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Compartmentalization of the inflammatory response is a key feature of sepsis and SIRS. Tissue injury can be initiated far away from a distant insult. Blood borne elements are supposed to prevent initiation of deleterious inflammatory response within tissues. However, other circulating elements contribute to the ignition of inflammation at remote sites.

Inflammation requires clearance of the inciting pathogen, then orchestrated removal of the burden of leukocytes and other cells influxed into the inflamed site along with dissipation of the pro (or anti) inflammatory mediator cascades. We now recognize that this resolution process is strictly controlled by a number of mediators and adhesion molecules. Apoptotic cell death, when timed appropriately, allows the non-phlogistic clearance of PMNs, monocytes and eosinophils. Macrophage engulfment of these apoptotic cells signals further anti-inflammatory processes, including additional programmed cell death, anti-inflammatory mediator release, and promotes active macrophage emigration which is the final route by which cell clearance is effected. Should these processes evolve successfully, then the tissue will return to its normal structure and function, but should this not proceed effectively then the body will limit further damage by evoking a fibrotic response to ‘heal and seal’ the damaged tissue.

Skeletal muscle is a significant player in MOF, showing marked metabolic and structural changes and contributing to the metabolic and inflammatory fluxes in the body. Muscle function is severely compromised, but muscle is a resilient organ and shows an excellent ability to recovery. As a highly plastic organ, muscle shows marked adaptation to activity levels and immobility, and in situations of whole body stress provides a major store of amino acids through controlled degradation. However, muscle provision of certain, conditionally essential amino acids can become limiting. The opportunity for specific nutritional interventions is encouraging.

In summary, the endothelium is a spatially distributed cell layer that displays significant heterogeneity in both structure and function. Endothelial heterogeneity reflects the capacity of the endothelium to meet the diverse needs of the underlying tissues. The endothelium plays an important role in mediating the host response to infection. Not only do endothelial cells express pattern recognition receptors, but they also govern local blood flow and vectorial transport of cells, solutes, and fluids across the vascular wall. The normal response to infection involves activation of endothelial cells without dysfunction. In sepsis, the endothelial response becomes excessive, sustained, and/or disseminated, at which point the activation phenotype poses a liability to the host and may be characterized as dysfunctional. Important goals for the future are to develop reliable diagnostic assays for monitoring the health of the endothelium and to elucidate those components of the endothelial response that are maladaptive and amenable to therapeutic targeting.

Sepsis induces profound metabolic and cardiovascular derangements. Although some indices indicate that cytopathic hypoxia may coexist, early correction of global hemodynamic alterations is essential. Regional blood flow alterations may persist after correction of systemic hemodynamics. Although a systematic increase in splanchnic blood flow may not be warranted, several arguments suggest that the maintenance of an adequate balance between oxygen supply and demand in the splanchnic area may be useful.

Sepsis induces profound metabolic and cardiovascular derangements. Although some indices indicate that cytopathic hypoxia may coexist, early correction of global hemodynamic alterations is essential. Regional blood flow alterations may persist after correction of systemic hemodynamics. Although a systematic increase in splanchnic blood flow may not be warranted, several arguments suggest that the maintenance of an adequate balance between oxygen supply and demand in the splanchnic area may be useful.

The microcirculation is a vulnerable organ in sepsis. At the same time, the diseased microcirculation fuels sepsis, leading to organ failure. Direct monitoring of the microcirculation itself or at least some indicator of regional perfusion may, therefore, be useful in assessing the course of disease.

However, it should be noted that the effectiveness of many microcirculatory recruitment maneuvers has not yet been confirmed in appropriate clinical trials. Similarly, although there is strong evidence that an improving microcirculation is associated with a better outcome, this is not necessarily a cause and effect relationship and resuscitation of the microcirculation has not been the subject of clinical investigation at the present time. Nevertheless, it is important to remember that normal or improving global hemodynamics or oxygen-derived parameters do not preclude microcirculatory dysfunction, multiple organ failure, and fatal outcome. The microcirculation may be the much-needed end-point of resuscitation of clinical sepsis and septic shock. In addition to accepted therapies, such as fluid resuscitation and inotropic support, promising microcirculatory resuscitating maneuvers including vasodilatation, iNOS inhibition, and multi-action drugs, such as APC, could complement the armamentarium of tomorrow’s ICUs.

As reviewed above, there is abundant evidence implicating autonomic dysfunction or cytokine excess in diseases with inflammatory pathology such as sepsis, Crohn’s disease, and rheumatoid arthritis. The identification of a vagus nerve mechanism that regulates cytokine activity and immune cell activation now suggests that some neurological or nervous system disorders may in fact manifest as inflammatory conditions, and thus alter the optimal treatment. The ability to rationally modulate vagus nerve activity through biofeedback techniques now makes it plausible to consider how to study the regulation of cytokine synthesis in volunteer subjects and patients under varying states of vagus nerve activity.

Severe sepsis triggers clotting, diminishes the activity of natural anticoagulant mechanisms, and impairs the fibrinolytic system. Augmented interactions between inflammation and coagulation can give rise to a vicious cycle, eventually leading to dramatic events such as manifested in severe sepsis and DIC. Unraveling the role of coagulation and inflammation in sepsis will pave the way for new treatment targets in sepsis that can modify the excessive activation of these systems. At present it remains unclear whether anticoagulant therapy improves survival in severe sepsis; in addition, it remains uncertain whether the beneficial effect of recombinant human APC derives from its anticoagulant properties. These issues will be clarified as our understanding of the interplay between coagulation and inflammation during sepsis improves further in the very near future.

Hyperglycemia in critically ill patients is a result of an altered glucose metabolism. Apart from the upregulated glucose production (both gluconeogenesis and glycogenolysis), glucose uptake mechanisms are also affected during critical illness and contribute to the development of hyperglycemia. The higher levels of insulin, impaired peripheral glucoseuptake and elevated hepatic glucose production reflect the development of insulin resistance during critical illness.

Hyperglycemia in critically ill patients has been associated with increased mortality. Simply maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in surgical and medical ICU patients, as shown by two large, randomized controlled studies. These results obtained from clinical studies were also confirmed in ‘real-life’ intensive care of a heterogeneous patient population admitted to a mixed medical/surgical ICU.

Prevention of glucose toxicity by strict glycemic control appears to be crucial, although other metabolic and non-metabolic effects of insulin, independent of glycemic control, may contribute to the clinical benefits.