Handling Oxygenation Targets in COVID-19 (HOT-COVID)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypoxemic Respiratory Failure; Oxygen Toxicity
• Intervention / Treatment: Drug: Oxygen; Drug: Oxygen

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)

• Study Type: Interventional
• Enrollment (Actual): 726
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Dept. of Intensive Care, Aalborg University Hospital
  • Copenhagen, Denmark, 2100
    • Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet
  • Herlev, Denmark, 2730
    • Dept. of Intensive Care, Herlev Hospital
  • Hillerød, Denmark, 3400
    • Dept. of Intensive Care, Hillerød Hospital
  • Kolding, Denmark, 6000
    • Dept. of Intensive Care, Kolding Hospital
  • Køge, Denmark, 4600
    • Dept. of Intensive Care, Køge Hospital
  • Randers, Denmark, 8930
    • Randers Hospital
  • Slagelse, Denmark, 4200
    • Dept. of Intensive Care, Slagelse Hospital
• Norway
  • Oslo, Norway
    • Oslo University Hospital
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low oxygenation target; Partial pressure of oxygen in arterial blood (PaO2) 8 kPa (60 mmHg)	Drug: Oxygen; Oxygen administration to achieve a PaO2 of 8 kPa (60 mmHg) from ICU admission to ICU discharge; Other Names: Inspired oxygen; Drug: Oxygen; Oxygen administration to achieve a PaO2 of 12 kPa (90 mmHg) from ICU admission to ICU discharge; Other Names: Inspired oxygen
Active Comparator: High oxygenation target; Partial pressure of oxygen in arterial blood (PaO2) 12 kPa (90 mmHg)	Drug: Oxygen; Oxygen administration to achieve a PaO2 of 8 kPa (60 mmHg) from ICU admission to ICU discharge; Other Names: Inspired oxygen; Drug: Oxygen; Oxygen administration to achieve a PaO2 of 12 kPa (90 mmHg) from ICU admission to ICU discharge; Other Names: Inspired oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive without organ support	Days alive and free from mechanical ventilation, circulatory support and renal replacement therapy	Within 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with one or more serious adverse events	Serious adverse events are defined as new episode of shock and new episodes of ischaemic events including myocardial or intestinal ischaemia or ischaemic stroke	Until ICU discharge, maximum 90 days
90-days mortality	All-cause mortality 90 days after randomisation	90 days
Days alive out of the hospital	Days alive out of the hospital	Within 90 days
1-year mortality	All-cause mortality 1 year after randomisation	1 year
Quality of life assessement using the EuroQoL EQ-5D-5L telephone interview	EQ-5D-5L 1-year after randomisation	1 year
Cognitive function 1-year after randomisation as assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score in selected sites	RBANS score 1 year after randomisation at selected sites. The overall RBANS global cognition score, as well as each cognitive domain score, range from 40 to 160 with 100 ± 15 being the age-adjusted mean ± standard deviation. Higher scores indicate better performance.	1 year
Carbon monoxide diffusion capacity	Carbon monoxide diffusion capacity (DLCO) 1 year after randomisation at selected sites.	1 year
A health economic analysis	Cost-effectiveness versus cost-minimisation analyses after completion of the trial, based on the primary outcome.	90 days

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Collaborators: Rigshospitalet, Denmark; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Principal Investigator: Bodil Steen Rasmussen, MD, PhD, Aalborg University Hospital, Denmark; Study Chair: Bodil Steen Rasmussen, MD, PhD, Aalborg University Hospital, Denmark

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Link to the HOT-COVID website

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Actual): March 8, 2023
• Study Completion (Estimated): March 8, 2024

Study Registration Dates

• First Submitted: June 5, 2020
• First Submitted That Met QC Criteria: June 10, 2020
• First Posted (Actual): June 11, 2020

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Critical illness; Critical care; Acute Respiratory Distress Syndrome; Mechanical ventilation; Oxygenation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: AAUH-ICU-03; 2017-000632-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All original records (incl. consent forms, electronic clinical report forms (eCRFs), and relevant correspondences) will be archived at trial sites for 15 years. The clean electronic trial database file will be delivered to the EudraCT Database and Zenodo data repository (https://zenodo.org/) and maintained for 15 years and anonymised if requested by the authorities.

IPD Sharing Access Criteria

Access Criteria:

Managed by the Steering Committee of the HOT-COVID trial.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No