Compensatory Anti-Inflammatory Response Syndrome (CARS)
Definition and Core Concept
CARS is a counter-regulatory immunosuppressive state that develops in response to excessive systemic inflammation (SIRS), characterized by global deactivation of immune function aimed at restoring homeostasis but resulting in increased susceptibility to secondary infections. 1
The syndrome was formally proposed by Roger Bone in 1997 to describe the consequences of counter-regulatory mechanisms initiated to limit overzealous inflammatory processes in patients with infectious sepsis or non-infectious systemic inflammatory response syndrome. 1
Pathophysiology
Immune Reprogramming
CARS represents a reprogramming rather than complete suppression of circulating leukocytes, where certain acute proinflammatory genes are silenced while genes involved in anti-infectious processes remain expressible. 1
The response is compartmentalized: circulating leukocytes show altered function, but tissue leukocytes remain primed or activated rather than immunosuppressed. 1
Anti-inflammatory cytokines (particularly IL-10) are elevated disproportionately relative to pro-inflammatory cytokines (IL-6), with this imbalance correlating exponentially with sepsis severity. 2
Temporal Relationship with SIRS
CARS often occurs concomitantly with SIRS rather than sequentially, a pattern termed Mixed Antagonist Response Syndrome (MARS). 3, 2
Early postoperative sepsis is characterized by simultaneous elevation of both IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory), with IL-10 levels correlating exponentially with IL-6 levels. 2
The timing and relative magnitude of CARS profoundly impact patient outcomes, with more severe sepsis associated with disproportionate anti-inflammatory responses. 2, 4
Clinical Significance
Enhanced Infection Susceptibility
The major clinical consequence of CARS is modification of immune status that favors enhanced susceptibility to nosocomial infections in intensive care patients. 1
Animal "two-hit" models demonstrate enhanced sensitivity to infection after an initial insult, though this is highly dependent on experimental conditions. 1
Prolonged Critical Illness
Patients who survive initial sepsis or surgical events may progress to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), which represents the dominant pathophysiology prolonging surgical ICU stays beyond 10 days. 5
PICS patients often survive to transfer to long-term care facilities but rarely achieve self-sufficiency, frequently returning to the ICU. 5
Key Clinical Pitfalls
Do not assume complete immunosuppression: CARS involves selective immune dysfunction rather than global immune failure, with preserved function in certain compartments. 1
Recognize that pro- and anti-inflammatory responses coexist: The sequential SIRS-then-CARS model is oversimplified; most critically ill patients exhibit MARS with simultaneous inflammatory and anti-inflammatory responses. 3, 2
Greater sepsis severity correlates with disproportionate anti-inflammatory responses: Monitor for this dysbalance as it predicts worse outcomes and increased infection risk. 2