The ICS triad in critical illness: a time-dependent pathological driver of mortality and organ dysfunction

Advances in intensive care have increased acute-phase survival, leading to a growing population of patients with prolonged ICU stays, a condition termed chronic critical illness (CCI). A key pathophysiological candidate is the triad of persistent inflammation, immunosuppression, and catabolism (ICS), yet its relationship to CCI and its independent prognostic impact remain poorly defined. The objective of this study was to investigate the impact of developing the ICS on hospitalization outcomes in critically ill patients.

We conducted a real-world data analysis of adult ICU patients using electronic health records from RICD (December 2017-July 2023). ICS was defined by concurrent C-reactive protein >20 mg/L, albumin <30 g/L, and lymphocytes <0.8 × 10^9/L. Outcomes included ICS incidence, mortality, organ support requirements, and multiple organ failure. Statistical analyses involved Kaplan-Meier estimates, Cox regression, and multivariate modeling.

Among 1,963 analyzed patients, 540 (27.5%) developed ICS. The cumulative risk of ICS was 21.3% by day 28 and 76.1% by week 16 of ICU stay. Patients with ICS had significantly higher hospital mortality (31% vs. 4.9%, p < 0.001), greater need for mechanical ventilation (67% vs. 41%, p < 0.001) and vasopressors (33% vs. 8.6%, p < 0.001). In multivariable analysis, ICS was an independent risk factor for hospital mortality (HR = 2.16, 95% CI 1.28-3.65, p = 0.004) and for multiple organ failure (HR = 1.25, 95% CI 1.05-1.47, p = 0.011).

The ICS triad is a common, time-dependent syndrome that independently predicts adverse outcomes, including hospital mortality and organ failure, in critically ill patients. Our data support the notion that ICS may play a role in the pathological substrate of CCI, and suggest the existence of a potentially modifiable 'prolonged critical state' that could precede the development of CCI. These findings highlight the potential value of shifting some clinical focus toward earlier recognition and prevention of the ICS triad, alongside the management of established CCI.