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

Schjørring, Olav Lilleholt; Klitgaard, Thomas; Perner, Anders; Wetterslev, Jørn; Lange, Theis; Keus, Frederik; Laake, Jon Henrik; Kift-Morgan, Ann; Bäcklund, Minna; Siegemund, Martin; Þormar, Katrín; Rasmussen, Bodil Steen

doi:10.1111/aas.13569

Cited by 17 publications

(60 citation statements)

References 41 publications

(72 reference statements)

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“…The HOT‐ICU trial is an ongoing, international, randomised, parallel group, investigator‐initiated trial of a lower versus a higher oxygenation target, conducted in adult patients (≥18 years) acutely admitted to the ICU with hypoxaemic respiratory failure 6,7 . Patients are randomised 1:1 to either an arterial partial pressure of oxygen (PaO 2 ) target of 8 kPa (intervention) or 12 kPa (control) during their ICU stay, including re‐admissions up to 90 days after inclusion.…”

Section: Methodsmentioning

confidence: 99%

“…The HOT‐ICU trial is approved by the Danish Health and Medicines Agency (AAUH‐ICU‐01, EudraCT no. 2017‐000632‐34); the Committee on Health Research Ethics in the North Denmark Region (N‐20170015); the Danish Data Protection Agency (2008‐58‐0028) and all required authorities in the participating countries, and registered prospectively at http://ClinicalTrials.gov (NCT03174002) 6,7 …”

Section: Methodsmentioning

confidence: 99%

“…Additional details on the HOT‐ICU trial, including variable definitions, are available in the primary protocol and the published statistical analysis plan 6,7 …”

Section: Methodsmentioning

confidence: 99%

“…We hypothesise an overall reduction in all‐cause 90‐day mortality with a lower oxygenation target as compared with a higher target 6,7 . Also, we hypothesise that patients with greater baseline severity of illness, higher degree of hypoxaemic respiratory failure, requirement for higher dose of noradrenalin, or higher concentration of plasma lactate will have greater reductions in 90‐day all‐cause mortality with a lower oxygenation target as compared with a higher target.…”

Section: Introductionmentioning

confidence: 99%

“…The ongoing Handling Oxygenation Targets in the Intensive Care Unit (HOT‐ICU) trial compares a lower versus a higher oxygenation target in adult patients acutely admitted to the ICU with hypoxaemic respiratory failure 6,7 . The results from this trial will more than double the available data, and improve the knowledge on the optimal oxygenation target in adult ICU patients with hypoxaemia.…”

Section: Introductionmentioning

confidence: 99%

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Bayesian and heterogeneity of treatment effect analyses of the HOT‐ICU trial—A secondary analysis protocol

Klitgaard

Schjørring

Lange

et al. 2020

Acta Anaesthesiol Scand

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Additional details on the HOT‐ICU trial, including variable definitions, are available in the primary protocol and the published statistical analysis plan 6,7 …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bayesian and heterogeneity of treatment effect analyses of the HOT‐ICU trial—A secondary analysis protocol

Klitgaard

Schjørring

Lange

et al. 2020

Acta Anaesthesiol Scand

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Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia

et al. 2022

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Purpose We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. Methods Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. Results We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93–1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50–80) in the lower oxygenation group versus 67 (50–80) in the higher oxygenation group ( p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. Conclusion Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa). Supplementary Information The online version contains supplementary material available at 10.1007/s00134-022-06695-0.

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

Nielsen,

Klitgaard,

Bruun

et al. 2024

Intensive Care Med

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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 (PaO 2 ) 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 PaO 2 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). Supplementary Information The online version contains supplementary material available at 10.1007/s00134-024-07523-3.

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

Cited by 17 publications

References 41 publications

Bayesian and heterogeneity of treatment effect analyses of the HOT‐ICU trial—A secondary analysis protocol

Bayesian and heterogeneity of treatment effect analyses of the HOT‐ICU trial—A secondary analysis protocol

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia

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

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