Patients
This prospective, randomized, double-blind, controlled trial was approved by the Institutional Review Board of the Beijing Jishuitan Hospital (Approval No.: 201606-09), and the patients signed written informed consent. The registration number of the clinical experiment was: ChiCTR-OON-16008691. Our study enrolled elderly patients with hip fracture treated in the Department of Anesthesiology, Beijing Jishuitan Hospital from October 2016 to January 2017.
The inclusion criteria were: 1) patients with hip fracture undergoing operation; 2) patients aged 65-90 years; 3) American Society of Anesthesiologists (ASA) physical status scale grade I-III [23].
The exclusion criteria were: 1) patients with a history of psychosis or of long-term psychotropic medication use (dementia, schizophrenia), history of chronic analgesic use or history of alcohol abuse; 2) patients with preoperative mini-mental state examination (MMSE [24]) score of ≤23, which was assessed at 1 day before surgery (T0); 3) patients who were illiterate; 4) patients with hearing and visual impairments as well as those who had any cerebrovascular accidents such as stroke or transient ischemic attack (TIA) within 3 months; 5) patients with severe infection; 6) patients with communication barriers who could not complete the cognitive function test.
A computer-generated random number scheme was used to assign the patients into two groups, the DEX group (n=110) and the normal saline (NS) group (n=108).
The patients and researchers (responsible for data recording and analysis, Confusion Assessment Method (CAM [25]) delirium scale assessment and POD diagnosis) were blinded to the groups, but the anesthesiologists knew about the medication of the patients.
Anesthetic management
Patients in both groups underwent proximal femoral nail anti-rotation (PFNA), cannulated screw fixation, hemi-arthroplasty, or total hip arthroplasty (THA). The surgical procedures were perfomred according to standard procedures. The operations for all patients were performed by the same attending physicians (vice-senior physicians) with 5-10 years of surgical experience.
The anesthetic management was the same for both groups of patients except for the administration of DEX. Electrocardiogram (ECG), arterial blood pressure (ABP), heart rate (HR) and pulse oxygen saturation (SpO2) results were monitored after the patients entered the operating room. The patients were in supine position, and a portable ultrasound unit (WISONIC CLOVER 60VET) with a 4-12 MHz Convex array probe was used to identify the femoral artery, femoral nerve and fascia. The puncture point was at the point 2 cm towards the caudal side from the point of 1/3 length externally along the line between the anterior superior iliac spine and the pubic tubercle. The in-plane needle approach was applied. After the nerve block needle reached the fascia iliaca compartment, 30 ml of 0.4% ropivacaine was injected. Twenty minutes after nerve block, the patients were assisted by 3 physicians into the spinal anesthesia position, thus the diseased side was on the top, and a subarachnoid block was performed in the lateral position. The puncture point was in the L3-4 gap, and 12 mg of 0.5 ropivacaine was injected through the subarachnoid space after the puncture was successful; otherwise, puncture was performed between L2-3. General anesthesia was performed if spinal anesthesia failed. Etomidate (0.3 mg/kg) was used in general anesthesia, sufentanil (0.1 μg/kg) was used for induction, and rocuronium (0.6 mg/kg) was also applied. After successful intubation, a ventilator was connected to control breathing. Propofol was continuously pumped in and sevoflurane anesthesia was inhaled during the operation to maintain the anesthesia. Anesthesia depth was maintained by continuous pumping in 2% sevoflurane and propofol. Dexmedetomidine (0.5 μg/kg/h) was intravenously infused 30 minutes before the start of anesthesia in the DEX group, and was continuously infused at 0.3 μg/kg/h during the operation. The same volume of normal saline was administrated for the NS group. The medication was discontinued 30 min before the end of surgery. Self-controlled analgesia was performed by administrating patient controlled intravenous analgesia (PCIA), and sufentanil combined with flurbiprofen ester immediately after the operation.
Data collection
Demographics and medical history of the patients in both groups were recorded, including gender, age, ASA grade, body mass index (BMI), education level, type of fracture, type of anesthesia, surgical procedure, operation time and comorbidities.
Primary endpoint
The primary endpoint was the incidence of POD, which was assessed using the Chinese version of the Richmond Agitation Sedation Scale (RASS) [26] and the CAM Scale at the first postoperative day (T1), the second postoperative day (T2), and the third postoperative day (T3).
CAM assessment was performed for patients with RASS of >-4. The diagnostic criteria for positive CAM [25] was as follows: (1) acute onset, and fluctuation of the disease condition; (2) distracted attention; (3) thinking disorder; (4) changes of consciousness. If patients showed characteristics of points 1 and 2 and any one of 3 and 4, then CAM was considered positive.
Patients with positive CAM at any time point during the follow-up period were diagnosed by a psychiatrist or psychologist based on the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) [27]. Delirium was diagnosed if the following 5 items were satisfied based on DSM-5: (1) Attention deficit disorder; (2) acute onset and repeated changes of symptoms; (3) combined with cognitive impairment; (4) standards (1) and (3) cannot be explained by existing neurological diseases, and arousal disorder was excluded; (5) it can be seen from medical history, physical examination or laboratory tests that it was direct physiological consequences of general physical conditions.
Two trained individuals in our department conducted the assessment of POD, and they were also blinded to the grouping.
Secondary endpoints
Biochemical tests
Five ml of venous blood from the side without infusion was extracted at 9:00 in the morning at T0, T1 and T3, and was centrifuged at 4000 r/min for 10 min. The serum was separated and stored at -80 °C. Before assay, all samples were thawed to room temperature and mixed by gentle swirling or inversion. All sera were assayed on the same day to avoid inter-assay variation. Plasma IL-1, IL-6 and TNF-α levels were measured by an enzyme-linked immunosorbent assay (ELISA) kit from Bender MedSystems (GmbH, Vienna, Austria). The ELISA methods were basically the same involving a two antibody sandwich ABC-ELISA method. The first antibody was anti-human TNF-α, IL-1, or IL-6 monoclonal antibody and the second antibody was a monoclonal antibody containing biotin. Enzyme-labelled streptavidin was bound to the biotin, o-phenylenediamine was added, and the mixture turned yellow. At this time, sulfuric acid was added, and the color became darker. The optical density (OD) value was measured at 492 nm and the concentrations of TNF-α, IL-1, and IL-6 were proportional to OD value. Concentration of TNF-α, IL-1, or IL-6 in the specimen were calculated by plotting a standard curve.
The antibodies used in this procedure have no known cross-reactivities with other cytokines. The lowest detectable limits of IL-1β, IL-6, and TNF-α, were 1.5 pg/mL, 5 pg/mL, and 1.7 pg/mL, respectively.
NRS scores
Postoperative pain was assessed at T1, T2 and T3 according to a numeric rating scale (NRS), where “0” means no pain at all and “10” means extremely serious pain. Patients with a NRS score of ≥4 after the operation were intravenously injected with 40 mg of parecoxib sodium for analgesia in both groups.
Adverse events
Invasive artery blood pressure (systolic (SBP), diastolic (DBP), mean arterial pressure (MAP)), HR, ECG, and SpO2 were routinely monitored during the operation. The number of intraoperative adverse reactions including hypertension, hypotension, bradycardia and tachycardia were recorded. Tachycardia was defined as heart rate >100 bpm; bradycardia was defined as heart rate <60 bpm; hypertension was defined as systolic pressure >160 mmHg or 20% of baseline; hypotension was defined as systolic pressure <90 mmHg or 20% of baseline. Patients with bradycardia were administrated with 0.1-0.3 mg of atropine, and patients with hypotension were intravenously injected with 4 ug of norepinephrine or intravenously infused at 200 ug/h.
Statistical analysis
The incidence of postoperative delirium in a comparable patient population of a previous study was 28% [4]. We; therefore, assumed that the incidence of delirium would be reduced by one third in the DEX group in this trial. With significance set at 0.05 and power set at 80%, the sample size required to detect differences was 196, calculated with Pass 11.0 software (NCSS, LLC. Kaysville, Utah, USA). Taking into account a loss-to-follow-up rate of about 6%, we planned to enroll 208 patients.
Continuous data with normal distribution were expressed as means ± standard deviation (SD) and analyzed by independent t test, and those with non-normal distribution were expressed as medians (interquartile range) and analyzed by the Mann-Whitney u test. Categorical variables were expressed as frequencies and percentages and analyzed with chi-square analysis or Fisher exact test. Repeated measurement analysis of variance was used to analyse levels of inflammatory factors. Statistical analyses were done on SPSS Statistics for Windows (version 22.0; IBM Corp., Armonk, New York, USA) with two-tailed tests wherever appropriate and P<0.05 were considered as statistical significant. The Clinical Research Ethics Committee from Beijing Jishuitan Hospital was involved in overseeing the data.