Materials and Methods
A multicenter, prospective, randomized, double-blind, controlled, superiority clinical trial using two parallel groups PECS I and PECS II in breast augmentation surgery was conducted from February 2016 to October 2019 in Montpellier and Nîmes teaching Hospitals, France. The Nîmes teaching hospital inclusion center was secondarily added after approval of the institutional review board and amended on clinicaltrial.gov due to the cessation of the aesthetic breast surgery at the Montpellier Center (unexpected surgeon departure). In accordance with the Declaration of Helsinki, the trial was approved by the ethics committee (institutional review board contact information: Comité de Protection des Personnes, Sud Méditerranée I, Montpellier-Nîmes, France, June 21, 2015, identification number 2015-A00678-41.) and was prospectively registered in ClinicalTrials.gov (NCT02682186; first registration: February 15, 2016; Principal investigator: Gérald Chanques). All patients provided written informed consent before inclusion.
Female adult patients, scheduled for prosthetic breast augmentation under general anesthesia, were eligible for participation in the study if they were affiliated with the national health insurance system and had an American Society of Anesthesiologists physical status I to III. Patients were not eligible if they were pregnant or breastfeeding, had cognitive impairment with difficulties in pain evaluation (vulnerable people), were protected minor or major patients with consent incapacity, had an allergy to local anesthetics or any contraindication to use the analgesics of our protocol, had severe coagulopathy, were on treatment for chronic pain, were participating in another research, or were scheduled for revision surgery or prosthesis change (Table 1). The latter criterion was added in October 2017, and the change was reported in the study protocol in clinicaltrial.gov. No other significant change to the protocol involving the design, outcomes, or treatment was made. Exclusion criteria were consent withdrawal or protocol deviation. During preoperative anesthesia consultation, an independent anesthesiologist evaluated eligibility, obtained informed consent, and enrolled the participants.
Patients were randomly assigned in a 1:1 ratio into either the PECS group or the control group using a computerized process. Group allocation and study number were concealed in sealed envelopes and opened on the day of surgery. The patient, the treating anesthesiologist and nurse ("treating team"), and the investigators performing follow-up visits were blinded to the group allocation. An independent anesthesiologist opened the sequentially numbered envelope containing the randomization assignment and performed the PECS block ("interventional team"). In both centers, the most common surgical technique used is breast augmentation with submuscular implants (retropectoral prosthesis) rather than subglandular (prepectoral prosthesis). However, the surgeon's choice was made on a case-by-case basis according to the known advantages and disadvantages of both techniques.
Standardized intraoperative protocol was performed in both groups. General anesthesia was induced with target- controlled infusion of remifentanil (Minto model; effect-site concentration, 4 to 6 ng/ml) and propofol (Schnider model; effect-site concentration, 4 to 6 μg/ml). Glottis local anesthesia with 5% lidocaine was performed for intubation. Immediately after endotracheal tube placement, remifentanil target was lowered to 1 ng/ml, and anesthesia was maintained with sevoflurane in air/oxygen. The remifentanil target was increased to 2 to 3 ng/ml just before surgical incision and then adjusted by 0.3-ng/ml steps to maintain heart rate and arterial blood pressure within 20% of the baseline values, targeting the lowest effective dose. Nitrous oxide, clonidine, dexmedetomidine, and ketamine administration were not allowed. Sevoflurane was maintained between 0.8 and 1.2 of minimum alveolar concentration fraction (measured, age-adjusted, and calculated by the ventilator). All patients were ventilated in volume-controlled mode, received cefazolin (2 g) for infection prophylaxis and 0.1 mg/kg dexamethasone after induction with 1.25 mg droperidol at the end of surgery for postoperative nausea and vomiting prophylaxis.
Immediately after general anesthesia, the "interventional team" replaced the "treating team" for 15 minutes for both groups to ensure the treating team's blinding. In the PECS group, the blocks were performed with patient in the supine position with the arm abducted. The skin was prepared with 2% chlorhexidine gluconate with 70% isopropyl alcohol (ChloraPrep, Becton Dickinson, USA). A high-frequency linear ultrasound probe (11 to 12 MHz, Vivid Q, GE Healthcare, USA) covered with a sterile sheath was placed longitudinally in the subclavian area, inferior to the clavicle, identifying axillary artery and vein, and then moved caudally and laterally so as to see the second and third ribs. The pectoralis major, pectoralis minor, and serratus anterior muscles were then visualized. Subsequently, the pectoral branch of the thoracoacromial artery was identified between the pectoralis muscles and the lateral pectoral nerve that are typically located closed to the artery. PECS was performed through a single puncture if possible and always via in-plane technique. The needle tip was first positioned in the plane between the pectoralis major and minor muscles, and 10 ml of ropivacaine (3.75 mg/ml) was injected. The needle was advanced into the space between the pectoralis minor and serratus anterior muscles, and a further 15 ml of ropivacaine (3.75 mg/ml) was injected. For control group, the PECS was not performed but the ultrasound location of the region of interest was carried out to maintain the blinding of the procedure for the treating team. At the end of the "PECS/control procedure," in both groups, a sterile dressing was applied on the puncture zone. No documentation was reported in the chart for both group. It was only specified in the chart that patients were included in current study to maintain the blind. Then the treating team was allowed to come back and take over anesthesia management.
No local anesthetic infiltration was performed in the surgical area. Thirty minutes before the end of surgery, 1,000 mg acetaminophen, 100 mg ketoprofen, and 20 mg nefopam were infused. The patients were extubated in the PACU, and extubation time defined the beginning of outcomes recording. We used a numerical rating scale from 0 to 10, with 0 for no pain and 10 for worst possible pain. Analgesia was assessed at rest, every 30 min for 2 h in the PACU, and then every 2 h until hour 6 in the ambulatory or surgical ward. If numerical rating scale was between 4 and 6, IV tramadol (50 to 100 mg) was administered according to patient's body weight (50 mg if the patient weighed less than 60 kg), and IV morphine titration, 2 to 3 mg every 5 min if the numerical rating scale was greater than 6. Postoperative nausea and vomiting were treated with IV ondansetron (4 mg). Maximal numerical rating scale and opioid consumption were recorded by nurses on medical charts in the PACU and in wards until the patient's discharge from the hospital and then self-reported by the patients at home. The data regarding the period after discharge from the hospital were recorded during a surgical consultation at day 1 and during an anesthesiological phone interview at day 5. All caring nurses, surgeons, and anesthesiologists who recorded these data were blinded to the allocation group.
At home for ambulatory care or in the surgical ward then at home after discharge, an oral analgesic management was protocolized including systematic 1,000 mg acetaminophen at 6-h intervals and 100 mg ketoprofen at 12-h intervals. If the numerical rating scale was greater than 3, a rescue analgesic was allowed, with 50 to 100 mg tramadol according to body weight or 5 to 10 mg oral morphine if the numerical rating scale was greater than 6. The patients were asked to self-evaluate their pain in the same manner as we had done up to discharge (using numerical rating scale pain score) and to record it at every analgesic consumption up to the end of the fifth postoperative day. We retrieved this data at day 1 during the surgeon's consultation (for the "hour 6 to day 1 period") and at day 5 during a phone interview (for the "day 1 to day 5 period"). Overall opioid consumption was measured using oral morphine equivalents. The conversion of tramadol to morphine was calculated as follows: 100 mg tramadol IV or oral equivalent to 30 or 21 mg oral morphine, respectively; 1 mg IV morphine equivalent to 3 mg oral morphine.
Global satisfaction was also assessed at day 5 using a 0 to 10 numerical rating scale with 0 signifying "completely dissatisfied" and 10 signifying "fully satisfied." All patient evaluation was performed by the anesthesiology treating team blinded to the allocated group. Ambulatory care or overnight hospitalization was left to the patient's choice. The distance between hospital and home and whether or not a third person was present at home were the two main criteria for this choice. Full trial protocol is available by request.
The primary outcome measure was the maximal numerical rating scale measured in the first 6 h after extubation. A priori secondary outcomes were the maximal numerical rating scale from hour 6 to day 1 (surgeon's consultation) and from day 1 to day 5 (phone interview), the intraoperative remifentanil consumption; the postoperative global opioid consumption in oral morphine equivalent, and the incidence of opioid side effects such as postoperative nausea and vomiting, constipation, and pruritus during the first 6 h, from hour 6 to day 1 (surgeon's consultation), and from day 1 to day 5 (phone interview), and global satisfaction at day 5. Any adverse effects, such as hypotension and respiratory depression, were recorded.
The sample size was estimated a priori with calculation based on expected maximal numerical rating scale. We used the studies by Bashandy et al. and McCarthy et al., which respectively found that patients reported a maximal numerical rating scale in the first 6 h of 4.0 ± 1.1 vs. 2.2 ± 0.9 and 4.6 ± 2.1 vs. 3.2 ± 1.8 (P = 0.01), respectively, for the intervention and control groups. Power calculation for an expected absolute difference of 30% in maximal numerical rating scale between the two groups, with a two-tailed α probability level of 0.05 and a power of 0.80 (1 − β) yielded a sample size of 36 patients/group. We initially planned to randomize 80 patients to anticipate possible postrandomization exclusions. This number was increased to 92 potentially randomized patients after the addition of Nîmes Center as a precaution to anticipate possible research issues (i.e., loss of follow-up that could preclude any measurement of the primary outcome). Anyway, the total number of patients needed to be analyzed for the primary outcome (n = 72) was not changed. The statistical analysis was carried out with intention to treat. Per-protocol analysis was planned in case of protocol deviation. Descriptive statistics are reported as number and percentage, mean and SD, or median and interquartile range, and the standardized mean difference between groups was calculated. The normality of the distribution of quantitative variables was determined using the Shapiro–Wilk test. Comparisons of quantitative variables between the two study groups were made using independent sample t test or the Wilcoxon–Mann–Whitney test according to the variable distribution; comparisons of categorical variables were realized using the chi-square test or Fisher's exact test, as appropriate. The primary outcome (maximal numerical rating scale within 6 h after extubation) was evaluated using the t test because of the normal distribution of the variable, as for two other secondary outcomes: the maximal numerical rating scale from hour 6 to day 1 and the maximal numerical rating scale from day 1 to day 5. Other secondary outcomes were evaluated by Wilcoxon–Mann–Whitney test for quantitative variables with nonnormal distribution, by chi-squared test or Fisher test for qualitative variables whenever applicable. The numerical rating scale was recorded every 30 min from extubation to hour 2, and then every 2 h to hour 6 was evaluated by a linear mixed model to take account of repeated measurements in the same patient. The numerical rating scale was the dependent variable. The randomization group and different measurement times were analyzed as fixed effects, and the patient was the random intercept. The slope, the group, and time interaction were tested. P < 0.05 was considered statistically significant. The statistical analyses were performed by a senior independent statistician blinded to the allocation group using SAS Enterprise guide, version 7.1 (SAS Institute, USA).
Anesthesiology. 2021;135(3):442-453. © 2021 American Society of Anesthesiologists | Lippincott Williams & Wilkins