Myocardial disarray: an architectural disorganization linked with adrenergic stress?

BACKGROUND: Myocardial disarray is a structural abnormality found in specific zones of the normal heart. In some conditions, such as hypertrophic cardiomyopathy (HCM), its occurrence represents a pathological process leading to myocardial asynergy. The incidence of "pathological" myocardial disarray in humans is still not known. It has been suggested that a link exists between adrenergic overactivity and myocardial disarray. The aim of the present study is to compare heart findings in conditions with and without chronic sympathetic overtone for evidence of possible linkage in humans. MATERIALS AND METHODS: A total of 340 hearts were studied. They were divided into seven groups: sudden/unexpected coronary death; sudden/unexpected death in silent Chagas' disease; brain haemorrhage following berry aneurysm rupture; transplanted hearts; congestive heart failure, AIDS and cocaine abuse. Findings in these hearts were compared with anatomic changes in 92 control hearts, where the decedent had died from head trauma, electrocution, or carbon monoxide intoxication. The frequency and presence of myocardial disarray were recorded and correlated to heart weight, extent of myocardial fibrosis, and contraction band necrosis (CBN). RESULTS: Hearts from patients with conditions that increased sympathetic tone showed an association of myocardial disarray and contraction band necrosis without any relationship to heart weight. CONCLUSIONS: Myocardial disarray was observed in cardiac areas where it is not found normally. It was associated with adrenergic myocardial stress morphologically expressed by a higher number of foci (p<0.01) and myocells (p<0.001) with CBN versus findings in normal subjects. The condition deserves further study as a possible myocardial asynergic and arrhythmogenic factor especially in sudden/unexpected death.

Comparison of urine to sweat patch test results in court ordered testing.

A former cocaine and methamphetamine abuser was continuously monitored with both sweat patch and urine testing for approximately 6 months. Thirteen sweat patches were applied and collected, five were positive for cocaine and/or methamphetamine, but all the urine specimens collected were negative at the analytical cut-off levels. The high incidence of false positive sweat patch tests in relation to the sensitivity, specificity, and efficiency of the sweat patch assay is discussed. Possible mechanisms, which can lead to false positive results, are presented. The results of our study raise further questions about the preferential use of the sweat patch in detecting new episodes of drug use in formerly chronic drug users.

Drugs in postmortem adipose tissues: evidence of antemortem deposition.

INTRODUCTION: Drug concentration measured in postmortem adipose tissue may or may not reflect antemortem concentration. To examine the possibility of whether the presence of basic drugs in adipose tissue is the result of postmortem change, we examined: tissues with and without livor mortis, concentration gradients within the adipose layer, and the stability of drug concentrations during the postmortem period. CASE REPORTS: Five drug-related deaths with case histories and analytical data are presented. Adipose tissues with and without livor mortis from the thigh area of the same decedent were analyzed for cocaine. The cocaine concentration of the tissue exhibiting 4+ livor was equivalent to the concentration observed in tissue without livor. Analyses of cross sections of adipose tissues containing cocaine and methamphetamine disclosed that drug concentrations were equally distributed throughout the layer, from just beneath the dermis to directly above the muscle. When morphine and temazepam concentrations were measured in adipose tissues collected from similar sites, but at different times, from the same cadaver, they remained essentially the same over 3 days (approximately 80 h). CONCLUSIONS: Since concentrations were the same in areas with and without livor mortis, the possibility of redistribution into adipose from blood or vascular channels is eliminated. The absence of a concentration gradient within the adipose layer rules out diffusion or permeation from muscle into the adipose layer, and the failure of morphine or temazepam concentration to change over time indicates that drugs in the adipose tissue are stable during the postmortem interval. Our findings support the notion that drugs identified in postmortem adipose tissue are there because of antemortem deposition and not because of any postmortem change or event.

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.

Drug deposition in adipose tissue and skin: evidence for an alternative source of positive sweat patch tests.

In a series of licit and illicit drug-related deaths, qualitative and quantitative analyses on extracts of adipose tissue and skin were performed by GC/MS. In all cases, the adipose tissue was found to contain drugs at concentrations lower than, approximately equal to, or even greater than the concentrations of the same analytes found in the blood, which may reflect a consequence of long-term chronic exposure, or acute intoxication, or some combination of both. Approximately one cubic inch of skin with adipose tissue was removed from the mid to lower abdominal region adjacent to the midline incision during autopsy. The drugs were recovered from the specimens following incubation and alkaline, acidic, and alkaline chloroform back extraction of one to three grams of tissue. Deuterated analogs of the analytes were added to the matrix at the beginning of the incubation period. Cocaine and free morphine (from heroin) were readily identified in several cases. The presence of these illicit drugs in adipose tissue raises significant forensic questions, especially the use of 'sweat patches' to monitor recent cocaine or heroin use in chronic drug users.

Toxicology and pathology of deaths related to methadone: retrospective review.

OBJECTIVES: To clarify the mechanisms and risk factors of methadone toxicity and to describe the findings of deaths related to methadone use Design Retrospective review of case notes in the records of the San Francisco Medical Examiner comparing the findings in cases where methadone was deemed the cause of death with findings in decedents where methadone was an incidental finding, and with 50 age-matched, disease and drug free, trauma victims. RESULTS: 38 cases out of the 3317 processed by our office during 1997-1998 were identified in which methadone had been detected. Cases were mostly male 28/38 (74%) and white, 28/38 (74%). In 17 of 38 cases death was deemed to have been caused by methadone toxicity. For the group the mean blood methadone concentration for all 38 patients, was 957 ng/ml SD = .681, SE = .14). The mean blood concentration of the main methadone metabolite (EDDP) was 253 ng/ml, SD = 529 ng/ml, SE = .089. The mean ratio of methadone in the blood to EDDP in the blood was 13.6:1 Values were not significantly different between cases in which methadone toxicity was the cause of death and in those in which it was an incidental finding. Cocaine, or the cocaine metabolite benzoylecgonine, was detected in the blood or urine of 16/38 cases (42%); morphine in one-third (13/38) and methamphetamine in only one. Pulmonary edema was evident in all cases, coronary artery disease in 9/38 (24%) and cirrhosis in 7/38 (18%) of the methadone users. Necrotizing fasciitis was the cause of death in 4 of the 38 methadone users (11%). Nationally, a sizeable percent of methadone deaths are from drugs diverted from treatment programs. CONCLUSIONS: The presence of methadone is often an incidental finding during postmortem examination which is unrelated to the cause of death. Postmortem measurements of methadone or its metabolite, or both, cannot be used in isolation to identify which deaths are associated with methadone toxicity.

Cocaine metabolism in hyperthermic patients with excited delirium.

The half-life of cocaine in clinical experiments has been reported to range from 60 to 90 min. It has been previously suggested that elevated temperature may accelerate the metabolism of cocaine. However, there is no clinical data to indicate the presence of hyperthermia like that seen in excited delirium alters the half-life of cocaine. We report the results of half-life determinations from serial cocaine concentrations in two patients with excited delirium. Both patients presented to the emergency department with classic findings of excited delirium that included hyperthermia, agitation, and cardiovascular aberrations. One patient died despite aggressive therapeutic intervention. Cocaine and metabolite concentrations were determined by an extractive alkylation mass spectrometry procedure. Presenting cocaine concentrations in patient 1 and patient 2 were 0.387 and 0.266 mg/L respectively. Results from pharmacokinetic modeling of the serial concentrations show that the half-life of cocaine was not significantly accelerated, despite the presence of hyperthermia. Data from these two cases provide further evidence that catastrophic reactions to cocaine are independent of amount or route of administration, and that the metabolism of cocaine, at least in these patients, was not altered by hyperthermia.

Methamphetamine-related deaths in San Francisco: demographic, pathologic, and toxicologic profiles.

A study was undertaken to develop demographic, toxicologic, and pathological profiles of methamphetamine-related deaths. Anatomic and toxicologic findings in 413 deaths where methamphetamine was detected were compared with findings in a control group of 114 drug-free trauma victims. The number of cases per year did not change significantly over the course of the study. Mean age was 36.8 years, but 11% were over the age of 50. Decedents were overwhelmingly male (85.2%) and Caucasian (75%). Blood concentrations of methamphetamine and amphetamine were indistinguishable in cases where methamphetamine was related to the cause of death (MR) and cases where it was not (non-MR) (2.08 vs. 1.78 mg/L, p = 0.65, and 0.217 vs. 0.19 mg/L, p = 0.82). Coronary artery disease, ranging from minimal to severe multivessel, was identified in 79 of the 413 drug users, but in only six of the 114 drug-free controls (p = 0.0004), and MR decedents had enlarged hearts compared with controls. There were also ten cases of subarachnoid and intracranial hemorrhage in the MR group. Abnormalities of the liver (34%) and lungs (24.7%) were frequent. In 65% of these cases, death was due to accidental methamphetamine toxicity. In the remaining cases, methamphetamine was an incidental finding. We conclude that, in our jurisdiction, neither the rate of detection nor the number of methamphetamine deaths has increased significantly in the past 13 years. Decedents are almost all Caucasian males, and many were approaching middle-age. Methamphetamine use is strongly associated with coronary artery disease and with subarachnoid hemorrhage.

Does ethanol enhance cocaine toxicity?

OBJECTIVES: Results of in vitro and animal studies suggest that ethanol enhances cocaine toxicity. If so, then that this implies that in ethanol users, postmortem blood cocaine concentrations should be lower, or anatomic evidence demonstrable. METHODS: Drug concentrations and autopsy findings were compared in a sample of 72 accidental deaths, where only cocaine, cocaine metabolites, and ethanol were detected. Findings in ethanol positive (E+) and negative (E-) deaths were compared using multiple Student's t-tests and chi2 testing for categorical variables. RESULTS: There were 47 E-decedents and 24E+. Mean ages were similar (40.2 +/- 8.7 and 37.5 +/- 11.1 years respectively). Mean E was 0.113 (range 0.030-0.350 g/dL), and less than 0.080 g/dL in 50% of the cases. Concentrations of C and BE were not significantly different in E- and E+ groups (C = 1.40 +/- 3.6 mg/L, and 0.76 +/- 1.93 mg/L respectively, BE = 3.04 +/- 5.36 mg/L and BE 2.09 +/- 3.77 mg/L, P = 0.4621 and 0.4520). Organ weights were pathologically increased in both groups, but not significantly different. Body Mass Index (BMI) was less (23.9 vs 25.5), and heart weight was greater (449 vs 407 g) than predicted. Over half the decedents had demonstrable heart disease, and 11% died of brain haemorrhage, though the rate for both disorders was similar in each group. CONCLUSIONS: In two-thirds of the cocaine-related deaths studied, no ethanol was detected. When ethanol was present, no differences between the two groups were identified. The findings suggest that acute cocaine toxicity is not enhanced by ethanol cocaine interactions. However, ethanol concentrations were generally low, and it is possible that increased toxicity is apparent when much larger quantities of alcohol have been consumed.

Diphenhydramine toxicity: comparisons of postmortem findings in diphenhydramine-, cocaine-, and heroin-related deaths.

Diphenhydramine (DPH)-related deaths in adults are extremely rare, and detailed autopsy studies are rarer still. Toxicologic and anatomic findings in 4 cases of suicidal DPH overdose are described and compared with findings in a database of cocaine- and heroin-related deaths. Blood DPH levels were many times higher than those considered therapeutic (5000-35,000 ng/ml versus 50-100 ng/ml). Marked pulmonary edema with visceral congestion was a constant finding. Mean lung-body weight ratios for DPH, cocaine, heroin, and trauma controls were 0.015, 0.015, 0.019, and 0.013, respectively. When normalized for body weight in this fashion, edema in DPH-related deaths was comparable to that in cocaine-related deaths. Cardiac enlargement was apparent in 3 of the 4 DPH cases, 1 with marked myocardial fibrosis. The finding of increased heart size suggests that preexisting heart disease may provide the necessary substrate for lethal cases of DPH toxicity. Pulmonary edema in these cases remains unexplained, with edema in cases of heroin-related toxicity significantly worse than that produced by cocaine or DPH (p < .0001). Because DPH and cocaine can exert similar effects on the heart, a common mechanism may produce pulmonary edema in both. A different mechanism may account for heroin-related edema.

Response times and outcomes for cardiac arrests in Las Vegas casinos.

This study was conducted to measure emergency medical services (EMS) response times in sudden out-of-hospital cardiac arrests and relate those times to probability of survival in cardiac arrest victims in Las Vegas casino-hotels from January 1993 to June 1996. Times from 911 activation to casino arrival and casino arrival to arrival at patient's side (time to first defibrillatory shock), as well as survival to hospital discharge, were studied with regression analysis. Sixty patients survived (29.3%). Response times to the hotels for survivors and nonsurvivors were similar (4.8 v 5.6 min, P = .44). However, times from arrival at the casino to arrival at the patient's side (5.0 v 6.88 min, P = .01) and elapsed times from 911 activation until first shock (9.88 v 12.46 min, P = .02) were substantially longer for nonsurvivors. Model fitting disclosed that with a 911-to-shock time of 4 minutes, survival probability was 36%. Odds decreased by 5% each minute, to 19% after 23 minutes. Ventricular fibrillation was the most common initial rhythm (187 cases) and was associated with the shortest times from 911 to shock (10.7 +/- 7.8 min). There was a strong trend to increased survival with ventricular fibrillation. The 911-to-shock times in this study are considerably better than in other published reports for large metropolitan EMS systems, but the time from 911 to shock was nearly 3 minutes longer for nonsurvivors, and even those defibrillated at 4 minutes had only a 36% chance of survival. New measures, including use of the automatic external difibrillator, to reduce the "vertical" response are urgently needed.

Relating cocaine blood concentrations to toxicity--an autopsy study of 99 cases.

UNLABELLED: We conducted a retrospective study of 48 men with cocaine-related deaths (CTOX), and a control group of 51 male cocaine users who died of lethal trauma (TRAU). Regression analysis and multiple t-tests were used to assess the relationship between cocaine and benzoylecgonire concentrations as well as autopsy measurements. FINDINGS: Mean age was similar (35.9 vs 34.8 years, p = .549). Cocaine blood concentrations were not significantly different (1.12 vs .487 mg/L, p = .10), but mean BE concentrations were higher in CTOX (1.54 vs .946 mg/L, p = .018). CTOX decedents had a lower Body Mass Index (BMI) (24.6 vs 30.6, p = < .0001), larger hearts (426 vs 369, p = .009), and heavier lungs, livers, and spleens (1275 g vs 1007 g, p = .009, 1896 g vs 1628 g, p = .008, 193 g vs 146 g, p = .001). CONCLUSIONS: (1) Blood cocaine concentrations in cocaine-related deaths are indistinguishable from postmortem concentrations in recreational users, but BE is higher in cocaine-related deaths. (2) Increased lung, liver and spleen weights are consistent with cocaine induced heart failure, but (3) Decreased BMI and increased heart weights in CTOX must be a consequence of long term cocaine use. Cardiac alterations may explain why equal blood cocaine concentrations may be lethal in some cases and innocuous in others, (4) Isolated measurements of postmortem cocaine and BE blood concentrations cannot be used to assess, or predict toxicity.

Field intubation of trauma patients: complications, indications, and outcomes.

Neither the success nor the complication rate for field intubation of trauma patients is known with any certainty. A retrospective audit of 94 severely injured patients who required field intubation was undertaken. Fifty percent (13 of 26) of survivors and 67% (37 of 71) of nonsurvivors were successfully intubated in the field (not significant). Mechanism of injury was similar in both groups, but survivors were younger (27 v 60 years, P= .049) and less critically injured, as reflected by their Injury Severity Scale scores, their Trauma Scores, and their field Glasgow Coma Scale scores (22.1 v 30.8, P = .0035; 7.7 v 4.2, P < .0002; and 6.3 v 3.3, P < .0001). When compared with previously published studies of medical patients with cardiac arrest, the success rate was lower in our trauma patients. When compared with patients having similar injuries intubated at the trauma center, field intubation was three times more likely to be associated with the development of nosocomial pneumonia than was hospital intubation.

Cocaine-associated agitated delirium and the neuroleptic malignant syndrome.

The incidence of this previously rare disorder, cocaine-associated agitated delirium, appears to have increased drastically within the last 18 months. The underlying neurochemical abnormalities have recently been characterized, but most clinicians have had little experience with management of agitated delirium. The basic clinical and pathological features of this disorder are reviewed, and common pitfalls in diagnosis and management that frequently lead to needless but very expensive litigation are discussed.