Post-bypass Prophylactic IVIG in Infants and Neonates

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

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).

Study Overview

• Status: Completed
• Conditions: Congenital Heart Disease; Hypogammaglobulinemia
• Intervention / Treatment: Drug: IVIG; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's of Alabama

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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 Names: Gamunex
Placebo Comparator: 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.	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.; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-Operative Infections	The primary endpoint of this study is incidence of post-operative infections through hospital discharge	until Hospital Discharge, an average of 30 days
Post-operative Infection	Any positive culture or treatment for culture negative sepsis within 1 week of surgery	within 1 week of surgery
Blood Stream Infection	Any positive blood culture during the post-operative period until hospital discharge	until Hospital Discharge, an average of 30 days
Blood Stream Infection Within 1 Week of Surgery		7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative Plasma Albumin	Plasma albumin will be assessed at 24 and 48 hours.	up to 48 hours post CPB
Fluid Overload Variables	The following fluid overload variables will be assessed in milliliters per kilogram at 0-24 hours post-cardiopulmonary bypass: blood product and albumin administration, chest tube output, urine output, peritoneal dialysis output, net fluid balance, and percent fluid overload. The total output the subject's produce (urine, chest tube, peritoneal drainage, etc.) will be subtracted from the total input (medications, blood products, albumin administration, etc) to determine the total fluid intake in milliliters. This total number will then be divided by the subject's weight in kilograms to determine the fluid overload in mL/kg.	0-24 hours post-CPB
Post-operative Inotrope Score	The average admit, 12 hour, 24 hour, and 48 hour post-operative inotrope score will be calculated excluding Milrinone. To calculate the inotrope score the following formula was used: (Epinephrine/Norepinephrine dose in mcg/kg/min x 100) + (Dopamine dose in mcg/kg/min x 1) + (Phenylephrine dose in mcg/kg/min x 10) + (Vasopressin dose unit/kg/hr x 60/10000). The higher the inotrope score the more cardiac support the subject requires. There is not a "normal" scale or range used for this calculation.	first 48 hours post-CPB
Respiratory Variables	Alive, ventilator free days will be recorded at hospital discharge.	until Hospital Discharge, an average of 30 days
Hospital Discharge	From admit post-operative to the Pediatric cardiac intensive care unit until discharge from the hospital in days.	Approximately 1 month
Plasma Immunoglobulins	Plasma Immunoglobulin levels will be checked pre-operatively, 12 hours post-op and 5 days post-op	5 days post-op
Interferon-gamma Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	Pre-operative to 48 hours post-operative
Immunoglobulin Concentration in Chest Tube Drainage	Immunoglobulin concentration will be measured from chest tube every 4 hours for first 12 hours post-operative and then 24 hours post-operative.	24 hours post-op
Mortality	Incidence of mortality from admit to Pediatric cardiac intensive care unit post-operatively until hospital discharge .	Approximately 1 month
Intensive Care Unit Length of Stay	The length of stay in the pediatric cardiac intensive care unit from admit post-operative until either discharge home, discharge to another unit/hospital/care facility, or death. This value is calculated in hours. Admit post-operative is recorded as hour 0.	1 month
Fluid Overload Variables	The following fluid overload variables will be assessed at 0-24 hours, 25-48 hours, and 0-48 hours post-cardiopulmonary bypass: blood product and albumin administration, chest tube output, urine output, peritoneal dialysis output, net fluid balance, and percent fluid overload.The total output the subject's produce (urine, chest tube, peritoneal drainage, etc.) will be subtracted from the total input (medications, blood products, albumin administration, etc) to determine the total fluid intake in milliliters. This total number will then be divided by the subject's weight in kilograms to determine the fluid overload in mL/kg.	0-48 hours post-CPB
Respiratory Variables	Time until first extubation in hours	until extubation, an average of 2 days
Respiratory Variables	Total time duration of post-operative length of mechanical ventilation until hospital discharge	until extubation, an average of 2 days
Interleukin-10 Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Interleukin-12p70 Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Interleukin-1b Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Interleukin-6 Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Interleukin-8 Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Tumor Necrosis Factor Plasma Cytokine Levels	Plasma cytokine levels measured preoperatively, 0, 4, 12, 24 hours, and 48 hours post-operatively.	pre-operative through 48 hours post-operative
Immunoglobulin Concentration in Peritoneal Dialysis Drainage	Immunoglobulin concentration will be measured from chest tube and peritoneal drain every 4 hours for first 12 hours post-operative and 24 hours post-operative.	24 hours post-op
Serum Creatinine	Pre-operative and 48 hour post-operative maximum creatinine recorded.	48 hours
Lactic Acid		pre-operative through 24 hours post-operative

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Grifols Biologicals, LLC
• Investigators: Principal Investigator: Jeffrey Alten, MD, University of Alabama at Birmingham Pediatric Cardiac Critical Care

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: January 14, 2014
• First Submitted That Met QC Criteria: January 21, 2014
• First Posted (Estimate): January 23, 2014

Study Record Updates

• Last Update Posted (Actual): April 13, 2017
• Last Update Submitted That Met QC Criteria: March 1, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Cardiopulmonary Bypass; congenital heart disease; Hypogammaglobulinemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Congenital Abnormalities; Hematologic Diseases; Blood Protein Disorders; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Agammaglobulinemia; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulins, Intravenous
• Other Study ID Numbers: F13114002 (Other Identifier: UAB Institutional Reveiw Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: IPD will not be shared with other individuals

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No