Normoxemic Versus Hyperoxemic Extracorporeal Oxygenation in Patients Supported by Veino-arterial ECMO for Cardiogenic Shock

Study Overview
=================
Brief Summary
-----------------
Because of dual oxygenation and oxygenator performance (PO2 postoxygenator up to 500 mmHg), hyperoxemia (PaO2 > 150 mmHg) is frequent in veino-arterial ECMO, especially in the lower part of the body, which is mainly oxygenated by ECMO. By enhancing oxygen free radicals' production, hyperoxemia might favor gut, kidney and liver dysfunction. We hypothesize that targeting an extracorporeal normoxemia (i.e. PO2 postoxygenator between 100 and 150 mmHg) will decrease gut, kidney and liver dysfunctions, compared to a liberal extracorporeal oxygenation.

Detailed Description
-----------------
Randomization: Patients will be randomized in the 6 hours following ECMO start in the normoxemia or in the hyperoxemia group. Randomization will be stratified on center, and medical or postcardiotomy indication for ECMO. Description of experimental arm (Normoxemia group): After randomization, extracorporeal normoxemia is targeted by setting the ECMO membrane oxygen fraction (FmO2) at 60%. The objective is to maintain oxygen partial pressure measured on the arterial cannula (PO2 postoxygenator) between 100 and 150 mmHg. PO2 postoxygenator is monitored at least twice a day by the nurse. If PO2 postoxygenator is less than 100 mmHg or more than 150 mmHg, FmO2 is modified by 10% and PO2 postoxygenator is monitored 10 minutes after. Ventilator's settings at let to the clinician's discretion. However, PaO2 on right radial artery will be monitored to ensure that is more that 80 mmHg. Intervention will be applied for 7 days after randomization. Description of the control arm (Hyperoxemia group): After randomization, extracorporeal hyperoxemia is targeted by setting the ECMO membrane oxygen fraction (FmO2) at 100%. The objective is to maintain PO2 postoxygenator higher than 300 mmHg. PO2 postoxygenator is monitored at least twice a day by the nurse. If PO2 postoxygenator is less than 300 mmHg, membrane change should be discussed. Ventilator's setting at let to the clinician's discretion. However, PaO2 on right radial artery will be monitored to ensure that is more that 80 mmHg. Intervention will be applied for 7 days after randomization.

Official Title
-----------------
Normoxemic Versus Hyperoxemic Extracorporeal Oxygenation : Impact on Organ Dysfunction in Patients Supported by Veino-arterial ECMO for Cardiogenic Shock

Conditions
-----------------
Cardiogenic Shock, Extracorporeal Membrane Oxygenation

Intervention / Treatment
-----------------
* Drug: Oxygen gas


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient supported by veino-arterial ECMO for cardiogenic shock for less than 6 hours Affiliation to social protection Exclusion Criteria: Age < 18 years old Pregnancy Opposition of the patient or his relatives Cannulation during cardiopulmonary resuscitation Cardiopulmonary resuscitation duration > 10 minutes before ECMO implantation Patient moribound on the day of randomization Chronic hemodialysis Chronic intestinal disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial with two arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extracorporeal normoxemia<br>After randomization, extracorporeal normoxemia is targeted by setting the ECMO membrane oxygen fraction (FmO2) at 60%. The objective is to maintain oxygen partial pressure measured on the arterial cannula (PO2 postoxygenator) between 100 and 150 mmHg. PO2 postoxygenator is monitored at least twice a day by the nurse. If PO2 postoxygenator is less than 100 mmHg or more than 150 mmHg, FmO2 is modified by 10% and PO2 postoxygenator is monitored 10 minutes after. Ventilator's setting at let to the clinician's discretion. However, PaO2 on right radial artery will be monitored to ensure that is more that 80 mmHg. Intervention will be applied for 7 days after randomization. | Drug: Oxygen gas<br>* Targeted PO2 postoxygenator is obtained by modulating ECMO Membrane oxygen fraction.<br>|
| Active Comparator: Extracorporeal hyperoxemia<br>After randomization, extracorporeal hyperoxemia is targeted by setting the ECMO membrane oxygen fraction (FmO2) at 100%. The objective is to maintain PO2 postoxygenator higher than 300 mmHg. PO2 postoxygenator is monitored at least twice a day by the nurse. If PO2 postoxygenator is less than 300 mmHg, membrane change should be discussed. Ventilator's setting at let to the clinician's discretion. However, PaO2 on right radial artery will be monitored to ensure that is more that 80 mmHg. Intervention will be applied for 7 days after randomization. | Drug: Oxygen gas<br>* Targeted PO2 postoxygenator is obtained by modulating ECMO Membrane oxygen fraction.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Enterocyte damage | Plasma Intestinal Fatty Acid Biding Protein (I-FABP) concentration | At day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of the oxygenation protocol | Percentage of time in the oxygenation target | From day 0 to day 6 | 
| Security of the oxygenation protocol | Number of right radial PaO2 below 80 mmHg | From day 0 to day 6 | 
| Organ failure | Death or severe stroke (NIHSS > 11) or mesenteric ischemia | From day 0 to day 30 | 
| Organ failure | Non cardiac component of the Sequential Organ Failure Assessment (SOFA) score | At day 0, day 2 and day 6 | 
| Organ failure | Plasma lactate concentration | At day 0, day 2 and day 6 | 
| Enterocyte damage | Plasma Intestinal Fatty Acid Biding Protein (I-FABP) concentration | At day 0, and day 1 | 
| Enterocyte function | Difference between plasma citrulline concentrations at day 0 and day 2 | At day 0 and day 2 | 
| Liver failure | Plasma Aspartate aminotransferase (ASAT) concentration | At day 0, day 2 and day 6 | 
| Liver failure | Prothrombine time | At day 0, day 2 and day 6 | 
| Renal failure | Plasma creatinine concentration | At day 0, day 2 and day 6 | 
| Renal failure | Need for renal replacement therapy | From 0 to day 6 | 
| Systemic inflammation | Plasma CRP, TNF alpha, IL6 and IL8 concentrations | At day 0, day 2 and day 6 | 
| Anti-oxydant stock | Plasma vitamin C, vitamin E, and Glutathion concentrations | At day 0, day 2 and day 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiogenic shock, Extracorporeal Membrane Oxygenation, Hyperoxia