We carried out this prospective randomized, placebo-controlled trial in Beijing Tuberculosis and Thoracic Tumor Research Institute (Beijing, China). The study protocol was approved by the local Clinical Research Ethics Committees (2017). Written informed consent was obtained from all individuals participating in the trial. Our study adheres to CONSORT guidelines and the CONSORT checklist was submitted as supplementary files. The trial was registered before patient enrollment at clinical trials.gov (ChiCTR1800015610; principal investigators: Tao Liu and Taijun Luo; date of registration: 11 April 2018).
Sixty-one patients who underwent an elective pulmonary surgical procedure were included from May to November 2018. Patients were excluded if they: had cerebrovascular disease, arrhythmia, sinus bradycardia, ischemic heart disease, history of obstructive sleep apnea, or known allergy to dexmedetomidine; were taking medication for mental disorders; had neurologic disease previously (e.g., stroke, seizures, dementia); had memory impairment.
Pulmonary resections, including wedge resection, lobectomy, bilobectomy, sleeve-lobectomy and pneumonectomy were selected on the basis of tumor location. Video-assisted Thoracoscopic Surgery was first choice and thoracotomy were performed when necessary. Unilateral pulmonary collapse was routinely performed in pulmonary surgeries for better surgical view and operation.
Grouping and drug administration
During the study period, patients were divided randomly into a placebo group and dexmedetomidine group using a computer-generated random-number table. Included patients were assigned randomly to receive dexmedetomidine or physiologic (0.9%) saline. In an emergency (e.g., unexpected, rapid deterioration in clinical status), an anesthesiologist could adjust or interrupt infusion of the study drug if indicated. Both the enrolled patients and the physicians in charge of POCD evaluation were blinded to the group allocation.
Study drugs (dexmedetomidine hydrochloride (200 μg/2 mL) and physiologic saline (2 mL)) were provided as clear aqueous solutions in identical 3-mL bottles (Jiangsu Heng rui Medicine, Jiangsu, China). Dexmedetomidine hydrochloride was diluted with physiologic saline to 50 mL (i.e., final concentration = 4 μg/mL) before administration. Premedication or sedation was not given to any participant. Patients breathed room air during the entire experiment.
Peripheral intravenous access was secured. Perioperative monitoring comprised electrocardiography, pulse oximetry, and continuous monitoring of arterial blood pressure (via a 20-G catheter inserted into the radial artery). The primary outcome is postoperative cognitive function and the second outcome is designed as rSO2 evaluation. The Bispectral Index (BIS), peripheral oxygen saturation (SpO2), rSO2, mean arterial blood pressure (MAP) and heart rate (HR) were secondary outcome, and were acquired at baseline before patients received dexmedetomidine or physiologic saline.
After SpO2, MAP, and HR at baseline had been recorded, patients in the dexmedetomidine group received dexmedetomidine (1 μg/kg), whereas patients received physiologic saline (0.25 mL/kg) in the placebo group, as recommended in other studies 19, 20. This dose ensured that patients in both groups received an equal dose of physiologic saline regardless of randomization. Drug solutions were prepared by an anesthesiologist and the volume maintained at 50 mL. Dexmedetomidine or physiologic saline was infused by a micro-pump for >20 min before the induction of anesthesia. Parameters were also monitored after patients regained consciousness. Demographic details (e.g., age, sex, weight, height) were also noted. Data were recorded by an investigator blinded to the study protocol and only attending anesthetist were required to guarantee quality control of the study.
Cognitive assessment was undertaken using the Montreal Cognitive Assessment (MoCA). The MoCA was developed to screen for mild or more serious cognitive dysfunction. The score of the MoCA ranges from 0 to 30, and is divided into seven subsets: visuospatial/executive; attention; abstraction; naming; memory; language; orientation. A MoCA score ≤25 is considered to denote cognitive impairment. Neuropsychologic evaluations were undertaken by a trained clinical anesthetist blinded to the study protocol. Evaluations were made at 1 day before surgery, as well as at postoperative day (POD)1, POD3, and POD7.
rSO2 was monitored continuously by near-infrared spectroscopy (NIRS) before anesthesia (EGOS-600A; Enginmed, Beijing, China)21, which provided continuous, non-invasive, real-time measurement of cerebral oxygenation22. This cerebral oximeter has two channels (right and left), which automatically registers which sensor is connected, and uses sensor-dependent algorithms for rSO2 calculation . The variable of brain oxygenation was defined as the mean value of oxygen saturation of the right and left sides of the brain. The BIS is a commonly used tool to measure the sedation level. A BIS-monitoring electrode (BIS™ Quatro; Aspect Medical Systems, Norwood, MA, USA) was placed on the forehead of the patient after careful cleaning of the skin according to manufacturer instructions. Then, an electrode was attached to a BIS monitor (BIS EEG Vista™; Aspect Medical Systems) which provided continuous, real-time surveillance.
Based on MoCA detected between the two groups in a pilot study, the mean value was 26 in the dexmedetomidine group and 24 in the placebo group. Hence, the size of the group sample needed to reach 23 for each group to achieve 90% power to detect a difference between these two groups, with an alpha of 0.05 using a two-sided two-sample t-test. Considering the prospects of inadequate cases and exclusion, we planned to enroll 30 cases for each group.
The independent Student’s t-test was used to compare the mean value between the dexmedetomidine group and placebo group at different times. p < 0.05 was considered significant. Statistical analyses were carried out using SAS v9.4 (SAS Institute, Cary, NC, USA).