Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A randomised controlled trial

Congenital Heart Disease ranks within the top causes of infant mortality in most 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; mainly 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. 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.

The pilot study from our group 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.

We aim to investigate in a multicentre randomised controlled trial if nitric oxide (NO) reduces length of mechanical ventilation as a primary outcome, and reduced LCOS/Extracorporeal Membrane Oxygenation (ECLS)/death as secondary outcomes thereby improving recovery leading to better short- and long-term outcomes.

Information for parents and guardians

Why are we conducting the Nitric Oxide study?

Often cardiac surgery requires cardiopulmonary bypass and children undergoing this often develop an inflammatory response to bypass. We know this inflammatory response contributes to complications after surgery and delayed recovery. Nitric Oxide has been shown to reduce this inflammatory response and we believe that administering Nitric Oxide into the cardiopulmonary bypass circuit could result in less post-operative complications.

If Nitric Oxide improves the post-operative outcome then this could change practice throughout the world, saving lives and reducing the amount of time children need to stay in hospital after heart surgery.

What is the aim of the Nitric Oxide study?

This study aims to develop a multicentre trial to determine if Nitric Oxide administered during cardiopulmonary bypass reduces the inflammatory response, which often results in complications after surgery and a prolonged hospital stay. Reducing this response could save many children from these complications. This trial will evaluate the post-operative course when Nitric Oxide is administered along with oxygen during cardiopulmonary bypass compared to when just oxygen is administered, which is current practice.

What is Nitric oxide?

Nitric Oxide is widely used throughout the world in paediatric intensive care units. This is not a new medical gas. Nitric Oxide is approved in Australia to treat newborn babies with pulmonary hypertension. It is often used for other severe diseases of the heart and lung in young children.

What is being investigated?

For this study, we are comparing Nitric oxide together with oxygen to the standard method of using just oxygen during cardiopulmonary bypass in children under 2 years requiring cardiac surgery.

Which patients can take part?

Children less than 2 years of age can be included in this study.

What does the Nitric Oxide study involve for the children participating in the trial?

Children undergoing surgery for congenital heart disease requiring cardiopulmonary bypass who are under 2 years of age are enrolled into the study. The children will be randomised to either of the treatment arms:

  1. Standard cardiopulmonary bypass with oxygen
  2. Nitric oxide with cardiopulmonary bypass and oxygen

The study is a randomised trial, which means that your child will be randomly allocated (50:50 chance) to one of two (2) groups. They will receive either standard cardiopulmonary bypass with oxygen or Nitric oxide with cardiopulmonary bypass and oxygen. Nitric Oxide is a gas which will be added to the bypass circuit during surgery. None of the surgical team will know which treatment your child has been allocated to. Only the perfusionist will know whether your child received standard care or Nitric Oxide as they are responsible for the running of the bypass circuit. Neither you nor the treating PICU team will know if Nitric Oxide was given or not. If your child requires further cardiac surgery with bypass before two years of age, your child can receive the same study treatment (Standard Cardiopulmonary Bypass or Cardiopulmonary Bypass with Nitric Oxide) to which they were originally allocated. This is to ensure that our long term developmental assessments are not influenced by subsequent cardiopulmonary bypass runs.

At certain times during the cardiopulmonary bypass and during the post-operative phase blood tests will be taken. Most of these blood tests are part of the standard care your child would receive if they were not taking part in the study. These samples will be taken from an arterial line that all children undergoing heart surgery have as a standard. This means that there will be no additional invasive procedures (e.g. needles) and no pain associated with blood tests. In order to find out how severe the inflammation in your child`s body is, we will sample additional blood from your child. These will be taken in the operating theatre, upon arrival to the PICU, and again at 12 and 24 hours in PICU. The total amount of study bloods taken during the whole time is approximately 10ml in total, which is much less than the routine bloods which will be taken in the operating theatre and PICU for standard clinical procedures. We do not anticipate any additional risks for your child from taking these additional bloods.

In addition to testing blood for inflammation of your child, we will keep the blood stored in a laboratory. This will allow us to further research the blood samples using the most modern techniques, including looking at markers and genetic factors which may influence the way your child responds to cardiac surgery and therapy for cardiac surgery. For this purpose, some study bloods will be sent to laboratories in Brisbane (University of Queensland).It is possible that further blood tests will need to be sent to other laboratories in Australia and overseas. All study blood tests will be labelled with a study number, and not with an identifier containing the identity of your child, to ensure confidentiality. Any use of your child’s blood other than what is approved for this study will require further review by our ethics committee and approval.

We will follow up your child at 12 months after discharge to see how they are going, either via a phone call or mail. We will be asking you questions around your child’s development and quality of life. These questions will take approximately 30 minutes.

Consent

The parent/guardian will be approached prior to the child’s planned surgery date, usually in a pre-admission clinic, regarding consent to participate in the study. The parent/guardian may also receive information via email.

Parent/Guardian’s rights

If at any time the parent/guardian wishes to opt out of the study they can do so by discussing this with their medical officer. This will in no way affect your current or future relationship with the hospital. It will also have no effect on your child’s treatment or your relationship with the people treating them.

Information for participating study centres

Background Nitric Oxide study

The incidence of congenital heart disease (CHD) is approximately 1/100 life born children, of which up to 50% at some stage during their life require cardiac surgery to correct the underlying abnormality. In Australia, over 2000 children are born each year with CHD, and over 30,000 children with CHD are currently living in Australia.

Postoperative paediatric cardiac surgical patients have a high consumption of intensive care resources and are at very high risk of major complications, including cardiac arrest, death, and long-term neurological impairment. LCOS is the major determinant of poor patient outcomes, translating into prolonged PICU and hospital length of stay, prolonged need for ventilation, higher risk of organ failure, brain damage, and renal replacement.

Nitric oxide is an endogenous anti-inflammatory mediator, with direct actions on endothelial bed and immunologically active cells. Previous studies suggest that the delivery of gaseous nitric oxide to bypass circuits results in myocardial protection and in a reduction in bypass-induced inflammation. We aim to utilize the knowledge from our pilot study and intend to confirm these single centre pilot data in a multicentre randomised controlled trial to determine whether adding nitric oxide to the oxygenator during CBP results in improved post-operative morbidity as measured by a reduction post-operative length of mechanical ventilation and reduced LCOS/ECLS/death as secondary outcomes.

Trial aim

The aim of the study is to investigate in a double blind randomized controlled trial in children undergoing open heart surgery;

  1. If NO exposure during CPB reduces the postoperative duration of invasive mechanical ventilation (defined as ventilator free days within 28 days post randomisation) compared to control.
  2. To demonstrate that NO reduces the incidence of LCOS, requirement for ECLS, and 90-day mortality.
  3. To demonstrate that NO reduces the length of PICU stay and health care costs.
  4. To demonstrate that NO reduces the inflammatory response following CPB.
  5. To demonstrate NO impacts on long-term outcome improvement.

Hypothesis

We hypothesise that:

  1. Infants and children undergoing cardiac surgery on CPB exposed to gaseous NO have compared to controls, less myocardial injury and a reduced inflammatory response, leading to reduced incidence of LCOS.
  2. Lower LCOS will translate into reduced secondary organ failure and a reduced postoperative intensive care resource utilisation measured by length of mechanical ventilation, and will ultimately result in a reduction in mortality and health care costs and improved long-term outcome.

Trial design

A multi-centre randomised controlled and blinded study in children < 2 years of age undergoing open heart surgery on cardiopulmonary bypass.

Sample size

The study sites will be recruiting 1470 patients who will be randomly allocated to NO or standard care, and stratified by age group (< 42 days, 42 days-24 months) and uni-versus biventricular lesions for each site. Randomisation will be done by using REDCap randomisation.

Outcomes, significance and innovation

Approximately 10% of children with CHD survive with major neurological sequelae postoperatively, resulting in a massive lifelong burden for patients, families, healthcare systems, and the society. The clinical significance of this study is to gain a true understanding on the efficacy and applicability of NO therapy in real-world conditions to reduce LCOS and hence the perioperative morbidity which has the potential to translate not only in a reduction in intensive care resource utilisation but also to impact positively on long-term outcome. This study would represent the first international population based interventional trial in cardiac surgical and paediatric intensive care patients.

Inclusion criteria

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

Exclusion criteria

Participants must NOT:

  • 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.
  • Patient is on ECLS prior to surgery
  • Concurrent known confirmed bacterial sepsis/septic shock, diagnosed within <48hours prior to surgery and being actively treated with antibiotics at time of surgery (suspected sepsis treated with antibiotics is not an exclusion criteria unless inotropes are required for treatment of septic shock at time of surgery)
  • Preoperative acute respiratory distress syndrome requiring HFOV ventilation <48 hours of surgery
  • Patient requires high doses of vasoactive drugs prior to surgery with an inotrope score ≥15 met within 24 hours prior to surgery: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS): 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).
  • Cardiac arrest within one week (7d) prior to surgery
  • Emergency cardiac surgery which may preclude obtaining informed consent (defined as acutely required life-saving procedure in a patient unlikely to survive the next hours without the surgery)
  • Pre-existing methaemoglobinemia (MetHb>3%)

Flowchart

Flow chart

Outcome measures

The primary outcome is to reduce 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 randomisation. 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.

Secondary outcome measures

The secondary outcomes of this study include:

  1. Reduction of incidence of LCOS, need for ECLS, and mortality
  2. Reduction of the length of stay in PICU, hospital length of stay and health care costs
  3. Reduction of levels of systemic inflammatory markers and markers of myocardial injury
  4. Improved long-term outcome.

Definitions

  • Length of mechanical ventilation: Length of mechanical ventilation is defined as the duration of invasive respiratory support for all episodes with an endotracheal tube in situ for the first 28 days post randomisation. 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.
    • For infants with tracheostomies, ventilation support will be considered completed at the time point when the patient reaches pre-intervention baseline respiratory support levels
  • LCOS: 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 a mixed venous saturation level less than 60% in a fully corrected heart (or the SaO2-SvO2 gradient >35% in uncorrected lesion) within the first 48 hours postoperatively; AND/OR
    • high inotrope requirement: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS): 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 ≥15 indicating LCOS.
  • eCRF: REDCap is a secure, web-based application for building and managing online databases and surveys. The Nitric on bypass trial uses REDCap for electronic data collection. If you have any concerns or questions please contact the Study Trial Co-Ordinator, Kerry Johnson.

Participating sites

  • Queensland Children’s Hospital, Brisbane, Queensland, Australia
  • Royal Children’s Hospital, Melbourne, Victoria, Australia
  • Westmead Children’s Hospital, Sydney, New South Wales, Australia
  • Princess Margaret Children`s Hospital, Perth, Western Australia
  • Starship Children’s Hospital, Auckland, New Zealand

Collaborators and sponsors

We are fortunate to be supported by funding grants from Children’s Hospital Foundation, Brisbane and Heart Kids Australia.

Successful grant application: National Health and Medical Research Council (NHMRC)

Our Collaborators include

  • Diamantina Institute, The University of Queensland
  • PSG (Paediatric Study Group)
  • ANZICS (Australia New Zealand Intensive Care Society)

Education and resources

References

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Location

Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Paediatric Critical Care Research Group
Level 7, 62 Graham Street
South Brisbane, Qld, 4101
Australia

Central team (CCHR – Brisbane)

For study queries contact

Study Coordinator

Kerry Johnson
e: Kerry.Johnson3@health.qld.gov.au
t: 07 3069 7478

Central Team Investigators

A/Prof Andreas Schibler
e: a.schibler@uq.edu.au

A/Prof Luregn Schlapbach
e: l.schlapbach@uq.edu.au

Debbie Long RN PhD
e: Debbie.Long2@health.qld.gov.au

Kerry Johnson
e: Kerry.Johnson3@health.qld.gov.au

Participating sites

Queensland Children’s Hospital, Brisbane, Queensland, Australia
Royal Children’s Hospital, Melbourne, Victoria, Australia
Westmead Children’s Hospital, Sydney, New South Wales, Australia
Princess Margaret Children`s Hospital, Perth, Western Australia
Starship Children’s Hospital, Auckland, New Zealand