Fatal Insulin Overdoses: Case Report and Update on Testing Methodology

Suicidal insulin overdoses are an under‐recognized and uncommon cause of death, often relying on scene and nonspecific autopsy findings. Here, we present a case report of a fatal exogenous insulin overdose in a patient with type 1 diabetes. In our case, there were no contributory autopsy findings; however, serum analog aspart insulin levels were c. 10× the predicted therapeutic upper limit (4000, reference 6.6–55 uU/mL), which correlated with scene findings. This was specifically determined by a newly developed immunocapture liquid chromatography–tandem mass spectrometry assay, able to discriminate between various synthetic insulin analogs. Total insulin levels by immunoassay were highly elevated on the Siemens Advia Centaur, but not the Roche platforms (4741 vs. 5.2 uU/mL, respectively), showing variable sensitivity of detection within the same analog depending on assay. We discuss the prevalence and features to look for at autopsy in these types of cases. Additionally, analytical options for testing insulin levels, including new methodologies, guidance on collection of samples, as well as an outline of available historical reference range data are discussed.     

Accidental insulin overdose

Exogenous insulin has been used for many years to treat diabetes mellitus. Due to the complex nature of insulin therapy, there have been numerous accidental overdoses by these patients. Unfortunately, in other instances, insulin has been used as an agent for suicide and homicide in diabetics as well as nondiabetics. Presented here is a fatal case of accidental insulin overdose in a nondiabetic. Following the case presentation, we review insulin pharmacology and the methods of diagnosing insulin overdose postmortem. In any case of insulin overdose, a comprehensive scene investigation to document the amount and type of insulin used, along with information revealing the source of the insulin is critical. In addition, a complete autopsy, including appropriate laboratory studies, is needed to make a diagnosis in these cases. Proper attention should be given to collection and storage of blood samples, as these specimens often yield the strongest evidence of insulin overdose.     

Postmortem tricyclic antidepressant concentrations. Lethal versus nonlethal levels

Evidence has accumulated that postmortem release of tissue-bound tricyclic antidepressants (TCAs) may cause falsely elevated postmortem blood levels, thus rendering it more difficult to determine if the cause of death was an overdose. This study, a review of 24 TCA-related deaths, is aimed at defining the practical significance of such a problem and providing a workable approach to interpreting postmortem TCA levels. Deaths clearly due to TCA drugs were compared with deaths that were not caused by TCA drugs, but in which the decedent's postmortem blood tested positive for TCA medications. There is little evidence that postmortem elevations in blood TCA levels cause frequent problems in differentiating lethal from nonlethal levels (overdose from nonoverdose cases). The data suggest that using a heart blood level of 0.100 mg/dl as an indicator of lethality is practical at the present time and poses little likelihood of error. Isolated cases suggest that postmortem TCA increases can occur; further work is needed in this area to clarify more fully the significance and frequency of such cases. At present, it seems prudent to utilize peripheral blood samples for TCA testing on autopsy material, if a conservative estimate of TCA concentration is desired, possibly augmented by liver TCA levels and parent-metabolite ratios if money, facilities, and time permit.     

Digoxin-like immunoreactive substance in postmortem blood of infants and children

A digoxin-like immunoreactive substance (DLIS) has been reported in the serum of infants not receiving digoxin. This study was undertaken to determine if DLIS is present in the postmortem blood and tissues of infants or children and whether the endogenous substance could interfere with forensic toxicological analysis in suspected overdose. Ninety blood specimens taken from the heart at autopsy of children or infants were screened for DLIS using commercial radioimmunoassay kits. The average age at death in these cases was 8.6 months, the median age was 2 months. DLIS equivalent to 0.25 to 2.0 ng/mL digoxin was found in one third of the cases. The incidence of positive findings was 5/6 stillborns, 10/45 Sudden Infant Death Syndrome (SIDS), 10/15 deaths as a result of infection, 4/7 homicides, 1/8 deaths caused by congenital defects, and 0/9 accidental deaths. The body distribution of DLIS was investigated and highest levels were found in the liver. Findings of DLIS in blood were correlated with renal failure, (elevated vitreous urea nitrogen), electrolyte imbalance, and liver trauma. Apparent concentrations were in the equivalent therapeutic range of digoxin and would not be confused with accidental or intentional overdose with digoxin.     

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.     

Beta-hydroxybutyric acid--an indicator for an alcoholic ketoacidosis as cause of death in deceased alcohol abusers

We analyzed the postmortem blood of a total of 100 fatal cases for beta-hydroxybutyric acid (BHBA). In 25 cases of sudden and unexpected death of alcoholics we found pathologically increased levels of BHBA of 1260 to 47200 (median 8000) micromol/L. This led us to the diagnosis of an alcoholic ketoacidosis (AKA) as cause of death in these cases. The control group of 69 postmortem cases revealed that BHBA concentrations below 500 can be regarded as normal, and values up to 2500 micromol/L as elevated. Our study shows that BHBA values over 2500 micromol/L could lead to death, if no medical attention is sought. During storage we did not find any indication of postmortem formation or decomposition of BHBA in blood in vitro or in the corpses. In our opinion, BHBA should be considered the diagnostic marker of choice for the postmortem determination of alcoholic ketoacidosis (AKA) as the cause of death. The classical indications of such deaths are: unexpected death of a chronic alcoholic; none or only traces of ethanol in the blood; increased acetone blood concentration; and neither autopsy, histology, microbiology, nor toxicology reveal the cause of death. In six further cases a diabetic ketoacidosis (DKA) was diagnosed as the cause of death.     

Site-dependent postmortem changes in blood cocaine concentrations

When a forensic toxicologist interprets postmortem blood cocaine findings he usually must make assumptions regarding perimortem drug concentrations. In-vitro studies have shown that cocaine rapidly hydrolyzes in unpreserved blood, particularly at elevated temperatures. However, other studies have demonstrated site-dependent postmortem release of some drugs from tissue stores accompanied by increases in drug concentrations in the blood. This study was undertaken to investigate whether blood cocaine concentrations change in the body during the postmortem interval and, if so, to measure the direction and magnitude of the changes. In medical examiner cases in which scene investigation suggested that the decreased was a cocaine user, blood samples were collected as soon after death as possible. At autopsy, a second set of samples was collected. Analysis of paired samples by gas chromatography/mass spectrometry (GC/MS) revealed dramatic differences in the cocaine concentration. The magnitude and direction of the change appears to be site dependent. Usually, but not invariably, cocaine concentration in subclavian vein blood decreases while that in heart, aorta, and femoral vein blood increases during the interval between death and autopsy. The findings emphasize the danger inherent in attempting to estimate the concentration of cocaine in blood at the time of death from postmortem data.     

Blood aspiration as a vital sign detected by postmortem computed tomography imaging

Blood aspiration is a significant forensic finding. In this study, we examined the value of postmortem computed tomography (CT) imaging in evaluating findings of blood aspiration. We selected 37 cases with autopsy evidence of blood in the lungs and/or in the airways previously submitted to total-body CT scanning. The CT-images were retrospectively analyzed. In one case with pulmonary blood aspiration, biopsy specimens were obtained under CT guide for histological examination. In six cases, CT detected pulmonary abnormalities suggestive of blood aspiration, not mentioned in the autopsy reports. CT reconstructions provided additional data about the distribution and extent of aspiration. In one needle-biopsied case, the pulmonary specimens showed blood in the alveoli. We suggest the use of CT imaging as a tool complementary to traditional techniques in cases of blood aspiration to avoid misdiagnosis, to guide the investigation of lung tissue, and to allow for more evidence-based inferences on the cause of death.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.     

Postmortem serum catecholamine levels in relation to the cause of death

Catecholamines are major humoral factors and neurotransmitters that contribute to various stress responses. However, they have been considered unstable due to agony, terminal medical care and postmortem interference. The present study was a comprehensive investigation of postmortem serum levels of adrenaline (Adr), noradrenaline (Nad) and dopamine (DA) with regard to the cause of death in serial medicolegal autopsy cases (n=542) including fatalities from various traumas and diseases. There was a slight tendency toward postmortem increases of Nad and DA in cardiac blood as well as Adr and Nad in peripheral blood, a slight age-dependent decrease in Adr and DA in right heart blood, and a marked increase in serum DA due to administration during critical medical care. When these factors were taken into consideration, significantly higher cardiac blood levels were observed for Adr and Nad in injury and asphyxiation cases and for Adr in fatal methamphetamine (MA) abuse and other poisoning cases, whereas those levels were lower in fatal hypothermia. Drowning, fire fatality, acute cardiac death and cerebrovascular disease showed intermediate Adr and Nad levels. The DA level was elevated in cases of injury, hyperthermia, MA fatality and other poisoning. Topographical analyses suggested that the major sources of increased serum catecholamines in cases of injury was abdominal viscera including adrenal glands, and that in cases of asphyxiation, drowning, fire fatality, hyperthermia, MA fatality, other poisoning, acute cardiac death and cerebrovascular disease was the extremities in addition to abdominal viscera. However, there was in part a large case-to-case difference in each marker related to individual causes of death. These findings differed markedly from clinical observations and suggest that the postmortem serum catecholamine levels may reflect the magnitude of physical stress responses during the process of death in individual cases.     

Acute fatal acetaminophen overdose without liver necrosis

Two unusual cases of suicidal overdose of acetaminophen (paracetamol) without the usual extensive centrilobular necrosis of the liver are reported. Both cases were subjected to comprehensive drug screening by immunoassay, and a combination of gas chromatography with mass spectrometry, nitrogen detection, and electron capture detection. Acetaminophen was detected in both cases. No other drugs were detected in case #1, and only a small amount of olanzapine (<0.1 mg/L) was detected in case #2. No anatomical cause of death was identified in either case. If untreated, the normal outcome of a large acetaminophen overdose would be massive hepatic necrosis with delayed death and low blood and tissue acetaminophen concentrations. In contrast, particularly high postmortem acetaminophen concentrations were measured in both our cases with little hepatic tissue damage. For case #1, femoral blood acetaminophen 1280 mg/L, vitreous 878 mg/L, and liver 729 mg/kg; in case #2, cardiac blood 1220 mg/L, vitreous 779 mg/L, liver 3260 mg/kg, and gastric 11,500 mg/500 g. Acetaminophen was measured using high performance liquid chromatography with UV detection (254 nm) using 3-hydroxyacetanilide as the internal standard. The very high concentrations of acetaminophen is these cases but relatively little hepatic damage suggests an alternative, possibly cardiac, mechanism of death.     

Fatalities Due to Failure of Continuous Subcutaneous Insulin Infusion Devices: A Report of Six Cases

Diabetes mellitus type 1 and type 2 are diseases characterized by impaired regulation of blood glucose due to decreased insulin production and insulin resistance, respectively. Management of diabetes mellitus often requires injection of exogenous insulin. Continuous subcutaneous insulin infusion (CSII or insulin pump) is a diabetes treatment modality utilizing a device to aid in regulation of glycemic control. Malfunctions in device components can have rare fatal consequences. Described in this report are six fatalities due to one such malfunction, the failure of plastic cannulas of CSII devices to penetrate the skin and deliver insulin, resulting in fatal diabetic ketoacidosis (DKA). The cases derive from four different death investigation systems. For each case, scene and autopsy findings are presented, as well as selected toxicology and histology findings. These cases illustrate the importance of careful examination of CSII devices in death investigations and introduce a discussion on discrepant manner of death classifications.     

An Examination of the Postmortem Redistribution of Fentanyl and Interlaboratory Variability,

Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter‐ and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.     

Toxicologic findings in suicide: a 10-year retrospective review of Kentucky medical examiner cases

Toxicologic analysis is an integral component in the investigation of suicide and requires correlation with a detailed scene inspection, with an extensive exploration into the decedent's medical and social background to uncover suicidal ideation or intent and a postmortem examination of the body. In this review, the authors analyzed 2864 cases classified as suicide upon autopsy and toxicologic examinations between 1993 and 2002 in the Kentucky Division of Medical Examiner's Services. Blood and urine were collected in 95.0% and 72.3% of cases, respectively. A total of 32.5% of the victims had negative blood toxicologic results, and 52.7% of urine toxicology screens yielded no drugs. Analysis of the data indicated that 3 times as many women had taken antidepressants and more than twice as many had consumed opioids. Drug toxicity ("overdose") ranked as the third (9.9%) leading cause of suicide after firearm injury (67.5%) and hanging (13.7%). Women succumbed to drug toxicity more than men (27.5% versus 5.9%). Of the overdose deaths, 66.5% had a negative blood alcohol concentration (BAC), while antidepressants, opioids, and benzodiazepines were detected in blood in 54.4%, 37.4%, and 29.2% of the subjects, respectively. The collection of these data serves the goals of public health and clinicians in devising strategies for suicide prevention.     

Morbus Fahr--considerations on a case of sudden death

This paper presents 21 cases related to cyanide intoxication by oral ingestion. Cyanide concentrations in biological specimens are especially different from the type of postmortem specimens, and very important in interpreting the cause of death in postmortem forensic toxicology. Besides the detection of cyanide in autopsy specimens, the autopsy findings were unremarkable. Biological samples (0.2mL or equal to less than 10μg of cyanide) were analyzed colorimetrically for cyanide. In a series of 21 cyanide fatalities, the concentration ranges (mean±SD) of cyanide in heart blood, peripheral blood and gastric contents were 0.1-248.6mg/L (38.1±56.6mg/L), 0.3-212.4mg/L (17.1±45.1mg/L) and 2.0-6398.0mg/kg (859.0±1486.2mg/kg), respectively. The ranges of the heart/peripheral blood concentration ratio and gastric contents/peripheral blood concentration ratio were 0.3-10.6 (mean 3.4) and 3.4-402.4 (mean 86.0), respectively. From the difference of cyanide concentration and the concentration ratio of cyanide in different types of postmortem specimens, the possibility of the postmortem redistribution of cyanide and death by oral ingestion of cyanide could be confirmed. We reported cyanide fatal cases along with a review of literature.     

Postmortem serum uric acid and creatinine levels in relation to the causes of death

Serum uric acid (UA) and creatinine (Cr) mainly derive from skeletal muscle tissues. Although, remarkable postmortem stability of the serum levels has been reported, there appears to be very poor knowledge of the diagnostic value in investigation of death, except for uremia. The aim of the present study was to evaluate postmortem serum UA and Cr levels using 395 forensic autopsy cases, in comparison with blood urea nitrogen (BUN), for investigation of the pathophysiology of death with special regard to the causes of death involving possible skeletal muscle damage, e.g. due to hypoxia, heat or agonal convulsions. Cr and BUN showed relatively good topographic stability in the cadaveric blood, whereas, UA was often much higher in the right heart blood than in the left heart and peripheral blood, independent of postmortem intervals. Moderate to marked elevation of Cr and BUN accompanied with hyperuricemia was observed in delayed death. In the acute death cases (survival time <30 min), UA, especially in the right heart blood, showed a considerable elevation in mechanical asphyxiation and drowning. The Cr level in fire victims with a lower carboxyhemoglobin (COHb) level (<60%) was significantly higher than in those with the possible fatal level (>60%). A similar elevation of Cr was observed in fatalities from heat stroke and methamphetamine (MA) poisoning. The observations suggested that hyperuricemia in acute death may be indicative of advanced hypoxia and that elevated Cr level may reflect the skeletal muscle damage, especially due to thermal influence.     

Features characteristic of homicide in cases of complete decapitation

Four cases of complete decapitation connected to homicidal acts are presented. In 3 cases, decapitation was inflicted postmortem after killing the victim. The motives for decapitation were considered defensive, aggressive, and a possible combination of the 2 in one case each. In one case, decapitation was a vital injury and accounted for death. In this case, an offensive motive for mutilation was suspected. The combination of death scene findings and autopsy results will in most cases distinguish between homicidal and other modes of death.     

Fatal intoxication involving 2-methyl AP-237

Novel synthetic opioids contribute considerably to the opioid epidemic, especially with the frequent emergence of structurally similar compounds. This case report describes a fatal intoxication involving 2-methyl AP-237. A 54-year-old Caucasian male was found deceased from an apparent drug overdose. A plastic container labeled “2MAP” and a cut straw were found in the decedent's backpack at the scene. A white substance found in the container tested positive for fentanyl by field testing. According to his medical history, the decedent was treated for a drug overdose 3 years prior to his death. With no diagnostic findings at autopsy, the case was submitted for toxicological analysis. An unknown substance was detected in peripheral blood and urine using gas chromatography with nitrogen phosphorous detection (GC-NPD). Further testing was conducted using gas chromatography–mass spectrometry (GC–MS) and liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) which confirmed the presence of 2-methyl AP-237 and potential metabolites in blood and urine. Quantitation by GC-NPD revealed concentrations of 2-methyl AP-237 in blood and urine at 480 ng/mL and 4200 ng/mL, respectively. The toxicological analysis also identified and quantitated alprazolam in the blood at 55 ng/mL. Additionally, the metabolism of 2-methyl AP-237 was investigated and three hydroxylated metabolites were identified in peripheral blood and urine. Limited literature is available for the detection and quantitation of 2-methyl AP-237 in postmortem specimens. Given the toxicological findings with unremarkable autopsy findings, this case is an example of a fatal intoxication involving 2-methyl AP-237.     

Oral abuse of fentanyl patches (Duragesic): seven case reports

In order to increase the understanding regarding the oral abuse and potential toxicity of fentanyl patches seven cases were identified over a 3-year period where fentanyl, either alone or in combination with other factors, contributed to death following the oral abuse of Duragesic patches. The decedents comprised three females and four males with ages ranging from 20 to 51 years. Postmortem blood fentanyl concentrations were determined in all cases and ranged from 7 to 97 ng/mL. Two deaths were classified as a fentanyl overdose, three deaths were classified as a fentanyl and ethanol overdose, one death was considered a mixed drug intoxication and the remaining death was determined to be a combination of fentanyl and medical causes. These cases represent the largest reported series of deaths following the oral administration of transdermal fentanyl patches and provide detailed information on the potential for the abuse of transdermal Duragesic patches via this route. The postmortem blood fentanyl concentrations detected for each of the decedents demonstrate the potentially fatal blood concentrations that can arise after this relatively rare route of administration.