Simvastatin in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Patient's experiences of endotracheal tubes and suction following cardiac surgery.

BACKGROUND: There is a growing body of evidence addressing the patient experience of intensive care, including patient reports that the presence of an endotracheal tube is bothersome and distressing, and that endotracheal suction is moderately to extremely painful. Yet there remains little information about the patient experience of the endotracheal tube and suction in those patients receiving planned short-term mechanical ventilation. AIMS AND OBJECTIVES: This study aimed to describe the patient experience of the endotracheal tube and suction, following mechanical ventilation in post-operative cardiac surgical patients. DESIGN: This qualitative study used inductive thematic analysis. Participants having planned cardiac surgery, anticipated to receive less than 12-hours mechanical ventilation, were approached pre-operatively and written consent provided. METHODS: Ten participants were recruited using purposive sampling. Semi-structured interviews were conducted between days four and six post-operatively. One researcher interviewed all participants; two researchers independently read, coded, and agreed themes. FINDINGS: None of the participants recalled endotracheal suction, while half had no recollection of the endotracheal tube. Three themes were identified; the experience of the endotracheal tube and extubation, the experience of emerging from sedation, and participants concerns about the future. The presence of the endotracheal tube was described as bothersome, whilst breathing through the tube and extubation were described as 'weird' and 'strange' but not painful. CONCLUSIONS: Knowledge of the patient experience can help inform nursing practice by improving pre and post-operative care planning. RELEVANCE TO CLINICAL PRACTICE: This study adds to the body of knowledge about the patient experience of the endotracheal tube and extubation. TRIAL REGISTRATION: Prospective registration with the Australian New Zealand Clinical Trials Registry. www.anzctr.org.au (ACTRN12616001515482).

Impact of Nonpharmaceutical Interventions on ICU Admissions During Lockdown for Coronavirus Disease 2019 in New Zealand-A Retrospective Cohort Study.

OBJECTIVES: Nonpharmaceutical interventions are implemented internationally to mitigate the spread of severe acute respiratory syndrome coronavirus 2 with the aim to reduce coronavirus disease 2019-related deaths and to protect the health system, particularly intensive care facilities from being overwhelmed. The aim of this study is to describe the impact of nonpharmaceutical interventions on ICU admissions of non-coronavirus disease 2019-related patients. DESIGN: Retrospective cohort study. SETTING: Analysis of all reported adult patient admissions to New Zealand ICUs during Level 3 and Level 4 lockdown restrictions from March 23, to May 13, 2020, in comparison with equivalent periods from 5 previous years (2015-2019). SUBJECTS: Twelve-thousand one-hundred ninety-two ICU admissions during the time periods of interest were identified. MEASUREMENTS: Patient data were obtained from the Australian and New Zealand Intensive Care Society Adult Patient Database, Australian and New Zealand Intensive Care Society critical care resources registry, and Statistics New Zealand. Study variables included patient baseline characteristics and ICU resource use. MAIN RESULTS: Nonpharmaceutical interventions in New Zealand were associated with a 39.1% decrease in ICU admission rates (p < 0.0001). Both elective (-44.2%) and acute (-36.5%) ICU admissions were significantly reduced when compared with the average of the previous 5 years (both p < 0.0001). ICU occupancy decreased from a mean of 64.3% (2015-2019) to 39.8% in 2020. Case mix, ICU resource use per patient, and ICU and hospital mortality remained unchanged. CONCLUSIONS: The institution of nonpharmaceutical interventions was associated with a significant decrease in elective and acute ICU admissions and ICU resource use. These findings may help hospitals and health authorities planning for surge capacities and elective surgery management in future pandemics.

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

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

Device-related pressure injuries in adult intensive care unit patients: An Australian and New Zealand point prevalence study.

BACKGROUND: Device-related pressure injuries (DRPIs) are an ongoing iatrogenic problem evident in intensive care unit (ICU) settings. Critically ill patients are at high risk of developing pressure injuries caused by devices. OBJECTIVE: The aim of the study was to determine the prevalence of DRPI in critically ill patients in intensive care and the location, stage, and attributable device of DRPI and describe the products and processes of care used to prevent these injuries. METHODS: This was a prospective, multicentre, cross-sectional point prevalence study of patients aged more than 16 years in Australian and New Zealand ICUs. The study was part of the Australian and New Zealand Intensive Care Society Clinical Trials Group Point Prevalence Program coordinated by The George Institute for Global Health. MAIN OUTCOME MEASURE: Identification of DRPI on the study day was the main outcome measure. RESULTS: Of the 624 patients included from 44 participating ICUs, 27 were found to have 35 identified DRPIs, giving a point prevalence DRPI rate of 4.3% (27/624). Study patients had a mean age of 59 years, and 60.3% were men. Patients with DRPI compared with patients without DRPI were significantly heavier (median: 92 kg versus 80 kg, respectively, p = 0.027), were less likely to survive the ICU (63.0% versus 85.9%, respectively, p = 0.015), had higher Acute Physiology and Chronic Health Evaluation II scores at admission to the ICU (median: 20 versus 16, respectively, p = 0.001), received mechanical ventilation more often (88.9% versus 43.5%, respectively, p < 0.001), and were more frequently diagnosed with respiratory conditions (37.0% versus 18.6%, respectively, p = 0.022). Processes of care activities were surveyed in 42 ICUs. Most DRPIs were attributed to endotracheal tubes and other respiratory devices. Forty-two ICUs reported processes of care to prevent DRPI, and just more than half of the participating sites (54.8%, 23/44) reported a dedicated ICU-based protocol for prevention of DRPI. CONCLUSION: DRPIs pose a burden on patients in the ICU. Our study showed a DRPI prevalence comparable with other studies. Prevention strategies targeting DRPI should be included in ICU-specific pressure injury prevention guidelines or protocols.

Study protocol: A randomized controlled trial assessing the avoidance of endotracheal suction in cardiac surgical patients ventilated for ≤ 12 hr.

AIMS: To assess the safety and efficacy of avoiding endotracheal suction in postoperative cardiac surgical patients mechanically ventilated for ≤ 12 hr. DESIGN: A prospective, single centre, single blind, non-inferiority, randomized controlled trial evaluating the safety and efficacy of avoiding suction in uncomplicated, postoperative, adult cardiac surgical patients mechanically ventilated for ≤ 12 hr. METHODS: Randomization will be performed on return to intensive care (ICU) with allocation to either usual postoperative care including suction or to usual care with no suction (intervention arm). The primary outcome is the ratio of partial pressure of oxygen (PaO2 ) to fraction of inspired oxygen (FiO2 ) (P/F) 6 hr after extubation. Pain assessments will be performed before, during and after endotracheal suction (ETS) and the patient experience will be investigated with a brief interview the following day. Ethics approval was received in October 2015. DISCUSSION: Endotracheal suction is performed as part of airway management but has potential complications and there is little robust evidence to guide practice. This study will add to the evidence base about the need and benefit of endotracheal suction in this patient cohort. IMPACT: As there is currently no published evidence about the safety of avoiding endotracheal suction. This study will provide the first evidence about avoidance of endotracheal suction in patients ventilated for less than 1 day. If non-inferior, the results have the capacity to change nursing practice by avoiding a potentially unnecessary procedure, it will build on the body of knowledge about the patient experience.

Endotracheal suction in intensive care: A point prevalence study of current practice in New Zealand and Australia.

BACKGROUND: Despite the evidence and available guidelines about endotracheal suction (ETS), a discrepancy between published guidelines and clinical practice persists. To date, ETS practice in the adult intensive care unit (ICU) population across New Zealand and Australia has not been described. OBJECTIVE: To describe ICU nurses' ETS practice in New Zealand and Australia including the triggers for performing endotracheal suction. METHODS: A single day, prospective observational, binational, multicentre point prevalence study in New Zealand and Australian ICUs. All adult patients admitted at 10:00 on the study day were included. MAIN OUTCOME MEASURES: In addition to patient demographic data, we assessed triggers for ETS, suction canister pressures, use of preoxygenation, measures of oxygenation, and ETS at extubation. RESULTS: There were 682 patients in the ICUs on the study day, and 230 were included in the study. Three of 230 patients were excluded for missing data. A total of 1891 ETS events were performed on 227 patients during the study day, a mean of eight interventions per patient. The main triggers reported were audible (n = 385, 63%) and visible (n = 239, 39%) secretions. Less frequent triggers included following auscultation (n = 142, 23%), reduced oxygen saturations (n = 140, 22%), and ventilator waveforms (n = 53, 9%). Mean suction canister pressure was -337 mmHg (standard deviation = 189), 67% of patients received preoxygenation (n = 413), and ETS at extubation was performed by 84% of nurses. CONCLUSION: Some practices were inconsistent with international guidelines, in particular concerning patient assessment for ETS and suction canister pressure.

A Multicenter, Randomized, Controlled Phase IIb Trial of Avoidance of Hyperoxemia during Cardiopulmonary Bypass.

BACKGROUND: Cardiac surgery utilizing cardiopulmonary bypass (CPB) is one of the most common forms of major surgery. Cardiac surgery-associated multiorgan dysfunction (CSA-MOD) is well recognized and includes acute kidney injury (AKI), hepatic impairment, myocardial damage, and postoperative neurologic deficit. Pathophysiology of CSA-MOD involves numerous injurious pathways linked to the use of CPB including oxidative stress and formation of reactive iron species. During cardiac surgery with CPB, arterial return blood is oxygenated to supranormal levels. This study aimed to determine whether the avoidance of arterial hyperoxemia decreased oxidative stress and reduced the severity of the multiorgan dysfunction in patients undergoing cardiac surgery utilizing CPB. METHODS: The study was a multicenter, open-label, parallel-group, randomized controlled study of the avoidance of arterial hyperoxemia versus usual care in patients undergoing cardiac surgery involving CPB. Primary outcome was the incidence and severity of AKI. Secondary outcomes included serum biomarkers for CSA-MOD, duration of mechanical ventilation, and length of intensive care and hospital stay. RESULTS: A total of 298 patients were randomized and analyzed at two hospitals in New Zealand and Australia. Mean PaO2 was significantly different between groups during CPB. There was no difference in the development of AKI (intervention arm 72.0% vs. usual care 66.2%; difference, -5.8% [95% CI, -16.1 to 4.7%]; P = 0.28), other markers of organ damage, or intensive care unit and hospital length of stay. CONCLUSIONS: Avoiding modest hyperoxemia during CPB failed to demonstrate any difference in AKI, markers of organ damage, or length of stay.

Management of severe acute respiratory distress syndrome in Australia and New Zealand (SAGE-ANZ): An observational study.

Objective: Acute respiratory distress syndrome (ARDS) is associated with significant mortality, morbidity, and cost. We aimed to describe characteristics and management of adult patients admitted to intensive care units (ICUs) in Australia and New Zealand with moderate-severe ARDS, to better understand contemporary practice. Design: Bi-national, prospective, observational, multi-centre study. Setting: 19 ICUs in Australia and New Zealand. Participants: Mechanically ventilated patients with moderate-severe ARDS. Main outcome measures: Baseline demographic characteristics, ventilation characteristics, use of adjunctive support therapy and all-cause mortality to day 28. Data were summarised using descriptive statistics. Results: 200 participants were enrolled, mean (±SD) age 55.5 (±15.9) years, 40% (n = 80) female. Around half (51.5%) had no baseline comorbidities and 45 (31%) tested positive for COVID-19. On day 1, mean SOFA score was 9 ± 3; median (IQR) PaO2/FiO2 ratio 119 (89, 142), median (IQR) FiO2 70% (50%, 99%) and mean (±SD) positive end expiratory pressure (PEEP) 11 (±3) cmH2O. On day one, 10.5% (n = 21) received lung protective ventilation (LPV) (tidal volume ≤6.5 mL/kg predicted body weight and plateau pressure or peak pressure ≤30 cm H2O). Adjunctive therapies were received by 86% (n = 172) of patients at some stage from enrolment to day 28. Systemic steroids were most used (n = 127) followed by neuromuscular blockers (n = 122) and prone positioning (n = 27). Median ventilator-free days (IQR) to day 28 was 5 (0, 20). In-hospital mortality, censored at day 28, was 30.5% (n = 61). Conclusions: In Australia and New Zealand, compliance with evidence-based practices including LPV and prone positioning was low in this cohort. Therapies with proven benefit in the treatment of patients with moderate-severe ARDS, such as lung protective ventilation and prone positioning, were not routinely employed.

Sodium bicarbonate infusion to reduce cardiac surgery-associated acute kidney injury: a phase II multicenter double-blind randomized controlled trial.

OBJECTIVES: Cardiac surgery-associated acute kidney injury occurs in up to 50% of patients and is associated with increased mortality and morbidity. This study aimed to discover if perioperative urinary alkalinization with sodium bicarbonate infusion reduces the prevalence of cardiac surgery-associated acute kidney injury. DESIGN: This study was a phase IIb multicenter double-blind randomized controlled trial. SETTING: This study was conducted in three tertiary hospitals in New Zealand and Australia. PATIENTS: A total of 427 patients scheduled to undergo elective cardiac surgery, who were at increased risk of development of cardiac surgery-associated acute kidney injury using recognized risk factors. MEASUREMENTS AND MAIN RESULTS: Patients were randomly allocated to receive either sodium bicarbonate (n = 215) or sodium chloride (n = 212) infusion, commencing at the start of anesthesia, in a dose of 0.5 mEq/kg/hr for the first hour and then 0.2 mmol/kg/hr for 23 hours. The primary outcome measure was the number of patients with development of cardiac surgery-associated acute kidney injury, defined as an increase in creatinine greater than 25% or 0.5 mg/dL (44 µmol/L) from baseline to peak value within the first five postoperative days. Significant differences among the groups in both plasma and urinary biochemistry were achieved 6 hours after commencement of the infusion, and these changes persisted for more than 24 hours. A total of 100 out of 215 patients (47% [95% CI, 40%-53%]) in the sodium bicarbonate group and 93 of 212 patients (44% [95% CI, 37%-51%]) in the sodium chloride group with development of acute kidney injury within the first five postoperative days (p = 0.58). There were also no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. CONCLUSIONS: Perioperative alkalinization of blood and urine using an infusion of sodium bicarbonate did not result in a decrease in the prevalence of acute kidney injury in patients following cardiac surgery.

Protocol summary and statistical analysis plan for the low oxygen intervention for cardiac arrest injury limitation (LOGICAL) trial.

Background: The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will be evaluated in the Low Oxygen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial. Objective: The objective of this study was to summarise the protocol and statistical analysis plans for the LOGICAL trial. Design setting and participants: LOGICAL is a randomised clinical trial in adults in the ICU who are comatose with suspected HIE (i.e., those who have not obeyed commands following return of spontaneous circulation after a cardiac arrest where there is clinical concern about possible brain damage). The LOGICAL trial will include 1400 participants and is being conducted as a substudy of the Mega Randomised registry trial comparing conservative vs. liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX). Main outcome measures: The primary outcome is survival with favourable neurological function at 180 days after randomisation as measured with the Extended Glasgow Outcome Scale (GOS-E). A favourable neurological outcome will be defined as a GOS-E score of lower moderate disability or better (i.e. a GOS-E score of 5-8). Secondary outcomes include survival time, day 180 mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, the proportion of patients discharged home, quality of life assessed at day 180 using the EQ-5D-5L, and cognitive function assessed at day 180 using the Montreal Cognitive Assessment (MoCA-blind). Conclusions: The LOGICAL trial will provide reliable data on the impact of conservative vs. liberal oxygen therapy in ICU patients with suspected HIE following resuscitation from a cardiac arrest. Prepublication of the LOGICAL protocol and statistical analysis plan prior to trial conclusion will reduce the potential for outcome-reporting or analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN12621000518864).

Transfusion practice in patients undergoing cardiac surgery in New Zealand-impact of the TRICS III study (the TRICS TRIPS study).

AIM: Cardiac surgery is the largest perioperative user of donated blood products. There is significant uncertainty as to the optimal threshold for RBC transfusion in patients undergoing cardiac surgery with little evidence to guide practice. We wished to determine whether the results of a large randomised controlled trial had changed practice. METHODS: A prospective observational study of red blood cell (RBC) transfusions of patients undergoing cardiac surgery utilising cardiopulmonary bypass was undertaken as well as a cross-sectional self-administered online practice survey of clinicians ordering red blood cell transfusions in all publicly funded cardiac centres in New Zealand. RESULTS: Significantly more transfusions were administered to a pre-transfusion haemoglobin <75g/L and thus considered in agreement with the restrictive arm of the TRICS III study after completion of TRICS III study enrolment and before results were known (T1)=44% when compared to after results were known (T2=56.7%, p=0.01). Most respondents in the clinician survey had participated in the TRICS III study. CONCLUSIONS: After the publication of the findings of a large multi-national clinical trial, clinicians involved in the care of cardiac surgery patients were more restrictive in their administration of red blood cell transfusions than before the trial findings were published.

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

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

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.

The effects of flow on airway pressure during nasal high-flow oxygen therapy.

BACKGROUND: Nasal high-flow oxygen therapy increases the mean nasopharyngeal airway pressure in adults, but the relationship between flow and pressure is not well defined. OBJECTIVE: To determine the relationship between flow and pressure with the Optiflow nasal high-flow oxygen therapy system. METHODS: We invited patients scheduled for elective cardiac surgery to participate. Measurements were performed with nasal high-flow oxygen at flows of 30, 40, and 50 L/min, with the patient's mouth both open and closed. Pressures were recorded over one minute of breathing, and average flows were calculated via simple averaging. RESULTS: With the mouth closed, the mean ± SD airway pressures at 30, 40, and 50 L/min were 1.93 ± 1.25 cm H(2)O, 2.58 ± 1.54 cm H(2)O, and 3.31 ± 1.05 cm H(2)O, respectively. There was a positive linear relationship between flow and pressure. CONCLUSIONS: The mean nasopharyngeal pressure during nasal high-flow oxygen increases as flow increases. Australian Clinical Trials Registry http://www.adhb.govt.nz/achicu/hot_2_airway_pressure.htm.

A preliminary randomized controlled trial to assess effectiveness of nasal high-flow oxygen in intensive care patients.

OBJECTIVE: In a cardiothoracic and vascular intensive care unit, to compare nasal high-flow (NHF) oxygen therapy and standard high-flow face mask (HFFM) oxygen therapy in patients with mild to moderate hypoxemic respiratory failure. METHODS: In a prospective randomized comparative study, 60 patients with mild to moderate hypoxemic respiratory failure were randomized to receive NHF or HFFM. We analyzed the success of allocated therapy, noninvasive ventilation rate, and oxygenation. RESULTS: Significantly more NHF patients succeeded with their allocated therapy (P = .006). The rate of noninvasive ventilation in the NHF group was 3/29 (10%), compared with 8/27 (30%) in the HFFM group (P = .10). The NHF patients also had significantly fewer desaturations (P = .009). CONCLUSIONS: NHF oxygen therapy may be more effective than HFFM in treating mild to moderate hypoxemic respiratory failure.

Avoidance of Routine Endotracheal Suction in Subjects Ventilated for ≤ 12 Hours Following Elective Cardiac Surgery.

BACKGROUND: Mechanical ventilation requires an endotracheal tube. Airway management includes endotracheal suctioning, a frequent procedure for patients in the ICU. Associated risks of endotracheal suctioning include hypoxia, atelectasis, and infection. There is currently no evidence about the safety of avoiding endotracheal suction. We aimed to assess the safety of avoiding endotracheal suction, including at extubation, in cardiac surgical patients who were mechanically ventilated for ≤ 12 h. METHODS: We conducted a single-center, noninferiority, randomized controlled trial in a cardiac ICU in a metropolitan tertiary teaching hospital. Subjects were assigned to either avoidance of endotracheal suction or to usual care including endotracheal suctioning during mechanical ventilation. In total, we screened 468 patients and randomized 249 subjects (usual care, n = 125; intervention, n = 124). Subjects were elective cardiac surgical patients anticipated to receive ≤ 12 h of mechanical ventilation. The primary outcome was the [Formula: see text]/[Formula: see text] on room air 6 h after extubation, with a noninferiority margin of 10% (lower bound of one-sided 95% CI to be < 30). RESULTS: There were no differences in group characteristics at baseline. The primary analysis was a per-protocol analysis performed on 154 subjects. The median [Formula: see text]/[Formula: see text] was 323 for the intervention group and 311 for the standard care group (median difference = 12, one-sided 95% CI -14.3). The results were consistent when using an intention-to-treat analysis and a 97.5% CI. There were no differences between groups in complications or safety measures, including the escalation of oxygen therapy. CONCLUSIONS: Endotracheal suctioning can be safely minimized or avoided in low-risk patients who have had cardiac surgery and are expected to be ventilated for < 12 h after surgery.