Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet Activation

Open heart surgery requires the use of a CPB circuit. As blood flows across the artificial
surfaces of the CPB circuit, platelets are consumed (1). The investigators recently completed
a prospective observational trial of neonates undergoing cardiac surgery requiring CPB. In
this trial the investigators demonstrated a dramatic decrease in platelet count from baseline
to intraoperatively. The platelet count rebounded with transfusion and normalized by the time
of admission to the cardiac intensive care unit (CICU). Despite prophylactic transfusion of
blood products to all patients, 41% experienced excessive postoperative bleeding (defined in
terms of chest tube output and need for reoperation).

Further investigation by Dr. Debra Newman in her lab at the Blood Research Institute
delineated the platelet defect associated with CPB in the neonates more clearly. Dr. Newman
found a significant decrease in the platelet responsiveness to thrombin receptor activating
protein (TRAP), thromboxane A2 analog (U46619), and collagen-related peptide (CRP). Further
analysis revealed that the effect of CPB on platelet responsiveness to TRAP and U46619 is
likely dependent on its effect on platelet count, whereas CPB affects platelet responsiveness
to CRP independently of platelet count.

In children, postoperative blood loss and transfusion of blood products has been shown to
contribute significantly to the morbidity and mortality of surgeries that require CPB (2, 3).
In addition to the need for blood product replacement, the activation of platelets
contributes to the intense inflammatory reaction seen in surgeries requiring CPB (4).
Patients with a less intense inflammatory response post-operatively generally do better with
less morbidity (5).

The oxygenator membrane surface of the CPB pump is a large contributor to the surface area of
CPB circuit. As a major contributor to the surface area of the circuit and the location of
the gas interface, the oxygenator is a significant contributor to the hemostatic and
inflammatory stimulus of CPB. Advances in oxygenator technology have modified the surface to
prevent interaction with the blood, but no artificial surface has been found to be as inert
as the natural endothelium of the vasculature (5).

A major mechanism by which endothelial surfaces inhibit activation of platelets is by
producing nitric oxide (6). Nitric oxide is lipophilic and traverses cellular membranes where
it acts on intracellular signaling pathways in platelets to prevent platelet activation and
aggregation (7). The artificial surface of the CPB pump does not produce nitric oxide and
hence is devoid of this potent inhibitor of platelet activation.

In multiple experimental ex-vivo models of CPB, the addition of nitric oxide to the sweep gas
of the oxygenator resulted in preserved platelet counts, preserved platelet function, and
decreased markers of platelet activation (8-11).

Multiple clinical trials of nitric oxide administration during CPB have shown positive
results. Chung et al. showed in a group of 41 adults undergoing coronary artery surgery
requiring CPB that the addition of nitric oxide to the oxygenator resulted in a preservation
of platelet numbers, a decrease in markers of platelet activation, and less post-operative
blood loss (12). Checchia et al. investigated the effect of nitric oxide in a group of
sixteen infants undergoing repair of tetralogy of Fallot and found the patients treated with
nitric oxide had an improvement in clinical outcomes of length of stay in the intensive care
unit and number of hours requiring mechanical ventilation (13). James et al. showed a 50%
decrease in the incidence of low cardiac output syndrome in a randomized trial of 198
children. The effect was most profound in the younger children and those undergoing the most
complex repairs (14). These patients are also the ones demonstrated to have the most intense
inflammatory reaction postoperatively (15).

Despite these promising studies, several questions remain. The mechanism of platelet
preservation has not been delineated. The collaboration between clinicians at Children's
Hospital of Wisconsin and Dr. Newman at the Blood Center of Wisconsin has been established
and has experience in investigating the effects of CPB on platelets in infants. This
collaboration is poised to help define the mechanism of nitric oxide in preserving platelet
function during CPB in infants. All studies to date have been single center and underpowered
to investigate clinical outcomes of interest such as mortality and length of hospital stay.
Dr. Niebler has begun to assemble a multi-center study team. Local data is necessary to help
guide the power calculation in determining the sample size for this larger study and to
demonstrate the capabilities of the local institution in leading a trial of this magnitude.

Inclusion Criteria:

- Infants less than one year of age

- Undergoing cardiac surgery with the use of cardiopulmonary bypass

Exclusion Criteria:

- Prior surgery requiring CPB within the same hospitalization

- Pre-operative need for extracorporeal membrane oxygenation or mechanical circulatory
support

- Known hypersensitivity to nitric oxide

- Known hemostatic or thrombotic disorder that results in an altered
transfusion/anticoagulation protocol