Critical Care Nutrition

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94 Critical Care Nutrition

Juan B. Ochoa, Daren K. Heyland, Stephen A. McClave

The overall efficacy of nutritional support, the need to start nutritional therapy (NT) in the first place, and its likelihood to impact patient outcome are all determined by a number of clinical factors. All patients need a thorough and careful evaluation of their capacity to eat and the quantity and quality of their nutritional intake. When spontaneous oral intake is not possible or insufficient, or feeding patterns are disrupted, nutritional intervention is valuable. The quantity and quality of nutritional intake varies constantly to adjust to physiologic needs and thus is highly individualized. Individual evaluations and plans for NT in patients who cannot eat should also be highly individualized. The appropriate route or specific design of therapy for one disease process cannot necessarily be extrapolated (or expected to be effective) for a different disease process. Severity of illness within the patient population, level of physiologic stress, and baseline nutritional status before injury often determine a patient’s need for and response to NT. Even when NT is indicated, factors related to overall amount, content, route, and timing may determine whether nutritional support influences outcome or is rendered ineffective.

Thinking about the true value of nutritional support in the intensive care unit (ICU) setting has undergone a paradigm shift. In the past, goals of nutritional support were to provide adjunctive therapy to support the stress response, provide exogenous nutrients to reduce the drain on endogenous stores and the depletion of lean body mass, and prevent the consequences of protein-calorie malnutrition. Today, providing early enteral feeding to critically ill patients is seen as a therapeutic tool or strategy to attenuate disease severity, modulate the immune response, restore or maintain gastrointestinal (GI) physiology, and through these effects, favorably impact patient outcome. Basic laboratory research and extensive clinical trials provide the basis for provision of NT to those patients who need it.

Less than ideal NT is unfortunately provided to a significant proportion of ICU patients. A recent evaluation of nutrition practices in 158 ICUs across 20 countries by Cahill et al.¹ reported significant deficits in meeting caloric and protein goals and adhering to the provision of specialized nutrition. For example, delivery of protein goals was only achieved 60.3% of the time.

One of the complex reasons for failing to prescribe and deliver NT as a standard of care is lack of awareness of its importance. Thus, this chapter emphasizes the importance of timely and adequate NT. Attaining access and initiating enteral feeding is considered part of the basic resuscitation of critically ill patients. Although any artificial nutritional support involves some risk, providing early enteral feeding is clearly an integral component of what should be considered optimal care.

Gut Use and Differential Response to Feeding and Starvation

Lack of adequate food intake is a frequent problem in the ICU. Diseases are frequently associated with significant anorexia and/or inability to eat. Surgical procedures and diagnostic tests often demand an empty stomach. A nil per os (NPO) order is too easily written even in the absence of a logical reason to do it. Despite physiologic differences between starvation in a healthy individual and lack of adequate intake during illness, it is essential to study starvation as an important aspect of nutritional care in the critically ill patient. The functional and structural integrity of the GI tract is affected by whether the gut is used and the patient receives enteral feeding. Animal and human studies suggest that enteral feeding maintains mucosal mass, stimulates cellular proliferation and production of brush-border enzymes, and maintains villus height.²^–⁴ Enteral nutrients maintain the integrity of tight junctions between intestinal epithelial cells, stimulate blood flow to the gut, and promote release of a variety of endogenous agents such as cholecystokinin, gastrin, bombesin, and bile salts—substances with trophic effects on intestinal epithelium. Bombesin, for example, can reverse all the histologic and functional deficits caused by parenteral feeding,⁵ and gastrin and cholecystokinin can encourage partial recovery of gut-associated lymphoid tissue after the use of parenteral nutrition (PN).⁶ Secretory immunoglobulin A (sIgA) and the production of bile salts help coat bacteria within the GI tract, preventing adherence. Along with the production of mucus and good GI contractility, this helps wash away bacteria in a caudad direction.³ These mechanisms, together with antimicrobial secretions such as pancreatic enzymes, proteases, and lactoferrin help keep the total number of bacteria in check. The normal predominant anaerobic flora of the gut is maintained, preventing overgrowth of more pathogenic organisms such as Enterobacteriaceae, a process referred to as colonization resistance.⁷

Gut disuse, with or without PN, can lead to deterioration of the functional and structural integrity of the gut. In animals, gut disuse is associated with a marked reduction in villus height, cellular proliferation, mucosal mass, and brush-border enzymes. Intestinal changes caused by starvation in humans are less pronounced than in rodents, but whereas gut disuse may result in a 40% decrease of mucosal mass in rats, the decrease in humans still appears to be about 10% to 15%.² In humans, loss of villus height in response to pancreatitis is diminished by enteral feeding.⁴ Villus atrophy is perpetuated in a time-dependent fashion with parenteral feeding.³ Starvation alone may be insufficient to increase gut permeability, but injury followed by starvation increases mucosal permeability proportional to the severity of disease.^3,⁸ Increased permeability is prevented through early feeding, and in burns inversely correlates with the amount of enteral feeding delivered.⁹ Increases in gut permeability are associated with systemic endotoxemia in humans.^8,¹⁰ Among burn patients, infection is associated with increased gut mucosal permeability.⁹ Increases in gut permeability in critically ill patients correlate with the development of organ dysfunction.¹¹

Lack of feeding in animals results in bacterial overgrowth and loss of mucosal defenses against bacterial invasion.^7,¹² Reduced peristalsis (ileus) can contribute to bacterial overgrowth. Reduced secretions of bile salts and sIgA promote bacterial adherence to the mucosa. Bacterial translocation, a process whereby bacteria transgress the mucosal barrier, is associated with aerobic bacterial overgrowth and decreased intestinal sIgA levels.³ Recent animal studies suggest that these gut-derived factors can reach the systemic circulation via the lymphatic system rather than via the portal bloodstream and thereby cause distant organ injury.¹³ Thus, animal models suggest that bacterial overgrowth in the lumen leads to bacterial translocation, potentially being a portal for development of sepsis and organ failure.

The significance of bacterial translocation in humans as a cause of systemic illness is still unclear.^14,¹⁵ Translocation of bacterial products such as endotoxin may also occur. Endotoxin itself, when infused in even small doses in normal volunteers, increases gut mucosal permeability.⁷ The intestinal secretion of sIgA is diminished within 5 days of gut disuse, with or without PN.^5,¹⁶ Respiratory tract secretion of IgA may be diminished even sooner. Reduction in the mucosal mass of gut-associated lymphoid tissue and decreased sIgA production increase susceptibility to infections normally controlled by IgA-mediated defenses in experimental animals.¹⁷ In mice, as little as 5 days of gut disuse with PN results in loss of protection against respiratory viral infection and reduces clearance of the virus.¹⁸ Refeeding with enteral nutrients restores antiviral defenses. Established antiviral mucosal immunity is lost when the GI tract is not stimulated by enteral feeding.¹⁷

Dendritic macrophages act as antigen-presenting cells that release cytokines and activate naive CD4⁺ helper T cells (T_H0).¹⁹ Secretion of interleukin (IL)-12 stimulates the naive cells to differentiate into T helper 1 (T_H1) lymphocytes, favoring a proinflammatory response and release of other proinflammatory cytokines such as IL-2, interferon gamma (IFN-γ), and tumor necrosis factor (TNF). T_H1 responses are associated with increased inflammation and are essential for host defenses against infection. Uncontrolled T_H1 responses, however, can result in self-injury. Production of IL-4 also stimulates differentiation of T_H0 into T_H2 lymphocytes,¹⁹ leading to secretion of additional IL-4, IL-6, and IL-10. The T_H2 response tends to curb or check the T_H1 inflammatory response. T_H2 responses are essential to prevent self-injury caused by inflammation. However, excessive regulation of inflammatory responses by T_H2 cytokines can lead to immune suppression.¹⁹

Gut disuse, with or without PN, alters the balance of these lymphocyte populations and the profile of associated cytokines. In animals, gut disuse with PN for 5 days decreases IL-4 and IL-10 secretion and markedly reduces sIgA levels.¹⁷ In human babies, use of PN reduces sIgA in intestinal immunocytes.²⁰ IFN-β, IL-5, and IL-6 production by T_H1 lymphocytes is not affected by gut disuse and PN.²¹ Thus, the absence of enteral nutrition (EN) can unbalance the ratio of proinflammatory to antiinflammatory responses.

Gut disuse affects expression of adhesion molecules required for proper homing by naive B cells to the intestinal lamina propria and gut-associated lymphoid tissue. MADCAM-1 is the primary ligand required for the proper homing of B cells, and decreased expression of this molecule interferes with the normal migration of B cells from the vascular space into the lamina propria, leading to atrophy of Peyer’s patches. In animals, there is a 60% decrease in MADCAM-1 expression within 4 days of initiating PN.¹⁷ Within 3 days of starting PN, the number of T and B cells in the lamina propria and Peyer’s patches decreases by about 50%.³ In this model, secretion of the T_H1 cytokine, IFN-γ, is unchanged, but secretion of the T_H2 cytokines, IL-4 and IL-10, decreases. Decreased production of IL-4 and IL-10 leads to increased expression of the adhesion molecules, ICAM-1 and E-selectin, in both the intestinal and pulmonary microvasculature. Increased E-selectin expression on endothelial cells in the pulmonary microvasculature promotes sequestration and extravasation of polymorphonuclear neutrophils.²²^–²⁴ As a result, any subsequent injury (e.g., ischemia-reperfusion) can promote accumulation of polymorphonuclear neutrophils in the lungs, exacerbating organ injury and even increasing mortality.^25,²⁶ Abundant data demonstrate that gut disuse through starvation, either caused by disease or through ill-advised physician orders or neglect, is a real problem that contributes to development of systemic infections, a systemic inflammatory response, and development of multiple organ failure.

EN, particularly if started early, prevents the ill effects of starvation. Normal enteral feeding stimulates proliferation of T_H2 CD4⁺ helper T lymphocytes and the production and release of IgA-stimulating cytokines including IL-4, IL-5, IL-6, IL-10, and IL-13.²⁷ This process is normally counterbalanced by proliferation of T_H1 CD4⁺ helper T lymphocytes and IgA-inhibitory cytokines including IFN-β, TNF, and IL-2. IL-4 stimulates naive CD4⁺ helper T lymphocytes to convert to IgA-positive B cells in Peyer’s patches. IL-10, IL-5, and IL-6 stimulate the differentiation of IgA-positive B cells into sIgA-secreting plasma cells in the lamina propria.¹⁷

Approximately 1 ton of food passes through the intestinal tract of an adult human every year.²⁰ About 1/100,000 of this intake represents intact immunologic antigen.²⁰ Oral tolerance refers to the process whereby the immune response is down-regulated to prevent excessive responses to common antigens found in food and in the commensal bacterial flora of the GI tract. During the induction of oral tolerance, an alternative pathway for CD4⁺ helper T-cell activation leads to proliferation of special regulatory T cells (T_H3 and Tr1) which produce the counter-regulatory cytokines, IL-10 and transforming growth factor beta (TGF-β).²⁰ The stimulation and proliferation of T_H3 cells induced by enteral feeding therefore promotes expression of a balanced T_H2/T_H1 profile. The large dietary and indigenous microbial antigenic load is extremely important for maintaining normal mucosal immunity.²⁰ Antigenic constituents of food clearly exert a stimulatory effect on the intestinal B-cell system, helping to explain why enteral feeding supports a high density of IgA-secreting immunocytes within the intestinal lamina propria. Continued enteral feeding, as well as maintenance of the indigenous microbial flora in the gut, may help keep a balance between the T_H1 and T_H2 profile and prevent an exaggerated T_H1 inflammatory response.

The importance of EN for modulating the inflammatory response was illustrated by a classic study of human volunteers challenged with a small dose of Escherichia coli lipopolysaccharide (endotoxin).²⁸ One group of subjects was maintained for 1 week without feeding and received PN, whereas another group was fed enterally during the same period. After 7 days of either PN or EN, both groups were challenged with lipopolysaccharide. The subjects in the PN group had an exaggerated response to the proinflammatory stimulus, manifested by higher circulating levels of cortisol and TNF, among other findings. Similarly, following injury or an inflammatory disease process, early enteral feeding can blunt the hypermetabolic response.^29,³⁰ Among patients with acute pancreatitis, those fed enterally rather than parenterally had significantly lower circulating levels of C-reactive protein, less evidence of oxidative stress, faster resolution of systemic inflammatory response syndrome (SIRS), and a greater decrease in their Acute Physiology and Chronic Health Evaluation (APACHE) II scores over a week of nutritional therapy.¹⁴ In another study of patients with acute pancreatitis, there was faster resolution of the disease process among patients treated with enteral feeding compared with similar patients receiving PN.³¹

The traditional model of SIRS and the compensatory antiinflammatory response syndrome (CARS) described in trauma and sepsis may be influenced by the differential immunologic response between enteral feeding and starvation or gut disuse.³² In SIRS, there appears to be an up-regulated, nonspecific activation of the innate immune system, with an increase in the expression of proinflammatory cytokines such as IL-1, TNF, IL-2, and IFN-γ. This profile is similar to that of the T_H1 subset response (in which IFN-γ, TNF, and IL-2 are produced). Intracellular bacteria and viruses absorbed through the intestinal epithelium may activate dendritic cells, macrophages, and natural killer cells to produce IL-2 and IFN-γ, which causes naive CD4 cells to proliferate into T_H1 cells. CARS, in contrast, appears to be a pattern of macrophage deactivation, reduced antigen presentation, and T-cell anergy, which results in a shift of the T–helper cell pattern to a T_H2 response.³² Gut disuse following injury or illness may promote a SIRS response through stimulation of both the innate immune system (causing a hyperinflammatory response from macrophages and natural killer cells) and the acquired immune system (resulting in a shift from a T_H2 to a T_H1 profile).

Compared with the metabolic response to enteral feeding, this exaggerated stress response to gut disuse with or without PN has been shown to exacerbate disease severity, increase the rate of complications, and lead to prolongation of the disease process.^14,³¹ There is thus little justification to prolonging NPO status in critically ill patients beyond the period absolutely necessary during resuscitation, surgery, or other procedures. Process-improvement efforts aimed at minimizing starvation is an important goal of any modern ICU.

Impact of Enteral Nutrition on Outcome

Based on the theoretical rationale presented so far, EN should be associated with improved clinical outcomes in critically ill patients. To evaluate the clinical evidence in support of using EN, we considered three groups of studies. The first are randomized trials that directly compared EN and PN. The second group includes studies that compared early EN (started within 24-48 hours of resuscitation) to more delayed forms of nutritional support (e.g., delayed EN, PN, or oral diet). The third group includes studies that evaluated various methods of delivering EN.

A recently published systematic analysis reviewed data from 13 randomized controlled studies comparing EN and PN in heterogeneous populations of ICU patients, including those with head trauma, abdominal trauma, sepsis, and severe acute pancreatitis, among other conditions.³³ When a meta-analysis was carried out, there was no apparent difference in mortality rate between patients treated with EN and those treated with PN (relative risk [RR] 1.08; 95% confidence interval [CI], 0.70-1.65; Figure 94-1). However, compared with PN, EN was associated with a significant reduction in infectious complications (RR 0.61; 95% CI, 0.44-0.84; Figure 94-2).

Figure 94-1 Studies comparing parenteral nutrition (PN) and enteral nutrition(EN) in terms of effect on mortality. CI, confidence interval; RR, relative risk.

Figure 94-2 Studies comparing parenteral nutrition (PN) and enteral nutrition (EN) in terms of effect on infectious complications. CI, confidence interval; RR, relative risk.

Eight randomized controlled trials that compared early EN with more delayed forms of nutrition were recently reviewed and analyzed.³³ When these studies were aggregated, early EN was associated with treatment benefits that approached statistical significance. Early EN was associated with reduced mortality (RR 0.52; 95% CI, 0.25-1.08; Figure 94-3) and fewer infectious complications (RR 0.66; 95% CI, 0.36-1.22; Figure 94-4) compared with delayed nutrient intake. These differences approached but did not achieve statistical significance. No differences in length of hospital stay were observed between the groups. All seven studies that reported nutritional endpoints (e.g., nitrogen balance) showed a significant benefit for early EN. There were no differences in complications between the groups.

Figure 94-3 Studies comparing early versus delayed nutrient intake in terms of effect on mortality. CI, confidence interval; EN, enteral nutrition; RR, relative risk.

Figure 94-4 Studies comparing early versus delayed nutrient intake in terms of effect on infectious complications. CI, confidence interval; EN, enteral nutrition; RR, relative risk.

A number of strategies can be employed to maximize the delivery of EN while minimizing the risks of gastric colonization, gastroesophageal regurgitation, and pulmonary aspiration (Box 94-1). By delivering enteral feeds into the small bowel beyond the pylorus, the frequency of regurgitation and aspiration is decreased.³⁴ In a recent meta-analysis, there were seven randomized trials that evaluated the effect of route of feeding on rates of ventilator-associated pneumonia.³⁵ When these results were aggregated, there was a significant reduction in ventilator-associated pneumonia with feeding distal to the pylorus (RR 0.76; 95% CI, 0.59-0.99). These studies also demonstrated that small-bowel feeding is associated with an increase in protein and calories delivered and a shorter time to attain the target dose of nutrition.

Box 94-1

Strategies to Optimize Benefits and Minimize Risks of Enteral Nutrition

Initiate early, within 24-48 h of admission.

Use small-bowel feedings.

Elevate head of the bed.

Use motility agents.

Reduce dose of narcotics prescribed.

Use feeding protocol that enables consistent evaluation of gastric residual volume and specifies when feeds should be interrupted.

Unless logistic problems represent an unacceptable hurdle, we recommend routine use of small-bowel feedings. If routine use of this strategy is not feasible, small-bowel feedings should be considered for patients at high risk for intolerance to EN (e.g., patients receiving inotropic or vasoactive drugs, continuous infusion of sedatives, or paralytic agents; or those with large volumes of nasogastric drainage) or at high risk for regurgitation and aspiration (e.g., patients kept supine). Finally, if obtaining small-bowel access is not feasible (e.g., because access to fluoroscopy or endoscopy is limited and blind techniques are not reliable), small-bowel feedings should be considered for selected patients who repeatedly have large gastric residual volumes and are not tolerating adequate amounts of EN intragastrically.³³ Additional strategies to maximize the benefits of EN while minimizing the risks (see Box 94-1) include caring for the patient with the head of the bed elevated 30 to 45 degrees,³⁶ using GI promotility agents, reducing doses of opioids,³⁷ and using nurse-directed feeding protocols that include frequent checking of gastric residual volumes.^38,³⁹

When data from all sources are considered, there is substantial clinical evidence, supported by a compelling theoretical rationale, that EN influences the clinical outcome of critically ill patients. EN is preferable to PN, and methods to maximize delivery and minimize risks should be considered in all critically ill patients receiving specialized nutritional support.

Assessment of the Critically Ill Patient

The clinician must first evaluate the level of stress in a critically ill patient to determine the likelihood of deterioration in nutritional status and to assess the overall need for aggressive nutritional support. Standardized scoring systems such as APACHE II or APACHE III, the Injury Severity Score (ISS), and the Abdominal Trauma Index (ATI) can be helpful for determining the level of stress and the likelihood of deterioration in nutritional status.^40,⁴¹ Scoring systems have also been used to assess the need for nutritional support in patients with acute pancreatitis.⁴² Patients with an APACHE II score greater than 10 and having more than three Ranson’s criteria require additional nutritional support.⁴²

Assessment of the patient’s nutritional status is difficult in the ICU. Classic chemical biomarkers, such as circulating levels of albumin and prealbumin, and immunologic parameters, such as lymphocyte counts, are all affected by the inflammatory response observed in critical illness. It is also the case for other parameters such as isokinetic dynamometry. Clinicians therefore have to be diligent at obtaining an excellent history and physical examination, identifying clinical signs of malnutrition. A history of poor nutrient intake and recent weight loss should alert the clinician that gut assimilation may be a problem, that more aggressive delivery of enteral or parenteral nutrients is appropriate, and that there is a greater need to meet calorie and protein requirements sooner in the hospital course (see Figure 94-2).

If the overall level of stress and severity of illness indicate the need for nutritional support, the clinician must next evaluate the status of the GI tract. Intravascular volume status should be optimized before initiating enteral feeds. It is not safe to infuse nutrients into the gut if there is ongoing ischemia or a high risk of mesenteric hypoperfusion. Feeding standard enteral formulas to patients with hypotension, hypovolemia, or septic shock, especially when vasopressors are being used to support blood pressure, may precipitate bowel ischemia.⁴³

The concept of ileus and the clinical impression that the gut is “not working” can be misleading because intestinal motility is segmental in nature. The adequacy of gastric emptying can be evaluated by determining the presence or absence of nausea and vomiting, high residual volumes, or high output from the nasogastric tube. Colonic motility is evaluated by determining whether the patient is passing stool or gas. Small-bowel motility is evaluated by determining the presence or absence of abdominal distention and bowel sounds. However, absorption of nutrients from the small bowel does not require intestinal motility. Infusing nutrients into the lumen of the small intestine (with or without simultaneous gastric decompression) actually can stimulate intestinal motility via the release of gastrin, bombesin, motilin, and other promotility hormones. Thus, the possible presence of ileus should not be used as an excuse to withhold oral or enteral intake; gut motility actually can improve with aggressive attempts to provide nutrition enterally.

When EN is started soon after the onset of critical illness (i.e., enteral nutrients have been lacking only a short time), one can presume that the integrity of the intestinal mucosa is well maintained, and a standard enteral formula can be used. If the period of gut disuse has been more prolonged, the clinician must consider the possibility that mucosal integrity is not normal. If there is evidence of malassimilation and diarrhea, enteral formulas containing oligopeptides may enhance absorption and assimilation of protein.⁴⁴ In a recent review of 19 prospective randomized trials in humans, 11 studies showed evidence of clinical benefit when oligopeptide-containing formulas were used instead of standard enteral (intact protein) formulas. Although there was no impact on patient outcome, the benefits of oligopeptide-based diets included significantly improved nitrogen absorption, higher visceral protein levels, more weight gain, less frequent stooling, and reduced stool volume.⁴⁴

Once EN is started, the clinician must monitor tolerance. Overall assimilation of nutrients by the enteral route is assessed clinically by checking for the presence or absence of diarrhea. Additionally, it is important to monitor circulating concentrations of glucose, triglycerides, urea nitrogen, and creatinine ratio. Risk factors for aspiration include age older than 60 years, decreased level of consciousness, bolus feeding, and supine position.⁴⁵^–⁴⁷ Gastric residual volumes, output from the gastric port of an aspiration or feeding tube, and passage of stool and gas are valuable indices of intestinal motility.

Practical Considerations

All critically ill patients require a nutritional evaluation, and many benefit from receiving nutritional therapy. The complexity and degree of nutritional intervention necessary is proportional to the patient’s severity of illness. In the ICU, nutritional intervention is subject to the same rules of any medical therapy demonstrating a mechanism of action, a benefit in clinical outcome, acceptable risks and side effects, and ideally a cost benefit. The form of nutritional intervention a given patient should get is not necessarily intuitive. In certain disease processes associated with high severity of illness—trauma, burns, acute pancreatitis, acute respiratory failure requiring mechanical ventilation, for example—the decision to use the parenteral rather than the enteral route for feeding can significantly affect outcome.^48,⁴⁹

The greater importance of EN among sicker patients was first shown by evaluating septic complications in trauma patients randomized at the time of surgery to receive either PN or EN.⁵⁰ Patients were ranked for severity of disease by their ATI scores. Among patients with ATI scores higher than 24, the incidence of septic complications was greater in the PN group than in the EN group (47.6% versus 11.1%; P < 0.05). Among patients with moderate illness and ATI scores lower than 24, there was no significant difference in the incidence of septic complications between the PN and EN groups (29.2% versus 20.8%; P = NS).⁵⁰

Further evidence of the importance of maintaining gut integrity in patients with more severe disease was provided by a series of prospective randomized controlled trials of EN versus PN in patients with acute pancreatitis.^14,^51,⁵² In the first trial published, feeding by the enteral route was shown to be safe, but only 19% of the patients had severe pancreatitis, and there were no differences in the rates of nosocomial infection, organ failure, or overall complications.⁵² In a second study, 38% of the patients had severe pancreatitis, and a significantly greater percentage of those fed enterally rather than parenterally had resolution of SIRS over the first week of therapy (81% versus 17%; P<0.05); nevertheless, there were no differences between the groups with respect to rates of nosocomial infection or complications.¹⁴ In a third study, 100% of the patients had severe pancreatitis, and septic complications were reduced from 50% in the PN group to 28% in the EN group (P<0.05); the overall rate of complications was reduced from 75% in the PN group to 44% in the EN group (P<0.05).⁵¹

For EN support, clinicians must determine caloric requirements in order to set a goal or mandatory threshold for the volume, or “dose,” of enteral feeding provided. Use of indirect calorimetry or simplistic equations (e.g., 25 kcal/kg/d) to estimate caloric requirements can help identify this threshold amount. Focusing on such a goal volume allows clinicians to determine a dose/response effect of enteral tube feeding; that is, the percentage of this goal volume required to achieve desired therapeutic endpoints (maintenance of gut integrity, containment of intestinal permeability, attenuation of the stress response, reduction of overall disease severity). In the early stages of critical illness, patients are in the throes of the hypermetabolic stress response and more prone to ileus owing to higher doses of narcotics, electrolyte abnormalities, and shifts in fluid volume. In this situation, it is difficult to provide full caloric requirements. The minimum amount or volume of feeds (as a percentage of total caloric requirements) sufficient to achieve the desired therapeutic effect is not known. Recent evidence suggests that “trophic” or “trickle” rates of feeding (usually meaning 10-30 mL/h of a nutritional formula containing ≈1 kcal/mL) are probably inadequate to provide demonstrable benefits. Data from clinical studies indicate that 50% to 65% of goal calories are needed to prevent increases in intestinal permeability in burn victims ^9,⁵³ and bone marrow transplant patients (M.T. Demeo, personal communication), promote better and faster return of cognitive function in head injury victims,⁵⁴ and reduce the duration of mechanical ventilation and ICU and hospital length of stay in critically ill patients.⁵⁵ When higher feeding rates are not feasible, trickle feeds may have limited value and should be provided, but efforts to infuse greater volumes should be continued.

Immunonutrition

An additional strategy to maximize the benefits of EN is to use formulas supplemented with specific nutrients thought to modulate the immune system, facilitate wound healing, and reduce oxidative stress. Enteral formulas have been developed that contain certain compounds such as L-glutamine, L-arginine, and omega-3 fatty acids, as well as selenium, vitamins E, C, and A, and beta carotene in supraphysiologic concentrations. Use of these products has been called immunonutrition, and these products have been called immune-enhancing diets. Although the overall effect of these individual nutrients in critically ill patients remains unknown, we have endeavored to review the efficacy and safety of products supplemented with arginine, glutamine, fish oils, and antioxidants.

L-arginine

The amino acid, L-arginine, plays fundamental roles in protein metabolism and polyamine synthesis and is a critical substrate for nitric oxide (NO) production.⁵⁶ L-Arginine stimulates the release of growth hormone, insulin growth factor, and insulin, all of which may stimulate protein synthesis and promote wound healing. The enzyme, L-arginase, metabolizes L-arginine to L-ornithine, an amino acid implicated in wound healing. NO is produced by a family of enzymes called nitric oxide synthases (NOSs) which exist in constitutive and inducible isoforms.⁵⁷ Under normal conditions and in some disease states, small quantities of NO are synthesized by the constitutive forms, which have a beneficial effect on tissue oxygenation, vasodilation, and immune function.⁵⁸

In the absence of illness, L-arginine supplementation fails to demonstrate any significant effects on immune function. Upon immune activation, L-arginine transport is significantly increased in both myeloid and lymphoid cells, although the metabolic effects of L-arginine in these cell lineages is significantly different. L-Arginine is an essential compound for T-lymphocyte proliferation. In the absence of L-arginine, T lymphocytes lose membrane expression of the T-cell receptor complex and expression of the ζ chain, which is an intracellular peptide of the T-cell receptor. Production of some cytokines such as IFN-γ is quite sensitive to L-arginine. IL-2 production is also decreased, albeit more modestly than IFN-γ. The development of memory also appears to be compromised.

Myeloid cells can metabolize L-arginine through two different enzymes: inducible nitric oxide synthase (iNOS) or arginase-1 (ARG1). Classic inflammatory signals such as IL-1, TNF, IFN-γ, and endotoxin induce iNOS expression and the production of large amounts of NO. Classically, large amounts of NO are produced in septic patients, where excess NO production may be responsible for uncontrolled vasodilation and hemodynamic instability. Myeloid cells that produce NO are (in general) mature macrophages.

In contrast, signals that induce ARG1 expression include prostaglandin E₂, IL-4, IL-13, TGF-β, and IL-10, which are classically described as antiinflammatory. Up-regulation of ARG1 results in depletion of L-arginine, which can be observed in local tissues (e.g., spleen, possibly thymus) or systemically. Myeloid cells that express ARG1 are for the most part immature cells. Through L-arginine depletion, these cells regulate T-cell function and NO production; hence, these cells are called myeloid-derived suppressor cells (MDSC).

Yet a third state of myeloid activation can result in induction of both ARG1 and iNOS. Under these conditions, L-arginine myeloid cells paradoxically may generate reactive oxygen and nitrogen species such as hydrogen peroxide and peroxynitrite.

A growing number of illnesses exhibit a significant decrease in circulating L-arginine associated with the presence of MDSC expressing ARG1. T-lymphocyte dysfunction is characterized by loss of membrane expression of the T-cell receptor (TCR), loss of the ζ chain, and decreased production of IL-2 and IFN-γ. These disease states include certain cancers such as renal cell carcinoma, infections such as tuberculosis, and after physical injury (including trauma and elective surgery). Interestingly, L-arginine plasma levels in sepsis vary significantly, and low, normal, or elevated L-arginine plasma levels have been reported in the literature.

The dichotomy of L-arginine metabolism observed in myeloid cells (ARG1 versus iNOS) is thus best characterized by two disease processes: physical injury and sepsis, though obviously, a significant amount of overlap exists. Because L-arginine metabolism can take such significantly different routes, its supplementation in the diet can have significantly different biological consequences and affect clinical outcomes. Patient selection is thus an essential aspect of any clinical trial designed to evaluate the value of L-arginine supplementation.

L-Arginine is traditionally ordered at supraphysiologic doses along with omega-3 fatty acids, nucleotides, and other so-called immune nutrients and has been tested in patients recovering from elective surgery, trauma victims, and other critically ill patients, including those with sepsis.

Immunonutrition is the best studied aspect of NT in the ICU, and L-arginine remains the best studied compound in this context. Significant confusion regarding interpretation and results of these studies exists in the literature, in great part because a mechanistic hypothesis was poorly delineated. However, clear guidelines now have been reported by different organizations so that clinicians can safely incorporate the use of L-arginine into clinical practice. These guidelines are the result of improved understanding of L-arginine metabolism, the discovery of disease processes associated with severe L-arginine depletion, the negative biological consequences stemming from L-arginine deficiency, and a more careful analysis of the multiple clinical studies available. Guidelines for arginine supplementation can be summarized as follows:

1 Higher than normal (supraphysiologic) L-arginine supplementation is necessary. Normal L-arginine intake is 3 to 5 g/d. Diets available contain significant variation in the amount of L-arginine. In general, effectiveness of L-arginine as a dietary supplement is observed with diets containing higher concentrations of this compound.

2 Dietary supplementation with L-arginine alone should not be used, as only diets that contain a combination of L-arginine, omega-3 fatty acids, and nucleotides have been extensively tested and proven to provide a clear clinical benefit. Interactions among the different “immune nutrients” has not been systematically evaluated, although it is possible that omega-3 fatty acids modulate the appearance of MDSC and blunt ARG1 expression, hence increasing L-arginine availability.

3 Patients undergoing major elective surgery benefit from the use of immunonutrition formulas containing L-arginine. The risk of infections is reduced approximately 40% (P < 0.0001). In addition, there is significant reduction in the number and severity of other complications. All these benefits translate to a decrease in length of stay of approximately 2 to 3 days (P < 0.0001).^59,⁶⁰ Cost benefits of these diets have been best studied in patients undergoing surgery for cancer, demonstrating savings of several thousand dollars per patient in a given surgical practice⁶¹; L-arginine-containing diets are now standard of care. There is no controversy regarding this point; it has been endorsed as a grade A recommendation by all major nutrition societies and the Society of Critical Care Medicine (SCCM).^62,⁶³

4 Immunonutrition incorporating supraphysiologic quantities of L-arginine ideally should be started preoperatively as an oral dietary supplement and continued in the postoperative period as early as possible, delivered in an enteral presentation if the patient cannot eat. In general, these diets should be started 5 days prior to surgery and continued 5 to 10 days postoperatively.

5 All elective surgical patient populations, including patients undergoing operations for head and neck cancer and patients undergoing cardiac or GI surgery, appear to benefit from the use of immunonutrition formulas containing L-arginine. A significant number of these patients will be considered critically ill and thus admitted to an ICU.

6 Trauma patients may benefit from the use of immunonutrition formulas containing L-arginine.⁶⁴ Immunonutrition containing glutamine (which is metabolized to arginine when given enterally) may be of particular benefit in trauma and burn patients.^65,⁶⁶ Harm has not been reported. However, the number of patients studied is low, and further research is advisable. Benefits from these diets appear to be observed in those trauma patients who receive higher volumes and have lesser degrees of injury.^62,⁶³

7 A clear benefit of L-arginine-containing immunonutrition has not been observed in medical patients, particularly those with sepsis. Thus, for these patients, administration of L-arginine in pharmacologic doses remains controversial. Potential evidence of harm has been suggested in severely septic patients.⁶⁷ It remains theoretically possible that increased L-arginine availability results in increased NO production and worsening of the hemodynamic state. This possibility, however, has not been demonstrated in clinical practice. The lack of clarity both in understanding basic L-arginine metabolism during sepsis and confusing clinical results (showing both increased and decreased mortality) has led to highly divergent clinical recommendations.⁶⁸ For example, the SCCM suggests a grade B recommendation in the presence of sepsis,^62,⁶³ while others recommend immunonutrition containing supraphysiologic quantities of L-arginine be withheld.⁶⁷ The authors of this chapter err on the safe side of clinical practice and urge caution with use of these diets during sepsis.

Omega-3 Fatty Acids

Dietary omega-3 and omega-6 fatty acids are incorporated into phospholipids and thereby influence the structure and function of cellular membranes. Omega-3 and omega-6 fatty acids also serve as substrates for the enzymes cyclooxygenase, lipoxygenase, and cytochrome P450 oxidase, leading to the formation of prostaglandins, thromboxanes, leukotrienes, and lipoxins. Metabolism of omega-6 fatty acids leads to the formation of arachidonic acid. Metabolism of arachidonate via the cyclooxygenase pathway results in the production of compounds containing two double bonds which are called bisenoic prostanoids and are designated by a subscript 2 (e.g., prostaglandin [PG]E₂). Metabolism of omega-3 fatty acids leads to the formation of eicosapentaenoic acid (EPA). Trienoic prostanoids (e.g., PGE₃) are derived from EPA. Products derived from arachidonic acid via the 5-LO pathway are designated by a subscript 4 (e.g., leukotriene [LT]B₄), whereas products resulting from the action of 5-lipoxygenase (5-LO) on EPA are designated by a subscript 5 (e.g., LTB₅). The 2-series prostanoids and the 4-series leukotrienes are potent biological mediators. In contrast, the 3-series prostanoids and the 5-series leukotrienes derived from EPA are much less active.

Experimentally increasing the quantity of omega-3 fatty acids (found in fish oils) in the diet reduces platelet aggregation, slows blood clotting, and limits the production of proinflammatory cytokines.⁶⁹ Data from studies using animal models suggest that a diet enriched with fish and borage oils can ameliorate inflammation-induced acute lung injury.^70,⁷¹ The only clinical study of fish oil (omega-3 fatty acid) supplementation pertinent to the care of critically ill patients was carried out by Gadek and colleagues.⁷² In a randomized multicenter double-blind clinical trial, these investigators studied the effects of a diet (Oxepa7; Ross Products, Columbus, Ohio) supplemented with fish oils (containing EPA and docosahexaenoic acid), borage oil (rich in γ-linolenic acid), and antioxidants on markers of lung inflammation and survival. Patients (n=146) with acute respiratory distress syndrome (ARDS) were randomized within 24 hours of meeting entrance criteria to either a high-fat, low-carbohydrate control diet or the experimental diet. Only 98 of the 146 patients were deemed evaluable and included in the efficacy analysis. Among the evaluable patients, those who received the experimental diet had higher plasma phospholipid fatty acid levels (i.e., dihomo-γ-linolenic acid, EPA, and EPA/arachidonic acid ratio) and fewer total cells and neutrophils recovered from bronchoalveolar lavage fluid obtained on study days 4 and 7.

In addition, PaO₂/FIO₂ ratios on days 4 and 7 showed greater improvement in patients receiving the experimental diet compared with control patients. There was a non-significant improvement in survival in the experimental group compared with controls (16% versus 25%; P=0.17). Patients fed the experimental diet required fewer days on supplemental oxygen (13.6 versus 17.1; P=0.078), required significantly fewer days of ventilatory support (9.6 versus 13.2; P=0.027), spent less time in the ICU (11.0 versus 14.8 days; P=0.016), and had fewer new organ failures (10% versus 25%; P=0.018). Thus, the findings from this study support the view that administration of dietary lipids rich in omega-3 fatty acids can modify the lipid profile and favorably affect clinical outcome among critically ill patients with ARDS. However, a high-fat diet may be harmful, at least in critically ill burn victims,⁷³ so the results of the Gadek study may be confounded by use of a high-fat control formula.⁷² Further, because of the addition of supplements other than fish oils (e.g., antioxidants), it is not possible to definitively attribute the beneficial effects of the experimental diet to its higher content of omega-3 fatty acids.

L-glutamine

The amino acid, L-glutamine, plays a central role in nitrogen transport within the body. It is used as a fuel by rapidly dividing cells, particularly lymphocytes and gut epithelial cells,⁷⁴^–⁷⁶ and is also a substrate for synthesis of the important endogenous antioxidant, glutathione. Although L-glutamine is not an essential amino acid under normal conditions, plasma L-glutamine concentration decreases during critical illness, and low circulating levels of L-glutamine have been associated with immune dysfunction⁷⁷ and increased mortality.⁷⁸ Thus, L-glutamine may be regarded as a “conditionally essential” amino acid.

The effects of L-glutamine supplementation on clinically important outcomes have been assessed in several randomized trials of surgical and critically ill patients,⁷⁹ and the results from these studies have been subjected to meta-analysis.⁸⁰ In the aggregate, L-glutamine supplementation is associated with a significant reduction in mortality (RR 0.78; 95% CI, 0.61-0.99; P=0.04), a trend toward a reduction in infectious complications (RR 0.89; 95% CI, 0.73-1.08; P=0.2), and no overall effect on length of stay (weighted mean difference in days, −1.30; 95% CI, −4.77 to 2.17). When route of administration (parenteral versus enteral) was assessed in a subgroup analysis, the majority of the treatment effect with respect to mortality and infectious complications was associated with parenteral administration of L-glutamine in patients receiving PN. Because the majority of L-glutamine provided enterally is metabolized in the gut and liver, it may not have a systemic effect. Only one small study in burn patients demonstrated a reduction in mortality with enteral L-glutamine.⁸¹ In a study of trauma patients, administration of an enteral formula supplemented with L-glutamine was associated with a non-significant decrease in the number of infections compared with the number of infections observed with administration of the control formula (20 of 35 [57%] versus 26 of 37 [70%]).⁸²

Therefore, for critically ill patients requiring PN, we recommend L-glutamine supplementation as long as the patient remains on PN. Enteral diets supplemented with L-glutamine can be considered for patients with major burns or trauma. Recommendations regarding L-glutamine supplementation (enteral or parenteral) in other critically ill patient populations are premature and warrant further study.

L-Glutamine unfortunately is unstable in aqueous solutions. To overcome this problem, L-glutamine is added to TPN solutions as a dipeptide (L-alanyl-L-glutamine). In patients receiving EN, L-glutamine powder can be dissolved into the nutrition formulation.

Antioxidants, Vitamins, and Trace Minerals

For a variety of inflammatory, infectious, and ischemic diseases, reactive oxygen species (ROS) represent a final common pathway. These toxic mediators (e.g., superoxide anion, hydroxyl radical, hydrogen peroxide, hypochlorous acid) can cause cellular injury by numerous mechanisms including destruction of cell membranes through the peroxidation of fatty acids; disruption of organelle membranes, such as those bounding lysosomes and mitochondria; degradation of hyaluronic acid and collagen; and disruption of key proteins and enzymes such as Na⁺/K⁺-ATPase or alpha₁-proteinase inhibitor. To protect tissues from ROS-induced injury, the body maintains a complex endogenous defense system including enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. These enzymes all have metals—notably, manganese, selenium, copper, or zinc—at their active sites. When these enzymatic antioxidants are overwhelmed, ROS are free to react with susceptible target molecules and cause cellular damage. Thus, cells have a secondary means of scavenging ROS using nonenzymatic antioxidants that are either water soluble, such as glutathione and vitamin C, or lipid soluble, such as vitamin E and beta carotene.⁸³

In critical illness, oxidative stress arises as the result of an imbalance between protective antioxidant mechanisms and generation of ROS. This imbalance may be due to excess generation of ROS, low antioxidant capacity, or both. Plasma and intracellular concentrations of the various antioxidants are abnormally low in subpopulations of critically ill patients.⁸⁴^–⁸⁶ In critical illness, evidence of oxidative stress includes high circulating levels of byproducts of lipid per oxidation, markers of protein oxidation, nitration or nitrosylation, or increased activity of ROS-producing enzymatic systems.⁸⁷

In a recent meta-analysis,⁸⁸ we aggregated results from 12 randomized trials that were designed to assess the value of administering exogenous antioxidants to critically ill patients.^87,⁸⁹^–⁹⁹ Of the included studies, several examined the effects of a single nutrient with antioxidant properties.^90,⁹²^–⁹⁴ ^,96 In most cases, the nutrient evaluated was selenium,^90,⁹²^–⁹⁴ but one study assessed the effect of zinc supplementation on outcome in ventilated patients with head trauma.⁹⁶ The effects of selenium combined with other antioxidants were assessed in four studies,⁸⁹^–⁹¹ ⁹⁹ and four studies focused on the effects of vitamin A, vitamin C, vitamin E, N-acetylcysteine, and glutathione.^87,^95,^97,⁹⁸ When the 12 trials were aggregated, antioxidants were associated with a significant reduction in mortality (RR 0.66; 95% CI, 0.45-0.95; P=0.03). Only five of these studies reported on infectious complications.^87,^90,^91,^95,⁹⁷ When these results were aggregated, antioxidants had no effect on infectious complications (RR 0.94; 95% CI, 0.63-1.40; P = 0.8). In further subgroup analysis, the majority of the treatment effect seemed to be related to parenteral rather than enteral administration of antioxidants or antioxidant nutrients, especially selenium. Thus for critically ill patients, selenium supplementation in combination with other antioxidants (vitamin E or alpha tocopherol, vitamin C, N-acetylcysteine, zinc) may be beneficial.

Appropriate Use of Total Parenteral Nutrition in the Intensive Care Unit

The enteral route of feeding is always preferable to the parenteral route, but EN is not always available, reliable, or safe. PN may be effective in specific circumstances when used correctly; in other circumstances, no nutritional therapy may be the most appropriate management. In the critical care setting, EN is clearly the first choice. In most cases, no nutritional support (other than glucose-containing intravenous fluids) is the second best alternative when EN is unavailable, impractical, or unsafe. PN is usually the choice of last resort.

Patient Selection

In almost all critical care patient populations involving a wide range of disease processes (from surgery and pancreatitis to trauma, burns, and critically ill patients on mechanical ventilation), EN is first-line therapy and should be chosen before PN. Reduction of infections by the use of EN compared with PN is consistent regardless of whether patients have cancer or protein-energy malnutrition.¹⁰⁰ In the critical care of an average patient with an intact GI tract, PN should never be selected ahead of EN. When studies from diverse critical care patient populations are combined, “standard therapy” in which no artificial nutritional support is provided has a more favorable impact on patient outcome than PN does. In a recent meta-analysis, Braunschweig and colleagues showed a statistically significant reduction in infections with standard therapy compared with PN (RR 0.77; 95% CI, 0.65-0.91).¹⁰⁰ If the patients were clearly well nourished, an even greater reduction in the incidence of infections was seen with standard therapy compared with PN (RR 0.61; 95% CI, 0.50-0.76).¹⁰⁰ There was a trend toward reduced overall complications with standard therapy, which just missed statistical significance (RR 0.87; 95% CI, 0.74-1.03).¹⁰⁰ Hospital length of stay was reduced significantly in 8 of the 14 studies reviewed by Heyland and coworkers in which standard therapy was compared with PN.¹⁰¹

The presence of protein-calorie malnutrition (PCM) reverses the choice between standard therapy and PN. In general, PN has greater efficacy in patients with PCM, and the chance of a favorable impact on patient outcome is more likely with PN than with standard therapy. PCM is most commonly defined by a greater than 10% to 15% weight loss ¹⁰¹ or a low body mass index.¹⁰² In patients with severe PCM, PN reduces infectious morbidity, overall major complications, and even mortality in comparison to standard therapy. In their meta-analysis, Heyland and coworkers showed a 48% reduction in risk of major complications with the use of total PN compared with standard therapy in malnourished surgery patients (RR 0.52; 95% CI, 0.30-0.91).¹⁰¹ In a diverse population of malnourished patients, giving no nutritional support and providing standard therapy are associated with a trend toward increased infection (RR 1.17; 95% CI, 0.88-1.56) and a significant threefold increase in mortality (RR 3.0; 95% CI, 1.09-8.56).¹⁰⁰ Those patients with severe PCM, the ones most likely to benefit from PN, usually represent a very small minority of patients. The prevalence of severe PCM in some studies of ICU patients ranged from 8.3% to 12.6%.¹⁰³^–¹⁰⁵

Critically ill patients with sepsis and multiple organ dysfunction respond poorly to PN. Heyland et al. showed a trend toward a 2.5-fold increase in complications (RR 2.40; 95% CI, 0.88-6.58) and a significant twofold increase in mortality (RR 0.178; 95% CI, 1.11-2.85) from the use of PN compared with standard therapy with no nutritional support.¹⁰¹

Thus, for critical care nutrition in general, the clinician should rarely choose PN over EN. Aggressive EN appears to be the first-line therapy for nutritional support in critical care and is associated with lower infectious morbidity compared with the parenteral route. EN appears to be superior to both PN and standard therapy with no nutritional support across diverse patient populations. When EN is not feasible, aggressive nutritional support may have to be held for 7 to 10 days following an injury or an acute event. These patients, despite critical illness, sepsis, and multiple organ dysfunction, are better managed by standard therapy with no PN support over this initial period. Only if there is evidence of PCM (and EN is not feasible) should PN be given preferentially over standard therapy in the first week.

Lipid Content

Use of emulsified lipids (Intralipid) with PN is controversial because previous studies have shown that long-chain fats can cause immune suppression.¹⁰⁶ Intralipid can promote dysfunction of the reticuloendothelial system, enhance formation of prostanoids and leukotrienes, increase generation of ROS, and adversely affect the composition of cell membranes.¹⁰⁶

Several reports demonstrate that intravenous lipids can adversely affect immune status and clinical outcome.¹⁰⁶^–¹⁰⁸ Results of a meta-analysis of PN suggest that the adverse effects of lipids may negate any beneficial effects of nonlipid PN supplementation.¹⁰¹ Two studies compared the use of lipids to no lipids in PN.^106,¹⁰⁹ Among trauma patients, the use of PN without lipids versus with lipids was associated with a significant reduction in pneumonia (48% versus 73%; P=0.05), catheter-related sepsis (19% versus 43%; P=0.04), length of ICU stay (18 versus 29 days; P=0.02), and length of hospital stay (27 versus 39 days; P=0.03).¹¹⁰ In another study, the group that received no lipids (hypocaloric group) showed a trend toward a reduction in infections compared with the group that received lipids (29% versus 53%; P=0.2).¹⁰⁹ Combining these two studies, a meta-analysis showed a significant reduction in infections in the group that received no lipids (RR 0.63; 95% CI, 0.42-0.93) and no difference in mortality (RR 1.29; 95% CI, 0.16-10.7).¹⁰¹

The long-term effects of fat-free PN are unknown. However, some fat—at least 5% of total calories—has to be provided as lipid emulsion to prevent essential fatty acid deficiency, although this issue is usually not important until after the first 10 days of hospitalization.¹⁰² Therefore, lipid-free PN is probably best given to those patients requiring only short-term PN (<10 days). This recommendation cannot be extrapolated to those who have an absolute contraindication to EN and need PN for a longer duration.

Effect of Hyperglycemia

Hyperglycemia might be a key factor in the reduced efficacy and increased rate of complications associated with PN. Hyperglycemia impairs neutrophil chemotaxis and phagocytosis,¹⁰⁰ leads to glycosylation of immunoglobulins,¹¹¹ impairs wound healing,¹¹² alters function of the complement cascade,¹¹³ and exacerbates inflammation.¹¹⁰

Compared with EN, PN more frequently leads to hyperglycemia. For a variety of reasons, patients receiving EN often receive fewer total calories than those receiving PN.¹⁰⁰ Whereas PN formulas typically contain 60% to 75% carbohydrate, EN formulas usually contain 40% to 55% carbohydrate.¹⁰⁰ The parenteral route of feeding has been shown to lead to an increased stress response compared with enteral feeding. This effect in turn may increase endogenous glucose production and decrease glucose oxidation.¹⁰⁰

The results from a number of early studies highlight the relationship between hyperglycemia and incidence of nosocomial infection. In an early meta-analysis by Moore et al. comparing parenteral and enteral routes of feeding in trauma patients, mean blood glucose concentration was greater than 200 mg/dL in the PN group on postoperative days 7 to 9, whereas it was only 132 mg/dL during the same period in patients receiving EN (P<0.05).¹¹⁰ Incidence of infection was 44% in the PN group and 17% in the EN group (P<0.05).¹¹⁰ In a different study, Kudsk and colleagues provided further evidence that hyperglycemia increases risk of infection.¹¹¹ Among trauma patients randomized to EN or PN, those with a blood glucose concentration greater than 220 mg/dL had a 53% incidence of infection, whereas those with a blood glucose concentration less than 220 mg/dL had 23% incidence of infection (P<0.03).

Van den Berghe et al. compared intensive insulin therapy (target range for blood glucose concentration, 4.4-6.1 mmol/L) and conventional treatment (target range for blood glucose concentration, 10.0-11.1 mmol/L) in critically ill patients receiving nutritional support.¹¹⁴ This was a large study (n=1548) of surgical ICU patients (predominantly elective cardiovascular surgery) with relatively low APACHE II scores (median 9). Study patients were started on a glucose load (200-300 g/day) and then were advanced to PN, combined PN-EN, or EN after 24 hours of admission. Intensive insulin therapy was associated with a lower incidence of sepsis (P=0.003), a trend toward a reduction in ventilator days, reduced ICU length of stay (P<0.04), and decreased hospital mortality (P=0.01) compared with conventional insulin therapy.¹¹⁴

Initial enthusiasm with Van den Berghe’s study led to widespread adoption of tight glycemic control even in the absence of additional trials. In 2009, results of the NICE-SUGAR trial became available. NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) was a prospective trial that randomized 6104 patients to tight glycemic control (80-108 mg/dL) or conventional glucose management (glucose < 180 mg/dL). A small but significant decrease in mortality was observed for the control group when compared to those receiving intensive insulin therapy (27.5% versus 24.9%, P=0.02). In addition, significantly more patients exhibited hypoglycemia (P < 0.0001). Differences in trial design between Van den Berghe’s study and the NICE-SUGAR study may account for these disparate results. For one, high glucose infusions were used in Van den Berghe’s trial. In addition, the studies used different techniques for glucose measurement.

From these studies, one can infer that hyperglycemia (defined as a circulating glucose concentration > 200 mg/dL) is associated with poor outcome in different critically ill patient populations including trauma, strokes, and acute coronary syndromes.¹¹⁵^–¹¹⁸ Using conventional glucose monitoring systems, glucose levels below 180 mg/dL should be maintained in critically ill patients.

Caloric Provision—Permissive Underfeeding

Several studies have shown a correlation between provision of excessive amounts of calories and increased rates of insulin resistance, infectious morbidity, and mortality. Hyperglycemia (blood glucose concentration > 220 mg/dL) has been shown to occur in greater than 50% of nondiabetic patients receiving PN in excess of 35 kcal/kg actual body weight per day.¹¹⁹ In a retrospective study, patients who received a high dose of carbohydrates (77% of total calories and 42.4 kcal/kg/d on average) were compared with patients who received a lower dose of carbohydrates (60.6% of total calories and 34.3 kcal/kg/d on average).¹²⁰ The group that received more carbohydrates had significantly more episodes of sepsis (14 episodes in 26 patients versus 4 episodes in 17 patients; P < 0.05) and significantly higher mortality (28% versus 10%; P < 0.05).¹²⁰ Although the group on the higher-carbohydrate regimen received less protein than the group on the lower-carbohydrate regimen (82.5 versus 98.7 g/day), this difference did not reach statistical significance.¹²⁰

In another study, children with greater than 60% total body surface area burns were randomized to either a control group that received a high-carbohydrate, normal-protein regimen of PN or a study group that received a reduced-carbohydrate, high-protein regimen.¹²¹ The control group received 87% of goal calories, whereas the study group received only 77.7% of goal calories (P<0.002). The number of bacteremic days was 11% in the control group but only 8% in the experimental group (P<0.05). Mortality was 44% in the control group and 0% in the experimental group (P<0.03).¹²¹

Two additional studies evaluated the effect of hypocaloric feeding in critically ill patients. To achieve a hypocaloric dose of PN, Choban et al.¹²² reduced both carbohydrates and lipids in morbidly obese critically ill patients, whereas McCowen et al.¹⁰⁹ withheld lipids in a heterogeneous group of patients including critically ill patients. In the study by McCowen’s group, hypocaloric feeding was associated with a trend toward a reduction in infectious complications (P=0.2)¹⁰⁹; infectious complications were not reported in the study by Choban’s group.¹²² There were no significant differences in mortality or length of stay between groups in either study.

Results of these studies suggest that insulin-resistant patients get hyperglycemic at lower rates of energy intake. Gain in body fat mass in response to excessive PN provision enhances the propensity to hyperglycemia and results in an increased incidence of sepsis. Isocaloric diets can have different effects depending on insulin resistance. Malnutrition and loss of body fat may increase insulin sensitivity. Patients with some degree of malnutrition seem to tolerate an infusion of carbohydrate and fat without hyperglycemia and hypertriglyceridemia and thus respond to nutritional support without added risk. Standard energy intake in patients with sepsis may actually exacerbate morbidity and mortality.

Thus, although increased protein intake is good, high nonprotein energy intake (from carbohydrates and fats) may reduce the benefits of nutritional support. “Permissive underfeeding,” in which total caloric provision is set at 20 kcal/kg actual body weight (or even ideal body weight) per day may optimize the efficacy of PN in critically ill (especially septic) patients.

Supplemental Total Parenteral Nutrition

Few studies have looked at the impact of supplemental PN in patients receiving an insufficient volume of enteral feeding. In a study of 120 critically ill patients, Bauer and colleagues compared a control group receiving EN alone with a study group treated with EN supplemented with PN; both groups were fed for at least 4 to 7 days after starting nutritional support.¹²³ Overall, there was no difference in morbidity or mortality between the two groups. Duration of stay in the ICU, duration of mechanical ventilation, incidence of respiratory infection, and mortality were equal between the two groups. Hospital length of stay was shorter in the study group receiving supplemental PN than in the control group (31.2 versus 33.7 days; P=0.002), but this effect was easily explained by a statistically significant earlier date of entry into the study (1.1 versus 1.5 days; P=0.002). The cost of nutritional support was doubled by the addition of supplemental PN.

Of greater concern was a study by Herndon and colleagues of patients with greater than 50% total body surface area burns.¹²⁴ Mortality was significantly higher among the 16 study patients treated with EN and supplemental PN than it was in the 23 control patients treated with EN alone (63% versus 26%; P<0.05). Supplemental PN added to EN in the study group decreased the amount of enteral calories patients tolerated. Although both groups exhibited depressed natural killer cell activity from days 0 to 14, the group receiving supplemental PN experienced greater depression of T cell helper-suppressor ratios from days 7 to 14.

A recent meta-analysis evaluated five randomized trials that addressed the clinical benefits of supplemental PN in critically ill patients.¹²⁵ The aggregated results demonstrated a trend toward increased mortality associated with the use of combination EN and PN (RR 1.27; 95% CI, 0.82-1.94; P=0.3). Supplemental PN was not associated with a difference in the incidence of infection (RR 1.14; 95% CI, 0.66-1.96; P=0.6). Supplemental PN had no effect on hospital stay (standardized mean difference −0.12 days; 95% CI, −0.45 to 0.2 days; P=0.5) or ventilator days. Thus, there appears to be no clinical evidence to support the practice of supplementing EN with PN when EN is initiated. Supplemental PN adds nothing and may actually worsen the outcome for patients already on EN.

Duration and Timing of Parenteral Nutrition

When EN is not feasible, providing standard therapy with no artificial nutritional support may be better than PN in well-nourished patients, regardless of their disease process. The timing of PN initiation is based on the underlying nutritional status of the patient. In a previously well-nourished but otherwise critically ill patient who has not resumed oral intake, it is reasonable to wait 7 to 10 days before initiating PN.^100,¹²⁶ Some experts recommend a longer waiting period (10 to 14 days) before initiating PN in a previously well-nourished patient who is not expected to resume oral intake soon.^92,⁹³ However, after 14 days, increased mortality is seen in most patients who are not yet eating and remain on standard therapy with no nutritional support.¹²⁷ After 14 days, initiating PN is clearly associated with less mortality than providing no nutritional support.¹²⁷ PN is indicated over standard therapy for the first 7 to 10 days when the enteral route is not available in malnourished patients (usually characterized by >10%-15% weight loss). PN should not be initiated unless more than 7 to 10 days of therapy is anticipated. No studies of short-term PN (<7 days) have shown it to be efficacious or to impact favorably on patient outcome.

Future Considerations

In the future, nutritional prescriptions will likely be complex recommendations that continue to consider protein and calorie requirements but, in addition, consider the key nutrients needed to modulate the stress response, maintain gut integrity, and ameliorate the pathophysiology of the underlying critical illness (Figure 94-5). It may turn out that prescription of key substrates will have a greater effect on outcome than provision of calories or protein per se. For example, consider a critically ill patient with clinical or biochemical evidence of hypoperfusion. Early in the course of the illness, current thinking would say that EN is contraindicated. However, providing L-glutamine or antioxidants enterally may be exactly what this patient needs to recover from the oxidative stress associated with critical illness. The need to meet protein and calorie requirements might occur much later in the course of the illness (see Figure 94-5). Although this example represents an extreme case, nutritional prescriptions in the future will have to be more cognizant of evolving pathophysiology and the ability of nutrients to modulate the integrity of the immune system, systemic inflammatory response, and the underlying disease in the early phases of the clinical course.