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Aims: To evaluate the effect of energy-dense vs routine enteral nutrition on day-90 mortality by ethnic group in critically ill adults., Methods: Pre-planned subgroup analysis of the 1,257 New Zealanders in a 4,000-participant randomised trial comparing energy-dense enteral nutrition (1.5kcal/mL) with routine enteral nutrition (1kcal/mL) in mechanically ventilated intensive care unit (ICU) patients. The primary purpose of this analysis was to evaluate responses to study treatment by ethnic group (European, Māori, and Pacific Peoples) using ethnicity data recorded in the clinical records. The secondary purpose was to compare the characteristics and outcomes of patients by ethnic group. The primary outcome was day-90 mortality., Results: Among 1,138 patients included in the primary outcome analysis, 165 of 569 (29.0%) assigned to energy-dense nutrition and 156 of 569 patients (27.4%) assigned to routine nutrition died by day 90 (odds ratio; 1.06; 95% CI, 0.92-1.22). There was no statistically significant interaction between treatment allocation and ethnicity with respect to day-90 mortality. Day-90 mortality rates did not vary statistically significantly by ethnic group., Conclusions: Among mechanically ventilated adults in New Zealand ICUs, the effect on day-90 mortality of energy-dense vs routine enteral nutrition did not vary by ethnicity., Competing Interests: Mrs Mackle reports grants from Health Research Council of NZ during the conduct of the study; Dr Ridley reports grants from Baxter Healthcare Corporation, personal fees from Nutricia Australia, personal fees from Baxter Australia, outside the submitted work.

Background: Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality., Results: The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias., Conclusions: In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825 .).

Objectives: Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality)., Data Sources: Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine., Study Selection: We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis., Data Extraction: Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index., Data Synthesis: The median fragility index was 2 (interquartile range, 1-3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index., Conclusions: In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians.

Background: Fresh frozen plasma (FFP) transfusion is used to manage coagulopathy and bleeding in cardiac surgery patients despite uncertainty about its safety and effectiveness. Methods: We performed a propensity score matched analysis of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database including patients from 39 centres from 2005 to 2018. We investigated the association of perioperative FFP transfusion with mortality and other clinical outcomes. Results: Of 119,138 eligible patients, we successfully matched 13,131 FFP recipients with 13,131 controls. FFP transfusion was associated with 30‐day mortality (odds ratio (OR), 1.41; 99% CI, 1.17–1.71; p <.0001), but not with long‐term mortality (hazard ratio (HR), 0.92; 99% CI, 0.85–1.00; p =.007, Holm–Bonferroni α = 0.0004). FFP was also associated with return to theatre for bleeding (OR, 1.97; 99% CI, 1.66–2.34; p <.0001), prolonged intubation (OR, 1.15; 99% CI, 1.05–1.26; p <.0001) and increased chest tube drainage (Mean difference (MD) in mL, 131; 99% CI, 120–141; p <.0001). It was also associated with reduced postoperative creatinine levels (MD in g/L, −6.33; 99% CI, −10.28 to −2.38; p <.0001). Conclusion: In a multicentre, propensity score matched analysis, perioperative FFP transfusion was associated with increased 30‐day mortality and had variable associations with secondary clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0–24] and 14 [0–24], number of days alive and discharged from the ICU through day 28 were 15 [0–22] and 10 [0–22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group. Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified. [ABSTRACT FROM AUTHOR]

Background: Anticoagulation for subsegmental pulmonary embolism (SSPE) is controversial. Aim: To assess the impact of clinical context on anticoagulation and outcomes of SSPE. Methods: We electronically searched computed tomography pulmonary angiogram reports to identify SSPE. We extracted demographic, risk factor, investigations and outcome data from the electronic medical record. We stratified patients according to anticoagulation and no anticoagulation. Results: From 1 January 2017 to 31 December 2019, we identified 166 patients with SSPE in 5827 pulmonary angiogram reports. Of these, 123 (74%) received anticoagulation. Compared with non‐anticoagulated patients, such patients had a different clinical context: higher rates of previous venous thromboembolism (11% vs 0%; P = 0.019), more recent surgery (26% vs 9%; P = 0.015), more elevated serum D‐dimer (22% vs 5%; P = 0.004), more lung parenchymal abnormalities (76% vs 61%; P = 0.037) and were almost twice as likely to require inpatient care (76% vs 42%; P < 0.001). Such patients also had twice the all‐cause mortality at 1 year (32% vs 16%). Conclusions: SSPE is diagnosed in almost 3% of pulmonary angiograms and is associated with high mortality, regardless of anticoagulation, due to coexistent disease processes rather than SSPE. Anticoagulation appears dominant but markedly affected by the clinical context of risk factors, alternative indications and illness severity. Thus, the controversy is partly artificial because anticoagulation after SSPE is clinically contextual with SSPE as only one of several factors. [ABSTRACT FROM AUTHOR]

RED CELL DISTRIBUTION WIDTH (RDW) is a routinely available biomarker of likely erythropoietic dysfunction, which may be associated with adverse outcomes after cardiac surgery. This systematic review and meta-analysis aimed to clarify the prognostic value of RDW in patients undergoing cardiac surgery. The authors searched MEDLINE, Embase, and the Cochrane Library from inception to May 10, 2022 for studies investigating the association between elevated RDW (as defined by the authors of included studies) and adverse outcomes after cardiac surgery. Herein, the authors extracted maximally adjusted hazard ratios (HRs) and odds ratios (ORs) with associated CIs, and pooled them using random-effects inverse- variance modeling. The authors explored interstudy heterogeneity using metaregression. The authors included 26 studies involving 48,092 patients who had undergone cardiac surgery. Elevated preoperative RDW was associated with long-term mortality (pooled HR 1.63, 95% CI 1.05-2.52), short-term mortality (pooled OR 2.16, 95% CI 1.21-3.87), acute kidney injury (AKI; pooled OR 1.30, 95% CI 1.19-1.41) and postoperative atrial fibrillation (POAF; pooled OR 1.44, 95% CI 1.05-1.96). Some studies suggested a significant association between preoperative RDW elevation and neurologic complications; however, their number was insufficient for meta-analysis. The postoperative RDW levels were less consistently reported and could not be meta-analyzed. In conclusion, the authors found that elevated preoperative RDW was associated with increased short- and long-term mortality, POAF, and AKI after cardiac surgery. Further research is needed to investigate its role in the risk stratification of patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Aim: To study the associations between baseline blood glucose levels (BGL), glycemic variability and clinical outcomes in patients with severe acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). Methods: We performed a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. A multivariate Cox regression model was used to assess the association between baseline BGL, glycemic variability and clinical outcomes. The primary outcome was all-cause mortality, and secondary outcomes were duration of hospital and intensive care unit (ICU) stay. Results: Baseline BGL data were available in 1404 out of 1508 patients from the RENAL study. Among them, 627 patients died within 90 days of randomization. Compared to patients in the second quartile (BGL 5.8–7.2 mmol/L), patients in the first quartile (BGL < 5.8 mmol/L) had increased mortality rate (90-day HR 1.48; p = 0.001; 28-day HR 1.47; p = 0.042). However, there were no significant differences in ICU and hospital length of stay (LOS) (p = 0.82 and p = 0.33, respectively). Glycemic variability data were from 1345 out of 1404 patients who had data for BG values within 28 days. Higher coefficient of variation (CV) (HR 1.02; P trend = 0.002) and standard deviation value (SD) (HR 1.29; P trend = 0.027) were associated with higher risk of death at day 90. Conclusions: We identified a low BGL within the normal physiological range at baseline and greater CV and SD values as significant modifiable risk factors for mortality in severe AKI patients in ICU, which may be a target for intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < .001), delirium (10% vs 4%; P < .001), longer LOS in the ICU and hospital, and increased new chronic care discharge (3% vs 1%; P < .001), with worse outcomes associated with increasing CFS category. Of patients with very severe frailty (CFS score, 8), 39% died in hospital vs 2% of very fit patients (CFS score, 1; multivariate categorical CFS score, 8 [reference, 1]; OR, 7.83 [95% CI, 6.39-9.59]; P < .001). After adjustment for illness severity, frailty remained highly significantly predictive of mortality, including among patients younger than 50 years, with improvement in the area under the receiver operating characteristic curve of the Acute Physiology and Chronic Health Evaluation III-j score to 0.882 (95% CI, 0.879-0.885) from 0.868 (95% CI, 0.866-0.871) with the addition of frailty (P < .001).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. [ABSTRACT FROM AUTHOR]

Background In patients treated with continuous renal replacement therapy (CRRT), early net ultrafiltration (NUF) rates may be associated with differential outcomes. We tested whether higher early NUF rates are associated with increased mortality in CRRT patients. Methods We performed a retrospective, observational study of all patients treated with CRRT within 14 days of intensive care unit admission. We defined the early (first 48 h) NUF rate as the volume of fluid removed per hour adjusted for patient body weight and analysed as a categorical variable (>1.75, 1.01–1.75 and <1.01 mL/kg/h). The primary outcome was 28-day mortality. To deal with competing risk, we also compared different time epochs. Results We studied 347 patients {median age 64 [interquartile range (IQR) 53–71] years and Acute Physiology and Chronic Health Evaluation III score 73 [IQR 54–90]}. Compared with NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h were associated with greater mortality rates in each epoch: Days 0–5, adjusted hazard ratio (aHR) 1.27 [95% confidence interval (CI) 1.21–1.33]; Days 6–10, aHR 1.62 (95% CI 1.55–1.68); Days 11–15, aHR 1.87 (95% CI 1.79–1.94); Days 16–26, aHR 1.92 (95% CI 1.84–2.01) and Days 27–28, aHR 4.18 (95% CI 3.98–4.40). For every 0.5 mL/kg/h NUF rate increase, mortality similarly increased during these epochs. Conclusion Compared with early NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h are associated with increased mortality. These observations provide the rationale for clinical trials to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Objective: Intravenous antimicrobial therapy within 1 h of the diagnosis of septic shock is recommended in international sepsis guidelines. We aimed to evaluate the association between antimicrobial timing and mortality in patients presenting to the ED with septic shock. Methods: Post‐hoc analysis of 1587 adult participants enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) multicentre trial of early goal‐directed therapy for whom the time of initial antimicrobial therapy was recorded. We compared participants who had initiation of antimicrobials within the first hour (early) or later (delayed) of ED presentation. A propensity score model using inverse probability of treatment weighting was constructed to account for confounding baseline covariates. The primary outcome was 90‐day mortality. Results: The median (interquartile range) time to initiating antimicrobials was 69 (39–112) min with 712 (44.9%) participants receiving the first dose within the first hour of ED presentation. Compared with delayed therapy, early administration was associated with increased baseline illness severity score and greater intensity of resuscitation pre‐randomisation (fluid volumes, vasopressors, invasive ventilation). All‐cause 90‐day mortality was also higher; 22.6% versus 15.5%; unadjusted odds ratio (OR) 1.58 (95% confidence interval [CI] 1.16–2.15), P = 0.004. After inverse probability of treatment weighting, the mortality difference was non‐significant; OR 1.30 (95% CI 0.95–1.76), P = 0.1. Live discharge rates from ICU (OR 0.81, 95% CI 0.72–0.91; P = 0.80) and hospital (OR 0.93, 95% CI 0.82–1.06; P = 0.29) were also not different between groups. Conclusion: In this post‐hoc analysis of the ARISE trial, early antimicrobial therapy was associated with increased illness severity, but 90‐day adjusted mortality was not reduced. [ABSTRACT FROM AUTHOR]

Introduction: In continuous renal replacement therapy (CRRT)-treated patients, a net ultrafiltration (NUF) rate >1.75 mL/kg/h has been associated with increased mortality. However, there may be heterogeneity of effect of NUF rate on mortality, according to patient characteristics. Methods: To investigate the presence and impact of heterogeneity of effect, we performed a secondary analysis of the "Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy" (RENAL) trial. Exposure was NUF rate (weight-adjusted fluid volume removed per hour) stratified into tertiles (<1.01 mL/kg/h; 1.01–1.75 mL/kg/h; or >1.75 mL/kg/h). Primary outcome was 90-day mortality. Patients were clustered according to baseline characteristics. Heterogeneity of effect was assessed according to clusters and baseline edema and related to the additional impact of baseline cardiovascular Sequential Organ Failure Assessment (SOFA) score. We excluded patients with missing values for baseline weight and/or treatment duration. Results: We identified 2 clusters. The largest (cluster 1; n = 941) included more severely ill patients, with more sepsis, more edema, and more vasopressor therapy (all p < 0.001). Compared to the middle tertile, the probability of harm was greater with the high tertile of NUF rate in patients in cluster 1 and in patients with baseline edema (probability of harm, cluster 1: 99.9%; edema: 99.1%). Moreover, higher baseline cardiovascular SOFA score also increased mortality risk with both high and low compared to middle NUF rates in cluster 1 patients and in patients with edema. Conclusions: In CRRT patients, both high and low NUF rates may be harmful, especially in those with edema, sepsis, and greater illness severity. Cardiovascular SOFA scores modulate this association. Additional studies are needed to test these hypotheses, and targeted trials of NUF rates based on risk stratification appear justified. Trial Registration: ClinicalTrials.gov identifier: NCT00221013. [ABSTRACT FROM AUTHOR]

Purpose: To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of lower or higher 90-day mortality according to age, and other identified clusters.Methods: Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation.Results: HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio [OR], 0.83 [95% credible interval [CrI] 0.68-1.00], with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 [95% CrI 1.02-1.56]. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 [95% CrI 0.65-1.14]) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2.Conclusion: In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood.Method: This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH < 7.3 and a Base Excess < -4 mEq/L, within 24-h of ICU admission) were included. Screening continued until 10 patients who received and 10 patients who did not receive sodium bicarbonate in the first 24 h (early bicarbonate therapy) were included at each site. The primary outcome was ICU mortality, and the association between sodium bicarbonate and the clinical outcomes were assessed using regression analysis with generalized linear mixed model.Results: We screened 9437 patients. Of these, 1292 had early metabolic acidosis (14.0%). Early sodium bicarbonate was given to 18.0% (233/1292) of these patients. Dosing, physiological, and clinical outcome data were assessed in 360 patients. The median dose of sodium bicarbonate in the first 24 h was 110 mmol, which was not correlated with bodyweight or the severity of metabolic acidosis. Patients who received early sodium bicarbonate had higher APACHE III scores, lower pH, lower base excess, lower PaCO2, and a higher lactate and received higher doses of vasopressors. After adjusting for confounders, the early administration of sodium bicarbonate was associated with an adjusted odds ratio (aOR) of 0.85 (95% CI, 0.44 to 1.62) for ICU mortality. In patients with vasopressor dependency, early sodium bicarbonate was associated with higher mean arterial pressure at 6 h and an aOR of 0.52 (95% CI, 0.22 to 1.19) for ICU mortality.Conclusions: Early metabolic acidosis is common in critically ill patients. Early sodium bicarbonate is administered by clinicians to more severely ill patients but without correction for weight or acidosis severity. Bicarbonate therapy in acidotic vasopressor-dependent patients may be beneficial and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: A threshold Clinical Frailty Scale (CFS) of 5 (indicating mild frailty) has been proposed to guide ICU admission for UK patients with coronavirus disease 2019 (COVID-19) pneumonia. However, the impact of frailty on mortality with (non-COVID-19) pneumonia in critical illness is unknown. We examined the triage utility of the CFS in patients with pneumonia requiring ICU.Methods: We conducted a retrospective cohort study of adult patients admitted with pneumonia to 170 ICUs in Australia and New Zealand from January 1, 2018 to September 31, 2019. We classified patients as: non-frail (CFS 1-4) frail (CFS 5-8), mild/moderately frail (CFS 5-6),and severe/very severely frail (CFS 7-8). We evaluated mortality (primary outcome) adjusting for site, age, sex, mechanical ventilation, pneumonia type and illness severity. We also compared the proportion of ICU bed-days occupied between frailty categories.Results: 1852/5607 (33%) patients were classified as frail, including1291/3056 (42%) of patients aged >65 yr, who would potentially be excluded from ICU admission under UK-based COVID-19 triage guidelines. Only severe/very severe frailty scores were associated with mortality (adjusted odds ratio [aOR] for CFS=7: 3.2; 95% confidence interval [CI]: 1.3-7.8; CFS=8 [aOR: 7.2; 95% CI: 2.6-20.0]). These patients accounted for 7% of ICU bed days. Vulnerability (CFS=4) and mild frailty (CFS=5) were associated with a similar mortality risk (CFS=4 [OR: 1.6; 95% CI: 0.7-3.8]; CFS=5 [OR: 1.6; 95% CI: 0.7-3.9]).Conclusions: Patients with severe and very severe frailty account for relatively few ICU bed days as a result of pneumonia, whilst adjusted mortality analysis indicated little difference in risk between patients in vulnerable, mild, and moderate frailty categories. These data do not support CFS ≥5 to guide ICU admission for pneumonia. [ABSTRACT FROM AUTHOR]

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843). [ABSTRACT FROM AUTHOR]

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about early (first 48 h) hourly and cumulative fluid balance (FB) during continuous renal replacement therapy (CRRT). Objectives: To study the characteristics and outcome associations of early hourly and cumulative FB. Methods: We studied FB in CRRT patients (2016–2018). Results: Among 350 patients, mean hourly FB became negative after 20 CRRT hours, but within 6 CRRT hours in patients with baseline fluid overload. A negative early FB was never achieved in patients receiving vasopressor therapy (p < 0.001). Mortality was 31%. The percentage of hourly negative FB was independently associated with decreased ICU mortality. A time-weighted hourly FB between 18.5 and –33 mL/h was also significantly and independently associated with decreased mortality. Conclusions: In CRRT patients, an early FB conservative approach is possible, modulated by patient characteristics, and associated with a low mortality. Moreover, avoidance of an early positive FB is associated with decreased mortality. [ABSTRACT FROM AUTHOR]

Background: Mortality in intensive care unit (ICU) patients with acute kidney injury (AKI) remains high. Previous studies have explored the role of HMG‐CoA reductase inhibitors (statins) with variable findings. Methods: The Randomized Evaluation of Normal versus Augmented Level Replacement Therapy (RENAL) Study recruited 1508 participants requiring dialysis in ICU between 2006 and 2009. Statin use was recorded at study baseline. Multivariate Cox modelling was used to assess associations of such statin use and all‐cause mortality. Propensity score analysis was performed for sensitivity analysis. The primary outcome was all‐cause mortality at 90 days. Results: Of the 1462 participants with the available data on statin usage, 187 (12.8%) received statin therapy at baseline. Participants who receiving statins were older (P < 0.001), less likely to have sepsis or require mechanical ventilation (P < 0.001). Multivariable analysis showed statin use did not have significant associations with mortality at both day 28 (hazard ratio (HR) = 1.053, 95% confidence interval (CI) = 0.784–1.415, P = 0.730) and day 90 (HR = 1.091, 95% CI = 0.836–1.424, P = 0.520). Propensity score analysis confirmed the lack of association between statin use and mortality at day 90 (HR = 1.042, 95% CI = 0.734–1.479, P = 0.819). However, in septic patients, multivariable analysis suggested statin therapy was associated with a trend to higher mortality at day 90 (HR = 1.688, 95% CI = 1.132–2.519, P = 0.010) and continuation of statins was associated with higher mortality (HR = 2.160, 95% CI = 1.296–3.599, P = 0.003), compared with statin withdrawal. Conclusion: In the RENAL study cohort, baseline statin use was not associated with mortality. Our findings do not support a protective role of statins in ICU patients with severe AKI. Clinical Trials registration number for the RENAL study: NCT00221013, the date of registration: September 14, 2005. SUMMARY AT A GLANCE: Among 1,462 patients requiring dialysis in the intensive care unit (ICU) between 2006 and 2009, there was no association between statin therapy and mortality. However, among patients with septic acute kidney injury (AKI) requiring dialysis, baseline statin use correlates with increased mortality. These findings do not support a protective role of statins in ICU patients with severe AKI, but raise caution about statin use among patients with septic AKI. [ABSTRACT FROM AUTHOR]

The article discusses a study which informs on continuous renal replacement therapy (CRRT) trial to test whether the independent association of net ultrafiltration (NUF) rate with mortality is mediated by the effect of NUF on daily fluid balance and whether this effect is further moderated by baseline fluid overload. It mentions that patients undergoing CRRT, high NUF rates were associated with increased mortality compared with moderate NUF rate.

Frailty is one of the major challenges for intensive care, affecting one-third of intensive care unit patients and being associated with a range of poor health outcomes. Determination of frailty in critical illness using the Clinical Frailty Scale has recently been adopted by the Australian and New Zealand Intensive Care Society, but it is not known whether this is able to be measured from the clinical record without interviewing patients or their relatives. The aims of this retrospective cohort study were to test whether a Clinical Frailty Scale score could be assigned in an intensive care unit population from the clinical record, and to assess the inter-rater reliability of frailty measured in this manner. A total of 144 patients were enrolled. Of these, 137 (95%) were able to have a Clinical Frailty Scale score assigned, and 22 (15%) were scored as frail (Clinical Frailty Scale ≥5). Cohen's kappa coefficient for inter-rater reliability between assessors was 0.67, confirming substantial agreement. Consistent with other critically ill cohorts, frailty was associated on multivariate analysis with age, Charlson comorbidity score, dependence with activities of daily living, and limitation of medical treatment, indicating validity of this approach to frailty measurement. Our results imply that frailty measurement is possible and feasible from the intensive care unit clinical record, which is of importance as routine measurement and reporting of frailty in intensive care units in our region increases. Future work should seek to validate an assigned Clinical Frailty Scale score with that obtained directly from patients or their next of kin. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the prognostic value of baseline SOFA coagulation score (SOFA‐CS) and change in platelet counts in patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). Methods: We performed a secondary analysis from the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. The primary endpoint was all‐cause mortality at 90 days after randomization. The association between baseline SOFA‐CS, changes in platelet counts, process of care, and clinical outcomes were analyzed using multivariate Cox model adjusted for baseline variables. Results: The complete SOFA‐CS data were available in 1454 out of 1508 patients from the RENAL study. Among them, 708 patients had an abnormal SOFA‐CS (defined as SOFA‐CS ≥ 1), while 746 patients had normal SOFA‐CS at baseline (SOFA‐CS = 0). An abnormal SOFA‐CS was independently associated with an increased risk of death at 90 days (HR = 1.27, 95% CI = 1.05–1.53, P = 0.015). An abnormal SOFA‐CS was associated with prolonged length of ICU stay and duration of mechanical ventilation as well. Furthermore, there was no significant association between changes in platelet counts in patients who survived beyond 4 days and 90 day mortality (HR = 1.26, 95% CI = 0.29–5.56, P = 0.76). However, on multivariable analysis a decline of ≥60% (HR = 1.93, 95% CI = 1.23–3.05, P = 0.004) was associated with 90 day mortality in patients who survived beyond the first 4 days. Conclusions: In the RENAL study, thrombocytopaenia is a common phenomenon in patients with severe AKI receiving CRRT. An abnormal baseline SOFA‐CS and reductions in platelet counts were associated with increased mortality at 90 days. Summary at a Glance: A secondary analysis of prospectively collected data from the RENAL study confirmed that an abnormal baseline SOFA CS (sequential organ failure assessment coagulation score), based on a reduced platelet count, was associated with increased 90‐day mortality in AKI patients on CRRT. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO).Methods: Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI.Results: Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09).Conclusions: Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI. [ABSTRACT FROM AUTHOR]

Purpose: Persistent critical illness has been described as a subtype of chronic critical illness, characterized as a transition after ICU admission where primary diagnosis and illness acuity are no better at predicting outcome than pre-hospital characteristics. Herein we describe the occurrence and outcomes associated with persistent critical illness in a large Canadian health region.Methods: In this multi-center observational cohort study, all patients aged older than 14 years admitted to 12 ICUs in Alberta, Canada, between June 2012 and December 2014 were included. Primary outcome was in-hospital mortality. Predictors at ICU admission were separated into: (1) antecedent characteristics component (e.g., demographics, chronic health component of the APACHE II score, comorbid conditions); and (2) acute illness component (e.g., APACHE II score at admission, SOFA score, primary diagnostic category, surgical status, acute organ support). Using multiple statistical methods and randomly splitting the cohort into development and validation samples for risk scoring using logistic regression, we examined mortality prediction of each of these components to characterize the timing of transition to persistent critical illness.Results: We included 17,783 patients with a median (IQR) age 61 years (49-71), 62% were male, and mean APACHE II score was 19.0 (7.9). In-hospital mortality was 16.8%. Among patients alive and in ICU, the acute illness component, which accurately predicted outcome at the time of admission [area under the receiver operating characteristics curve (AUC) 0.861; 95% CI 0.860-0.862], progressively lost predictive ability and was no longer more predictive than antecedent characteristics after 9 days. This transition defined the onset of persistent critical illness and comprised 16.1% (n = 2856) of the cohort. Transition ranged between 5 and 21 days across subgroups. In-hospital mortality was greater for those with persistent critical illness [23.9% vs. 15.5%, odds ratio (OR) 1.54; 95% CI 1.43-1.67, p < 0.001]. Persistently critically ill patients accounted for 54.5% of 97844 ICU bed-days and 36.3% of 420119 hospital bed-days, respectively.Conclusions: Persistent critical illness occurred in one in six patients admitted to Alberta ICUs and portended greater risk of death, prolonged ICU and hospital stay, and disproportionate use of health resources compared to patients without persistent critical illness. [ABSTRACT FROM AUTHOR]

The article offers information on a study of the provision of supplemental oxygen is perhaps the most ubiquitous therapeutic intervention in critical care medicine. It mentions aim of the study was to examine the association between longitudinal exposure to hyperoxemia; and also mentions the association between exposure to hyperoxemia and mortality risk in critical illness has been reported in a number of studies.

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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). Background: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. Methods: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. Results: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33–1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12–0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66–3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. Conclusions: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma. [ABSTRACT FROM AUTHOR]

Aims: To study the association between higher versus lower continuous renal replacement therapy (CRRT) intensity and mortality in critically ill patients with combined acute kidney injury and liver dysfunction. Methods: Post-hoc analysis of patients with liver dysfunction (Sequential Organ Failure Assessment liver score ≥2 or diagnosis of liver failure/transplant) included in the Randomized Evaluation of Normal versus Augmented Level renal replacement therapy (RENAL) trial. Results: Of 444 patients, 210 (47.3%) were randomized to higher intensity (effluent flow 40 mL/kg/h) and 234 (52.7%) to lower intensity (effluent flow 25 mL/kg/h) therapy. Overall, 79 and 86% of prescribed effluent flow was delivered in the higher-intensity and lower-intensity groups, respectively (p < 0.001). In total, 113 (54.1%) and 120 (51.3%) patients died in each group. On multivariable Cox regression analysis, we found no independent association between higher CRRT intensity and mortality (HR 0.93, 95% CI 0.70-1.24; p = 0.642). Conclusions: In RENAL patients with liver dysfunction, higher CRRT intensity was not associated with reduced mortality. [ABSTRACT FROM AUTHOR]