Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with hypoxic ischaemic encephalopathy (HIE) following a cardiac arrest who are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: To summarise the protocol and statistical analysis plan for the Mega-ROX HIE trial. Design setting and participants: Mega-ROX HIE is an international randomised clinical trial that will be conducted within an overarching 40,000-participant registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol approximately 4000 participants with suspected HIE following a cardiac arrest who are receiving invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX HIE will compare the effect of conservative vs. liberal oxygen therapy regimens on day-90 in-hospital mortality in adults in the ICU with suspected HIE following a cardiac arrest. The protocol and planned analyses are reported here to mitigate analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).

The Effects of Early-Phase, Low- or Standard-Intensity Continuous Renal Replacement Therapy on Acid-Base Control and Clinical Outcomes: An Observational Study.

INTRODUCTION: The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline recommends administering an effluent volume of 20-25 mL/kg/h during continuous renal replacement therapy (CRRT) for acute kidney injury. Recent evidence on CRRT initiation showed that less intervention might be beneficial for renal recovery. This study aimed to explore the association between early-phase low CRRT intensity and acid-base balance corrections and clinical outcomes. METHODS: This was a single-centre, retrospective, observational study at a tertiary intensive care unit (ICU) in Japan. All adult patients requiring CRRT in the ICU were included. Eligible patients were classified into the Low group (dialysate flow rate [QD] 10.0-19.9 mL/kg/h) and the Standard group (QD ≥20 mL/kg/h) by the intensity of CRRT at the beginning. The primary outcomes were acid-base parameters 6 h after CRRT initiation. We used an inverse probability of treatment weighting analysis to estimate the association between the intensity group and the outcomes. RESULTS: Overall, 194 patients were classified into the Low group (n = 144) and the Standard group (n = 50). The Standard group presented with more severe acid-base disturbances, including lower pH and base excess (BE) at baseline. At 6 h after CRRT initiation, pH, BE, and strong ion difference values were comparable, even after adjusting for baseline severity. Despite the efficient correction, no evident differences were observed in clinical outcomes between the two groups. CONCLUSIONS: The initial standard intensity appeared to be efficient in correcting acid-base imbalance at the early phase of CRRT; however, further studies are needed to assess the impact on clinical outcomes.

From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

Dose of nafamostat mesylate during continuous kidney replacement therapy in critically ill patients: a two-centre observational study.

BACKGROUND: Nafamostat mesylate is an anticoagulant used for critically ill patients during continuous kidney replacement therapy (CKRT), characterised by its short half-life. However, its optimal dosage remains unclear. This study aimed to explore the optimal dosage of nafamostat mesylate during CKRT. METHODS: We conducted a two-centre observational study. We screened all critically ill adult patients who required CKRT in the intensive care unit (ICU) from September 2013 to August 2021; we included patients aged ≥ 18 years who received nafamostat mesylate during CKRT. The primary outcome was filter life, defined as the time from CKRT initiation to the end of the first filter use due to filter clotting. The secondary outcomes included safety and other clinical outcomes. The survival analysis of filter patency by the nafamostat mesylate dosage adjusted for bleeding risk and haemofiltration was performed using a Cox proportional hazards model. RESULTS: We included 269 patients. The mean dose of nafamostat mesylate was 15.8 mg/hr (Standard deviation (SD), 8.8; range, 5.0 to 30.0), and the median filter life was 18.3 h (Interquartile range (IQR), 9.28 to 36.7). The filter survival analysis showed no significant association between the filter life and nafamostat mesylate dosage (hazard ratio 1.12; 95 CI 0.74-1.69, p = 0.60) after adjustment for bleeding risk and addition of haemofiltration to haemodialysis. CONCLUSIONS: We observed no dose-response relationship between the dose of nafamostat mesylate (range: 5 to 30 mg/h) and the filter life during CKRT in critically ill patients. The optimal dose to prevent filter clotting safely needs further study in randomised controlled trials. TRIAL REGISTRATION: Not applicable.