Three homicides with darts tainted with succinylcholine: autopsy and toxicology.

In emergency departments, intoxication with the muscle relaxant succinylcholine (SUX) often leads to a potentially lethal respiratory paralysis or other deleterious side effects. However, homicide cases with SUX poisoning are very rare because the toxic or lethal concentration ranges of SUX have not yet been determined. We described three uncommon homicide cases due to acute poisoning by darts contaminated with SUX. All the victims died quickly (less than 30 min) after being shot by an especially designed dart gun. Succinylmonocholine (SMC), a metabolite of SUX, was used as a marker to detect the latter. HPLC-MS/MS analysis demonstrated the presence of SUX in the droplet residues of the darts and SMC in the blood and urine in all cases. SMC concentrations of 0.45, 14.0, and 17.9 ng/ml were detected in the victims' blood and 259.0 ng/ml in the urine from the third case. The main pathological changes consisted of hemorrhage of the injured soft tissues, visceral congestion, severe pulmonary edema, and multifocal petechial hemorrhage of the heart and lungs. Taken together, the findings supported a diagnosis of fatal SUX poisoning. Futhermore, our study provided a reference for the lethal concentrations of SUX poisoning.

Domoic acid epileptic disease.

Domoic acid epileptic disease is characterized by spontaneous recurrent seizures weeks to months after domoic acid exposure. The potential for this disease was first recognized in a human case study of temporal lobe epilepsy after the 1987 amnesic shellfish-poisoning event in Quebec, and was characterized as a chronic epileptic syndrome in California sea lions through investigation of a series of domoic acid poisoning cases between 1998 and 2006. The sea lion study provided a breadth of insight into clinical presentations, unusual behaviors, brain pathology, and epidemiology. A rat model that replicates key observations of the chronic epileptic syndrome in sea lions has been applied to identify the progression of the epileptic disease state, its relationship to behavioral manifestations, and to define the neural systems involved in these behavioral disorders. Here, we present the concept of domoic acid epileptic disease as a delayed manifestation of domoic acid poisoning and review the state of knowledge for this disease state in affected humans and sea lions. We discuss causative mechanisms and neural underpinnings of disease maturation revealed by the rat model to present the concept for olfactory origin of an epileptic disease; triggered in dendodendritic synapases of the olfactory bulb and maturing in the olfactory cortex. We conclude with updated information on populations at risk, medical diagnosis, treatment, and prognosis.

Nurse induced respiratory depression by succinylcholine--the 'hero syndrome'.

A nurse administered the neuromuscular blocking agent succinylcholine (SUX) to at least one patient and gave first aid in the therapy of unexpected respiratory depression. SUX is regarded as an undetectable and thus perfect poison due to its short half-life and degradation to the endogenous compounds choline and succinic acid. However, SUX and especially its metabolite succinylmonocholine (SMC) were found in plasma and urine a few hours after administration by means of high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Compared to clinical studies, the window of detection was sufficient to gain definite proof; in other cases no samples were collected. The nurse enjoyed high reputation with the doctors. According to the court she wanted to present herself spectacularly as the first and decisive rescuer to demonstrate her special abilities and capacities, perhaps to receive a better job in the hospital. Considering the actual case, the hero syndrome is not limited to fire-fighters.

Applicability of succinylmonocholine as a marker for succinylcholine administration--comparative analysis of samples from a fatal succinylcholine-intoxication versus postmortem control specimens.

Doubts concerning the applicability of succinylmonocholine (SMC) as a succinylcholine (SUX) marker have been issued. A comparative analysis of previously discussed tissues, i.e. brain, liver and kidney, was conducted to further elucidate this question by searching for diagnostically useful differences in analyte content in samples of SUX- versus non-SUX-associated fatalities. Furthermore, possible advantages of vitreous humor as a novel and promising target matrix for SUX analytics were assessed. Sample material of SUX-negative controls as well as the fatal SUX-intoxication was derived from frozen archive material and current autopsies. Samples were analyzed according to a modified protocol of a previously published and validated method employing ion-pairing solid-phase extraction and subsequent HPLC-MS/MS analysis. Standard addition was employed for quantification as well as an estimation of the analytical limits of the method. In all tested matrices, the method was proven to be sufficiently sensitive for the intended application. No indication of native SMC was found in controls of fresh tissues, nor in fresh or frozen vitreous humor. However, most of the samples were found to be positive for a previously reported interference with SMC's main ion transition, thereby falsely suggesting an SMC content of up to 139 ng/g, 126 ng/g, 165 ng/g and 93 ng/ml in brain, liver, kidney and vitreous humor, respectively. Contrasting the results for fresh sample material, SMC was detectable in some of the initially non-putrefied liver samples after long-term storage, as well as in massively decomposed SUX-negative control bodies. In this context, a microbial origin of the analyte may be assumed. All tissues as well as the vitreous humor of the fatal SUX-intoxication were negative for SUX and SMC. Just like serum, tissue and vitreous humor samples therefore do not allow a reliable diagnosis of a SUX-intoxication: in tissues this is due to the pronounced instability of both target analytes in these esterase-containing matrices, for vitreous humor an additional reason could be their insufficient incorporation into this medium.

Euthanasia in patients dying at home in Belgium: interview study on adherence to legal safeguards.

BACKGROUND: Euthanasia became legal in Belgium in 2002. Physicians must adhere to legal due care requirements when performing euthanasia; for example, consulting a second physician and reporting each euthanasia case to the Federal Review Committee. AIM: To study the adherence and non-adherence of GPs to legal due care requirements for euthanasia among patients dying at home in Belgium and to explore possible reasons for non-adherence. DESIGN OF STUDY: Large scale, retrospective study. SETTING: General practice in Belgium. METHOD: A retrospective mortality study was performed in 2005-2006 using the nationwide Belgian Sentinel Network of General Practitioners. Each week GPs reported medical end-of-life decisions taken in all non-sudden deaths of patients in their practice. GP interviews were conducted for each euthanasia case occurring at home. RESULTS: Interviews were conducted for nine of the 11 identified euthanasia cases. Requirements concerning the patient's medical condition were met in all cases. Procedural requirements such as consultation of a second physician were sometimes ignored. Euthanasia cases were least often reported (n = 4) when the physician did not regard the decision as euthanasia, when only opioids were used to perform euthanasia, or when no second physician was consulted. Factors that may contribute to explaining non-adherence to the euthanasia law included: being unaware of which practices are considered to be euthanasia; insufficient knowledge of the euthanasia law; and the fact that certain procedures are deemed burdensome. CONCLUSION: Substantive legal due care requirements for euthanasia concerning the patient's request for euthanasia and medical situation were almost always met by GPs in euthanasia cases. Procedural consultation and reporting requirements were not always met.

Mad honey sex: therapeutic misadventures from an ancient biological weapon.

STUDY OBJECTIVE: "Mad honey" poisoning occurs from ingestion of honey produced from grayanotoxin-containing nectar, often in the setting of use as an alternative medicine. This study is designed to assess the clinical effects, demographics, and rationale behind self-induced mad honey poisoning. METHODS: The study consisted of 2 components: a standardized chart review of the signs, symptoms, and treatment of patients with mad honey ingestion, treated in our emergency department between December 2002 and January 2008; and a cross-sectional survey of a convenience sample of beekeepers specializing in the production and distribution of mad honey. RESULTS: We identified 21 cases. Patients were overwhelmingly men (18/21) and older (mean [SD]), 55 [11] years. Local beekeepers (N=10) ranked sexual performance enhancement as the most common reason for therapeutic mad honey consumption in men aged 41 through 60 years. Symptoms began 1.0 hour (SD 0.6 hour) after ingestion and included dizziness, nausea, vomiting, and syncope. Abnormal vital signs included hypotension (mean arterial pressure 58 mm Hg [SD 13 mm Hg]) and bradycardia (mean 45 beats/min [SD 9 beats/min]). Seventeen patients had sinus bradycardia and 2 had junctional rhythm. Nine patients were treated with atropine; 1 patient received dopamine. All patients were discharged 18 to 48 hours after admission. CONCLUSION: A dietary and travel history should be included in the assessment of middle-aged men presenting with bradycardia and hypotension. A mad honey therapeutic misadventure may be the cause rather than a primary cardiac, neurologic, or metabolic disorder.

Poisoning necessitating pediatric ICU admissions: size of pupils does matter.

INTRODUCTION: Childhood poisonings are common, but usually trivial, and infrequently necessitate intensive care unit (ICU) admissions. METHODS: A retrospective record review was conducted to analyze the pattern of severe poisoning-associated ICU admissions at a teaching hospital between May 2002 and December 2007. RESULTS: Six cases (4 boys and 2 girls, aged 2 months to 11 years) of drug poisoning-associated ICU admissions were identified. Methadone was the culprit in 3 boys and 1 girl, resulting in respiratory failure, depressed conscious state and pinpoint pupils. As relevant exposure history was not immediately apparent, diagnosis at the emergency department was only made correctly in 2 patients. Phenobarbitone overdose occurred in 1 girl with past history of phenobarbitone overdose as a clue. She was also considered to have pinpoint pupils that were unresponsive to naloxone. Features consistent with cholinergic toxidrome, including small pupils, and increased secretion occurred in an infant fed with milk prepared with an herbal broth suspected to have been adulterated with a pesticide. Atropine as an antidote was used when the child was in the pediatric ICU. All children made an uneventful recovery following their short ICU stay. CONCLUSIONS: Life-threatening poisonings requiring ICU support can pose diagnostic difficulties and challenges to frontline medical officers at the emergency department. Children from all age groups can be affected. Prompt diagnosis is based on relevant history, careful clinical examination and a high index of suspicion in patients known to be at risk. The pupillary size and its reaction following treatment serves as an important diagnostic clue.

A fully validated isotope dilution HPLC-MS/MS method for the simultaneous determination of succinylcholine and succinylmonocholine in serum and urine samples.

A high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method for the simultaneous detection of succinylcholine (SUX) and its metabolite succinylmonocholine (SMC) in serum and urine is presented. For internal standardization using isotope dilution, the deuterated compounds SUX-d(18) and SMC-d(3) were employed. Full validation was performed according to international guidelines. Solid-phase extraction (SPE) of acidified samples was accomplished using Strata-X polymeric reversed phase cartridges together with heptafluorobutyric acid (HFBA) as ion-pairing reagent. Separation was achieved within 13 min on a Phenomenex Synergi Hydro RP C18 column (4 microm, 150 x 2 mm) using a gradient of 5 mM ammonium formate buffer pH 3.5 and acetonitrile.To ensure the method's applicability in forensic as well as clinical toxicology, the specific demands of both research fields were taken into account, and the method was thus validated for a low and high concentration range. For both serum and urine as sample matrix, the validation revealed good intraday and interday precisions, consistently ranging below 15% for the lowest and below 10% for elevated concentrations. Accuracy was likewise good and never exceeded 10%. Extraction recovery was excellent, ranging between 88.1 and 103.9% for SUX and SMC in both tested matrices. Matrix effects were significant, the otherwise optimized extraction and detection methods, however, allowed for a very satisfactory sensitivity of the described method: For serum, the limits of detection and quantitation were determined to be 1.9 and 6.0 ng/ml for SUX, as well as 2.5 and 8.6 ng/ml for SMC, respectively; for urine, the corresponding values were established to be 1.4 and 4.0 ng/ml (SUX), as well as 1.5 and 4.9 ng/ml (SMC).The presented method was successfully applied to authentic samples of two forensic cases investigated in the institute of forensic medicine in Bonn, allowing the diagnosis of SUX intoxications.

Anesthesiologist suicide with atracurium.

Atracurium is a nondepolarizing skeletal muscle relaxant used to facilitate endotracheal intubation and to induce skeletal muscle relaxation during surgery or mechanical ventilation. The drug undergoes a spontaneous non-enzymatic biotransformation, yielding laudanosine and an acrylate moiety. This report documents the case of a 45-year-old anesthesiologist who was found dead at the hospital where he worked. The victim was known to be depressed and undergoing treatment with venlafaxine. An empty syringe was found near the body. Toxicological analysis revealed the presence of laudanosine in the syringe, 0.6 mg/L of laudanosine in heart blood, 0.3 mg/L in urine, and 0.02 mg/L in vitreous humor. Meanwhile, concentrations of venlafaxine and O-desmethyl-venlafaxine, its active metabolite, were 0.7 and 1.1 mg/L in heart blood, 1.7 and 5.2 mg/L in urine, 0.5 and 0.7 mg/L in vitreous humor, and 400 and 20 mg in gastric content, respectively. All drugs and metabolites involved in the case were detected using gas chromatography with nitrogen-phosphorus detection (GC-NPD) and confirmed using GC-mass spectrometry in full scan mode after solid-phase extraction using Bond-Elut Certify columns. Additional high-performance liquid chromatography coupled to diode-array detection screening also obtained the same results. Quantitation of laudanosine and venlafaxine together with its metabolite was carried out using GC-NPD. No other drugs, including ethanol, were detected. Recoveries for laudanosine and venlafaxine were 89% and 86%, respectively, at 0.5 mg/L; intraday and interday precisions were 2% and 6%, and 3% and 7%, respectively; and limits of detection and quantitation were 6 and 20 ng/mL and 18 and 59 ng/mL, respectively. The linearity of the blood calibration curves was excellent for both drugs with r(2) values of > 0.999 (range 0.1-2.0 mg/L). Based on the autopsy findings, case history, and toxicology results, the forensic pathologists ruled that the cause of death was an overdose of atracurium, and the manner of death was suicide.

A case of serial homicide by injection of succinylcholine.

The abstract of this paper was presented at the 14th Meeting of the International Association of Forensic Sciences, Tokyo in 1996. We report a bizarre criminal case of suspected serial homicide by injection of a muscle relaxant (succinylcholine). Five victims were found buried in a rural area. In two victims showing moderate decomposition (about three months after death), intense pulmonary oedema with pleural effusion was observed. Evidence of a puncture site was found in one of the victims. Succinylcholine could not be detected in the victims, but was identified in a syringe found near the corpses. The 40-mg ampule dose of succinylcholine administered intramuscularly to the victims, possibly causing prolonged apnea, was considered to be at least around the minimum lethal dose, although the combined effect of the sedation with hypnotics also used was not negligible.

Sea bird mortality at Cabo San Lucas, Mexico: evidence that toxic diatom blooms are spreading.

Domoic acid was found to be responsible for an isolated event involving the massive death of brown pelicans (Pelecanus occidentalis) in January 1996, at the tip of the Baja California peninsula. The death of these sea birds was the result of feeding on mackerel (Scomber japonicus) contaminated by domoic acid-producing diatoms (Pseudonitzschia sp.). The number of dead birds (150 animals) found during a period of 5 days caused alarm and called for a governmental task force that would help to implement emergency measurements to protect other species of bird. Also, local canneries were inspected to verify the safety of their recent production and prevent the toxin entering the human market. Fortunately, the timing, response and coordination of this task force enabled identification of the origin and nature of the toxin that provoked such a phenomenon. Future monitoring is recommended to avoid a larger impact of domoic acid spreading and the occurrence of similar toxic events.

Ribosomal DNA sequences discriminate among toxic and non-toxic Pseudonitzschia species.

Cultured isolates of Pseudonitzschia australis Frenguelli, P. delicatissima (Cleve) Heiden, P. americana (Hasle) Fryxell, P. pungens (Grunow) Hasle, and P. pungens f. multiseries (Hasle) Hasle from Monterey Bay, California, were compared on the basis of their large-subunit ribosomal RNA gene (LsrDNA). Pseudonitzschia australis, P. pungens f. multiseries, and P. delicatissima were previously shown to produce the neurotoxin domoic acid; the remaining isolates are considered non-toxic. For each isolate approximately 800 base pairs of LsrDNA, encompassing both evolutionarily conserved and evolutionarily variable regions of the molecule, were amplified using the polymerase chain reaction (PCR) and sequenced. Phylogenetic trees generated by parsimony analysis of aligned sequences afford a preliminary view of the organisms genetic relationships. Species defined by morphological criteria are also distinguishable by LsrDNA sequence. Organisms known or suspected to produce domoic acid cluster at different termini on the phylogenetic tree. Two genetically distinct strains of P. australis and P. pungens were identified. Development of a restriction fragment length polymorphism (RFLP) assay of the LsrDNA is described. The RFLP assay discriminates each species, including distinguished strains of P. australis and P. pungens. The restriction test provides a rapid and convenient method for screening isolates' LsrDNA, facilitating further tests of the apparent positive correlation between Pseudonitzschia species' ribosomal gene signatures, morphology, and capacity to produce domoic acid.

Transfer constants for blood-brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid.

The cause of the toxic mussel poisoning episode in 1987 was traced to a plankton-produced excitotoxin, domoic acid. Experiments were undertaken to quantitate the degree to which blood-borne domoic acid can permeate the microvasculature to enter the brain. Pentobarbital-anesthetized, adult rats received an i.v. injection of 3H-domoic acid which was permitted to circulate for 3-60 min. Transfer constants (Ki) describing blood-to-brain diffusion of tracer were calculated from analysis of the relationship between brain vs plasma radioactivity with time. Mean values (mL.g-1.s-1 X 10(6] for permeation into 7 brain regions (n = 10 rats) ranged from 1.60 +/- 0.13 (SE) to 1.86 +/- 0.33 (cortex, pons-medulla respectively), and carrier transport or regional selectivity in uptake were not evident. Nephrectomy prior to domoic acid injection resulted in the elevation of circulating plasma tracer level and brain uptake. The Ki values are comparable to those for other polar compounds such as sucrose, and indicate that the blood-brain barrier greatly limits the amount of toxin that enters the brain. Together with absorbed dosage, integrity of the cerebrovascular barrier and normal kidney function are important to the outcome of accidentally ingesting domoic acid.