Diapositiva 1

Total Splanchnic Resuscitation: SIRS AND MODS
Paul Marik, MD
Department of Medicine
Washington Hospital Center
110 Irving St NW
Washington DC
20010-2975
Tel: 202 877-7856 (Office)
Fax: 202 291-0386
Page: 202 877-6550 pager 9184
e-mail: pmarik@erols.com

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".

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