Intravenous Immunoglobulin for Early Prevention of Cardiopulmonary Bypass Induced Hypogammaglobulinemia in Infants and Neonates

The intense post-CPB systemic inflammatory response syndrome (SIRS) is well described in
neonates and infants. Increased production and release of pro-inflammatory cytokines,
including Tumor Necrosis Factor, Interleukin1-B, and Interleukin-6 may suppress myocardial
contractility, induce capillary leak, and activate complement and the clotting cascade -
together leading to potential organ injury and death. SIRS is also frequently accompanied by
impairment of the humoral immune response. One potential reason for this acquired
immunodeficiency after cardiac surgery is the removal of immunoglobulins (Ig)s from the
vascular space into other compartments where they are either sequestered or lost from the
body altogether. We recently demonstrated that such Ig depletion from the intravascular
compartment occurs in neonates following cardiac surgery. In a retrospective study of 53
children <3 months of age, we showed that plasma Immunoglobulin G (IgG) concentration drops
precipitously after cardiac surgery and does not return to preoperative levels by 7 days;
51% of patients had hypogammaglobulinemia.

An important question is whether post-CPB low IgG has clinical consequence. IgG plays an
essential role in the humoral immune system, activating complement and inducing the
phagocytic system to neutralize pathogens. IgG deficiency is a known risk factor for
infections in other pediatric populations. We were the first to demonstrate that post-CPB
hypogammaglobulinemia is associated with worse clinical outcomes, including increased
secondary infections (37% vs.12% in those without low IgG, p<0.05). These novel findings are
paramount in that they identify a potential modifiable risk factor to improve outcomes after
pediatric cardiac surgery with CPB. Additionally, low IgG is accompanied by fluid overload
and prolonged mechanical ventilation. Igs constitute an important component of plasma
oncotic pressure, so hypogammaglobulinemia may exacerbate anasarca, prolonging postoperative
convalescence and increasing the morbidities associated with increased ICU length of stay.9

Igs have an increasingly recognized role in modulating the innate immune response. Present
use of IVIG exceeds mere antibody replacement and extends to the treatment of autoimmune and
inflammatory conditions. In fact, more than 75% of IVIG use in the U.S. today is for the
treatment of inflammatory conditions, where proposed mechanisms include reduction of
pro-inflammatory cytokine and adhesion molecule expression, superantigen neutralization,
restoration of glucocorticoid responsiveness, and blockade of complement fragment
deposition. It is plausible that IVIG could benefit neonates after cardiac surgery not only
via restoration of humoral opsonization capacity, but also as a modulator of innate immunity
and SIRS. According to this model, tissue injury, CPB, and shock trigger SIRS, leading to
hypogammaglobulinemia and resultant increased susceptibility to inflammatory dysregulation
which might be ameliorated via administration of IVIG.

In an adult study, IVIG failed to benefit postoperative cardiac patients with severe SIRS.
However, the dose of IVIG given was relatively small compared with that typically given for
autoimmune and inflammatory conditions. Neonates and infants may be more susceptible to the
harmful effects of acquired hypogammaglobulinemia than adults as they may be unable to
generate adequate quantities of antibodies in response to pathogens, relying mainly on
maternal Igs until around the 4th to 6th month of life. In addition, they display an
exaggerated inflammatory response to CPB as compared with older children and adults, so they
might stand to benefit more from IVIG as an immunomodulator.

Because of the increased vulnerability to acquired infection and other morbidities in the
setting of hypogammaglobulinemia as result of enhanced SIRS and immune dysfunction, it is
feasible that normalization of IgG concentration in the neonatal and infant population may
improve clinical outcomes via restoration of the humoral immune system, modulation of the
innate immune system, and restoration of intravascular oncotic pressure. The appropriate IgG
level threshold for treatment and optimal plasma IgG level to target after administration of
IVIG are presently unknown.

Inclusion Criteria:

- Infants <6 months old

- Successfully weaned off cardiopulmonary bypass after cardiac surgery

Exclusion Criteria:

- Requirement of extra corporeal membrane oxygenation in the operating room

- Known immune deficiency

- Current Do Not Resuscitate or limitation of care order

- Current enrollment in another interventional clinical study

- Refusal of parental consent