The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose.

Historically, intravenous acetylcysteine has been delivered at a fixed dose and duration of 300 mg/kg over 20 to 21 hours to nearly every patient deemed to be at any risk for hepatotoxicity following acetaminophen overdose. We investigated a 12-hour treatment regimen for selected low-risk patients. This was a multicenter, open-label, cluster-controlled trial at six metropolitan emergency departments. We enrolled subjects following single or staggered acetaminophen overdose with normal serum alanine transaminase (ALT) and creatinine on presentation and at 12 hours, and less than 20 mg/L acetaminophen at 12 hours. Patients were allocated to intervention (250 mg/kg over 12-hour) or control (300 mg/kg over 20-hour) regimens by site. The primary outcome was incidence of "hepatic injury" 20 hours following initiation of acetylcysteine treatment, defined as ALT doubling and peak ALT greater than 100 IU/L, indicating the need for further antidotal treatment. Secondary outcomes included incidence of hepatotoxicity (ALT > 1,000 IU/L), peak international normalized ratio (INR), and adverse drug reactions. Of the 449 acetaminophen overdoses receiving acetylcysteine, 100 were recruited to the study. Time to acetylcysteine (median 7 hours [interquartile ratio 6,12] versus 7 hours [6,10]) and initial acetaminophen (124 mg/L [58,171] versus 146 mg/L [66,204]) were similar between intervention and control groups. There was no difference in ALT (18 IU/L [13,22] versus 16 IU/L [13,21]) or INR (1.2 versus 1.2) 20 hours after starting acetylcysteine between groups. No patients developed hepatic injury or hepatotoxicity in either group (odds ratio 1.0 [95% confidence interval 0.02, 50]). No patients represented with liver injury, none died, and 96 of 96 were well at 14-day telephone follow-up. Conclusion: Discontinuing acetylcysteine based on laboratory testing after 12 hours of treatment is feasible and likely safe in selected patients at very low risk of liver injury from acetaminophen overdose.

Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol.

OBJECTIVES: In Australia, the treatment guideline for patients with repeated supratherapeutic ingestion (RSTI) of paracetamol recommends an abbreviated acetylcysteine regimen if the paracetamol concentration is low (<10 mg/L) and alanine aminotransferase (ALT) is normal or static after 8 hours of infusion. There are currently no studies of this recommendation. METHOD: A retrospective review of paracetamol overdose presentations from October 2009 to August 2016 in two hospital toxicology networks was performed. All cases of RSTI treated with acetylcysteine were extracted. RESULTS: Of the 2249 paracetamol overdose presentations, 91 cases of RSTI were treated with acetylcysteine. Median time to initial blood tests was 6 hours post-last paracetamol dose (IQR 4-6). Sixty-three (69%) presentations had an initial detectable paracetamol concentration, median 30 mg/L (IQR 18-60). Median ALT on presentation was 48 IU/L (IQR 18-109). After 8 hours of acetylcysteine infusion, median ALT was 34 IU/L (IQR 16-71) in those receiving abbreviated treatment and 74 IU/L (IQR 40-231) in those continuing acetylcysteine. Thirty-nine presentations (43%) had an abbreviated regimen. Nine (10%) patients had an initial ALT ≥50 IU/L and subsequently developed hepatotoxicity (ALT >1000 IU/L). No patients with an initial ALT <50 IU/L developed hepatotoxicity. Median duration of acetylcysteine infusion for those receiving a non-abbreviated regimen was 20 hours (IQR 20-25) vs. 10.4 hours (IQR 4.8-12.0) who received an abbreviated regimen. There were no re-presentations with hepatotoxicity. CONCLUSIONS: An 8-hour acetylcysteine infusion regimen for treatment of paracetamol RSTI may be safe and is likely to reduce length of stay for patients at low risk of hepatotoxicity. Larger prospective studies are needed to examine the efficacy of this abbreviated acetylcysteine protocol.

Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose.

OBJECTIVE: Acetylcysteine (NAC), an effective antidote for paracetamol poisoning, is commonly associated with adverse reactions. This has been postulated to be related to the rapid initial infusion rate (150 mg/kg over 1 h) of the traditional three-bag protocol. We hypothesized that a slower rate would result in fewer adverse reactions. Our institution in Western Sydney moved to a modified two-bag protocol in February 2015 - first bag: 200 mg/kg over 4 h (50 mg/kg/h) and second bag: (100 mg/kg over 16 h). METHODS: Data was extracted from our database on paracetamol overdoses treated with NAC from August 2010 to September 2016. We compared adverse reactions in patients receiving the modified two-bag protocol with a historical control (traditional three-bag regimen with initial bolus of 150 mg/kg/h). RESULTS: Over the study period 1011 paracetamol poisonings presented to our toxicology service, of which 476 required NAC (three-bag = 313, two-bag = 163). Demographic characteristics of the two groups were similar. Fewer anaphylactoid reactions (itch, rash, and swelling) occurred using the two-bag regimen (14% versus 5%, p = .002), a relative reduction of 66%. Similarly, there were fewer prescriptions of anti-allergy medications in the two-bag group (11% versus 4%, p = .01). There was no difference in incidence of hepatotoxicity. CONCLUSIONS: Adverse reactions to NAC were less common with the two-bag regimen. These results add to the accumulating evidence that reducing the initial NAC infusion rate reduces the risk of adverse reactions.

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

INTRODUCTION: Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. METHODS: We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). RESULTS: Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. CONCLUSIONS: The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations.

CONTEXT: Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. CASE DETAILS: A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 µg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. DISCUSSION: In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.

Accuracy of computed tomography of the kidneys, ureters and bladder interpretation by emergency physicians.

OBJECTIVE: The study aims to determine the interpretation accuracy of computed tomography of the kidneys, ureters and bladder (CT-KUB) by emergency physicians (EPs) compared with the formal radiology report, as the reference standard, in patients with suspected acute urinary tract calculous disease. METHODS: A sample of 20 consecutive CT-KUB scans for suspected acute calculous disease was compiled from the medical imaging department of an adult tertiary teaching hospital. Ten EPs with a minimum of 2 years' experience post-Fellowship interpreted each scan using a template form. The total sample of 200 reports by EPs was compared with the formal radiology report for agreement in detecting renal tract stones, signs of obstruction and other clinical findings. Interrater agreement and the kappa statistic were used for comparative data analysis. RESULTS: There was a high level of agreement (%, kappa value) between EPs and radiologists for the detection of large (≥5 mm) calculi (94.5%, κ 0.89), signs of obstruction (93%, κ 0.86) and clinically significant findings (90%, κ 0.78). The level of agreement was low for the detection of small (<5 mm) calculi (79%, κ 0.48) and clinically non-significant findings (67.5%, κ 0.33). CONCLUSION: EPs can accurately detect clinically significant acute calculous disease and signs of obstruction on CT-KUB, allowing for ongoing acute management and early disposition of the patient. However, their findings should be verified against the formal radiology report when available.

Energy drinks: health risks and toxicity.

OBJECTIVES: To describe the epidemiology and toxicity of caffeinated energy drink exposures in Australia. DESIGN, SETTING AND SUBJECTS: Retrospective observational study analysing data from calls regarding energy drink exposures recorded in the database of an Australian poisons information centre over 7 years to 2010. MAIN OUTCOME MEASURES: Type of exposure; co-ingestants; symptoms reported; and reported hospitalisations. RESULTS: Callers reported 297 exposures to energy drinks, which showed an increasing annual trend from 12 in 2004 to 65 in 2010. Median age for the 217 subjects with recreational exposure was 17 years (interquartile ratio [IQR], 15-21; range, 11-60) and 57% were male. One hundred recreational users co-ingested other substances, predominantly alcohol (50) or other caffeinated products (44). The number of energy drinks consumed in one session varied greatly (median, 5 units; IQR, 3-8; range, 1-80). Most subjects who reported recreational use reported experiencing symptoms (87%). The most common symptoms were palpitations, agitation, tremor and gastrointestinal upset. Twenty-one subjects had signs of serious cardiac or neurological toxicity, including hallucinations, seizures, arrhythmias or cardiac ischaemia. At least 128 subjects (57 with no co-ingestants) required hospitalisation. CONCLUSIONS: Reports of caffeine toxicity from energy drink consumption are increasing, particularly among adolescents, warranting review and regulation of the labelling and sale of these drinks. Educating adolescents and increasing the community's awareness of the hazards from energy drinks is of paramount importance.

Brainstem anaesthesia after retrobulbar block: a rare cause of coma presenting to the emergency department.

Local anaesthesia, in particular retrobulbar block, is commonly used to perform cataract surgery. Known complications of retrobulbar block include cranial nerve palsies, seizures and cardiorespiratory arrest. We report a case of brainstem anaesthesia causing apnoea and loss of consciousness in a man who received retrobulbar block. The likely mechanism is inadvertent dural puncture of the optic nerve sheath and local anaesthetic injection into the cerebrospinal fluid space. As in this case, the literature reports a short-lived period of anaesthesia with usually no long-term sequelae. Although rare, it is a life-threatening complication if the patient is not appropriately resuscitated. This case highlights the need for trained personnel, with suitable monitoring and adequate resuscitation facilities in order to perform this technique.