The incidence of critical-illness-related-corticosteroid-insufficiency is associated with severity of traumatic brain injury in adult rats

Abstract

Traumatic brain injury (TBI) causes deleterious critical-illness-related-corticosteroid-insufficiency (CIRCI), leading to high mortality and morbidity. However, the incidence of CIRCI following different TBI severities is not fully defined. This study was designed to investigate mechanistically the effects of injury severity on corticosteroid response and the development of CIRCI in a rat model of experimentally controlled TBI. Adult male Wistar rats were randomly assigned to sham, mild injury, moderate injury or severe injury groups. TBI was induced using a fluid percussion device at magnitudes of 1.2-1.4 atm (mild injury), 2.0-2.2 atm (moderate injury), and 3.2-3.5 atm (severe injury). We first assessed the effects of injury severity on the mortality and CIRCI occurrence using electrical stimulation test to assess corticosteroid response. We also investigated a series of pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), among different injury group including: apoptosis detected by a TUNEL assay, blood-brain-barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and Claudin-5 expression and transmission electron microscopy. We made the following observations. First, 6.7% of mild-injured, 13.3% of moderate-injured, and 68.8% of severe-injured rats developed CIRCI, with a peak incidence on post-injury day 7. Second, TBI-induced CIRCI is closely correlated with injury severity. As the injury severity rises both the incidence of CIRCI and mortality surge; Third, increased level of injury severity reduces the expression of endothelial tight junction protein, aggravate BBB permeability and exacerbate the ensuing neural apoptosis in the PVN of hypothalamus. These findings indicate that increased severity of TBI aggravate the incidence of CIRCI by causing damage to tight junctions of vascular endothelial cells and increasing neuronal apoptosis in the PVN of hypothalamus.

Keywords: Blood–brain barrier; Brain edema; Corticosteroid response; Critical illness related corticosteroid insufficiency; Traumatic brain injury.