Fatality from olanzapine induced hyperglycemia

A case history of a 31-year-old male schizophrenic patient is presented. The man was treated with olanzapine for three weeks before he died. After one week on a 10 mg daily dose of olanzapine, his fasting blood glucose was elevated to 11.3 mmol/L (203 mg/dL). In order to treat more aggressively his psychosis, the olanzapine dose was raised to 20 mg daily resulting in his fasting blood glucose climbing to 15.8 mmol/l (284 mg/dL). On the days preceding his death, he became progressively weaker, and developed polydipsia with polyuria. He had no personal or family history of diabetes mellitus and he was on no other medication at the time of his death. Postmortem blood, vitreous humor, and urine glucose concentrations were 53 mmol/L (954 mg/dL), 49 mmol/L (882 mg/dL), and 329 mmol/L (5922 mg/dL), respectively. Drug screen on urine and blood indicated only a small amount or olanzapine and no alcohols. Peripheral blood olanzapine concentration was within therapeutic limits, 45 ng/mL. Analysis of vitreous humor and urine revealed severe dehydration with small amounts of ketones. Death was attributed to hyperosmolar nonketotic diabetic coma, and olanzapine was felt most likely to be the cause. Another atypical neuroleptic, clozapine, has also been associated with the development and exacerbation of diabetes mellitus or diabetic ketoacidosis. We recommend including vitreous glucose and beta-hydroxybutyrate analysis as part of postmortem toxicology work up when the drug screen reveals the presence of either olanzapine or clozapine.     

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.     

Polydrug fatality involving metaxalone

A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.     

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.     

Hypothermia: autopsy findings and vitreous glucose

Anatomic lesions associated with hypothermia are variable and nonspecific. Only a few gross lesions and no microscopic pathology were noted in the acute deaths of this series. An interesting anatomic observation was the low weight of the lungs in 45% of the hypothermic deaths. Hypothermia is recognized as frequently producing hyperglycemia and 80% of a group of such patients clinically treated at the Hennepin County Medical Center had elevated blood sugar values. This correlates with an average vitreous glucose of 82.6 mg/dL in the hypothermic deaths. By contrast, the average vitreous glucose value found in each of two separate control groups was 37 mg/dL. Establishing hypothermia as the cause of death requires a proper history of exposure and the absence of any other clear-cut lethal factor. Certain biochemical tests may provide supporting evidence. Among these is an elevated vitreous glucose in a nondiabetic individual.     

Infant Death Following Home Birth: A Case Report of Fatal Neonatal Hypoglycemia

Infants born to diabetic mothers are at increased risk for symptomatic hypoglycemia and death after birth. A 36-year-old G4P3 mother with a history of gestational diabetes and newly diagnosed type II insulin-dependent diabetes gave birth at home, in the care of a midwife, to a macrosomic infant girl (10 lbs.). Several hours after birth, the infant became lethargic and was found to be hypoglycemic (blood sugar: 28 mg/dL). Glucose and sugar water were administered by the midwife; however, the infant continued to decompensate. Emergency medical services were called, and the infant was transported to the hospital where, despite resuscitative efforts, she died. An autopsy and review of the literature was performed. At autopsy, characteristic features of maternal–fetal glucose dysregulation were identified, including fetal macrosomia, cardiomegaly, hepatomegaly, and severe pancreatic islet cell hypertrophy/hyperplasia. Developmental abnormalities and other potential causes of death were not identified. Although deaths due to hypoglycemia cannot be reliably diagnosed postmortem using vitreous glucose levels, a clinical history of maternal glucose dysregulation in combination with certain gross and histologic findings should prompt a pathologist to consider maternal–fetal glucose dysregulation as a diagnosis of exclusion and cause of death.     

HbA1c as a postmortem tool to identify glycemic control

Estimates suggest that more than 5A million U.S. citizens unknowingly have diabetes and are at increased risk of morbidity and mortality. We evaluated an immunoturbidimetric measurement of glycated hemoglobin (%HbA1c) as a postmortem tool to identify such individuals. Although postmortem samples undergo some degradation, the effects are not sufficient to invalidate the use of the test or method. Using two study populations whose medical history of diabetes was known, we found the mean %HbA1c of the non-diabetics (5.8+/-0.3) to be statistically different from that of the diabetics (12.4+/-2.8). For the population whose disease status was unknown, the %HbA1c ranged from 4.7 to 16.8. For six unknowns whose values exceeded 7.0%. the mean was 11.7%, which did not differ statistically from the diabetic mean (p = 0.6615). These studies suggest that postmortem blood samples can be used to characterize HbA1c values.     

Clinical and forensic examinations of glycemic marker 1,5-anhydroglucitol by means of high performance liquid chromatography tandem mass spectrometry

Postmortem diagnosis of diabetes and a diabetic coma can be difficult because of the lack of characteristic morphological findings. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for reabsorption in the kidneys. Therefore, diabetics with a permanent hyperglycemia show significantly lower serum concentrations of 1,5-AG than non-diabetics. A liquid chromatography-mass spectrometric method for the determination of 1,5-AG in serum and postmortem blood was developed and validated according to international guidelines. Linearity was given between 1μg/ml and 50μg/ml. Recovery rates ranged between 70.8% and 89.8%, the limit of quantification of the procedure was 0.20μg/ml, limit of quantification was 0.55μg/ml. Serum of 199 diabetics and 116 non-diabetics and femoral blood of 31 diabetic and 27 non-diabetic deceased was measured. Average concentrations were significantly (p<0.001) higher in non-diabetics compared to diabetics ante and postmortem. Seven of the diabetics may have died because of a hyperglycemic coma indicated by a sum formula of Traub>450mg/dl. 1,5-AG average concentrations in these deceased were not significantly different to diabetics which did not die because of a diabetic coma. Concentrations of 1,5-AG give a hint for not well controlled diabetes antemortem and postmortem and can be assumed as an additional and alternative information postmortem to the measurement of HbA1c or fructosamine.     

Biochemical measurements of glucose metabolism in relation to cause of death and postmortem effects

This study was performed to examine the relationship between postmortem biochemical values and cause of death. The follow samples were taken from 399 corpses: cerebrospinal fluid (CSF; n = 376, suboccipital), blood (n = 158, femoral vein), and urine (n = 101, at autopsy). (See Table 1 for causes of death) All samples were stored at -80 degrees C. A further 100 samples of blood were later taken and stored at +4 degrees C before testing. Biochemical determinations made were: glucose in CSF, blood, and urine (hexokinase method); lactate (LDH/GPT) and free acetone (HS-gas chromatography) in CSF; hemoglobin A1 in blood (microcolumn technique). In 34 cases fatal diabetic coma was considered verified by morphological and chemical findings. One hundred cases of sudden cardiac death were chosen as the main control group. In 32 of the 34 cases defined above, the value of the formula of Traub (glucose + lactate in CSF) exceeded 415 mg/dl. It is not influenced significantly by hyperglycemia or hyperlactatemia due to factors other than diabetes (i.e., carbon monoxide, asphyxia). After death the value rose till the 30th hpm, then remained stable for at least 1 week. Fatal coma was defined as the ketoacidotic form if free acetone in CSF ranged above 21 mg/l. In these cases, CSF glucose and free acetone correlated positively. Hemoglobin A1 remained stable after death. Its amount was independent from postmortem blood glucose, postmortem interval and total hemoglobin. Furthermore, the manner of storage (-80 degrees or +4 degrees C) had no significant influence on its values. In 29 of 34 cases of fatal coma, Hb A1 exceeded 12.1%. Analysis of urine glucose showed elevated levels (over 500 mg/dl) in diabetic comas. On conclusion, fatal diabetic coma seems indicated as the cause of death if measured values of postmortem biochemistry exceed the following limits: CSF-Traub 415 mg/dl, free acetone (CSF) 21 mg/l; Hb A1 12.1%; urine glucose 500 mg/dl. Most important are the Traub formula and hemoglobin A1. Usually, in fatal coma both values are elevated. If both of them are normal, diabetic coma can nearly be excluded. Combined evaluation of all values is absolutely necessary. Morphology must also always be taken into account. Consequently, a diagnosis of fatal coma can be obtained by a process of elimination.     

Glycated hemoglobin: a useful post-mortem reference marker in determining diabetes

Glycated hemoglobin (HbA(1c)) has been demonstrated to be a useful marker for long-term glucose control in diabetes. This parameter characterizes each non-enzymatic fixation of glucose on hemoglobin. It is a useful test in addition to periodic glycemia controls since it reflects the mean glycemia of the past 60 days. We studied the conservation of HbA(1c) at 4 degrees C as a function of time with different anti-coagulants and preservatives (3, 6 months, 1 year). A total of 106 tests were performed using the high performance liquid chromatography (HPLC) method dedicated to the semi-automatic analysis of HbA(1c) (Bio-Rad) and we applied the method in forensic cases. Conservation at 4 degrees C was good for as long as 3 months in blood samples collected with fluoride and 6 months in samples collected in a dry or in a heparinized tube. In non-diabetic subjects, HbA(1c) reference values obtained from forensic samples were identical to those of living controls (3.5-6.25% of total hemoglobin). All positive HbA(1c) results were confirmed by a medical evaluation. This method was successfully applied to five forensic cases. In cases of increased acetonemia, acetone or isopropanol are easily measured. However, in some unexplained post-mortem circumstances, increased HbA(1c) permits to differentiate alcoholic or starvation ketoacidosis from the diabetic cases. Glycated hemoglobin should, therefore, be considered the forensic marker of choice in the post-mortem diagnosis of a diabetic disorder and demonstrates its usefulness in post-mortem validation.     

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.     

Cocaine and sudden "natural" death

The cardiovascular effects of cocaine may culminate in clinical episodes of angina pectoris, myocardial infarction, arrhythmias, and intracranial hemorrhage. To clarify whether or not cocaine causes fatalities by these mechanisms, we studied 24 cases of sudden, apparently natural deaths as a result of coronary arteriosclerosis (15 cases), hypertensive cardiovascular disease (4 cases), and intracranial hemorrhage (5 cases) associated with cocaine use. In 11 cases, cocaine was found in the blood (average concentration: 0.57 mg/L, range: 0.05 to 1.45 mg/L), whereas in the remainder, cocaine or its major metabolite was found in the urine or other tissues. In the majority of decedents, autopsy disclosed the existence of severe natural disease which could have been exacerbated by the administration of stimulant drugs, including cocaine. These data, and a review of the current medical literature, indicate that cocaine may precipitate the sudden death of an individual with undiagnosed cardiovascular disease. A contributory role of cocaine should be considered in any apparently natural death occurring in a population where cocaine abuse is prevalent.     

Measurement of Postmortem 1,5‐anhydroglucitol in Vitreous Humor for Forensic Diagnosis

In forensic diagnosis, postmortem blood glucose is known to be susceptible to change after death. However, the 1,5‐anhydroglucitol (1,5‐AG) concentrations in plasma and cerebrospinal fluid (CSF) reflect the mean blood glucose level for a short period of time. In this study, we compared the postmortem 1,5‐AG concentrations in vitreous humor and CSF in 47 subjects to evaluate the utility of this concentration in the vitreous humor for forensic diagnosis. The postmortem 1,5‐AG concentrations in vitreous humor (mean±SD: 20.2 ± 8.7 μg/mL) and CSF (16.8 ± 8.7 μg/mL) did not differ significantly and showed a strong correlation (r² = 0.87, p < 0.01). These results suggest that the vitreous humor 1,5‐AG concentration provides useful information on the antemortem blood glucose level, in addition to the HbA1c value and the CSF 1,5‐AG concentration.     

GHB. Club drug or confusing artifact?

GHB can be produced either as a pre- or postmortem artifact. The authors describe two cases in which GHB was detected and discuss the problem of determining the role of GHB in each case. In both cases, NaF-preserved blood and urine were analyzed using gas chromatography. The first decedent, a known methamphetamine abuser, had GHB concentrations similar to those observed with subanesthetic doses (femoral blood, 159 microg/ml; urine, 1100 microg/ml). Myocardial fibrosis, in the pattern associated with stimulant abuse, was also evident. The second decedent had a normal heart but higher concentrations of GHB (femoral blood, 1.4 mg/ml; right heart, 1.1 mg/ml; urine, 6.0 mg/ml). Blood cocaine and MDMA levels were 420 and 730 ng/ml, respectively. Both decedents had been drinking and were in a postabsorptive state, with blood to vitreous ratios of less than 0.90. If NaF is not used as a preservative, GHB is produced as an artifact. Therefore, the mere demonstration of GHB does not prove causality or even necessarily that GHB was ingested. Blood and urine GHB concentrations in case 1 can be produced by a therapeutic dose of 100 mg, and myocardial fibrosis may have had more to do with the cause of death than GHB. The history in case 2 is consistent with the substantial GHB ingestion, but other drugs, including ethanol, were also detected. Ethanol interferes with GHB metabolism, preventing GHB breakdown, raising blood concentrations, and making respiratory arrest more likely. Combined investigational, autopsy, and toxicology data suggest that GHB was the cause of death in case 2 but not case 1. Given the recent discovery that postmortem GHB production occurs even in stored antemortem blood samples (provided they were preserved with citrate) and the earlier observations that de novo GHB production in urine does not occur, it is unwise to draw any inferences about causality unless (1) blood and urine are both analyzed and found to be elevated; (2) blood is collected in NaF-containing tubes; and (3) a detailed case history is obtained.     

A fatal poisoning involving Bromo-Dragonfly

This paper reports a fatal overdose case involving the potent hallucinogenic drug Bromo-Dragonfly (1-(8-bromobenzo[1,2-b; 4,5-b′]difuran-4-yl)-2-aminopropane). In the present case, an 18-year-old woman was found dead after ingestion of a hallucinogenic liquid. A medico-legal autopsy was performed on the deceased, during which liver, blood, urine and vitreous humour were submitted for toxicological examination. Bromo-Dragonfly was identified in the liver blood using UPLC–TOFMS, and was subsequently quantified in femoral blood (0.0047 mg/kg), urine (0.033 mg/kg) and vitreous humour (0.0005 mg/kg) using LC–MS/MS. Calibration standards were prepared from Bromo-Dragonfly isolated from a bottle found next to the deceased. The structure and purity of the isolated compound were unambiguously determined from analysis of UPLC–TOFMS, GC–MS, HPLC–DAD, ¹H and ¹³C NMR data and by comparison to literature data.The autopsy findings were non-specific for acute poisoning. However, based on the toxicological findings, the cause of death was determined to be a fatal overdose of Bromo-Dragonfly, as no ethanol and no therapeutics or other drugs of abuse besides Bromo-Dragonfly were detected in the liver, blood or urine samples from the deceased. To our knowledge, this is the first report of quantification of Bromo-Dragonfly in a biological specimen from a deceased person. This case caused the drug to be classified as an illegal drug in Denmark on 5th December 2007.     

Dispensing error causing fatal chlorpropamide intoxication in a nondiabetic

A 38-year-old nondiabetic female developed fatal hypoglycemia when chlorpropamide (Diabinese) was accidentally substituted for acetaminophen (Tylenol) with codeine no. 3 in a pharmacy dispensing error. When found, the patient's serum glucose was less than 20 mg/dL. The serum chlorpropamide level on hospital admission was 124 micrograms/mL. The possibility of dispensing error should be considered whenever unexpected drug effects are encountered. In cases of suspected drug overdose, labels and contents of medicine vials found at the scene should be checked for discrepancy.