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.

The relative lethal toxicity of pharmaceutical and illicit substances: A 16-year study of the Greater Newcastle Hunter Area, Australia.

AIMS: We aim to calculate 2 metrics of relative lethal toxicity; the fatal toxicity index (FTI; number of deaths per year of a daily dose) and the case fatality (CF; number of deaths per overdose) with a focus on opioids, antidepressants, antipsychotics, benzodiazepines and illicit drugs. METHODS: This descriptive cohort study used the Australian National Coronial Information System (NCIS) to identify a population of individuals with drug-associated deaths in the Greater Newcastle Hunter Area between January 2002 and December 2016. This was combined with Australian medicine dispensing data and corresponding data from the Hunter Area Toxicology Service to calculate FTI and CF. RESULTS: There were 444 drug-related deaths and 21,296 overdoses during the study period. FTI and CF were well correlated (Spearman's rho 0.64, P < .001). Of the classes of interest, opioids had the highest FTI (40.3 95% confidence interval [CI] 35.2-45.4 deaths per 100 years of use at the defined daily dose or deaths/DDD/100 years) and CF (12.4% 95%CI 11.0-13.9). Fentanyl, methadone and morphine had the highest relative fatal toxicity within this class. Tricyclic antidepressants had the highest relative fatal toxicity of all antidepressants (FTI 14.5 95%CI 9.7-19.3 deaths/DDD/100 years and CF 7.1% [95%CI 4.8-9.3]) and benzodiazepines appeared to be more associated with multiple agent deaths than single. Of the illicit drugs, heroin had the highest CF (26.4%, 95%CI 19.1-33.7). CONCLUSION: Knowledge of relative lethal toxicity is useful to prescribers and medicines and public health policy makers in restricting access to more toxic drugs and may also assist coroners in determining cause of death.

The socio-economic burden of snakebite in Sri Lanka.

BACKGROUND: Snakebite is a major problem affecting the rural poor in many of the poorest countries in the tropics. However, the scale of the socio-economic burden has rarely been studied. We undertook a comprehensive assessment of the burden in Sri Lanka. METHODS: Data from a representative nation-wide community based household survey were used to estimate the number of bites and deaths nationally, and household and out of pocket costs were derived from household questionnaires. Health system costs were obtained from hospital cost accounting systems and estimates of antivenom usage. DALYs lost to snakebite were estimated using standard approaches using disability weights for poisoning. FINDINGS: 79% of victims suffered economic loss following a snakebite with a median out of pocket expenditure of $11.82 (IQR 2-28.57) and a median estimated loss of income of $28.57 and $33.21 for those in employment or self-employment, respectively. Family members also lost income to help care for patients. Estimated health system costs for Sri Lanka were $ 10,260,652 annually. The annual estimated total number of DALYS was 11,101 to 15,076 per year for envenoming following snakebite. INTERPRETATION: Snakebite places a considerable economic burden on the households of victims in Sri Lanka, despite a health system which is accessible and free at the point of care. The disability burden is also considerable, similar to that of meningitis or dengue, although the relatively low case fatality rate and limited physical sequelae following bites by Sri Lankan snakes means that this burden may be less than in countries on the African continent.

Pneumatic tube transport of blood-stained cerebrospinal fluid specimens has no clinically relevant effect on rates of haemolysis compared to manual transport.

BACKGROUND: Pneumatic tube transport of pathology specimens from the emergency department to the laboratory for analysis is a widely used practice. When compared to manual specimen transport, it results in savings in both time and labour. Sampling of cerebrospinal fluid still forms part of the workup of patients with suspected subarachnoid haemorrhage. There are claims in the literature that transport of cerebrospinal fluid samples by pneumatic tube results in excess haemolysis, which interferes with cerebrospinal fluid analysis for the presence of bilirubin. The aim of our study was to ascertain whether pneumatic tube transport of blood-stained cerebrospinal fluid to the laboratory, results in clinically significantly higher levels of haemolysis compared with manual transport of the same specimens. METHODS: Stored cerebrospinal fluid was spiked with varying amounts of red blood cells creating 72 specimens of varying red cell concentration. Half of these specimens were transported to the laboratory manually while the other half were sent by pneumatic tube transport. The rates of haemolysis were compared between the pneumatic tube and manual transport samples. RESULTS: There was no clinically significant difference in the rates of haemolysis between the samples transported to the laboratory by pneumatic tube compared with those moved manually. CONCLUSIONS: Pneumatic tube transport of cerebrospinal fluid to the laboratory is not associated with clinically significantly higher rates of haemolysis when compared to manual transport.

Interventions for the symptoms and signs resulting from jellyfish stings.

BACKGROUND: Jellyfish envenomations are common amongst temperate coastal regions and vary in severity depending on the species. Stings result in a variety of symptoms and signs, including pain, dermatological reactions and, in some species, Irukandji syndrome (including abdominal/back/chest pain, tachycardia, hypertension, sweating, piloerection, agitation and sometimes cardiac complications). Many treatments have been suggested for the symptoms and signs of jellyfish stings. However, it is unclear which interventions are most effective. OBJECTIVES: To determine the benefits and harms associated with the use of any intervention, in both adults and children, for the treatment of jellyfish stings, as assessed from randomised trials. SEARCH METHODS: We searched the following electronic databases in October 2012 and again in October 2013: the Cochrane Central Register of Controlled Trials (CENTRAL;The Cochrane Library, Issue 9, 2013); MEDLINE via Ovid SP (1948 to 22 October 2013); EMBASE via Ovid SP (1980 to 21 October 2013); and Web of Science (all databases; 1899 to 21 October 2013). We also searched reference lists from eligible studies and guidelines, conference proceedings and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and contacted content experts to identify trials. SELECTION CRITERIA: We included randomised controlled trials that compared any intervention(s) to active and/or non-active controls for the treatment of symptoms and signs of jellyfish sting envenomation. No language, publication date or publication status restrictions were applied. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted study selection and data extraction and assessed risk of bias using a standardised form. Disagreements were resolved by consensus with a third review author when necessary. MAIN RESULTS: We included seven trials with a total of 435 participants. Three trials focused on Physalia (Bluebottle) jellyfish, one trial on Carukia jellyfish and three on Carybdea alata (Hawaiian box) jellyfish. Two ongoing trials were identified.Six of the seven trials were judged as having high risk of bias. Blinding was not feasible in four of the included trials because of the nature of the interventions. A wide range of interventions were assessed across trials, and a wide range of outcomes were measured. We reported results from the two trials for which data were available and reported the effects of interventions according to our definition of primary or secondary outcomes.Hot water immersion was superior to ice packs in achieving clinically significant (at least 50%) pain relief at 10 minutes (one trial, 96 participants, risk ratio (RR) 1.66, 95% confidence interval (CI) 1.01 to 2.72; low-quality evidence) and 20 minutes (one trial, 88 participants, RR 2.66, 95% CI 1.71 to 4.15; low-quality evidence). No statistically significant differences between hot water immersion and ice packs were demonstrated for dermatological outcomes.Treatment with vinegar or Adolph's meat tenderizer compared with hot water made skin appear worse (one trial, 25 participants, RR 0.31, 95% CI 0.14 to 0.72; low-quality evidence).Adverse events due to treatment were not reported in any trial. AUTHORS' CONCLUSIONS: This review located a small number of trials that assessed a variety of different interventions applied in different ways and in different settings. Although heat appears to be an effective treatment for Physalia (Bluebottle) stings, this evidence is based on a single trial of low-quality evidence. It is still unclear what type of application, temperature, duration of treatment and type of water (salt or fresh) constitute the most effective treatment. In addition, these results may not apply to other species of jellyfish with different envenomation characteristics. Future research should further assess the most effective interventions using standardised research methodology.

Hyperbaric oxygen for carbon monoxide poisoning.

BACKGROUND: Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. OBJECTIVES: To examine randomised trials of the efficacy of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. SEARCH STRATEGY: We searched the following electronic databases; Cochrane Injuries Group Specialised Register (searched June 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (Ovid SP) 1950 to June 2010, EMBASE (Ovid SP) 1980 to June 2010, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to June 2010, ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to June 2010. SELECTION CRITERIA: All randomised controlled trials of HBO compared to NBO, involving non-pregnant adults who are acutely poisoned with carbon monoxide (regardless of severity). DATA COLLECTION AND ANALYSIS: Two authors independently extracted from each trial information on: the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. MAIN RESULTS: Seven randomised controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials involving 1361 participants, two found a beneficial effect of HBO for the reduction of neurologic sequelae at one month, while four others did not. One of these is an incomplete publication (an abstract of an interim analysis). Although pooled random effects meta-analysis does not suggest a significant benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by a high risk of bias introduced during the analysis including an apparent change in the primary outcome. Both were also stopped early 'for benefit', which is likely to have inflated the observed effect. In contrast three negative trials had low power to detect a benefit of HBO due to exclusion of severely poisoned patients in two and very poor follow-up in the other. One trial that was said to be finished around eight years ago has not reported the final analysis in any forum. AUTHORS' CONCLUSIONS: Existing randomised trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomised controlled trial.

The in vitro effects of two chirodropid (Chironex fleckeri and Chiropsalmus sp.) venoms: efficacy of box jellyfish antivenom.

The pharmacological and biochemical isolation of cnidarian venoms has been hindered by difficulties with both extracting pure venom from nematocysts and venom stability. The development of a new technique to extract active, pure venom of Chironex fleckeri and Chiropsalmus sp. has enabled identify both neurotoxic and myotoxic activity in their venoms. These activities are similar, but not identical in each species. Venom (50 micro g/ml) from both species significantly inhibited indirect and direct twitches of the chick biventer nerve-muscle preparation. Pre-incubation with 1U/ml box jellyfish antivenom did not have any significant effect on venom-induced reductions of indirect twitches. However, this activity was markedly attenuated by prior addition of 5U/ml antivenom, albeit to a lesser degree for Chiropsalmus sp. In contrast, prior addition of 5U/ml box jellyfish antivenom did not neutralise the myotoxic activity of C. fleckeri venom (50 micro g/ml), although it did inhibit the myotoxicity produced by Chiropsalmus sp. venom (50 micro g/ml). Antivenom (5U/ml) added 1h after the addition of C. fleckeri venom (50 micro g/ml) had no effect on the indirect or direct twitches of the skeletal muscle preparation. However, it partially restored the reduction in indirect twitch height caused by Chiropsalmus sp. venom (50 micro g/ml). Myotoxicity was confirmed in muscle preparations stained with hematoxylin and eosin.Therefore, although antivenom was able to neutralize the neurotoxic effects of both species, and the myotoxic effects of Chiropsalmus sp., when added prior to venom, it was unable to reverse the effects after venom addition. This suggests that antivenom is unlikely to be useful in the treatment of neurotoxic or myotoxic effects in patients, although these effects are rarely seen clinically.

Pesticide poisoning in the developing world--a minimum pesticides list.

In parts of the developing world, pesticide poisoning causes more deaths than infectious diseases. Use of pesticides is poorly regulated and often dangerous; their easy availability also makes them a popular method of self-harm. In 1985, the UN Food and Agriculture Organisation (FAO) produced a voluntary code of conduct for the pesticide industry in an attempt to limit the harmful effects of pesticides. Unfortunately, a lack of adequate government resources in the developing world makes this code ineffective, and thousands of deaths continue today. WHO has recommended that access to highly toxic pesticides be restricted--where this has been done, suicide rates have fallen. Since an Essential Drugs List was established in 1977, use of a few essential drugs has rationalised drug use in many regions. An analogous Minimum Pesticides List would identify a restricted number of less dangerous pesticides to do specific tasks within an integrated pest management system. Use of safer pesticides should result in fewer deaths, just as the change from barbiturates to benzodiazepines has reduced the number of deaths from pharmaceutical self-poisoning.