Search

Objective The aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. Design This is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. Setting The study was conducted in New Zealand. Participants and intervention Patients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. Main outcome measures Healthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. Results Of 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. Conclusions In New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.

BACKGROUND: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis. OBJECTIVE: To describe a statistical analysis plan for the BLING III study. METHODS: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. RESULTS AND CONCLUSIONS: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. TRIAL REGISTRATION: ClinicalTrials.gov Registry NCT03212990.

To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57–25.47 vs. HR 0.64, 95%CI 0.13–3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28–1.09 vs. HR 1.32 95%CI 0.67–2.60, p for interaction 0.01). In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogene...

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Two recent randomized controlled trials (Adjunctive Glucocorticoid Therapy in Patients with Septic Shock [ADRENAL] and Activated Protein C and Corticosteroids for Human Septic Shock [APROCCHSS]) of corticosteroids in patients with septic shock reported different treatment effects on 90-day mortality. Both trials enrolled patients who met the criteria for septic shock using the second international consensus definitions for sepsis and septic shock (Sepsis-2), but the APROCCHSS trial mandated a greater severity of shock as an inclusion criterion. Methods The authors conducted post hoc sensitivity analyses of the ADRENAL trial to determine the effects of hydrocortisone versus placebo in subgroups selected using third international consensus definitions for sepsis and septic shock (Sepsis-3) diagnostic criteria or APROCCHSS inclusion criteria. Results There were 1,950 subjects (973 hydrocortisone and 977 placebo) who met the Sepsis-3 criteria (ADRENAL–Sepsis-3 cohort) and 905 patients (455 hydrocortisone and 450 placebo) who met the APROCCHSS criteria (ADRENAL–APROCCHSS cohort). At 90 days after randomization, in the ADRENAL–Sepsis-3 cohort, 312 of 963 (32.4%) and 337 of 958 (35.2%) patients assigned to hydrocortisone and placebo, respectively, had died (odds ratio, 0.86; 95% CI, 0.70 to 1.06; P = 0.166). The corresponding figures for the ADRENAL–APROCCHSS cohorts were 187 of 453 (41.3%) and 200 of 445 (44.9%), respectively (odds ratio, 0.84; 95% CI, 0.60 to 1.17; P = 0.303). There was no statistically significant difference in the time to death between the groups during the 90 days after randomization (hazard ratio = 0.87; 95% CI, 0.75 to 1.02; P = 0.082 for ADRENAL–Sepsis-3; and hazard ratio = 0.86; 95% CI, 0.71 to 1.06; P = 0.156 for ADRENAL–APROCCHSS cohorts). In both cohorts, patients assigned to hydrocortisone had faster resolution of shock. In the ADRENAL–Sepsis-3 cohort, patients assigned to hydrocortisone had an increase in the number of days alive and free of mechanical ventilation (57.0 ± 37.2 vs. 53.7 ± 38.2 days; 95% CI, 0.40 to 7.04; P = 0.028) and the number of days alive and free of the intensive care unit (54.3 ± 36.0 vs. 51.0 ± 37.1; 95% CI, 0.82 to 7.24; P = 0.014). Conclusions In a post hoc analysis of the ADRENAL trial participants who fulfilled either the Sepsis-3 or the APROCCHSS inclusion criteria, a continuous infusion of hydrocortisone did not result in a lower 90-day mortality than placebo in septic shock.

Objectives To evaluate the effect of the combination of hydroxychloroquine (HCQ) and standard personal protective equipment (PPE) compared to the use of standard personal protective equipment alone on the proportion of laboratory confirmed COVID-19 infections among frontline healthcare workers(HCWs) in India Trial design HOPE is an investigator initiated multi-centre open-label parallel group randomized controlled trial. Participants All HCWs currently working in an environment with direct exposure to patients with confirmed COVID-19 infection are eligible to participate in the trial. The trial aims to be conducted across 20-30 centres (public and private hospitals) in India. HCWs who decline consent, who have a confirmed COVID-19 infection, those who are already on chloroquine/HCQ for any indication, or if pregnant or breast-feeding, or have known QT prolongation or are on medications that when taken with HCQ can prolong the QTc will be excluded. Intervention and comparator The interventions to be compared in this trial are standard practice (use of recommended PPE) and HCQ plus standard practice. In the standard practice arm, HCWs will use recommended PPE as per institutional guidelines and based on their roles. They will be discouraged from taking HCQ to prevent contamination and contacted every week for the duration of the study to ascertain if they have taken any HCQ. Any such use will be reported as a protocol violation. In the intervention arm, HCWs will be administered 800mg of HCQ as a loading dose on the day of randomization (as two 400mg doses 12hrs apart) and subsequently continued on 400mg once a week for 12 weeks. This will be in addition to the use of recommended PPE as per institutional guidelines and based on their roles. HCWs will collect the drug once every week from designated research and pharmacy staff at site. A weekly phone reminder will be provided to participants in this arm to ensure compliance. An ECG will be performed between 4-6 weeks in this arm and if the QTc is prolonged (greater than 450milliseconds), the drug will be stopped. Follow-up will however continue. Participants in both arms will receive a weekly phone call for evaluation of the primary outcome, to monitor protocol compliance and development of any adverse events (in the HCQ group). Main outcomes Participants will be followed on a weekly basis. The primary outcome is the proportion of HCWs developing laboratory confirmed COVID-19 infection within 6 months of randomization. We will also evaluate a number of secondary outcomes, including hospitalization related to suspected/confirmed COVID-19 infection, intensive care unit or high-dependency unit admission due to suspected/confirmed COVID-19 infection, all-cause mortality, need for organ support ( non-invasive or invasive ventilation, vasopressors and renal replacement therapy), ICU and hospital length of stay, readmission, days off work and treatment-related adverse events. Randomisation Randomisation will be conducted through a password-protected, secure website using a central, computer-based randomisation program. Randomisation will be stratified by participating institutions and by the role of HCW – nursing, medical and other. Participants will be randomised 1:1 to either standard practice only or HCQ plus standard practice. Allocation concealment is maintained by central web-based randomisation Blinding (masking) This is an unblinded study: study assigned treatment will be known to the research team and participant. Bias will be mitigated through an objective end point (laboratory confirmed COVID-19 infection). Numbers to be randomised (sample size) A total of 6,950 HCWs will be enrolled (3475 to the intervention) and (3475 to the standard practice group) to detect a 25% relative reduction, or 2.5% absolute reduction, in the infection rate from an estimated baseline infection rate of 10%, with 80% statistical power using a two-sided test at 5% level of significance. Available data from China and Italy indicate that the rate of infection among frontline healthcare workers varies between 4% to 12%. We therefore assumed a baseline infection rate of 10% among HCWs. This sample size allows for a potential loss to follow-up rate of 10% and a potential non-compliance rate of 10% in both the treatment and control arms. Trial Status HOPE protocol version 3.0 dated June 3rd 2020. Recruitment started on 29th June 2020 and currently 56 participants have been enrolled. Planned completion of enrolment is January 31st 2021. Trial registration Clinical Trials Registry of India: CTRI/2020/05/025067 (prospectively registered) Date of registration: 6th May 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expedited dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background: Healthcare workers (HCWs),particularly from lower-middle income countries (LMIC), are at high risk of acquiring COVID-19. Limited data exist on the effectiveness of hydroxychloroquine as prophylaxis. Our trial evaluated the effectiveness of a 12-week regimen of hydroxychloroquine among HCWs on the risk of laboratory-confirmed COVID-19 in the 6 months after randomization Methods: We conducted a multicentre parallel-group open-label randomized controlled trial in 9 centres across India. HCWs serving in an environment with exposure to COVID-19 were eligible and randomized in a 1:1 ratio to hydroxychloroquine plus standard practice or to standard practice alone (role-appropriate personal protective equipment). In the intervention arm, participants received 2 doses of 400mg hydroxychloroquine at randomization followed by a weekly dose for 12 weeks. The primary outcome was the proportion of laboratory-confirmed COVID-19 in the 6 months after randomization using an intention-to-treat analysis. The trial was registered on Clinical Trials Registry of India(CTRI/2020/05/025067). Findings: From 29th June 2020 to 4th February 2021, 886 participants were screened and 416 were randomized (203-standard practice and 213- hydroxychloroquine plus standard practice). In the 6 months after randomization (primary analysis population=413), 11 participants assigned to the hydroxychloroquine group and 12 participants assigned to the standard practice group met the primary end point[ 5.1% vs 5.9%; OR 0.85, [95% CI 0.35-2.06] p=0.71]. There was no heterogeneity of treatment effect on the primary outcome in any of the pre-specified subgroups. There were no significant differences in any of the secondary outcomes. The adverse event rates were 9.9% and 6.9% in the hydroxychloroquine and standard practice arms respectively. There were no serious adverse events in either group. Interpretation: Hydroxychloroquine along with standard practice was not superior to standard practice alone on the proportion of lab-confirmed COVID-19. However, conclusions are limited by the premature trial cessation. Trial Registration: Clinical Trials Registry of India (CTRI/2020/05/025067). Funding: Wesley Medical Research, Australia Declaration of Interest: OJ reports being a member of the WHO R&D Blueprint Safety Monitoring Team, ACT Acclerator-R&D Digital Health working group and COVID-19 Clinical Research Coalition data sharing working group. Remaining authors have nothing to declare. Ethical Approval: Written informed consent was obtained from all participants. The trial was approved by the Ethics Committee at all participating sites (coordinating centre EC approval number: The George Institute Ethics Committee:08-2020)

Background Randomised controlled trials (RCT) may be hindered by slow recruitment rates, particularly in critically ill patients. While statistical models to predict recruitment rates have been described, no systematic assessment has been conducted of the distribution of recruitment across sites, temporal trends in site participation and impact of competing trials on patient recruitment. Methods We used recruitment and screening logs from the SAFE, NICE-SUGAR, RENAL, CHEST and ADRENAL trials, five of the largest critical care RCTs. We quantified the extent of recruitment asymmetry between sites using Lorenz curves and Gini coefficients and assessed whether the recruitment distribution across sites follow the Pareto principle, which states that 80% of effects come from 20% of causes. Peak recruitment rates and growth in participating sites were calculated. Results In total, 25,412 patients were randomised in 99 intensive care units (ICUs) for the five trials. Distribution of recruitment was asymmetric, with a small number of ICUs recruiting a large proportion of the patients. The Gini coefficients ranged from 0.14 to 0.52. The time to peak recruitment rate ranged from 7 to 41 months and was variable (7, 31, 41, 10 and 40 months). Over time, the proportion of recruitment at non-tertiary ICUs increased from 15% to 34%. Conclusions There is asymmetry of recruitment with a small proportion of ICUs recruiting a large proportion of patients. The distributions of recruitment were not consistent with the Pareto principle. There has been increasing participation of non-tertiary ICUs in clinical trials.

To investigate the impact of hydrocortisone treatment and illness severity on health-related quality of life (HRQoL) at 6 months in septic shock survivors from the ADRENAL trial. Using the EuroQol questionnaire (EQ-5D-5L) at 6 months after randomization we assessed HRQoL in patient subgroups defined by hydrocortisone or placebo treatment, gender, illness severity (APACHE II

Background Whether hydrocortisone reduces mortality among patients with septic shock is unclear. Methods We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. Results From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P

Objectives To determine the association between intensive care unit (ICU) characteristics and clinicians’ decision to decline eligible patients for randomization into a multicentered pragmatic comparative-effectiveness controlled trial. Methods Screening logs from the Adjunctive Glucocorticoid Therapy in Septic Shock Trial (ADRENAL) and site-level data from the College of Intensive Care Medicine and Australia New Zealand Intensive Care Society were examined. The effects of ICU characteristics such as tertiary academic status, research coordinator availability, number of admissions, and ICU affiliations on clinicians declining to randomize eligible patients were calculated using mixed effects logistic regression modelling. Results There were 21,818 patients screened for inclusion in the ADRENAL trial at 69 sites across five countries, out of which 5,501 were eligible, 3,800 were randomized and 659 eligible patients were declined for randomization by the treating clinician. The proportion of eligible patients declined by clinicians at individual ICUs ranged from 0 to41%. In the multivariable model, none of the ICU characteristics were significantly associated with higher clinician decline rate. Conclusions Neither tertiary academic status, nor other site-level variables were significantly associated with increased rate of clinicians declining eligible patients.

BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.)

Background Whether hydrocortisone reduces mortality among patients with septic shock is unclear. Methods We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. Results From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P

Aims: The study aims to describe the use of dialysis catheters in critically ill patients treated with continuous renal replacement therapy (CRRT) and to study the impact of femoral versus non-femoral access on CRRT dose. Methods: Statistical analysis and predictive modelling of data from the Randomized Evaluation of Normal vs. Augmented Level renal replacement therapy trial. Results: The femoral vein was the first access site in 937 (67%) of 1,399 patients. These patients had higher Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores (p = 0.009) and lower pH (p < 0.001) but similar mortality to patients with non-femoral access (44 vs. 45%; p = 0.63). Lower body weight was independently associated with femoral access placement (OR 0.97, 95% CI 0.96-0.98). Femoral access was associated with a 1.03% lower CRRT dose (p = 0.05), but a 4.20% higher dose was achieved with 13.5 Fr catheters (p = 0.03). Conclusions: Femoral access was preferred in lighter and sicker patients. Catheter gauge had greater impact than catheter site in CRRT dose delivery. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=439581.

Background Platelet transfusions are commonly used to treat critically ill patients with thrombocytopenia. Whether platelet transfusions are associated with a reduction in the risk of major bleeding is unknown. Patients/Methods Observational cohort study nested in a previous multicenter, randomized thromboprophylaxis trial in the intensive care unit (ICU). The objective was to evaluate the association between platelet transfusions and adjudicated major bleeding events. Platelet transfusion episodes were reviewed for timing of administration, product type, and dose. Major bleeding with and without platelet transfusions was adjusted for severity of thrombocytopenia, use of anti‐platelet agents, surgery and other covariates. Secondary outcomes were thrombosis, death in ICU and platelet count increment. Results Among 2,256 patients, 71 (3.1%) received 190 platelet transfusions. Of those, 121 (63.7%) were administered to 54 non‐bleeding, thrombocytopenic patients. Adjusted rates of major bleeding were not statistically different with or without the administration of platelet transfusions (hazard ratio for transfused patients 0.85; 95% confidence interval, 0.42‐1.72). We did not find a significant association between platelet transfusion use and thrombosis or death in ICU in adjusted analyses. Thrombocytopenia, anemia, major or minor bleeding and use of anticoagulants were associated with platelet transfusion administration. The median post‐transfusion platelet count increment was 20×109/L at 3.5 hours post‐transfusion. Conclusions Rates of major bleeding were not different for patients who did and did not receive platelet transfusions. Inferences were limited by the small number of transfused patients. Clinical trials are needed to better investigate the potential hemostatic benefit and potential harms of platelet transfusions for this high‐risk population.

Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials.The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143).Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily.The trial was conducted in 67 centers in 6 countries.A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P.001 for those with10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs,0.5; P.001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P.001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P.001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P.001).Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial.

The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P0.001).In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

OBJECTIVE To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy. DESIGN Post hoc analysis of data from a multicenter, randomized, controlled trial. SETTING Thirty-five ICUs in Australia and New Zealand. PATIENTS Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study. INTERVENTIONS Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes. MEASUREMENTS AND MAIN RESULTS Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p < 0.001). Mean daily hemoglobin was 88 ± 7 and 99 ± 12 g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316 ± 261 mL of RBC, whereas nonsurvivors received 302 ± 362 mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital. CONCLUSIONS In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials.

Objectives:To determine whether tryptophan metabolism to kynurenine contributes to the direct regulation of vascular tone in human septic shock.Background:Indoleamine 2,3-dioxygenase 1 is an inducible enzyme that converts tryptophan to kynurenine and shares functional similarities with inducible nit

The intravenous fluid 6% hydroxyethyl starch (130/0.4) (6% HES 130/0.4) is used widely for resuscitation but there is limited information on its efficacy and safety. A large-scale multi-centre randomised controlled trial (CHEST) in critically ill patients is currently underway comparing fluid resuscitation with 6% HES 130/0.4 to 0.9% sodium chloride on 90-day mortality and other clinically relevant outcomes including renal injury. This report describes the study protocol.CHEST will recruit 7,000 patients to concealed, random, parallel assignment of either 6% HES 130/0.4 or 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU). The primary outcome will be all-cause mortality at 90 days post-randomisation. Secondary outcomes will include incident renal injury, other organ failures, ICU and hospital mortality, length of ICU stay, quality of life at 6 months, health economic analyses and in patients with traumatic brain injury, functional outcome. Subgroup analyses will be conducted in four predefined subgroups. All analyses will be conducted on an intention-to-treat basis.The study run-in phase has been completed and the main trial commenced in April 2010. CHEST should generate results that will inform and influence prescribing of this commonly used resuscitation fluid.

To determine the effect of random assignment to fluid resuscitation with albumin or saline on organ function and mortality in patients with severe sepsis.Pre-defined subgroup analysis of a randomized controlled trial conducted in the intensive care units of 16 hospitals in Australia and New Zealand.Of 1,218 patients with severe sepsis at baseline, 603 and 615 were assigned to receive albumin and saline, respectively. The two groups had similar baseline characteristics. During the first 7 days mean arterial pressure was similar in the two groups, but patients assigned albumin had a lower heart rate on days 1 and 3 (p = 0.002 and p = 0.03, respectively) and a higher central venous pressure on days 1-3 (p0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment score of the two groups; 113/603 (18.7%) of patients assigned albumin were treated with renal replacement therapy compared to 112/615 (18.2%) assigned saline (p = 0.98). The unadjusted relative risk of death for albumin versus saline was 0.87 [95% confidence interval (CI) 0.74-1.02] for patients with severe sepsis and 1.05 (0.94-1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52-0.97; p = 0.03).Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death.

Recombinant factor VIIa (rFVIIa) is used in the treatment of life-threatening haemorrhage that is refractory to conventional treatment. The evidence supporting this practice in patients with liver disease is very limited. It has been used as a salvage therapy in end-stage liver disease (ESLD), in orthotopic liver transplant (OLT), other surgery, and upper gastrointestinal bleeding (UGIB) subpopulations. It has also been used prior to procedures in patients with ESLD. Data were collected by the Australia and New Zealand Haemostasis Registry (ANZHR) to perform a retrospective cohort study on the different subgroups of liver patients. This included 115 cases of use of rFVIIa in liver patients from 20 hospitals. A retrospective cohort study on the different subgroups of liver patients was performed. Main outcome measures were reduction or cessation of bleeding and 28-day mortality. Variables previously shown to predict response to bleeding after administration of rFVIIa were examined to determine whether correlations exist. Salvage therapy with rFVIIa was associated with reduction or cessation in bleeding in 24 of 36 OLT patients, 24 of 36 UGIB patients and 15 of 26 of other surgery patients. Clinical response to rFVIIa in OLT patients and other surgery patients was associated with a significantly lower mortality compared to nonresponders (P = 0.003 and 0.022, respectively). There was no relationship between mortality and bleeding response in patients with UGIB. Variables including acidosis, hypothermia, hypofibrinogenaemia, thrombocytopenia and Model of End-Stage Liver Disease (MELD) score were not associated with clinical response to rFVIIa. Five cases of use prior to procedures are described. Recombinant FVIIa is used as rescue therapy in surgical patients with ESLD and refractory haemorrhage in Australia and New Zealand. Traditional haemostasis variables were not associated with clinical response to rFVIIa in this cohort. Response to rFVIIa is associated with decreased mortality in ESLD patients undergoing OLT and other surgery, but not in UGIB.

Aims and objective. To examine the relationship between observed delirium in ICU and patients' recall of factual events up to two years after discharge. Background. People, the environment, and procedures are frequently cited memories of actual events encountered in ICU. These are often perceived as stressors to the patients and the presence of several such stressors has been associated with the development of reduced health-related quality of life or post-traumatic stress syndrome. Design. Prospective cohort study using interview technique. Method. The cohort was assembled from 152 patients who participated in a previously conducted multi-centre study of delirium incidence in Australian ICUs. The interviews involved a mixture of closed- and open-ended questions. Qualitative responses regarding factual memories were analysed using thematic analysis. A five-point Likert scale with answers from 'always' to 'never' was used to ask about current experiences of dream, anxiety, sleep problems, fears, irritability and/or mood swings. Scoring ranged from 6 to 30 with a mid-point value of 18 indicating a threshold value for the diagnosis of post-traumatic stress syndrome. A P-value of

To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine.Multicenter, parallel group randomized controlled trial.Seven ICUs in Australia and New Zealand.Critically ill adults requiring continuous renal replacement therapy.Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine.The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1-6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36-3.03]; p0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1-48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3-34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011).Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events.

Ville Pettilä on työryhmien ARISE Investigators ja ANZICS Clinical Trials Grp jäsen. BACKGROUND Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (+/- SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964 +/- 1415 ml vs. 1713 +/- 1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P CONCLUSIONS In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.)

Introduction Long-term ventilated intensive care patients frequently require tracheostomy. Although overall risks are low, serious immediate and late complications still arise. Real-time ultrasound guidance has been proposed to decrease complications and improve the accuracy of the tracheal puncture. We aimed to compare the procedural safety and efficacy of real-time ultrasound guidance with the traditional landmark approach during percutaneous dilatational tracheostomy (PDT). Methods A total of 50 patients undergoing PDT for clinical indications were randomly assigned, after obtaining informed consent, to have the tracheal puncture procedure carried out using either traditional anatomical landmarks or real-time ultrasound guidance. Puncture position was recorded via bronchoscopy. Blinded assessors determined in a standardised fashion the deviation of the puncture off midline and whether appropriate longitudinal position between the first and fourth tracheal rings was achieved. Procedural safety and efficacy data, including complications and number of puncture attempts required, were collected. Results In total, 47 data sets were evaluable. Real-time ultrasound guidance resulted in significantly more accurate tracheal puncture. Mean deviation from midline was 15 ± 3° versus 35 ± 5° (P = 0.001). The proportion of appropriate punctures, defined a priori as 0 ± 30° from midline, was significantly higher: 20 (87%) of 23 versus 12 (50%) of 24 (RR = 1.74; 95% CI = 1.13 to 2.67; P = 0.006). First-pass success rate was 20 (87%) of 23 in the ultrasound group and 14 (58%) of 24 in the landmark group (RR = 1.49; 95% CI = 1.03 to 2.17; P = 0.028). The observed decrease in procedural complications was not statistically significant: 5 (22%) of 23 in the ultrasound group versus 9 (37%) of 24 in the landmark group (RR = 0.58; 95% CI = 0.23 to 1.47; P = 0.24). Conclusions Ultrasound guidance significantly improved the rate of first-pass puncture and puncture accuracy. Fewer procedural complications were observed; however, this did not reach statistical significance. These results support wider general use of real-time ultrasound guidance as an additional tool to improve PDT. Trial registration Australian New Zealand Clinical Trials Registry ID: ACTRN12611000237987 (registered 4 March 2011) Electronic supplementary material The online version of this article (doi:10.1186/s13054-014-0514-0) contains supplementary material, which is available to authorized users.

Introduction Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes. Methods We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models. Results Overall, mean DCI during treatment in ICU was low at only 10.9 ± 9 Kcal/kg/day for non-survivors and 11 ± 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90-days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling. Conclusions In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes. Trial registration ClinicalTrials.gov number, NCT00221013

Clinical handover is an area of critical concern, because deficiencies in handover pose a patient safety risk. Redesign of handover must allow for input from frontline staff to ensure that designs fit into existing practices and settings. The HELiCS (Handover--Enabling Learning in Communication for Safety) tool uses a "video-reflexive" technique: handover encounters are videotaped and played back to the practitioners involved for analysis and discussion. Using the video-reflexive process, staff of an emergency department and an intensive care unit at two different tertiary hospitals redesigned their handover processes. The HELiCS study gave staff greater insight into previously unrecognised clinical and operational problems, enhanced coordination and efficiency of care, and strengthened junior-senior communication and teaching. Our study showed that reflexive and "bottom-up" handover redesign can produce outcomes that harbour local fit, practitioner ownership and (to date) sustainability.

Traditionally, intensive care unit (ICU) delirium was viewed as benign and was under-diagnosed in the absence of ICU-appropriate screening tools. Research suggests that up to half of all ICU patients experiencing delirium will continue to do so after discharge to the ward, and half of those experiencing delirium in the ward will die within 1 year of delirium diagnosis. ICU-specific screening tools are now available. The purpose of this study was to identify the incidence of delirium in ICU and explore its associations to clinical factors and outcomes. A secondary aim was to evaluate the usefulness of the intensive care delirium screening checklist (ICDSC). A total of 185 patients in six ICUs in Australia and New Zealand were screened for delirium using the ICDSC over two 12-hour periods per day for the duration of their ICU admission. Some 84 patients (45%) developed delirium. Development of delirium was associated with increased severity of illness (acute physiology and chronic health evaluation--APACHE II--and sequential organ failure assessment--SOFA), ICU length of stay (LOS), and use of psycho-active drugs. Delirious patients showed no statistically significant difference in ICU and hospital mortality rates, nor prolonged hospital LOS. The ICDSC was found to be user-friendly. The incidence of delirium, observed characteristics and outcomes for patients admitted to Australian and New Zealand ICUs for > 36 hours without any history of altered mental state fell in the mid-range and were generally consistent with previous literature. An ICU-specific delirium assessment, such as the ICDSC, should be included in routine ICU observations to minimise under-diagnosis of this serious phenomenon.

Martin Gallagher and colleagues examine the long-term outcomes of renal replacement therapy (RRT) dosing in patients with acute kidney injury randomized to normal vs. augmented RRT. Please see later in the article for the Editors' Summary, Background The incidence of acute kidney injury (AKI) is increasing globally and it is much more common than end-stage kidney disease. AKI is associated with high mortality and cost of hospitalisation. Studies of treatments to reduce this high mortality have used differing renal replacement therapy (RRT) modalities and have not shown improvement in the short term. The reported long-term outcomes of AKI are variable and the effect of differing RRT modalities upon them is not clear. We used the prolonged follow-up of a large clinical trial to prospectively examine the long-term outcomes and effect of RRT dosing in patients with AKI. Methods and Findings We extended the follow-up of participants in the Randomised Evaluation of Normal vs. Augmented Levels of RRT (RENAL) study from 90 days to 4 years after randomization. Primary and secondary outcomes were mortality and requirement for maintenance dialysis, respectively, assessed in 1,464 (97%) patients at a median of 43.9 months (interquartile range [IQR] 30.0–48.6 months) post randomization. A total of 468/743 (63%) and 444/721 (62%) patients died in the lower and higher intensity groups, respectively (risk ratio [RR] 1.04, 95% CI 0.96–1.12, p = 0.49). Amongst survivors to day 90, 21 of 411 (5.1%) and 23 of 399 (5.8%) in the respective groups were treated with maintenance dialysis (RR 1.12, 95% CI 0.63–2.00, p = 0.69). The prevalence of albuminuria among survivors was 40% and 44%, respectively (p = 0.48). Quality of life was not different between the two treatment groups. The generalizability of these findings to other populations with AKI requires further exploration. Conclusions Patients with AKI requiring RRT in intensive care have high long-term mortality but few require maintenance dialysis. Long-term survivors have a heavy burden of proteinuria. Increased intensity of RRT does not reduce mortality or subsequent treatment with dialysis. Trial registration www.ClinicalTrials.gov NCT00221013 Please see later in the article for the Editors' Summary, Editors' Summary Background Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease (caused, for example, by diabetes) gradually destroys the kidneys' filtration units (the nephrons), eventually leading to life-threatening end-stage kidney disease. However, the kidneys can also stop working suddenly because of injury, infection, or poisoning. Acute kidney injury (AKI) is much more common than end-stage kidney disease and its incidence is increasing worldwide. In the US, for example, the number of hospitalizations that included an AKI diagnosis rose from 4,000 in 1996 to 23,000 in 2008. Moreover, nearly half of patients with AKI will die shortly after the condition develops. Symptoms of AKI include changes in urination, swollen feet and ankles, and tiredness. Treatments for AKI aim to prevent fluid and waste build up in the body and treat the underlying cause (e.g., severe infection or dehydration) while allowing the kidneys time to recover. In some patients, it is sufficient to limit the fluid intake and to reduce waste build-up by eating a diet that is low in protein, salt, and potassium. Other patients need renal replacement therapy (RRT), life-supporting treatments such as hemodialysis and hemofiltration, two processes that clean the blood by filtering it outside the body. Why Was This Study Done? The long-term outcomes of AKI (specifically, death and chronic kidney disease) and the effects of different RRT modalities on these outcomes are unclear. A recent controlled trial that randomly assigned patients with AKI who were managed in intensive care units (ICUs) to receive two different intensities of continuous hemodiafiltration (a combination of hemodialysis and hemofiltration) found no difference in all-cause mortality (death) at 90 days. Here, the researchers extend the follow-up of this trial (the Randomized Evaluation of Normal vs. Augmented Levels of renal replacement therapy [RENAL] study) to investigate longer-term mortality, the variables that predict mortality, treatment with long-term dialysis (an indicator of chronic kidney disease), and functional outcomes in patients with AKI treated with different intensities of continuous RRT. What Did the Researchers Do and Find? For the Prolonged Outcomes Study of RENAL (POST-RENAL), the researchers extended the follow-up of the RENAL participants up to 4 years. Over an average follow-up of 43.9 months, 63% of patients in the lower intensity treatment group died compared to 62% of patients in the higher intensity group. Overall, a third of patients who survived to 90 days died during the extended follow-up. Among the survivors to day 90, 5.1% and 5.8% of patients in the lower and higher intensity groups, respectively, were treated with maintenance dialysis during the extended follow-up. Among survivors who consented to analysis, 40% and 44% of patients in the lower and higher intensity groups, respectively, had albuminuria (protein in the urine, an indicator of kidney damage). Patients in both groups had a similar quality life (determined through telephone interviews). Finally, increasing age, APACHE III score (a scoring system that predicts the survival of patients in ICU), and serum creatinine level (an indicator of kidney function) at randomization were all predictors of long-term mortality. What Do These Findings Mean? These findings indicate that patients with AKI in ICUs who require RRT have a high long-term mortality. They show that few survivors require maintenance dialysis for chronic kidney disease but that there is a substantial rate of albuminuria among survivors despite relative preservation of kidney function. The findings also suggest that the intensity of RRT has no significant effect on mortality or the need for dialysis. Because these findings were obtained in a randomized controlled trial, they may not be generalizable to other patient populations. Moreover, although data on mortality and maintenance dialysis were available for all the trial participants, clinical and biochemical outcomes were only available for some participants and may not be representative of all the participants. Despite these study limitations, these findings suggest that survivors of AKI may be at a high risk of death or of developing chronic kidney disease. Survivors of AKI are, therefore, at high risk of further illness and long-term albuminuria reduction strategies may offer a therapeutic intervention for this group of patients. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001601. The US National Kidney and Urologic Diseases Information Clearinghouse provides information about the kidneys and about all aspects of kidney disease and its treatment; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish) The Mayo Clinic provides information for patients about acute kidney injury Wikipedia has a page on acute kidney injury (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including a link to a video about acute kidney injury World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations (IFKF), aims to raise awareness about kidneys and kidney disease; its website provides information about acute kidney injury The MedlinePlus Encyclopedia has a pages about acute kidney failure and about renal dialysis The UK National Institute for Health and Care Excellence (NICE) recently published new guidelines on the treatment of acute kidney injury; a clinical practice guideline for acute kidney injury produced by KDIGO (a not-for-profit organization that aims to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines) is available; the Acute Kidney Injury app provides a fast and simple way to explore guidelines on the diagnosis, prevention, and management of AKI

The enzyme indoleamine 2,3-dioxygenase (IDO) convertsthe amino acid tryptophan (Trp) to kynurenine (Kyn).IDO, which shares many functional similarities withiNOS [1], is also induced in sepsis [2]. Here, we investi-gated whether IDO plays a role in human septic shock andmouse endotoxemia akin to iNOS.

Contemporary clinical work involves the collaboration of different health care practitioners to provide safe, effective, and high quality services. Yet practitioner collaboration is often fraught with political, professional and ideological divergences. For these reasons opportunities for health care practitioners to come together and develop a shared meaning of practice is often constrained by organizational and professional agendas. The methodology reported on here has allowed health care practitioners to critically engage with their own practice, and the practice of their colleagues, in a way that enables them to negotiate and mitigate their differences and divergent opinions and practices. Through the use of video reflexive methods health care practitioners were able to articulate systematizing or 'meta discursive' solutions to address previously taken-as-given organizational and clinical (handover) practices.

Introduction During the first winter of exposure, the H1N1 2009 influenza virus placed considerable strain on intensive care unit (ICU) services in Australia and New Zealand (ANZ). We assessed the impact of the H1N1 2009 influenza virus on ICU services during the second (2010) winter, following the implementation of vaccination. Methods A prospective, cohort study was conducted in all ANZ ICUs during the southern hemisphere winter of 2010. Data on demographic and clinical characteristics, including vaccination status and outcomes, were collected. The characteristics of patients admitted during the 2010 and 2009 seasons were compared. Results From 1 June to 15 October 2010, there were 315 patients with confirmed influenza A, of whom 283 patients (90%) had H1N1 2009 (10.6 cases per million inhabitants; 95% confidence interval (CI), 9.4 to 11.9) which was an observed incidence of 33% of that in 2009 (P < 0.001). The maximum daily ICU occupancy was 2.4 beds (95% CI, 1.8 to 3) per million inhabitants in 2010 compared with 7.5 (95% CI, 6.5 to 8.6) in 2009, (P < 0.001). The onset of the epidemic in 2010 was delayed by five weeks compared with 2009. The clinical characteristics were similar in 2010 and 2009 with no difference in the age distribution, proportion of patients treated with mechanical ventilation, duration of ICU admission, or hospital mortality. Unlike 2009 the incidence of critical illness was significantly greater in New Zealand (18.8 cases per million inhabitants compared with 9 in Australia, P < 0.001). Of 170 patients with known vaccination status, 26 (15.3%) had been vaccinated against H1N1 2009. Conclusions During the 2010 ANZ winter, the impact of H1N1 2009 on ICU services was still appreciable in Australia and substantial in New Zealand. Vaccination failure occurred.