Operationalizing perioperative clearance reserve: a reserve-load interaction model for neurocognitive outcomes in...

Older patients who undergo similar operations and receive comparable anesthetic care do not always recover cognitively in the same way. Inflammation explains an important part of perioperative brain injury, yet it does not fully account for why the response settles quickly in one patient and persists in another. We suggest that this difference may reflect an interaction between the patient's preoperative capacity for brain fluid and solute clearance and the load imposed by surgery and anesthesia. In the proposed model, baseline clearance reserve is a continuous latent phenotype informed primarily in initial human studies by structural and transport measures of the glymphatic and meningeal lymphatic systems; molecular-cellular features are evaluated in nested or translational studies. Postoperative change is treated separately and followed as a recovery trajectory within each patient. Perioperative load is measured across mechanical-fluid, inflammatory, and surgical domains. The main statistical test is the interaction between baseline reserve and a prespecified load measure after adjustment for baseline confounders and for perioperative predictors not used to construct that load measure. Mechanotransduction may connect physical load with altered clearance. PIEZO1 is included as a tractable candidate within this pathway, rather than as a required cause. Initial human validation should focus on adults aged 65 years or older undergoing elective major noncardiac, nonintracranial surgery; cardiac and intracranial procedures require separate analyses. The theory can be tested by asking whether preoperative clearance measures add information beyond established risk factors, whether reserve modifies the effect of perioperative load, and whether postoperative clearance trajectories are related to neuroimmune and cognitive outcomes. This approach makes clearance reserve measurable while keeping it distinct from a clinical score.