Systematic reviews and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: mortality, morbidity, and organ failure.

BACKGROUND: Mortality, morbidity, and organ failure are important and common serious harms after surgery. However, there are many candidate measures to describe these outcome domains. Definitions of these measures are highly variable, and validity is often unclear. As part of the International Standardised Endpoints in Perioperative Medicine (StEP) initiative, this study aimed to derive a set of standardised and valid measures of mortality, morbidity, and organ failure for use in perioperative clinical trials. METHODS: Three domains of endpoints (mortality, morbidity, and organ failure) were explored through systematic literature review and a three-stage Delphi consensus process using methods consistently applied across the StEP initiative. Reliability, feasibility, and patient-centredness were assessed in round 3 of the consensus process. RESULTS: A high level of consensus was achieved for two mortality time points, 30-day and 1-yr mortality, and these two measures are recommended. No organ failure endpoints achieved threshold criteria for consensus recommendation. The Clavien-Dindo classification of complications achieved threshold criteria for consensus in round 2 of the Delphi process but did not achieve the threshold criteria in round 3 where it scored equivalently to the Post Operative Morbidity Survey. Clavien-Dindo therefore received conditional endorsement as the most widely used measure. No composite measures of organ failure achieved an acceptable level of consensus. CONCLUSIONS: Both 30-day and 1-yr mortality measures are recommended. No measure is recommended for organ failure. One measure (Clavien-Dindo) is conditionally endorsed for postoperative morbidity, but our findings suggest that no single endpoint offers a reliable and valid measure to describe perioperative morbidity that is not dependent on the quality of deli-vered care. Further refinement of current measures, or development of novel measures, of postoperative morbidity might improve consensus in this area.

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

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

Comparison of 6-month outcomes of sepsis versus non-sepsis critically ill patients receiving mechanical ventilation.

BACKGROUND: Data on long-term outcomes after sepsis-associated critical illness have mostly come from small cohort studies, with no information about the incidence of new disability. We investigated whether sepsis-associated critical illness was independently associated with new disability at 6 months after ICU admission compared with other types of critical illness. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort study in six metropolitan intensive care units in Australia. Adult patients were eligible if they had been admitted to the ICU and received more than 24 h of mechanical ventilation. There was no intervention. RESULTS: The primary outcome was new disability measured with the WHO Disability Assessment Schedule 2.0 (WHODAS) 12 level score compared between baseline and 6 months. Between enrollment and follow-up at 6 months, 222/888 (25%) patients died, 100 (35.5%) with sepsis and 122 (20.1%) without sepsis (P < 0.001). Among survivors, there was no difference for the incidence of new disability at 6 months with or without sepsis, 42/106 (39.6%) and 106/300 (35.3%) (RD, 0.00 (- 10.29 to 10.40), P = 0.995), respectively. In addition, there was no difference in the severity of disability, health-related quality of life, anxiety and depression, post-traumatic stress, return to work, financial distress or cognitive function. CONCLUSIONS: Compared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis admitted to ICU have an increased risk of death, but survivors have a similar risk of new disability at 6 months. Trial registration NCT03226912, registered July 24, 2017.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

Evaluation of medical emergency team medication management practices in acute hospitals: A multicentre study.

BACKGROUND: Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. OBJECTIVES: The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. METHODS: A prospective multicentre audit of intensive care unit-equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. RESULTS: Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8-37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4-16) and neurological medications (median and mode = 6, range = 0-11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. CONCLUSIONS: Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.

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

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

Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic.

OBJECTIVES: To describe the characteristics and outcomes of patients with COVID-19 admitted to intensive care units (ICUs) during the initial months of the pandemic in Australia. DESIGN, SETTING: Prospective, observational cohort study in 77 ICUs across Australia. PARTICIPANTS: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 during 27 February - 30 June 2020. MAIN OUTCOME MEASURES: ICU mortality and resource use (ICU length of stay, peak bed occupancy). RESULTS: The median age of the 204 patients with COVID-19 admitted to intensive care was 63.5 years (IQR, 53-72 years); 140 were men (69%). The most frequent comorbid conditions were obesity (40% of patients), diabetes (28%), hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (24%), and chronic cardiac disease (20%); 73 patients (36%) reported no comorbidity. The most frequent source of infection was overseas travel (114 patients, 56%). Median peak ICU bed occupancy was 14% (IQR, 9-16%). Invasive ventilation was provided for 119 patients (58%). Median length of ICU stay was greater for invasively ventilated patients than for non-ventilated patients (16 days; IQR, 9-28 days v 3 days; IQR, 2-5 days), as was ICU mortality (26 deaths, 22%; 95% CI, 15-31% v four deaths, 5%; 95% CI, 1-12%). Higher Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores on ICU day 1 (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.09-1.21) and chronic cardiac disease (aHR, 3.38; 95% CI, 1.46-7.83) were each associated with higher ICU mortality. CONCLUSION: Until the end of June 2020, mortality among patients with COVID-19 who required invasive ventilation in Australian ICUs was lower and their ICU stay longer than reported overseas. Our findings highlight the importance of ensuring adequate local ICU capacity, particularly as the pandemic has not yet ended.

Long-Term Outcomes after Severe Traumatic Brain Injury in Older Adults. A Registry-based Cohort Study.

Rationale: Older adults (≥65 yr old) account for an increasing proportion of patients with severe traumatic brain injury (TBI), yet clinical trials and outcome studies contain relatively few of these patients.Objectives: To determine functional status 6 months after severe TBI in older adults, changes in this status over 2 years, and outcome covariates.Methods: This was a registry-based cohort study of older adults who were admitted to hospitals in Victoria, Australia, between 2007 and 2016 with severe TBI. Functional status was assessed with Glasgow Outcome Scale Extended (GOSE) 6, 12, and 24 months after injury. Cohort subgroups were defined by admission to an ICU. Features associated with functional outcome were assessed from the ICU subgroup.Measurements and Main Results: The study included 540 older adults who had been hospitalized with severe TBI over the 10-year period; 428 (79%) patients died in hospital, and 456 (84%) died 6 months after injury. There were 277 patients who had not been admitted to an ICU; at 6 months, 268 (97%) had died, 8 (3%) were dependent (GOSE 2-4), and 1 (0.4%) was functionally independent (GOSE 5-8). There were 263 patients who had been admitted to an ICU; at 6 months, 188 (73%) had died, 39 (15%) were dependent, and 32 (12%) were functionally independent. These proportions did not change over longer follow-up. The only clinical features associated with a lower rate of functional independence were Injury Severity Score ≥25 (adjusted odds ratio, 0.24 [95% confidence interval, 0.09-0.67]; P = 0.007) and older age groups (P = 0.017).Conclusions: Severe TBI in older adults is a condition with very high mortality, and few recover to functional independence.

Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults.

BACKGROUND: It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults. METHODS: In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality. RESULTS: From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P=0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P=0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome. CONCLUSIONS: The age of transfused red cells did not affect 90-day mortality among critically ill adults. (Funded by the Australian National Health and Medical Research Council and others; TRANSFUSE Australian and New Zealand Clinical Trials Registry number, ACTRN12612000453886 ; ClinicalTrials.gov number, NCT01638416 .).

Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery.

BACKGROUND: Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. METHODS: In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher's exact test). CONCLUSIONS: Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .).

Characteristics and Outcomes of Critically Ill Trauma Patients in Australia and New Zealand (2005-2017).

OBJECTIVES: To compare the characteristics of adults admitted to the ICU in Australia and New Zealand after trauma with nonelective, nontrauma admissions. To describe trends in hospital mortality and rates of discharge home among these two groups. DESIGN: Retrospective review (2005-2017) of the Australia and New Zealand Intensive Care Society's Center for Outcome and Resource Evaluation Adult Patient Database. SETTING: Adult ICUs in Australia and New Zealand. PATIENTS: Adult (≥17 yr), nonelective, ICU admissions. INTERVENTION: Observational study. MEASUREMENTS AND MAIN RESULTS: We compared 77,002 trauma with 741,829 nonelective, nontrauma patients. Trauma patients were younger (49.0 ± 21.6 vs 60.6 ± 18.7 yr; p < 0.0001), predominantly male (73.1% vs 53.9%; p < 0.0001), and more frequently treated in tertiary hospitals (74.7% vs 45.8%; p < 0.0001). The mean age of trauma patients increased over time but was virtually static for nonelective, nontrauma patients (0.72 ± 0.02 yr/yr vs 0.03 ± 0.01 yr/yr; p < 0.0001). Illness severity increased for trauma but fell for nonelective, nontrauma patients (mean Australia and New Zealand risk of death: 0.10% ± 0.02%/yr vs -0.21% ± 0.01%/yr; p < 0.0001). Trauma patients had a lower hospital mortality than nonelective, nontrauma patients (10.0% vs 15.8%; p < 0.0001). Both groups showed an annual decline in the illness severity adjusted odds ratio (odds ratio) of hospital mortality, but this was slower among trauma patients (trauma: odds ratio 0.976/yr [0.968-0.984/yr; p < 0.0001]; nonelective, nontrauma: odds ratio 0.957/yr [0.955-0.959/yr; p < 0.0001]; interaction p < 0.0001). Trauma patients had lower rates of discharge home than nonelective, nontrauma patients (56.7% vs 64.6%; p < 0.0001). There was an annual decline in illness severity adjusted odds ratio of discharge home among trauma patients, whereas nonelective, nontrauma patients displayed an annual increase (trauma: odds ratio 0.986/yr [0.981-0.990/yr; p < 0.0001]; nonelective, nontrauma: odds ratio 1.014/yr [1.012-1.016/yr; p < 0.0001]; interaction: p < 0.0001). CONCLUSIONS: The age and illness severity of adult ICU trauma patients in Australia and New Zealand has increased over time. Hospital mortality is lower for trauma than other nonelective ICU patients but has fallen more slowly. Trauma patients have become less likely to be discharged home than other nonelective ICU patients.

Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial.

Rationale: Open lung ventilation strategies have been recommended in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine whether a maximal lung recruitment strategy reduces ventilator-free days in patients with ARDS.Methods: A phase II, multicenter randomized controlled trial in adults with moderate to severe ARDS. Patients received maximal lung recruitment, titrated positive end expiratory pressure and further Vt limitation, or control "protective" ventilation.Measurements and Main Results: The primary outcome was ventilator-free days at Day 28. Secondary outcomes included mortality, barotrauma, new use of hypoxemic adjuvant therapies, and ICU and hospital stay. Enrollment halted October 2, 2017, after publication of ART (Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial), when 115 of a planned 340 patients had been randomized (57% male; mean age, 53.6 yr). At 28 days after randomization, there was no difference between the maximal lung recruitment and control ventilation strategies in ventilator-free days (median, 16 d [interquartile range (IQR), 0-21 d], n = 57, vs. 14.5 d [IQR, 0-21.5 d], n = 56; P = 0.95), mortality (24.6% [n = 14/56] vs. 26.8% [n = 15/56]; P = 0.79), or the rate of barotrauma (5.2% [n = 3/57] vs. 10.7% [n = 6/56]; P = 0.32). However, the intervention group showed reduced use of new hypoxemic adjuvant therapies (i.e., inhaled nitric oxide, extracorporeal membrane oxygenation, prone; median change from baseline 0 [IQR, 0-1] vs. 1 [IQR, 0-1]; P = 0.004) and increased rates of new cardiac arrhythmia (n = 17 [29%] vs. n = 7 [13%]; P = 0.03).Conclusions: Compared with control ventilation, maximal lung recruitment did not reduce the duration of ventilation-free days or mortality and was associated with increased cardiovascular adverse events but lower use of hypoxemic adjuvant therapies.Clinical trial registered with www.clinicaltrials.gov (NCT01667146).

Stopping vs. Continuing Aspirin before Coronary Artery Surgery.

BACKGROUND: Most patients with coronary artery disease receive aspirin for primary or secondary prevention of myocardial infarction, stroke, and death. Aspirin poses a risk of bleeding in patients undergoing surgery, but it is unclear whether aspirin should be stopped before coronary artery surgery. METHODS: We used a 2-by-2 factorial trial design to randomly assign patients who were scheduled to undergo coronary artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin trial are reported here. Patients were randomly assigned to receive 100 mg of aspirin or matched placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Among 5784 eligible patients, 2100 were enrolled; 1047 were randomly assigned to receive aspirin and 1053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P=0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P=0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P=0.08). CONCLUSIONS: Among patients undergoing coronary artery surgery, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. (Funded by the Australian National Health and Medical Research Council and others; Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.).

Fresh Red Cells for Transfusion in Critically Ill Adults: An Economic Evaluation of the Standard Issue Transfusion Versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Clinical Trial.

OBJECTIVES: Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults. DESIGN: Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics. SETTING: Fifty-nine ICUs in five countries. PATIENTS: Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit. INTERVENTIONS: Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service. MEASUREMENTS AND MAIN RESULTS: EuroQol 5-dimension 3-level utility scores were similar at 6 months-0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, -0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, -5.3 to -0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, -$2,358; 95% CI, -$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, -0.003 to 0.008). CONCLUSIONS: Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice.

Low-Dose Versus Therapeutic Anticoagulation in Patients on Extracorporeal Membrane Oxygenation: A Pilot Randomized Trial.

OBJECTIVES: To determine whether randomization of patients undergoing extracorporeal membrane oxygenation to either therapeutic or a low-dose anticoagulation protocol results in a difference in activated partial thromboplastin time and anti-Xa. DESIGN: Randomized, controlled, unblinded study. SETTING: Two ICUs of two university hospitals. PATIENTS: Patients admitted to the ICU, who required extracorporeal membrane oxygenation (venovenous or venoarterial) and who did not have a preexisting indication for therapeutic anticoagulation. INTERVENTIONS: Therapeutic anticoagulation with heparin (target activated partial thromboplastin time between 50 and 70 s) or lower dose heparin (up to 12,000 U/24 hr aiming for activated partial thromboplastin time < 45 s). MEASUREMENTS AND MAIN RESULTS: Thirty-two patients were randomized into two study groups that were not significantly different in demographics and extracorporeal membrane oxygenation characteristics. There was a significant difference in the daily geometric mean heparin dose (11,742 U [95% CI, 8,601-16,031 U] vs 20,710 U [95% CI, 15,343-27,954 U]; p = 0.004), daily geometric mean activated partial thromboplastin time (48.1 s [95% CI, 43.5-53.2 s] vs 55.5 s [95% CI, 50.4-61.2 s]; p = 0.04), and daily geometric mean anti-Xa (0.11 international units/mL [95% CI, 0.07-0.18] vs 0.27 [95% CI, 0.17-0.42]; p = 0.01). We found similar results when considering only venovenous extracorporeal membrane oxygenation episodes; however, no difference in daily geometric mean activated partial thromboplastin time between groups when considering only venoarterial extracorporeal membrane oxygenation episodes. CONCLUSIONS: Allocating patients on extracorporeal membrane oxygenation to two different anticoagulation protocols led to a significant difference in mean daily activated partial thromboplastin time and anti-Xa levels between groups. When considering subgroups analyses, these results were consistent in patients on venovenous extracorporeal membrane oxygenation. Our results support the feasibility of a larger trial in patients undergoing venovenous extracorporeal membrane oxygenation to compare different anticoagulation protocols; however, this study does not provide evidence on the optimal anticoagulation protocol for patients undergoing extracorporeal membrane oxygenation.

Supplemental parenteral nutrition versus usual care in critically ill adults: a pilot randomized controlled study.

BACKGROUND: In the critically ill, energy delivery from enteral nutrition (EN) is often less than the estimated energy requirement. Parenteral nutrition (PN) as a supplement to EN may increase energy delivery. We aimed to determine if an individually titrated supplemental PN strategy commenced 48-72 hours following ICU admission and continued for up to 7 days would increase energy delivery to critically ill adults compared to usual care EN delivery. METHODS: This study was a prospective, parallel group, phase II pilot trial conducted in six intensive care units in Australia and New Zealand. Mechanically ventilated adults with at least one organ failure and EN delivery below 80% of estimated energy requirement in the previous 24 hours received either a supplemental PN strategy (intervention group) or usual care EN delivery. EN in the usual care group could be supplemented with PN if EN remained insufficient after usual methods to optimise delivery were attempted. RESULTS: There were 100 patients included in the study and 99 analysed. Overall, 71% of the study population were male, with a mean (SD) age of 59 (17) years, Acute Physiology and Chronic Health Evaluation II score of 18.2 (6.7) and body mass index of 29.6 (5.8) kg/m2. Significantly greater energy (mean (SD) 1712 (511) calories vs. 1130 (601) calories, p < 0.0001) and proportion of estimated energy requirement (mean (SD) 83 (25) % vs. 53 (29) %, p < 0.0001) from EN and/or PN was delivered to the intervention group compared to usual care. Delivery of protein and proportion of estimated protein requirements were also greater in the intervention group (mean (SD) 86 (25) g, 86 (23) %) compared to usual care (mean (SD) 53 (29) g, 51 (25) %, p < 0.0001). Antibiotic use, ICU and hospital length of stay, mortality and functional outcomes were similar between the two groups. CONCLUSIONS: This individually titrated supplemental PN strategy applied over 7 days significantly increased energy delivery when compared to usual care delivery. Clinical and functional outcomes were similar between the two patient groups. TRIAL REGISTRATION: Clinical Trial registry details: NCT01847534 (First registered 22 April 2013, last updated 31 July 2016).

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial.

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. Design, Setting, and Participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. Conclusions and Relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury. Trial Registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.

Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study.

We aimed to compare hypofibrinogenaemia prevalence in major bleeding patients across all clinical contexts, fibrinogen supplementation practice, and explore the relationship between fibrinogen concentrations and mortality. This cohort study included all adult patients from 20 hospitals across Australia and New Zealand who received massive transfusion between April 2011 and October 2015. Of 3566 patients, 2829 (79%) had fibrinogen concentration recorded, with a median first and lowest concentration of 2·0 g/l (interquartile range [IQR] 1·5-2·7) and 1·8 g/l (IQR 1·3-2·4), respectively. Liver transplant (1·7 g/l, IQR 1·2-2·1), trauma (1·8, IQR 1·3-2·5) and vascular surgery (1·9 g/l, IQR 1·4-2·5) had lower concentrations. Total median fibrinogen dose administered from all products was 7·3 g (IQR 3·3-13·0). Overall, 1732 (61%) received cryoprecipitate and 9 (<1%) fibrinogen concentrate. Time to cryoprecipitate issue in those with initial fibrinogen concentration <1 g/l was 2·5 h (IQR 1·2-4·3 h). After adjustment, initial fibrinogen concentration had a U-shaped association with in-hospital mortality [adjusted odds ratios: fibrinogen <1 g/l, 2·31 (95% confidence interval (CI) 1·48-3·60); 1-1·9 g/l, 1·29 (95% CI 0·99-1·67) and >4 g/l, 2·03 (95% CI 1·35-3·04), 2-4 g/l reference category]. The findings indicate areas for practice improvement including timely administration of cryoprecipitate, which is the most common source of concentrated fibrinogen in Australia and New Zealand.

Goal-directed resuscitation for patients with early septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS: In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS: Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay. CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).

Readmissions to Intensive Care: A Prospective Multicenter Study in Australia and New Zealand.

OBJECTIVES: To determine factors independently associated with readmission to ICU and the independent association of readmission with subsequent mortality. DESIGN: Prospective multicenter observational study. SETTING: Forty ICUs in Australia and New Zealand. PATIENTS: Consecutive adult patients discharged alive from ICU to hospital wards between September 2009 and February 2010. INTERVENTIONS: Measurement of hospital mortality. MEASUREMENTS AND MAIN RESULTS: We studied 10,210 patients and 674 readmissions. The median age was 63 years (interquartile range, 49-74), and 6,224 (61%) were male. The majority of readmissions were unplanned (84.1%) but only deemed preventable in a minority (8.9%) of cases. Time to first readmission was shorter for unplanned than planned readmission (3.2 vs 6.9 d; p < 0.001). Primary diagnosis changed between admission and readmission in the majority of patients (60.2%) irrespective of planned (58.2%) or unplanned (60.6%) status. Using recurrent event analysis incorporating patient frailty, we found no association between readmissions and hospital survival (hazard ratios: first readmission 0.88, second readmission 0.90, third readmission 0.44; p > 0.05). In contrast, age (hazard ratio, 1.03), a medical diagnosis (hazard ratio, 1.43), inotrope use (hazard ratio, 3.47), and treatment limitation order (hazard ratio, 17.8) were all independently associated with outcome. CONCLUSIONS: In this large prospective study, readmission to ICU was not an independent risk factor for mortality.