Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.

PURPOSE: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. METHODS: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. RESULTS: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. CONCLUSIONS: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.

Protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial.

BACKGROUND: Body temperature can be reduced in febrile patients in the intensive care unit using medicines and physical cooling devices, but it is not known whether systematically preventing and treating fever reduces body temperature compared with standard care. OBJECTIVE: To describe the study protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial. DESIGN, SETTING AND PARTICIPANTS: Protocol for a phase II, multicentre trial to be conducted in Australian and New Zealand ICUs admitting adult patients. We will recruit 184 adults without acute brain injury who are expected to be ventilated in the ICU beyond the day after randomisation. We will use open, random, parallel assignment to systematic prevention and treatment of fever, or to standard temperature management. MAIN OUTCOME MEASURES: The primary end point will be mean body temperature, calculated from body temperatures measured 6-hourly for 7 days (168 hours) or until ICU discharge, whichever is sooner. Secondary end points are ICU-free days, in-hospital and cause-specific mortality (censored at Day 90) and survival time to Day 90 (censored at hospital discharge). RESULTS AND CONCLUSIONS: The trial will determine whether active temperature control reduces body temperature compared with standard care. It is primarily being conducted to establish whether a phase III trial with a patient-centred end point of Day 90 mortality is justified and feasible.

Overview of the study protocols and statistical analysis plan for the Saline versus Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program.

BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world but recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline might increase the risk of developing acute kidney injury. OBJECTIVE: To provide an overview of the study protocols and statistical analysis plan for the six studies making up the (0.9% Saline v Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program. METHODS: The SPLIT study consists of six integrated clinical trials, including a double-blind, cluster, randomised, double-crossover study in intensive care unit patients, incorporating two nested studies within it; an open-label, before-and-after study in emergency department (ED) patients; a single-centre, double-blind, crossover trial in major surgical patients; and a randomised, double-blind study in ICU patients. All studies focus on biochemical and renal outcomes but will also provide preliminary data on patient-centred outcomes including inhospital mortality and requirements for dialysis. RESULTS AND CONCLUSION: The SPLIT study program will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma-Lyte 148 for IV fluid therapy in ED, surgical and ICU patients.

A protocol for the 0.9% saline versus Plasma-Lyte 148 for intensive care fluid therapy (SPLIT) study.

BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world. However, recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline to intensive care unit patients might increase their risk of acute kidney injury (AKI). OBJECTIVE: To describe the protocol for the 0.9% Saline v Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) study. METHODS: This is a multicentre, cluster-randomised, double crossover feasibility study to be conducted in four New Zealand tertiary ICUs over a 28-week period and will enroll about 2300 participants. All ICU patients who need crystalloid IV fluid therapy (except those with established renal failure needing dialysis and those admitted to the ICU for palliative care) will be enrolled. Participating ICUs will be randomly assigned to 0.9% saline or Plasma-Lyte 148 as the routine crystalloid IV fluid, in a blinded fashion, in four alternating 7-week blocks. MAIN OUTCOME MEASURES: The primary outcome will be the proportion of patients who develop AKI in the ICU. Secondary outcomes will include the difference between the most recent serum creatinine level measured before study enrollment and the peak serum creatinine level in the ICU; use of renal replacement therapy; and ICU and in hospital mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSION: The SPLIT study started on 1 April 2014 and will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma- Lyte 148 as the routine IV fluid therapy in ICU patients.

Statistical analysis plan for the HEAT trial: a multicentre randomised placebo-controlled trial of intravenous paracetamol in intensive care unit patients with fever and infection.

BACKGROUND AND OBJECTIVE: We describe the statistical analysis plan (SAP) for the Permissive Hyperthermia through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (HEAT) trial, a 700-patient, prospective, randomised, Phase 2b, multicentre, double-blind, parallel-groups, placebo-controlled trial of paracetamol administration for the treatment of fever in critically ill patients with known or suspected infection. METHODS: The data fields described are those outlined in the study protocol published previously. We describe the plan for the presentation and comparison of baseline characteristics, process measures and outcomes. We describe baseline characteristics, and define and categorise trial outcomes according to their assigned importance. RESULTS AND CONCLUSIONS: We developed an SAP for the HEAT trial, and produced a mock Consolidated Standards of Reporting Trials diagram and tables. Our prespecified SAP accords with high-quality standards of internal validity and should minimise future analysis bias.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

The HEAT trial: a protocol for a multicentre randomised placebo-controlled trial of IV paracetamol in ICU patients with fever and infection.

BACKGROUND AND OBJECTIVE: Paracetamol is commonly administered to febrile critically ill patients with infection. However, there is limited information on the efficacy and safety of using paracetamol in this setting. We describe the study protocol for a Phase IIb multicentre randomised controlled trial (the Permissive Hyperthermia Through Avoidance of Paracetamol in Known or Suspected Infection in ICU [HEAT] trial) comparing intravenous paracetamol to placebo in the treatment of fever in critically ill adults with known or suspected infection. DESIGN AND SETTING: A pilot study followed by the main trial from November 2012. 700 patients will be recruited for concealed, random, parallel assignment of either 1 g of intravenous paracetamol or placebo (100mL of 5% dextrose) 6-hourly to treat fever while they remain on antimicrobial therapy in the intensive care unit. The primary end point will be ICU support-free survival at 28 days after randomisation. Secondary end points will include peak daily and mean daily body temperatures, prevalence of liver dysfunction requiring cessation of study treatment, degree of renal injury (based on delta creatinine), other organ failures, and Day 28 and Day 90 mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The HEAT trial should generate results that will inform and influence the prescribing of paracetamol. It will also determine if a large-scale Phase III trial of paracetamol is required in this patient group and whether such a trial is feasible. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12612000513819).

Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function.

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.