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Nutrición Hospitalaria

versión On-line ISSN 1699-5198versión impresa ISSN 0212-1611

Nutr. Hosp. vol.26 no.1 Madrid ene./feb. 2011




Revising concepts of artificial nutrition in contemporary surgery: from energy and nitrogen to immuno-metabolic support

Revisando los conceptos en nutrición artificial en la cirugía contemporánea



L. Gianotti1 and M. Braga2

1Department of Surgery. Milano-Bicocca University. S. Gerardo Hospital. Monza. Italy.
2Deparment of Surgery. S. Raffaele University. Milan. Italy.





Profound changes in perioperative management, namely "fast track surgery" have been recently proposed. This is a bundle of various techniques used for subjects undergoing elective operations that allows an improved well-being, faster recovery, shorter hospitalization and better outcome. From a nutritional point of view this new approach translates into a more rapid return of bowel function and thus to safely tolerate oral re-feeding within 1-3 days even after major operations. Nevertheless, the classic indications for perioperative artificial nutritional support remain valid but they should now apply only to a minority of patients.
Extensive research in the last 20 years has clearly shown that modifying the composition of standard nutritional feeds by adding supernormal doses of specific substrates that have immuno-modulatory, anti-inflammatory, anabolic, and tissue protective ability often translates into improved surgical outcome. The most convincing and reproducible results were obtained on the reduction of infectious complication by the perioperative use of enteral formulas enriched with arginine and omega-3 fatty acids.

Key words: Surgery. Fast track. Artificial nutrition. Immunonutrition. Glutamine. Probiotics. Glucose metabolism. Outcome. Complications.


Recientemente, se han propuesto cambios notables en el manejo perioperatorio, denominado «cirugía du curso rápido». Esto es un conjunto de técnicas diversas empleadas en individuos sometidos a cirugías programadas que permiten una mejora del bienestar, una recuperación más rápida, una hospitalización más corta y mejores resultados. Desde un punto de vista nutricional, este nuevo abordaje se traduce en una recuperación más rápida de la función intestinal y, por lo tanto, tolerar de forma segura la realimentación n 1-3 días, incluso después de intervenciones mayores. Sin embargo, las indicaciones clásicas del soporte nutricional artificial perioperatorio siguen siendo válidas pero serían aplicables hoy en día a una minoría de pacientes.
La extensa investigación de los últimos 20 años ha demostrado claramente que la modificación de la alimentación nutricional estándar añadiendo dosis supranormales de sustratos específicos que poseen propiedades inmunomoduladoras, antiinflamatorias, anabólicas y protectoras de los tejidos a menudo se traduce en una mejora del resultado quirúrgico. Los resultados más convincentes y reproducibles se obtuvieron con la reducción de las complicaciones infecciosas mediante el uso perioperatorio de fórmulas enterales enriquecidas con arginina y ácidos grasos omega-3.

Palabras clave: Cirugía. Curso rápido. Nutrición artificial. Inmunonutrición. Glutamina. Probióticos. Metabolismo de la glucosa. Resultado. Complicaciones.



In the last years, profound changes in the perioperative management have been proposed and proven, in several randomized clinical trials, to be effective in enhancing patient recovery and improving outcome after surgery.1-6 Most of these new protocols were originally proposed and implemented by Kehlet and colleagues. 7-9 This innovative approach to patient care, namely "fast track surgery" is a bundle of various techniques used for subjects undergoing elective operations ith the aim of controlling surgery-related stress response and organ dysfunction. The method includes everal interventions. Among the most important are: use of epidural anaesthesia, minimally invasive surgical techniques, prevention of hypothermia and perioperative fasting, optimal pain control, intravenous fluid restriction, minimum use or early removal of drains, naso-gastric tube, and catheters, early mobilization and ambulation.7-11 From a nutritional point of view this approach allows a faster recovery of bowel function and thus the possibility to tolerate normal food by mouth within 1-2 days after colorectal surgery1-11 and even 2-3 days after upper GI major operations.12-14 Consequently, the classic indications for perioperative artificial nutritional support, that howbeit remain valid, should now apply only to a minority of patients. These are predominantly subjects who are at high risk of developing complications after surgery, such as patients who have suffered substantial preoperative weight loss, have very low body mass index (BMI) or exhibit an hyperinflammatory state. Once patients have developed complications impairing the resumption of oral feeding or affecting the metabolic homeostasis, artificial nutritional support is generally required.


The classic artifical nutritional support: energy and nitrogen substrates

Surgery, like any injury to the body, elicits a series of reactions including release of stress hormones and inflammatory mediators. This relase of mediators to the circulation has a major impact on body metabolism. They cause catabolism of glycogen, fat and protein with release of glucose, free fatty acids and amino acids into the circulation, so that substrates are in part diverted from the purposes they serve in the nonstressed state (i.e. physical activity) to the task of raising an adequate organ function and healing response. For optimal organ function, rehabilitation and wound ealing, the body needs to be nourished adequately to obilise enough substrates, largely derived from muscle and adipose tissue, with nutritional support to allow synthesis of acute phase proteins, white cells, fibroblasts, collagen and other tissue components of the wounded area. Thus, in surgical patients the main goals of nutritional support are to reduce consumption of self energy stores and minimize negative protein balance, with the purpose of maintaining tissue and organ functions.

The preoperative nutritional support

It is now well established and documented that severe undernutrition is an independent factor for the occurrence of postoperative complications, as well as increased mortality, length of hospital stay, and sanitary costs.15-20 Moreover, undernutrition is often associated with other diseases such as cancer, chronic inflammation or organ dysfunction which further expose patients to increased surgical risk.

A period of preoperative nutritional support of at least 7-10 days before surgery is recommended21-23 if a patient exhibits one or more of the following conditions: weight loss > 15% within 3-6 months, BMI < 18 kg/m2, albumin < 30 g/L (with no evidence of hepatic or renal dysfunction), or grade C at the subject global assessment.24

The postoperative nutritional support

Inadequate oral intake for more than two weeks after major operations is associated with a significant increase of morbidity and mortality.25 Even shorter periods of starvation or insufficient caloric and protein intake are strongly correlated with worse surgical outcome.26

Therefore, several guidelines21-23 recommend to administer artificial nutrition immediately after surgery when patients are expected not to meet their caloric requirement within 7-10 days in the postoperative course independently from their preoperative nutritional status. Artificial nutrition is also recommended as soon as possible when a patient has developed complications impairing the resumption of oral feeding or affecting the metabolic homeostasis such as sepsis.

Striking scientific evidences offered by fast track surgery implementation have shown that oral re-feeding very shortly after major surgery is safe and feasible in most of the patients undergoing colorectal, gynaecologic, urologic and pelvic operations1-11 as well in upper gastrointestinal procedures such as laryngectomy with primary pharyngeal closure, gastric, pancreatic, and hepato-biliary resection.12-14 Thus, the number of patients routinely requiring postoperative nutritional support is progressively declining.

Oral intake can be carried out with normal food or liquid oral nutritional supplements (ONS) according to individual tolerance and gastrointestinal function.26-31 ONS may have the advantages of having more calories and proteins than normal food for matching volume.

Nevertheless, there are clinical situations where early postoperative oral intake can be still contraindicated or difficult to achieve such as major trauma, unconsciousness states, swelling impairment, partial intestinal obstruction or prolonged ileus, or delayed gastric emptying. In these patients surgeons should consider the placement of a feeding jejunostomy or naso-jejunal tube at the time of surgery or in the postoperative course.

The route of feeding

When AN is indicated, the enteral route should be preferred to the parenteral one. This recommendation is now undersigned by all international guidelines21-23 because enteral feeding is considered more physiological, cheaper, and associated with better outcome particularly in undernourished, critically ill and trauma patients.32-38 The use of total parenteral nutrition (TPN) should be restricted to the following circumstances: in undernourished patients in whom enteral nutrition is not feasible or not tolerated; in patients with postoperative complications impairing gastrointestinal function who are unable to receive and absorb adequate amounts of enteral feeding for at least 7-10 days; in patients with suspected intestinal ischemia or hypoperfusion; in patients with high output (> 600 mL) intestinal fistulae.

The combination of enteral and parenteral nutrition should be considered in patients in whom at least 60% of energy needs cannot be met via the enteral route.

In completely obstructing lesions, surgery should not be postponed because of the risk of aspiration or severe bowel distension leading to bacterial translocation and peritonitis.

In patients with shock of any cause, AN (both enteral and parenteral) is not indicated until complete correction of the vital functions has been obtained.

Energy and nitrogen requirement

In acute and chronic disease the resting metabolic rate is elevated above the values calculated by the Harris-Benedict equations. The degree of hypermetabolism is on average not more than 110-120% of predicted.39-42 Only during selected situations such as major burn injury, severe sepsis, and major trauma this value may be increased substantially to 160-180%.41,43-45

Therefore, 25 kcal/kg of ideal body weight furnish an approximate estimate of daily energy expenditure and requirements, and under conditions of severe stress requirements may approach 30 kcal/kg of ideal body weight.

The main consideration when giving energy, particularly during parenteral nutrition is to avoid overfeeding.42,46,47 This is mostly true in severely undernourished subjects. To avoid this problem, calorie and nitrogen requirement should be calculated with indirect calorimetry or based on usual body weight. Moreover, in such cachectic patients care should be taken to increase the amount of calories and protein slowly to prevent the refeeding syndrome. Hyperalimentation is known to increase energy expenditure, oxygen consumption and carbon dioxide production48,49 and especially in patients with low cardiac and respiratory reserve these effects may be deleterious.50 In addition, hyperalimentation may induce fatty liver and lead to hypertriglyceridemia with harmful effects on immune function. Thus, at present, it is recommended to maintain the glucose:fat calorie ratio at 60:40 or even 70:30 of the non-protein calories. When fluid restriction is indicated a 50:50 ratio is accepted.

It is well established that muscle protein degradation during stress conditions is regulated by pro-inflammatory modulators like tumour necrosis factor-alpha, interleukin 1, 6 and others, and therefore cannot be or only partially reversed by nutrition.51-54 The value of nutritional support comes instead from its support of protein synthesis in the muscle limiting net whole body protein loss, in the liver yielding acute phase proteins, and in the immune system yielding white cells crucial in the response to trauma or disease. As for energy need, protein/nitrogen requirement should be calculated on the basis of ideal body weight. Proteins and amino acids given enterally and parenterally are used by the host in part for anabolic pathways and to some extent to produce energy. Therefore, the caloric rate of nitrogen should be included in the calculation of the total calorie required.

In illness/stressed conditions a daily nitrogen delivery equivalent to a protein intake of 1.5 g/kg ideal body weight (or approximately 20% of total energy requirements) is generally effective to limit nitrogen losses.


The metabolic and immune support: the new targets of nutritional therapy

Although the above concepts and indications of classic AN remain valid, extensive clinical research in the last 20 years has clearly shown that perioperative administration of supernormal doses of specific nutritional substrates may have immuno-modulatory, antiinflammatory, anabolic, and tissue protective ability and this often translate into improved surgical outcome when compared with standard nutritional formulas or traditional treatment protocols. For this reason this new area of nutritional therapy has been generically named immunonutrition or pharmaconutrition.

The use of preoperative carbohydrate load and glucose metabolism

Recent strong evidences show that fasting patient overnight before elective surgery is useless. In fact, free intake of clear fluids until 2 hours before anaesthesia is safe and beneficial in most of the subjects55-57 and does not increase the risk of aspiration except for those patients with impaired gastric outlet or proven gastroesophageal reflux. Allowing patients to drink relieves the feeling of thirst that many patients experience before surgery. Even more important are the metabolic effects of undergoing surgery in a non-fasted state.58

A fed state may be induced prior to elective surgery by providing a carbohydrate load. The induced changes in metabolism upon entering surgery has been shown to have several effects on the response to the operation. In particular, studies have reported positive effects in the postoperative recovery period such as improved protein balance,59 improved preservation of lean body mass60 and muscle strength61 and reduced length of hospital stay after operation.62,63 Moreover, for those patients without contraindication to free intake of fluids, carbohydrate drinks has been also shown to minimise insulin resistance, postoperative hyperglycaemia, heighten insulin sensitivity, reduce stress response, anxiety and postoperative nausea and vomiting in general and orthopaedic surgery, and to be cardioprotective in cardiac surgery.64-66 A recent large randomized trial by Mathur et al., did not confirm a beneficial role of preoperative carbohydrate loading on fatigue and discomfort, glucose metabolism, insulin resistance, muscle strength, protein synthesis and postoperative morbidity and length of hospitalization in abdominal surgery.67

The overwhelming majority of the data available in this field is based on studies in non-diabetic patients.

When given orally, the drink is a mixture of complex carbohydrates, i.e. maltodextrins, in a concentration of about 12% in a volume of 400-800 mL and dispensed between the evening before operation and 2 hrs before anaesthesia induction.68,69

For those who cannot eat or are not allowed to drink preoperatively for whatever reason, a glucose infusion at a rate of 5 mg/kg/min will have very similar effects on postoperative insulin resistance. When given intravenously, carbohydrate loading is achieved using a glucose solution with a higher concentration, usually 20%, to administer a sufficient quantity in a low volume to ensure a sufficient insulin response.70 Studies where i.v. glucose loading or oral carbohydrate intake alone or in combination with other nutrients or insulin have been reviewed in more detail in recent years.58,62,71-78

In patients with normal glucose tolerance, preoperative glucose administration will also ensure glycemic control when greater quantities of glucose are infused (i.e. earlier postoperative AN) without the development of hyperglycaemia.79

Since hyperglycaemia is one of the most important independent factor for the development of postoperative complications (in particular infectious one),80-82 it will be challenging to see, in future large randomized trial, if preoperative carbohydrate loading and subsequent better control of glucose metabolism will be associated with a significant decrease of septic morbidity after major elective surgery.

The use of nutritional substrates with immune modulating activity

Extensive laboratory and clinical research in the last 30 years has shown that there are nutritional substrates affecting the host response to injury. Among the most studied are: glutamine, arginine, and omega-3 fatty acids. Their mechanisms of action have been reviewed by several Authors.83-85

Formulas containing multiple substrates may have conceptual limitations. In fact, it is impossible to fully understand the potential mechanism of protection of these multiple component diets and to attribute a specific biologic effect to each single substrate. Moreover, it may be that a fix formulation is not the optimal one in all type of patients and in the various phases of the post-operative or post-injury course. Nevertheless, pragmatically speaking it was important to test if the clinical use of these diets could offer some true outcome advantages over standard formulas.

The use of formulas enriched with different mixtures of such nutrients in the clinical arena is still under investigation, but there are now sufficient data to strongly suggest the routine use in some cohort of surgical patients.21,22,86-88

Several Authors have consistently highlighted that some these new diets may improve host defense mechanisms and effectively modulate the inflammatory response.89-92 In particular, patients receiving supplemented formulas had a significant higher lymphocyte T and B count and improved function, increased levels of immunoglobulins, CD4+ cells, IL-2 and its receptors, phagocytosis ability of macrophages, delayedtype hypersensitivity response to skin tests. Decreased plasma levels of proinflammatory cytokines (IL-6, TNF-alpha) and eicosanoids, and nitrogen loss have been reported.

The first clinical experiences with immunonutrition were focused, for technical reasons, on postoperative infusion. A series of trials showed that this approach was moderately effective in reducing complications. Daly and colleagues, in two subsequent studies,90,93 were the first to report that the postoperative administration of an immune-enhancing formula, containing arginine, omega-3 fatty acids and RNA, significantly reduced the infection rate of more than 50% compared to standard enteral diets. However, in one of those studies,90 the control diet was not isonitrogenous compared to the experimental formula. In three large subsequent trials94-96 these advantages on morbidity by postoperative immunonutrition were not fully confirmed. In particular, an Italian trial94 showed 15% infectious complications in the group receiving immunonutrition and 23% in the group receiving the standard diet (p NS). Instead, the severity of the septic episodes (as measured by sepsis score) was significantly lower in the immunonutrition group than in the control group. Length of postoperative stay (LOS) was 16 days versus 19 days respectively (p = 0.01). More pronounced effects of postoperative immunonutrition were found in subgroups of high risk surgical patients such as malnourished or receiving homologous blood transfusion. 97 These results were confirmed in head and neck cancer patients.98

A multicenter German trial95 reported similar results, in a similar population, with an overall complication rate of 22% in the patients treated with postoperative enteral immunonutrition versus 31% in the control group (p NS). However, the Authors found, in the treated group, a significant reduction of infections occurring after postoperative 5. The mean LOS was shorter in the immunonutrition group than in the controls (27 versus 30.6 days).

An American trial by Heslin et al.96 did not find any difference in postoperative complications by comparing groups of GI cancer patients postoperatively Artificial nutrition treated with either immune-enhancing diet or simple crystalloid and fluid replacement. The treated patients had 44% complication rate versus 33% in the control group. Also the median LOS was similar in the two groups (11 versus 10 days respectively). It was noteworthy that in the treated group the average intake of immune-nutrients was very limited, approximately 30% of the nutritional goal.

More recent publications confirmed previous results showing that the benefits of postoperative administration of immune-enhancing diets compared to standard enteral feeds were sparse.99,100 Noteworthy, in a randomized study by Farreras et al.,101 patients with gastric cancer receiving postoperative enteral immunonutrition, exhibited an higher wound deposition of hydroxyproline (59.7 nmol vs. 28.0 nmol P = 0.0018) and a significant lower rate of surgical wound healing complications (0% vs. 26.7%; P = 0.005) when compared to patients fed with the control formula. These findings might also account for the lower rate of anastomotic leak found in patients treated with immunonutrition.88

All the above trials underlined somehow the intrinsic limitation of the postoperative approach to the issue of enteral immunonutrition. If it is believed that these nutrients have pharmacological effects, it should be also clear that to obtain positive results, adequate plasma and tissue levels need to be accomplished at the time of operation and in the early postoperative course. Enteral nutrition requires a progressive increase of the infusion rate during the first 3-4 days after injury to be tolerated and reach the full strength. Thus, however enteral feeding is begun early postoperatively, the amount of immuneenhancing substrates given in the first days might be insufficient to elicit a prompt modulation of the host response. Yet, the first days after surgery represent the critical "window" for the development of infectious complications because during this period the injuryinduced immunosuppression is maximal.

Conceptually a more rational approach is to anticipate the administration of immuno-enhancing diets before an operation to obtain efficacious concentrations of immunonutrients both at the time of surgical injury and in the early postoperative phase. This approach was technically possible when oral formulation of these feeds became available on the market.

In phase II RCTs102-104 patients receiving immunonutrition before and after surgery (perioperative approach) exhibited a more controlled postoperative depression of both polymorphonuclear cells and lymphocyte function, an attenuation of the post-operative exuberant inflammatory response and an improved intraoperative gut microperfusion and intramucosal jejunal pH. In patients perioperatively fed with a supplemented or a standard diet, our group also evaluated the in vivo intestinal tissue oxygen pressure that was measured during the entire surgical procedure and afterward. The results showed that immunonutrition was capable of markedly improving the splanchnic oxygen supply during surgery and throughout the 7 post-operative days.

These findings were probably due to adequate plasma and tissue concentrations of the immunonutrients already being available at the time of surgical stress and thus stimulated further trials to evaluate the possible benefit of perioperative immunonutrition on outcome.

A study by McCarter et al.105 evaluated the effect of a seven-day preoperative oral supplementation with diets enriched either in arginine, arginine plus omega-3 PUFAs or placebo in patients scheduled to undergo surgery for GI cancer. They did not find any difference for T cell function, eicosanoid production, proinflammatory cytokine levels and postoperative infection rate among groups. The Authors themselves suggested that the small sample size (approximately 12 patients per group), the lack of demonstrability of correct oral intake and absorption of substrates, did not allow any firm conclusion. Different results were obtained in two large randomized controlled double-blind phase 3 trials, carried out in patients with gastrointestinal malignancy. The first study106 enrolled 206 patients who were randomized to drink 1 liter/day of either a control diets or the same formula enriched with arginine, omega-3 fatty acids and RNA for 7 days before operation. Jejunal infusion with the same diets was started 6 hours after surgery and continued until postoperative day 7. Intent-to-treat analysis showed a 14% infectious complication rate in the supplemented group versus 30% in the control group (p = 0.009). LOS was 11 versus 13 days respectively. The second trial107 was performed in 154 patients who were treated with a very similar perioperative nutritional protocol as above. Also in this study, significantly fewer infectious complications occurred in the immunonutrition group compared to the control group (14 versus 27; p = 0.05).

Some trials also addressed the cost-effectiveness analysis of immunonutrition because the high cost on these new enriched formulas represents a major concern and it may be considered a major drawback for their wide and routine use. In our study108 the cost of perioperative immunonutrition was substantially higher than standard enteral diet (347 euros and 104 respectively). However, this additional cost of immuno-enhancing diet was largely overcompensated by the substantial reduction (about 2,400 euros per complication-free patient) of health care resources consumed to treat postoperative infections. Moreover, the total costs to manage postoperative complications represents a 7.5% consumption of the Disease-related-group reimbursement rate in the immunonutrition group versus 23.1% in the control group. These economic findings were consistent with the data reported in other studies.107,109 Yet none of the mentioned trials106,107 was designed to randomize separately malnourished and well-nourished patients. Thus, we run a subsequent post-hoc analysis showing that immunonutrition was effective in reducing post-operative complications regardless the baseline nutritional status. Moreover, we observed in an additional post-hoc analysis that the patients receiving only pre-operative immunonutrition, because non-compliant to post-operative enteral infusion had a significant reduction of morbidity, suggesting that the simple pre-operative approach might be sufficient to improve outcome when compared to standard diet. To better understand the impact of perioperative immunonutrition on outcome, in both malnourished patients (weight loss > 10%) and well-nourished (weight loss < 10%) patients, we designed two new prospective studies. In the first trial110 well-nourished patients (n = 305) were randomized to receive: no peri-operative nutritional support (group A), only pre-operative oral immunonutrition (group B), or peri-operative enteral immunonutrition (group C). The overall postoperative morbidity was 31% in group A, 14% in group B, and 16% in group C (p = 0.03), and LOS was 14.0 days, 11.6, and 11.2 respectively (p = 0.01). The protective effect of preoperative immunonutrition was shown also in a subgroup of obese patients which should be considered at high surgical risk despite they do not experience weight loss. This is probably due to the ability of immunonutrients to control the metabolic syndrome and the hyperinflamatory state that characterize obese subjects.

In the second trial,111 malnourished patients (n = 150) were randomized to receive three different nutritional regimens: only post-operative standard enteral nutrition (group A), pre-operative oral immunonutrition plus post-operative standard enteral nutrition (group B), or peri-operative enteral immunonutrition (group C). The results showed that the rate of complication was 42% in group A, 28% in group B, and 18% in group C (p = 0.02) and LOS was 15.3 days, 13.2, and 12.0 respectively (p = 0.01). These data suggest that the simple preoperative oral supplementation with immunonutrition is the optimal approach in well-nourished patients, while the perioperative treatment should be preferred in malnourished subjects.

A further cost-effectiveness analysis confirmed that preoperative immunonutrition in well-nourished patients allowed a substantial and significant saving of health care resources when compared to standard treatment.112

In 2006 Waitzberg et al. performed a systematic review of published and unpublished clinical trials concerning the issue of immunonutrition.88 The results are summarized in table I.

The advantages of pre- or perioperative immuneenhancing diets on surgical outcomes have been subsequently confirmed in several subsequent trials113-119 but not in others.120

Also supernormal doses of glutamine, as a single key nutrient, has been studied extensively.

Exogenous glutamine supplementation might be important in critical, catabolic and stress conditions because there is a flux of endogenous glutamine from muscles to other tissues/organs with rapid cell turnover and metabolism, such as gut, bone marrow, brain, immune cells, and fibroblasts which use glutamine as their principal metabolic fuel.121 Patients receiving glutamine supplementation maintain glutamine tissue and plasma pool with improved immune response, increased protein synthesis, less negative nitrogen balance, preserved gut barrier structure and function, improved wound healing, reduced oxidative stress, and better glucose metabolism.121-125 Clinical benefits of intravenous glutamine supplementation have been reported in elective surgery, however this regimen has been tested in few underpowered trials. From these studies, Novak et al.,126 generated a meat-analysis with total of 220 elective surgical patients. They could demonstrated that the administration of glutamine dipeptide was associated with a significant reduction of complication rate (RR: 0.36, 95% CI: 0.14-0.92) and length of hospital stay (-3.54 days). A more recent meta-analysis by Zheng et al.,127 included 5 trials with a total of 215 patients. The combined analysis indicated that the use of glutamine dipeptide significantly reduced postoperative infective events (OR: 0.24, 95% CI: 0.06-0.93, p = 0.04) and duration of hospitalization (-3.55 days). A third meta-analysis128 evaluating studies performed in Asia and Europe reached similar conclusions.

More recently, glutamine supplementation was tested by Jo et al.,129 after pancreatoduodenectomy in 60 patients and showed no clinical advantages in terms of postoperative morbidity. All patients had cancer, the vast majority of them were well-nourished, and the dose of free glutamine was 0.20 g/kg/day. Oguz and colleagues130 used an association of high dose perioperative glutamine dipeptide (1g/kg/day) and enteral feeding in 109 patients undergoing elective colorectal surgery for cancer. Also in this report most of the patients had a normal nutritional status or mild malnutrition. They could show a significant reduction of wound infection and dehiscence and abdominal abscess formation with an associated reduction of hospitalization in the group receiving glutamine.

A large, Italian multicentre trial including 428 wellnourished patients candidate to elective major gastrointestinal surgery for cancer, did not confirm any clinical benefit of glutamine supplementation. Patients were randomized to receive either intravenous infusion of L-alanine-L-glutamine dipeptide (0.40 g/kg/day; equal to 0.25 g of free glutamine) (Ala-Glu group, n = 212), or no supplementation (control group, n = 216). Glutamine infusion begun the day before operation and continued postoperatively for at least five days. Overall postoperative complication rate was 34.9% in Ala-Glu and 32.9% in control group (p = 0.65). Infectious morbidity was 19.3% in Ala-Glu group and 17.1% in controls (p = 0.55). The rate of major complications was 7.5% in treated patients and 7.9% (17/216) in controls (p = 0.90). Mean length of hospital stay was 10.2 days vs. 9.9 days in treated and control subjects respectively (p = 0.90).131

The indication to glutamine supplementation in patients with severe weight loss and high risk of surgical morbidity still remains an open issue. They might represent cohorts with more elevated glutamine demand, increased glutamine metabolism, and/or baseline deficits.132 This subgroups of surgical patients may be more similar to critically ill and trauma patients in whom glutamine supplementation has been proven to decrease morbidity and mortality.133-135

The use of lipids in AN, particularly long-chain triglycerides (LCT), is not without metabolic effects. In fact, LCT may affect the physiologic response of the arterial vascular bed. Moreover, the consequences of n-6 poly-unsaturated fatty acids (PUFAs) administration on immune and inflammatory response remain controversial. A recent meta-analysis136 did not support an immunosuppressive effect of n-6 PUFAs while other systematic review showed that they have a pro-inflammatory effect and trials tend to show lower complication rates in patients receiving PN containing fewer of these fatty acids.137,138

In view of these considerations attempts have been made to reduce the long-chain PUFA content without a net loss of lipid calories. This has been obtained by replacing part of the lipid by medium-chain triglycerides (MCT), by administering synthetic lipids which consist of a glycerol backbone randomly esterified with MCT or LCT, or by a substantial replacement with n-9 LCT (olive oil). All such emulsions contain lower amounts of n-6 fatty acids and appear to have fewer immunological effects.138

Most of research has been focused on n-3 PUFAs which have a proven anti-inflammatory effect. In a blinded randomized trial by Kenler et al.139 studied 50 patients who were jejunally fed either an enteral diet containing a fish oil/medium-chain triglyceride structured lipid or a isocaloric diet for 7 days postoperatively. A 50% decline in the total number of gastrointestinal complications and infections as well as an improved liver and renal function was observed in the treated group.

When associated with gamma linolenic acid and given enterally in ICU, n-3 PUFAs have been shown in prospective randomized trials to improve pulmonary inflammation, to shorten days on the ventilator and overall ICU stay.140-142 In open label cohort studies, increasing dosage of n-3 PUFAs has been associated with reduced ICU stay following major abdominal surgery,143 and in a randomised trial inclusion of n-3 PUFAs in PN was associated with reduced overall hospital stay.144

Thus, at present there is some evidence that increasing the percent of lipids in favour of n-3 fatty acids particularly during TPN may benefit organ function and reduce length of stay in patients undergoing major surgery or admitted to the surgical ICU.145 However, these trends will need to be substantiated in adequately powered randomised trials.

The use of prebiotics, probiotics and synbiotics

Prebiotics, probiotics, and synbiotics may all be beneficial for the host by improving the characteristics of indigenous microflora. The composition and the equilibrium of microbiota are known to influence important host activities among them the local immune response and several intestinal metabolic traits.146-151

Despite, the effects of their administration has been intensively investigated in vitro, in animal models, in healthy volunteers, and in some human gastrointestinal diseases (i.e. inflammatory bowel diseases, alimentary allergy, infectious diarrhea, pouchitis, etc..)147-151 little is known on the possible cross-interactions among treatment, changes of intestinal flora and local immune response in surgical patients. Prebiotics, probiotics and synbiotics enriched enteral formulas were used in patients candidate to gastrointestinal operations with the aim of affecting microbiota that contains bacteria responsible for postoperative infections. The results of randomized clinical trials are conflicting with significant reduction of infection rate in upper gastrointestinal surgery152-154 and lack of clinical benefits in other type of operations and clinical settings.155-157 One trial by Reddy et al.,158 was selective for colorectal patients. They reported a synergistic positive effect of synbiotics, neomycin and bowel preparation on the prevalence of enterobacteriaceae colonization and bacterial translocation but these events were not associated with a significant reduction of septic morbidity. These studies have been reviewed by Van Santvoort and colleagues. 159 Part of the inconsistency in surgical outcome may be the substantial difference in study design, dose and strain, duration, period and combination of treatments.

We recently evaluated whether probiotics given perioperatively in patients undergoing colorectal resection for cancer may adhere to the colonic mucosa, reduce concentration of pathogens in stools and modulate intestinal immunity.160 Thirty-one subjects were randomly and blindly assigned to receive two doses/day either of placebo (group A; n = 10), or a mixture of Bifidobacterium longum (BB536) and Lactobacillus jonhsonii (La1) (concentration 107 CFU/dose; group B; n = 11), or the same mixture at a concentration of 109 CFU/dose (group C, n = 10) for three days before and three days after operation. During operation colonic mucosa and stool samples were harvested to evaluate the presence of BB536 and La1 by random amplified polymorphism DNA method.

The results showed that BB536 was never found at any of time-point studied. At surgery, La1 was recovered in 6 of 10 patients in either stools or biopsy in group C, in 3 of 11 in group B, and none in group A (p = 0.02 C vs. A). There was a linear correlation between dose given and number of adherent La1 (P = 0.01). The rate of mucosal colonization by enterobacteriaceae was 30% in C, 82% in B and 70% in A group (p = 0.03 C vs. B). Enterobacteriaceae count in stools was 2.4 ± 0.3 (log10 scale) in C, 4.2 ± 0.4 in B, and 4.5 ± 0.2 in A. Same trend was observed for colonizing enterococchi. We observed greater expression of CD3, CD4, CD8, naive and memory lymphocyte subsets in group C than A with a dose response trend (C > B > A). Treatment did not affect dendritic cell phenotype or activation, but after ex vivo stimulation with lpopolysaccharides, groups C and B had a lower proliferation rate compared to group A (P = 0.04). Moreover, dendritic phenotypes CD83-123, CD83-HLADR, and CD83-11c (markers of activation) were significantly less expressed in patients colonized with LA1 (p = 0.03 vs. not colonized).

At present there are stimulating but insufficient results to show consistent and reproducible benefits of prebiotics, probiotics and synbiotic administration in surgical patients. Further trials are warrant to understand if better results may be obtained by different single or mixture of probiotic strains, increased dose, prebiotics alone or synbiotic preparation, longer treatment period or different timing of administration. The future results should be taken in consideration before designing phase III trials.



Patients undergoing major abdominal operation may be safely and effectively managed with new protocols that avoid preoperative fasting and allow early return to oral feeding, enhance recovery and well-being, reduce hospitalization and improve outcome after surgery. These new strategies have substantially reduced the need of perioperative artificial nutritional support.

Evidences that nutritional formulas enriched with specific substrates may improve surgical outcome when compared to standard feeds, has profoundly changed the classic thought of simple perioperative energy and nitrogen support. The augmentation of the host immune response, the reduction of oxidative stress, the control of glucose metabolism, the protection of organ/tissue function, and the modulation of inflammatory response in the perioperative period should represent the new targets of nutritional therapy.



1. Khoo CK, Vickery CJ, Forsyth N, Vinall NS, Eyre-Brook IA. A prospective randomized controlled trial of multimodal perioperative management protocol in patients undergoing elective colorectal resection for cancer. Ann Surg 2007; 245: 867-872.         [ Links ]

2. Ionescu D, Iancu C, Ion D, Al-Hajjar N, Margarit S, Mocan L, Mocan T, Deac D, Bodea R, Vasian H. Implementing fast-track protocol for colorectal surgery: a prospective randomized clinical trial. World J Surg 2009; 33: 2433-2438.         [ Links ]

3. Muller S, Zalunardo MP, Hubner M, Clavien PA, Demartines N. A fast-track program reduces complications and length of hospital stay after open colonic surgery. Gastroenterology 2009; 136: 842-847.         [ Links ]

4. Serclova Z, Dytrych P, Marvan J, Nova K, Hankeova Z, Ryska OJ, Slegrova Z, Buresova L, Travnikova L, Antos F. Fast-track in open intestinal surgery: Prospective randomized study. Clinical Nutrition 2009; 28: 618-624.         [ Links ]

5. Basse L, Jakobsen DH, Bardram L, Billesbølle P, Lund C, Mogensen T, Rosenberg J, Kehlet H. Functional recovery after open versus laparoscopic colonic resection. A randomized, blinded study. Ann Surg 2005; 241: 416-423.         [ Links ]

6. Wind J, Polle SW, Fung Kon Jin PHP, Dejong CHC, Von Meyenfeldt MF, Ubbinkl DT, Gouma DJ, Bemelman WA. Systematic review of enhanced recovery programmes in colonic surgery. British Journal of Surgery 2006; 93: 800-809.         [ Links ]

7. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth 1997; 78 (5): 606-17.         [ Links ]

8. Kehlet H. Fast-track colorectal surgery. Lancet 2008; 371: 791-793.         [ Links ]

9. Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg 2008; 248: 189-198.         [ Links ]

10. Bisgaard T, Kehlet H. Early oral feeding after elective abdominal surgery—what are the issues? Nutrition 2002; 18: 944-948.         [ Links ]

11. Andersen HK, Lewis SJ, Thomas S. Early enteral nutrition within 24h of colorectal surgery versus later commencement of feeding for postoperative complications. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004080.         [ Links ]

12. Balzano G, Zerbi A, Braga M, Rocchetti S, Beneduce A, Di Carlo V. Fast-track recovery programme after pancreaticoduodenectomy reduces delayed gastric emptying. Br J Surg 2008; 95 (11): 1387-93.         [ Links ]

13. Lassen K, Kjaeve J, Fetveit T, Tranø G, Sigurdsson HK, Horn A, Revhaug A Allowing normal food at will after major upper gastrointestinal surgery does not increase morbidity: a randomized multicenter trial. Ann Surg 2008; 247 (5): 721-9.         [ Links ]

14. Seven H, Calis AB, Turgut S. A randomized controlled trial of early oral feeding in laryngectomized patients. Laryngoscope 2003; 113 (6): 1076-9.         [ Links ]

15. Velanovich V. The value of routine preoperative laboratory testing in predicting postoperative complications: a multivariate analysis. Surgery 1991; 109: 236-43.         [ Links ]

16. Jagoe RT, Goodship TH, Gibson GJ. The influence of nutritional status on complications after operations for lung cancer. Ann Thorac Surg 2001; 71: 936-43.         [ Links ]

17. Van Bokhorst-De van der Schuer, Van Leeuwen PA, Kuik DJ, Klop WM, Sauerwein HP, Snow GB, et al. The impact of nutritional status on the prognoses of patients with advanced head and neck cancer. Cancer 1999; 86: 519-27.         [ Links ]

18. Rey-Ferro M, Castano R, Orozco O, Serna A, Moreno A. Nutritional and immunologic evaluation of patients with gastric cancer before and after surgery. Nutrition 1997; 13: 878-81.         [ Links ]

19. Mohler JL, Flanigan RC. The effect of nutritional status and support on morbidity and mortality of bladder cancer patients treated by radical cystectomy. J Urol 1987; 137: 404-7.         [ Links ]

20. Bozzetti F, Gianotti L, Braga M, Di Carlo V, Mariani L. Postoperative complications in gastrointestinal cancer patients: the joint role of the nutritional status and the nutritional support. Clin Nutr 2007; 26: 698-709.         [ Links ]

21. Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F. ESPEN guidelines on parenteral nutrition: Surgery. Clinical Nutrition 2009; 28: 378-386.         [ Links ]

22. Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P. ESPEN guidelines on enteral nutrition: Surgery including organ transplantation. Clinical Nutrition 2006; 25: 224-244.         [ Links ]

23. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 26 (1 Suppl.): 1SA-138SA.         [ Links ]

24. Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status? JPEN 1987; 11 (1): 8-13.         [ Links ]

25. Sandstrom R, Drott C, Hyltander A, Arfvidsson B, Schersten T, Wickstrom I. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg 1993; 217: 185-95.         [ Links ]

26. Lewis SJ, Egger M, Sylvester PA, Thomas S. Early enteral feeding versus "nil by mouth" after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 2001; 323 (7316): 773-6.         [ Links ]

27. Jeffery KM, Harkins B, Cresci GA, Martindale RG. The clear liquid diet is no longer a necessity in the routine postoperative management of surgical patients. Am Surg 1996; 62 (3): 167-70.         [ Links ]

28. Reissman P, Teoh TA, Cohen SM, Weiss EG, Nogueras JJ, Wexner SD. Is early oral feeding safe after elective colorectal surgery? A prospective randomized trial. Ann Surg 1995; 222 (1): 73-7.         [ Links ]

29. Choi J, O´Connell TX. Safe and effective early postoperative feeding and hospital discharge after open colon resection. Am Surg 1996; 62 (10): 853-6.         [ Links ]

30. Detry R, Ciccarelli O, Komlan A, Claeys N. Early feeding after colorectal surgery. Preliminary results. Acta Chir Belg 1999; 99 (6): 292-4.         [ Links ]

31. Bronnimann S, Studer M, Wagner HE. Early postoperative nutrition after elective colonic surgery. Langenbecks Arch Chir 1998; 115: 1094-5.         [ Links ]

32. Doig GS, Heighes PT, Simpson F, Sweetman EA, Davies AR Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med 2009; 35 (12): 2018-27.         [ Links ]

33. Kudsk KA, Croce MA, Fabian TC et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992; 215 (5): 503-11.         [ Links ]

34. Meyenfeldt von M, Meijerink W, Roufflart M, Builmaassen M, Soeters P. Perioperative nutritional support: a randomized clinical trial. Clin Nutr 1992; 11: 180-6.         [ Links ]

35. Beier-Holgersen R, Boesby S. Influence of postoperative enteral nutrition on postsurgical infections. Gut 1996; 39 (96): 833-5.         [ Links ]

36. Braga M, Gianotti L, Gentilini O, Parisi V, Salis C, Di Carlo V. Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition. Crit Care Med 2001; 29 (2): 242-8.         [ Links ]

37. Mack LA, Kaklamanos IG, Livingstone AS, et al. Gastric decompression and enteral feeding through a double-lumen gastrojejunostomy tube improves outcomes after pancreaticoduodenectomy. Ann Surg 2004; 240 (5): 845-51.         [ Links ]

38. 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; 358 (9292): 1487-92.         [ Links ]

39. Chiolero R, Revelly JP, Tappy L. Energy metabolism in sepsis and injury. Nutrition 1997; 13 (Suppl. 9): 45S-51S.         [ Links ]

40. Reid CL. Nutritional requirements of surgical and critically-ill patients: do we really know what they need? Proc Nutr Soc 2004; 63: 467-72.         [ Links ]

41. Zauner A, Schneeweiss B, Kneidinger N, Lindner G, Zauner C. Weight-adjusted resting energy expenditure is not constant in critically ill patients. Intensive Care Med 2006; 32: 428-34.         [ Links ]

42. Kan MN, Chang HH, Sheu WF, Cheng CH, Lee BJ, Huang YC. Estimation of energy requirements for mechanically ventilated, critically ill patients using nutritional status. Crit Care 2003; 7: R108-15.         [ Links ]

43. Berger MM, Binnert C, Chiolero R, Reeves C, Revelly JP, Cayeux MC et al. Trace element supplementation after major burns modulates antioxidant status and clinical course by way of increased tissue trace element concentrations. Am J Clin Nutr 2007; 85: 1293-300.         [ Links ]

44. Chiolero R, Schutz Y, Lemarchand T, Felber JP, de Tribolet N, Freeman J. Hormonal and metabolic changes following severe head injury or noncranial injury. J Parenter Enteral Nutr 1989; 13: 5-12.         [ Links ]

45. Chiolero RL, Breitenstein E, Thorin D, Christin L, De Tribolet N, Freeman J, et al. Effects of propranolol on resting metabolic rate after severe head injury. Crit Care Med 1989; 17: 328-34.         [ Links ]

46. Alexander JW, Gonce SJ, Miskell PW, Peck MD, Sax H. A new model for studying nutrition in peritonitis. The adverse effect of overfeeding. Ann Surg 1989; 209: 334-40.         [ Links ]

47. McClave SA, Lowen CC, Kleber MJ, Nicholson JF, Jimmerson SC, McConnell JW, Jung LY et al. Are patients fed appropriately according to their caloric requirements? J Parenter Enteral Nutr 1998; 22: 375-81.         [ Links ]

48. Muller TF, Muller A, Bachem MG, Lange H. Immediate metabolic effects of different nutritional regimens in critically ill medical patients. Intensive Care Med 1995; 21: 561-6.         [ Links ]

49. Liposky JM, Nelson LD. Ventilatory response to high caloric loads in critically ill patients. Crit Care Med 1994; 22: 796-802.         [ Links ]

50. Pimiento SK, Vergara A, Savino P, Rodríguez M, Escallon J. Hypocaloric support in the critically ill. World J Surg 1999; 23: 553-9.         [ Links ]

51. Ishibashi N, Plank LD, Sando K, Hill GL. Optimal protein requirements during the first 2 weeks after the onset of critical illness. Crit Care Med 1998; 26: 1529-35.         [ Links ]

52. Scheinkestel CD, Kar L, Marshall K, Bailey M, Davies A, Nyulasi I et al. Prospective randomized trial to assess caloric and protein needs of critically ill, anuric, ventilated patients requiring continuous renal replacement therapy. Nutrition 2003; 19: 909-16.         [ Links ]

53. Wolfe R, Goodenough RD, Burke JF, Wolfe MH. Response of protein and urea kinetics in burn patients to different levels of protein intake. Ann Surg 1983; 197: 163-71.         [ Links ]

54. Hart DW, Wolf SE, Chinkes DL, Ramzy PI, Obeng MK, Ferrando AA, Wolfe RR. Persistence of muscle catabolism after severe burn. Surgery 2000; 128: 312-9.         [ Links ]

55. Maltby JRYP. Fasting from midnight - the history behind the dogma. Best Pract Res Clin Anaesthesiol 2006; 20: 363-78.         [ Links ]

56. Brady M, Kinn S, Stuart P. Preoperative fasting for adults to prevent perioperative complications. Cochrane Database Syst Rev 2003; 4: CD004423.         [ Links ]

57. Ljungqvist O, Soreide E. Preoperative fasting. Br J Surg 2003; 90: 400-6.         [ Links ]

58. Ljungqvist O, Nygren J, Thorell A. Modulation of post-operative insulin resistance by pre-operative carbohydrate loading. Proc Nutr Soc 2002; 61: 329-36.         [ Links ]

59. Crowe PJ, Dennison A, Royle GT. The effect of pre-operative glucose loading on postoperative nitrogen metabolism. Br J Surg 1984; 71: 635-7.         [ Links ]

60. Yuill KA, Richardson RA, Davidson HI. The administration of an oral carbohydrate- containing fluid prior to major elective uppergastrointestinal surgery preserves skeletal muscle mass postoperatively - a randomised clinical trial. Clin Nutr 2005; 24: 32-7.         [ Links ]

61. Henriksen MG, Hessov I, Dela F, Hansen HV, Haraldsted V, Rodt SA. Effects of preoperative oral carbohydrates and peptides on postoperative endocrine response, mobilization, nutrition and muscle function in abdominal surgery. Acta Anaesthesiol Scand 2003; 47: 191-9        [ Links ]

62. Ljungqvist O. Preoperative nutrition - elective surgery in the fed or the overnight fasted state. Clin Nutr 2001; 20 (Suppl. 1): 167-71.         [ Links ]

63. Noblett SE, Watson DS, Huong H, Davison B, Hainsworth PJ, Horgan AF. Preoperative oral carbohydrate loading in colorectal surgery: a randomized controlled trial. Colorectal Dis 2006; 8: 563-9        [ Links ]

64. Breuer JP, von Dossow V, Von Heymann C, Griesbach M, Von Schickfus M, Mackh E et al. Preoperative oral carbohydrate administration to ASA III-IV patients undergoing elective cardiac surgery. Anesth Analg 2006; 103: 1099-108.         [ Links ]

65. Lazar H, Phillippides G, Fitzgerald C, Lancaster D, Shemin RJ, Apstein C et al. Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997; 113: 354-60.         [ Links ]

66. Oldfield GS, Commerford PJ, Opie LH. Effects of preoperative glucose-insulin- potassium on myocardial glycogen levels and on complications of mitral valve replacement. J Thorac Cardiovasc Surg 1986; 91: 874-8.         [ Links ]

67. Mathur S, Plank LD, McCall JL, Shapkov P, McIlroy K, Gillanders LK, Merrie AEH, Torrie JJ, Pugh F, Koea JB, Bissett IP, Parry BR. Randomized controlled trial of preoperative oral carbohydrate treatment in major abdominal surgery. Br J Surg 2010; 97: 485-494.         [ Links ]

68. Nygren J, Thorell A, Jacobsson H, Larsson S, Schnell PO, Hylen L et al. Preoperative gastric emptying. Effects of anxiety and oral carbohydrate administration. Ann Surg 1995; 222: 728-34.         [ Links ]

69. Wang ZG, Wang Q, Wang WJ, Qin HL. Randomized clinical trial to compare the effects of preoperative oral carbohydrate versus placebo on insulin resistance after colorectal surgery. Br J Surg 2010; 97: 317-327.         [ Links ]

70. Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism 1979; 28: 210-20.         [ Links ]

71. Ljungqvist O et al. Perioperative nutrition therapy - novel developments. Scand J Nutr 2000; 44: 3-7.         [ Links ]

72. Ljungqvist O, Nygren J, Thorell A. Insulin resistance and elective surgery. Surgery 2000; 128: 757-60.         [ Links ]

73. Ljungqvist O. To fast or not to fast? Metabolic preparation for elective surgery. Scand J Nutr 2004; 48: 77-82.         [ Links ]

74. Ljungqvist O, Nygren J, Soop M, Thorell A. Metabolic perioperative management: novel concepts. Curr Opin Crit Care 2005; 11: 295-9.         [ Links ]

75. Ljungqvist O. To fast or not to fast before surgical stress. Nutrition 2005; 21: 885-6.         [ Links ]

76. Nygren J, Thorell A, Ljungqvist O. Preoperative oral carbohydrate nutrition: an update. Curr Opin Clin Nutr Metab Care 2001; 4: 255-9.         [ Links ]

77. Nygren J, Thorell A, Ljungqvist O. New developments facilitating nutritional intake after gastrointestinal surgery. Curr Opin Clin Nutr Metab Care 2003; 6: 593-7.         [ Links ]

78. Soop M, Nygren J, Ljungqvist O. Optimizing perioperative management of patients undergoing colorectal surgery: what is new? Curr Opin Crit Care 2006; 12 (2): 166-70.         [ Links ]

79. Soop M, Carlson GL, Hopkinson J, Clarke S, Thorell A, Nygren J et al. Randomized clinical trial of the effects of immediate enteral nutrition on metabolic responses to major colorectal surgery in an enhanced recovery protocol. Br J Surg 2004; 91: 1138-45.         [ Links ]

80. Ramos M, Khalpey Z, Lipsitz S, Steinberg J, Panizales MT, Zinner M, Rogers SO. Relationship of perioperative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg 2008; 248: 585-591.         [ Links ]

81. Gustafsson UO, Thorell A, Soop M, Ljungqvist O, Nygren J. Haemoglobin A1c as a predictor of postoperative hyperglycaemia and complications after major colorectal surgery. Br J Surg 2009; 96: 1358-1364.         [ Links ]

82. Turina M, Miller FN, Tucker CF, Polk HC. Short-term hyperglycemia in surgical patients and a study of related cellular mechanisms. Ann Surg 2006; 243: 845-853.         [ Links ]

83. Roth E. Immune and cell modulation by amino acids. Clin Nutr 2007; 26 (5): 535-44.         [ Links ]

84. Coster J, McCauley R, Hall J. Glutamine: metabolism and application in nutrition support. Asia Pac J Clin Nutr 2004; 13: 25-31.         [ Links ]

85. Galli C, Calder PC. Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Ann Nutr Metab 2009; 55 (1-3): 123-39.         [ Links ]

86. Strickland A, Brogan A, Krauss J, Martindale R, Cresci G. Is the use of specialized nutritional formulations a cost-effective strategy? A national database evaluation. J Parenter Enteral Nutr 2005; 29 (1 Suppl.): S81-91.         [ Links ]

87. Consensus recommendations from the US summit on immune-enhancing enteral therapy. J Parenter Enteral Nutr 2001; 25 (2 Suppl.): S61-3.         [ Links ]

88. 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.         [ Links ]

89. Braga M, Vignali A, Gianotti L, et al. Immune and nutritional effects of early enteral nutrition after major abdominal operations. Eur J Surg 1996; 162: 105-112.         [ Links ]

90. Daly JM, Lieberman MD, Goldfine J et al. 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.         [ Links ]

91. Kemen M, Senkal M, Homann HH et al. Early postoperative enteral nutrition with arginine, omega-3 fatty acids and ribonucleic acidsupplemented diet versus placebo in cancer patients: an immunologic evaluation of Impact®. Crit Care Med 1995; 23: 652-659        [ Links ]

92. Senkal M, Kemen M, Homann HH et al. Modulation of postoperative immune response by enteral nutrition with a diet enriched with arginine, RNA, and omega-3 fatty acids in patients with upper gastrointestinal cancer. Eur J Surg 1995; 161: 115-122.         [ Links ]

93. Daly JM, Weintraub FN, Shou J et al. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg 1995; 221: 327-338.         [ Links ]

94. Gianotti L, Braga M, Vignali A et al. Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignancy. Arch Surg 1997; 132: 1222-1230.         [ Links ]

95. Senkal M, Mumme A, Eickhoff U et al. Early postoperative enteral nutrition: clinical outcome and cost-comparison analysis in surgical patients. Crit Care Med 1997; 25: 1489-1496.         [ Links ]

96. Heslin MJ, Latkany L, Lennig D et al. A prospective randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg 1997; 226: 567-577.         [ Links ]

97. Braga M, Gianotti L, Vignali A et al. Artificial nutrition after abdominal surgery: Impact of route of administration and composition of the diet. Crit Care Med 1998; 26: 24-30.         [ Links ]

98. Riso S, Aluffi P, Brugnani M et al. Postoperative enteral immunonutrition in head and neck cancer patients. Clin Nutr 2000; 19: 407-412.         [ Links ]

99. Gianotti L, Braga M, Gentilini O, Balzano G, Zerbi A, Di Carlo V. Artificial nutrition after pancreaticoduodenectomy. Pancreas 2000; 21(4): 344-51.         [ Links ]

100. 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 (2): 212-20.         [ Links ]

101. 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; 24 (1): 55-65.         [ Links ]

102. Braga M, Gianotti L, Cestari A et al. Gut function, immune and inflammatory responses in patients perioperatively fed with supplemented formulas. Arch Surg 1996; 131: 1257-1265.         [ Links ]

103. Gianotti L, Braga M, Fortis C et al. A prospective randomized clinical trial on perioperative feeding with arginine, omega-3 fatty acids, and RNA-enriched enteral diet: effect on host response and nutritional status. JPEN 1999; 23: 314-320.         [ Links ]

104. Braga M, Gianotti L, Vignali A, Di Carlo V. Immunonutrition in gastric cancer surgical patients. Nutrition 1998; 14: 831-835        [ Links ]

105. McCarter MD, Gentilini OD, Gomez ME et al. Preoperative oral supplementation with immunonutrients in cancer patients. JPEN 1998; 22: 206-211.         [ Links ]

106. Braga M, Gianotti L, Radaelli G et al. Perioperative immunonutrition in patients undergoing cancer surgery. Results of a randomized double-blind phase 3 trial. Arch Surg 1999; 134: 428-433.         [ Links ]

107. Senkal M, Zuntobel V, Bauer KH et al. Outcome and costeffectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized study. Arch Surg 1999; 134: 1309-1316.         [ Links ]

108. Gianotti L, Braga M, Frei A et al. Health care resources consumed to treat postoperative infections: cost saving by perioperative immunonutrition. Shock 2000; 14: 325-330.         [ Links ]

109. Snyderman CH, Kachman K, Molseed L et al. Reduced postoperative infections with an immune-enhancing nutritional support. Laryngoscope 1999; 109: 915-921.         [ Links ]

110. Gianotti L, Braga M, Nespoli L, Radaelli G, Beneduce A, Di Carlo V. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer. Gastroenterology 2002; 122: 1763-70.         [ Links ]

111. 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: 174-80.         [ Links ]

112. Braga M, Gianotti L, Vignali A, Schmid A, Nespoli L, Di Carlo V. Hospital resources consumed for surgical morbidity: effects of preoperative arginine and omega-3 fatty acid supplementation on costs. Nutrition 2005; 21 (11-12): 1078-86.         [ Links ]

113. Braga M, Gianotti L, Vignali A, Di Carlo V. Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer. Surgery 2002; 132: 805-14.         [ Links ]

114. Xu J, Zhong Y, Jing D, Wu Z. Preoperative enteral immunonutrition improves postoperative outcome in patients with gastrointestinal cancer. World J Surg 2006; 30 (7): 1284-9.         [ Links ]

115. Okamoto Y, Okano K, Izuishi K, Usuki H, Wakabayashi H, Suzuki Y. Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg 2009; 33 (9): 1815-21.         [ Links ]

116. Giger U, Büchler M, Farhadi J, Berger D, Hüsler J, Schneider H, Krähenbühl S, Krähenbühl L. Preoperative immunonutrition suppresses perioperative inflammatory response in patients with major abdominal surgery-a randomized controlled pilot study. Ann Surg Oncol 2007; 14 (10): 2798-806.         [ Links ]

117. Gunerhan Y, Koksal N, Sahin UY, Uzun MA, Ek ioglu-Demiralp E. Effect of preoperative immunonutrition and other nutrition models on cellular immune parameters. World J Gastroenterol 2009; 15 (4): 467-72.         [ Links ]

118. 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 (7): 1175-9.         [ Links ]

119. Celik JB, Gezginç K, Ozçelik K, Celik C. The role of immunonutrition in gynecologic oncologic surgery. Eur J Gynaecol Oncol 2009; 30 (4): 418-21.         [ Links ]

120. Helminen H, Raitanen M, Kellosalo J. Immunonutrition in elective gastrointestinal surgery patients. Scand J Surg 2007; 96 (1): 46-50.         [ Links ]

121. Roth E. Nonnutritive effects of glutamine. J Nutr 2008; 138: S2025-2031.         [ Links ]

122. Melis GC, ter Wengel N, Boelens PG et al. Glutamine: recent developments in research on the clinical significance of glutamine. Curr Opin Clin Nutr Metab Care 2004; 7: 59-70.         [ Links ]

123. Furst P, Alteheld B, Stehle P. Why should a single nutrientglutamine-improve outcome? Clin Nutr 2004: 1 (Suppl. 1): 13-15.         [ Links ]

124. Wishmeyer PE. Glutamine: mode of action in critical illness. Crit Care Med 2007; 35 (Suppl. 9): S541-544.         [ Links ]

125. Saito H, Furukawa S, Matsuta T. Glutamine as an immunoenhancing nutrients. J Parent Enter Nutr 1999; 23: S59-61.         [ Links ]

126. Novak F, Heyland DK, Avenell A et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002; 30: 2022-9.         [ Links ]

127. Zheng YM, Li F, Zhang MM et al. Glutamine dipeptide for parenteral nutrition in abdominal surgery: a meta-analysis of randomized controlled trials. World J Gastroenterol 2006; 12: 7537-41.         [ Links ]

128. Jiang Z-M, Jiang H, Furst P. The impact of glutamine dipeptides on outcome of surgical patients: systematic review of randomized controlled trials for Europe and Asia. Clin Nutr 2004: 1 (Suppl. 1): 17-23.         [ Links ]

129. Jo S, Choi SH, Heo JS et al. Missing effect of glutamine supplementation on the surgical outcome after pancreaticoduodenectomy for periampullary tumors: a prospective, randomized, double-blind, controlled clinical trial. World J Surg 2006; 30: 1974-82.         [ Links ]

130. Oguz M, Kerem M, Bedirli A et al. L-alanine-L-glutamine supplementation improves the outcome after colorectal surgery for cancer. Colorectal Dis 2007; 9: 515-20.         [ Links ]

131. Gianotti L, Braga M, Biffi R, Bozzetti F, Mariani L, for the GlutamItaly Research Group of the Italian Society of Parenteral and Enteral Nutrition. Perioperative intravenous glutamine supplemetation in major abdominal surgery for cancer. A randomized multicenter trial. Ann Surg 2009; 250 (5): 684-690.         [ Links ]

132. Van Acker BAC, Hulsewè KWE, Wagenmakers AJM et al. Response of glutamine metabolism to glutamine-supplemented parenteral nutrition. Am J Clin Nutr 2000; 72: 790-795.         [ Links ]

133. Houndijk APJ, Rijnsburger ER, Jansen J et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352: 772-776.         [ Links ]

134. Dechelotte P, Hasselmann M, Cynober L et al. L-alanyl-Lglutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind multicenter study. Crit Care Med 2006: 34: 598-604.         [ Links ]

135. Estivariz CF, Griffith DP, Luo M, et al. Efficacy of parenteral nutrition supplemented with glutamine dipeptide to decrease hospital infections in critically ill surgical patients. J Parenter Enteral Nutr 2008; 32: 389-402.         [ Links ]

136. Wirtitsch M, Wessner B, Spittler A, Roth E, Volk T, Bachmann L, Hiesmayr M. Effect of different lipid emulsions on the immunologic function in humans: a systematic review with meta-analysis. Clin Nutr 2007; 26: 302-13.         [ Links ]

137. Heyland DK, Montalvo M, MacDonald S, Keefe L, Su XY, Drover JW. Total parenteral nutrition in the surgical patient: a meta-analysis. Can J Surg 2001; 44: 102-11.         [ Links ]

138. Wanten G. An update on parenteral lipids and immune function: only smoke, or is there any fire? Curr Opin Nutr Metab Care 2006; 9: 79-83.         [ Links ]

139. Kenler, AS, Swails WS, Driscoll DF et al. Early enteral feeding in postsurgical cancer patients. Fish oil structured lipidbased polymeric formula versus a standard polymeric formula. Ann Surg 1996; 223: 316-333.         [ Links ]

140. Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral nutrition in ARDS study group. Crit Care Med 1999; 27: 1409-20.         [ Links ]

141. Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34: 1033-8.         [ Links ]

142. Pontes-Arruda A, Arago AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med 2006; 34: 2325-33        [ Links ]

143. Heller AR, Rossler S, Litz RJ, Stehr SN, Heller SC, Koch R et al. Omega-3 fatty acids improve the diagnoses-related clinical outcome. Crit Care Med 2006; 34: 972-9.         [ Links ]

144. Wichmann MW, Thul P, Czarnetzki HD et al. Evaluation of clinical safety and beneficial effects of a fish oil containing lipid emulsion (Lipoplus, MLF541): data from a prospective, randomized, multicentre trial. Crit Care Med 2007; 35: 700-6        [ Links ]

145. Calder PC. Hot topics in parenteral nutrition. Rationale for using new lipid emulsions in parenteral nutrition and a review of the trials performed in adults. Proc Nutr Soc 2009; 68 (3): 252-60.         [ Links ]

146. Holzapfel WH, Haberer P, Snel J et al. Overview of gut flora and probiotics. Int J Food Microbiol 2001; 41: 85-101.         [ Links ]

147. Hopper LV, Gordon JI. Commensal host-bacterial relationship in the gut. Science 2001; 292: 1015-8.         [ Links ]

148. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003; 361: 512-9.         [ Links ]

149. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nature Immunol Rev 2009; 9: 313-23.         [ Links ]

150. Romeo J, Nova E ,Wärnberg J, Gómez-Martínez S, Díaz Ligia DE, Marcos A. Immunomodulatory effect of fibres, probiotics and synbiotics in different life-stages. Nutr Hosp 2010; 25 (3): 341-349.         [ Links ]

151. Reid G, Jass J, Secùbulsky M et al. Potential use of probiotics in clinical practice. Clin Microbiol Rev 2003; 16: 658-72.         [ Links ]

152. Rayes N, Seehofer D, Theruvath T, et al. Effect of enteral nutrition and synbiotics on bacterial infection rates after pylorus-preserving pancreatoduodenectomy: a randomized, double blind trial. Ann Surg 2007; 246: 36-41.         [ Links ]

153. Sugawara G, Nagino M, Nishio H et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006; 244: 706-14.         [ Links ]

154. Kanazawa H, Nagino M, Kamiya S et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390: 104-13.         [ Links ]

155. Anderson AD, McNaught CE, Jain PK et al. Randomised clinical trial of synbiotic therapy in elective surgical patients. Gut 2004; 53: 241-5.         [ Links ]

156. McNaught CE, Woodcock NP, Anderson ADG, et al. A prospective randomised trial of probiotics in critically ill patients. Clin Nutr 2005; 24: 211-9.         [ Links ]

157. Besselink MG, van Santvoort HC, Buskens E et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis: a randomized, double-blind, placebo-controlled trial. Lancet 2008; 371: 651-9.         [ Links ]

158. Reddy BS, Macfie J, Gatt M et al. Randomized clinical trial of effect of synbiotics, neomycin and mechanical bowel preparation on intestinal barrier function in patients undergoing colectomy. Br J Surg 2007; 94: 546-54.         [ Links ]

159. Van Santvoort HC, Besselink MG, Timmerman HM et al. Probiotics in surgery. Surgery 2008; 143: 1-7.         [ Links ]

160. Gianotti L, Morelli L, Galbiati F, Rocchetti S, Coppola S, Beneduce A, Gilardini C, Zonenschain D, Nespoli A, Braga M. A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol 2010; 16 (2): 152-16.         [ Links ]



Luca Gianotti.
Department of Surgery (4.o piano B).
Ospedale San Gerardo.
Via Pergolesi, 33.
20052 Monza, Italy.

Recibido: 1-VIII-2010.
Aceptado: 2-IX-2010.

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