Pharmaceutical error resulting in fatal diabetic ketoacidosis

A 41-year-old male with a 25-year history of diabetes mellitus requiring 25 to 30 units of neutral protamine hagedorn (NPH) insulin daily was found dead at home. Recent history revealed that he was well until the last four days of life when he had the onset of nausea, vomiting, and anorexia coinciding with procurement of a new bottle of insulin from his pharmacist. Pertinent autopsy findings included coronary and aortic atherosclerosis, a peptic ulcer, and diabetic glomerulopathy. Chemical analysis of the vitreous humor, including glucose (813 mg/dL) and acetone (40 mg/dL), revealed that he died of diabetic ketoacidosis. Further investigation revealed that the pharmacist had accidentally substituted regular insulin, with a duration of action of up to 6 h as opposed to 24 to 28 h, for NPH. Cultures of blood and of the regular insulin yielded no growth. Analysis of this case emphasizes the importance of obtaining a careful medical and medication history and the usefulness of vitreous electrolytes when investigating a sudden death in a diabetic.     

Investigation of markers to indicate and distinguish death due to alcoholic ketoacidosis, diabetic ketoacidosis and hyperosmolar hyperglycemic state using post-mortem samples

Data from 191 post-mortem cases where post-mortem blood beta-hydroxybutyrate (βHB) and acetone concentrations and vitreous humor glucose concentrations (where available) had been measured were retrospectively investigated to determine the markers required to identify and distinguish between Alcoholic Ketoacidosis (AKA), Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS). Blood βHB concentrations above 250 μg/mL were considered significant and it was shown to be the preferred marker of ketoacidosis. All cases with significant βHB detected also had acetone present (greater than 2mg/dL) demonstrating that acetone can be used as a marker to identify ketoacidosis and can be used to indicate when βHB measurement is necessary. Vitreous humor glucose concentrations above 6.9 mmol/L were considered high and indicative of hyperglycemia prior to death. Vitreous humor glucose concentrations can be used to distinguish between DKA and ketoacidosis from other causes and to identify deaths due to HHS. The data showed that ketoacidosis can occur without a history of alcoholism or diabetes. Many diabetics are undiagnosed for many years. Therefore, DKA or HHS should be considered in sudden or unexplained deaths and glucose should be routinely measured especially in cases with risk factors for diabetes including obesity, old age, a history of mental health problems or treatment with atypical antipsychotic drugs including clozapine, olanzapine, quetiapine and risperidone.     

High urine ethanol and negative blood and vitreous ethanol in a diabetic woman: a case report, retrospective case survey, and review of the literature

Several studies have shown that ethanol can be produced in urine infected with yeast or bacteria in vitro. We present the unusual case of a diabetic woman in whom ethanol was produced in her urine in vivo. The decedent was a 19-year-old woman who was noncompliant with her diabetes treatment. She presented to a local hospital in severe diabetic ketoacidosis and died shortly thereafter. Upon arrival at the hospital, a blood glucose of 553 mg/dL was detected. A urinalysis was positive for ketones (> 80 mg/dL), glucose (> 1000 mg/dL), and large budding yeast forms. A drug screen performed on the urine was positive for ethanol. At the coroner/medical examiner office, an autopsy was negative for significant anatomic findings. Toxicology analysis revealed a urine ethanol level 0.32 g/dL, although no ethanol was detected in blood or vitreous samples. A urine gram stain and culture identified Candida glabrata. A retrospective case review of all deaths related to diabetes examined at the coroner/medical examiner office from 1986 to 2003 did not reveal other cases with similar findings. This case of a noncompliant, juvenile-diabetic woman illustrates a rare finding of apparent in vivo glucose fermentation by C. glabrata to form ethanol in the urine. This case also highlights a potential difficulty in toxicologic analysis and interpretation using urine only.     

Vitreous Fluid and/or Urine Glucose Concentrations in 1335 Civil Aviation Accident Pilot Fatalities*

Abstract: During aviation accident investigations, vitreous fluid and urine samples from pilot fatalities are analyzed for glucose and blood for hemoglobin A_1c (HbA_1c) to monitor diabetic pilots and to discover other pilots with undiagnosed/unreported diabetes. The prevalence of elevated glucose concentrations in fatally injured pilots was evaluated by searching the Civil Aerospace Medical Institute’s Toxicology Database for the period 1998–2005. Out of 1335 pilots involving 363 vitreous fluid, 365 urine, and 607 vitreous fluid and urine analyses, 43 pilots had elevated glucose in vitreous fluid (>125 mg/dL) and/or in urine (>100 mg/dL). Of the 20 pilots whose blood samples were analyzed, nine had >6% HbA_1c—four were known diabetics, and five were unknown diabetics. Urinary glucose levels were elevated in all 13 known hyperglycemic pilots. A considerable number of pilots (30 of 43) had elevated glucose and HbA_1c (5 of 20), suggesting undiagnosed/unreported diabetic conditions.     

Postmortem diagnosis of unsuspected diabetes mellitus established by determination of decedent's hemoglobin A1c level.

Although approximately 15.7 million Americans have diabetes mellitus, with the vast majority having type 2 diabetes, it is estimated that as many as 5.4 million are undiagnosed. The present case illustrates that undiagnosed diabetes can be a factor in otherwise unexplained deaths. A 39-year-old white male with no significant past medical history other than alcohol abuse was found deceased at his residence. The manner of death appeared to be natural, but no anatomic cause was found. Toxicological analysis revealed a blood ethanol level of 0.02 g/dL and was negative for drugs of abuse. Analysis of the vitreous fluid revealed a glucose level of 502 mg/dL. The blood glucose level was 499 mg/dL, and the hemoglobin A1c (HbA1c) level was 10.6%. Only trace urine ketones were detected, suggesting that the death was the result of hyperglycemic hyperosmolar non-ketosis (HHNK) from unsuspected diabetes. The postmortem HbA1c value serves as a definitive indicator of prolonged hyperglycemia. In order to aid the interpretation of the clinical data, this case is discussed in conjunction with a similar case of a known diabetic patient.     

Ethyl sulphate and ethyl glucuronide in vitreous humor as postmortem evidence marker for ethanol consumption prior to death

To clarify the circumstances of death, the degree of inebriation is of importance in many cases, but for several reasons the determination of the ethanol concentration in post-mortem samples can be challenging and the synopsis of ethanol and the direct consumption markers ethyl glucuronide (EtG) and ethyl sulphate (EtS) has proved to be useful. The use of a rather stable matrix like vitreous humor offers further advantages. The aim of this study was to determine the concentrations of ethanol and the biomarkers in the robust matrix of vitreous humor and to compare them with the respective levels in peripheral venous blood and urine. Samples of urine, blood from the femoral vein and vitreous humor were taken from 26 deceased with suspected ethanol consumption prior to death and analyzed for ethanol, EtS and EtG. In the urine samples creatinine was also determined. The personal data, the circumstances of death, the post-mortem interval and the information about ethanol consumption prior to death were recorded. EtG and EtS analysis in urine was performed by LC-ESI-MS/MS, creatinine concentration was determined using the Jaffé reaction and ethanol was detected by HS-GC-FID and by an ADH-based method. In general, the highest concentrations of the analytes were found in urine and showed statistical significance. The mean concentrations of EtG were 62.8mg/L (EtG100 206.5mg/L) in urine, 4.3mg/L in blood and 2.1mg/L in vitreous humor. EtS was found in the following mean concentrations: 54.6mg/L in urine (EtS100 123.1mg/L), 1.8mg/L in blood and 0.9mg/L in vitreous humor. Ethanol was detected in more vitreous humor samples (mean concentration 2.0g/kg) than in blood and urine (mean concentration 1.6g/kg and 2.1g/kg respectively). There was no correlation between the ethanol and the marker concentrations and no statistical conclusions could be drawn between the markers and matrices.     

Glucose and lactate in vitreous humor compared with the determination of fructosamine for the postmortem diagnosis of diabetes mellitus

Diabetes mellitus is a chronic metabolic illness responsible for a great number of deaths. In postmortem diagnosis, because of the difficulty involved in interpreting blood glucose levels and relatively nonspecific pathologic features, biochemical markers in vitreous humor are useful. The aim of this study was to compare the results obtained for the combined determination of lactate and glucose with fructosamine levels recorded in the vitreous humor of two diagnostic groups (one diabetic and the other nondiabetic). The authors intended to ascertain the capacity of different markers measured in vitreous humor to diagnose diabetes mellitus. Fifty-one cadavers (mean age, 58.7 years; standard deviation, 17.09) were studied. The mean postmortem interval was 16.4 hours (standard deviation, 9.05). Cases were assigned to two diagnostic groups according to whether they were previously diagnosed as either diabetic or nondiabetic. Statistically significant differences for glucose, fructosamine, and the sum values of glucose and lactate were found between the two diagnostic groups. The highest levels were obtained in the group of cases with a previous diagnosis of diabetes mellitus. After the comparison of receiver operating characteristic curves, the sum values of glucose and lactate in vitreous humor is a better predictor of antemortem diabetes mellitus than the fructosamine.     

A fatality involving clomipramine

A fatality following ingestion of the tricyclic antidepressant clomipramine (Anafranil), alprazolam (Xanax), and ethyl alcohol is described. Clomipramine and N-desmethylclomipramine were quantitated by high performance liquid chromatography and alprazolam by gas liquid chromatography. Concentrations of clomipramine and N-desmethylclomipramine were: in blood--0.84 and 1.4 mg/L; in urine--0.56 and 0.62 mg/L. Alprazolam concentration in blood was 0.069 mg/L. Ethyl alcohol was measured by headspace gas chromatography and found to be 375, 385, and 435 mg/dL in blood, urine, and vitreous humor, respectively. These findings are compared to previous reports of clomipramine related fatalities and alprazolam toxicity combined with ethyl alcohol.     

Fatal Diabetic Ketoacidosis—A Potential Complication of MDMA (Ecstasy) Use

A 19‐year‐old woman with insulin‐dependent diabetes mellitus was found dead in bed having allegedly recently taken ecstasy and consumed alcohol. At autopsy, there were microhemorrhages in the brain with subnuclear vacuolization and Armanni–Ebstein changes in renal tubules. Biochemical analyses confirmed diabetic ketoacidosis (vitreous glucose—46.5 mmol/L; β‐OH butyrate—13.86 mmol/L.). Toxicological analyses of blood showed a low level of 3,4‐methylenedioxy‐methamphetamine (MDMA) (0.01 mg/L), with acetone but no alcohol or other common drugs. Death was attributed to diabetic ketoacidosis most likely provoked by mixed MDMA/alcohol ingestion. Although the use of illicit drugs by young individuals with diabetes mellitus is being increasingly recognized, it has been noted that there is minimal information about the relationship between drug use and acute diabetic complications. Toxicological screening of cases of lethal diabetic ketoacidosis in the young may clarify lethal mechanisms in individual cases and also help to determine the extent of this problem.     

How Useful is Basal Renal Tubular Epithelial Cell Vacuolization as a Marker for Significant Hyperglycemia at Autopsy?

Basal vacuolization of renal tubular epithelial cells (so-called Armanni-Ebstein phenomenon) has been attributed to hyperglycemia causing accumulation of cytoplasmic glycogen. Review of 34 autopsy cases with significant hyperglycemia (vitreous glucose ≥ 15 mmol/L/270 mg/dL) was undertaken to determine whether there was any significant association between the degree of hyperglycemia and the severity of this morphological change (graded as 0, 1+, 2+, and 3+). No association was demonstrated. Review of the subgroup of 14 cases with terminal hyperglycemia without ketoacidosis was then undertaken to assess the effect of hyperglycemia in isolation on renal tubular epithelial cells. Vitreous glucose levels in these 14 cases ranged from 17 to 49.7 mmol/L (306-894.6 mg/dL) with a mean of 26.25 mmol/L (472.5 mg/dL) and β-hydroxybutyrate levels ranged from 0.02 to 2.55 mmol/L (0.36-45.9 mg/dL) with a mean 0.79 mmol/L (14.22 mg/dL). Not one of the latter cases displayed basal vacuolization. No relationship between basal vacuolization of renal tubular epithelial cells at autopsy and terminal hyperglycemia could, therefore, be demonstrated.     

Postmortem Fluid Concentrations of Heroin Biomarkers and Their Metabolites

Only limited data exist concerning the utility of complementary specimens in heroin-related deaths. As such, this report employed a validated LC-MS-MS method to quantify 6-monoacetylmorphine (6-MAM), 6-acetylcodeine (6-AC), and their metabolites morphine and codeine in blood with (BN) and without preservative (B) and the additional unpreserved specimens of vitreous humor, urine, stomach contents, and bile from 20 postmortem cases in which heroin was the primary cause of death. The median concentration of 6-MAM in BN was 0.011 mg/L, B was 0.008 mg/L, urine was 0.186 mg/L, vitreous humor was 0.022 mg/L, stomach contents was 0.147 mg/L, and bile was 0.012 mg/L. Only one case was found to be positive for 6-AC in B (case 6, 0.002 mg/L), and the median concentration of 6-AC was 0.002 mg/L in BN, 0.012 mg/L in urine, 0.003 mg/L in vitreous humor, 0.057 mg/L in stomach contents, and 0.004 mg/L in bile. These findings present new information on the distribution of these analytes in complementary matrices and support their inclusion for accurately determining the role of heroin in opioid-related deaths.     

Bupropion Overdose Resulted in a Pharmacobezoar in a Fatal Bupropion (Wellbutrin®) Sustained‐release Overdose: Postmortem Distribution of Bupropion and its Major Metabolites

Bupropion (BUP) overdose commonly causes generalized seizures and central nervous system depression. The case of a 28‐year‐old woman who died from a massive lethal overdose with sustained‐release bupropion (Wellbutrin^® 300 mg) is herein presented. The autopsy revealed the presence of a pharmacobezoar consisting of at least 40 tablets in the stomach. Determination of bupropion and its active metabolites (hydroxybupropion, threobupropion, erythrobupropion) was achieved by a liquid chromatographic mass spectrometry (LC‐MS/MS) method. Postmortem concentrations for bupropion, hydroxybupropion, threobupropion, and erythrobupropion were obtained in intracranial blood, urine, bile, liver, kidney, and vitreous humor. In this case, intracranial blood level of the parent drug was 1.9 mg/L. Threobupropion was the most abundant metabolite in both blood and urine, 59.3 and 890.6 mg/L. Tissue distribution showed the highest concentration in the liver, 12.3 mg/kg. The 0.8 bupropion concentration ratio vitreous/blood suggested that vitreous could be a valuable specimen for toxicological analysis should postmortem blood be unavailable.     

Armanni–Ebstein Lesions in Terminal Hyperglycemia

Armanni–Ebstein lesions (AEL) occur in deaths related to uncontrolled diabetes mellitus. To investigate the relationship between AEL and terminal hyperglycemia, we retrospectively reviewed 71 cases with vitreous glucose levels ≥11.1 mmol/L; 27 (38%) cases had AEL (vitreous glucose 14.0–77.3 mmol/L); and 44 cases (62%) did not (vitreous glucose 11.1–91.9 mmol/L). There was no significant difference (p = 0.271) in vitreous glucose levels between the cases with AEL (mean 39.2, SD 16.7 mmol/L) and those without (mean 34.2, SD 19.8 mmol/L). Similarly, there was no difference in the degree of dehydration, renal failure, or osmolality. However, there was a significantly higher level of β‐hydroxybutyrate among the cases with AEL compared to those without (p = 0.007), suggesting that ketoacidosis may facilitate the development of AEL. Given the possible synergistic role of β‐hydroxybutyrate, the correlation between AEL and terminal hyperglycemia in animal studies may not be applicable to humans. AEL may also possibly occur with sublethal elevations in glucose.     

Heroin fatality due to penile injection

Death due to heroin overdose and/or rapid injection of heroin is a frequent occurrence among opioid addicts. We present an unusual case of heroin fatality due to the injection of the drug in the penis. Blood, urine, bile, and vitreous humor concentrations of morphine were 0.68, 0.49, 0.32 and 0.062 microg/ml, respectively. Ethanol was detected at concentrations of 104, 124, 106, and 94 mg/dl in the blood, urine, bile, and vitreous humor, respectively. The cause of death was determined to be due to heroin and ethanol intoxication.     

A Case of Fatal Dehydration During Police Custody

In the forensic literature, fatal dehydration predominantly concerns young children or incapacitated elderly persons. The postmortem diagnosis of fatal dehydration can be challenging to confirm, especially if the preceding circumstances are unknown. Here presented is a case of a 23‐year‐old man who died while held in an isolation cell during police custody for 18 days. Autopsy findings were unspecific, but vitreous fluid analysis showed 192 mmol/L sodium, 179 mmol/L chloride, 16 mmol/L potassium, 352 μmol/L (3.98 mg/dL) creatinine, and 81 mmol/L (226.9 mg/dL) urea nitrogen. Based on the findings and circumstances, the cause of death was determined as severe dehydration and manner of death accident. This case illustrates the importance of performing postmortem biochemistry.     

Postmortem vitreous Beta-hydroxybutyrate: interpretation in a forensic setting*

Abstract: Vitreous beta‐hydroxybutyrate (BHB) was retrospectively analyzed in 1795 forensic cases using the Pointe Scientific method. Comparison of vitreous BHB with vitreous glucose in 1781 of the cases showed moderately good correlation r = 0.731. Comparison with blood alcohol levels in 1561 of the cases showed no correlation r = ?0.053. Vitreous BHB was a marker of diabetic ketoacidosis when above 6.0 mM with a vitreous glucose over 200 mg/dL. It was an indicator (>50%) for alcoholic ketoacidosis when above 6.0 mM with a vitreous glucose below 200 mg/dL. Recommendations for interpretation of vitreous BHB: <0.4 mM normal; 0.41–1.2 mM slightly elevated, rarely (<1%) of concern; 1.21–2.0 mM moderately elevated, less rarely (2.5%) of concern; 2.01–6.0 mM significantly elevated, frequently of concern (12–48%); >6.0 mM usually (100% in this study) indicated life‐threatening conditions. Vitreous BHB was helpful evaluating cases with ketogenic conditions, especially diabetes and alcoholism.     

Fatal intoxication with 1,4-butanediol: Case report and comprehensive review of the literature

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) “Butandiol 1,4” (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.     

A mixed-drug intoxication involving venlafaxine and verapamil

This case report describes the suicide of a 52-year-old woman whose cause of death was attributed to a mixed-drug intoxication involving venlafaxine and verapamil. Venlafaxine is prescribed for the treatment of depression and should be used with caution in patients with cardiovascular disease. Verapamil is a calcium channel blocker primarily used for treatment of cardiovascular disorders. The following drug concentrations were determined in postmortem fluids: verapamil--3.5 mg/L (femoral blood), 9.4 mg/L (subclavian blood), and 1.0 mg/L (vitreous fluid); norverapamil--1.0 mg/L (femoral blood), 2.1 mg/L (subclavian blood), and 0.20 mg/L (vitreous fluid); verapamil and norverapamil could not be detected in bile or urine due to the high levels of erythromycin present; venlafaxine--6.2 mg/L (femoral blood), 8.6 mg/L (subclavian blood), 5.3 mg/L (vitreous fluid), 54.0 mg/L (bile), and 72.3 mg/L (urine); and O-desmethylvenlafaxine--5.4 mg/L (femoral blood), 8.3 mg/L (subclavian blood), positive (vitreous fluid), 29.2 mg/L (bile), and 9.5 mg/L (urine). The cause of death was determined to be a mixed-drug intoxication resulting from an overdose of verapamil and venlafaxine. The manner of death was determined to be suicide.     

Postmortem blood and vitreous humor ethanol concentrations in a victim of a fatal motor vehicle crash

A 20-year-old male was found on the passenger side of a small car after a collision with a semi-trailer truck. Postmortem blood, collected from the chest cavity, and vitreous humor samples were collected following harvesting of the heart and bones. Gas chromatographic analysis revealed a blood ethanol concentration of 0.32 g/dL and a vitreous humor ethanol concentration of 0.09 g/dL. The stomach was intact and full of fluid and food, but its contents were not collected. Possible explanations for the large difference between the two results include diffusion of ethanol from the stomach into the chest cavity, contamination of the blood sample prior to collection, and ingestion of a large quantity of ethanol shortly before death. This case demonstrates the importance of proper quality assurance procedures in collecting postmortem specimens and of collecting a vitreous humor sample for ethanol analysis in postmortem toxicology cases.