Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay). We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. F Hoffmann-La Roche.

OBJECTIVE—Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake. RESEARCH DESIGN AND METHODS—Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects. RESULTS—Caffeine decreased insulin sensitivity by 15% (P < 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P < 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P < 0.0005), and smaller increases were recorded in plasma norepinephrine (P < 0.02) and blood pressure (P < 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P < 0.01). CONCLUSIONS—Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect.

We assess the efficacy and safety of tamsulosin compared with placebo as medical expulsive therapy in patients with distal ureteric stones less than or equal to 10 mm in diameter. This was a randomized, double-blind, placebo-controlled, multicenter trial of adult participants with calculus on computed tomography (CT). Patients were allocated to 0.4 mg of tamsulosin or placebo daily for 28 days. The primary outcomes were stone expulsion on CT at 28 days and time to stone expulsion. There were 403 patients randomized, 81.4% were men, and the median age was 46 years. The median stone size was 4.0 mm in the tamsulosin group and 3.7 mm in the placebo group. Of 316 patients who received CT at 28 days, stone passage occurred in 140 of 161 (87.0%) in the tamsulosin group and 127 of 155 (81.9%) with placebo, a difference of 5.0% (95% confidence interval -3.0% to 13.0%). In a prespecified subgroup analysis of large stones (5 to 10 mm), 30 of 36 (83.3%) tamsulosin participants had stone passage compared with 25 of 41 (61.0%) with placebo, a difference of 22.4% (95% confidence interval 3.1% to 41.6%) and number needed to treat of 4.5. There was no difference in urologic interventions, time to self-reported stone passage, pain, or analgesia requirements. Adverse events were generally mild and did not differ between groups. We found no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.

The optimal approach for peripheral intravenous catheter (PIVC) insertion in adult hospitalised patients with difficult intravenous access (DIVA) is unknown. The present study aimed to critically appraise the quality of (i) assessment instruments and (ii) clinical practice guidelines (CPGs) or escalation pathways for identifying and managing patients with DIVA. Cochrane Central Register of Controlled Trials, EBSCO MEDLINE, EMBASE (OVID) and EBSCO CINAHL databases were searched on 22 March 2021. Studies describing a DIVA assessment measure, CPG or escalation pathway for PIVC insertion in adults (≥18 years of age) were included. Data were extracted using a standardised data extraction form including study design, type of resource and reported clinical outcomes. Quality of DIVA assessment instruments were reviewed using the COnsensus‐based Standards for the selection of health Measurement Instruments checklist. Methodological quality of CPGs and escalation pathways was assessed using the Appraisal of Guidelines for Research and Evaluation‐II (AGREE‐II) instrument. Overall, 24 DIVA resources comprising 16 DIVA assessment instruments and nine CPGs or escalation pathways (including one combined assessment instrument and escalation pathway) were identified. Instruments commonly focused on vein visibility and palpability as indicators of DIVA. CPGs and escalation pathways unanimously recommended use of vessel visualisation technology for patients with or suspected of DIVA. Methodological quality of the resources was mixed. Consensus and standardisation of resources to identify DIVA and recommendations for managing patients with DIVA is limited. Adopting consistent, evidence‐based CPGs, escalation pathways or DIVA assessment instruments may significantly improve clinical outcomes.

Haemorrhage is a leading cause of death in severe trauma. Fibrinogen plays a critical role in maintaining haemostasis in traumatic haemorrhage. Early fibrinogen replacement is recommended by several international trauma guidelines using either fibrinogen concentrate (FC) or cryoprecipitate (Cryo). There is limited evidence to support one product over the other with widespread geographic and institutional variation in practice. This pilot trial is the first randomised controlled trial comparing FC to Cryo in traumatic haemorrhage. The Fibrinogen Early In Severe Trauma studY (FEISTY) is an exploratory, multicentre, randomised controlled trial comparing FC to Cryo for fibrinogen supplementation in traumatic haemorrhage. This trial will utilise thromboelastometry (ROTEM®) to guide and dose fibrinogen supplementation. The trial will recruit 100 trauma patients at four major trauma centres in Australia. Adult trauma patients with evidence of haemorrhage will be enrolled on arrival in the trauma unit and randomised to receiving fibrinogen supplementation with either FC or Cryo. The primary outcome is the differential time to fibrinogen supplementation. There are a number of predetermined secondary outcomes including: effects of the intervention on plasma fibrinogen levels, feasibility assessments and clinical outcomes including transfusion requirements and mortality. The optimal method for replacing fibrinogen in traumatic haemorrhage is fiercely debated. In this trial the feasibility and efficacy of fibrinogen supplementation using FC will be compared to Cryo. The results of this pilot study will facilitate the design of a larger trial with sufficient power to address patient-centred outcomes. ClinicalTrials.gov, ID: NCT02745041 . Registered 4 May 2016.