Clinical trial NCT02321072: Optimal Oxygenation in the Intensive Care Unit
Official title: The Effects of Hyperoxia on Organ Dysfunction and Outcome in Critically Ill Patients With SIRS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Systemic Inflammatory Response Syndrome
Keywords: oxygen
hypoxia
hyperoxia
critical care
intensive care
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Tergooi Hospital
First posted: 2014-12-22
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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)

Eligibility criteria: 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

Primary outcomes:
measure: Daily Delta Sequential Organ Failure Assessment Score
timeFrame: 14 days
Secondary outcomes:
measure: total maximum SOFA score minus SOFA score on admission
timeFrame: 14 days
measure: SOFA rate of decline
timeFrame: 14 days
measure: Total maximum SOFA score, total maximum SOFA score minus SOFA score on admission, SOFA rate of decline
timeFrame: 14 days
measure: Mortality
timeFrame: 14 days, in-ICU (max 90 days), in-hospital (max 90 days)
measure: Hypoxic events (PaO2 <55 mmHg)
timeFrame: 14 days
measure: Vasopressor / Inotrope requirements
timeFrame: 14 days
measure: Renal function, fluid balance
timeFrame: 14 days
measure: Oxidative stress (F2-isoprostanes)
timeFrame: days 1, 3, 7
measure: Duration of mechanical ventilation and ventilator-free days
timeFrame: 14 days
measure: Length of stay (ICU)
timeFrame: average expected 2 to 28 days
measure: Length of stay (hospital)
timeFrame: average expected 10 to 28 days
measure: Systemic Vascular Resistance Index
timeFrame: 14 days
measure: Cardiac Index
timeFrame: 14 days
measure: Microcirculatory flow index and Perfused vessel density
timeFrame: 14 days
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: A.M.E. de Man, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.