Euan A. Sandilands

Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial

BACKGROUND Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. METHODS We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). FINDINGS Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024). INTERPRETATION In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. FUNDING Chief Scientist Office of the Scottish Government.

Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment

Aims In September 2012 the UK’s Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single ‘100 mg l−1’ nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning. Methods Data were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose. Results There were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI –4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million–10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million–21.5 million). Conclusions The changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.

Co‐proxamol withdrawal has reduced suicide from drugs in Scotland

AIM To determine what effect the withdrawal of co-proxamol from the UK market has had on mortality from poisoning in Scotland. METHODS This was a retrospective, observational study of mortality relating to poisoning by single agents in Scotland for the period 2000-2006. Mortality data were obtained from the General Register Office Scotland, and primary care prescribing data from the Information and Statistics Division of the Scottish Executive Health Department. RESULTS A significant reduction in the proportion of poisoning deaths due to co-proxamol was observed following legislation [mean 2000-2004, 37 deaths (21.8% of total poisoning deaths); 2006, 10 (7.8%); P < 0.0001]. The most significant reduction was seen in male out-of-hospital deaths [mean 2000-2004, 17 (21.8%); 2006, two (2.9%); P < 0.0001]. This was associated with a decline in prescriptions by 60% within 6 months of legislation. The total number of poisoning deaths also fell, slightly earlier than the full impact on co-proxamol deaths (mean 2000-2004, 171.2; mean 2005-2006, 129.5; P = 0.005). CONCLUSIONS Legislation has resulted in a major reduction in the number of deaths associated with co-proxamol poisoning in Scotland, with no compensatory rise in mortality from poisonings from other common analgesics. We estimate from this study that a minimum of 300 lives across the UK will have been saved by the withdrawal of co-proxamol.

Impact of a focussed teaching programme on practical prescribing skills among final year medical students

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Medication errors, and particularly prescribing errors, are common in UK hospitals. Junior doctors make the majority of prescribing errors. Deficiencies in prescribing education and training have been closely linked to the high frequency of medication errors. WHAT THIS STUDY ADDS Focussed prescribing teaching can lead to an improvement in prescribing ability. Prescribing confidence can be significantly improved through education. Education is insufficient alone in eradicating prescribing errors. AIM To assess the impact of prescribing teaching on final year medical students. METHODS Students randomly allocated to two hospitals completed a prescribing assessment. Prescribing teaching was delivered to the intervention group while no additional teaching was provided for the control group. All students then completed a second prescribing assessment. RESULTS Teaching improved the assessment score: mean assessment 2 vs. 1, 70% vs. 62%, P= 0.007; allergy documentation: 98% vs. 74%, P= 0.0001; and confidence. However, 30% of prescriptions continued to include prescribing errors. CONCLUSION Medical students make significant errors in prescribing. Teaching improves ability and confidence but is insufficient alone in eradicating errors.

'Ivory wave' toxicity in recreational drug users; integration of clinical and poisons information services to manage legal high poisoning

Abstract Background. Novel psychoactive substances or ‘legal highs’ can be defined as psychoactive substances that have been developed to avoid existing drug control measures. Consistency of name, but with change in the content of the product, may cause harm. This could result in clusters of users being poisoned and developing unexpected physical and psychiatric symptoms. We describe such an event and the clinical phenotypes of a cluster of patients poisoned with a novel psychoactive substance in ‘ivory wave’ and analyze data from the National Poisons Information Service (NPIS) to estimate use across the United Kingdom. In addition, the likely active ingredient in this cluster of ‘ivory wave’ poisonings was identified. Methods. An analysis of consecutive patients attending the Royal Infirmary of Edinburgh emergency department in July and August 2010 with self-reported ‘ivory wave’ use was performed. Over a similar time frame, poisons enquiries regarding ‘ivory wave’ to the UK NPIS, by telephone and via the internet-based TOXBASE® poisons database (www.toxbase.org), were analyzed. A sample of ‘ivory wave’ powder and biological fluids from poisoned patients were investigated to determine the active ingredient. Results. Thirty four emergency attendances due to ‘ivory wave’ toxicity were identified. The mean +/− SD (range) age was 28.6 +/− 7.8 (16–44) years. Patients demonstrated a toxidrome which lasted several days, characterized by tachycardia (65%), tachypnoea (76%), dystonia (18%), rhabdomyolysis (96%), leucocytosis (57%), agitation (62%), hallucinations (50%), insomnia (32%) and paranoia (21%). Enquiries to NPIS suggest that ‘ivory wave’ poisoning occurred throughout the United Kingdom. A sample of ‘ivory wave’ powder was analyzed and found to contain desoxypipradrol, which was also identified in biological fluids from 4 out of 5 patients tested. Discussion. A cluster of cases presenting after use of a novel psychoactive substance was identified in Edinburgh and desoxypipradrol was identified as the likely cause. It was associated with prolonged psychiatric symptoms as a key feature. This chemical was regulated in response to the wider UK outbreak, which NPIS data suggest was geographically widespread but probably short lived. Conclusion. Novel psychoactive substances can produce significant toxicity and data from poisons centres may be used to indirectly detect new ‘legal highs’ that are causing clinical toxicity.

Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP)

BackgroundParacetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.Methods/DesignWe designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.DiscussionThis study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.Trial registrationEudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270

An integrated care pathway improves the management of paracetamol poisoning

Background Paracetamol poisoning remains a major cause of morbidity and mortality. Clinical care of paracetamol poisoning depends on a range of patient variables and typically involves both medical and nursing care. An integrated care pathway (ICP) is a multidisciplinary management plan that incorporates guidelines and best practice to enhance care and documentation for a specific patient group. Paracetamol overdose is thus amenable to an ICP. Aim To evaluate the introduction of an ICP on process of care of the paracetamol poisoned patient. Methods A retrospective case note review of consecutive patients admitted to the Royal Infirmary of Edinburgh following a paracetamol overdose was conducted. Data were collected for a 3-month period before and after introduction of the ICP to the emergency department and toxicology inpatient unit. Results The ICP was used in 77% of cases in the time period studied and was associated with improvements in initial documentation of patient assessment (pre-ICP vs post-ICP: 87/161 (54%) vs 101/113 (89%), p<0.0001) and appropriateness of blood sampling (146/161 (91%) vs 111/113 (98%), p=0.01), but no change in timely blood sampling (pre 124/161 (77%) vs post 93/113 (82%)). All aspects of intravenous acetylcysteine administration also significantly improved: administration of acetylcysteine if indicated (pre-ICP vs post-ICP: 57/71 (80%) vs 71/71 (100%), p<0.0001); acetylcysteine commenced in a timely fashion (33/71 (46%) vs 55/71 (77%), p=0.0002); and acetylcysteine correctly prescribed (44/58 (76%) vs 71/71 (100%), p<0.0001). Conclusions Implementation of an ICP for paracetamol poisoning significantly improved patient management and helped to standardise inter-professional decision making in this challenging patient group. This is likely to improve patient outcome.

Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.

BackgroundContrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease.Methods/DesignWe designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance.DiscussionContrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials.Trial registrationClinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

Measurement of renal function in patients with chronic kidney disease

Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.

European Medicines Evaluation Agency bans dextropropoxyphene: A landmark decision for clinical toxicology?

Dextropropoxyphene, widely used in combination with paracetamol, is a weak opioid unique among its class in its propensity to block two receptor groups, opioid and sodium channels. It achieved popularity as an analgesic in many countries despite a lack of clinical evidence of improved efficacy over other simple therapies, including standard dose paracetamol. 1 Concerns about the toxicity of dextropropoxyphene first arose in the 1980s, 2 when it was suggested that patients who took the drug in overdose died more rapidly than with other paracetamol–opioid combination products. The precise reason for sudden death was unclear as many deaths occurred out of hospital. Within the clinical setting, dextropropoxyphene was perceived to be relatively safe in overdose, in that patients who reached hospital rarely presented with major complications of the opioid. This paradox probably contributed to the uncertainty surrounding the debate as to exactly how toxic this agent was. In Europe and particularly in the United Kingdom, it is pertinent to note that drugs have traditionally been licensed on the basis of safety and efficacy in clinical use. Thus, although it was recognized that the drug might be more toxic in overdose than comparator agents this was not deemed to be a sufficient reason to implement major restrictions, other than to maintain it as a prescription-only product. In the United Kingdom, the government announced a suicide prevention strategy and focus fell on the combination product co-proxamol (dextropropoxyphene 32.5 mg, paracetamol 325 mg), as more evidence of excess mortality associated with this product began to emerge. We examined the ratio of deaths to prescriptions and poisons information enquiries in Scotland. The combination of co-proxamol is 10 times more likely to cause death for every million prescriptions issued than the other compound paracetamol opioid preparations with codeine and dihydrocodeine that are widely used in United Kingdom. In contrast episodes of poisoning notified to the UK National Poisons Information Service were in proportion to prescription numbers, confirming that the differences in mortality were indeed related to excess toxicity rather than disproportionate use in overdose. 3 Furthermore subsequent work showed that the vast majority of patients who died in association with dextropropoxyphene did so out of hospital before reaching any medical care. 4 The hypothesis advanced at that time was that the combination of sodium channel blocking effects of propoxyphene or perhaps propoxyphene and its principal metabolite norproxyphene on the myocardium, together with hypoxia caused by central sedation because of the opioid property of the drug, resulted in hypoxia, increased arrhythmia risk, and sudden death. 4