Study design and experimental procedures. (A) Part I: to evaluate the effect of stress-dose hydrocortisone (HC) on corticosteroid responses and incident critical illness-related corticosteroid insufficiency after traumatic brain injury; HC or methylprednisolone (MP), or saline in the case of injury controls, was intraperitoneally (i.p.) injected daily from 0 to 7 days after fluid percussion injury (FPI). Electrical stimulation (ES) was administered to 30 rats randomly assigned from each of the four groups: pre-injury day 7, and post-injury day 3, day 7 and day 14. (B) Part II: the remaining rats were injected with HC or MP or saline once a day for 7 days after FPI to evaluate the extent of brain edema, BBB integrity and permeability, and apoptosis in the hypothalamal cells; 22 rats from each of the two groups (naïve and normal HC) and 50 from each of the three groups (injury control, low-dose MP, and stress-dose HC) were sacrificed at each time point (post-injury day 3, 7 and 14) to measure brain water content, to detect Evans blue extravasation and expression of CD31 and claudin-5, and to quantify terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in the hypothalamus.