Dynamic Evolution of Quantitative Electroencephalography During Graded Intracranial Hypertension and Screening of Candidate Early-Warning Features in a Rabbit Model

Background and Objectives: Elevated intracranial pressure (ICP) is common to many encephalopathies, but the evolution of quantitative electroencephalography (qEEG) indices along a pressure gradient—and their relative suitability for early warning—have not been systematically compared. In this exploratory study we established a stepwise, steady-state rabbit model of graded intracranial hypertension and screened candidate early-warning features against prespecified criteria. Materials and Methods: Eight male New Zealand rabbits were studied; two were excluded—one for circulatory failure during catheterization and one for refractory status epilepticus that reached a humane endpoint—leaving six that completed the protocol. Repeated small-volume inflation of a left parenchymal water balloon was used to define five windows: baseline (BL; ICP < 10 mmHg), 15–20, 25–30 and 35–40 mmHg, and an end stage (END). Eight-channel EEG was recorded synchronously, and δ, θ, α and β power, together with the amplitude-integrated EEG (aEEG) upper margin, lower margin and bandwidth, were computed. Seven candidate features and three criteria (evolution timing, individual consistency and strength of association with ICP) were fixed before analysis; selection stability was assessed by leave-one-rabbit-out (LORO) cross-validation. Results: ICP rose in a controlled manner from 5.43 ± 1.09 to 35.93 ± 1.48 mmHg (Kendall W = 0.96), without systematic changes in respiratory mechanics. As ICP increased, absolute θ and α power declined progressively (ρ = −0.77 and −0.53), whereas absolute δ power did not increase and its rising relative share merely reflected redistribution after the loss of faster activity. The three aEEG components changed asynchronously: the lower margin shifted downward early and persistently (ρ = −0.87 with ICP; W = 0.86), whereas the upper margin changed only terminally and bandwidth showed no consistent direction. Concurrently, MAP rose through the Cushing response, with heart-rate slowing, but the rise was insufficient and CPP fell from 64.78 to 41.24 mmHg, approaching the rabbit lower limit of autoregulation (~50 mmHg CPP) only in the later windows. Because ICP and CPP were tightly coupled within animals, their independent effects on the EEG could not be separated. In leave-one-rabbit-out cross-validation, the lower margin was selected in five of six folds, with a median out-of-sample ρ of −1.00 (a discrete value based on four windows per animal). Conclusions: In this exploratory study in a small cohort (n = 6), qEEG indices evolved asynchronously along the ICP gradient; the aEEG lower margin appeared earliest and remained relatively stable across leave-one-rabbit-out folds, making it a candidate early-warning feature worthy of priority validation. However, because rising ICP and falling CPP were tightly coupled and could not be separated in this model, its early decline cannot be uniquely attributed to either ICP elevation or hypoperfusion. Its alarm threshold and early-warning value still require confirmation in larger independent cohorts with simultaneous CPP and cerebral blood flow monitoring.