Clinical trial NCT02043379: Post-bypass Prophylactic IVIG in Infants and Neonates
Official title: Intravenous Immunoglobulin for Early Prevention of Cardiopulmonary Bypass Induced Hypogammaglobulinemia in Infants and Neonates
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypogammaglobulinemia
Congenital Heart Disease
Keywords: congenital heart disease
Cardiopulmonary Bypass
Hypogammaglobulinemia
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Grifols Biologicals, LLC
First posted: 2014-01-23
Enrollment: 50
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Post-Operative Infections
timeFrame: until Hospital Discharge, an average of 30 days
measure: Post-operative Infection
timeFrame: within 1 week of surgery
measure: Blood Stream Infection
timeFrame: until Hospital Discharge, an average of 30 days
measure: Blood Stream Infection Within 1 Week of Surgery
timeFrame: 7 days
Secondary outcomes:
measure: Post-operative Plasma Albumin
timeFrame: up to 48 hours post CPB
measure: Fluid Overload Variables
timeFrame: 0-24 hours post-CPB
measure: Post-operative Inotrope Score
timeFrame: first 48 hours post-CPB
measure: Respiratory Variables
timeFrame: until Hospital Discharge, an average of 30 days
measure: Hospital Discharge
timeFrame: Approximately 1 month
measure: Plasma Immunoglobulins
timeFrame: 5 days post-op
measure: Interferon-gamma Plasma Cytokine Levels
timeFrame: Pre-operative to 48 hours post-operative
measure: Immunoglobulin Concentration in Chest Tube Drainage
timeFrame: 24 hours post-op
measure: Mortality
timeFrame: Approximately 1 month
measure: Intensive Care Unit Length of Stay
timeFrame: 1 month
measure: Fluid Overload Variables
timeFrame: 0-48 hours post-CPB
measure: Respiratory Variables
timeFrame: until extubation, an average of 2 days
measure: Respiratory Variables
timeFrame: until extubation, an average of 2 days
measure: Interleukin-10 Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Interleukin-12p70 Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Interleukin-1b Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Interleukin-6 Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Interleukin-8 Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Tumor Necrosis Factor Plasma Cytokine Levels
timeFrame: pre-operative through 48 hours post-operative
measure: Immunoglobulin Concentration in Peritoneal Dialysis Drainage
timeFrame: 24 hours post-op
measure: Serum Creatinine
timeFrame: 48 hours
measure: Lactic Acid
timeFrame: pre-operative through 24 hours post-operative
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham Pediatric Cardiac Critical Care
name: Jeffrey Alten, MD
role: PRINCIPAL_INVESTIGATOR
References: