Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period (T-NOX)

Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period (T-NOX)

This clinical trial is studying the use of different levels of oxygen exposure during and after cardiopulmonary bypass in eligible infants to learn about its safety during heart surgery.

In addition to having the various doses of oxygen, participants will also have blood samples, ultrasounds of the head, and brain wave patterns monitored.

The hypotheses of this trial are:

• that there will be no difference with regards to adverse events between the infants in the normoxia group compared to the infants in the standard of care group
• there will be a significant difference in the measured partial pressure of oxygen (PaO2) values between the two treatment groups.
• the use of normoxia during cardiopulmonary bypass and in the immediate post-operative period will result in clinically significant decrease in oxidative stress as measured by thiobarbituric acid reactive substances (TBARS) after cardiac surgery

Study Overview

• Status: Completed
• Conditions: Tetralogy of Fallot; Cardiopulmonary Bypass; Hypoplastic Left Heart Syndrome; Transposition of the Great Arteries; Double Outlet Right Ventricle, Subpulmonary VSD; Pulmonary Atresia With Ventricular Septal Defect; Truncus Arteriosus; Total Anomalous Pulmonary Venous Return; Double Outlet Right Ventricle With Subaortic Ventricular Septal Defect and Pulmonary Stenosis
• Intervention / Treatment: Other: Standard of care ventilation; Other: Normoxia (with controlled re-oxygenation)

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 weeks (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age less than 30 days of age at time of surgery with need for cardiopulmonary bypass with cardioplegic arrest (with or without deep hypothermic circulatory arrest)

• Diagnosis with cyanosis at baseline (pre-operative PaO2 of less than 50mmHG) due to:

  • Complete admixture lesion (example: hypoplastic left heart syndrome, total anomalous pulmonary venous return, truncus arteriosus, pulmonary atresia with VSD)
  • Transposition physiology (example: D-Transposition of the great arteries or Double outlet right ventricle with subpulmonary VSD)
  • Right-to-left shunt (example: Tetralogy of Fallot, double outlet right ventricle with subaortic VSD and pulmonary stenosis)

Exclusion Criteria:

• Corrected gestation at time of surgery less than 37 weeks
• Prior cardiac arrest
• Current or prior history of extracorporeal membrane oxygenation (ECMO) support
• Current or prior history of needing renal replacement therapy with dialysis
• Prior cardiac surgery requiring cardiopulmonary bypass
• Diagnosis of Ebstein's Anomaly
• Known genetic syndrome other than Trisomy 21 or DiGeorge Syndrome

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normoxia; On bypass, goal PaO2 on cardiopulmonary bypass of 60-100 mm Hg using lower fraction of inspired oxygen (FiO2) (blended sweep gas) via oxygenator Post-bypass, goal of PaO2 <100 mm Hg by anesthesia and in ICU via oxygen titration via mechanical ventilator for 24 hours post-op.	Other: Normoxia (with controlled re-oxygenation); Participants will receive lower levels of oxygen during surgery and after surgery on the ventilator. As cardiopulmonary bypass is being weaned, anesthesia will initiate mechanical ventilation with an FiO2 of 50% or less (unless clinically necessary) to achieve oxygen saturation and PaO2 goals that fit within the expected range for the participant's physiology: Single ventricle patients (PaO2:35-45 and oxygen saturation 75%-85%); Two ventricle patients (PaO2: 60-100 and oxygen saturation >92%)
Active Comparator: Standard of care; Frequent blood gases will be checked per protocol on bypass and correlated with the blood parameter monitoring system to maintain a PaO2 of 200-300 per standard practice	Other: Standard of care ventilation; As cardiopulmonary bypass is being weaned, anesthesia will initiate mechanical ventilation per standard protocols. Ventilation will be continued in the ICU and adjusted per standard goals per the intensivist.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic Oxidative Stress Based on Thiobarbituric Acid Reactive Substances (TBARS)	Oxidative stress (OS) reflects an imbalance between the production and accumulation of reactive oxygen species. Oxidation of lipids leads to the generation of lipid peroxides which can be detected as Thiobarbituric acid reactive substances (TBARS). Thus, levels of serum TBARS were assessed in participants as indicators of OS. TBARS levels were assessed at three separate time points in the first 24 hours after surgery (2, 6, and 24 hours). Each participant's post-operative (PO) samples were normalized to their baseline pre-operative sample and described as a fold-of-change from baseline. The fold-of-change describes how much a quantity changes between an original and a subsequent measurement and is calculated as TBARS level at each PO time point / TBARS at baseline. The mean values of the fold of change from baseline between the two groups at each PO time-point were compared.	Up to 24 hours following surgery
Rate of Observed Adverse Events Between the Two Groups	The count of each of the adverse events within 30 days after the index cardiac surgery, listed here: mortality, cardiac arrest, need for mechanical circulatory support, seizures (clinical or subclinical based on EEG), and need for dialysis is presented below.	30 days after surgery
Post-operative Length of Stay	Calculated as number of days in the hospital after surgery.	30 days after surgery
Days Alive and Out of the Intensive Care Unit (ICU) at 30 Days After Surgery	This composite measure reflects the number of days alive and not admitted to the ICU. Non-survivors at day 30 were considered to have no ICU-free days.	30 days after surgery
Composite Outcome of Major Adverse Events	The composite endpoint assessed in this study combines in-hospital mortality, cardiac arrest, ECMO, seizures, and dialysis and reflects the number of participants affected by one or more of these outcomes.	30 days after surgery
Global Rank Score	Per NCT03229538, a composite mortality, major morbidity and length of stay global rank endpoint with endpoints ranked according to severity. For this endpoint, each randomized patient will be assigned a rank based upon their most-severe outcome. Rank of 91= Post-operative length of stay > 90 days, 92= Post-op cardiac arrest, multi-system organ failure, renal failure with temporary dialysis, or prolonged ventilator support, 93= Reoperation for bleeding, unplanned delayed sternal closure, or post-op unplanned interventional cardiac catheterization, 94= Post-operative mechanical circulatory support or unplanned cardiac reoperation (exclusive of reoperation for bleeding), 95= Renal failure with permanent dialysis, neurologic deficit persistent at discharge, or respiratory failure requiring tracheostomy; 96= Heart transplant (during hospitalization); 97= Operative mortality. Ranks 1 through 90 correspond to the post-operative length of stay in days. A lower score means a better outcome.	30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic Oxidative Stress Based on Protein Carbonyl Levels After Surgery	Protein carbonyls are generated upon oxidation of proteins and are a marker of oxidative stress. Serum protein carbonyl contents were assessed at three separate time points in the first 24 hours after surgery (2, 6, and 24 hours). Each participant's post-operative (PO) samples were normalized to their baseline sample and described as a fold-of-change from baseline. The mean values of the fold of change from baseline between the two groups at each PO time-point were compared. The fold-of-change describes how much a quantity changes between an original and a subsequent measurement and is calculated as Protein Carbonyl level at each PO time point / Protein Carbonyl at baseline.	Up to 24 hours after surgery
Systemic Oxidative Stress Based on Total Antioxidant Capacity (TAC)	TAC assays measure serum antioxidants in biological samples. Therefore, lower values reflect depletion of antioxidants in the setting of oxidative stress. Serum TAC was assessed at three separate time points in the first 24 hours after surgery (2, 6, and 24 hours). Each participant's post-operative (PO) samples were normalized to their baseline sample and described as a fold-of-change from baseline. The mean values of the fold of change from baseline between the two groups at each PO time-point were compared. The fold-of-change describes how much a quantity changes between an original and a subsequent measurement and is calculated as TAC level at each PO time point / TAC at baseline.	Up to 24 hours after surgery
Systemic Oxidative Stress Based on 8-Isoprostane Levels After Surgery	8-isoprostane is a stable oxidative stress marker formed by non-enzymatic perioxidation of lipids. Serum levels of 8-isoprostane were assessed at three separate time points in the first 24 hours after surgery (2, 6, and 24 hours). Each participant's post-operative (PO) samples were normalized to their baseline sample and described as a fold-of-change from baseline. The mean values of the fold of change from baseline between the two groups at each PO time-point were compared. The fold-of-change describes how much a quantity changes between an original and a subsequent measurement and is calculated as 8-isoprostane level at each PO time point / 8-isoprostane at baseline.	Up to 24 hours after surgery

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institutes of Health (NIH); National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Nathaniel Sznycer-Taub, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2021
• Primary Completion (Actual): April 20, 2023
• Study Completion (Actual): April 20, 2023

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 27, 2020
• First Posted (Actual): June 30, 2020

Study Record Updates

• Last Update Posted (Actual): June 18, 2024
• Last Update Submitted That Met QC Criteria: May 22, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Open heart surgery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Heart Valve Diseases; Ventricular Outflow Obstruction; Cardiovascular Abnormalities; Vascular Malformations; Respiratory System Abnormalities; Aortopulmonary Septal Defect; Heart Diseases; Heart Septal Defects; Tetralogy of Fallot; Heart Defects, Congenital; Pulmonary Valve Stenosis; Hypoplastic Left Heart Syndrome; Transposition of Great Vessels; Heart Septal Defects, Ventricular; Pulmonary Atresia; Double Outlet Right Ventricle; Truncus Arteriosus, Persistent; Scimitar Syndrome
• Other Study ID Numbers: HUM00175086; 5UL1TR002240-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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