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The importance of the stress response in survival from critical illness is not in dispute. Adrenalectomized animals or patients with documented adrenal insufficiency have a high mortality when exposed to physiological stress [, ]. However, in the setting of critical illness, attempting to determine what constitutes an appropriate stress response is not straightforward.

Recently, stress hyperglycemia, occurring in the vast majority of critically ill patients, has become a major therapeutic target in the intensive care unit (ICU). Stress associated with critical illness induces the release of counter-regulatory hormones. In addition, several clinical interventions, such as administration of cortico-steroids, enteral or parenteral nutrition, or dialysis, further predispose patients to hyperglycemia. Moreover, in critical illness, changes in carbohydrate metabolism occur resulting in insulin resistance and relative insulin deficiency.

Community-acquired pneumonia (CAP) is a major health problem, even in developed countries, being the leading cause of death due to infectious diseases in the USA []. CAP has a wide clinical spectrum of severity: up to 80% of patients are successfully managed in primary care, but 1 % of patients with CAP are classified as having severe disease, needing intensive care unit (ICU) admission, with 20–50% dying despite all available support and treatment options being utilized. is the most common cause of CAP, enclosing the subset group of patients having severe disease []. Moreover, bacteremia is not uncommon in pneumococcal CAP (20%) and has been associated with increased severity and mortality compared with non-bacteremic pneumonia [].

It is more than half a century ago that Robert Chanock and co-workers recovered a cytopathogenic agent from lung secretions of young infants with lower respiratory tract disease that was similar to an agent that had been identified in an outbreak of infection resembling the common cold in chimpanzees [, ]. Because of its characteristic cytopathologic findings in tissue culture where it forms syncytia in epithelial cells, the virus was named respiratory syncytial virus (RSV) []. From serological studies, it was observed that almost all children have been infected by RSV by the age of two years []. Epidemiological research carried out since its discovery has designated RSV as the most important causative agent of viral lower respiratory tract disease []. Approximately 100,000 infants are admitted annually with RSV-induced bronchiolitis in the United States, and the number of hospitalizations is increasing []. Because of this, RSV-associated disease imposes a major burden on health care resources []. More recently, RSV is increasingly being recognized as an important pathogen causing severe lower respiratory tract disease in elderly and immunocompromised patients [].

Pneumocystis pneumonia remains one of the leading causes of morbidity and mortality among patients with acquired immunodeficiency syndrome (AIDS) all over the world []. However, pneumocystis pneumonia is also a life-threatening opportunistic infection that can occur in other immunocompromised patients, mainly in solid organ transplant recipients, in patients with cancer, and those treated for autoimmune or inflammatory diseases [].

Neutrophils are the first cells to be activated in the host immune response to infection or injury and are critical cellular effectors in both humoral and innate immunity, central to the pathogenesis of sepsis and multi-organ dysfunction []. However, the neutrophil capacity for bacterial killing lacks selectivity, despite stringent regulation, and thereby carries the potential to inflict collateral damage to, and destruction of host tissue []. Host tissue damage characterizes both autoimmune and inflammatory conditions and may arise via a variety of mechanisms including premature neutrophil activation during migration, extracellular release of cytotoxic molecules during microbial killing, removal of infected or damaged host cells or debris during host tissue remodeling, and failure to terminate acute inflammatory responses []. Sepsis-induced neutrophil mediated tissue injury has been demonstrated in a variety of organs including the lungs [, ], kidneys [], and liver [].

The Acute Respiratory Distress Syndrome Network (ARDSnet) group compared low tidal volume ventilation with standard ventilatory strategies []; early goal directed therapy (EGDT) advocated administering fluids, blood products, and dobutamine to achieve oxygen delivery goals to septic patients on arrival in the emergency department []; and intensive insulin therapy was used to maintain tight glucose parameters in surgical patients []. These are landmark but disparate trials that have demonstrated major improvements in outcome and feature in the Surviving Sepsis Campaign Guidelines for managing sepsis []. In this chapter, we discuss the role mito-chondrial dysfunction plays in critical illness and its manifestation as a disruption of cellular energetics. We suggest that the positive outcomes from the above-mentioned trials relate to a reduction of impaired mitochondrial function and a reduction in the subsequent generation of inflammatory signals.

Most patients with sepsis have underlying co-morbidities. Co-existing disease is typically thought to influence the pathophysiology and outcome of sepsis by reducing physiological reserve. Certainly this is true: A patient with chronic obstructive pulmonary disease (COPD) will tolerate pneumonia less well than a patient with previously healthy lungs. Additionally, many chronic disease states (or their treatments) alter the pre-existing inflammatory and immune milieu. This effect ranges from the obvious (as in the case of patients taking immunosuppressant therapy) to the under-appreciated (as in the inflammatory dysregulation associated with obesity). In seeking explanations for differences in the host response to infection, much has been made of the possible effects of genetic variability. However, subtle variations in the underlying state of the immune and inflammatory systems have received little attention.

Postoperative patients are prone to develop infectious complications, and the phenomenon of immunoparalysis, defined as a diminished capacity of immunocompetent cells to respond to infectious agents, has been implicated as a major contributing factor. When inflammatory postoperative disorders are already established, intervention is difficult. However, if perioperative modulation of the inflammatory response were possible, this may influence postoperative outcome. General anesthetics exert a variety of effects, including sedation, amnesia, and analgesia. Current research focuses primarily on the effects of these compounds on membrane proteins in the central nervous system (CNS), to elucidate the molecular mechanism of their action. The (side-) effects of general anesthetics on other organ systems have been less extensively investigated. In this chapter, we will discuss the data available on the immunomodulatory effects of general anesthetics and the potential clinical implications of these effects on the development of (postoperative) infections.

Despite the use of Centers for Disease Control and Prevention (CDC) recommended practices to minimize infection risk, nosocomial sepsis and multiple organ failure (MOF) remain a leading cause of morbidity and mortality in critically ill patients. It is well documented that the use of immunosuppressant therapies dramatically increases this risk in patients with cancer, transplantation, and immunologic disease. Although immune monitoring has yet to be universally embraced, withdrawal of immunosuppressant therapies and use of immune restoration therapies is the standard of care when these patients develop sepsis. Critical illness stress can also induce a level of immunosuppression which is as life-threatening as is seen in the purposefully immunosuppressed patient. This chapter reviews the role of critical illness stress-induced immunosuppression in the development of nosocomial sepsis and MOF, and outlines clinical strategies which can be employed to maintain and restore immune function, and reduce morbidity and mortality in critically ill patients.