Asleep-awake-asleep regimen for epilepsy surgery: a prospective study of target-controlled infusion versus manually controlled infusion technique

Journal of Clinical Anesthesia (2016) 32, 92–100

Original contribution

Asleep-awake-asleep regimen for epilepsy surgery: a prospective study of target-controlled infusion versus manually controlled infusion technique☆,☆☆,★,★★ Xiaohua Wang MD, PhD a,1 , Tianlong Wang MD, PhD a,⁎, Zhaolong Tian MS a,1 , David Brogan MD b , Jingsheng Li MS a , Yanhui Ma MD a a

Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, NO 45 Chang Chun Road, Xi Cheng District, Beijing 100053, P. R. China b Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA Received 24 December 2014; revised 19 April 2015; accepted 23 November 2015

Keywords: Asleep-awake-asleep; Epilepsy surgery; TCI; Target-controlled infusion; MCI; Manually-controlled infusion

Abstract Background: Asleep-awake-asleep (AAA) protocol for epilepsy surgery is a unique opportunity to accurately map epilepsy foci involved in motor and eloquent areas, allowing the operator to optimize the resection. Two different application modes of intravenous anesthesia for AAA craniotomies are widely used: infusion by means of target-controlled infusion (TCI) and traditional manually-controlled infusion (MCI). We conducted this study to examine whether intravenous anesthesia using the TCI system with propofol and remifentanil would be a more effective method than MCI in AAA epilepsy surgery. Methods: This prospective and single center study compared patients undergoing either TCI or MCI techniques for functional AAA epilepsy surgery. 35 cases used TCI including TCI-E (resection of epileptogenic foci in an eloquent area, n = 18) and TCI-M (resection of epileptogenic foci in a motor area, n = 17). Thirty-six cases used MCI including MCI-E (epileptogenic foci in an eloquent area, n = 16) and MCI-M (epileptogenic foci in a motor area, n = 20). Bispectral index value and hemodynamic profiles at different time points during the awake phase were recorded along with time for awakening and the occurrences of adverse events. Results: The TCI technique significantly shortened intraoperative awakening times during the third phase, TCI-E vs MCI-E 12.82 min ± 6.93 vs 29.9 min ± 9.04 (P = .000) and TCI-M vs MCI-M 16.8 min ± 5.19 vs 30.91 min ± 15.32 (P = .010). During the awake phase, the highest bispectral index score values appeared in the

☆

Sources of financial support for the work:This work was supported by Anesthesiology departmental funding of Xuan Wu hospital. Number of words: The number of words in the Abstract is 292; in the Introduction, 335; and in the Discussion, 955. ★ This article has no conflicts of interest. ★★ TCI vs MCI for epilepsy AAA ⁎ Corresponding author at: Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, 45 Chang Chun Road, Xi Cheng District, Beijing 100053, P. R. China. E-mail address: [email protected] (W. Tianlong). 1 These two authors contributed equally to this work. ☆☆

http://dx.doi.org/10.1016/j.jclinane.2015.11.014 0952-8180/© 2016 Elsevier Inc. All rights reserved.

93 TCI-E group at all-time points. Mean arterial pressure and heart rate were more stable in the TCI-E group compared with the MCI-E group during the awake phase. Tachycardia and hypertension were most common in the MCI-E group (52.9% and 29.4%, P = .001 and P = .064). Conclusion: We found the superiority of TCI, which is faster intraoperative awakening and better hemodynamics along with secure airway management conditions. It is suggested that the TCI technique may be a feasible and effective technique and it might be a viable replacement of the MCI technique for AAA epilepsy surgery. © 2016 Elsevier Inc. All rights reserved.

1. Introduction

2. Methods

Epilepsy is one of the most common brain disorders in the world [1]. As epileptogenic foci frequently involve or arise within close proximity to eloquent and motor brain areas, preservation of neurological function is a major concern for neurosurgeons. Motor-related cortex is one of the areas that, if removed, will result in loss of motor ability. The most common areas of eloquent cortex are in the left temporal and frontal lobes, if this area removed will result in loss of sensory processing or linguistic ability. The intraoperative asleep-awake-asleep (AAA) technique allows the operator to optimize the resection while preserving the patient's quality of life. However, in the AAA craniotomy, challenges present to the anesthesiologist in the form of providing suitable sedatives, analgesic depth, and stable hemodynamics along with providing secure airway management conditions. In addition, reducing the physiological and psychological distress of the patient, ensuring awakening patients timely for neurological testing remain concerns. Target-controlled infusion (TCI) is an emerging intravenous technique that has already been widely used in various types of surgery and has shown promising results. It can achieve a desired drug plasma or effect-site concentration using pharmacokinetic models incorporated into computerized pumps [2]. These continuously calculate the concentration of the drug in different compartments using individual covariates as the weight, gender, or age, and taking into account the distribution and elimination of the drug. In this way, these target-controlled infusion systems allow rapid establishment of a stable blood concentration of the drug, which the anesthesiologist can easily assess via the effect on different clinical measures. In a series of studies, TCI was associated with a faster recovery time, better hemodynamic stability, less drug consumption, and reduced relative risk of desaturation and PONV (postoperative nausea and vomiting) [3–5]. In this study, based on the promising potential of TCI stated above, we tested the hypothesis that TCI offers advantages over routine MCI. We highlight issues faced during the awake phase just like the time for awakening, bispectral index score (BIS) value, hemodynamic parameters, and occurrence of adverse events ultimately evaluated the feasibility and effectivity of TCI.

2.1. Patients' profile and study setting The Xuanwu Hospital Ethics Committee approved this study. Patients were explained the process of AAA epilepsy surgery and written informed consent. Between July 2011 and September 2013, this study enrolled 71 consecutive patients of American Society of Anesthesiology (ASA) class I to II, ranging in age from 18 to 60 years. Exclusion criteria were ASA N II, IQ b 80(Wechsler Adult Intelligence Scale, WAIS-RC), non-cooperators, emergency surgery, morbid obesity (BMI N 35 kg/m2), and gastroesophageal reflux. Different medicine doses and different procedures of airway, motor (TCI-M, MCI-M), and eloquent (TCI-E and MCI-E) groups were delineated from each other. Thirty-four cases presented with epileptogenic foci in eloquent brain areas, including 18 cases using the TCI technique and 16 cases using the MCI technique. For specific airway management, we used laryngeal mask airway (ATLAN; Royal Fornia Medical Equipment Co Ltd, ShenZhen, China). During the awakening phase for the procedures involving eloquent areas, the laryngeal mask airways (LMA) were removed at the beginning of the phase and then the LMA was reinserted before the closure of the dura and remained in place until the end of surgery. Thirty-seven cases presented with epileptogenic foci in motor brain areas, including 17 cases using the TCI technique and 20 cases using the MCI technique, in which there was no need to remove LMA during the awake phase due to the use of moving limbs to implement intra-operative cortical motor function mapping. Both the neurosurgeons and the anesthesiologists were experienced in AAA craniotomy and familiar with both techniques. Before giving the patients preoperative drugs, we measured each patient's heart rate and blood pressure to establish a baseline.

2.2. Anesthesia and surgical protocol Two peripheral intravenous catheters were placed in all patients before induction. Propofol and remifentanil infusion were used in all patients. Anesthesia and surgical protocol included 4 phases (Fig. 1).

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Fig. 1

Study design of AAA epilepsy surgery using TCI or MCI.

2.2.1. First phase (Induction phase) TCI group was induced using TCI propofol (Marsh Pk model; Silugao Science & Technology Co, Beijing, China) at a target plasma concentration of 3 μg ml− 1 and remifentanil (Minto Pk model; Silugao Science &Technology Co, Beijing, China) at a target plasma concentration of 4 ng ml− 1. To avoid hypnotic and narcotic over-shoot and hemodynamic instability, plasma concentration instead of an effect site concentration was used for target concentration. Two minutes after delivery of propofol and remifentanil, an injection of cis-atracurium 0.2 mg kg− 1 was given. The cisatracurium was injected only one time at induction time and not be given except the fourth phase. Four minutes after induction of anesthesia, we placed the LMA. The MCI group received intravenous induction with propofol 2 mg kg− 1, remifentanil 1 μg kg− 1, and cis-atracurium 0.2 mg kg− 1. After induction, airway was also secured using LMA. Mechanical ventilation was done with a tidal volume of 6 to 8 ml·kg− 1 to maintain end-tidal CO2 Pressure (PETCO2) at 36 to 38 mm Hg. We routinely gave tropisetron 2.5 to 5 mg to decrease the incidence of nausea and vomiting and penehyclidine 0.1-0.3 mg to reduce salivary and bronchial secretions. Dexmedetomidine simulates normal sleep and does not hamper the ventilatory drive [6]; if it used an adjunct can help lower the stress response to skull pin fixation and awake phase [7]. The lower range of dexmedetomidine dosing is advisable to provide optimal conditions for awake intraoperative mapping [8]. Hence, avoiding a loading dose, low infusion rates (0.1 μg kg−1·h−1), discontinuation before wake-up and functional testing are recommended [9,10]. Therefore, we adopted this recommendation of dexmedetomidine for all patients in all phases. There is evidence that the pharmacokinetic set developed in a European population for TCI dose not apply to Chinese patients, and predicted plasma and effect-site concentration of propofol and BIS value at LOC (loss of consciousness) in Chinese patients were lower than those in previously

published studies of white population [11]. Actually, no data were provided regarding how much plasma concentration (Cp) of propofol and remifentanil for Chinese patients to induce LOC at this surgery. So, in our preliminary 26 cases experiments (these data didn’t publish in this study), we found that the medicine are given using TCI as the dose recommended by other human race at other geographic location, the patients can not be awakening timely and cooperated properly. By preliminary experiments we found the optimal dose which got better response of Chinese patients, ultimately used it in this study. 2.2.2. Second phase (Craniotomy phase) TCI groups maintained with propofol 1 to 3 μg ml− 1 and remifentanil 2 to 4 ng ml− 1. MCI groups maintained with propofol 2 to 4 mg kg− 1 h− 1 and remifentanil 0.05-0.2 μg kg− 1 ·min− 1 . All 4 groups maintained without muscle relaxants. Local anesthetic (50:50 mixture of 1% lidocaine with 1:100,000 epinephrine; and 0.25% bupivacaine) infiltration was performed by a surgeon before application of the head frame at the pin and incision sites. 2.2.3. Third phase (Intraoperative awakening and awake phase) Ten minutes before wake-up, the medications were reduced as follows: in the TCI-E and TCI-M group, propofol adjusted to 0.5 to 1 μg ml− 1 and remifentanil adjusted to 1.5 to 2 ng ml− 1. In the MCI-M and MCI-E group, propofol adjusted to 1 to 2 mg kg− 1 h− 1, remifentanil to 0.05 to 0.1 μg kg− 1 min− 1. Dexmedetomidine 0.1 μg kg− 1 h− 1 was used in all four groups during this phase. Then, the patients were attempted to wake up when BIS value reached to 60 to 75 in the TCI-M and MCI-M groups, or BIS value reached to 70 to 95 in the TCI-E and MCI-E groups. We didn’t stop the medication and infused at lower dose continuously to make patients tolerate uncomfortable of the head frame, the pin and incision sites. The comfort of the patients during third phase

95 is essential for cooperation. In TCI-E and MCI-E group, sensory mapping is performed by evaluating sensations elicited by direct cortical stimulation. Language mapping involves application of an electrical stimulus to discreet areas of the cortex while the patient performs language tasks. The LMA removed for performing language tasks in the TCI-E and MCI-E groups during the awake phase. LMA removal was performed when the patient opened his eyes and had sufficient spontaneous breathing. In TCI-M and MCI-M group, motor mapping is performed by identifying phase reversal of sensory evoked potentials, by direct electrical stimulation of the cortex while observing motor or electromyographic responses, and by continuous motor task performance, just like squeeze hands and wiggle toes. We did not remove the LMA to reduce the risk of airway management for TCI-M and MCI-M groups. We use relatively more medicine to maintain the depth of anesthesia in order to overcome discomfort caused by the LMA keeping in the pharynx. Patients in all groups were kept awake throughout the awake phase allowing for modification of the resection of the epileptogenic foci. 2.2.4. Fourth phase (Closure phase) When the third phase was completed, the concentrations of propofol and remifentanil in four groups were both restored to their previous concentrations until the end of surgery. For the TCI-E and MCI-E groups, we needed to give muscle relaxants to complete secondary laryngeal mask insertion. In this phase the use of muscle relaxants is not limited in all groups. Big different dose of muscle relaxant during this phase will affect time of LMA removed at the finish of operation, but it is not our concern of this study. We close skull until complete all the parts of resection.

2.3. Routine monitoring, variables sources and measurements Times of awakening were measured from reduction of medications until achievement of a purposeful motor response (TCI-M, MCI-M group) or until achievement of a verbal response (TCI-E, MCI-E group). There are some standard to mark the moment that a patient was fully cooperative, just as squeeze hand, wiggle toes, solve an algebraic equation, and answer some question. Mean arterial pressure (MAP), heart rate (HR), respiratory rate, oxygen saturation (SPO2), and the BIS value were continuously monitored throughout the operation and recorded. PETCO2 was monitored excepted awake phase in eloquent patients. HR, MAP, BIS variables were measured and recorded after awakening at 1, 3, 5, 10, 15, 20, 30, 40, 50, and 60 min during the awake phase. The incidence of untoward events during the awake phases, such as hypertension (SBP N 180 mmHg or DBP N 110 mg), tachycardia (HR N 110), respiratory depression (SaO2b 90%), coughing, vomiting and seizures were recorded. Collection of the data was

assigned to a single physician and was conducted in a blinded fashion. Additionally, we evaluated the duration of the craniotomy, awake phase, operation, anesthesia, and LMA removal at the end of the operation. The time of awake phase was defined as the period from patient having reached motor or verbal response, until deepen anesthetic at the beginning of forth phase. The person noting this time blinded to the anesthetic technique.

2.4. Data analysis and statistical methods All data are presented as mean ± SD unless otherwise specified. Data processing and statistical analysis were performed with SPSS 16.0 software (Chicago, IL, USA). A P b .05 was considered statistically significant. Repeated measure analysis of variance data was used to analyze MAP, HR, and BIS values during the awake phase for all four groups, whereas the Specify Fisher`s least significant difference (LSD) was performed for multiple comparisons of the differences among these groups at one time point. Continuous independent data were compared with one-way analysis of variance. The Student-Newman-Keuls method was used for multiple comparisons among these groups. Categorical data were compared with the χ2 test.

3. Results 3.1. Participant characteristics and intraoperative data Baseline characteristics and demographics were comparable in four groups (Table 1). There were no significant differences regarding patients' age, gender, height, weight and BMI among the groups. The mean durations of craniotomy, anesthesia, operation, and LMA removal at the end of operation were comparable and are not statistically significantly different in any group. All patients remained awake and cooperative throughout the time of neurological testing. All of the routine intra-operative data are summarized in Table 1.

3.2. Times of awakening The awakening time required in the TCI-E group was significantly shorter than the MCI-E group (12.82 min ± 6.93 vs 29.9 min ± 9.04, P = .000). In the TCI-M group, the awakening time was 16.8 min ± 5.19, which was significantly shorter than the MCI-M group (30.91 min ± 15.32, P = .010). TCI may have essential role to decrease it to very short time. No significant difference was observed between the MCI-E and MCI-M groups (29.9 min ± 9.04 vs 30.91 min ± 15.32, P = .795). There is also no significant difference between the TCI-E and TCI-M groups (12.82 min ± 6.93 vs 16.8 min ± 5.19, P = .294) (Fig. 2).

96 Table 1

X. Wang et al. Demographic and intra-operative data. TCI-E group (n = 18) MCI-E group (n = 16) TCI-M group (n = 17) MCI-M group (n = 20)

Biometrical data Age (y) Sex (M/F) (%) Weight (kg) Height (cm) BMI (kg/m2) HR (b/min) Mean BP (mmHg) Time duration (min) Craniotomy Awake phase Operation Anesthesia LMA removal at end of operation

29.06±7.86 9/9 63.65±12.60 166.82±8.23 22.69±2.98 86.19±12.36 90.05±9.22

24.33±6.69 7/10 59.27±14.96 168±11.3 21.31±3.70 85.17±8.02 88.31±9.34

23.60±12.14 10/6 64.17±16.00 166.47±9.13 23.35±4.55 79.13±8.31 91.5±7.32

24±11.15 11/9 64.18±18.45 165.92±10.28 23.29±5.84 87.14±10.86 87.92±8.22

42±13.94 54.76±21.85 287.53±55.18 339.12±54.94 8.82±5.33

37.08±12.90 60.83±28.35 241.08±59.71 300.17±72.83 13.58±3.12

46.6±30.74 52.6±33.31 262.46±64.46 310.92±73.84 10.46±3.41

42.05±16.16 51.59±37.11 233.65±74.96 288.64±77.83 9.91±5.14

Data presented as the mean ± SD. ‡ P b .05 for group TCI-E vs group MCI-E; † P b .05 for group TCI-M vs group MCI-M. a P b .05 for group TCI-E vs group TCI-M; bP b .05 for group TCI-E vs group MCI-M; cP b .05 for group MCI-E vs group TCI-M; dP b .05 for group MCI-E vs group MCI-M.

3.3. BIS value and hemodynamic change The TCI-E group had the highest BIS values compared with other groups at 1, 5, 10, 15, 20, 30, 40, 50, and 60 min time points during the third phase (Fig. 3). The BIS values in the TCI-M group were significantly higher than the values in the MCI-M group at seven time points (Fig. 3). With respect to the baseline, no statistically significant difference in HR was detected amongst the four groups (Table 1); however, HR in the MCI-E group exhibited highest amongst the four groups suggesting impaired hemodynamic stability during the awake phase at 1, 15, 20, 30, 40, 50, and 60 min time points (Fig. 4). No differ in MAP baseline was apparent among four groups (Table 1). MAP was significantly lower in TCI-E than in MCI-E patients at 5, 10, 30, and 40 min time points during the awake phase (Fig. 5). There was no significant difference of MAP between TCI-M and MCI-M groups. The incident of hypertension was significantly lower in the TCI-E group than the MCI-E group (Fig. 5).

3.4. Incidence of adverse events The incidence of tachycardia was most frequent in the MCI-E group (52.9%, P = .001). Episodes of hypertension were also more common in the MCI-E group, but statistical significance was not attained (29.4%, P = .064). Due to mechanical ventilation, no cases of respiratory depression (the Sao2b 90%) were recorded in the TCI-M and MCI-M groups during the awake phase. Despite a higher incidence of temporary episodes of desaturation and hypoventilation in the TCI-E and MCI-E groups after LMA remove, no adverse clinical consequences were observed. Coughing, vomiting, and seizure were not statistically different amongst the

groups. Changes in SPO2, respiratory rate and PETCO2 were similar amongst the four groups throughout the study (PETCO2 were not monitored during autonomous respiration). The occurrence of all adverse events is depicted in Table 2.

4. Discussion Our data reflected that TCI significantly shortened awakening time intra-operation. As we observed, both the TCI-E group and TCI-M group had a statistically significant shorter awakening time than the MCI-E group and MCI-M group, respectively (Fig. 2). The TCI technique based on the pharmacokinetic (Pk) model for regulating the blood concentrations of propofol and remifentanil, allowing for rapid awakening to a level of consciousness where a response to commands can be accomplished [7,12,13]. Our data, in terms of speed of awakening from anesthesia, suggests that the TCI system could steer anesthesia better than MCI in AAA protocol for epilepsy surgery [13,14]. Furthermore, with the TCI system, the anesthesiologists adjust the blood or effect-site target concentration of the drug when needed [15], Then TCI system calculated and infuse the proper dose based on every individual. Thus, the TCI technique with propofol and remifentanil may be preferable to MCI when conducting AAA epilepsy surgery. Our study makes stable vital signs and comfort of the patients a precondition for adjusted propofol and remifentanil, eventually got the BIS value reached as high as possible during awakening and awake phase. Our data shows that the TCI-E group, compared with the other groups, had the highest BIS values during the third phase (Fig. 3), indicating

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Fig. 2 Awakening times of the four groups. Data presented as mean plus standard deviation.‡ P b .05 for group TCI-E vs group MCI-E; † P b .05 for group TCI-M vs group MCI-M; aP b .05 for group TCI-E vs group TCI-M; bP b .05 for group TCI-E vs group MCI-M; cP b .05 for group MCI-E vs group TCI-M; dP b .05 for group MCI-E vs group MCI-M.

Fig. 3 BIS values at subsequent time points in each group during the awake phase. #P b .05 for group TCI-E vs group MCI-E; * P b .05 for group TCI-M vs group MCI-M.

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Fig. 4 HR at subsequent time points in each group during the awake phase. # P b .05 for group TCI-E vs group MCI-E; * P b .05 for group TCI-M vs group MCI-M.

that patients of the TCI-E group may achieve the highest level of consciousness. Furthermore, BIS values in the TCI-M group were significantly higher than in the MCI-M group during the third phase (Fig. 3). BIS values correlate significantly with the patient's level of consciousness [6,16,17], and objectively assesses not only the depth of general anesthesia but also sedation [18–20]. The return of BIS to the pre-induction values during the third phase appeared to indicate full recovery of consciousness, thereby allowing reliable language and motor response testing [21,22]. Thus, in terms of BIS values, our results indicate that the TCI technique provided more effective awake states than the MCI technique during AAA procedures in epilepsy surgery. Our findings demonstrated that the hemodynamic profile was different amongst the four groups; in particular the MAP and HR were highest in the MCI-E group (Figs. 4 and 5). Furthermore, hemodynamic fluctuation occurred significantly less in TCI-E and TCI-M groups during the awake phase. One potential explanation is that the stable medication plasma concentration in TCI-E and TCI-M groups could have prevented the MAP and HR surge. Thus, as shown by our results, the different methods of delivery for AAA anesthesia, TCI or MCI, may induce profound alterations to

the hemodynamic state of patients. In previous studies, it is a common observation that patients undergoing TCI demonstrated better control of HR and blood pressure than patients receiving MCI [23,24], and it is an observation that the results concur with our current study. Furthermore, in our study, HR in the TCI-M and MCI-M groups only fluctuate slightly and both groups have minimal hemodynamic disturbances during the third phase (Figs. 4 and 5). It is conceivable that there are at least 2 possible reasons causing this phenomenon: one, hemodynamic effects of mechanical ventilation in the TCI-M and MCI-M groups, with a decrease in venous return and an increase in right ventricular outflow impedance, may lead to a relatively low MAP value. Another, it is possible that motor area epilepsy in TCI-M and MCI-M groups need deeper anesthetics than TCI-E and MCI-E groups for tolerant LMA keeping, meanwhile the deeper anesthesia make hemodynamic stability is easier to maintain and tachycardia and hypertension occur less. Hypertension and tachycardia were most frequent in the MCI-E group than any other group (Table 2), which indirectly reflects a high stress response in that group. Thus, we can infer that, to achieve an acceptable level of consciousness in patients to permit surgery, the patient

Fig. 5 MAP at subsequent time points in each group during the awake phase. #P b .05 for group TCI-E vs group MCI-E; *P b .05 for group TCI-M vs group MCI-M.

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Adverse events during the awake phase.

Respiratory depression (SaO2b 90%), No. (%) Hypertension, No. (%) Tachycardia, No. (%) Cough, No. (%) Vomiting, No. (%) Seizures, No. (%)

TCI-E group (n = 18)

MCI-E group (n = 16)

TCI-M group (n = 17)

MCI-M group (n = 20)

P value

4 (22.2) a,b 1 (5.6) 3 (16.7) 0 (0) 0 (0) 1 (5.6)

4 (23.5) c,d 5 (29.4) 9 (52.9)‡, c,d 1 (5.9) 1 (5.9) 3 (17.6)

0 1 1 2 0 3

0 (0) 1 (5.0) 2 (10.0) 3 (15.0) 1 (5.0) 4 (20)

0.027 0.064 0.001 0.361 0.595 0.608

(0) (6.3) (6.3) (12.5) (0) (18.8)

Respiratory depression (SaO2b 90%); hypertension (SBP N 180 mmHg or DBP N 110 mg); Tachycardia (HR N 110). ‡ Pb .05 for group TCI-E vs group MCI-E; † P b .05 for group TCI-M vs group MCI-M. a P b .05 for group TCI-E vs group TCI-M. b P b .05 for group TCI-E vs group MCI-M. c P b .05 for group MCI-E vs group TCI-M. d P b .05 for group MCI-E vs group MCI-M.

undergoing the higher stress response in MCI-E and MCI-M groups than TCI-E and TCI-M groups respectively. It should be expected that respiratory events would be more frequent both in TCI-E and MCI-E groups compared with TCI-M and MCI-M. In conjunction, patients using controlled air ways (TCI-M and MCI-M groups) had lower respiratory depression, which coincides with Skucas et al's result [21]. Regarding this issue, In TCI-E and MCI-E groups, as would be expected in a population of sedated patients breathing spontaneously and patients had no ventilatory support during the awake phase. No differ exist between TCI-E and MCI-E groups. Additionally, coughing, vomiting, and seizures were relatively rare in all groups, and were not significantly different among the four groups (Table 2). Only 6 patients amongst all of the groups experienced coughing during the awakening period, 3 of which had a history of tobacco use (1 in the MCI-E group and 2 in the MCI-M group). Those 3 patients experienced large amounts of secretion in their airway during the LMA removal time following the operation. Vomiting was uncommon in all 4 groups due to the use of prophylactic tropisetron. Seizures occurred when a surgery required a certain frequency and intensity stimulation to further determine the resection area, but the rate of occurrence is no different among the 4 groups. In other studies, when comparing TCI and MCI during elective otorhinolaryngology performed under general anesthesia with spontaneous ventilation, the TCI group presented with fewer movements at insertion of the laryngoscope, improved hemodynamic stability, fewer episodes of apnea, reduced respiratory acidosis after endoscopy, and a shorter recovery time (time to opening eyes or verbal response) [25,26]. That was coincident with our study.

5. Limitation Our study is a prospective randomized design for comparison TCI and MCI advantage issues. We did not discuss the amount of the medicine, although it may help us

explore the results. In the fourth phase of this study, the dosage of muscle relaxants is not limited and a large number of muscle relaxants will impact on the need of propofol and remifentanil dose. Therefore, the discussion based on the total amount will be misleading. In addition, medication dose has a close relation to the difference of human race, and variability in drug responses could result from both genetic and environmental factors [27]. The impact of racial and genetic differences in the population studied was not accounted for in this study. In conclusion, TCI promoted quicker recovery from sedation, and reached the satisfactory awake state accompanied with higher BIS values. TCI achieved a less disturbed condition of hemodynamics and respiration than MCI. There are more advantages than MCI and suggested that TCI is a useful tool for the patients undergoing AAA epilepsy surgery.

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