Molecular mechanisms of postintensive care syndrome

Abstract

Effectiveness of intensive care must be evaluated not only by short-term survival after a critical illness, but also by the recovery to an adequate quality of life. The increased evidence of long-term functional disabilities in intensive care survivors led to the definition of post-intensive care syndrome (PICS) [1]. Early diagnosis and effective treatments for these newly recognized conditions are warranted. However, most of the initial efforts to limit long-term sequelae have not yielded satisfactory results [2]. The objective of this review is to identify the molecular mechanisms that lead to organ dysfunction after intensive care and to summarize them into several plausible unifying hypotheses. From these mechanisms, novel therapeutic targets with the potential to prevent PICS may arise [3], allowing for earlier interventions during acute organ failure aimed to improve the quality of life of intensive care unit (ICU) survivors. Cost-effective strategies based on growing pathogenetic evidence on PICS would hence allocate research efforts and funding to implement preventive treatments, to impede pathogenetic mechanisms triggered during ICU stay, rather than exclusively rehabilitate long-term sequelae when they are already established.

Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities

“…As virtually all the homeostatic mechanisms during critical illness, the continued, dysregulated activation of senescence favors tissue damage, usually caused by persistent inflammation and fibrosis. This raises the hypothesis that the so-called Post-intensive care syndrome can be, at least in part, the manifestation of accelerated aging [ 45 ]. Knowledge of these senescence pathways can allow their monitoring and pharmacological manipulation, probably in specific time windows, to improve the outcome of critical care patients.…”

“…All this evidence fits into a model in which senescence is activated early as part of the acute phase response, contributing to organ homeostasis and repair. Prolonged or dysregulated senescent mechanisms can become injurious [ 45 ], favoring a prolonged pro-inflammatory and pro-fibrotic state that can spread beyond the initial site of injury (Fig. 1 ).…”

Beyond survival: understanding post-intensive care syndrome

“…TNF-α propagates catabolic pathways by promoting increased expression of genes associated with the ubiquitin-proteasome system responsible for massive intracellular proteolysis. IL-1, which is often found in the blood of patients with critical illnesses, has also been identified as a contributor to skeletal muscle atrophy by inhibiting protein synthesis, while IL-6 is involved in both the regulation of protein synthesis and protein degradation [ 16 , 17 ].…”