The Compensatory Anti-inflammatory Response Syndrome (CARS) in Critically Ill Patients
Section snippets
Background/history
The studies that led to this concept came from two different streams of medical research, one that was new at the time of Bone's article and one quite old. The new information to which Bone referred in his paper was the large set of data that recently had emerged from numerous studies in which agents that blocked inflammation were used in human sepsis patients.2 In stark contrast to the animal data, the human studies showed poor efficacy of these agents and even suggested that harm could be
What defines the compensatory anti-inflammatory response syndrome?
To better understand CARS, it is helpful to understand what responses characterize the proinflammatory state that precedes it. It now is known that inflammation can be triggered in two main ways, either by infections with pathogens like bacteria, or by the products of tissue destruction. The innate immune system describes a network of immune cells and their surface receptors designed to recognize and react to either dead tissue or pathogens. When elements of either of these encounter certain
Monocytes
Critical to the inflammatory response are the recognition and killing of invading organisms by monocytes. Equally important, monocytes present antigens by means of expression of HLA receptors and secrete proinflammatory cytokines to amplify the immune response.23 Multiple studies have demonstrated clearly that following either trauma or sepsis, monocytes have diminished capacity for both these responses. Specifically, they secrete fewer cytokines when stimulated and down-regulate expression of
Dendritic cells
Dendritic cells (DC) function as an important mediator in immune responses. Several investigators have found that their numbers decrease following the cecal ligation and puncture (CLP) model of sepsis in rodents.32, 33
In people, Guisset and colleagues34 have observed that septic patients who survived exhibited significantly higher circulating blood DC counts than those who died. In a postmortem study of spleen from 26 septic patients and 20 trauma patients, Hotchkiss and colleagues35 observed
Apoptosis
Regulation of apoptosis of immune cell populations during sepsis and other traumatic states may play a crucial role balancing the hyperactive inflammatory state with excessive injury to the host. Several studies suggest this balance is critical to outcome of experimental animals and possibly septic patients.48, 49 The immunoparalysis that has been shown to be a hallmark of CARS response in sepsis may be a pathologic result of increased immune effector cell apoptosis. Additionally, it has been
Biomarkers
In addition to the studies mentioned previously, there have been many efforts to study the magnitude of the CARS response in relation to patient outcomes. This has led some to see CARS biomarkers as a possible tool for prognosis and therapy.58 In an early study, Keane and colleagues59 looked at lymphocytes removed and cultured from 31 patients who had severe trauma. They found that, overall, lymphocyte response to stimulation with mitogens was reduced markedly from controls. Furthermore,
Summary
It has become clear that during sepsis or other major inflammatory stresses, there is a carefully orchestrated balance within the host organism. The proinflammatory forces rise to eliminate pathogens and dead tissue, and in doing so, often cause injury to the host. The timely arrival of anti-inflammatory responses such as the CARS response seeks to limit the damage while not interfering with the pathogen elimination. Just like its mirror image SIRS, however, the CARS response can be dangerous
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