Editorial
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2011; 3(9): 128-130
Published online Sep 15, 2011. doi: 10.4251/wjgo.v3.i9.128
Are we jumping the gun with pharmaconutrition (immunonutrition) in gastrointestinal onoclogical surgery?
Emma Jane Osland, Muhammed Ashraf Memon
Emma Jane Osland, Department of Nutrition, Ipswich Hospital, Ipswich, QLD 4305, Australia
Muhammed Ashraf Memon, Department of Surgery, University of Queensland, Brisbane, QLD 4072, Australia
Muhammed Ashraf Memon, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD 4226, Australia
Muhammed Ashraf Memon, Faculty of Health and Social Sciences, University of Bolton, Bolton, Lancashire, BL3 5AB, United Kingdom
Author contributions: All authors were involved in drafting the manuscript and revising it critically for important intellectual content; furthermore, all authors have participated sufficiently in the work to take public responsibility for its content.
Correspondence to: Muhammed Ashraf Memon, FRCS, FRACS, Professor, McCullough Centre, Suite 9, 259 McCullough Street, Sunnybank, QLD 4109, Australia. mmemon@yahoo.com
Telephone: +61-448614170 Fax: +61-7-38101592
Received: April 19, 2011
Revised: August 21, 2011
Accepted: August 26, 2011
Published online: September 15, 2011

Abstract

Over the last 20 years there has been considerable research into the use of immunonutrition, also referred to as pharmaconutrition, in the management of patients undergoing and recovering from elective gastrointestinal surgery for malignancy. In this group of patients, the use of pharmaconutrition seems to confer superior outcomes to standard nutrition formulations with regards to postoperative infective complications and length of hospital stay. It is therefore frequently recommended for use in elective gastrointestinal oncological surgical populations. However, it remains unclear whether the data supporting these recommendation is robust. Studies reporting improved outcomes with pharmaconutrition frequently compare this intervention with non-equivalent control groups, do not report on the actual nutritional provision received by study participants, overlook the potential impact of industry funding on the conduct of research and do not adopt a multi-disciplinary approach to the research undertaken. For these reasons, an urgent critical re-appraisal of the use and recommendations of pharmaconutrition in this group of patients is warranted to resolve some of the above mentioned issues.

Key Words: Pharmaconutrition, Immunonutrition, Arginine, Gastrointestinal malignancy, Elective surgery



INTRODUCTION

Nutrition is an important consideration in the management of patients undergoing and recovering from elective gastrointestinal surgery for malignancy. Malnutrition is highly prevalent in this group of patents due to the numerous predisposing factors such as cancer cachexia, dysphagia, small or large bowel obstruction, nausea, vomiting, diarrhoea and/or loss of appetite - all of which are often exacerbated by the effect of neo-adjuvant or adjuvant chemoradiotherapies[1]. Given that malnourished patients with gastrointestinal malignancies have been shown to experience a greater than two-fold increase in postoperative complications and require significantly longer hospital admissions than their well nourished counterparts[1], timely and appropriate nutritional intervention has the potential to positively influence postoperative surgical outcomes in this patient group[2].

In surgical populations nutrition provides important substrates such as proteins and micronutrients for wound healing, as well as energy derived from lipids and carbohydrates to power the metabolic processes which facilitate recovery while preserving lean body tissue. In addition to this traditional view of nutrition, the last two decades has seen the development of the concept of providing supraphysiological doses of nutrients (primarily arginine, often in conjunction with omega-3 fatty acids, RNA, antioxidants and/or glutamine) to support the immune system in times of physiological stress[3]. This concept has been referred to as “immunonutrition”, and more recently as “pharmaconutrition”[3].

PHARMACONUTRITION IN ELECTIVE SURGICAL ONCOLOGICAL PATIENTS

Much has been written about the use of pharmaconutrition in patients receiving elective surgery for gastrointestinal malignancies. In this group of patients when compared with conventional nutritional provision, pharmaconutrition has been reported to decrease postoperative infective complications and length of hospital stay, both of which have positive financial implications for the hospital and insurance companies[4-9]. While there have been concerns about increased mortality rates in a critically ill population, when feeding products containing high levels of argininie[6], no such effect is reported with the use of pharmaconutrition in elective surgical populations[4-9].

This general conclusion has recently gained support from six recent meta-analyses investigating the benefits of pharmaconutrition in elective gastrointestinal surgical patients, most of whom were oncology patients[5]. Given the increasing support for the benefits of pharmaconutrition, it is not surprising that many practice guidelines now incorporate the available evidence and recommend the use of these products in this population[10,11]. However, it remains unclear whether the current evidence underpinning the use pharmaconutrition in this patient group is sufficiently robust.

LIMITATIONS OF STUDIES INVESTIGATING PHARMACONUTRITION IN ELECTIVE GAS-TROINTESTINAL ONCOLOGICAL PATIENTS

While many trials and meta-analyses are now adopting CONSORT[12] and PRISMA[13] reporting guidelines, these were never designed to provide guidance on or evaluation of important considerations regarding a study’s protocol. As a result, a well reported study or analysis may still contain fundamental flaws that can produce spurious results. For example, close examination of a large percentage of the papers that report investigations into the benefits of pharmaconutrition do not use equivalent control groups or control formulas. Pharmaconutrition has been studied in comparison to no nutritional intervention (nil by mouth)[14] or to control products that contain 50% to 80% less protein than the intervention product[15-20]. The effect of which may be to produce a benefit favouring the intervention product (i.e., pharmaconutrition group), independent of the immune-modulating components, due to a greater nitrogen provision. Pharmaconutrition has also been given as a preoperative supplement in addition to dietary intake, for which no equivalent product was provided to the control group[21-23]. The issue of non-equivalent control groups is a frequent concern in studies that are heavily funded by industry, and possibly representing a deliberate attempt to favour the product under investigation[24]. Given the high percentage of studies funded by companies that produce pharmaconutrition products, this issue warrants greater scrutiny than is currently evident in the literature on this topic.

Another issue of concern is the limited reporting of the actual volumes of pharmaconutrition or control formula received by patients randomised to each intervention. While most studies report the desired nutritional goals, few report the average volumes received by the patients in each group. Because of this, protocol violations or feed intolerance may go undetected, possibly resulting in inappropriate conclusions being drawn from results where significant differences in macronutrients are provided between groups, thus potentially providing greater clinical benefit to whichever intervention group receives nutrition closer to adequate or goal requirements.

Inspection of authorship of many of the papers investigating pharmaconutrition reveals a lack of multi-disciplinary involvement, with surgical departments accounting for the large majority of authors. Given that nutrition is the particular area of expertise of dietitians and nutrition professionals, it would seem reasonable that multi-disciplinary involvement in a research topic so closely tied with nutritional provision should involve dietetic consultation both in the protocol development stages and throughout the trial. The multi-disciplinary collaboration with closer dietetic involvement would alleviate some of the issues outlined above and lead to a better design of randomised controlled trials in the future.

CONCLUSION

Pharmaconutrition represents an exciting paradigm shift in the way health professionals conceptualise nutrition and its potential to facilitate superior postoperative outcomes in elective surgical oncological patients is appealing. However, as in all evidence based practice, it remains important to critically appraise the available data. The increasing trend towards recommending pharmaconutrition may be premature, given that the concerns expressed above have received little mention in the literature, and no studies, to date, have adequately addressed them. It would behove health professionals to carefully re-examine the supporting literature before adopting pharmaconutrition as standard practice for patients receiving elective surgical management of gastrointestinal malignancies.

Footnotes

Peer reviewer: Kenneth K Wu, MD, PhD, Distinguished Investigator and President, National Health Research Institutes, 35, Keyan Road, Zhunan Township, Miaoli County 350, Taiwan, China

S- Editor Wang JL L- Editor Hughes D E- Editor Li JY

References
1.  Garth AK, Newsome CM, Simmance N, Crowe TC. Nutritional status, nutrition practices and post-operative complications in patients with gastrointestinal cancer. J Hum Nutr Diet. 2010;23:393-401.  [PubMed]  [DOI]
2.  Lewis SJ, Andersen HK, Thomas S. Early enteral nutrition within 24 h of intestinal surgery versus later commencement of feeding: a systematic review and meta-analysis. J Gastrointest Surg. 2009;13:569-575.  [PubMed]  [DOI]
3.  Jones NE, Heyland DK. Pharmaconutrition: a new emerging paradigm. Curr Opin Gastroenterol. 2008;24:215-222.  [PubMed]  [DOI]
4.  Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med. 1999;27:2799-2805.  [PubMed]  [DOI]
5.  Cerantola Y, Hübner M, Grass F, Demartines N, Schäfer M. Immunonutrition in gastrointestinal surgery. Br J Surg. 2011;98:37-48.  [PubMed]  [DOI]
6.  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;286:944-953.  [PubMed]  [DOI]
7.  Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer: a meta-analysis of randomized controlled clinical trials. Ann Surg. 1999;229:467-477.  [PubMed]  [DOI]
8.  Waitzberg DL, Saito H, Plank LD, Jamieson GG, Jagannath P, Hwang TL, Mijares JM, Bihari D. Postsurgical infections are reduced with specialized nutrition support. World J Surg. 2006;30:1592-1604.  [PubMed]  [DOI]
9.  Zheng Y, Li F, Qi B, Luo B, Sun H, Liu S, Wu X. Application of perioperative immunonutrition for gastrointestinal surgery: a meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr. 2007;16 Suppl 1:253-257.  [PubMed]  [DOI]
10.  Lochs H, Dejong C, Hammarqvist F, Hebuterne X, Leon-Sanz M, Schütz T, van Gemert W, van Gossum A, Valentini L, Lübke H. ESPEN Guidelines on Enteral Nutrition: Gastroenterology. Clin Nutr. 2006;25:260-274.  [PubMed]  [DOI]
11.  Lawrence VA, Cornell JE, Smetana GW. Strategies to reduce postoperative pulmonary complications after noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med. 2006;144:596-608.  [PubMed]  [DOI]
12.  Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.  [PubMed]  [DOI]
13.  Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.  [PubMed]  [DOI]
14.  Heslin MJ, Latkany L, Leung D, Brooks AD, Hochwald SN, Pisters PW, Shike M, Brennan MF. A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg. 1997;226:567-577; discussion 577-580.  [PubMed]  [DOI]
15.  Klek S, Kulig J, Sierzega M, Szybinski P, Szczepanek K, Kubisz A, Kowalczyk T, Gach T, Pach R, Szczepanik AM. The impact of immunostimulating nutrition on infectious complications after upper gastrointestinal surgery: a prospective, randomized, clinical trial. Ann Surg. 2008;248:212-220.  [PubMed]  [DOI]
16.  Chen DW, Wei Fei Z, Zhang YC, Ou JM, Xu J. Role of enteral immunonutrition in patients with gastric carcinoma undergoing major surgery. Asian J Surg. 2005;28:121-124.  [PubMed]  [DOI]
17.  Jiang XH, Li N, Zhu WM, Wu GH, Quan ZW, Li JS. Effects of postoperative immune-enhancing enteral nutrition on the immune system, inflammatory responses, and clinical outcome. Chin Med J (Engl). 2004;117:835-839.  [PubMed]  [DOI]
18.  Daly JM, Lieberman MD, Goldfine J, Shou J, Weintraub F, Rosato EF, Lavin P. Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome. Surgery. 1992;112:56-67.  [PubMed]  [DOI]
19.  Schilling J, Vranjes N, Fierz W, Joller H, Gyurech D, Ludwig E, Marathias K, Geroulanos S. Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions. Nutrition. 1996;12:423-429.  [PubMed]  [DOI]
20.  Gunerhan Y, Koksal N, Sahin UY, Uzun MA, Ekşioglu-Demiralp E. Effect of preoperative immunonutrition and other nutrition models on cellular immune parameters. World J Gastroenterol. 2009;15:467-472.  [PubMed]  [DOI]
21.  Braga M, Gianotti L, Nespoli L, Radaelli G, Di Carlo V. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg. 2002;137:174-180.  [PubMed]  [DOI]
22.  Xu J, Zhong Y, Jing D, Wu Z. Preoperative enteral immunonutrition improves postoperative outcome in patients with gastrointestinal cancer. World J Surg. 2006;30:1284-1289.  [PubMed]  [DOI]
23.  Finco C, Magnanini P, Sarzo G, Vecchiato M, Luongo B, Savastano S, Bortoliero M, Barison P, Merigliano S. Prospective randomized study on perioperative enteral immunonutrition in laparoscopic colorectal surgery. Surg Endosc. 2007;21:1175-1179.  [PubMed]  [DOI]
24.  Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003;326:1167-1170.  [PubMed]  [DOI]