Effect of Low-dose Lidocaine on Motor Evoked Potentials in Patients Undergoing Intracranial Tumor Resection With Propofol Anesthesia

Object To investigate the effect of low-dose lidocaine on motor evoked potentials (MEP) in patients undergoing intracranial tumor resection with propofol anesthesia. Methods Forty patients undergoing intracranial tumor resection and required MEP monitoring were selected.They were randomly divided into the lidocaine group (Group L, n=20) and control group (Group C, n=20) by computer generated randomization. All patients were given propofol anesthesia under the guidance of bispectral index (BIS).In Group L, lidocaine 1 mg/kg was injected intravenously during anesthesia induction. Then, lidocaine was continuously pumped at the speed of 1 mg/kg·h until the operation start. Group C was given the equal volume of normal saline. Heart rate (HR), mean artery pressure (MAP), and BIS were recorded before anesthesia induction (T0), 2 min after tracheal intubation (T1), 35 min (T2) and 50 min (T3) after anesthesia induction. The amplitude and latency of MEP at T2 and T3, the total dosage of propofol, and adverse events before T3 were recorded. Compared with No difference and between and The total and no difference between the two groups at each time point.


Introduction
Intracranial tumors are considered one of the most feared tumors, which may lead to severe disability and physical dysfunction (1). At present, intracranial tumors are commonly treated by surgery. Motor evoked potentials (MEP) monitoring can effectively reduce the occurrence of postoperative neurological complications and improve the overall tumor resection rate (2). However, MEP monitoring is easily affected by surgical procedures, anesthetic drugs, and other factors. A Delphi consensus indicates that total intravenous anesthesia (TIVA) is the most reliable anesthesia method to obtain high-quality MEP signals. Propofol, the most commonly used drug in TIVA, inhibits MEP signals in a dose-dependent manner. Maintaining low-dose propofol infusion by adding adjuvant drugs is considered to be bene cial for good MEP signal acquisition. (3) Previous studies have shown that injection of low-dose lidocaine reduces the use of propofol during TIVA.(4) However, there is no evidence that reduced propofol by lowdose lidocaine injection can improve MEP monitoring. In the present study, we intend to explore the effect of low-dose lidocaine on MEP in patients undergoing intracranial tumor resection with propofol anesthesia. We hope to provide some reference for clinical medicine.

Materials And Methods
This study has been approved by the Medical Ethics Committee of the Brain Hospital A liated to Nanjing Medical University (2020-KY119-02). And it also has been registered at http://www.chictr.org.cn (15/11/2021,ChiCTR2100053218) . The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines.Written informed consent was obtained from patients and their families.

Subjects
Patients undergoing intracranial tumor resection and required MEP monitoring at the Brain Hospital A liated to Nanjing Medical University from June 1, 2020 to July 30, 2021 were eligible for inclusion.
Inclusion criteria were: age range, 18 to 65 years; American Society of Anesthesiologists (ASA) grade, I to II; and Body Mass Index, 18.5 to 30. Exclusion criteria were: lidocaine allergy; contraindication to transcranial electrical stimulation; neuromuscular transmission dysfunction; neuropsychosis or the use of corresponding drugs; diabetes mellitus with peripheral nerve ending lesions; and severe heart, lung, liver, and kidney dysfunction.

Sample size calculation
The sample size is calculated by G-Power software (version 3.1). Based on the pre-experimental results, the dosage of propofol was 256.00 ± 19.14 mg in group L and 280.00 ± 27.24 mg in Group C. The test level α was taken as 0.05. The power level, 1-β, was taken as 0.8. Therefore, a sample size of 14 was required in each group. Taking into account the rate of withdrawal (-15%), the nal sample size for each group was 20.

Anesthesia preparation
All patients were given fasting and drinking before operation. After entering the operating room, electrocardiogram, noninvasive arterial blood pressure, peripheral oxygen saturation, and bispectral index (BIS) were monitored.

Anesthesia induction
Midazolam 0.05 mg/kg, propofol 1.5mg/kg, sufentanil 0.3ug/kg, and cis-atracurium 0.1 mg/kg were used for anesthesia induction. In Group L, lidocaine 1 mg/kg was administered during induction; in Group C, equal volume of normal saline was given. Endotracheal intubation and mechanical ventilation were performed after the above drugs took effect. The end-expiratory carbon dioxide partial pressure (PetCO 2 ) was maintained between 30 and 35 mmHg. The BIS value was maintained between 40 and 60.
Anesthesia maintenance: After endotracheal intubation, both groups continued to pump propofol 4-12 mg/kg·h under the guidance of BIS until the end of operation. In Group L, lidocaine 1 mg/kg·h was continuously pumped until the operation start; while in Group C, equal volume of normal saline was continuously pumped. In both groups, 10 ug sufentanil was administered intravenously 5 min before head xation and skin incision.

MEP monitoring
Endevor® neuroelectrophysiological monitor was used for MEP monitoring. After anesthesia induction, disposable sterile needles were punctured into the patient's muscles. Thenar muscle was selected as the recording electrode. MEP was induced through transcranial electrical stimulation with 5 short pulses: stimulation interval, 0.1 ms; stimulation intensity, 150V.

Observation indices
Heart rate (HR), mean artery pressure (MAP) and BIS before anesthesia induction (T0), 2 min after tracheal intubation (T1), 35 min (T2) and 50 min (T3) after anesthesia induction were recorded. The amplitude and latency of MEP at T2 and T3, the total dosage of propofol, and adverse events before T3 were also recorded.

Statistical analysis
Data were analyzed by SPSS 21.0. The counting data are represented by frequencies or percentages and analyzed by chi-square test. The measurement data are expressed as the mean ± standard deviation (SD). The HR, MAP, BIS, and MEP of the two groups were compared by repeated measurement analysis of variance. The dosage of propofol use of the two groups was compared by independent-samples t-test.
P<0.05 was considered as statistically signi cant.

Results
Baseline Characteristics of the study subjects A total of 40 patients were included in the present study. As showed in Table 1, there were no signi cant differences in terms of gender, age, weight and BMI between Group L and Group C.
Changes of HR, MAP, and BIS As showed in Table 2 and 3: Compared with Group C, HR and MAP were signi cantly lower at T1 in Group L. No signi cant differences were observed in HR and MAP at T0, T2, and T3 between groups. As shown in Table 4, there was no signi cant difference in BIS between groups at each time point.

Comparison of MEP
As showed in Table 5, there were no signi cant differences in the amplitude and latency of MEP between the two groups at each time point.

Propofol usage
The dosage of propofol use in Group L was 246.50 ± 27.44mg, compared with 273.35 ± 33.79mg in Group C. The total dosage of propofol use was signi cantly decreased in Group L than in Group C before T3 (t=2.759, P=0.009).

Adverse events
As showed in Table 6, the incidence of adverse events (coughing, hypertension, or bradycardia) was signi cantly lower in Group L than in Group C before T3.

Discussion
Optimizing anesthesia scheme and obtaining satisfactory MEP waveforms is one of the tasks of anesthesiologists in neurosurgery under MEP monitoring. To date, muscle relaxants and inhaled anesthetics have been shown to exert strong inhibitory effects on MEP production. Muscle relaxants act directly on neuromuscular junctions, causing a decrease in the amplitude of MEP and failure of MEP monitoring. Although some studies have shown that MEP signals can be successfully obtained by the application of low concentration of inhaled anesthetics, a stronger stimulation is required to induce MEP in inhaled anesthetics than propofol.(5) In the present study, TIVA was therefore selected as the anesthesia scheme. In order to avoid the in uence of muscle relaxants on MEP monitoring, cisatracurium 0.1mg/kg was given during anesthesia induction. The clinical muscle relaxant maintenance time of cis-atracurium was about 30 minutes. Although MEP was not induced at T2 on one case in each group, the induction rate of MEP waveform in both groups at T3 was 100%.
Propofol is often used as anesthetics in neurosurgery because of its constriction of cerebral blood vessels and reduction of intracranial pressure. However, propofol inhibits the activity of spinal gray matter α motor neurons and has a dose-dependent inhibitory effect on MEP induction.(6) Therefore, we need to reasonably reduce the use of propofol in MEP monitoring during neurosurgery. Previous studies have shown that low-dose lidocaine reduces the use of propofol during general anesthesia.(4) Lidocaine inhibits noxious stimulation by blocking sodium channels in pain conduction pathway, so as to reduce the dose of propofol and opioids. (7) The recommended dose of intravenous lidocaine is 1.0-2.0 mg/kg, followed by 1.0-2.0 mg/kg·h continuous intravenous injection. However, it is needed to gradually reduce the continuous infusion rate of lidocaine in a long-term surgery. (8) The duration of neurosurgery is relatively long (>2 hours); therefore, the minimum safe dose of lidocaine 1.0 mg/kg and 1.0 mg/kg·h was selected in the present study. Our results showed that the dosage of propofol in Group L was 246.50 ± 27.44mg, which was less than 273.35 ± 33.79mg in Group C. Interestingly, no signi cant difference was observed in MEP amplitude and latency between the two groups. We speculated that: rst, the reduction in propofol did not reach the threshold which could induce MEP change; Second, lidocaine offset the improvement of MEP signal caused by the reduction in propofol. Further studies will be needed to explore the reasons.
Intravenous injection of lidocaine produces analgesic, sedative, and anti-in ammatory effects. Moreover, it also inhibits the release of adrenaline and catecholamine, and alleviates the stress response caused by surgical operation.(9, 10) Studies have shown that intravenous application of 1.5mg/kg lidocaine reduces hemodynamic changes during endotracheal intubation, extubation, and operation.(11) Our results showed that MAP decreased at T1 in both groups, however, they were signi cantly decreased in Group L, not in Group C HR decreased at T1 in Group L.These results indicate that low-dose lidocaine reduces the stress response caused by endotracheal intubation. Moreover, lidocaine has a good effect of maintaining hemodynamic stability. In the present study, the incidence of adverse events (hypertensive, bradycardia) was signi cantly lower in Group L than that in Group C.
A small dose of lidocaine was used in the present study. No allergic or toxic reactions were observed throughout the process. The sample size of our study was small and lidocaine was not continuously infused during the operation. Therefore, it needs further veri cation in the future.
In conclusion, low-dose lidocaine has no obvious effect on MEP during propofol anesthesia, but it reduces the use of propofol, inhibits the reaction to endotracheal intubation, maintains the stability of hemodynamics, and decreases the incidence of adverse reactions. It is recommended that lidocaine can be used during MEP monitoring in intracranial tumor resection surgery.