The traditional therapeutic treatment of organophosphate cholinesterase inhibitor (nerve agents) poisoning consists of co-treatment with an antimuscarinic (atropine) and a reactivator of inhibited acetylcholinesterase (AChE), which contains a nucleophilic oxime function. Two oximes are presently widely available for clinical use, pralidoxime and obidoxime (toxogonin), but both offer little protection against important nerve agent threats. This has highlighted the real need for the development and availability of more effective oximes for human use, a search that has been going on for up to 30 years. However, despite the demonstration of more effective and safe oximes in animal experiments, no additional oximes have been licensed for human use. HI-6, (1-[[[4(aminocarbonyl)-pyridinio]methoxy]methyl]-2(hydroxyimino)pyridinium dichloride; CAS 34433-31-3) has been studied intensively and has been proved effective in a variety of species including non-human primates and appears from clinical experience to be safe in humans. These studies have led to the fielding of HI-6 for use against nerve agents by the militaries of the Czech republic, Sweden, Canada and under certain circumstances the Organisation for the Prohibition of Chemical Weapons. Nevertheless HI-6 has not been granted a license for clinical use, must be used only under restricted guidelines and is not available for civilian use as far as is known. This article will highlight those factors relating to HI-6 that pertain to the licensing of new compounds of this type, including the mechanism of action, the clinical and pre-clinical demonstration of safety and its efficacy against a variety of nerve agents particularly in non-human primates, since no relevant human population exists. This article also contains important data on the use of HI-6 in baboons, which has not been available previously. The article also discusses the possibility of successful therapy with HI-6 against poisoning in humans relative to doses used in non-human primates and relative to its ability to reactivate inhibited human AChE.

Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.

The present clinical use of serum osmometry is erroneous in two respects. The first, and the most important, is the incorrect assumption that serum behaves as a dilute ‘ideal’ solution and that the osmotic activity of a substance depends solely on the number of solute particles. The amount of variance from ideal behaviour of serum containing an exogenous substance is expressed by the osmotic coefficient (ϕ). We have calculated the osmotic coefficient for serum containing ethanol (alcohol) and recommend that the osmotic coefficient for serum containing other low molecular weight substances such as methanol (methyl alcohol), isopropyl alcohol and ethylene glycol also be calculated. This is necessary for the accurate calculation of the contribution of these substances to the serum osmolality. Secondly, the practice of subtracting the calculated serum molarity from measured serum osmolality is not valid since it represents a mathematically improper expression. The units of these two terms are different. The ‘osmole gap’ (OG) is typically viewed as the difference between serum osmolality determined by an osmometer and the estimated total molarity of solute in serum by directly measuring the concentration of several substances and then substituting them into a published formula. Some authors call this sum the calculated or estimated osmolarity but, because the concentrations are measured directly and not with an osmometer, the calculated term represents molarity. The units of osmolality are mmol/kg of H2O and the units of molarity are mmol/L. Therefore, the practice of subtracting calculated serum molarity from measured serum osmolality is not mathematically sound and is an oversimplification for ease of application. This mathematical transgression necessarily adds an error to the incorrectly calculated OG. Despite this, the OG is commonly used in clinical medicine. Serum osmolality can be converted to molarity provided the weight percentage and the density of the solution are known and thus, we recommend that this conversion be done prior to calculation of the gap. We recommend that the gap between measured serum osmolarity and calculated serum molarity be called the ‘osmolar gap’. After having corrected for non-ideality for serum and for inconsistency of units, the standard value and reference range for this gap must be determined in an adequate number of patient populations and in a variety of clinical settings. An example of this determination, using data from a group of ethanol-poisoned patients is given. This correction should be applied before the evaluation of the osmolar gap as a screening test for other low molecular weight substances proceeds.

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GHB was synthesised over 40 years ago and its presence in the brain and a number of aspects of its biological, pharmacological and toxicological properties have been elucidated over the last 20–30 years. However, widespread interest in this compound has arisen only in the past 5–10 years, primarily as a result of the emergence of GHB as a major recreational drug and public health problem in the US. There is considerable evidence that GHB may be a neuromodulator in the brain. GHB has multiple neuronal mechanisms including activation of both the γ-aminobutyric acid type B (GABAB) receptor, and a separate GHB-specific receptor. This complex GHB-GABAB receptor interaction is probably responsible for the protean pharmacological, electroencephalographic, behavioural and toxicological effects of GHB, as well as the perturbations of learning and memory associated with supra-physiological concentrations of GHB in the brain that result from the exogenous administration of this drug in the clinical context of GHB abuse, addiction and withdrawal. Investigation of the inborn error of metabolism succinic semialdehyde deficiency (SSADH) and the murine model of this disorder (SSADH knockout mice), in which GHB plays a major role, may help dissect out GHB- and GABAB receptor-mediated mechanisms. In particular, the mechanisms that are operative in the molecular pathogenesis of GHB addiction and withdrawal as well as the absence seizures observed in the GHB-treated animals.

The erythrocyte is a highly specialised cell with a limited metabolic repertoire. As an oxygen shuttle, it must continue to perform this essential task while exposed to a wide range of environments on each vascular circuit, and to a variety of xenobiotics across its lifetime. During this time, it must continuously ward off oxidant stress on the haeme iron, the globin chain and on other essential cellular molecules. Haemolysis, the acceleration of the normal turnover of senescent erythrocytes, follows severe and irreversible oxidant injury. A detailed understanding of the molecular mechanisms underlying oxidant injury and its reversal, and of the clinical and laboratory features of haemolysis is important to the medical toxicologist. This review will also briefly review glucose-6-phosphate deficiency, a common but heterogeneous range of enzyme-deficient states, which impairs the ability of the erythrocyte to respond to oxidant injury.

The rapid and accurate diagnosis of toxic alcohol poisoning due to methanol (methyl alcohol) [MeOH] and ethylene glycol (EG), is paramount in preventing serious adverse outcomes. The quantitative measurement of specific serum levels of these substances using gas chromatography is expensive, time consuming and generally only available at major tertiary-care facilities. Therefore, because these toxic substances are osmotically active and the measurement of serum osmolality is easily performed and more readily available, the presence of an osmole gap (OG) has been adopted as an alternative screening test. By definition, the OG is the difference between the measured serum osmolality determined using the freezing point depression (Osmm) and the calculated serum molarity (Mc), which is estimated from the known and readily measurable osmotically active substances in the serum, in particular sodium, urea, glucose, and potassium and ethanol (alcohol). Thus, the OG = Osmm − Mc, and an OG above a specific threshold (the threshold of positivity) suggests the presence of unmeasured osmotically active substances, which could be indicative of a toxic exposure. The objectives of this study were to review the principles of evaluating screening tests, the theory behind the OG as a screening test and the literature upon which the adoption of the OG as a screening test has been based. This review revealed that there have been numerous equations derived and proposed for the estimation of the Mc, with the objective of developing empirical evidence of the best equation for the determination of the OG and ultimately the utility of OG as a screening test. However, the methods and statistical analysis employed have generally been inconsistent with recommended guidelines for screening test evaluation and although many equations have been derived, they have not been appropriately validated. Specific evidence of the clinical utility of the OG requires that a threshold of positivity be definitively established, and the sensitivity and specificity of the OG in patients exposed to either EG or MeOH be measured. However, the majority of studies to date have only evaluated the relationship between the Osmm (mmol/kg H2O) and the Mc (mmol/L) in patients that have not been exposed to either MeOH or EG. While some studies have evaluated the relationship between the OG and serum ethanol concentration, these findings cannot be extrapolated to the use of the OG to screen for toxic alcohol exposure. This review shows that there has not been an appropriately designed empirical evaluation of the diagnostic utility of the OG and that its clinical utility remains hypothetical, having been theoretically extrapolated from the non-poisoned population.

Toxicogenic and psychogenic theories have been proposed to explain idiopathic environmental intolerance (IEI). Part 2 of this article is an evidence-based causality analysis of the psychogenic theory using an extended version of Bradford Hill’s criteria. The psychogenic theory meets all of the criteria directly or indirectly and is characterised by a progressive research programme including double-blind, placebo-controlled provocation challenge studies. We conclude that IEI is a belief characterised by an overvalued idea of toxic attribution of symptoms and disability, fulfilling criteria for a somatoform disorder and a functional somatic syndrome. A neurobiological diathesis similar to anxiety, specifically panic disorder, is a neurobiologically plausible mechanism to explain triggered reactions to ambient doses of environmental agents, real or perceived. In addition, there is a cognitively mediated fear response mechanism characterised by vigilance for perceived exposures and bodily sensations that are subsequently amplified in the process of learned sensitivity. Implications for the assessment and treatment of patients are presented.