Study Design and Settings
This prospective, randomized, controlled, double-blinded trial was approved by the institutional review board of Xuanwu Hospital, Capital Medical University (LYS [2019]051) and registered with the Chinese Clinical Trial Registry (number: ChiCTR1900025241; date of registration: 17/08/2019). All participants provided verbal and written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.
Participants
The investigators assessed the study participants the day before surgery (or on Friday for participants scheduled for surgery the following Monday). The same surgical and anesthesia teams performed all of the procedures. The inclusion criteria for elderly patients were as follows: (1) patients undergoing elective laparoscopic urological surgery; (2) age 65–85 years old; (3) American Society of Anesthesiologists (ASA) grade I-III; (4) at least 6 years of education. The exclusion criteria were as follows: (1) severe impairment of vision, hearing, and language communication; (2) Mini-Mental State Examination (MMSE) ≤ 23; (3) change in surgical procedure following anesthesia; (4) return to the intensive care unit following surgery; (5) conditions causing severe hemodynamic fluctuations (such as severe allergic reactions or major bleeding); (6) refusal or unexpected discharge.
Randomization And Blinding
Before surgery, elderly patients were randomized into the control group or the IoC group. A stratification-free randomization sequence was generated using a computer and sealed in consecutively numbered envelopes. When a patient who met the inclusion criteria was enrolled, the anesthesiologist opened the corresponding envelope, and the patient received the treatment corresponding to their allocated group. The patients and the outcome assessor were blinded to group assignment.
Study Procedures
None of the patients received sedatives or anticholinergics before anesthesia induction. The following parameters were continuously monitored: blood pressure, heart rate, finger pulse oxygen saturation, partial pressure of end-tidal carbon dioxide (PETCO2), and body temperature. For monitoring blood gas and hemodynamics, an arterial catheter was placed into the radial artery. For anesthesia induction, sufentanil 0.3–0.5 µg.kg− 1 and etomidate 0.2–0.3 mg.kg− 1 were injected intravenously until the patient lost consciousness, following which rocuronium 0.6 mg.kg− 1 was injected intravenously. Tracheal intubation was performed, and the patient was ventilated with a 50% O2-air combination at a PETCO2 of 30–35 mmHg. The initial pumping dose for anesthesia maintenance was set as 4 mg.kg− 1.h− 1 for propofol and 0.2–0.4 µg.kg− 1.min− 1 for remifentanil. The dosage was adjusted according to the IoC range in the IoC group (IoC1: 40–60, IoC2: 30–50) and the BIS range in the control group (BIS: 40–60). For both groups, goal-directed fluid therapy was performed intraoperatively to maintain pulse pressure variation (PPV) < 13%. To maintain patients’ intraoperative blood pressure above 20% from baseline, norepinephrine was preventatively infused and regulated at a dosage of 0.03 µg.kg− 1.min− 1 to 0.10 µg.kg− 1.min− 1. The nasopharyngeal temperature was monitored and maintained between 36°C and 37°C using an intraoperative warming device. After surgery, all patients received patient-controlled intravenous analgesia (oxycodone 0.5 mg.kg− 1 and ondansetron 8 mg diluted to 100 mL with normal saline). A bolus dose of oxycodone 1 mg and a locking time of 5 min were set as PCIA parameters.
IoC1 (sedation depth) and IoC2 (analgesia depth) monitoring was performed in the IoC group. IoC1 and IoC2 indices were set in the range of 40–60 and 30–50, respectively, during anesthesia maintenance. When the IoC1 index was more than 60 beyond 1 min, the propofol infusion rate was regulated by 0.4 mg.kg− 1.h− 1 increment to less than 60. When the IoC1 index was less than 40 for 1 min, the propofol infusion rate decreased by 0.4 mg.kg− 1.h− 1 dosage to more than 40. When the IoC2 index range could not be easily modulated, the IoC1 index was first regulated between 40 and 60 to ensure the appropriate depth of sedation. When the IoC2 index was more than 50 beyond 1 min, the dosage of remifentanil infusion was increased by 0.04 µg.kg− 1.min− 1 increment or bolus injection of 1 µg.kg− 1 was administered to reach an IoC2 index of less than 50 intervals. When the IoC2 index was less than 30 beyond 1 min, the infusion rate of remifentanil was down regulated by 0.04 µg.kg− 1.min− 1 to reach an IoC2 index of less than 30. Propofol and remifentanil infusion was stopped at the end of the surgery. The patient reached the awakened state when the IoC index was increased (IoC1 index of more than 70 and IoC2 index of more than 90) (Fig. 1).
Patients in the control group received the general anesthesia procedure. The BIS value was kept between 40 and 60 during anesthesia maintenance. When the BIS index was more than 60 for 1 min, the infusion rate of propofol was increased by 0.4 mg.kg− 1.h− 1 to a BIS index of less than 60. When the BIS index was less than 40 for 1 min, the infusion rate was down regulated by 0.4 mg.kg− 1.h− 1 to a BIS index of more than 40. The infusion rate of remifentanil during anesthesia maintenance was determined by surgical stress, hemodynamic parameters, and the anesthesiologist’s experience. Propofol and remifentanil infusion was stopped at the end of the surgery. The patient reached the awakened state when the BIS index was more than 90.
Data Source And Collection
The same neuropsychologist performed both MMSE and Montreal Cognitive Assessment (MoCA) assessments for patients 1 day before the surgery (T0) and 7 days after the surgery (T4). Data from the practical effect collected by the research group [19] in the past were used to calculate incidence of POCD: the practical effect was 1.92 ± 1.19, and the Z-score was calculated using the following formula: [MoCA score (T4) − MoCA score (T0) − practice effect (mean)]/practice effect (standard deviation). When the Z-score was ≥ 1.96, a diagnosis of POCD was determined.
Blood samples were collected from patients’ radial artery at T1 (before anesthesia induction) and T2 (end of surgery) for blood gas analysis. Blood gases were analyzed and measured using the standard ABL800 FLEX (Radiometer Medical, Denmark) in a standard blood gas syringe. The analysis was performed immediately after the blood samples were collected from the patient (approximately 1–3 min).
Venous blood samples (4 mL) were obtained thrice: before anesthesia induction (T1), end of surgery (T2), and 24 h after surgery (T3). The blood samples were centrifuged at 1,000 rpm for 15 min, and the supernatant was stored at − 80°C. Serum levels of C-reactive protein (CRP) and glial fibrillary acidic protein (GFAP) were measured using enzyme-linked immunosorbent assay kits (CUSABIO, Wuhan, Hubei, China) according to the manufacturer’s instruction.
Demographic and clinical information, namely; age; gender; body mass index (BMI); ASA grade; education level; history of hypertension, diabetes, and coronary artery disease; and preoperative diagnosis was collected from the patients 1 day before the surgery. Additionally, the intraoperative dosage of propofol, remifentanil, and norepinephrine; anesthesia duration; pneumoperitoneum duration; Infusion volume; bleeding volume; and urine output were recorded. Postoperative complications (stroke, acute myocardial injury, acute myocardial infarction, arrhythmia, heart failure, pulmonary infection, pulmonary atelectasis, respiratory failure, pulmonary embolism, acute kidney injury, and urinary tract infection), and length of stay were also recorded.
Primary And Secondary Endpoints
The primary endpoint was the incidence of POCD, which was evaluated using MoCA. The secondary endpoints included inflammatory markers (CRP and GFAP), arterial blood gas analysis (pH, PaCO2, blood lactic acid levels, blood glucose concentration), new postoperative complications of brain, heart, lung, kidney, and urinary tract infections, and length of hospital stay.
Statistical Analysis
The sample size was calculated to determine the estimated incidence of POCD, which is the primary outcome. In a pilot study, 30 patients who met the eligibility requirements were randomly allocated to two groups, with 15 patients in each group. In the IoC and control groups, POCD incidence was 1/15 and 4/15, respectively. The sample size was estimated using PASS15 software, and based on α = 0.05 and 1-β = 0.80, 51 patients were needed in each group. After accounting for 10% of missed visits, the final sample size for each group was estimated to be 56 cases.
SPSS Statistics 25 software was used for statistical analyses. Distributions of quantitative variables were normalized using boxplots, histograms, and Kolmogorov-Smirnov tests. Variables with normal distribution were denoted as \(\overline {x} \pm s\), non-normally distributed variables were denoted as median (interquartile range), and qualitative variables were denoted as frequencies. A completely randomized design with an independent samples t-test was used to analyze parameters with a normal distribution (age; BMI; education level; dosage of sufentanil, propofol, remifentanil, and norepinephrine; pneumoperitoneum duration, and anesthesia duration; volume of infusion, bleeding, and urine; MMSE, MoCA, GFAP, CRP, serum pH, PaCO2, blood lactic acid, blood glucose, and length of hospital stay). Mann-Whitney U test was used to analyze the indicators of non-normal distribution (ASA grade). Qualitative indicators (sex ratio; hypertension; diabetes; coronary artery disease; POCD; cerebral, cardiac, pulmonary, and renal complications; urinary tract infections; and total complications) were analyzed using the chi-square test. Differences were considered statistically significant at P ≤ 0.05.