Evaluation of continuous intravenous lidocaine on brain relaxation, intraoperative opioid consumption, and surgeon’s satisfaction in adult patients undergoing craniotomy tumor surgery: A randomized controlled trial

Background:

In craniotomy tumor removal, brain relaxation after dura opening is essential. Lidocaine is known to have analgesic and antiinflammatory effects. It is excellent in decreasing cerebral metabolic rate of oxygen, cerebral blood flow, and cerebral blood volume; and can potentially reduce intracranial pressure, resulting in exceptional brain relaxation after dura opening. However, no study has examined continuous intravenous lidocaine infusion on brain relaxation, intraoperative opioid consumption and surgeon’s satisfaction in adult patients undergoing craniotomy tumor removal.

Methods:

A total of 60 subjects scheduled for craniotomy tumor removal were enrolled in a double-blind, randomized controlled trial with consecutive sampling. Patients received either an intravenous bolus of lidocaine (2%) 1.5 mg/kg before induction followed by 2 mg/kg/h continuous infusion up to skin closure (lidocaine group) or placebo with similar volume (NaCl 0.9%). Neurosurgeons evaluated brain relaxation and surgeon’s satisfaction with a 4-point scale, total intraoperative opioid consumption was recorded in μg and μg/kg/min.

Results:

All sixty subjects were included in the study. Lidocaine group showed better brain relaxation after dura opening (96.7% vs 70%; lidocaine vs placebo, P < .006), less intraoperative fentanyl consumption (369.2 μg vs 773.0 μg; P < .001, .0107 vs .0241 μg/kg/min; lidocaine vs placebo, P < .001). Higher surgeon’s satisfaction was found in lidocaine group (96.7% vs 70%, P = .006). No side effects were observed during this study.

Conclusions:

Continuous lidocaine intravenous infusion improves brain relaxation after dura opening, and decreases intraoperative opioid consumption, with good surgeon satisfaction in adult patients undergoing craniotomy tumor removal.

1. Introduction

Annually, an estimated 22.6 million patients have neurological disorders or injuries that require the expertise of a neurosurgeon, 13.8 million among them require surgery, and 735,000 cases that require surgery are brain tumors.^[1] Craniotomy is performed for various indications, including brain tumor resection.^[2] Brain relaxation is essential in anesthesia for craniotomy surgery because optimal brain relaxation can improve surgical conditions, facilitate surgeons to access the area that will be resected, and reduce the risk of injury from retraction injury and ischemia from compression.^[3] Rasmussen et al^[4] found that the incidence of mild or moderate brain swelling at the time of dura opening was approximately 35.7% in brain tumor resection surgery. There may be an increase in surgical complications and poor outcomes related to poor brain relaxation. Subjective assessment by the neurosurgeon, based on visualization and tactile, is still the primary assessment for brain relaxation.^[3] In addition, to avoid increases in intracranial pressure (ICP), uncontrolled hypertension should be avoided during high-intensity noxious stimuli, such as during intubation, insertion of headpins, skin incisions, and extubation.^[2]

Lidocaine, a drug that belongs to the class of amide local anesthetics, is a classic drug that has been used for a long time in the field of anesthesia. However, its use is still limited for local anesthesia. The previous studies show that systemic lidocaine has analgesic, anti-hyperalgesia, and antiinflammatory properties.^[5–8] Its clinical effect was known to benefit abdominal, thoracic, gynecology, and ambulatory surgery to reduce intra- and postoperative pain and opioid consumption, reduce hypnotic agent requirement (sparing effect), decrease ileus, reduce postoperative nausea and vomiting and decrease the length of stay after surgery.^[9–11] In neurosurgery, lidocaine also has the benefit to minimize postoperative pain.^[12] In mammal experimental, lidocaine infusion can reduce cerebral metabolic rate of oxygen (CMRO₂) by inhibiting synaptic transmission and sodium channel block mechanism in brain cell membranes, resulting in decreased electrophysiological function and membrane stabilization effect.^[13–15] Furthermore, lidocaine infusion can reduce cerebral blood flow (CBF) due to cerebral vasoconstrictor properties that are perceived in response to a reduction in cerebral metabolism.^[16–18]

However, clinical studies of lidocaine in neurosurgical patients are limited. From extrapolated data of mammal experimental, lidocaine can reduce CMRO₂ and CBF; it is hypothesized that lidocaine can improve brain relaxation in craniotomy surgery. Based on our knowledge, no clinical study has examined the effect of systemic lidocaine on brain relaxation during dura opening in tumor craniotomy surgery yet. In addition, this study will also assess opioid consumption and surgeon’s satisfaction intraoperatively.

2. Methods

2.1. Study design

This study was an experimental study with a double-blind, randomized controlled trial design. The study was conducted at the Integrated Surgical Unit, Cipto Mangunkusumo Hospital, Indonesia, between February 28th and August 31st, 2021. We used the sample size formula to compare 2 proportions with a confidence interval of 95% and 80% power. We deemed 30 % to be a clinically significant difference in this calculation. We calculated the sample size to be 27 for each group, anticipating a drop out of 10%; each group required 30 subjects, with a total sample of 60 subjects for this study. Sampling was carried out with consecutive sampling after obtaining approval from the Ethics Committee of the Faculty of Medicine, Universitas Indonesia

2.2. Ethical approval and consent to participate

The study protocol was approved by the Ethics and Research Committee of Universitas Indonesia (1450/UN2.F1/ETIK/PPM.00.02/2020; protocol no: 20-11-1437; approval date: December 7th, 2020) and was registered on February 26th, 2021, in ClinicalTrials.gov (NCT04773093). Written informed consent to participate was obtained from each participant. No organs or tissues were obtained from participants.

2.3. Inclusion and exclusion criteria

Inclusion criteria included adult patients >18 years of age who were scheduled to undergo craniotomy for tumor removal with dura opening, the physical status of American Society of Anesthesiology Classification 1 to 3, baseline Glasgow Coma Scale is 15, and surgery using headpins fixation. Exclusion criteria included the patient or family refusing to participate in the study; the patient had an atrioventricular block, severe hepatic and renal function impairment, signs of hemodynamic instability, midline shift > 5.4 mm, diagnosis of glioblastoma multiforme or metastases, aneurysm or arteriovenous malformation surgery, using cerebrospinal fluid drainage (external ventricular drain, ventriculoperitoneal shunt, or lumbar drain) intraoperatively, routinely taking adrenergic agonist or antagonist drugs (e.g., beta-blockers, a2 agonists, vasodilators, vasoconstrictors or inotropes), patients routinely taking opioids within 2 last week, and a history of allergy to lidocaine.

2.4. Study protocol

Adult patients scheduled to undergo craniotomy tumor surgery who fulfilled the inclusion criteria but not the exclusion criteria were asked to give informed consent 1 day before the surgery. Subjects were randomized using software to generate a unique identification number. The number was written on paper and was placed in a nontransparent sealed envelope. Once the patients who fulfilled the inclusion criteria arrived at the patient’s reception room, the envelope was opened. The pharmacy pre-prepared 2 sets of drugs in 10 mL syringes for bolus and 20 mL for continuous infusion, assuming the same 20 mg/mL concentration. Tumor size was measured using method specified by Rasmussen et al.^[4] The anesthesiology resident on duty in the operating room (OR) took the pre-prepared intervention according to the subjects’ allocation (drug A and drug B).

During induction, the patient was given intravenous fentanyl, the experimental drugs A or B according to subject allocation at a 1.5 mg/kg (loading dose 3 minutes before intubation), propofol, and rocuronium. The patient was then intubated, and then the central venous line and arterial line were inserted. The experimental drug was followed by a continuous infusion of 2 mg/kg/h immediately after administering the bolus. Anesthesia was maintained using sevoflurane, intermittent fentanyl, and continuous atracurium infusion. End-tidal CO₂ was maintained in normocapnia. A forced-air warming blanket was used to maintain normothermia. Before headpin fixation, the patient was given a 1 μg/kg bolus of fentanyl and was allowed an additional 1 μg/kg if necessary. When the surgeon began to drill the skull, the patient was given 20% mannitol at 0.5 g/kg (finished within 30 minutes). Immediately after the dura was opened, the neurosurgeon assessed brain relaxation. Data were recorded by the research team in charge of taking notes in the OR. If the brain was swelling, the mannitol dose could be repeated if needed. Intraoperative fluid administration was adjusted to maintain normovolemia. The experimental drug was discontinued when the surgeon finished suturing the skin. Postoperative analgesia and antiemetic regiment were given intravenously (paracetamol, ketorolac, ondansetron). Muscle paralysis was reversed with intravenous neostigmine. The decision to extubate the patient in the OR or the intensive care unit was depended on the intraoperative condition. A level of consciousness was noted after extubation. All patient was admitted to the intensive care unit for postoperative monitoring. The trial stopped if there was any hemodynamic instability such as arrhythmias or hypotension during surgery that did not improve with fluid resuscitation and needed an anti-arrhythmia, inotropic or vasopressor agent.

2.5. Outcome assessment

Brain relaxation was assessed immediately after dura opening. The neurosurgeon carried the assessment subjectively (inspection and palpation) with a standardized scale of 4 grades: the brain is very relaxed, at the level below the dura; the brain is quite relaxed, at the level of dura; moderate brain swelling; and pronounced brain swelling.^[3,4] Grades 1 and 2 indicated good brain relaxation, while 3 and 4 indicated poor brain relaxation.

Intraoperative opioid consumption was calculated based on the total number of fentanyl use for intraoperative analgesia (in μg) and the number of fentanyl use divided by body weight and surgery duration calculated from intubation ending when the last skin suture was completed (in μg/kg/min).

The surgeon’s satisfaction with the operation was assessed at the end of the procedure. The surgeon’s satisfaction in this study was divided into 4 grades: very satisfied; satisfied; less satisfied; and very dissatisfied. We consider grades 1 and 2 to indicate good surgeon’s satisfaction, while grades 3 and 4 show dissatisfaction.

2.6. Statistical analysis

The data obtained were then analyzed using the Statistical Package for Social Sciences computer program version 26 (IBM Corporation, 2019). Categorical data were presented in numbers and percentages (n [%]). In addition, numerical data were introduced using mean ± standard deviation if the data distribution is normal or the median (minimum–maximum value) if the distribution is not normal. Student t test and Mann–Whitney test were used to analyze 2 numerical variables. The results of the analysis were considered significant if the P value < .05.

3. Results

We enrolled 60 patients who met the inclusion criteria and signed the informed consent to participate in the study from February 28th to August 31st, 2021. The subjects were randomly assigned into 2 groups and received their allocated intervention (Fig. 1).

Figure 1.

CONSORT flow diagram.

There was no statistical significance between the 2 groups in gender, diagnosis, American Society of Anesthesiology physical status, tumor location, brain edema, or midline shift (<5.4 mm) on computed tomography scan or magnetic resonance imaging, craniotomy, or re-craniotomy, and preoperative steroid use. Similarly, based on the characteristics of age, height, weight, tumor size, duration of anesthesia, duration of surgery, preoperative hemoglobin, and postoperative hemoglobin, there was no statistical significance between the lidocaine and placebo groups (Table 1).

Table 1.

Demographic and perioperative variables.

	Placebo group (n = 30)	Lidocaine group (n = 30)	P value
Age (yr)	43 + 2.0	42 + 1.7	.811
Height (cm)	161 (140–170)	161.5 (145–170)	.483
Weight (kg)	58.1 + 11.8	57.5 + 9.4	.828
Sex (M/F)	3/27	6/24	.472
ASA degree (II/III)	26/4	24/6	.488
Tumor size (cm2)	14.5 (2.5–56.6)	17.5 (7.1–58.1)	.348
Duration of surgery (min)	489.2 + 150.2	547.3 + 176.9	.175
Duration of anesthesia (min)	573.8 + 151.2	633.0 + 182.5	.177
Hb preoperative	13.0 (10.5–16.7)	13.5 (10.2–15.1)	.468
Hb postoperative	11.7 + 1.2	11.6 + 1.4	.714
Diagnosis			1.000
Meningioma	21	22
Glioma low grade	3	2
Astrocytoma	2	2
Other	4	4
Tumor location			1.000
Supratentorial	27	26
Infratentorial	3	4
Imaging finding
Brain edema	16	18	.602
Midline shift <5.5 mm	10	11	.787
Preoperative steroid	4	2	.671

Data are expressed as mean ± SD, median (minimal–maximal), or numbers. Compared with the placebo group, P < .05.

ASA = American Society of Anesthesiology, Hb = hemoglobin.

In the lidocaine group, the proportion of good brain relaxation in the lidocaine group was higher than in the placebo group (96.7% vs 70%; P = .006) (Table 2). Relative risk was 0.11, and the number needed to treat was 4.

Table 2.

Comparison between lidocaine and placebo group on brain relaxation and intraoperative opioid consumption.

		Placebo group (n = 30)	Lidocaine group (n = 30)	P value
Brain relaxation after opening the duramater	Relax	21 (70.0)	29 (96.7)	.006*
	Swelling	9 (30.0)	1 (3.3)
Intraoperative fentanyl consumption	Total (μg)	773.0 + 265.7	369.2 + 140.5	<.001†
	μg/kg/min	0.0241 + 0.0065	0.0107 + 0.0042	<.001†

Relax means brain below the dura or at the level of the dura. Swelling means moderate brain swelling or pronounced brain swelling.

^*Chi-square test.

^†Unpaired t test.

There was a lower total intraoperative opioid consumption (fentanyl) in the lidocaine group compared with the placebo group (Table 2). Intraoperative opioid (fentanyl) consumption mean difference between 2 groups was 403.8 μg (95% CI 293.3–514.4 μg; P < .001).

The proportion of very satisfied and satisfied surgeons was higher in the lidocaine group with P < .001 (Table 3).

Table 3.

Comparison between lidocaine and placebo group on surgeon’s satisfactory.

	Surgeon’s satisfactory, n (%)				P value
	Very satisfied	Satisfied	Less satisfied	Very unsatisfied n
Lidocaine group	21 (70.0)	8 (26.7)	1 (3.3)	0 (0.0)	<.001*
Placebo group	3 (10.0)	18 (60.0)	9 (30.0)	0 (0.0)
Total	24 (40.0)	26 (43.3)	10 (16.7)	0 (0.0)

^*Chi-square test.

Overall, there was lower mean arterial blood pressure and heart rate intraoperative in the lidocaine group than in the placebo group, especially in a noxious event such as intubation, headpin fixation, skin incision, and extubation (Fig. 2).

Figure 2.

(A) Average intraoperative mean arterial blood pressure in lidocaine versus placebo group with 95% CIs. (B) Average heart rate in lidocaine versus placebo group with 95% CIs. CI = confidence interval.

4. Discussion

4.1. Effects of continuous intravenous lidocaine infusion on brain relaxation and surgeon satisfaction

The incidence of brain swelling after dura opening in this study was 16.7%. It appears that the effect of intravenous lidocaine infusion can improve brain relaxation condition after opening the dura compared to placebo. The proportion of good brain relaxation in the lidocaine group was 96.7% and, in the placebo group, was 70% (statistically significant, P = .006).

Its effect on cerebral metabolism can explain the effect of intravenous lidocaine on brain relaxation after dura opening. In mammal experiments done by Astrup et al, lidocaine infusion resulting in flat electroencephalogram concluded that spontaneous electrocortical activity is abolished by lidocaine, similar to barbiturate action.^[13,14] The abolition of electrocortical activity reduces 60% of energy consumption or brain metabolism.^[19] In addition, lidocaine also affects Na-K leak fluxes. From the experimental model, in the ischemic brain, the Na-K ion pump fails to maintain homeostasis due to energy depletion, resulting in Na ion leaks into and K ion out of cell passively following electrochemical gradient and membrane permeability. The grade of ion K leaks outside the brain cell can be measured by microelectrodes inserted into the surface of the brain cortex. After lidocaine infusion, ion K leaks outside brain cells are reduced and slowed, indicating that lidocaine reduces Na-K exchange leak fluxes. The effect of reducing ion leak fluxes is also seen in hypothermia but not in thiopental, indicating lidocaine, not thiopental, has a membrane-sealing effect.^[13] This membrane sealing effect (membrane stabilization) is related to energy to maintain cellular integrity that accounts for 40% of brain metabolism.¹⁹ In this experiment, Astrup et al also measured the effect of lidocaine on CMRO₂ and cerebral metabolic rate for glucose (CMRgluc) by the sagittal sinus outflow method that allows continuous measurement of oxygen and glucose consumption. The result is that lidocaine can reduce CMRO₂ and CMRgluc when given alone and after thiopental infusion. This effect is specific to lidocaine, supporting the hypothesis that lidocaine can block Na-K leak fluxes and oxygen and glucose consumption for active ion transport.^[13] Based on these experimental results, lidocaine can reduce cerebral metabolism by inhibiting synaptic transmission and membrane sealing effect that reduces ion transport demand.¹³ Sakabe et al also studied lidocaine effect on cerebral metabolism in mammal experimental using a lower dose of lidocaine and have the similar result that lidocaine can decrease CMRO₂ significantly.^[15]

Furthermore, lidocaine can reduce CBF due to decreased cerebral metabolism and cerebrovascular vasoconstrictor properties.¹⁶ Lam et al study in humans during normocapnia and hypocapnia support this postulate based on data that lidocaine infusion 5 mg/kg loading dose over 30 minutes followed by infusion of 45 μg/kg/min in normocapnia patient can reduce CBF and CMRO₂ by 24% and 20% respectively.^[17] In Grover et al^[18] study, 1.5 mg/kg lidocaine loading dose can decrease ICP by reducing cerebral blood volume and cerebral metabolism. Based on data supporting the hypothesis, lidocaine can reduce cerebral metabolism and CBF, it can explain its effect on brain relaxation after dura opening during craniotomy surgery.

In the surgeon’s satisfaction outcome, the proportion of very satisfied and satisfied surgeons in the lidocaine group was 70% and 26.7%, respectively. In contrast, in the placebo group, it was 10% and 60%, respectively (P < .001). Further analysis between surgeon’s satisfaction and brain relaxation when the dura opens found that 100% of the surgeon is very satisfied and satisfied is when the brain relaxation is good. Based on our knowledge, currently, there is no validated checklist or surgeon’s satisfaction questionnaire yet, so this study assesses surgeon’s satisfaction intraoperatively by subjectively evaluating the surgeon using a satisfaction scale.

4.2. Effect of continuous intravenous lidocaine infusion on intraoperative opioid consumption

Continuous infusion of intravenous lidocaine can reduce total intraoperative fentanyl for tumor resection craniotomy surgery by 403.8 μg (95% CI 293.3–514.4; P < .001). Furthermore, if adjustments were made to the duration of anesthesia and the duration of surgery as well as body weight, continuous infusion of intravenous lidocaine could reduce the need for intraoperative fentanyl by 0.0134 μg/kg/min (95% CI 0.0105–0.0162; P < .001).

In their study of patients undergoing surgical resection of brain tumors, Carrales et al^[20] found a 48.2% decrease in intraoperative use of fentanyl to 0.0367 μg/kg/min in the lidocaine group compared to the placebo group. Another study of intravenous lidocaine in craniotomy surgery for supratentorial tumors by Peng et al^[14] concluded that continuous intraoperative intravenous lidocaine infusion had a clinical analgesic effect by significantly reducing the proportion of subjects with acute postoperative pain. The analgesic effect of continuous intraoperative intravenous lidocaine that can reduce intraoperative opioid requirements in the group of patients undergoing craniotomy surgery was also seen in this study.

The effect of continuous intravenous lidocaine to decrease intraoperative opioid requirements is due to the analgesic effect of lidocaine on the central and peripheral nervous systems.^[5,8] In injured nerves, systemic lidocaine can prevent depolarization of neuronal membranes.^[5,8] Systemic lidocaine can also decrease or prevent neoproliferation of active sodium channels and block their spontaneous firing, especially in traumatized tissues.^[8] In acute pain, intravenous lidocaine exhibits significant analgesic, anti-hyperalgesic, and antiinflammatory effects.^[5] Lidocaine also has the effect of decreasing the sensitivity and activity of neurons in the spinal cord (central sensitization) and decreasing the N-methyl-D-aspartate receptor-mediated postsynaptic depolarization.^[5,8] Lidocaine also has a direct effect on opioid receptors.^[8] In terms of antiinflammatory, systemic lidocaine exhibits effects on polymorphonuclear cells (PMNs) and inflammatory signals through an inhibitory mechanism on PMN cell priming, when exposure of PMNs to certain mediators results in an exaggerated response by releasing cytokines and reactive oxygen species.^[6–8]

4.3. Side effect

Side effects that can occur due to intravenous lidocaine administration include tinnitus, numbness or metallic taste in the mouth area, twitching, lightheadedness, seizures, arrhythmias, and hypotension. These side effects generally occur when plasma lidocaine levels exceed 10 μg/mL.^[5] Beaussier et al^[9] concluded that with a lidocaine bolus dose of 1.5 mg/kg followed by continuous infusion of 2 mg/kg/hour, plasma lidocaine levels remained < 5 μg/mL. The patient’s cannot subjectively explain the side effects since the patient was under general anesthesia. Therefore, we can only assess the side effects using objective data such as ECG changes or hemodynamic instability. Based on intraoperative monitoring in this study, no side effects such as bradycardia or arrhythmia were found during intraoperative. All subjects given continuous lidocaine were fully conscious after extubation.

4.4. Study limitation and recommendation

There were several limitations in this study. First, in this study, a fundoscopic examination was not performed (due to hospital policy during a pandemic) to find the presence of papilledema, which indicates a significant increase in ICP as additional data besides symptoms and signs from a computed tomography scan or magnetic resonance imaging. Second, brain relaxation was not assessed by the same neurosurgeon. This assessment causes bias between observers. Third, this study only used subjective measurement for evaluating brain relaxation. Objective and measurable evaluations by measuring subdural pressure with a special needle and transducer were not carried out due to the lack of available tools. Nevertheless, surgeon’s visual and tactile assessments are still the main foundation for evaluating brain relaxation during surgery, while objective measurement provides valuable and supplements information. Fourth, this study did not use any objective and measurable monitoring tools to assess the depth of anesthesia. Lastly, the measurement of lidocaine plasma levels was not carried out, so it is impossible to know with certainty the plasma levels of lidocaine with the dose of lidocaine in this study (1.5 mg/kg bolus and continued maintenance of 2 mg/kg/h during surgery).

5. Recommendation

Intraoperative continuous intravenous lidocaine can be used as an anesthetic adjuvant for tumor resection craniotomy surgery to improve brain relaxation, reduce intraoperative opioid consumption, and increase the surgeon’s satisfaction while paying attention to contraindications lidocaine administration according to the patient’s clinical condition.

It is necessary to continue the same research using objective and measurable measurements to assess brain relaxation after dura opening (e.g., using a transducer to assess subdural pressure), evaluating the outcome of observing brain relaxation during dura opening by 2 or more assessors (neurosurgeon) for all subjects, using the measurement of the depth of anesthesia, as well as measuring plasma levels of lidocaine, so that it can be known objectively whether the dose is continuous intravenous lidocaine given is still within a safe range or below toxic plasma levels.

6. Conclusion

Intraoperative continuous intravenous lidocaine infusion in craniotomy tumor surgery resulted in better brain relaxation at dura opening, decreased intraoperative fentanyl opioid consumption, and improved surgeon satisfaction. In addition, lidocaine seemed to prevent intraoperative hemodynamic instability during noxious stimulation.

Acknowledgments

We would like to thank all the staff in Cipto Mangunkusumo General Hospital and Faculty of Medicine, Universitas Indonesia for the continuous and unending support for this study.

Author contributions

Conceptualization: Susilo Chandra, Pryambodho, Andy Omega.

Data curation: Andy Omega.

Formal analysis: Andy Omega.

Funding acquisition: Andy Omega.

Investigation: Susilo Chandra, Pryambodho, Andy Omega.

Methodology: Susilo Chandra, Pryambodho, Andy Omega.

Project administration: Pryambodho, Andy Omega.

Software: Andy Omega.

Supervision: Susilo Chandra, Pryambodho.

Validation: Susilo Chandra, Pryambodho, Andy Omega.

Writing – original draft: Andy Omega.

Writing – review & editing: Susilo Chandra, Pryambodho.