Book Description

The critical care community is challenged on a day to day basis by the increasing complexity of managing patients who have sepsis, shock, severe trauma or major operations. Numerous reviews focus on the basic science of immunity in abovementioned states, and various reviews concentrate on the clinical management of patients with these critical injuries that lead to altered immunity. The purpose of this book is to delineate the current understanding of the immune response to critical injury on the one hand, and lay a foundation on which we can understand and apply therapeutic advances in the management of this altered immunity on the other hand. Models of critical injuries have been successfully used to unravel the pathophysiologic processes during sepsis shock, severe trauma or major operations. Though basic research revealed several promising immunomodulating agents for the treatment of sepsis, such as neutralizing antibodies against the various inflammatory mediators involved in the exaggerated immune response during sepsis, most clinical trials evaluating the efficacy of these new immunomodulating agents in septic patients showed disappointing results. Why is it that these new innovative strategies did not work in the clinical arena while they proved to be very effective in the laboratory? In chapter 1 the several explanations for this discrepancy are discussed. The lungs of critically ill patients are at a constant threat of diverse inflammatory reactions. First, critically ill patients may develop acute lung injury or the acute respiratory distress syndrome, which can be the result of either a pulmonary insult, like pneumonia or direct trauma, or an indirect insult, such as sepsis or shock. Although frequently mandatory and life saving, mechanical ventilation puts patients at additional risks for secondary pulmonary inflammatory processes. Indeed, mechanically ventilated patients are prone to pneumonia (so called ventilator associated pneumonia), causing substantial additional morbidity and mortality. But mechanical ventilation may aggravate pulmonary inflammation (so called ventilator associated lung injury), which leads to a decreased change of survival. Recent reports even suggest that mechanical ventilation may initiate lung injury by itself. Mechanical ventilation may also contribute to the development of multiple organ failure. Causative immunological mechanisms include the concept suppression of peripheral immune responses, suggesting several potential therapeutic approaches. In chapter 2 the concepts of biotrauma, and loss of compartmentalization with mechanical ventilation are discussed. The proposed mechanisms linking mechanical ventilation to multiple organ failure suggest several novel therapeutic approaches. Severe systemic inflammatory response are almost invariably associated with disturbances in the blood clotting system, leading to the establishment of a procoagulant milieu. It is increasingly recognized that inflammation induced coagulation is not only encountered in the systemic circulation, but also on a local level, i.e. in the organs. Indeed, lung injury eliciting pulmonary inflammation is also characterized by a disturbed haemostatic balance, however mainly restricted to the bronchoalveolar compartment. Disturbances in pulmonary coagulopathy are discussed with regard to sepsis and lung injury in chapter 3. Adequate and timely detection of pulmonary inflammatory processes is severely hampered in clinical practice. Indeed, clinical manifestations of acute lung injury or the acute respiratory distress syndrome include rapid onset of bilateral chest radiographic consolidations consistent with edema and critical hypoxemia these clinical criteria, however, are at times hard to recognize. Similar diagnostic problems apply for the diagnosis of pneumonia in mechanically ventilated patients. In addition, neither chest radiograph findings nor clinical parameters can be used to monitor the effects of mechanical ventilation (i.e., the development of ventilator associated lung injury) in individual patients. A role for several types of biological markers for pulmonary injury in critically ill patients can be suggested. These include proteins that detect damage to the alveolar epithelium and pulmonary endothelium or increased permeability of the air blood barrier as well as recently discovered biological markers of infection. Examples of such biological markers are discussed in chapter 4. Corticosteroids were introduced in the treatment of severe infection mid last century. Several randomized controlled trials of high dose corticosteroids given for a short period of time in the early course of severe sepsis or acute respiratory distress syndrome did not show benefit. The link between septic shock and adrenal insufficiency and systemic inflammation induced corticoid receptor resistance prompted renewed interest of a replacement therapy with low doses of corticosteroids during longer periods. The key role of corticosteroids in the host response to critical injury is reviewed in chapter 5. In this chapter new validated indications of corticosteroids treatment in the ICU are presented. Toll like receptors are essential in the host defense against microorganisms they are the first to detect host invasion by pathogens, and initiate immune responses. Toll like receptors form the crucial link between the innate and adaptive immune systems. Chapter 6 focuses on the new insights in the pathogenesis of sepsis that is offered by the discovery of the Toll like receptors and its possible implications for intensive care medicine. Manipulation of the Toll like receptor pathway has great therapeutic potential the first clinical trials that evaluate the use of Toll like receptor modulating drugs in sepsis are being performed. Endothelial cells participate in many homeostatic processes, including control of vasomotor tone, trafficking of cells and nutrients, maintenance of blood fluidity, and regulation of permeability. During critical injury endothelial cells can be viewed as both a victim as well as a perpetrator of the inflammatory response. Chapter 7 summarizes endothelial physiology and pathophysiology and discusses both endothelial injury as well as the role of the endothelium in orchestrating the host response during injury, specifically sepsis. The potential value of the endothelium as a target for future therapy is discussed. Chapter 8 deals with one of these therapeutic options that influence endothelial activation and function. Intensive insulin therapy aiming at strict regulation of glucose concentration in critically ill patients, has gained much interest in recent years in view of its beneficial effects on morbidity and mortality. Intensive insulin therapy has been shown to reduce endothelial activation and end-organ dysfunction in patients with prolonged critical illness, but also affects the inflammatory process itself by anti-inflammatory effects, the preservation of mitochondrial ultrastructure, and maintaining cellular integrity.