Ultrasound-Guided Pectoral Nerve Block With Tr Ansverse Thoracic Muscle Plane Block Enhanced World Health Organization on Quality of Life Brief Scale Scores 6 Months After M Odi ed Radical Mastectomy : A Randomized, Placebo-controlled and Double-Blind Clinical Trial

Tianxiao Liu Guangxi Medical University First A liated Hospital Lina Chen Guangxi Medical University First A liated Hospital Min Shi Guangxi Medical University First A liated Hospital Weixin Dai Guangxi Medical University First A liated Hospital Jing Chen Guangxi Medical University First A liated Hospital Yubo Xie (  xybdoctor@163.com ) Guangxi Medical University First A liated Hospital https://orcid.org/0000-0002-7198-7506


Introduction
According to the 2018 global cancer statistics published by the American Cancer Society, 24.2% of the 8.6 million new cases of female cancer were breast cancer patients, ranking rst in female cancer incidence. Approximately 630,000 women die of breast cancer every year (1). Surgical resection is the most important treatment for breast cancer at present. The wide incision easily causes a strong perioperative stress response and may lead to chronic pain and intractable pain after the operation. The incidence of persistent pain after breast cancer surgery (PPBCS) is 15-25%, and some patients' postoperative pain lasts for several years (2). When ultrasound guided nerve block is applied during the perioperative period in breast cancer patients, it can signi cantly shorten the anesthesia time, reduce the amount of intraoperative infusion, reduce the incidence of postoperative complications, improve the comfort of patients, effectively promote the rehabilitation of patients, and improve the quality of life of patients with breast cancer. The aim of our current study was to evaluate the effect of the ultrasoundguided Pec + Pec +TTP block in patients with MRM, the relevant indexes after the operation and the impact on the long-term quality of life of patients to provide a reference for the selection of an anesthesia scheme during the perioperative period in breast cancer patients.
The primary hypothesis was that the implementation of ultrasound-guided Pec + Pec +TTP block would reduce the level of in ammatory factors and improve the long-term quality of life and the incidence of chronic pain.

Materials And Methods
This randomized, placebo-controlled and double-blind study was conducted at the Department of Anesthesiology at the First A liated Hospital of Guangxi Medical University, from 29 May 2020 to 23 Sep. 2020. The study was conducted according to the Consolidated Standards of Reporting Trials statement.

Study design
The inclusion criteria were participants with an American Society of Anesthesiologists class , an age ≥ 18 years, a BMI ≤ 30 kg/m 2 and scheduled for MRM. The exclusion criteria were participants with an inability to cooperate, an allergy to local anesthetics (LA) or opioids, a local infection at the site of injection or systemic infection and Pecs , and TTP block administration failure. One day before the operation, a routine preoperative visit was carried out to obtain the understanding and cooperation of patients, and all preoperative preparations were made. After entering the OR, peripheral venous access was routinely achieved, and noninvasive blood pressure, pulse oxygen saturation and bispectral index (BIS) were monitored.
Anesthesia maintenance: During the operation, target-controlled input (TCI) propofol and remifentanil to maintain a BIS of 40 ~ 55 so that heart rate and blood pressure would not exceed 10% of the base value and rocuronium were administered intravenously at a single dose of 0.1-0.2 mg/kg. Patients in both groups were given an intravenous patient-controlled analgesia (PCA) pump 15 minutes before the end of surgery. The PCA pump containing 1 µg/ml sufentanil with the following settings: background dose of 3 ml/h, press dose of 3 ml/h, lockout time of 20 min and maximum of 10 ml/h. Patients were instructed to administer a bolus whenever the numerical rating scale (NRS) pain scores exceeded 3/10. All patients were transferred to the postanesthesia care unit (PACU) after surgery.

Blinding
Participants were randomly assigned to receive either active or placebo unilateral Pecs , , TTP block.
The random number table method was used to ensure equal distribution in the two groups. A resident, not involved in the anesthesia of the study participants, would open the sealed opaque envelope containing the group allocation and (according to written instructions) prepare two 40-mL syringes with either 40 mL of 0.25% ropivacaine or 0.9% saline. Thereafter, another resident controlled the procedure, and both signed the allocation paper before resealing the envelopes. The envelopes would only be opened by the investigators at the end of the study. Thus, the investigators, participants, care providers and those assessing outcomes were all blinded to the group allocation.
Pecs , , and TTP block procedure After general anesthesia, the Pecs , , and TTP block procedures were performed with the patient in the supine position with the arm abducted using an ultrasound unit (SonoSite M-Turbo) and a high frequency linear probe (6 ~ 13 MHz). The skin was prepared with the application of iodophor and covered with a sterile hole towel. The ultrasound probe was covered with a sterile plastic sheath. Pecs block (3): Using a similar probe position to that used when performing an infraclavicular brachial plexus block. Once the pectoralis major muscle (PMm) and pectoralis minor muscle (Pmm) had been identi ed, the location of the pectoral branch of the thoraco-acromial artery between the pectoralis muscles was checked with color Doppler. The lateral and median pectoral nerves were consistently located adjacent to the artery. A 22G, 100-mm needle (PAJUNK, UniPlex NanoLine, Germany) was in ltrated into the interfacial plane with 10 ml of 0.25% ropivacaine. Pecs block (4): The ultrasound probe was placed at the midclavicular level inferolaterally to locate the axillary artery and vein and was then moved laterally until the lateral border of the Pmm and serratus anterior muscles (Sam) were identi ed at the level of the third rib. The 22G, 100mm needle was advanced in the potential space between the Pmm and Sam, and 20 ml of 0.25% ropivacaine was deposited in this space. TTP block: The TTP block injection was administered as follows: 10 ml of 0.25% ropivacaine was injected between the transversus thoracic muscle and the internal intercostal muscle between the third and fourth left ribs connecting at the sternum. The nerve block procedure described above and ultrasonic image processing were completed by the same skilled anesthesiologist (> 200 blocks).

Outcome measures
The primary outcomes were the changes in CRP, IL-6 and WBC values on the rst day before the operation and the rst and third days after the operation, the changes in blood glucose levels before and after surgery, and the World Health Organization on QOL scores evaluated 6 months after the operation.
The secondary outcomes were the NRS pain scores of the patients 3, 6, 12, 24 and 48 hours after the operation, the operation time, the length of stay, the consumption of propofol and remifentanil during the operation, and the press times of the PCA pump at different time points after the operation; postoperative nausea and vomiting (PONV) was assessed using a four-point numerical scale (0 = no PONV, 1 = mild nausea, 2 = severe nausea or vomiting once, and 3 = vomiting more than once), and adverse events were assessed including pneumothorax, vascular puncture, and local anesthetic toxicity.
The QOL scores was used to investigate the patients six months after surgery, and the evaluation included appetite, mental state, sleep quality, physical activity, postoperative chronic pain, family understanding and support, and patients' attitudes toward treatment and daily life. The total score was 60: a score of 51 ~ 60 was considered excellent, 41 ~ 50 was good, 31 ~ 40 was average, 21 ~ 30 was poor, and < 20 was extremely poor quality of life.
Statistical analysis and sample size calculation IBM SPSS Statistics version 23 was used to test the normality of data by the Kolmogorov-Smirnov test.
The normally distributed data were compared using Student's unpaired t test, whereas nonparametric data were compared by the χ2 test or Fisher's exact test for intergroup differences. Variables are presented as the mean (SD), median (IQR), and range. The following variables were compared by using the Mann-Whitney U-test for pairwise comparisons: CRP, IL-6, WBC, and blood glucose values; NRS pain scores; length of stay; PONV numerical scale scores; and press times of the PCA pump.
Con dence intervals were calculated for statistically signi cant differences. The sample size was calculated on the basis of a pilot study. This pilot study revealed that the median (IQR) CRP and IL-6 levels were 22 (19.75-24.25) mg/l and 22.35 (13.6-26.375) pg/ml, respectively, on the rst day after the operation. For a difference in the 50% reduction of CRP and IL-6 levels on the rst day after the operation at a signi cance level of 0.05 (two sided) and power of 0.8, we required a minimum of 33 patients in each group. Assuming a 15% loss rate at the 6-month follow-up, we eventually enrolled 38 patients in each group.

Results
One hundred patients scheduled for MRM were screened for eligibility, and 76 participants were enrolled ( Fig. 1). Two patients lost contact, ve patients refused to conduct a questionnaire survey during followup, one patient developed tumor recurrence, and the other patient was seriously ill and died within 6 months after surgery. All the above patients were withdrawn from the follow-up study.

Discussion
As is well known, MRM is associated with a large incision range, high intraoperative stress, a high incidence of postoperative acute pain, and long-term development of chronic pathological pain. Regional block has been used to optimize perioperative analgesia management, reduce the consumption of opioids, and promote the recovery of gastrointestinal function, and early postoperative functional exercise has been conducive to the rehabilitation of patients. This management mode has achieved remarkable results in the operation of patients with liver cancer (5), gastric cancer (6) and colorectal cancer (7). It can effectively reduce the stress response of patients during the perioperative period, accelerate the recovery of patients, reduce the length of hospital stay, and reduce the economic burden of patients.
At present, most studies focus on reducing the consumption of opioids and the postoperative pain scores of breast cancer patients after MRM by Pecs nerve block or thoracic paravertebral block (8). However, there are few studies on the objective evaluation of the perioperative stress response by some stressrelated serological indicators and on the long-term follow-up evaluation of postoperative quality of life and the incidence of chronic pain.
In our study, ultrasound-guided Pecs , , and TTP block signi cantly reduced CRP, IL-6 and WBC values; signi cantly increased the QOL scale scores and the incidence of chronic pain 6 months after the operation; signi cantly reduced the consumption of opioids during and after the operation; signi cantly reduced the NRS pain scores at each time point after the operation; signi cantly reduced the PONV scores; shortened the length of stay; and promoted the rapid recovery of patients.
Since Blanco et al. proposed a series of novel types of nerve block, Pecs (3), Pecs (9), and anterior serratus plane block (10), these new techniques have been widely used in clinical practice. With the deepening of clinical practice, limitations have been constantly reported, such as the fact that Pecs block is not able to block the anterior branches of those nerves (2nd ~ 6th), which collect the sensory innervation of the medial part of the breast (11). Ueshima (12) et al. proposed the TTP, which can effectively block the medial breast region. Our study con rmed that the intraoperative consumption of propofol and remifentanil was signi cantly reduced in patients with Pecs , Pecs and TTP combined with general anesthesia, the need for analgesics was reduced within 48 hours after surgery, and the length of stay was shorter, which was consistent with some studies (13). In addition, we also observed that the NRS pain score in group PT was lower than that in group C. However, the duration of the analgesic effect was much longer than that of local anesthetics. We considered that the regional block may be associated with the reduction of peripheral and central pain sensitization due to lower levels of in ammation and a better immune response (14). The CRP, IL-6 and WBC values in group PT were signi cantly lower than those in group C on the rst day after the operation, and the CRP level was still signi cantly lower than that in group C on the third day after the operation, which indicated that Pecs , Pecs and TTP block could effectively reduce the stress response of MRM, even lasting until the third day after operation. This may partly explain why the NRS score 48 h after the operation was still lower than that in group C.
It has been the common goal of all doctors to promote the rapid recovery of cancer patients. Rapid recovery should not only reduce the pain of patients but also reduce the hospitalization expenses of patients, which is very important for both patients and medical insurance bureau. Moreover, it should improve the long-term quality of life of patients and reduce the recurrence and metastasis of cancer. Our study also has some limitations: the QOL scores evaluation was only conducted 6 months after surgery, and no longer follow-up evaluations were conducted. In the future, we will carry out a longer follow-up evaluation to observe the QOL scores of these patients. It has been reported that regional block can reduce the recurrence and metastasis of tumor patients. However, this idea is still controversial, and more multicenter studies are needed to eliminate multiple interfering factors. Therefore, we plan to continue to observe whether the Pecs , Pecs and TTP block, is associated with cancer recurrence and metastasis in breast cancer patients postoperatively.

Conclusions
Ultrasound-guided Pecs , , and TTP block signi cantly reduced the CRP, IL-6 and WBC values; signi cantly increased the QOL scores and the incidence of chronic pain 6 months after the operation; signi cantly reduced the consumption of opioids during and after the operation; signi cantly reduced the NRS pain scores at each time point after the operation; signi cantly reduced the PONV scores; shortened the length of stay; and promoted the rapid recovery of patients. Declarations Ethics approval and consent to participate Ethical approval was obtained from the ethics committee of the First A liated Hospital of Guangxi Medical University (KY-E-093). Written informed consent was obtained from all participants before enrolling for the study. No data from participants are reported.

Consent for publication
Not applicable.

Availability of data and materials
The datasets generated and/or analysed during the current study are held by the First A liated Hospital of Guangxi Medical University. Any requests for anonoymised data should be made to First A liated Hospital of Guangxi Medical University