- Email: [email protected]
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL IN CRITICALLY ILL PATIENTS
CONTROVERSIES IN CRITICAL CARE MEDICINE
0749-0704/96 $0.00
+
.20
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL IN CRITICALLY ILL PATIENTS Paul L. Marino, MD, PhD, FCCM, and Matthew J. Finnegan, MD
What is food to one man may be fierce poison to others. LUCRETIUS
Although feeding the sick is a traditional symbol of caring and compassion, the prevailing expert opinion is that nutrition support by way of the enteral or parenteral route is a form of medical the rap^.^ As is demonstrated in this article, there is little evidence to indicate that nutritional support is a beneficial form of therapy in seriously ill patients. In fact, the derangements in nutrient processing that accompany critical illness can transform nutrition support into a toxic intervention. NUTRITION SUPPORT AND CLINICAL OUTCOME
Because nutrition support is considered a therapeutic intervention, its value will be determined by risk-benefit and clinical-outcomes analyses applied to all medical therapies. The following is a brief review of the accumulated experience with nutrition support and clinical outcomes in critically ill patients.
From the University of Pennsylvania, School of Medicine (PLM, MJF); and the Department of Surgery (PLM) and Nutrition Support Service (MJF), Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, Pennsylvania
CRITICAL CARE CLINICS VOLUME 12 * NUMBER 3 * JULY 1996
667
668
MARINO & FINNEGAN
Postoperative Patients
Most of the clinical trials of nutrition support in hospitalized patients have involved patients undergoing major surgical procedures. These studies are organized in the next sections according to the methods of nutritional support being investigated. Parenteral Nutrition The earliest clinical studies focused on the value of total parenteral nutrition (TPN) in the perioperative period in unselected patients (both adequately nourished and malnourished) undergoing major abdominal surgery. Based on a meta-analysis of the studies published prior to 1987,15the American College of Physicians published a policy statement concluding that ”the routine use of perioperative parenteral nutrition for unselected patients having major surgery is not j ~ s t i f i e d . ”This ~ ~ was followed by a multicenter, randomized study of perioperative TPN (including at least 7 days of preoperative TPN) of malnourished patients undergoing major abdominal and noncardiac thoracic pr0cedures.4~The results of this study demonstrated that perioperative TPN did not reduce the incidence of postoperative complications. In fact, patients receiving perioperative TPN had a significantly higher rate of infectious complications when compared to the control patients. This study of malnourished patients, combined with the previous studies in unselected patients,15 indicates that perioperative TPN is not beneficial and may even be harmful for nourished and malnourished patients undergoing major noncardiac surgical procedures. Enteral Nutrition More recent interest has focused on the value of total enteral nutrition (TEN) in selected surgical patients. Much of this interest stems from the discovery that luminal nutrients may play an important role in maintaining the functional integrity of the bowel m u ~ o s aBecause .~~ the bowel wall serves as a physical and immunologic barrier to the movement of intestinal pathogens,14,28, 46 TEN could prove beneficial by maintaining the gut mucosal barrier and reducing the risk for ”translocation” of enteric pathogens into the systemic cir~ulation.~ Only one study has focused on the clinical benefit of early TEN in postoperative patients, and this study was limited to previously healthy trauma victims who underwent laparotomy for blunt and penetrating abdominal injuries.33Patients who received early TEN had a jejunostomy tube placed at the time of surgery, and tube feedings were initiated within 18 hours after surgery and gradually advanced to full nutritional support over the ensuing 72 hours. The control group of patients had no nutritional interventions during the first 5 postoperative days. Although early TEN did not result in a decrease in the total incidence of postoperative complications, the patients receiving early TEN had fewer
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
669
infectious complications than the control patients (99'0 versus 299'0, P less than 0.05). The authors of this study concluded that early TEN is effective in reducing postoperative infections in selected trauma victims. This study is cited widely as evidence that early TEN reduces the risk for bacterial translocation and bowel sepsis in selected surgical patients. The authors of this study, however, failed to determine if the postoperative infections were causally linked to the translocation of enteric pathogens. In fact, some of the postoperative infections in the study are unlikely to originate from translocation of bowel pathogens (e.g., pneumonia), and when these infections are eliminated, the incidence of postoperative infections is not significantly different in the patients receiving early TEN. Early TEN Versus Early TPN
A number of studies have compared TEN with TPN initiated in the 32, 34 These first 5 to 7 days following major abdominal surgery.', 21, studies have involved trauma victims with abdominal injuries', 26, 32, 34 and patients undergoing major abdominal surgery unrelated to trauma.*', 32 A meta-analysis of the prospective, randomized, controlled trials32shows no difference in the incidence of postoperative sepsis with early TEN versus early TPN in patients with penetrating abdominal injuries and in patients undergoing nontraumatic abdominal surgery. Early TEN was associated, however, with a lower incidence of postoperative infections in patients undergoing laparotomy for blunt abdominal trauma. It is important to emphasize that studies comparing different routes of nutritional support do not address the value of nutritional support per se as a therapeutic intervention. If the results of studies comparing early TEN and early TI" are combined with the studies of perioperative 43 however, then the following conclusions are TPN cited previ~usly,'~, possible. First, because perioperative TI" does not reduce the incidence of postoperative complication^,^^, 43 studies showing comparable rates of postoperative complications with early TEN and early TPN can be interpreted as indicating that perioperative TEN is also ineffective in reducing postoperative complications. Second, because perioperative TPN can be associated with a higher incidence of postoperative infection~:~studies showing fewer postoperative infections with early TEN can be interpreted as reflecting the higher risk of infection associated with TPN rather than the ability of early TEN to reduce the risk of postoperative infections. Standard Versus "Designer" TEN
The most recent interest has focused on the use of specialized enteral-feeding formulas that are designed to promote immunocompetence in the host. One such feeding formula (Impact, Sandoz Nutrition, Minneapolis, MN) that contains arginine, nucleotides, and fish oils to
670
MARINO & FINNEGAN
improve immune function has been compared to a conventional feeding formula (Osmolite HN, Ross Laboratories, Columbus, OH) for early TEN in patients undergoing cancer-related abdominal surgery.12Patients given the "designer" feeding formula in this study had a lower incidence of selected postoperative infections (i.e., pneumonia, wound, abdominal, and systemic infections) and a shorter length of stay in the hospital. The incidence of all other postoperative complications, including urinary tract infections, was not influenced by the type of feeding formula used in this study. The authors of the study concluded that early TEN with a feeding formula designed to promote immunocompetence can reduce the incidence of postoperative infections and shorten the hospital stay in patients undergoing cancer-related abdominal surgery.12This conclusion does not imply, however, that early TEN is itself beneficial, because the study did not include a control group of patients who received no nutrition support in the early postoperative period. Furthermore, the proposed benefit of specialized feeding formulas is not supported by the results of another study, which showed that early TEN with the same specialized feeding formula (i.e., Impact) was associated with a higher mortality rate than early TEN with a conventional feeding formula in patients with sepsis and systemic inflamrnati~n.~ Thermal Injury
Acute burn injury often is accompanied by splanchnic vasoconstriction, which can damage the bowel mucosa and promote the translocation 7,25 Because this of intestinal pathogens into the systemic circ~lation.~, mucosal injury appears in the first few hours after the burn injury, early enteral nutrition has been advocated for protecting the bowel mucosa in burn victims.2,40 Only one study has evaluated the influence of early TEN on clinical outcome variables in burn victims. This study, published 15 years ago, showed that early TEN with a high-protein feeding formula was associated with a lower mortality rate in pediatric burn victims.2A more recent study compared early TEN with three different feeding formulas in adult burn victim^.'^ The results of this study reveal no difference in the incidence of postburn sepsis or mortality in relation to the type of feeding formula selected for early TEN. Thus, there is little evidence to support the proposed benefit of early enteral feeding in burn victims. In fact, because the mucosal injury that accompanies thermal injury is the result of splanchnic vasoconstriction, and enteral feeding can be harmful in the presence of splanchnic ischemia: the recommendations for early and aggressive enteral nutrition in burn victims should be reconsidered. Systemic Inflammation and Sepsis
Systemic infection and inflammation also are accompanied by splanchic hypoperfusion that can result in bowel ischemia and disruption of
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
671
the bowel mu~osa.~, 7, 17, 25 When this occurs, translocation of pathogens and endotoxin across the bowel mucosa can create a vicious cycle of sepsis and systemic inflammation that eventually leads to multiorgan failure.6,l7 Early and aggressive enteral nutrition has been proposed as a means of protecting the bowel mucosa in patients with sepsis. Only one study, however, has evaluated the ability of early TEN to reduce the risk for prolonged sepsis and multiorgan failure in patients with sepsis." The results of this study show that early TEN provides no advantage over early TI" in reducing the incidence of prolonged sepsis and multiorgan failure. Another more recent study evaluated the relative merits of two enteral feeding formulas in critically ill patients with sepsis or systemic inflammation. This multicenter, prospective trial compared early TEN with a feeding formula (Impact) designed to improve immune function to early TEN with a more standard feeding formula (O~molite).~ Overall, there was no difference in the incidence of nosocomial infections, nosocomial bacteremias, or length of hospital stay related to the two feeding formulas. The overall mortality rate, however, was twofold higher in the patients given the specialized feeding formula. In the subgroup of patients with sepsis, the length of hospital stay was shorter for patients who received the specialized feedings. The mortality rate, however, was threefold higher in the septic patients fed with the specialized formula, and this might explain the shorter hospital stay in this group of patients. The results of this study reveal that little or no benefit and possible harm are associated with the use of specialized enteral feeding formulas in patients with sepsis. At the present time, there is no evidence to indicate that enteral feedings with any feeding formula are effective in improving the clinical condition of critically ill patients with sepsis or systemic inflammation. Furthermore, because sepsis and systemic inflammation commonly are associated with a reduction in mesenteric blood flow? 7, 17, 25 and enteral feedings can provoke bowel ischemia when mesenteric flow is the value of early and aggressive enteral feedings in this patient population should be questioned.
Summary The available studies reveal little evidence to indicate that nutrition support with any nutrient formula delivered by any route can result in an improved or more rapid recovery in critically ill patients. Furthermore, most of the clinical studies evaluating nutrition support have focused on patients recovering from acute and self-limited insults (e.g., surgery and trauma), instead of patients with ongoing or progressive disease (e.g., shock and multiorgan failure). As will be demonstrated, the latter group of patients may be even less likely to benefit from nutrition support because of abnormal nutrient processing.
672
MARINO & FINNEGAN
NUTRIENT PROCESSING IN CRITICAL ILLNESS The benefit of nutritional support in any illness is based on the premise that nutrient intake can prevent or correct the malnutrition that accompanies the illness. The malnutrition (nutrient deficiency) that accompanies critical illness, however, is driven by the underlying disease pr0cess,2~and the ability of nutrient intake to correct the malnourished condition will be determined primarily by the activity of the underlying In other words, the activity and severity of the underlying disease will determine the consequences and eficacy of nutrient intake in critically ill patients. When an illness is severe enough to result in abnormal nutrient processing, the intake of nutrients can have adverse effects. The remaining sections highlight some of the undesirable consequences of nutrient intake in critically ill patients. Appetite Suppression Appetite suppression is a common and early manifestation in many acute illnesses, particularly those associated with systemic inflammation. This phenomenon is the result of two inflammatory cytokines: (1)tumor necrosis factor, formerly known as cachectin, and (2) interleukin-1, formerly known as endogenous pyr~gen.*~ The anorexia produced by these cytokines reduces the intake of nutrients during the active phase of the illness. Although it is not clear if this is an adaptive response, it suggests that nutrient intake may not always be desirable in the setting of an acute illness. The toxic effects of nutrient intake highlighted in the following paragraphs may serve as an impetus for the body to reduce the intake of nutrients in acute disease. Enteral Intake Enteral nutrition is widely accepted as an effective means of protecting the bowel mucosa in critically ill patients. Several conditions can promote splanchnic hypoperfusion in critically ill patients? 7, 14, 17, 25, 46 however, and when splanchnic blood flow is impaired, enteral feedings can damage rather than protect the bowel mucosa. The oral ingestion of bulk nutrients normally is accompanied by a 50% to 60% increase in mesenteric blood This response facilitates nutrient absorption by providing energy for the absorption process across the bowel mucosa. When mesenteric blood flow is impaired, enteral feedings can create an energy deficit in the bowel mucosa and can thereby provoke bowel ischemia.8 The potential for enteral nutrition to be harmful in patients with impaired splanchnic flow is acknowledged in the guidelines for enteral nutrition published by the American Society of Parenteral and Enteral Nutrition. According to these guidelines, “limiting enteral feeding is
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
673
advised in hemodynamically unstable patients because of reduced splanchnic f l ~ w . "Considering ~ that reduced flow in the bowel wall has been demonstrated in a majority of patients admitted to the intensive care it may be advisable to limit rather than encourage enteral feedings in larger populations of intensive care unit patients.
Glucose Intake Standard nutritional support regimens rely on carbohydrates to provide 70% to 75% of daily energy requirements. The value of carbohydrates as an energy source, however, can be impaired severely in critically ill patients. Under normal conditions, as much as 50% of exogenously administered glucose will be oxidized to provide energy, whereas less than 5% is metabolized to form lactate.20,36 In the presence of acute stress or injury, however, as much as 85% of an exogenous glucose load can be recovered as lactate.20Inhibition of glucose oxidation can occur in patients with only mild-to-moderate levels of stress. This is demonstrated by the observation that routine intraoperative infusion of 150 to 200 grams of glucose (3 to 4 liters of 5% dextrose) can raise serum lactate levels to as high as 6 mEq/L.'* The enhanced production of lactate could serve as an alternative source of energy (i.e., the lactate shuttle).31If the oxidation of lactate is impaired by anaerobic conditions or reduced organ flow, however, the lactate will accumulate and produce local and systemic acidosis. Tissue accumulation of organic acid may be responsible for the ability of glucose infusions to promote central nervous system damage and renal injury in patients with shock and circulatory arrest.'O(35 The changes in carbohydrate metabolism cited previously indicate that in the presence of a serious illness, glucose becomes less of a source of energy and more of a source of metabolic toxins (i.e., organic acids). Because glucose is the major energy source in standard nutrition support regimens, the tendency for glucose to drive the production of metabolic toxins is an important issue when considering aggressive nutrition support in critically ill patients. Lipid Intake
Lipid intake has the same problems associated with glucose intake in critically ill patients; that is, diminished potency as an energy source and an enhanced ability to produce metabolic toxins. Although lipids are a potent energy source (9 kcal/g), standard nutrition support regimens use lipids to provide only 25% to 30% of the daily energy requirements. The limited role of exogenous lipids as an energy source can be curtailed further in critically ill patients as a result of impaired fatty acid metabolism. The proportion of exogenous lipids that are used for energy production can be reduced to 10% to 12% in critically ill patients.18 One of the mechanisms for this diminished energy production may be a
674
MARINO & FINNEGAN
deficiency in camitine, a transporter protein that moves long-chain fatty acids into mitochondria to produce energy through beta-oxidation.44 Because medium-chain fatty acids (8 to 10 carbon atoms) do not require carnitine for transport into mitochondria,44the substitution of mediumchain for long-chain triglycerides has been encouraged to improve the energy yield from exogenous lipids. Lipids and Oxidant Injury
One of the very real dangers of lipid intake in critically ill patients is the risk for oxidant-induced cell injury. The tendency for exogenous lipids to promote cell injury is illustrated by the fact that infusion of oleic acid (a long-chain triglyceride that contributes 25% of the lipid content of standard intravenous lipid emulsions) is the standard method for producing the acute respiratory distress syndrome in animals.4I This toxicity is caused by the oxidative decomposition of lipids, the same process that produces rancidity in dietary fats.I6 The oxidation of circulating lipoproteins can result in widespread damage to the vascular endothelium,38 whereas the oxidation of membrane lipids can lead to progressive and lethal cell inj~ry.3~ Oxidation-prone dietary fats, such as the polyunsaturated fats in plant and fish oils, can promote cell injury by undergoing direct oxidationz7or by enhancing the oxidation of circulating and membrane lipids.zz,z7, 30 The tendency to generate toxic oxidants will be magnified in a systemic inflammatory illness because of the enhanced rates of biologic oxidation that accompany inflammati0n.4~ Considering that systemic inflammation and unopposed biologic oxidation play prominent roles in the organ failure that accompanies critical illness: the potential for exogenous lipids to generate toxic oxidants is a real concern in critically ill patients. SUMMARY
The introductory remark by Lucretius serves as a reminder that nutrient intake can have very different consequences in different subjects. In the patient with an acute or serious illness, metabolic derangements can transform a substance that is normally a source of energy into a source of metabolic toxins. The potential for organic nutrients to become organic toxins in the diseased host is a phenomenon that deserves more attention in the debate about the value of nutrition support in critically ill patients. References 1. Adams S, Dellinger EP, Wertz MJ, et al: Enteral versus parenteral nutritional support following laparotomy for trauma: A randomized prospective trial. J Trauma 26:882891, 1986
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
675
2. Alexander JW, MacMillan BG, Stinett JD, et al: Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 192:505-517, 1980 3. Alverdy JC, Aoys E, Moss G S Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 104185-190, 1984 4. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parent Ent Nutr 17(suppl):lSA-5lSA, 1993 5. Baron P, Traber LD, Traber DL, et al: Gut failure and translocation following bum and sepsis. J Surg Res 57197-204, 1994 6. Beal AL, Cerra FB: Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA 271:226-233, 1994 7. Benjamin E, Oropello JM, Iberti TJ: Acute mesenteric ischemia: Pathophysiology, diagnosis and treatment. Disease-a-Month 39:133-210, 1993 8. Boley SJ, Brandt LJ, Veith FJ, et a1 A new provocative test for chronic mesenteric ischemia. Am J Gastroenterol 86888-891, 1991 9. Bower RH, Cerra FB, Bershadsky B, et al: Early enteral administration of formula (Impact) supplemented with arginine, nucleotides and fish oil in intensive care unit patients: Results of a multicenter, prospective, randomized clinical trial. Crit Care Med 23:43&449, 1995 10. Browning RG, Olson DW, Steuvun HA, et al: 50% dextrose: Antidote or toxin. Ann Emerg Med 19:683-687, 1990 11. Cerra FB, McPherson JP, Konstantinides FN, et al: Enteral nutrition does not prevent multiple organ failure syndrome (MOFS) after sepsis. Surgery 104:727-733, 1988 12. Daly JM, Lieberman MD, Goldfine J, et al: Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: Immunologic, metabolic, and clinical outcome. Surgery 112:56-67, 1992 13. Degoute C-S, Ray M-J, Manchon M, et al: Intraoperative glucose infusion and blood lactate: Endocrine and metabolic relationships during abdominal aortic surgery. Anesthesiology 71:355-361, 1989 14. Deitch EA,Winterton J, Berg R The gut as a portal of entry for bacteremia. Ann Surg 205:6814192, 1987 15. Detsky AS, Baker JP, ORourke K, et a1 Perioperative parenteral nutrition: A metaanalysis. Ann Intern Med 107195-203,1987 16. Dormandy TL: Biological rancidification. Lancet 23684-688, 1969 17. Fiddian-Green RG: Studies in splanchnic ischemia and multiple organ failure. In Marston A, Bulkley GB, Fiddian-Green RG, et a1 (eds): Splanchnic Ischemia and Multiple Organ Failure. St. Louis, CV Mosby Co, 1989, pp 349-363 18. Goodenough RD, Wolfe RR: Effect of total parenteral nutrition on free fatty acid metabolism in bumed patients. J Parent Ent Nutr 8:357-360, 1984 19. Gottschlich MM, Jenkins M, Warden GD, et al: Differential effects of three enteral dietary regimens on selected outcome variables in bum patients. J Parent Ent Nutr 14225236,1990 20. Gunther B, Jauch K-W, Hart1 W, et a1 Low-dose glucose infusion in patients who have undergone surgery. Arch Surg 122765771, 1987 21. Hamaoui E, Lefkowitz R, Olender L, et al: Enteral nutrition in the early postoperative period: A new semi-elemental formula versus total parenteral nutrition. J Parent Ent Nutr 14:501-507, 1990 22. Harats D, Debach Y, Hollander G, et al: Fish oil ingestion in smokers and non-smokers enhances peroxidation of plasma lipoproteins. Atherosclerosis 90:127-139, 1991 23. Hardin TC: Cytokine mediators of malnutrition: Clinical implications. Nutr Clin Pract 8:55-59, 1993 24. Health and Public Policy Committee, American College of Physicians: Perioperative parenteral nutrition. Ann Intern Med 107252-253, 1987 25. Jones WG 11, Barber AE, Minei JP, et a1 Differential pathophysiology of bacterial translocation after thermal injury and sepsis. Ann Surg 2142430, 1991 26. Kudsk KA, Croce MA, Fabian TC, et al: Enteral vs. parenteral feeding: Effects on septic morbidity following blunt and penetrating abdominal trauma. Ann Surg 215:503-513, 1992
676
MARINO & FINNEGAN
27. L‘abbe MR, Trick KD, Beare-RogersJ: Dietary (N-3) fatty acids affect rat heart, liver and aorta protective enzymes activities and lipid peroxidation. J Nutr 121:1331-1340, 1991 28. Langkamp-Henken B, Glezer JA, Kudsk KA: Immunologic structure and function of the gastrointestinal tract. Nutr Clin Pract 7100-108, 1992 29. Levine GM, Deren JJ, Steiger E, et al: Role of oral intake in maintenance of gut mass and disaccharide activity. Gastroenterology 67975-982, 1974 30. Meydani SN, Dinarello C A Influence of dietary fatty acids on cytokine production and its clinical implications. Nutr Clin Pract 8:65-72, 1993 31. Mizock BA: Alterations in carbohydrate metabolism during stress: A review of the literature. Am J Med 98:75-84, 1995 32. Moore FA, Feliciano DV, Andrassay RJ, et al: Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. AM Surg 216:172-183, 1991 33. Moore FA, Moore EE, Jones TN: Benefits of immediate jejunostomy feeding after major abdominal trauma: A prospective randomized study. J Trauma 262374-881, 1986 34. Moore FA, Moore EE, Jones TN, ef al: TEN versus TPN following major abdominal trauma-reduced septic morbidity. J Trauma 29:916-923, 1989 35. Moursi M, Rising CL, Zelenock GB, et al: Dextrose administration exacerbates the acute renal ischemic damage in anesthetized dogs. Arch Surg 122:790-794, 1987 36. Mullany CJ, Wolfe RR, Burke J F The fate of glucose infusion in fasting and fed guinea pigs. J Surg Res 29:11&125, 1980 37. Niki E, Yamamoto Y, Komuro E, et al: Membrane damage due to lipid oxidation. Am J Clin Nutr 53:201%205S, 1991 38. Panasenko OM, Vol’Nova TV, Azizova OA, et a1 Free radical modification of lipoproteins and cholesterol accumulation in cells upon atherosclerosis. Free Radic Biol Med 10~137-148,1991 39. Qamar MI, Read AE: Effects of ingestion of carbohydrate, fat, protein and water on the mesenteric blood flow in man. Scand J Gastroenterol 23:2&30, 1988 40. Saito H, Trocki 0, Alexander JW, et al: The effect of route of nutrient administration on the nutritional state, catabolic hormone secretion, and gut mucosal integrity after burn injury. J Parent Ent Nutr 1l:l-7, 1987 41. Schuster DP: ARDS: Clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 149245-260, 1994 42. Shaw JHF, Holdaway CM: Protein-sparing effect of substrate infusion in surgical patients is governed by the clinical state, and not by the individual substrate infused. J Parent Ent Nutr 12:433-440, 1988 43. Veterans Affair Total Parenteral Nutrition Cooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 325:525-532, 1991 44. Vockley J: The changing face of disorders of fatty acid oxidation. Mayo Clin Proc 69~249-257,1994 45. Weiss SJ: Oxygen, ischemia and inflammation. Acta Physiol Scand 548:9-37, 1986 46. Wilmore DW, Smith RJ, ODweyer ST, et al: The gut: A central organ after surgical stress. Surgery 104:917-923, 1988 47. Zuckerman GR, Shuman R Therapeutic goals and treatment options for prevention of stress ulcer syndrome. Am J Med 83(suppl 61\):29-35, 1987 Address reprint requests to Paul L. Marino, MD, PhD, FCCM Department of Surgery Presbyterian Medical Center 39th and Market Street Philadelphia, PA 19104
0749-0704/96 $0.00
+
.20
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL IN CRITICALLY ILL PATIENTS Paul L. Marino, MD, PhD, FCCM, and Matthew J. Finnegan, MD
What is food to one man may be fierce poison to others. LUCRETIUS
Although feeding the sick is a traditional symbol of caring and compassion, the prevailing expert opinion is that nutrition support by way of the enteral or parenteral route is a form of medical the rap^.^ As is demonstrated in this article, there is little evidence to indicate that nutritional support is a beneficial form of therapy in seriously ill patients. In fact, the derangements in nutrient processing that accompany critical illness can transform nutrition support into a toxic intervention. NUTRITION SUPPORT AND CLINICAL OUTCOME
Because nutrition support is considered a therapeutic intervention, its value will be determined by risk-benefit and clinical-outcomes analyses applied to all medical therapies. The following is a brief review of the accumulated experience with nutrition support and clinical outcomes in critically ill patients.
From the University of Pennsylvania, School of Medicine (PLM, MJF); and the Department of Surgery (PLM) and Nutrition Support Service (MJF), Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, Pennsylvania
CRITICAL CARE CLINICS VOLUME 12 * NUMBER 3 * JULY 1996
667
668
MARINO & FINNEGAN
Postoperative Patients
Most of the clinical trials of nutrition support in hospitalized patients have involved patients undergoing major surgical procedures. These studies are organized in the next sections according to the methods of nutritional support being investigated. Parenteral Nutrition The earliest clinical studies focused on the value of total parenteral nutrition (TPN) in the perioperative period in unselected patients (both adequately nourished and malnourished) undergoing major abdominal surgery. Based on a meta-analysis of the studies published prior to 1987,15the American College of Physicians published a policy statement concluding that ”the routine use of perioperative parenteral nutrition for unselected patients having major surgery is not j ~ s t i f i e d . ”This ~ ~ was followed by a multicenter, randomized study of perioperative TPN (including at least 7 days of preoperative TPN) of malnourished patients undergoing major abdominal and noncardiac thoracic pr0cedures.4~The results of this study demonstrated that perioperative TPN did not reduce the incidence of postoperative complications. In fact, patients receiving perioperative TPN had a significantly higher rate of infectious complications when compared to the control patients. This study of malnourished patients, combined with the previous studies in unselected patients,15 indicates that perioperative TPN is not beneficial and may even be harmful for nourished and malnourished patients undergoing major noncardiac surgical procedures. Enteral Nutrition More recent interest has focused on the value of total enteral nutrition (TEN) in selected surgical patients. Much of this interest stems from the discovery that luminal nutrients may play an important role in maintaining the functional integrity of the bowel m u ~ o s aBecause .~~ the bowel wall serves as a physical and immunologic barrier to the movement of intestinal pathogens,14,28, 46 TEN could prove beneficial by maintaining the gut mucosal barrier and reducing the risk for ”translocation” of enteric pathogens into the systemic cir~ulation.~ Only one study has focused on the clinical benefit of early TEN in postoperative patients, and this study was limited to previously healthy trauma victims who underwent laparotomy for blunt and penetrating abdominal injuries.33Patients who received early TEN had a jejunostomy tube placed at the time of surgery, and tube feedings were initiated within 18 hours after surgery and gradually advanced to full nutritional support over the ensuing 72 hours. The control group of patients had no nutritional interventions during the first 5 postoperative days. Although early TEN did not result in a decrease in the total incidence of postoperative complications, the patients receiving early TEN had fewer
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
669
infectious complications than the control patients (99'0 versus 299'0, P less than 0.05). The authors of this study concluded that early TEN is effective in reducing postoperative infections in selected trauma victims. This study is cited widely as evidence that early TEN reduces the risk for bacterial translocation and bowel sepsis in selected surgical patients. The authors of this study, however, failed to determine if the postoperative infections were causally linked to the translocation of enteric pathogens. In fact, some of the postoperative infections in the study are unlikely to originate from translocation of bowel pathogens (e.g., pneumonia), and when these infections are eliminated, the incidence of postoperative infections is not significantly different in the patients receiving early TEN. Early TEN Versus Early TPN
A number of studies have compared TEN with TPN initiated in the 32, 34 These first 5 to 7 days following major abdominal surgery.', 21, studies have involved trauma victims with abdominal injuries', 26, 32, 34 and patients undergoing major abdominal surgery unrelated to trauma.*', 32 A meta-analysis of the prospective, randomized, controlled trials32shows no difference in the incidence of postoperative sepsis with early TEN versus early TPN in patients with penetrating abdominal injuries and in patients undergoing nontraumatic abdominal surgery. Early TEN was associated, however, with a lower incidence of postoperative infections in patients undergoing laparotomy for blunt abdominal trauma. It is important to emphasize that studies comparing different routes of nutritional support do not address the value of nutritional support per se as a therapeutic intervention. If the results of studies comparing early TEN and early TI" are combined with the studies of perioperative 43 however, then the following conclusions are TPN cited previ~usly,'~, possible. First, because perioperative TI" does not reduce the incidence of postoperative complication^,^^, 43 studies showing comparable rates of postoperative complications with early TEN and early TPN can be interpreted as indicating that perioperative TEN is also ineffective in reducing postoperative complications. Second, because perioperative TPN can be associated with a higher incidence of postoperative infection~:~studies showing fewer postoperative infections with early TEN can be interpreted as reflecting the higher risk of infection associated with TPN rather than the ability of early TEN to reduce the risk of postoperative infections. Standard Versus "Designer" TEN
The most recent interest has focused on the use of specialized enteral-feeding formulas that are designed to promote immunocompetence in the host. One such feeding formula (Impact, Sandoz Nutrition, Minneapolis, MN) that contains arginine, nucleotides, and fish oils to
670
MARINO & FINNEGAN
improve immune function has been compared to a conventional feeding formula (Osmolite HN, Ross Laboratories, Columbus, OH) for early TEN in patients undergoing cancer-related abdominal surgery.12Patients given the "designer" feeding formula in this study had a lower incidence of selected postoperative infections (i.e., pneumonia, wound, abdominal, and systemic infections) and a shorter length of stay in the hospital. The incidence of all other postoperative complications, including urinary tract infections, was not influenced by the type of feeding formula used in this study. The authors of the study concluded that early TEN with a feeding formula designed to promote immunocompetence can reduce the incidence of postoperative infections and shorten the hospital stay in patients undergoing cancer-related abdominal surgery.12This conclusion does not imply, however, that early TEN is itself beneficial, because the study did not include a control group of patients who received no nutrition support in the early postoperative period. Furthermore, the proposed benefit of specialized feeding formulas is not supported by the results of another study, which showed that early TEN with the same specialized feeding formula (i.e., Impact) was associated with a higher mortality rate than early TEN with a conventional feeding formula in patients with sepsis and systemic inflamrnati~n.~ Thermal Injury
Acute burn injury often is accompanied by splanchnic vasoconstriction, which can damage the bowel mucosa and promote the translocation 7,25 Because this of intestinal pathogens into the systemic circ~lation.~, mucosal injury appears in the first few hours after the burn injury, early enteral nutrition has been advocated for protecting the bowel mucosa in burn victims.2,40 Only one study has evaluated the influence of early TEN on clinical outcome variables in burn victims. This study, published 15 years ago, showed that early TEN with a high-protein feeding formula was associated with a lower mortality rate in pediatric burn victims.2A more recent study compared early TEN with three different feeding formulas in adult burn victim^.'^ The results of this study reveal no difference in the incidence of postburn sepsis or mortality in relation to the type of feeding formula selected for early TEN. Thus, there is little evidence to support the proposed benefit of early enteral feeding in burn victims. In fact, because the mucosal injury that accompanies thermal injury is the result of splanchnic vasoconstriction, and enteral feeding can be harmful in the presence of splanchnic ischemia: the recommendations for early and aggressive enteral nutrition in burn victims should be reconsidered. Systemic Inflammation and Sepsis
Systemic infection and inflammation also are accompanied by splanchic hypoperfusion that can result in bowel ischemia and disruption of
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
671
the bowel mu~osa.~, 7, 17, 25 When this occurs, translocation of pathogens and endotoxin across the bowel mucosa can create a vicious cycle of sepsis and systemic inflammation that eventually leads to multiorgan failure.6,l7 Early and aggressive enteral nutrition has been proposed as a means of protecting the bowel mucosa in patients with sepsis. Only one study, however, has evaluated the ability of early TEN to reduce the risk for prolonged sepsis and multiorgan failure in patients with sepsis." The results of this study show that early TEN provides no advantage over early TI" in reducing the incidence of prolonged sepsis and multiorgan failure. Another more recent study evaluated the relative merits of two enteral feeding formulas in critically ill patients with sepsis or systemic inflammation. This multicenter, prospective trial compared early TEN with a feeding formula (Impact) designed to improve immune function to early TEN with a more standard feeding formula (O~molite).~ Overall, there was no difference in the incidence of nosocomial infections, nosocomial bacteremias, or length of hospital stay related to the two feeding formulas. The overall mortality rate, however, was twofold higher in the patients given the specialized feeding formula. In the subgroup of patients with sepsis, the length of hospital stay was shorter for patients who received the specialized feedings. The mortality rate, however, was threefold higher in the septic patients fed with the specialized formula, and this might explain the shorter hospital stay in this group of patients. The results of this study reveal that little or no benefit and possible harm are associated with the use of specialized enteral feeding formulas in patients with sepsis. At the present time, there is no evidence to indicate that enteral feedings with any feeding formula are effective in improving the clinical condition of critically ill patients with sepsis or systemic inflammation. Furthermore, because sepsis and systemic inflammation commonly are associated with a reduction in mesenteric blood flow? 7, 17, 25 and enteral feedings can provoke bowel ischemia when mesenteric flow is the value of early and aggressive enteral feedings in this patient population should be questioned.
Summary The available studies reveal little evidence to indicate that nutrition support with any nutrient formula delivered by any route can result in an improved or more rapid recovery in critically ill patients. Furthermore, most of the clinical studies evaluating nutrition support have focused on patients recovering from acute and self-limited insults (e.g., surgery and trauma), instead of patients with ongoing or progressive disease (e.g., shock and multiorgan failure). As will be demonstrated, the latter group of patients may be even less likely to benefit from nutrition support because of abnormal nutrient processing.
672
MARINO & FINNEGAN
NUTRIENT PROCESSING IN CRITICAL ILLNESS The benefit of nutritional support in any illness is based on the premise that nutrient intake can prevent or correct the malnutrition that accompanies the illness. The malnutrition (nutrient deficiency) that accompanies critical illness, however, is driven by the underlying disease pr0cess,2~and the ability of nutrient intake to correct the malnourished condition will be determined primarily by the activity of the underlying In other words, the activity and severity of the underlying disease will determine the consequences and eficacy of nutrient intake in critically ill patients. When an illness is severe enough to result in abnormal nutrient processing, the intake of nutrients can have adverse effects. The remaining sections highlight some of the undesirable consequences of nutrient intake in critically ill patients. Appetite Suppression Appetite suppression is a common and early manifestation in many acute illnesses, particularly those associated with systemic inflammation. This phenomenon is the result of two inflammatory cytokines: (1)tumor necrosis factor, formerly known as cachectin, and (2) interleukin-1, formerly known as endogenous pyr~gen.*~ The anorexia produced by these cytokines reduces the intake of nutrients during the active phase of the illness. Although it is not clear if this is an adaptive response, it suggests that nutrient intake may not always be desirable in the setting of an acute illness. The toxic effects of nutrient intake highlighted in the following paragraphs may serve as an impetus for the body to reduce the intake of nutrients in acute disease. Enteral Intake Enteral nutrition is widely accepted as an effective means of protecting the bowel mucosa in critically ill patients. Several conditions can promote splanchnic hypoperfusion in critically ill patients? 7, 14, 17, 25, 46 however, and when splanchnic blood flow is impaired, enteral feedings can damage rather than protect the bowel mucosa. The oral ingestion of bulk nutrients normally is accompanied by a 50% to 60% increase in mesenteric blood This response facilitates nutrient absorption by providing energy for the absorption process across the bowel mucosa. When mesenteric blood flow is impaired, enteral feedings can create an energy deficit in the bowel mucosa and can thereby provoke bowel ischemia.8 The potential for enteral nutrition to be harmful in patients with impaired splanchnic flow is acknowledged in the guidelines for enteral nutrition published by the American Society of Parenteral and Enteral Nutrition. According to these guidelines, “limiting enteral feeding is
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
673
advised in hemodynamically unstable patients because of reduced splanchnic f l ~ w . "Considering ~ that reduced flow in the bowel wall has been demonstrated in a majority of patients admitted to the intensive care it may be advisable to limit rather than encourage enteral feedings in larger populations of intensive care unit patients.
Glucose Intake Standard nutritional support regimens rely on carbohydrates to provide 70% to 75% of daily energy requirements. The value of carbohydrates as an energy source, however, can be impaired severely in critically ill patients. Under normal conditions, as much as 50% of exogenously administered glucose will be oxidized to provide energy, whereas less than 5% is metabolized to form lactate.20,36 In the presence of acute stress or injury, however, as much as 85% of an exogenous glucose load can be recovered as lactate.20Inhibition of glucose oxidation can occur in patients with only mild-to-moderate levels of stress. This is demonstrated by the observation that routine intraoperative infusion of 150 to 200 grams of glucose (3 to 4 liters of 5% dextrose) can raise serum lactate levels to as high as 6 mEq/L.'* The enhanced production of lactate could serve as an alternative source of energy (i.e., the lactate shuttle).31If the oxidation of lactate is impaired by anaerobic conditions or reduced organ flow, however, the lactate will accumulate and produce local and systemic acidosis. Tissue accumulation of organic acid may be responsible for the ability of glucose infusions to promote central nervous system damage and renal injury in patients with shock and circulatory arrest.'O(35 The changes in carbohydrate metabolism cited previously indicate that in the presence of a serious illness, glucose becomes less of a source of energy and more of a source of metabolic toxins (i.e., organic acids). Because glucose is the major energy source in standard nutrition support regimens, the tendency for glucose to drive the production of metabolic toxins is an important issue when considering aggressive nutrition support in critically ill patients. Lipid Intake
Lipid intake has the same problems associated with glucose intake in critically ill patients; that is, diminished potency as an energy source and an enhanced ability to produce metabolic toxins. Although lipids are a potent energy source (9 kcal/g), standard nutrition support regimens use lipids to provide only 25% to 30% of the daily energy requirements. The limited role of exogenous lipids as an energy source can be curtailed further in critically ill patients as a result of impaired fatty acid metabolism. The proportion of exogenous lipids that are used for energy production can be reduced to 10% to 12% in critically ill patients.18 One of the mechanisms for this diminished energy production may be a
674
MARINO & FINNEGAN
deficiency in camitine, a transporter protein that moves long-chain fatty acids into mitochondria to produce energy through beta-oxidation.44 Because medium-chain fatty acids (8 to 10 carbon atoms) do not require carnitine for transport into mitochondria,44the substitution of mediumchain for long-chain triglycerides has been encouraged to improve the energy yield from exogenous lipids. Lipids and Oxidant Injury
One of the very real dangers of lipid intake in critically ill patients is the risk for oxidant-induced cell injury. The tendency for exogenous lipids to promote cell injury is illustrated by the fact that infusion of oleic acid (a long-chain triglyceride that contributes 25% of the lipid content of standard intravenous lipid emulsions) is the standard method for producing the acute respiratory distress syndrome in animals.4I This toxicity is caused by the oxidative decomposition of lipids, the same process that produces rancidity in dietary fats.I6 The oxidation of circulating lipoproteins can result in widespread damage to the vascular endothelium,38 whereas the oxidation of membrane lipids can lead to progressive and lethal cell inj~ry.3~ Oxidation-prone dietary fats, such as the polyunsaturated fats in plant and fish oils, can promote cell injury by undergoing direct oxidationz7or by enhancing the oxidation of circulating and membrane lipids.zz,z7, 30 The tendency to generate toxic oxidants will be magnified in a systemic inflammatory illness because of the enhanced rates of biologic oxidation that accompany inflammati0n.4~ Considering that systemic inflammation and unopposed biologic oxidation play prominent roles in the organ failure that accompanies critical illness: the potential for exogenous lipids to generate toxic oxidants is a real concern in critically ill patients. SUMMARY
The introductory remark by Lucretius serves as a reminder that nutrient intake can have very different consequences in different subjects. In the patient with an acute or serious illness, metabolic derangements can transform a substance that is normally a source of energy into a source of metabolic toxins. The potential for organic nutrients to become organic toxins in the diseased host is a phenomenon that deserves more attention in the debate about the value of nutrition support in critically ill patients. References 1. Adams S, Dellinger EP, Wertz MJ, et al: Enteral versus parenteral nutritional support following laparotomy for trauma: A randomized prospective trial. J Trauma 26:882891, 1986
NUTRITION SUPPORT IS NOT BENEFICIAL AND CAN BE HARMFUL
675
2. Alexander JW, MacMillan BG, Stinett JD, et al: Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 192:505-517, 1980 3. Alverdy JC, Aoys E, Moss G S Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 104185-190, 1984 4. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parent Ent Nutr 17(suppl):lSA-5lSA, 1993 5. Baron P, Traber LD, Traber DL, et al: Gut failure and translocation following bum and sepsis. J Surg Res 57197-204, 1994 6. Beal AL, Cerra FB: Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA 271:226-233, 1994 7. Benjamin E, Oropello JM, Iberti TJ: Acute mesenteric ischemia: Pathophysiology, diagnosis and treatment. Disease-a-Month 39:133-210, 1993 8. Boley SJ, Brandt LJ, Veith FJ, et a1 A new provocative test for chronic mesenteric ischemia. Am J Gastroenterol 86888-891, 1991 9. Bower RH, Cerra FB, Bershadsky B, et al: Early enteral administration of formula (Impact) supplemented with arginine, nucleotides and fish oil in intensive care unit patients: Results of a multicenter, prospective, randomized clinical trial. Crit Care Med 23:43&449, 1995 10. Browning RG, Olson DW, Steuvun HA, et al: 50% dextrose: Antidote or toxin. Ann Emerg Med 19:683-687, 1990 11. Cerra FB, McPherson JP, Konstantinides FN, et al: Enteral nutrition does not prevent multiple organ failure syndrome (MOFS) after sepsis. Surgery 104:727-733, 1988 12. Daly JM, Lieberman MD, Goldfine J, et al: Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: Immunologic, metabolic, and clinical outcome. Surgery 112:56-67, 1992 13. Degoute C-S, Ray M-J, Manchon M, et al: Intraoperative glucose infusion and blood lactate: Endocrine and metabolic relationships during abdominal aortic surgery. Anesthesiology 71:355-361, 1989 14. Deitch EA,Winterton J, Berg R The gut as a portal of entry for bacteremia. Ann Surg 205:6814192, 1987 15. Detsky AS, Baker JP, ORourke K, et a1 Perioperative parenteral nutrition: A metaanalysis. Ann Intern Med 107195-203,1987 16. Dormandy TL: Biological rancidification. Lancet 23684-688, 1969 17. Fiddian-Green RG: Studies in splanchnic ischemia and multiple organ failure. In Marston A, Bulkley GB, Fiddian-Green RG, et a1 (eds): Splanchnic Ischemia and Multiple Organ Failure. St. Louis, CV Mosby Co, 1989, pp 349-363 18. Goodenough RD, Wolfe RR: Effect of total parenteral nutrition on free fatty acid metabolism in bumed patients. J Parent Ent Nutr 8:357-360, 1984 19. Gottschlich MM, Jenkins M, Warden GD, et al: Differential effects of three enteral dietary regimens on selected outcome variables in bum patients. J Parent Ent Nutr 14225236,1990 20. Gunther B, Jauch K-W, Hart1 W, et a1 Low-dose glucose infusion in patients who have undergone surgery. Arch Surg 122765771, 1987 21. Hamaoui E, Lefkowitz R, Olender L, et al: Enteral nutrition in the early postoperative period: A new semi-elemental formula versus total parenteral nutrition. J Parent Ent Nutr 14:501-507, 1990 22. Harats D, Debach Y, Hollander G, et al: Fish oil ingestion in smokers and non-smokers enhances peroxidation of plasma lipoproteins. Atherosclerosis 90:127-139, 1991 23. Hardin TC: Cytokine mediators of malnutrition: Clinical implications. Nutr Clin Pract 8:55-59, 1993 24. Health and Public Policy Committee, American College of Physicians: Perioperative parenteral nutrition. Ann Intern Med 107252-253, 1987 25. Jones WG 11, Barber AE, Minei JP, et a1 Differential pathophysiology of bacterial translocation after thermal injury and sepsis. Ann Surg 2142430, 1991 26. Kudsk KA, Croce MA, Fabian TC, et al: Enteral vs. parenteral feeding: Effects on septic morbidity following blunt and penetrating abdominal trauma. Ann Surg 215:503-513, 1992
676
MARINO & FINNEGAN
27. L‘abbe MR, Trick KD, Beare-RogersJ: Dietary (N-3) fatty acids affect rat heart, liver and aorta protective enzymes activities and lipid peroxidation. J Nutr 121:1331-1340, 1991 28. Langkamp-Henken B, Glezer JA, Kudsk KA: Immunologic structure and function of the gastrointestinal tract. Nutr Clin Pract 7100-108, 1992 29. Levine GM, Deren JJ, Steiger E, et al: Role of oral intake in maintenance of gut mass and disaccharide activity. Gastroenterology 67975-982, 1974 30. Meydani SN, Dinarello C A Influence of dietary fatty acids on cytokine production and its clinical implications. Nutr Clin Pract 8:65-72, 1993 31. Mizock BA: Alterations in carbohydrate metabolism during stress: A review of the literature. Am J Med 98:75-84, 1995 32. Moore FA, Feliciano DV, Andrassay RJ, et al: Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. AM Surg 216:172-183, 1991 33. Moore FA, Moore EE, Jones TN: Benefits of immediate jejunostomy feeding after major abdominal trauma: A prospective randomized study. J Trauma 262374-881, 1986 34. Moore FA, Moore EE, Jones TN, ef al: TEN versus TPN following major abdominal trauma-reduced septic morbidity. J Trauma 29:916-923, 1989 35. Moursi M, Rising CL, Zelenock GB, et al: Dextrose administration exacerbates the acute renal ischemic damage in anesthetized dogs. Arch Surg 122:790-794, 1987 36. Mullany CJ, Wolfe RR, Burke J F The fate of glucose infusion in fasting and fed guinea pigs. J Surg Res 29:11&125, 1980 37. Niki E, Yamamoto Y, Komuro E, et al: Membrane damage due to lipid oxidation. Am J Clin Nutr 53:201%205S, 1991 38. Panasenko OM, Vol’Nova TV, Azizova OA, et a1 Free radical modification of lipoproteins and cholesterol accumulation in cells upon atherosclerosis. Free Radic Biol Med 10~137-148,1991 39. Qamar MI, Read AE: Effects of ingestion of carbohydrate, fat, protein and water on the mesenteric blood flow in man. Scand J Gastroenterol 23:2&30, 1988 40. Saito H, Trocki 0, Alexander JW, et al: The effect of route of nutrient administration on the nutritional state, catabolic hormone secretion, and gut mucosal integrity after burn injury. J Parent Ent Nutr 1l:l-7, 1987 41. Schuster DP: ARDS: Clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 149245-260, 1994 42. Shaw JHF, Holdaway CM: Protein-sparing effect of substrate infusion in surgical patients is governed by the clinical state, and not by the individual substrate infused. J Parent Ent Nutr 12:433-440, 1988 43. Veterans Affair Total Parenteral Nutrition Cooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 325:525-532, 1991 44. Vockley J: The changing face of disorders of fatty acid oxidation. Mayo Clin Proc 69~249-257,1994 45. Weiss SJ: Oxygen, ischemia and inflammation. Acta Physiol Scand 548:9-37, 1986 46. Wilmore DW, Smith RJ, ODweyer ST, et al: The gut: A central organ after surgical stress. Surgery 104:917-923, 1988 47. Zuckerman GR, Shuman R Therapeutic goals and treatment options for prevention of stress ulcer syndrome. Am J Med 83(suppl 61\):29-35, 1987 Address reprint requests to Paul L. Marino, MD, PhD, FCCM Department of Surgery Presbyterian Medical Center 39th and Market Street Philadelphia, PA 19104