Post-bypass Prophylactic IVIG in Infants and Neonates

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hypogammaglobulinemia, Congenital Heart Disease

Intervention / Treatment
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* Drug: IVIG
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IVIG<br>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<br>* 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.<br>* Other names: Gamunex;|
| Placebo Comparator: Normal Saline<br>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<br>* 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.<br>* Other names: Normal Saline;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congenital heart disease, Cardiopulmonary Bypass, Hypogammaglobulinemia