Post-bypass Prophylactic IVIG in Infants and Neonates

NCT ID: NCT02043379

Last Updated: 2017-04-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2015-06-30

Brief Summary

The purpose of this study protocol is to determine if administering Intravenous Immunoglobulin (IVIG) for treatment of cardiopulmonary bypass (CPB) induced hypogammaglobulinemia in the early post-operative period can impact post-surgical outcomes (i.e., infection, fluid overload, and associated morbidities).

Detailed Description

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.

Conditions

Hypogammaglobulinemia; Congenital Heart Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

IVIG

Those randomized to the study arm will receive a dose of IVIG 1 gram/kg at 12 hours post-cardiopulmonary bypass. This is a one time only dose and will be administered per hospital standards for IVIG administration.

Group Type: EXPERIMENTAL

IVIG

Intervention Type: DRUG

Those randomized to the study arm will receive a one time dose of IVIG at 12 our post-Cardiopulmonary bypass. This is significantly early than our current standard of care.

Normal Saline

Subject's randomized into the placebo arm of the study will receive a volume of normal saline that is comparative to that if they were to receive IVIG. This will be at 12 hours post-cardiopulmonary bypass. This volume is to ensure blinding of study drug. This infusion will be administered as if the subject is receiving IVIG according to hospital policy.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

If the subject is randomized to the placebo group they will receive a volume of normal saline that is equivalent to the volume of IVIG to be administered based on their weight.

Interventions

IVIG

Those randomized to the study arm will receive a one time dose of IVIG at 12 our post-Cardiopulmonary bypass. This is significantly early than our current standard of care.

Intervention Type: DRUG

Placebo

If the subject is randomized to the placebo group they will receive a volume of normal saline that is equivalent to the volume of IVIG to be administered based on their weight.

Intervention Type: OTHER

Other Intervention Names

Gamunex; Normal Saline

Eligibility Criteria

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

• Maximum Eligible Age: 6 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Grifols Biologicals, LLC

INDUSTRY

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Jeffrey Alten, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeffrey Alten, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham Pediatric Cardiac Critical Care

Locations

Children's of Alabama

Birmingham, Alabama, United States

Countries

United States

Other Identifiers

F13114002

Identifier Type: OTHER

Identifier Source: secondary_id

F13114002

Identifier Type: -

Identifier Source: org_study_id