Clinical trial NCT04425031: Handling Oxygenation Targets in COVID-19
Official title: Handling Oxygenation Targets in COVID-19 Patients With Acute Hypoxaemic Respiratory Failure in the Intensive Care Unit: A Randomised Clinical Trial of a Lower Versus a Higher Oxygenation Target
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypoxemic Respiratory Failure
Oxygen Toxicity
Keywords: Oxygenation
Acute Respiratory Distress Syndrome
Mechanical ventilation
Critical illness
Critical care
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Copenhagen Trial Unit, Center for Clinical Intervention Research
First posted: 2020-06-11
Enrollment: 726
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Patients with COVID-19 and hypoxaemic respiratory failure and admitted to the intensive care unit (ICU) are treated with supplementary oxygen as a standard. However, quality of quantity evidence regarding this practise is low. The aim of the HOT-COVID trial is to evaluate the benefits and harms of two targets of partial pressure of oxygen in arterial blood (PaO2) in guiding the oxygen therapy in acutely ill adult COVID-19 patients with hypoxaemic respiratory failure at ICU admission.

Detailed description: Acutely ill adult COVID-19 patients with hypoxaemic respiratory failure admitted to the intensive care unit (ICU) are at risk of life-threatening hypoxia, and are provided supplementary oxygen. Liberal use of supplementary oxygen may increase the number of serious adverse events including death. However, the use of supplementary oxygen therapy, and the optimal oxygenation target in COVID-19 patients have not yet been studied.

The World Health Organisation (WHO) recommends an oxygen therapy during resuscitation of COVID-19 patients to achieve an SpO2 of 94% or more, and 90% or more when stable (non-pregnant patients). The Surviving Sepsis Campaing (SSC) recommends a conservative oxygenation strategy for COVID-19 patients targeting an SpO2 no higher than 96%. Both are based on a systematic review and metanalysis from 2018, investigating the association with mortality and higher versus lower oxygenation strategies in critically ill patients in general.

COVID-19 patients admitted to the ICU and treated with positive pressure ventilation fulfil the 2012 Berlin criteria for acute respiratory distress syndrome (ARDS). Current practice regarding supplementary oxygen therapy in patients with ARDS follows the regimen used in an randomised clinical trial (RCT) from 2000 comparing lower versus higher tidal volumes; i.e. a partial pressure of arterial oxygen (PaO2) of 55-80 mmHg (7.3-10.7 kPa) or a peripheral oxygen saturation (SpO2) of 88-95%.

Of note, a recent published RCT demonstrated a lowered all-cause mortality when targeting a higher oxygenation target (PaO2: 12-14 kPa \[90-105 mmHg\]) compared to a lower oxygenation target (PaO2: 7.3-9.3 \[55-70 mmHg\]) in ARDS patients.

The quality and quantity of the current body of evidence regarding oxygenation targets in ARDS is still low.

The aim of the HOT-COVID trial is to evaluate the benefits and harms of two targets of partial pressure of oxygen in arterial blood (PaO2) in guiding the oxygen therapy in acutely ill adults COVID-19 patients with hypoxaemic respiratory failure at ICU admission.

The HOT-COVID trial is an amendment to the HOT-ICU trial (NCT03174002)

Eligibility criteria: Inclusion Criteria:

* Acutely admitted to the ICU AND
* Aged ≥ 18 years AND
* Receives supplemental oxygen with a flow of at least 10 L per minutes in an open system including high-flow systems OR recieves supplemental oxygen in a closed system including invasive or non-invasive ventilation or continuous positive airway pressure (CPAP)-systems AND
* Expected to receive supplemental oxygen for at least 24 hours in the ICU AND
* Having an arterial line for PaO2 monitoring AND
* Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in the time leading to or during current hospital admission

Exclusion Criteria:

* Cannot be randomised within twelve hours after present ICU admission
* Chronic mechanical ventilation for any reason
* Use of home oxygen
* Previous treatment with bleomycin
* Organ transplant during current hospital admission
* Withdrawal from active therapy or brain death deemed imminent
* Fertile woman (\< 50 years of age) with positive urine human gonadotropin (hCG) or plasma-hCG
* Carbon monoxide poisoning
* Cyanide poisoning
* Methaemoglobinaemia
* Paraquat poisoning
* Any condition expected to involve the use of hyperbaric oxygen (HBO)
* Sickle cell disease
* Consent not obtainable according to national regulations
* Previously randomised into the HOT-COVID trial

Primary outcomes:
measure: Days alive without organ support
timeFrame: Within 90 days
Secondary outcomes:
measure: 90-days mortality
timeFrame: 90 days
measure: Days alive out of the hospital
timeFrame: Within 90 days
measure: Number of patients with one or more serious adverse events
timeFrame: Until ICU discharge, maximum 90 days
measure: 1-year mortality
timeFrame: 1 year
measure: Quality of life assessement using the EuroQoL EQ-5D-5L telephone interview
timeFrame: 1 year
measure: Cognitive function 1-year after randomisation as assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score in selected sites
timeFrame: 1 year
measure: Carbon monoxide diffusion capacity
timeFrame: 1 year
measure: A health economic analysis
timeFrame: 90 days
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Dept. of Intensive Care, Aalborg University Hospital
city: Copenhagen
country: Denmark
facility: Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet
city: Herlev
country: Denmark
facility: Dept. of Intensive Care, Herlev Hospital
city: Hillerød
country: Denmark
facility: Dept. of Intensive Care, Hillerød Hospital
city: Kolding
country: Denmark
facility: Dept. of Intensive Care, Kolding Hospital
city: Køge
country: Denmark
facility: Dept. of Intensive Care, Køge Hospital
city: Randers
country: Denmark
facility: Randers Hospital
city: Slagelse
country: Denmark
facility: Dept. of Intensive Care, Slagelse Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Basel
country: Switzerland
facility: Universitätsspital Basel
Study officials:
affiliation: Aalborg University Hospital, Denmark
name: Bodil Steen Rasmussen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aalborg University Hospital, Denmark
name: Bodil Steen Rasmussen, MD, PhD
role: STUDY_CHAIR
References:
citation: Schjorring OL, Perner A, Wetterslev J, Lange T, Keus F, Laake JH, Okkonen M, Siegemund M, Morgan M, Thormar KM, Rasmussen BS; HOT-ICU Investigators. Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU)-Protocol for a randomised clinical trial comparing a lower vs a higher oxygenation target in adults with acute hypoxaemic respiratory failure. Acta Anaesthesiol Scand. 2019 Aug;63(7):956-965. doi: 10.1111/aas.13356. Epub 2019 Mar 18.
citation: Barbateskovic M, Schjorring OL, Jakobsen JC, Meyhoff CS, Rasmussen BS, Perner A, Wetterslev J. Oxygen supplementation for critically ill patients-A protocol for a systematic review. Acta Anaesthesiol Scand. 2018 Aug;62(7):1020-1030. doi: 10.1111/aas.13127. Epub 2018 Apr 30.
citation: Barbateskovic M, Schjorring OL, Russo Krauss S, Jakobsen JC, Meyhoff CS, Dahl RM, Rasmussen BS, Perner A, Wetterslev J. Higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit. Cochrane Database Syst Rev. 2019 Nov 27;2019(11):CD012631. doi: 10.1002/14651858.CD012631.pub2.
citation: Rasmussen BS, Perner A, Wetterslev J, Meyhoff CS, Schjorring OL. Oxygenation targets in acutely ill patients: still a matter of debate. Lancet. 2018 Dec 8;392(10163):2436-2437. doi: 10.1016/S0140-6736(18)32201-3. No abstract available.
citation: Schjorring OL, Klitgaard TL, Perner A, Wetterslev J, Lange T, Keus F, Laake JH, Morgan M, Backlund M, Siegemund M, Thormar KM, Rasmussen BS. The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: Detailed statistical analysis plan. Acta Anaesthesiol Scand. 2020 Jul;64(6):847-856. doi: 10.1111/aas.13569. Epub 2020 Mar 4.
citation: Nielsen FM, Klitgaard TL, Bruun NH, Moller MH, Schjorring OL, Rasmussen BS. Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis. Intensive Care Med. 2024 Aug;50(8):1275-1286. doi: 10.1007/s00134-024-07523-3. Epub 2024 Jul 11.
citation: Nielsen FM, Klitgaard TL, Siegemund M, Laake JH, Thormar KM, Cole JM, Aagaard SR, Bunzel AG, Vestergaard SR, Langhoff PK, Pedersen CH, Hejlesen JO, Abdelhamid S, Dietz A, Gebhard CE, Zellweger N, Hollinger A, Poulsen LM, Weihe S, Andersen-Ranberg NC, Pedersen UG, Mathiesen O, Andreasen AS, Brix H, Thomsen JJ, Petersen CH, Bestle MH, Wichmann S, Lund MS, Mortensen KM, Brand BA, Haase N, Iversen SA, Marcussen KV, Brochner AC, Borup M, Grofte T, Hildebrandt T, Kjaer MN, Engstrom J, Lange T, Perner A, Schjorring OL, Rasmussen BS; HOT-COVID Trial Group. Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial. JAMA. 2024 Apr 9;331(14):1185-1194. doi: 10.1001/jama.2024.2934.