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Purpose: Prostate cancer (PC) is the second most common cause of cancer related death in men. A number of key limitations with prostate specific antigen (PSA), currently the standard detection test, has justified evaluation of new biomarkers. We have assessed the diagnostic potential of Engrailed-2 (EN2) protein, a homeodomain-containing transcription factor expressed in PC cell lines and secreted into the urine by PC in men.Experimental Design: EN2 expression in PC cell lines and prostate cancer tissue was determined by semi-quantative RT-PCR and immunohistochemistry. First pass urine [without prior digital rectal examination (DRE)] was collected from men presenting with urinary symptoms (referred to exclude/confirm the presence of prostate cancer) and from controls. EN2 protein was measured by ELISA in urine from men with PC (n = 82) and controls (n = 102).Results: EN2 was expressed and secreted by PC cell lines and PC tissue but not by normal prostate tissue or stroma. The presence of EN2 in urine was highly predictive of PC, with a sensitivity of 66% and a specificity of 88.2%, without requirement for DRE. There was no correlation with PSA levels. These results were confirmed independently by a second academic center.Conclusions: Urinary EN2 is a highly specific and sensitive candidate biomarker of prostate cancer. A larger multicenter study to further evaluate the diagnostic potential of EN2 is justified. Clin Cancer Res; 17(5); 1090–8. ©2011 AACR.

Supplementary Figures S1-S3.

Acute illness severity predicts mortality in intensive care unit (ICU) patients, however, its predictive value decreases over time in ICU. Typically after 10 days, pre-ICU (antecedent) characteristics become more predictive of mortality, defining the onset of persistent critical illness (PerCI). How patient frailty affects development and death from PerCI is unknown.We conducted a secondary analysis of data from a prospective binational cohort study including 269,785 critically ill adults from 168 ICUs in Australia and New Zealand, investigating whether frailty measured with the Clinical Frailty Scale (CFS) changes the timing of onset and risk of developing PerCI and of subsequent in-hospital mortality. We assessed associations between frailty (CFS ≥ 5) and mortality prediction using logistic regression and area under the receiver operating characteristics (AUROC) curves.2190 of 50,814 (4.3%) patients with frailty (CFS ≥ 5) versus 6624 of 218,971 (3%) patients without frailty (CFS ≤ 4) developed PerCI (P 0.001). Among patients with PerCI, 669 of 2190 (30.5%) with frailty and 1194 of 6624 without frailty (18%) died in hospital (P 0.001). The time point defining PerCI onset did not vary with frailty degree; however, with increasing length of ICU stay, inclusion of frailty progressively improved mortality discrimination (0.1% AUROC improvement on ICU day one versus 3.6% on ICU day 17).Compared to patients without frailty, those with frailty have a higher chance of developing and dying from PerCI. Moreover the importance of frailty as a predictor of mortality increases with ICU length of stay. Future work should explore incorporation of frailty in prognostic models, particularly for long-staying patients.

Rationale: Frailty in critically ill patients is associated with higher mortality and prolonged length of stay, however little is known about the impact on the duration of mechanical ventilation. O...

Rationale: Hypercapnia may affect the outcome of sepsis. Very few clinical studies conducted in noncritically ill patients have investigated the effects of hypercapnia and hypercapnic acidemia in the context of sepsis. The effect of hypercapnia in critically ill patients with sepsis remains inadequately studied. Objectives: To investigate the association of hypercapnia with hospital mortality in critically ill patients with sepsis. Methods: This is a retrospective study conducted in three tertiary public hospitals. Critically ill patients with sepsis from three intensive care units between January 2011 and May 2019 were included. Five cohorts (exposure of at least 24, 48, 72, 120, and 168 hours) were created to account for immortal time bias and informative censoring. The association between hypercapnia exposure and hospital mortality was assessed with multivariable models. Subgroup analyses compared ventilated versus nonventilated and pulmonary versus nonpulmonary sepsis patients. Results: We analyzed 84,819 arterial carbon dioxide pressure measurements in 3,153 patients (57.6% male; median age was 62.5 years). After adjustment for key confounders, both in mechanically ventilated and nonventilated patients and in patients with pulmonary or nonpulmonary sepsis, there was no independent association of hypercapnia with hospital mortality. In contrast, in ventilated patients, the presence of prolonged exposure to both hypercapnia and acidemia was associated with increased mortality (highest odds ratio of 16.5 for ⩾120 hours of potential exposure; P = 0.007). Conclusions: After adjustment, isolated hypercapnia was not associated with increased mortality in patients with sepsis, whereas prolonged hypercapnic acidemia was associated with increased risk of mortality. These hypothesis-generating observations suggest that as hypercapnia is not an independent risk factor for mortality, trials of permissive hypercapnia avoiding or minimizing acidemia in sepsis may be safe.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

OBJECTIVE Hospitalised frail older patients are at risk of clinical deterioration. Early goals of care documentation (GOC) is vital to avoid futile/unwarranted interventions in the event of deterioration. We aimed to investigate the impact of frailty on timely GOC and its association with clinical outcomes in hospitalised older patients. DESIGN, SETTING, PARTICIPANTS Single-centre retrospective study of all medical patients aged ≥80 years admitted to acute medical unit between 1/3/2015 and 31/8/2015, with GOC derived from electronic records. Frailty was measured using Hospital Frailty Risk Score (HFRS) derived from hospital coding data. MAIN OUTCOME MEASURES Primary outcome compared proportions timely GOC within 72-h between frail (HFRS≥5) and non-frail (HFRS

Background/Objectives Traditional indirect calorimetry is unable to capture complete gas exchange in patients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO). We aimed to determine the feasibility of using a modified indirect calorimetry protocol in patients receiving VA ECMO, report measured energy expenditure (EE) and compare EE to control critically ill patients. Subjects/Methods Mechanically ventilated adult patients receiving VA ECMO were included. EE was measured within 72 h of VA ECMO commencement (timepoint one [T1]) and on approximately day seven of Intensive Care Unit (ICU) admission (timepoint two [T2]). Traditional indirect calorimetry via the ventilator was combined with calculations of oxygen consumption and carbon dioxide production derived from pre- and post-ECMO membrane blood gas analyses. Completion of ≥60% EE measurements was deemed feasible. Measured EE was compared between T1 and T2 and to control patients not receiving VA ECMO. Data is presented as n(%) and median[interquartile range (IQR)]. Results Twenty-one patients were recruited; 16(76%) male, aged 55[42–64] years. The protocol was feasible to complete at T1 (14(67%)) but not at T2 (7(33%)) due to predominantly ECMO decannulation, extubation or death. EE was 1454[1213–1860] at T1 and 1657[1570–2074] kcal/d at T2 (P = 0.043). In patients receiving VA ECMO versus controls, EE was 1577[1434–1801] versus 2092[1609–2272] kcal/d, respectively (P = 0.056). Conclusion Modified indirect calorimetry is feasible early in admission to ICU but is not possible in all patients receiving VA ECMO, especially later in admission. EE increases during the first week of ICU admission but may be lower than EE in control critically ill patients.

Purpose To investigate the association between sex and illness severity and mortality of ICU patients. Methods We performed systematic searches of MEDLINE and EMBASE for observational studies of adult ICU patients that explicitly examined the association between sex and illness severity or mortality. We used a random effects model to calculate standardised mean differences in illness severity scores and pooled odds ratios for mortality of women compared to men. Results We identified 21 studies with 505,138 participants in total (43.1% women). There was substantial heterogeneity among studies. Only two studies were at low risk of bias overall. At ICU admission, there was a pattern of higher illness severity scores among women (standardised mean difference 0.04, 95% CI -0.01-0.09). Women had higher risk-adjusted mortality than men at ICU discharge (OR 1.25 95% CI 1.03–1.50) and 1 year (OR 1.08, 95% CI 1.02–1.13), however this finding was not robust to sensitivity analysis. Conclusions Women tend to have higher illness severity scores at ICU admission. Women also appear to have higher risk-adjusted mortality than men at ICU discharge and at 1 year. Given the heterogeneity and risk of bias in the existing literature, additional studies are needed to confirm or refute these findings.

Background Frailty is associated with poor outcomes in critical illness. However, it is unclear whether frailty screening on admission to the ICU can be conducted routinely at the population level and whether it has prognostic importance. Research Question Can population-scale frailty screening with the Clinical Frailty Scale (CFS) be implemented for critically ill adults in Australia and New Zealand (ANZ) and can it identify patients at risk of negative outcomes? Study Design and Methods We conducted a binational prospective cohort study of critically ill adult patients admitted between July 1, 2018, and June 30, 2020, in 175 ICUs in ANZ. We classified frailty with the CFS on admission to the ICU. The primary outcome was in-hospital mortality; secondary outcomes were length of stay (LOS), discharge destination, complications (delirium, pressure injury), and duration of survival. Results We included 234,568 critically ill patients; 45,245 (19%) were diagnosed as living with frailty before ICU admission. Patients with vs without frailty had higher in-hospital mortality (16% vs 5%; P Interpretation Large-scale population screening for frailty degree in critical illness was possible and prognostically important, with greater frailty (especially CFS score of ≥ 6) associated with worse outcomes, including among younger patients.

Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10–8) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10–6 to 10–8p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.

Objective: The accuracy of different non-invasive body temperature measurement methods in intensive care unit (ICU) patients is uncertain. We aimed to study the accuracy of three commonly used methods. Design: Prospective observational study. Setting: ICUs of two tertiary Australian hospitals. Participants: Critically ill patients admitted to the ICU. Interventions: Invasive (intravascular and intra-urinary bladder catheter) and non-invasive (axillary chemical dot, tympanic infrared, and temporal scanner) body temperature measurements were taken at study inclusion and every 4 hours for the following 72 hours. Main outcome measures: Accuracy of non-invasive body temperature measurement methods was assessed by the Bland–Altman approach, accounting for repeated measurements and significant explanatory variables that were identified by regression analysis. Clinical adequacy was set at limits of agreement (LoA) of 1C compared with core temperature. Results: We studied 50 consecutive critically ill patients who were mainly admitted to the ICU after cardiac surgery. From over 375 observations, invasive core temperature (mostly pulmonary artery catheter) ranged from 33.9C to 39C. On average, the LoA between invasive and non-invasive measurements methods were about 3C. The temporal scanner showed the worst performance in estimating core temperature (bias, 0.66C; LoA, 1.23C, +2.55C), followed by tympanic infrared (bias, 0.44C; LoA, 1.73C, +2.61C) and axillary chemical dot methods (bias, 0.32°C; LoA, 1.64C, +2.28C). No methods achieved clinical adequacy even accounting for significant explanatory variables. Conclusions: The axillary chemical dot, tympanic infrared and temporal scanner methods are inaccurate measures of core temperature in ICU patients. These non-invasive methods appeared unreliable for use in ICU patients.

Background Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability. Methods We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization. Results The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P=0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P=0.005). Conclusions Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).

Sedation Practice in Intensive Care Evaluation (SPICE-III) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation.to quantify the association of different infusion rates of dexmedetomidine or propofol, given in combination, with mortality and if this is modified by age.We included 1177 patients randomized in SPICE-III to receive dexmedetomidine and given supplemental propofol, stratified by age (65 or ≤65 years). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine, while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression, adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality.Younger patients 598/1177(50.8%) received a significantly higher dose of both sedatives compared with older patients, to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 mcg/kg/h) was associated with reduced adjusted mortality in younger, but not older patients. This was consistent with multivariable regression modelling [hazard ratio: 0.59(95% Confidence Interval 0.43-0.78),P0.0001], adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality [HR:1.30(95%CI 1.03-1.65), P=0.029].In patients ≤ 65 years sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registration available at www.gov, ID: NCT01728558.

In hospital cardiac arrest (IHCA) affects approximately 3000 patients annually in Australia. Introduction of the National Standard for Deteriorating Patients in 2011 was associated with reduced IHCA-related ICU admissions and reduced in-hospital mortality of such patients.To assess whether the reduction in IHCA-related ICU admissions from hospital wards seen following the implementation of National Standard (baseline period 2013-14) was sustained over the follow-up period (2015-2019) in Australia.Multi-centre retrospective cohort study to compare the characteristics and the outcomes of IHCA admitted to the ICU between baseline and follow-up periods. The primary outcome was the proportion of patients admitted to ICU from the ward following IHCA. Secondary outcomes included ICU and hospital mortality of IHCA-related ICU admissions. Data were analyzed using hierarchical multivariable logistic regression.The proportion of cardiac arrest related admissions from the ward was lower in the follow-up period, when compared to baseline (4.1 vs 3.8%; p=0.04). Such patients had lower illness severity and were more likely to have limitations of treatment (LOMT) at admission. However, after adjustment for severity of illness, the likelihood of being admitted to ICU following cardiac arrest on the ward increased in the follow-up period [OR 1.13 (1.05-1.22); p=0.001]. Hospital mortality was lower in the follow-up period (50.3 vs. 46.3%; p=0.02), but after adjustment the likelihood of death did not differ between the periods [OR 1.0 (0.86-1.17); p=0.98].After adjustment for severity of illness the likelihood of being admitted to ICU after IHCA slightly increased in the follow-up period. This article is protected by copyright. All rights reserved.

BACKGROUND: The COVID-19 pandemic has led to unprecedented demand for ICUs, with the need to triage admissions along with the development of ICU triage criteria. However, how these criteria relate to outcomes in patients already admitted to the ICU is unknown, as is the incremental ICU capacity that triage of these patients might create given existing admission practices. RESEARCH QUESTION: What is the short- and long-term survival of low- vs high-priority patients for ICU admission according to current pandemic triage criteria? STUDY DESIGN AND METHODS: This study analyzed prospectively collected registry data (2007-2018) in 23 ICUs in Victoria, Australia, with probabilistic linkage with death registries. After excluding elective surgery, admissions were stratified according to existing ICU triage protocol prioritization as low (age ≥ 85 years, or severe chronic illness, or Sequential Organ Failure Assessment [SOFA] score = 0 or ≥ 12), medium (SOFA score = 8-11) or high (SOFA score = 1-7) priority. The primary outcome was long-term survival. Secondary outcomes were in-hospital mortality, ICU length of stay (LOS) and bed-day usage. RESULTS: This study examined 126,687 ICU admissions. After 5 years of follow-up, 1,093 of 3,296 (33%; 95% CI, 32-34) of "low-priority" patients aged ≥ 85 years or with severe chronic illness and 86 of 332 (26%; 95% CI, 24-28) with a SOFA score ≥ 12 were still alive. Sixty-three of 290 (22%; 95% CI, 17-27) of patients in these groups followed up for 10 years were still alive. Together, low-priority patients accounted for 27% of all ICU bed-days and had lower in-hospital mortality (22%) than the high-priority patients (28%). Among nonsurvivors, low-priority admissions had shorter ICU LOS than medium- or high-priority admissions. INTERPRETATION: Current SOFA score or age or severe comorbidity-based ICU pandemic triage protocols exclude patients with a close to 80% hospital survival, a > 30% five-year survival, and 27% of ICU bed-day use. These findings imply the need for stronger evidence-based ICU triage protocols.

Rationale: Both 2009 pandemic influenza A (H1N1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are transmitted by respiratory secretions and in severe cases result in a viral pneumonitis, requiring intensive care unit (ICU) admission. However, no studies have compared the clinical characteristics and outcomes of such patients. Objectives: To report and compare the demographic characteristics, treatments, use of critical care resources, and outcomes of patients admitted to an Australian ICU with H1N1 influenza during the winter of 2009, and SARS-CoV-2 during the winter of 2020. Methods: This was a multicenter project, using national data from previous and ongoing epidemiological studies concerning severe acute respiratory infections in Australia. All ICUs admitting patients with H1N1 or coronavirus disease (COVID-19) were included and contributed data. We compared clinical characteristics and outcomes of patients with H1N1 admitted to ICU in the winter of 2009 versus patients with COVID-19 admitted to ICU in the winter of 2020. The primary outcome was in-hospital mortality. Potential years of life lost (PYLL) were calculated according to sex-adjusted life expectancy in Australia. Results: Across the two epochs, 861 patients were admitted to ICUs; 236 (27.4%) with COVID-19 and 625 (72.6%) with H1N1 influenza. The number of ICU admissions and bed-days occupied were higher with 2009 H1N1 influenza. Patients with COVID-19 were older, more often male and overweight, and had lower Acute Physiology and Chronic Health Evaluation II scores at ICU admission. The highest age-specific incidence of ICU admission was among infants (0–1 yr of age) for H1N1, and among the elderly (≥65 yr) for COVID-19. Unadjusted in-hospital mortality was similar (11.5% in COVID-19 vs. 16.1% in H1N1; odds ratio, 0.68 [95% confidence interval (95% CI), 0.42–1.06]; P = 0.10). The PYLL was greater with H1N1 influenza than with COVID-19 at 154.1 (95% CI, 148.7–159.4) versus 13.6 (95% CI, 12.2–15.1) PYLL per million inhabitants. Conclusions: In comparison with 2009 H1N1 influenza, COVID-19 admissions overwinter in Australia resulted in fewer ICU admissions, and lower bed-day occupancy. Crude in-hospital mortality was similar, but because of demographic differences in affected patients, deaths due to 2009 H1N1 influenza led to an 11-fold increase in the number of PYLL in critically ill patients.

OBJECTIVES: Previous case series reported an association between dexmedetomidine use and hyperthermia. Temperature data have not been systematically reported in previous randomized controlled trials evaluating dexmedetomidine. A causal link between dexmedetomidine administration and elevated temperature has not been demonstrated. DESIGN: Post hoc analysis. SETTING: Four ICUs in Australia and New Zealand. PATIENTS: About 703 mechanically ventilated ICU patients. INTERVENTIONS: Early sedation with dexmedetomidine versus usual care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean daily body temperature. Secondary outcomes included the proportions of patients with body temperatures greater than or equal to 38.3°C and greater than or equal to 39°C, respectively. Outcomes were recorded for 5 days postrandomization in the ICU. The mean daily temperature was not different between the dexmedetomidine (n = 351) and usual care (n = 352) groups (36.84°C ± sd vs 36.78°C ± sd; p = 0.16). Over the first 5 ICU days, more dexmedetomidine group (vs usual care) patients had a temperature greater than or equal to 38.3°C (43.3% vs 32.7%, p = 0.004; absolute difference 10.6 percentage points) and greater than or equal to 39.0°C (19.4% vs 12.5%, p = 0.013; absolute difference 6.9 percentage points). Results were similar after adjusting for diagnosis, admitting temperature, age, weight, study site, sepsis occurrence, and the time from dexmedetomidine initiation to first hyperthermia recorded. There was a significant dose response relationship with temperature increasing by 0.30°C ±0.08 for every additional 1 μg/kg/hr of dexmedetomidine received p < 0.0002. CONCLUSIONS: Our study suggests potentially important elevations in body temperature are associated with early dexmedetomidine sedation, in adults who are mechanically ventilated in the ICU.

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.

Background ICU-specific tables of antimicrobial susceptibility for key microbial species (‘antibiograms’), antimicrobial stewardship (AMS) programmes and routine rounds by infectious diseases (ID) physicians are processes aimed at improving patient care. Their impact on patient-centred outcomes in Australian and New Zealand ICUs is uncertain. Objectives To measure the association of these processes in ICU with in-hospital mortality. Methods The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database and Critical Care Resources registry were used to extract patient-level factors, ICU-level factors and the year in which each process took place. Descriptive statistics and hierarchical logistic regression were used to determine the relationship between each process and in-hospital mortality. Results The study included 799 901 adults admitted to 173 ICUs from July 2009 to June 2016. The proportion of patients exposed to each process of care was 38.7% (antibiograms), 77.5% (AMS programmes) and 74.0% (ID rounds). After adjusting for confounders, patients admitted to ICUs that used ICU-specific antibiograms had a lower risk of in-hospital mortality [OR 0.95 (99% CI 0.92–0.99), P = 0.001]. There was no association between the use of AMS programmes [OR 0.98 (99% CI 0.94–1.02), P = 0.16] or routine rounds with ID physicians [OR 0.96 (99% CI 0.09–1.02), P = 0.09] and in-hospital mortality. Conclusions Use of ICU-specific antibiograms was associated with lower in-hospital mortality for patients admitted to ICU. For hospitals that do not perform ICU-specific antibiograms, their implementation presents a low-risk infection management process that might improve patient outcomes.

Objectives: The 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) provides a standardised method for measuring health and disability. This study aimed to determine its reliability, validity and responsiveness and to establish the minimum clinically important difference (MCID) in critically ill patients. Design: Prospective, multicentre cohort study. Setting: Intensive care units of six metropolitan hospitals. Participants: Adults mechanically ventilated for > 24 hours. Main outcome measures: Reliability was assessed by measuring internal consistency. Construct validity was assessed by comparing WHODAS 2.0 scores at 6 months with the EuroQoL visual analogue scale (EQ VAS) and Lawton Instrumental Activities of Daily Living (IADL) scale scores. Responsiveness was evaluated by assessing change over time, effect sizes, and percentage of patients showing no change. The MCID was calculated using both anchor and distribution-based methods with triangulation of results. Main results: A baseline and 6-month WHODAS 2.0 score were available for 448 patients. The WHODAS 2.0 demonstrated good correlation between items with no evidence of item redundancy. Cronbach α coefficient was 0.91 and average split-half coefficient was 0.91. There was a moderate correlation between the WHODAS 2.0 and the EQ VAS scores (r = 0.72; P < 0.001) and between the WHODAS 2.0 and the Lawton IADL scores (r = 0.66; P < 0.001) at 6 months. The effect sizes for change in the WHODAS 2.0 score from baseline to 3 months and from 3 to 6 months were low. Ceiling effects were not present and floor effects were present at baseline only. The final MCID estimate was 10%. Conclusion: The 12-item WHODAS 2.0 is a reliable, valid and responsive measure of disability in critically ill patients. A change in the total WHODAS 2.0 score of 10% represents the MCID.

Introduction: Fewer women than men are admitted to intensive care units (ICUs) worldwide. Objectives: To quantify the relative contribution of each major diagnostic category to the overall sex balance in ICU admissions in Australia and New Zealand, and to describe changes in the sex balance over time and with patient age. Methods: Retrospective cross-sectional study of Australian and New Zealand ICU admissions recorded in the Australian and New Zealand Intensive Care Society Adult Patient Database between 2005 and 2018. Multivariate logistic regression for the likelihood of female admission considered key explanatory variables: diagnostic category, patient age, admission year, geographic region, hospital type, and planned versus unplanned ICU admission. Results: Overall, 42.3% of 1 616 856 Australian and New Zealand ICU patients were women (99% CI, 42.2–42.4%). 247 988 more men than women were admitted to an ICU during the 14-year study period. There was a sex imbalance in most diagnostic categories: less than 48% women in 15 of 23 diagnostic categories, and greater than 52% women in four diagnostic categories (P < 0.001). Admissions following cardiovascular surgery accounted for over half of the total sex imbalance. The percentage of ICU patients who are women increased linearly from 40.8% in 2005 to 43.6% in 2018 (R2 = 93.1%; P < 0.001). Compared with admission in 2005, the adjusted odds ratio for female admission in 2018 was 1.03 (99% CI, 1.01–1.06). Conclusion: There is a significant sex imbalance in ICU admissions in Australia and New Zealand, widespread across the diagnostic categories. Cardiovascular admissions contribute most to the observed preponderance of men. The proportion of female ICU patients is steadily increasing.

OBJECTIVE: To develop a simple model for the prediction of acute kidney injury (AKI) and renal replacement therapy (RRT) that could be used in clinical or research risk stratification. DESIGN: Retrospective analysis. SETTING: Multi-institutional. PARTICIPANTS: All cardiac surgery patients from September 2016 to December 2018. INTERVENTIONS: Observational. MEASUREMENTS AND MAIN RESULTS: The study cohort was divided into a development set (75%) and validation set (25%). The following 2 data epochs were used: preoperative data and immediate postoperative data (within 4 h of intensive care unit admission). Univariate statistics were used to identify variables associated with AKI or RRT. Stepwise logistic regression was used to develop a parsimonious model. Model discrimination and calibration were evaluated in the test set. Models were compared with previously published models and with a more comprehensive model developed using the least absolute shrinkage and selection operator. The study included 22,731 patients at 33 hospitals. The incidences of AKI (any stage) and RRT for the present analysis were 5,829 patients (25.6%) and 488 patients (2.1%), respectively. Models were developed for AKI, with an area under the receiver operating curve (AU-ROC) of 0.67 and 0.69 preoperatively and postoperatively, respectively. Models for RRT had an AU-ROC of 0.77 and 0.80 preoperatively and postoperatively, respectively. These models contained between 3 and 5 variables. Comparatively, comprehensive least absolute shrinkage and selection operator models contained between 21 and 26 variables, with an AU-ROC of 0.71 and 0.72 for AKI and 0.84 and 0.87 for RRT respectively. CONCLUSION: In the present study, simple, clinically applicable models for predicting AKI and RRT preoperatively and immediate postoperatively were developed. Even though AKI prediction remained poor, RRT prediction was good with a parsimonious model.

To describe characteristics and outcomes of Māori and European patients admitted to New Zealand intensive care units (ICUs) between 2009 and 2018.A retrospectively designed prospective cohort study. New Zealand Ministry of Health National Minimum Dataset matched to the Australia New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database. The primary outcome was day-180 mortality. Secondary outcomes were ICU mortality, hospital mortality, discharge to home, ICU length of stay, hospital length of stay and survival time. We report associations between Māori ethnicity and each outcome, with European as the reference category, using regression analyses to adjust sequentially for site, deprivation status, sex, year of admission, the Charlson comorbidity index, age, admission source and type, ICU admission diagnosis, ventilation status and illness severity based on physiological parameters.Māori admitted to ICU were on average 13 years younger than European patients. A total of 968 of 9,681 (10%) Māori and 2,732 of 42,871 (5.2%) European patients were admitted after trauma, and 740 of 9,681 (7.6%) and 2,318 of 42,871 (4.4%) were admitted with sepsis respectively. A total of 1,550 of 9,681 (16.0%) Māori and 6,407 of 42,871 (14.9%) European patients died within 180 days of ICU admission; odds ratio (OR) 1.08; 95% CI, 1.02 to 1.15. When adjusted for age, the OR for day-180 mortality for Māori versus European patients increased substantially. The OR decreased after adjustment for admission source and type, and after accounting for Māori having a higher comorbidity index and more severe illness than European patients. In the final model, incorporating adjustment for all specified variables, Māori ethnicity was not associated with day-180 mortality (adjusted OR 1.01; 95%CI, 0.92 to 1.10). Findings were similar for all secondary outcomes.Compared to European patients, Māori were markedly more likely to be admitted to the ICU after trauma or with sepsis. Despite Māori being on average 13 years younger at ICU admission than their European counterparts, they had more co-morbidities, higher illness severity and a higher risk of dying within 180 days.

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.

Objective: To characterise the assessment and management of delirium in patients admitted to intensive care units (ICUs) in Australia and New Zealand. Methods: We conducted a multicentre observational point prevalence study across 44 adult Australian and New Zealand ICUs. Data were extracted for all patients in the ICU in terms of assessment and treatment of delirium. ICU-level data were collected regarding the use of explicit protocols related to delirium. Results: We studied 627 patients, with 54% (336/627) having at least one delirium screening assessment performed. The Confusion Assessment Method for the ICU (CAM-ICU) was the most frequently used tool (88%, 296/336). Of patients assessed, 20% (68) were identified to have delirium. Eighteen per cent (111) of patients were administered a drug to manage delirium, with 41% (46) of those receiving a drug having no recorded assessment for delirium on that day. Of the drugs used to treat delirium, quetiapine was the most frequently administered. Physical restraints were applied to 8% (48/626) of patients, but only 17% (8/48) of such patients had been diagnosed with delirium. Most physically restrained patients either did not have delirium diagnosed (31%, 15/48) or had no formal assessment recorded (52%, 25/48) on that day. Conclusions: On the study day, more than 50% of patients had a delirium screening assessment performed, with 20% of screened patients deemed to have delirium. Drugs that are prescribed to treat delirium and physical restraints were frequently used in the absence of delirium or the formal assessment for its presence.

Aim The effect of conservative versus liberal oxygen therapy on mortality rates in post cardiac arrest patients is uncertain. Methods We undertook an individual patient data meta-analysis of patients randomised in clinical trials to conservative or liberal oxygen therapy after a cardiac arrest. The primary end point was mortality at last follow-up. Results Individual level patient data were obtained from seven randomised clinical trials with a total of 429 trial participants included. Four trials enrolled patients in the pre-hospital period. Of these, two provided protocol-directed oxygen therapy for 60 min, one provided it until the patient was handed over to the emergency department staff, and one provided it for a total of 72 h or until the patient was extubated. Three trials enrolled patients after intensive care unit (ICU) admission and generally continued protocolised oxygen therapy for a longer period, often until ICU discharge. A total of 90 of 221 patients (40.7%) assigned to conservative oxygen therapy and 103 of 206 patients (50%) assigned to liberal oxygen therapy had died by this last point of follow-up; absolute difference; odds ratio (OR) adjusted for study only; 0.67; 95% CI 0.45 to 0.99; P = 0.045; adjusted OR, 0.58; 95% CI 0.35 to 0.96; P = 0.04. Conclusion Conservative oxygen therapy was associated with a statistically significant reduction in mortality at last follow-up compared to liberal oxygen therapy but the certainty of available evidence was low or very low due to bias, imprecision, and indirectness. PROSPERO registration number CRD42019138931.

Background Over the last two decades, technological advancements in the delivery of extra corporeal membrane oxygenation (ECMO) have seen its use broaden and results improve. However, in the post cardiotomy ECMO patient group, survival remains very poor without significant improvements over the last two decades. Our study aims to report on the Australian experience, with the intention of providing background data for the formation of guidelines in the future. Methods Retrospective analysis of prospectively collected data from the Australian and New Zealand Society of Cardiothoracic Surgeons (ANZSCTS) Database was performed. The ANZSCTS database captures at least 60% of cardiac surgical data in Australia, annually. Data was collected on adult patients who received ECMO post cardiotomy from September 2016 to November 2017 inclusive. Transplant and primary cardiomyopathy patients were excluded. Results Of the 16,605 adult patients undergoing cardiac surgery in the 15-month period of the study, 87 patients required post cardiotomy ECMO (0.52%). The average age of the entire cohort was 56 years. Overall survival to discharge was 43.7% (n=38). Multivariable logistic regression analysis demonstrated that multiorgan failure (MOF), increasing age and longer cardiopulmonary bypass time were significant predictors of in hospital mortality. Conclusions Post cardiotomy ECMO support is an uncommon condition. Survival in this study appears to be better than historical reports. Identification of poor prognostic indicators in this study may help inform the development of guidelines for the most appropriate use of this support modality.

This study explores the antecedents of public support for government surveillance of the private electronic communications and internet browsing of American citizens. The National Security Agency whistleblower, Edward Snowden, famously hoped that uncovering surveillance by the state would create awareness of those practices that would be sufficient to induce public opposition. Other theories suggest that support for these policies might be driven by perceptions of terrorist threat or personal risk of surveillance. We suspect, however, that most citizens do not imagine their own privacy rights to be at risk due to government surveillance, but instead believe members of other groups will be targeted. Therefore, we hypothesize that empathy toward vulnerable outgroups should strongly dampen enthusiasm for surveillance, above and beyond awareness and personal concerns and interests. A nationally representative survey finds knowledge about government surveillance to be higher than many presume, but variation in knowledge or personal interests are largely uncorrelated with support. As hypothesized, empathy for outgroups strongly predicts opposition to these policies, above and beyond a host of other factors. Two experiments further corroborate the result: Outgroup empathy, not exposure to information about actual surveillance practices, boosts public opposition.

Rationale: ICU discharge delay occurs when a patient is considered ready to be discharged but remains in the ICU. The effect of discharge delay on patient outcomes is uncertain.Objectives: To investigate the association between discharge delay and patient outcomes including hospital mortality, readmission to ICU, and length of hospital stay after ICU discharge.Methods: Data were accessed from the Australian and New Zealand Intensive Care Society Adult Patient Database between 2011 and 2019. Descriptive analyses and hierarchical logistic and Cox proportional hazards regression were used to examine association between discharge delay and adjusted outcomes. Patients were stratified and analyzed by categories of mortality risk at ICU admission.Measurements and Main Results: The study included 1,014,540 patients from 190 ICUs: 756,131 (75%) were discharged within 6 hours of being deemed ready, with 137,042 (13%) discharged in the next 6 hours; 17,656 (2%) were delayed 48-72 hours; 31,389 (3.1%) died in hospital; and 45,899 (4.5%) patients were readmitted to ICU. Risk-adjusted mortality declined with increasing discharge delay and was lowest at 48-72 hours (adjusted odds ratio, 0.87; 95% confidence interval, 0.79-0.94). The effect was seen in patients with predicted risk of death on admission to ICU of greater than 5% (adjusted odds ratio, 0.77; 95% confidence interval, 0.70-0.84). There was a progressive reduction in adjusted odds of readmission with increasing discharge delay.Conclusions: Increasing discharge delay in ICUs is associated with reduced likelihood of mortality and ICU readmission in high-risk patients. Consideration should be given to delay the discharge of patients with high risk of death on ICU admission.

Purpose Liberal use of oxygen may contribute to secondary brain injury in patients with hypoxic-ischaemic encephalopathy (HIE). However, there are limited data on the effect of different oxygen regimens on survival and neurological disability in HIE patients. Methods We undertook a post-hoc analysis of the 166 patients with suspected HIE enrolled in a trial comparing conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary endpoint for the current analysis was death or unfavourable neurological outcome at day 180. Key secondary outcomes were day 180 mortality, and cause-specific mortality. Results Patients with HIE allocated to conservative oxygen spent less time in the ICU with an SpO2 ≥ 97% (26 h [interquartile range (IQR) 13–45 vs. 35 h [IQR 19–70], absolute difference, 9 h; 95% CI − 21.4 to 3.4). A total of 43 of 78 patients (55.1%) assigned to conservative oxygen and 49 of 72 patients (68.1%) assigned to usual oxygen died or had an unfavourable neurological outcome at day 180; odds ratio 0.58; 95% CI 0.3–1.12; P = 0.1 adjusted odds ratio 0.54; 95% CI 0.23–1.26; P = 0.15. A total of 37 of 86 patients (43%) assigned to conservative oxygen and 46 of 78 (59%) assigned to usual oxygen had died by day 180; odds ratio 0.53; 95% CI 0.28–0.98; P = 0.04; adjusted odds ratio 0.56; 95% CI 0.25–1.23; P = 0.15. Cause-specific mortality was similar by treatment group. Conclusions Conservative oxygen therapy was not associated with a statistically significant reduction in death or unfavourable neurological outcomes at day 180. The potential for important benefit or harm from conservative oxygen therapy in HIE patients is not excluded by these data. Electronic supplementary material The online version of this article (10.1007/s00134-020-06196-y) contains supplementary material, which is available to authorized users.