The impact of early nutrition on metabolic response and postoperative ileus Maria Isabel Toulson Davisson Correia and Rodrigo Gomes da Silva

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1 The impact of early nutrition on metabolic response and postoperative ileus Maria Isabel Toulson Davisson Correia and Rodrigo Gomes da Silva Purpose of review Early nutrition has been evaluated and used as a possible strategy to decrease the negative impact of the metabolic response to injury and postoperative ileus. The metabolic response to injury, be it surgical or traumatic, is a physiological mechanism that, according to the magnitude and duration of the event, can impact on the patient s morbidity and survival. The adequate initial approach is a determinant factor that might influence its outcome. Simultaneously, gastrointestinal tract motility is transiently impaired, leading to the so-called postoperative ileus. The latter not only causes patient discomfort, but is also related to abdominal complications and worsening of the nutritional status, as well as increased length of hospital stay and costs. Recent findings Multimodal surgical strategies such as preoperative intake of a carbohydrate drink, together with patient education of the postoperative care plan, efficacious analgesia and early nutrition have been described to significantly decrease the stress response and improve the ileus. Therefore, these strategies accelerate rehabilitation and, as a consequence, decrease complications and length of hospital stay and its related costs. Summary Understanding perioperative pathophysiology and implementing care regimes through a multimodal approach in order to reduce the stress of the operation and the related postoperative ileus are major challenges. These factors will certainly impact on patient outcomes. Keywords metabolic response, postoperative ileus, early nutrition, analgesia, multimodal approach Curr Opin Clin Nutr Metab Care 7: # 2004 Lippincott Williams & Wilkins. Federal University of Minas Gerais, Belo Horizonte, and Alfa Institute of Gastroenterology, Hospital das Clínicas, MG, Brazil Correspondence to Maria Isabel Toulson Davisson Correia MD PhD, Professor of Surgery, Rua Gonçalves Dias 332 apt. 602, Belo Horizonte, MG, , Brazil Tel: ; fax: ; isabel_correia@uol.com.br Current Opinion in Clinical Nutrition and Metabolic Care 2004, 7: # 2004 Lippincott Williams & Wilkins Introduction The importance of nutrition in surgery has been the focus of repeated randomized studies, metaanalyses, and reviews over recent years. However, the subject is still a matter of controversy, especially when considering its impact on metabolic response and postoperative ileus since many questions remain unanswered. Undergoing surgery after a carbohydrate load has been shown to be superior to the fasted state with regard to postoperative metabolism and insulin resistance [1]. Several experimental and clinical studies have demonstrated that early postoperative nutrition reduces gut permeability and presumed bacterial translocation, decreases the metabolic response and infection rates, and improves outcome [2 6]. Also, early postoperative feeding via oral or nasoenteric/ostomy administration of nutrients has been suggested as a way to decrease ileus. The logic behind early feeding is that food intake may stimulate a reflex that produces coordinated propulsive activity and elicits the secretion of gastrointestinal hormones, causing an overall positive effect on bowel motility. Its role remains unclear, however, because there are many other factors that influence postoperative ileus such as local intestinal inflammation, anesthesia and postoperative analgesia drug side effects, hydration, and patient early mobilization. Therefore, some studies support and others refute the benefit of early feeding in shortening postoperative ileus [7 10]. In the complicated and intricate web of the metabolic response and postoperative ileus, there is a tendency to view nutrition as a positive impact factor. Future studies with specific nutrients could further enlighten the effect of nutrition on these two conditions. In this review we assess the impact of early nutrition on metabolic response and postoperative ileus, among other factors that interfere with these conditions. We attempt to give those working with surgical patients a critical, practical and up-to-date regimen that might improve the patient s outcome and quality of life, as well as decreasing length of hospitalization and costs. The metabolic response The metabolic response is triggered by multiple stimuli, including arterial and venous pressure and volume, 577

2 578 Nutrition and the gastrointestinal tract osmolality, ph, arterial oxygen content, pain, anxiety, and toxic mediators from infection and tissue injury. These stimuli reach the hypothalamus and then stimulate the sympathetic nervous system and the adrenal medulla. Indeed, the metabolic response to stress is a physiological response to an insult that might become pathological depending on the intensity and duration of injury. Actually, the metabolic response can be seen as the fight or flight response to adverse phenomena that can become highly associated with increased morbidity and mortality if perpetuated for long periods. The ultimate goal of the metabolic response is to restore homeostasis. Intermediate goals are to limit further blood loss, to increase blood flow, allowing greater delivery of nutrients and elimination of waste products, to debride necrotic tissue, and to initiate wound healing. Although, one cannot fully go against the development of the metabolic response, recognizing its magnitude and knowing its different particularities might help minimize the risks of perpetuating its duration. Thus, a reduction of morbidity and mortality related to the metabolic response might be ensured. Indeed, mortality from prolonged critical illness is high: almost three out of 10 adult patients with an intensive care stay of more than 3 weeks do not survive [11]. Despite the fact that modern surgery has become less aggressive with the so-called minimal approach procedures, the incidence of trauma cases, by contrast, has greatly increased due to urban violence and wars. Thus, it is extremely important to be acquainted with the complex mechanisms of the stress response in order to act early and possibly prevent some of its deleterious effects. The magnitude of the response and the adequate initial approach are determinant factors that might influence the patient s outcome. Feeding and the metabolic response Nutrition has been attributed the role of a possible downregulator of the metabolic stress response. Both preoperative carbohydrate loading and early postoperative nutrition are possible strategies that can impact on a decreased metabolic response. Two recent studies in patients undergoing orthopedic [12] and major abdominal surgery [13 ] showed that patients in the carbohydrate-treated group displayed less hepatic insulin resistance and lower nitrogen losses 3 days after surgery [12], and less reduced muscle strength up to 1 month after surgery [13 ]. Postoperative insulin sensitivity and nitrogen balance during isocaloric nutrition were also achieved in the treated groups [13 ]. In addition, these patients maintained normal glucose control during postoperative enteral nutrition. This fact may also have implications on the clinical outcome since improved glucose control by insulin treatment in critically ill patients was shown to markedly decrease morbidity and mortality [14]. Contrary to fasting or restricted oral intake, which contributes to catabolism with loss of weight and skeletal muscle, early oral and enteral nutrition can ameliorate the metabolic response [15,16]. Several studies have shown that enteral nutrition improves albumin and globulin synthesis, lowers the levels of urinary catecholamine excretion, accelerates anastomotic wound healing and shortens hospitalization both in elective and trauma surgical patients [4 6,16,17]. However, feeding is rightfully feared as a double-edged sword. Two randomized studies concluded that early enteral nutrition was detrimental after abdominal elective operations due to intestinal intolerance translated by increased incidence of nausea, vomiting, abdominal distension and pulmonary effects, possibly secondary to abdominal distension [9,10]. Nonetheless, we may be able to minimize these negative side effects by titrating feeding according to the gut s reduced capability (postoperative ileus). As with sepsis and other techniques to reduce local and systemic trauma, surgeons are obligated to understand, protect, and maximally exploit their patients gastrointestinal function [18]. It has been shown that even in patients in whom quantitatively sufficient enteral nutrition is impossible, low amounts of enteral nutrients can help support intestinal functions (minimal enteral nutrition) [19]. Furthermore, nutrients known to enhance immunocompetence have been added to enteral diets in an attempt to decrease morbidity (mainly infectious complications) mortality, length of hospital stay and costs [20 22]. These nutrients seem to interfere with the inflammatory response by blocking important pathways. Further studies are needed, however, to advocate the routine use of these diets in all surgical patients in an attempt to attenuate the metabolic response. Postoperative ileus The definition of postoperative ileus has been a matter of confusion and controversy in the literature. Livingston and Passaro [23] defined ileus as the inhibition of propulsive bowel activity, irrespective of pathogenic mechanisms. Fanning and Yu-Brekke [24] defined postoperative ileus as bowel distention, decreased bowel sounds, and delay of defecation after surgical procedure. Resnick et al. [25] diagnosed postoperative ileus when the patient complained of nausea, emesis, bloating, or a sense of abdominal fullness. Conversely, Luckey et al. [26 ] described postoperative ileus as a physiological response following surgery, resolving spontaneously within 2 3 days, and paralytic postoperative ileus would be a form of ileus lasting more than 3 days after surgery (not necessarily abdominal surgery), caused by perpetuating or different mechanisms of the initial motility impairment. Sometimes ileus has been defined as diet

3 The impact of early nutrition Correia and da Silva 579 intolerance. For instance, DiFronzo et al.. [27 ] reported overall 78 of 87 patients (89.6%) tolerated early feeding. Five patients (5.7%) initially tolerated a diet but required readmission for ileus [page 747]. Thus, the authors directly related diet intolerance to ileus. This association leads to confusion in the definition of ileus, because herein lies the question: did only the five patients who had diet intolerance have ileus or did all 87 patients have ileus, but did not express it through clinical symptoms and signs? Indeed, postoperative ileus has been interchangeable and possibly inadequately defined as an expected physiologic change with or without symptoms and signs, or as a clinical state in which the patient does not tolerate feeding. These statements should not be used with the same objective of defining postoperative ileus for the following reasons. (1) There is, in fact, a physiologic response experienced by all patients and triggered by the surgical trauma and all other variables considered. (2) The clinical presentation (symptoms and signs) varies according to the magnitude of the operation, the patient s genetic profile and the possible interventions used to help resolve it. It is known that some patients might not present with any symptoms (nausea, bloating, fullness sensation) or signs (abdominal distension, vomiting). (3) Its cessation cannot be expressed by varying end points such as bowel sounds because this would demand frequent auscultation, their presence does not necessarily indicate propulsive activity, and they can be the result of small-bowel activity and not colonic function. Flatus is not the ideal end point because it requires a conscious patient who is comfortable in reporting it to the attending physician and because there is also some question as to the correlation between its elimination and bowel movements [28]. (4) Early postoperative feeding has been tolerated by a great number of patients even when they are under the early physiologic phase of motility impairment [29,30] (lasting up to 2 3 days), whereas other patients will have diet intolerance for longer periods, no matter what type of diet is offered or when. It may be more correct to define postoperative ileus as a primary physiological response in that it is an inevitable response to surgical trauma that is triggered by several factors and may lack clinical alterations or may present with several symptoms and signs [25]. The key issue is that the economic impact brought about by gut dysmotility may be close to US$1 billion per year in the United States [31]. Such ambiguities have prompted surgeons to wait for the patient to eliminate flatus or stools before initiating feeding. Thus, traditional practice believes that allowing patients to have meals before these events occur would result in postoperative ileus, in other words, intolerance to feeding. However, it seems that there are two different issues. The first is a normal physiological response and the second is diet intolerance. It is well established that the stomach recovers motility within h of surgery, whereas colonic function takes h to be restored [25]. Although this is a normal response, recent studies have shown that it should not be perceived as intolerance to feeding. For instance, Bufo et al. [29] have shown that immediate postoperative oral intake was successfully tolerated in 86% of all patients regardless of the presence of bowel sounds or flatus. In another study, very early feeding, 6 h after an operation, contributed to a faster recovery of bowel function [30]. In a prospective, randomized trial, Stewart et al. [7] showed that patients who were fed early tolerated the diet (80%), passed flatus, and used their bowels earlier than the control group. The key question is why would 80 90% of patients tolerate diets within the period of time some authors define as the postoperative ileus period? This may be explained by the different factors influencing postoperative recovery. Until very recently, the most widely accepted explanation for postoperative ileus was based on the idea that manipulation of the abdominal content inhibited gastrointestinal motor function through some sort of neurologic reflex response, associated with the side effects of anesthetic agents and postoperative pain relievers, and intraoperative fluid resuscitation, among other factors [32. ] (Table 1). The study by Kalff et al. [33 ], however, is directed at characterizing the role of inflammatory cells in the pathogenesis of intestinal ileus, adding more controversy to the complex intricate causes of postoperative ileus. In their study, the investigators sought full-thickness samples of human small intestine during open abdominal procedures performed to treat real and in some cases acute illness. The strategy for investigation was the evaluation of specimens of small intestine taken early (within min of skin incision) or late (43 h after incision). In four patients, they were able to Table 1. Possible mechanisms of postoperative ileus Mechanisms Autonomic nervous system Enteric nervous system Hormones and neuropetides Inflammation Anesthesia Narcotics Malnutrition Factors involved Sympathetic inhibitory pathways Nitric oxide Vasoactive intestinal peptide; corticotropin releasing factor ligands Macrophage and neutrophil infiltration with cytokine and other inflammatory production of mediators General anesthetics (fluorane); epidural blockade Opiates Decreased splanchnic flow

4 580 Nutrition and the gastrointestinal tract assess sequential analysis, both early and late. Compared with early harvested specimens, late harvest specimens demonstrated activation of macrophages. In addition, muscularis extracts from late specimens showed marked and significant elevations in levels of mrna encoding cytokines such as IL-6, the cyclooxygenase isoform COX-2 and inducible nitric oxide synthetase. These markers represent major pathways by which activated leukocytes elicit acute and chronic inflammation. These findings show a strong association between surgical manipulation and activation of inflammation, increased metabolic response and postoperative ileus, to which the magnitude of the response is determined by several variables: the patient s genetic profile, local surgical manipulation and care, together with adequate multimodal pre and postoperative strategies. It should be noted, therefore, that a large proportion of patients start eliminating flatus without any of the above-mentioned symptoms. Furthermore, there are also conflicting reports about when postoperative ileus ceases. Feeding and postoperative ileus Some surgical dogmas, such as the routine use of nasogastric tubes for postoperative ileus, oral feeding and its sequential liberation (clear liquids to solid diets) after the resolution of ileus have not been supported by the recent evidence. The routine use of nasogastric tubes in gastrointestinal operations has been evaluated in several studies. A study from our department [34] in 1992 indicated that the routine prophylactic use of nasogastric tubes was not only unnecessary in gastrointestinal operations but was also associated with higher morbidity, especially pulmonary complications. Not so long ago, a metaanalysis [35] showed that for every patient who required the insertion of a nasogastric tube in the postoperative period, at least 20 patients did not need nasogastric decompression, therefore concluding that routine nasogastric decompression use is not supported by the literature. Traditional surgical postoperative care also recommends withholding postoperative feeding until flatus or stools have passed. This frequently happens around the fourth postoperative day. As a consequence, length of hospital stay is increased. After colorectal operations, patients remain in hospital for 6 12 days [36] as it is believed that early feeding might cause abdominal distension, nausea and vomiting. Casto et al. [37] states this dates back for more than 100 years ago when the incidence of postoperative emesis was much higher because of older anesthetic agents [page 571]. Some authors have been studying the impact of early feeding on postoperative recovery and these paradigms have been challenged. Several papers have showed that it is possible to discharge patients even on the second or third day following an open colorectal operation [38 ]. This leads to decreased patient discomfort, shorter hospital stay and, therefore, decreased hospital costs. The question is, why should we wait for the passage of flatus or stools in the postoperative period before we start feeding our patients? Up to now there have been two answers to justify this attitude. First, it is believed that one should wait for the transient impairment of bowel motility (postoperative ileus) to be restored to normal. This has been thoroughly discussed above. Second, early feeding could increase the risk of an anastomotic leak, which, nowadays, is known not to be the case. Healing of anastomosis and postoperative complications are directly affected by several factors such as a patient s previous nutritional status [39], use of immunosuppressive drugs like corticoids, local abdominal conditions translated as inflammation or the presence of neoplasic disease, adequate splanchnic flow and good surgical technique [40]. Conversely, it is known that early feeding improves wound healing, increases splanchnic flow, stimulates gut motility, decreases intestinal stasis and impacts on the incidence of morbidity and mortality [4 6]. In a Brazilian prospective randomized study, Aguilar-Nascimento and Goelzer [41] found no significant difference in the rate of anastomotic dehiscence in the early fed versus the conventionally treated group. Early enteral feeding has been shown to be safe and tolerated, even as early as 4 12 h after the operation [4 7,42,43]. In fact, early enteral feeding can stimulate a reflex that produces coordinated propulsive activity and elicits the secretion of gastrointestinal hormones, shortening instead of causing postoperative ileus. Anderson et al. [44. ] showed that after colorectal surgery, the group of patients who received several stimulatory measures, such as early nutrition, recovered faster with gastrointestinal function restored earlier than the control group, with a statistically significant difference median 48 h (33 55 h) versus 76 h ( h). Conventional postoperative management, which is still practiced in most centers, recommends fasting combined with administration of fluids until passage of flatus or stools. There is a lack of guidance to rationalize postoperative feeding in the majority of centers. For instance, in 78.5% of obstetric units in UK that were surveyed, the decision to start feeding after a caesarean section was made without following any guidelines [45]. In the majority of colorectal units, the personal preference of surgeons guides the period of starvation [44. ]. As mentioned above, the etiology of postoperative ileus is multifactorial. Alterations in the autonomic nervous

5 The impact of early nutrition Correia and da Silva 581 system, neurotransmitters, local inflammatory factors and inflammatory/metabolic responses, hormones, anesthesia, and postoperative analgesia have been described as causal factors. Thus, a multimodal treatment approach should be used to treat or minimize the physiologic impairment of motility after a major surgical procedure [8,23,25,35,46]. Early feeding is one of these modalities that should be associated with epidural anesthesia, minimally invasive surgery, antinausea medications, early postoperative mobilization, pain control and patient psychological preparation, among other factors. Indeed, studies that did not associate early feeding with other approaches to reduce gut dismotility have not shown benefits on postoperative outcome. In a prospective randomized study, Stewart et al. [7] have shown that patients undergoing colorectal resection who were permitted to ingest free fluids as early as 4 h after the operation could tolerate nutrient ingestion well. Eighty percent of patients in the early diet group tolerated a meal within 48 h. The rates of vomiting, nasogastric reinsertion, and abdominal distension were not significantly different between the control and the study groups, though the timing of these complications was earlier in the study group. However, the incidence of vomiting might be higher in patients who are fed earlier. Studies from the gynecologic literature have shown rates of emesis of 40 49% [47,48]. Nevertheless, in a recent randomized study, Steed et al. [49] did not find significant differences in the number of episodes of emesis in patients undergoing major abdominal gynecologic surgery. More recently, in a prospective randomized trial, Delaney et al. [50 ] found that only two out of 31 patients in the early feeding group needed nasogastric tube insertion due to postoperative vomiting. In 2003, Anderson et al. [44. ] used multimodal strategies in postoperative care of patients undergoing colonic resection. The authors used a large number of variables that are believed to accelerate postoperative recovery, including free fluids on the day of operation, light diet on day 1, and full diet on day 2. The so-called optimization group demonstrated a return to normal gastrointestinal function earlier than the control group. More recently, Basse et al. [38 ] showed that defecation occurred on day 4.5 (median) in the conventionally treated group and on day 2 in the multimodal treated group. Elderly patients are more susceptible to complications, and are known to have longer hospital stays. Recent studies have analyzed the response of the elderly population to early feeding with varying outcomes. Delaney et al. [50 ] were not able to demonstrate great benefit of early feeding in patients older than 70 years old. In their overall group, the reduction in length of stay for primary hospital admissions was not significant. Only on secondary analysis of patients younger than 70 years old were they able to show a reduction in the total length of stay, from 7.1 to 5 days. By contrast, DiFronzo et al. [27 ] studied patients older than 70 years and showed that 89.6% tolerated early feeding and hospitalization time was only 3.9 days. It is reasonable to expect that a multimodal approach would result in a shorter hospital stay. However, different modalities to improve recovery and different end points have been used, which may confound the results. Although, Reissman et al. [42] showed that 79% of patients receiving early feeding tolerated the diet, the authors could not find significant differences in length of hospitalization. Several other studies, however, have shown shorter lengths of hospitalization [7,29,38,47]. Stewart et al. [7] showed a statistically significant reduction in hospital stay in an early fed group. A recent metaanalysis [43], which included early enteral and oral feeding, showed a significant decrease in hospital stay: 0.84 day ( days). Basse et al. [38 ] studied 130 patients receiving multimodal fast track rehabilitation, including early feeding, and reported a median hospital stay of only 2 days. It is difficult to compare these studies because of different definitions of postoperative dysmotility, small sample sizes, differences in operations performed, anesthesia protocols provided both intraoperatively and postoperatively, patient co-morbidities, and variations in the measured end points, such as the time to the presence of bowel sounds, flatus, or bowel movements, discharge from the hospital or tolerance of solid food. It seems, however, that there is a clear tendency for a multimodal approach to be beneficial when it comes to the overall postoperative outcome, impacting on length of hospitalization and costs. The progression of nutrients, from clear liquids to solid diets, has been another controversial discussion among surgeons who traditionally believe that this oral modality sequence should be respected. In a prospective, randomized study from our department, however, Sanches et al. [51] studied 165 patients undergoing digestive elective operations in whom oral diets were progressed to a free diet or sequential diet (clear liquids to regular diet) after the passage of flatus. The authors did not find any difference in the incidence of surgical complications or intolerance to diets between the two groups. The patients who received free solid diets ingested more calories than the group who received liquid diets ( versus calories on the first day of feeding). The authors recommended a free (solid) diet as the first meal in the postoperative period. Another study from Jeffery et al. [52] comparing oral intake of solid food versus progression of clear liquids to solid diet after abdominal surgery showed that there was similar

6 582 Nutrition and the gastrointestinal tract incidence of complications in both groups (7.5% versus 8.1%). The authors advocated the use of the solid regime as the first option to be offered to patients since it is well tolerated, offers better palatability, might be easier to swallow and decreases the time till hospital discharge because surgeons do not have to wait for diet tolerance observation. In the future, new perspectives will have to be assessed and possibly used [53 ]. Recently, a simple technique such as the effect of gum chewing to enhance postoperative recovery from ileus after laparoscopic colectomy was evaluated as a convenient method [54 ]. A total of 19 patients who underwent elective laparoscopic colectomy for colorectal cancer participated in the study. The patients in the gum-chewing group chewed gum three times a day from the first postoperative morning until oral intake. The times of the first passage of flatus and defecation were recorded precisely. The first passage of flatus was seen, on average, on postoperative day 2.1 in the gum-chewing group and on day 3.2 in the control group (P50.01). The first defecation was 2.7 days sooner in the gum-chewing group (postoperative day 3.1) than in the control group (day 5.8; P50.01). All patients tolerated gum chewing on the first operative morning. The postoperative hospital stay for the gum-chewing and control groups were and days, respectively. The authors concluded that gum chewing aids early recovery from postoperative ileus and is an inexpensive and physiologic method for stimulating bowel motility. According to them, gum chewing should be added as an adjunct treatment in postoperative care because it might contribute to shorter hospital stays. Conclusion The metabolic response to stress and postoperative ileus continues to be a significant problem after abdominal and other types of surgery. In both cases the response is physiological and when perpetuated impacts on morbidity and mortality. Its etiology is multifactorial and it is best treated with a combination of different approaches, of which nutrition plays an important role. As science evolves, it is important that old dogmas based on empiric decisions be questioned by randomized clinical trials. When different results are depicted, new strategies should be attempted and followed in order to improve clinical outcome and patient comfort, adding to cost reduction. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:. of special interest of outstanding interest 1 Nygren J, Thorell A, Ljungqvist O. Preoperative oral carbohydrate nutrition: an update. Curr Opin Clin Nutr Metab Care 2001; 4: Enzi G, Casadei A, Sergi G, et al. Metabolic and hormonal effects of early nutritional supplementation after surgery in burn patients. Crit Care Med 1990; 18: Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feedings, compared with parenteral reduces postoperative septic complications: the results of a meta-analysis. Ann Surg 1992; 216: Kudsk KA. Gut mucosal nutritional support: enteral nutrition as primary therapy after multiple system trauma. Gut 1994; 35:S52 S54. 5 Gianotti L, Nelson JW, Alexander JW, et al. Postinjury hypermetabolic response and magnitude of bacterial translocation: prevention by early enteral nutrition. Nutrition 1994; 10: Braga M, Gianotti L, Gentilini O, et al. Feeding the gut early after digestive surgery: results of a nine-year experience. Clin Nutr 2002; 21: Stewart BT, Woods RJ, Collopy BT, et al. Early feeding after elective open colorectal resections: a prospective randomized trial. Aust N Z J Surg 1998; 68: Di Fronzo LA, Vymerman J, Oçonnel TX. Factors affecting early postoperative feeding following elective open colon resection. Arch Surg 1999; 134: Heslin MJ, Latkany L, Leung D, et al. A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg 1997; 226: Watter JM, Kirkpatrick SM, Norris SB, et al. Immediate postoperative feeding results in impaired respiratory mechanics and decreased mobility. Ann Surg 1997; 226: Van Den Berghe G, Baxter RC, Weekers F, et al. A paradoxical gender dissociation within the growth hormone insulin-like growth factor I axis during protracted critical illness. J Clin Endocrinol Metab 2000; 85: Soop M, Nygren J, Mammarqvist F, et al. Preoperative oral carbohydrate treatment attenuates postoperative whole body nitrogen losses and hepatic insulin resistance. Clin Nutr 2001; (Suppl 1): Henriksen MG, Hessov I, Dela F, et al. Effects of preoperative oral carbohydrates and peptides on postoperative endocrine response, mobilization, nutrition and muscle function in abdominal surgery. Acta Anaesthesiol Scand 2003; 47: A good study showing the impact of preoperative carbohydrate load on postoperative endocrine response and muscle function. 14 Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg 2002; 183: Brodner G, van Aken H, Hertle L, et al. Multimodal perioperative management combining thoracic epidural analgesia, forced mobilization, and oral nutrition reduces hormonal and metabolic stress and improves convalescence after major urologic surgery. Anesth Analg 2001; 92: Moss G, Koblenz G. Postoperative positive nitrogen balance: effect upon wound and plasma protein synthesis. Surg Forum 1970; 21: Moss G. Enteral hyperalimentation benefits patients with postoperative hypermetabolic stress. Arch Surg 2002; 137: Omura K, Hirano K, Kanehira E, et al. Small amount of low residue diet with parenteral nutrition can prevent decreases in intestinal mucosal integrity. Ann Surg 2000; 231: Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002; 30: Lin E, Goncalves JA, Lowry SF. Efficacy of nutritional pharmacology in surgical patients. Curr Opin Clin Nutr Metab Care 1998; 1: Heys SD, Walker LG, Smith I, et al. 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: Livingston EH, Passaro EP. Postoperative ileus. Dig Dis Sci 1990; 35: Fanning J, Yu-Brekke S. Postoperative trial of aggressive postoperative bowel stimulation following radical hysterectomy. Gynecol Oncol 1999; 73: Resnick J, Greenwald DA, Brandt LJ. Delayed gastric emptying and postoperative ileus after nongastric abdominal surgery: part I. Am J Gastroent 1997; 92: Luckey A, Livingston E, Tache Y. Mechanism and treatment of postoperative ileus. Arch Surg 2003; 138: Very interesting and complete review on the mechanisms of postoperative ileus.

7 The impact of early nutrition Correia and da Silva DiFronzo LA, Yamin N, Patel K, O Connell TX. Benefits of early feeding and early hospital discharge in elderly patients undergoing open colon resection. J Am Coll Surg 2003; 197: The authors evaluated the impact of early feeding in elderly patients undergoing elective open colon resection. Early feeding resulted in a short hospital stay and low postoperative morbidity. 28 Waldhausen JH, Shaffrey ME, Skenderis BS II, et al. Gastointestinal myolectric and clinical patterns of recovery after laparotomy. Ann Surg 1990; 211: Bufo AAJ, Feldman S, Daniels GA, Lieberman RC. Early postoperative feeding. Dis Colon Rectum 1994; 37: Velez JP, Lince LF, Restrepo JI. Early enteral nutrition in gastrointestinal surgery: a pilot study. Nutrition 1997; 13: Prasad M, Matthews JB. Deflating postoperative ileus. Gastroenterology 1999; 117: Zinner MJ. Ileus and the macrophage. Ann Surg 2003; 237: Nice editorial about Kalff et al. s paper [33 ]. Kalff JC, Turler A, Schwartz NT, et al. Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg 2003; 237: This paper brings new insights into the risk factors of postoperative ileus, mainly the inflammatory pathway. 34 Savassi-rocha PR, Conceição AS, Ferreira JT, et al. Evaluation of the routine use of the nasogastric tube in digestive operation by a prospective controlled study. Surg Gynecol Obstet 1992; 174: Cheatham ML, Chapman WC, Key SP, Sawyers JL. A meta-analysis of selective versus routine nasogastric decompression after elective laparotomy. Ann Surg 1995; 221: Basse L, Jakobsen DH, Billesbolle P, et al. A clinical pathway to accelerate recovery after colonic resection. Ann Surg 2002; 200;232: Casto CJ, Krammer J, Drake J. Postoperative feeding: a clinical review. Obstet Gynecol Surv 2000; 55: Basse L, Thorbol JE, Lossl C, Kehlet H. Colonic surgery with accelerated rehabilitation or conventional care. Dis Colon Rectum 2004; 47: Basse et al. compared a series of patients who underwent colonic surgery under conventional care and another group who received a multimodal approach. Although not a randomized study, the data are valuable due to the large number of patients followed. 39 Correia MITD, Waitzberg DL. The impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis. Clin Nutr 2003; 22: Campos AC, Andrade DF, Campos GM, et al. A multivariate model to determine prognostic factors in gastrointestinal fistulas. J Am Coll Surg 1999; 188: Aguilar-Nascimento JE, Goelzer J. Early feeding after intestinal anastomosis: risks or benefits? Rev Assoc Med Bras 2002; 48: Reissman P, Teoh TA, Cohen SM, et al. Is early oral feeding safe after elective colorectal surgery? A prospective randomized trial. Ann Surg 1995; 222: 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: Anderson ADG, McNaught CE, MacFie J, et al. Randomized clinical trial of multimodal optimization and standard perioperative surgical care. Br J Surg 2003; 90: Although this study only included a small group of patients, it was able to show that optimization of surgical care, by a 10-point optimization scale, significantly improved patients physical and psychological function in the early postoperative period and facilitated early hospital discharge. 45 Worthington LM, Mulcahy AJ, White S, Flynn P. Attitudes to oral feeding following Caesarean section. Anaesthesia 1999; 54: Henriken MG, Hansen HV, Hessov I. Early oral nutrition after elective colorectal surgery: influence of balanced analgesia and enforced mobilization. Nutrition 2002; 18: Schilder JM, Hurteau JA, Look KY, et al. A prospective controlled trial of early postoperative oral intake following major abdominal gynecologic surgery. Gynecol Oncol 1997; 67: Pearl ML, Valae FA, Fischer M, et al. A randomized controlled trial of early postoperative feeding in gynecologic oncology patients undergoing intraabdominal surgery. Obstet Gynecol 1998; 92: Steed S, Capstick V, Flood C, et al. A randomized controlled trial of early versus traditional postoperative oral intake after major abdominal gynecologic surgery. Am J Obstet Gynecol 2002; 186: Delaney CP, Zutshi M, Senagore AJ, et al. Prospective, randomized, controlled trial between a pathway of controlled rehabilitation with early ambulation and diet and traditional postoperative care after laparotomy and intestinal resection. Dis Colon Rectum 2003; 46: This randomized study shows the importance of a multimodal perioperative strategy in the recovery of post laparotomy and intestinal resection. 51 Sanches MD, Castro LP, Sales TRA, et al. Comparative study about progressive versus free oral diet in postoperative period of digestive surgeries. Gastroenterology 1996; 110: Jeffery KM, Harkins B, Cresci G, Martindale RG. The clear liquid diet is no longer a necessity in the routine postoperative management of surgical patients. Am Surgeon 1996; 62: Nygren J, Thorell Am, Ljungqvist O. New developments facilitating nutritional intake after GI surgery. Curr Opin Clin Nutr Metab Care 2003; 6: Excellent review on the different approaches facilitating nutritional intake after gastrointestinal surgery. 54 Asao T, Kuwano H, Nakamura J, et al. Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy. J Am Coll Surg 2002; 195:30 32.