Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

Importance: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. Objective: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Interventions: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. Conclusion and Relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit.

BACKGROUND: This is an updated review concerning 'Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit'. Supplementary oxygen is provided to most patients in intensive care units (ICUs) to prevent global and organ hypoxia (inadequate oxygen levels). Oxygen has been administered liberally, resulting in high proportions of patients with hyperoxemia (exposure of tissues to abnormally high concentrations of oxygen). This has been associated with increased mortality and morbidity in some settings, but not in others. Thus far, only limited data have been available to inform clinical practice guidelines, and the optimum oxygenation target for ICU patients is uncertain. Because of the publication of new trial evidence, we have updated this review. OBJECTIVES: To update the assessment of benefits and harms of higher versus lower fractions of inspired oxygen (FiO2) or targets of arterial oxygenation for adults admitted to the ICU. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, BIOSIS Previews, and LILACS. We searched for ongoing or unpublished trials in clinical trial registers and scanned the reference lists and citations of included trials. Literature searches for this updated review were conducted in November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared higher versus lower FiO2 or targets of arterial oxygenation (partial pressure of oxygen (PaO2), peripheral or arterial oxygen saturation (SpO2 or SaO2)) for adults admitted to the ICU. We included trials irrespective of publication type, publication status, and language. We excluded trials randomising participants to hypoxaemia (FiO2 below 0.21, SaO2/SpO2 below 80%, or PaO2 below 6 kPa) or to hyperbaric oxygen, and cross-over trials and quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Four review authors independently, and in pairs, screened the references identified in the literature searches and extracted the data. Our primary outcomes were all-cause mortality, the proportion of participants with one or more serious adverse events (SAEs), and quality of life. We analysed all outcomes at maximum follow-up. Only three trials reported the proportion of participants with one or more SAEs as a composite outcome. However, most trials reported on events categorised as SAEs according to the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) criteria. We, therefore, conducted two analyses of the effect of higher versus lower oxygenation strategies using 1) the single SAE with the highest reported proportion in each trial, and 2) the cumulated proportion of participants with an SAE in each trial. Two trials reported on quality of life. Secondary outcomes were lung injury, myocardial infarction, stroke, and sepsis. No trial reported on lung injury as a composite outcome, but four trials reported on the occurrence of acute respiratory distress syndrome (ARDS) and five on pneumonia. We, therefore, conducted two analyses of the effect of higher versus lower oxygenation strategies using 1) the single lung injury event with the highest reported proportion in each trial, and 2) the cumulated proportion of participants with ARDS or pneumonia in each trial. We assessed the risk of systematic errors by evaluating the risk of bias in the included trials using the Risk of Bias 2 tool. We used the GRADEpro tool to assess the overall certainty of the evidence. We also evaluated the risk of publication bias for outcomes reported by 10b or more trials. MAIN RESULTS: We included 19 RCTs (10,385 participants), of which 17 reported relevant outcomes for this review (10,248 participants). For all-cause mortality, 10 trials were judged to be at overall low risk of bias, and six at overall high risk of bias. For the reported SAEs, 10 trials were judged to be at overall low risk of bias, and seven at overall high risk of bias. Two trials reported on quality of life, of which one was judged to be at overall low risk of bias and one at high risk of bias for this outcome. Meta-analysis of all trials, regardless of risk of bias, indicated no significant difference from higher or lower oxygenation strategies at maximum follow-up with regard to mortality (risk ratio (RR) 1.01, 95% confidence interval (C)I 0.96 to 1.06; I2 = 14%; 16 trials; 9408 participants; very low-certainty evidence); occurrence of SAEs: the highest proportion of any specific SAE in each trial RR 1.01 (95% CI 0.96 to 1.06; I2 = 36%; 9466 participants; 17 trials; very low-certainty evidence), or quality of life (mean difference (MD) 0.5 points in participants assigned to higher oxygenation strategies (95% CI -2.75 to 1.75; I2 = 34%, 1649 participants; 2 trials; very low-certainty evidence)). Meta-analysis of the cumulated number of SAEs suggested benefit of a lower oxygenation strategy (RR 1.04 (95% CI 1.02 to 1.07; I2 = 74%; 9489 participants; 17 trials; very low certainty evidence)). However, trial sequential analyses, with correction for sparse data and repetitive testing, could reject a relative risk increase or reduction of 10% for mortality and the highest proportion of SAEs, and 20% for both the cumulated number of SAEs and quality of life. Given the very low-certainty of evidence, it is necessary to interpret these findings with caution. Meta-analysis of all trials indicated no statistically significant evidence of a difference between higher or lower oxygenation strategies on the occurrence of lung injuries at maximum follow-up (the highest reported proportion of lung injury RR 1.08, 95% CI 0.85 to 1.38; I2 = 0%; 2048 participants; 8 trials; very low-certainty evidence). Meta-analysis of all trials indicated harm from higher oxygenation strategies as compared with lower on the occurrence of sepsis at maximum follow-up (RR 1.85, 95% CI 1.17 to 2.93; I2 = 0%; 752 participants; 3 trials; very low-certainty evidence). Meta-analysis indicated no differences regarding the occurrences of myocardial infarction or stroke. AUTHORS' CONCLUSIONS: In adult ICU patients, it is still not possible to draw clear conclusions about the effects of higher versus lower oxygenation strategies on all-cause mortality, SAEs, quality of life, lung injuries, myocardial infarction, stroke, and sepsis at maximum follow-up. This is due to low or very low-certainty evidence.

Lower or higher oxygenation targets for acute Hypoxaemic respiratory failure: Protocol for an individual patient data meta-analysis.

BACKGROUND: Supplemental oxygen therapy is central to the treatment of acute hypoxaemic respiratory failure, a condition which remains a major driver for morbidity and mortality in intensive care. Despite several large randomised clinical trials comparing a higher versus a lower oxygenation target for these patients, significant differences in study design impede analysis of aggregate data and final clinical recommendations. METHODS: This paper presents the protocol for conducting an individual patient data meta-analysis where full individual patient data according to the intention-to-treat principle will be pooled from the HOT-ICU and HOT-COVID trials in a one-step procedure. The two trials are near-identical in design. We plan to use a hierarchical general linear mixed model that accounts for data clustering at a trial and site level. The primary outcome will be 90-day all-cause mortality while the secondary outcome will be days alive without life-support at 90 days. Further, we outline 14 clinically relevant predefined subgroups which we will analyse for heterogeneity in the intervention effects and interactions, and we present a plan for assessing the credibility of the subgroup analyses. CONCLUSION: The presented individual patient data meta-analysis will synthesise individual level patient data from two of the largest randomised clinical trials on targeted oxygen therapy in intensive care. The results will provide a re-analysis of the intervention effects on the pooled intention-to-treat populations and facilitate subgroup analyses with an increased power to detect clinically important effect modifications.

Association between days alive without life support/out of hospital and health-related quality of life.

BACKGROUND: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL. METHODS: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations. RESULTS: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate. CONCLUSION: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Lower versus higher oxygenation targets in critically ill patients with severe hypoxaemia: secondary Bayesian analysis to explore heterogeneous treatment effects in the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial.

BACKGROUND: In the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial, a lower (8 kPa) vs a higher (12 kPa) PaO2 target did not affect mortality amongst critically ill adult patients. We used Bayesian statistics to evaluate any heterogeneity in the effect of oxygenation targets on mortality between different patient groups within the HOT-ICU trial. METHODS: We analysed 90-day all-cause mortality using adjusted Bayesian logistic regression models, and assessed heterogeneous treatment effects according to four selected baseline variables using both hierarchical models of subgroups and models with interactions on the continuous scales. Results are presented as mortality probability (%) and relative risk (RR) with 95% credibility intervals (CrI). RESULTS: All 2888 patients in the intention-to-treat cohort of the HOT-ICU trial were included. The adjusted 90-day mortality rates were 43.0% (CrI: 38.3-47.8%) and 42.3% (CrI: 37.7-47.1%) in the lower and higher oxygenation groups, respectively (RR 1.02 [CrI: 0.93-1.11]), with 36.5% probability of an RR <1.00. Analyses of heterogeneous treatment effects suggested a dose-response relationship between baseline norepinephrine dose and increased mortality with the lower oxygenation target, with 95% probability of increased mortality associated with the lower oxygenation target as norepinephrine doses increased. CONCLUSIONS: A lower oxygenation target was unlikely to affect overall mortality amongst critically ill adult patients with acute hypoxaemic respiratory failure. However, our results suggest an increasing mortality risk for patients with a lower oxygen target as the baseline norepinephrine dose increases. These findings warrant additional investigation. CLINICAL TRIAL REGISTRATION: NCT03174002.

Higher versus lower oxygenation targets in COVID-19 patients with severe hypoxaemia (HOT-COVID) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Respiratory failure is the main cause of mortality and morbidity among ICU patients with coronavirus disease 2019 (COVID-19). In these patients, supplemental oxygen therapy is essential, but there is limited evidence the optimal target. To address this, the ongoing handling oxygenation targets in COVID-19 (HOT-COVID) trial was initiated to investigate the effect of a lower oxygenation target (partial pressure of arterial oxygen (PaO2 ) of 8 kPa) versus a higher oxygenation target (PaO2 of 12 kPa) in the ICU on clinical outcome in patients with COVID-19 and hypoxaemia. METHODS: The HOT-COVID is planned to enrol 780 patients. This paper presents the protocol and statistical analysis plan for the conduct of a secondary Bayesian analysis of the primary outcome of HOT-COVID being days alive without life-support at 90 days and the secondary outcome 90-day all-cause mortality. Furthermore, both outcomes will be investigated for the presence heterogeneity of treatment effects based on four baseline parameters being sequential organ failure assessment score, PaO2 /fraction of inspired oxygen ratio, highest dose of norepinephrine during the 24 h before randomisation, and plasma concentration of lactate at randomisation. CONCLUSION: The results of this pre-planned secondary Bayesian analysis will complement the primary frequentist analysis of the HOT-COVID trial and may facilitate a more nuanced interpretation of the trial results.

Long-term effects of lower versus higher oxygenation levels in adult ICU patients-A systematic review.

BACKGROUND: Oxygen therapy is a common treatment in the intensive care unit (ICU) with both potentially desirable and undesirable long-term effects. This systematic review aimed to assess the long-term outcomes of lower versus higher oxygenation strategies in adult ICU survivors. METHODS: We included randomised clinical trials (RCTs) comparing lower versus higher oxygen supplementation or oxygenation strategies in adults admitted to the ICU. We searched major electronic databases and trial registers. We included all non-mortality long-term outcomes. Prespecified co-primary outcomes were the long-term cognitive function measures, the overall score of any valid health-related quality of life (HRQoL) evaluation, standardised 6-min walk test, and lung diffusion capacity. The protocol was published and prospectively registered in the PROSPERO database (CRD42021223630). RESULTS: The review included 17 RCTs comprising 6592 patients, and six trials with 825 randomised patients reported one or more outcomes of interest. We observed no difference in cognitive evaluation via Telephone Interview for Cognitive Status (one trial, 409 patients) (mean score: 30.6 ± 4.5 in the lower oxygenation group vs. 30.4 ± 4.3 in the higher oxygenation group). The trial was judged at overall high risk of bias and the certainty of evidence was very low. Any difference was neither observed in HRQoL measured via EuroQol 5 dimensions 5 level questionnaire and EQ Visual Analogue Score (one trial, 499 patients) (mean score: 70.1 ± 22 in the lower oxygenation group vs. 67.6 ± 22.4 in the higher oxygenation group). The trial was judged as having high risk of bias, the certainty of evidence was very low. No trial reported neither the standardised 6-min walk test nor lung diffusion test. CONCLUSION: The evidence is very uncertain about the effect of a lower versus a higher oxygenation strategy on both the cognitive function and HRQoL. A lower versus a higher oxygenation strategy may have a little to no effect on both outcomes but the certainty of evidence is very low. No evidence was found for the effects on the standardised 6-min walking test and diffusion capacity test.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

The long-term effects of lower versus higher oxygenation levels in adult ICU patients - protocol for a systematic review.

BACKGROUND: Many organs can remain impaired after discharge from the intensive care unit (ICU) leading to temporal or permanent dysfunctions. Long-term impairments may be affected by supplemental oxygen, a common treatment in ICU, having both potential beneficial and harmful long-lasting effects. This systematic review aims to assess the long-term outcomes of lower versus higher oxygen supplementation and/or oxygenation levels in adults admitted to ICU. METHODS: We will include trials differentiating between a lower and a higher oxygen supplementation or a lower and a higher oxygenation strategy in adults admitted to the ICU. We will search major electronic databases and trial registers for randomised clinical trials. Two authors will independently screen and select references for inclusion using Covidence and predefined data will be extracted. The methodological quality and risk of bias of included trials will be evaluated using the Cochrane Risk of Bias tool 2. Meta-analysis will be performed if two or more trials with comparable outcome measures will be included. Otherwise, a narrative description of the trials' results will be presented instead. To assess the certainty of evidence, we will create a 'Summary of findings' table containing all prespecified outcomes using the GRADE system. The protocol is submitted on the PROSPERO database (ID 223630). CONCLUSION: No systematic reviews on the impact of oxygen treatment in the ICU on long-term outcomes, other than mortality and quality of life, have been reported yet. This systematic review will provide an overview of the current evidence and will help future research in the field.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU trial: protocol and statistical analysis plan.

BACKGROUND: Although supplemental oxygen can be lifesaving, liberal oxygen administration causing hyperoxaemia may be harmful. The targets for oxygenation in patients with acute hypoxaemic respiratory failure acutely admitted to the intensive care unit (ICU) are strongly debated, and consensus on which targets to recommend has not been reached. The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2  = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure. In this study, we aim to evaluate the effects of these targets on long-term cognitive and pulmonary function in Danish patients, enrolled in the HOT-ICU trial and surviving to 1-year follow-up. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: All patients enrolled in the HOT-ICU trial at Danish sites and surviving to 1 year after randomisation are eligible to participate. The last patient is expected to be included by November 2021. A Repeatable Battery for the Assessment of Neuropsychological Status and a body plethysmography, including diffusion capacity for carbon monoxide, both pre-planned secondary long-term outcomes of the HOT-ICU trial, will be obtained. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on cognitive and pulmonary function in adult ICU patients with acute hypoxaemic respiratory failure.

Health-related quality of life and days alive without life support or out of hospital: Protocol.

BACKGROUND: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain. METHODS: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%. DISCUSSION: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population.

Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.

BACKGROUND: Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. METHODS: In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2 ) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients. RESULTS: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant. CONCLUSIONS: Targeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.

Handling oxygenation targets in ICU patients with COVID-19-Protocol and statistical analysis plan in the HOT-COVID trial.

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a ß of 20%. An interim analysis is planned after 90-day follow-up of 390 patients. CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

Bayesian and heterogeneity of treatment effect analyses of the HOT-ICU trial-A secondary analysis protocol.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial is an ongoing randomised clinical trial exploring the benefits and harms of targeting a lower (8 kPa) versus a higher (12 kPa) arterial oxygenation target in adult patients acutely admitted to the intensive care unit (ICU) with hypoxaemic respiratory failure. METHODS: This protocol describes a secondary analysis of the primary trial outcome, 90-day all-cause mortality. We will analyse the primary outcome using Bayesian methods, which allows quantification of probabilities of all effect sizes. We will explore the presence of heterogeneity of treatment effects (HTE) using Bayesian hierarchical models in subgroups based on baseline parameters: (a) severity of illness (Sequential Organ Failure Assessment (SOFA) score), (b) severity of hypoxaemic respiratory failure (partial pressure of arterial oxygen (PaO2 )/fraction of inspired oxygen (FiO2 ) ratio), (c) vasopressor requirement (highest noradrenaline dose in the 24 hours prior to randomisation), and (d) plasma lactate concentration (latest prior to randomisation). Additionally, we will perform separate assessments of the treatment effect interaction with each of the baseline parameters above on the continuous scale and present these using conditional effects plots. CONCLUSIONS: This secondary analysis will aid the interpretation of the HOT-ICU trial by evaluating probabilities of all effect sizes. In addition, we will evaluate whether HTE is present, thus, further evaluating benefits and harms of a lower versus a higher oxygenation target in adult ICU patients with acute hypoxaemic respiratory failure.

The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: Detailed statistical analysis plan.

BACKGROUND: No solid evidence exists on optimal oxygenation targets in intensive care patients. The handling oxygenation targets in the intensive care unit (HOT-ICU) trial assesses the effects of a targeted arterial oxygen tension of 8 vs 12 kPa on 90-day mortality in acutely admitted adult patients with hypoxaemic respiratory failure. This article describes the detailed statistical analysis plan for the predefined outcomes and supplementary analyses in the HOT-ICU trial. METHODS: The trial will include 2928 patients to be able to detect or reject a true 20% relative risk reduction in the primary outcome of 90-day all-cause mortality with an α of 5% and a ß of 10%. Analyses of the primary and secondary outcomes will be conducted according to the intention-to-treat principle and adjusted for stratification variables. The primary outcome and dichotomous secondary outcomes will be analysed using a generalised linear model with a log-link and binomial error distribution. For the primary outcome, a 95% confidence interval (CI) not including 1.00 for the risk ratio will be considered statistically significant. Continuous secondary outcomes will be analysed using a generalised linear model or nonparametric test. CIs adjusted for the multiple secondary outcomes not including the null effect will be considered statistically significant. One planned interim analysis has been conducted. CONCLUSIONS: The HOT-ICU trial and the pre-planned statistical analyses are designed to minimise bias and produce high quality data on the effects of a lower vs a higher oxygenation target throughout ICU admission in acutely admitted adult patients with hypoxaemic respiratory failure. REGISTRATION: ClinicalTrials.gov identifier: NCT03174002, date of registration: June 2, 2017. European clinical trials database, EudraCT number 2017-000632-34.

Spontaneous versus controlled mechanical ventilation in patients with acute respiratory distress syndrome - Protocol for a scoping review.

BACKGROUND: In caring for mechanically ventilated adults with acute respiratory distress syndrome (ARDS), clinicians are faced with an uncertain choice between controlled or spontaneous breathing modes. Observational data indicate considerable practice variation which may be driven by differences in sedation and mobilisation practices. The benefits and harms of either strategy are largely unknown. METHODS: A scoping review will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. We will review the clinical literature on controlled vs spontaneous breathing in mechanically ventilated patients with ARDS of any severity. Studies reporting on qualitative and/or quantitative data from any world region will be considered. For inclusion, studies must include data on mechanically ventilated patients with ARDS who are allowed spontaneous (triggered ventilation). Searches will be conducted in four electronic databases without any limitation on publication date and language. We will assess the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, where appropriate. CONCLUSION: We will perform a scoping review of the clinical literature on controlled vs spontaneously breathing in mechanically ventilated patients who fulfil ARDS criteria (including acute lung injury). This is to elucidate if a pragmatic clinical trial comparing controlled and spontaneous mechanical ventilation is warranted and will allow us to formulate relevant research questions.

Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis.

PURPOSE: Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8-12 kPa in adult ICU patients, assessing both benefits and harms. METHODS: We assessed 90-day all-cause mortality and days alive without life support in 90 days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). RESULTS: At 90 days, mortality was 40.4% (724/1792) in the 8 kPa group and 40.9% (733/1793) in the 12 kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92-1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8 kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12 kPa (low credibility). CONCLUSION: This study reported no overall differences comparing a PaO2 target of 8-12 kPa on mortality or days alive without life support in 90 days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).