Immunonutrition in Cardiac Surgery

Cardiac Surgery Clinical Trial

Official title:

The Effect of Pre- and Postoperative Supplemental Enteral Nutrition in High-Risk Patients Undergoing Elective Cardiac Surgery. A Prospective Double Blind Study.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00247793
• Other study ID #: 96.17.066
• Secondary ID: Mec 95/232
• Status: Completed
• Phase: N/A
• First received: November 1, 2005
• Last updated: November 1, 2005
• Start date: July 1996
• Est. completion date: December 1998

Study information

• Verified date: November 2005
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

Effect of two preoperative oral immune-enhancing nutritional supplements in patients at high risk of infection after cardiac surgery: a randomized placebo-controlled study.

Introduction: In our first study we showed that the use of a preoperative oral immune-enhancing nutritional supplement (OIENS) resulted in an improved patients’ host-defence with a reduction in postoperative infectious morbidity in ‘high-risk’ cardiac surgery patients. The use of the OIENS resulted also in less postoperative organ dysfunction. Experimental studies have shown that additional glycine results in less ischemia-reperfusion damage and that glycine has anti-inflammatory properties.

Objective: The use of an OIENS in the preoperative period in patients at high risk of infection after elective cardiac surgery with the use of cardiopulmonary bypass (CPB) results in a reduction in infections as in our first study. The addition of 9.6 gram glycine per sachet OIENS results in a further reduction in postoperative dysfunction.

Design: A prospective randomized placebo controlled study with two oral immune enhancing nutritional formula’s and an isocaloric control formula. Patients: Seventy-four consecutive patients undergoing cardiac surgery with the use of an CPB who met one or more of the following inclusion criteria: Age 70 years or older, mitral valve replacement or cardiac ejection fraction less then 40%. Exclusion criteria were age < 18 years, proven malignancy, use of corticosteroids, severe renal and liver failure. Definition of a protocol violation was the intake of less then 5 L or more then 10 L of the nutritional supplement in the preoperative period.

Intervention: Patients were split up in three groups by concealed randomisation. One group received the arginine, omega3-PUFAs and nucleotides enriched formula (OIENS). Another group received the OIENS further enriched with glycine (OIENS+glyc). The control group received an isocaloric nutritional supplement without the enrichments.

Description:

Objective To study the effect of two preoperative immune enhancing nutritional supplements compared with a control nutritional supplement in 'high risk' risk cardiac surgery patients

Introduction: Elderly patients and patients with a poor ventricular function undergoing cardiac operations with hypothermic cardiopulmonary bypass (CPB), have an increased postoperative morbidity and mortality. Host defence may be diminished due to nutritional deficiencies, hypoperfusion, anaesthesia and operative trauma. Immune function is additionally depressed by the use of CPB and hypothermia. It has been suggested that L-arginine can improve postoperative outcome in cardiac surgery patients, glycine may have a role in protecting tissues against insults such as ischemia-reperfusion and hypoxia, and omega-3 polyunsaturated fatty acids (omega3-PUFA's) can limit the postoperative generalised inflammatory response.

Experimental studies have shown that the use of nutritional supplements containing L-arginine, omega3-PUFA's or nucleotides, boost immune responsiveness after surgery or trauma. L-arginine is a semi-essential amino acid and precursor of nitrous oxide (NO), the most important endothelial vasodilator. In experimental studies, L-arginine improved wound healing, restored postoperative depressed macrophage function and lymphocyte responsiveness and augmented resistance to infections. Arginine protected against ischemia-reperfusion injury by increasing oxygen delivery upon reflow, thereby improving cardiac function. The intake of additional omega3-PUFA's alters cell membrane phospholipid content and prostaglandin synthesis. This might be an important factor in limiting the generalised inflammatory response and subsequent immunosuppression and capillary leakage following major surgery. Purines and pyrimidines are essential nutrients for rapidly dividing cells. The administration of nucleotides in the form of yeast-RNA has improved the host immune response to an infectious challenge. In experimental studies glycine has been proven cytoprotective in stomach, kidney, liver and cardiovascular system. The metabolic response to oral glycine is that it facilitates the uptake op glucose from the circulation.

The immunonutrients, arginine, omega3-PUFA’s and yeast-RNA, have been combined into a single oral immune enhancing nutritional supplement (OIENS). In cancer surgery, trauma and critically ill patients ‘post event’ nutrition with this immune enhancing formula has improved immunocompetence, reduced infections and shortened length of stay in the hospital (LOSH). The onset of the effect of postoperative immune enhancing nutrition starts after 3 days and seems to be dose dependent. For this reason, it can be hypothesised that it may be beneficial to commence an oral immune enhancing nutritional supplement (OIENS) before surgery. A recent published clinical trail showed that the OIENS with these three immunonutrients in high risk cardiac surgery patients improves preoperative clinical relevant immunological parameters, reduced postoperative infectious morbidity and attenuated postoperative organ dysfunction. Recently, the three immunonutrients have been combined with glycine into a new single OIENS. Aim of the present study in ‘high risk’ cardiac surgery patients was to determine whether the intake of the new OIENS for minimally five days improves preoperative host defence and subsequently reduces postoperative infections and organ dysfunction.

Study design: A prospective randomized placebo-controlled three armed double blind study

Setting: Departments of cardiopulmonary surgery, anesthesiology and intensive care of the Academic Medical Center, Amsterdam, The Netherlands

Patients: Eligible patients will be included in the study after obtaining written informed consent Inclusion criteria: Patients who met one or more of the inclusion criteria: aged 70 years or more, undergoing cardiac surgery with the use of CPB, or patients with a poor left ventricular function (Ejection fraction < 0.40) or patients undergoing a mitral valve replacement.

Exclusion criteria: Age < 21 years, pregnancy, insulin dependent diabetes mellitus, hepatic cirrhosis, known malignancy, the use of chemotherapy, NSAIDs (excluding acetyl salic acid) or corticosteroids, schizophrenia, severe renal insufficiency (creatinine clearance < 25 mL/h), patients with an organ transplantation in the past

Randomization: 74 patients will be randomized by closed envelop method

Intervention: All patients will receive one of the three enteral nutritional supplements. A formula enriched with arginine, omega-3 PUFA's and nucleotides or the enriched formula further enriched with additional glycine or a control formula. Patients that needs postoperative enteral nutritional support will receive the same formula as preoperative. Patients that need no postoperative enteral nutrition nasogastric tube feeding will not receive the nutritional supplement

Endpoints: Patient compliance, infections, postperfusion phenomena, post-operative organ function (need of postoperative support e.g. inotropic, vasopressor support, fluids, myocardial infarction, ventilation parameters, renal function) time of recovery, mortality

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. completion date: December 1998
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

Patients undergoing cardiac surgery with the use of cardiopulmonary bypass, who met one of the following criteria

• age >= 70 years

• poor left ventricular function (ejection fraction < 0.4)

• mitral valve replacement

Exclusion Criteria:

• Age =< 21 years

• Pregnancy

• Insulin dependent diabetes mellitus

• Hepatic Cirrhosis

• Known malignancy

• Use of chemotherapy, NSAIDs (except ASA), or corticosteroids

• Schizophrenia

• Severe renal failure (creatinine clearance < 25 mL/h) before study entrance

• Patients with an organ transplantation in the past

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiac Surgery
• Cardiopulmonary Bypass
• Thoracic Surgery

Intervention

Drug:
• Oral Impact (preoperative enteral nutritional supplement)

Locations

Country	Name	City	State
Netherlands	Cardiopulmonary Surgery, Academic Medical Center	Amsterdam	NH

Sponsors (1)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Country where clinical trial is conducted

Netherlands, 

References & Publications (40)

Beale RJ, Schneider H, Sorensen f, Smithies MN, Bennet ED, Bihari DJ. A multicentre randomised, controlled trial comparing enteral feeding with IMPACT versus IMPACT with Glycine. Intensive Care Medicine 26(suppl 3):S300,2000

Bozzetti F, Braga M, Gianotti L, Gavazzi C, Mariani L. Postoperative enteral versus parenteral nutrition in malnourished patients with gastrointestinal cancer: a randomised multicentre trial. Lancet. 2001 Nov 3;358(9292):1487-92. — View Citation

Braga M, Gianotti L, Cestari A, Vignali A, Pellegatta F, Dolci A, Di Carlo V. Gut function and immune and inflammatory responses in patients perioperatively fed with supplemented enteral formulas. Arch Surg. 1996 Dec;131(12):1257-64; discussion 1264-5. — View Citation

Daly JM, Weintraub FN, Shou J, Rosato EF, Lucia M. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg. 1995 Apr;221(4):327-38. — View Citation

Davies SJ, Wilson RJ. Preoperative optimization of the high-risk surgical patient. Br J Anaesth. 2004 Jul;93(1):121-8. Epub 2004 Apr 30. Review. — View Citation

De Backer D, Creteur J, Vincent JL. Perioperative optimization and right heart catheterization: what technique in which patient? Crit Care. 2003 Jun;7(3):201-2. Epub 2003 Mar 14. — View Citation

Engelman DT, Watanabe M, Maulik N, Cordis GA, Engelman RM, Rousou JA, Flack JE 3rd, Deaton DW, Das DK. L-arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion. Ann Thorac Surg. 1995 Nov;60(5):1275-81. — View Citation

Farreras N, Artigas V, Cardona D, Rius X, Trias M, González JA. Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr. 2005 Feb;24(1):55-65. — View Citation

Fernandez J, Chen C, Anolik G, Brdlik OB, Laub GW, Anderson WA, McGrath LB. Perioperative risk factors affecting hospital stay and hospital costs in open heart surgery for patients > or = 65 years old. Eur J Cardiothorac Surg. 1997 Jun;11(6):1133-40. — View Citation

Flancbaum L, Ziegler DW, Choban PS. Preoperative intensive care unit admission and hemodynamic monitoring in patients scheduled for major elective noncardiac surgery: a retrospective review of 95 patients. J Cardiothorac Vasc Anesth. 1998 Feb;12(1):3-9. — View Citation

Garner JS. The CDC Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1993 Jun;21(3):160-2. — View Citation

Gessler P, Pfenninger J, Pfammatter JP, Carrel T, Dahinden C. Inflammatory response of neutrophil granulocytes and monocytes after cardiopulmonary bypass in pediatric cardiac surgery. Intensive Care Med. 2002 Dec;28(12):1786-91. Epub 2002 Oct 17. — View Citation

Hall JC. Glycine. JPEN J Parenter Enteral Nutr. 1998 Nov-Dec;22(6):393-8. Review. — View Citation

Heller AR, Fischer S, Rössel T, Geiger S, Siegert G, Ragaller M, Zimmermann T, Koch T. Impact of n-3 fatty acid supplemented parenteral nutrition on haemostasis patterns after major abdominal surgery. Br J Nutr. 2002 Jan;87 Suppl 1:S95-101. — View Citation

Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA. 2001 Aug 22-29;286(8):944-53. Review. — View Citation

Higgins TL, Estafanous FG, Loop FD, Beck GJ, Blum JM, Paranandi L. Stratification of morbidity and mortality outcome by preoperative risk factors in coronary artery bypass patients. A clinical severity score. JAMA. 1992 May 6;267(17):2344-8. Erratum in: JAMA 1992 Oct 14;268(14):1860. — View Citation

Jones SM, Thurman RG. L-arginine minimizes reperfusion injury in a low-flow, reflow model of liver perfusion. Hepatology. 1996 Jul;24(1):163-8. — View Citation

Kaplan LJ, McPartland K, Santora TA, Trooskin SZ. Start with a subjective assessment of skin temperature to identify hypoperfusion in intensive care unit patients. J Trauma. 2001 Apr;50(4):620-7; discussion 627-8. — View Citation

Kendall SJ, Weir J, Aspinall R, Henderson D, Rosson J. Erythrocyte transfusion causes immunosuppression after total hip replacement. Clin Orthop Relat Res. 2000 Dec;(381):145-55. — View Citation

Kirk SJ, Barbul A. Role of arginine in trauma, sepsis, and immunity. JPEN J Parenter Enteral Nutr. 1990 Sep-Oct;14(5 Suppl):226S-229S. Review. — View Citation

Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. The impact of nosocomial infections on patient outcomes following cardiac surgery. Chest. 1997 Sep;112(3):666-75. — View Citation

Kress HG, Scheidewig C, Schmidt H, Silber R. Reduced incidence of postoperative infection after intravenous administration of an immunoglobulin A- and immunoglobulin M-enriched preparation in anergic patients undergoing cardiac surgery. Crit Care Med. 1999 Jul;27(7):1281-7. — View Citation

Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol. 1992 Feb;262(2 Pt 2):H611-5. — View Citation

Kulkarni AD, Rudolph FB, Van Buren CT. The role of dietary sources of nucleotides in immune function: a review. J Nutr. 1994 Aug;124(8 Suppl):1442S-1446S. Review. — View Citation

Luiking YC, Poeze M, Dejong CH, Ramsay G, Deutz NE. Sepsis: an arginine deficiency state? Crit Care Med. 2004 Oct;32(10):2135-45. Review. — View Citation

MacFie J, Woodcock NP, Palmer MD, Walker A, Townsend S, Mitchell CJ. Oral dietary supplements in pre- and postoperative surgical patients: a prospective and randomized clinical trial. Nutrition. 2000 Sep;16(9):723-8. — View Citation

Niessen HW, Lagrand WK, Visser CA, Meijer CJ, Hack CE. Upregulation of ICAM-1 on cardiomyocytes in jeopardized human myocardium during infarction. Cardiovasc Res. 1999 Mar;41(3):603-10. — View Citation

Nijveldt RJ, Houdijk AP, Boelens PG, van Leeuwen PA. Nutritional supplementation after cardiac surgery. Lancet. 2002 Jan 19;359(9302):256; author reply 257-8. — View Citation

Nonami Y. The role of nitric oxide in cardiac surgery. Surg Today. 1997;27(7):583-92. Review. — View Citation

O'Leary MJ, Coakley JH. Nutrition and immunonutrition. Br J Anaesth. 1996 Jul;77(1):118-27. Review. — View Citation

Rebollo MH, Bernal JM, Llorca J, Rabasa JM, Revuelta JM. Nosocomial infections in patients having cardiovascular operations: a multivariate analysis of risk factors. J Thorac Cardiovasc Surg. 1996 Oct;112(4):908-13. — View Citation

Sato H, Zhao ZQ, McGee DS, Williams MW, Hammon JW Jr, Vinten-Johansen J. Supplemental L-arginine during cardioplegic arrest and reperfusion avoids regional postischemic injury. J Thorac Cardiovasc Surg. 1995 Aug;110(2):302-14. — View Citation

Setty S, Tune JD, Downey HF. Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res. 2004 Dec 1;64(3):431-6. — View Citation

Shorr AF, Jackson WL, Kelly KM, Fu M, Kollef MH. Transfusion practice and blood stream infections in critically ill patients. Chest. 2005 May;127(5):1722-8. — View Citation

Takala J, Uusaro A, Parviainen I, Ruokonen E. Lactate metabolism and regional lactate exchange after cardiac surgery. New Horiz. 1996 Nov;4(4):483-92. Review. — View Citation

Tepaske R, Velthuis H, Oudemans-van Straaten HM, Heisterkamp SH, van Deventer SJ, Ince C, Eÿsman L, Kesecioglu J. Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial. Lancet. 2001 Sep 1;358(9283):696-701. — View Citation

Vanschoonbeek K, de Maat MP, Heemskerk JW. Fish oil consumption and reduction of arterial disease. J Nutr. 2003 Mar;133(3):657-60. Review. — View Citation

Weimann A, Bastian L, Bischoff WE, Grotz M, Hansel M, Lotz J, Trautwein C, Tusch G, Schlitt HJ, Regel G. Influence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma. Nutrition. 1998 Feb;14(2):165-72. — View Citation

Zhong Z, Thurman RG. A fish oil diet minimizes hepatic reperfusion injury in the low-flow, reflow liver perfusion model. Hepatology. 1995 Sep;22(3):929-35. — View Citation

Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ. L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):229-40. Review. — View Citation

* Note: There are 40 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postoperative infectious morbidity
Primary	Mortality
Secondary	Immunological measurements
Secondary	Postoperative organ function/support
Secondary	Recovery (Length of ICU stay, postoperative length of hospital stay)