Use of N-acetylcysteine in clinical toxicology.

The major use of N-acetylcysteine in clinical toxicology is in the treatment of acetaminophen (paracetamol) overdosage. The hepatorenal toxicity of acetaminophen is mediated by a reactive metabolite normally detoxified by reduced glutathione. If glutathione is depleted, covalent binding to macromolecules and/or oxidation of thiol enzymes can lead to cell death. Oral or intravenous N-acetylcysteine or oral D,L-methionine mitigates acetaminophen-induced hepatorenal damage if given within 10 hours, but becomes less effective thereafter. In vivo, N-acetylcysteine forms L-cysteine, cystine, L-methionine, glutathione, and mixed disulfides; L-methionine also forms cysteine, thus giving rise to glutathione and other products. Oral therapy with N-acetylcysteine or methionine for acetaminophen poisoning is contraindicated in the presence of coma or vomiting, or if activated charcoal has been given by mouth. Nausea, vomiting, and diarrhea may also occur as a result of oral N-acetylcysteine administration. Anaphylactoid reactions including angioedema, bronchospasm, flushing, hypotension, nausea/vomiting, rash, tachycardia, and respiratory distress may occur 15-60 minutes into N-acetylcysteine infusion (20 hours intravenous regimen) in up to 10% of patients. Following accidental intravenous overdosage, the adverse reactions of N-acetylcysteine are similar but more severe; fatalities have occurred. A reduction in the loading dose of N-acetylcysteine may reduce the risk of adverse reactions while maintaining efficacy. Administration of N-acetylcysteine for a longer period might provide enhanced protection for patients in whom acetaminophen absorption or elimination is delayed. N-acetylcysteine may also have a role in the treatment of toxicity from carbon tetrachloride, chloroform, 1,2-dichloropropane, and other compounds. The possible use of N-acetylcysteine and other agents in the prevention of the neuropsychiatric sequelae of acute carbon monoxide poisoning is an important area for future research.

A chloroform-related death: analytical and forensic aspects.

Chloroform is still encountered occasionally in clinical and forensic toxicology, hence knowledge of the special problems presented in the detection and measurement of this compound in biological specimens may be required. The aim of this paper is to review the available documentation on this topic in the context of a chloroform-related death. Early one morning in February 1999 a 34-year-old female was found dead fully clothed on a path near to a neighbour's garden. Amfetamine intoxication combined with hypothermia was accepted as the cause of the death in the absence of any other identifiable cause. Further investigation 17 months later revealed a blood chloroform concentration of 31 mg/L and the cause of death was revised to chloroform poisoning. A murder trial ensued, the indictment specifying forced inhalation as the route of exposure. The liver chloroform concentration measured 38 months after collection was reported as 1064 mg/kg and opinions were offered at trial that the autopsy findings, which included a gastritis, but no evidence of injury to the inside of the mouth and oesophagus, excluded the possibility of ingestion of a toxic dose of chloroform. It was asserted that the explanation for the high liver concentration was that the liver had concentrated chloroform from blood after death against a concentration gradient. At appeal against conviction 7 years later the conviction was quashed. It was found that the liver concentration should have been reported at trial as 1 mg/kg. Moreover, chloroform found in the stomach contents (162 mg/kg) 86 months after collection was irrefutable evidence that some, if not all, of the chloroform had been ingested. Screening for volatile poisons should always be considered if a cause of death is not immediately obvious, especially in young people and in known substance abusers. If the presence of an unstable or volatile analyte is suspected then sample collection, transport, and storage must be performed with the analysis in mind. Quantitative analysis of all available specimens should proceed forthwith once the presence of an unstable analyte is established if the cause of death is in doubt or if prosecution may follow. In the case of chloroform especial precautions are needed: (i) headspace analysis should be performed at 35 degrees C to preclude the possibility of artefactual formation from trichloroacetic acid, (ii) precautions to prevent cross-contamination of biological samples in the laboratory must be taken, and (iii) interpretation of analytical results must take account of the widespread presence of chloroform in the environment on the one hand, and that the toxicity of chloroform varies greatly depending on the circumstances and intensity of exposure on the other.

Detection and identification of volatile organic compounds in blood by headspace gas chromatography as an aid to the diagnosis of solvent abuse.

A gas chromatographic method has been developed for the detection and identification of some volatile organic compounds in whole blood, plasma or serum. After incubation of the sample (200 microliters) together with the internal standard solution in a sealed vial, a portion of the headspace is analysed using a 2-m glass column packed with 0.3% (w/w) Carbowax 20M on Carbopack C, 80-100 mesh. The column oven, after a 2-min isothermal period, is programmed from 35 to 175 degrees C at 5 degrees/min and held for 8 min. The effluent is monitored by both flame-ionisation and electron-capture detection, and peak assignment is by means of retention time and relative detector response. The method has proved applicable to the detection of bromochlorodifluoromethane, n-butane, carbon tetrachloride, chlorobutanol, cryofluorane (Halon 114), dichlorodifluoromethane (Halon 12), ethyl acetate, halothane, isobutane, isopropanol, isopropyl nitrate, methyl ethyl ketone, propane, tetrachloroethylene, toluene, 1,1,1-trichloroethane, 2,2,2-trichloroethanol, trichloroethylene and trichlorofluoromethane (Halon 11) in blood specimens obtained from patients suspected of abusing these agents.

Acute trazodone poisoning: clinical signs and plasma concentrations.

A total of 70 patients presenting with suspected acute trazodone poisoning were notified to the Poisons Unit (National Poisons Information Service for England) from August 1980 until March 1983. Detailed follow-up information was obtained on 41 patients, 22 of whom were thought to have ingested trazodone alone. In these latter patients drowsiness (11), ataxia (5), nausea/vomiting (4) and dry mouth (2) were the manifestations of toxicity reported most frequently, only 2 patients became unconscious (grade 2 or 3 coma), and all recovered uneventfully with no more than minimal supportive therapy. The presence of trazodone was confirmed in 8 out of 9 patients from whom specimens (blood and urine) were received. The highest plasma trazodone concentrations (15 and 19 mg/l, respectively) were both associated with only drowsiness and ataxia. However, in 2 further patients moderate plasma trazodone concentrations (4.2 and 8.2 mg/l, respectively) were associated with deep (grade 3-4) coma, although 1 of these latter patients had also ingested ethanol (plasma concentration 3.0 g/l). Although acute trazodone poisoning does not appear to be associated with cardiac arrhythmias or convulsions, these results emphasise that drowsiness and ataxia are commonly encountered, while coma may occur in severe cases. The possible contribution of metabolites of trazodone to toxicity and the potentiating effect of co-ingested drugs or alcohol must be remembered.