Toxicology

Medical toxicology of natural substances. Foods, fungi, medicinal herbs, plants, and venomous animals. Donald G Barceloux. New York: Wiley, 2008 (xxi + 1157 pp). ISBN 978 0 471 72761 3. Books on clinical toxicology are usually either pocket-sized manuals offering quick and easy reference to doctors treating acutely poisoned patients, or enormous tomes of information, much of it not directly relevant to the clinician and often out of touch with current management. Barceloux’s Medical toxicology of natural substances breaks out of that mould. This book is the first of a series of four major textbooks replacing Ellenhorn’s Medical toxicology, reflecting the rapid growth in clinical toxicology and its evidence base over the past decade. Planned further volumes cover recreational, occupational, and pharmaceutical poisoning. The text’s layout is consistent throughout, with historical facts providing an interesting backdrop to more detailed analytical and toxicokinetic data, before clinical and management issues are discussed. A Californian emergency physician, Barceloux is clearly very comfortable with acute management; his recommendations are current and evidence-based, and the book could easily be used to guide acute management despite its size and impressive detail. Textbooks published in the United States are often reluctant to consider other parts of the world — in contrast, Barceloux provides a detailed region-by-region examination where necessary. Of minor irritation, secondary rather than primary references are cited. As well, the publisher hasn’t supported the outstanding content with comparable publication quality. A decent cover and coloured illustrations throughout, rather than just a few pages in the middle, would have improved the overall package. Nevertheless, from lepidopterism to latrodectism, syndromes caused by the squirting cucumber to licorice, cholera to platypus envenoming, this wonderful book covers an enormous subject with attention to detail and direct clinical relevance in a style that is surprisingly easy to read. The remaining volumes will be eagerly awaited by clinical toxicologists everywhere.

George A Jelinek

A 49-year-old man presented with verapamil toxicity complicated by hypotension and a junctional rhythm, in the context of deliberate self-poisoning with multiple drugs. The patient’s hypotension normalised following the early use of high-dose insulin euglycaemic therapy (HIET), without the need for additional vasopressors; it recurred when HIET was prematurely stopped, and again stabilised when HIET was recommenced. Consideration should be given to the early use of HIET in treating severe calcium channel blocker toxicity, rather than as a last resort after other therapies have failed. (MJA 2009; 191: 350-352) Clinical recordA 49-year-old man presented to a peripheral hospital emergency department 1–1.5 h after deliberately ingesting multiple medications: verapamil (unknown amount), controlled-release morphine sulfate (20 × 30 mg), diazepam (50 × 5 mg) and tramadol (15 × 200 mg). He was a smoker with a history of depression, ethanol misuse, chronic back pain, hypertension and a previous instance of deliberate self-poisoning with multiple drugs. At initial assessment, the patient’s vital signs were: temperature, 36.8°C; pulse, 84 beats/min; respiratory rate, 19 breaths/min; blood pressure (BP), 115/80 mmHg; oxygen saturation, 95% on room air; and Glasgow Coma Scale score, 14/15. He was drowsy, disorientated to time, and had 2 mm pupils that were equal and reactive. He had ataxia, dysarthria and was generally weak. His breath ethanol concentration was 0.172 mg%. Thirty minutes later, the patient was hypotensive (BP, 85/45 mmHg; pulse, 72 beats/min). He was treated with oxygen, 2 L intravenous (IV) 0.9% saline, a naloxone IV infusion (400 μg/h), and 10 mL IV 10% calcium gluconate. He was transferred to a tertiary referral centre and, on arrival (at 2.25 h after initial presentation), his BP was 85/45 mmHg, pulse was 64 beats/min, and an electrocardiogram (ECG) showed a junctional rhythm. Rapid sequence intubation (with propofol 40 mg + 20 mg IV and suxamethonium 100 mg IV) was performed for airway protection and ongoing management of haemodynamic instability, while metaraminol IV boluses (total, 0.7 mg) were administered. Activated charcoal (50 g) was given, and sedation was maintained with a propofol infusion. The patient remained hypotensive (BP, 75/45 mmHg; pulse, 56 beats/min) after intubation, so high-dose insulin euglycaemic therapy (HIET) was commenced at 3.5 hours after presentation. He was given dextrose (50 mL 50% glucose) and a 30 IU short-acting insulin IV bolus (~ 0.5 IU/kg), followed by a further bolus of 50 mL 50% glucose and a short-acting insulin IV infusion (30 IU/h) (Box 1). His BP improved to 110/70 mmHg at 4 hours, with a pulse of 82 beats/min and sinus rhythm on ECG, and he remained stable during transfer to the intensive care unit (ICU). The insulin infusion was abruptly stopped 5.5 hours after presentation, on arrival in the ICU. The patient’s hypotension subsequently recurred (systolic BP, 70 mmHg; pulse, 75 beats/min), prompting administration of 500 mL IV Gelofusine (a colloidal plasma volume substitute; B. Braun, Sydney, NSW) and commencement of an adrenaline IV infusion (20 μg/min). The insulin infusion (30 IU/h) was restarted at 8.5 hours, and his BP again stabilised (Box 1). The propofol IV infusion was gradually increased from 50 mg/h to 150 mg/h between 5.5 hours and 11.5 hours after presentation, and a noradrenaline IV infusion was commenced at 9.5 hours to maintain normotension. At 15.5 hours, pulmonary artery catheter measurements showed a high cardiac index (5.1 L/min/m2; reference range [RR], 2.5–4.0 L/min/m2) and a low systemic vascular resistance index (1047 dynes·s/cm5/m2; RR, 1900–2400 dynes·s/cm5/m2); the patient’s pulse was 85 beats/min and BP was 140/60 mmHg. HIET was continued and the patient remained haemodynamically stable. Adrenaline and noradrenaline were weaned off (at 17.5 hours and 23.5 hours, respectively), despite the propofol infusion rate being increased to 500 mg/h at 18.5 hours. Once sedation was withdrawn, the patient was extubated at 26.5 hours. Insulin was weaned over 5 h and discontinued at 30.5 hours; dextrose was stopped 1 h later. The patient was transferred to the observation ward and discharged well later that day, after psychiatric clearance. During treatment with HIET, the patient’s blood glucose levels were checked hourly and ranged from 6.6 mmol/L to 13.2 mmol/L (RR, 3.5–5.5 mmol/L). He received about 25 g/h of dextrose (mostly as 50% dextrose infusions). Potassium and magnesium levels were also serially monitored; the minimum potassium level was 2.7 mmol/L (RR, 3.5–5.0 mmol/L) at 8.75 hours, and the magnesium level troughed at 0.5 mmol/L (RR, 0.75–1.05 mmol/L) at 15 hours. These were corrected with a total of 200 mmol of potassium chloride and 20 mmol magnesium chloride. DiscussionHIET is an increasingly accepted therapy for calcium channel blocker (CCB) toxicity, but reports of its use are limited and it remains controversial. Indeed, the scarcity of severe CCB poisoning cases means that a randomised controlled trial of HIET may not be feasible.1 Treating clinicians who seek advice from clinical toxicologists are often hesitant about the high doses required and the potential for adverse effects. Such hesitancy is potentially harmful, as a hypotensive patient with a CCB overdose who otherwise appears well is at risk of abrupt lethal cardiovascular collapse.1 HIET is traditionally recommended after other therapies have failed.2,3 This case report aims to raise awareness of HIET for the treatment of CCB toxicity and supports its early use, rather than as a last resort.4 Verapamil binds the alpha-1 subunit of L-type calcium channels, preventing the intracellular influx of calcium.5 These channels are functionally important in cardiac myocytes, vascular smooth muscle cells, and islet beta cells.5 Verapamil’s cardiac toxicity results from excessive negative inotropy, negative chronotropy and negative dromotropy, characterised by myocardial depression, sinus bradycardia, and atrioventricular node blockade.4 Vascular smooth muscle tone is impaired, resulting in decreased afterload, systemic hypotension, and coronary vasodilation.5 Less well known are the metabolic effects of CCBs such as verapamil. Under the stress of the drug-induced shock state, the cardiac myocytes shift from using free fatty acids, their favoured “resting state” energy substrate, to carbohydrates.3,4 CCB toxicity also impairs the uptake of glucose and free fatty acids by cardiac myocytes3,4 and inhibits calcium-dependent mitochondrial activity required for glucose catabolism.3,4 Furthermore, insulin release is dependent on calcium influx into islet beta cells through L-type calcium channels.3,4 Thus, CCB toxicity can cause hypoinsulinaemia,3,4 which, in conjunction with CCB-induced insulin resistance, may lead to hyperglycaemia and a ketoacidotic state.6 Atropine, calcium boluses and infusions, glucagon, inotropes, vasopressors, and cardiac pacing have all been advocated for managing CCB toxicity, despite questionable efficacy.3,4,7-9 For instance, the evidence for glucagon is limited to small, non-blinded animal studies where no survival benefit or improvement in mean arterial pressure was shown, although heart rate improved in some cases.7 Rarely, heroic measures such as extracorporeal circulatory support and intra-aortic balloon counterpulsation have been successfully employed.5,10 HIET was first used to treat verapamil toxicity in humans in 1993, with a favourable outcome.6 Since then, in addition to animal studies, there have been nearly 70 cases reporting the beneficial use of HIET in humans, with an overall survival rate of 85%.8 However, to our knowledge, use of HIET in humans before the administration of glucagon or vasopressors has only been reported once.6 There have been some reports of HIET failure in treating CCB toxicity, although the dosing of insulin was low or uncertain, or it was used late.6,8 Early use of HIET may be more effective than HIET rescue therapy, as CCB-induced insulin resistance is greatest in the first 24 hours2 and the maximal haemodynamic benefit of HIET may not occur immediately.6 HIET may allow the heart to overcome metabolic starvation in CCB toxicity, which compounds the direct CCB impairment of myocardial contractility.3,4 Insulin increases glucose and lactate uptake by myocardial cells and improves function without increased oxygen demand.11,12 It also induces pyruvate dehydrogenase, hastening myocardial lactate oxidation, and helps clear the cytosol of glycolytic byproducts that impair calcium handling and cause diastolic dysfunction.3 Insulin promotes excitation–contraction coupling and contractility because enhanced glycolysis promotes increased sarcoplasmic reticulum-associated calcium ATPase activity and increased cytoplasmic calcium concentrations, and promotes calcium entrance into mitochondria and sarcolemma.3 HIET may be best used adjunctively with other measures such as catecholamines, for two reasons. First, insulin-mediated inotropy is not catecholamine-mediated, and is not affected by β blockers.3 Second, although insulin appears to improve myocardial contractility, it has no chronotropic effect and may cause vasodilation.3,8 HIET is safe, and adverse events are predictable, uncommon, and easily managed.2,8 The maximum safe dose of insulin is unknown, but loading doses of 0.5–1.0 IU/kg followed by infusions of 0.1–2.5 IU/kg/h are typically used.8 Interestingly, neither the inadvertent administration of a 1000 IU insulin loading dose for verapamil toxicity13 nor treatment of toxic cardiogenic shock for 2 days with a 6 IU/kg/h insulin infusion had any adverse effects.14 Adverse effects of HIET include hypoglycaemia, hypokalaemia, hypomagnesaemia, and hypophosphataemia.2,6,8 Although these are rarely clinically significant, they necessitate careful monitoring. Hypoglycaemia (blood glucose < 3.3 mmol/L) occurred in 16% of 55 published cases,8 and no cases of hypoglycaemia within 24 hours of CCB overdose were noted in Greene and colleagues’ series of seven cases.2 Greene et al also reported a mean dextrose requirement of 0.05 g/kg/h (range, 0–0.17 g/kg/h), although the mean blood glucose level exceeded the euglycaemic range.2 Some cases of severe CCB toxicity in patients presenting with hyperglycaemia do not require any additional glucose administration despite high-dose insulin therapy,15 and hypoglycaemia may be more likely in milder cases without marked hypotension.8 In addition, hypokalaemia (potassium < 3.5 mmol/L) was noted in only two patients in Greene et al’s small series, with a minimum potassium level of 2.8 mmol/L.2 Excessive correction of hypokalaemia should be avoided, because it reflects the intracellular shift of potassium from the extracellular compartment due to the action of insulin, rather than a potassium-depleted state.4 Interestingly, hypokalaemia in HIET may augment myocardial contractility by enhancing calcium entry during systole, and increased intracellular potassium may have a membrane-stabilising effect in excitable cells.4,6 In conclusion, we advocate consideration of the early use of HIET (as detailed in Box 2) for the prevention and treatment of life-threatening complications from potentially lethal CCB overdoses. HIET is safe, inexpensive and freely available, and suitable for use even in remote settings before transfer to a referral centre. 1 Early changes in the patient’s systolic blood pressure (SBP) and heart rate, relative to treatment with high-dose insulin and adrenaline infusions Following administration of a 0.5 IU/kg short-acting insulin bolus 3.5 hours after presentation, a short-acting insulin intravenous infusion (0.5 IU/kg/h) was commenced (black line), and the patient’s blood pressure improved. The infusion was abruptly discontinued 2 hours later and the patient again became hypotensive. This resolved following commencement of an adrenaline infusion (20 μg/min) (grey arrow), and the insulin infusion (0.5 IU/kg/h) was restarted 8.5 hours after presentation (black arrow). 2 Recommended high-dose insulin euglycaemic therapy protocol,3,4,9 based on the clinical experience of the Western Australian Toxicology Service, published case reports, reviews and animal studies Commence therapy with: Glucose 25 g (50 mL of 50% solution) IV bolus, unless marked hyperglycaemia (blood glucose > 22 mmol/L) is present Short-acting insulin 1 IU/kg bolus to maximally saturate insulin receptors Continue therapy with: Short-acting insulin infusion starting at 0.5 IU/kg/h and titrated every 30 min to a maximum of 5 IU/kg/h* Dextrose 25 g/h IV infusion titrated to maintain euglycaemia (blood glucose, 5.5–14 mmol/L); central venous access may be required to allow use of concentrated solutions (eg, 50% dextrose) and limit excess volume administration Monitor: Glucose — every 20 min for first hour, then every 1 h Potassium — replace only if < 2.5 mmol/L and there is a source of potassium loss Therapeutic end points: Improvement in myocardial ejection fraction (> 50%); increased BP (systolic BP > 90 mmHg in adults) Adequate heart rate (> 60 beats/min) Resolution of acidaemia; euglycaemia; adequate urine output (1–2 mL/kg/h) Reversal of cardiac conduction abnormalities (QRS interval < 120 ms) Improved mentation Therapy is weaned after the withdrawal of other vasopressors, as cardiotoxicity resolves. Dextrose may be required after cessation of insulin. IV = intravenous. BP = blood pressure. * The maximum safe and effective rate of infusion is unknown but may be even higher than 5 IU/kg/h. In animal studies, insulin infusions as high as 10 IU/kg/h have been safely used.11

Christopher P Nickson MB ChB, DTMH, GCertClinTox · Mark Little FACEM, DTMH, MPHTM

Clinical records Patient 1 A 73-year-old woman presented to a Western Australian metropolitan hospital in September 2007. She described having a dry mouth, lethargy and difficulty mobilising about an hour after eating two scones prepared with lupin flour. On arrival at hospital, her condition was much improved, and lethargy and dry mucous membranes were the only symptoms recorded. However, the treating doctor was not aware of the potential for anticholinergic effects, and may not have been looking for specific anticholinergic features. The patient was discharged several hours after presenting; her symptoms were attributed to a presumed allergic reaction. Patient 2 A 66-year-old woman presented to the same hospital 3 days later in September 2007. This patient had developed symptoms 15 minutes after eating pancakes prepared with lupin flour. She reported more typical anticholinergic features of blurred vision, dry mouth, lethargy and light-headedness. On examination she was found to have a sinus tachycardia of 100 beats/min, mildly dilated pupils, dry mouth, blurred vision and a residual bladder volume of 590 mL after voiding, indicating a moderate degree of urinary retention. Anticholinergic syndrome after ingesting lupins was diagnosed. She was kept in hospital overnight and her symptoms had resolved by morning. Recognition of a possible link After Patient 2 was diagnosed with anticholinergic syndrome caused by eating lupins, consulting physicians recalled that Patient 1 had also reported lupin consumption. After reviewing the clinical notes from Patient 1, it was recognised that this patient also had anticholinergic symptoms and that the two cases might be linked. Case investigation The two patients were interviewed in regard to their food consumption before becoming ill. Patient 1 had purchased lupin flour from a specialty grocery chain and made scones with the flour. She remarked that the two scones she ate tasted very bitter. Patient 2 had purchased both lupin flour and lupin beans from a different store of the same grocery chain as that reported by Patient 1. She also remarked on the bitterness of the pancakes she had made with the flour. In addition, she reported soaking lupin beans she had purchased overnight, boiling them and eating one lupin bean, which tasted bitter. The store identified by Patient 2 was inspected 2 days after she had bought the lupin flour. Questioning revealed that after the normal supply of sweet lupin flour was exhausted, a storeman had had 125 kg of bitter lupin beans (Lupinus albus) milled into flour. He was unaware of the danger associated with consuming untreated bitter lupins. It was this flour that was purchased and consumed by the two patients. The bitter lupin flour was distributed to a number of stores within the grocery chain. Further investigation revealed another two complaints of bitter-tasting bread made from the lupin flour, but no other cases of anticholinergic syndrome were reported. Following the investigation, the proprietor removed the bitter lupin flour from sale. Samples of both bitter lupin beans and the bitter lupin flour were submitted for chemical analysis. The total alkaloid levels for the bitter lupin beans and flour were 1.92% and 2.01%, respectively. This was about 100 times the permissible alkaloid level for flour of 0.02%, or 200 mg/kg, as detailed in the Australia New Zealand Food Standards Code.1 No standard exists in the code for allowable alkaloid levels in whole lupin beans. Lupins (Lupinus spp) are legumes, otherwise known as pulses. There are about 450 Lupinus species, with L. angustifolius and L. albus being the main species cultivated in Australia. While lupins have been predominantly used for animal feed, recent research has shown that eating them can provide health benefits for humans. The addition of sweet lupin flour to bread has been shown to reduce its glycaemic index, reduce energy intake and increase satiety of study participants compared with those who consumed standard white bread.2,3 The addition of sweet lupin flour to sausages was shown to decrease fat intake and increase satiety in study participants when compared with those who consumed full-fat sausages.4 Lessons from practice Anticholinergic syndromes vary in their severity, but any combination of blurred vision; mydriasis; tachycardia; dry, flushed skin; dry mucous membranes; urinary retention; ileus; or delirium should raise suspicion of this diagnosis. Most anticholinergic syndromes are caused by medications used therapeutically or in the misuse setting. However, naturally occurring toxins from foods or plants should be considered where appropriate. Clinicians should question patients who present with symptoms of anticholinergic syndrome about their recent food consumption, particularly consumption of lupin-containing products. With increasing community interest in foods with a low glycaemic index, it is important that lupin flour suppliers understand the importance of distinguishing between sweet and bitter lupins in flour preparation. Adverse consequences of eating lupins can be divided into toxic and allergic reactions. Studies have identified both serological and clinical cross-reactivity between peanut and lupin, although lupin allergy can also occur without allergy to other legumes.5,6 Lupins are separated into sweet varieties, which have an alkaloid content of approximately 130–150 mg/kg,7 and bitter varieties, which need to undergo a debittering process to remove potent alkaloids before consumption (these are left with an alkaloid content of approximately 500 mg/kg after debittering).7 The debittering process involves soaking beans in repeated changes of water. The alkaloids leach from the beans into the water, which is then discarded. Solvents can also be used for debittering. Failure to remove, or incomplete removal of, alkaloids can result in lupin toxicity, manifesting as anticholinergic syndrome. Anticholinergic syndrome can also be caused by various drugs, including some antihistamines, antipsychotics, antispasmodics and antidepressants, as well as by eating some mushrooms and plants.8,9 Plants known to cause anticholinergic syndrome when ingested include Datura spp (jimson weed, angel’s trumpet), Salvia divinorum (diviner’s sage), Atropa belladonna (deadly nightshade), Hyoscyamus niger (black henbane) and Mandragora officinarum (mandrake).9,10 Fatal cases of lupin poisoning have been reported, with the lethal dose calculated as about 30 mg/kg bodyweight.7 Bitter lupins are commonly eaten by people of Mediterranean origin, and these traditional users are aware of the need to debitter the lupins before consumption. There are relatively few published reports of acute lupin toxicity overseas,9-12 and only one in Australia,13 which involved a Mediterranean woman who had eaten lupin beans that had not been sufficiently debittered. In light of the increasing consumption of lupin products, we recommend that information be provided to food suppliers and consumers about the dangers of selling and eating products containing bitter lupins that have not been appropriately pretreated to remove toxic alkaloids. Clinicians should question patients who present with symptoms of anticholinergic syndrome about their recent food consumption, particularly consumption of lupin-containing products.

Nevada M Pingault BSc(Hons), MASM, MAIMS · Robyn A Gibbs BSc, PhD · Alexander M Barclay MAIFST, MAIEH · Mark Monaghan MB BS, FACEM

Objective: To describe demographic, geographical and clinical features of envenoming by the rough-scaled snake (RSS) (Tropidechis carinatus).Design, setting and participants: Prospective cohort study of RSS snakebite victims, recruited between January 2004 and December 2008, as part of the Australian Snakebite Project. RSS envenoming cases were confirmed by snake identification and/or venom-specific enzyme immunoassay.Main outcome measures: Clinical and laboratory features of envenoming.Results: There were 24 confirmed cases of RSS envenoming, nearly all occurring in coastal areas between northern New South Wales and south-eastern Queensland. Twenty-three patients had local bite-site effects and 17 had at least three non-specific systemic effects (eg, nausea, headache). All 24 had venom-induced consumption coagulopathy (VICC), and 19 had an international normalised ratio > 3.0. Six had bleeding from the bite site or intravenous cannula site, 10 had blood detected on urinalysis, and one had a major intra-abdominal haemorrhage. Mild neurotoxicity developed in two patients, and one patient developed myotoxicity with generalised myalgia, myoglobinuria and a peak creatine kinase level of 59 700 IU/L. Twenty-three patients were treated with antivenom (21 with tiger snake antivenom, two with polyvalent antivenom). Free venom was undetectable in 19 of 20 blood samples taken after antivenom administration.Conclusion: RSS envenoming occurs predominantly in coastal areas of northern NSW and southern Queensland, and within this range, most envenoming is due to the RSS rather than tiger snakes. Clinically it is characterised by VICC, with mild neurotoxicity and myotoxicity in some cases. Tiger snake antivenom appears to be effective against RSS envenoming.

Melissa Gan MB BS · Margaret A O’Leary PhD · Simon G A Brown MB BS, FACEM, PhD · Tamara Jacoby BSc · David Spain MB BS, FACEM · Alan Tankel FACEM · Chris Gavaghan MB BS, FACEM · Peter Garrett MB BS, FACEM · Geoffrey K Isbister BSc, FACEM, MD

Therapeutic guidelines. Toxicology and wilderness. Emergency Medicine Expert Group. Melbourne: Therapeutic Guidelines, 2008 (xxii + 311 pp). ISBN 978 0 9804764 0 8. Poisoning is a common presentation to Australian emergency departments and a common cause of death in those under 40, yet there is a real paucity of Australasian toxicology texts. Toxicology and wilderness, a new release in the Therapeutic Guidelines series, is a subset of topics prepared by the Emergency Medicine expert writing group for the electronic eTG complete. Toxicology and wilderness sensibly starts with in-depth information on the many aspects of resuscitation. There is a good overview on the approach to the poisoned patient, with a great nomogram to help assess the risk of torsades from a prolonged QT. The majority of the book is based on the toxicology of individual agents. It approaches each agent in a structured manner, detailing the indicators for toxicity, clinical presentation, key investigations and treatment. It has much helpful and sensible advice. The authors seem to advocate routine activated charcoal for most poisonings that present within 1 hour, which I would disagree with. The discussion on antidotes is understandably brief, although I was curious to read in detail about dicobalt edetate for the treatment of cyanide poisoning, and not the currently recommended and far safer hydroxocobalamin. I felt that there were sections where better emphasis on the potential for severity of the poisoning or management issues could have occurred. The book ends with a well written section on envenoming, then the unusual bedfellow of wilderness medicine. I think the strength of this book lies in the ready access of the electronic format for hospital practitioners. I found the information a good starting point but, due to the restrictions of the structure of this series, a little light in some areas. As to whether it sits on your bookshelf — you need to browse through to see if it fits a need.

Mark Little

A 66-year-old, previously well man presented with colicky abdominal pain and vomiting. He was a cigarette smoker and consumed homemade spirits daily. On physical examination, the patient had poor dentition, a bluish pigment along the gingival line (Figure, arrow), and generalised abdominal tenderness with no peritonism; he was afebrile with a heart rate of 68 beats/min, blood pressure of 190/90 mmHg with no postural drop, and oxygen saturation of 99% in room air; and all other results were normal. Full blood examination revealed normocytic anaemia (haemoglobin, 90 g/L; reference range, 130–180 g/L) and basophilic stippling. The patient’s blood lead level was elevated at 7.10 μmol/L (reference range, < 0.48 μmol/L), but fell to 2.28 μmol/L after 3 weeks of treatment with the chelating agent 2,3-dimercaptosuccinic acid (DMSA). Burton’s lead line indicates lead poisoning and occurs due to deposition of lead sulfide, the result of a reaction between sulfur produced by oral flora and lead.1,2 The source of this patient’s lead exposure is unknown. Distilling equipment, especially for spirits, can be a source of lead exposure,3 but testing of this patient’s equipment ruled it out as a source.

Jayne E Camuglia · George Grigoriadis · Christopher P Gilfillan

To the Editor: Recently, we treated a patient with fatal paramethoxyamphetamine (PMA) poisoning. We believe this is the first PMA poisoning to be reported in the Australian Capital Territory. PMA (street name, “death”) was first reported in the early 1970s during the emergence of recreational use of 3,4-methylenedioxymethamphetamine (MDMA [“ecstasy”]).1,2 Hyperthermia, coma and seizures are features of MDMA and PMA poisoning, but they are more severe with PMA ingestion; features of hypoglycaemia, hyperkalaemia and QRS interval prolongation are suggestive of PMA poisoning.3 Our patient was a 20-year-old man who was conveyed to the emergency department by ambulance after presumed MDMA ingestion. On presentation, he was unconscious (Glasgow Coma Score, 4/15) and had the following signs: temperature, 42.8°C; heart rate, 90 beats/min; QRS interval, 160 ms (reference range [RR], < 100 ms); blood pressure, 171/148 mmHg; oxygen saturation, 76% (RR, 95%–100%); and respiratory rate, 40 breaths/min. After intubation, external cardiac compressions and multiple DC shocks were required to restore circulation. The initial serum potassium level was 8.9 mmol/L (RR, 3.2–5.0 mmol/L). Hypoxaemia persisted, and a chest x-ray showed extensive bilateral airspace consolidation. The patient’s associates alleged that he habitually used equine clenbuterol and ovine androgen preparations in addition to ecstasy. The subsequent days were notable for resistant shock, rhabdomyolysis, cardiomyolysis and severe coagulopathy refractory to therapy. Oliguric renal failure necessitated extracorporeal blood purification. Hepatic failure and hypoglycaemia were pronounced. The most extreme biochemical derangements recorded in this case are listed in the Box. Five days after admission, the patient’s pupils were sluggishly reactive. Oculocephalic and oculocaloric reflexes were present but abnormal, while gag and cough reflexes were absent. A cerebral computed tomography scan showed extensive cerebral oedema. By Day 8, the patient had fixed pupils and worsening haemodynamic instability. He died 10 days after ingestion of PMA. The patient’s antemortem blood concentration of PMA was 2.3 mg/L — 2.0 mg/L above the typical fatal threshold of 0.3 mg/L previously reported.2-4 MDMA, methylenedioxyamphetamine (MDA) and methylecgonine were also detected at low levels. Since 2005, the Pharmacy Guild of Australia has instituted its “Pseudo Watch” program to reduce diversion of pseudoephedrine to illicit methamphetamine manufacture by a combination of retail restrictions and recording details of purchasers judged genuine. Supporting legislation varies by state.5 However, PMA is made from the readily available and unmonitored precursor, anethole. Further, PMA has a slower onset of action than MDMA, leading to the possibility of additional doses being ingested while awaiting effects. We believe medical practitioners should consider PMA poisoning in cases of severe reactions to ecstasy, especially those in which hypoglycaemia and hyperkalaemia are present. A “market” shift in drug use towards the more lethal PMA because of reduced availability of pseudoephedrine would be a cause for concern. Laboratory markers of multisystem organ dysfunction in a case of PMA poisoning Biochemical marker Extreme value (peak or nadir) Reference range Creatine kinase (U/L) 58 358 20–200 Troponin I (U/L) 85.83 < 0.06 Bilirubin (μmol/L) 412 2–20 ALT (U/L) 3961 < 55 Ammonia (μmol/L) 219 10–50 Platelet count (× 109/L) 18 150–400 ALT = alanine aminotransferase. PMA = paramethoxyamphetamine.

Paul G Lamberth · Geoff K A Ding · Liisa A Nurmi

A 2-year-old boy and a 10-year-old girl presented to the emergency department with a decreased level of consciousness. The girl had had persistent vomiting and a seizure. Urine metabolic screening tests were positive for γ-hydroxybutyrate (GHB). Samples from toy beads ingested by both children contained 1,4-butanediol, which is metabolised to GHB in humans. Regulatory authorities were notified, leading to an international recall of the toy beads. Clinical recordsPatient 1 A 2-year-old boy presented to the emergency department (ED) with a decreased level of consciousness. Earlier, he had been playing with his siblings in the backyard. He had been unsteady on his feet an hour before and then became difficult to rouse. There was no history of trauma, ingestion of medicines or plants or intercurrent illness. He had been well previously and was the youngest of 10 siblings. On arrival at the ED, his Glasgow Coma Score (GCS) fluctuated between 7 and 12, with no focal neurological deficit. Pupils were 2 mm, equal and reactive. A pustular vesicle on his right cheek was the only other significant finding. He was afebrile and had no neck stiffness. An electrocardiogram showed sinus bradycardia at 60 beats/min. He was hypotensive, with blood pressure of 59/39 mmHg. Blood glucose level was 5.2 mmol/L. Without a history of ingestion, we initially considered a postictal state or encephalitis. Laboratory investigations, including full blood count, electrolytes, and renal and liver function tests, were all within normal limits. Computed tomography of the brain showed no intracranial abnormality. Lumbar puncture was not attempted because of the child’s fluctuating level of consciousness. He was investigated and treated with cefotaxime and acyclovir for suspected intracranial infection. Urine was sent for toxicology and metabolic screening. Seven hours after presentation, remarkable clinical improvement was noted, and he became fully alert and cooperative. At this point he vomited and also passed a substantial number of coloured beads in his stool. The family were further questioned about a history of ingestion; the boy’s mother divulged that he had been playing with Bindeez brand toy beads (Moose Enterprise, Melbourne, Vic) (Box). With no obvious diagnosis, he was admitted to hospital for observation and further investigation. An electroencephalogram showed no abnormalities. The urine toxicology screen returned with a negative result for illicit drugs. The urine metabolic screen became available on Day 5 and was positive for γ-hydroxybutyrate (GHB). The source of GHB in this patient was thought to be either exogenous (that is, poisoning) or an inborn error of metabolism. The latter was excluded when a repeat metabolic screen from urine taken on Day 3 returned with a negative result for GHB. In searching for an exogenous source of GHB, toy beads from the boy’s home, similar to those ingested, were sent for analysis and subsequently found to contain 1,4-butanediol (1,4-BD). The patient recovered completely and was discharged on Day 7 with no residual sequelae of his poisoning. Patient 2A 10-year-old girl presented to the ED after a 4-minute generalised seizure. She had been unrousable by family an hour earlier. She had then vomited up to 100 Bindeez beads and then had the seizure. She had been well earlier in the day, and there was no history of intercurrent illness or trauma. The patient had a further seven episodes of vomiting and was persistently drowsy. She had a background of Asperger’s syndrome and attention deficit hyperactivity disorder, for which she took extended-release methylphenidate. On arrival at the ED, she was drowsy, with a GCS of 14 and no focal neurological signs. Her heart rate was 70 beats/min, she was normotensive and physical examination was otherwise normal. On advice from the New South Wales Poisons Information Centre, a urine sample was collected, and beads from the patient’s home, similar to those ingested, were sent for analysis. Five hours after ingestion, she became alert and communicated appropriately. She was admitted to hospital for overnight observation and discharged the following day with no further complications. The urine metabolic screen was positive for GHB, and the beads were found to contain 1,4-BD. Public health responseAfter confirmation of GHB poisoning in Patient 1 from 1,4-BD detected in Bindeez toy beads, the NSW Poisons Information Centre was notified. The Centre and the NSW Biochemical Genetics Service alerted the NSW Office of Fair Trading about the product. They in turn contacted the company marketing the product to investigate the formulation of the toy beads. When the manufacturer in Hong Kong was contacted, it supplied a list of ingredients in the production of the toy beads; this list did not include 1,4-BD, but did mention the agent 1,5-pentanediol. Meanwhile, two further samples of Bindeez toy beads were tested at our institution. Both samples tested positive for 1,4-BD. None of the beads tested contained 1,5-pentanediol. With confirmation of similar biochemical analyses from the beads in the second case, the NSW Department of Health and the NSW Office of Fair Trading were further alerted about banning the product. The following day, the NSW Minister for Fair Trading issued an interim ban on the sale of Bindeez products in NSW; other Australian states rapidly followed suit. Further cases of GHB poisoning in Australia came to light during the ensuing days. Staff of the Poisons Information Centre also alerted toxicologists and poisons control centres worldwide where similar products are marketed (eg, Bindeez in the United Kingdom and Aqua Dots in North America) and the potential for GHB poisoning may have existed. With worldwide media coverage and similar cases in North America, an international recall soon followed. DiscussionGHB is an endogenously occurring neurotransmitter derived from γ-amino butyric acid (GABA).1 Its known metabolic precursors are 1,4-BD and γ-butyrolactone. A potent sedative and anaesthetic agent, it was initially synthesised in the 1960s.2 GHB and its precursors have recently found notoriety as recreational and club drugs. In 2000, GHB became a banned substance by the United States Drug Enforcement Agency and classified as Schedule 1 by the US Food and Drug Administration.2,3 1,4-BD is a widely available industrial chemical used as a solvent and in the manufacture of some types of plastics and fibres. When ingested, it is metabolised rapidly by alcohol and aldehyde dehydrogenases to GHB.4,5 Hence, the toxicity and clinical features of 1,4-BD poisoning are similar to those of GHB. While 1,4-BD is not a scheduled drug in Australia, it is a category 1 precursor under the Drug Misuse and Trafficking Regulations 2006, which restrict the supply of 1,4-BD (Pharmaceutical Services, NSW Department of Health, personal communication, 12 Nov 2007). GHB is an agonist at inhibitory GABAB receptors and is excitatory at specific GHB receptors. There is a dose–response relationship in GHB toxicity. Low doses result in vomiting, drowsiness, visual disturbance and disinhibition, while higher-dose effects include confusion, coma, bradycardia and myoclonic (seizure-like) movements.3 Routine urine toxicology screens do not detect GHB in their profile. Specific analysis with gas chromatography–mass spectrometry (GC–MS) or as part of a urine metabolic screen is required. The urine sample from Patient 1 was investigated for possible inherited metabolic diseases, including urinary organic acid analysis by GC–MS.6 This showed a marked increase in GHB (a metabolite seen in succinic semialdehyde dehydrogenase deficiency) but without any increase in 4,5-dihydroxyhexanoate lactone, as would be expected in the inborn error. This pattern strongly suggested an exogenous source of GHB, which was confirmed by the compound being undetectable in a second urine sample taken 3 days later. Treatment of GHB poisoning is primarily supportive and may involve airway and ventilatory intervention, and atropine for symptomatic bradycardia7 Gastrointestinal decontamination with activated charcoal is not indicated, owing to the rapid absorption of this liquid poison. Additionally, there are no specific antidotes that reliably reverse GHB toxicity.7 Where patients are suspected of ingesting Bindeez toy beads (containing 1,4-BD), they should be observed in the ED for depressed level of consciousness. Patients who remain asymptomatic after 4 hours are unlikely to have ingested enough beads to cause toxicity and can be safely discharged from hospital. Patients developing symptoms should be managed in a similar way to those with GHB intoxication. Moderately intoxicated patients may be managed and observed in the coma position until awake, while patients with airway compromise or respiratory failure may require intubation and mechanical ventilation until toxicity resolves. The identification of these cases highlights the important role of poisons centres in toxicovigilance and monitoring of potential clusters of poisoning related to new pharmaceuticals and chemical agents. Rapid electronic communication of these cases to worldwide toxicological networks enables health authorities to make a risk assessment of similar toy products overseas. So far, this has resulted in identification of similar suspected cases of GHB poisoning in children and an international withdrawal of the product. Chinese authorities confirmed that toy beads from the Hong Kong manufacturer contained a substance which metabolised to GHB.8 Bindeez bead set “Make, spray and they stay! Bindeez are magic beads that you use to create colourful and fun designs. Just lay out your design in the special Bindeez tray, then spray them with water and your artwork will magically set in place!” (from an advertisement for the toy).

Naren Gunja MB BS, FACEM · Evelyn Doyle MB BCh, BAO, MRCPCH · Kevin Carpenter PhD, FHGSA · Olivia T Chan BSc, MB BS · Simon Gilmore BPharm, MRPSGB · Gary Browne MD, FRACP, FACEM · Andis Graudins PhD, FACEM, FACMT

Over a 6-month period, two patients presented to a community hospital emergency department with perforated gastric ulcers as the result of recreational misuse of over-the-counter ibuprofen–codeine preparations. Misuse of these medications appears to be an emerging cause of significant morbidity in patients with codeine addiction. Clinical recordsPatient 1A 39-year-old woman was referred by her general practitioner to the emergency department (ED) of our community hospital with a 24-hour history of acute epigastric pain. She had a past history of alcohol misuse, codeine misuse and pancreatitis. While in the ED, she described recreationally taking 16–24 Nurofen Plus tablets (Reckitt Benckiser, Sydney, NSW) (containing ibuprofen and codeine) per day for the previous 3 weeks. Clinical examination revealed pallor, mild diaphoresis, a heart rate of 130 beats/min and blood pressure of 92/60 mmHg. The patient’s abdomen was grossly distended and maximally tender on palpation in the epigastrium. Bowel sounds were absent. Intravenous access was established and infusion of 2 L crystalloid fluid was commenced. An erect chest x-ray confirmed the presence of gas under the diaphragm (Box 1). An urgent laparotomy revealed a perforated anterior gastric antrum ulcer and 2.6 L of green turbid fluid in the peritoneal cavity. The patient was given an additional four units of packed red cells intraoperatively, and her ulcer was oversewn. Postoperatively, she was transferred to an intensive care unit at another hospital. Patient 2A 41-year-old man presented to our ED with a 12-hour history of progressively worsening severe abdominal pain. The patient had been recreationally taking “a packet” of Nurofen Plus each day for the past year. To ease the abdominal pain, he had already tried a liquid paraffin-based laxative (Parachoc [Paedpharm, Sydney, NSW]) and an osmotic laxative (Microlax [Johnson & Johnson Pacific, Sydney, NSW] at home, with no relief of his discomfort. Clinical examination revealed generalised abdominal tenderness, with no guarding, and the presence of bowel sounds. He had a heart rate of 93 beats/min and blood pressure of 143/93 mmHg. The pain initially settled in the ED after the patient had received a total of 10 mg intravenous morphine over a 2-hour period. After admission for observation, he developed a slight fever (37.8°C), his heart rate increased to 120 beats/min, and his abdomen became increasingly distended. Pain recurred on the ward, and was not responsive to 20 mg intravenous morphine given over a 2-hour period. Intravenous contrast computed tomography revealed the presence of free fluid and gas in the peritoneal cavity (Box 2). An urgent laparotomy revealed a 1.5 cm gastric antrum ulcer with gross peritoneal contamination. Postoperatively, the patient was offered care at an inpatient drug and alcohol service, but absconded before transfer could be arranged. DiscussionIbuprofen–codeine preparations first entered the Australian over-the-counter (OTC) market in October 2002. The leading product in the market, Nurofen Plus, contains 200 mg ibuprofen and 12.8 mg codeine phosphate in each tablet,1 making it the strongest codeine tablet available in Australia without prescription. Codeine phosphate is a known drug of misuse. Ibuprofen–codeine products are particularly vulnerable to misuse because of the relatively high amount of codeine contained in each preparation and the absence of toxicity in overdose that is associated with paracetamol preparations. Several cases of severe hypokalaemia secondary to ibuprofen-induced renal tubule acidosis after Nurofen Plus misuse have been reported in the literature.2-4 One study showed that patients with acute upper gastrointestinal presentations were 5.2 times more likely to have consumed high-dose OTC non-aspirin non-steroidal anti-inflammatory drugs within the previous week, and the increased risk was dose-dependent.5 To our knowledge, the two cases described here are the first reports of perforated gastric ulcers associated with recreational Nurofen Plus misuse. The database of Australia’s Adverse Drug Reactions Advisory Committee (ADRAC) relies on voluntary reporting, and a drug’s adverse reaction profile becomes better defined as the market gains experience with it. As at July 2007, there had been 26 cases reported to ADRAC of adverse events in patients taking Nurofen Plus (Dr Patrick Purcell, Medical Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, personal communication). ADRAC records show that Nurofen Plus was the sole suspected agent associated with two duodenal ulcer perforations. The first case involved a 28-year-old woman who took eight tablets a day “for a period of months” for back pain, and the second involved a 24-year-old woman for which there was no further clinical information. ADRAC has received no reports of perforated gastric ulcers associated with Nurofen Plus, and only one report of this condition in a patient taking an ibuprofen-only preparation. With only two patients presenting to our community hospital with perforated gastric ulcer in the past 6 months, the presentation is unusual. Misuse of ibuprofen–codeine analgesics, associated with both cases, appears to be a new and important aetiology for this condition. Vigilant reporting of adverse drug reactions to ADRAC, tighter enforcement of legislative requirements for the dispensing of pharmacy-only medicines, or reformulation of this product (as has occurred with OTC pseudoephedrine products) may help to minimise the health sequelae of ibuprofen–codeine misuse. 1 Erect portable chest x-ray of a 39-year-old woman with acute abdominal pain A = free air under the diaphragm. 2 Computed tomography image of the abdomen of a 41-year-old man with acute abdominal pain A = free air within the peritoneal cavity. F = free fluid within the peritoneal cavity. L = liver.

Martin J Dutch MB BS(Hons), BMedSci(Hons)

To the Editor: We report elevated mercury levels in three infants, each the only child of Chinese parents living in Sydney. All three children had eaten fish congee (a rice and fish porridge) as a weaning food and ate fish regularly as toddlers. Their parents had sought medical advice for either developmental delay or neurological symptoms in the children. A 2-year-old boy had demonstrated increasingly aggressive behaviour for the past 6 months. A general practitioner had diagnosed mercury poisoning in the boy’s father 2 months earlier, following investigation for complaints of allergies, rashes, abdominal pain and diarrhoea. The family ate fish (usually salmon, barramundi or snapper) at least five times a week, and had used unspecified herbal medicines in the past. The child had eaten fish regularly since weaning. The boy’s blood mercury level was 158 nmol/L (normal range [NR], < 50 nmol/L), a random urine mercury/creatinine (Hg/Cr) ratio was 9 nmol/mmol (NR, < 6 nmol/mmol*), and his hair mercury level was 1.42 mg% (NR, < 0.18 mg%). The boy’s father and mother (who was pregnant) also had elevated hair mercury levels, of 4.3 mg% and 6.0 mg%, respectively. The father and child were treated with chelation therapy elsewhere. * The two laboratories reported different normal ranges for the urine Hg/Cr ratio. A boy aged 2 years and 10 months presented with delayed speech and some autistic features. Since weaning, he had eaten fish (barramundi, sea perch, salmon and rock cod) up to eight times a week. He had no history of herbal medicine use, and his thyroid function, blood lead level, and a DNA screen for fragile X syndrome were normal. The child’s blood mercury level was 350 nmol/L and urine Hg/Cr ratio was 14 nmol/mmol (NR, < 10 nmol/mmol*). The boy’s father did not eat fish, and his blood mercury level was 19 nmol/L. The child’s mother did eat fish, and had a blood mercury level of 27 nmol/L. Two weeks after removing fish from the diet, the child’s blood mercury level had fallen to 99 nmol/L and his urine Hg/Cr ratio to 7 nmol/mmol. However, his behaviour did not improve, and he was subsequently diagnosed with classical autism. A 15-month-old boy presented with delayed development since birth. Fish had been introduced to his diet at 8 months of age, and he had since continued to consume fish four to five times a week. He had recently eaten either ling or salmon. The boy’s mother had consumed ling three to four times a week after the fifth month of her pregnancy. The child’s thyroid function, DNA screen for fragile X syndrome, chromosome karyotype, and urinary metabolic screen were normal. His blood mercury level was 143 nmol/L, but fell to 19 nmol/L over a period of 1 year after ceasing fish intake. His longer-term developmental status is unknown. Fish congee, made with either freshwater species or locally caught fish, is a common weaning food in coastal regions of southern China and South-East Asia.1 Adding fish to the weaning diet has health benefits,1,2 such as reducing anaemia, and is actively promoted. However, fish, particularly the large pelagic (open ocean) species more likely to be bought in Australia, may also contain mercury. Excessive consumption of mercury has been associated with neurological impairment.3-5 The Box shows that the consumption by infants of fish congee made from portions of large fish species may exceed the provisional tolerable weekly intake (PTWI)7 for methylmercury of 1.6 μg/kg bodyweight/week (the limit considered sufficient to protect a developing fetus). Food Standards Australia New Zealand’s most recent risk assessment concluded that median-level consumers of fish are unlikely to exceed the PTWI for methylmercury,6 but frequent consumers might if all their consumption is of predatory or long-lived fish species, which tend to acccumulate higher concentrations of mercury. It has been previously noted in the Journal that public health policy regarding fish consumption needs to balance the health benefits for cardiovascular disease and anaemia with the possible ill effects of mercury on neurological development in infants.8 We recommend that multilingual information about fish and mercury be made available to pregnant women and mothers, especially targeting groups who are likely to be frequent consumers of fish and who use fish in weaning and infant foods. Regulatory and health promotion activities could also be informed by surveillance of blood or hair mercury levels in infants from ethnic groups at high risk of mercury intoxication, and of the frequency of fish consumption in this age group (by type of fish). Estimated weekly mercury intake in infants consuming fish congee Mean mercury concentrations in fish tissue* (μg/kg fish) Child’s estimated weekly mercury intake† (μg/kg bodyweight/week) Fish fillets‡ Maximum 50 1.25 Median 16 0.40 Minimum 5 0.13 Barramundi Maximum 310 7.75 Minimum 40 1.00 Snapper Maximum 520 13.00 Minimum 52 1.05 * For species consumed in Australia.6 † For a 12-month-old child weighing 10 kg; weekly fish consumption is estimated to be 0.25 kg, assuming 50 g servings five times per week. Provisional tolerable weekly intake for methylmercury = 1.6 μg/kg bodyweight/week.7 ‡ Average concentrations of all fillets purchased.

Stephen J Corbett · Christopher C S Poon

We seldom identify the holiday season with medical matters, but perhaps we have been remiss in not doing so. Many holiday customs have medical significance — some positive, some negative. Christmas and the following 2 weeks host the highest cardiac and non-cardiac mortality of the major holidays,1 but few people seem to dread the approach of December as a threat to their physical health. On the positive side, some ancient kinds of Christmas gifts turn out to have modern medical applications, while, not so positively, some modern decorations cause a fair degree of morbidity. Here, solely to amuse and pique curiosity, not to provide an exhaustive review, we explore the pharmacology of the first Christmas gifts, as well as the potential benefits and hazards of some modern Christmas decorations. Ancient gifts that keep on giving today The first holiday custom we thought might have a medical application is the giving of Christmas gifts. This apparently originated with the arrival of the Magi, the three wise men, some time around the year 1 CE. Given the apostle Luke’s vocation as a physician, we felt it only fitting to use his biblical account of the three wise men bearing gifts to the baby Jesus. But, alas, his gospel includes no account of this exchange, so we were forced to quote Matthew, a tax collector: “Then they opened their treasure chests and gave him gifts of gold, frankincense and myrrh”.2 Interestingly, all three of these items have modern medical applications. Gold is the most obvious. As sulfhydryl-containing organic gold compounds, it has been used for rheumatoid arthritis and tuberculosis since the early 1920s, although elemental (metallic) gold was used for many centuries before. Elemental gold is largely inert, not reacting to any chemicals it encounters inside the body; however, it can be deposited in the soft tissue of the skin and eye, leading to a condition known as chrysiasis. Unfortunately, the gold deposits are actually an unappealing grey–blue, rather than the metallic gold glow that might be considered festive. Although the use of gold is not as common today as it was in previous years, exposure to modern therapeutic technology, such as the Q-switch laser, or even ultraviolet light, has resulted in chrysiasis many years after gold therapy was discontinued.3 Gold also causes its share of problems when combined with another holiday tradition: ethanol. Case reports indicate that Goldschlager, a liquor that contains gold flakes, has been associated with lichen planus.4 Although frequently having a lacy white pattern, known as Wickham’s striae, lichen planus too is unappealing, rather than festive. The next gift of the Magi, frankincense, has several medical uses. This substance is obtained from trees of the genus Boswellia, by slashing the tree trunk longitudinally and harvesting the liquid released after it has dried to “tears”.5 It has been valued greatly since ancient times, although its mechanism of action has only recently been discovered. Frankincense inhibits leukotriene synthesis via the inhibition of 5-lipoxygenase, but, interestingly, it does not block cyclo-oxygenase or 12-lipoxygenase.6 This mechanism is similar to that of the leukotriene-receptor antagonist, monteleukast, and indeed frankincense has been shown to prevent exacerbations of asthma much more efficiently than placebo in a small study.7 Frankincense also appears to be bacteriostatic and larvicidal, and may yet prove beneficial as an antimicrobial.8 Further, it seems to have activity against skin cancer as an escharotic agent and stimulates apoptosis in colon cancer cells.5 It has also shown some cytotoxic activity against meningioma.5 Finally, myrrh, a secretion of plants of the genus Commiphora,9 is proving to have its own set of medical benefits. It appears to have an analgesic effect through action on opioid receptors.9 It also seems to have antimicrobial activity, and has recently been touted as a highly effective treatment for schistosomiasis in Egypt.10 Myrrh extracts have shown antibacterial activity against common pathogens such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus.11 On a more practical level, myrrh combined with bee propolis (a hive sealant used as an alternative to beeswax) and, paradoxically, honey has been used to treat wounds in patients with diabetes mellitus, with great success in limited trials.12 Another product of plants of the genus Commiphora, guggulipid, is purported to have a favourable effect on lipids — causing a modest decrease in low-density lipoprotein (LDL) cholesterol concentration, but a profound increase in high-density lipoprotein (HDL) cholesterol.13 However, randomised trials have failed to show this effect.14 Traditional decorationsMistletoe, a plant popular as a decoration around the Christmas holidays, is also finding a myriad of medicinal uses. This tree parasite, thought to have been sacred to the Druids, and blamed for the death of the Norse god Balder, is commonly used as an excuse for stealing a kiss during the Christmas season. But mistletoe does not, to our knowledge, have any aphrodisiac qualities. However, it has been found to inhibit peristalsis, and has been suggested as a treatment for colic.15 A mistletoe extract has shown antihypertensive effects in rats, although safety in humans has not been established.16 Mistletoe extracts also apparently have activity against bladder carcinoma in both mice and rats.17 In humans, mistletoe has been used to treat prostate cancer.18 Modern decorations or dealers of disease?The humble Christmas tree can be a source of disease, as well as providing pleasure. A young man in Molokai, Hawaii, contracted ophthalmomyiasis while unloading a Christmas tree.19 Perhaps the larvicidal effect of frankincense would have been of benefit to him in this situation (as it might be to a herd of reindeer — flying or otherwise — infested by botfly larva). As might be expected, children are not immune from the dangers of Christmas trees. A 2-year-old Canadian child with recurrent pneumonia eventually underwent a thoracotomy and right lower lobectomy for the disorder. The pathology examination revealed a 3 cm by 0.5 cm foreign body resembling the distal branch of an evergreen tree.20 Similarly, a 2-year-old Australian child apparently inhaled an ornament shaped like a Christmas tree, which caused asthma-like symptoms until it was removed laryngoscopically.21 Even artificial trees have been the source of disease. A 44-year-old English woman had a relapse of bird fancier’s lung a long time after she got rid of her fine, feathered friend.22 Apparently, her symptoms were triggered by an artificial Christmas tree that had been her bird’s favourite perch — protein deposits left on the branches were enough to cause the recurrence. Christmas trees have also been — unfairly — blamed for sporotrichosis. It seems that, although Christmas-tree farming has been associated with this disorder, it is actually the sphagnum moss used to wrap the roots of the trees, rather than the trees themselves, that are the culprit.23 Christmas trees are not the only unfairly maligned plant of the Christmas season. Perhaps the most notable medical feature of a common Christmas decorative plant — the poinsettia (Euphorbia pulcherrima) — is actually the lack of any adverse events associated with it. This festive red and green plant is used throughout the United States as both a Christmas gift and a holiday decoration, despite the widespread public notion that it is highly toxic. Recent investigations failed to show any fatalities — and indeed very few adverse events at all — associated with poinsettia ingestion.24 Likewise, that common Christmas plant, holly (Ilex aquifolium), is traditionally thought of as poisonous, but a PubMed search of this genus and species revealed no reports of ill effects associated with traditional European holly. That said, there were also no reports on the safety of European holly ingestion either, so it is probably a dish best avoided. Other members of this species have been shown to have toxic effects when ingested in tea form.25 So, as families and friends gather this Christmas holiday season, they can delight in the fact that most of the decorations in their homes are medically relevant. The traditional biblical gifts of gold, frankincense and myrrh are all doing their part to stamp out disease. The humble tree parasite, mistletoe, despite its toxic nature, has its place in the medical pharmacopoeia. Parents need not fear their toddlers drifting too close to the poinsettia, because the plants are pretty much harmless. On the other hand, they should keep an eye on that Christmas tree . . .

Stuart M Smith MD · B James McCallum MD, FACP

A 16-year-old boy presented with rapidly progressive ascending paralysis 1 hour after eating raw salmon. Seafood poisoning was initially considered. Although salmon is not a common cause of toxic seafood poisoning, cases have been reported in the Pacific region. The patient rapidly developed acute left heart and respiratory failure, and investigations revealed a rare tracking intramedullary haematoma of the spinal cord. Structural abnormalities of the central nervous system may present with acute paralysis and spinal shock, mimicking toxicological syndromes. Clinical recordA 16-year-old boy presented to the emergency department with severe epigastric pain, headache and ascending lower limb weakness 1 hour after eating raw salmon. The weakness ascended rapidly over the next hour to involve the upper limbs. In hospital, he was alert, but was soft-voiced and in obvious respiratory distress. He had tachycardia (heart rate, 110 beats per min), hypertension (blood pressure, 205/128 mmHg), tachypnoea (22 breaths per min) and oxygen saturation of 89% (using a non-rebreathing oxygen mask). Although his sensation and mental state appeared normal, he had profound quadriparesis. Pupils were 3 mm in diameter, equal and sluggishly reactive to light. Because of a rapid deterioration in his respiratory status, the patient was intubated, ventilated, and sedated with a propofol infusion before a more complete neurological examination could be completed. The patient’s medical history included thalassaemia minor and a short viral illness 2 weeks previously. He denied using any regular medications or substance misuse. Initial chest radiography revealed clear lung fields, but, 10 minutes after intubation, pinkish frothy sputum was noted from the endotracheal tube, and there were widespread crackles. An urgent echocardiogram showed severe global hypokinesis with a left ventricular ejection fraction estimated as less than 30%. Laboratory tests revealed neutrophilia, but all other results of a full blood count, serum electrolyte concentrations, renal function, liver function tests and coagulation screen were normal. Serum creatine kinase and creatine kinase-MB concentrations were raised, and peaked the following day at 2716 U/L (reference range [RR], 30–135 U/L) and 10 μg/L (RR, < 0.7 μg/L), respectively, suggesting myocardial injury. An electrocardiogram showed sinus rhythm with voltage criteria for left ventricular hypertrophy, but no acute ischaemic changes. Provisional diagnosis at this stage was a neurological or toxicological aetiology. The fact that the patient’s mother also ate the salmon without becoming unwell counted against seafood poisoning but did not exclude it (eg, in puffer-fish poisoning, a specific part of the fish is most poisonous). To exclude a cervical lesion, magnetic resonance imaging (MRI) of the spine and brain was performed urgently, with the intention of proceeding to nerve conduction studies if MRI results were normal. The MRI showed an extensive intramedullary haemorrhage within the spinal cord, originating at the T7/T8 vertebral level, and extending from the conus caudally to the cervicomedullary junction rostrally (Box 1). The patient was managed supportively in the intensive care unit, with complete resolution of pulmonary oedema and normalisation of cardiac function by Day 3. A spinal angiogram confirmed the presence of an arteriovenous malformation arising from the anterior spinal cord at the T9 vertebral level. The malformation was excised the following week, and histopathological examination of the resection specimen confirmed the radiological diagnosis (Box 2). After 6 months of intensive rehabilitation, the patient had restored power in one arm, but remained paralysed below the T9 cord level. DiscussionInitially, this case represented a diagnostic challenge, with acute onset, rapidly progressive ascending paralysis associated with left ventricular failure, and a history of seafood ingestion. MRI gave the correct diagnosis, obviating the need for peripheral neurophysiological investigations. Useful clues to the diagnosis of myelopathy, such as sphincter dysfunction and the level of sensory loss, were difficult to assess because of the patient’s sudden cardiorespiratory deterioration. The initial differential diagnosis is summarised in Box 3. Toxicological considerationsPoisoning from ingested seafood is a global and increasing problem that should be considered in the emergency department. Seafood associated with medically important poisoning include puffer fish (fugu), ciguateric fish, several types of shellfish and mussels, as well as fish from the Scombridae family (eg, mackerel and tuna). Salmon is not known as a major cause of seafood toxin poisoning, although scombroid and ciguatera have been described after salmon ingestion.1-3 Tetrodotoxin from fugu fish causes a rapid descending paralysis and cardiovascular collapse in severe cases.4 Paralysis is uncommon in ciguatera, which is caused by a toxin produced by marine dinoflagellates.5 Paralytic shellfish poisoning is clinically similar to tetrodotoxin poisoning and typically causes a descending paralysis. Autonomic disturbance can also be a feature of marine neurotoxin poisoning. Other toxins that can cause paralysis include botulinum, diphtheria and tick paralysis toxin, but these have slower onset of action and produce prodromal symptoms. Organophosphate poisoning is also worth considering: paralysis and copious bronchial secretions consistent with cholinergic toxicity are seen. Neurological considerationsThe hyperacute onset of our patient’s symptoms suggested an acute inflammatory demyelinating polyneuropathy, especially in view of the preceding infective illness. Even so, the presentation and progression of the weakness were unusually rapid. Similarly, autoimmune neuromuscular junction disorders, such as myasthenia gravis and Lambert–Eaton myasthenic syndrome, run a more subacute, relapsing course. Periodic paralysis can cause sudden weakness, but there is often a history of recurrent attacks. Toxic and inflammatory myopathies and neuropathic heavy metal poisoning have a more chronic and progressive course. The cause in our patient was an intradural intramedullary arteriovenous malformation, the most common form of spinal cord vascular lesion in childhood and adolescence.6 These lesions can haemorrhage and cause catastrophic autonomic dysregulation accompanied by spinal shock. Complications include neurogenic pulmonary oedema, with the sympathetic storm contributing to transient myocardial impairment via direct neurogenic and humoral mechanisms. ConclusionThis patient illustrates an uncommon scenario of rapidly progressive flaccid paralysis presenting to the emergency department. Emergency physicians need to consider a broad neurological and toxicological differential diagnosis in the patient with flaccid paralysis. Structural abnormalities of the central nervous system may present with acute paralysis and spinal shock, mimicking toxicological syndromes. 1 Magnetic resonance image of the cervical spinal cord A sagittal T2-weighted image showed a high signal (arrow) within the cervical cord caused by blood breakdown products (intracellular methaemoglobin). 2 Lesion excised from the spinal cord Histopathological examination of the resection specimen showed abnormally clustered vessels of venous (V) and arterial (A) type intermingled with spinal nerve bundles (N). This vascular configuration is typical of an arteriovenous malformation. (Haematoxylin and eosin stain; original magnification, × 40.) 3 Toxicological and neurological causes of acute paralysis Ascending paralysis Toxicological: tick paralysis (Ixodes spp.) Neurological (peripheral): acute inflammatory demyelinating polyradiculoneuropathy (Guillain–Barré syndrome) Descending paralysis Toxicological: puffer-fish (tetrodotoxin) poisoning, paralytic shellfish poisoning, snake bite, botulism, diphtheria Neurological (peripheral): myasthenia gravis Other Toxicological: ciguatera, neurotoxic shellfish poisoning, organophosphate poisoning Neurological (peripheral): myopathies (including myositis and periodic paralysis), acute poliomyelitis and toxic neuropathies

Naren Gunja FACEM · Robert P Dowsett FACEM · Karl Ng MRCP, FRACP

Three cases of cholera in women aged 71, 72 and 84 years were notified in November 2006 in Sydney, New South Wales. This is the first reported cluster of cholera in Australia for over 30 years, and was an unusual outbreak in patients with no history of recent travel to cholera-endemic areas. A food trace-back investigation found that the only exposure common to all cases was consumption of raw whitebait imported from Indonesia. This outbreak demonstrates that the practice of eating raw whitebait does occur in Australia, albeit in the process of taste-testing uncooked fritter batter. All three patients were undergoing long-term therapy with proton-pump inhibitors, which may have contributed to their susceptibility to the disease. A review of importation practices of food from cholera-endemic regions may be required to prevent future transmission.

Bradley Forssman MB BS, MPHTM, FAFPHM · Trish Mannes BAppSci, MPH · Jennie Musto MPH · Thomas Gottlieb MB BS, FRACP, FRCPA · Graham Robertson MSc · Jonathan D Natoli BSc · Craig Shadbolt PhD · Brian Biffin · Leena Gupta MB BS, MPH, FAFPHM

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity — serotonin toxicity. Serotonin toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach’s 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.

Geoffrey K Isbister MB BS, MD, FACEM · Nicholas A Buckley BMed, MD, FRACP · Ian M Whyte MB BS, FRACP

A woman in her 20s presented to the emergency department, malnourished and dehydrated, and with acute paralysis of the lower limbs. Over the previous 10 days, she had inhaled nitrous oxide from “whipped-cream bulbs” (10–20 per day) for pain caused by a sprained ankle. She had a history of intravenous drug use and was on a methadone program. The nitrous oxide misuse combined with the malnutrition, with low vitamin B12 levels, apparently resulted in subacute combined degeneration of the spinal cord — a rare complication of nitrous oxide misuse. Clinical recordA young woman in her 20s presented to the emergency department with a history of increasing difficulty in mobilising over the previous week. For the 3 days before presentation, she had been confined to the back seat of a car (from which she was extricated with difficulty on arrival at the emergency department). An estimated 60 empty “whipped-cream bulbs” were found on the floor of the car. She had a history of intravenous drug use and was on a methadone program, but there was no other significant medical history. She had sprained her ankle 10 days before presentation, and had been inhaling nitrous oxide from whipped-cream bulbs for the pain (10–20 per day). Further immobility and boredom had increased her usage. On examination, she was pleasant, but dishevelled and malnourished, with evidence of needle track marks from intravenous drug use on her extremities. She had a Glasgow Coma Scale score of 14/15 (best eye response, 4; best verbal response, 4; best motor response, 6); her respiratory rate was 20 breaths/min; heart rate, 95 beats/min; blood pressure, 95/63 mmHg; temperature, 35.6°C; and oxygen saturation in room air was 94%. She had a 1/5 flaccid proximal weakness of the lower limbs (Medical Research Council [United Kingdom] scale), with a flicker of power preserved distally, but absent plantar and knee-jerk reflexes. She had a patchy sensory level to T10, and absent vibration sense to her anterior superior iliac spines bilaterally. There was a proprioception deficit to her feet, knees and hips bilaterally. She was in urinary retention, and 1800 mL was drained through an indwelling urinary catheter. Rectal examination showed atony of the anal sphincter. There were mild pressure areas on the dorsal surfaces of her legs and buttocks, with diffuse oedema of the lower limbs. The rest of the examination was unremarkable. InvestigationsDifferential diagnoses included a space-occupying lesion of the spinal cord, transverse myelitis, HIV myelopathy, Guillain–Barré syndrome, and multiple sclerosis. We were concerned about the presence of a neurological toxin in the whipped-cream bulbs, given the history of neurological deterioration coinciding with the patient’s excessive use of the bulbs. Our diagnosis was initially delayed, as we were unable to ascertain the exact constituents of a whipped-cream bulb. Magnetic resonance imaging (MRI) of the whole spine and brain was performed and was initially reported as showing no abnormality. Initial laboratory investigations showed: a raised serum creatine kinase level of 9000 U/L (reference range [RR], < 150 U/L); acute renal failure, with a creatinine level of 490 μmol/L (RR, 80–140 μmol/L) and a urea level of 41 mmol/L (RR, 2.5–7.5 mmol/L); a troponin leak of 0.7 μg/L (RR, < 0.05 μg/L); and a normocytic anaemia, with a haemoglobin level of 83 g/L (RR, 120–140 g/L) and a mean cell volume of 95 fL. Vitamin B12 levels were 124 pmol/L (RR, > 210 pmol/L). A lumbar puncture was attempted but, on sitting the patient upright, she had a bradycardiac arrest and required cardiopulmonary resuscitation (CPR) for 30 s, resulting in spontaneous return to circulation and heart rate. Her arrested circulation was most likely the result of her being dehydrated (as evidenced by prerenal renal failure). Given her clinically demonstrated neuropathy, it is possible that a combination of autonomic neuropathy and reduced intravascular volume from dehydration, together with orthostatic stress on positioning, resulted in the precipitous fall in blood pressure, bradycardia, and arrest. This would explain the rapid return to cardiac output on return to a supine position, with only transient CPR. A Doppler ultrasound scan of the lower limbs showed bilateral deep venous thrombosis (DVT) to the level of the common femoral arteries. Indirect evidence of pulmonary embolus (PE) included a large alveolar–arterial gradient of > 100 mmHg (RR, 10–25 mmHg) and electrocardiogram changes — tachycardia and a right bundle branch block. It was decided not to perform a computed tomography pulmonary angiography, given the strongly supportive evidence for PE, and an intravenous contrast load was contraindicated given her acute renal failure. A further PE on upright positioning may also have contributed to her cardiac arrest; however, her rapid return to baseline clinical status on returning to a supine position does not support this. Clinical courseThe patient was resuscitated in the emergency department, with fluid loading for prerenal renal failure and as therapy for rhabdomyolysis. She was then transferred to the intensive care unit (ICU) for observation, and given vitamin B12 replacement therapy and methionine. Her acute prerenal failure resolved with rehydration, and she was given an intravenous heparin infusion as anticoagulation therapy for bilateral proximal DVT, and subsequently given warfarin for a target international normalised ratio of 2.0–3.0. Further imaging, such as a ventilation–perfusion scan for the presence of PE, was not performed as it would not have contributed to her management. After 2 days in the ICU, she was transferred to a general medical unit. An MRI scan on review 2 weeks after her admission showed an increased T2 signal within the posterior columns of the spinal cord. She slowly regained partial motor function of her limbs and normal sensory levels over the following 5 months. She was discharged after 7 months of rehabilitation and inpatient care. She was able to walk short distances, with the aid of a walking frame, but had residual neurological deficits affecting the distal lower-limb muscle groups. DiscussionNitrous oxide is a colourless, odourless gas with a weak anaesthetic but useful analgesic action.1 It is used during short, painful procedures. Because of its ability to elevate mood, nitrous oxide is colloquially known as “laughing gas”, and is a common drug of misuse. “Nagging” or “nanging” are terms used to describe the recreational use of nitrous oxide, derived from the repetitive sound distortions experienced by nitrous oxide users.2,3 In a New Zealand survey of first-year university students, 57% were aware of its recreational use and 12% used it regularly.2 Nitrous oxide is readily available from most supermarkets and online, as it is used as the aerator and propellant for whipped-cream dispensers. The average bulb used for aerating whipped cream contains 8 g of nitrous oxide. Pathophysiology and diagnosisSubacute combined degeneration of the spinal cord is a recognised complication of vitamin B12 deficiency or of nitrous oxide exposure (with or without pre-existing normal vitamin B12 levels). This complication is well documented in anaesthesia literature in relation to frequent nitrous oxide exposure in anaesthesia, such as during multiple operations, or analgesic use for repeated dressing changes for burns patients.4,5 Patients with long-term nitrous oxide recreational use are reported to have neurological symptoms ranging from paraesthesias to incoordination and autonomic dysfunction.6-9 There is no known neurological toxicity threshold for nitrous oxide exposure. Toxicity is related not to the frequency or level of nitrous oxide exposure, but to the patient’s levels of vitamin B12. Spinal cord degeneration resulting from a single short exposure to nitrous oxide anaesthesia, in association with vitamin B12 deficiency, has been reported.10,11 The neuropathological changes observed in the affected spinal cord include initial swelling and irregularity of the myelin sheath surrounding the nerve cell axons (reversible), followed by frank demyelination and loss of axons (irreversible).12 This occurs in the central regions of the posterior columns and, to a lesser extent, in the posterolateral regions of the spinal cord. The changes manifest as high-signal lesions on MRI T2-weighted scans caused by increased water content secondary to oedema.10,11 Nitrous oxide inhibits the active form of vitamin B12, rendering it unavailable to form the myelin sheath proteins, resulting in axonal swelling and eventual axonal loss. The mechanism of action is the inactivation of vitamin B12 (cobalamin) from its monovalent, active cobalt form (Co+) to the inactive, bivalent cobalt form (Co2+). The irreversibly inactivated vitamin B12 (Co2+) results in failure of methylation of proteins in the myelin sheaths4 and a loss of nerve cell axon integrity.12 Another contributing factor to the toxicity of nitrous oxide is the role of vitamin B12 as a cofactor of the methionine synthase reaction. The enzyme catalyses the reaction in which homocysteine is converted to methionine; tetrahydrofolate is also formed, which is a cofactor in the metabolism of nucleic acids (eg, DNA).9 Thus, nitrous oxide has a direct effect on DNA synthesis, as well as nerve axon integrity. Other postulated mechanisms of action for central nervous system toxicity of nitrous oxide include inhibitory effects on N-methyl-d-aspartate receptors, stimulatory effects on dopamine neurones, stimulation of descending noradrenergic neuronal pathways, provoked release of noradrenaline in dorsal horn neurones, and sympathetic action via α-1-adrenergic stimulation.8,9 A diagnosis of subacute combined degeneration of the spinal cord can be confirmed by MRI, in association with low serum vitamin B12 levels, but in some cases MRI scans show no abnormality.11 The differential diagnoses include demyelination, neoplasms, infections (eg, with Listeria spp., or HIV), myelopathy, and syringomyelia. Treatment and prognosisTreatment involves ceasing nitrous oxide use and giving vitamin B12 replacement therapy. Administration of methionine may also be required as an adjunct, given the direct effects of nitrous oxide on methionine synthase. Exogenous methionine would provide a direct substrate for methionine synthase, while the body slowly replaces the inactive vitamin B12 and commences repletion of endogenous methionine. Two patients receiving vitamin B12 replacement therapy experienced a worsening of their neurological symptoms until the addition of oral methionine, which halted the neurological decline and accelerated their recovery.9 Reported recovery periods vary from 1 week to 1 year. Partial versus full recovery will depend on the extent of the neuropathological damage to the spinal cord; spinal cord oedema and myelin sheath loss will resolve, but axon loss is permanent.

Michaela Cartner MB BS, FACEM · Michael Sinnott MB BS, FACEM, FRACP · Peter Silburn MB BS, PhD, FRACP

Objective: To describe the prevalence, characteristics and outcomes of amphetamine-related presentations to a tertiary hospital emergency department (ED).Design, setting and participants: Prospective observational study of amphetamine-related presentations to the ED of the Royal Perth Hospital (RPH), an adult, inner-city, tertiary referral hospital, between 3 August and 2 November 2005. For all patients presenting to the ED, the treating doctors were automatically prompted by the computerised data entry system to consider amphetamine use.Main outcome measures: Proportion of ED presentations related to amphetamine use; demographic features and usage practices of amphetamine users; characteristics of presentations and admissions; associated psychiatric illnesses and use of other drugs.Results: Over the study period, there were 13 125 presentations, of which 156 (1.2%) were judged to be causally related to amphetamine use. Of those 156 patients, over half were habitual drug users (89 [57.1%] used amphetamines at least weekly), and the majority were men (111 [71.2%]). The mean age was 28 years (range, 16–55 years). Presentations were of high acuity: 104 patients [66.7%] were rated 1, 2 or 3 on the Australasian Triage Scale; 50 (32.1%) arrived by ambulance; and 25 (16.0%) arrived with police. The mean time spent in the ED was 6 h (range, 0.5–24 h). Fifty patients (32.1%) required sedation, and the likelihood of requiring sedation increased almost threefold if the heart rate was over 100 beats/min on presentation. Sixty-two patients (39.7%) were admitted and 58 (37.2%) required psychiatric evaluation. Repeat attendance was common, with 71 patients (45.5%) having previous amphetamine-related presentations to the RPH ED.Conclusions: Amphetamine-related presentations comprise 1.2% of all ED attendances and have a major impact on hospital EDs. Patients are often agitated and aggressive, require extensive resources, and frequently re-attend. The burden of amphetamine-related illnesses on EDs is likely to increase in the future.

Suzanne D Gray MB BS · Daniel M Fatovich MB BS, FACEM · David L McCoubrie MB BS, FACEM · Frank F Daly MB BS, FACEM

Objective: To study drug prescribing by brand name versus generic name in an Australian teaching hospital.Results: Overall, 53% of drugs were prescribed by brand name. Brand names were preferred when they were shorter and easier to remember and spell, when there was only one brand on the market, and when the brand name ended in an x.Conclusion: Doctors might be encouraged to prescribe generically if generic names were devised using the same principles marketers use for devising brand names.

Jonathan Bromley MB ChB · Nicholas A Buckley MD, FRACP

To the Editor: “Out of the blue”, I received a personal message from a retired nursing sister of a children’s hospital, who had earlier written to the MJA1 describing “a cluster of neonates [who had] simultaneously turned blue” in the 1950s. Her letter to me followed one of mine in the Journal, describing methaemoglobinaemia (MetHgb) in infantile keto-acidosis, where the cyanosis responded rapidly to diabetic control alone.2 Rare as MetHgb is, it has previously been recognised as a presentation of infantile acidosis.3 The cause of the colour change in the neonate cluster “was traced to dye from the hospital’s brandmarks on a batch of new cotton nappies (which had been washed before being marked)”.1 The dye was understood to have been “absorbed into the infants’ circulation via their raw umbilical areas”. As it turns out, nappy dyes have been incriminated in MetHgb.4 The POISINDEX® System (Thomson Micromedex, Denver, Colo, USA) revealed that the aniline group is among the compounds capable of causing MetHgb through any portal of entry, even intact skin (Stephen Gibbins, Poisons Information Specialist, Victorian Poisons Information Centre, Melbourne, personal communication). Another textile ink, aminophenol, may also lead to the disorder.5 Other common causes of MetHgb are given in the Box. Causes of methaemoglobinaemia (MetHgb) MetHgb can be genetic, through faulty haemoglobins or cytochrome deficiency. On exposure to appropriate exogenous toxins, heterozygotes tend to be particularly susceptible, as are infants per se without any such trait.4 Nappy dyes have been incriminated.4 In the United Kingdom between 1961 and 1980, the most common industrial causes of acquired MetHgb were chloroaniline, p-toluidine, nitrobenzene, nitrochlorobenzene, nitrates and amines — frequently by dermal exposure. Nitrates, nitrites in food, local anaesthetics (particularly benzocaine), and other medicinal agents, such as chloroquine, dapsone, para-aminosalicylic acid and resorcinol, have also been implicated.5,6 Aniline dyes were discovered in the 19th century and found useful for inks and for dyeing leather, which they penetrate as they do living skin. They were also used in wood stains, textiles, and oriental rug-making. Because aniline dyes are not indelible and are toxic, they are being superseded by chrome dyes. The hospital linen room concerned1 reports that they now apply dry, colour-fast pigments using heat-pressed or stamped “transfers” (Administrative Officer, Metropolitan Linen Services, Brisbane, personal communication). It is not possible to confirm what the “Baby blues”1 dye was — aniline or other. Nor can we now establish whether the dusky colour of the babes was due to absorbed dye circulating passively. Circumstantially however, MetHgb would seem to have been a likely possibility.4 In differential diagnosis, when cyanotic infants or adults without cardiorespiratory signs are encountered, we should not forget MetHgb, drugs and chemical toxins. In patients with MetHgb, the blood will be “chocolate-brown”; and yes — do remember to take a sniff for that exhaled acetone.2

Ivan Cher

We report a fatal case of acute selenium poisoning in a 75-year-old man. After reading on the Internet about a possible role of selenium in prostate cancer, the patient ingested 10 g of sodium selenite. Despite intensive care treatment, he suffered a cardiac arrest and died 6 hours after ingestion. This case illustrates the risks of failing to critically evaluate Internet information and exposes the myth that natural therapies are inherently safe. Clinical recordAfter a single test showing a raised level of prostate-specific antigen, a 75-year-old man became concerned about prostate cancer. Without confirmation of the diagnosis, he researched prostate cancer on the Internet and discovered that selenium may have a role in its prevention and treatment. He purchased sodium selenite powder and tablets from two separate pharmacies for supplementation. He presented to the emergency department with vomiting and diarrhoea at 10:30 am, 3.5 hours after ingesting 10 g of sodium selenite (purity, 96%). He had significant abdominal pain, poor perfusion, and hypotension, with a pulse rate of 76 beats per minute, blood pressure of 75/45 mmHg, and prolonged QT interval. Arterial blood gas examination (breathing 60% O2) showed pH, 7.325 (reference range [RR], 7.35–7.45); PO2, 122 mmHg (RR, 85–100 mmHg); Pco2, 22.4 mmHg (RR, 35–45 mmHg); and HCO3 concentration, 11 mmol/L (RR, 22–28 mmol/L). He also had hypokalaemia (serum potassium concentration, 3.4 mmol/L [RR, 3.5–5.0 mmol/L]). A blood specimen collected at this time later showed a serum selenium level of 68.0 μmol/L (RR, 0.6–2.3 μmol/L). The patient was transferred to the intensive care unit, where fluid resuscitation was continued, and a dobutamine infusion was begun. He remained hypotensive (blood pressure, 85/50 mmHg) but conscious. At 12:10, he developed significant ventricular tachycardia, interspersed with normal complexes with ST depression. Repeat blood gas tests showed worsening acidosis and hypokalaemia. Magnesium (10 mmol) and potassium (25 mmol) were administered intravenously over 40 minutes. Dysrhythmia persisted and worsened. Lignocaine was added with no response. The patient suffered a cardiac arrest, and cardiopulmonary resuscitation was begun. Arterial blood gas analysis performed during the arrest revealed a sudden rise in serum potassium level, to 8.8 mmol/L. Throughout the arrest, rhythms varied, from asystole to broad complex bradycardia to some narrow complexes with an output. Despite cardiopulmonary resuscitation, asystole became permanent and unresponsive. The patient’s pupils became fixed and dilated, and cardiopulmonary resuscitation was ceased. The case was referred to the Coroner who confirmed the cause of death to be acute selenium toxicity. DiscussionThe growth in the use of complementary and alternative medicine in Australia has been well documented.1 Selenium is an essential trace element and an important constituent of the antioxidant glutathione peroxidase.2,3 It is found in many foods, including seafood, grains and eggs,2 and dietary intake is usually 20–300 μg/day.4 An intake below 400 μg/day is considered safe for almost all individuals.5 In Australia, selenium tablets are marketed as a health supplement, while sodium selenite powder is mainly used as a livestock supplement for animals grazing on selenium-deficient soil. Selenium has been discussed in many epidemiological investigations into prevention and treatment of cancer, especially prostate carcinoma.6,7 Excessive doses of selenium result in intoxication, which is characterised by continuous vomiting, garlicky breath, mucosal irritation, abdominal pain, hypersalivation, haemolysis, necrosis of the liver, cerebral and pulmonary oedema, coma and death.3,8 Selenium presents a nutritional conundrum because of its dual status as an essential but highly toxic trace element.9 The exact mechanism of selenium toxicity is as yet unknown.8,10 It has been suggested that the ready substitution of selenium for sulfur in biochemical reactions may inactivate the sulfhydryl enzymes necessary for oxidative reactions in cellular respiration,10 contributing to the acute toxic effect. Cases of selenium poisoning are rare, with Gasmi et al citing only 18 documented cases before 1997, half of them fatal, generally as a result of cardiocirculatory failure and/or pulmonary oedema.11 Although there is no defined point at which selenium becomes toxic, our patient consumed about 10 g of sodium selenite and, 4 hours after ingestion, had a serum level of 68.0 μmol/L (RR, 0.6–2.3 μmol/L), which proved fatal. The ingested quantity of 10 g was about 10 000 times the recommended daily dose of supplemental selenium. It is almost impossible to rapidly reduce a patient’s serum selenium level, as absorbed selenium is mostly contained in erythrocytes or bound to α- or β-globulins. For this reason, haemodialysis is not an established treatment for selenium intoxication, but may reduce serum selenium levels slightly.8 In regard to our patient’s hyperkalaemia, the extracellular potassium level is expected to increase in metabolic acidosis. However, our patient showed a progressively worsening metabolic acidosis with a falling potassium level. The administration of 25 mmoles of potassium over 40 minutes would be expected to raise the serum potassium level, but did not account for the sudden and dramatic rise, from 3.2 mmol/L to 8.8 mmol/L. This sudden hyperkalaemia has not been described in previous cases of selenium toxicity. A brief Internet search revealed 287 000 sites discussing the use of selenium in prevention and treatment of prostate cancer. This provides the public with large amounts of information that is not critically evaluated for validity. After reading Internet information on the possible link between selenium and prevention and treatment of prostate cancer, our patient was able to purchase 200 g of sodium selenite powder without adequate instructions. He selected a dose himself, with catastrophic consequences. This case highlights the risks associated with failure to critically evaluate Internet material and exposes the myth that natural therapies are inherently safe. Internet sites which fail to disclose the potentially fatal effects of advocated treatments are an emerging threat to health. The World Health Organization has devised guidelines to help consumers evaluate medical information on the Internet, which are available online through the Therapeutic Goods Administration.12 Adverse outcomes of complementary and alternative medicines should be better publicised and more stringently reported to the Adverse Drug Reactions Advisory Committee (ADRAC), in tandem with adverse outcomes of conventional medications, to create a database of side effects of all current therapies.

Katharine A See · Peter S Lavercombe FRACP, FJFICM, MBA(Dist) · Jasmine Dillon MB BS, BSci · Riesa Ginsberg FRACEM

Although clinical trials of the antipsychotic amisulpride revealed no cardiac adverse effects, four patients with severe cardiac toxicity after overdose were reported to Australian poisons information centres in 2004–2005. All four had QT prolongation over 500 ms, two had rate-dependent bundle branch block, two developed torsades de pointes, and one died after cardiac arrest. Pending further studies, we recommend electrocardiogram assessment until at least 16 h after amisulpride overdose and, if QT interval is prolonged, cardiac monitoring until the patient is clinically well and conduction intervals are normal. Clinical recordsPatient 1A 39-year-old woman presented to a rural hospital 2 hours after ingesting 24 g of amisulpride (therapeutic dose, 50–1200 mg/day), and unknown quantities of nitrazepam and diazepam. On examination, she was drowsy with a Glasgow Coma Score (GCS) of 14, heart rate of 100 beats per min (bpm), and systolic blood pressure of 70 mmHg. Activated charcoal (50 g) and intravenous normal saline (2 L) were administered, and the hypotension resolved. She was transferred to a tertiary emergency department. On arrival, 7 h after the overdose, her condition remained unchanged. An electrocardiogram (ECG) showed sinus rhythm, heart rate of 67 bpm, QRS interval of 128 ms, prolonged QT interval of 560 ms and bifid T waves (Box 1). Twelve hours after ingestion, her level of consciousness decreased (GCS, 4), and broad complex tachycardia was observed on the electrocardiography monitor and subsequent ECG. No hypotension was recorded. She was intubated, hyperventilated, given NaHCO3, magnesium and calcium gluconate, and transferred to the intensive care unit. The QRS interval narrowed to 112 ms within 4 h, but the QT interval remained prolonged for another 12 h. Patient 2A 40-year-old man presented to a hospital emergency department after ingesting amisulpride (32 g), mirtazapine (300mg), valproate (7 g), amitriptyline (1.25 g) and omeprazole (unknown quantity). On arrival, he had a GCS of 14, heart rate of 90 bpm, and blood pressure of 120/70mmHg. An ECG at presentation showed sinus rhythm with a heart rate of 90 bpm, QT interval of 460ms and bifid T waves. He was admitted to the intensive care unit. About 12.5 h after ingestion, he developed a broad complex tachycardia with rate 120 bpm (left bundle branch pattern), but remained haemodynamically stable. The QRS complex did not significantly narrow when the patient was treated with a bolus of NaHCO3. An NaHCO3 infusion was started, and he was intubated and ventilated. Eighteen hours after ingestion, the QT interval was 560ms, with heart rate of 79 bpm and a normal QRS interval (Box 2A). About 29 h after ingestion, the patient developed pulseless torsades de pointes, but sinus rhythm with a QT interval of 560ms was restored after a single direct current cardioversion shock (Box 2B). He had a second episode of torsades de pointes 32.5 h after ingestion, and an episode of ventricular tachycardia 34 h after ingestion. By 5 days after the overdose, the QT interval had shortened to 360ms (Box 2C). Serum amisulpride level was measured by high performance liquid chromatography using a modified method of Bohbot et al,1 and was 23.2 mg/L at 12.5 h after ingestion. Patient 3A 39-year-old woman presented to hospital about 12 hours after ingesting amisulpride (16–24 g). At presentation, she was drowsy, with a heart rate of 59 bpm and blood pressure of 81/44 mmHg. She was given 1 L of intravenous fluid. An ECG demonstrated sinus rhythm with heart rate of 62 bpm, and QT interval of 600 ms. Two hours after presentation, her condition deteriorated rapidly, with a GCS of 7, heart rate of 99 bpm, and blood pressure of 109/42 mmHg. Multiple intubation attempts were made, and the oxygen saturation fell, but recovered between intubation attempts (91% after 25 minutes). She was successfully intubated 28 minutes after her condition deteriorated. She then developed bradycardia, pulse became undetectable, and cardiac pulmonary resuscitation was begun 30 minutes after the deterioration. Despite resuscitation, she died 17 minutes later. No ECG or telemetry traces were recorded during the resuscitation. Postmortem toxicology analysis performed by the Division of Analytical Laboratories, Sydney, was made available by the coroner: amisulpride (140 mg/L) and fluoxetine (0.2 mg/L) were found in serum, but no tricyclic antidepressants or drugs of abuse. Patient 4A 22-year-old man presented to hospital 2 h 20 min after ingesting amisulpride (4.6 g). There was no family history of sudden death or cardiac arrhythmias. On arrival, he was alert and oriented, had a heart rate of 69 bpm, and blood pressure of 136/61 mmHg. The ECG showed sinus rhythm, heart rate of 63 bpm, and QT interval of 600 ms (Box 3A). Repeat ECGs showed QT intervals between 580 ms and 640 ms. Seven hours after ingestion, he had an episode of pulseless torsades de pointes (Box 3B). Cardioversion was achieved with a 200 J direct current shock. As the QT interval remained prolonged (600 ms), therapy with isoprenaline (60 μg/h) was begun. After an hour, the dose was decreased to 30 μg/h and continued for 20 h. The patient had a second episode of torsades de pointes almost 24 h after ingestion. This was asymptomatic and resolved spontaneously within 30 seconds. He had bradycardia (heart rate, 40 bpm) for 24 h after isoprenaline was ceased. The QT interval gradually decreased to 460 ms at 62 hours after ingestion and was 360 ms 3 weeks later (Box 3C). Box 3D illustrates the time course of serum amisulpride concentration and absolute QT interval over the first 60 h after ingestion. DiscussionAmisulpride is an antipsychotic that has been available on the Pharmaceutical Benefits Scheme in Australia since 2003. A benzamide derivative, it is well tolerated, with relatively few side effects and minimal behavioural toxicity in doses with antipsychotic effect.2 Amisulpride overdoses were first reported to Australian poisons information centres in early 2004, and about 60 telephone calls about amisulpride overdose were made from hospitals to the New South Wales and Western Australian Poisons Information Centres between July 2004 and June 2005, including the four cases reported here. A review of clinical trials of amisulpride reported that it had no effect on the ECG in therapeutic doses and did not produce arrhythmias.3 There are no published data on animal toxicity. It was therefore surprising that such severe effects were seen in overdose. There were a few published reports of overdose in the literature before its introduction in Australia,4,5 and a reference to QT prolongation and torsades de pointes in the manufacturer’s product information, but little indication that overdose could have effects as severe as those reported here, including the first cases of torsades de pointes. During the past decade, there have been sporadic reports of amisulpride poisoning, including two deaths.4-9 Significant QT prolongation was reported in a recent series of eight cases with limited clinical details9 and in another two cases, where it was suggested to be related to hypocalcaemia.7 A patient who suffered multiple cardiac arrests has also been reported. Although torsades de pointes was suspected, it was not confirmed on ECG.6 These cases demonstrate that amisulpride overdose may be associated with clinically significant QT prolongation. The absolute QT interval was over 500ms in all four of our cases and close to 600ms in three. Amisulpride overdose was associated with ECG-confirmed torsades de pointes in two cases and a cardiac arrest resulting in death in another. Unfortunately, no ECG was available to determine if torsades de pointes had occurred in that patient. The magnitude of the effect on the QT interval and the number of cases of torsades de pointes from about 60 cases of overdose reported to the Poisons Information Centres suggests that amisulpride overdose is associated with significant cardiac toxicity. Amisulpride also caused a ratedependent bundle branch block in two cases. Although this coincided with a decreased level of consciousness, it was unlikely to have caused it. Drowsiness occurred in three of the four patients and profound sedation in two, suggesting that amisulpride also causes central nervous system depression. Amisulpride was detected in high concentrations in three of our patients — three to four orders of magnitude above that reported in therapeutic studies.2 In these studies, the peak concentration after a dose of 50mg of amisulpride was 55.7 µg/L (SD, 3.7). Citalopram is another drug that appeared to cause minor or no cardiac effects in clinical trials of therapeutic doses,10 but in overdose has been associated with moderate QT prolongation,11,12 rate-dependent bundle branch block and, rarely, torsades de pointes.13,14 A pharmacokinetic and pharmacodynamic model of citalopram intoxication clearly demonstrated a dose-dependent relationship between drug concentration and QT interval.12 Fortunately, citalopram-associated torsades de pointes appears very rare, with only two published reports. This case series underlies the importance of overdose surveillance by poisons information centres after the introduction of new drugs, or the introduction of new formulations. Clinicians should be aware that amisulpride overdose can cause severe cardiac toxicity, including QT prolongation, bundle branch block and torsades de pointes. Until the risk assessment can be further refined, we recommend assessing the ECG until at least 16 hours after ingestion of an amisulpride overdose. If there is QT prolongation, we recommend cardiac monitoring in a critical care area until the patient is clinically well, and conduction intervals are normal. 1 Electrocardiogram changes in Patient 1 Electrocardiogram 7 hours after ingestion of amisulpride showed sinus rhythm with a prolonged QT interval of 560 ms. 2 Electrocardiogram changes in Patient 2 A: Eighteen hours after ingestion, the electrocardiogram (ECG) showed prolonged QT interval of 560 ms. B: About 29 hours after ingestion, the ECG showed segment of torsades de pointes, before direct current cardioversion and recovery of sinus rhythm. C: Five days after the overdose, ECG showed shortening of QT to 360 ms. 3 Electrocardiogram changes and amisulpride levels in Patient 4 A: Prolonged QT interval on admission (2.3 hours after ingestion). B: Torsades de pointes 7 hours after ingestion. C: A normal QT interval D: Plasma amisulpride concentration (logarithmic scale) and absolute QT interval over the first 60 hours after ingestion.

Geoffrey K Isbister FACEM, MD · Lindsay Murray MB BS, FACEM · Sally John MB BS · L Peter Hackett MRSC · Tedo Haider MB BS · Phebe O'Mullane MB BS · Sophie Gosselin MD · Frank Daly MB BS, FACEM

An infant, born at 35 weeks’ gestation to a woman who sniffed petrol, had a cord blood lead level eight times the accepted limit. Treatment with oral dimercaptosuccinic acid promptly reduced his blood lead levels. To our knowledge, this is the first reported case of congenital lead poisoning secondary to maternal petrol sniffing. We suggest that at-risk pregnancies should be identified, cord blood lead levels tested, and chelation therapy and developmental follow-up offered to affected infants. Clinical recordA 27-year-old Indigenous woman, who had sniffed petrol since childhood, presented for antenatal care during her first pregnancy. At the age of 14 years, she had severe lead encephalopathy that led to chronic neurological deficits, including permanent ataxia and memory impairment. Her serum lead levels at 8 and 35 weeks’ gestation were raised at 1.48 and 2.21 μmol/L, respectively (recommended level, ≤ 0.48 μmol/L1). At 35 weeks’ gestation, she went into spontaneous labour and gave birth vaginally to a boy. The infant’s Apgar score was 9 at both 1 and 5 minutes, and birth weight was 2280 g. He was admitted to the special care nursery because of prematurity, and required nasogastric tube feeding because of poor sucking and general sleepiness. On Day 6, the infant developed temperature instability and diarrhoea, with associated dehydration and metabolic acidosis (Box 1). He was treated with 48 hours of intravenous antibiotics and intravenous fluids. No pathogen was grown from blood cultures, urine or stool. Cord blood lead levels were available on Day 10 and were raised at 3.98 μmol/L. No signs of lead encephalopathy were found on examination: muscle tone and reflexes were normal, and there were no signs of seizure activity. Treatment was begun with oral succimer (dimercaptosuccinic acid [DMSA]) on Day 11, at a dose of 10 mg/kg three times daily for 5 days, followed by 10 mg/kg twice daily for 14 days. No adverse effects of chelation therapy (such as vomiting, diarrhoea, fever, rash, or elevated serum transaminase levels) were noted. The infant’s blood lead levels decreased with succimer treatment (Box 2), liver function results remained in the reference range, and his alertness and feeding improved by the 5th day of treatment. At 28 days of age, the infant was feeding well on formula and weighed 3160 g. He was discharged into foster care, and succimer therapy was ceased on Day 35. His growth and development were monitored. At the age of 12 months, he had global developmental delay, with an overall Denver Developmental level of 6–7 months.2 His blood lead levels at 4, 6 and 9 months of age were at least twice the upper acceptable limit (Box 2), although not at the level at which chelation therapy is recommended (> 2.16 μmol/L).3 DiscussionLead exposure in early childhood has long been known to have significant adverse effects on cognitive development.4,5 The National Health and Medical Research Council recommends that lead levels for all Australians be less than 0.48 μmol/L (10 μg/dL).1 However, intellectual impairment is seen in children with lower blood lead levels, and there may be no safe lower limit.6 Chelation therapy is recommended for any child with blood lead levels of 2.16 μmol/L and over.3 Although chelation therapy in early childhood lowers blood levels, recent studies have not shown significant improvement in cognitive and behavioural measurements compared with untreated children.3,4,7 There are a few case reports of neonatal lead intoxication that occurred from maternal exposure to lead through pica, home renovation, or use of contaminated herbal medications.8-10 Petrol sniffing is a form of substance misuse that is widespread in some Indigenous communities in Australia, and is associated with elevated serum lead levels.11 Changing the available petrol to an unleaded form should theoretically lessen the burden of lead toxicity in petrol sniffers. However, the aromatic hydrocarbons in both forms of petrol still cause considerable acute neurotoxicity,12 and petrol sniffers appear to prefer leaded petrol.13 Infants born to women who sniff petrol are more likely to have a birth weight < 2500 g than the infants of non-sniffers, and to require admission to a neonatal nursery for care, although this may be related to other associated lifestyle factors such as smoking and alcohol use.14 Lead freely crosses the placenta and is found in cord blood, amniotic fluid and fetal tissues.8 Cord blood lead levels are often higher than maternal blood levels,8,10 which might indicate preferential placental transfer,8 or be related to the higher neonatal haematocrit.9 In our patient, the cord blood lead level (3.98 μmol/L) was higher than levels in maternal blood collected 2 days before delivery (2.21 μmol/L). Reported effects of congenital lead exposure include intrauterine growth restriction, long-term cognitive problems, and radiographic abnormalities, such as increased bone density at the metaphyses.8,9 Acute neurotoxicity manifested as encephalopathy and peripheral neuropathy has also been described.10 Chelating agents used in the management of lead poisoning include intravenous sodium calcium edetate (CaNa2EDTA) and oral succimer (DMSA).3 Oral succimer is as effective as parenteral CaNa2EDTA.15 It has been previously reported that oral DMSA therapy has not been effective in the chelation of lead in newborns,10 although it is a proven and safe therapy in older children and adults.4,15 In our infant patient, blood lead level decreased spontaneously by 11% (0.45 μmol/L) during the first 10 days of life. After chelation therapy began, serum lead levels fell by 55% in 9 days. No drug-related side effects were noted in the infant.16 This infant did not show clinical signs of acute encephalopathy. His feeding and alertness improved after the start of chelation, but it is uncertain if this was due to falling lead levels or to the normal maturation of the premature infant. After the completion of therapy, serial blood lead levels showed a slow decline, but remained above the recommended level. This was most likely due to a slow release of bound lead from bone,8 but could also have resulted from ongoing exposure to environmental lead. As in similar cases, the infant had global developmental delay at 12 months of age despite chelation therapy.10 Factors other than lead, including malnutrition, recurrent infections and socioeconomic deprivation, might also have contributed to a poor developmental outcome. Petrol sniffing is a significant problem in some Indigenous communities, and it is likely that more infants will be born with lead exposure. Ideally, women who sniff petrol should be identified early in pregnancy. Interventions that might reduce the burden of fetal lead exposure include stopping further petrol sniffing, and giving calcium supplements to the mother to reduce bone resorption, as mobilisation of lead from maternal bone stores is a significant source of fetal lead exposure.17 Chelation agents are contraindicated in pregnancy, and are used only if maternal lead poisoning is life-threatening.8 Cord blood lead levels should be tested in at-risk infants, and chelation therapy given if levels are levels are over 2.16 μmol/L.3 Affected children are at high risk of neurodevelopmental delay. Follow-up and formal developmental assessment is made difficult in remote Indigenous communities by communication barriers, social and economic deprivation, and geographic isolation. Every effort should be made to offer early intervention services, as well as measures to optimise nutrition and general health. 1 Laboratory results for a neonate with lead poisoning and suspected sepsis Reference range* Day 4 Day 5 10:00 13:00 19:35 07:30 Serum levels Sodium (mmol/L) 133–146 140 140 141.6 140 Potassium (mmol/L) 4.6–6.7 4.9 4.5 4.7 4.8 Urea (mmol/L) 1.1–9.1 3.1 2.8 1.3 Creatinine (μmol/L) 56–146 65 65 43 HCO3 (mmol/L) 18–25 12.5 12.8 14.5 21.3 Venous pH 7.35–7.45 7.17 7.19 7.26 7.35 Base excess (mmol/L) − 4 to + 3 − 17.6 − 17.3 − 14.7 − 3.8 Haemoglobin (g/L) 150–170 179 Blood counts (× 109/L)† White cells 5.0–21.0 7.7 Neutrophils 1.5–10.0 1.6 Platelets 150–350 217 * For preterm infant. † Blood film appeared normal for a preterm infant, with no basophilic stippling of red blood cells. 2 Serial blood lead levels in an infant with lead poisoning * Chelation treatment with dimercaptosuccinic acid was given from Days 11 to 29 at a dose of 10 mg/kg, initially three times daily, reducing to twice daily from Day 16. † Maximum acceptable blood level of lead = 0.48 μmol/L. ‡ Urine lead level was raised at 0.82 μmol/L (maximum acceptable level = 0.02 μmol/L).

Suzanna T Powell FRACP · Srinivas Bolisetty FRACP · Gavin R Wheaton FRACP

Elizabeth A Hender,* Corrine R Balit† * Scientific Officer, Hazardous Substances Section, Environmental Health Service, Department of Health, PO Box 6 Rundle Mall, Adelaide, SA 5000; † Research Pharmacist, New South Wales Poisons Information Centre, The Children’s Hospital, Westmead, NSW. elizabeth.henderAThealth.sa.gov.au To the Editor: Although there are few deaths due to poisoning in Australian children, from 1993 to 1997 there was an average of more than 2500 admissions to hospital per year for assessment of poisoning with medicines in children younger than 5 years.1 Child-resistant packaging has been effective in preventing accidental poisoning with prescription medicines and aspirin in young children in the United States.2,3 In the US, both reclosable and non-reclosable (blister or strip) packaging used for pharmaceuticals required to be in child-resistant packaging is tested to confirm its effectiveness in preventing access by children.4 In Australia, only reclosable packaging is required to be child-tested. Blister or strip packaging, which has not usually been child-tested, is accepted as an alternative to child-resistant reclosable packaging.5 We conducted a study at the New South Wales Poisons Information Centre (NSWPIC) over 9 weeks from 18 July to 17 September 2003. Our aims were to ascertain which medicines children younger than 5 years access directly from blister or strip packaging, and whether assessment at a hospital was recommended. The study was approved by the Ethics Committee of the Children’s Hospital, Westmead. Callers ringing about a suspected accidental ingestion of a solid dose medicine in a child younger than 5 years were asked whether the child accessed the medicine directly from a blister or strip pack. There were 318 accidental exposures to solid dose medicines in these children during the study period. In 186 exposures (58%), the caller said the medicine was normally in a blister or strip pack and the child obtained it directly from the pack. A wide range of medicines (40 different drugs or drug groups) were associated with the exposures; the most common were oral contraceptives (49 exposures) and paracetamol (27 exposures). Some of the exposures involved medicines that can cause severe toxicity when children ingest a small number of dose units, such as clonidine, olanzapine, narcotic analgesics, and tricyclic antidepressants. In 36 exposures where the child obtained the medicine directly from the pack, the caller was advised to take the child to hospital (Box). Many of the medicines associated with these exposures (eg, paracetamol, preparations containing narcotic analgesics, antidepressants, antihistamines, iron and clonidine) are required to be in child-resistant packaging.5 Our study shows that blister or strip packs currently in use did not prevent children accessing drugs. This finding calls into question whether blister or strip packaging that has not been child-tested presents an adequate safety barrier. No outcomes of drug ingestion are known in this study, which is a limitation. However, assessment of these children in hospital represents a financial burden to the health care system regardless of the outcome. Further studies would be required to quantify the harm associated with exposures to medications packaged in blister or strip packaging in young children and to assess the effectiveness of such packaging in the prevention of poisoning. Drugs accessed from blister or strip packs where child required referral to hospital Drug or drug group Number of exposures Paracetamol 8 Paracetamol/narcotic combination analgesics 3 Selective serotonin re-uptake inhibitors 3 Antidepressant: other/unknown 2 Antiemetics 2 Antihistamines 2 Cough/cold preparations, no paracetamol 2 Iron 2 Other (eg, clonidine, olanzapine) 12 Total 36

Elizabeth A Hender · Corrine R Balit

Envenoming is rare in Australia — multicentre studies are needed to improve the tenuous evidence base Whether it’s the live snake that escapes in an emergency department or the farmer, bitten by a brown snake, who drops into his wife’s work to say he will be in hospital, and then collapses and has a seizure on arriving in hospital — bites and stings are a fascinating topic and the occasional envenoming presenting to hospital makes the local news. Unfortunately, the rarity of envenoming in Australia has meant the evidence base in clinical toxinology is tenuous, with considerable reliance on case reports and anecdotes of successful treatment. Although case reports can be essential in providing information about rare effects, more importantly they help to develop hypotheses for further studies. Randomised controlled trials (RCTs) of antivenoms are difficult to undertake in clinical toxinology because of the rarity of envenoming, the rapid course of life-threatening effects, and the potential for complete reversal of effects with antivenom. Funnel-web spider envenoming and major box jellyfish envenoming by Chironex fleckeri are two contrasting examples of such situations, with very different outcomes over the past 30 years following the introduction of their respective antivenoms. Despite the absence of an RCT of funnel-web spider antivenom, most people would agree that its introduction has prevented death in some cases and changed the outcome in many more cases over the past 25 years. It is highly unlikely that any ethics committee would now sanction an RCT, except perhaps to conduct a short n-of-1 trial, randomising patients initially to antivenom or placebo, and providing rescue treatment after 1–2 hours.1 The initial prospective study of nine successfully treated patients,2 another study demonstrating a significant reduction in hospital length of stay,3 as well as the fact that there have been no fatal bites since the introduction of funnel-web spider antivenom, provide more than single-case or anecdotal evidence for its efficacy. In contrast, the introduction of C. fleckeri antivenom has been somewhat different, with reported deaths despite the administration of antivenom, and continuing controversy about its use intramuscularly in the prehospital setting and in treating non-life-threatening effects.4 Recent animal work suggests that pretreatment with antivenom is not completely effective in preventing cardiovascular collapse and adds to the concerns regarding the efficacy of this antivenom.5 Irukandji syndrome has come to the attention of most Australians over the past few years, with at least one confirmed death from Irukandji syndrome in far north Queensland,6 and reports of significant numbers of cases in northern Western Australia in this issue of the Journal ().7 This has attracted significant media attention, threatened tourism in Queensland, and prompted the rapid introduction of untested treatments.8 Unfortunately, this appears to have overshadowed the far more lethal C. fleckeri envenoming, which continues to claim lives, with recent deaths of young children in far north Queensland. Treatment for C. fleckeri envenoming remains controversial, with concerns about the efficacy of antivenom,4 disagreement over the role of pressure immobilisation bandaging9 and non-evidence-based ongoing support for the potentially dangerous adjunctive treatment with verapamil.10 Recent animal studies provide evidence that pressure bandaging in C. fleckeri envenoming may increase venom discharge,11 and a review of the literature found no evidence for the recommendation of pressure immobilisation in major jellyfish stings.9 A recent animal study investigating treatments for C. fleckeri envenoming demonstrated that pretreatment with antivenom only prevented cardiovascular collapse in 40% of rats.5 The addition of verapamil did not prevent any deaths, supporting previous studies showing that verapamil worsens outcome in C. fleckeri stings.12 Another finding was that the addition of intravenous magnesium sulfate to antivenom, as a pretreatment, prevented death in 100% of cases.5 Future studies will need to further evaluate antivenom and the possible benefits of magnesium. However, it must be emphasised that early resuscitation is likely to be the single most important measure in severe C. fleckeri envenoming. Back on land, Australia is extremely fortunate to have some of the safest and most efficacious snake antivenoms in the world and the only commercially available snake venom detection kits for patient management. Despite this, the management of snakebite continues to be dominated by anecdotes and case reports, with limited information on antivenom dosing and redose timing. In addition, many snakebites occur in rural or remote areas, necessitating use of retrieval services and telephone advice. In this issue of the Journal, Yeung et al () report a retrospective study of severe brown snake envenoming in Western Australia, suggesting that larger overall doses of antivenom are required.13 Although the authors have moved to using 10 ampoules as their initial dose, their study does not provide conclusive evidence to allow absolute recommendations for antivenom dosing, particularly in other parts of Australia. However, it reinforces the problems with severe brown snake envenoming in rural and remote areas, and the need for sufficient antivenom being available for a first dose (at least five ampoules) for patients with suspected snakebite being retrieved to larger centres. The study by Yeung et al13 also provides the impetus for prospective studies of snakebite to define the initial antivenom dose and the need for further doses. Such studies are only possible if there is serial estimation of venom concentrations in blood to determine the antivenom dose required to completely neutralise circulating venom.14 Because of the rarity of snake envenoming, a multicentre study is required. The study by Currie () demonstrates just how uncommon snakebite envenoming is in Australia.15 Despite enrolling patients at a hospital that has large numbers of snakebite presentations, the study period required was about 10 years. Multicentre studies are currently being conducted throughout Australia, with collaborative research between clinical toxinologists and emergency physicians in more than 30 hospitals. In addition to answering questions about antivenom dosing, these studies will prospectively evaluate the effectiveness of pressure bandaging with immobilisation. Many questions remain about the use of snake antivenom. The treatment of and premedication to prevent snake antivenom reactions is still of concern. There have been three RCTs,16,17 but because of problems with small numbers and methodology18 many questions remain. Such studies are difficult in Australia because of the infrequency of administration of antivenom in single centres. Again, we need either large multicentre studies or, alternatively, studies conducted in rural tropical countries such as Papua New Guinea or Sri Lanka, where snakebite envenoming is common and a major public health issue. Collaborative work between these countries and Australia will both improve the care of patients and contribute to our understanding of snake antivenoms.

Geoffrey K Isbister BSc FACEM MD

Objective: To investigate the doses of antivenom administered to adult patients with severe brown snake envenoming.Design and setting: Review of charts from Western Australian adult teaching hospitals, December 1991 to December 2001.Patients: 35 patients with severe brown snake envenoming, defined prospectively as afibrinogenaemia (< 0.3 g/L) after a bite by a brown snake (genus Pseudonaja).Main outcome measure: The dose of antivenom required to neutralise venom, defined prospectively as the dose of antivenom given before the return of detectable fibrinogen levels.Results: Of 88 patients with brown snake envenoming admitted over the 10 years, at least 35 had severe envenoming. Afibrinogenaemia persisted for 10 hours (range, 1.4–68 hours) after the first dose of antivenom; in four patients afibrinogenaemia lasted more than 24 hours. The dose of antivenom given before venom neutralisation ranged from one to 23 ampoules. In two-thirds of cases, venom was neutralised with five ampoules, and 89% had venom neutralised with 10 ampoules. Two patients died, and another had serious bleeding complications. Another patient died during the study period from intracerebral haemorrhage, but did not have fibrinogen levels measured.Conclusions: Patients received initial doses of antivenom too small to neutralise circulating venom, and remained afibrinogenaemic for prolonged periods, with serious consequences. The authors now use 10 ampoules as an initial dose in severe brown snake envenoming.

Justin M Yeung MB BS, FACEM · Frank F S Daly MB BS, FACEM · Mark Little FACEM, MPHTM, DTMH · Lindsay M Murray MB BS, FACEM · George A Jelinek MD, FACEM, DipDHM

Paul Prociv Honorary Research Consultant, School of Molecular and Microbial Sciences, University of Queensland, Brisbane, QLD 4072. p.procivATmailbox.uq.edu.au To the Editor: In their brief review of water and public health, Leder et al1 uncritically attributed the Palm Island “epidemic” of 19792 to algal toxicity, commenting that it was the only recorded manifestation of this phenomenon in Australia. The original report described a hepatitis-like illness (associated in many with dehydration and bloody diarrhoea) in 138 children and 10 adults of Aboriginal and Torres Strait Islander descent living on Great Palm Island, northeast of Townsville, Queensland.2 No causative agent was actually identified. My investigation in the early 1980s of Toxocara pteropodis, a parasite of flying foxes, excluded it as a likely aetiological agent in the Palm Island outbreak, and compelled a critical reanalysis of other possibilities, which led me to conclude that subacute copper toxicity was the most plausible explanation. My rationale was published as a hypothesis.3 Sadly, discretion (to protect local technicians) compelled me to withhold critical information that explained how the community had been inadvertently exposed to excessive levels of copper in its water supply. Now that water management is becoming a major societal concern and algal blooms seem to be increasing in frequency, the issue needs to be resolved — and sufficient time may have elapsed for details to be revealed without impugning individuals. In 1985, having concluded that copper poisoning was the most likely explanation, I contacted the environmental health personnel who had overseen the mixing of algicide into the Palm Island water supply in 1979. They were aware that the actual volume of water to be treated had probably been grossly overestimated, because Solomon Dam’s water level was very low at the time. This meant that an excessive dose of copper sulfate was added to the dam, but it was assumed that this would be “erring on the safe side”. Further, the copper sulfate was not distributed uniformly through the water in the dam: a local resident with a dinghy had been contracted and instructed to spread the bags of copper salt around the dam, but had instead dumped it all at one place — immediately over the outlet pipe which carried the island’s drinking water. This would readily explain how the community encountered a sustained pulse of high copper levels in its tap water. While chronic copper poisoning can lead to infantile hepatic cirrhosis,4 acute gastrointestinal symptoms (as manifested during the Palm Island episode) are also well documented.5,6 In the absence of laboratory confirmation of copper toxicity, the cause of the “Palm Island mystery disease” must remain speculative. However, in any future similar outbreaks, copper poisoning should be excluded before attributing the cause to algal toxicity.

Paul Prociv