Nutrition in Clinical Practice

http://ncp.sagepub.com/ Nutrition Optimization Prior to Surgery

David C. Evans, Robert G. Martindale, Laszlo N. Kiraly and Christopher M. Jones Nutr Clin Pract 2014 29: 10 originally published online 17 December 2013 DOI: 10.1177/0884533613517006 The online version of this article can be found at: http://ncp.sagepub.com/content/29/1/10

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NCPXXX10.1177/0884533613517006Nutrition in Clinical PracticeEvans et al

Invited Review

Nutrition Optimization Prior to Surgery

David C. Evans, MD1; Robert G. Martindale, MD, PhD2; Laszlo N. Kiraly, MD2; and Christopher M. Jones, MD3

Nutrition in Clinical Practice Volume 29 Number 1 February 2014 10 21 2013 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533613517006 ncp.sagepub.com hosted at online.sagepub.com

Abstract
Optimization of metabolic state prior to major surgery leads to improved surgical outcomes. Nutrition screening protocols should be implemented in the preoperative evaluation, possibly as part of a bundle. Strategies to minimize hyperglycemia and insulin resistance by aggressive preoperative nutrition and carbohydrate loading may promote maintenance of a perioperative anabolic state, improving healing, reducing complications, and shortening the time to recovery of bowel function and hospital discharge. Short courses of preoperative immune-modulating formulas, using combinations of arginine, -3 fatty acids, and other nutrients, have been associated with improved surgical outcomes. These immune-modulating nutrients are key elements of metabolic pathways that promote attenuation of the metabolic response to stress and improve both wound healing and immune function. Patients with severe malnutrition and gastrointestinal dysfunction may benefit from preoperative parenteral nutrition. Continuation of feeding through the intraoperative period for severely stressed hypermetabolic patients undergoing nongastrointestinal surgery is another strategy to optimize metabolic state and reduce prolonged nutrition deficits. In this paper, we review the importance of preoperative nutrition and strategies for effective preoperative nutrition optimization. (Nutr Clin Pract. 2014;29:10-21)

Keywords
preoperative period; preoperative care; surgery; nutritional support; nutrition assessment; enteral nutrition; parenteral nutrition

Importance of Preoperative Nutrition on Surgical Outcomes

Preoperative evaluation prior to elective surgery is routinely performed with the goal of optimizing patient outcomes. The purpose of a preoperative evaluation is not to clear patients for elective surgery but rather to evaluate them and, if necessary, implement measures to prepare higher risk patients for surgery. A thorough evaluation usually includes a history and physical examination, focusing on risk factors for cardiac, pulmonary, and infectious complications, along with a determination of a patients functional capacity. The nutrition state of the patient, however, is often omitted from this preoperative assessment. Malnourishment may be present for a variety of reasons in patients undergoing elective surgery, including metabolic perturbations from inflammatory or neoplastic disease, altered nutrient utilization secondary to the metabolic state, poor access to adequate nutrition, or alimentary track dysfunction. Ideally, these nutritionally at-risk patients should be identified during a preoperative evaluation, and nutrition goal-directed therapy should be implemented prior to surgery. Nutrition goals, at the most basic level, should be to provide caloric and nitrogenous support for wound healing and to avoid excessive loss of lean body mass. As our understanding of nutrition therapy has progressed, these goals have broadened to include modulating inflammation and the immune response, optimizing glucose control, attenuating the hypermetabolic response to surgery, and providing micro- and macronutrients to optimize healing and recovery. Hypermetabolism can last for

weeks or months after major surgery or trauma, entailing significant protein losses of lean body mass, primarily from muscle.1 Numerous studies have shown a clear association between malnutrition and poor surgical outcomes.27 These outcomes include not only increased overall mortality but also morbidity, such as increased hospital stay, increased intensive care unit (ICU) admissions, delayed wound healing, central line-associated bloodstream infections, surgical site infections, and other infectious complications. A well-performed study in Geneva, Switzerland, examined lean body mass at hospital admission and found lean body mass depletion to be an independent risk factor for increased length of hospital stay.8
From 1The Ohio State University, Department of Surgery, Columbus, Ohio; 2Oregon Health & Science University, Department of Surgery, Portland, Oregon; and 3University of Louisville, Department of Surgery, Louisville, Kentucky. Financial disclosure: None declared. This article originally appeared online on December 17, 2013. Corresponding Author: Christopher M. Jones, MD, University of Louisville, Hiram C. Polk Jr MD Department of Surgery, Ambulatory Care Building, 2nd Floor, Louisville, KY 40292, USA. Email: christopher.jones.1@louisville.edu

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Meta-analysis of several well-designed trials has shown benefit from preoperative enteral nutrition supplementation.9 A randomized prospective trial of >1000 patients was assessed using a simple screening tool: Nutrition Risk Screening (NRS-2002).10 Patients deemed to be at high nutrition risk were randomized to nutrition intervention vs standard of care. The standard of care was to proceed with surgical intervention without the preoperative nutrition intervention, despite the screening. Preoperative nutrition intervention in the high-risk group was reported to have decreased major morbidity by 50%.11 According to a systematic review, other prospective randomized clinical trials have reported a decrease in infectious complications as well as decreased length of hospital and ICU stay, although no mortality benefit has been shown.12

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per se. The large prospective Preoperative Risk Assessment Study conducted by the U.S. Department of Veterans Affairs reported that the single most valuable predictor of poor outcome was a serum albumin level <3.0 g/dL.18 Other nutrition assessments, such as the NRS-2002, guide the practitioner to initiate a nutrition care plan in the perioperative period for patients who meet sufficient scores based on weight loss, reduced intake, and illness. Although several nutrition screening tools are available and validated in nonsurgical and geriatric patient populations, to date the only validated assessment method for surgical patients is the NRS-2002.10 It appears that the future of perioperative assessment will involve using crosssectional radiology studies, such as computed tomography, where the ratio of lean body tissue to adipose mass can be calculated and associated with outcomes, as recently reported by the Hopkins Pancreatic Group.19 For those deemed severely malnourished and at high risk, specialized preoperative nutrition support should be initiated orally, enterally, or via parenteral route in specific conditions. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) and the Society of Critical Care Medicine (SCCM) nutrition guidelines state that for those who cannot take adequate calories with oral supplementation alone, enteral nutrition via feeding tube should be considered and is preferred over parenteral nutrition (PN) if the gastrointestinal tract is functional.10 Given that obesity, poor diet, and a sedentary lifestyle are increasingly common in Western society, practitioners should implement preoperative nutrition assessment tools. These tools should be a standard part of the patients preoperative anesthesia evaluation. These tools are not used to clear a patient for surgery but rather to help practitioners optimize surgical outcomes in high-risk populations.

Preoperative Nutrition Assessment

An important factor affecting outcome and recovery from surgical stress is preoperative nutrition status and the patients metabolic response to the surgical insult. The Joint Commission requires nutrition screening to be initiated within 24 hours of admission and a full assessment to be performed for at-risk patients.13 The question raised, however, is what constitutes atrisk or malnourished. The traditional concept of malnutrition brings to mind low body mass index (BMI) and decreased muscle mass (sarcopenia). Several categories, however, have been proposed that take into account both chronic and acute states of inflammation associated with disease and injury, and these must be considered when assessing ones nutrition status. When assessing preoperative nutrition status, practitioners need tools that take into account previous operations and disease processes that may affect nutrition status.14 Obesity, for example, is categorized as malnutrition of chronic disease with inflammation. It is not uncommon to see sarcopenia in this population group. Sarcopenia is usually associated with the geriatric population, where decreased functional and hormonal imbalances are present, but it is also seen in the obese, who are subject to the same imbalances. Although obesity is most commonly associated with macronutrient excess, it is reported that at least 15%20% of obese patients may be nutritionally deficient in at least one micronutrient.15,16 Sarcopenic obesity is common in the bariatric population; this results in a dramatic increase in perioperative morbidity, including an increased need for postoperative ventilator support, increased duration of ICU stay, and worsening infectious complications. A variety of nutrition screening and assessment tools are available. They consist of historical and physical examination data, such as weight loss history, fat store loss, muscle wasting, and BMI, as well as laboratory data such as lymphocyte count and serum levels of albumin, prealbumin, and cholesterol.17 Visceral proteins are important as predictors of risk but are not indicative of actual measures of malnutrition

Preoperative Nutrition Strategies Perioperative Glycemic Control

Perioperative maintenance of normoglycemia is frequently emphasized to improve surgical outcomes and may be the single most important factor to prevent surgical site infection.20 This is true regardless of whether the patient has been diagnosed with diabetes.21 Early studies demonstrated that aggressive preoperative, intraoperative, and postoperative glucose control in diabetic patients significantly reduced sternal wound complications after cardiac surgery.22,23 Glycemic control in the perioperative period should be considered in 3 separate and distinct periods. In elective patients, it has been shown that glucose control in the 3060 days prior to surgery is beneficial in decreasing perioperative complications. Dronge et al,23 evaluating patients from Veterans Administration hospitals, found that surgical site infections were reduced in patients whose HbA1c was <7%, and the authors recommended that HbA1c <7% be a preoperative target.

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Although intraoperative intensive insulin management seems to be a logical strategy to address hyperglycemia, a recent single-center, randomized clinical trial enrolling both diabetic and nondiabetic patients did not demonstrate improved outcomes despite better glucose control.24 A Cochrane Review of 5 randomized trials in adults (diabetic and nondiabetic) did not demonstrate significant benefits to intensive regimens either.25 Strategies that combine continuous perioperative insulin and glucose infusions may provide glucose control with antiinflammatory benefits.26 An intraoperative infusion of 20% glucose with insulin has been shown to improve glycemic control and reduce glycemic variability.27 If this strategy is started as a preoperative infusion, it should achieve the same benefits as oral carbohydrate loading, reducing insulin levels at the induction of anesthesia and minimizing hyperglycemia in surgery. Meta-analysis has shown that this strategy attenuates postoperative insulin resistance.28

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Preoperative Enteral Feeding

Numerous well-designed, prospective, multicenter studies have examined preoperative oral supplementation and have shown that immune and metabolic modulating formulations carry benefit.12 Surprisingly few trials, however, show benefit of preoperative supplementation with tube feedings of any composition. In one of the most recent studies of aggressive preoperative nutrition optimization prior to abdominal surgery, very few patients with malnutrition (defined as NRS-2002 score of 36) were able to achieve their goal caloric intake by enteral tube feeding without the use of supplemental PN.11 The reasons for the ineffectiveness of tube feedings were not clear. A small Turkish study assigned patients to standard enteral tube feedings, immunonutrition, and control arms. Only the immunonutrition group had any improvement in outcome.43 Several trials have shown that patients with dysphagia or severe anorexia may benefit from preoperative enteral feeds. These are commonly patients with head and neck cancers and esophageal neoplastic disease. Many centers now place a feeding jejunostomy during the staging laparoscopy. The jejunostomy is then used for nutrition supplementation during neoadjuvant treatments and the subsequent esophagectomy.44

Enteral Strategies
Oral and enteral nutrition should form the cornerstone of any preoperative nutrition regimen. A large body of literature touts the benefits of immune-modulating nutrition in the preoperative setting, with most showing a statistically significant benefit, although several well-done studies have not shown the same benefit. Data evaluating standard oral protein supplements are limited. Several studies demonstrated no major impact from the use of standard oral preoperative supplements.2931 One study that evaluated preoperative supplementation with standard oral supplement vs control nutrition demonstrated less postoperative weight loss and fewer minor complications with preoperative supplementation.32 Gastrointestinal intolerance, anorexia, noncompliance, and other factors may have minimized any potential benefit, as total caloric intake was minimally improved with the addition of the oral supplements. Nutrition supplementation can promote a shift to the anabolic state and can be part of a muscle-strengthening protocol.33,34 Many surgically and critically ill patients experience catabolic effects on muscle attributable to bed rest or limitations in activity in the preoperative period, either voluntarily or because of their disease. This leads to decreased muscle mass and weakness that shifts the metabolism toward a catabolic state.35,36 Interest has developed in the early mobilization of critically ill patients. Multiple studies have demonstrated improved functional outcomes.37,38 We hypothesize that as-yet undescribed metabolic effects of these protocols may emerge with additional study.39 These concepts are inspired by the same biochemical pathways and physiological strategies harnessed by preworkout nutrition supplementation in healthy adults.40 Elderly men who participate in light resistance exercise are able to use higher doses of supplemental whey protein to build muscle.41 Similarly, in elderly Japanese women, exercise combined with amino acid supplementation resulted in reversal of sarcopenia.42

Metabolic Modulating Nutrition

In the past 15 years, there has been a surge of interest in immunonutrition, more precisely described as immune and metabolic modulation in the perioperative period. Common immune-modulating nutrition products are hydrolyzed peptide-based highprotein formulas that include some combination of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), arginine, nucleic acids, and antioxidants. Biochemical effects of these formulas include increased cell membrane stability, improved gastrointestinal mucosal integrity, enhanced cell-mediated immune responses, attenuation of the inflammatory response to stress, and improved blood flow to poorly vascularized and ischemic tissues. Published trials often blur the lines between preoperative supplementation, postoperative enteral feeding, or both. Additionally, some studies are limited to surgical patients, and others include mixed critical care populations. It is therefore often difficult to decipher which perioperative trials of immune-modulating nutrition are applicable to specific patient populations. Most studies of immune and metabolic modulation have focused on postoperative nutrition without a preoperative supplement. When compared with standard enteral nutrition, several meta-analyses have demonstrated that postoperative immune-modulating nutrition in critically ill patients results in reduced infectious complications but no change in mortality.4549 Two meta-analyses demonstrated decreased ventilator days.46,50 One meta-analysis of early enteral postoperative immune-modulating nutrition also demonstrated a reduction in anastomotic leaks.51 Preoperative oral supplementation offers the greatest prospect for biological benefits that we can optimize for the body

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Table 1. Systematic Reviews and Meta-analyses Examining the Effectiveness of Immunonutrition in Surgery. Author Waitzberg et al, 2006 Marik and Zaloga, 201047 Cerantola et al, 201156 Drover et al, 201112 Marimuthu et al, 201248
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RCTs 17 21 21 35 26

Control Group Standard EN/parenteral Standard EN Standard EN Standard EN Standard EN

Patients 2305 1908 2730 3445 2496

Short-Term Outcome Lower rate of infection Shorter LOS Lower morbidity Shorter LOS Lower morbidity Shorter LOS Lower morbidity Shorter LOS Lower morbidity Shorter LOS

Patients Who Benefit GI cancer Malnourished and well nourished Upper GI Lower GI GI and non-GI Upper/lower GI receiving Impacta GI cancer

EN, enteral nutrition; GI, gastrointestinal; LOS, length of stay; RCT, randomized clinical trial. a Nestl HealthCare Nutrition (Florham Park, NJ). Reprinted with permission from Brage M, Wischmeyer PE, Drover J, Heyland DK. Clinical Evidence for Pharmaconutrition in Major Elective Surgery. J Parenter Enteral Nutr. 2013;37(5):66S-72S.

prior to the stress response (Figure 1).51 There was strong initial evidence that preoperative immune-modulating nutrition reduces complications and length of stay.5254 This was confirmed by a Cochrane Library analysis, which demonstrated decreased total and infectious complications with the use of preoperative immune-modulating nutrition.55 There is some evidence that the beneficial effects of preoperative therapy may be most pronounced in patients undergoing higher risk gastrointestinal surgery, where the potential for postoperative critical illness and metabolic stress may be higher (Table 1).48 One weakness of trials and meta-analyses in this area is that some of the literature appears to consist of updated publications and various subanalysis trials with overlapping/duplicate research subjects. This creates the possibility that many patients were double-counted as some meta-analyses were assembled.56 Additionally, most classic preoperative trials were not balanced with appropriate and isonitrogenous control nutrition.57 There has been interest in the use of immunemodulating nutrition in head and neck cancer surgery, both before and after surgery. Although this field offers an excellent study population, due to relative homogeneity of patients and surgical procedures, the total data are still weak and only demonstrate decreased length of stay following the use of immune-modulating diets.58 This group has relatively low rates of serious postoperative complications, and much of the preoperative immune-modulation literature focuses on lower risk populations. A recent randomized controlled trial demonstrated improved functional capacity with immune-modulating nutrition.59 Meta-analyses and clinical trials of preoperative immunemodulating nutrition in the last 23 years have been more mixed. Cerantola et al56 aggregated pre- and perioperative data, attempting to identify subjects who were reported in multiple trials; using Jadad quality analysis, the authors concluded that immune-modulating nutrition reduced complications (infectious and otherwise). The most recent meta-analysis

decidedly showed no benefit to preoperative intervention only, although postoperative and perioperative regimens continue to demonstrate benefit.60 This may be the highest quality but also most stringent meta-analysis in the field to date. Since the publication of that meta-analysis, several small randomized and, importantly, isonitrogenous trials of preoperative immunemodulating nutrition in well-nourished patients prior to gastrointestinal surgery did not show any benefit.6163 A randomized, double-blinded controlled trial of preoperative immune-modulating nutrition in malnourished patients (defined as NRS-2002 score 3) also failed to show benefit.64 Although the data are becoming a bit confusing, primarily as a result of the heterogeneity of the samples, the general consensus appears falls in favor of the concept of preoperative metabolic modulation prior to onset of surgical stress to attenuate the catabolic effect of major surgical insult.65

Carbohydrate Loading
Carbohydrate loading has been proposed as a technique to minimize the catabolic influence and insulin resistance associated with postoperative stress. Prevention of postoperative insulin resistance and the need for exogenous insulin can be achieved by a strategy that focuses on preoperative carbohydrate intake and minimization of the time that oral nutrition is withheld preoperatively. Historically, oral nutrition has been withheld after midnight the day before surgery in an effort to minimize the risk of aspiration by minimizing the volume of gastric contents and the acidity of the stomach.66 The time of midnight is often chosen, regardless of the time surgery is actually scheduled, frequently resulting in preoperative fasts in excess of 816 hours. This strategy leads to insulin resistance, hyperglycemia with its inherent risks, the need for exogenously administered insulin, and failure to achieve an anabolic state.67 Several studies from Sweden have examined carbohydrate loading, using oral and intravenous solutions. The goal is to

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achieve a carbohydrate load typical of a normal meal. This was first achieved using preoperative infusions of 5 mg/kg/min of glucose.68 Oral protocols using 12.5% iso-osmolar high-carbohydrate beverages to administer 100 g of carbohydrate the night before surgery and 50 g of carbohydrate 2 hours before surgery were then tested in a variety of settings.69 Both protocols were effective in reducing postoperative insulin resistance.70 Fat oxidation is suppressed by carbohydrate loading protocols, but there is conflicting evidence regarding whether glucose oxidation is also suppressed. A key study has suggested attenuation of pyruvate dehydrogenase kinase expression after carbohydrate loading.71 Despite the exact metabolic mechanism, well-performed clinical trials have consistently demonstrated improved insulin sensitivity and decreased preoperative thirst, hunger, and anxiety.72 A small trial involving colorectal surgery patients demonstrated earlier return of bowel function, shorter length of stay, and improved muscle strength after preoperative carbohydrate loading.73 A meta-analysis of 21 trials of widely varying quality demonstrated shorter lengths of stay after abdominal surgery and improvements in insulin resistance but little additional impact.74 These carbohydrate loading strategies have been particularly embraced in colorectal surgery and form part of the Enhanced Recovery After Surgery (ERAS) protocol.75 Guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN) include carbohydrate loading as an accepted form of metabolic preparation.76 The risk of aspiration has long been recognized as a complication of general anesthesia and endotracheal intubation. This risk has been reduced in the modern era and can be further mitigated by rapid sequence induction techniques. The American Society of Anesthesiologists guidelines stipulate a minimum fasting period of 2 hours for clear liquids and 6 hours for a light meal, but in practice, patients are frequently withheld oral feeding for longer periods of time.77 There is evidence that even intraoperative feeding is safe and does not increase the risk of aspiration, particularly in hypermetabolic burn patients.78 A protocol administering tube feeds until 45 minutes before surgery was studied in trauma patients and found to be safe and feasible, but it was underpowered to demonstrate a benefit and was plagued by poor protocol compliance.79

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converted into ornithine and then proline, and may then contribute to collagen deposition and healing of colonic epithelium.83 Most studies of immune-modulating nutrition have included arginine as one of the key constituents. A large metaanalysis of perioperative use of arginine-containing formulations, performed by Drover et al,12 identified a major reduction in infectious complications and hospital length of stay in patients receiving perioperative arginine-containing diets. Concern has been raised that supplemental arginine, when given to septic patients, particularly nonsurgical septic patients, may result in elevated nitrate and nitrite levels. This unproven hypothesis states that the elevation in nitric oxide would then result in exaggerated vasodilation, hemodynamic instability, and worsening outcomes in sepsis.84 Pharmacological doses not seen in enteral feedings, when delivered by intravenous route as a bolus, have been demonstrated to cause transient hypotension.85 Other data that point to hypotension or poor outcomes with supplemental arginine in sepsis are quite limited and not consistent.86 The large preponderance of current data demonstrate that arginine is safe and may actually be deficient in sepsis and other hyperdynamic states.8791 Despite some earlier literature which hypothesized that arginine was potentially harmful, multiple human studies have now been completed in which supplemental arginine was delivered to septic patients with no ill effects.82,88,90,92,93 Most patients showed improved tissue perfusion and cardiac output. One recent randomized trial in medical septic shock patients demonstrated reduced mortality with an arginine-containing formula.92 Fish oil (EPA and DHA). The objective of preoperative -3 fatty acid (EPA/DHA) supplementation is to reduce inflammation without escalating risk of infection. The beneficial influence of anti-inflammatory lipids, primarily EPA and DHA, has been well documented in numerous chronic nonsurgical inflammatory diseases, including rheumatoid arthritis, Crohns disease, ulcerative colitis, systemic lupus erythematosus, multiple sclerosis, and reactive airway disease.9497 The use of specific anti-inflammatory lipid substrates in the acute surgical setting to maintain vital organ function and to modulate key processes such as immunity, inflammation, and antioxidant defenses has now become routine in many surgical practices.98 The -3 fatty acids EPA and DHA have been reported in numerous human randomized clinical trials to partially attenuate the metabolic response, reverse or minimize the loss of lean body tissue, prevent oxidative injury in a variety of tissues, and improve outcome by modulating gene production of proinflammatory and anti-inflammatory mediators.98101 A myriad of mechanisms have been proposed to explain these benefits, such as changes in cell membrane phospholipids, alterations in gene expression, and modifications to endothelial expression of intracellular adhesion molecule-1, E-selectin, and other endothelial receptors regulating vascular integrity and function. Additionally, EPA and DHA derivatives,

Active Nutrients
Arginine. Arginine is a conditionally essential amino acid that plays an important role in cell growth and proliferation (such as for wound healing in surgery) and production of nitric oxide (important for microvascular perfusion, particularly in postoperative and septic states). Arginine supplies are rapidly depleted during surgery and major metabolic stress.80 This depletion is likely associated with downstream T-cell dysfunction and immune deficits.81,82 In-depth research has identified a mechanism by which arginine is transported into the colonocyte, is

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including resolvins, docosatrienes, and neuroprotectins, have been shown to be potent active effectors of the resolution of inflammation.99,102 Resolvins, for example, regulate polymorphonuclear neutrophil transmigration, whereas neuroprotectins have been shown to decrease neutrophil infiltration, proinflammatory gene signaling, and nuclear factor-B binding. These bioactive protective mediators generated from EPA and DHA are found to be highly conserved among species, from primitive fish to mammals.103 Data have recently been published reporting the potential beneficial influence of EPA on preventing loss of diaphragm function in sepsis104 and resistance to gramnegative pathogens, such as Pseudomonas.105 Recent evidence supports the concept that EPA and DHA do not simply modulate the inflammatory process passively but rather are actively involved in the resolution of inflammation via these bioactive endogenous mediators.106,107 Although -3 fatty acids attenuate inflammation by several mechanisms, they also inhibit activation and migration of inflammatory cells in response to arachidonic acid. They have been shown to suppress T-cell activation and natural killer cell activity.108 DHA has been demonstrated to lessen the burden on protein peroxidation in acute oxidative stress in muscles cells.109 The use of fish oils in cardiac surgery has drawn much attention. A small Italian randomized controlled trial showed that 2 g/d of EPA and DHA in a 1:2 ratio administered for at least 5 days before surgery significantly reduced atrial fibrillation following coronary artery bypass grafting.110 This triggered additional trials in both cardiac surgery and atrial fibrillation of other origins, with mixed results.111 This is not particularly surprising, given that atrial fibrillation after surgery is frequently the result of an inflammatory response.112 Atrial fibrillation from other causes is less likely to respond to an anti-inflammatory treatment approach. In another trial conducted in cardiac surgery patients, an intravenous lipid emulsion with fish oil both pre- and postoperatively resulted in EPA and DHA incorporation in cardiac tissue and platelets.113 The study was underpowered to demonstrate significant clinical benefits, but administration of fish oil was safe; did not cause bleeding; attenuated inflammatory markers, including interleukin (IL)-6, IL-8, and IL-10; reduced hyperglycemia; and reduced lactate and carboxyhemoglobin levels.113 Improvements in Acute Physiology and Chronic Health Evaluation scores were nearly statistically significant (P = .058).113 In rodents, -3 fatty acids have been associated with reduction of postoperative intestinal inflammation and dysmotility.114,115 The gastrointestinal effects in humans are less understood, but uptake of orally administered DHA and EPA has been demonstrated in liver, gut mucosa, and tumor tissue prior to abdominal oncologic operations.116 Significant uptake of -3 fatty acids is noted within 57 days of the start of enteral therapy.117 Parenterally administered preoperative -3 fatty acids have been shown to lower levels of IL-6 and tumor

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necrosis factor- in patients who underwent hepatectomy for hepatocellular carcinoma.118 Human trials of isolated fish oils used in surgical patients are plagued by inconsistency in the fish oil source, DHA/EPA ratios, and doses. Most studies examining oral -3 fatty acid use in surgical patients involve a commercial immune-modulating formula. Historically, there have been concerns regarding perioperative coagulopathy caused by fish oil, but further studies evaluating these issues have shown that at the dose of fish oil delivered clinically, these concerns are unfounded.119,120

Vitamins and Trace Minerals

Preoperative vitamins remain understudied and relatively controversial. Preoperative use of multivitamins is not frequently discussed in the literature. Specific deficiencies are addressed in wound healing and burn research, but there is no scientifically based discussion of these issues in the preoperative setting. Both vitamin A and zinc levels are low in patients following gastrointestinal surgery.121 Both have known roles in wound healing, but there is no evidence of a need for these supplements outside of proven deficiency or burn and wound care settings. A variety of preoperative supplements have been demonstrated to increase serum and tissue antioxidant levels, but it is unclear what the benefit is, as there is an absence of high-quality data.65 There has been some suggestion of decreased pneumonia rates with selenium, zinc, and copper supplementation in burn patients, but data are too sparse to extrapolate to surgical patients in general.122 Supplementation of zinc and other vitamins has typically targeted a goal of returning serum concentration to normal levels.123 In an Iraqi burn study, zinc supplementation improved wound healing time, eschar formation, and mortality.124 Vitamin A is known to play a role in wound healing, but there is minimal data regarding supplementation. For patients taking corticosteroids on a chronic basis, 25,00050,000 international units are sometimes empirically given daily, but this is based on a 1967 rat study and a 1982 rabbit corneal abrasion model.125,126

Supplemental Branched Chain Amino Acids

Branched chain amino acids, leucine in particular, have been of interest for years for reduction of muscular protein losses and improved visceral protein synthesis. Two randomized trials were conducted in the 1980s, with some potential benefit, but the topic has not been explored recently in the surgical literature.127,128

Altering the Microbiome

Emerging data suggest that the gastrointestinal microbiome may play a role in nutrition outcomes. Outside factors, such as administration of probiotics or antibiotics, can cause shifts in

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the gastrointestinal flora. These alterations in the microbiome may result in clinically significant outcomes by effecting changes in energy utilization in the host.129 Little research has been done on this topic in the surgical arena, but Rayes et al130,131 examined the use of Lactobacillus plantarum for 4 days after major abdominal surgery and liver transplant with some evidence of reduced infection. The potential for manipulation of the intestinal flora in the surgical setting is now a reality. It has been shown that manipulation of the microbiome can decrease surgical site infections as well antibiotic-associated diarrheas, like antibiotic-associated and Clostridium difficile diarrhea. The technology is now available for high-quality studies that will elucidate the changes observed and the potential outcome benefits from replacing healthy flora.132134

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Figure 1. The perioperative timeline. Eval, evaluation; NOS, night of surgery; OR; operating room; Post-op, postoperative; Pre-op, preoperative. Reprinted with permission from Miller K R et al. JPEN J Parenter Enteral Nutr 2013;37:39S-50S.

Parenteral Nutrition
Although enteral nutrition is always preferred over PN, a small population of patients with a dysfunctional gastrointestinal tract and preexisting protein-calorie malnutrition will benefit from preoperative PN supplementation. This is particularly true for patients undergoing upper gastrointestinal surgery.135 To achieve a clinical benefit from PN, therapy should be provided for at least 7 days before surgery, after which continued adequate enteral intake can resume.136 The major drawbacks to preoperative initiation of PN include glycemic variability, central line complications, risk for infection, electrolyte imbalances, and logistical issues including the need for a line, frequent glucose checks, and daily laboratory testing, all of which typically require admission. With delivery of PN to the severely malnourished, refeeding syndrome, with its associated hypokalemia and hypophosphatemia, is a concern.137 These electrolyte imbalances are particularly dangerous in the perioperative period.138 Starting PN at least 7 days before surgery allows time to address any electrolyte disturbances that may occur. The foremost trial of PN in the perioperative period was the Veterans Administrations 1991 study.139 The trial examined the use of PN for 715 days before surgery and 3 days after surgery vs no PN. This trial demonstrated that the subgroup of severely malnourished patients who received PN had lower rates of noninfectious complications (5% vs 43%) and similar infection rates. When the population was broadened to include all malnourished patients, infection rates were higher in the PN group than in controls (14.1% vs 6.4%). Several potential explanations other than delivery of PN have been given to explain these differences. During the time period of this study, glycemic control was not meticulously maintained, and excessive parenteral lipid calories were commonly given. The increased infection rates may have been due to overfeeding and resultant hyperglycemia, particularly in the less severely malnourished groups. Patients were given parenteral feedings, totaling resting energy expenditure, plus an additional 1000

kcal. This was in addition to any oral intake (mean 834 kcal orally).140 This amounts to far more calories than typically given in clinical practice today.141 PN started preoperatively should typically be continued through the perioperative period. Few data are available to guide PN during the procedure and in the immediate perioperative period. Care must be taken to maintain the PN infusion independent of other medications to avoid drug incompatibility. When PN is stopped before surgery, glucose levels must be closely followed. Jie et al11 examined the implementation of a protocol for nutrition assessment and optimization prior to surgery. This multicenter study screened >1000 patients preoperatively before abdominal surgery, using the NRS-2002. The investigators then randomized malnourished patients (defined as NRS-2002 score of 3) to preoperative nutrition support vs PN. Among those patients with elevated NRS scores, few were able to achieve goal preoperative nutrition support (as defined by calorie intake). Seventy-three percent of those patients achieved goal caloric intake with the use of PN. Very few patients achieved goal support with enteral formulas. In the severely malnourished patients (NRS-2002 score 56), preoperative nutrition support (mostly with PN) reduced complications.11

Intraoperative Feeding
There is some experience in the United States with intraoperative feeding for burn surgery and nongastrointestinal trauma surgery, but few randomized controlled trials have been published. Intraoperative feeding has been shown to improve caloric intake, decrease wound infections, and increase serum albumin levels.78 Multiple mechanisms have been proposed, but enhancing splanchnic blood flow and secondarily increasing oxygen delivery with preservation of gut integrity seem to be the leading theory of the mechanism of benefit.142

Postoperative Feeding
Research has been conducted in the field of postoperative feeding for more than 3 decades, and discussing all of the data is beyond the scope of this review. This is discussed extensively

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elsewhere.135,143 Principles of postoperative feeding include early enteral feeding (including proximal to an anastomosis) within the first 2448 hours, but many other issues should be evaluated. The opinion that patients receiving fairly constant doses of vasopressors for hemodynamic support should not be enterally fed is no longer valid. The issue of gastric residuals and ability to feed is becoming of historic interest, as several large trials now show no benefit in obtaining gastric residuals in most patients.135,144 Unfortunately, acceptance by the broader clinical audience is lacking (Table 2).145 Emerging data, particularly from Europe, have emphasized the use of bundles, such as the ERAS protocol and other fast-track protocols, to achieve rapid return of bowel function.146,147
Table 2. Early Feeding in the Surgical Population: Why Is It Such a Problem Getting Enteral Nutrition Started? Lack of team understanding of the potential benefits of early feeding Poor understanding of postoperative ileus Waiting for flatus or signs of bowel activity Concern for complications Aspiration Ischemic bowel Feeding will cause a leak of recent bowel anastomosis Lack of skills for tube placement Perception of inability to feed while on pressors Lack of communication between team members

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Incorporation of Nutrition Into a Preoperative Bundle

As definitions of malnutrition become more focused and disease-specific, reimbursement for care is increasingly linked to performance. As clinicians and administrators see the link between malnutrition and poor outcomes, we can expect to see more attention paid to these issues.148 Quality initiatives like the National Surgical Quality Improvement Project are bringing quality issues like malnutrition to the forefront with reliable data in a scientific and risk-adjusted fashion.149 Care bundles and checklists are increasingly used to deliver consistent quality care, and we can expect that nutrition will come to the forefront of a preoperative bundle. At most hospitals, the idea of postponing surgery for nutrition optimization is a foreign concept that will predictably change as these data become widely accepted. A major quality improvement project has been initiated in Washington State, based on the administration of preoperative immune-modulating nutrition, along with glycemic control, smoking cessation, and careful medication review.150 Although not a randomized trial, this grassroots quality improvement program is wide-reaching, including community hospitals and major teaching hospitals. Should it be successful, preoperative oral immune-modulating nutrition is likely to take a more prominent place in the surgeons preoperative optimization strategy.

Reprinted with permission from Martindale RG, McClave SA, Taylor B, Lawson CM. Perioperative nutrition: What is the current landscape? J Parenter Enteral Nutr. 2013;37(5):5S-20S.

noted the same beneficial results. PN has similar benefits in rare cases of severe malnutrition, where the gastrointestinal tract is not functional, but not in other patients. Observations that severely malnourished patients benefit most from supplemental nutrition may be founded on the concept that these patients experience a more profound shift from the fasted to the fed state with preoperative feeding, preservation of glycogen stores, decreased insulin resistance, and establishment of an anabolic milieu going into surgery.151 Preoperative carbohydrate loading and traditional preoperative feeding may in fact both work by this mechanism, setting a precedent for building muscle mass and promoting postoperative healing. Emerging research will continue to define the underpinnings of nutritions impact at the cellular and molecular level.152 Effective nutrition supplementation and metabolic manipulation have the potential to enhance effective cell metabolism to ensure a successful stress response for the cell and ultimately improve surgical outcomes.

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Summary and Conclusion

Identifying preoperative malnutrition and intervening with oral, enteral, or parenteral preoperative nutrition support is important to optimize the patients status and achieve the best possible outcome. Tools currently available, such as the NRS-2002, can help with this screening and are becoming increasingly important in clinical practice. Preoperative supplementation with immune-modulating formulas reduces infectious and noninfectious complications and shortens length of stay. Although these beneficial effects are noted consistently across various surgical specialties, not all of the literature has

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