Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP)

BACKGROUND: Paracetamol (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/DESIGN: We 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. DISCUSSION: This 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 REGISTRATION: EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT0105027

Differences in safety climate among hospital anesthesia departments and the effect of a realistic simulation-based training program

BACKGROUND: Safety climate is often measured via surveys to identify appropriate patient safety interventions. The introduction of an insurance premium incentive for simulation-based anesthesia crisis resource management (CRM) training motivated our naturalistic experiment to compare the safety climates of several departments and to assess the impact of the training. METHODS: We administered a 59-item survey to anesthesia providers in six academic anesthesia programs (Phase 1). Faculty in four of the programs subsequently participated in a CRM program using simulation. The survey was readministered 3 yr later (Phase 2). Factor analysis was used to create scales regarding common safety themes. Positive safety climate (% of respondents with positive safety attitudes) was computed for the scales to indicate the safety climate levels. RESULTS: The usable response rate was 44% (309/708) and 38% (293/772) in Phases 1 and 2 respectively. There was wide variation in response rates among hospitals and providers. Eight scales were identified. There were significantly different climate scores among hospitals but no difference between the trained and untrained cohorts. The positive safety climate scores varied from 6% to 94% on specific survey questions. Faculty and residents had significantly different perceptions of the degree to which residents are debriefed about their difficult clinical situations. CONCLUSIONS: Safety climate indicators can vary substantially among anesthesia practice groups. Scale scores and responses to specific questions can suggest practices for improvement. Overall safety climate is probably not a good criterion for assessing the impact of simulation-based CRM training. Training alone was insufficient to alter engrained behaviors in the absence of further reinforcing actions

Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers

BACKGROUND: A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine. METHODS: Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models. RESULTS: The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P \u3c 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1. CONCLUSIONS: The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form

Oxygen generation via water splitting by a novel biogenic metal ion binding compound.

Methanobactins (MBs) are small (<1,300 Da) post-translationally modified copper-binding peptides and represent the extracellular component of a copper acquisition system in some methanotrophs. Interestingly, MBs can bind a range of metal ions, with some reduced after binding, e.g., Cu2+ reduced to Cu+ Other metal ions, however, are bound but not reduced, e.g., K+ The source of electrons for selective metal ion reduction has been speculated to be water but never empirically shown. Here, using H218O, we show that when MB from Methylocystis sp strain SB2 (MB-SB2) and Methylosinus trichosporium OB3b (MB-OB3) were incubated in the presence of either Au3+, Cu2, and Ag+, 18,18O2 and free protons were released. No 18,18O2 production was observed either in presence of MB-SB2 or MB-OB3b alone, gold alone, copper alone, silver alone or when K+ or Mo2+ was incubated with MB-SB2.In contrast to MB-OB3b, MB-SB2 binds Fe3+ with an N2S2 coordination and will also reduce Fe3+ to Fe2+ Iron reduction was also found to be coupled to oxidation of 2H2O and generation of O2 MB-SB2 will also couple Hg2+, Ni2+ and Co2+ reduction to the oxidation of 2H2O and generation of O2, but MB-OB3b will not, ostensibly as MB-OB3b binds but does not reduce these metal ions.To determine if the O2 generated during metal ion reduction by MB could be coupled to methane oxidation, 13CH4 oxidation by Methylosinus trichosporium OB3b was monitored under anoxic conditions. The results demonstrate O2 generation from metal ion reduction by MB-OB3b can support methane oxidation.IMPORTANCEThe discovery that MB will couple the oxidation of H2O to metal ion reduction and the release of O2 suggests that methanotrophs expressing MB may be able to maintain their activity in hypoxic/anoxic conditions through "self-generation" of dioxygen required for the initial oxidation of methane to methanol. Such an ability may be an important factor in enabling methanotrophs to not only colonize the oxic-anoxic interface where methane concentrations are highest, but also tolerate significant temporal fluctuations of this interface. Given that genomic surveys often show evidence of aerobic methanotrophs within anoxic zones, the ability to express MB (and thereby generate dioxygen) may be an important parameter in facilitating their ability to remove methane, a potent greenhouse gas, before it enters the atmosphere