Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III).

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 µg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

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.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

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

Quality of Life and 1-Year Survival in Patients With Early Septic Shock: Long-Term Follow-Up of the Australasian Resuscitation in Sepsis Evaluation Trial.

OBJECTIVES: To examine long-term survival and quality of life of patients with early septic shock. DESIGN: Prospective, randomized, parallel-group trial. SETTING: Fifty-one hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland. PATIENTS: One-thousand five-hundred ninety-one patients who presented to the emergency department with early septic shock between October 2008 and April 2014, and were enrolled in the Australasian Resuscitation in Sepsis Evaluation trial. INTERVENTIONS: Early goal-directed therapy versus usual care. MEASUREMENTS AND MAIN RESULTS: Long-term survival was measured up to 12 months postrandomization. Health-related quality of life was measured using the EuroQoL-5D-3L, Short Form 36 and Assessment of Quality of Life 4D at baseline, and at 6 and 12 months following randomization. Mortality data were available for 1,548 patients (97.3%) and 1,515 patients (95.2%) at 6 and 12 months, respectively. Health-related quality of life data were available for 85.1% of survivors at 12 months. There were no significant differences in mortality between groups at either 6 months (early goal-directed therapy 21.8% vs usual care 22.6%; p = 0.70) or 12 months (early goal-directed therapy 26.4% vs usual care 27.9%; p = 0.50). There were no group differences in health-related quality of life at either 6 or 12 months (EuroQoL-5D-3L utility scores at 12 mo early goal-directed therapy 0.65 ± 0.33 vs usual care 0.64 ± 0.34; p = 0.50), with the health-related quality of life of both groups being significantly lower than population norms. CONCLUSIONS: In patients presenting to the emergency department with early septic shock, early goal-directed therapy compared with usual care did not reduce mortality nor improve health-related quality of life at either 6 or 12 months.

Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries.

BACKGROUND: Pandemics of new and emerging infectious diseases are unpredictable, recurrent events that rapidly threaten global health and security. We aimed to identify public views regarding provision of information and consent to participate in primary and critical care clinical research during a future influenza-like illness pandemic. METHODS: Descriptive-interpretive qualitative study, using focus groups (n = 10) and semi-structured interviews (n = 16), with 80 members of the public (>18 years) in Belgium, Spain, Poland and the UK. Local qualitative researchers followed a scenario-based topic guide to collect data. Data were transcribed verbatim, translated into English and subject to framework analysis. RESULTS: Public understandings of pandemics were shaped by personal factors (illness during the previous H1N1 pandemic, experience of life-threatening illness) and social factors (historical references, media, public health information). Informants appreciated safeguards provided by ethically robust research procedures, but current enrolment procedures were seen as a barrier. They proposed simplified enrolment processes for higher risk research and consent waiver for certain types of low-risk research. Decision making about research participation was influenced by contextual, research and personal factors. Informants generally either carefully weighed up various approaches to research participation or responded instinctively. They supported the principle of using routinely collected, anonymized clinical biological samples for research without explicit consent, but regarded this as less acceptable if researchers were motivated primarily by commercial gain. CONCLUSIONS: This bottom-up approach to ascertaining public views on pandemic clinical research has identified support for more proportionate research protection procedures for publically funded, low-risk studies.

The Efficacy of Earplugs as a Sleep Hygiene Strategy for Reducing Delirium in the ICU: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis to assess the efficacy of earplugs as an ICU strategy for reducing delirium. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of controlled trials were searched using the terms "intensive care," "critical care," "earplugs," "sleep," "sleep disorders," and "delirium." STUDY SELECTION: Intervention studies (randomized or nonrandomized) assessing the efficacy of earplugs as a sleep hygiene strategy in patients admitted to a critical care environment were included. Studies were excluded if they included only healthy volunteers, did not report any outcomes of interest, did not contain an intervention group of interest, were crossover studies, or were only published in abstract form. DATA EXTRACTION: Nine studies published between 2009 and 2015, including 1,455 participants, fulfilled the eligibility criteria and were included in the systematic review. Studies included earplugs as an isolated intervention (n = 3), or as part of a bundle with eye shades (n = 2), or earplugs, eye shades, and additional sleep noise abatement strategies (n = 4). The risk of bias was high for all studies. DATA SYNTHESIS: Five studies comprising 832 participants reported incident delirium. Earplug placement was associated with a relative risk of delirium of 0.59 (95% CI, 0.44-0.78) and no significant heterogeneity between the studies (I, 39%; p = 0.16). Hospital mortality was reported in four studies (n = 481) and was associated with a relative risk of 0.77 (95% CI, 0.54-1.11; I, 0%; p < 0.001). Compliance with the placement of earplugs was reported in six studies (n = 681). The mean per-patient noncompliance was 13.1% (95% CI, 7.8-25.4) of those assigned to receive earplugs. CONCLUSIONS: Placement of earplugs in patients admitted to the ICU, either in isolation or as part of a bundle of sleep hygiene improvement, is associated with a significant reduction in risk of delirium. The potential effect of cointerventions and the optimal strategy for improving sleep hygiene and associated effect on patient-centered outcomes remains uncertain.

Early mobilisation in intensive care units in Australia and Scotland: a prospective, observational cohort study examining mobilisation practises and barriers.

INTRODUCTION: Mobilisation of patients in the intensive care unit (ICU) is an area of growing research. Currently, there is little data on baseline mobilisation practises and the barriers to them for patients of all admission diagnoses. METHODS: The objectives of the study were to (1) quantify and benchmark baseline levels of mobilisation in Australian and Scottish ICUs, (2) compare mobilisation practises between Australian and Scottish ICUs and (3) identify barriers to mobilisation in Australian and Scottish ICUs. We conducted a prospective, observational, cohort study with a 4-week inception period. Patients were censored for follow-up upon ICU discharge or after 28 days, whichever occurred first. Patients were included if they were >18 years of age, admitted to an ICU and received mechanical ventilation in the ICU. RESULTS: Ten tertiary ICUs in Australia and nine in Scotland participated in the study. The Australian cohort had a large proportion of patients admitted for cardiothoracic surgery (43.3%), whereas the Scottish cohort had none. Therefore, comparison analysis was done after exclusion of patients admitted for cardiothoracic surgery. In total, 60.2% of the 347 patients across 10 Australian ICUs and 40.1% of the 167 patients across 9 Scottish ICUs mobilised during their ICU stay (p < 0.001). Patients in the Australian cohort were more likely to mobilise than patients in the Scottish cohort (hazard ratio 1.83, 95% confidence interval 1.38-2.42). However, the percentage of episodes of mobilisation where patients were receiving mechanical ventilation was higher in the Scottish cohort (41.1% vs 16.3%, p < 0.001). Sedation was the most commonly reported barrier to mobilisation in both the Australian and Scottish cohorts. Physiological instability and the presence of an endotracheal tube were also frequently reported barriers. CONCLUSIONS: This is the first study to benchmark baseline practise of early mobilisation internationally, and it demonstrates variation in early mobilisation practises between Australia and Scotland.

Preparing ICUs for pandemics.

PURPOSE OF REVIEW: Influenza pandemics occur intermittently and represent an existential global infectious diseases threat. The purpose of this review is to describe clinical and research preparedness for future pandemics. RECENT FINDINGS: Pandemic influenza typically results in large numbers of individuals with life-threatening pneumonia requiring treatment in ICUs. Clinical preparedness of ICUs relates to planning to provide increased 'surge' capacity to meet increased demand and requires consideration of staffing, equipment and consumables, bed-space availability and management systems. Research preparedness is also necessary, as timely clinical research has the potential to change the trajectory of a pandemic. The clinical research response during the 2009 H1N1 influenza pandemic was suboptimal. SUMMARY: Better planning is necessary to optimize both clinical and research responses to future pandemics.

Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study.

Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55-78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5-19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6-23) days versus 8 (4-15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65-0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.

The cost-effectiveness of early goal-directed therapy: an economic evaluation alongside the ARISE trial.

Objective: To determine the cost-effectiveness of early goal-directed therapy (EGDT) for patients with early septic shock. Design: Within-trial cost-effectiveness evaluation. Setting: Nineteen hospitals in Australia and New Zealand. Participants and interventions: Patients with early septic shock enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial were randomly assigned to EGDT versus usual care. A subgroup of patients participated in a nested economic evaluation study in which detailed resource use data were collected until 12 months after randomisation. Outcome measures: Clinical outcomes included lives saved, life-years gained and quality-adjusted life-years (QALYs), with mortality collected until 12 months and health-related quality of life assessed at baseline, 6 and 12 months using the 3-level EuroQol five dimensions questionnaire (EQ-5D-3L). Economic outcomes included health care resource use, costs and cost-effectiveness from the Australian health care payer perspective. Results: A total of 205 patients (100 EGDT, 105 usual care) participated in the nested economic evaluation study, of which 203 had complete resource use data. Unadjusted mean health care costs to 12 months were $67 223 (standard deviation [SD], $72 397) in the EGDT group and $54 179 (SD, $61 980) in the usual care group, with a mean difference of $13 044 (95% CI, -$5791 to $31 878). There was no difference between groups with regards to lives saved (EGDT, 69.4% v usual care, 68.6%; P = 1.0), life-years gained (mean EGDT, 0.746 [SD, 0.406] v usual care, 0.725 [SD, 0.417]; P = 0.72) or QALYs (mean EGDT, 0.318 [SD, 0.291] v usual care, 0.367 [SD, 0.295]; P = 0.24). EGDT was dominated (higher costs, lower effectiveness) by usual care in 80.4% of bootstrap replications. For a willingness-to-pay threshold of $50 000 per QALY, the probability of EGDT being cost-effective was only 6.4%. Conclusions: In patients presenting to the emergency department with early septic shock, EGDT compared with usual care was not cost-effective. Clinical trial registration:ClinicalTrials.gov number NCT00975793.

Comparison of Critical Care Occupancy and Outcomes of Critically Ill Patients during the 2020 COVID-19 Winter Surge and 2009 H1N1 Influenza Pandemic in Australia.

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

Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial.

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.

Comparison of baseline characteristics, treatment and celinical outcomes of critically ill COVID-19 patients admitted in the first and second waves in Australia.

Objective: To report longitudinal differences in baseline characteristics, treatment, and outcomes in patients with coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) between the first and second waves of COVID-19 in Australia. Design, setting and participants: SPRINT-SARI Australia is a multicentre, inception cohort study enrolling adult patients with COVID-19 admitted to participating ICUs. The first wave of COVID-19 was from 27 February to 30 June 2020, and the second wave was from 1 July to 22 October 2020. Results: A total of 461 patients were recruited in 53 ICUs across Australia; a higher number were admitted to the ICU during the second wave compared with the first: 255 (55.3%) versus 206 (44.7%). Patients admitted to the ICU in the second wave were younger (58.0 v 64.0 years; P = 0.001) and less commonly male (68.9% v 60.0%; P = 0.045), although Acute Physiology and Chronic Health Evaluation (APACHE) II scores were similar (14 v 14; P = 0.998). High flow oxygen use (75.2% v 43.4%; P < 0.001) and non-invasive ventilation (16.5% v 7.1%; P = 0.002) were more common in the second wave, as was steroid use (95.0% v 30.3%; P < 0.001). ICU length of stay was shorter (6.0 v 8.4 days; P = 0.003). In-hospital mortality was similar (12.2% v 14.6%; P = 0.452), but observed mortality decreased over time and patients were more likely to be discharged alive earlier in their ICU admission (hazard ratio, 1.43; 95% CI, 1.13-1.79; P = 0.002). Conclusion: During the second wave of COVID-19 in Australia, ICU length of stay and observed mortality decreased over time. Multiple factors were associated with this, including changes in clinical management, the adoption of new evidence-based treatments, and changes in patient demographic characteristics but not illness severity.

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration.

INTRODUCTION: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed. METHODS: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate. RESULTS: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials. DISCUSSION: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.

Very old patients admitted to intensive care in Australia and New Zealand: a multi-centre cohort analysis.

INTRODUCTION: Older age is associated with higher prevalence of chronic illness and functional impairment, contributing to an increased rate of hospitalization and admission to intensive care. The primary objective was to evaluate the rate, characteristics and outcomes of very old (age >or= 80 years) patients admitted to intensive care units (ICUs). METHODS: Retrospective analysis of prospectively collected data from the Australian New Zealand Intensive Care Society Adult Patient Database. Data were obtained for 120,123 adult admissions for >or= 24 hours across 57 ICUs from 1 January 2000 to 31 December 2005. RESULTS: A total of 15,640 very old patients (13.0%) were admitted during the study. These patients were more likely to be from a chronic care facility, had greater co-morbid illness, greater illness severity, and were less likely to receive mechanical ventilation. Crude ICU and hospital mortalities were higher (ICU: 12% vs. 8.2%, P < 0.001; hospital: 24.0% vs. 13%, P < 0.001). By multivariable analysis, age >/= 80 years was associated with higher ICU and hospital death compared with younger age strata (ICU: odds ratio (OR) = 2.7, 95% confidence interval (CI) = 2.4 to 3.0; hospital: OR = 5.4, 95% CI = 4.9 to 5.9). Factors associated with lower survival included admission from a chronic care facility, co-morbid illness, nonsurgical admission, greater illness severity, mechanical ventilation, and longer stay in the ICU. Those aged >or= 80 years were more likely to be discharged to rehabilitation/long-term care (12.3% vs. 4.9%, OR = 2.7, 95% CI = 2.6 to 2.9). The admission rates of very old patients increased by 5.6% per year. This potentially translates to a 72.4% increase in demand for ICU bed-days by 2015. CONCLUSIONS: The proportion of patients aged >or= 80 years admitted to intensive care in Australia and New Zealand is rapidly increasing. Although these patients have more co-morbid illness, are less likely to be discharged home, and have a greater mortality than younger patients, approximately 80% survive to hospital discharge. These data also imply a potential major increase in demand for ICU bed-days for very old patients within a decade.

Priority Needs for Conducting Pandemic-relevant Clinical Research With Children in Europe: A Consensus Study With Pediatric Clinician-researchers.

BACKGROUND: Infectious disease (ID) pandemics pose a considerable global threat and can disproportionately affect vulnerable populations including children. Pediatric clinical research in pandemics is essential to improve children's healthcare and minimize risks of harm by interventions that lack an adequate evidence base for this population. The unique features of ID pandemics require consideration of special processes to facilitate clinical research. We aimed to obtain consensus on pediatric clinician-researchers' perceptions of the priorities to feasibly conduct clinical pediatric pandemic research in Europe. METHODS: Mixed method study in 2 stages, recruiting pediatric clinician-researchers with experience of conducting pediatric ID research in clinical settings in Europe. Stage 1 was an expert stakeholder workshop and interviews. Discussions focused on participant's experience of conducting pediatric ID research and processes to facilitate pandemic research. Information informed stage 2, an online consensus survey to identify pediatric inician-researchers priorities to enable ID pandemic research. RESULTS: Twenty-three pediatric clinician-researchers attended the workshop and 39 completed the survey. Priorities were primarily focused on structural and operational requirements of research design and regulation: (1) clarity within the European Clinical Trials Directive for pediatric pandemic research; (2) simplified regulatory processes for research involving clinical samples and data; and (3) improved relationships between regulatory bodies and researchers. CONCLUSIONS: Results suggest that changes need to be made to the current regulatory environment to facilitate and improve pediatric research in the pandemic context. These findings can provide expert evidence to research policy decision-makers and regulators and to develop a strategy to lobby for change.

Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.

PURPOSE: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. METHODS: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. RESULTS: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. CONCLUSIONS: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.