| Age seems to be an important factor for hypnotic requirement. Many narcotics present an increasing pharmacodynamic sensitivity in elderly patients. For dexmedetomidine, the only pharmacokinetic process that recently has been reported to change with aging is a dramatic and relatively linear decrease in clearance. A recent research on rabbits also revealed that the youths were less sensitive to the sedative of dexmedetomidine. Zhifei Zhou studied the pharmacodynamics of dexmedetomidine by a target-controlled infusion on the patients scheduled for lower abdominal or extremity operation under combined spinal and epidural anesthesia. The EC50 and EC95 of dexmedetomidine for loss of consciousness (an OAA/S score of≤2) were significantly lower in the elderly (aged 65～85 yr) than in younger patients (aged 18～55 yr). But this research still had some shortages that it had ignored the difference between lower abdominal surgery and lower extremity surgery, and its criteria of sedation assessment could be further enhanced. Besides, the TCI of dexmedetomidine have not yet been popular and commercialized in clinical practice. Constant rate infusion still be the most common use of dexmedetomidine clinically. So the first section of our study was to calculate the median effective dose (ED50) of dexmedetomidine in different age patients when used for intraoperative sedation in lower limb orthopedic surgery during combined lumbar and peridural anesthesia, and estimate the influence of age on dexmedetomidine sedation.Combined lumbar plexus and sciatic nerve block and spinal anesthesia are widely used in lower limb orthopedic surgery. Compared with spinal anesthesia, combined lumbar plexus and sciatic nerve block by the guide of peripheral nerve stimulator (PNS) has some advantages of uncomplicated position and steady respiration-hemodynamics. Besides, combined lumbar plexus and sciatic nerve block has minimal effects on total body system and gastrointestinal function. But patients under nerve block or spinal anesthesia would feel anxious and terrified when keeping awake during surgery. As a highly specific α2-adrenoceptor agonist with centrally mediated sympatholytic, sedative and analgesic effects, dexmedetomidine produces unique properties of dose-dependent sedation that patients can be aroused by verbal command at recommended doses, with a low propensity to depress respiration. Now dexmedetomidine plays an important role as an assisted sedative in lower limb orthopedic surgery. Some researches had proved that spinal anesthesia could save the dose of sedative and provide a sedative effect depended on block level. In addition, small dose of local anesthetic (eg. lidocaine) absorbed into blood would mildly inhibit the central nervous system (CNS) and lead to an effect of drowsiness. Combined lumbar plexus and sciatic nerve block whether affect the requirement of the sedative, due to this reason, has not ascertained. So we would determine the ED50 of dexmedetomidine for providing adequate sedation of deep sedation, to guide the use of dexmedetomidine during combined lumbar plexus and sciatic nerve block. And then compare the effect of two different anesthesia of combined lumbar plexus and sciatic nerve block and combined spinal and epidural anesthesia on the sedation of dexmedetomidine.OBJECTIVE1. To calculate the ED50 of dexmedetomidine in different age patients when used for intraoperative sedation in lower limb orthopedic surgery during combined lumbar and peridural anesthesia, and estimate the influence of age on dexmedetomidine sedation.2. To determine the ED50 of dexmedetomidine for providing adequate sedation of deep sedation during combined lumbar plexus and sciatic nerve block, and compare the effect of two different anesthesia of combined lumbar plexus and sciatic nerve block and combined spinal and epidural anesthesia on the sedation of dexmedetomidine.METHODSThis study was approved by the local ethics board (Guangzhou General Hospital of Guangzhou Military Command Medical Ethics Committee) and registered at ClinicalTrials.gov (ID:NCT02099253, date of registration:03/26/2014). After written informed consent for the trail obtained,103 patients scheduled for lower limb orthopedic surgery under combined spinal and epidural anesthesia or combined lumbar plexus and sciatic nerve block, American Society of Anesthesiologists (ASA) physical status Ⅰ or Ⅱ, aged 18 to 79 yr, were enrolled. Patients were divided into four groups on the basis of age and anesthesia:the group of combined spinal and epidural anesthesia (group 1, patients aged 18 to 39 year; group 2, patients aged 40 to 64 year; and group 3, patients aged 65 to 79 year); the group of combined lumbar plexus and sciatic nerve block group (the nerve block group), patients aged 18 to 39 year.No drink or food were administered to all patients for 8 hours, without any sedative premedication. On arrival in the operating room, an intravenous cannula was inserted in the dorsum of a hand and 8～10 ml/kg of Ringer’s lactate infusion was administered. Electrocardiogram, blood oxygen saturation (SpO2), noninvasive blood pressure and BIS index were monitored. Patients in group of combined lumbar plexus and sciatic nerve block were assigned to receive lumbar plexus block and sciatic nerve block both using 0.33% ropivacaine 30 ml guided by PNS, while the other three groups were performed with 0.5% hyperbaric bupivacaine 8～10 mg for spinal anesthesia. After spinal anesthesia, an epidural catheter was inserted 3～4 cm upward and adjusted the patient’s position to make sure the upper block level was below T10. Oxygen was supplemented via venturi mask at a flow rate of 3 L/min throughout the surgery. The dermatomal extension of block was determined by needle punching.We recorded the baseline BIS value and asked patients to put on a pair of anti-noise earplugs after the upper level of sensory block was ascertained. The dose of dexmedetomidine for each subsequent patients was determined by a modified Dixon’s up-and-down method. The initial dose was 0.7μg/kg in elderly group for 15 min, whereas 1.0μg/kg in other three groups. We evaluated the degree of a patient’s sedation combining with BIS value and OAA/S scores at 26 min after starting dexmedetomidine infusions. If the desired degree of sedation was not achieved for a particular patient, we raised the dose for the next patient by a step of 0.05μg/kg. If the desired sedation was achieved, a decrease of 0.05μg/kg was made. The process was repeated until the sixth cross-over point was achieved at least. The ED50 of dexmedetomidine was determined by calculating the mean of the midpoint dose of each independent pair of patients who manifested crossover from "adequate sedation" to "inadequate sedation" within four groups.The works of recording BIS and OAA/S assessment were carried out by two different observers independently and the observer was blinded to the BIS value when he administered the OAA/S assessment. BIS value was recorded immediately prior to the OAA/S assessment. A desired sedation degree of deep sedation was defined as below:an OAA/S of≤2; or an OAA/S of 3 but along with a BIS value of≤46. Besides, only when SQI was above 70% and EMG below 50db, the BIS value would be accepted. The up-and-down data were also analyzed by a probit analysis, which enabled us to derive the ED50 and ED95 of dexmedetomidine dose with 95% CI.RESULTSExcept age, no other demographic data (gender, height, weight, sensory block level, serum albumin concentration, baseline BIS value, OAA/S scores, SQI and EMG included) were found statistically different among three different age groups during combined lumbar and peridural anesthesia (P>0.05). There is no significant difference in age, gender, height, weight, serum albumin concentration, baseline BIS value, OAA/S scores, SQI and EMG at 26min between the group of combined lumbar plexus and sciatic nerve block and group 1 (P>0.05). The SQI at 26 min were all above 70% and EMG less than 50db.The ED50 of dexmedetomidine for providing adequate sedation of deep sedation during combined lumbar and peridural anesthesia was (1.21±0.06)μg/kg in group 1, (1.16±0.08)μg/kg in group 2, (0.88±0.07) μg/kg in group 3. And the ED50 of dexmedetomidine for providing adequate sedation of deep sedation during combined lumbar plexus and sciatic nerve block was (1.27±0.12)μg/kg. A remarkable difference could be found among three different age groups during combined lumbar and peridural anesthesia (F=87.84, P=0.000). The dose of dexmedetomidine which was applied to elderly patients for adequate sedation was less than that of the rest two groups (versus group 1, P<0.001; versus group 2, P<0.001). There was no distinct difference in the dose of dexmedetomidine between group 1 and group 2 (P=0.069). No statistically difference was found between the nerve block group and group 1 (F=1.406,P=0.247).The ED50s and their 95% CI of dexmedetomidine calculated by the probit analysis were 1.21 μg/kg (95%CI:1.13～1.31μg/kg) in group 1,1.15 μg/kg (95%CI:1.09～1.24μg/kg) in group 2,0.89μg/kg (95%CI:0.83～0.96μg/kg) in group 3 and 1.30μg/kg (95%CI:1.20～1.66μg/kg) in the nerve block group. The ED95s and their 95% CI of dexmedetomidine calculated by the probit analysis were 1.44μg/kg (95%CI:1.32～1.85μg/kg) in group 1,1.38μg/kg (95%CI:1.27～1.76μg/kg) in group 2,1.06μg/kg (95%CI:0.97～1.35μg/kg) in group 3, and 1.69μg/kg(95%CI: 1.46～5.07μg/kg) in the nerve block group. The estimate of relative median potency between group 1 and group 3 was 1.36 and its 95% CI was 1.09～2.77, didn’t included 1, which meant the difference of the sedative efficiency of dexmedetomidine between two groups was statistically significant. It was also the same between group 2 and group 3 [Estimate:1.30 (95% CI:1.07～2.42)]. Besides, dose-response curve of group 3 was prominently leftward, compared with the other two different age groups. Results calculated by the probit analysis were similar with the ones calculating from the midpoint doses.The BIS value was positively correlated to the OAA/S score in group 1 (r=0.584, P=0.002), the same with the other groups (r=0.687, P<0.001 in group 2;r=0.501, P=0.013 in group 3, and r=0.778, P<0.001 in the nerve block group). Patients of group 1 experienced 1 case of glossoptosis and relieved after turning his head to one side. There was 1 case in group 2 and 2 cases in group 3 that needed to treated with atropine because of bradycardia. Three patients in the nerve block group received an assistant general anesthesia for their insufficiency of nerve block.CONCLUSIONThe estimaged ED50 of dexmedetomidine for providing adequate sedation of deep sedation during combined lumbar and peridural anesthesia was (1.21±0.06) μg/kg in group 1, (1.16±0.08)μg/kg in group 2, (0.880.07)μg/kg in group 3.And the ED50 of dexmedetomidine for providing adequate sedation of deep sedation during combined lumbar plexus and sciatic nerve block was (1.27±0.12)μg/kg.The ED95 and their 95% CI were 1.44μg/kg (95%CI:1.32～1.85μg/kg) in group 1,1.38 μg/kg (95%CI:1.27～.76μg/kg) in group 2, and 1.06μg/kg (95%CI:0.97～1.35 μg/kg) in group 3 and 1.69μg/kg (95%CI:1.46～5.07μg/kg) in the nerve block group, respectively. No statistically difference to dexmedetomidine sedation was found between the two different anesthesia of combined lumbar plexus and sciatic nerve block and combined spinal and epidural anesthesia, which block level was below T10·But elderly patients (≥65 years) were more sensitive to the drug when compared with the youths, and more likely to suffer bradycardia during combined lumbar and peridural anesthesia. There is no need to adjust the loading dose of dexmedetomidine when using for intraoperative sedation during combined lumbar plexus and sciatic nerve block or spinal anesthesia at a low block level (below T10). But we suggest that an anesthetist should decrease dexmedetomidine dose to avoid the excessively deep sedation level and bradycardia in elderly patients (≥65 years). |
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