Use of low-dose dexmedetomidine in general anesthesia improves postoperative recovery of patients with supratentorial tumors: study protocol for a randomized controlled trial

Yue Yun, Ling Pei＊

First Hospital of China Medical University, Shenyang, Liaoning Province, China

Background

Rapid awakening, a stable blood pressure and heart rate,absent or mild pain, and tolerance of endotracheal intubation can avoid the increased intracranial pressure, elevated blood pressure, and rapid heart rate caused by choking,suffocation, and agitation and can reduce postoperative cerebral edema and the risk of bleeding. Additionally,excellent recovery from anesthesia allows surgeons to evaluate postoperative patients’ neurologic function in a timely manner (Ren et al., 2015a). Many techniques and drugs have been used to improve the quality of the recovery period, but each has flaws. Dexmedetomidine (Dex) is an emerging anesthetic adjuvant characterized by a stable hemodynamic recovery period, and neither its sedative nor analgesic effects influence the evaluation of neurological function. Therefore, use of this drug can help surgeons to evaluate patients’ neurologic function in the early stage after surgery (Al-Zaben et al., 2015; Sokhal et al., 2015;Volkov et al., 2015).

Dex is a central α2-adrenoceptor agonist with the chemical name (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole. It has a structure and pharmacological activity similar to those of clonidine. Both Dex and clonidine are α2-adrenoceptor agonists, but Dex is 10-fold more effective than clonidine(Li et al., 2015). Dex was initially developed as a blood pressure-lowering agent and, similarly to clonidine, can lower both the blood pressure and heart rate. It also has a strong anesthetic effect (Man et al., 2015). Dex is currently used for systemic anesthesia, anesthetic monitoring, and conscious sedation in intensive care settings. Dex has sedative, sleep-producing, analgesic, and anxiolytic properties,and it is superior to other sedative drugs because it induces cooperative sedation and no respiratory depression (John et al., 2015).

When perceiving a nociceptive stimulus, the body produces stress responses characterized by an increased heart rate and blood pressure (Song et al., 2015). Dex can, to a large extent, inhibit the stress responses of the cardiovascular system caused by tracheal intubation and extubation and improve the outcomes of tracheal intubation and extubation(Sun et al., 2012). General anesthetics should make patients lose consciousness, prevent them from perceiving pain,and inhibit harmful stimulus-induced intraoperative stress responses such as hypertension and tachycardia (Ren et al.,2015b). Therefore, one of main responsibilities of anesthetic physicians is to maintain stable cardiovascular functions in their patients (Bakri et al., 2015).

The most common methods used to control excessive stress responses are to increase the concentration of inhaled anesthetics and increase the dose of opioid medications.There is evidence that Dex for general anesthesia can greatly lower tracheal intubation-induced cardiovascular stress responses (Wu et al., 2007; Ulsal et al., 2012). The clinically recommended loading dose of Dex is 1.0 µg/kg, the time to onset is appropriately 15 minutes, and the elimination half-life is appropriately 2 hours (Gerlach et al., 2009).However, an excessively high one-time dose or too-rapid infusion of Dex likely lowers the heart rate and blood pressure. Therefore, we hypothesize that intravenous bolus injections of low-dose (0.4 µg/kg) Dex during anesthesia within minutes before the end of surgery in patients undergoing craniotomy can improve the quality of recovery from general anesthesia and thereby benefit the evaluation of early-stage neurological function after surgery.

Methods/design

Study design

A randomized controlled trial.

Study setting

This study is being conducted at the Department of Neurosurgery, First Hospital of China Medical University,China.

Study participants

Patients with supratentorial tumors who undergo craniotomy under general anesthesia from December 2013 to December 2014 at the Department of Neurosurgery, First Affiliated Hospital of China Medical University, China and who fulfill the following criteria are eligible.

Inclusion criteria

● American Society of Anesthesiologists class I or II (Rao et al., 2015)

● Age of 35–65 years

● Either gender

● Preoperative magnetic resonance imaging diagnosis of a supratentorial space-occupying lesion (glioma, meningioma, or neurofibroma) and tumor diameter of ≤ 40 mm.

● Full Glasgow coma score (Hassani et al., 2015)

● Estimated operation time of ≤ 6 hours and anesthesia time of ≤ 8 hours

● Written informed consent to undergo the therapeutic regimen

Exclusion criteria

● Participation in other clinical trials within 4 weeks beforethe present trial

● Current or past therapy with a β-receptor blocker (metoprolol) within 2 weeks before the beginning of the present trial

● A history of two or more craniotomies

● A history of heart disease (complicated by sinus bradycardia [preoperative heart rate of ≤ 50 beats/min by electrocardiography), sick sinus syndrome, myocardial infarction, grade ≥ II cardiac function) and severe hypertension (systolic blood pressure of ≥ 180 mmHg or diastolic blood pressure of ≥ 110 mmHg)

● A history of lung disease (blood oxygen content of ＜ 95%when breathing air in an awake state)

● A history of liver dysfunction (≥ 1.5 times the normal value)

● A history of kidney dysfunction (serum creatinine and blood urea nitrogen levels outside the normal range),hypersensitive (allergic) to Dex, tolerant to Dex, drug and/or alcohol abuse

● Body weight beyond ± 15% of the standard body weight range (standard body weight (kg) = body height (cm) −100)

● Pregnant or lactating women

Rejection criteria

● Lack of compliance with study protocol after recruitment

● Absence of normal medical records

● Suspected postoperative intracranial hemorrhage

Table 1: Trial outcome measurement schedule

Figure 1: Trial protocol flow chart.

● Surgery time of ＞ 6 hours, anesthesia time of ＞ 8 hours

● Perioperative blood loss of ＞ 1,500 mL

Withdrawal criteria

Study termination by researchers from a medical perspective or by the patient himself or herself.

Intervention measures

Randomization procedureThe subjects are allocated into groups using a computerbased simple randomization method, then randomly coded and provided with a corresponding emergency envelope.Blind codes are preserved by the drug administer. The subjects are randomly assigned to three groups (n = 50) and receive 0.4 or 0.8 µg/kg of Dex (200 µg per 2 mL ampoule;Chinese medicine permission No. H20090248; Jiangsu Hengrui Medicine Co., Ltd., China) (low-dose and middledose Dex groups) or an equal dose of physiological saline(100 mL/bag; control group) via intravenous administration.All drugs are diluted with physiological saline to 20 mL and infused within 20 minutes through the use of an injection pump. The researchers performing the experiments or measuring the results and all of the patients are blinded to the group assignments to avoid measurement bias.

Drug preparation and administration

Drugs/placebos are provided by Central Pharmacy, First Hospital of China Medical University, China. Pharmacists prepare the drugs according to the assigned group and planned protocol as follows: 2 mL of 100 µg/mL Dex stock solutions are added to 98 mL of physiological saline to prepare 2 µg/mL Dex. Drugs at the doses required according to the patient’s body weight (kg) and grouping are diluted with physiological saline to 20 mL for use. For patients in the control group, 20 mL of physiological saline is used. All drugs or physiological saline are infused at the speed of 2 mL/min within 10 minutes. The injectors are then tagged based on the patient’s code and preserved by the drug administrators for use.

Outcome measures

Primary outcomes

● The end of anesthesia: Awakening time (from the end of surgery to eye opening in response to voices), spontaneous breathing recovery time (from the end of surgery to recovery of spontaneous breathing), extubation time(from the end of surgery to extubation)

● Cough assessment at tracheal extubation (using a 4-point subjective scale (Andrzejowski and Francis, 2002)

● Degree of sedation [Richmond Agitation-Sedation Scale(RASS) is used for sedation assessment, with a score range of −5 (no response to voice or physical stimulation)to +4 (overtly combative or violent; immediate danger to staff] (Kim et al., 2015)

● A verbal numerical rating scale (VNRS) was used for assessment of pain intensity (PI) after extubation: 0, no pain;1–3, mild pain; 4–6, moderate pain; and 7–10, severe pain

Secondary outcomes

● Postoperative hemodynamic indices, including blood pressure (systolic blood pressure, diastolic blood pressure, and mean arterial pressure), heart rate, and blood oxygen content

● Sedative effectives [Verbal Numerical Rating Scale(VNRS) with a score range of 0 to 10 is used for assessment of pain intensity (Kim et al., 2012)]

● Anesthesia time (from anesthesia induction to termination of anesthetic infusion); and operative time (from skin incision to the end of suturing)

The above indices are recorded by the PACU nurses, who are blinded to the study protocol and group assignments. The trial outcome measurement schedule is shown in Table 1.

A trial protocol flow chart is shown in Figure 1.

Management of anesthetic complications

When the mean arterial pressure is ＞ 90 mmHg (1 mmHg= 0.133 kPa) during maintenance of anesthesia, the dose of anesthetic drugs is increased; i.e., the inhalation concentration of sevoflurane, propofol infusion dose, and/or remifentanil infusion dose is increased. If the effect is still not satisfactory, a single dose of nicardipine (0.5–1.0 mg)is intravenously infused. When the mean arterial pressure is ＜ 60 mmHg, a single intravenous injection of ephedrine(5–10 mg) is added; the mean arterial pressure can also be adjusted by fluid replacement and reduction of the anesthetic doses (such as the inhalation concentration of sevoflurane, propofol infusion dose, and/or remifentanil infusion dose). If the effect is still not satisfactory, continuous infusion of 2% norepinephrine is recommended to maintain blood pressure within the target range. When the heart rate is ＞ 90 beats/min or ST-T segment abnormalities on electrocardiogram appeared during maintenance of anesthesia, a single dose of 5 to 10 mg of esmolol is given intravenously; meanwhile, fluid replacement is also recommended. When the heart rate is ＜ 45 beats/min, a single dose of 0.3 to 0.5 mg atropine is infused intravenously. If the effect is not satisfactory, repeated administrations are performed until the maximum cumulative amount of 2 mg is reached. Isoproterenol (1 mg per 500 mL) is then intravenously given, and the infusion speed is adjusted according to the patient’s heart rate. If the RASS score is ≥ 2 during emergence from general anesthesia, a bolus injection of propofol (1.5–2.5 mg/kg) is applied when necessary. If the patient exhibits chills upon emergence from general anesthesia, an intravenous injection of tramadol hydrochloride(0.1 g) is given slowly for heat preservation. If nausea and vomiting appear, an intravenous injection of tropisetron hydrochloride (Xinbei, 5 mg) is given. If the VNRS score is ＞ 6 during emergence from anesthesia, a single bolus injection of sufentanil (5 µg) is given. If pain is not alleviated, this injection is repeated after 5 minutes; the total dose does not exceed 10 µg (Kim et al., 2012).

Safety assessments

During the trial, any adverse events including abnormal laboratory examination findings will be carefully inquired and investigated. All adverse events will be assessed with consideration of the nature, severity, and correlation with drugs, and the assessment results will be strictly entered in the medical records.

The intensity or severity of adverse events will be classified into the following three grades. Mild: Transient hypertension, lowered heart rate (with no need for interventions because the patient is in the anesthetic state). Moderate:Sinus bradycardia, escape beat (an intravenous infusion of 0.3–1.0 mg atropine), and complicated hypotension (an intravenous bolus of 10–15 mg ephedrine). Severe: Sinus arrest (cardiopulmonary resuscitation when necessary).

Correlations between adverse events and drug use will be categorized as positively correlated, much likely correlated, likely correlated, likely unrelated, or unrelated.The incidence rate of adverse events will be calculated by summing positively correlated, much likely correlated, and likely correlated adverse events.

Management of adverse events during and after the trial will be performed as follows. The turnover of all adverse events will be followed up and recorded, and patients who withdraw from the experiments because of adverse events will be followed up until complete resolution of the adverse events. Whether the adverse events are related to drug use will be determined, and related supporting evidence will be provided.

Severe adverse events including hospitalization, prolonged hospital stay, disablement, limited work capacity,life-threatening events, death, and congenital malformations will be reported to the sponsor within 24 hours and recorded.

Emergency break methods

When severe adverse events occur, the researcher in charge will open the group assignment envelope and the reasons for and date regarding the emergency break will be recorded in the medical record. The researcher in charge will then determine whether this patient will drop out of the trial.

Data collection, management, and statistical analysis

The medical records acquired from the trial will be collected by staff members who will ensure that the records are highquality and accurate. The filled case report forms will also be retrieved by these staff members. After confirmation, the correct information will be input into the database. Medical records will be disclosed for the first time. These medical records will be divided into the aforementioned groups and processed by the trial director.

All data will be statistically calculated using SAS9.0 software. Numeration data will be expressed as percentages and measurement data as the mean ± SD. The chisquare test will be used to compare differences among numeration data, and analysis of variance and Tukey’s post hoc test will be used to compare differences among measurement data. A P level of ＜ 0.05 will be considered statistically significant and a level of ＜ 0.01 highly significant. After statistical analysis, the medical records will be disclosed for the second time. Two Dex groups and one control group will be designated.

Data preservation

All records will be kept in a secure, locked storage area with limited access for later review by appropriate trial staff only.According to China Drug Clinical Trial Management Specification, all records will be preserved for at least 5 years.

Trial quality assurance and control

Two researchers in charge and five staff members will perform the trial. Each step will be strictly performed according to the trial protocol. One researcher will be designated for quality control. Each step of quality control of measured outcomes will be performed according to the standard operating procedure and quality control procedure. SI units will be used for each examination item. The trial reports will include the date, examined items, results, and range of normal values.

Ethical review and informed consent

Written approval of the trial protocol, medical reports, and signed informed consent will be received from the Ethics Committee, First Hospital of China Medical University,China. The benefits and risks of participation in the trial will be explained to each patient, legal deputy, or witness by the sponsors or their designee, and written informed consent will be obtained before the trial. The informed consent with the signature of the patient, legal deputy, and person who explained the benefits or risks will be preserved by the researchers. The trial will be conducted in accordance with the Declaration of Helsinki.

DISCUSSION

There is evidence that a bolus injection of Dex (0.4 µg/kg)within 30 minutes after induced anesthesia stabilizes the heart rate and blood pressure during emergence from general anesthesia after thyroid gland surgery and shortens the awakening time and extubation time (Zhao et al., 2014).However, related studies involving brain surgery have not been reported. A favorable quality of recovery from general anesthesia in neurosurgical patients is an important goal for anesthesiologists. In this trial, a bolus intravenous injection of low-dose (0.4 µg/kg) Dex in patients undergoing craniotomy under general anesthesia is expected to reduce the emergency responses caused by the harmful operation, maintain stable cardiovascular function, and reduce adverse events (such as low heart rate and blood pressure) during emergence from general anesthesia. It is also expected to provide benefits for early recovery from anesthesia and subsequent assessment of neurological function recovery.

This trial will be strictly performed in a double-blinded,randomized, and controlled manner, and the number of clinical cases should accumulate to planned quantitation.There are no obvious differences in the patients’ general data between the two study groups, and therefore they are well comparable. Placebo as a control is more conducive to assessment of the effects of drugs used. The trial results will provide more insight into whether rational use of Dex before the end of surgery for supratentorial tumors can improve the quality of recovery from general anesthesia.

Trial status

Data management and analysis at time of submission.

Conflicts of interest

None declared.

Author contributions

YY conceived and designed this trial protocol and wrote the paper. PL revised the paper. Both authors approved the final version of this paper.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reivewed by international expert reviewers.

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