This single-center and randomized study was conducted in Beijing Tiantan Hospital, Capital Medical University. The study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (reference number was ky-2010-018-02). Written informed consent was obtained from all participants. The study was registered with the Chinese Clinical Trial Registry (the reference number was ChiCTR-TRC-14004229).
Patients
We recruited patients scheduled for elective thoracic spinal cord tumor resection based on magnetic resonance imaging (MRI) studies. Other inclusion criteria included age between 18 and 60 years old and American Society of Anesthesiologists (ASA) physical status I or II. The patients who were pregnant and/or lactating, chronic using or addiction of analgesics were excluded from the study. The patients who were with illegal drug or alcohol abuse, obesity (BMI ≥ 30 kg/m2), anemia (hemoglobin < 11 g/dl), and major organ dysfunctions were also excluded from the study.
Grouping
Patients who met the recruitment criteria were randomly assigned to one of the three study groups, labeled “propofol group”, “DP adjusted group”, or “DP unadjusted group”. Randomization was based on a computer generated random digits table (SPSS Inc., Chicago, IL). Permuted-block randomization was used with a block size of 3 and an allocation ratio of 1:1:1. Since anesthesiologist was in charge of the anesthesia management and all evaluation of outcomes were based on the result of electrophysiological monitoring, the anesthesiologist could not be blinded. Neurophysiologists and patients were blinded to the study group till the evaluation finished. In propofol group, the anesthesia was maintained using propofol and remifentanil infusions only. The blood plasma concentration of remifentanil was fixed at 4 ng/ml while the propofol infusion was adjusted to maintain the BIS measurement between 40 and 50. In DP adjusted group, dexmedetomidine (0.5 μg/kg loading dose infused over 10 min followed by a constant infusion rate of 0.5 μg/kg/h) was added to propofol and remifentanil infusions. While the dexmedetomidine infusion was standardized and the blood plasma concentration of remifentanil was fixed at 4 ng/ml while the propofol infusion was adjusted to maintain the BIS measurement between 40 and 50 for 90 % of anesthesia time and no deviations for more than 5 min. In DP unadjusted group, the anesthesia was maintained using propofol and remifentanil infusions as in propofol group. After BIS was maintained between 40 and 50, dexmedetomidine was then added (0.5 μg/kg loading dose infused over 10 min followed by a constant infusion rate of 0.5 μg/kg/h). The propofol was not adjusted as in DP unadjusted group.
Anesthesia and management
The patients did not receive premedication. Anesthesia was induced by propofol (5 μg/ml) infusion managed with a Diprifusor propofol infusion device (Marsh model, Master Target Control infusion system, Fresenius-Vial, Brezins, France), remifentanil (4 ng/ml) infusion managed with an infusion device (Minto model CP-600TCI, Beijing Slgo Medical Technology Co., Ltd., Beijing, China) and rocuronium (0.6 mg/kg). Then patients received endotracheal intubation and mechanical ventilation adjusting to maintain the end-tidal carbon dioxide between 35 and 40 mmHg. In addition to the routine ASA monitors, patients received MEP (Cascade, Cadwell Laboratories Inc, WA, USA), SSEP (Cascade, Cadwell Laboratories Inc, WA, USA), bispectral index (BIS) (BIS™, Covidien, San Jose, CA, USA) and intra-arterial blood pressure monitoring. Bradycardia, defined as the heart rate (HR) < 50 bpm, was treated with atropine (0.5 mg) bolus administration. Hypotension, defined as a decreasing of mean arterial pressure (MAP) more than twenty percentage of the baseline, was treated by using a dopamine infusion titrated. The baseline blood pressure value was determined based on preoperative evaluation on the day before surgery.
Motor- and somatosensory-evoked potential monitoring
MEP was recorded from paired needle electrodes placed bilaterally in the tibias anterior and extensor digital muscles, and hand muscles. Electrical current delivered to corkscrew electrodes were inserted at the C3 and C4 sites (international 10–20 system) with train of six to nine pulses, 300 to 500 volts, 75 ms interval pause (ISI) and one to four microsecond of inter-stimulus interval using Cadwell Cascade neurophysiologic monitoring system (Cascade, Cadwell Laboratories Inc, WA, USA). Anodal stimulation was applied to trigger contralateral MEP responses. The number of pulses and voltage were established at baseline and maintained throughout the surgery. Surface-stimulating electrodes for SSEP monitoring were placed over each ulnar nerve at the wrists and over each posterior tibial nerve at the ankles. Needle electrodes were placed over the somatosensory hand cortex at scalp sites C3′-Fz, C4′-Fz, Cz′-Fz and C3′-C4′ to record the primary cortical responses. Ulnar and posterior tibial nerves were stimulated synchronously at 2.79/s and averaged over 500 stimuli. Ulnar nerves were stimulated at 15 mA, and posterior tibial nerves were stimulated at 25 mA. Then europhysiologists were blinded to the group till the evaluation finished.
Prior to surgery, the muscle strength of the left and right lower extremity was assessed by the attending neurosurgeon who was blinded to the randomization using a 0-2-5 scale, with 5 indicating normal strength and 0 complete paralysis. MEP, SSEP, BIS, mean arterial pressure (MAP) and heart rate (HR) were measured at 4 different time points (Fig. 1). T1 was the baseline value obtained 30 min after anesthesia induction and endotracheal intubation but before the dexmedetomidine infusion. T2 was 10 min after T1 when the dexmedetomidine loading dose infusion (0.5 μg/kg over 10 min) was just finished in DP adjusted group and DP unadjusted group. All variables were recorded again when the dexmedetomidine maintenance infusion (0.5 μg/kg/h) has lasted for 10 (T3) and 20 (T4) minutes, respectively, in both groups. The muscle relaxation related to rocuronium was reversed using neostigmine (0.05–0.07 mg/kg) if necessary before the first measurement. A T4/T1 90 % recovery of the muscle strength based on the train-of-four ratio was deemed acceptable for the study. All measurements were done with the patient in the lateral position and prior to skin incision in order to avoid the confounding effect of surgical manipulation on MEP and SSEP monitoring. More than 50 % decrease of the amplitude and more than 10 % prolongation of the latency of both SSEP and MEP monitoring from the baseline values were defined as clinically meaningful changes [18].
Statistical analysis
Sample size calculation was performed by PASS 2008 software (NCSS LLC, USA) for windows. Based on the study in which used MEP amplitude (500 μV; SD,110) to detect a 50 % difference in MEP amplitude (decrease from 500 to 250 μV) [13], 20 patients were required to detect an effect size of 0.8, assuming a power of 80 % and a 2-sided α level of 5 %. Considering the possibility of early termination during the study and 20–30 % for a drop-out rate, therefore 30 patients were recruited in each group.
Statistical analyses were performed using the Statistical Package for Social Sciences (Version 19.0, SPSS Inc., Chicago, IL). All quantitative data were analyzed for normal distribution and homogeneity of variance. Data that showed a normal distribution were presented as the means ± SD. The non-normal distribution data were presented as median. One-way analysis of variance (ANOVA) of repeated measurements was used to evaluate differences between the means at different time points in one group. Variables between groups underwent Student-Newman-Keuls tests with multiple comparison correction. All P values were two sided, and α level of 0.05 was considered statistically significant.