Aims This trial aims to assess whether dexmedetomidine can reduce the incidence of postoperative cognitive dysfunction in elderly orthopaedic patients and explore the specific mechanism. Background Postoperative cognitive dysfunction is a common complication after orthopaedic surgery that results in poor prognosis and increases the length of hospital stays and costs. Dexmedetomidine has been confirmed as a drug that can improve postoperative cognitive dysfunction in some studies. However, to date, the specific mechanism by which dexmedetomidine improves postoperative cognitive dysfunction is still elusive. Methods/design A single-centre, prospective, double-blinded, randomized controlled trial will be conducted at Hebei General Hospital. Ninety-six elderly patients who undergo total hip or knee replacement will be studied in this trial and randomly divided into two groups. Patients in the experimental group will receive a loading dose of 0.5 μg/kg dexmedetomidine for 10 min and then a maintenance dose of 0.5 μg/kg/h dexmedetomidine until 30 min before the end of the operation, and patients in the control group will be infused with an equal volume of normal saline. The incidence of postoperative cognitive dysfunction will be the primary outcome. Changes in the balance of T helper 17 cell and regulatory T cell; the levels of matrix metalloproteinase 9, S-100β, IL-17A, and IL-10; perioperative complications; hospitalization duration; and intraoperative blood loss will be the secondary outcomes. Discussion The consequences of this trial will show that dexmedetomidine can improve postoperative cognitive dysfunction in elderly orthopaedic patients, which may be related to the balance of T helper 17/regulatory T cells. Trial registration Chinese Clinical Trial Registry ChiCTR2200055802. Registered on 20 January 2022

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