Glutamine to Improve Outcomes in Cardiac Surgery

Study Overview
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Brief Summary
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Patients undergoing heart surgery with a heart-lung machine (termed cardiopulmonary bypass) are at an increased risk of having abnormal inflammation in their body after surgery. Such inflammation can contribute to slower recovery from surgery, an increased risk of infection, an increased risk of damage to organs other than the heart, and a more complicated course. Prior research has suggested that using an oral protein supplement made of glutamine (an essential amino acid normally found in your body) can reduce the risk of inflammation, infection and the length of stay in hospital in patients who have suffered major trauma or a burn injury. The investigators believe reducing such inflammation after heart surgery may help promote recovery and reduce the risk of adverse events and complications. The purpose of this preliminary study is to see if oral glutamine supplementation after heart surgery is practical, and contributes to a reduction in inflammation. The oral glutamine proposed in this study is based on what has been previously studied and what is considered safe.

Detailed Description
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Hypothesis: We believe that early post-operative administration of enteral glutamine following cardiac surgery with cardiopulmonary bypass (CPB) in high risk patients will reduce inflammation and nonscomial infections, reduce length of ventilator support, reduce need for vasoactive support, reduce secondary organ dysfunction, reduce length of hospital stay in the CVICU, and reduce mortality. Objectives: To assess the feasibility of early glutamine supplementation To evaluate the safety profile of early glutamine supplementation To evaluate efficacy the impact of early glutamine on clinically important post-operative complications and outcomes, including: systemic inflammation, nosocomial infections, mortality, and health resource utilization Methods: Study Design, Setting, and Patient Population: The proposed study is a Phase II, randomized, blinded, placebo-controlled trial. This trial will be performed in the Cardiovascular Surgical Intensive Care Unit (CVICU) of the Mazankowski Alberta Heart Institute (MAHI), Alberta Health Services. The proposed trial plans to enroll 100 consecutive eligible patients. Inclusion: Consent (obtained pre-operatively) Adult - aged 18 years or older; Planned cardiac surgery with CPB; Elevated risk for post-operative morbidity, defined by a pre-operative European System for Operative Cardiac Risk Evaluation (EuroSCORE) > 6. Able to receive enteral nutrition through nasal/oral gastric or post-pyloric feeding tube. Exclusion: Planned heart or lung transplantation Planned cardiac surgery without cardiopulmonary bypass; Peri-operative support with extracorporeal membrane oxygenation (ECMO) or left ventricular assist device (LVAD). Study Protocol: Eligible patients will be identified during pre-operative assessment in the pre-operative clinic (PAC). All eligible patients or their surrogate decision-making/legal guardian will then be approached to obtain informed written consent. Each consenting participant will be randomly allocated (1:1) to receive post-operative enteral glutamine or identical placebo. Investigators, surgeons, intensivists, bedside nurses and participants will remain blinded to study allocation. Glutamine supplementation will be dosed at 0.5 g/kg satisfactory body weight (SBW)/day divided every 8 hours, starting 6 hours post-operatively and continued for 5 days. The dose of 0.5 g/kg SBW/day was effective in clinical studies using enteral glutamine in critically ill and/or burn injured and major trauma patients. The glutamine supplementation or placebo will be delivered via naso- or oro-gastric feeding tube after confirmation of placement by chest X-ray. For participants who are extubated prior to 5 days, enteral glutamine will be given by mouth for the duration of the 5 day period. Glutamine and placebo will be mixed in orange juice to maintain blinding.

Official Title
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GLutamine Enterally After carDiac Surgery for Inflammation Attenuation and ouTcOme impRovement (GLADIATOR): A Phase II Randomized, Blinded, Placebo-Controlled Trial

Conditions
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Nosocomial Infection

Intervention / Treatment
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* Dietary Supplement: Glutamine
* Dietary Supplement: Maltodextrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consent (obtained pre-operatively) Adult - aged 18 years or older; Planned cardiovascular surgery with cardiopulmonary bypass; Increased risk for post-operative morbidity, defined by a pre-operative European System for Operative Cardiac Risk Evaluation (EuroSCORE) > 6; Able to receive enteral nutrition through nasal/oral gastric or post-pyloric feeding tube. Exclusion Criteria: Planned heart or lung transplantation Planned cardiovascular surgery without cardiopulmonary bypass; Peri-operative support with extracorporeal membrane oxygenation (ECMO) or left ventricular assist device (LVAD).

Ages Eligible for Study
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Minimum Age: 18 Years

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Glutamine
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glutamine<br>Oral/enteral glutamine 0.5 g/kg satisfactory body weight per day (divided doses every 8 hours) starting 6 hours post-operatively | Dietary Supplement: Glutamine<br>* Enteric L-Glutamine<br>* Other names: L-Glutamine;|
| Placebo Comparator: Maltodextrin<br>Oral/enteral maltodextrin 0.5 g/kg satisfactory body weight per day (divided doses every 8 hours) starting 6 hours post-operatively | Dietary Supplement: Maltodextrin<br>* Enteric Maltodextrin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Eligible Patients Providing Consent to Participate | Assess the FEASIBILITY of the protocol to (i) achieve >75% consent rate in eligible patients | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Kidney Injury |  | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Duration of mechanical ventilation |  | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Duration of vasoactive support |  | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Blood transfusion |  | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Organ Dysfunction Score | Post-operative changes to the Sequential Organ Failure Assessment score | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Adverse events | Evaluate the SAFETY and ADVERSE EFFECTS of (i) enteral glutamine; and (ii) COMPLICATIONS from feeding tube placement, including: epistaxis, feeding tube malposition, pneumothorax, esophageal injury, gastric mucosal irritation, gastrointestinal bleeding, unplanned feeding tube removal, and need for feeding tube reinsertion | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Systemic inflammation | Systemic Inflammation/immunomodulation: We will evaluate for increases and changes in systemic inflammation stratified by study intervention. This will aid in providing proof-of-concept of the biologic plausibility of the study intervention. The investigators propose to evaluate serial measures of C-reactive protein (CRP), chemiluminescent endotoxin activity assay (EAA), and interleukin-6 (IL-6). | Date of surgery until the end of planned study intervention, expected 5-days | 
| Nosocomial infection | Nosocomial infections: The investigators will specifically examine for the following infections during the period of hospitalization after surgery: superficial and deep sternal wound infections; mediastinitis; saphenous vein graft harvest site wound infections; ventilator associated and hospital acquired pneumonia; urinary tract infections; bloodstream infections; catheter-related blood stream infections; and decubitus ulcers. | Date of surgery until date of hospital discharge, an expected average of 2 weeks | 
| Proportion of Randomized Patients Achieving Protocol Adherence | Obtain > 90% protocol adherence | 5-days (date of surgery until the end of planned study intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac surgery, Cardiac bypass, Intensive Care, Nosocomial infection, Glutamine, Randomized trial