Twelve-month mortality outcomes for Indigenous and non-Indigenous people admitted to intensive care units in Australia: a registry-based data linkage study.

OBJECTIVE: To compare longer term (12-month) mortality outcomes for Indigenous and non-Indigenous people admitted to intensive care units (ICUs) in Australia. DESIGN, SETTING, PARTICIPANTS: Retrospective registry-based data linkage cohort study; analysis of all admissions of adults (16 years or older) to Australian ICUs, 1 January 2017 - 31 December 2019, as recorded in the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD), linked using the SLK-581 key to National Death Index data. MAIN OUTCOME MEASURES: Unadjusted and adjusted mortality risk, censored at twelve months from the start of index ICU admission. Secondary outcomes were unadjusted and adjusted mortality twelve months from admission to the ICU. RESULTS: The APD recorded 330 712 eligible ICU admissions during 2017-2019 (65% of all ICU admissions registered), of which 11 322 were of Indigenous people (3.4%). Median age at admission was lower for Indigenous patients (51.2 [IQR, 36.7-63.6] years) than for non-Indigenous patients (66.5 [IQR, 52.7-76.1] years). Unadjusted mortality risk was similar for Indigenous and non-Indigenous patients (hazard ratio, 1.01; 95% CI, 0.97-1.06), but was higher for Indigenous patients after adjusting for age, admission diagnosis, illness severity, hospital type, jurisdiction, remoteness and socio-economic status (adjusted hazard ratio, 1.20; 95% CI, 1.14-1.27). Twelve-month mortality was higher for Indigenous than non-Indigenous patients (adjusted odds ratio, 1.24; 95% CI, 1.16-1.33). CONCLUSIONS: Twelve-month mortality outcomes are poorer for people admitted to ICUs in Australia than for the general population. Further, after adjusting for age and other factors, survival outcomes are poorer for Indigenous than non-Indigenous people admitted to ICUs. Critical illness may therefore contribute to shorter life expectancy among Indigenous Australians.

Incidence of death or disability at 6 months after extracorporeal membrane oxygenation in Australia: a prospective, multicentre, registry-embedded cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an invasive procedure used to support critically ill patients with the most severe forms of cardiac or respiratory failure in the short term, but long-term effects on incidence of death and disability are unknown. We aimed to assess incidence of death or disability associated with ECMO up to 6 months (180 days) after treatment. METHODS: This prospective, multicentre, registry-embedded cohort study was done at 23 hospitals in Australia from Feb 15, 2019, to Dec 31, 2020. The EXCEL registry included all adults (≥18 years) in Australia who were admitted to an intensive care unit (ICU) in a participating centre at the time of the study and who underwent ECMO. All patients who received ECMO support for respiratory failure, cardiac failure, or cardiac arrest during their ICU stay were eligible for this study. The primary outcome was death or moderate-to-severe disability (defined using the WHO Disability Assessment Schedule 2.0, 12-item survey) at 6 months after ECMO initiation. We used Fisher's exact test to compare categorical variables. This study is registered with ClinicalTrials.gov, NCT03793257. FINDINGS: Outcome data were available for 391 (88%) of 442 enrolled patients. The primary outcome of death or moderate-to-severe disability at 6 months was reported in 260 (66%) of 391 patients: 136 (67%) of 202 who received veno-arterial (VA)-ECMO, 60 (54%) of 111 who received veno-venous (VV)-ECMO, and 64 (82%) of 78 who received extracorporeal cardiopulmonary resuscitation (eCPR). After adjustment for age, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, days between ICU admission and ECMO start, and use of vasopressors before ECMO, death or moderate-to-severe disability was higher in patients who received eCPR than in those who received VV-ECMO (VV-ECMO vs eCPR: risk difference [RD] -32% [95% CI -49 to -15]; p<0·001) but not VA-ECMO (VA-ECMO vs eCPR -8% [-22 to 6]; p=0·27). INTERPRETATION: In our study, only a third of patients were alive without moderate-to-severe disability at 6 months after initiation of ECMO. The finding that disability was common across all areas of functioning points to the need for long-term, multidisciplinary care and support for surviving patients who have had ECMO. Further studies are needed to understand the 180-day and longer-term prognosis of patients with different diagnoses receiving different modes of ECMO, which could have important implications for the selection of patients for ECMO and management strategies in the ICU. FUNDING: The National Health and Medical Research Council of Australia.

Sex Differences in Mortality of ICU Patients According to Diagnosis-related Sex Balance.

Rationale: Women have worse outcomes than men in several conditions more common in men, including cardiac surgery and burns. Objectives: To describe the relationship between sex balance within each diagnostic group of ICU admissions, defined as the percentage of patients who were women, and hospital mortality of women compared with men with that same diagnosis. Methods: We studied ICU patients in the Australian and New Zealand Intensive Care Society's Adult Patient Database (2011-2020). We performed mixed effects logistic regression for hospital mortality adjusted for sex, illness severity, ICU lead time, admission year, and hospital site. We compared sex balance with the adjusted hospital mortality of women compared with men for each diagnosis using weighted linear regression. Measurements and Main Results: There were 1,450,782 admissions (42.1% women), with no difference in the adjusted hospital mortality of women compared with men overall (odds ratio, 0.99; 99% confidence interval [CI], 0.97 to 1). As the percentage of women within each diagnosis increased, the adjusted mortality of women compared with men with that same diagnosis decreased (regression coefficient, -0.015; 99% CI; -0.020 to -0.011; P < 0.001), and the illness severity of women compared with men at ICU admission decreased (regression coefficient, -0.0026; 99% CI, -0.0035 to -0.0018; P < 0.001). Conclusions: Sex balance in diagnostic groups was inversely associated with both the adjusted mortality and illness severity of women compared with men. In diagnoses with relatively few women, women were more likely than men to die. In diagnoses with fewer men, men were more likely than women to die.

Comparison of 6-Month Outcomes of Survivors of COVID-19 versus Non-COVID-19 Critical Illness.

Rationale: The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established. Objectives: We aimed to investigate new disability at 6 months in mechanically ventilated patients admitted to Australian ICUs with COVID-19 compared with non-COVID-19. Methods: We included critically ill patients with COVID-19 and non-COVID-19 from two prospective observational studies. Patients were eligible if they were adult (age ⩾ 8 yr) and received ⩾24 hours of mechanical ventilation. In addition, patients with COVID-19 were eligible with a positive laboratory PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Measurements and Main Results: Demographic, intervention, and hospital outcome data were obtained from electronic medical records. Survivors were contacted by telephone for functional outcomes with trained outcome assessors using the World Health Organization Disability Assessment Schedule 2.0. Between March 6, 2020, and April 21, 2021, 120 critically ill patients with COVID-19, and between August 2017 and January 2019, 199 critically ill patients without COVID-19, fulfilled the inclusion criteria. Patients with COVID-19 were older (median [interquartile range], 62 [55-71] vs. 58 [44-69] yr; P = 0.019) with a lower Acute Physiology and Chronic Health Evaluation II score (17 [13-20] vs. 19 [15-23]; P = 0.011). Although duration of ventilation was longer in patients with COVID-19 than in those without COVID-19 (12 [5-19] vs. 4.8 [2.3-8.8] d; P < 0.001), 180-day mortality was similar between the groups (39/120 [32.5%] vs. 70/199 [35.2%]; P = 0.715). The incidence of death or new disability at 180 days was similar (58/93 [62.4%] vs. 99/150 [66/0%]; P = 0.583). Conclusions: At 6 months, there was no difference in new disability for patients requiring mechanical ventilation for acute respiratory failure due to COVID-19 compared with non-COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04401254).

Sex Differences in Treatment of Adult Intensive Care Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate and synthesize the available literature on sex differences in the treatment of adult ICU patients. DATA SOURCES: MEDLINE and EMBASE. STUDY SELECTION: Two reviewers independently screened publications to identify observational studies of adult ICU patients that explicitly examined the association between sex and ICU treatment-specifically, mechanical ventilation, renal replacement therapy, and length of stay. DATA EXTRACTION: We extracted data independently and in duplicate: mean age, illness severity, use of mechanical ventilation and renal replacement therapy, and length of stay in ICU and hospital. We assessed risk of bias using the Newcastle-Ottawa Scale. We used a DerSimonian-Laird random-effects model to calculate pooled odds ratios (ORs) and mean differences between women and men. DATA SYNTHESIS: We screened 4,098 publications, identifying 21 eligible studies with 545,538 participants (42.7% women). The study populations ranged from 246 to 261,255 participants (median 4,420). Most studies (76.2%) were at high risk of bias in at least one domain, most commonly representativeness or comparability. Women were less likely than men to receive invasive mechanical ventilation (OR, 0.83; 95% CI, 0.77-0.89; I2 = 90.4%) or renal replacement therapy (OR, 0.79; 95% CI, 0.70-0.90; I2 = 76.2%). ICU length of stay was shorter in women than men (mean difference, -0.24 d; 95% CI, -0.37 to -0.12; I2 = 89.9%). These findings persisted in meta-analysis of data adjusted for illness severity and other confounders and also in sensitivity analysis excluding studies at high risk of bias. There was no significant sex difference in duration of mechanical ventilation or hospital length of stay. CONCLUSIONS: Women were less likely than men to receive mechanical ventilation or renal replacement therapy and had shorter ICU length of stay than men. There is substantial heterogeneity and risk of bias in the literature; however, these findings persisted in sensitivity analyses.

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study.

BACKGROUND: There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. METHODS: In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. RESULTS: Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51-70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06-13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, - 0.19 [- 0.28 to - 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. CONCLUSIONS: At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning. Clinical trial registration NCT04401254 May 26, 2020.

Age of red blood cells is not associated with in-hospital mortality in massively transfused patients.

BACKGROUND: Studies comparing mortality following massive transfusion (MT) with fresher versus longer-stored red blood cells (RBCs) have focused on trauma patients. The Australian and New Zealand Massive Transfusion Registry collects data on all adult MT cases (≥5 RBCs within 4 hours, any bleeding context, ≥18 years) at participating hospitals. METHODS: Years 2007 to 2018 data from 29 hospitals were analyzed to quantify the association between mortality and RBC storage time in adult MT cases. We ran three logistic regression models separately on each of seven bleeding contexts, with in-hospital mortality as the outcome and, in turn, (1) mean storage time (STmean) quartiles, (2) proportion of RBCs ≥30 days old (propOLD), and (3) scalar age of blood index as predictors. RESULTS: A total of 8,685 adult MT cases involving transfusion of 126,622 RBCs were analyzed with Australian and New Zealand data analyzed separately. Mean storage times for these cases were (by quartile in ascending order) as follows: Australia, 12.5 days (range, 3.1-15.5 days), 17.7 (15.5-19.9), 22.3 (19.9-24.9), and 29.8 (24.9-41.7); New Zealand, 11.3 days (3.6-13.7), 15.3 (13.7-16.8), 18.7 (16.8-20.7), and 24.5 (20.7-35.6). The odds ratios comparing in-hospital mortality for each quartile with that of the control first quartile (freshest blood), proportion of longer-stored (≥30 days) RBCs, and scalar age of blood index were not statistically significant across all bleeding contexts. CONCLUSION: We find no correlation between in-hospital mortality and storage time of transfused RBCs in a large cohort of adult MT patients representing all bleeding contexts. These results are consistent with those of recent large multicenter trials. LEVEL OF EVIDENCE: Epidemiologic, level III; Therapeutic, level IV.

A Multicenter, Open-Label, Randomized Controlled Trial of a Conservative Fluid Management Strategy Compared With Usual Care in Participants After Cardiac Surgery: The Fluids After Bypass Study.

OBJECTIVES: There is little evidence to guide fluid administration to patients admitted to the ICU following cardiac surgery. This study aimed to determine if a protocolized strategy known to reduce fluid administration when compared with usual care reduced ICU length of stay following cardiac surgery. DESIGN: Prospective, multicenter, parallel-group, randomized clinical trial. SETTING: Five cardiac surgical centers in New Zealand conducted from November 2016 to December 2018 with final follow-up completed in July 2019. PATIENTS: Seven-hundred fifteen patients undergoing cardiac surgery; 358 intervention and 357 usual care. INTERVENTIONS: Randomization to protocol-guided strategy utilizing stroke volume variation to guide administration of bolus fluid or usual care fluid administration until desedation or up to 24 hours. Primary outcome was length of stay in ICU. Organ dysfunction, mortality, process of care measures, patient-reported quality of life, and disability-free survival were collected up to day 180. MEASUREMENTS AND MAIN RESULTS: Overall 666 of 715 (93.1%) received at least one fluid bolus. Patients in the intervention group received less bolus fluid (median [interquartile range], 1,000 mL [250-2,000 mL] vs 1,500 mL [500-2,500 mL]; p < 0.0001) and had a lower overall fluid balance (median [interquartile range], 319 mL [-284 to 1,274 mL] vs 673 mL [38-1,641 mL]; p < 0.0001) in the intervention period. There was no difference in ICU length of stay between the two groups (27.9 hr [21.8-53.5 hr] vs 25.6 hr [21.9-64.6 hr]; p = 0.95). There were no differences seen in development of organ dysfunction, quality of life, or disability-free survival at any time points. Hospital mortality was higher in the intervention group (4% vs 1.4%; p = 0.04). CONCLUSIONS: A protocol-guided strategy utilizing stroke volume variation to guide administration of bolus fluid when compared with usual care until desedation or up to 24 hours reduced the amount of fluid administered but did not reduce the length of stay in ICU.

Characteristics and Outcomes of Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Australia and New Zealand.

Rationale: The characteristics and outcomes of patients presenting with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) requiring intensive care unit (ICU) admission are poorly understood and there are sparse epidemiological data.Objectives: The objectives were to describe epidemiology and outcomes of patients admitted to an ICU with COPD and to evaluate whether outcomes varied over time.Methods: We studied adult ICU admissions across Australia and New Zealand between 2005 and 2017 with a diagnosis of AECOPD and used an admission diagnosis of asthma as comparator for trends over time. We measured changes in characteristics and outcomes over time using logistic regression, adjusting for illness severity using the Australian New Zealand Risk of Death model.Results: We studied 31,991 admissions with AECOPD and 11,096 with asthma. Mean (standard deviation) age for AECOPD patients was 68.3 (11.2) years, with 35.4% mechanically ventilated. For patients with AECOPD, the percentage of deaths in an ICU was 8.7% and in a hospital was 15.4% of admissions, with the proportion of 69.2% discharged home and 5.6% discharged to a high-level care facility. During the study period, the proportion of ICU admissions with AECOPD per 10,000 admissions decreased at an annual rate of 2.0 (95% confidence interval [CI], 0.8-3.2; P = 0.009) but their admission rate per million population increased annually by 4.5 (95% CI, 3.7-5.3; P < 0.0001). There was a linear reduction in mortality for AECOPD but not for asthma admissions (odds ratio annual decline: AECOPD, 0.94 [0.93-0.95] and asthma, 1.01 [0.97-1.05]; P = 0.001) and an increase in AECOPD admissions discharged to home (odds ratio annual increase, AECOPD, 1.04 [1.03-1.05] and asthma, 1.01 [0.99-1.03]; P = 0.01). The reduction in mortality was sustained after adjusting for illness severity.Conclusions: Across Australia and New Zealand, the rate of ICU admissions due to AECOPD is increasing but mortality rates are decreasing, with a corresponding increase in the home discharge rates.

Singapore SPICE: sedation practices in intensive care evaluation in Singapore - a prospective cohort study of the public healthcare system.

INTRODUCTION: A study was conducted to describe the sedation practices of intensive care units (ICUs) in Singapore in terms of drug use, sedation depth and the incidence of delirium in both early (< 48 hours) and late (> 48 hours) periods of ICU admission. METHODS: A prospective multicentre cohort study was conducted on patients who were expected to be sedated and ventilated for over 24 hours in seven ICUs (surgical ICU, n = 4; medical ICU, n = 3) of four major public hospitals in Singapore. Patients were followed up to 28 days or until ICU discharge, with four-hourly sedation monitoring and daily delirium assessment by trained nurses. The Richmond Agitation and Sedation Scale (RASS) and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were used. RESULTS: We enrolled 198 patients over a five-month period. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25.3 ± 9.2, and 90.9% were emergency hospital admissions. Patients were followed up for 1,417 ICU patient days, of which 396 days were in the early period and 1,021 days were in the late period. 7,354 RASS assessments were performed. Propofol and fentanyl were the sedative agents of choice in the early and late periods, respectively. Patients were mostly in the light sedation range, especially in the late period. At least one episode of delirium was seen in 23.7% of patients. CONCLUSION: Sedation practices in Singapore ICUs are characterised by light sedation depth and low incidence of delirium, possibly due to the drugs used.

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.

Trauma-related admissions to intensive care units in Australia: the influence of Indigenous status on outcomes.

OBJECTIVES: To investigate the admission characteristics and hospital outcomes for Indigenous and non-Indigenous patients admitted to intensive units (ICUs) after major trauma. DESIGN, SETTING: Retrospective analysis of Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database data from 92 Australian ICUs for the 6-year period, 2010-2015. PARTICIPANTS: Patients older than 17 years of age admitted to public hospital ICUs with a primary diagnosis of trauma. MAIN OUTCOME MEASURES: ICU and overall hospital lengths of stay, hospital discharge destination, and ICU and overall hospital mortality rates for Indigenous and non-Indigenous patients. RESULTS: 23 804 people were admitted to Australian public hospital ICUs after major trauma; 1754 (7.4%) were Indigenous Australians. The population-standardised incidence of admissions was consistently higher for Indigenous Australians than for non-Indigenous Australians (847 per million v 251 per million population; incidence ratio, 3.37; 95% CI, 3.19-3.57). Overall hospital mortality rates were similar for Indigenous and non-Indigenous patients (adjusted odds ratio [aOR], 1.04; 95% CI, 0.82-1.31). Indigenous patients were more likely than non-Indigenous patients to be discharged to another hospital (non-Indigenous v Indigenous: aOR, 0.84; 95% CI, 0.72-0.96) less likely to be discharged home (non-Indigenous v Indigenous: aOR, 1.17; 95% CI, 1.04-1.31). CONCLUSION: The population rate of trauma-related ICU admissions was substantially higher for Indigenous than non-Indigenous patients, but hospital mortality rates after ICU admission were similar. Indigenous patients were more likely to be discharged to a another hospital and less likely to be discharged home than non-Indigenous patients.

Sexual Dimorphism of Resting-State Network Connectivity in Healthy Ageing.

OBJECTIVES: The onset of many illnesses is confounded with age and sex. Increasing age is a risk factor for the development of many illnesses, and sexual dimorphism influences brain anatomy, function, and cognition. Here, we examine frequency-specific connectivity in resting-state networks in a large sample (n = 406) of healthy aged adults. METHOD: We quantify frequency-specific connectivity in three resting-state networks known to be implicated in age-related decline: the default mode, dorsal attention, and salience networks, using multiband functional magnetic resonance imaging. Frequency-specific connectivity was quantified in four bands: low (0.015-0.027 Hz), moderately low (0.027-0.073 Hz), moderately high (0.073-0.198 Hz), and high (0.198-0.5 Hz) frequency bands, using mean intensity and spatial extent. Differences in connectivity between the sexes in each of the three networks were examined. RESULTS: Each network showed the largest intensity and spatial extent at low frequencies and smallest extent at high frequencies. Males showed greater connectivity than females in the salience network. Females showed greater connectivity than males in the default mode network. DISCUSSION: Results in this healthy aged cohort are compatible with those obtained in young samples, suggesting that frequency-specific connectivity, and differences between the sexes, are maintained into older age. Our results indicate that sex should be considered as an influencing factor in studies of resting-state connectivity.

A cluster randomised, crossover, registry-embedded clinical trial of proton pump inhibitors versus histamine-2 receptor blockers for ulcer prophylaxis therapy in the intensive care unit (PEPTIC study): study protocol.

BACKGROUND: The balance of risks and benefits with using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RB) 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 H2RB as the preferred agent. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000481471).

Sedation Intensity in the First 48 Hours of Mechanical Ventilation and 180-Day Mortality: A Multinational Prospective Longitudinal Cohort Study.

OBJECTIVES: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. DESIGN: Harmonized data from prospective multicenter international longitudinal cohort studies SETTING:: Diverse mix of ICUs. PATIENTS: Critically ill patients expected to be ventilated for longer than 24 hours. INTERVENTIONS: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. MEASUREMENTS AND MAIN RESULTS: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (SD) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47-8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15-1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10-1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73-0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04-1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival. CONCLUSIONS: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal.