Two-hit model of postintensive care syndrome induced by lipopolysaccharide challenge and subsequent chronic unpredictable stress in mice.


Department of Anesthesiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [Email]


Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness. However, there is still a lack of a clinically relevant animal model. Thus, development of a PICS model is essential for understanding the mechanism underlying PICS and screening treatment methods for this neuropsychiatric disorder. The purpose of this study was to establish a clinically relevant PICS model based on the two-hit concept, in which lipopolysaccharide (LPS, 3 mg/kg) injection was served as the first hit and subsequent modified chronic unpredictable stress as the second hit. In order to pharmacologically verify the proposed model of PICS, we studied the effectiveness of fluoxetine to reverse the behavioral and molecular abnormalities in this model. In the present study, body- and adrenal weight changes proved our model was effective, as reflected by body weight loss, increased adrenals weight, and a significantly increased level of plasma corticosterone. Moreover, our PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments. Neurobiological investigations revealed a significant up-regulation of the microglial marker CD68 and pro-inflammatory cytokine IL-6 in the hippocampus of stressed mice. Notably, chronic treatment with fluoxetine for three weeks reversed most of the affected parameters. In summary, we believe that we have developed a new model of PICS that is clinically relevant, which could advance the mechanism research and the development of therapeutic strategies.


Animal model,Behavioral outcomes,Fluoxetine,Sepsis,Stressor,