Optimal Oxygenation in the Intensive Care Unit (O2-ICU)

The Effects of Hyperoxia on Organ Dysfunction and Outcome in Critically Ill Patients With SIRS

Objectives:

1. To study the short- and long-term effect of two different PaO2 targets on circulatory status, organ dysfunction and outcome in patient admitted to the ICU with Systemic Inflammatory Response Syndrome (SIRS) criteria.
2. To study underlying mechanisms of hyperoxia by determining differences in oxidative stress response between the hyperoxic and the normoxic patients.

Study design:

Randomized, prospective multicentre clinical trial

Study population:

Patients admitted to the Intensive Care unit with ≥ 2 positive SIRS-criteria and an expected ICU stay of more than 48 hours

Intervention:

Group 1: target PaO2 120 (105 - 135) mmHg (high-normal)

Group 2: target PaO2 75 (60 - 90) mmHg (low-normal)

Primary endpoints:

The primary endpoint will be cumulative daily delta SOFA score (CDDS) from day 1 to day 14.

Study Overview

• Status: Completed
• Conditions: Systemic Inflammatory Response Syndrome
• Intervention / Treatment: Drug: Oxygen

Detailed Description

Rationale:

Contrary to hypoxia, many physicians do not consider hyperoxia harmful for their patients. To prevent hypoxia, superfluous administration of oxygen is common practice, and hyperoxia is seen in many patients, especially on Intensive Care units. However, an increasing number of studies not only confirm the known negative pulmonary effects of chronic oxygen oversupply, but also important and more acute circulatory effects, characterised by decreased cardiac output (CO), increased systemic vascular resistance (SVR), and impaired microvascular perfusion. These phenomena can impair perfusion of organs, which may outweigh higher arterial oxygen content, resulting in a net loss of oxygen delivery and perturbed organ function. This may for example be responsible for hyperoxia-associated increased infarct size and increased mortality after myocardial infarction and cardiac arrest. The underlying mechanisms are not clarified yet, but probably involve increased oxidative stress with systemic vasoconstriction.

On the other hand, hyperoxia can also induce several favourable effects. The majority of ICU-patients have a systemic inflammatory response syndrome (SIRS) with concomitant vasoplegia due to trauma, sepsis or ischemia/reperfusion injury. Vasoconstriction could benefit these patients with severe SIRS, reducing the need for intravenous volume resuscitation and vasopressor requirements. Furthermore, hyperoxia may exert a preconditioning effect in patients with ischemia/reperfusion injury and prevent new infections due to its antibacterial properties.

Hypothesis:

Hyperoxia during SIRS ultimately has unfavourable effects on organ function, especially on a longer term.

Objectives:

1. To study the short- and long-term effect of two different PaO2 targets on circulatory status, organ dysfunction and outcome.
2. To study underlying mechanisms of hyperoxia by determining differences in oxidative stress response between the hyperoxic and the normoxic patients.

Study design:

Randomized, prospective multicentre clinical trial

Study population:

Patients admitted to the Intensive Care unit with ≥ 2 positive SIRS-criteria and an expected ICU stay of more than 48 hours

Intervention:

We will investigate 2 groups with PaO2 targets both within the range of current practice

Group 1: target PaO2 120 (105 - 135) mmHg (high-normal)

Group 2: target PaO2 75 (60 - 90) mmHg (low-normal)

• Study Type: Interventional
• Enrollment (Actual): 400
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• ≥2 positive SIRS-criteria:

  • Temperature >38 deg.C or hypothermia <36 deg.C
  • Heart rate >90 bpm
  • Respiratory rate >20 /min or pCO2 <32 mmHg (4.3 kPa)
  • Number of leucocytes >12 x 10^9/l of <4 x 10^9/l of >10% bands
• Within 12 hours of admittance to the ICU
• Expected stay of more than 48 hours as estimated by the attending physician

Exclusion Criteria:

• Elective surgery
• Carbon monoxide poisoning
• Cyanide intoxication
• Methemoglobinemia
• Sickle cell anemia
• Severe pulmonary arterial hypertension (WHO class III or IV)
• Known severe Acute Respiratory Distress Syndrome (ARDS) (PaO2/FiO2 ≤100 mmHg and PEEP ≥ 5 cm H2O)
• Known cardiac right to left shunting
• Pregnancy
• Severe Chronic Obstructive Pulmonary Disease (COPD) (Gold class III or IV) or other severe chronic pulmonary disease
• Patients participating in other interventional trials

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High-normal PaO2; In patients requiring respiratory monitoring, supplemental oxygen is titrated to achieve a PaO2 of 120 mmHg (16 kPa), range 105-135 mmHg (14-18 kPa).	Drug: Oxygen
Active Comparator: Low-normal PaO2; In patients requiring respiratory monitoring, supplemental oxygen is titrated to achieve a target PaO2 of 75 mmHg (10 kPa), range 60-90 mmHg (8-18 kPa).	Drug: Oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Delta Sequential Organ Failure Assessment Score	The primary endpoint will be cumulative daily delta SOFA score (CDDS) from day 1 to day 14, calculated as the sum of [daily SOFA score minus admission SOFA score] from day 2 to day 14. Daily SOFA score is calculated as the total of maximum scores for each organ system excluding respiratory system (because of possible PaO2/FiO2 distortion). For patients discharged from the ICU, SOFA score will be registered as 0 from the day of discharge to day 14. Death in the ICU will be registered as a score of 20 (maximum) from the day of death to day 14.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
total maximum SOFA score minus SOFA score on admission		14 days
SOFA rate of decline		14 days
Total maximum SOFA score, total maximum SOFA score minus SOFA score on admission, SOFA rate of decline		14 days
Mortality		14 days, in-ICU (max 90 days), in-hospital (max 90 days)
Hypoxic events (PaO2 <55 mmHg)		14 days
Vasopressor / Inotrope requirements		14 days
Renal function, fluid balance		14 days
Oxidative stress (F2-isoprostanes)		days 1, 3, 7
Duration of mechanical ventilation and ventilator-free days		14 days
Length of stay (ICU)		average expected 2 to 28 days
Length of stay (hospital)		average expected 10 to 28 days
Systemic Vascular Resistance Index	In a random subpopulation.	14 days
Cardiac Index	In a random subpopulation.	14 days
Microcirculatory flow index and Perfused vessel density	In a random subpopulation. Composite endpoint for two sidestream dark-field microcirculatory measurements.	14 days

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); ZonMw: The Netherlands Organisation for Health Research and Development; Tergooi Hospital
• Investigators: Principal Investigator: A.M.E. de Man, MD, PhD, Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Gelissen H, de Grooth HJ, Smulders Y, Wils EJ, de Ruijter W, Vink R, Smit B, Rottgering J, Atmowihardjo L, Girbes A, Elbers P, Tuinman PR, Oudemans-van Straaten H, de Man A. Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):940-948. doi: 10.1001/jama.2021.13011.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: December 15, 2014
• First Posted (Estimate): December 22, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 13, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: critical care; intensive care; oxygen; hypoxia; hyperoxia
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Shock; Systemic Inflammatory Response Syndrome
• Other Study ID Numbers: 2014/459; 2014-003468-19 (EudraCT Number)