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Trial registered on ANZCTR

Registration number

ACTRN12617000821392

Ethics application status

Approved

Date submitted

5/05/2017

Date registered

5/06/2017

Date last updated

28/11/2022

Date data sharing statement initially provided

22/12/2021

Date results provided

28/11/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A Randomised Controlled Trial.

Scientific title

In infants and children < 2 years of age with congenital heart defects, what is the effect of Nitric Oxide during open heart surgery with Cardio Pulmonary Bypass on postoperative length of mechanical ventilation? - A Randomised Controlled Trial.

Secondary ID [1]

NIl known

Universal Trial Number (UTN)

NA yet

Trial acronym

NA yet

Linked study record

Health condition

Health condition(s) or problem(s) studied:

congenital heart disease

Condition category

Condition code

Cardiovascular

Other cardiovascular diseases

Surgery

Other surgery

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Patients allocated to the study gas arm will receive nitric oxide (NO), which will be blended into the fresh gas flow for the CPB oxygenator and maintained at 20 ppm via an Ikaria INOmax DSIR (Ikaria, NJ, USA), with continuous sampling of NO and NO2 concentration from an access port just prior to the oxygenator. NO will be started when the patient is on CPB and ceased once coming off CPB.
Perfusionists will maintain an protected electronic documentation start time, stop time of the study drug and achieved maximal and minimal NO concentration (in ppm). This documentation will be blinded for other study investigators.The lead perfusionists at each site are responsible to audit biweekly the documentation.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

For patients allocated to the Placebo arm will receive standard respiratory gases (oxygen-air mix) during bypass.

Control group

Placebo

Outcomes

Primary outcome [1]

Length of mechanical ventilation as defined as the duration of respiratory support for all episodes with an endotracheal tube in situ for the first 28 days post start of cardiopulmonary bypass. The outcome will be reported using ventilator free days (VFD). A systematically zero value will be assigned for patients who die to allow important weight to death as the most pejorative outcome.

Timepoint [1]

28 days post procedure

Secondary outcome [1]

Composite outcome of Incidence of Low cardiac output syndrome, need for Extracorporeal Life Support (during the first 48 hours after cardiopulmonary bypass start), and Mortality: The components of the composite outcome are defined as below: LCOS is defined as the inability of the myocardium to provide adequate oxygen delivery (DO2) to the tissue. DO2 measurements are not feasible in daily practice, hence accepted surrogate measures are commonly used. For the purpose of this study, LCOS will be defined as: - blood lactate level greater than 4 mmol/l with an oxygen extraction greater than 35% (SaO2-SvO2 gradient >35%) within the first 48 hours postoperatively and/or - high inotrope requirement: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS) (2): VIS = dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) + 100 x adrenaline dose (mcg/kg/min) + 100 x noradrenaline dose (mcg/kg/min) + 10 x milrinone dose (mcg/kg/min) + 10,000 x vasopressin dose (U/kg/min). A score greater than or equal to 15 indicating low cardiac output syndrome.
ECLS will be assessed if initiated in theatre or postoperatively in intensive care using prospective data capture in PICU and the ward. Death will be assessed post-operatively using prospective data capture in PICU and the ward.

Timepoint [1]

28 days post procedure

Secondary outcome [2]

Length of stay in PICU will be defined by the time span from start time of cardiopulmonary bypass to the first discharge from PICU following the cardiac surgery. This definition is required as some children are admitted to PICU pre surgery, depending on institutional practices, severity, and other diseases leading to PICU admission pre-surgery.
PICU admission dates and time in hours:minutes are captured as a default mandatory data field in all contributing units, and are part of the mandatory ANZPICR dataset.

Timepoint [2]

Duration of hospitalization in PICU

Secondary outcome [3]

Composite of levels of systemic inflammatory markers and levels of markers of myocardial injury, including TNF, IL6, BNP and Troponin I. An expanded panel of markers may be used depending on availability/costs.

Timepoint [3]

Blood markers for myocardial injury and inflammatory response will be collected on induction of anaesthetics (baseline – pre bypass), at admission to PICU (0 hours – post bypass) and at 12, and 18-24 hours for the following purposes: i) to test the impact of the intervention on markers of inflammation; ii) to stratify patients in to high- versus low inflammatory groups; iii) to biochemically define responders to the intervention (to identify patient subgroups that are more likely to respond to a specific treatment), iv) to develop improved markers of outcome post cardiac surgery. Marker measurement will occur in batch.

Secondary outcome [4]

Length of stay in hospital will be defined by the time span from start time of cardiopulmonary bypass to the first discharge from hospital following the cardiac surgery. This definition is required as some children are admitted to hospital pre surgery, depending on institutional practices, severity, and other diseases leading to hospital admission pre-surgery.
PICU and Hospital admission dates and time in hours:minutes are captured as a default mandatory data field in all contributing units, and are part of the mandatory ANZPICR dataset.

Timepoint [4]

Duration of hospitalization

Secondary outcome [5]

Health care costs:
A with-in trial economic evaluation will be undertaken from the health system perspective to compare the cost of providing NO to that of usual care. Resources to be measured and costed will include the numeric length of stay (in PICU and/or non-intensive stay), and the length of ECLS treatment. Costs will be assigned by the hospital cost centre or standard national sources (e.g. Independent Hospital Pricing Authority).

Timepoint [5]

Direct health care costs related to the duration of hospital admission

Secondary outcome [6]

Neurodevelopment and long term outcome, using the Ages and Stages Questionnaire (ASQ).

Timepoint [6]

Baseline and 12 months post intervention. Baseline assessment completed by parents prior to intervention. 12 month assessments completed via mail, phone or in person.

Eligibility

Key inclusion criteria

All infants and children < 2 years of age undergoing elective open heart surgery on CPB, and consent of parents/guardian.

Minimum age

0 Days

Maximum age

2 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Signs of persistently elevated pulmonary vascular resistance preoperatively requiring iNO or preoperative use of drugs involved in the NO pathway such as GTN within 48 hours prior to CPB (oral sildenafil treatment alone is not an exclusion)
2. Patient is on ECLS immediately prior to surgery
3. Receiving ongoing treatment with antimicrobials for confirmed or suspected sepsis or septic shock diagnosed within 48hours prior to the time of surgery
4. Preoperative acute respiratory distress syndrome requiring HFOV ventilation within 48 hours prior to surgery
5. Patient requires high doses of vasoactive drugs prior to surgery with a score equal or greater than 15 met within 24 hours prior to surgery: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS) (2): VIS = dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) + 100 x adrenaline dose (mcg/kg/min) + 100 x noradrenaline dose (mcg/kg/min) + 10 x milrinone dose (mcg/kg/min) + 10,000 x vasopressin dose (U/kg/min).
6. Cardiac arrest within one week (7d) prior to surgery
7. Emergency cardiac surgery (defined as acutely required life-saving procedure in a patient unlikely to survive the next 48hours without the surgery)
8. pre-existing methaemoglobinemia (MetHb>3%)
9. Patients that were previously enrolled and randomized into the study with surgical procedure performed that required use of cardio-pulmonary bypass will not get re-randomized. Previously enrolled and randomized patients will undergo the same treatment allocation for subsequent surgeries, unless parents opt out.
10. Chronic ventilator dependency

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation concelement: central randomisation by computer using web-based randomization.

Blinding arrangements: Of the investigating team, only the study perfusionist will be aware of the randomisation and NO delivery. Blinding arrangement in the operating theatre will be achieved by covering the NO delivery system with drapes. The dedicated study NO delivery system will be in connected to the patient at all times, independent of randomization. The surgeons, anaesthetists and ICU staff will be not aware which treatment arm a patient been allocated to. The perfusionists will be advised that all aspects of CPB except for provision of NO (or not) should be performed in a standard fashion for study participants. The perfusionist is not attending the surgical handover in PICU. The data safety monitoring board will be unblinded in the event of an adverse event.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Study patients will be randomly allocated to NO or control and stratified by age group (<42 days, 42 days -24 months) and uni-versus biventricular cardiac lesion for each site. Randomisation will done by using webpage allocation. For incomplete data or withdrawal of consent the intention to treat principle will be applied.
Stratification
- age group (0-42 days and 42 days to 2 years)
- uni-versus biventricular (cyanotic vs acyanotic)
- study site

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

A pilot study showed an approximate 66 hours (0.33 SD) reduction in ventilator-free days (VFD) associated with the study intervention. Based on the primary outcome measure VFD, 1,320 patients (660 per group) would be required to demonstrate a significant increase in VFD assuming a minimally clinically significant small effect size (0.2 SD), 90% power, two-sided alpha level of significance of 5%, 10% withdrawals, and 15% increase in sample size to account for a non-normal distribution of VFD. In Australia and New Zealand approximately 800 of children < 2 years of age undergo surgery for a congenital heart defect requiring CPB each year, including patients with multiple procedures. The consent rate of eligible patients was 78% in the pilot trial[26]. With an expected conservative estimate 60% enrolment rate of eligible patients, we expect a three to four year recruitment period for the study taking into account recruitment difficulties related to COVID-19 pandemic.
Descriptive statistics will be utilised to report on the baseline characteristics of the total study cohort and each subgroup, as well as by site. The primary outcome measure investigating length of mechanical ventilation will be analysed using quantile regression, allowing for stratification and site variables. Logistic regression analyses will be used including age group and physiology as fixed effects, and site as a random effect, with unadjusted and adjusted odds ratios (ORs) and 95% CIs reported) for binary secondary outcome measures. Survival outcomes (length of PICU stay, length of hospital stay) will be visually presented using a Kaplan-Meier plot and a Cox proportional hazard model will be used to assess differences between treatment groups with treatment group and stratification variables as fixed effects and site as a random effect (i.e. utilising a shared frailty model). The hazard ratio and 95% CI will be presented as an estimate of treatment effect. Continuous outcomes will be analysed using linear regression adjusting for age group and physiology as fixed effects, and site as a random effect, with mean difference and 95% CI reported. If the residuals demonstrate non-normality, quantile regression will instead be used in the same manner as for the primary outcome. All analyses will be by intention-to-treat. Statistical significance will be set at the 0.05 level for the primary outcomes. Post-hoc power analyses may be undertaken to determine if results found in sub-group analyses are reliable.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/07/2017

Actual

19/07/2017

Date of last participant enrolment

Anticipated

31/12/2020

Actual

23/04/2021

Date of last data collection

Anticipated

31/12/2021

Actual

30/05/2022

Sample size

Target

1320

Accrual to date

Final

1371

Recruitment in Australia

Recruitment state(s)

NSW,QLD,WA,VIC

Recruitment hospital [1]

Lady Cilento Children's Hospital - South Brisbane

Recruitment hospital [2]

The Royal Childrens Hospital - Parkville

Recruitment hospital [3]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [4]

Perth Children's Hospital - Nedlands

Recruitment postcode(s) [1]

4101 - South Brisbane

Recruitment postcode(s) [2]

3052 - Parkville

Recruitment postcode(s) [3]

2145 - Westmead

Recruitment postcode(s) [4]

6009 - Nedlands

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Country [2]

Netherlands

State/province [2]

Utrecht

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Children`s Health Foundation Queensland

Address [1]

Children’s Hospital Foundation Queensland
PO Box 8009
Woolloongabba QLD 4102

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Heart Kids Australia

Address [2]

HeartKids Australia Inc
Street Address:
Suite 301, Level 2 / 39 Hume Street
Crows Nest NSW 2065
Postal Address:
PO Box 149
Crows Nest NSW 1585

Country [2]

Australia

Funding source category [3]

Government body

Name [3]

NHMRC

Address [3]

GPO Box 1421
Canberra ACT 2601

Country [3]

Australia

Primary sponsor type

Individual

Name

A/Prof Andreas Schibler

Address

Paediatric Intensive Care Unit -
Level 4, Lady Cilento Children's Hospital
Raymond Tce
South Brisbane, QLD 4101

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

A/Prof Luregn Schlapbach

Address [1]

Paediatric Intensive Care Unit -
Level 4, Lady Cilento Children's Hospital
Raymond Tce
South Brisbane, QLD 4101

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

CHILDREN’S HEALTH QUEENSLAND HOSPITAL AND HEALTH SERVICE HUMAN RESEARCH ETHICS COMMITTEE

Ethics committee address [1]

Level 7, Centre for Children’s Health Research
Lady Cilento Children’s Hospital Precinct
62 Graham Street, South Brisbane QLD 4101

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/03/2017

Approval date [1]

26/04/2017

Ethics approval number [1]

HREC/17/QRCH/43

Ethics committee name [2]

Northern A Health and Disability Ethics Committee

Ethics committee address [2]

Ministry of Health
133 Molesworth St
PO Box 5013, Wellington 6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

06/11/2017

Approval date [2]

09/01/2018

Ethics approval number [2]

17/NTA/156

Summary

Brief summary

Each year, over 2000 children are born with congenital heart disease in Australia, of which the majority requires surgical intervention. Congenital heart disease ranks still within the top causes of infant mortality in industrialized countries. Despite considerable advances over the past decade, the exposure to cardiopulmonary bypass (CPB), which is needed for most surgeries, remains responsible for major side effects: The exposure of patient blood to large artificial surfaces in the CPB circuit triggers a very strong systemic inflammatory syndrome, which leads in a third of patients to low cardiac output syndrome (LCOS). LCOS is defined as a condition with a reduced oxygen delivery to end organs due the postoperative heart not being able to meet the circulatory demand. LCOS manifests with severe organ dysfunction such as respiratory and renal failure, and can lead to brain hypoperfusion, cardiac arrest, and death. Survivors are at increased risk for long term neurological impairment. Patients with LCOS require increased length of respiratory support, prolonged length of stay in intensive care and hospital, resulting in significantly increased health care costs, and translating into lifelong costs due to neurological impairment. Previous attempts to reduce the detrimental inflammatory effects of CPB using immunomodulating drugs such as corticosteroids have failed to show a demonstrable benefit. Nitric oxide is a endogenous anti-inflammatory mediator, with direct actions on endothelial bed and immunologically active cells. Previous studies suggest that the delivery of gaseous nitric oxide (NO) to bypass circuits results in myocardial protection and in a reduction in bypass-induced inflammation. We have therefore performed a randomised controlled single centre pilot trial and showed that the delivery of gaseous nitric oxide (NO) to the oxygenator of the CPB circuit for children undergoing cardiac surgery for congenital heart defect resulted in a twofold reduced incidence of LCOS, and improved patient-centred outcomes including less need for extracorporeal life support post surgery, and shorter duration of mechanical ventilation, with a trend to improved mortality. 
In order to confirm these single centre pilot data we aim to investigate in a multicentre randomised controlled trial if NO reduces length of mechanical ventilation as a primary outcome, and reduced LCOS/ECLS/death as secondary outcomes.

Trial website

Trial related presentations / publications

Trial pilot publication:
https://www.ncbi.nlm.nih.gov/pubmed/27686343
James C, Millar J, Horton S, Brizard C, Molesworth C, Butt W. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial.
Intensive Care Med. 2016 Nov;42(11):1744-1752. Epub 2016 Sep 30.

Public notes

Contacts

Principal investigator

Name

A/Prof Andreas Schibler

Address

Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101

Country

Australia

Phone

+61 (0)730681111

Fax

[email protected]

Contact person for public queries

Name

Andreas Schibler

Address

Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101

Country

Australia

Phone

+61 (0)730681111

Fax

[email protected]

Contact person for scientific queries

Name

Luregn Schlapbach

Address

Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101

Country

Australia

Phone

+61 (0)730681111

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
14521	Study protocol	Schlapbach, L. J., et al. (2019). "Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial." BMJ Open 9(8): e026664	https://www.ncbi.nlm.nih.gov/pubmed/31420383
14522	Statistical analysis plan	Gibbons, K. S. et al (2021). "Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial." Critical Care and Resuscitation 2021; 23 (1): 47-58.

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): A randomised controlled trial.	2019	https://dx.doi.org/10.1136/bmjopen-2018-026664
Embase	Invited Commentary: Efficacy of Nitric Oxide Administration During Neonatal Cardiopulmonary Bypass.	2020	https://dx.doi.org/10.1177/2150135120920625
Embase	Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.	2022	https://dx.doi.org/10.1001/jama.2022.9376
Dimensions AI	Platelet reactivity in young children undergoing congenital heart disease surgery: a NITRIC randomized clinical trial substudy	2024	https://doi.org/10.1007/s44253-024-00037-2

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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