Oral Glutamine in Cardiopulmonary Bypass
Condition: Ischemic Heart Disease
MeSH terms: Heart Diseases; Myocardial Ischemia; Coronary Artery Disease
Study type: Interventional

Summary: 
      Introduction: Glutamine (GLN) is the most abundant free amino acid in the body. It modulates
      immune cell function and is an important energy substrate for most cells (especially for
      enterocytes and lymphocytes) in critical patients. GLN levels significantly decreased during
      sepsis/critical illness leading to an increase in infectious complications, organ failure and
      mortality. Moreover, in cases of ischemia/reperfusion injury in the myocardium, GLN increases
      the levels of Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) ratio and prevents
      intracellular lactate accumulation. Recently, the perioperative effect of intravenous and
      oral GLN treatment been associated in lowering levels of cardiac injury markers such as
      Troponin-I (TROP-I) and the number of postoperative complications in patients who underwent
      Cardiopulmonary Bypass (CPB). The aim of the study was to analyze the oral dose of
      preoperative oral GLN treatment in patients who underwent CPB with extracorporeal circulation
      in Mexican patients.
    

Detailed description: 
      INTRODUCTION Glutamine (GLN) is the most abundant free amino acid in the body, and commonly
      known as a non-essential amino acid due to the ability of most cells to produce it. It has
      many essential metabolic functions in the organism; it is an energy substrate for most cells
      (especially for enterocytes and lymphocytes), a precursor for nucleotide, glutamate, and (in
      particular) glutathione synthesis, and an important cellular antioxidant. It plays a central
      role in nitrogen transport within the body, and is the most important substrate for renal
      ammoniagenesis.

      Studies have demonstrated that the presence of GLN in the medium regulates glutamine
      synthetase expression via a post-transcriptional mechanism, where the rate of glutamine
      synthetase protein degradation is diminished and its activity, augmented, in the presence of
      low GLN concentration. This amino acid modulates immune cell function and production of
      cytokines via attenuation of multiple pathways of inflammation, such as Nuclear Factor kB
      (NF-kB), protein kinases, inhibition of increases in Nitric Oxide Synthase (iNOS) expression.

      It has been shown to be beneficial for the metabolically stressed patient, especially the
      critically ill patients. During acute illnesses, patients experience nutritional depletion,
      which correlates with low plasma and low mucosal GLN concentrations.

      GLN levels are significantly decreased in critical illness, leading to an increase in
      infectious complications, organ failure and mortality. Moreover, in cases of
      ischemia/reperfusion injury, GLN increases the myocardial ATP/ADP ratio and prevents
      intracellular lactate accumulation.

      GLN has been shown to be a key nutrient in the body's response to stress and injury described
      in multiple studies with in vitro and in vivo myocardial injury following I/R. These include
      enhanced myocardial glutathione, adenosine triphosphate (ATP), and glutamate (a major stress
      substrate for the stressed myocardium) post-I/R injury, and induction of heat shock proteins,
      especially Heat Shock Protein-70 (HSP-70) in critically ill patients. The stress tolerance
      provided by HSP-70 can protect against cellular injury, lung injury, ischemia/reperfusion
      injury, and septic shock, by the GLN influences on the inflammatory response, oxidative
      stress, apoptosis modulation, and the integrity of gut barrier.

      Protection of the myocardium following ischemia and reperfusion injury is crucial in the
      perioperative management of patients after cardiopulmonary bypass (CPB). This ischemia is the
      most important factor of reversible perioperative risk for cardiovascular complications.
      Patients undergoing CPB 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.

      Numerous experimental and clinical trials have demonstrated the cardioprotective effects of
      GLN, including dose-dependent enhanced myocardial functional recovery following acute
      normothermic ischemia in the rat. GLN has also been shown to reduce infarct size to
      approximately 39% in a rabbit model following ischemia/reperfusion injury.[19] GLN treatment
      also increased load tolerance in patients with ischemic heart disease (IHD).

      In 2012, a clinical study observed a significant decrease in TROP-I in patients with ischemic
      heart disease who underwent CPB with extracorporeal circulation who received (0.4 g/kg of
      GLN, Dipeptiven solution) one day before surgery. The case group (n=25) showed reduced levels
      of TROP-I compared to control group (1.2 ng/ml to 2.4 ng/ml), p=0.035 on the first
      postoperative day. Also, the median cardiac index and median stroke index were higher in case
      group following CPB, improving myocardial function.

      In another study, the authors observed significantly decreased TROP-I levels in their
      pilot-clinical trial. They performed an oral intervention in patients undergoing CPB, giving
      25 g twice of GLN supplement. TROP-I levels were significantly lower at 24, 48, and 72
      postoperatively hours (all p < 0.05).

      Despite the varied experimental data showing the cardioprotective effects of GLN, there is a
      lack of clinical trials with CPB patients. The finding that lower levels of cardiac injury
      markers are observed in patients treated with oral GLN prior to CPB can have major
      implications in these patients. The purpose of this study is to analyze the effect of a
      preoperative oral supplementation of GLN in reducing postoperative levels of Troponin-I in
      Mexican patients who underwent CPB under extracorporeal circulation. The oral GLN proposed in
      this study is based on what has been previously studied and what is considered safe.

      MATERIALS AND METHODS. A controlled clinical trial performed in 28 patients who underwent
      cardiopulmonary bypass with confirmed diagnosis of ischemic heart disease. The protocol was
      made between January 2013 and December 2014 in the Specialty Hospital of the Western National
      Medical Center, Mexican Institute of Social Security.

      The protocol received ethics approval by the Local Committee of Ethics in Research and
      Health. All patients gave informed consent prior to participation.

      Participants were men or nonpregnant women, aged 40-70 years. Participants were excluded on
      the basis of preexisting kidney, liver dysfunction or other comorbid conditions such as drug
      or alcohol abuse, positivity to human immunodeficiency virus (HIV), hepatitis B / C or
      allergies against components of GLN. Participants were also excluded on the basis of signs of
      ongoing ischemia, defined by persistent elevation of TROP-I and CK-MB levels. They were also
      excluded if they were on a diet with any supplemental GLN.

      Treatment Following study enrollment, patients were randomized (blinded envelopes that were
      opened sequentially by a blinded study pharmacist), to receive either oral GLN supplement
      group or control group (CONT) with maltodextrin (as isocaloric complex carbohydrate).

      All investigators and clinical caregivers were blinded to study intervention. All patients in
      the GLN group received a GLN supplement. The total GLN/maltodextrin dose given to patients
      was standardized to 0.5 g/kg/day during 3 days prior to CPB, and taking one final dose of
      0.25 g/kg/day of GLN/maltodextrin in the morning of surgery 4 hours prior to initiation of
      anesthesia.

      Compliance with ingestion of the study drug was assessed via daily reminder calls from the
      study investigator and required empty package returns.

      Patient Sample Collection and Analysis Blood was collected at baseline (one hour before
      surgery), and then one hour after surgery and 12 and 24 postoperative hours. After
      collection, blood was processed for analysis of cardiac injury markers: TROP-I, creatine
      phosphokinase (CPK) and creatine phosphokinase-Mb (CPK-Mb) and were analyzed using Meso Scale
      technology (Meso Scale Discovery, Gaithersburg, MD).

      Clinical Data Collection All patients had essential demographic information collected as well
      as preoperative cardiac ejection fraction at study enrollment. In addition, postoperative
      complications were evaluated, including stroke, infections and postoperative vasopressor
      therapy. The time of time of aortic clamp during surgery and days in the Critial Care Unit
      (UCI) were measured. Mortality in the postoperative period was also collected.

      Statistical Analysis Qualitative variables are expressed as raw numbers and proportions,
      whereas the quantitative variables are expressed as means ± standard deviations. To compare
      quantitative variables in the the results between the two groups, the U Mann Whitney test was
      used. Qualitative variables were measured using Chi 2 of Fisher's exact test in any expected
      values below 5. A p value of 0.05 or less was considered significant. The analysis was
      performed using Excel 2013 and Statistical Package for the Social Sciences (SPSS) version 20
      for Windows (IBM Corp., NY, USA).

      Ethical Considerations The study was conducted according to the principles of the Declaration
      of Helsinki and the Guidelines for Health Research in Mexico. The protocol was approved by
      the Local Committee on Health Research.
    

Intervention name(s): Supplement/placebo intake
Intervention type(s): Dietary Supplement
Intervention description(s): Patients will receive either GLN or placebo prior to cardiovascular surgery under extracorporeal circulation, during 3 days and one final dose 4 hours prior to anesthesia.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Cardiac Surgical Procedures; Cardiovascular Surgical Procedures; Dietary Supplements; Glutamine; TROPONIN I; cardiopulmonary bypass