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Surgery_Schwartz. matrix). DC are fre-quently referred to as “professional APCs” since their principal function is to capture, process, and present both endogenous and exogenous antigens, which, along with their co-stimulatory molecules, are capable of inducing a primary immune response in resting naive T lymphocytes. In addition, they have the capac-ity to further regulate the immune response, both positively and negatively, through the upregulation and release of immuno-modulatory molecules such as the chemokine CCL5 (RANTES) and the CXC chemokine CXCL5. Finally, they have been impli-cated both in the induction and maintenance of immune toler-ance as well as in the acquisition of immune memory.209 There are distinct classes and subsets of DC, which are functionally heterogeneous. Different levels of damage-sensing receptors (e.g., TLR) that dictate a preferential response to DAMPs at that site. While relatively small in number relative to the total leukocyte population, the diverse distribution of DC


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Surgery_Schwartz. receptors (e.g., TLR) that dictate a preferential response to DAMPs at that site. While relatively small in number relative to the total leukocyte population, the diverse distribution of DC in virtually all body tissues underlines their potential for a collaborative role in the initiation of the trauma-induced sterile systemic inflam-matory response. Data support a phenotypic alteration in these cells following traumatic injury.210PlateletsPlatelets are small (2 µm), circulating fragments of a larger cell precursor, the megakaryocyte that is located chiefly within the bone marrow. Although platelets lack a nucleus, they contain both mRNA and a large number of cytoplasmic and surface pro-teins that equip them for diverse functionality. While their role in hemostasis is well described, more recent work suggest that platelets play a role in both local and systemic inflammatory responses, particularly following ischemia reperfusion. Plate-lets express functional scavenger and Toll-like


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Surgery_Schwartz. recent work suggest that platelets play a role in both local and systemic inflammatory responses, particularly following ischemia reperfusion. Plate-lets express functional scavenger and Toll-like receptors (TLR) that are important detectors of both pathogens and “damage”-associated molecules.211 At the site of tissue injury, complex interactions between platelets, endothelial cells, and circulating leukocytes facilitate cellular activation by the numerous local alarmins and immune mediators. For example, platelet-specific TLR4 activation can cause thrombocytes to bind to and activate neutrophils to extrude their DNA to form neutrophil extracel-lular traps or NETs, an action that facilitates the capacity of the innate immune system to trap bacteria but also leads to local endothelial cell damage.212Once activated, platelets adopt an initial proinflamma-tory phenotype by expressing and releasing a variety of adhe-sion molecules, cytokines, and other immune modulators, including high


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Surgery_Schwartz. damage.212Once activated, platelets adopt an initial proinflamma-tory phenotype by expressing and releasing a variety of adhe-sion molecules, cytokines, and other immune modulators, including high mobility group 1 protein (HMGB1), interleukin (IL)-1β, and CD40 ligand (CD40L, CD154). However, acti-vated platelets also express large amounts of the immunosup-pressive factor, transforming growth factor-β (TGFβ), that has been implicated in Treg cell homeostasis. Recently, in a large animal model of hemorrhage, TGF-b levels were shown to be significantly increased 2 hours post injury, suggesting a pos-sible mechanism for injury-related immune dysfunction.213 And, while soluble CD154 was not increased following hemorrhage and traumatic brain injury in that study, in a murine model of mesenteric ischemia-reperfusion injury, platelet expression of CD40 and CD154 was linked to remote organ damage.Mast CellsMast cells are important in the primary response to injury because they are located in


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Surgery_Schwartz. ischemia-reperfusion injury, platelet expression of CD40 and CD154 was linked to remote organ damage.Mast CellsMast cells are important in the primary response to injury because they are located in tissues. TNF release from mast cells has been found to be crucial for neutrophil recruitment and pathogen clearance. Mast cells are also known to play an impor-tant role in the anaphylactic response to allergens. On activation from stimuli including allergen binding, infection, and trauma, mast cells produce histamine, cytokines, eicosanoids, proteases, and chemokines, which leads to vasodilatation, capillary leak-age, and immunocyte recruitment. Mast cells are thought to be important cosignaling effector cells of the immune system via the release of IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, and IL-14, as well as macrophage migration–inhibiting factor.214ENDOTHELIUM-MEDIATED INJURYVascular EndotheliumUnder physiologic conditions, the vascular endothelium has important anticoagulant properties


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Surgery_Schwartz. as well as macrophage migration–inhibiting factor.214ENDOTHELIUM-MEDIATED INJURYVascular EndotheliumUnder physiologic conditions, the vascular endothelium has important anticoagulant properties and forms a critical barrier to regulate the tissue migration of circulating cells. Following injury, endothelial cells are differentially modulated, resulting in a procoagulant shift that may lead to microthrombosis and organ injury. Recent work has associated postinjury vascular dysfunc-tion (traumatic endotheliopathy) with circulating levels of syn-decan-1, a surrogate marker for disruption of the endothelial cell glycocalyx.215 In a cohort of over 400 severely injured patients, higher syndecan-1 measurements correlated with ISS and plasma catecholamine levels and, ultimately, with mortality in this group. The authors’ hypothesize that the increased disruption of the endothelial glycocalyx results in endothelial cell injury and an altered phenotype resulting in a prothrombotic state that


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Surgery_Schwartz. in this group. The authors’ hypothesize that the increased disruption of the endothelial glycocalyx results in endothelial cell injury and an altered phenotype resulting in a prothrombotic state that leads to microvascular thrombosis and ensuing organ dysfunction.Neutrophil-Endothelium InteractionThe regulated inflammatory response to infection facilitates neutrophil and other immunocyte migration to compromised regions through the actions of increased vascular permeabil-ity, chemoattractants, and increased endothelial adhesion fac-tors referred to as selectins that are elaborated on cell surfaces (Table 2-7). In response to inflammatory stimuli released from sentinel leukocytes in the tissues, including chemokines, throm-bin, leukotrienes, histamine, and TNF, vascular endothelium are activated and their surface protein expression is altered. Within 10 to 20 minutes, prestored reservoirs of the adhesion molecule P-selectin are mobilized to the cell surface where it can mediate


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Surgery_Schwartz. are activated and their surface protein expression is altered. Within 10 to 20 minutes, prestored reservoirs of the adhesion molecule P-selectin are mobilized to the cell surface where it can mediate neutrophil recruitment (Fig. 2-12). After 2 hours, endothelial cell transcriptional processes provide additional surface expression of E-selectin. E-selectin and P-selectin bind P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophils to orchestrate the capture and rolling of these leukocytes and allow targeted immunocyte extravasation. Immobilized chemo-kines on the endothelial surface create a chemotactic gradient to further enhance immune cell recruitment.216 Also important are secondary leukocyte-leukocyte interactions in which PGSL-1 and L-selectin binding facilitates further leukocyte tethering. Brunicardi_Ch02_p0027-p0082.indd 5601/03/19 6:49 PM 57SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Table 2-7Molecules that mediate leukocyte-endothelial adhesion,


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Surgery_Schwartz. tethering. Brunicardi_Ch02_p0027-p0082.indd 5601/03/19 6:49 PM 57SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Table 2-7Molecules that mediate leukocyte-endothelial adhesion, categorized by familyADHESION MOLECULEACTIONORIGININDUCERS OF EXPRESSIONTARGET CELLSSelectins L-selectin P-selectin E-selectinFast rollingSlow rollingVery slow rollingLeukocytesPlatelets and endotheliumEndotheliumNativeThrombin, histamineCytokinesEndothelium, platelets, eosinophilsNeutrophils, monocytesNeutrophils, monocytes, lymphocytesImmunoglobulins ICAM-1 ICAM-2 VCAM-1 PECAM-1Firm adhesion/transmigrationFirm adhesionFirm adhesion/transmigrationAdhesion/ transmigrationEndothelium, leukocytes, fibroblasts, epitheliumEndothelium, plateletsEndotheliumEndothelium, platelets, leukocytesCytokinesNativeCytokinesNativeLeukocytesLeukocytesMonocytes, lymphocytesEndothelium, platelets, leukocytesβ2-(CD18) Integrins CD18/11a CD18/11b (Mac-1) CD18/11cFirm adhesion/transmigrationFirm


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Surgery_Schwartz. lymphocytesEndothelium, platelets, leukocytesβ2-(CD18) Integrins CD18/11a CD18/11b (Mac-1) CD18/11cFirm adhesion/transmigrationFirm adhesion/transmigrationAdhesionLeukocytesNeutrophils, monocytes, natural killer cellsNeutrophils, monocytes, natural killer cellsLeukocyte activationLeukocyte activationLeukocyte activationEndotheliumEndotheliumEndotheliumβ1-(CD29) Integrins VLA-4Firm adhesion/transmigrationLymphocytes, monocytesLeukocyte activationMonocytes, endothelium, epitheliumICAM-1 = intercellular adhesion molecule-1; ICAM-2 = intercellular adhesion molecule-2; Mac-1 = macrophage antigen 1; PECAM-1 = platelet-endothelial cell adhesion molecule-1; VCAM-1 = vascular cell adhesion molecule-1; VLA-4 = very late antigen-4.Although there are distinguishable properties among individ-ual selectins in leukocyte rolling, effective rolling most likely involves a significant degree of functional overlap.217ChemokinesChemokines are a family of small proteins (8–13 kDa) that were first


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Surgery_Schwartz. selectins in leukocyte rolling, effective rolling most likely involves a significant degree of functional overlap.217ChemokinesChemokines are a family of small proteins (8–13 kDa) that were first identified through their chemotactic and activating effects on inflammatory cells. They are produced at high levels follow-ing nearly all forms of injury in all tissues, where they are key attractants for immune cell extravasation. There are more than 50 different chemokines and 20 chemokine receptors that have been identified. Chemokines are released from endothelial cells, mast cells, platelets, macrophages, and lymphocytes. They are soluble proteins, which when secreted, bind to glycosamino-glycans on the cell surface or in the extracellular matrix. In this way, the chemokines can form a fixed chemical gradient that promotes immune cell exit to target areas. Supporting the idea of their importance in leukocyte recruitment post injury, a sub-set of chemokines are elevated early following


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Surgery_Schwartz. chemical gradient that promotes immune cell exit to target areas. Supporting the idea of their importance in leukocyte recruitment post injury, a sub-set of chemokines are elevated early following traumatic injury in both survivors and nonsurvivors.218Chemokines are distinguished (in general) from cyto-kines by virtue of their receptors, which are members of the G-protein–coupled receptor superfamily. Most chemokine receptors recognize more than one chemokine ligand leading to redundancy in chemokine signaling.The chemokines are subdivided into families based on their amino acid sequences at their N-terminus. For example, CC chemokines contain two N-terminus cysteine residues that are immediately adjacent (hence the “C-C” designation) while the N-terminal cysteines in CXC chemokines are separated by a single amino acid. The CXC chemokines are particularly impor-tant for neutrophil (PMN) proinflammatory function. Members of the CXC chemokine family, which include IL-8 (CXCL8), induce


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Surgery_Schwartz. separated by a single amino acid. The CXC chemokines are particularly impor-tant for neutrophil (PMN) proinflammatory function. Members of the CXC chemokine family, which include IL-8 (CXCL8), induce neutrophil migration and secretion of cytotoxic granu-lar contents and metabolites. Additional chemokine families include the Cand CX3C-chemokines.216Recent studies support the idea that a subset of chemo-kines, monokine induced by γ-interferon (MIG), monocyte chemotactic protein 1 (MCP-1), and interferon γ-induced pro-teins 10 (IP-10) may work in concert to regulate the inflam-matory response post injury and may serve as biomarkers for clinical outcome in trauma patients.218,219 These investigators propose that MIG, MCP-1, and IP-10 function as a “chemo-kine switch” in which the relative levels of each chemokine may promote its own expression, which suppresses the expres-sion of the other two according to the severity and type of injury.220 In this way, the authors propose that the


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Surgery_Schwartz. levels of each chemokine may promote its own expression, which suppresses the expres-sion of the other two according to the severity and type of injury.220 In this way, the authors propose that the balance between these three chemokines, by regulating inflammatory mediator production (e.g., IL-6) may help to correlate with long-term outcomes.Brunicardi_Ch02_p0027-p0082.indd 5701/03/19 6:49 PM 58BASIC CONSIDERATIONSPART ICaptureFastrollingSlowrollingArrest50–150 µm/sec20–50 µm/sec10–20 µm/sec0–10 µm/secVelocity:LeukocyteSeconds0Velocity (µm/second)1501000501234EndotheliumFigure 2-12. Simplified sequence of selectin-mediated neutrophil-endothelium interaction after an inflammatory stimulus. CAPTURE (tethering), predominantly mediated by cell L-selectin with contri-bution from endothelial P-selectin, describes the initial recognition between leukocyte and endothelium, in which circulating leuko-cytes marginate toward the endothelial surface. FAST ROLLING (20 to 50 μm/s) is a


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Surgery_Schwartz. P-selectin, describes the initial recognition between leukocyte and endothelium, in which circulating leuko-cytes marginate toward the endothelial surface. FAST ROLLING (20 to 50 μm/s) is a consequence of rapid L-selectin shedding from cell surfaces and formation of new downstream L-selectin to endo-thelium bonds, which occur in tandem. SLOW ROLLING (10 to 20 μm/s) is predominantly mediated by P-selectins. The slowest rolling (3 to 10 μm/s) before arrest is predominantly mediated by E-selec-tins, with contribution from P-selectins. ARREST (firm adhesion) leading to transmigration is mediated by β-integrins and the immu-noglobulin family of adhesion molecules. In addition to interact-ing with the endothelium, activated leukocytes also recruit other leukocytes to the inflammatory site by direct interactions, which are mediated in part by selectins. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Selectin neutralization: does it make biological sense? Crit Care Med. 1999


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Surgery_Schwartz. by direct interactions, which are mediated in part by selectins. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Selectin neutralization: does it make biological sense? Crit Care Med. 1999 Sep;27(9):2050-2053.)Nitric OxideNitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle. Normal vascular smooth muscle cell relaxation is maintained by a constant output of NO that is regulated in the endothe-lium by both flowand receptor-mediated events. NO can also reduce microthrombosis by reducing platelet adhesion and aggregation (Fig. 2-13) and interfering with leukocyte adhe-sion to the endothelium. NO easily traverses cell membranes and has a short half-life of a few seconds. Endogenous NO formation is derived largely from the action of NO synthase (NOS), which is constitutively expressed in endothelial cells (NOS3, eNOS). Nitric oxide synthase generates NO by cata-lyzing the degradation of L-arginine to


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Surgery_Schwartz. largely from the action of NO synthase (NOS), which is constitutively expressed in endothelial cells (NOS3, eNOS). Nitric oxide synthase generates NO by cata-lyzing the degradation of L-arginine to L-citrulline and NO, in the presence of oxygen and NADPH. There are two addi-tional isoforms of NOS: neuronal NOS (NOS1, nNOS) and inducible NOS (iNOS/NOS2), which is expressed in response to cytokines and bacterial products. The vasodilatory effects of NO are mediated by guanylyl cyclase, an enzyme that is found in vascular smooth muscle cells and most other cells of the body. When NO is formed by endothelium, it rapidly diffuses into adjacent cells where it binds to and activates gua-nylyl cyclase. This enzyme catalyzes the dephosphorylation of GTP to cGMP, which serves as a second messenger for many important cellular functions, particularly for signaling smooth muscle relaxation.NO synthesis is increased due to the upregulation of iNOS expression in response to proinflammatory


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Surgery_Schwartz. for many important cellular functions, particularly for signaling smooth muscle relaxation.NO synthesis is increased due to the upregulation of iNOS expression in response to proinflammatory media-tors such as TNF-α, and IL-1β, as well as microbial products.221,222 In fact, studies in both animal models and humans have shown that severe systemic injury and asso-ciated hemorrhage produce an early upregulation of iNOS in the liver, lung, spleen, and vascular system. In these cir-cumstances, NO is reported to function as an immunoregu-lator, which is capable of modulating cytokine production and immune cell development.223 In particular, recent data supports a role for iNOS/eNOS in the regulation of T-cell dysfunction in the setting of trauma as evidenced by sup-pressed proliferative and TH1 cytokine release. In particular, the formation of S-nitrosothiols, which can serve as a molec-ular switch to regulate protein functions, may explain many signaling effects of both iNOSand


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Surgery_Schwartz. and TH1 cytokine release. In particular, the formation of S-nitrosothiols, which can serve as a molec-ular switch to regulate protein functions, may explain many signaling effects of both iNOSand eNOS-derived NO in the immune system with regard to T-cell activation and signaling through the T cell receptor. In T cells, NO effects have been implicated in the regulation of the immune synapse as well as the regulation of mitochondrial bioenergetics indicating that NO may play an important role as a link between innate and adaptive immunity.224Inhibition of NO production seemed initially to be a promising strategy in patients with severe sepsis. However, a randomized clinical trial in patients with septic shock determined that treatment with a nonselective NOS inhibitor was associated with an increase in mortality compared with placebo.225 More recent data utilizing an ovine model of perito-nitis demonstrated that selective iNOS inhibition reduced pul-monary artery hypertension and gas


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Surgery_Schwartz. increase in mortality compared with placebo.225 More recent data utilizing an ovine model of perito-nitis demonstrated that selective iNOS inhibition reduced pul-monary artery hypertension and gas exchange impairment and promoted higher visceral organ blood flow, coinciding with lower plasma cytokine concentrations.226 These data suggest that specific targeting of iNOS in the setting of sepsis may remain a viable therapeutic option.Recent work using an animal model of traumatic brain injury (TBI) showed that acute TBI results in endothelial dys-function in a remote vascular bed.227 The investigators linked the effect of TBI with impaired nitric oxide (NO) production and also with an increase in arterial arginase activity, implicat-ing the depletion of L-arginine by arginase with the decreased NO production.ProstacyclinThe immune effects of prostacyclin (PGI2) have been discussed previously. The best-described effects of PGI2 are in the car-diovascular system, however, where it is


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Surgery_Schwartz. NO production.ProstacyclinThe immune effects of prostacyclin (PGI2) have been discussed previously. The best-described effects of PGI2 are in the car-diovascular system, however, where it is produced by vascular endothelial cells. Prostacyclin is a potent vasodilator that also inhibits platelet aggregation. In the pulmonary system, PGI2 reduces pulmonary blood pressure as well as bronchial hyper-responsiveness. In the kidneys, PGI2 modulates renal blood flow and glomerular filtration rate. Prostacyclin acts through its receptor (a G-protein–coupled receptor of the rhodopsin family) to stimulate the enzyme, adenylate cyclase, allowing the syn-thesis of cyclic adenosine monophosphate (cAMP) from ATP. Brunicardi_Ch02_p0027-p0082.indd 5801/03/19 6:49 PM 59SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2cAMPcAMPcGMPcGMPNONOPGI2AAPlateletETETPGI2Big ETL-arginineEndotheliumSmooth muscleRelaxationFigure 2-13. Endothelial interac-tion with smooth muscle cells and with


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Surgery_Schwartz. AND METABOLIC SUPPORTCHAPTER 2cAMPcAMPcGMPcGMPNONOPGI2AAPlateletETETPGI2Big ETL-arginineEndotheliumSmooth muscleRelaxationFigure 2-13. Endothelial interac-tion with smooth muscle cells and with intraluminal platelets. Prosta-cyclin (prostaglandin I2, or PGI2) is derived from arachidonic acid (AA), and nitric oxide (NO) is derived from L-arginine. The increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine mono-phosphate (cGMP) results in smooth muscle relaxation and inhibition of platelet thrombus formation. Endo-thelins (ETs) are derived from “big ET,” and they counter the effects of prostacyclin and NO.This leads to a cAMP-mediated decrease in intracellular cal-cium and subsequent smooth muscle relaxation.During systemic inflammation, endothelial prostacyclin expression is impaired, and thus the endothelium favors a more procoagulant profile. Exogenous prostacyclin analogues, both intravenous and inhaled, have been utilized to improve oxygen-ation in patients with


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Surgery_Schwartz. is impaired, and thus the endothelium favors a more procoagulant profile. Exogenous prostacyclin analogues, both intravenous and inhaled, have been utilized to improve oxygen-ation in patients with acute lung injury. Early clinical studies with prostacyclin have delivered some encouraging results.228 However, a recent study examining the administration of epo-prostenol in the setting of severe injury and TBI demonstrated and attenuation of the inflammatory response as measured by serologic markers had no effect on long-term outcome.229EndothelinsEndothelins (ETs) are potent mediators of vasoconstriction ET-1, synthesized primarily by endothelial cells, is the most potent endogenous vasoconstrictor, and is estimated to be 10 times more potent than angiotensin II. ET release is upregu-lated in response to hypotension, LPS, injury, thrombin, TGF-b, IL-1, angiotensin II, vasopressin, catecholamines, and anoxia. ETs release is transcriptionally regulated and occurs at the ablu-minal side


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Surgery_Schwartz. in response to hypotension, LPS, injury, thrombin, TGF-b, IL-1, angiotensin II, vasopressin, catecholamines, and anoxia. ETs release is transcriptionally regulated and occurs at the ablu-minal side of endothelial cells. Very little is stored in cells; thus, a plasma increase in ET is associated with a marked increase in production. Three endothelin receptors have been identified and function via the G-protein–coupled receptor mechanism. ETB receptors are associated with increased NO and prostacyclin production, which may serve as a feedback mechanism. Atrial ETA receptor activation has been associated with increased inotropy and chronotropy. ET-1 infusion is associated with increased pulmonary vascular resistance and pulmonary edema and may contribute to pulmonary abnormalities during sepsis. At low levels, in conjunction with NO, ETs regulate vascular tone. However, at increased concentrations, ETs can disrupt the normal blood flow and distribution and may compromise oxy-gen delivery


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Surgery_Schwartz. At low levels, in conjunction with NO, ETs regulate vascular tone. However, at increased concentrations, ETs can disrupt the normal blood flow and distribution and may compromise oxy-gen delivery to the tissue. Recent data links endothelin expres-sion in pulmonary vasculature with persistent inflammation associated with the development of pulmonary hypertension.230 Endothelin expression is linked to posttranslational and tran-scriptional initiation of the unfolded protein response in the affected cells, which results in the production of inflammatory cytokines.231 Persistent endothelin-1 stimulation may play a role in decreased vascular reactivity that is evident following hemor-rhagic shock.232Platelet Activating FactorPhosphotidylcholine is a major lipid constituent of the plasma membrane. Its enzymatic processing by cytosolic phospho-lipase A2 (cPLA2) or calcium-independent phospholipase A2 (iPLA2) generates powerful small lipid molecules, which func-tion as intracellular second


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Surgery_Schwartz. Its enzymatic processing by cytosolic phospho-lipase A2 (cPLA2) or calcium-independent phospholipase A2 (iPLA2) generates powerful small lipid molecules, which func-tion as intracellular second messengers. One of these is arachi-donic acid, the precursor molecule for eicosanoids. Another is platelet-activating factor (PAF). During acute inflammation, PAF is released by immune cells following the activation of PLA2. The receptor for PAF (PAFR), which is constitutively expressed by platelets, leukocytes, and endothelial cells, is a G-protein–coupled receptor of the rhodopsin family. Ligand binding to the PAFR promotes the activation and aggregation of platelets and leukocytes, leukocyte adherence, motility, chemotaxis, and invasion, as well as ROS generation.233 Addi-tionally, PAF activation of human PMNs induces extrusion of neutrophil extracellular traps (NETs), while platelet activa-tion induces IL-1 via a novel posttranscriptional mechanism. Finally, PAFR ligation results not only


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Surgery_Schwartz. of human PMNs induces extrusion of neutrophil extracellular traps (NETs), while platelet activa-tion induces IL-1 via a novel posttranscriptional mechanism. Finally, PAFR ligation results not only in the upregulation of numerous proinflammatory genes, including COX-2, iNOS, and IL-6, but also in the generation of lipid intermediates such as arachidonic acid and lysophospholipids through the Brunicardi_Ch02_p0027-p0082.indd 5901/03/19 6:49 PM 60BASIC CONSIDERATIONSPART IBrainRBCWBCNerveKidneyMuscleHeartKidneyMuscleAminoacidsGlycerol16gFattyacid160g40gFatty acid120gKetone60gGlucose180g36g144g36gLactate + PyruvateLIVERGlycogen75gGluconeogenesisOxidationFuel utilization in short-term fasting man (70 kg)Muscleprotein75gFat storestriglycerides160gFigure 2-14. Fuel utilization in a 70-kg man during short-term fasting with an approximate basal energy expenditure of 1800 kcal. During starvation, muscle proteins and fat stores provide fuel for the host, with the latter being most abundant.


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Surgery_Schwartz. during short-term fasting with an approximate basal energy expenditure of 1800 kcal. During starvation, muscle proteins and fat stores provide fuel for the host, with the latter being most abundant. RBC = red blood cell; WBC = white blood cell. activation of Phospholipase A2. Antagonists to PAF recep-tors have been experimentally shown to mitigate the effects of ischemia and reperfusion injury. Of note, human sepsis is associated with a reduction in the levels of PAF-acetylhydro-lase, which inactivates PAF by removing an acetyl group. Indeed, PAF-acetylhydrolase administration in patients with severe sepsis has yielded some reduction in multiple organ dysfunction and mortality234; however, larger phase III clinical trials failed to show benefit.Natriuretic PeptidesThe natriuretic peptides, atrial natriuretic factor (ANP) and brain natriuretic peptide (BNP), are a family of peptides that are released primarily by atrial and ventricular tissue respectively, but are also synthesized by


Surgery_Schwartz

Surgery_Schwartz. atrial natriuretic factor (ANP) and brain natriuretic peptide (BNP), are a family of peptides that are released primarily by atrial and ventricular tissue respectively, but are also synthesized by the gut, kidney, brain, adrenal glands, and endothelium. The functionally active forms of the peptides are C-terminal fragments of a larger pro-hormone, and both Nand C-terminal fragments are detectable in the blood (referred to a N-terminal pro-BNP and pro-ANF, respectively). ANF and BNP share most biological properties, including diuretic, natri-uretic, vasorelaxant, and cardiac remodeling properties that are affected by signaling through a common receptor: the guanylyl cyclase(GC-) A receptor. They are both increased in the setting of cardiac disorders; however, evidence indicates some distinctions in the setting of inflammation. For example, elevated proBNP has been detected in septic patients in the absence of myocardial dysfunction and appears to have prognostic significance.235 More


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Surgery_Schwartz. in the setting of inflammation. For example, elevated proBNP has been detected in septic patients in the absence of myocardial dysfunction and appears to have prognostic significance.235 More recently, investigators examined changes in N-terminal pro-BNP (NT-proBNP) in a cohort of severely injured patients and deter-mined that persistently high level of NT-proBNP in major trauma patients is indicative of poor outcome.236SURGICAL METABOLISMThe initial hours after surgical or traumatic injury are metaboli-cally associated with a reduced total body energy expenditure and urinary nitrogen wasting. With adequate resuscitation and stabilization of the injured patient, a reprioritization of substrate use ensues to preserve vital organ function and to support repair of injured tissue. This phase of recovery also is characterized by functions that participate in the restoration of homeostasis, such as augmented metabolic rates and oxygen consumption, enzymatic preference for readily oxidizable


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Surgery_Schwartz. recovery also is characterized by functions that participate in the restoration of homeostasis, such as augmented metabolic rates and oxygen consumption, enzymatic preference for readily oxidizable substrates such as glucose, and stimulation of the immune system. Understanding of the collective alterations in amino acid (protein), carbohy-drate, and lipid metabolism characteristic of the surgical patient lays the foundation upon which metabolic and nutritional sup-port can be implemented.Metabolism During FastingFuel metabolism during unstressed fasting states has historically served as the standard to which metabolic alterations after acute injury and critical illness are compared (Fig. 2-14). To maintain basal metabolic needs (i.e., at rest and fasting), a normal healthy adult requires approximately 22 to 25 kcal/kg per day drawn from carbohydrate, lipid, and protein sources. This requirement can substantially increase during severe stress states, such as those seen in patients with


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Surgery_Schwartz. 22 to 25 kcal/kg per day drawn from carbohydrate, lipid, and protein sources. This requirement can substantially increase during severe stress states, such as those seen in patients with burn injuries.In the healthy adult, principal sources of fuel during short-term fasting (<5 days) are derived from muscle protein and body fat, with fat being the most abundant source of energy (Table 2-8). The normal adult body contains 300 to 400 g of carbohydrates in the form of glycogen, of which 75 to 100 g are stored in the liver. Approximately 200 to 250 g of glycogen are stored within skeletal, cardiac, and smooth muscle cells. The greater glycogen stores within the muscle are not read-ily available for systemic use due to a deficiency in glucose-6-phosphatase but are available for the energy needs of muscle cells. Therefore, in the fasting state, hepatic glycogen stores are rapidly and preferentially depleted, which results in a fall of serum glucose concentration within hours (<16


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Surgery_Schwartz. needs of muscle cells. Therefore, in the fasting state, hepatic glycogen stores are rapidly and preferentially depleted, which results in a fall of serum glucose concentration within hours (<16 hours).During fasting, a healthy 70-kg adult will utilize 180 g of glucose per day to support the metabolism of obligate glycolytic cells such as neurons, leukocytes, erythrocytes, and the renal medullae. Other tissues that use glucose for fuel are skeletal muscle, intestinal mucosa, fetal tissues, and solid tumors.Brunicardi_Ch02_p0027-p0082.indd 6001/03/19 6:49 PM 61SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2RBCWBCNerveKidneyMuscleMuscleProteinpyruvateKetoneLactate + PyruvateFattyacidGlucoseKetoneGlucoseAlanineGlucose-alanine cycleCori cycleLIVERGluconeogenesisFigure 2-15. The recycling of peripheral lactate and pyruvate for hepatic gluconeogenesis is accomplished by the Cori cycle. Alanine within skeletal muscles can also be used as a precursor for hepatic gluconeogenesis.


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Surgery_Schwartz. of peripheral lactate and pyruvate for hepatic gluconeogenesis is accomplished by the Cori cycle. Alanine within skeletal muscles can also be used as a precursor for hepatic gluconeogenesis. During starvation, such fatty acid provides fuel sources for basal hepatic enzymatic function. RBC = red blood cell; WBC = white blood cell.Glucagon, norepinephrine, vasopressin, and angiotensin II can promote the utilization of glycogen stores (glycogenolysis) during fasting. Although glucagon, epinephrine, and cortisol directly promote gluconeogenesis, epinephrine and cortisol also promote pyruvate shuttling to the liver for gluconeogen-esis. Precursors for hepatic gluconeogenesis include lactate, glycerol, and amino acids such as alanine and glutamine. Lac-tate is released by glycolysis within skeletal muscles, as well as by erythrocytes and leukocytes. The recycling of lactate and pyruvate for gluconeogenesis is commonly referred to as the Cori cycle, which can provide up to 40% of plasma


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Surgery_Schwartz. skeletal muscles, as well as by erythrocytes and leukocytes. The recycling of lactate and pyruvate for gluconeogenesis is commonly referred to as the Cori cycle, which can provide up to 40% of plasma glucose during starvation (Fig. 2-15).Lactate production from skeletal muscle is insufficient to maintain systemic glucose needs during short-term fasting (simple starvation). Therefore, significant amounts of protein must be degraded daily (75 g/d for a 70-kg adult) to provide the amino acid substrate for hepatic gluconeogenesis. Proteolysis during starvation, which results primarily from decreased insu-lin and increased cortisol release, is associated with elevated urinary nitrogen excretion from the normal 7 to 10 g/d up to 30 g or more per day.237 Although proteolysis during starvation occurs mainly within skeletal muscles, protein degradation in solid organs also occurs.In prolonged starvation, systemic proteolysis is reduced to approximately 20 g/d and urinary nitrogen excretion


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Surgery_Schwartz. occurs mainly within skeletal muscles, protein degradation in solid organs also occurs.In prolonged starvation, systemic proteolysis is reduced to approximately 20 g/d and urinary nitrogen excretion stabilizes at 2 to 5 g/d (Fig. 2-16). This reduction in proteolysis reflects the adaptation by vital organs (e.g., myocardium, brain, renal cortex, and skeletal muscle) to using ketone bodies as their prin-cipal fuel source. In extended fasting, ketone bodies become an important fuel source for the brain after 2 days and gradually become the principal fuel source by 24 days.Enhanced deamination of amino acids for gluconeogen-esis during starvation consequently increases renal excretion of ammonium ions. The kidneys also participate in gluconeo-genesis by the use of glutamine and glutamate and can become the primary source of gluconeogenesis during prolonged star-vation, accounting for up to one-half of systemic glucose production.Table 2-8A. Body fuel reserves in a 70-kg man and B. Energy


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Surgery_Schwartz. can become the primary source of gluconeogenesis during prolonged star-vation, accounting for up to one-half of systemic glucose production.Table 2-8A. Body fuel reserves in a 70-kg man and B. Energy equivalent of substrate oxidationA. COMPONENTMASS (kg)ENERGY (kcal)DAYS AVAILABLEWater and minerals4900Protein6.024,00013.0Glycogen0.28000.4Fat15.0140,00078.0Total70.2164,80091.4B. SUBSTRATEO2 CONSUMED (L/g)CO2 PRODUCED (L/g)RESPIRATORY QUOTIENTkcal/gRECOMMENDED DAILY REQUIREMENTGlucose0.750.751.04.07.2 g/kg per dayDextrose———3.4—Lipid2.01.40.79.01.0 g/kg per dayProtein1.00.80.84.00.8 g/kg per dayBrunicardi_Ch02_p0027-p0082.indd 6101/03/19 6:50 PM 62BASIC CONSIDERATIONSPART IWOUNDRBCWBCNerveKidneyMuscleHeartKidneyMuscleAminoacidsGlycerol17gFattyacid170g40gFatty acid130gKetone60gGlucose360g180g180gLactate+PyruvateKIDNEYGluconeogenesisGluconeogenesisLIVEROxidationFuel utilization following traumaMuscleProtein250gFat storesTriglycerides170gFigure 2-17. Acute injury is associated with


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Surgery_Schwartz. utilization following traumaMuscleProtein250gFat storesTriglycerides170gFigure 2-17. Acute injury is associated with significant alterations in substrate utilization. There is enhanced nitrogen loss, indicative of catabolism. Fat remains the primary fuel source under these circumstances. RBC = red blood cell; WBC = white blood cell.Fuel utilization in long-term fasting man (70 kg)HeartKidneyMuscleAminoacidsGlycerol18gFattyacid180g45gFatty acid135gKetone68gGlucose80g44g36gLactate + PyruvateKIDNEYGluconeogenesis15g5g40g40g10g (100 mEq) in urine44g36g58gMuscleProtein20gFat storesTriglycerides180gBrainRBCWBCNerveKidneyMuscleLIVERGlycogenGluconeogenesisOxidationFigure 2-16. Fuel utilization in extended starvation. Liver glycogen stores are depleted, and there is adaptive reduction in proteolysis as a source of fuel. The brain uses ketones for fuel. The kidneys become important participants in gluconeogenesis. RBC = red blood cell; WBC = white blood cell. Lipid stores within adipose tissue


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Surgery_Schwartz. as a source of fuel. The brain uses ketones for fuel. The kidneys become important participants in gluconeogenesis. RBC = red blood cell; WBC = white blood cell. Lipid stores within adipose tissue provide 40% or more of caloric expenditure during starvation. Energy requirements for basal enzymatic and muscular functions (e.g., gluconeogenesis, neural transmission, and cardiac contraction) are met by the mobilization of triglycerides from adipose tissue. In a resting, fasting, 70-kg person, approximately 160 g of free fatty acids and glycerol can be mobilized from adipose tissue per day. Free fatty acid release is stimulated in part by a reduction in serum insulin levels and in part by the increase in circulating glucagon and catecholamine. Such free fatty acids, like ketone bodies, are used as fuel by tissues such as the heart, kidney (renal cortex), muscle, and liver. The mobilization of lipid stores for energy importantly decreases the rate of glycolysis, gluconeogenesis, and


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Surgery_Schwartz. are used as fuel by tissues such as the heart, kidney (renal cortex), muscle, and liver. The mobilization of lipid stores for energy importantly decreases the rate of glycolysis, gluconeogenesis, and proteolysis, as well as the overall glucose requirement to sustain the host. Furthermore, ketone bodies spare glucose utili-zation by inhibiting the enzyme pyruvate dehydrogenase.Metabolism After InjuryInjuries or infections induce unique neuroendocrine and immu-nologic responses that differentiate injury metabolism from that of unstressed fasting (Fig. 2-17). The magnitude of metabolic expenditure over time appears to be directly proportional to the severity of insult, with thermal injuries and severe infections having the highest energy demands (Fig. 2-18). Of note, the first few days following both sepsis and trauma are not hyper-metabolic states, with the more severe insults associated with increased “metabolic hibernation.” However, by week 2, the total energy expenditure increases


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Surgery_Schwartz. both sepsis and trauma are not hyper-metabolic states, with the more severe insults associated with increased “metabolic hibernation.” However, by week 2, the total energy expenditure increases dramatically.238 The increase Brunicardi_Ch02_p0027-p0082.indd 6201/03/19 6:50 PM 63SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 201020304050% REE100752550125150175200225Days after injuryMajor burnsSepsis/peritonitisSkeletal traumaNormalrangeElective surgeryStarvationFigure 2-18. Influence of injury severity on resting metabolism (resting energy expenditure, or REE). The shaded area indicates normal REE. (Reproduced with permission from Long CL, Schaffel N, Geiger JW, et al: Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorim-etry and nitrogen balance, JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-456.)DietarytriglyceridesIntestinal lumenLymphatic ductPancreaticlipaseGutenterocyteMonoglyceridesTriglyceridesMonoglyceride +


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Surgery_Schwartz. nitrogen balance, JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-456.)DietarytriglyceridesIntestinal lumenLymphatic ductPancreaticlipaseGutenterocyteMonoglyceridesTriglyceridesMonoglyceride + 2 Fatty acyI-CoAFatty acidsChylomicron+ ProteinFigure 2-19. Pancreatic lipase within the small intestinal brush borders hydrolyzes triglycerides into monoglycerides and fatty acids. These components readily diffuse into the gut enterocytes, where they are re-esterified into triglycerides. The resynthesized triglycerides bind car-rier proteins to form chylomicrons, which are transported by the lymphatic system. Shorter triglycerides (those with <10 carbon atoms) can bypass this process and directly enter the portal circulation for transport to the liver. CoA = coenzyme A.in energy expenditure is mediated in part by sympathetic acti-vation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human sub-jects. Lipid metabolism after injury is


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Surgery_Schwartz. mediated in part by sympathetic acti-vation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human sub-jects. Lipid metabolism after injury is intentionally discussed first because this macronutrient becomes the primary source of energy during stressed states.239Lipid Metabolism After InjuryLipids are not merely nonprotein, noncarbohydrate fuel sources that minimize protein catabolism in the injured patient. Lipid metabolism potentially influences the structural integrity of cell membranes as well as the immune response during systemic inflammation. Adipose stores within the body (triglycerides) are the predominant energy source (50% to 80%) during critical ill-ness and after injury. Fat mobilization (lipolysis) occurs mainly in response to catecholamine stimulus of the hormone-sensitive triglyceride lipase. Other hormonal influences that potentiate lipolysis include adrenocorticotropic hormone (ACTH), cat-echolamines, thyroid


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Surgery_Schwartz. to catecholamine stimulus of the hormone-sensitive triglyceride lipase. Other hormonal influences that potentiate lipolysis include adrenocorticotropic hormone (ACTH), cat-echolamines, thyroid hormone, cortisol, glucagon, growth hor-mone release, and reduction in insulin levels.240Lipid Absorption. Although the process is poorly understood, adipose tissue provides fuel for the host in the form of free fatty acids and glycerol during critical illness and injury. Oxidation of 1 g of fat yields approximately 9 kcal of energy. Although the liver is capable of synthesizing triglycerides from carbohy-drates and amino acids, dietary and exogenous sources provide the major source of triglycerides. Dietary lipids are not readily absorbable in the gut but require pancreatic lipase and phospho-lipase within the duodenum to hydrolyze the triglycerides into free fatty acids and monoglycerides. The free fatty acids and monoglycerides are then readily absorbed by gut enterocytes, which resynthesize


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Surgery_Schwartz. within the duodenum to hydrolyze the triglycerides into free fatty acids and monoglycerides. The free fatty acids and monoglycerides are then readily absorbed by gut enterocytes, which resynthesize triglycerides by esterification of the mono-glycerides with fatty acyl coenzyme A (acyl-CoA) (Fig. 2-19). Long-chain triglycerides (LCTs), defined as those with 12 car-bons or more, generally undergo this process of esterification Brunicardi_Ch02_p0027-p0082.indd 6301/03/19 6:50 PM 64BASIC CONSIDERATIONSPART Iand enter the circulation through the lymphatic system as chy-lomicrons. Shorter fatty acid chains directly enter the portal circulation and are transported to the liver by albumin carriers. Hepatocytes use free fatty acids as a fuel source during stress states but also can synthesize phospholipids or triglycerides (i.e., very-low-density lipoproteins) during fed states. Systemic tissue (e.g., muscle and the heart) can use chylomicrons and triglycerides as fuel by hydrolysis with


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Surgery_Schwartz. phospholipids or triglycerides (i.e., very-low-density lipoproteins) during fed states. Systemic tissue (e.g., muscle and the heart) can use chylomicrons and triglycerides as fuel by hydrolysis with lipoprotein lipase at the luminal surface of capillary endothelium.241 Trauma or sepsis suppresses lipoprotein lipase activity in both adipose tissue and muscle, presumably mediated by TNF.Lipolysis and Fatty Acid Oxidation. Periods of energy demand are accompanied by free fatty acid mobilization from adipose stores. This is mediated by hormonal influences (e.g., catecholamines, ACTH, thyroid hormones, growth hormone, and glucagon) on triglyceride lipase through a cAMP pathway (Fig. 2-20). In adipose tissues, triglyceride lipase hydrolyzes triglycerides into free fatty acids and glycerol. Free fatty acids enter the capillary circulation and are transported by albumin to tissues requiring this fuel source (e.g., heart and skeletal mus-cle). Insulin inhibits lipolysis and favors triglyceride


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Surgery_Schwartz. fatty acids enter the capillary circulation and are transported by albumin to tissues requiring this fuel source (e.g., heart and skeletal mus-cle). Insulin inhibits lipolysis and favors triglyceride synthesis by augmenting lipoprotein lipase activity as well as intracellu-lar levels of glycerol-3-phosphate. The use of glycerol for fuel depends on the availability of tissue glycerokinase, which is abundant in the liver and kidneys.Free fatty acids absorbed by cells conjugate with acyl-CoA within the cytoplasm. The transport of fatty acyl-CoA from the outer mitochondrial membrane across the inner mito-chondrial membrane occurs via the carnitine shuttle (Fig. 2-21). Medium-chain triglycerides (MCTs), defined as those 6 to 12 carbons in length, bypass the carnitine shuttle and readily cross the mitochondrial membranes. This accounts in part for the fact that MCTs are more efficiently oxidized than LCTs. Ideally, the rapid oxidation of MCTs makes them less prone to fat deposition,


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Surgery_Schwartz. cross the mitochondrial membranes. This accounts in part for the fact that MCTs are more efficiently oxidized than LCTs. Ideally, the rapid oxidation of MCTs makes them less prone to fat deposition, particularly within immune cells and the reticu-loendothelial system—a common finding with lipid infusion in parenteral nutrition.242 However, exclusive use of MCTs as fuel in animal studies has been associated with higher metabolic demands and toxicity, as well as essential fatty acid deficiency.Within the mitochondria, fatty acyl-CoA undergoes b-oxidation, which produces acetyl-CoA with each pass through the cycle. Each acetyl-CoA molecule subsequently enters the tricarboxylic acid (TCA) cycle for further oxidation to yield 12 adenosine triphosphate (ATP) molecules, carbon dioxide, and water. Excess acetyl-CoA molecules serve as precursors for ketogenesis. Unlike glucose metabolism, oxidation of fatty acids requires proportionally less oxygen and produces less car-bon dioxide. This is


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Surgery_Schwartz. Excess acetyl-CoA molecules serve as precursors for ketogenesis. Unlike glucose metabolism, oxidation of fatty acids requires proportionally less oxygen and produces less car-bon dioxide. This is frequently quantified as the ratio of carbon dioxide produced to oxygen consumed for the reaction and is known as the respiratory quotient (RQ). An RQ of 0.7 would imply greater fatty acid oxidation for fuel, whereas an RQ of 1 indicates greater carbohydrate oxidation (overfeeding). An RQ of 0.85 suggests the oxidation of equal amounts of fatty acids and glucose.KetogenesisCarbohydrate depletion slows the entry of acetyl-CoA into the TCA cycle secondary to depleted TCA intermediates and enzyme activity. Increased lipolysis and reduced systemic carbo-hydrate availability during starvation diverts excess acetyl-CoA Hormone-receptoractivationCapillaryAdiposecellFFAcAMPProtein kinaseTriglyceride lipaseTriglycerideDiglycerideMonoglycerideGlycerolFFAFFAFFAFigure 2-20. Fat mobilization in adipose


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Surgery_Schwartz. excess acetyl-CoA Hormone-receptoractivationCapillaryAdiposecellFFAcAMPProtein kinaseTriglyceride lipaseTriglycerideDiglycerideMonoglycerideGlycerolFFAFFAFFAFigure 2-20. Fat mobilization in adipose tissue. Triglyceride lipase activation by hormonal stimulation of adipose cells occurs through the cyclic adenosine monophosphate (cAMP) pathway. Triglycerides are serially hydrolyzed with resultant free fatty acid (FFA) release at every step. The FFAs diffuse readily into the capillary bed for transport. Tissues with glycerokinase can use glycerol for fuel by forming glycerol-3-phosphate. Glycerol-3-phosphate can esterify with FFAs to form triglycerides or can be used as a precursor for renal and hepatic gluconeogenesis. Skeletal muscle and adipose cells have little glycerokinase and thus do not use glycerol for fuel.Brunicardi_Ch02_p0027-p0082.indd 6401/03/19 6:50 PM 65SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Carnitineacyltransferase


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Surgery_Schwartz. little glycerokinase and thus do not use glycerol for fuel.Brunicardi_Ch02_p0027-p0082.indd 6401/03/19 6:50 PM 65SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Carnitineacyltransferase ITransportproteinCytosolMitochondriaFFAAcetyl-CoABeta OxidationCarnitineCarnitineacyltransferase IICoACarnitineMitochondrialmembraneORCCarnitineORCCoAROCCoAORCCarnitineCoAFigure 2-21. Free fatty acids (FFAs) in the cells form fatty acyl-coenzyme A (CoA) with CoA. Fatty acyl-CoA cannot enter the inner mitochondrial membrane and requires carnitine as a carrier protein (carnitine shuttle). Once inside the mitochondria, carnitine dissociates, and fatty acyl-CoA is reformed. The carnitine molecule is transported back into the cytosol for reuse. The fatty acyl-CoA undergoes β-oxidation to form acetyl-CoA for entry into the tri-carboxylic acid cycle. “R” represents a part of the acyl group of acyl-CoA.toward hepatic ketogenesis. A number of extrahepatic tissues, but not the liver itself, are


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Surgery_Schwartz. for entry into the tri-carboxylic acid cycle. “R” represents a part of the acyl group of acyl-CoA.toward hepatic ketogenesis. A number of extrahepatic tissues, but not the liver itself, are capable of using ketones for fuel. Ketosis represents a state in which hepatic ketone production exceeds extrahepatic ketone utilization.The rate of ketogenesis appears to be inversely related to the severity of injury. Major trauma, severe shock, and sepsis attenuate ketogenesis by increasing insulin levels and by caus-ing rapid tissue oxidation of free fatty acids. Minor injuries and infections are associated with modest elevations in plasma free fatty acid concentrations and ketogenesis. However, in minor stress states ketogenesis does not exceed that in nonstressed starvation.Carbohydrate MetabolismIngested and enteral carbohydrates are primarily digested in the small intestine, where pancreatic and intestinal enzymes reduce the complex carbohydrates to dimeric units. Disaccharidases (e.g.,


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Surgery_Schwartz. and enteral carbohydrates are primarily digested in the small intestine, where pancreatic and intestinal enzymes reduce the complex carbohydrates to dimeric units. Disaccharidases (e.g., sucrase, lactase, and maltase) within intestinal brush bor-ders dismantle the complex carbohydrates into simple hexose units, which are transported into the intestinal mucosa. Glu-cose and galactose are primarily absorbed by energy-dependent active transport coupled to the sodium pump. Fructose absorp-tion, however, occurs by concentration-dependent facilitated diffusion. Neither fructose and galactose within the circulation nor exogenous mannitol (for neurologic injury) evokes an insu-lin response. Intravenous administration of low-dose fructose in fasting humans has been associated with nitrogen conservation, but the clinical utility of fructose administration in human injury remains to be demonstrated.Discussion of carbohydrate metabolism primarily refers to the utilization of glucose. The


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Surgery_Schwartz. conservation, but the clinical utility of fructose administration in human injury remains to be demonstrated.Discussion of carbohydrate metabolism primarily refers to the utilization of glucose. The oxidation of 1 g of carbohy-drate yields 4 kcal, but sugar solutions such as those found in intravenous fluids or parenteral nutrition provide only 3.4 kcal/g of dextrose. In starvation, glucose production occurs at the expense of protein stores (i.e., skeletal muscle). Hence, the primary goal for maintenance glucose administration in surgical patients is to minimize muscle wasting. The exog-enous administration of small amounts of glucose (approxi-mately 50 g/d) facilitates fat entry into the TCA cycle and reduces ketosis. Unlike in starvation in healthy subjects, in septic and trauma patients provision of exogenous glucose never has been shown to fully suppress amino acid degrada-tion for gluconeogenesis. This suggests that during periods of stress, other hormonal and proinflammatory


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Surgery_Schwartz. provision of exogenous glucose never has been shown to fully suppress amino acid degrada-tion for gluconeogenesis. This suggests that during periods of stress, other hormonal and proinflammatory mediators have a profound influence on the rate of protein degradation and that some degree of muscle wasting is inevitable. The administra-tion of insulin, however, has been shown to reverse protein catabolism during severe stress by stimulating protein synthe-sis in skeletal muscles and by inhibiting hepatocyte protein degradation. Insulin also stimulates the incorporation of ele-mental precursors into nucleic acids in association with RNA synthesis in muscle cells.In cells, glucose is phosphorylated to form glucose-6-phosphate. Glucose-6-phosphate can be polymerized during glycogenesis or catabolized in glycogenolysis. Glucose catabolism occurs by cleavage to pyruvate or lactate (pyruvic acid pathway) or by decarboxylation to pentoses (pentose shunt) (Fig. 2-22).Excess glucose from


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Surgery_Schwartz. or catabolized in glycogenolysis. Glucose catabolism occurs by cleavage to pyruvate or lactate (pyruvic acid pathway) or by decarboxylation to pentoses (pentose shunt) (Fig. 2-22).Excess glucose from overfeeding, as reflected by RQs >1.0, can result in conditions such as glucosuria, thermogenesis, and conversion to fat (lipogenesis). Excessive glucose adminis-tration results in elevated carbon dioxide production, which may be deleterious in patients with suboptimal pulmonary function, as well as hyperglycemia, which may contribute to infectious risk and immune suppression.Injury and severe infections acutely induce a state of peripheral glucose intolerance, despite ample insulin produc-tion at levels several-fold above baseline. This may occur in part due to reduced skeletal muscle pyruvate dehydrogenase activity after injury, which diminishes the conversion of pyru-vate to acetyl-CoA and subsequent entry into the TCA cycle. The three-carbon structures (e.g., pyruvate and lactate)


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Surgery_Schwartz. dehydrogenase activity after injury, which diminishes the conversion of pyru-vate to acetyl-CoA and subsequent entry into the TCA cycle. The three-carbon structures (e.g., pyruvate and lactate) that consequently accumulate are shunted to the liver as substrate for gluconeogenesis. Furthermore, regional tissue catheteriza-tion and isotope dilution studies have shown an increase in net splanchnic glucose production by 50% to 60% in septic patients and a 50% to 100% increase in burn patients.242 The increase in plasma glucose levels is proportional to the severity of injury, and this net hepatic gluconeogenic response is believed to be under the influence of glucagon. Unlike in the nonstressed sub-ject, in the hypermetabolic, critically ill patient the hepatic glu-coneogenic response to injury or sepsis cannot be suppressed by exogenous or excess glucose administration but rather persists. Hepatic gluconeogenesis, arising primarily from alanine and glutamine catabolism, provides a ready


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Surgery_Schwartz. or sepsis cannot be suppressed by exogenous or excess glucose administration but rather persists. Hepatic gluconeogenesis, arising primarily from alanine and glutamine catabolism, provides a ready fuel source for tissues such as those of the nervous system, wounds, and erythrocytes, which do not require insulin for glucose transport. The elevated glucose concentrations also provide a necessary energy source for leukocytes in inflamed tissues and in sites of microbial invasions.Brunicardi_Ch02_p0027-p0082.indd 6501/03/19 6:50 PM 66BASIC CONSIDERATIONSPART IThe shunting of glucose away from nonessential organs such as skeletal muscle and adipose tissues is mediated by cat-echolamines. Experiments with infusing catecholamines and glucagon in animals have demonstrated elevated plasma glu-cose levels as a result of increased hepatic gluconeogenesis and peripheral insulin resistance. Interestingly, although glucocorti-coid infusion alone does not increase glucose levels, it does


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Surgery_Schwartz. glu-cose levels as a result of increased hepatic gluconeogenesis and peripheral insulin resistance. Interestingly, although glucocorti-coid infusion alone does not increase glucose levels, it does pro-long and augment the hyperglycemic effects of catecholamines and glucagon when glucocorticoid is administered concurrently with the latter.Glycogen stores within skeletal muscles can be mobilized by epinephrine activation of b-adrenergic receptors, GTP-binding proteins (G-proteins), which subsequently activates the second messenger, cAMP. The cAMP activates phosphorylase kinase, which in turn leads to conversion of glycogen to glucose-1-phosphate. Phosphorylase kinase also can be activated by the second messenger, calcium, through the breakdown of phos-phatidylinositol phosphate, which is the case in vasopressin-mediated hepatic glycogenolysis.243Protein and Amino Acid MetabolismThe average protein intake in healthy young adults ranges from 80 to 120 g/d, and every 6 g of protein yields


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Surgery_Schwartz. case in vasopressin-mediated hepatic glycogenolysis.243Protein and Amino Acid MetabolismThe average protein intake in healthy young adults ranges from 80 to 120 g/d, and every 6 g of protein yields approximately 1 g of nitrogen. The degradation of 1 g of protein yields approxi-mately 4 kcal of energy, similar to the yield in carbohydrate metabolism. After injury, the initial systemic proteolysis, medi-ated primarily by glucocorticoids, increases urinary nitrogen excretion to levels in excess of 30 g/d, which roughly corre-sponds to a loss in lean body mass of 1.5% per day. An injured individual who does not receive nutrition for 10 days can theo-retically lose 15% lean body mass. Therefore, amino acids can-not be considered a long-term fuel reserve, and indeed excessive protein depletion (i.e., 25% to 30% of lean body weight) is not compatible with sustaining life.244Protein catabolism after injury provides substrates for gluconeogenesis and for the synthesis of acute phase proteins.


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Surgery_Schwartz. (i.e., 25% to 30% of lean body weight) is not compatible with sustaining life.244Protein catabolism after injury provides substrates for gluconeogenesis and for the synthesis of acute phase proteins. Radiolabeled amino acid incorporation studies and protein anal-yses confirm that skeletal muscles are preferentially depleted acutely after injury, whereas visceral tissues (e.g., the liver and kidney) remain relatively preserved. The accelerated urea excretion after injury also is associated with the excretion of intracellular elements such as sulfur, phosphorus, potassium, magnesium, and creatinine. Conversely, the rapid utilization of elements such as potassium and magnesium during recovery from major injury may indicate a period of tissue healing.The net changes in protein catabolism and synthesis corre-spond to the severity and duration of injury (Fig. 2-23). Elective operations and minor injuries result in lower protein synthesis and moderate protein breakdown. Severe trauma, burns,


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Surgery_Schwartz. corre-spond to the severity and duration of injury (Fig. 2-23). Elective operations and minor injuries result in lower protein synthesis and moderate protein breakdown. Severe trauma, burns, and sepsis are associated with increased protein catabolism. The rise in urinary nitrogen and negative nitrogen balance can be detected early after injury and peak by 7 days. This state of pro-tein catabolism may persist for as long as 3 to 7 weeks. The patient’s prior physical status and age appear to influence the degree of proteolysis after injury or sepsis. Activation of the ubiquitin-proteosome system in muscle cells is one of the major path-ways for protein degradation during acute injury. This response is accentuated by tissue hypoxia, acidosis, insulin resistance, and elevated glucocorticoid levels.NUTRITION IN THE SURGICAL PATIENTThe goal of nutritional support in the surgical patient is to prevent or reverse the catabolic effects of disease or injury. Although several important biologic


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Surgery_Schwartz. IN THE SURGICAL PATIENTThe goal of nutritional support in the surgical patient is to prevent or reverse the catabolic effects of disease or injury. Although several important biologic parameters have been used to measure the efficacy of nutritional regimens, the ultimate validation for nutritional support in surgical patients should be improvement in clinical outcome and restoration of function.Estimation of Energy RequirementsAll patients admitted to the hospital should have their nutritional status assessed. Overall nutritional assessment is undertaken to 7GlycogenGlucoseGlucose-6-Phosphate6-PhosphogluconatePyruvicacidLacticacidPentosemonophosphateshuntTricarboxylic acidFigure 2-22. Simplified schema of glucose catabolism through the pen-tose monophosphate pathway or by breakdown into pyruvate. Glucose-6-phosphate becomes an important “crossroad” for glucose metabolism.Brunicardi_Ch02_p0027-p0082.indd 6601/03/19 6:50 PM 67SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER


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Surgery_Schwartz. Glucose-6-phosphate becomes an important “crossroad” for glucose metabolism.Brunicardi_Ch02_p0027-p0082.indd 6601/03/19 6:50 PM 67SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Nitrogen excretion (g/d)128041620242832DaysMajor burnsSevere sepsisSkeletal traumaInfection010203040Elective surgeryPartial starvationTotal starvationFigure 2-23. The effect of injury sever-ity on nitrogen wasting. (Reproduced with permission from Long CL, Schaffel N, Geiger JW, et al: Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance, JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-456.)determine the severity of nutrient deficiencies or excess and to aid in predicting nutritional requirements. Pertinent information is obtained by determining the presence of weight loss, chronic illnesses, or dietary habits that influence the quantity and quality of food intake. Social habits predisposing to malnutrition and the


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Surgery_Schwartz. is obtained by determining the presence of weight loss, chronic illnesses, or dietary habits that influence the quantity and quality of food intake. Social habits predisposing to malnutrition and the use of medications that may influence food intake or urina-tion should also be investigated. Physical examination seeks to assess loss of muscle and adipose tissues, organ dysfunction, and subtle changes in skin, hair, or neuromuscular function reflecting frank or impending nutritional deficiency. Anthropo-metric data (i.e., weight change, skinfold thickness, and arm cir-cumference muscle area) and biochemical determinations (i.e., creatinine excretion, albumin level, prealbumin level, total lym-phocyte count, and transferrin level) may be used to substantiate the patient’s history and physical findings. This information, in conjunction with nutritional risk assessment scoring, can iden-tify patients who may benefit from early nutritional support.For critically ill and injured patients,


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Surgery_Schwartz. findings. This information, in conjunction with nutritional risk assessment scoring, can iden-tify patients who may benefit from early nutritional support.For critically ill and injured patients, validated scoring systems such as the Nutritional Risk Screening (NRS)245 or the Nutrition Risk in the Critically Ill (NUTRIC)246 score should be employed to make this determination and should be performed in conjunction with assessment of GI tract function and risk of aspiration. Appreciation for the stresses and natural history of the disease process, in combination with nutritional assess-ment, remains the basis for identifying patients in acute or anticipated need of nutritional support. Currently, specialized enteral nutrition can be avoided in patients who are deemed to be a low nutritional risk with low disease severity for up to one week. However, their nutritional status should be reassessed regularly.247A fundamental goal of nutritional support is to meet the energy requirements for


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Surgery_Schwartz. risk with low disease severity for up to one week. However, their nutritional status should be reassessed regularly.247A fundamental goal of nutritional support is to meet the energy requirements for essential metabolic processes and tissue repair. Failure to provide adequate nonprotein energy sources will lead to consumption of lean tissue stores. The requirement for energy may be measured by indirect calorimetry, which is the gold standard in hospitalized patients and is recommended for the critically ill.243 However, the use of indirect calorimetry, particularly in the critically ill patient, may not be available or feasible in this setting. Moreover, it may lead to an overestima-tion of caloric requirements, which has been associated with increased risk of infectious complications.248In the absence of indirect calorimetry, resting energy expenditure may also be estimated using a published predictive equation. Adjusted for the type of surgical stress, such equations are suitable


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Surgery_Schwartz. the absence of indirect calorimetry, resting energy expenditure may also be estimated using a published predictive equation. Adjusted for the type of surgical stress, such equations are suitable for estimating energy requirements in the major-ity of hospitalized patients. Alternately, a simple weight-based equation of 25 to 30 kcal/kg (using dry or usual body weight) per day is appropriate with a low risk of overfeeding and is con-sistent with current recommendations from ASPEN (American Society of Parenteral and Enteral Nutrition) in the ICU setting.247 After trauma or sepsis, energy substrate demands are increased during the recovery phase and may necessitate greater nonpro-tein calories beyond calculated energy expenditure (Table 2-9). These additional nonprotein calories provided after injury are usually 1.2 to 2.0 times greater than calculated resting energy expenditure, depending on the type of injury. It is seldom appro-priate to exceed this level of nonprotein energy intake


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Surgery_Schwartz. injury are usually 1.2 to 2.0 times greater than calculated resting energy expenditure, depending on the type of injury. It is seldom appro-priate to exceed this level of nonprotein energy intake during the height of the catabolic phase. Currently, standard enteral nutri-tion delivers 49% to 53% of calories as carbohydrate and 29% to 30% of calories as fat, which is consistent with current recom-mendations. For parenteral nutrition, dextrose-containing stock solutions are prepared and available in different concentrations. The percentage of calories that is contributed by dextrose should be determined on a per-patient basis according to the severity of injury/illness and the estimated caloric needs. Lipid emul-sions can be included in the total mixture or be administered separately in 10% or 20% solutions with 1.1 kcal/ml and 2 kcal/ml, respectively.The second objective of nutritional support is to meet the substrate requirements for protein synthesis. Protein nutritional support is


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Surgery_Schwartz. or 20% solutions with 1.1 kcal/ml and 2 kcal/ml, respectively.The second objective of nutritional support is to meet the substrate requirements for protein synthesis. Protein nutritional support is especially important for maintaining immune func-tion and lean body mass and is more closely linked to positive outcomes than total caloric intake. Although the mean protein requirement of healthy individuals is defined as 0.8 g/kg per day by the Food and Nutrition Board of the U.S. National Research Council, current recommendations for protein dosing exceed this Brunicardi_Ch02_p0027-p0082.indd 6701/03/19 6:50 PM 68BASIC CONSIDERATIONSPART Iamount (1.2–2 gm protein/kg per day), especially for the critically ill and injured. Higher protein intake seems to support improved nitrogen balance and high-protein nutritional support is currently recommended for patients with body mass index >30.247Vitamins and MineralsThe requirements for vitamins and essential trace minerals usu-ally can be


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Surgery_Schwartz. and high-protein nutritional support is currently recommended for patients with body mass index >30.247Vitamins and MineralsThe requirements for vitamins and essential trace minerals usu-ally can be met easily in the average patient with an uncom-plicated postoperative course. Therefore, vitamins usually are not given in the absence of preoperative deficiencies. Patients maintained on elemental diets or parenteral hyperalimenta-tion require complete vitamin and mineral supplementation. Commercial enteral diets contain varying amounts of essential minerals and vitamins. It is necessary to ensure that adequate replacement is available in the diet or by supplementation. Numerous commercial vitamin preparations are available for intravenous or intramuscular use, although most do not contain vitamin K and some do not contain vitamin B12 or folic acid. Supplemental trace minerals may be given intravenously via commercial preparations. Essential fatty acid supplementation also may be


Surgery_Schwartz

Surgery_Schwartz. vitamin K and some do not contain vitamin B12 or folic acid. Supplemental trace minerals may be given intravenously via commercial preparations. Essential fatty acid supplementation also may be necessary, especially in patients with depletion of adipose stores.OverfeedingOverfeeding usually results from overestimation of caloric needs, as occurs when actual body weight is used to calculate the BEE in patient populations such as the critically ill with sig-nificant fluid overload and the obese. Indirect calorimetry can be used to quantify energy requirements but frequently overes-timates BEE by 10% to 15% in stressed patients, particularly if they are receiving ventilatory support. In these instances, esti-mated dry weight should be obtained from preinjury records or family members. Adjusted lean body weight also can be cal-culated. Overfeeding may contribute to clinical deterioration via increased oxygen consumption, increased carbon dioxide production and prolonged need for


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Surgery_Schwartz. Adjusted lean body weight also can be cal-culated. Overfeeding may contribute to clinical deterioration via increased oxygen consumption, increased carbon dioxide production and prolonged need for ventilatory support, fatty liver, suppression of leukocyte function, hyperglycemia, and increased risk of infection.ENTERAL NUTRITIONRationale for Enteral NutritionEnteral nutrition (EN) is preferred over parenteral nutrition (PN) based on the lower cost of enteral feeding and the associ-ated risks of the intravenous route, including vascular access complications.249 Of further consideration are the consequences of gastrointestinal tract disuse, which include diminished solu-ble IgA production and cytokine production as well as bacterial overgrowth and altered mucosal barrier function and immune defenses. In support of this idea, recent meta-analysis demon-strated a significant reduction in infectious complications in criti-cally ill or injured patients receiving EN when compared to PN as


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Surgery_Schwartz. defenses. In support of this idea, recent meta-analysis demon-strated a significant reduction in infectious complications in criti-cally ill or injured patients receiving EN when compared to PN as well as ICU length of stay.250 However, no increase in overall survival was noted. While EN is recommended as the first choice for nutritional support in patients who can tolerate it, a recent large trial from Europe comparing early isocaloric EN vs. PN in adult critically ill patients with shock did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications including intestinal ischemia.251The benefits of enteral feeding in patients undergoing elective surgery appear to be linked to their preoperative nutri-tional status. Historical studies comparing postoperative enteral and parenteral nutrition in patients undergoing gastrointestinal surgery have demonstrated reduced infectious complications and acute phase protein production


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Surgery_Schwartz. studies comparing postoperative enteral and parenteral nutrition in patients undergoing gastrointestinal surgery have demonstrated reduced infectious complications and acute phase protein production in those fed by the enteral route. Yet prospectively randomized studies of patients with adequate nutritional status (albumin ≥4 g/dL) undergoing gas-trointestinal surgery demonstrate no differences in outcome and complications between those administered enteral nutrition and those given maintenance intravenous fluids alone in the initial days after surgery.252Early vs. Late FeedingCurrent recommendations support early enteral nutrition (within 48 hours) in critically ill patients, but with a caveat.253 Early “full nutrition” is likely to be harmful and is associated with a higher infection rate. The aim therefore is a caloric target below the actual energy expenditure, with the goal of providing >80% of estimated total energy goals gradually by 3 to 4 days. Early EN may be protective of


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Surgery_Schwartz. The aim therefore is a caloric target below the actual energy expenditure, with the goal of providing >80% of estimated total energy goals gradually by 3 to 4 days. Early EN may be protective of the enteral epithelial barrier func-tion and help to maintain the diversity of the microbiome. While early caloric limitation seems to benefit the critically ill patient when compared to overfeeding, the restriction likely creates a significant shortfall in protein provision considering the low protein-to-calorie ratio of most enteral products.254In this regard, it is important to distinguish “permissive underfeeding” in which the total calories provided average 1500 kcal/d with 40 gm/d of protein from hypocaloric nutri-tion which has the same total calories with 140 gm/d protein. Hypocaloric nutrition is currently recommended for critically ill obese patients, but some investigators argue that this nutritional strategy may also benefit nonobese patients especially during Table 2-9Caloric


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Surgery_Schwartz. nutrition is currently recommended for critically ill obese patients, but some investigators argue that this nutritional strategy may also benefit nonobese patients especially during Table 2-9Caloric adjustments above basal energy expenditure (BEE) in hypermetabolic conditionsCONDITIONkcal/kg PER DAYADJUSTMENT ABOVE BEEGRAMS OF PROTEIN/ kg PER DAYNONPROTEIN CALORIES: NITROGENNormal/moderate malnutrition25–301.11.0150:1Mild stress25–301.21.2150:1Moderate stress301.41.5120:1Severe stress30–351.62.090–120:1Burns35–402.02.590–100:1Brunicardi_Ch02_p0027-p0082.indd 6801/03/19 6:50 PM 69SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2the early acute period of critical illness.255 This recommendation excludes those patients whose pre-ICU weight loss indicate that they are malnourished.As the patient enters the recovery period of their illness, total protein and caloric requirements are likely to significantly increase. Based on our understanding of starvation, increased


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Surgery_Schwartz. the patient enters the recovery period of their illness, total protein and caloric requirements are likely to significantly increase. Based on our understanding of starvation, increased extrinsic delivery of both calories and protein are likely to be required during this period.For patients undergoing elective surgery, healthy patients without malnutrition who are undergoing uncomplicated sur-gery can tolerate 10 days of partial starvation (i.e., maintenance intravenous fluids only) before any clinically significant protein catabolism occurs. Earlier intervention is likely indicated for patients in whom preoperative protein-calorie malnutrition has been identified. Other clinical scenarios for which the benefits of enteral nutritional support have been substantiated include permanent neurologic impairment, oropharyngeal dysfunction, short-bowel syndrome, and bone marrow transplantation.Initiation of enteral nutrition should occur as soon as fea-sible after adequate resuscitation, most


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Surgery_Schwartz. impairment, oropharyngeal dysfunction, short-bowel syndrome, and bone marrow transplantation.Initiation of enteral nutrition should occur as soon as fea-sible after adequate resuscitation, most readily determined by adequate urine output. The presence of bowel sounds and the passage of flatus or stool are not absolute prerequisites for ini-tiation of enteral nutrition, but in the setting of gastroparesis feedings should be administered distal to the pylorus. Gastric residuals of 200 mL or more in a 4to 6-hour period or abdomi-nal distention requires cessation of feeding and adjustment of the infusion rate. Concomitant gastric decompression with dis-tal small-bowel feedings may be appropriate in certain patients such as closed-head injury patients with gastroparesis. There is no evidence to support withholding enteric feedings for patients after bowel resection or for those with low-output enterocutane-ous fistulas of <500 mL/d. In fact, a recent systematic review of studies of early


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Surgery_Schwartz. to support withholding enteric feedings for patients after bowel resection or for those with low-output enterocutane-ous fistulas of <500 mL/d. In fact, a recent systematic review of studies of early enteral feeding (within 24 hours of gastro-intestinal surgery) showed no effect on anastomotic leak and a reduction in mortality. Early enteral feeding is also associated in reduced incidence of fistula formation in patients with open abdomen. Enteral feeding should also be offered to patients with short-bowel syndrome or clinical malabsorption, but necessary calories, essential minerals, and vitamins should be supple-mented using parenteral modalities.Intermittent vs. Continuous Enteral FeedingEnteral nutrition can be administered either continuously or intermittently; however, the standard choice for critically injured adults is continuous enteral feeding (CEF) due to the lower complication rates.247 Data also suggest that CEF may promote protein anabolism by inhibiting protein


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Surgery_Schwartz. choice for critically injured adults is continuous enteral feeding (CEF) due to the lower complication rates.247 Data also suggest that CEF may promote protein anabolism by inhibiting protein breakdown.256Enteral FormulasFor most critically ill patients, the choice of enteral formula will be determined by a number of factors and will include a clinical judgment as to the “best fit” for the patients’ needs. In general, feeding formulas to consider are GI tolerance-promot-ing, anti-inflammatory, immune-modulating, organ support-ive, and standard enteral nutrition. In addition, guidelines from professional nutrition societies identify certain populations of patients who can benefit from formulations with specific pharmaconutrients.257 For many others, each physician must use his or her own clinical judgment about what formula will best meet the patient’s needs.The functional status of the gastrointestinal tract deter-mines the type of enteral solutions to be used. Patients with an intact


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Surgery_Schwartz. judgment about what formula will best meet the patient’s needs.The functional status of the gastrointestinal tract deter-mines the type of enteral solutions to be used. Patients with an intact gastrointestinal tract will tolerate complex solutions, but patients who have not been fed via the gastrointestinal tract for prolonged periods are less likely to tolerate complex carbohy-drates. In those patients who are having difficulty tolerating standard enteral formulas, peptideand medium-chain triglyc-eride-based formulas with prebiotics can lessen GI tolerance problems. Additionally, in patients with demonstrated malab-sorption issues, such as with inflammatory bowel diseases or short bowel syndrome, current guidelines endorse the provision of hydrolyzed protein formulas to improve absorption. Guide-lines have not yet been made with regard to the fiber content of enteral formulas. However, recent evidence indicates that supplementation of enteral formulas with soluble dietary fiber may


Surgery_Schwartz

Surgery_Schwartz. Guide-lines have not yet been made with regard to the fiber content of enteral formulas. However, recent evidence indicates that supplementation of enteral formulas with soluble dietary fiber may be beneficial for improving stool consistency in patients suffering from diarrhea.Factors that influence the choice of enteral formula also include the extent of organ dysfunction (e.g., renal, pulmonary, hepatic, or gastrointestinal), the nutrients needed to restore optimal function and healing, and the cost of specific products. There are still no conclusive data to recommend one category of product over another, and nutritional support committees typically develop the most cost-efficient enteral formulary for the most commonly encountered disease categories within the institution.As discussed extensively in the first sections of this chap-ter, surgery and trauma result in a significant “sterile” inflamma-tory response that impacts for the innate and adaptive immune systems. The provision


Surgery_Schwartz

Surgery_Schwartz. extensively in the first sections of this chap-ter, surgery and trauma result in a significant “sterile” inflamma-tory response that impacts for the innate and adaptive immune systems. The provision of immune-modulating nutrients, termed “immunonutrition,” is one mechanism by which the immune response can be supported and an attempt made to lower infec-tious risk. At present, the best studied of immune-nutrients are glutamine, arginine, and omega-3 PUFAs.“Immunonutrients.” As discussed extensively in the first sections of this chapter, surgery and trauma result in a sig-nificant “sterile” inflammatory response that impacts both the innate and adaptive immune systems. The provision of immune-modulating nutrients, termed “immunonutrition,” is one mecha-nism by which the immune response can be supported and an attempt made to lower infectious risk. Studies have shown that a variety of nutrients, including amino acids (glutamine and arginine); lipids (omega-3 PUFAs); and micronutrients


Surgery_Schwartz

Surgery_Schwartz. be supported and an attempt made to lower infectious risk. Studies have shown that a variety of nutrients, including amino acids (glutamine and arginine); lipids (omega-3 PUFAs); and micronutrients (e.g., vitamin C and selenium) can provide support to the immune system. While current evidence does not support their use uni-versally, benefit may exist for individual patients.258 At present, the best studied of immune-nutrients are glutamine, arginine, and omega-3 PUFAs.Glutamine is the most abundant amino acid in the human body, comprising nearly two thirds of the free intracel-lular amino acid pool. Considered a nonessential amino acid, glutamine is a necessary substrate for nucleotide synthesis in most dividing cells and hence provides a major fuel source for enterocytes. It also serves as an important fuel source for immu-nocytes. During stress states, peripheral glutamine stores are rapidly depleted, and the amino acid is preferentially shunted as a fuel source toward the visceral


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Surgery_Schwartz. as an important fuel source for immu-nocytes. During stress states, peripheral glutamine stores are rapidly depleted, and the amino acid is preferentially shunted as a fuel source toward the visceral organs and tumors, respectively.259 These situations create, at least experimentally, a glutamine-depleted environment with potential immune consequences, thus generating interest in both enteral and parenteral glutamine supplementation. However, recently reported data from two large randomized controlled clinical trials in which critically ill patients received glutamine supplementation demonstrated Brunicardi_Ch02_p0027-p0082.indd 6901/03/19 6:50 PM 70BASIC CONSIDERATIONSPART Iincreased 6-month mortality in the patients who received glutamine.260 Therefore, glutamine supplementation in the criti-cally ill patient is not currently recommended.247Arginine, also a nonessential amino acid in healthy sub-jects, first attracted attention for its immunoenhancing proper-ties, wound-healing


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Surgery_Schwartz. the criti-cally ill patient is not currently recommended.247Arginine, also a nonessential amino acid in healthy sub-jects, first attracted attention for its immunoenhancing proper-ties, wound-healing benefits, and association with improved survival in animal models of sepsis and injury.261 However, arginine can be metabolized to nitric oxide, via nitric oxide synthase (NOS). If NOS is upregulated, with arginine as avail-able substrate, NO production can also increase, which can have a negative impact on the critically ill patient. As with glutamine, the benefits of experimental arginine supplementa-tion during stress states are diverse. In clinical studies involv-ing critically ill and injured patients and patients who have undergone surgery for certain malignancies, enteral adminis-tration of arginine has led to net nitrogen retention and pro-tein synthesis, whereas isonitrogenous diets have not. Some of these studies also provide in vitro evidence of enhanced immunocyte function.


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Surgery_Schwartz. of arginine has led to net nitrogen retention and pro-tein synthesis, whereas isonitrogenous diets have not. Some of these studies also provide in vitro evidence of enhanced immunocyte function. The clinical utility of arginine supple-mentation in improving overall patient outcome remains an area of investigation.262As previously discussed, omega-3 polyunsaturated fatty acids (PUFAs, canola oil, or fish oil) displaces omega-6 fatty acids in cell membranes, which theoretically reduces the pro-inflammatory response from prostaglandin production. Hence, there has been significant interest in reducing the ratio of omega-6 to omega-3. The data regarding supplementation of enteral feedings with fish oil as a source for omega-3 PUFAs has been mixed, however, with no demonstrated improvement in respiratory complications in severe trauma patients and pos-sible benefits in patients with mild sepsis.166Standard Polymeric Formulas. Most polymeric formulas provide a caloric density from 1 to 2


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Surgery_Schwartz. respiratory complications in severe trauma patients and pos-sible benefits in patients with mild sepsis.166Standard Polymeric Formulas. Most polymeric formulas provide a caloric density from 1 to 2 kcal/mL, and approxi-mately 1500 to 1800 mL are required to meet daily require-ments. These compositions provide baseline carbohydrates, protein, electrolytes, water, fat, and fat-soluble vitamins (some do not have vitamin K). These contain no fiber bulk and there-fore leave minimum residue. These solutions usually are consid-ered to be the standard or first-line formulas for stable patients with an intact gastrointestinal tract. Normal digestive function is required for this formula.Fiber-Containing Formulas. Isotonic formulas with fiber contain soluble and insoluble fiber, which is most often soy based. Physiologically, fiber-based solutions delay intestinal transit time and may reduce the incidence of diarrhea compared with nonfiber solutions. It is most beneficial in this regard in


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Surgery_Schwartz. soy based. Physiologically, fiber-based solutions delay intestinal transit time and may reduce the incidence of diarrhea compared with nonfiber solutions. It is most beneficial in this regard in patients who have a high number of loose stools.263 Fiber stimu-lates pancreatic lipase activity and is degraded by gut bacteria into short-chain fatty acids (SCFA), an important fuel for colo-nocytes. Recent data have also demonstrated the expression of SCFA receptors on leukocytes, suggesting that fiber fermenta-tion by the colonic microbiome may indirectly regulate immune cell function. Another potential plus of fiber-containing formu-las is the inclusion of prebiotic fibers with the goal of positively impacting bacterial targets in the gut as well as gut barrier func-tion. While there has been limited research in this area to deter-mine the possible impact on clinical outcomes, addition of these fermentable soluble fiber additives is something that should be considered in the ICU patient


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Surgery_Schwartz. limited research in this area to deter-mine the possible impact on clinical outcomes, addition of these fermentable soluble fiber additives is something that should be considered in the ICU patient as a measure that can aid in the maintenance or restoration of a healthy balance of commensal gut bacteria.Immune-Enhancing Formulas. Immune-enhancing formulas are fortified with special nutrients that are purported to enhance various aspects of immune or solid organ function as previously discussed. Such additives include glutamine, arginine, omega-3 fatty acids, and nucleotides.264 Although several trials have pro-posed that one or more of these additives reduce surgical com-plications and improve outcome, these results have not been uniformly corroborated by other trials. The Canadian Clinical Practice Guidelines currently do not recommend the addition of arginine supplements for critically ill patients due to the poten-tial for harm when used in septic patients.265 Omega-3 PUFAs results


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Surgery_Schwartz. Practice Guidelines currently do not recommend the addition of arginine supplements for critically ill patients due to the poten-tial for harm when used in septic patients.265 Omega-3 PUFAs results from the EDEN-Omega study demonstrated that twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.266 Glutamine supplemen-tation should be strictly guided by the individual patient condi-tion for the reasons discussed previously.Calorie-Dense Formulas. The primary distinction of calorie-dense formulas is a greater caloric value for the same volume. Most commercial products of this variety provide 1.5 to 2 kcal/mL and therefore are suitable for patients requiring fluid restriction or those unable to tolerate large-volume infusions. As expected, these solutions have higher osmolality than standard formulas and are


Surgery_Schwartz

Surgery_Schwartz. therefore are suitable for patients requiring fluid restriction or those unable to tolerate large-volume infusions. As expected, these solutions have higher osmolality than standard formulas and are suitable for intragastric feedings.High-Protein Formulas/Bariatric Formulas. High-protein formulas are available in isotonic and nonisotonic mixtures and are proposed for critically ill or trauma patients with high protein requirements. These formulas have nonprotein-calorie to nitrogen ratios between 80:1 and 120:1. While some obser-vational studies show improved outcomes with higher protein intakes in critically ill patients, there is limited data from ran-domized trials that prevents making strong conclusions about the dose of protein in critically ill patients.As discussed previously, there has been support for high-protein, hypocaloric feeding in obese patients. As such, enteral formulas termed “bariatric formulas” have been developed. As an example, one product has 1 kcal/mL of


Surgery_Schwartz

Surgery_Schwartz. there has been support for high-protein, hypocaloric feeding in obese patients. As such, enteral formulas termed “bariatric formulas” have been developed. As an example, one product has 1 kcal/mL of formula, with 37% of the calories coming from protein. As the evidence for high-protein, hypocaloric feeding is low grade, it is unclear whether clinical outcomes with respect to survival and infectious com-plications is improved, and more data is required for definitive recommendation.267Elemental Formulas. Elemental formulas contain predigested nutrients and provide proteins in the form of small peptides. Complex carbohydrates are limited, and fat content, in the form of MCTs and LCTs, is minimal. The primary advantage of such a formula is ease of absorption, but the inherent scarcity of fat, associated vitamins, and trace elements limits its long-term use as a primary source of nutrients. Due to its high osmolarity, dilution, or slow infusion rates usually are necessary, particu-larly


Surgery_Schwartz

Surgery_Schwartz. associated vitamins, and trace elements limits its long-term use as a primary source of nutrients. Due to its high osmolarity, dilution, or slow infusion rates usually are necessary, particu-larly in critically ill patients. These formulas have been used frequently in patients with malabsorption, gut impairment, and pancreatitis, but their cost is significantly higher than that of standard formulas. To date, there has been no evidence of their benefit in routine use.Renal-Failure Formulas. The primary benefits of renal for-mulas are the lower fluid volume and concentrations of potas-sium, phosphorus, and magnesium needed to meet daily calorie requirements. This type of formulation almost exclusively Brunicardi_Ch02_p0027-p0082.indd 7001/03/19 6:50 PM 71SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2contains essential amino acids and has a high nonprotein-calorie to nitrogen ratio; however, it does not contain trace elements or vitamins. Current guidelines suggest that


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Surgery_Schwartz. METABOLIC SUPPORTCHAPTER 2contains essential amino acids and has a high nonprotein-calorie to nitrogen ratio; however, it does not contain trace elements or vitamins. Current guidelines suggest that patients with chronic kidney disease (CKD) who require enteral feeding should be placed on “standard enteral formulations.” Moreover, standard recommendations for both protein and calories support are also recommended.263Hepatic-Failure Formulas. Close to 50% of the proteins in hepatic-failure formulas are branched-chain amino acids (e.g., leucine, isoleucine, and valine). The goal of such a formula is to reduce aromatic amino acid levels and increase the levels of branched-chain amino acids, which can potentially reverse encephalopathy in patients with hepatic failure.268 The use of these formulas is controversial, however, because no clear bene-fits have been proven by clinical trials. Protein restriction should be avoided in patients with end-stage liver disease because such patients