Balasubramanian Venkatesh’s research while affiliated with Gold Coast University Hospital and other places

International clinical practice guidelines addressing corticosteroid treatment for patients hospitalised with non-viral community-acquired pneumonia (CAP) are inconsistent. We conducted a systematic review of randomized controlled trials (RCTs) evaluating the use of corticosteroids in hospitalised adult patients with suspected or probable CAP. We performed random effects pairwise, Bayesian, and dose–response meta-analyses using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed certainty of evidence using GRADE methodology. We identified 30 eligible RCTs, including a total of 7519 patients. The prednisone-equivalent doses ranged between 29 mg/day and 100 mg/day. Corticosteroids probably reduced short-term (28–30 days) mortality (RR 0.82 [95% CI 0.74–0.91]; moderate certainty) while the reduction in longer term (60–90 day) mortality is less certain (RR 0.89 [95% CI 0.76–1.03]; low certainty). Corticosteroids reduced the need for invasive mechanical ventilation (IMV) (RR 0.63 [95% CI 0.48–0.82]; high certainty) and may reduce duration of ICU stay (MD 1.53 days fewer [95% CI 0.31–2.75 days fewer]; low certainty), and hospital stay (MD 2.30 days fewer [95% CI 0.81–3.81 days fewer]; low certainty). Corticosteroids probably increased hyperglycaemia requiring intervention (RR 1.32 [95% CI 1.12–1.56]; moderate certainty) but probably have no effect on secondary infections (RR 0.97 [95% CI 0.85–1.11]; moderate certainty). Corticosteroids probably reduced short-term mortality and reduce the need for invasive mechanical ventilation in hospitalised patients with CAP. CRD42024521536.

Background Fever is associated with brain injury after cardiac arrest. It is unknown whether fever management with a feedback‐controlled device impacts patient‐centered outcomes in cardiac arrest patients. This trial aims to investigate fever management with or without a temperature control device after out‐of‐hospital cardiac arrest. Methods The TEMP‐CARE trial is part of the 2 × 2 × 2 factorial Sedation, TEmperature and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial, a randomized, international, multicenter, parallel‐group, investigator‐initiated, superiority trial that will evaluate sedation strategies, temperature management, and blood pressure targets simultaneously in nontraumatic/nonhemorrhagic out‐of‐hospital cardiac arrest patients following hospital admission. For the temperature management component of the trial described in this protocol, patients will be randomly allocated to fever management with or without a feedback‐controlled temperature control device. For those managed with a device, if temperature ≥37.8°C occurs within 72 h post‐randomization the device will be started targeting a temperature of ≤37.5°C. Standard fever treatment, as recommended by local guidelines, including pharmacological agents, will be provided to participants in both groups. The two other components of the STEPCARE trial evaluate sedation and blood pressure strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. A physician blinded to the intervention will determine the neurological prognosis following European Resuscitation Council and European Society of Intensive Care Medicine guidelines. The primary outcome is all‐cause mortality at six months post‐randomization. To detect a 5.6% absolute risk reduction (90% power, alpha .05), 3500 participants will be enrolled. Secondary outcomes include poor functional outcome at six months, intensive care‐related serious adverse events, and overall health status at six months. Conclusion The TEMP‐CARE trial will investigate if post‐cardiac arrest management of fever with or without a temperature control device affects patient‐important outcomes after cardiac arrest.

Background Basic management for patients who have suffered a cardiac arrest and are admitted to an intensive care unit (ICU) after resuscitation includes setting targets for blood pressure and managing sedation and temperature. However, optimal targets and management are unknown. Methods The STEPCARE (Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation) trial is a multicenter, parallel‐group, randomized, factorial, superiority trial in which sedation, temperature, and blood pressure strategies will be studied in three separate comparisons (SED‐CARE, TEMP‐CARE, and MAP‐CARE). The trial population will be adults admitted to intensive care who are comatose after resuscitation from out‐of‐hospital cardiac arrest. The primary outcome will be all‐cause mortality, and the secondary outcomes will be poor functional outcome (modified Rankin Scale 4–6), Health‐Related Quality of Life using EQ‐VAS, and specific serious adverse events in the intensive care unit predefined for each trial. All outcomes will be assessed at 6 months after randomization. The prognosticators, outcome assessors, statisticians, data managers, steering group, and manuscript writers will be blinded to treatment allocation. This statistical analysis plan includes a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Analyses will be conducted according to the intention‐to‐treat principle, that is, all randomized participants with available data will be included. The analyses will be performed independently by two statisticians following the present plan. Conclusion This statistical analysis plan describes the statistical analyses for the STEPCARE trial in detail. The aim of this predefined statistical analysis plan is to minimize the risk of analysis bias.

Background Sedation is often provided to resuscitated out‐of‐hospital cardiac arrest (OHCA) patients to tolerate post‐cardiac arrest care, including temperature management. However, the evidence of benefit or harm from routinely administered deep sedation after cardiac arrest is limited. The aim of this trial is to investigate the effects of continuous deep sedation compared to minimal sedation on patient‐important outcomes in resuscitated OHCA patients in a large clinical trial. Methods The SED‐CARE trial is part of the 2 × 2 × 2 factorial Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) trial, a randomized international, multicentre, parallel‐group, investigator‐initiated, superiority trial with three simultaneous intervention arms. In the SED‐CARE trial, adults with sustained return of spontaneous circulation (ROSC) who are comatose following resuscitation from OHCA will be randomized within 4 hours to continuous deep sedation (Richmond agitation and sedation scale (RASS) −4/−5) ( intervention ) or minimal sedation (RASS 0 to −2) ( comparator ), for 36 h after ROSC. The primary outcome will be all‐cause mortality at 6 months after randomization. The two other components of the STEPCARE trial evaluate sedation and temperature control strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. Neurological prognostication will be performed according to European Resuscitation Council and European Society of Intensive Care Medicine guidelines by a physician blinded to the allocation group. To detect an absolute risk reduction of 5.6% with an alpha of 0.05, 90% power, 3500 participants will be enrolled. The secondary outcomes will be the proportion of participants with poor functional outcomes 6 months after randomization, serious adverse events in the intensive care unit, and patient‐reported overall health status 6 months after randomization. Conclusion The SED‐CARE trial will investigate if continuous deep sedation (RASS −4/−5) for 36 h confers a mortality benefit compared to minimal sedation (RASS 0 to −2) after cardiac arrest.

Background The optimal choice of fluid therapy for patients with diabetic ketoacidosis (DKA) is uncertain, though preliminary data suggest that buffered crystalloid solutions (Plasma-Lyte® 148) may offer some advantages over 0.9% saline. Objective To describe the study protocol for the ‘Balanced Electrolyte Solution versus Saline Trial for Diabetic Ketoacidosis’ (BEST-DKA) trial. Design, setting and participants BEST-DKA is a Phase 3 cluster-crossover, blinded, pragmatic, randomised, controlled trial comparing the effects of saline or buffered crystalloid solution in patients with moderate to severe DKA treated in the emergency department and/or intensive care unit at twenty hospitals in Australia. Each hospital will be randomised to use either saline or buffered crystalloid solution for a period of 12 months before crossing over to the alternate fluid for the next 12 months. The blinded study fluid will be used for all resuscitation and maintenance purposes for included patients. Main outcome measures This cluster-randomised, crossover randomised controlled trial (RCT) has been designed with the aim of enrolling a minimum of 400 patients, which will provide >91.4% power to detect a 2-day increase in the primary outcome, days alive and out of hospital to day 28, chosen with consumer representation. Secondary outcomes include quality of life and fatigue scores at day 28, intensive care unit and hospital lengths of stay, acute kidney injury, and time to resolution of DKA. All analyses will be conducted on an intention-to-treat basis. A prespecified statistical analysis plan will be developed prior to interim analysis. Results and conclusion The BEST-DKA trial commenced enrolment in March 2024 and should generate results that will determine whether treatment with Plasma-Lyte® 148, compared with saline, results in increased days alive, and out of hospital to day 28 for patients with moderate or severe DKA.

To determine whether there is an interaction between baseline serum chloride concentration and pH and treatment effects in Intensive Care Unit (ICU) patients receiving intravenous fluid therapy with balanced solution versus 0.9% sodium chloride (saline). A secondary analysis of a randomized controlled trial in which patients were divided into cohorts according to quartiles of baseline serum chloride concentration and pH. The primary outcome was day-90 mortality. From 4846 patients with outcome data available, 4823 with relevant baseline data were included in this analysis, with 1347, 1333, 993 and 1150 patients in the chloride quartiles of < 102, 102–106, 107–109 and > 109 mmol/L, respectively. Data were also analysed in pH quartiles of ≤ 7.27, 7.27–7.34, 7.34–7.39 and > 7.39. The risk-adjusted odds ratio (95% confidence interval [CI]) for day-90 mortality for patients assigned balanced solution compared to saline was 1.23 (0.95–1.58), 0.95 (0.73–1.25), 0.88 (0.64–1.21), and 0.76 (0.57–1.01) for lowest to highest chloride subgroups, respectively (P value for interaction = 0.10), and 0.89 (95% CI 0.69–1.15), 0.94 (0.70–1.27), 0.96 (0.67–1.38) and 1.15 (0.82–1.60) for pH quartiles from lowest to highest, respectively (P value for interaction = 0.63). There were no significant differences in the treatment effect of balanced solutions compared to saline according to baseline serum chloride concentration or pH.

Objectives Randomized clinical trials informing clinical practice (e.g., like large, pragmatic, and late-phase trials) should ideally mostly use harmonized outcomes that are important to patients, family members, clinicians, and researchers. Core outcome sets for specific subsets of ICU patients exist, for example, respiratory failure, delirium, and COVID-19, but not for ICU patients in general. Accordingly, we aimed to develop a core outcome set for adult general ICU patients. Design We developed a core outcome set in Denmark following the Core Outcome Measures in Effectiveness Trials Handbook. We used a modified Delphi consensus process with multiple methods design, including literature review, survey, semi-structured interviews, and discussions with initially five Danish research panels. The core outcome set was internationally validated and revised based on feedback from research panels in all countries. Setting There were five Danish research panels and 17 panels in 13 other countries. Interviews and the three-round Delphi survey was conducted in Denmark, followed by validation of the core outcome set across 14 countries in Europe, Australasia, and India. Subjects Adult ICU survivors, family members, clinicians, and researchers. Interventions None. Measurements and Main Results We identified 329 published outcomes, of which 50 were included in the 264 participant Delphi survey. In semi-structured interviews of 82, no additional outcomes were added. The first Delphi survey round was completed by 249 (94%) participants, and 202 (82%) contributed to the third and final round. The initial core outcome set comprised six outcomes. International validation involved 217 research panel members and resulted in the final core outcome set comprising survival, free of life support, free of delirium, out of hospital, health-related quality of life, and cognitive function. Conclusions We developed and internationally validated a core outcome set with six core outcomes to be used in research, specifically clinical trials involving adult general ICU patients.

Objectives Pediatric sepsis results in significant morbidity and mortality worldwide. There is an urgent need to investigate adjunctive therapies that can be administered early. We hypothesize that using vitamin C combined with hydrocortisone increases survival free of inotropes/vasopressors support until day 7 compared with standard care. Here we describe the Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) trial protocol, which aims to address this hypothesis. Design Randomized, open label, controlled, parallel-group, three-arm trial with integrated economic evaluation. Setting Nine Australia and New Zealand PICUs, with interest from additional international sites. Patients Children between 7 days and younger than 18 years old who are treated for suspected or confirmed sepsis and receiving inotropes/vasopressors for greater than 1 hour. Interventions IV vitamin C (100 mg/kg [maximum 5 g] every 6 hr) and hydrocortisone (1 mg/kg [maximum 50 mg] every 6 hr), or IV hydrocortisone alone (1 mg/kg [maximum 50 mg] every 6 hr) or standard care. Measurements and Main Results Three hundred eighty-four children will be randomly assigned to receive the interventions, or standard care in a 1:1:1 ratio with stratification by steroid administration pre-randomization and hospital site. The primary outcome is time alive and free of inotropes/vasopressors, censored at 7 days. Secondary outcomes include 28-day mortality, survival free of organ support, PICU length of stay, quality of life, functional status and neurodevelopmental vulnerability at 6 months post-enrollment, and hospitalization-related costs. Statistical analysis will be based on an intention-to-treat principle. The study has ethical approval (HREC/20/QCHQ/69922, dated December 21, 2020), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12621000247875), commenced recruitment on December 8, 2021, and is expected to finish recruitment by mid-2026. Conclusions Dissemination of the results will occur through publication in peer-reviewed journals, presentations at international conferences, and additional consumer-informed pathways.

Background: Reported results of clinical trials assessing higher-dose anticoagulation in patients hospitalized for COVID-19 have been inconsistent. Purpose: To estimate the association of higher- versus lower-dose anticoagulation with clinical outcomes. Data sources: Randomized trials were identified from the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov with no restriction by trial status or language. Study selection: Eligible randomized trials assigned patients hospitalized for COVID-19 to higher- versus lower-dose anticoagulation. Data extraction: 20 eligible trials provided data in a prospectively agreed format. Two further studies were included based on published data. The primary outcome was all-cause mortality 28 days after randomization. Secondary outcomes were progression to invasive mechanical ventilation or death, thromboembolic events, and major bleeding. Data synthesis: Therapeutic- compared with prophylactic-dose anticoagulation with heparins reduced 28-day mortality (OR, 0.77 [95% CI, 0.64 to 0.93]; I 2 = 29%; 11 trials, 6297 patients, of whom 5456 required low or no oxygen at randomization). The ORs for 28-day mortality were 1.21 (CI, 0.93 to 1.58; I 2 = 0%) for therapeutic-dose compared with intermediate-dose anticoagulation (6 trials, 1803 patients, 843 receiving noninvasive ventilation at randomization) and 0.95 (CI, 0.76 to 1.19; I 2 = 0%; 10 trials, 3897 patients, 2935 receiving no or low oxygen at randomization) for intermediate- versus prophylactic-dose anticoagulation. Treatment effects appeared broadly consistent across predefined patient subgroups, although some analyses were limited in power. Higher- compared with lower-dose anticoagulation was associated with fewer thromboembolic events, but a greater risk for major bleeding. Conclusion: Therapeutic-dose compared with prophylactic-dose anticoagulation reduced 28-day mortality. Mortality was similar for intermediate-dose compared with prophylactic-dose anticoagulation and higher for therapeutic-dose compared with intermediate-dose anticoagulation, although this comparison was not estimated precisely. Primary funding source: No direct funding. (PROSPERO: CRD42020213461).