyl-positive 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 microg/L, liver fentanyl tissue (n = 9) ranged from 37.0 to 179 microg/kg, and heart fentanyl tissue (n = 3) ranged from 52.8 to 179 microg/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.

Free oxycodone concentrations in 67 postmortem cases from the Hennepin County medical examiner's office.

Heart blood free oxycodone concentrations in oxycodone-related and mixed drug overdose deaths were compared with those found incidentally at autopsy in medical examiner cases. Between 2000 and 2005, 67 oxycodone-positive postmortem cases were identified. Thirty of 67 cases (44.8%) were determined to be drug overdoses. Oxycodone alone was responsible for 7 of the 30 (23.3%) overdose deaths. Mean (median) oxycodone concentrations were 1.060 mg/L (0.824 mg/L) with a range of 0.270-3.390 mg/L. Three cases were accidents, three were suicides, and one was undetermined. The remaining 23 were mixed drug overdoses. Mean (median) oxycodone concentrations in these cases were 0.820 mg/L (0.470 mg/L) with a range of 0.014-3.800 mg/L. Sixteen mixed drug overdoses were accidental, and seven were suicidal. Where oxycodone was an incidental finding, 24 were natural, 6 accident, 4 suicide, 1 homicide, and 2 undetermined. The mean (median) concentrations in the incidental finding group were 0.330 mg/L (0.150 mg/L) with a range of 0.017-1.300 mg/L. In conclusion, the findings substantiate the considerable overlap that exists with blood oxycodone concentrations in cases where oxycodone alone was determined to be the cause of death compared with mixed drug overdoses and incidental findings. Free oxycodone concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.

Fentanyl concentrations in 23 postmortem cases from the hennepin county medical examiner's office.

The purpose of this study was to compare blood fentanyl concentrations in fentanyl-related deaths with fentanyl concentrations found incidentally at autopsy, as well as with fentanyl concentrations found in hospitalized patients receiving fentanyl. Between the years 1997 to 2005, 23 fentanyl-positive postmortem cases were identified. Nineteen of 23 (82.6%) cases were deemed to be drug overdoses. Fentanyl alone was responsible for 8 of the 19 (42.1%) overdose deaths. Mean and median fentanyl concentrations were 36 (SD 38) microg/L and 22 microg/L, respectively, range 5-120 microg/L. Seven of the cases were accidental, one undetermined. The remaining 11 of the 19 (57.9%) cases were mixed drug overdoses. Fentanyl concentrations in these cases were 31 (SD 46) microg/L, range 5-152 microg/L. All of the mixed drug overdoses were determined to be accidental. Four cases where fentanyl was considered an incidental postmortem finding were determined to be natural deaths. In hospitalized inpatients (n = 11) receiving fentanyl 2 of the patients receiving fentanyl for chronic pain for more than 3 months had concentrations of 8.5 microg/L and 9.9 microg/L. The other nine inpatient concentrations were less than 4 microg/L. In conclusion, blood fentanyl concentrations found in cases where fentanyl alone was determined to be the cause of death were similar to cases where fentanyl was part of a mixed drug overdose. There was also considerable overlap between fentanyl concentrations in fentanyl-related overdose deaths compared to hospitalized patients being treated for chronic pain. Fentanyl concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.

Measurement of chemical analytes in vitreous humor: stability and precision studies.

The analytic accuracy and precision for measurement of chemical analytes in vitreous humor (VH) are critical if results are to be used in forensic pathology. The purpose of our study was to demonstrate the stability and the reproducibility of VH sodium, potassium, chloride, glucose, urea nitrogen, acetone, and beta-hydroxybutyrate in specimens obtained from both eyes in medical examiner cases. We also compared with calculated VH osmolalities. Small but significant increases were observed in VH electrolyte concentrations in specimens refrigerated 6-12 months: sodium pre 144 mmol/L, post 151 mmol/L; potassium pre 12.0 mmol/L, post 12.8 mmol/L; chloride pre 121 mmol/L, post 123 mmol/L. No differences were observed between eyes, and within-day precision for all electrolyte measurements were excellent, (<1%). Frozen specimens showed significantly higher measured (439 mOsmol/kg) as compared with calculated osmolality (305 mOsmol/kg), with 1% within-day precision and no significance between eye variation for glucose and urea nitrogen. In 20 of 24 medical cases selected for possible ketoacidosis, measurement of beta-hydroxybutyrate concentrations appears to be a promising diagnostic biomarker for confirming suspected ketosis in medical examiner cases by means of VH analysis.