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

Epidemiology of Congenital Heart disease - expected impact on the next decades:
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 the Netherlands,
1300-1500 children are born each year with CHD. In comparison, in Australia,
over 2000 children are born with CHD each year.2 CHD ranks still within the top
five causes of infant mortality in most industrialized countries. >75% of
infants born with a critical CHD (requiring surgical intervention to survive)
survive to one year of age. Over 80% of cardiac surgical procedures require
cardiopulmonary bypass (CPB). While the cardiac surgical and intensive care
mortality in children following cardiac surgery is low with an 2-5%
perioperative death rate dependent on the complexity of the procedure, major
postoperative morbidity is common and translates into an increased rate of
long-term mortality, morbidity, and disability.

Life-threatening side effects of cardiopulmonary bypass (CPB) and myocardial
ischemia during surgery - Excessive systemic inflammation leads to Low Cardiac
Output Syndrome (LCOS): Despite major improvements in CPB devices, the exposure
of host blood to large artificial organ surfaces combined with myocardial
injury during planned myocardial ischaemia, albeit partially protected by
cardioplegia, result in a significant systemic inflammatory response of the
patient. Indeed, the strong CPB triggered systemic inflammatory syndrome, is
responsible for the most serious and potentially life-threatening side effects
after heart surgery. CPB, hypoxic-ischemic injury, and the release of
damage-associated molecular patterns trigger an inflammatory cascade closely
related to sepsis induced systemic inflammatory response syndrome (SIRS). 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. During CPB applying
cardioplegic arrest allows the surgeon to operate on a still heart. While the
heart is arrested, myocardial blood flow stops, which results in ischemia and
myocardial injury. With restoration of blood circulation at the release of
cross-clamping, CPB provides full flows with high oxygen content which can lead
to reperfusion injury. Central to the pathophysiology of reperfusion injury is
a robust local inflammatory response, children appearing to be particularly
susceptible to developing multisystem organ failure as a result of these
processes. As a result of the combined effects of direct CPB-related
inflammation, myocardial ischemia, and reperfusion, the newly operated on heart
is unable to meet the metabolic demands of the body resulting in organ
hypoperfusion. This situation is called Low Cardiac Output Syndrome (LCOS), and
is commonly defined as increased need for inotropes, increased arterial-venous
oxygen extraction, increase in blood lactate levels (metabolic acidosis),
decrease in urine output (oliguria) and need for extracorporeal lifes support
(ECLS). This CPB triggered systemic inflammatory response leads to acute
cardiac dysfunction, with limited reserve to respond to meet the metabolic
demands of the vital organs. This situation is defined as Low Cardiac Output
Syndrome (LCOS).

Children post bypass commonly develop a low cardiac output syndrome (LCOS)
which may be life threatening and represents the major determinant of
postoperative outcomes. LCOS manifests with severe organ dysfunction such as
respiratory and renal failure, and can lead to organ and brain hypoperfusion,
cardiac arrest, and death. The severity of the LOCS is influenced as well by
the type of surgery performed, pre-surgical condition of the patient and
strongly dependent on non-surgical injury of the heart muscle due to CPB.
Several studies have shown that postoperative morbidity and mortality are
strongly determined by LCOS (Table 1), which is present in ca. 25-40% of
children post CPB in the hours immediately following heart surgery. LCOS may
lead to a transient or permanent organ damage, brain ischemia, cardiac arrest
and death. Long-term outcome may be affected by acute injury of the developing
brain caused by brain ischemia during LCOS.

CPB-related injuries are most pronounced in infants and young children for
several reasons, including higher metabolic rate, stronger inflammatory
response, higher bypass circuit to patient blood volume, and altered
homeostasis. At the same time this is the cardiac surgical group with highest
mortality, and with the highest risk of long-term neurological sequelae due to
the vulnerability of the immature developing brain. In addition, bypass-induced
modulation of inflammatory cytokines can lead to subsequent immunoparalysis
enhancing the risk of postoperative invasive infections. Should LCOS become
apparent, the level of support that the newly operated on heart receives is
increased using fluid boluses and inotropes. Organ replacement such as renal
dialysis and prolonged mechanical ventilation may be required. In the most
severe cases, the heart is supported mechanically with extracorporeal life
support (ECLS). Considering the severe impact of LCOS on patient centred
outcomes after surgery for congenital heart disease in children, improved
strategies targeting LCOS are urgently needed. Interventions leading to reduced
LCOS have a high likelihood to lead to a reduction in the incidence of organ
failure, reduce the severe major events such as need for mechanical support of
the heart with ECLS, and shorten postoperative ventilation and ICU length of
stay.

Current strategies to reduce LCOS are insufficient and lack evidence for
benefit:

Steroids. The most common but controversial approach to reduce LOCS is using
steroids
given preoperatively to reduce the inflammatory response. There have been few
prospective randomized controlled trials of corticosteroids in children
undergoing cardiac surgery with conflicting results. Patients randomized to
dexamethasone in a relatively small study had significantly less fever,
required less supplemental fluid, had greater preservation of renal function
and less impairment of oxygenation, and experienced a significantly shortened
duration of mechanical ventilation and length of stay in the intensive care
unit. In another trial investigating the effect of methylprednisolone 4 h prior
to CPB and in the bypass prime showed that these patients who received two
doses of methylprednisolone had significantly less fever, required less fluid,
had a significantly reduced oxygen extraction ratio and experienced a trend
toward reduced length of stay in the intensive care unit (p = 0.07). A recent
multicentre study on infants undergoing Norwood surgery reported increased
mortality in patients receiving intraoperative steroids, confirming previous
concerns about risks and lack of benefit of steroids. The latest adult data
suggests that steroids are not beneficial or even could cause more harm than
benefit.

Modified Ultra Filtration (MUF). Another prophylactic attempt is using modified
ultrafiltration which is used in the vast majority of paediatric cardiac
centres. Ultrafiltration removes water, reverses haemodilution and eliminates
low-molecular-weight substances, including inflammatory mediators.
Ultrafiltration may be used during CPB (i.e., conventional ultrafiltration,
CUF) or once CPB is completed (i.e., MUF), with the composition of filtrates
being identical and the assertion that a greater amount of fluid and therefore
solute may be removed following CPB than can be removed with CUF alone. While
some studies have shown a significant beneficial effect of MUF on the
postoperative course, others have failed to do so.

The proposed physio

Primary objective of this trial is to investigate in a double blind randomized
controlled trial in children undergoing open heart surgery 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.

Secondary Objectives are:
1. To investigate if NO reduces the incidence of low cardiac output syndrome
(LCOS),
requirement for extracorporeal life support (ECLS), and 90-day mortality.
2. To investigate if NO reduces the length of PICU stay and health care costs
3. To investigate if NO reduces the inflammatory response following CPB.
4. To investigate if NO reduces the negative effects of CPB on platelet
activation and platelet function. (This question is answered within the
subgroup of children included at the Utrecht study side)
5. To investigate if NO reduces the ischaemic cerebral damage following
congenital heart surgery with CPB. (This question is answered within a subgroup
of neonates included at the Utrecht study side that receive a pre- and
postoperative MRI as part of their usual care)

A multi-centre randomised controlled and blinded study in children < 2 years of
age undergoing open heart surgery on cardiopulmonary bypass. The study is
performed in the following paediatric cardiac centres: Lady Cilento Children*s
Hospital Brisbane, Australia;
Royal Children*s Hospital Melbourne, Australia; Starship Children*s Hospital
Auckland, New Zealand; Westmead Children`s Hospital Sydney, Australia; Princess
Margareth Children`s Hospital Perth, Australia; and Wilhemina Children*s
Hospital Utrecht, The Netherlands. The expected duration of the trial is 2-3
years. Participants are randomized in either the intervention arm, where they
receive NO during CPB, or to the control arm, where they receive standard care
according to the local treatment protocol.

Patients allocated to the study intervention arm will receive NO, which will be
blended into the fresh gas flow kept at 3L/min for the CPB oxygenator with NO
levels maintained at 20 ppm via a NO-A nitric delivery system (EKU Elektronik
GmbH, Leiningen, Germany) or Ikaria INOmax DSIR (Ikaria, NJ, USA)). Continuous
sampling of NO and NO2 concentration will be undertaken. NO will be started
immediately when the patient is on CPB and ceased once coming off CPB. Patients
allocated to the Placebo arm will receive standard respiratory gases
(oxygen-air mix) during bypass at a flow rate of 3L/min. Partial pressures of
CO2 have to be maintained constantly in both study arms as per the
institutional practice. Note: If patients require several CPB runs during the
same procedure, the treatment will be provided for each run using the same
treatment allocation for every run (i.e. patients allocated to study gas arm
will receive NO at 20ppm for every run). Subsequent CPB procedures: Patients
that were previously enrolled and randomised into the study with surgical
procedure performed that required use of CPB will not get re-randomised.
Previously enrolled and randomised patients will undergo the same treatment
allocation for subsequent surgeries, unless parents opt out. The study
perfusionists at each study site have access to the treatment allocation, which
will remain blinded for all other study team members.
Perioperative Care: No specific definition of methods of anaesthesia, surgical
technique or method on CPB perfusion will be done.
Note: Patients undergoing CPB that are considered by treating physicians
(surgeons, anaesthetists, or intensivists) to require inhaled NO can receive
iNO at any time of the study (during or after surgery), independently of
treatment allocation, delivered as inhalational gas at doses defined by the
clinicians (usually 0 to 20ppm).

NO administration in the oxygenator of the CPB has been studied in a pilot
randomized trial that included almost 200 children who needed heart surgery for
congenital anomalies. This trial showed a significant reduction of LCOS when NO
was administered during CPB. This effect was particularly spectacular in
neonates where LCOS reduced from 52% to 20%. LCOS is associated with higher
morbidity. We expect that participating patients who receive NO benefit by
three pathways: (1) NO reduces the strong inflammatory response associated with
CPB, (2) NO reduces platelet activation during CPB, and (3) NO reduces
myocardial cell apoptosis. By these mechanisms NO administration in the
oxygenator of the CPB is expected to reduce morbidity and mortality in children
that need heart surgery for congenital heart disease. Potential risks
associated with NO delivery are the formation of nitrogen dioxide (NO2) and
methaemoglobin (MetHb). Exposure to nitrogen dioxide (NO2) can produce
toxicological responses depending on the severity of the concentration and
duration of exposure. In the conducted pilot trial, no toxic levels of NO2 or
MetHb were detected and adjustment of the NO concentration was not necessary.
Extrapulmonary effects of NO2 reported are a blood pressure decrease when
exposed to NO2 concentrations > 4 ppm, plasma histamine release, and formation
of MetHb. MetHb, an ineffective oxygen carrier, forms when NO binds to
oxyhaemoglobin in erythrocytes and is rapidly reduced by methaemoglobin
reductase. None of these effects were reported with 20 ppm NO administration
during CPB in the pilot study, the trial of Checchia et al, the available adult
data, nor in the current trial that already commenced in Australia and New
Zealand. NO2 levels and MetHb will be monitored during NO administration.