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

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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04452188

Acronym

T-NOX

Enrollment

Registered

2020-06-30

Start date

2021-01-18

Completion date

2023-04-20

Last updated

2024-06-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cardiopulmonary Bypass, Double Outlet Right Ventricle, Subpulmonary VSD, Double Outlet Right Ventricle With Subaortic Ventricular Septal Defect and Pulmonary Stenosis, Hypoplastic Left Heart Syndrome, Pulmonary Atresia With Ventricular Septal Defect, Tetralogy of Fallot, Total Anomalous Pulmonary Venous Return, Transposition of the Great Arteries, Truncus Arteriosus

Keywords

Open heart surgery

Brief summary

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

Interventions

OTHERNormoxia (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: 1. Single ventricle patients (PaO2:35-45 and oxygen saturation 75%-85%) 2. Two ventricle patients (PaO2: 60-100 and oxygen saturation \>92%)

OTHERStandard 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 29 Days

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Global Rank Score	30 days after surgery	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.
Post-operative Length of Stay	30 days after surgery	Calculated as number of days in the hospital after surgery.
Days Alive and Out of the Intensive Care Unit (ICU) at 30 Days After Surgery	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.
Composite Outcome of Major Adverse Events	30 days after surgery	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.
Systemic Oxidative Stress Based on Thiobarbituric Acid Reactive Substances (TBARS)	Up to 24 hours following surgery	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.
Rate of Observed Adverse Events Between the Two Groups	30 days after surgery	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.

Other

Measure	Time frame	Description
Systemic Oxidative Stress Based on Total Antioxidant Capacity (TAC)	Up to 24 hours after surgery	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.
Systemic Oxidative Stress Based on 8-Isoprostane Levels After Surgery	Up to 24 hours 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.
Systemic Oxidative Stress Based on Protein Carbonyl Levels After Surgery	Up to 24 hours 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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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. 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 patient's physiology: 1. Single ventricle patients (PaO2:35-45 and oxygen saturation 75%-85%) 2. Two ventricle patients (PaO2: 60-100 and oxygen saturation \>92%)	15
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 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.	14
Total	29

Baseline characteristics

Characteristic	Normoxia	Standard of Care	Total
Age, Continuous	5 days	5 days	5 days
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants	12 Participants	25 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) White	14 Participants	13 Participants	27 Participants
Region of Enrollment United States	15 Participants	14 Participants	29 Participants
Sex: Female, Male Female	2 Participants	5 Participants	7 Participants
Sex: Female, Male Male	13 Participants	9 Participants	22 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 15	1 / 14
other Total, other adverse events	7 / 15	3 / 14
serious Total, serious adverse events	3 / 15	3 / 14

Outcome results

Primary

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.