Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery

Abstract

As early as the 1990s, chronic critical illness, a distinct syndrome of persistent high-acuity illness requiring management in the ICU, was reported under a variety of descriptive terms including the "neuropathy of critical illness," "myopathy of critical illness," "ICU-acquired weakness," and most recently "post-intensive care unit syndrome." The widespread implementation of targeted shock resuscitation, improved organ support modalities, and evidence-based protocolized ICU care has resulted in significantly decreased in-hospital mortality within surgical ICUs, specifically by reducing early multiple organ failure deaths. However, a new phenotype of multiple organ failure has now emerged with persistent but manageable organ dysfunction, high resource utilization, and discharge to prolonged care facilities. This new multiple organ failure phenotype is now clinically associated with the rapidly increasing incidence of chronic critical illness in critically ill surgery patients. Although the underlying pathophysiology driving chronic critical illness remains incompletely described, the persistent inflammation, immunosuppression, and catabolism syndrome has been proposed as a mechanistic framework in which to explain the increased incidence of chronic critical illness in surgical ICUs. The purpose of this review is to provide a historic perspective of the epidemiologic evolution of multiple organ failure into persistent inflammation, immunosuppression, and catabolism syndrome; describe the mechanism that drives and sustains chronic critical illness, and review the long-term outcomes of surgical patients who develop chronic critical illness.

Figure 1

Model of Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) and the role of Myeloid-Derived Suppressor Cells. After the simultaneous inflammatory and immunosuppressive responses, patients may return to a homeostatic immune state, leading to a rapid recovery, or develop chronic critical illness and subsequently PICS, resulting from protein catabolism, cachexia, organ failure, and secondary infections. A substantial number of these patients fail to ever recover and suffer an indolent death. Key drivers of this persistent inflammation and immunosuppression are myeloid-derived suppressor cells (MDSCs). MDSCs can influence almost every cell of host innate and adaptive immunity. CARS = compensatory anti-inflammatory response syndrome, MOF = multi-organ failure, SIRS = systemic inflammatory response syndrome. Adapted from Mira, et al.(16)

Figure 2

Six-month mortality of sepsis patients with Chronic Critical Illness (CCI) versus those of Rapid Recovery (RAP). We enrolled 145 critically ill surgical sepsis patients in a prospective observational study and classified each as CCI or RAP.(11) CCI was defined as an ICU duration of stay greater than or equal to 14 days with evidence of persistent organ dysfunction, measured using components of the Sequential Organ Failure Assessment (SOFA) score at 14 days (i.e. cardiovascular SOFA ≥ 1, or score in any other organ system ≥ 2). In addition, patients with an ICU duration of stay of less than 14 days would also qualify for CCI if they were discharged to another hospital, a long-term acute care facility, or to a hospice and demonstrated evidence of organ dysfunction at the time of discharge. Those patients experiencing death within 14 days of the onset of sepsis were excluded from the analysis. RAP was defined as any patient who did not meet criteria for CCI or early death. The Kaplan-Meier analysis demonstrates their cumulative survival rate over six months in CCI versus RAP patients (*Log-rank; p<0.0001). Patients who had yet to reach six months after their initial sepsis event were censored and are denoted with tick marks. Adapted from Stortz, et al.(11)

Figure 3

Depiction of the myelodysplasia of PICS. The vicious cycle and immune dyscrasia of PICS and its subsequent outcomes. PICS is more likely to occur when combined with certain chronic conditions or aging; interventions currently under investigation,however, could potentially disrupt the vicious cycle of PICS. HSC = hematopoietic stem cells, MDSCs = myeloid-derived suppressor cells.