Study purpose:
(1) Primary purpose: To investigate neurologic function in the early postoperative period for patients with supratentorial intracranial gliomas under inhalational general anesthesia compared to intravenous general anesthesia. The hypothesis is that the difference in postoperative National Institute of Health Stroke Scale (NIHSS or modified NIHSS) score changes under the two general anesthesia methods are not different, with the score difference within -1 to 1.
(2) Secondary purpose: To compare the effects of inhalational general anesthesia versus intravenous general anesthesia on neurocognition, hemodynamics, cerebral physiology, anesthesia recovery quality, pain scores, anesthesia expenses, and stress responses in patients with supratentorial intracranial gliomas undergoing elective craniotomy.
Trial design
The study is a prospective, single-center, open label, randomized parallel arm equivalent clinical trial comparing sevoflurane and propofol, both combined with remifentanil, general anesthesia (Sevoflurane-remifentanil versus Propofol-remifentanil group) in patients with supratentorial gliomas; it will be carried out in the neurosurgical operation room in Beijing Tiantan Hospital (a large city), Capital Medical University, Beijing, China.
Populations
Adult male and female patients scheduled for elective craniotomy under general anesthesia with supratentorial (frontal-parietal-temporal) gliomas diagnosed by magnetic resonance imaging (MRI) are eligible for the study. All patients must sign institutional approval and informed consent before enrollment, the written informed consent will be obtained one day or a few days before operation, when patients are seen by anesthesiologists in the ward. The information and reasons why eligible patients are not recruited to the trial will be documented. The inclusion and exclusion criteria are listed in Table 1.
Table 1. Inclusion and exclusion criteria
Inclusion Criteria
|
Patients aged between 18 to 65 years old with American Society of Anesthesiology (ASA) status I~II who are scheduled for elective craniotomy for the treatment of supratentorial gliomas must fulfill the following:
|
1
|
Frontal-Parietal-Temporal glioma diagnosed by preoperative MRI
|
2
|
Glasgow score of 15 without preoperative symptomatic elevated intracranial pressure
|
3
|
New and/or recurrent intracranial gliomas are allowed
|
Exclusion Criteria
|
1
|
Unable to comprehend and cooperate with the neurologic examination
|
2
|
Emergency craniotomy or changed to emergency from elective craniotomy
|
3
|
Insular lobe is invaded by glioma
|
4
|
Scheduled intraoperative motor evoked potential monitoring
|
5
|
Patients with traumatic brain injury, intracerebral hemorrhage, or cerebral vascular diseases
|
6
|
Patients with prolonged emergence, postoperative mechanical ventilation, and/or sedation dependence due to a definite reason (e.g., surgery itself or tumor location)
|
7
|
Hypothalamic dysfunction
|
8
|
Radiotherapy and/or chemotherapy before surgery
|
9
|
Uncontrolled hypertension or severe heart disease that impairs cardiac function (New York Heart Association Functional Classification ≥ III)
|
10
|
History of related anesthetic allergy
|
11
|
Severe endocrine system dysfunction that impair metabolic index
|
12
|
Impaired mental status
|
13
|
Drug and/or alcohol abuse
|
14
|
Pregnant and/or lactation period patients
|
15
|
Neuromuscular diseases
|
16
|
Infectious and/or immune diseases with positive biomarker(s)
|
17
|
Body mass index >=35
|
Patients will be recruited in Beijing Tiantan Hospital, Beijing, China. The potentially eligible patient will be screened and contacted by a trial team member who explains the study and ascertains the patient’s interest one or two days before the scheduled operation day. If interested in enrolment, the patient will receive the detailed trial explanation and written consent form.
Randomization and blinding
Permuted-block randomization will be used with a block size of 4 and an allocation ratio of 1:1 to either sevoflurane-remifentanil group or propofol-remifentanil group. Random allocation sequence will be based on a computer-generated random digits table. One investigator who will not participate in anesthetic management or follow-up will implement the randomization and enroll patients, and allocation will be concealed in a sealed opaque envelope until patient enters the operating room. Randomization will occur for patients conforming to the above criteria, and written informed consent will then be obtained from themselves or their next-of-kin. Since the two general anesthetic administration routes are distinct (inhalational versus intravenous), patients and anesthesiologists cannot be blinded. An independent team who is not involved in the intraoperative management will be in charge of postoperative follow-up and is blinded to the intervention.
Interventions
Standard Anesthetic Management
On the day of operation, patients will be admitted into the operating room to be randomly assigned into either the sevoflurane-remifentanil or propofol-remifentanil group. Vital signs including electrocardiography (ECG), blood pressure (BP), heart rate (HR), pulse oxygen saturation (SpO2), end-tidal carbon dioxide (ETCO2), body temperature, and urine output will be monitored throughout the study. 100% fraction of oxygen will be provided by mask to the patients for preoxygenation for 5 minutes prior to anesthetic induction. No premedication will be given.
All patients will be induced with 0.3μg/kg sufentanil, 2-2.5mg/kg propofol, and 0.7-0.8mg/kg rocuronium or cisatracurium. After tracheal intubation, mechanical ventilation will be established, at a tidal volume of 8-10ml/kg, respiratory rate of 12-15/min, inspiratory:expiratory ratio of 1:2, fraction of inhaled fresh oxygen as 60%, and flow rate of fresh gas as 1.5L/min. After induction, anesthesia will be maintained according to one of the two group allocations: (1) 6-8mg/kg propofol with 0.05-0.2μg/kg remifentanil for the propofol group or (2) 1.3-1.5 Minimum Alveolar Concentration (MAC) sevoflurane with 0.05-0.2μg/kg remifentanil for the sevoflurane group. The dosage of anesthetic will be adjusted according to the bispectral index (BIS) value, which will be maintained between 40-50. 0.5% ropivacaine 1 to 2mL for each injection point will be used for scalp nerves block before the start of surgeries. Sufentanil 5-10 mcg can be given, by anesthesiologist discretion, to alleviate potent stress responses when head pins are placed or scalp incision is performed, based on the hemodynamic parameters. The muscle relaxant cisatracurium will be infused at 0.1mg/kg/h during the operation for all patients and stopped once the bone flap is secured. Propofol and sevoflurane will be reduced according to BIS and hemodynamic parameters once the bone flap is fixed and stopped at skin dressing.
At the end of the operation, ondansetron 4mg will be prophylactically administered to all patients to prevent nausea and vomiting, and tramadol 1.5-2mg/kg will be given if patients are experiencing rigors/chills. Neostigmine 1-2mg and atropine 0.5-1mg will be available to antagonize residual muscle relaxation when deemed necessary by train-of-four (TOF) twitch monitoring.
Adverse hemodynamic responses will be recorded and classified as hypertension, hypotension, tachycardia, or bradycardia, which require standard treatment according to the protocol (Table 2). These episodes of blood pressure and heart rate changes and the medication administered during their treatment will be recorded as “hypertension” (MAP >20% above preoperative baseline value) or “hypotension” (MAP <20% below preoperative baseline value), Tachycardia and bradycardia are defined as HR>100bpm and HR<45bpm, respectively. Standard treatment for hemodynamic disturbances are shown in Table 2.
Patient-controlled intravenous analgesia (PCIA) will be used for postoperative pain control with 100mcg sufentanil and 16mg ondansetron diluted to a total volume of 100ml within normal saline being prepared, with a bolus dose set at 0.5ml, a lockout time set at 15 minutes, and a background infusion of 2 ml/h. PCIA will be started after the patient is discharged from the operating room.
Table 2.
Hemodynamic Fluctuation
|
Definition
(if any of the below changes are sustained for equal and/or longer than 5 minutes)
|
Standard Treatment Algorithm
|
Hypertension Episode
|
MAP >20% above preoperative baseline
|
Increase propofol or sevoflurane concentration according to BIS, increase remifentanil infusion rate, or administer 5mcg sufentanil; if correction still not achieved, nicardipine will be given as bolus and/or infusion
|
Hypotension Episode
|
MAP <20% below preoperative baseline
|
Adequate volume loading and/or vasoactive agent administration (dopamine, norepinephrine, or phenylephrine), with the dose and infusion rate adjusted according to the blood pressure response
|
Tachycardia
Episode
|
HR >100bpm
|
Esmolol bolus and/or infusion according to heart rate response
|
Bradycardia
Episode
|
HR <45bpm
|
Atropine administration
|
MAP: mean arterial pressure; HR: heart rate; bpm: beat per minute.
|
Anesthesia monitoring
Anesthesia management will aim to achieve targeted physiological parameters. The blood pressure will be monitored by radial artery catheter placement, and the target value is defined as the range of ±20% of the baseline MAP value, which is defined as the average MAP of the first three values measured after the patient enters the operating room and before induction. When the blood pressure is out of this range, measures will be taken such as changing the infusion rate of crystalloid or colloid and remifentanil, or giving bolus injection of sufentanil or vasoactive agent (such as 0.5μg/kg/min phenylephrine or 0.01μg/kg/min norepinephrine). Heart rate will be maintained between 50-90 beats per minute. SpO2 will be kept ≥98% during the operation. End-tidal CO2 will be maintained between 30-35 mmHg by adjusting ventilation parameters. Core body temperature will be kept between 36-37 degree Celsius. Plasma glucose concentration will be maintained between 5.0-7.8mmol/L.
Discontinuation Criteria
Massive hemorrhage or massive transfusion
Massive intraoperative bleeding can occur, and this study defines massive bleeding as blood loss exceeding the entire blood volume within 24 hours from the start of operation or 50% of circulating blood volume loss within 3 hours during operation requiring emergency intervention. Intraoperative massive transfusion (transfusion of more than 10 units of packed red blood cells) may be needed if massive hemorrhage is encountered. If bleeding occurs to this extent and meets either or both of the above criteria, the trial will be discontinued for this particular patient.
Anaphylaxis during the operation
Anaphylaxis rarely but occasionally occurs intraoperatively, especially in the setting of antibiotic and muscle relaxant administration, but also with the administration of other medications, and normally can be treated quickly. If such a reaction occurs and is severe, necessitating discontinuation of the operation, the patient will be withdrawn from the trial. Anaphylaxis will be reported as an adverse event.
Venous air embolism
Significant venous air embolism has been observed in rare cases, but neurosurgery carries the potential risk for this sometimes intractable complication, especially when the operative intervention occurs near venous sinuses or in the sitting position[12-14]. Venous air embolism may result in severe hypoxia and hypotension which can impair cerebral perfusion and oxygenation. If this happens, timely intervention and resuscitation needs to be carried out and the patient will be withdrawn from the trial. This will be reported as an adverse event.
Postoperative coma
If the patient is in a coma (nonresponsive) after operation for any reason, the subject will not be able to cooperate with any neurological assessment, the subsequent follow-up will need to be discontinued, and this will be noted in the neurologic complication section. The patient will be withdrawn from the trial.