This article was downloaded by: [New York University] On: 04 October 2014, At: 00:18 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20

Immediate enteral nutrition following multisystem trauma: a decade perspective. a

a

E E Moore & F A Moore a

Department of Surgery, Denver General Hospital, Colorado 80204. Published online: 02 Sep 2013.

To cite this article: E E Moore & F A Moore (1991) Immediate enteral nutrition following multisystem trauma: a decade perspective., Journal of the American College of Nutrition, 10:6, 633-648, DOI: 10.1080/07315724.1991.10718183 To link to this article: http://dx.doi.org/10.1080/07315724.1991.10718183

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Immediate Enterai Nutrition Following Multisystem Trauma: A Decade Perspective Ernest E. Moore, MD, FACN, and Frederick A. Moore, MD Department of Surgery, Denver General Hospital, and the University of Colorado Health Sciences Center, Denver

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Key words: trauma, nutrition, metabolism, enterai, jejunostomy, hepatic proteins Metabolic support is an integral component of surgical critical care. Although prompt restoration of oxygen availability is clearly essential, the timing, composition, and route of nutritional support may also be decisive factors. The ensuing discussion will focus on: (a) timing of substrate delivery and (b) route of administration based on our clinical investigation over the past decade. The acutely injured patient was selected as a model of ICU hypermetabolism because of relative homogeneity with respect to age, comorbid factors, and stress level. Our first study hypothesis was that early nutritional support would improve outcome in the severely injured, but previously wellnourished patient. During an 18-month period, all patients undergoing laparotomy with a abdominal trauma index (ATI) > 15 were randomized to a control or total enterai nutrition (TEN) group. The control patients were given total parenteral nutrition (TPN) after POD 5, whereas the TEN cohort had a needle catheter jejunostomy (NCJ) inserted at laparotomy and received an elemental diet within 12 hours. The control (n = 31) and TEN (n = 32) groups were otherwise comparable with respect to risk stratification. The TEN patients, of course, shared improved nitrogen balance (p < 0.001), but also had significantly (p < 0.025) less septic morbidity. Nine (29%) of the controls developed major infections, contrasted to three (9%) of the TEN patients. Acknowledging the benefit of early nutrition, the next issue we addressed was the optimal route of substrate delivery; i.e., TEN vs TPN. The hypothesis was that TEN, compared to TPN, would reduce the injury stress response as reflected by the prioritization of hepatic protein synthesis. TEN given via NCJ and a nutritionally matched TPN solution were administered during the same postopera­ tive period. Indeed, the TEN patients (n = 23) had significantly (p < 0.05) higher constitutive proteins and lower acute-phase proteins, whereas the TPN patients manifested the opposite protein profile as measured by crossed immunoelectrophoresis. In view of these findings, we continued the study to ascertain clinical impact. Ultimately, 75 patients were randomized, providing groups with equivalent risk factors. Eleven (37%) of the TPN patients developed septic complications compared to five (17%) of the TEN group, and the incidence of major infection was six (20%) following TPN vs one (3%) with TEN. Thus, immediate TEN provided an additional clinical benefit compared to early TPN in these high-risk surgical patients.

Abbreviations: otj-AT = α,-antitrypsin, o^-M = oCj-macroglobulin, ARDS = adult respiratory distress syndrome, ARF = acute renal failure, ΑΉ = abdominal trauma index, BCAA = branched-chain amino acids, CNS = central nervous sys­ tem, DGH = Denver General Hospital, FEC02 = fractional excretion of carbon dioxide, FE02 = fractional excretion of oxygen, FIC02 = fractional inspired carbon dioxide concentration, FI0 2 = fractional inspired oxygen concentration, GALT = gut-associated lymphoid tissue, GI = gastrointestinal, IgA = immunoglobulin A, I H = interleukin-1, IVC = inferior vena cava, LPS = lipopolysaccharide, MAP = mean arterial pressure, MLN = mesenterio lymph node, MOF = multiple organ failure, NCJ = needle catheter jejunostomy, N 2 = nitrogen, PAF = platelet activat­ ing factor, PGE2 = prostaglandin Ej, REE = resting energy expenditure, RTS = revised trauma score, SIgA = secretory immunoglobulin A, TBSA = total body surface area, TEN = total enterai nutrition, TNF = tumor necrosis factor, TPN = total parenteral nutrition, VC0 2 = carbon dioxide production, V0 2 = oxygen consumption

Presented in part at the 31st Annual Meeting of the American College of Nutrition, Albuquerque, New Mexico, October 13-15,1990. Address reprintrequeststo Ernest E. Moore, M.D., Chief, Department of Surgery, Denver General Hospital, 777 Bannock Street, Denver, Colorado 80204.

Journal of the American College of Nutrition, Vol. 10, No. 6, 633-648 (1991) © 1991 John Wiley & Sons, Inc.

CCC 0731-5724/91/060633-16$04.00

Immediate Enterai Feeding

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INTRODUCTION Metabolic support is an integral component of surgical critical care. Indeed, the route of administration, as well as the timing of nutritional intervention, may be decisive factors in the seriously ill patient at risk for multiple organ failure (MOF). Based on this concept, we presented our preliminary date in 1982 [1], and in the current report we summarize the ensuing clinical investigation. We selected the acutely injured patient as a model of stress-induced hypermetabolism because of relative homogeneity with respect to critical risk factors. The basic questions addressed were: (a) Does immediate nutritional support benefit the acutely stressed but previously well-nourished patient? (b) Does total enterai nutrition (TEN) provide a physiologic advantage compared to total parenteral nutrition (TPN) in the high-risk patient?

POSTINJURY HYPERMETABOLISM Injury Stress Response The metabolic response to injury teleologically optimizes the internal environment for survival as well as facilitates wound repair; these changes fundamentally maximize oxygen delivery to vital organs while promoting substrate mobilization from dispensable supportive tissue. The resultant hypermetabolism/hypercatabolism has been well characterized physiologically, but the intricate driving mechanism is redefined continuously. The neuroendocrine component has been recognized for decades; the activated hypothalamic-pituitary-adrenal axis produces elevated plasma levels of catecholamines, glucocorticoids, and glucagon. Infusing various combinations of these counterregulatory hormones into healthy volunteers, this synergistic interaction reproduces the hypennetabolism observed after major trauma [1]. However, the same triple-hormone infusion does not provide the hypercatabolism observed clinically, implicating other factors responsible for the obligatory proteolysis of critical illness [2]. Metabolic research over the past 10 years has concentrated on the postinjury cell-to-cell interaction, identifying a multitude of inflammatory mediators (e.g., activated complement, cyclooxygenase products, lipoxygenase products, toxic oxygen metabolites, neutrophil proteases, platelet activating factor (PAF), and various cytokines). Although interleukin-1 (EL-1) and tumor necrosis factor (TNF) are presently considered the primary signals for protein breakdown [3,4], there appear to be other critical elements [5]. Thus,

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the postinjury stress response is the net result of a complex interdependent cascade of cell-generating inflammatory mediators as well as neuromediated counterregulatory hormones.

Substrate Demands The corresponding rise in energy demands correlates with the magnitude of the injury as well as injury mechanism. Energy expenditure typically increases 80100% after major burns, 50-60% after severe closedhead injury, and 30-50% after multisystem trauma. Net somatic muscle proteolysis occurs as protein catabolism exceeds synthesis [6]. Carcass protein stores are mobilized to support the more critical visceral organs. The branched-chain amino acids (BCAA) leucine, isoleucine, and valine become important oxidative fuel [7,8], while the glucogenic amino acids, principally alanine, are taken up by the liver to produce greater quantities of glucose. Glutamine becomes the preferred oxidative fuel for the gastrointestinal (GI) tract, an important energy source for the immune system, and is critical for glutathione synthesis in the liver [9]. Circulating amino acids also provide the necessary substrate for hepatic acute-phase proteins, wound healing, and maintenance of other vital organ functions [10,11]. Abnormal glucose tolerance exists, but insulin levels are normal or even elevated. Insulin no longer has the predominate role in glucose kinetics; instead, hyperglycemia is the net result of persistent hepatic gluconeogenesis [12]. Overall, glucose utilization is elevated due to increased demands by the central nervous system (CNS) and hematopoietic system, as well as injured tissue, while clearance by skeletal muscle and adipose tissue is blunted. The kinetics of fat metabolism after injury is not well defined, but, in general, lipolysis is enhanced, fatty acid oxidation accelerated, and ketosis relatively suppressed [13-15]. The typical postinjury decline in the respiratory quotient corroborates that fat is a major energy source during this stress period [16]. Hypercatabolism is also a prominent feature of the early postinjury stress response. The obligatory rate of protein turnover parallels the rise in metabolic rate after trauma, with the notable exception of high spinal cord injury [17]. The ultimate fate of catabolized amino acid carbon skeletons is energy production via the Krebs cycle, while the resultant ammonia is detoxified in the liver and excreted primarily as urea. Thus, the magnitude of protein degradation is reflected in the urinary excretion of urea nitrogen. Our experience in the metabolic assessment of the injured patient [1,18-24] is outlined in Table 1. Patients sustaining multisystem trauma lost 13-

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Immediate Enterai Feeding Table LMetabolic Stratification of the Injured Patient* Qinical status

ISS

ATI

V02I (ml/min/m2)

UUN2 (g/kg/day)

Mild Moderate Severe

>16 16-25 >25

40

140 140-200 > 200

0.18 0.18-28 >0.28

a

ISS = injury severity index; ΑΉ = abdominal trauma index; VO,I = oxygen consumption index; UUN2 = urine urea nitrogen.

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18 g/day of N2; if compounded by closed-head injury with increased intracranial pressure or long bone pelvic fractures, N2 excretion is frequently > 25 g/day. Risk Stratification Nutritional-immunologic assessment of the acutely injured patient is essential, both to identify the need for aggressive nutritional support and to ascertain its ef­ ficacy. Our clinical work confirms that, even in an urban hospital with a large indigent population, most young trauma patients are nutritionally intact at the time of in­ jury [1]. Standard nutritional indices developed for the elective surgical patient, however, are unreliable in the early postìnjury period. The obligatory weight gain due to sodium retention after hemorrhagic shock renders anthropométrie measurements virtually uninterpretable. Visceral protein markers, reflected by serum transport protein levels, are likewise distorted by fluid shifts [25] and reprioritization of hepatic protein synthesis [24,26]. Albumin a constitutive protein, is shifted out of the intravascular space after hemorrhagic shock [27]. Our studies [19] have shown that early postìnjury depression in serum albumin most specifically correlates with acute blood loss. The sensitivity of these transport proteins also relates to their body pool size and half-life. Prealbumin and retinol-binding protein reflect protein deprivation more acutely than serum albumin or transferrin because of their relatively small body pool size and short half-life. On the other hand, the unique sensitivity of these rapid-turnover proteins compromises their specificity. Cell-mediated immunity, as quantitated by delayed hypersensitivity skin testing, had been embraced as a simple technique to ascertain the impact of malnutri­ tion on host defense [28]. But in the acute postìnjury period, tissue disruption, acute hemorrhage, hypovolemic shock, anesthesia, and surgery all significantly depress immune function. Our interest in postìnjury nutritional assessment focused on selecting which patients sustaining ab­

dominal trauma warrant early aggressive nutritional sup­ port. Due to the inaccuracy of conventional nutritional indices representing physiologic and biologic markers, as outlined above, we devised an anatomical index based on intraoperative findings at laparotomy [18,21]. A com­ plication risk factor (range 1-5) was assigned to each organ system and then multiplied by a severity of injury estimate for each organ (Table 2). The complication risk factor (range 1-5) was based on the reported incidence of morbidity after specific organ injuries. The individual organ severity estimate was graded (range 1-5) on a scale modified from the Abbreviated Injury Scale: 1 = minimal, 2 = minor, 3 = moderate, 4 = major, and 5 = maximum. The sum of individual organ scores com­ prised the final abdominal trauma index (ATI) score. Despite its simplicity, the ATI has been proven to be sensitive and reasonably specific in predicting morbidity after major abdominal trauma. ATI scores of < 16 reflect low risk of septic morbidity, 16-25 moderate risk, and > 25 high risk. Stress is probably best estimated clinically by indirect calorimetry [29]. With the advent of the mobile metabo­ lic cart, it is feasible to measure respiratory gas exchange to determine C0 2 production (VCOÏ) and oxygen con­ sumption (V0 2 ). Although the various metabolic carts differ in their specific instrumentation, their operation is fundamentally the same. Concentration of inspired oxygen (FI02), expired oxygen (FEOj), inspired C0 2 (FIC02), expired C0 2 (FEC02), and the expired minute ventilation are accurately measured by open circuit tech­ niques. Interpretation of these data, however, requires a knowledge of the patient's condition at the time of the study [30]. Daily nursing care activities or patient agita­ tion produces transient elevations in the resting energy expenditure (REE). C0 2 , unlike oxygen, is stored within the body, and this equilibrium is readily disturbed by the changes in acid-base status, body temperature, and ventilatory pattern. Frequent measurements taken over several hours are necessary to select steady state num­ bers. Mechanical ventilation in itself has pitfalls impact-

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Immediate Enterai Feeding Table 2. The Abdominal Trauma Index (ATI) Organ risk factor 5 = Colon, pancreas 4 = Duodenum, liver, major vascular, pelvic fracture 3 = Spleen, ureter, extrahepatic biliary, spine fracture 2 = Small bowel, kidney, stomach, diaphragm 1 = Bladder, genital, soft tissue

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Organ injury severity 5 = Maximum 4 = Major 3 = Moderate 2 = Minor 1 = Minimal Calculating Organ 1: Organ 2: Organ 3: Organ x:

the ΑΉ score Risk factor multiplied by injury severity Risk factor multiplied by injury severity Risk factor multiplied by injury severity

= = = =

Score 1 Score 2 Score 3 Score x

ATI = Sum of organ scores.

ing on the interpretation of indirect calorimetry. The FI0 2 must be stable, and variations as small as 0.5% result in large calculation errors. FI0 2 fluctuations may also occur with changes in the pressure of the oxygen line source, an unstable internal air-oxygen bender of a ventilator, or mixing of inspired and expired gases. At higher FI0 2 values, analytic determination of the dif­ ference between FI0 2 and FE0 2 creates a greater per­ centage of error. Exhaled tidal volume must be measured accurately; leaks due to a deflated endotracheal cuff, bronchopleural fistula, or other problems within the sys­ tem grossly distort this volume. Thus, a good under­ standing of both the metabolic cart and the ventilator is essential to obtain meaningful data.

RATIONALE FOR EARLY NUTRITIONAL SUPPORT MOF Cofactors Timing of nutritional support in the severely injured but previously well-nourished patient has been a con­ troversial issue. The postinjury metabolic stress response peaks at 3-4 days and, if not driven by another insult, subsides in 7-10 days. However, the immutable as­ sociated hypercatabolism can produce significant protein

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malnutrition in this short period. Accelerated protein turnover permits a limited protein pool to be used effi­ ciently, but when exogenous amino acid supply is insuf­ ficient these amino acids must be diverted from limited endogenous sources [6,31-39]. Skeletal muscle is the first reserve, but when the demand for amino acid con­ tinues, more crucial protein pools are depleted, i.e., vis­ ceral structure elements and circulating proteins. Indeed, animal studies and clinical observation have documented that acute protein malnutrition is associated with cardiac, pulmonary, hepatic, GI, and immunologie dysfunction. In essence, a subclinical MOF syndrome evolves, rendering the patient at greater risk for overwhelming infection. Conceptually, MOF is uncontrolled systemic inflam­ mation, resulting in a regional imbalance between supply and demand in life-sustaining systems. Postinjury hypermetabolism is the fundamental background which primes the host for a second or third physiologic insult that precipitates this sequential failure of organ systems. Postinjury MOF generally follows two patterns [40-43]. The early-onset variant becomes manifested with 12 hours of an extended perfusion deficit, and is heralded by adult respiratory distress syndrome (ARDS) with subclinical acute renal failure (ARF) and hepatic dysfunc­ tion. The more common delayed-onset MOF is charac­ teristically associated with the sepsis syndrome, and

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Immediate Enterai Feeding Table 3. Qinical Benefits of Early Postinjury Nutritional Support* Total lymphocyte count (cell/mm3)

N2 balance (g/day)

Control (n = 31) Day 1 Day 4 Day 7

1408 ± 158 1175 ±176 1482 ±138

-13.2 ± 0.5 -11.4 ±0.7 -11.1 ±0.7

9 (29%)

Enterai (n = 32) Day 1 Day 4 Day 7

1831 ±206 1344 ±166 2054 ±164

-13.7 ± 0.7 -3.9 ± 1.6 -5.2 ± 1.3

3 (9%)

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Study group

Sepsis

Hospital cost/patient

$19,636

$16,280

"Data values ±SEM; *p < 0.0S; N 2 - nitrogen.

ARDS, ARF, and hepatic failure typically evolve concurrently. Irrespective of the pattern, the most frequent comorbid factors for postinjury MOF are direct injury, e.g., pulmonary contusion, major hepatic resection, or preexisting disease such as hepatic cirrhosis, ischemie heart disease, or chronic pulmonary dysfunction. In 1976, Border et al [31] suggested that acute protein malnutrition is another insidious risk factor for MOF, i.e., when the oxidative amino acid metabolic demands cannot be met by skeletal muscle proteolysis, the autocannibalism progresses to erode crucial visceral protein. Souba [44] recently documented enhanced glutamine release from the lung as well as skeletal muscle in stressed animals, suggesting an early sacrifice of visceral protein to support the host. Thus, it is conceivable mat failure to provide adequate nutritional support in the first 3-5 days after major trauma predisposes the patient to MOF. This concept has been supported by recent experimental work [45-48], and clinical evidence is beginning to emerge [49]. Clinical Validation: Early Nutrition Our first clinical investigation was designed to ascertain whether early nutritional support would influence patient outcome after severe trauma. Traditional practice had been to delay nutritional support for 5-7 days in the previously well-nourished injured patient, and then TPN was initiated if the individual was unable to consume adequate oral intake. In 1979, stimulated by the success of needle catheter jejunostomy (NCJ) after elective GI surgery reported by Page et al [50], we completed a prospective trial to confirm the feasibility of NCJ in

patients who had sustained major abdominal trauma. Indeed, immediate enterai feeding was categorically successful despite extensive injuries, including the small bowel and colon [20]. Convinced of the efficacy and safety of the NCJ and prepared with the ATI to identify the high-risk patient, we then conducted a randomized prospective investigation to critically analyze the impact of immediate postinjury nutritional support [22]. During a 2.5-year period, all patients undergoing celiotomy at the Denver General Hospital (DGH) with an ATI score > 15 were enrolled in this prospective randomized study; 75 (20%) of the 371 injured patients requiring laparotomy met this criterion. Such patients were randomized to either a control or enteral-fed group. Control patients received conventional D5W (approximately 100 g/day) IV during the first five postoperative days, and then high-nitrogen TPN (NP calories:N2 = 133:1) by central vein if they were not tolerating a regular diet at that time. The enterally fed group had an NCJ placed just before abdominal closure. Infusion of an elemental diet (Vivonex HN, Norwich Eaton Pharmaceuticals, Norwich, NY; NP calories:N2 = 150:1) was begun via the NCJ within 12 hours postoperatively and advanced to meet the metabolic demands at 72 hours. Nutritional-immunologic assessment was performed within 12 hours of laparotomy and repeated by the DGH Nutritional Support Service every third day. Results of this study are summarized in Table 3. The control (n = 31) and enteral-fed (n = 32) groups were comparable with respect to age, sex, race, injury mechanism, shock at admission, colon wound, splenectomy, and ATI score. The groups were also equivalent according to initial nutritional assessment of weight,

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Immediate Enterai Feeding

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triceps, skinfold thickness, and REE based on the adjusted Harris-Benedict equation. Twenty (63%) of the 32 enteral-fed patients were maintained on the elemental diet for > 5 days (range 5-20, mean 9 days), while four (12%) received TPN. Nine (29%) of the 31 controls developed abdominal abscess. Moreover, the mean ATI score of patients developing complications in the control group was 31, while in the enterai group it was 48. Finally, the cost savings based on a review of actual hospital bills exceeded $3000/patient in the enteral-fed group. Thus, this prospective randomized study demonstrated a statistically significant reduction in septic morbidity after major abdominal trauma as a result of immediate postinjury nutritional support in previously wellnourished individuals.

RATIONALE FOR ENTERAL FEEDING Gut Bacterial Translocation Acknowledging the benefit of early nutrition in the high-risk patient, the next issue we addressed was the optimal route of substrate delivery, i.e., TEN or TPN [51]. Safety, convenience, and cost have been commonly stated advantages of enterai nutrition, but the theoretical physiologic benefits are far more compelling. The gut has been inappropriately perceived as a dormant organ after stress. Gastric decompression is typically required for 1-2 days postinjury due to gastric atony, while colon peristalsis is impaired for 3-5 days; however, small bowel motility and absorption remain functionally intact despite laparotomy. Moreover, recent work has established that the gut is metabolically active [9,52-54], immunologically important [44,55,56], and bacteriologically decisive in the stressed patient. Central to this concept is an emerging consensus that gut-derived bacteria and endotoxin are primary factors in the genesis of postinjury MOF [57-60]. Transmural migration of viable GI tract organisms (bacterial translocation) was demonstrated experimentally 40 years ago. In 1950, Fine et al [61] reported a canine model of chemical peritonitis which documented peritoneal seeding with gut-derived l31 I-tagged E. coli. Indeed, in the ensuing two decades this group completed a number of innovative studies. In a review article 25 years ago, Fine concluded that the absorption of endotoxin from the GI tract in conjunction with reduced hepatic detoxification was the fundamental basis for irreversible postinjury shock [62]. More recently, the animal models of Deitch et al have comprehensively addressed the factors that govern this phenomenon. In their shock model [63], rats were bled to a mean arterial pressure (MAP) of 30 mm Hg for 30,

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60, and 90 minutes and sacrificed at 24 hours postshock. Mesenterio lymph nodes (MLNs), spleens, and livers were then cultured quantitatively. Thirty and 60 minutes of shock had roughly equivalent effects: Approximately half the MLN cultures were positive, spread to liver and spleen was 20%, while mortality was 15 and 20%, respectively. In contrast, after 90 minutes of shock, all MLNs were culture-positive and grew significantly greater numbers of enteric bacteria, spread to systemic organs was 60%, and mortality increased to 40%. The most common bacteria recovered from solid viscera were E. coli; other species included Enterococcus, Pseudomonas, Proteus, and Staphylococcus. Of interest, only 33% of the rats had positive blood cultures. In another model, bacterial translocation to MLNs was induced by simply altering normal gut flora (oral antibiotic administration followed by feeding a specific strain of E. coli). Once the E. coli count exceeded 107g in the cecum, MLN cultures became consistently positive. This induced bacterial overgrowth exaggerated the response to their standard 40% total body surface area (TBSA) burn, and induced consistent spread of bacteria beyond MLNs [64]. Additionally, they found that neither 72 hours of starvation nor 21 days of protein deprivation was associated with translocation, but when E. coli endotoxin was administered, bacteria were recovered in 80% of the MLNs and 60% of the livers and spleens [58]. Alverdy and others [65] have identified further cofactors that include depressed cell-mediated immunity, TPN [66], as well as specific nutrients [40,67]. Rush et al have also conducted a series of studies where rats were exposed to profound hemorrhagic shock (MAP of 30 mm Hg until 80% of shed blood was returned) [60,68-71]. On average, this represented a shock period exceeding 4 hours and was thus considerably different from Deitch's model. Blood cultures became positive 30 minutes into the shock period and bacteremia continued throughout the ensuing 48 hours of observation. Pseudomonas and enterococcus predominated early, and cultures became polymicrobial over time [68]. Germ-free rats subjected to the same shock model were noted to have significantly better 24-, 48-, and 72-hour survival (62, 30, 25 vs 24, 11, 5%) [70]. In another study, rats were fed E. coli labeled with 14C oleic acid [71]. After hemorrhagic shock, half were noted to have increased plasma 14C activity; these animals had blood cultures positive for E. coli and died within 80 hours. In contrast, 83% of the animals without plasma l4C activity survived. Serendipitously, Wells et al [72] found bacterial translocation in experimental abdominal abscesses. Enteric bacteria were recovered from more than half of fibrin clot/Bacteroides fragilis inocula within a week; the most frequent organisms were enterococci, E. coli, and

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Immediate Enterai Feeding Staphylococci. Additionally, Inoue et al [73] demonstrated the translocation of Candida albicans across gut mucosa into MLNs of burned guinea pigs, which quantitatively correlated with injury severity. In sum, these animal data provide convincing evidence that bacterial translocation follows a variety of stressful insults which can be modulated by a number of environmental factors. . Although bacterial translocation has been consistently demonstrated in these experimental models, its occurrence in man is uncertain and its precise role and specific mechanisms of initiating distant organ dysfunction remain to be established. Secondary endotoxemia appears to be the most plausible link. Presumably, the same elements that favor bacterial translocation will promote escape of their toxic cell membrane from the gut lumen. Rush et al [60] found endotoxemia is one-third of their rats after 30 minutes of profound shock and in 88% after 2 hours. In other studies, oral nonabsorbable antibiotics have attenuated the endotoxemia associated with intestinal ischemia [74]. Moreover, endotoxin-specific antibodies have been shown to reduce mortality in hemorrhagic shock models [75]. Endotoxin is known to recruit, activate, and prime neutrophils; damage endothelium and alter receptors; induce cytokine release; and trigger the complement and clotting cascades. The liver appears to be the primary site of endotoxin clearance [76,77]. The vast hepatic sinusoidal network, lined with Kupffer cells, is strategically located to interact with gut-derived endotoxin and represents more than 80% of the total reticuloendothelial cell mass. In addition to clearing blood of bacteria and endotoxin, Kupffer cells are a rich source of inflammatory mediators, e.g., TNF, interleukins, platelet-activating factor, as well as arachidonic acid metabolites. In fact, these cytokines have been strongly implicated as the principle mediators of the systemic response to critical illness [54,78-82]. Plasma TNF levels have been shown to rise 60-90 minutes after intravenous administration of lipopolysaccharide (LPS) to human volunteers, and this was typically associated with chills, myalgias, and nausea [83]. Animal models indicate that TNF plays a central role in mediating the toxic effect of endotoxemia, and prior administration of monoclonal antibodies to TNF ablate many of the pathophysiologic changes seen with lethal doses of endotoxin [79]. In contrast, BL-1, also an LPS-stimulated macrophage-derived cytokine, has a less toxic effect than TNF, but appears to be a potent modulator of stress metabolism [4]. Prostaglandin Ej (PGE2), an immunosuppressant that is elevated following major torso trauma [84,85], is also an important product of these activated macrophages [82]. Cena et al [86] have shown in a rat

cell culture preparation that LPS-activated Kupffer cells modulate adjacent hepatocyte protein synthesis. In an in vivo model, Marshall et al [81] found that E. coli infused into the portal vein of rats suppressed delayed type hypersensitivity response, whereas the same E. coli challenge via the inferior vena cava (IVC) had no effect. In a similar model, Kahky et at [87] documented increased toxicity and mortality in rats that had TNF infused via the portal vein compared to the IVC. Collectively, these animal data suggest that gut-derived endotoxin is a plausible mechanism and that the liver may be the pivotal organ regulating the systemic manifestations of MOE

Gut Regulatory Functions The gut mucosa represents a critical interface between the body's external and internal environment. This complex epithelial surface provides not only a barrier, but absorbs and secretes. The enterocyte is metabolically active [9,52-54] and no doubt elaborates a number of important enzymes, hormones, and growth factors, as well as a variety of mediators. The intestinal mucosa undergoes rapid turnover and is therefore extremely vulnerable to starvation [34]. Additionally, the gut derives critical nutrients from luminal contents, as well as via the circulation. GI atrophy is a well-defined phenomenon, documented in humans as well as animals fed exclusively by vein. In fact, Johnson et al [88] recognized marked atrophy of the stomach, duodenum, jejunum, and pancreas in parenterally supported animals during their pioneering work on TPN. More recent work has established reduced villous height and suppressed crypt cell proliferation in the inactive small bowel. Other investigators have confirmed substantial changes in systemic levels of gut-derived hormones such as gastrin, glucagon, insulin, gastric inhibitory peptide, and vasoactive intestinal peptide associated with parenteral nutrition [89]. A number of studies suggest important endocrine, paracrine, and exocrine roles for the gut. Substrate utilization may be more efficient when nutrients are infused via the jejunum [90,91] or portal vein [92] compared to TPN. Saito et al [48] have also shown an attenuated stress response in burned animals that were fed through the gut vs parenterally. Although this finding has been attributed to blunted cortisol and catecholamine release, gut-derived hormones cannot be excluded as a contributing mechanism. The Gì mucosa may also have important immune regulatory functions in the critically ill patient. The lymphoid structure of the gut includes Peyer patches, which are basically mucosal lymphoid follicles that process bacteria and other intraluminal antigenic material. The resulting activated lymphocytes then migrate to other

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Immediate Enterai Feeding

Fig. 1. A needle catheter jejunostomy is placed via the antimesenteric border of the proximal jejunum at initial laparotomy in the high-risk trauma patient.

mucosal epithelial sites, e.g., tracheobronchial, genito­ urinary, and salivary glands, to prepare the mucosal sur­ face for an enhanced response to a second antigenic en­ counter. Additionally, stimulated gut B cells produce secretory immunoglobulin (SIgA), which is also dis­ persed systemically and transported across epithelial cells to enhance local host defense. Alverdy et al [45] have shown that enterai feeding maintains normal biliary levels of SIgA in animals, while TPN is associated with a precipitous fall. Concentrated SIgA in bile is consistent with the concept that immunoglobulin A (IgA) may also clear immune complexes through the hepatobiliary cir­ culation. T cells are also a conspicuous element of gutassociated lymphoid tissue (GALT). T cells no doubt play a number of roles in GALT, and inflammatory bowel disease is a convincing example of their impact

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when deranged [56]. Maddaus et al [55] believe that T cell integrity is key in eradicating gut bacteria translo­ cated to mesenteric lymph nodes. Recent investigation suggests that the gut is metabolically active in the critically injured patient. The most convincing evidence is the elucidation of glutamine kinetics by Souba, Wilmore, and colleagues [9,44,53, 54]. During stress, amino acids are exported from skele­ tal muscle for visceral fuel, gluconeogenesis, host defense, and wound repair. Glutamine and alanine repre­ sent the majority of this N2 efflux. Under normal condi­ tions, glutamine is the most abundant amino acid in plas­ ma and in the free intracellular pool. However, glutamine levels fall precipitously in whole blood and skeletal muscle after injury, while glutamine uptake is markedly enhanced in the intestine. A stress dose of cor-

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Immediate Enterai Feeding TP

ALB

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I 6.0-

l~3.5£

5.0-

250 .

-3.0

TRF

RBP 3.0

200 H2.5 £ 50 2.0

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1001

5

10 1 Days Poet-Trauma

10

Fig. 2. The TEN (solid line) vs TPN (dashed line) clinical study demonstrated consistent improvement in standard visceral protein markers (TP = total protein; ALB - albumin; TRF = transferrin; RBP = retinol binding protein) in enterally fed patients; p < 0.05.

ticosteroids will increase glutaminase activity in jejunal mucosa of animals, a suggested mechanism for this postinjury phenomenon [93]. Fundamentally, the gut adapts to spare glucose for obligate users by relying on glutamine as its primary oxidative fuel, while processing other nitrogen and carbon for hepatic ureagenesis (am­ monia) and gluconeogenesis (alanine). Teleologically, this "gut-glutamine cycle" may be related to intestinalderived endotoxin [54]. Most recently, Souba has ob­ served that the lung releases glutamine similar to muscle in response to stress [44].

Clinical Validation: Enterai Feeding Our initial clinical investigation of major abdominal trauma, demonstrating s significant reduction in septic complications as a result of immediate TEN, prompted further study asking whether early TPN would produce equivalent benefits [24]. Fifty patients with an ATI score > IS and < 40 were randomized at initial laparotomy to receive either TEN (Vivonex TEN) or TPN (Freamine HBC 6.9% and Trophamine 6%) (Kendalt-McGaw Laboratories, Irvine, CA); both regimens contained 2.5% fat, 33% BCAA, and had an NP calorie:N2 ratio of 150:1 (see Appendix). Nutritional support was initiated within 12 hours postoperatively in both groups, and infused at a rate sufficient to render the patients in positive N2 balance within 48 hours. TEN was delivered via an NCJ, as in our previous clinical work (Fig. 1). The study

groups (TEN = 23, TPN = 27) were comparable in age (28.3 ± 1.9 vs 31.4 ± 2.4 hr), ATI (24.5 ± 1.3 vs 24.2 ± 1.2), ISS (28.8 ± 2.8 vs 25.8 ± 2.0), and initial metabolic stress [day 1 urine urea N2 (UUN2) = 13.0 ± 1.5 vs 12.4 ± 0.7 g]. Jejunal feeding was tolerated unconditionally in 21 (91%) of the TEN patients; the remaining two re­ quired a transitional period with supplemental TPN. The TPN group received a slight advantage in overall protein-calorie intake, but N2 balance remained equiv­ alent throughout the study period (day 5: TEN 0.4 ± 1.6 vs TPN 0.8 ± 1.0 g/day). Of note, standard visceral protein markers (total protein, albumin, transferrin, and retinol-binding protein) all increased over the study period in the TEN group, while decreasing in TPN patients (Fig. 2). To test the hypothesis that enterai nutrition reduces bacterial translocation, we examined prioritization of hepatic protein synthesis, defined as the relative balance of acute-phase proteins compared to constitutive proteins (nonacute phase). Specific serum protein levels were profiled by crossed immunoelectrophoresis. When segregated by treatment group, divergent patterns of protein synthesis emerged. Prealbumin and o^-macroglobulin (ctj-M) are displayed as representative constitu­ tive proteins, while haptoglobin, orosomucoid, and α,antitrypsin (α,-ΑΤ) are shown to reflect changes in acute-phase protein synthesis. Figure 3 demonstrates equal depression of o^-M levels in the TPN and TEN groups on day 1, and by day 5 levels had risen slightly.

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Day· Post-Trauma

Daya Poat-Trauma

Fig. 3. Constitutive proteins, represented by Oj-macroglobulin, normalized in the TEN group (solid line), but remained depressed in the TPN patients (dashed line).

Fig. 4. Acute phase proteins, represented by α,-antitrypsin, remained elevated to a greater extent in the TPN group (dashed line) compared to the TEN patients (solid line).

On day 10, however, the c^-M level in the TEN group had returned to normal, but remained depressed in the TPN group. Similar trends were seen for prealbumin. In contrast, serum levels of the acute-phase protein α,-ΑΤ increased to a greater degree in the TPN group compared to the TEN group. Figure 4 depicts α,-ΑΤ values for the TEN and TPN treatment groups on days 1, 5, and 10 posttrauma. Baseline levels were similar for both groups. On day 5, however, a r A T levels in the TPN group in­ creased more than in the TEN group. Levels in both groups fell slightly by day 10. These data suggest that TEN ameliorates reprioritization of hepatic protein syn­ thesis after major torso trauma. Although speculative, we believe this reflects a reduction in bacterial translocation via preservation of gut mucosa! integrity. In view of these findings, we continued this study to ascertain the clinical impact [23]. Ultimately, 75 patients (39 TEN, 36 TPN) of 407 undergoing emergent laparotomy were prospectively randomized; 16 patients were subsequently excluded from the study, leaving 59 évaluable subjects (29 TEN, 30 TPN). Reasons for exclusion were early death (four patients), reoperation within 72 hours (three patients), significant chronic medical disease (three patients), an ATI score > 40 (two patients), head injury requiring fluid restriction (two patients), mechanical failure of TEN delivery (one patient), and early transfer (one patient). The study groups were comparable at presentation with respect to age (TEN 28 ± 2 vs TPN 32 ± 2 years), injury mechanism (28 vs 36% blunt), ISS (28.7 ± 2.3 vs 25.1 ± 1.0), ATI (24.7 ± 1.1 vs 24.0 ± 1.0), and physiologic status [revised trauma score (RTS 6.9 ± 0.2 vs 6.9 ± 0.3]. Equivalent TRISS scores (probability of survival = 0.49

± 0.05 vs 0.55 ± 0.04) further corroborate comparability. Of the évaluable TEN patients, four (14%) subjects failed to tolerate the protocol increments in the enterai diet, three patients responded to manipulation in the feeding schedule, and the remaining patient was transitioned to TPN on day 7 due to moderate intolerance in the face of persistent hypermetabolism. All were retained in the TEN group for analysis. On day 5, caloric and N2 intake were higher in TPN patients compared with patients receiving TEN. Despite this slight advantage in protein-calorie intake via the parenteral route, no significant differences for N2 balance were noted between the two groups at day 5 (-0.3 ± 1.0 vs 0.1 ± 0.8 g/day). As shown previously, albumin, transferrin, and retinolbinding protein levels increased throughout the study in patients receiving TEN (Fig. 2). On day 5, the difference between treatment groups reached statistical significance for albumin, and day 10 albumin and transferrin were significantly higher in TEN patients. Abnormalities in liver function were observed and, of note, bilirubin and alkaline phosphatase levels were higher in patients receiving TPN. Glucose levels also tended to be higher in TPN patients, but this failed to reach statistical significance. However, glucose levels were maintained at acceptable levels by exogenous insulin in five (17%) of the TPN group compared to one (3%) of the TEN group, and insulin levels by day 5 were significantly elevated in patients receiving TPN. Of interest, plasma glutamine levels were preserved in the enterai patients on day 5 but fell in the parenteral group (241 ± 31 vs 178 ± 20 nmol/ml, respectively).

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Complications occurred in ten TEN patients (34%) compared to 17 TPN patients (57%). Seven patients in

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Immediate Enterai Feeding Table 4. Septic Complications of Total Enterai Nutrition vs Total Parenteral Nutrition Study Groups after Major Trauma" Group Complications Major infections Abdominal abscess

TEN

TPN

(n = 29)

(n = 30)

2

1

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1(3%) Pneumonia

0

6

Minor infections Wound Catheter

3 0

1 2 4 (14%)

Urinary Miscellaneous Total patients

p value

6 (20%)

0.03

5 (17%)

NS

1 2

0 1 5 (17%)

11 (37%)

*TEN = total enterai nutrition; TPN = total parenteral nutrition.

the TPN group and six patients in the TEN group ex­ perienced nonseptic complications including pancreatitis (five patients), atelectasis (three patients), recurrent pneumothorax (one patient), biliary fistula (one patient), breakdown of exteriorized colon repair (one patient), and cerebrospinal fluid leak (one patient). Septic complica­ tions are summarized in Table 4. The overall incidence of septic morbidity was five (17%) patients in the TEN group and 11 (37%) patients in the TPN group. There was a significant difference with respect to major infec­ tions (pneumonia and intraabdominal abscess), i.e., one (3%) patient in the TEN group compared to six (20%) in the TPN group. All six pneumonia cases were in the TPN group. The mechanism of injury for these patients were blunt in three and gunshot wounds in three; the mean ATI score was 27.8 ± 2.2, and the mean ISS was 2S.0 ± 3.7. One patient had an associated chest injury; two others underwent splenectomy. Three (50%) had early pneumonias, developing within five days postinjury. Pathogens identified by sputum culture included two Staphylococcus aureus and one each of E. coli, Strep­ tococcus pneumoniae, Pseudomonas aeruginosa, Proteus mirabilia, Serratia marcescens, and Citrobacter sp. In conclusion, this prospective, randomized study demonstrated a statistically significant reduction in sep­ tic morbidity in high-risk patients receiving early TEN

compared to early TPN. Border et al [57] have sub­ sequently corroborated these findings in a comprehen­ sive, albeit retrospective, statistical analysis of patients sustaining blunt multisystem trauma.

CURRENT POLICY FOR POSTINJURY NUTRITIONAL SUPPORT Aggressive Enterai Feeding Our nutritional support protocol for major abdominal trauma is summarized in Figure 5. An ATI score > 15, or the equivalent using another injury severity index, prompts NCJ placement at emergent laparotomy unless reexploration is planned within 24 hours. In the latter situation the catheter is placed more safely at the second operation. Additionally, NCJ is warranted for patients with an ATI score < 16 in whom associated extraab­ dominal injuries, such as severe head injury or major pelvic crush, prolong their catabolic state. However, in these patients, as well as in patients with extensive in­ traabdominal injury (ΑΠ > 40) or massive blood loss (> 25 U/24 hr) in whom reflex small bowel ileus is likely [94], TPN is initiated with transition to jejunostomy feeding within 3-5 days. Finally, an NCJ is placed in

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Immediate Enterai Feeding

/f NEEDLE * • CATHETER V JEJUNOSTOMY

A.T.I. >15

y4

/ / Celiotomy for Abdominal Trauma ^ X AT. I. • • £15

AT. I. >40

*

•

TOTAL PARENTERAL NUTRITION 3 - 5 DaysN X

X A.T.I. £40

I

Z

*

ENTERAL FEEDING

Head Injury Pelvic Fractur B

n

*

I RELAPAROTOMY

I

/

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x . Oral / Diet v

>*. Extraabdc»minai Complicat ion

*

NASOENTERAL INTUBATION

Fig. 5. Our nutritional support protocol following multisystem trauma emphasizes the early administration of enterai feed­ ing to maintain the intestinal mucosa.

patients undergoing reoperation for presumed abdominal infection. Sepsis does not precluded jejunal feeding in this clinical setting [95].

FUTURE CONSIDERATIONS Much remains to be learned about the complex meta­ bolic, immunologie, and bactériologie regulatory func­ tions of the GI tract and how they are altered by acute stress. The strong interdependence of the gut and other organs is now appreciated, perhaps most noteworthy being the recent metabolic association with the lung. Ad­ ditionally, there are numerous unresolved issues: (a) op­ timal nutrients for the critically ill patient; e.g., BCAA (leucine), specific amino acids (glutamine, arginine), fatty acids (n-3, MCT), dietary fiber, minerals (zinc), vitamins (A, C), etc.; (b) the relative balance of sub­ strate; e.g., NP calorie:N2 ratio, fatxarbohydrate ratio, peptides vs amino acids, etc.; and (c) tailoring nutrients for the patient with pulmonary, hepatic, or renal failure. Indeed, clinical confirmation of improved gut preserva­ tion [96,97] and enhanced N2 retention [98] with glutamine-enriched TPN has clear implications in the patient who cannot be fed enterally.

644

Another area that appears promising is the addition of growth factors with TPN to restore GI integrity [98,99]. A variety of peptide growth factors, e.g., epidermal growth factor, transforming growth factor-B, fibroblast growth factor, platelet-derived growth factor, etc., have been shown to stimulate cellular proliferation by autocrine or paracrine activity. Epidermal growth factor has been shown to have trophic effects on small bowel mucosa in animals which are additive to those achieved by glutamine-enriched TPN [98]. Other studies [94] have shown that both systemic and luminal epidermal growth factor increase intestinal sub­ strate absorption without changes in mucosa DNA levels. Presumably, the gut releases growth factors which have local effects on intestinal epithelium, as well as direct impact on the liver via the portal vein, and on distant organs through the lymphatic circulation. Thus, while the current focus is on gut-derived endotoxin, other factors released by the GI tract may have a more profound influence on the response to injury and ul­ timate risk of developing lethal MOE

ACKNOWLEDGMENT The authors thank Catherine Naranjo for preparing this manuscript.

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Immediate Enterai Feeding Appendix. Amino Acid Comparison of TEN and TPN 1000 ml TPN solution: Freamine HBC 6.9%, Trophamine-.6% % g/L

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Vivonex TEN g/L

%

3.17 6.33 3.17 1.93 1.40 1.97 1.53 0.50

(8.27) (16.56) (8.27) (5.10) (3.66) (5.16) (4.00) (1.28)

3.56 6.23 3.71 2.82 1.33 1.82 1.42 0.67

(9.37) (16.40) (9.77) (7.42) (3.50) (4.79) (3.74) (1.75)

20.00

(52.30)

21.56

(56.74)

Nonessential AA L-alanine L-aiginine L-aspartic acid L-glutamine Glycine L-histidine L-proline L-serine L-tyrosine

1.97 2.92 2.67 4.90 1.53 0.09 1.87 1.10 0.33

(5.18) (7.64) (7.01) (12.85) (4.01) (2.36) (4.88) (2.93) (0.84)

2.13 4.13 0.76 1.19 1.55 1.48 2.95 1.60 0.57

(5.16) (10.86) (2.00) (3.12) (4.09) (3.89) (7.77) (4.22) (1.50)

Total nonEAA

18.19

(47.70)

16.36

(43.06)

Total AA %BCAA %AAA BCAA:AAA NPC:N

38.19 33.10 6.00 7.4:1 149:1

Essential AA L-isoleucine L-leucine L-vai ine L-lysine L-methionine L-phenylalanine L-threonine L-tryptophan Total EAA

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Received October 1990; revision accepted March 1991.

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