Research Design
The single center trial took a prospective, randomized, parallel group design. The present research was conducted at Department of Anesthesiology, Affiliated Hospital of Inner Mongolia Medical University (IHIMMU) (Hohhot, China) from September first, 2018 to April first,2019. The research protocol was approved by the hospital’s Ethics Committee (KY2018022), which was performed in accordance with the Declaration of Helsinki (2014). After approval, the clinical research was registered in the Chinese Clinical Trial Registry (website: www.chictr.org.cn, ChiCTR-1900021309) and adhered to CONSORT guidelines. After enrolment and before start of the experiments, the researchers clearly explained the experimental procedures, the objectives of the study, possible benefits, and side effects of the study to all elderly patients and obtained the signed consent form for participation in the research. Verbal and written informed consents were obtained from all the included patients.
Patients
Elderly patients with lumbar disk herniation or lumbar spondylolisthes undergone elective lumber spinal fusion were recruited into the research. The type of surgery was selected as posterior lumbar discectomy combined with pedicle screw fixation and intertransverse fusion. The inclusion criteria was the elderly patients with ASA grade less than III and aged 60 ~ 85 years. The exclusion criteria was confined as patients refusal to participate in the research at any time. Patients with bradycardia (heart rate < 50 bpm), cardiac morbidities, heart block greater than the first degree, abnormal liver or renal function, hyperthyroidism, vascular diseases and bowel disease (e.g, ulcerative colitis, Crohn’s disease, and irritable bowel syndrome) were excluded.
Randomization and Blinding
Randomization was achieved by a statistician using an online random number generator. Patient codes were placed into sequentially numbered sealed opaque envelopes by a research assistant who was not involved in the research. An anesthesiologist resident not involved in the patient management was responsible for opening the envelope and preparing the research’s drug according to the instructions in each envelope. All surgeons, patients, attending anesthesiologists, nurses and follow-up anesthesiologists were blinded to group assignments.
Interventions
At the holding area, an IV line was established with an18-gauge IV cannula in the forearm, and an infusion of Ringer’s lactate (RL) solution was started at a minimal rate to keep the vein open. The baseline mean arterial pressure (MAP) was measured three times in the supine position and average computed. The readings were recorded 1 min apart for the assessment of the noninvasive blood pressure with an automated device. One hundred and eight patients were randomly divided into three groups by dosage of norepinephrine infusion: 0.030 µg.kg− 1.min− 1, 0.060 µg.kg− 1.min− 1,and the 0.090 µg.kg− 1.min− 1 group (n = 36). All patients was continuouslly infused norepinephrine by the dosage of 0.030 µg.kg− 1.min− 1, 0.060 µg.kg− 1.min− 1and 0.090 µg.kg− 1.min− 1, respectively before the initiation of general anesthesia.
In the operating room, standard monitoring were performed by ECG, Heart Rate, noninvasive blood pressure, and pulse oximetry (SpO2). A radial artery cannula was inserted, and the pressure transducer was set to zero at the mid-axillary level to ambient pressure. The patients in three groups were given a predefined dosage of norepinephrine infusion before the initiation of general anesthesia. Then, general anesthesia was induced with fentanyl (20 to 30 µg− 1.kg− 1 IV), lidocaine (1.5 mg− 1.kg− 1 IV), and etomidate (up to 0.3 mg− 1.kg− 1 IV) and maintained with propofol (1.5 ~ 3 mg.kg− 1.h− 1) and remifentanil (0.1 ~ 0.2 µg·kg− 1·min− 1). Neuromuscular blockade was achieved with rocuronium (0.1 mg− 1.kg− 1, IV). Following endotracheal intubation, mechanical ventilation was performed without positive end-expiratory pressure using an inspired oxygen concentration of 50% and tidal volumes of 10 ml− 1.kg− 1 to maintain an end-expiratory PETCO2 at 4 ~ 4.5 kPa. The patients’ lungs were ventilated with a tidal volume of 10 mg− 1.kg− 1 of ideal body weight and an inspiration and expiration ratio of 1:2.0 with positive-end expiratory pressure (PEEP) of 5 ~ 8cmH20. After the final measurement of the assessed variables, the tidal volume was reduced to 8 mL/kg of the ideal body weight. The anesthesia was maintained with continuous infusion of remifentanil (0.3 ~ 0.4 µg.kg− 1.min− 1) and propofol (4 ~ 6 kg− 1·h− 1) with bispectral index range between 50 ~ 60. The arterial pressure waveforms were monitored with Phillips Intellivue MP70 monitors (Intellivue MP70, Philips Medical Systems, Suresnes, France). The primary and secondary outcomes were monitored at four intervals of T0,T1,T2, and T3 corresponding to before induction, 15 min following anesthesia induction with patient in a supine position, 60 min following surgery, and at the end of the surgery, respectively. At T1,T2,T3 timepoints, PPV was measured and recorded. The MAP and HR were recorded at T0,T1,T2 and T3 timepoints.
All patients were continuouslly prophylacticly infused norepinephrine of 0.030 µg.kg− 1.min− 1, 0.060 µg.kg− 1.min− 1and 0.090 µg.kg− 1.min− 1, respectively before the initiation of general anesthesia. The RL 5 ml− 1.kg− 1 was infused as a bolus volume before general anesthesia induction. Then, the infusion rate was reduced to keep the vein open following endotracheal intubation. If PPV was less than 13%, the maintenance volume of RL was infused at a rate of 2 ml.kg− 1.h− 1. If PPV was more than 13%, the hydroxyethyl starch (HES, 130/0.4, Voluven) of 3 ml− 1.kg− 1 (ideal body weight) was infused during 3 min to test the fluid response to guide the individual fluid therapy. A PPV less than 13% was defined as the negative fluid responsiveness. If PPV was within the target range and MAP was below the baseline, the ephedrine 5 ~ 10 mg was started and the case was excluded. If PPV was within the target range and MAP was > 20% of the baseline, 12.5 ~ 25 mg urapidil was administered. If PPV was within the target range and blood pressure fluctuated within 20% of the base blood pressure, norepinephrine infusion was continued until 5 min after sewing.
The day before surgery, all patients were instructed on the use of a 10-point numeric rating scale to assess their pain intensity (0 = no pain, 10 = worst possible pain). Postoperative patient- controlled intravenous analgesia was performed with sufentanil (1.5 µg− 1.kg− 1) combined with ondansetron 8 mg. All patients received a basal dose of (0.015 µg.kg− 1.h− 1) and PCA (0.030 µg− 1.kg− 1). The interval time was set at 10 min, and patient-controlled intravenous analgesia was maintained up to 72 h following surgery to make sure all patient numeric rating scale scores were below 3.
Data Collection
Demographic data, including age, gender, body mass index, duration of surgery, American Society of Anesthesiologists grade and perioperative complications were recorded. The mean blood pressure and heart rate were monitored and recorded at baseline (before induction), 15 min following anesthesia induction with the patient in a supine position, 60 min following incision and at the end of the surgery. The PPV was recorded at 15 min following anesthesia induction with the patient in a supine position, 60 min following surgery, and at the end of the surgery. The surgical indices, including blood loss, urine output, autologous blood transfusion and fluid infusion volume (crystalloids and colloids) were recorded. The bradycardia, atropine requirements, intraoperative hypotension and hypertension, postoperative hospital stay were recorded. The incidence of nausea and vomiting, first flatus, first ambulation, first intake timing were self-reported by patients and recorded by a follow-up anesthesiologist who was blinded to group assignments during follow-up.
Our primary outcome was set as the incidence of complications, such as cerebral complications, renal complications, pulmonary complications, cardiac complications and other complications (the incidence of fever, wound infection and delayed wound healing). The definition of delayed wound healing was set as the duration of wound healing more than fourteen days. The pulmonary infection, respiratory failure, pulmonary infarction and pulmonary embolism were recorded as pulmonary complications. Acute myocardial injury and acute myocardial infarction were included as cardiac complications. Progressive neurological deficit and acute cerebral infarction were a part of the cerebral complications, and oliguria and acute kidney injury (AKI) were included in the renal complications.
Secondary outcomes included the incidence of intraoperative nausea and vomiting, the frequency of hypertension, the frequency of hypotension, first intake, first flatus, ambulation timing, postoperative hospital stay, the volume of autologous transfusion, the intraoperative blood loss volume, the urine output volume and postoperative hospital stay (days from admission).
The intraoperative hypotension and hypertension were defined as a decrease and increase of > 20% of the baseline level, respectively. The definition of bradycardia was set as an HR < 50 beats/minute (bpm). If the HR was < 45 bpm, atropine bolus 0.3 ~ 0.5 mg, depending on the patient’s HR, was injected.
Sample Size Calculation
The sample size was calculated with PASS 2019 Software (Power Analysis and Sample Size). The primary outcome is defined as the incidence of postoperative complications. The preliminary experimental results showed that the incidence of postoperative complications were found in about 40% of the elderly patients undergoing spinal surgery without norepinephrine infusion, while only 10% incidence of postoperative complications following prophylactic dosage of 0.060 µg.kg− 1.min− 1 norepinephrine infusion. At the alpha error of 0.05, we calculated that eighty seven patients (twenty nine patients/group) would give 80% power to detect a 20% absolute reduction in the incidence of postoperative complications in the treatment group. However, to allow the comparisons between the control and each treatment group, the required sample size was assigned as one hundred and eight patients (thirty six patients for each group).
Statistical Analysis
Statistical Package for Social Science software, version 15 for Microsoft Windows (SPSS Inc., Chicago, IL, USA) was used for data analysis. Categorical data were expressed as frequency (%). Continuous data were tested for normality and presented as mean (SD) using the Shapiro–Wilk test. The primary outcome (frequency of complications) was analyzed with Fisher’s exact test. Continuous data were analyzed with one-way ANOVA. For repeated measures, a two-way repeated-measures ANOVA was used to evaluate the dose (between-groups factor) and time (repeated measures). Post hoc pairwise comparison was performed with an LSD test. A P-value ≤ 0.05 was considered statistically significant.