|Year : 2016 | Volume
| Issue : 4 | Page : 177-185
Bispectral index-guided fast track anesthesia by sevoflurane infusion combined with dexmedetomidine for intracranial aneurysm embolization: study protocol for a multi-center parallel randomized controlled trial
Chao-liang Tang1, Juan Li2, Bo Zhao3, Zhong-yuan Xia3
1 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province; Department of Anesthesiology, Southern Branch of Anhui Provincial Hospital, Hefei, Anhui Province, China
2 Department of Anesthesiology, Southern Branch of Anhui Provincial Hospital, Hefei, Anhui Province, China
3 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
|Date of Web Publication||7-Nov-2016|
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province
Source of Support: This study was supported by the National Natural Science Foundation of China (No. 81471844 and 81671891)., Conflict of Interest: None
Background: After intracranial aneurysm embolization, rapid recovery from general anesthesia is necessary for timely monitoring of adverse events. Fast-track anesthesia using a balanced technique or combination of drugs at their minimum required dosages is preferred for these neurosurgical patients. However, fast-track anesthesia is still limited by a lack of standardization and quality control standards.
Methods/Design: A multi-center, parallel, randomized controlled clinical trial will be conducted at Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China. One hundred and twenty patients with intracranial aneurysm will be randomly assigned to a normal saline group and a dexmedetomidine group. General anesthesia will be induced intravenously with propofol. Additionally, either 1.0 μg/kg dexmedetomidine or normal saline will be delivered completely within 10 minutes before anesthesia induction. Once anesthesia has begun, dexmedetomidine (0.3 μg/kg per hour) or normal saline will be continuously infused. Intraoperatively, anesthesia will be maintained with 2-3% sevoflurane. Primary outcomes will be anesthesia time, operative time, time from the end of anesthesia until recovering spontaneous breathing, time until eye opening on command, and time until orientation to time and place. Secondary outcomes will be dose of sevoflurane, Visual Analogue Scale score, and bispectral index.
Discussion: In this trial, we will assess the clinical efficacy of sevoflurane anesthesia with dexmedetomidine as a fast track anesthesia for intracranial aneurysm embolization.
Trial registration: This protocol was registered at Chinese Clinical Trial Registry (identifier: ChiCTR-IPR-16008113) on 17 March 2016.
Ethics: Written approval for this trial has been obtained from the Ethics Committee of the Anhui Provincial Hospital of China (approval No. 2015-31). This study will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Prior to the trial, participants and their family members will be informed of the risks and benefits of this trial. Written informed consent will be obtained from each participant.
Keywords: clinical trials; bispectral index; dexmedetomidine; sevoflurane; fast-track anesthesia; intracranial aneurysm embolization; multicenter, parallel, randomized, controlled clinical trials
|How to cite this article:|
Tang Cl, Li J, Zhao B, Xia Zy. Bispectral index-guided fast track anesthesia by sevoflurane infusion combined with dexmedetomidine for intracranial aneurysm embolization: study protocol for a multi-center parallel randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:177-85
|How to cite this URL:|
Tang Cl, Li J, Zhao B, Xia Zy. Bispectral index-guided fast track anesthesia by sevoflurane infusion combined with dexmedetomidine for intracranial aneurysm embolization: study protocol for a multi-center parallel randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2020 Jul 12];1:177-85. Available from: http://www.actnjournal.com/text.asp?2016/1/4/177/193145
| Background|| |
An intracranial aneurysm is a local bulge or ballooning of an arterial wall in the brain that forms under arterial partial pressure to thin arteries in the brain. When an intracranial aneurysm ruptures, the result is a subarachnoid hemorrhage or intraparenchymal hemorrhage, accompanied by severe headache, vomiting, different levels of consciousness (Brisman et al., 2006).
Although surgical clipping was the first treatment introduced for intracranial aneurysms, in recent years, evidence has shown that interventional embolization is more effective (Brilstra et al., 1999; Raja et al., 2008). To embolize an intracranial aneurysm, a detachable balloon or a special electrolysis-spring microcatheter is inserted into the aneurysm (Xu, 2000). It is a highly promising method, characterized by not needing a craniotomy, and causing less trauma and less bleeding than currently available methods (Bai and Yang, 2007). However, during intracranial aneurysm embolization, elevated blood pressure or excessively decreased intracranial pressure that results from anesthesia can increase transmural pressure and stress to the blood vessel wall, increasing the risk of aneurysm rupture. Given this, careful selection of the anesthetic agent and anesthetic method is preferred.
Fast-track anesthetic techniques contribute to a rapid recovery from general anesthesia, which is important for timely processing of adverse events in patients (Ali Hassan, 2015; Aniskevich and Pai, 2015). Despite the usefulness of these fast-track techniques, uniform standards for them are lacking. Fast-track anesthesia can be achieved using a balanced anesthesia technique and a combination of drugs given at the minimum dosage required to obtain the best effect. Because of the low demand for muscular relaxation, fast-track anesthesia is preferred for intracranial aneurysm embolization.
Sevoflurane is a commonly used anesthetic drug for aneurysm embolization. As a new, safe, and effective inhalable anesthetic, sevoflurane is characterized by rapid absorption/discharge and good controllability (Sakai et al., 2005), along with neuroprotective effects such as reducing brain metabolic rate and having little effect on cerebral blood flow. However, sevoflurane can also elevate intracranial pressure (Holmström and Akeson, 2004) and trigger respiratory depression (Doi and Ikeda, 1987). Therefore, a low dose of sevoflurane can be used to reduce the likelihood of adverse reactions during an aneurysm embolization surgery.
Dexmedetomidine (DEX) is a novel, highly selective adrenoceptor agonist (Cormack et al., 2005) that produces dose-dependent sedative, anxiolytic, and analgesic effects, and also has anti-sympathetic and anti-shivering properties (Yuen et al., 2007). It exhibits mild effects on respiratory depression, strong intrinsic activity, has a short elimination half-life, and is non-addictive. Thus, DEX can be used for semi-arousable sedation and cooperative sedation, acting as an auxiliary analgesic to enhance sedative and analgesic effects, maintain hemodynamic stability, and reduce the necessary analgesic dosage of other analgesic agents (Paris and Tonner, 2005; Giovannitti et al., 2015). While DEX effects have been retrospectively examined in many studies ([Table 1]), its clinical applications as an auxiliary analgesic for sevoflurane anesthesia in intracranial aneurysm embolization have not been adequately investigated in prospective, parallel, randomized controlled trials. By retrieving ClinicalTrial.gov and Chinese Clinical Trial Register, we found that several study protocols are ongoing for prospective parallel randomized controlled trials using sevoflurane anesthesia combined with DEX in intracranial aneurysm embolization ([Table 2]).
|Table 1: International studies about dexmedetomidine (DEX) as an auxiliary analgesic|
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|Table 2: Clinical trials using dexmedetomidine (DEX) as an adjunct to sevoflurane anesthesia in intracranial aneurysm embolization that are registered in ClinicalTrial.gov or the Chinese Clinical Trial Register|
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Here, a randomized controlled clinical trial is designed to explore the use of rapid-track anesthesia with DEX combined with sevoflurane in intracranial aneurysm embolization by monitoring the bispectral index (BIS). We will attempt to realize a balanced anesthesia and rapid recovery in neurosurgical patients, which should help surgeons to treat adverse events in a timely manner.
| Methods/Design|| |
This will be a multi-center, parallel, randomized controlled trial, which will be conducted at Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China. One hundred and twenty patients with intracranial aneurysm will be enrolled and randomly assigned to either a normal saline group or a DEX group (n = 60 per group). While monitoring the BIS, patients will be given intravenous infusion of 1.0 μg/kg DEX or normal saline for at least 10 minutes before anesthesia induction via propofol (see below), followed by continuous infusion of DEX (0.3 μg/kg per hour) or normal saline once anesthesia has been induced. Intraoperatively, anesthesia will be maintained with 2-3% sevoflurane in both groups.
BIS is mainly used to monitor the depth of anesthesia. BIS values have been shown to be highly associated with sedation, consciousness, and memory. The BIS index is a useful tool for monitoring normal physiological sleep and sedative components at different anesthetic depths (Bresil et al., 2013; Kim et al., 2014). The use of BIS monitoring helps to determine anesthesia depth, adjust amount of anesthetic agents administered, and reduce recovery time from general anesthesia (Bresil et al., 2013; Kim et al., 2014). Data from BIS monitoring will thus improve the anesthetic effect of DEX infusion combined with sevoflurane in patients undergoing intracranial aneurysm embolization.
Anesthetic effects, postoperative recovery times from anesthesia, sevoflurane dosages, Ramsay Sedation Scale (RSS) scores, Visual Analogue Scale (VAS) scores, and BIS values will be compared between the two groups. Additionally, changes in physiological indicators and incidence of adverse events will be recorded. A flow chart of the trial protocol is shown in [Figure 1].
|Figure 1: Flow chart of the trial.|
Note: T0: At baseline; T1: before induction of anesthesia; T2: before insertion of laryngeal mask airway (LMA); T3: immediately after LMA insertion; T4: immediately after femoral artery catheterization; T5: at the moment of aneurysm embolization; T6: immediately after surgery; T7: at the moment of LMA removal; T8: 10 minutes after LMA removal; T9: 1 hour after surgery. DEX: Dexmedetomidine; BIS: bispectral index; VAS: Visual Analogue Scale.
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Patients undergoing intracranial aneurysm embolization will be recruited from Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China.
Patients must meet all the criteria below for recruitment in the trial:
- Diagnosed with intracranial aneurysm as shown by computed tomographic angiography/digital subtraction angiography
- Eligible for interventional therapy
- 18-70 years of age
- American Society of Anesthesiologists (ASA) physical status classification, grade I-IV (Fitz-Henry, 2011)
Patients will be excluded from the trial if they meet any of the following criteria:
- Coagulation dysfunction
- Have previous history of drug allergy to DEX and sevoflurane
- Severe hypertension and cardiovascular disease
- Liver or kidney dysfunction
- Use of sedatives within 2 days before surgery
- Sinus bradycardia
Time from the end of anesthesia until spontaneous breathing recovery will be recorded as main outcome measure for sample size calculation. As previously reported (Gu et al., 2013; Xu et al., 2013; Huang and Jiao, 2015), the time of recovering spontaneous breathing from sevoflurane anesthesia alone is about 6.5 minutes, while the recovery time from sevoflurane anesthesia with DEX infusion is expected to drop to 5.0 minutes, with a standard deviation of 2.3. If α = 0.05 and 1 - β = 0.9, (where tα and tβ are the values corresponding to α and β, respectively; s is overall standard deviation for the two estimates; and δ is the mean difference in the two groups). Given a dropout rate of 20%, at least 50 patients will be needed per group. Funding for this trial allows us to recruit 60 patients per group.
Ongoing recruitment of patients will be carried out by attending physicians at Anhui Provincial Hospital and Renmin Hospital of Wuhan University. After written informed consent is given, patients will be screened using the inclusion and exclusion criteria.
One hundred and twenty patients will be randomly numbered by statisticians according to the date of hospitalization, and will be evenly divided into a normal saline group (sevoflurane anesthesia with normal saline) and a DEX group (sevoflurane anesthesia with DEX). Evaluators will be unaware of study allocation.
1.0 μg/kg DEX (Sichuan Guorui Pharmaceutical Co., Ltd., Leshan, Sichuan Province, China) will be formulated by 0.9% normal saline into 4 μg/mL, and infused intravenously within 10 minutes before anesthesia induction. Then, anesthesia will be maintained by continuous infusion of 0.166 mL/kg/h (0.3 μg/kg/h).
Normal saline group
Patients will be given intravenous infusion of 0.9% normal saline for 10 minutes before anesthesia induction, followed by continuous infusion of 0.9% sodium chloride at a flow rate of 0.166 mL/kg/h.
Intracranial aneurysm embolization
- Induction of anesthesia: patients will be intravenously given 1.5-2 mg/kg propofol (AstraZeneca, Italy) and 0.1-0.15 mg/kg cisatracurium (Shanghai Hengrui Pharmaceutical Co., Ltd.). After induction, an I-gel laryngeal mask airway (LMA) (Intersurgical Ltd., Wokingham, Berkshire, UK) will be inserted. LMA size will be determined according to patient weight: size # 3 for weights of 30-60 kg and #4 for weights of 50-90 kg. Successful LMA insertion will be defined as proper movement of the chest, a smooth end-tidal CO 2 tension wave without air leakage at an airway pressure > 20 cmH 2 O. Then, a gastric tube will be inserted via the LMA and connected to a Datex-Ohmeda S/5 Avance Anesthesia Machine (Datex-Ohmeda Inc., Madison, WI, USA) followed by mechanical ventilation at a capacity control mode (tidal volume: 6-8 mL/kg; frequency: 10-12 times/min). Intraoperative end-tidal CO 2 level will be set to a normal range of 35-45 mmHg.
- Maintenance of anesthesia: Intraoperative anesthesia will be maintained with 2-3% sevoflurane inhalation (Maruishi Pharmaceutical Co., Ltd., Osaka, Japan).
- Endovascular coiling of the aneurysm: Surgical treatment of aneurysm by endovascular coiling in all enrolled patients will be completed by the same surgeon. Using the Seldinger technique, a catheter will be inserted into the right femoral artery via a 6-ft-long braided introducer sheath and passed through the blood vessels into the aneurysm. A guglielmi detachable coil (ev 3 Inc., Plymouth, MN, USA) will be inserted via the catheter, aided by cerebral angiography. The coil will be packed into the aneurysm to initiate a thrombotic reaction and block normal blood flow in the aneurysm. If successful, the sheath will be removed and a pressure bandage will be applied at the puncture site.
- Recovery from anesthesia: The evaporator will be closed at about 10 minutes before the end of surgery, and the flow rate of fresh gas will be reduced to 0.3-0.5 L/min. When the surgeon sutures the femoral artery using a vascular closure device (Abbott, Santa Clara, CA, USA), the flow rate of fresh gas will be increased to 4 L/min and anesthesia will be terminated.
- Postoperative management: Patients will be given routine treatments including lowering intracranial pressure, dehydration, and continuous intravenous infusion of 0.15% nimodipine (Bayer, Leverkusen, Germany) to prevent cerebral vasospasm.
Primary outcomes will include anesthesia time, operative time, time from the end of anesthesia until recovering spontaneous breathing, time until eye opening on command, and time until the patient is oriented to time and place.
- Dose of sevoflurane: The total amount of sevoflurane that is used during anesthesia maintenance will be recorded when the LMA is removed.
- RSS score: RSS scores will be determined at baseline and 1 hour after aneurysm coiling. RSSis a traditional method to assess the level of sedation at six different levels (Kress and Hall, 2006). Higher levels indicate greater sedation.
- VAS score: VAS scores for pain will be assessed at baseline and 1 hour after aneurysm coiling. The VAS is a scale to measure subjective sensations that has few influencing factors, and is widely used in clinical and basic research (Collins et al., 1997). When responding to a VAS item, a pastient will specify the level of pain by marking a point along a 100-mm horizontal line between two end-points that represent no pain and severest pain, respectively. A lower score indicates greater anesthesia.
- BIS value: BIS is a simple quantitative index that indicates whether the cerebral cortex is excited or depressed (Mitchell-Hines et al., 2016). The BIS value varies depending on sedation, consciousness, and memory. It is a preferred tool for monitoring sedative components at different anesthetic depths. It has a range from 0 to 100 (0, coma; 40-65, general anesthesia; 65-85, sedated state; 100, awake). If < 40, the patient is likely to present with outburst inhibition (Recart et al., 2003; Punjasawadwong et al., 2007).
In this trial, the following additional outcomes will be recorded: physiological indexes including systolic blood pressure, diastolic blood pressure, and heart rate at different stages of anesthesia, blood biochemical parameters including levels of venous blood glucose, plasma neuron-specific enolase, S100β, interleukin-1β, 6, 8, and 10, tumor necrosis factor α, malondialdehyde, and superoxide dismutase before and after anesthesia. We will also record incidences of adverse events when inserting or removing the LMA, such as cough, restlessness, and chills.
Baseline data of patients will be listed in [Table 3].
Flowchart of the trial process is shown in [Table 4].
Data collection, management, analysis, and open access
- Data collection: All data from patients will be collected on paper and electronic case report forms. Only the persons who have permission will have the right to query the ResMan database for data entry, modification, and access. Others will be not allowed to query the database or access any clinical data. These measures will ensure the safety and confidentiality of the database.
- Data management: whenever any changes or corrections in the paper case-report form are recorded, the original records should be clearly retained. Additionally, the date of change/correction, signature, and a reason should be noted. Any data entry, including alterations, deletions, and additions, will be recorded by an electronic data capture system beginning at the first data entry. Track inspectors should be set to be protected by this system, and no artificial modification or editing will be allowed. Complete rights management must be established for the ResMan database, and only authorized personnel will be allowed to query the database.
- Data analysis: All data will be statistically analyzed by professional statisticians. An independent data monitoring committee will be responsible for data monitoring and management throughout the entire trial to ensure scientific accuracy, stringency, authenticity, and integrity.
- Open data: Anonymized published data will be released at http://www.figshare.com .
All data will be statistically analyzed by statisticians using the SPSS 23.0 statistical software package (IBM Corp., Armonk, NY, USA) in line with the intention-to-treat principle. All measurement indexes will be expressed as the mean ± SD, except for incidence of adverse events, followed by a normal distribution analysis. Normally distributed data will be compared using independent samples t-test, and non-normally distributed data compared using the Wilcoxon test. Chi-squared tests will be used to compare incidences of adverse events between groups. A value of P < 0.05 will be considered statistically significant.
During the trial, all serious adverse events will be recorded in detail, including the date of occurrence, type of event, onset duration, symptoms, time of drug withdrawal, treatments, and outcomes, all of which will be reported to the responsible department, bid unit, ethics committee, drug regulatory department, and any other relevant administrative departments within 24 hours. Once any adverse events occur, the patient will be given corresponding therapeutic measures and drugs will be withdrawn in a timely manner.
Trial progress will be reported to the ethics committee of Anhui Provincial Hospital and Renmin Hospital of Wuhan University every 6 months or every year. Between reports, relevant data will be updated in the registration database.
The research group and the medical institution to which it belongs will have the right to use all data from the trial without compensation. Patient information will be encrypted and stored by the Anhui Provincial Hospital and Renmin Hospital of Wuhan University. Ethics committee of the Anhui Provincial Hospital and Renmin Hospital of Wuhan University, drug regulatory department, and trial executors will have free access to patient information, but will not be allowed to disclose these data. Unless required by law, patient identity will not be disclosed. Findings of this trial will be published without revealing the identity of patients.
All research data related to this clinical trial will belong to the Anhui Provincial Hospital.
| Trial status|| |
Recruiting at the time of submission.
| Discussion|| |
During intracranial aneurysm embolization, the anesthesiologist should help the patient maintain an appropriate level of sedation and analgesia, ensuring stable vital signs and systemic heparin administration. For an anesthesiologist, understanding all the risks and hazards of an intracranial aneurysm that can occur at different points in the procedure and maintaining close cooperation with the surgeon responsible for neurovascular intervention comprise the basis of intraoperative management. The purpose of this management is to prevent potentially fatal ischemia and bleeding. A rapid recovery from anesthesia assists the surgeon because the nervous system function can be assessed as early as possible.
DEX as an adjunct drug for general anesthesia and sedation can shorten the time until awakening and extubation, stabilize hemodynamic parameters, and reduce adverse events. Thus, DEX is currently a well-regarded and popular drug. As previously reported (Gu et al., 2013; Xu et al., 2013; Huang and Jiao, 2015), this trial will use DEX as an anesthetic supplement to sevoflurane anesthesia in patients undergoing endovascular aneurysm coiling. The authors will provide objective evaluation of DEX anesthesia. However, because of differences in the etiology, disease course, and sex of the patients recruited in the trial, future research will need to focus on these potential confounding factors.
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
CLT and ZYX designed this trial protocol; and JL and BZ will collect data. All authors read and approved the final version of this manuscript for publication.
This manuscript was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
[Table 1], [Table 2], [Table 3], [Table 4]