Allister Vale

Carbon monoxide poisoning

Carbon monoxide is a tasteless, odourless, colourless, and non-irritating gas produced by incomplete combustion of organic materials. It is also produced in man during the catabolism of haemoglobin. The normal endogenous production of carbon monoxide is sufficient to saturate 0 4-0 7% ofthe bodys haemoglobin-that is, 0 4-0 7% carboxyhaemoglobinaemia-at rest, but a national survey in North America found 1-2% carboxyhaemoglobinaemia in urban nonsmokers as a result of environmental exposure and 5-6% in smokers (cigarette smoke contains about 4% carbon monoxide).2 Although mortality from carbon monoxide poisoning has fallen since natural gas was substituted for coal gas, about 1000 people die annually in England and Wales from this

Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning.

Introduction:u2002This article reviews data on the efficacy of succimer (dimercaptosuccinic acid, DMSA) in the treatment of human inorganic lead poisoning, the adverse effects associated with its use, and summarizes current understanding of the pharmacokinetic and pharmacodynamic aspects. Methods. Medline, Toxline, and Embase were searched and 912 papers were identified and considered. Pharmacokinetics and pharmacodynamics. DMSA is absorbed rapidly but incompletely after oral administration, probably through an active transporter. There is evidence that enterohepatic circulation occurs. Most DMSA in plasma is protein (mainly albumin)-bound through a disulfide bond with cysteine; only a very small amount is present as free drug, which is filtered at the glomerulus then extensively reabsorbed into proximal tubule cells. Nonfiltered protein-bound DMSA in peritubular capillaries is also available for uptake into proximal tubule cells by active anion transport at the basolateral membrane. DMSA therefore accumulates in the kidney where it is extensively metabolized in humans to mixed disulfides of cysteine. Some 10–25% of an orally administered dose of DMSA is excreted in urine, the majority within 24 h and most (>90%) as DMSA–cysteine disulfide conjugates. It is not known whether protein-bound DMSA can chelate lead; there is evidence that the mixed disulfides of cysteine are the active chelating moiety in humans. If this is the case, this suggests that chelation occurs principally, if not exclusively, in the kidney. Dose. DMSA 30 mg/kg/day is more effective than either 10 or 20 mg/kg/day in enhancing urine lead excretion. Duration of therapy. Initial clinical studies with DMSA involved the administration of a 5-day course of treatment. Subsequently, a 19- to 26-day regimen was introduced with the intent of preventing or at least blunting a rebound in the blood lead concentration. Studies suggest, however, that repeated courses of DMSA 30 mg/kg/day for at least 5 days are equally efficacious if a treatment-free period of at least 1 week between courses is included to allow redistribution of lead from bone to soft tissues and blood. There is also evidence that in more severely poisoned patients DMSA 30 mg/kg/day can be given for more than 5 days with benefit. Efficacy. DMSA 30 mg/kg/day significantly increases urine lead elimination and significantly reduces blood lead concentrations in lead-poisoned patients, though there is substantial individual variation in response. Over a 5-day course, mean daily urine lead excretion exceeds baseline by between 5- and 20-fold and blood lead concentrations fall to 50% or less of the pretreatment concentration, with wide variation. Maximum enhancement of urine lead elimination typically occurs with the first dose. Most symptomatic patients report improvement after 2 days of treatment. However, DMSA did not improve cognition in children <u20093 years old with mild lead poisoning, presumably because lead-induced neurological damage occurred during development in utero and/or early infancy. DMSA in pregnancy and in the neonate. DMSA is not teratogenic but did produce maternal toxicity (decreased weight gain) and fetotoxicity when given in high dose (100–1,000 mg/kg/day) in experimental studies. For this reason sodium calcium edetate is generally preferred in pregnancy. Adverse effects. A transient modest rise in transaminase activity during chelation occurs in up to 60% of patients but has not resulted in clinically significant sequelae. Skin reactions occur in approximately 6% of treated patients and are occasionally severe. DMSA also increases urine copper and zinc excretion but not to a clinically important extent. Conclusions. DMSA is an effective lead chelator that primarily chelates renal lead. It is generally well tolerated but may occasionally cause clinically important adverse effects. DMSA may now be considered as an alternative to sodium calcium edetate, particularly when an oral antidote is preferable.

A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning

Introduction. This article reviews the experimental and clinical studies that have compared the efficacy (impact on urine lead excretion, blood and tissue lead concentrations, resolution of features and survival) of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. It also summarizes the pharmacokinetic and pharmacodynamic aspects and the adverse effects of treatment. Methods. Medline, Toxline, and Embase were searched for all available years to June 2009. Pharmacokinetics and pharmacodynamics. The absorption of oral DMSA is more complete than sodium calcium edetate; the latter has to be administered parenterally. Both antidotes are distributed predominantly extracellularly. Sodium calcium edetate is not metabolized, whereas DMSA is extensively metabolized to mixed disulfides of cysteine. The two antidotes have elimination half-lives of less than 60 min. There is no evidence that either antidote crosses the blood–brain barrier to any major extent. Sodium calcium edetate chelates lead by displacement of the central Ca2+ ion with Pb2+. The nature of the DMSA–lead chelate is less clearly defined. There is evidence that the mixed disulfides of cysteine are the active chelating moiety in humans. If this is the case, this suggests that chelation occurs principally, if not exclusively, in the kidney. The primary source of lead mobilized by sodium calcium edetate is bone with an additional contribution from kidney and liver. Efficacy. Comparison of the experimental studies is complicated by substantial variations in study design, particularly the antidote dose, the route and duration of treatment, the amount and duration of lead dosing, and lack of direct comparison between antidotes (comparison was usually made with control). In experimental studies that used equimolar and clinically relevant antidote doses and assessed the impact of DMSA and sodium calcium edetate on urine lead excretion and/or blood lead concentrations, similar results were found, though no direct comparison between antidotes was undertaken. DMSA was more effective than sodium calcium edetate in reducing the kidney lead concentration, sodium calcium edetate was more effective than DMSA in reducing bone lead concentrations, and there was no consistently observed effect of chelation therapy on brain lead concentrations in these experimental studies. Only two clinical studies have compared equimolar or similar antidote doses in enhancing urine lead excretion; there was no statistical difference between the antidotes, though both studies had limitations. DMSA and sodium calcium edetate had a comparable impact on lowering blood lead concentrations in a clinical study using similar molar antidote doses. Adverse effects. Sodium calcium edetate causes dose-related nephrotoxicity. Both agents deplete zinc and copper, the effect on zinc being significantly greater with sodium calcium edetate. A transient increase in hepatic transaminase activity has been reported with both antidotes but appears to be more common with DMSA and neither has been associated with clinically significant hepatic toxicity. Skin lesions during treatment with sodium calcium edetate are unusual and have been attributed to zinc deficiency. DMSA has occasionally been associated with a severe mucocutaneous reaction necessitating discontinuation of therapy. Conclusions. Oral DMSA and parenteral sodium calcium edetate are both effective chelators of lead. There are currently insufficient data, however, to conclude that either antidote is superior in enhancing lead excretion. Both antidotes resolve the symptoms of moderate and severe lead toxicity rapidly. Although there is greater clinical experience with sodium calcium edetate, particularly in the treatment of lead encephalopathy, oral DMSA may now be considered as an alternative in circumstances where oral therapy is preferable.

Laboratory analyses for poisoned patients: joint position paper

To enable consistency of investigation and the establishment of best practice standards, consensus guidelines have been formulated jointly by the UK National Poisons Information Service (NPIS) and the Association of Clinical Biochemists (ACB). The types of laboratory investigation required for poisoned patients were categorized as either (a) essential common laboratory investigations or (b) specific toxicological assays, and also as either (i) common or (ii) specialist or infrequent. Tests in categories (a) and (bi) are expected to be available 24 h per day, with a maximum turnaround time of 2 h. For the specialist assays, i.e. category (bii), availability and turnaround times have been specified individually. The basis for selection of these times has been clinical utility. The adoption of these guidelines, along with the use of the NPIS online poisons information resource TOXBASE (www.spib.axl.co.uk), will enable the poisoned patient to receive appropriate, best practice investigations according to their clinical needs and will avoid the use of unnecessary investigations.

National audit of antidote stocking in acute hospitals in the UK

Background Inadequate stocking of essential antidotes in hospitals for the treatment of poisoned patients has been reported worldwide. Joint National Poisons Information Service (NPIS)/College of Emergency Medicine (CEM) guidelines for antidote stocking in UK emergency departments and acute hospitals were published in 2008. Aim To determine the impact of these guidelines by surveying the availability of antidotes in acute hospitals in the UK. Methods A two-page questionnaire consisting of antidote stocking information was distributed in 2010 to the Chief Pharmacist in all acute hospitals in the UK. The availability of 28 antidotes in the NPIS/CEM antidote guidelines as well as that of Intralipid was surveyed. Results Surveys were completed for 196 of the 224 (87.5%) hospitals. Over 90% of hospitals had acetylcysteine, activated charcoal, dantrolene, desferrioxamine, naloxone, flumazenil and vitamin K available within the recommended time period. Pralidoxime was reported to be held in only 33% of hospitals, though pralidoxime is supplied by the Department of Health to 95 hospitals in the UK that act as holding centres. Cyproheptadine and viper venom antiserum were held in around 50% of acute hospitals. For the treatment of cyanide and toxic alcohol poisoning, more than one antidote is available. For cyanide poisoning, most hospitals held at least one antidote (usually dicobalt edetate) but 9 (5%) held none of the four antidotes. For toxic alcohol and glycol poisoning, most hospitals held ethanol for intravenous use but not fomepizole and 30 (15%) did not stock any antidote for toxic alcohol poisoning. Conclusion Stocking of less commonly used antidotes is inconsistent. This is likely to result in delayed access to treatment and worse patient outcomes.

Organophosphorus and carbamate insecticide poisoning.

Both organophosphorus (OP) and carbamate insecticides inhibit acetylcholinesterase (AChE), which results in accumulation of acetylcholine (ACh) at autonomic and some central synapses and at autonomic postganglionic and neuromuscular junctions. As a consequence, ACh binds to, and stimulates, muscarinic and nicotinic receptors, thereby producing characteristic features. With OP insecticides (but not carbamates), aging may also occur by partial dealkylation of the serine group at the active site of AChE; recovery of AChE activity requires synthesis of new enzyme in the liver. Relapse after apparent resolution of cholinergic symptoms has been reported with OP insecticides and is termed the intermediate syndrome. This involves the onset of muscle paralysis affecting particularly upper-limb muscles, neck flexors, and cranial nerves some 24-96 hours after OP exposure and is often associated with the development of respiratory failure. OP-induced delayed neuropathy results from phosphorylation and subsequent aging of at least 70% of neuropathy target esterase. Cramping muscle pain in the lower limbs, distal numbness, and paresthesiae are followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. The therapeutic combination of oxime, atropine, and diazepam is well established experimentally in the treatment of OP pesticide poisoning. However, there has been controversy as to whether oximes improve morbidity and mortality in human poisoning. The explanation may be that the solvents in many formulations are primarily responsible for the high morbidity and mortality; oximes would not be expected to reduce toxicity in these circumstances. even if given in appropriate dose.

Patterns of presentation and clinical toxicity after reported use of alpha methyltryptamine in the United Kingdom. A report from the UK National Poisons Information Service

Abstract Objective. To characterise the patterns of presentation, clinical effects and possible harms of acute toxicity following recreational use of alpha methyltryptamine (AMT) in the United Kingdom, as reported by health professionals to the National Poisons Information Service (NPIS) and to compare clinical effects with those reported after mephedrone use. Methods. NPIS telephone enquiries and TOXBASE® user sessions, the NPIS online information database, related to AMT were reviewed from March 2009 to September 2013. Telephone enquiry data were compared with those for mephedrone, the recreational substance most frequently reported to the NPIS, collected over the same period. Results. There were 63 telephone enquiries regarding AMT during the period of study, with no telephone enquiries in 2009 or 2010, 19 in 2011, 35 in 2012 and 9 in 2013 (up to September). Most patients were male (68%) with a median age of 20 years. The route of exposure was ingestion in 55, insufflation in 4 and unknown in 4 cases. Excluding those reporting co-exposures, clinical effects recorded more frequently in AMT (n = 55) compared with those of mephedrone (n = 488) users including acute mental health disturbances (66% vs. 32%; Odds Ratio [OR], 4.00; 95% Confidence Intervals [CI], 2.22–7.19), stimulant effects (66% vs. 40%; OR, 2.82; 95% CI 1.57–5.06) and seizures (14% vs. 2%; OR, 9.35; 95% CI 3.26–24.18). Conclusions. Although still infrequent, toxicity following reported exposure to AMT has been encountered in the United Kingdom since January 2011. Stimulant features, acute mental health disturbances and seizures are more frequently reported than in those presenting following reported use of mephedrone.

Patterns of presentation and clinical features of toxicity after reported use of ([2-aminopropyl]-2,3-dihydrobenzofurans), the 'benzofuran' compounds. A report from the United Kingdom National Poisons Information Service.

Abstract Objective. To characterise the patterns of presentation and clinical features of toxicity following reported recreational use of benzofuran compounds ((2-aminopropyl)-2,3-dihydrobenzofurans) in the UK, as reported to the National Poisons Information Service (NPIS), and to compare clinical features of toxicity with those after reported mephedrone use. Methods. NPIS patient-specific telephone enquiries and user sessions for TOXBASE®, the NPIS online information database, related to (2-aminopropyl)-2,3-dihydrobenzofurans and associated synonyms were reviewed from March 2009 to August 2013. These data were compared with those of mephedrone, the recreational substance most frequently reported to NPIS, collected over the same period. Results. There were 63 telephone enquiries concerning 66 patients and 806 TOXBASE® user sessions regarding benzofuran compounds during the period of study. The first telephone enquiry was made in July 2010 and the highest numbers of enquiries were received in August 2010 (33 calls, 112 TOXBASE® sessions). Patients were predominantly male (82%) with a median age of 29 years; 9 reported co-ingestion of other substances. Comparing the 57 patients who reported ingesting benzofuran compounds alone with 315 patients ingesting mephedrone alone, benzofurans were more often associated with stimulant features, including tachycardia, hypertension, mydriasis, palpitation, fever, increased sweating, and tremor, (72% vs. 38%, odds ratio [OR] 4.2, 95% confidence interval [CI] 2.27–7.85, P < 0.0001) and mental health disturbances (58% vs. 38%, OR 2.3, 95% CI 1.29–4.07, P = 0.006). Other features reported after benzofuran compound ingestion included gastrointestinal symptoms (16%), reduced level of consciousness (9%), chest pain (7%), and creatinine kinase elevation (5%). Conclusions. Reported ingestion of benzofuran compounds is associated with similar toxic effects to those of amphetamines and cathinones. Mental health disturbances and stimulant features were reported more frequently following reported ingestion of benzofuran compounds than after ingestion of mephedrone.

Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS).

Abstract Background: Poisoning with methanol and ethylene glycol can cause serious morbidity and mortality. Specific treatment involves the use of antidotes (fomepizole or ethanol) with or without extracorporeal elimination techniques. Methods: A prospective audit of patients with methanol or ethylene glycol poisoning reported by telephone to the National Poisons Information Service (NPIS) in the UK was conducted during the 2010 calendar year and repeated during the 2012 calendar year. The study was conducted to determine the frequency of clinically significant systemic toxicity and requirement for antidote use and to compare outcomes and rates of adverse reaction and other problems in use between ethanol and fomepizole. Results: The NPIS received 1315 enquiries involving methanol or ethylene glycol, relating to 1070 individual exposures over the 2-year period. Of the 548 enquiries originating from hospitals, 329 involved systemic exposures (enteral or parenteral as opposed to topical exposure), of which 216 (66%) received an antidote (204 for ethylene glycol and 12 for methanol), and 90 (27%) extracorporeal treatment (86 for ethylene glycol and 4 for methanol). Comparing ethanol with fomepizole, adverse reactions (16/131 vs. 2/125, pu2009<u20090.001) and administration errors, lack of monitoring, or inappropriate use (45/131 vs. 6/125, pu2009<u20090.0001) were reported more commonly, whereas non-availability and inadequate stocks were reported less commonly (6/125 vs. 33/131, pu2009<u20090.0001). Eight fatalities and complications or sequelae occurred in 21 patients. Poor outcome (death, complications, or sequelae) was significantly associated with older age, higher poisoning severity scores, and lower pH on admission (pu2009<u20090.001). Conclusions: Systemic poisoning with ethylene glycol or methanol results in hospitalisation at least 2–3 times per week on average in the UK. No difference in outcome was detected between ethanol and fomepizole-treated patients, but ethanol was associated with more frequent adverse reactions.

Specific substancesParacetamol (acetaminophen)

Paracetamol poisoning is common. If untreated, liver and/or renal failure can develop. The administration of acetylcysteine within 8–10 hours of overdose will minimize or prevent hepatic damage and ensure survival irrespective of the magnitude of the ingestion. Important prognostic factors are the international normalized ratio, pH and plasma creatinine concentration.