Total Splanchnic Resuscitation: SIRS AND MODS
	With the widespread use of advanced technology for organ support, patients rarely die from their presenting disease but rather from its patho-physiological consequences, namely, the sequential dysfunction and failure of several organ-systems.1 This syndrome has been termed "multi-organ dysfunction syndrome" (MODS).  MODS has an extraordinarily high mortality and, for many patients, the support of this syndrome does not improve survival but rather prolongs the dying process.2-4 Sepsis is the most common diagnosis leading to MODS in both the non-operative and operative patients. Patients may develop MODS as a consequence of a primary infection, or, as is more commonly the case, following nosocomial infections.4-7
	The Gut Hypothesis is currently the most popular theory to explain the development of MODS in critically ill patients.2,8,9  Splanchnic hypoperfusion is a common finding following multiple trauma, sepsis, shock, or thermal injuries.10-13 The gut is highly susceptible to diminished tissue perfusion and oxygenation as it has a higher critical oxygen requirement (DO2) than the whole body and other vital organs, and the mucosal counter-current microcirculation renders the villi particularly vulnerable to ischemia.14,15 Gut mucosal ischemia increases intestinal permeability with the translocation of bacteria, endotoxin, and other mediators into the systemic circulation.11,12,14,14 It is postulated that this results in activation of the pro-inflammatory cascade with local and systemic tissue injury leading to the multiple organ dysfunction syndrome (MODS).14 Increased intestinal mucosal permeability may therefore be central to the development of MODS. Indeed, Doig and colleagues demonstrated an excellent relationship between increased intestinal permeability on admission to the ICU and the subsequent development of MODS.16
	In patients with sepsis it is likely that a number of mechanisms leads to intestinal mucosal injury. Furthermore, it is probable that both structural changes and alterations in cellular function lead to increased mucosal permeability. Although total hepato‑splanchnic blood flow may be increased in sepsis,17,18 a reduction in gastric and ileal mucosal flow appears to be a consistent finding, suggesting redistribution away from the mucosa.17,19,20 The intramural redistribution of blood flow may partly be explained by the fact that endotoxin causes a dose dependant reduction in the diameter of the central arteriole of the villus.21-24 Endotoxin may, however, cause mucosal injury in the absence of  mucosal ischemia. Fink and coworkers have demonstrated that endotoxin causes a decrease in mucosal pH and an increase in mucosal permeability despite maintenance of normal mucosal blood flow.25 In addition, these authors have demonstrated that intestinal epithelial cells incubated in the presence of endotoxin display evidence of significant cellular dysfunction with decreased ATP production, increased permeability and diminished mitochondrial oxidative activity.26-29  These effects could be attenuated by NO• scavengers, inducible nitric oxide synthetase (iNOS) inhibition, dimethylsulfoxide (a hydroxyl radical scavenger) and ascorbate (a peroxynitrous acid scavenger).
	Peroxynitrite, a potent oxidant, is formed by the reaction of NO• with superoxide ( O2 -). Peroxynitrite is a particularly stable anion at physiologic pH (Pka 6.8) allowing it to diffuse through cells to exert its toxic effects.  When protonated under acidic conditions forming peroxynitrous acid it becomes a more powerful oxidant reacting with protein thiols, zinc fingers and iron / sulfur centers of structural proteins and enzymes such as actin and aconitase.30,31 Particularly important during sepsis is the nitrosylation of tyrosine groups on proteins by peroxynitrite and peroxynitrous acid forming nitrosotyrosine. Of note, myocytes obtained from patients with sepsis have been shown to have extensive nitrosylation of actin.32,33  This may contribute to the myocardial depression encountered in sepsis. Tight junctions and epithelial paracellular permeability are controlled physiologically by intracellular mediators (calcium, cAMP) probably through modulation of the actin-based  cytoskeletal ring. 34,35 Hypoxia with ATP depletion increases paracellular permeability in intestinal epithelial monolayers.36. Peroxynitrate is a potent trigger of DNA strand breakage, which in turn activates the nuclear repair enzyme poly-ADP ribosyltransferase (PARP), resulting in a cellular energy deficit.37 In addition, it is likely that nitrosylation of actomyosin results in disruption of the cytoskeletal ring with increased paracellular permeability.
	The preservation of gastrointestinal mucosal integrity may require a combination of therapeutic interventions, or so called "total splanchnic resuscitation (TSR)."  The enterocyte requires glutamine for cell differentiation and division.38  The early institution of a glutamine‑supplemented enteral diet may play a important role in maintaining the gut mucosal barrier function and preventing bacterial translocation.39-41 In addition, enteral and systemic antioxidants may reduce enterocyte damage and limit the increase in mucosal  permeability. In a preliminary report Kirton and colleagues have demonstrated that an "antioxidant cocktail" together with gastric mucosal pH (pHi) driven resuscitation may improve the outcome of critically injured patients.42 However, the use of vasoactive agents which selectively increase gastrointestinal mucosal blood flow may play a central role in "splanchnic resuscitation".
	References
	1.    Knaus WA, Draper EA, Wagner DP, Zimmerman JE.  Prognosis in acute organ-system failure.  Ann Surg 1985;  202:685-672.
	2.    Carrico CJ, Meakins JL, Marshall JC.  Multiple organ failure syndrome.  Arch Surg 1986;  121:196-202.
	3.    Cerra FB.  Multiple organ failure syndrome.  Dis Mon 1992;  38:843-947.
	4.    Fry DE.  Multiple system organ failure.  Surg Clin North Am 1988;  68:107-122.
	5.    Eiseman B, Beart R, Norton L.  Multiple system organ failure.  Surg Gynecol Obstet 1977;  144:323-326.
	6.    Knaus WA, Wagner DP.  Multiple systems organ failure: Epidemiology and prognosis.  Crit Care Clin 1989;  5:221-232.
	7.    Slotman GJ, Quinn JV.  Multivariate regression modeling for the prediction of inflammation, systemic pressure, and end-organ function in severe sepsis.  Shock 1997;  8:225-231.
	8.    Deitch EA.  Multiple organ failure: pathophysiology and potential future therapy.  Ann Surg 1992;  216:117-134.
	9.    Dorinsky PM, Gadek JE.  Multiple organ failure.  Clin Chest Med 1990;  11:581-591.
	10.    Fink MP.  Adequacy of gut oxygenation in endotoxemia and sepsis.  Crit Care Med 1993;  21:S4-S8
	11.    Antonsson JB, Boyle CC, Kruithoff KL, Wang H, Sacristan E, Rothschild HR, et al.   Validation of tonometric measurement  of gut intramucosal pH during endotoxemia and mesenteric occlusion in pigs.  Am J Physiol 1990;  259:G519-G523
	12.    O'Boyle CJ, MacFie J, Mitchell CJ, Johnstone D, Sagar PM, Sedman PC.  Microbiology of bacterial translocation in humans.  Gut 1998;  42:29-35.
	13.    Kale IT, Kuzu MA, Berkem H, Berkem R, Acar N.  The presence of hemorrhagic shock increases the rate of bacterial translocation in blunt abdominal trauma.  J Trauma 1998;  44:171-174.
	14.    Pastores SM, Katz DP, Kvetan V.  Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome.  Am J Gastroenterol 1996;  91:1697-1710.
	15.    Nelson D, Beyer C, Samsel R, Wood LDH, Schumacker PT.  Pathologic supply dependence of systemic and intestinal O2 uptake during bacteremia in the dog.  J Appl Physiol 1987;  63:1487-1489.
	16.    Doig CJ, Sutherland LR, Sandham JS, Fick GH, Verhoef M, Meddings JB.  Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patiens.  Am J Respir Crit Care Med 1998;  158:444-451.
	17.    Booke M, Hinder F, McGuire R, Traber LD, Traber DL.  Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep.  Crit Care Med 1996;  24:835-844.
	18.    Ruokonen E, Takala J, Kari A, Saxen H, Mertsola J, Hansen EJ.  Regional blood flow and oxygen transport in septic shock.  Crit Care Med 1993;  21:1296-1303.
	19.    Winslow C, Dorinsky PM.  Regional blood flow distribution in endotoxin-treated dogs: Modification by ibuprofen.  J Crit Care 1994;  9:159-168.
	20.    Neviere R, Chagnon JL, Vallet B, Lebleu N, Marechal X, Mathieu D, et al.   Dobutamine improves gastrointestinal mucosal blood flow in a porcine model of endotoxic shock.  Crit Care Med 1997;  25:1371-1377.
	21.    Schmidt H, Secchi A, Wellmann R, Bach A, Bohrer H, Gebhard MM, et al.   Effect of endotoxemia on intestinal villus microcirculation in rats.  J Surg Res 1996;  61:521-526.
	22.    Secchi A, Wellmann R, Martin E, Schmidt H.  Dobutamine maintains intestinal villus blood flow during normotensive endotoxemia: An intravital microscope study in the rat.  J Crit Care 1997;  12:137-141.
	23.    Whitworth PW, Cryer HM, Garrison RN, Baumgarten TE, Harris PD.  Hypoperfusion of the intestinal microcircualtion withou decreased cardiac output during live Escherichia coli sepsis in rats.  Circ Shock 1989;  27:111-122.
	24.    Theuer CJ, Wilson MA, Steeb GD, Garrison RN.  Microvascular vasoconstriction and mucosal hypoperfusion of rat small intestine during bacteremia.  Circ Shock 1993;  40:61-68.
	25.    VanderMeer TJ, Wang H, Fink MP.  Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock.  Crit Care Med 1995;  23:1217-1226.
	26.    Salzman AL, Menconi MJ, Unno N, Ezzell RM, Casey DM, Gonzalez PK, et al.   Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelial monolayers.  Am J Physiol 1995;  268:G361-G373
	27.    Unno N, Hodin RA, Fink MP.  Acidic conditions exacerbate interferon-g-induced intestinal epithelial hypermeability: role of peroxynitrous acid.  Crit Care Med 1998; (in press)
	28.    Unno N, Wang H, Menconi MJ, Tytgat SH, Larkin V, Smith, et al.   Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats.  Gastroenterology 1997;  113:1246-1257.
	29.    Unno N, Menconi MJ, Fink MP.  Nitric oxide-induced hyperpermeability of human intestinal epithelial monolayers is augmented by inhibition of the amiloride-sensitive Na(+)-H+ antiport: potential role of peroxynitrous acid.  Surgery 1997;  122:485-491.
	30.    Castro LM, Rodriguez M, Radi R.  Aconitase is readily activated by peroxynitrate, but not its precursor, nitric oxide.  J Biol Chem 1994;  269:29409-29415.
	31.    Radi R, Rodriguez M, Castro L, Telleri R.  Inhibition of mitochondrial electron transport by peroxynitrite.  Arch Biochem Biophys 1994;  308:89-95.
	32.    Ungureanu-Longrois D, Balligand JL, Kelly RA, Smith TW.  Myocardial contractile dysfunction in the systemic inflammatory response syndrome:role of cytokine-induced nitric oxide synthesase in cardiac myocytes.  J Mol Cell Card 1995;  27:155-167.
	33.    Beckman JS, Ye YZ, Anderson J, Chem J, Accavetti M, Tarpey MM, et al.   Extensive nitration of protein tyrosinases observed in human atherosclerosis detected by immunohistochemistry.  Biol Chem Hoppe Sci 1994;  375:81-88.
	34.    Perez M, Barber A, Ponz F.  Modulation of intestinal paracellular permeability by intracellular mediators and cytoskeleton.  Can J Physiol Pharmacol 1997;  75:287-292.
	35.    Turner JR, Rill BK, Carlson SL, Carnes D, Kerner R, Mrsny RJ, et al.   Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation.  Am J Physiol 1997;  273:C1378-C1385
	36.    Unno N, Baba S, Fink MP.  Cytosolic ionized Ca2+ modulates chemical hypoxia-induced hyperpermeability in intestinal epithelial monolayers.  Am J Physiol 1998;  274:G700-G708
	37.    Szabo C, Zingarelli B, Salzman AL.  Role of poly-ADP ribosyltransferase activation in the vascular and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite.  Circ Res 1996;  78:1051-1063.
	38.    Buchman AL.  Glutamine: is it a conditionally required nutrient for the human gastrointestinal system?  Journal of the American College of Nutrition 1996;  15:199-205.
	39.    Moore EE, Jones TN.  Benefits of feeding after major abdominal trauma - a prospective randomized study.  J Trauma 1986;  26:874-881.
	40.    Gianotti L, Alexander JW, Gennari R, Pyles T, Babcock GF.  Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis.  JPEN 1995;  19:69-74.
	41.    Qiu JG, Delany HM, Teh EL, Freundlich L, Gliedman ML, Steinberg JJ, et al.   Contrasting effects of identical nutrients given parenterally or enterally after 70% hepatectomy: bacterial translocation [see comments].  Nutrition 1997;  13:431-437.
	42.    Kirton O, Civeta J, Hudson-Civatta J, Gomez E, Shatz D, Byers P, et al.   Gastric intramucosal pH (pHi) driven resuscitation and antioxidants: Normalized pHi is associated with high survival.  Crit Care Med 1998;  26(Suppl):A142