Acetaminophen Metabolites on Presentation Following an Acute Acetaminophen Overdose (ATOM-7).

Acetaminophen (APAP) is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of APAP metabolites on presentation following an acute APAP poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak alanine aminotransferase > 1,000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two poison information centers and four toxicology units. Patients following an acute APAP ingestion presenting < 24 hours post-ingestion were recruited. Initial samples were analyzed for APAP metabolites, those measured were the nontoxic glucuronide (APAP-Glu) and sulfate (APAP-Sul) conjugates and NAPQI (toxic metabolite) conjugates APAP-cysteine (APAP-Cys) and APAP-mercapturate (APAP-Mer). The primary outcome was hepatotoxicity. In this study, 200 patients were included, with a median ingested dose of 20 g, 191 received acetylcysteine at median time of 5.8 hours post-ingestion. Twenty-six patients developed hepatotoxicity, one had hepatotoxicity on arrival (excluded from analysis). Those who developed hepatotoxicity had significantly higher total CYP metabolite concentrations: (36.8 µmol/L interquartile range (IQR): 27.8-51.7 vs. 10.8 µmol/L IQR: 6.9-19.5) and these were a greater proportion of total metabolites (5.4%, IQR: 3.8-7.7) vs. 1.7%, IQR: 1.3-2.6, P < 0.001)]. Furthermore, those who developed hepatotoxicity had lower APAP-Sul concentrations (49.1 µmol/L, IQR: 24.7-72.2 vs. 78.7 µmol/L, IQR: 53.6-116.4) and lower percentage of APAP-Sul (6.3%, IQR: 4.6-10.9 vs. 13.1%, IQR, 9.1-20.8, P < 0.001)]. This study found that those who developed hepatotoxicity had higher APAP metabolites derived from CYP pathway and lower sulfation metabolite on presentation. APAP metabolites may be utilized in the future to identify patients who could benefit from increased acetylcysteine or newer adjunct or research therapies.

Ketamine as a rescue treatment for severe acute behavioural disturbance: A prospective prehospital study.

OBJECTIVE: Rapidly and safely managing severe acute behavioural disturbance (ABD) in the prehospital setting is important for the welfare of both patient and prehospital clinician alike. We investigated the safety and effectiveness of ketamine as rescue sedation in patients with severe ABD. METHODS: This prospective observational study investigated ketamine use by a state ambulance service as rescue sedation for patients with severe ABD who remained agitated following droperidol administration. The primary outcome was the proportion of adverse events (vomiting, hypersalivation, emergence, over-sedation, airway obstruction, laryngospasm, hypoxia, bradypnoea and intubation). Secondary outcomes included time to sedation, requirement for additional sedation and rate of successful sedation. RESULTS: There were 105 presentations (males 69/102 [69%]; median age 31 years (16-83 years). The commonest causes of ABD were illicit drug (39%) and alcohol (33%) intoxication. The median total dose of intramuscular ketamine was 200 mg (interquartile range [IQR] 150-200 mg). There were 64 adverse events in 40 (38%) patients. Four had vomiting, two had hypersalivation, two had emergence, 15 were oversedated, four had hypoxia, three had bradypnoea and 16 were intubated. Sedation was achieved in 103 (98%) patients at a median time post-ketamine of 8 min (IQR 5-13 min). Additional sedation was administered to 41 patients (nine prehospital and 37 within 1 h of arriving to hospital). In 44 (42%) patients, ketamine successfully sedated the patient with no adverse effects and no ongoing sedation requirement. CONCLUSION: The use of ketamine as rescue sedation in prehospital patients with severe ABD is effective. Adverse events are common but can be managed supportively.

Prospective study of the safety and effectiveness of droperidol in elderly patients for pre-hospital acute behavioural disturbance.

OBJECTIVE: Acute behavioural disturbance in the elderly (≥65 years) is a significant issue for emergency medical services with increasing prevalence of dementia and aging populations. We investigated the pre-hospital safety and effectiveness of droperidol in the elderly with acute behavioural disturbance. METHODS: This was a pre-hospital prospective observational 1-year study of elderly patients with acute behavioural disturbance. The primary outcome was proportion of adverse events (AEs) (airway intervention, oxygen saturation <90% and/or respiratory rate <12/min, systolic blood pressure <90 mmHg, sedation assessment tool score of -3 and dystonic reactions). Secondary outcomes included time to sedation, additional sedation, proportion with successful sedation. RESULTS: There were 149 patients (males 78 [52%], median age 78 years; 65-101 years) presenting on 162 occasions. Dementia was the commonest cause (107/164 [65%]) of acute behavioural disturbance. There were six AEs in five patients (5/162 [3%]; 95% confidence interval 1-7). Three had hypotension, one with associated hypoxia (80%); and two had respiratory AEs (respiratory rate, 10/min [no hypoxia] and hypoxia [88%] which required oxygen). Median time to sedation was 19 min (interquartile range 12-29 min). Additional sedation was given in 2/162 patients during ambulance transfer and 16/162 within an hour of hospital arrival; 24/162 (15%) failed to sedate in the ambulance; 16 subsequently settled in ED and 8/24 received additional sedation. Of 162, 123 (76%) patients successfully sedated, without AEs or additional sedation. Of 162, 114 (70%) patients received 5 mg, 46 (29%) received two doses of 5 mg and two patients (1%) received three doses. CONCLUSIONS: Droperidol appeared to be safe and effective for pre-hospital sedation of acute behavioural disturbance in elderly patients.

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study).

BACKGROUND: Previous studies of paracetamol overdose treatment show that a 2-bag, 20-h intravenous (IV) acetylcysteine regimen decreased the incidence of non-allergic anaphylactic reactions compared to the 3-bag, 21 h IV regimen, but have not examined efficacy of the 20-h 2 bag regimen. METHODS: This was a multi-centre observational study of paracetamol overdose presentations treated with a 2-bag IV acetylcysteine regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) compared to a 3-bag regimen, performed from 2009 to 2019. Patients were referred from the emergency department to the inpatient toxicology units for continued management. For the primary non-inferiority analysis: subjects had single, acute ingestions, a serum paracetamol-concentration performed 4 to 8-h post-ingestion. The primary outcome was development of acute liver injury (ALI), defined as peak ALT>150 U/L; and > double admission baseline ALT (for presentations within 24 h post-overdose). Secondary outcomes included adverse reactions to acetylcysteine (cutaneous and systemic). FINDING: Out of 6419 paracetamol overdoses, 2763 received acetylcysteine. For the primary analysis, 1003 received the 2-bag and 783 the 3-bag acetylcysteine regimen. When presentation bloods were performed 4 to 8-h post-overdose, 21 (3.1%) developed ALI with the 2-bag regimen vs 16 (2.9%) with the 3-bag regimen (Difference: 0.2%, 95%CI:-1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference -0.4%, 95%CI -1.75, 0.91). When presentation bloods were performed 8 to 24-h post-overdose, 70 (21%) developed ALI with the 2-bag regimen vs 46 (23%) with the 3-bag regimen (Difference: -2%, 95%CI -9.12 to 5.36). There were significantly less cutaneous and systemic non-allergic anaphylactic reactions recorded after treatment with the two-bag than the three-bag regimen (1.3% [n = 17] and 7.1% [n = 65], Difference: -5.8%, 95%CI -7.6 to -4.0, p < 0.0001), respectively. INTERPRETATION: A two-bag intravenous acetylcysteine regimen was found to be non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol overdose. No important differences were seen for any other presentations. The two-bag regimen also decreased the incidence of both non-allergic anaphylactic reactions and gastrointestinal adverse events from acetylcysteine treatment. FUNDING: AW is funded by a National Health and Medical Research Council (NHMRC) Early Career Fellowship ID 1159907. GI is funded by a NHMRC Senior Research Fellowship ID 1061041. The NHMRC had no role in the design, writing of this manuscript. The corresponding author (AW) had full access to all the data in the study and final responsibility for the decision to submit the manuscript for publication.

One single large intramuscular dose of naloxone is effective and safe in suspected heroin poisoning.

OBJECTIVE: Naloxone is an established antidote for the treatment of heroin poisoning; however, dosing regimens vary widely, with a current trend towards small titrated intravenous dosing. This study aims to characterise naloxone use in the treatment of patients presenting with suspected heroin poisoning. METHODS: This was a retrospective review of poisoned patients presenting to a clinical toxicology unit in Brisbane from January 2015 to December 2017. Patient demographics, clinical effects, naloxone dosing, observation periods and complications were extracted from the patient's medical records. RESULTS: There were 117 presentations accounted for by 108 patients. Prehospital naloxone was provided to 57 (49%) patients, 46 of which received a standardised 1.6 mg i.m. dose. The remaining 60 (51%) patients received their first naloxone in hospital, with 58 (97%) receiving this by titrated i.v. doses. A subsequent naloxone infusion was required significantly more often in those treated with i.v. titrated naloxone compared to i.m. dose (27/69 [39%] vs 5/48 [10%], P = 0.0006). The need for parenteral sedation to manage acute behavioural disturbance following naloxone provision was rare (3/117 [3%]). CONCLUSIONS: In this retrospective observational study, a single large i.m. dose of naloxone reversed the toxicity of suspected heroin overdose in the majority of patients. In addition, patients were less likely to require repeated intermittent doses or naloxone infusion than those treated solely with i.v. naloxone. Further comparison in a prospective study is warranted to validate these observations in confirmed heroin overdose. Requirement for sedation secondary to acute behavioural disturbance was rare regardless of the route.

Neurotoxicity in chronic lithium poisoning.

BACKGROUND: Lithium-induced neurotoxicity typically occurs with chronic accumulation rather than following acute overdose. There is little emphasis in the literature on the protracted nature of lithium neurotoxicity long after the lithium concentration returns to the therapeutic range. AIMS: To characterise lithium neurotoxicity, with a view of increasing awareness of this important phenomenon. METHODS: This is a retrospective observational study of patients presenting with lithium-induced neurotoxicity over a 5-year period to a clinical toxicology unit. Patients were identified through the unit's database, and clinical notes were analysed. RESULTS: There were 22 patients, with a median age of 65 (range: 36-89) years. Six patients (27%) had previous lithium toxicity, and nine (41%) were regularly prescribed medications that impair lithium excretion. The median lithium concentration on presentation was 2.2 mmol/L, taking a median of 3 days to return to the therapeutic range. Reversible acute kidney injury was observed in 21 patients (95%) on presentation. The median length of stay was 13 (range: 3-95) days due mostly to delayed neurological recovery. Confusion was the predominant symptom, present in 21 (95%) patients, followed by tremors (18(82%)) and ataxia (16(73%)). Multiple investigations were performed to exclude delirium differentials, including 11 computed tomography (CT) and five magnetic resonance imaging (MRI) brain scans, all unremarkable. CONCLUSIONS: Lithium neurotoxicity has a prolonged course. Its severity correlates poorly with lithium concentrations, which normalise quickly. Most poisonings occur in elderly patients with acute kidney injury. Prolonged delirium often prompts multiple unnecessary investigations. Rationalisation of lithium therapy is important in elderly patients.

Use of a tablet-based application for clinical handover and data collection.

Context: Inpatient toxicology services undertake remote as well as inpatient management of poisoned patients. The aim of this study is to describe the introduction of a tablet-based electronic data collection tool allowing data to be captured on inpatient and remote consultations.Methods: Retrospective review of all cases entered in the database from 1 March 2014 to 28 February 2016. Data collected included demographics (age, sex), clinical details (exposure category), presentation facility and disposition.Results: The database included 3616 cases: 59 (1.6%) were excluded due to inadequate details, 122 (3.4%) had no electronic medical record available, 1985 (54.9%) presented to the inpatient unit facility and 1450 (40.1%) were external consultations. Of these 1450, 223 (6.2%) were paediatric (aged less than 12 years), 395 (10.9%) adolescent (12-17 years) and 832 (23.0%) adults (18 years and over). The proportion of paediatric cases (median age 2 y; 45.7% females) with pharmaceutical ingestions was 122 (54.7%; 95% confidence intervals (CIs): 48.2-61.1) compared with 345 (87.3%; 95% CI: 83.7-90.3) in adolescents (median age 15 y; 79.5% females). Of the adult presentations, 659 (18.2%) were metropolitan/regional facility presentations and 173 (4.8%) rural facilities with 125 (3.4%) adults subsequently transferred to the inpatient facility. Median age was 38 years (interquartile range (IQR) 35-52) with 338 (51.4%) females in the metropolitan group and 37 years (IQR 26-48) with 51 (30.5%) females in the rural group. There were more bites and stings in the rural group, 41 (23.7%; 95% CI: 18.0-30.6) versus 54 (8.2%; 95% CI: 6.3-10.5), more recreational substance exposures 27 (15.6%; 95% CI: 11.0-21.8) versus 40 (6.1%; 95% CI: 4.5-8.2) and less pharmaceutical exposures 93 (53.8%; 95% CI: 46.3-61.0) versus 462 (70.1%; 95% CI: 66.5-73.5).Conclusions: The tablet based database provided useful information on populations of poisoned patients not accessible previously. It demonstrated important differences in the types of patients presenting to rural versus metropolitan hospitals.

A Prospective Study of the Safety and Effectiveness of Droperidol in Children for Prehospital Acute Behavioral Disturbance.

Study objective: Although uncommon, children (<16 years) with acute behavioral disturbance are a significant issue for emergency medical service providers. In this study, we aimed to investigate the safety and effectiveness of droperidol in children with prehospital acute behavioral disturbance. Methods: This was a prospective observational study over 1 year investigating the use of droperidol (0.1-0.2 mg/kg) for children (< 16 years) with acute behavioral disturbance. Inclusion criteria for acute behavioral disturbance were defined by a sedation assessment tool score of ≥2 determined by the attending paramedic. The primary outcome was the proportion of adverse effects (need for airway intervention, oxygen saturation <90% and/or respiratory rate <12, systolic blood pressure <90 mmHg, sedation assessment tool score of -3 and dystonic reactions). Secondary outcomes included time to sedation (sedation assessment tool score decreased by 2 or more, or a score of zero), requirement for additional sedation, failure to sedate and proportion of sedation success defined as the number of patients successfully sedated who did not suffer any adverse events or receive additional sedation. Results: There were 96 patients (males 51 [53%], median age 14 years [range 7-15 years]) who presented on 102 occasions over the one year study period. Self-harm and/or harm to others was the commonest (74/105 [70%]) cause of acute behavioral disturbance followed by alcohol (16/105 [15%]). There were 9 adverse events in 8 patients (8/102 [8%]; 95% confidence intervals [CI]: 3-13%) Five patients had hypotension, all asymptomatic and only one required treatment; 2 dystonic reactions managed with benztropine and one patient with respiratory depression. Median time to sedation was 14 min (interquartile range (IQR): 10-20 min; range: 3-85 min). There was no requirement for prehospital additional sedation (0/102 [0%]; 95% CI: 0-4%) and additional sedation in the first hour of arrival to hospital was required by 4 patients (4/102 [4%]; 95% CI: 1-10%). Overall successful sedation was achieved in 89 (87%) patients. Conclusions: The use of droperidol in children for acute behavioral disturbance in the prehospital setting is both safe and effective.

Clinical outcomes from early use of digoxin-specific antibodies versus observation in chronic digoxin poisoning (ATOM-4).

Introduction: In our previous study on chronic digoxin poisoning, there was a minor improvement after treatment with digoxin-specific antibody (digoxin-Fab). We hypothesised patients with elevated digoxin concentrations may derive little benefit from digoxin-Fab because their presenting complaint was more closely related to their multiple co-morbidities. We aimed to compare the outcome of patients who were initially treated with digoxin-Fab with those that received supportive care. Method: Patients were prospectively recruited to the study if they had an elevated digoxin concentration, signs or symptoms of toxicity thought to be from digoxin. Patients who were initially managed with digoxin-Fab were compared with those not initially receiving digoxin-Fab (observation group). Patients presented with ventricular arrhythmias before initial assessment were excluded from the analysis. Primary outcome was mortality. Secondary outcomes were length of stay (LOS), change in heart rate (HR) and potassium concentration. Results: From September 2013 to January 2018, 128 patients were recruited of which 78 (61%) received initial digoxin-Fab. Digoxin-Fab and supportive care groups had an initial median heart rate of 46 (range: 20-120) vs 52 bpm (range: 29-91) (p = .06), systolic blood pressure of 110 mmHg (range: 65-180) vs 125 mmHg (range: 90-184) (p = .009), respectively. Digoxin concentrations 4.4 nmol/L (range: 3.3-9) vs 4.2 (range: 2-11.2) (p = .42) and potassium concentrations 5.4 mmol/L (range: 3-11) vs 5.1 mmol/L (range: 3.5-8.2) (p = .33) were similar. Median dose of digoxin-Fab used was 1.5 vials (IQR: 1-2). There were 9 (12%) deaths in the Fab group compared to 7 (14%) in those treated with supportive care (risk difference -2.5%; 95% CI: -14 to 9%; p = .68). The median LOS was six days in both groups. Mean changes in potassium concentration [-0.5 ± 0.1 vs. -0.4 ± 0.1 mmol/L; difference -0.1 (95% CI: -.02, 0.4), p = .70] and HR within 4 h [8 ± 1 vs. 7 ± 3 bpm; difference -1.0 (95% CI: -6.7, 4.8), p = 0.74] were similar in the two groups. Conclusions: This study did not appear to show any benefit from the routine use of digoxin-Fab in patients thought to have chronic digoxin poisoning. These patients have multiple co-morbidities that may be contributing to their clinical features, other treatments are often equally effective.

Methamphetamine presentations to an emergency department: Management and complications.

OBJECTIVE: There is little recent published data characterising methamphetamine intoxication. The present study aims to describe the clinical effects, management, complications and disposition of patients with methamphetamine exposure. METHODS: This is a retrospective review of patients presenting with methamphetamine intoxication to an ED in 2016. All presentations were extracted from a relational database and each medical record reviewed. Demographics, clinical features, complications and disposition were extracted. RESULTS: There were 378 presentations of 329 patients (234 men [71%]), median age 31 years (range 16-68 years). The most common clinical effect was acute behavioural disturbance, occurring in 295 (78%) presentations. This was successfully managed with oral sedation alone in 180 (61%) patients, with the remainder receiving parenteral sedation. Other effects included tachycardia in 212 (56%), hypertension in 160 (42%) and hyperthermia in 17 (5%) presentations. No anti-hypertensives were given. One patient was actively cooled. Complications included 21 (30%) presentations with rhabdomyolysis and 41 (13%) presentations with acute kidney injury. There were two seizures, three intracranial bleeds and one myocardial infarction. The majority (317 [84%]) of patients were managed solely within the ED. The median length of stay was 14 h. There were 41 (11%) mental health admissions. Two deaths occurred: one following an out-of-hospital cardiac arrest and the other a subarachnoid haemorrhage. CONCLUSION: The main toxicity seen with methamphetamines is acute behavioural disturbance, which is managed well with sedation. Complications, apart from rhabdomyolysis and acute kidney injury, are rare. Most patients are managed within the ED and discharged home.

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose.

OBJECTIVE: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose. CASE REPORT: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17. DISCUSSION: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

A Prospective Before and After Study of Droperidol for Prehospital Acute Behavioral Disturbance.

STUDY OBJECTIVE: Acute behavioral disturbance is a common problem for emergency medical services. We aimed to investigate the safety and effectiveness of droperidol compared to midazolam in the prehospital setting. METHODS: This was a prospective before and after study comparing droperidol to midazolam for prehospital acute behavioral disturbance, when the state ambulance service changed medications. The primary outcome was the proportion of adverse effects (airway intervention, oxygen saturation < 90%, respiratory rate < 12, systolic blood pressure < 90 mmHg, sedation assessment tool score -3 and dystonic reactions) in patients receiving sedation. Secondary outcomes included time to sedation, requirement for additional sedation, staff and patient injuries, and prehospital time. RESULTS: There were 141 patients administered midazolam and 149 patients administered droperidol in the study. Alcohol was the most common cause of acute behavioral disturbance. Fewer patient adverse events occurred with droperidol (11/149) compared to midazolam (33/141) (7% vs. 23%; absolute difference 16%; 95% confidence interval [CI]: 8% to 24%; p = 0.0001). Median time to sedation was 22 min (interquartile range [IQR]:18 to 35 min) for droperidol compared to 30 min (IQR:20 to 45 min) for midazolam. Additional prehospital sedation was required in 6/149 (4%) droperidol patients and 20/141 (14%) midazolam patients, and 11 (7%) droperidol and 59 (42%) midazolam patients required further sedation in the emergency department. There were no differences in patient or staff injuries, or prehospital time. CONCLUSIONS: The use of droperidol for acute behavioral disturbance in the prehospital setting is associated with fewer adverse events, a shorter time to sedation, and fewer requirements for additional sedation.

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

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.

The safety of high-dose insulin euglycaemia therapy in toxin-induced cardiac toxicity.

CONTEXT: High-dose insulin euglycaemia (HIE) is recommended in the management of toxin-induced cardiac toxicity, with increasing insulin doses now being used. We aimed to investigate the safety of HIE in toxin-induced cardiac toxicity. METHODS: This was a retrospective review of cases from two clinical toxicology units. Demographics, toxin(s) ingested, clinical effects, investigations (serum glucose, electrolytes), treatments (insulin, glucose, electrolyte replacement), length of stay (LOS) and outcomes were extracted from the patients' medical records. Associations between insulin and glucose/electrolyte homeostasis were explored by comparing insulin administration and glucose or electrolyte concentrations and replacement. RESULTS: There were 22 patients (12 females), median age 57 years (15-88 years) treated with HIE. There were 12 beta-blocker, six calcium channel blocker and three combined beta-blocker and calcium channel blocker ingestions. A total of 19 patients had a systolic blood pressure <80mmHg and 18 patients required inotropes in addition to HIE. There were three deaths. Despite glucose and electrolyte replacement, 16 patients (73%) developed hypoglycaemia (Reference range [RR] < 3.5 mmol/L or <63 mg/dl). In 7 patients, hypoglycaemia was mild (2.5-3.4 mmol/L or 45-62 mg/dl) and in nine was severe (<2.5 mmol/L or <45 mg/dl). There were no neurological effects from hypoglycaemia. A total of 18 patients (82%) developed hypokalaemia (<3.5 mEq/L). In 16 patients, this was mild (2.5-3.4 mEq/L). There were no cardiac arrhythmias associated with this hypokalaemia. There was no apparent association between insulin dosing and severity of hypoglycaemia or hypokalaemia, or in glucose or potassium replacement. Median insulin loading dose was 80U (range 50-125 U) and the median maximum insulin infusion rate was 150 U/h (range 38-1500 U/h). Median glucose infusions rates were 37.5g/h (range 4-75g/h). There was no apparent association between insulin and glucose administration. Glucose was administered for a median of 18h after ceasing insulin. The duration of glucose administration after ceasing insulin increased with the rate and total insulin administered during HIE. DISCUSSION: Despite the benefits of HIE in toxin-induced cardiac toxicity, it caused significant disruption to glucose and electrolyte homeostasis, although there were no apparent complications from this. There was no association by comparing the amount of insulin administered on adverse effects or glucose administered, suggesting higher doses of insulin are associated with no more adverse effects.

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

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.

The Australian Snakebite Project, 2005-2015 (ASP-20).

OBJECTIVE: To describe the epidemiology, treatment and adverse events after snakebite in Australia. DESIGN: Prospective, multicentre study of data on patients with snakebites recruited to the Australian Snakebite Project (2005-2015) and data from the National Coronial Information System. Setting, participants: Patients presenting to Australian hospitals with suspected or confirmed snakebites from July 2005 to June 2015 and consenting to participation. MAIN OUTCOME MEASURES: Demographic data, circumstances of bites, clinical effects of envenoming, results of laboratory investigations and snake venom detection kit (SVDK) testing, antivenom treatment and adverse reactions, time to discharge, deaths. RESULTS: 1548 patients with suspected snakebites were enrolled, including 835 envenomed patients (median, 87 per year), for 718 of which the snake type was definitively established, most frequently brown snakes (41%), tiger snakes (17%) and red-bellied black snakes (16%). Clinical effects included venom-induced consumption coagulopathy (73%), myotoxicity (17%), and acute kidney injury (12%); severe complications included cardiac arrest (25 cases; 2.9%) and major haemorrhage (13 cases; 1.6%). There were 23 deaths (median, two per year), attributed to brown (17), tiger (four) and unknown (two) snakes; ten followed out-of-hospital cardiac arrests and six followed intracranial haemorrhages. Of 597 SVDK test results for envenomed patients with confirmed snake type, 29 (4.9%) were incorrect; 133 of 364 SVDK test results for non-envenomed patients (36%) were false positives. 755 patients received antivenom, including 49 non-envenomed patients; 178 (24%), including ten non-envenomed patients, had systemic hypersensitivity reactions, of which 45 (6%) were severe (hypotension, hypoxaemia). Median total antivenom dose declined from four vials to one, but median time to first antivenom was unchanged (4.3 hours; IQR, 2.7-6.3 hours). CONCLUSIONS: Snake envenoming is uncommon in Australia, but is often severe. SVDKs were unreliable for determining snake type. The median antivenom dose has declined without harming patients. Improved early diagnostic strategies are needed to reduce the frequently long delays before antivenom administration.

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

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.