Nitric Oxide During Bypass for Arterial Switch Operation

The incidence of congenital heart disease (CHD) is approximately 1/100 live born children, of
which up to 50% require cardiac surgery to correct the underlying abnormality at some stage
during their life. (Centre for Disease Control and Prevention, USA). Despite major
improvements in CPB devices, the exposure of host blood to large artificial organ surfaces,
combined with myocardial injury during planned myocardial ischemia, results in a significant
systemic inflammatory response. CPB-triggered systemic inflammatory syndrome is responsible
for the most serious and potentially life-threatening side effects associated with cardiac
surgery. It is characterized by endotoxin release, leukocyte and complement activation, and
widespread activation of inflammatory mediators, resulting in endothelial leak, increased
oxygen consumption, and organ dysfunction.

NO is an endogenous anti-inflammatory mediator that helps to protect endothelial beds and
immunologically active cells. NO has a myocardial protective effect by reducing reperfusion
injury. NO generation is essential for regulation of endothelial function and microvascular
inflammation. However, dysregulation of endogenous NO during CPB may aggravate the subsequent
inflammatory response.

A randomized controlled study adding NO into the bypass circuit was conducted by the Royal
Children's Hospital in Melbourne on 198 children. This pilot study confirmed the positive
effects of gaseous NO reported in the U.S. trial, as well as a reduction in the incidence of
low cardiac output syndrome (LCOS). Other improved patient outcomes included a reduced need
for extracorporeal life support (ECLS), trends towards a reduced length of stay, and shorter
duration of ventilation. In light of these promising preliminary results from these two
separate studies, a large multicentre trial to test these findings in children requiring
cardiac surgery is needed.

The NASO study is running concurrently with the Nitric Oxide during Cardio Pulmonary Bypass
during surgery for congenital heart defects: A Randomised Controlled Trial study (ANZCTR
Trial Registry ID: ACTRN12617000821392) within Australia (run by Lady Cilento, Brisbane).
This study is aiming to look at the effects of Nitric Oxide on all children under the age of
2 years undergoing bypass surgery for CHD.

TGA presents in 5-7% of all patients with congenital heart disease and isolated TGA is
managed in a similar manner all over the world. The surgical treatment for this is the ASO.
Hence this single operation and diagnosis provides an appropriate setting to evaluate the
efficacy of NO in the CPB circuit. By allowing each centre to have their own protocols of
care (pre, intra and postoperatively) and only collecting 'routine clinical data", the
investigators anticipate each centre having high rates of screening and consent.

Patients will be stratified by centre and by age at time of surgery. Participants will be
randomized into one of two arms:

- Intervention arm will receive NO 20 parts per million (ppm) into the oxygenator of a
cardio-pulmonary bypass circuit

- Control arm will not receive NO

At the end of CPB, the participants will return to the Intensive Care Unit where normal care
will continue.

A total of 800 participants will be enrolled in the study and will be stratified by centre
and age at time of surgery.

Study aims to investigate whether exposure to gaseous NO reduces the incidence of
postoperative major adverse events in infants on cardiopulmonary bypass.

Inclusion criteria;

Each participant must meet all of the following criteria to be enrolled in this study:

- Infant aged greater than or equal to 36 weeks gestation

- Infants less than 2 years

- Diagnosed with TGA and requiring Arterial Switch Operation

- Consent of parents/guardian.

Exclusion criteria

Potential participants will be excluded if they meet any of the following criteria:

- They have multiple major congenital anomalies (anomalies which affect the infant's
life expectancy or health status)

- They have multiple other cardiac abnormalities (with the exception of ASD, VSD or PDA)

- They weigh less than 2.2kgs.

- Prior surgical exposure to cardio-pulmonary bypass