Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
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 information initially provided
22/12/2021
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] 291759 0
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 302984 0
Condition category
Condition code
Cardiovascular 302596 302596 0 0
Other cardiovascular diseases
Surgery 302616 302616 0 0
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] 297871 0
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] 301861 0
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] 301861 0
28 days post procedure
Secondary outcome [1] 334136 0
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] 334136 0
28 days post procedure
Secondary outcome [2] 334539 0
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] 334539 0
Duration of hospitalization in PICU
Secondary outcome [3] 334541 0
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] 334541 0
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] 334703 0
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] 334703 0
Duration of hospitalization
Secondary outcome [5] 334704 0
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] 334704 0
Direct health care costs related to the duration of hospital admission
Secondary outcome [6] 353111 0
Neurodevelopment and long term outcome, using the Ages and Stages Questionnaire (ASQ).
Timepoint [6] 353111 0
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?
No
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] 7939 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [2] 7940 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 12216 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 12217 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 15909 0
4101 - South Brisbane
Recruitment postcode(s) [2] 15910 0
3052 - Parkville
Recruitment postcode(s) [3] 24395 0
2145 - Westmead
Recruitment postcode(s) [4] 24396 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 8840 0
New Zealand
State/province [1] 8840 0
Auckland
Country [2] 20945 0
Netherlands
State/province [2] 20945 0
Utrecht

Funding & Sponsors
Funding source category [1] 296259 0
Charities/Societies/Foundations
Name [1] 296259 0
Children`s Health Foundation Queensland
Country [1] 296259 0
Australia
Funding source category [2] 296260 0
Charities/Societies/Foundations
Name [2] 296260 0
Heart Kids Australia
Country [2] 296260 0
Australia
Funding source category [3] 300984 0
Government body
Name [3] 300984 0
NHMRC
Country [3] 300984 0
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] 295175 0
Individual
Name [1] 295175 0
A/Prof Luregn Schlapbach
Address [1] 295175 0
Paediatric Intensive Care Unit -
Level 4, Lady Cilento Children's Hospital
Raymond Tce
South Brisbane, QLD 4101
Country [1] 295175 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297604 0
CHILDREN’S HEALTH QUEENSLAND HOSPITAL AND HEALTH SERVICE HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [1] 297604 0
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] 297604 0
Australia
Date submitted for ethics approval [1] 297604 0
06/03/2017
Approval date [1] 297604 0
26/04/2017
Ethics approval number [1] 297604 0
HREC/17/QRCH/43
Ethics committee name [2] 301745 0
Northern A Health and Disability Ethics Committee
Ethics committee address [2] 301745 0
Ministry of Health
133 Molesworth St
PO Box 5013, Wellington 6011
Ethics committee country [2] 301745 0
New Zealand
Date submitted for ethics approval [2] 301745 0
06/11/2017
Approval date [2] 301745 0
09/01/2018
Ethics approval number [2] 301745 0
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 74222 0
A/Prof Andreas Schibler
Address 74222 0
Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101
Country 74222 0
Australia
Phone 74222 0
+61 (0)730681111
Fax 74222 0
Email 74222 0
[email protected]
Contact person for public queries
Name 74223 0
A/Prof Andreas Schibler
Address 74223 0
Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101
Country 74223 0
Australia
Phone 74223 0
+61 (0)730681111
Fax 74223 0
Email 74223 0
[email protected]
Contact person for scientific queries
Name 74224 0
A/Prof Luregn Schlapbach
Address 74224 0
Paediatric Critical Care Research Group,
Paediatric Intensive Care Unit
Lady Cilento Children`s Hospital
Raymond Tce
South Brisbane
QLD 4101
Country 74224 0
Australia
Phone 74224 0
+61 (0)730681111
Fax 74224 0
Email 74224 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14521Study protocolSchlapbach, 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): e026664https://www.ncbi.nlm.nih.gov/pubmed/31420383 
14522Statistical analysis planGibbons, 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

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Schlapbach LJ, Gibbons KS, Horton SB, Johnson K, L... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStudy protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): A randomised controlled trial.2019https://dx.doi.org/10.1136/bmjopen-2018-026664
EmbaseEffect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.2022https://dx.doi.org/10.1001/jama.2022.9376
EmbaseInvited Commentary: Efficacy of Nitric Oxide Administration During Neonatal Cardiopulmonary Bypass.2020https://dx.doi.org/10.1177/2150135120920625
Dimensions AIPlatelet reactivity in young children undergoing congenital heart disease surgery: a NITRIC randomized clinical trial substudy2024https://doi.org/10.1007/s44253-024-00037-2
N.B. These documents automatically identified may not have been verified by the study sponsor.