Angela L. Chiew

Carbon monoxide poisoning in the 21st century

The world has experienced some very large shifts in the epidemiology of carbon monoxide poisoning, but it remains one of the most important toxicological global causes of morbidity and mortality. The diagnosis can be quickly confirmed with blood gases (pulse oximeters lack both sensitivity and specificity). Several strong predictors for serious neurological sequelae (prolonged loss of consciousness and elevated S100B) and reduced life expectancy (elevated troponin) are now reasonably well established. Despite this clearly defined high-risk group and extensive research into the pathophysiology, there has been little translation into better treatment. Much of the pathophysiological research has focused on hyperbaric oxygen. Yet it is apparent that clinical trials show little evidence for benefit from hyperbaric oxygen, and the most recent even raises the possibility of harm for repeated courses. More logical and promising potential antidotes have been under-researched, although recently both animal and small human studies suggest that erythropoietin may reduce S100B and prevent neurological sequelae. Major breakthroughs are likely to require further research on this and other treatments that may inhibit post-hypoxic inflammatory responses and apoptosis.

Summary statement: New guidelines for the management of paracetamol poisoning in Australia and New Zealand

Alarge proportion of accidental paediatric exposures and deliberate self-poisoning incidents involve paracetamol; it is the leading pharmaceutical agent responsible for calls to Poisons Information Centres in Australia and New Zealand. Management of paracetamol poisoning has altered since the previous guidelines were published in 2008, so that they do not reflect current practice by clinical toxicologists. The key changes from the previous guidelines concern the indications for administration of activated charcoal; the management of patients taking large or massive overdoses; modified-release and supratherapeutic ingestions; and paediatric liquid paracetamol ingestion.

Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol

A modified‐release formulation of paracetamol is currently available in Australasia and marketed under a number of different trade names. These include: Panadol Osteo, Panadol Extend Tablets, and Duatrol SR. We report four cases of intentional overdose with this formulation resulting in delay to peak plasma paracetamol concentrations and prolonged paracetamol absorption. Physicians must be aware that a single plasma paracetamol estimation four or more hours post‐ingestion may not be adequate in the risk assessment of patients requiring treatment with N‐acetylcysteine (NAC). Current Australasian guidelines for the management of modified‐release paracetamol overdose advise empiric commencement of NAC if the suspected ingested dose is greater than 10 grams or 200 mg/kg (whichever is the least), an initial plasma paracetamol concentration should be assayed four or more hours post‐ingestion and a second assay should be estimated four hours after the first. Treatment with NAC should continue if either concentration falls above the paracetamol treatment nomogram line. With massive ingestions of this paracetamol formulation (>50 grams) plasma concentrations may be elevated for several days and prolonged treatment with NAC is recommended. When modified‐release paracetamol overdose is suspected a clinical toxicologist or Poisons Information Centre should be consulted to help guide management decisions.

Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2)

Abstract Context: Paracetamol is commonly taken in overdose, with increasing concerns that those taking “massive” overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of “massive” (≥ 40 g) paracetamol overdoses. Methods: Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥ 40 g ingested over ≤ 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4–16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT >1000 U/L). Results: Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45–60 g) and median paracetamol ratio 1.9 (IQR: 1.4–2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4–9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1–1.6) versus 2.2 (n = 140, IQR: 1.5–3.0) (p < .0001) (paracetamol concentration measured ≥ 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI: <0.001–0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002–1.74)]. Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08–0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio. Conclusion: Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity.

Catecholamine-induced cardiomyopathy resulting from life-threatening funnel-web spider envenoming.

Wepresent twocasesof cardiomyopathy in life-threatening funnel-webspider envenoming.A33-yearoldman bitten by amale Sydney funnel-web spider developed autonomic and neuromuscular excess, pulmonary oedema, hypotension and cardiogenic shock. Hewas treatedwith antivenom, dobutamine, noradrenaline and high-dose insulin, and recovered over 4 days. Echocardiograms showed severe systolic dysfunction, andhigh catecholamineconcentrationsweremeasured in his blood. A 13-year-old girl developed cardiogenic shock after a funnel-web spider bite, confirmed on echocardiogram treated with antivenom and dobutamine. Funnel-web spider envenoming appears to cause catecholamineinduced cardiomyopathy and cardiogenic pulmonary oedema resulting from catecholamine excess. Antivenom did not reverse the cardiomyopathy.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion

Abstract Context: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. Case details: Case 1: A 50-year-old female presented 18 h post-ingestion of 200  mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO2 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low (<10 mL/min). Conclusion: CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support.

N-Acetylcysteine in the Poisoned Patient

N-Acetylcysteine (NAC) is the mainstay of treatment for paracetamol poisoning, and its use has led to a significant reduction in both the mortality and morbidity following paracetamol overdose. NAC efficacy as a specific antidote for paracetamol poisoning relies mainly on its ability to stimulate glutathione synthesis. Furthermore, it also supplies thiol groups, which can directly bind with N-acetyl-p-benzoquinone imine in hepatocytes and enhances non-toxic sulphate conjugation. As NAC is the cornerstone of treatment in paracetamol poisoning, trials have mainly focused around optimising dose, duration, rate and route of administration, with the primary aim to decrease rates of adverse events, shorten treatment time and maintain efficacy.

Comparison of Wells and YEARS Clinical Decision Rules with D-dimer for Low Risk Pulmonary Embolus Patients: Comparison of Novel PE Decision Rules

Assessment of pulmonary embolism (PE) remains a diagnostic and investigative burden to emergency departments. The decision of which D‐dimer cut‐off to use in low‐risk patients remains controversial.

Bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning could be a bad combination

We would like to provide further research findings following the case reports on “2-methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion” by Chiew et al. [1]. This reported a characteristic toxicity profile of hyperthermia, hypercapnia and metabolic acidosis in two patients that responded to aggressive active cooling and supportive treatment. Both MCPA and bromoxynil can cause cellular dysfunction from uncoupling of oxidative phosphorylation and disrupting lipid peroxidation [2]. However, MCPA appears to mainly cause gastrointestinal effects resulting in hypovolemia, rhabdomyolysis, hepatitis and renal failure. It may sometimes cause vasodilatory shock and myocardial toxicity and has a 5–20% mortality rate [2–4]. Less is known about the acute toxicity of bromoxynil, a benzonitrile herbicide. Small studies suggest that related ioxynil compounds have a high mortality rate (64%) and a similar characteristic toxidrome with tachycardia, hyperthermia, increased carbon dioxide (CO2) production, sweating, coma and asystolic cardiac arrest [4,5]. We undertook a retrospective study of all acute bromoxynil and/or MCPA poisonings referred through the New South Wales Poisons Information Centre and three clinical toxicology units (Prince of Wales Hospital, Mater Calvary Hospital and Princess Alexandra Hospital). The data was cross referenced with the National Coronial Information System (NCIS) in Australia. Bromoxynil and MCPA serum concentrations were measured using liquid chromatography mass spectrophotometry in six fatal cases. From January 2010 to August 2016, there were 22 cases. 20 had ingested MCPA with other herbicides such as dicamba or bromoxynil. (Table 1). There were two fatal cases that reported just bromoxynil ingestion but both had detectable MCPA concentrations (Tables 1 and 2). Hence all 22 cases had ingested MCPA. Of these, eight had also taken dicamba or other herbicides and 14 had co-ingested bromoxynil (Table 1). This includes the two cases that Chiew et al. [1] reported. There were eight fatalities, seven were characterized by tachycardia, tachypnoea, hyperthermia, rising CO2 production, acidosis and sudden asystolic arrest. Death occurred between 12 and 30 hours post-ingestion. The median maximum temperature and partial pressure of CO2 were 39.3 C (range: 37.9–43 C) and 80mmHg (range: 44–122mmHg), respectively. Of the seven fatalities with this toxidrome, six had apparently taken bromoxynil with MCPA, with one of these also taking glyphosate and bromadiolone. Note this includes the two that did not report MCPA co-ingestion. There were two fatalities that were related to MCPA and dicamba or moxidectin co-ingestion (Tables 1 and 2). One patient had the same toxidrome and one died on day 7 from

Modified release paracetamol overdose: a prospective observational study (ATOM-3)

Abstract Background: Modified-release (MR) paracetamol is available in many countries as 665 mg tablets of which 69% is MR and 31% is immediate release. There are concerns that MR paracetamol overdose has higher rates of liver injury despite standard treatment algorithms. The objective of this study was to describe the clinical characteristics and outcomes of acute MR paracetamol overdose. Methods: Prospective observational study, recruiting patients from January 2013 to June 2017, from five clinical toxicology units and calls to two Poisons Information Centres in Australia. Included were patients >14 years who ingested ≥10 g or 200 mg/kg (whichever is less) of MR paracetamol. Data collected included demographics, ingestion history, pathology results, treatments, and outcomes including hepatotoxicity (ALT >1000 U/L). Results: In total, 116 patients were recruited, 85(73%) were female. The median dose ingested was 32 g (IQR: 20–49 g) and median time to presentation was 3 h (IQR: 2–9 h). 78(67%) had an initial paracetamol concentration above the nomogram line (150 mg/L at 4 h). A further 12(10%) crossed the nomogram after repeat paracetamol measurements, of which five crossed after two non-toxic levels 4 h apart. Six had a double paracetamol peak, in three occurring >24 h post-ingestion. 113(97%) received acetylcysteine of which 67 received prolonged treatment beyond the standard 21 h. This was because of an elevated paracetamol concentration at the completion of acetylcysteine in 39 (median paracetamol concentration 25 mg/L, IQR: 16–62 mg/L). 21 (18%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal and double doses of acetylcysteine did not significantly decrease the risk of hepatotoxicity. Conclusions: Drug regulatory authorities are considering restrictions on MR paracetamol preparations. Following an acute MR paracetamol overdose, this study found that many patients had a persistently elevated paracetamol concentrations, many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. Furthermore, activated charcoal and increased acetylcysteine did not appear to significantly alter the risk of liver injury. Hence, research into better treatment strategies is required. Trial registration: Australian Toxicology Monitoring (ATOM) Study – Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.