Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

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<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. Conclusions Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .)

Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.

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

Traditional landmark versus ultrasound guided tracheal puncture during percutaneous dilatational tracheostomy in adult intensive care patients : a randomised controlled trial

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)10 page(s

Does asymmetry in patient recruitment in large critical care trials follow the Pareto principle?

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

The ADRENAL study protocol: ADjunctive corticosteroid tREatment iN criticAlly ilL patients with septic shock

There is considerable global uncertainty on the role of low-dose corticosteroids in septic shock, which translates into variations in prescribing practices.To describe the protocol for a large-scale multicentre randomised controlled trial in critically ill patients with septic shock, comparing the effects of hydrocortisone and placebo (in addition to standard treatment) on 90-day mortality and other outcomes such as shock reversal, duration of mechanical ventilation and quality of life.We will recruit 3800 critically ill patients with septic shock treated in an intensive care unit, to concealed, randomised, parallel assignment of hydrocortisone or placebo. The primary outcome will be all-cause mortality at 90 days postrandomisation. Secondary outcomes will include ICU and hospital mortality, length of ICU stay and quality of life at 6 months. Subgroup analyses will be conducted in two predefined subgroups. All analyses will be conducted on an intention-to-treat basis.The run-in phase has been completed and the main trial commenced in February 2013. The trial should generate results that will inform and influence prescribing of corticosteroids in septic shock

The Crystalloid versus Hydroxyethyl Starch Trial: Protocol for a multi-centre randomised controlled trial of fluid resuscitation with 6% hydroxyethyl starch (130/0.4) compared to 0.9% sodium chloride (saline) in intensive care patients on mortality

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

Конспект лекций. Введение в этнологию.

Participating investigator: Athanasios Flabouris for the University of AdelaideBACKGROUND: 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.govNCT00221013.Martin Gallagher, Alan Cass, Rinaldo Bellomo, Simon Finfer, David Gattas, Joanne Lee, Serigne Lo, Shay McGuinness, John Myburgh, Rachael Parke, Dorrilyn Rajbhandari, for the POSTRENAL Study Investigators and the ANZICS Clinical Trials Grou

Hydrocortisone Compared with Placebo in Patients with Septic Shock Satisfying the Sepsis-3 Diagnostic Criteria and APROCCHSS Study Inclusion Criteria A Post Hoc Analysis of the ADRENAL Trial

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