Fasting in the Perioperative Period

Time elapsed from last oral intake is perhaps the most immediate and relevant issue regarding how nutrition affects the delivery of anesthesia to patients. The risk of aspiration on induction presents a severe, potentially modifiable risk to patients, such that the American Society of Anesthesiology promulgates fasting guidelines for patients undergoing elective procedures requiring anesthesia. The most recent 2017 guidelines recommend fasting times for clear liquids of 2 or more hours, 4 or more hours for breast milk, 6 or more hours for a light meal, and eight or more hours for a fatty meal, prior to undergoing general anesthesia, regional anesthesia, or sedation.

With the emergence of Enhanced Recovery After Surgery (ERAS) pathways, there has been renewed interest in nutritional optimization in the immediate perioperative period. The thought that major elective surgery is stressful and strenuous has led investigators to question whether preoperative carbohydrate loading might improve outcomes. In a recent meta-analysis, Amer et al. showed that a carbohydrate load of at least 10 g of glucose within 4 hours of surgery conferred a small, but real benefit in hospital length of stay (LOS) when compared to fasting. It appears that “carbo loading” may yield attenuation of the insulin resistance associated with the surgical insult.

If not for the risk of aspiration, might it be optimal to continue nutrition through the surgical period? While it is standard care to continue parenteral nutrition (PN) through surgery, as there is no increased risk for aspiration, best practices for enteral nutrition (EN) are still the subject of debate and research. It is clear that there are certain populations of patients who benefit from EN up to and during surgical interventions. In critically injured burn patients, it has become common practice at many centers to feed through operations with significant improvement in total calories delivered. Feeding up to and through surgery has also been reported in orthopedic procedures and has recently been extended to other surgical groups. There are also data to suggest that continuing postpyloric tube feeding in the critically ill intubated patient presenting for nonabdominal surgery does not increase the incidence of aspiration, suggesting that EN can be safely continued in the perioperative period.

Benefits of Early Enteral Feeding

Early EN in the ICU has myriad reports explaining the diverse mechanisms to support the observed benefits ( Table 33.1 ). The gastrointestinal tract comprises the largest immune organ in the body and is responsible for the production of over 80% of the immunoglobulin transported to extraintestinal sites. The ability of the gut to function appropriately as an immune organ is dependent on the maintenance of both structural and functional integrity. The integrity of the gut, in turn, is greatly dependent on continued exposure to luminal nutrient substrates. Both adaptive and innate immune defenses are active in this process. Innate mechanisms are dependent on epithelial tight junctions and secretory capabilities of the mucosa. Secretory immunoglobulin A (IgA) is an important component of the adaptive immune system, as antigens are tagged and presented to dendritic cells within Peyer patches, which are in highest concentration in the distal small bowel. Gut disuse over a period of as little as 5 days has been shown to dramatically decrease the mass of gut-associated lymphoid tissue (GALT) and the production of secretory intestinal IgA. These changes are completely reversed with reinstitution of EN therapy. Increases in intestinal permeability have been shown to correlate with the development and severity of multi-organ failure (MOF) syndrome. Using EN to modify the severity of the systemic inflammatory responses by attenuating metabolic and oxidative stress is a primary goal of nutritional therapy in the surgical or critically ill patient.

Timing of Nutrient Delivery

The optimal time to start nutrition support is influenced by a host of factors, including age, premorbid conditions, route of nutrient delivery, metabolic state, and organ perfusion and function. As previously noted, literature evaluating nutritional support for critically ill patients has analyzed heterogeneous populations. Nevertheless, these diverse studies provide a foundation to guide nutritional therapy in a wide range of ICU patient types (e.g., burn, trauma, abdominal surgery, oncologic surgery, and so on).

The reported physiologic benefits of early EN are, among others, prevention of adverse structural and functional alterations in the mucosal barrier, augmentation of visceral blood flow, and enhancement of local and systemic immune response. The clinical benefits of early EN, defined as within 24 to 48 hours of ICU admission, include reduced infectious morbidity, LOS, and, in some reports, reduced mortality, all with minimal risk of harm to the patient. Despite these acknowledged benefits, nutrition delivery remains suboptimal in a significant percentage of critically ill patients.

Acknowledging that the early initiation of nutrition support constitutes best practice, a multidisciplinary approach to determining appropriate timing in the individual patient cannot be overemphasized. Enteral feeding should not proceed until appropriate resuscitation has been undertaken ( Table 33.2 ). Early resuscitation remains a cornerstone of ICU therapy. Early and aggressive resuscitation, or “early goal-directed therapy,” involves the placement of invasive lines for monitoring, drug delivery, and volume resuscitation, with vasopressors if the patient fails to respond appropriately to volume expansion. While there is no one laboratory or hemodynamic parameter signaling the successful resuscitation of the critically ill patient, trends in hemodynamic parameters—including mean arterial pressures, central venous pressures, and pressor requirements in conjunction with urine output, arterial base deficit, serum lactate, and venous oxygen saturations—are utilized in order to determine the relative success of resuscitation.

Splanchnic circulation can increase by as much as 40% to 60% in the setting of enteral feeding. The specific actions of digestion and absorption increase the metabolic demand and oxygen utilization by the gastrointestinal tract. If supply falls short of demand, rare but devastating complications, such as nonocclusive mesenteric ischemia (NMI), can ensue ( Fig. 33.1 ). Fortunately, nonocclusive mesenteric ischemia is a very rare complication, but since its effects can be devastating, with mortality rates reported as high as 80%, enteral feeding in the hemodynamically unstable patient should be undertaken with extreme caution.

Pathophysiology of splanchnic hypoperfusion often associated with critical illness. GI, Gastrointestinal; MODS, multiple organ dysfunction syndrome.

(Modified from Schmidt H, Martindale R. The gastrointestinal tract in critical illness: nutritional implications. Curr Opin Clin Nutr Metab Care. 2003;6:587–591; and Mutlu GM, et al. GI complications in patients receiving mechanical ventilation. Chest. 2001;119:1222–1241.)

Following adequate resuscitation and assuming that no other absolute contraindication to enteral feeding exists (e.g., bowel obstruction), enteral support should be initiated as soon as possible, regardless of the status of traditional markers of bowel function (bowel sounds, flatus, passage of stool).

Numerous reports support the concept that the initiation of EN should not be delayed while waiting for evidence of bowel function, though the absence of the clinical markers of bowel function may be predictive of worse patient clinical outcomes and higher rates of EN intolerance. The approach of waiting for these signs leads to unnecessary delays in feeding. In a randomized trial, oral feeding initiated within 48 hours of gastrectomy, without waiting for traditional predictors of feeding tolerance (e.g., passing flatus) demonstrated the safety of the approach. There was no increase in morbidity, and there was a reduction in LOS. A recent meta-analysis, examining 15 studies and 1240 patients with gastrointestinal anastomoses, demonstrated reduced postoperative complications when feeding was initiated within 24 hours of operation. Other meta-analyses, specifically in ICU and trauma patients, report a significant decrease in mortality and infectious complications.

Recent approaches to maximize gut function in the postoperative and critical care settings include maintenance of visceral perfusion; glycemic control; electrolyte correction; early EN; and minimization of medications that alter gastrointestinal function, such as anticholinergic agents, opioids, and high-dose vasopressors. Gastrointestinal intolerance should be continually reassessed, as it can manifest clinically in a variety of forms, including acidosis, abdominal distension, increased gastric residual volumes or nasogastric output, abdominal pain, or diarrhea. The segmental contractility of the gastrointestinal tract should be considered, as dysmotility can be focal (affecting predominantly either the proximal or distal bowel) or diffuse. Impaired gastric and proximal gastrointestinal motility ( Fig. 33.2 ) can be overcome rather efficiently through the placement of postpyloric feeding tubes. Postpyloric tubes can be successfully placed at the bedside in greater than 80% of patients.

Mechanisms involved in gastric dysmotility in the intensive care unit population. GES, Gastroesophageal sphincter; PPW, pyloric pressure wave.

(Modified from Caddell KA, Martindale R, McClave SA, et al. Can the intestinal dysmotility of critical illness be differentiated from postoperative ileus? Curr Gastroenterol Rep. 2011;13:358–367.)

Prokinetic agents can be used early and are helpful in some patients. Erythromycin acts on motilin receptors, resulting in increased motility, and can be used on a short-term basis but is limited due to tachyphylaxis. Metoclopramide, a 5-hydroxytryptamine (5HT ₄ ) receptor agonist, works via cholinergic stimulation and is primarily efficacious in the proximal gut. When using metoclopramide (see Chapter 32 ), one must also consider the potential for extrapyramidal side effects, especially in patients with altered mental status from traumatic head injury or cerebral vascular events. Alvimopam (see Chapters 17 and 18 ), a peripherally acting µ-antagonist, has demonstrated some success in the setting of dysmotility associated with opioid administration in the postoperative setting. No single prokinetic agent will have uniform success in the ICU, and the factors contributing to gastrointestinal dysmotility in each patient must be considered. Caution should be taken when using prokinetic agents on patients at high risk for bowel necrosis or obstruction.

Early EN is best accomplished in the ICU and postoperative settings, using standardized protocols. Protocolizing early enteral feedings in appropriately selected patients can reduce duration of mechanical ventilation, infectious complications, hospital LOS, and mortality.

Pharmaconutrition-Immunonutrition

In 1794, John Hunter described in his book, A Treatise on Blood, Inflammation and Gunshot Wounds, A Mechanism of Inflammation , an observation that “many types of injury produce a similar inflammation.” Similarly, in 1904, Sir William Osler stated, “except on few occasions the patient appears to die from the body’s response to infection rather than from it.” These two extremely insightful and prophetic comments were both made over 100 years ago. The current strategy in the ICU of using nutrition therapy to modulate inflammation and immune response in the surgical, traumatically injured, and critically ill populations is now widely accepted. This strategy of nutrition therapy, sometimes called pharmaconutrition or immunonutrition, uses specific nutrients to attenuate or control the body’s metabolic response to stress and trauma rather than allowing systemic inflammatory response syndrome (SIRS) to progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The metabolic response to stress that can ultimately lead to PICS has been well described, which includes a hyperdynamic cardiac and pulmonary state, insulin resistance, hyperglycemia, accelerated protein catabolism from muscle, poor adaptation to starvation, and increased oxidative stress. Unabated, the metabolic response to stress can culminate in immune suppression. During this hyperdynamic phase of critical illness, surgery, or trauma, the loss of lean body mass continues, despite delivery of seemingly adequate enteral or parenteral protein and calories. In effect, administration of standard “calories and protein” to the hyperdynamic patient will not reverse the adverse effects of ongoing loss of lean body tissue. The hyperdynamic induced loss of lean body tissue is made worse by “muscle unloading” ( Fig. 33.3 ). Several reports have now shown that using specific nutrients—such as fish oils, selected amino acids (e.g., arginine, glutamine, leucine), antioxidants, and nucleic acids—in quantities greater than necessary for “normal” metabolism has resulted in multiple outcome benefits, including shortened length of ICU and hospital stays, decreased incidence of infections, and reduced mortality in some cases.

Explanation for muscle loss during unloading of muscle in the intensive care unit. These effects culminate in prolonged, generalized muscle weakness. Weakness lasts for weeks to months; up to 50% of survivors do not return to pre-ICU function at 1 year.

A wide range of select specific nutrients have been reported to benefit the critically ill patient when delivered at pharmacologic quantities. Many of these compounds are now considered to be therapeutic agents in the management of complex, catabolically stressed patients ( Table 33.3 ). A collaboration between the Society of Critical Care Medicine (SCCM) and the American Society of Parenteral and Enteral Nutrition (ASPEN) resulted in Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient, which has been recently updated. These guidelines summarize the available evidence, and recommend that postoperative surgical ICU patients and patients with traumatic brain injury benefit from EN with immunomodulating formulas.

Several immune and/or metabolic modulating enteral formulas are now available globally. These products contain a variable quantity of nutrients identified and reported as beneficial during critical illness. Well over 100 prospective randomized human trials have been conducted with different combinations of these immune and metabolic modulating nutrients in various ICU, surgical, and medical populations. A wide range of methodologic quality is observed in these studies from relatively small, poorly designed studies to large prospective randomized clinical trials with intention-to-treat analysis. Most of the larger studies have been extensively analyzed and methodologically scrutinized by numerous reviewers. Despite the heterogeneity of the study designs, the majority of these studies report a clear benefit of reduced intensive care and hospital LOS, decreased antibiotic use, and reduced rates of infection. In particular, evidence cited in ASPEN/SCCM Guidelines suggests clinical effects of specific pharmaconutrients. These nutrients—including glutamine, fish oils, and arginine—have been credited with a reduction in infections and LOS in surgical patients. They produce a similar favorable impact on these outcomes in other ICU populations, although less dramatic benefit is noted.

Specific Nutrients

For decades, amino acids were believed to modulate intermediary metabolism, but the clinical outcome benefits of specific amino acids have only been reported over the last 15 years. Dietary supplementation with the amino acids glutamine, arginine, and leucine has been the focus of the majority of clinical trials, but other amino acids—specifically, glycine, taurine, citrulline, and glutamate—have received interest recently. This chapter will present only a brief summary of amino acid and Omega-3 fatty acid supplementation.

Arginine

Arginine is considered a nonessential amino acid under normal physiologic conditions of cell growth and development. Arginine becomes conditionally essential in the stressed mammalian host and plays a significant role in the intermediary metabolism of the critically ill patient. Key contributions of arginine include it being a secretagogue for the release of growth hormone, prolactin, and insulin, as well as stimulation of proliferation and activation of T cells. L-Arginine is available to the host from endogenous synthesis as part of the urea cycle (via citrulline conversion in the kidney), from endogenous protein breakdown, and from dietary protein sources ( Fig. 33.4 ). A typical western diet only contributes about 20% to 25% of total arginine.

Metabolic pathways for arginine. In critical illness, the exogenous supply of L-arginine is reduced and endogenous demand is increased by increases in arginase and iNOS activity. Reduced levels of L-arginine lead to T-cell dysfunction and impaired immune responses, resulting in infection. ASL, Arginosuccinate lyase; ASS, arginosuccinate synthase; NO, nitric oxide; NO ₂ ⁻ , nitrate; NO ₃ ⁻ , nitrate; iNOS, inducible nitric oxide synthase; OTC, ornithine transcarbamylase.

Arginine is a prominent intermediate in polyamine synthesis (one of the primary regulators of cell growth and proliferation), proline synthesis (wound healing and collagen synthesis), and is the only biosynthetic substrate for nitric oxide (NO) production from the three isoforms of nitric oxide synthase (eNOS, iNOS, nNOS). NO is a potent intracellular signaling molecule influencing virtually every mammalian cell type. Arginine also serves as a potent modulator of immune function via its effects on lymphocyte proliferation and differentiation, as well as its benefits in improved bactericidal action via the arginine NO pathway.

The de novo synthesis and dietary intake is reduced in acute surgical and major metabolic insults. Following these insults, immature cells of myeloid origin are present in the circulation and lymph tissue; these cells express high levels of arginase-1, an enzyme that degrades arginine to ornithine. While exogenous and endogenous supply of arginine is decreased, the host’s cellular demand for arginine is increased. This accelerated demand for arginine in the settings of trauma, surgery, sepsis, and critical illness is driven mainly by the upregulation of arginase in several tissue beds (arginase I and arginase II) yielding urea and ornithine and of iNOS yielding NO and citrulline. This state of relative arginine deficiency is manifested in the suppression of T-lymphocyte function and proliferation. Other signs of T-cell dysfunction after surgery or trauma include a decrease in the number of circulating CD4 cells, increased production of interleukin-2 and interferon gamma, and the loss of the zeta chain peptide, which is essential in the T-cell receptor complex. These changes in arginase activity result in impaired immune function at multiple levels of the immune response. This defect in immunocompetence can contribute to an increased risk of infection for critically ill patients.

Making generalized statements about amino acid metabolism in critical care is extremely difficult because the ICU population is such a heterogeneous group. Without strong scientific evidence validating the toxicity or benefits of today’s most popular dietary supplements, let alone an amino acid with the metabolic complexity of arginine, making global recommendations is naïve. Both animal and human data are available to support arguments for and against the use of supplemental arginine in the ICU populations. These results will strongly depend on dose given, model chosen to study, and duration of therapy. Trends are beginning to show the majority of the literature supporting use of arginine supplementation in both medical and surgical populations.

Clinical Outcome Studies Using Arginine

Of all the pharmaconutrients, arginine has prompted the most controversy. The theoretical concept that arginine may pose a threat to the surgical or critically ill patient is mainly based on the perception that postoperative or septic surgical patients are often hemodynamically unstable, with upregulated iNOS enzyme activity. Consequently, by delivering supplemental arginine in metabolic states of upregulated iNOS, an increase in NO will result in vasodilation and hypotension, leading to even greater hemodynamic instability and organ dysfunction. This hypothesis has not held up in clinical practice; a nonselective NOS inhibitor was administered in high doses to counteract vasodilation and hypotension in patients with severe sepsis in septic shock. The 28-day mortality rate was significantly increased when compared to patients receiving placebo (5% dextrose), 59% versus 49%, respectively ( P < 0.001). In fact, in this study, the highest mortality occurred within 72 hours in the treatment group. An alternate, equally valid hypothesis would be that controlled vasodilation would be beneficial in critical illness and sepsis. Shock, by definition, is inadequate delivery of oxygen and nutrients to maintain normal tissue and cellular function. It is logical to think that the vasodilation resulting from supplemental arginine is a cellular adaptive mechanism attempting to increase delivery of oxygen to the cell. This concept was illustrated in a study in which investigators attempted to modulate asymmetric-dimethylarginine (ADMA) in septic patients by tight glycemic control but was unsuccessful in altering the course of sepsis. As with other studies, the investigators were left to question whether the effect of an endogenous inhibitor of NOS synthases is preferable to potentially beneficial effects of arginine.

ADMA has been shown to increase in states of inflammation in acute infections and other stress models and has been well described. It has been suggested that an imbalance of arginine and ADMA is associated with altered endothelial cell function and cardiac dysfunction. Some investigators reported that elevated arginine and lower ADMA resulted in improved mortality in septic patients. A lower ratio of arginine to ADMA resulted in poor organ perfusion and decreased cardiac output. Until recently, few studies had evaluated supplemental arginine as a single agent in the critically ill and septic patient population. An elaborate series of tracer studies in a clinical trial dealing with citrulline and arginine metabolism in septic patients has shed light on this controversy. The complex metabolic alterations noted in sepsis that contribute to reduced citrulline and arginine availability suggest that supplemental arginine may, in fact, be beneficial in the septic population. In another study using tracer technology, investigators evaluated arginine in sepsis and also concluded that arginine may be deficient in sepsis because of inadequate de novo synthesis.

Arginine is perhaps the most controversial of the immunomodulating nutrients, but it is important to reiterate that investigations examining the physiologic impact of arginine and its related enzymes, the NOSs, have been conducted in different critically ill populations (medical vs. surgical, severely septic vs. nonseptic, and so on) using variable dosing, making generalizations to all ICU populations difficult. Current expert opinion suggests that there may be subgroups of patients whose vascular function is improved by L-arginine supplementation and there may be other subgroups of patients who simply do not benefit from L-arginine dietary supplementation. At this time, the ASPEN/SCCM 2016 guidelines do not recommend routine arginine supplementation for medical ICU patients, but do recommend its routine use in surgical and trauma patients, including those with traumatic brain injury. Arginine dose and patient selection are likely important factors affecting any study outcome.

Arginine is available to the host from numerous sources. “Normal” arginine intake for a western diet is between 5 and 7 g/d, while endogenous production of arginine is estimated at 15 to 20 g. Studies using different doses of arginine, from 5 to 30 g/d in the normal host, have shown varying results. It appears that orally delivered arginine supplementation up to 30 g/d is safe, with few gastrointestinal side effects. The current routinely used critical care enteral formulas deliver between 0 to 18.7 g of supplemental arginine per liter of formula. It is estimated that, on average, an ICU patient receiving arginine supplemented enteral feeding at prescribed rates would receive between 15 to 30 g/d of supplemental arginine. Several factors must be considered when deciding if arginine fits into the therapeutic plan of the critically ill patient. One must evaluate organ systems involved, timing of nutrient delivery, and location and route of delivery and, interestingly, coadministration without other “immune” or “metabolically” active agents (e.g., fish oils or nucleic acids). In very different models, several studies have both shown that delivery of an omega-3 fatty acid (FA) with arginine will significantly alter the arginine metabolism via arginase and iNOS, possibly yielding more available arginine. Ornithine alpha-ketoglutarate (OKG) and citrulline are other nutrients that have been reported to have potential interaction with arginine. Citrulline is poorly metabolized by the liver, essentially bypassing the first-pass hepatic nutrient metabolism, making it highly bioavailable via oral route. Citrulline is then converted to arginine in the kidney, making citrulline a key component in arginine homeostasis, especially in the critically ill population. Ultimately, it can be difficult to tease out the separate effects, as immunonutrients are often given together with overall good clinical outcomes in both critically ill patients and those who are not critically ill.

The appropriate arginine level and supplemental dose of arginine in the critically ill or hypermetabolic patient in which a proinflammatory state exists is difficult to determine and remains to be defined. Arginine is very tightly regulated within the cell by multiple mechanisms—including regulation of arginine membrane transporters, as well as arginase and NOS enzymatic activity—and the colocalization of enzymes in the membrane leads to variable concentration within the intracellular space. Arginine appears safe and beneficial in the levels delivered by commercially available formulations containing supplemental arginine. It is clear that additional research is needed on the influence of arginine in specific populations, specific disease conditions, and the gene–nutrient interactions.

Recommendations Regarding Delivery of Arginine

It appears from review of human data that arginine is safe and beneficial at doses delivered in immune and metabolic modulating formulas for most all hemodynamically stable ICU populations able to tolerate enteral feeding. This would include medical and surgical ICU patients, trauma patients, major surgical patients, and those post-myocardial infarction or with pulmonary hypertension. Elective major surgical patients across multiple surgical specialties can be expected to benefit from a reduction of surgical infections when arginine-containing formulations are applied in the perioperative setting.

Omega-3 Fatty Acids

Although lipids are a mainstay in nutritional therapy for the critically ill and surgical populations and numerous choices exist ( Table 33.4 ). Controversy still exists regarding lipid digestion, absorption, and utilization in hyperdynamic surgical settings. The heterogeneous nature of the ICU population makes lipid administration in these groups somewhat challenging. Although uncertainty exists on which lipid formulation to deliver, there is no debate regarding the need to meet the essential FA and cellular oxidation requirements. The use of lipids in this manner replaces malabsorbed lipid nutrients and serves as a daily source of calories shown to be equally nitrogen sparing with glucose when administered continuously for 4 days. The beneficial antiinflammatory effects of n-3 FAs, primarily eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA, respectively), have been well documented in several chronic inflammatory diseases, including rheumatoid arthritis, Crohn disease, ulcerative colitis, lupus, multiple sclerosis, and asthma (see Table 33.4 ).

TABLE 33.4

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