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Importance: Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown., Objective: To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis., Design, Setting, and Participants: Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital., Interventions: Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs)., Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay., Results: Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group., Conclusions and Relevance: Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication., Trial Registration: anzctr.org.au Identifier: ACTRN12616000481471.

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.

Background: The balance of risks and benefits with using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H 2 RB) for stress ulcer prophylaxis in patients who are invasively ventilated in the intensive care unit (ICU) is uncertain., Objective: To describe the study protocol and statistical analysis plan for the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) study., Design, Setting and Participants: Protocol for a prospective, multicentre, randomised, open-label, cluster crossover, registry-embedded trial to be conducted in 50 ICUs in Australia, Canada, Ireland, New Zealand and the United Kingdom. The PEPTIC study will compare two approaches to stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU. One approach is to use PPIs as the default therapy and the other approach is to use H2RBs as the default therapy when stress ulcer prophylaxis is prescribed. Each ICU, by random allocation, will use one approach for 6 months and will then switch to the opposite approach for the next 6 months. The PEPTIC study began recruitment in August 2016 and will complete recruitment in January 2019., Main Outcome Measures: The primary end point will be in-hospital mortality. Secondary outcomes include clinically significant upper gastrointestinal bleeding, Clostridium difficile infection, ICU length of stay and hospital length of stay., Results and Conclusions: The PEPTIC study will compare the effect on in-hospital mortality of implementing, at the level of the ICU, the use of PPI as the preferred agent for stress ulcer prophylaxis in mechanically ventilated adults in the ICU with using H 2 RB as the preferred agent., Trial Registration: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000481471).

Background: The balance of risks and benefits of conservative v standard care oxygen strategies for patients who are invasively ventilated in the intensive care unit (ICU) is uncertain., Objective: To describe the study protocol and statistical analysis plan for the ICU randomised trial comparing two approaches to oxygen therapy (ICU-ROX)., Design, Setting and Participants: Protocol for a multicentre, randomised, participant and outcome assessor-blinded, standard care-controlled, parallel-group, two-sided superiority trial to be conducted in up to 22 ICUs in Australia and New Zealand. 1000 adults who are mechanically ventilated in the ICU and expected to remain ventilated beyond the day after recruitment will be randomly assigned to conservative oxygen therapy or standard care in a 1:1 ratio. ICU-ROX began with an internal pilot phase in September 2015. It is anticipated that recruitment will be completed in 2018., Main Outcome Measures: The primary endpoint will be alive, ventilator-free days to Day 28. Secondary outcomes include 90- and 180-day all-cause mortality, survival time to 180 days, and quality of life and cognitive function at 180 days. All analyses will be conducted on an intentionto- treat basis., Results and Conclusions: ICU-ROX will compare the effect of conservative v standard oxygen therapy in critically ill mechanically ventilated adults who are expected to be ventilated beyond the day after recruitment on ventilatorfree days to Day 28., Trial Registration: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12615000957594).

Objective: The objective of the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX) pilot phase, which included the first 100 patients of an overall sample of 1000, was to examine feasibility., Design: Investigator-initiated, prospective, parallel-group, pilot randomised controlled trial., Setting: Six medical-surgical intensive care units (ICUs) in Australia and New Zealand, with participants recruited from September 2015 through June 2016., Participants: 100 patients ≥ 18 years of age who required invasive mechanical ventilation in the ICU and were expected to be receiving it beyond the next calendar day at the time of randomisation., Interventions: Conservative oxygen therapy or standard care., Main Outcome Measures: Eligibility, recruitment rate, and separation in oxygen exposure (fraction of inspired oxygen [FiO 2 ] and oxygen saturation measured by pulse oximetry [SpO 2 Z])., Results: 94 of 99 participants (94.9%) were confirmed by study monitors to fulfil the study eligibility criteria. 3.6 patients per site per month were enrolled (95% confidence interval [CI], 2.5-4.7). Patients allocated to conservative oxygen therapy spent significantly more time on an FiO 2 of 0.21 in the ICU; median, 31.5 hours (interquartile range [IQR], 7-63.5) for conservative oxygen therapy patients v 0 hours for standard oxygen therapy patients (IQR, 0-10; midpoint difference, 21.5 hours; 95% CI, 9-34; P < 0.0001). Patients allocated to conservative oxygen therapy spent less time in the ICU with an SpO 2 Z of ≥ 97% than patients allocated to standard oxygen therapy; median, 18.5 hours (IQR, 5-46) for conservative oxygen therapy patients v 32 hours for standard oxygen therapy (IQR, 17-80; midpoint difference, 13.5 hours; 95% CI, 2-25; P = 0.02)., Conclusions: Our findings confirm the feasibility of completing the ICU-ROX trial without the need for substantive changes to the study protocol for the remaining 900 trial participants., Trial Registration: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12615000957594).

Objective: To evaluate the effect of Plasma-Lyte 148 (PL-148) compared with 0.9% saline (saline) on blood product use and postoperative bleeding in patients admitted to the intensive care unit (ICU) following cardiac surgery., Design: A post hoc subgroup analysis conducted within a multicenter, double-blind, cluster-randomized, double-crossover study (study 1) and a prospective, single-center nested-cohort study (study 2)., Setting: Tertiary-care hospitals., Participants: Adults admitted to the ICU after cardiac surgery requiring crystalloid fluid therapy as part of the 0.9% saline vs. PL-148 for ICU fluid therapy (SPLIT) trial., Interventions: Blinded saline or PL-148 for 4 alternating 7-week blocks., Measurements and Main Results: 954 patients were included in study 1; 475 patients received PL-148, and 479 received saline. 128 of 475 patients (26.9%) in the PL-148 group received blood or a blood product compared with 94 of 479 patients (19.6%) in the saline group (OR [95% confidence interval], 1.51 [1.11-2.05]; p = 0.008). In study 2, 131 patients were allocated to PL-148 and 120 patients were allocated to saline. There were no differences between groups in chest drain output from the time of arrival in the ICU until 12 hours postoperatively (geometric mean, 566 mL for the PL-148 group v 547 mL in the saline group; p = 0.60)., Conclusions: The findings did not support the hypothesis that using PL-148 for fluid therapy in ICU following cardiac surgery reduces transfusion requirements compared to saline. The significantly increased proportion of patients receiving blood or blood product with allocation to PL-148 compared to saline was unexpected and requires verification through further research., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

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.

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.

Objective: To identify intensive care patients dying within 2 years of discharge from hospital and assess whether the cause of death was related to the diagnosis at hospital discharge., Design, Setting and Participants: A retrospective cohort study of all patients admitted to the intensive care unit at Wellington Hospital, New Zealand, between 1 July 2001 and 30 June 2003, using data from the ICU database. Mortality data were obtained from the New Zealand National Death Registry., Main Outcome Measures: Death within 2 years of hospital discharge; cause of death and its relation to the hospital discharge diagnosis., Results: Of 1984 patients discharged home, 193 died within 2 years. One-year and 2-year survival rates were 93.8% and 90.3%, respectively. Two-year mortality rates were 4.6% in elective cardiac surgical patients, 19.7% in elective noncardiac surgical patients, 16.9% in acute patients admitted from the operating room, and 10.2% in other acute patients. Among the 193 patients who died after discharge, 124 deaths (64.2%) were related to the diagnosis at hospital discharge. The mortality rate in this group was highest at 3 months (90.5%) and lower at 6 months (75.0%), then averaged 51.4% after 6 months. Cause of death was related to discharge diagnosis in 46.2% of elective cardiac surgical patients, 66.6% of elective non-cardiac surgical patients, 60.5% of acute patients admitted from the operating room, and 75.4% of other acute patients. Cancer was the cause of death in 34.2% of elective cardiac surgical patients, 66.7% of elective non-cardiac surgical patients, 48.8% of acute patients admitted from the operating room, and 29.0% of other acute patients., Conclusion: Survival rates of ICU patients after discharge from hospital are high. Deaths are closely related to the discharge diagnosis only in the first 6 months after discharge. Cancer is a common cause of death. Elective non-cardiac surgical patients have the worst outcomes.