A Comparison Between Scalp Nerve Block and Local Anesthetic Infiltration on the Inflammatory Response, Hemodynamic Response, and Postoperative Pain in Patients undergoing Craniotomy for Cerebral Aneurysms: A Randomized Controlled Trial

The purpose of this study was to compare the effects of the scalp nerve block (SNB) and local anesthetic infiltration (LA) with ropivacaine 0.75% on postoperative inflammatory response, intraoperative hemodynamic response, and postoperative pain control in patients undergoing craniotomy. Moderate to severe postoperative pain after craniotomy has an incidence as high as 80% (1). Uncontrolled postoperative pain may contribute to increased intracranial pressure (ICP) and hypertension, which may be detrimental, especially for patients with cerebral aneurysms(2).Therefore, postoperative pain control should be a priority for neurosurgical patients. An increasing number of studies have suggested that multimodal pain treatment, which combines systemic analgesics local optimizes pain relief and limits adverse effects of For example, scalp nerve block and local infiltration of the have proposed to blunt hemodynamic response to opioid consumption, pain Additionally, both scalp blocks and local anesthetic were recommended for enhanced recovery after surgery for oncological craniotomies, although the current evidence is not sufficient to create a standardized ERAS protocol for oncological craniotomy However, whether scalp nerve block or local infiltration is more effective for analgesia has not been evaluated in craniotomy cerebral aneurysms. can initiate the


Background
Moderate to severe postoperative pain after craniotomy has an incidence as high as 80% (1). Uncontrolled postoperative pain may contribute to increased intracranial pressure (ICP) and hypertension, which may be detrimental, especially for patients with cerebral aneurysms (2).Therefore, postoperative pain control should be a priority for neurosurgical patients.
An increasing number of studies have suggested that multimodal pain treatment, which combines systemic analgesics and local anesthetics, optimizes pain relief and limits adverse effects of opioids (3,4). For example, scalp nerve block and local anesthetic infiltration of the scalp have been proposed to blunt hemodynamic response to craniotomy, decrease opioid consumption, and reduce postoperative pain perception (5)(6)(7).
Additionally, both scalp blocks and local anesthetic infiltration were recommended for enhanced recovery after surgery (ERAS) for oncological craniotomies, although the current evidence is not sufficient to create a standardized ERAS protocol for oncological craniotomy (8). However, whether scalp nerve block or local anesthetic infiltration is more effective for analgesia has not been evaluated in craniotomy for cerebral aneurysms.
Surgery can initiate the inflammatory stress response. Surgical stress induces the migration of inflammatory cells that release cytokines, primarily interleukin (IL)-6, causing a local inflammatory response at the injured site. Then, when cytokines subsequently release into human plasma, systemic inflammation may occur that leads to an increase in C-reactive protein (CRP) and T-and B-cell activation in bone marrow and blood (9). Later, compensatory anti-inflammatory cytokines, such as IL-10, are produced that cause a reduction in pro-inflammatory cytokine synthesis (10,11). Accordingly, acute-phase proteins, such as CRP, and cytokines, such as IL-6 and IL-10, are thought to be early measures of inflammatory response induced by surgical trauma. Local anesthetics via a nerve block have been demonstrated to attenuate the local inflammatory response (12).
For instance, previous animal experiments have demonstrated that C-fiber blockade may inhibit peripheral inflammation in the corresponding innervated zone (12,13). Furthermore, in postoperative patients, peripheral nerve blocks have been shown to attenuate postoperative inflammatory response in knee arthroplasty (14,15). The scalp is densely innervated with C-fibers (unmyelinated) and A-delta fibers (thinly myelinated) (16).
However, as far as we know, no study has attempted to investigate the impact of scalp nerve block on inflammatory response in the craniotomies. Therefore, the goal of this prospective, randomized, controlled study was to compare the impact of scalp nerve block and local anesthetic infiltration with 0.75% ropivacaine on postoperative inflammatory response, intraoperative hemodynamic response, pain scores, and oxycodone consumption in the first 48 hrs postoperatively in patients undergoing craniotomy for cerebral aneurysms.

Patients
After written informed consent was obtained, 57 adult patients (ASA I or II, aged 18 to 65 years) who were scheduled for an elective craniotomy for surgical clipping of cerebral 5 aneurysm located in the anterior cerebral circulation were included.
We did not enroll patients if they (1) had difficult surgical anatomy or multiple or giant aneurysms, (2) had a previous craniotomy incision, (3) had a history of allergy to opioids or local anesthetics, (4) had a history of drug dependence and alcohol abuse, or (5) could not understand a visual analog scale (VAS) or communicate [scheduled to be sedated postoperatively or a GSC (Glasgow coma score) < 14]. The first author (X.Y.) enrolled the patients in the study.

Anesthesia, surgery and postoperative pain relief
The patients included in the current study were anesthetized by the same anesthesiologist and operated on by the same surgeon. Patients received 0.03 mg/kg IV midazolam as a preanesthetic medication, and 0.25 mg prophylaxis of postoperative nausea and vomiting (PONV) was achieved with palonosetron for all patients.
Anesthesia and monitoring were standardized for all patients. Electrocardiography, pulse oximetry, noninvasive blood pressure, end-tidal CO2 (ETCO2), nasopharyngeal temperature, and bispectral index (BIS) were continuously monitored during anesthesia and were recorded at fixed intervals of 5 min. Before anesthesia induction, four electrodes for measuring EEG signals were applied to the patient's forehead, as recommended by the manufacturer (BIS Sensor, Covidien B.V. Zaltbommel, Netherlands), and were used to measure BIS values, signal quality index (SQI) and electromyography (EMG). BIS was displayed using an Aspect EEG monitor (A-2000, version 3.2; Aspect Medical Systems, Newton, M.A.). To reduce skin/electrode impedance, the skin over the forehead was cleaned with an alcohol-impregnated skin wipe. The BIS values were only considered valid when SQI 6 was above 50%. If SQI was < 50% for longer than 20% of the total study period, all data for the patient were excluded from analysis. General anesthesia was induced with 1.5-2.0 mg/kg propofol and 0.5-0.8 µg/kg sufentanil, and 0.2 mg/kg cis-atracurium was administered to facilitate orotracheal intubation. After intubation, we placed an arterial catheter to monitor mean arterial pressure (MAP) and collect a blood sample, and an intravenous catheter was placed in the right jugular vein. After intubation, all patients were ventilated mechanically with a tidal volume of 8 ml/kg, and the respiratory rate was adjusted accordingly to maintain 35-40 mmHg of paCO2 (partial pressure of carbon dioxide in the artery). Then, 4-9 mg/kg/h propofol was infused continuously to maintain anesthesia.
The infusion rate of propofol was adjusted to keep the BIS within 40-60. Remifentanil was adjusted according to the degree of surgical manipulation (0.1-0.5 μg/kg/min). If intraoperative MAP and heart rate (HR) increased by more than 20% from baseline, supplemental doses of 0.5 μg/kg remifentanil were administered, and the infusion rate of remifentanil was increased by 0.05 μg/kg/min. If the increased MAP and HR did not respond to higher remifentanil infusion rate, nicardipine or esmolol was administered, as appropriate. Considering intraoperative neurophysiological monitoring, we did not administer additional neuromuscular blocker during the surgery. Normothermia was maintained throughout the surgery. Volume was replaced by 0.9% sodium chloride and 130/0.4 hydroxyethyl starch. Patients were extubated after the operation in the postanesthetic care unit (PACU) when awake and in a neurologically stable condition before being transferred to the neurosurgical intensive care unit (NICU).
All patients were administered oxycodone (0.1 mg/kg) 30 mins before the end of surgery.
Oxycodone was also used as rescue analgesia in the first 48 hrs postoperatively. Pain was evaluated with visual analogue scale (VAS) scores from 0 to 10 (0 = no pain, 10 = worst pain). If a patient reported a VAS more than 3, 7 an intravenous injection of 2 mg of oxycodone was given by a nurse as the rescue analgesia. This dose was administered at 15-minute intervals until VAS was less than 3.
Oxycodone consumption in the first 48 postoperative hrs and the time to first rescue requirement were recorded.

Randomization
A randomization list was generated, and patients were assigned consecutively to one of three groups by the third author (R.D.), who was not involved in patient care. Scalp nerve block was performed in Group S, local anesthetic infiltration was performed in Group I, and patients in Group C only received sufentanil, remifentanil and oxycodone as analgesics during the intraoperative period.
The patients and the second author (J.M.) who followed the hemodynamic response to skin incision, drew the blood samples, and recorded postoperative pain scores and rescue analgesic consumption were blinded in every case.

Scalp nerve block and local anesthetic infiltration
In Group S, the scalp blocks were performed bilaterally with 15 mL of 0.75% ropivacaine 10 mins before the incision by the anesthesiologist using the method described by Pinosky et al. (17). The supraorbital and supratrochlear nerves emerge from the orbit, and a 25gauge needle was introduced above the eyebrow perpendicular to the skin. These nerves were blocked bilaterally with 4 mL of 0.75% ropivacaine. The zygomatico-temporal nerve emerges lateral to the orbit, equal to the position of pterion, and this nerve was blocked bilaterally with 2 mL of 0.75% ropivacaine. The auriculotemporal nerve was blocked bilaterally 1.5 cm anterior to the ear at the level of the tragus, the needle was introduced perpendicularly to the skin and infiltration was performed deep into the fascia and superficially as the needle was withdrawn. Care must be taken to avoid destroying the superficial temporal artery. These nerves were blocked bilaterally with 2 mL of 0.75% 8 ropivacaine. The greater, lesser, and third occipital nerves were blocked bilaterally with 7 mL 0.75% ropivacaine injected using a 22-gauge needle along the superior nuchal line, approximately halfway between the occipital protuberance and the mastoid process.
In Group I, the surgical incision sites were infiltrated with 15 mL of 0.75% ropivacaine 10 mins before the incision by the neurosurgeon. Neither scalp blocks nor local infiltration was performed in Group C.

Statistical analysis
The data are expressed as the mean ± standard deviation (SD), median and interquartile range (IQR, 25-75% percentile) or number (%). The Kolmogorov-Smirnov test was used to assess the normality and homogeneity of all the variables.
Continuous variables were presented as the mean±SD and analyzed using one-way ANOVA with post hoc correction for multiple comparisons (Bonferroni correction) to determine differences among groups. Categorical variables were described as numbers (%) and were compared using chi-square tests. Biological data (CRP, IL-6, and IL-10 levels) and hemodynamic data (HR, MAP) were compared among groups and over time using repeatedmeasures ANOVA. Nonnormally distributed continuous variables, such as pain scores, were presented as median and interquartile range (IQR, 25-75 percentile) and were analyzed with nonparametric tests (Kruskal-Wallis test and Mann-Whitney U-test with Bonferroni correction).
On the basis of a previous study (7), we assumed that a difference of 20% in MAP was clinically relevant, and setting α equal to 0.05 and β equal to 0.2, we calculated a necessary sample size of 15 patients per group. Values of P < 0.05 were considered significant. SPSS statistical software, version 21.0 (SPSS, Inc, Chicago, Illinois, USA), was used for data analysis.

Patient Demographics and Perioperative Characteristics
Fifty-seven patients agreed and were randomized into the study, and 6 patients were excluded from the study after randomization due to unexpected sedation after surgery and delayed extubation (n=5, 1 in Group C, 2 in Group I and 2 in Group S) or reoperation (n=1 in group I). Thus, the remaining 51 patients were analyzed (18 in Group S, 16 in Group I and 17 in Group C). The consort diagram showed the flow of participants through each stage of a randomized trial (Figure 1).
The three groups were similar in age, gender, BMI, ASA, type of aneurysm, duration of operation, duration of anesthesia, cumulative dose of propofol, total loss of blood, urine volume and infusion volume. There were significant differences among the study groups (F=205.377; P<0.001,  There were no significant differences in HRs between Group S and Group I at any time point (P>0.05) ( Figure 3A).
There were significant differences in MAP among the three groups at T3, T4, T5 and T6 There was no significant difference in oxycodone consumption between Groups I and C (P=0.386) ( Figure 5B).

Pain control-related adverse events during the study period
Adverse events 48 hrs after surgery, such as respiration depression, cutaneous pruritus, subcutaneous hematomas, scalp infection, and local anesthetic toxicity were not observed.
However, the incidence of PONV was significantly different among the three groups 14 (P=0.017, Table 2.). Five patients (29.4%) in Group C, 4 patients (25%) in Group I and 2 patients (11.1%) in Group S suffered from PONV, and PONV occurred less frequently in Group S than Group C ( P=0.012, Table 2). There were no significantly differences in the incidence of fever or dizziness among groups ( P=0.721, P=0.462, respectively, Table 2). Neurogenic inflammation is a process in which substances released by sensory nerve terminals produce inflammation in their target tissue (18). The main trigger of neurogenic inflammation is the activation of primary afferents giving rise to dorsal root reflexes in the spinal cord (19). Blocking the nerve through local anesthetics can reduce the release of substances, such as substance P and calcitonin gene-related peptide, and block neural transmission at the site of tissue injury, thereby alleviating the neurogenic inflammatory response (20). However, the exact mechanisms are still largely 15 unclear.

Discussion
Therefore, it is possible that in the current study, the reduced concentrations of proinflammatory cytokines CRP and IL-6, as well as the increased concentration of antiinflammatory cytokine IL-10 in plasma, compared to local anesthetic infiltration and routine analgesia, were related to the local anti-inflammatory effects of scalp nerve block. It is possible that scalp nerve block has a greater deafferentation effect than local anesthetic infiltration that prevents the development of peripheral and systemic inflammation. There is also evidence suggesting that inflammation and pain are related (21). In the current study, patients in the scalp nerve block group had lower postoperative pain intensity and longer duration before the first dose of oxycodone than patients in the local anesthetic infiltration and routine analgesia groups, supporting our findings that scalp nerve block inhibited craniotomy-induced inflammation.
The effects of neuraxial blockade with local anesthetics on postoperative inflammatory response are still controversial. For example, a previous study suggested that a combined continuous lumbar plexus and sciatic nerve blocks with 0.2% ropivacaine contributed to the attenuation of postoperative inflammatory response, which was demonstrated by decreased CRP and IL-6 concentrations in plasma 24 and 48 hrs postoperatively (14). Another clinical study using more extensive nerve blocks, such as epidural analgesia, have also indicated attenuated ex vivo pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 production after visceral surgery (22). However, Moore and coworkers found that the circulating CRP and IL-6 response to pelvic surgery was unaffected by extradural analgesia (23). This finding is in contrast with the present study where the scalp nerve block inhibited CRP and IL-6. Such discrepancies could originate from the nerve block technique, the type of surgery, and probably the assay used to measure the inflammatory mediator concentration (i.e., ex vivo or in vivo assays).
Of note is that, in our study, scalp nerve block only had modest anti-inflammatory effects.
Previous studies have indicated the impacts of remifentanil on systemic inflammation. For example, remifentanil has been indicated to reduce plasma IL-6 levels on the seventh day after abdominal surgery (24). It has also been demonstrated to inhibit exaggerated inflammation after cardiac surgery with cardiopulmonary bypass (25). In the present study, we found that patients in the scalp nerve block group consumed less remifentanil during the operation than patients in the local anesthetic infiltration group and the routine analgesia group. Therefore, remifentanil requirements may be a confounding factor that hampered the interpretation of the effects of different analgesic modalities on the inflammatory response caused by craniotomy. Furthermore, our study might have been underpowered because of the small study group size, which could also explain the modest antiinflammatory effects of scalp nerve block. Collectively, our findings suggest a potential anti-inflammatory effect of scalp nerve block with 0.75% ropivacaine, pending further investigations.
Acute increases in MAP and HR could be deleterious for neurosurgical patients with cerebral aneurysm, given that acute arterial hypertension and tachycardia may result in ruptured cerebral aneurysms. In the current study, we found that scalp nerve block blunted hemodynamic response to skin incision and dura opening better than local anesthetic infiltration or routine anesthesia. These results are in line with the study by Geze et al (7), in which scalp nerve block with 0.5% bupivacaine was shown to be better at blunting the hemodynamic response to strong nociceptive stimulus, such as head pinning, than local infiltration or routine analgesia (7). However, the it has also been reported that local infiltration promotes intraoperative hemodynamic stability in patients undergoing craniotomy (26)(27)(28). Our study is inconsistent with these studies. The discrepancy may be It is noteworthy that in our study, PONV occurred less frequently in the scalp nerve block group than the local infiltration group and the control group. It is possible that the lower incidence of PONV in the scalp nerve block group was related to less intraoperative remifentanil consumption and postoperative oxycodone use.
The current study has several limitations. First, 0.75% ropivacaine (15 mL, 112.5 mg) was used for the scalp nerve block and local infiltration, but the plasma concentration was not measured, and the maximum recommended dose of ropivacaine is 225 mg with or without epinephrine (32). Furthermore, in our study, no patient developed side effects related to local anesthetic toxicity. Second, we did not apply isotonic sodium chloride for the scalp

Conclusions
In conclusion, the present study shows that scalp nerve block with 0.75% ropivacaine attenuated inflammatory response to craniotomy for cerebral aneurysms, blunted hemodynamic response to scalp incision, and controlled postoperative pain better than  Values are expressed as mean±SD or number of patients(%).
Group C: control group, Group I: local anesthesic infiltrationgroup, Group S: scalp nerve block group.

24
The differences among groups were not significant except for the consumption of remifentanil and the use of nicardipine.
# P<0.05 for Group I and Group S compared with group C. *P < 0.05 among three groups.
Abbreviations: ASA = American society of Anaesthesiologists, NA = not applicable, NS = not significant