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

Congenital Heart Disease Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02043379
• Other study ID #: F13114002
• Secondary ID: F13114002
• Status: Completed
• Phase: N/A
• First received: January 14, 2014
• Last updated: July 14, 2015
• Start date: May 2014
• Est. completion date: June 2015

Study information

• Verified date: May 2015
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 6 Months

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Agammaglobulinemia
• Congenital Heart Disease
• Heart Defects, Congenital
• Heart Diseases
• Hypogammaglobulinemia

Intervention

Drug:
• 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.

Other:
• 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.

Locations

Country	Name	City	State
United States	Children's of Alabama	Birmingham	Alabama

Sponsors (2)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Grifols Biologicals Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post-Operative Infections	The primary endpoint of this study is incidence of post-operative infections through hospital discharge	Hospital Discharge	Yes
Secondary	Renal variables	Plasma albumin & plasma total protein will be assessed at 24 and 48 hours. Maximum plasma creatinine within the first 48 hours will also be assessed.	24 & 48 hours post CPB	Yes
Secondary	Fluid Overload Variables	The following fluid overload variables will be assessed at 24 and 48 hours post-cardiopulmonary bypass: blood product and albumin administration, chest tube output, urine output, peritoneal dialysis output, net fluid balance, and percent fluid overload.	24 and 48 hours post-CPB	Yes
Secondary	Hemodynamic variables	The maximum and average inotrope score will be calculated, the incidence of low cardiac output syndrome will be recorded, and the maximum plasma lactic acid will be recorded for the the specified time frame.	first 48 hours post-CPB	Yes
Secondary	Respiratory variables	Alive, ventilator free days and duration of oxygen therapy will be recorded at hospital discharge.	hospital discharge	Yes
Secondary	Hospital Discharge	From admit to the Pediatric cardiac intensive care unit until discharge from the hospital in days.	Approximately 1 month	Yes
Secondary	Plasma Immunoglobulins	Plasma Immunoglobulin levels will be checked pre-operatively, 12 hours post-op and 5 days post-op	5 days post-op	Yes
Secondary	Plasma cytokine levels	Plasma cytokine levels:Interferon-gamma, Interleukin-10, Interleukin-12p70, Interleukin-1b, Interleukin-6, Interleukin-8, Tumor Necrosis Factor a will be measured preoperatively, immediately postoperatively and 4, 12, and 24 hours.	24 hours post-op	Yes
Secondary	Immunoglobulin concentration in fluid loss	Immunoglobulin concentration will be measured from chest tube, peritoneal drain, and urine outputs every 4 hours for first 12 hours.	12 hours post-op	Yes
Secondary	Mortality	Incidence of mortality from admit to Pediatric cardiac intensive care unit post-operatively until hospital discharge .	Approximately 1 month	Yes
Secondary	Intensive Care Unit Length of Stay	The majority of the subject's enrolled into this protocol (complex neonates) are discharged home from the Pediatric Cardiac Intensive Care unit (PCICU). All others enrolled in the study are usually discharged from the PCICU within a week after surgery. This is measured in days.	1 week	Yes