Nitric Oxide on ExtraCorporeal Membrane Oxygenation: a randomised trial to reduce ECMO related mortality in neonates and children “NECTAR-KIDS Trial”

When a child is critically ill and admitted to the intensive care unit because of a life threatening condition, children often develop heart or lung failure and reach maximum conventional treatment. In this group of children mortality exceeds >80% in these situations, Extracorporeal Membrane Oxygenation (ECMO, also referred to as Extracorporeal Life Support, ECLS) has become the standard rescue treatment or neonates and children.

ECMO is provided by a device similar to a portable heart lung machine, which includes a pump and an oxygenator to replace the heart and lung function of the child for days to weeks. Mortality in children treated with ECMO remains around 30-40% in most centres around the world. Despite improvements in ECMO devices, the exposure of host blood combined with organ injury due to underlying disease can result in an activation of both the coagulation as well as the inflammatory system. The two systems interact and lead to an even more pronounced response. The response triggered in both systems is responsible for some the most serious and life-threatening side effects of ECMO.

The aim of this project is to evaluate whether administering Nitric Oxide to the ECMO circuit in addition to the gases normally used will influence mortality related to ECMO treatment.

Information for parents and guardians of our patients

Why are we conducting the NECTAR Trial?

We are doing this trial to evaluate whether administering Nitric Oxide to the ECMO circuit in addition to the gases normally used will influence mortality related to ECMO treatment. In addition, we will measure how clotting complications as well as the inflammatory response are changed by Nitric Oxide administration through the ECMO circuit. We are comparing the Nitric Oxide treatment to the current practice. If Nitric Oxide improves recovery on ECMO practices worldwide will change, saving lives and reducing the amount of time children need to stay in hospital when supported by ECMO.

What is the aim of the NECTAR Trial?

The aim of this project is to evaluate whether administering Nitric Oxide to the ECMO circuit in addition to the gases normally used will influence mortality related to ECMO treatment.

What is NECTAR?

Nitric Oxide on ExtraCorporeal Membrane Oxygenation – a randomized TriAl to Reduce ECMO related mortality in neonates and children (NECTAR-KIDS trial) is a single-centre randomised controlled trial in neonates to children <18 years of age requiring ECMO. The purpose of the trial is to evaluate whether giving Nitric Oxide to the ECMO circuit in addition to the gases normally used will influence mortality related to ECMO treatment.

What is being investigated?

To investigate in neonates and children treated on ECMO whether treatment with Nitric Oxide into the oxygenator leads to shorter length of ECMO, and the impact on mortality. To also investigate whether it increases the time alive and free of ventilation, multiple organ dysfunction, and decreases PICU length of stay and hospital length of stay.

Which patients can take part?

All neonates and children <18 years requiring ECMO for respiratory or cardiovascular dysfunction can be included in this trial.

What does the NECTAR Trial involve for the children in the study?

The study is a randomised trial, which means that your child has been randomly allocated (50:50 chance) to one of two groups. They will receive either standard ECMO treatment with oxygen alone, or ECMO treatment where Nitric Oxide is used in addition to oxygen. Nitric Oxide is a gas which will be added to the ECMO circuit during the ECMO run. If your child comes off ECMO but requires a second ECMO run we will ask you again to participate in this study, and we will randomise your child (should you permit this) again to either one of the treatment arms (ECMO with or ECMO without Nitric Oxide).

At defined times during the ECMO run blood tests will be taken. Most of these blood tests are part of the standard care your child would receive regardless of whether they are taking part in the study. These samples will be taken from an arterial line that all children who are supported by ECMO 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 at various times throughout the first 48 hours.

Throughout the study approximately 10 to 15 mls of study blood will be taken, which is much less than the routine bloods that will be taken for routine ECMO care. We do not anticipate any additional risks for your child from taking these additional bloods.

In addition to testing blood for clotting and 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 ECMO. 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 and approval by our human 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.

Consent

Consent to Continue
Because of the severity of the illness ECMO had to be commenced without delay, and we had to randomly assign one of the treatment arms to your child. Therefore, your child has already been enrolled into this study and we are now approaching you for your permission to continue your child in the study and to collect information for the study. There are two reasons why we didn’t approach you at the time of your child’s intubation: first, we believe this is a very stressful time for parents to make a decision to participate in a study and this could have delayed the best care for your child. Second, we don’t have any proof currently if standard care or the addition of Nitric Oxide leads to better outcomes.
The use of the consent to continue process has been reviewed and approved by the Children’s Health Queensland Hospital and Health Service, Human Research Ethics Committee (HREC) and complies with the requirements of the NHMRC National Statement for Ethical Conduct in Human Research.
Should decide not to participate in the study we will not collect any data from your child for the study, and we will treat your child according to our usual practice.

Information for participating study centres

Background on the NECTAR-KIDS Trial

When critically ill children develop heart or lung failure that is refractory to any conventional treatment, mortality exceeds >80%. In these situations, the provision of Extracorporeal Membrane Oxygenation (ECMO, also referred to as Extracorporeal Life Support, ECLS) has become the standard rescue treatment for neonates and children. ECMO is provided by a device similar to a portable heart lung machine, which includes a pump and an oxygenator to replace the heart and lung function of the child for days to weeks. Mortality in children treated with ECMO remains around 30-40% in most centres around the world. Despite improvements in ECMO devices, the exposure of host blood to large artificial organ surfaces combined with organ injury due to underlying disease and reperfusion, results in an activation of both the coagulation as well as the inflammatory system. The two systems interact and leading to an even more pronounced response. The response triggered in both systems is responsible for some the most serious and life-threatening side effects of ECMO. Most children who die on ECMO have either clotting or bleeding complications. All these clinical conditions (activation of the coagulation and inflammation system) are associated with increased length of respiratory support, prolonged length of stay in intensive care and hospital and result in significantly increased health care costs. They may also translate into lifelong costs due to neurological impairment. The inflammatory response also results in profound endothelial and coagulation alterations. Nitric oxide (NO) is a molecule that is usually produced in the endothelium and leads to a suppression of inflammation as well as a regulation of the coagulation response. It has direct protective actions on blood vessels, the coagulation and inflammatory system, and blood cells. During ECMO, the normal NO production of the body is severely hampered due to an endothelial activation, consumption of NO and reduced production. The benefit of administering Nitric Oxide as a medical gas into heart lung machines has been explored in the past years and pilot studies have demonstrated its safety and benefit. Our group is currently leading a large NHMRC funded trial on nitric oxide on heart-lung machines during heart surgery.

The benefits of NO observed in cardiopulmonary bypass indicate a need to test the intervention on ECMO – a patient group with much higher morbidity and mortality related to prolonged exposure to extracorporeal circuits and their surfaces.

We will perform a pilot feasibility RCT to investigate if NO on ECMO reduces length of duration of ECMO, and whether clotting and bleeding complications and the inflammatory response are reduced. This study presents a unique opportunity to improve the outcome of children needing ECMO. The available data suggest the intervention has the potential to result in significant improvement of important endpoints such as morbidity and mortality. This pilot ECMO study is extending from our ongoing trial on nitric oxide on cardiopulmonary bypass in children which is being conducted as part of an Australia and New Zealand-wide study.

We expect that the NECTAR study will yield the data to design a larger multicentre RCT. The findings should have major potential to improve patient-centred outcomes and reduce health care costs. Overall, this is expected to result in improved neurodevelopmental outcomes in this patient group and may have a tremendous impact on the quality of life of these children.

Specifics of Trial

Trial Aim

The primary aim of this study is to investigate the feasibility of a randomized controlled trial in children on ECMO. The pilot will assess delivery of Nitric Oxide (NO) at 20ppm into the oxygenator circuit of ECMO.
Specific aims include:

  1. To estimate feasibility of the trial:
    1. To assess compliance with study protocol
    2. To establish recruitment rates; with focus on i) proportion of eligible randomized, and ii) proportion of eligible consented using deferred consent.
  2. To assess potential impact of the interventions:
    1. To investigate in a randomized controlled pilot trial in neonates and children treated on ECMO, whether treatment with Nitric Oxide into the oxygenator leads to shorter length of ECMO, and the impact on mortality.
    2. To investigate whether the intervention increases the time alive and free of ventilation, multiple organ dysfunction, and decreases PICU length of stay and hospital length of stay.
    3. To investigate whether the intervention decreases the need for blood products.
  3. To measure impact of the intervention on host inflammation and coagulation profile
    1. To measure serum cytokines during the first 24 hours post cannulation to compare the inflammatory profiles of neonates and children treated with NO versus standard treatment on ECMO.
    2. To measure the coagulation profile, clot characteristics, and platelet function.
    3. To assess oxygenator failure rates.
  4. Additional aims
    1. To establish a biobank of patient samples enrolled in the trial for biomarker studies.
    2. To establish a structured consumer engagement and follow-up to assess long term patient outcomes, and to improve design of patient centered research and interventions.
    3. To establish robust health economic measures of short-term costs related to ECMO and compare the impact of the interventions on costs.

Hypothesis

Infants and children treated with ECMO exposed to gaseous nitric oxide (NO) have – compared to controls – a reduced inflammatory response, reduced secondary organ failure, reduced ECMO circuit clot formation and as a result a reduced need for blood products, shorter ECMO runs length, which then ultimately translate into a reduction in mortality, improved long term outcomes, and reduced health care costs.

Trial design

A single-centre randomised controlled open label study in neonates and children < 18 years of age requiring ECMO.

Study setting

Cardiac and Paediatric Intensive Care Services at Queensland Children’s Hospital Brisbane.

Sample size

The project will run for two years and we expect 50 children to take part in the study which will run at QCH PICU. Half of the children will receive Nitric Oxide in addition to oxygen and half will receive oxygen alone into their ECMO circuit.

Outcomes, significance and innovation

Feasibility outcomes:

  • Monthly recruitment rate
  • Randomised to screened patient ratio
  • Compliance with study protocol (with focus on timing of initiation of NO, and maintenance of NO for the duration of the study)

In addition, the pilot will serve to establish baseline rates for incidence and length of multiple organ dysfunction.
Primary outcome
The primary outcome is defined as survival free of ECMO, censored at 30 and at 90 days post randomization. Patients dying within 30, and 90 days, respectively, of presentation will be considered as zero days to correct for the competing effect of mortality on ECMO free survival.
Secondary outcomes

  • Survival free of PICU (censored at 90 days)
  • Hospital length of stay post randomization
  • Average daily blood product usage
  • Bleeding and clotting complications in the patient and the circuit respectively
  • Platelet activation measurements
  • Host systemic inflammation levels at 1 and at 24 hours, and upon repeat sampling
  • Parental assessment on value of healthcare measured at discharge and 6 months post discharge
  • Direct hospitalization-related costs

Inclusion criteria

  • All neonates and children <18 years requiring ECMO for respiratory or cardiovascular dysfunction including extracorporeal cardiopulmonary resuscitation (eCPR)
  • Elective cardiac surgery and consent of parents/guardian.

Recruitment and identification of potential participants

Every patient considered for ECMO is eligible for the study. Study instructions will be placed at every ECMO circuit. The full equipment for NO delivery will be installed at every ECMO circuit not in use.

Collaborators and sponsors

We are fortunate to be supported by The Children’s Health Foundation, Brisbane.

Our Collaborators include:

The University of Queensland
Children Hospital Foundation
Critical Care Research Group, The University of Queensland (Prof. John Fraser)

References

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Location

Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Paediatric Critical Care Research Group: NECTAR
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

Dr Adrian Mattke, Director Queensland ECMO Service
e: Adrian.Mattke@health.qld.gov.au

A/Prof Luregn Schlapbach, Paediatric Critical Care Research Group
e: l.schlapbach@uq.edu.au

A/Prof Andreas Schibler, Paediatric Critical Care Research Group
e: a.schibler@uq.edu.au

Dr Prem Venogupal, Queensland Paediatric Cardiac Surgical Service and ECMO Board
e: Prem.Venugopal@health.qld.gov.au

A/Prof John Roy, Paediatric Haematology
e: John.Roy@health.qld.gov.au

Kerry Johnson, Paediatric Critical Care Research Group
e: Kerry.Johnson3@health.qld.gov.au