Quality of Recovery After Breast Surgery: A Multicenter Randomized Clinical Trial Comparing Pectoral Nerves Interfascial Plane (Pectoral Nerves II) Block With Surgical Infiltration : Anesthesia & Analgesia

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Quality of Recovery After Breast Surgery: A Multicenter Randomized Clinical Trial Comparing Pectoral Nerves Interfascial Plane (Pectoral Nerves II) Block With Surgical Infiltration

Barrington, Michael J. PhD*,†; Seah, Gloria J. FANZCA*,‡; Gotmaker, Robert MBiostat*; Lim, Daniel MPharmPrac§; Byrne, Kelly FANZCA

Author Information
doi: 10.1213/ANE.0000000000004371

Abstract

KEY POINTS

  • Question: Do pectoral nerve (PECS II) blocks improve patient-reported quality of recovery after breast surgery?
  • Findings: In this randomized clinical trial, there were no differences in patient-reported quality of recovery in patients who received PECS blocks compared to those who received local infiltration.
  • Meanings: PECS II blocks did not improve quality of recovery after minor breast surgery.

See Article, p 1556

Acute postoperative pain after breast cancer surgery is a risk factor for persistent postsurgical pain. The severity of acute pain and incidence of chronic pain after breast surgery are reduced by high-quality postoperative analgesia provided by techniques such as epidural and paravertebral blockade.1

Ultrasound-guided blockade of the pectoral and intercostal nerves, known as “pectoral nerves (PECS II) block,” was developed as a less invasive regional analgesia technique for breast surgery compared to paravertebral block. Distinguishing features of PECS block are the ease with which the sonographic landmarks can be identified and the block performed. PECS block has been shown to reduce postoperative pain scores and opioid consumption after breast surgery in randomized clinical trials.2,3 Further trials are required to improve both the robustness of the evidence and generalizability of previous results when PECS block is used for breast surgery.

Thus, in this randomized clinical trial, we tested the primary hypothesis that a PECS block when compared to local anesthetic infiltration by the surgeon will improve global score of the multidimensional (pain, comfort, independence, psychological, emotional) patient-reported quality of recovery (QoR)-15 questionnaire measured 24 hours postoperatively.4 Our secondary hypothesis is that PECS block will reduce persistent pain and its interference with physical and emotional functioning at 3 months measured using the Brief Pain Inventory.

METHODS

This was a multicenter, parallel-group, randomized superiority clinical trial. This study was conducted at St Vincent’s Hospital Melbourne, Victoria, Australia, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia, and Waikato Hospital, Hamilton, New Zealand. The Human Research Ethics Committees’ of St Vincent’s Hospital, Melbourne (HREC/16/SVHM/7), Peter MacCallum Cancer Centre (HREC16/166), and the Health and Disability Ethics Committees, New Zealand (17/STH/63) approved this study, and written informed consent was obtained from all subjects participating in the trial. The trial was registered before patient enrollment at the Australian and New Zealand Clinical Trials Registry (ANZCTR; ID12616000298415; principal investigator: G.J.S.; date of registration: March 7, 2016). This study conforms to reporting standards of the Consolidated Standards of Reporting Trials (CONSORT) and the CONSORT extension for trials reporting patient-rated outcomes.5,6

Eligibility criteria were as follows: female, 18–80 years of age, American Society of Anesthesiologists physical status I–III patients having elective unilateral breast surgery (wide local excision with sentinel lymph node biopsy, axillary clearance/dissection, mastectomy, partial mastectomy, mastectomy with no reconstruction, or implant). Exclusion criteria were body mass index >40 kg/m2, pregnancy, and inability to understand English or communicate with research personnel; allergy or contraindication to drugs on protocol; or had alcohol, substance abuse, or opioid dependence.

Study Intervention, Randomization, and Blinding

The randomization schedule was computer generated in 1:1 permuted blocks of 4 stratified by breast surgery involving mastectomy or surgery not involving mastectomy (eg, wide local excision). Personnel not involved in the trial prepared study group assignments. At St Vincent’s Hospital, Melbourne, and Peter MacCallum Cancer Centre, group assignments were stored in the pharmacy at St Vincent’s Hospital. At Waikato Hospital, group assignments were stored in opaque sealed envelopes prepared externally. Personnel not involved in the trial and not involved in the clinical care of the patient prepared identical syringes containing study injectate (local anesthetic or 0.9% saline). The study injectate was either 0.45 mL/kg ropivacaine 0.475% or the same volume of 0.9% saline (maximum volume was 40 mL). Participants were randomly allocated to either PECS or infiltration groups. Those randomly allocated to the PECS group received a PECS II block with local anesthetic and surgical infiltration with 0.9% saline. Participants randomly allocated to the infiltration group received a PECS block with 0.9% saline and surgical infiltration with local anesthetic. That is, all participants received both interventions, with local anesthetic at one location and 0.9% saline at the other location, depending on group allocation. Study participants, health care providers (the anesthetist performing the intervention, anesthetic nurse, the surgeon, anesthetist providing intraoperative care, other theater and ward doctors, nurses), and research personnel were blinded to group allocation. The PECS block intervention was performed 20–30 minutes before surgical incision. A linear array high- or intermediate-frequency ultrasound transducer in a sterile sleeve was placed in longitudinal orientation so that the pectoralis major and minor muscles were imaged in the sagittal plane. The transducer was translated caudally and posteriorly toward the midaxillary line to identify the third to sixth ribs and the serratus anterior muscle. An in-plane technique (injecting either the local anesthetic: ropivacaine 0.475% or 0.9% saline) was performed using a 100-mm 21-gauge SonoPlex needle (Pajunk, Geisingen, Germany). The study injectate was injected between (1) the pectoralis major and minor muscles (0.2 mL/kg) over the third rib and (2) the pectoralis minor and serratus anterior muscles (0.25 mL/kg) over the fourth to fifth ribs. Surgical preference resulted in the protocol defining surgical infiltration of local anesthetic or 0.9% saline in the subcutaneous and cutaneous tissues toward completion of the surgery.

Study participants received standardized anesthetic and multimodal analgesic regimens. Preventive analgesia comprised oral paracetamol 1 g and sustained release tapentadol 50 mg or oxycodone 10 mg (depending on availability), 60 minutes preoperatively. Anxiolysis and further analgesia were provided with intravenous (IV) midazolam and fentanyl. General anesthesia was induced with fentanyl 1–2 µg/kg and propofol 1–2.5 mg/kg. Choice of airway and additional intraoperative fentanyl were at the discretion of the anesthetist. Anesthesia was maintained with sevoflurane. Intraoperative monitoring comprised monitors mandated by the Australian and New Zealand College of Anaesthetists. Antiemetic therapy comprised dexamethasone 4 mg and ondansetron 4 mg. In the postanesthesia care unit (PACU), pain was assessed using a Numerical Rating Scale (NRS; 0–10: 0, no pain; 10 worst imaginable) and was recorded. Fentanyl 25 µg IV was titrated every 5 minutes to 200 µg (or 100 µg if over 70 years) until their NRS <3. The postoperative analgesic regimen consisted of regular oral paracetamol 1000 mg every 6 hours and oral opioids: either tapentadol 50 mg or oxycodone 5–10 mg according to availability. Oral morphine equivalence was calculated using oral morphine equivalence conversions: fentanyl 0.2, tapentadol 0.4, and oxycodone 1.5.7

Outcome Measures

The primary outcome was the global score of the QoR-15, a multidimensional patient-reported instrument that has been used to assess functional recovery. QoR-15 comprises 5 domains of testing: pain (2 questions), physical comfort (5 questions), physical independence (2 questions), psychological support (2 questions), and emotional state (4 questions). Each question uses a 10-point scale ranging from 0 = “none of the time” to 10 = “all of the time” (scoring is reversed for negative questions).4 The sum of the individual domains generates an aggregate (or global) score with the maximum score (best recovery) obtained being 150. A QoR-15 score of 118 is considered consistent with good recovery and the difference in QoR-15 that patients consider important, the minimal clinically important difference has been estimated as 8.8 The QoR-15 score was administered before surgery (baseline) and at 24 hours postoperatively.

The secondary outcome was the global score of the Brief Pain Inventory (short form).9 The Brief Pain Inventory instrument assesses 2 domains: pain and pain-related interference with physical and emotional functioning. Pain is evaluated with 4 questions with “worst,” “average,” “least,” and “current” pain levels each assessed using a NRS (0–10: 0, no pain; 10 worst imaginable), with the pain subscale ranging from 0 (optimal) to 40 (worst possible). A further question on relief provided by pain treatments is calculated as follows: percentage pain relief divided by 10 and then subtracted from 10 (0, complete relief; 10, no relief). Pain-related interference with physical and emotional functioning is evaluated with 7 questions using an 11-point Likert scale (0, no interference; 10 complete interference with general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). The interference subscale ranges from 0 (optimal) to 70 (worst possible). Values for the global score of the Brief Pain Inventory (0, optimal; 120, worst possible) comprise pain and interference subscales combined with the question on percentage relief. A lower Brief Pain Inventory score indicates less dysfunction. An initial question asks patients to localize their pain. The Brief Pain Inventory was administered postoperatively 24 hours and at 3 months.

Statistical Methods

The primary outcome measure was the global score of the QoR-15 measured 24 hours postoperatively. Continuous or discrete baseline characteristics were described using median and quartiles or mean and standard deviation (SD) as appropriate. Categorical data were summarized with frequencies and proportions. Standardized differences were reported to compare imbalance in baseline characteristics. The standardized difference is the difference in group means or proportions scaled by the pooled SD.10 Differences <0.1 in prognostic baseline covariates were considered negligible, and differences <0.2 were considered small. Adjustment for baseline covariates with >20% imbalance would be performed as part of a sensitivity analysis. We assessed the effect of PECS block versus local anesthetic infiltration on all continuous and discrete outcome measures using the Wilcoxon rank-sum test and reported the Hodges–Lehmann estimate and 95% confidence interval (CI).11 The 2-sample Hodges–Lehmann estimate of the median difference is the median of all (n1 × n2) pairwise differences between observations in the 2 study groups, where n1 and n2 are the 2 respective sample sizes. We refer to the Hodges–Lehmann estimate as the median difference noting that this is not necessarily equal to the difference in the medians of the 2 groups. The median difference is reported as infiltration minus PECS. Robust 95% CIs for the median pairwise difference were estimated using the “cendif” program in Stata Version 14 (StataCorp, College Station, TX).12 To account for baseline QoR-15 imbalance between groups, a sensitivity analysis using quantile regression was performed. The median, 25th and 75th quantiles of the 24-hour QoR-15 were compared between groups after adjusting for baseline QoR-15 scores. This is similar to using linear regression to estimate the conditional mean after adjusting for baseline values in an analysis of covariance. For all analyses, P value <.05 was considered statistically significant.

Sample Size Estimation.

We estimated that 84 participants would be required to detect a minimal clinically important difference of 10 (SD, 14) in the QoR-15 score with 2-sided α of .05 and power of 0.9 using an independent samples t test. The expected SD for the sample size calculation was estimated by Stark et al.4 To allow for loss to follow-up, greater than expected variance in QoR-15, and nonparametric hypothesis testing, we increased the sample by 20 participants to 104. The sample size calculation and analyses were performed using Stata Version 14.

RESULTS

Table 1. - Patient and Procedural Information
Characteristic PECS
(n = 53)
Infiltration
(n = 51)
Standardized Difference
Age, y 60.0 (10.3) 59.2 (11.3) 0.072
Weight, kg 76.4 (14) 77.7 (15.7) 0.082
Height, cm 164.4 (6.0) 163.2 (6.7) 0.181
Diabetes mellitus, n (%) 3 (6) 3 (6) 0.001
ASA physical status III, n (%) 7 (13) 9 (18) 0.123
Baseline QoR-15 135 [129, 143] 139 [127, 143] 0.033
Wide local excision, n (%)
 With sentinel node dissection 38 (72) 32 (63) 0.190
 With axillary clearance 6 (11) 8 (16) 0.126
 Alone 4 (8) 4 (5) 0.011
Mastectomy, n (%)
 With axillary clearance 3 (6) 4 (8) 0.086
 Alone 2 (4) 3 (6) 0.097
Fentanyl, µg
 During block 25 [0, 50] 0 [0, 50] 0.007
Surgical duration (min) 80 [70, 103] 92 [74, 115] 0.087
Values reported as mean (standard deviation), frequency (%), or median [quartiles] as appropriate. The standardized difference is the difference in group means scaled by their pooled standard deviation. Absolute standardized differences of <0.1 are considered negligible.
Abbreviations: ASA, American Society of Anesthesiologists; PECS, pectoral nerves; QoR, quality of recovery.

F1
Figure 1.:
Patient flow through study. BMI indicates body mass index; PECS, pectoral nerves.

From August 17, 2016 to June 8, 2018, 108 patients were recruited. Of 277 patients who were assessed for eligibility, 90 did not meet the inclusion criteria, 36 declined to participate, 34 were not recruited because of resource/logistical issues, and 9 were recruited to an alternate trial (Figure 1). After recruitment, 4 patients were withdrawn before receiving the study intervention (2 patients because of concerns expressed by surgeon that the intervention would interfere with the surgery, 1 patient had clinical features consistent with anaphylaxis and surgery was abandoned, and 1 patient did not receive preoperative oral analgesia required by protocol). The primary outcome, QoR-15 global score, was analyzed for 104 study participants (Figure 1). Patient and procedural information is described in Table 1, with 12 patients from 104 having mastectomy. The baseline QoR-15 global score reported as median [quartiles] was 135 [129, 143] in the PECS group and 139 [127, 143] in the infiltration group (Tables 1 and 3). Irrespective of group allocation, the QoR-15 global score reported as median [quartiles] was 137.5 [127, 143] at baseline and 129 [117, 142] at 24 hours (P < .001). The change in QoR-15 global score from baseline to 24 hours, reported as median [quartiles], was 4 [−2, 17] in the PECS group and 7 [−5, 20] in the infiltration group (P =.84), with a median difference (95% CI) of 1 (−5 to 7).

Primary Outcome

The 24-hour QoR-15 global score reported as median [quartiles] was 131 [116, 140] in the PECS group and 123 [117, 143] in the infiltration group (P =.60), with median difference (95% CI) of −2 (−9 to 5) (Figure 2, Tables 2–3). The median difference (95% CI) between groups for QoR-15 domains were pain 0 (−2 to 1), physical comfort −1 (−3 to 2); physical independence 0 (−2 to 1), psychological support 0 (0–0), and emotions 0 (−1 to 2) (P > .28) (Tables 2–3). The number of patients (n [%]) with a QoR-15 global score ≥118 (good recovery) was 38 (72) in the PECS group and 38 (75) in the infiltration group (P = .83). The number of patients with a reduction in QoR-15 of 8 (minimal clinically important difference) or greater was 22 (42) and 24 (47) (n [%]) (P = .69). The individual QoR-15 items with results at both baseline and 24 hours are listed in Table 3.

Table 2. - Results
Outcome PECS
(n = 53)
Infiltration
(n = 51)
Median Difference P Valuea
QoR-15
 QoR-15 (24 h) 131 [116, 140] 123 [117, 143] −2 (−9 to 5) 0.60
 QoR-15 domains (24 h)
  Pain 17 [14, 19] 16 [13, 19] 0 (−2 to 1) 0.88
  Physical comfort 43 [38, 48] 42 [37, 47] −1 (−3 to 2) 0.62
  Physical independence 16 [13, 18] 15 [13, 18] 0 (−2 to 1) 0.84
  Psychological support 20 [20, 20] 20 [20, 20] 0 (0–0) 0.29
  Emotions 35 [30, 38] 36 [30, 38] 0 (−1 to 2) 0.57
BPI 24 h
 Pain subscale 7 [2, 13] 10 [5, 17] 2 (−1 to 5) 0.15
 Interference subscale 11 [3, 21] 10 [2, 24] 0 (−4 to 5) 0.84
 Percentage relief 90 [80, 100] 90 [70, 100] 0 (−10 to 0) 0.46
 Total 20 [7, 36] 23 [10, 43] 4 (11 to −4) 0.34
BPI 3 mo
 Pain subscale 0 [0, 6.5] 0 [0, 4] 0 (0–0) 0.72
 Interference subscale 0 [0, 4] 0 [0, 5] 0 (0–0) 0.96
 Percentage relief 100 [75, 100] 100 [100, 100] 0 (0–0) 0.48
 Total 0 [0, 14] 0 [0, 11] 0 (0–0) 0.85
Other outcomes
 PACU duration, min 60 [38, 105] 65 [40, 95] −4 (−18 to 10) 0.64
 Hospital duration, d 1 [0, 1] 1 [0, 1] 0 (0–0) 0.50
 Intraoperative fentanyl, µg 150 [100, 250] 200 [125, 250] 25 (−20 to 50) 0.34
 Fentanyl, PACU, µg 0 [0, 50] 0 [0, 75] 0 (0–0) 0.94
 PACU morphine oral equivalents, mg 0 [0, 20] 7.5 [0, 20] 0 (0–1) 0.61
 PACU, worst pain score (0–10 NRS) .5 [0, 5] 2 [0, 6] 0 (0–2) 0.21
 Oral morphine equivalents 24 h, mg 20 [0, 40] 20 [0, 60] 0 (0–15) 0.62
Values reported as median [quartiles]. The median difference (reported with 95% confidence intervals) is the median of all pairwise differences between observations in the 2 groups. It is not the difference between the group medians.
Abbreviations: BPI, brief pain inventory; NRS, Numerical Rating Score; PACU, postanesthesia care unit; PECS, pectoral nerves; QoR, quality of recovery.
aWilcoxon rank-sum test used to compare distributions of outcome measures.

Table 3. - Individual Quality of Recovery-15 Responses, Domain, and Global Scores at Baseline and at 24 Hours
Outcome Baseline 24 h Median Difference
PECS
(n = 53)
Infiltration
(n = 51)
PECS
(n = 53)
Infiltration
(n = 51)
Quality of recovery-15 item scores
 1. Able to breathe easy 10 [9, 10] 10 [9, 10] 10 [10, 10] 10 [9, 10] 0 (0–0)
 2. Been able to enjoy food 10 [10, 10] 10 [9, 10] 10 [8, 10] 10 [8, 10] 0 (0–0)
 3. Feeling rested 8 [7, 9] 9 [7, 10] 8 [6, 10] 8 [7, 10] 0 (0 to −1)
 4. Have had a good sleep 7 [6, 10] 7 [5, 9] 7 [5, 9] 6 [4, 9] 0 (0 to −1)
 5. Able to look after personal toilet and hygiene 10 [10, 10] 10 [10, 10] 10 [9, 10] 10 [9, 10] 0 (0–0)
 6. Able to communicate with family and friends 10 [10, 10] 10 [10, 10] 10 [10, 10] 10 [9, 10] 0 (0–0)
 7. Getting support from hospital doctors and nurses 10 [10, 10] 10 [10, 10] 10 [10, 10] 10 [10, 10] 0 (0–0)
 8. Able to return to work or usual home activities 10 [10, 10] 10 [9, 10] 7 [3, 8] 5 [4, 8] 0 (0 to −1)
 9. Feeling comfortable and in control 10 [8, 10] 10 [8, 10] 9 [8, 10] 8 [7, 10] 0 (0 to −1)
 10. Having a feeling of general well-being 9 [8, 10] 10 [8, 10] 9 [7, 10] 9 [7, 10] 0 (0 to −1)
 11. Moderate pain 10 [9, 10] 10 [9, 10] 7 [5, 9] 7 [5, 9] 0 (0 to −1)
 12. Severe pain 10 [10, 10] 10 [10, 10] 10 [8, 10] 10 [8, 10] 0 (0–0)
 13. Nausea and vomiting 10 [10, 10] 10 [10, 10] 10 [9, 10] 10 [9, 10] 0 (0–0)
 14. Feeling worried or anxious 7 [6, 9] 8 [5, 9] 10 [7, 10] 9 [8, 10] 0 (0–0)
 15. Feeling sad or depressed 9 [8, 10] 9 [8, 10] 10 [9, 10] 10 [9, 10] 0 (0–0)
Quality of recovery-15 domain scores
 Pain (0–20) 20 [19, 20] 20 [19, 20] 17 [14, 19] 16 [13, 19] 0 (−2 to 1)
 Physical comfort (0–50) 44 [41, 48] 45 [39, 48] 43 [38, 48] 42 [37, 47] −1 (−3 to 2)
 Physical independence (0–20) 20 [19, 20] 20 [19, 20] 16 [13, 18] 15 [13, 18] 0 (−2 to 1)
 Psychological support (0–20) 20 [20, 20] 20 [20, 10] 20 [20, 20] 20 [20, 20] 0 (0–0)
 Emotions (0–40) 35 [30, 38] 36 [30, 38] 35 [30, 38] 36 [30, 38] 0 (−1 to 2)
Quality of recovery-15 total score (0–150) 135 [129, 143] 139 [127, 143] 131 [116, 140] 123 [117, 143] −2 (−9 to 5)
Values reported as median [quartiles]. The median difference (reported with 95% confidence intervals) is the median of all pairwise differences between observations in the 2 groups. It is not the difference between the group medians.
Abbreviation: PECS, pectoral nerves.
aWilcoxon rank-sum test was used to compare distributions of outcome measures. Quality of recovery; items 1–10 preceded by question “How have you been feeling in the past 24 h?” and evaluated using rating scale 0–10, where 0 = none of the time (poor) and 10 = all of the time (excellent). Items 11–15 preceded by question “Have you had any of the following in the past 24 h?” and evaluated using rating scale 10–0, where: 10 = none of the time (excellent) and 0 = all of the time (poor). The sum of the individual domains generates an aggregate (or global) score with the maximum score (best recovery) obtained being 150.

F2
Figure 2.:
Box plots of QoR score in PECS and infiltration study groups. QoR-15, 15-item QoR score, maximum score 150 (best recovery). Solid box represents median and quartiles. PECS indicates pectoral nerves; QoR, quality of recovery.

After adjusting for baseline values, there was no evidence that the PECS block group had higher median, 25th quantile or 75th quantile QoR-15 scores. There was no evidence that the effect of PECS block is different in the 25th quantile compared to the 75th. The difference (95% CI) between coefficients (Q25–Q75) is −2.4 (−8.0 to 3.2) (P = .4).

Secondary Outcomes

F3
Figure 3.:
Box plots of pain and interference subscales for BPI. BPI at 24 h and 3 mo postoperatively (lower score indicates less dysfunction). Solid box represents median and quartiles. BPI indicates brief pain inventory; PECS, pectoral nerves.

Twenty-five patients reported chronic pain at 3 months and 15 localized their pain to the breast (PECS, 6; infiltration, 9; P = .41). No patients were taking potent opioids at 3 months (1 patient was taking tapentadol). There was no difference in the Brief Pain Inventory global score or subscales between groups at 24 hours or at 3 months (Table 2; Supplemental Digital Content, Table 1, https://links.lww.com/AA/C911; Figure 3). The global score at 24 hours reported as median [quartiles] was 20 [7, 36] in the PECS group and 23 [10, 43] in the infiltration group (P = .34), with median difference (95% CI) of 4 (11 to −4). The Brief Pain Inventory global score at 3 months reported as median [quartiles] was 0 [0, 14] in the PECS group and 0 [0, 11] in the infiltration group (P =.85), with median difference (95% CI) of 0 (0–0). The individual items with results for subscales are listed in Supplemental Digital Content, Table 1, https://links.lww.com/AA/C911. There were no significant differences in all other secondary outcomes including PACU and hospital length of stay and opioid consumption (Table 2).

Adverse Events and Protocol Deviations

Five patients had postoperative neurological features (all in the PECS group): 1 patient had numbness over upper lateral extremity, 1 patient had numbness in palmar aspect of hand, 1 had a sensory abnormality over thumb and index finger, 1 had numbness in middle finger, and 1 had numbness in the posterior axilla. All neurological features resolved by postoperative day 2. Three patients (all in the PECS group) reported bruising at the injection site at 7 days postoperatively. One patient had a surgical site infection (infiltration group), and 2 patients had surgically related hematoma (1 in each group) requiring repeat surgery. One patient in the infiltration group had intraoperative arrhythmias requiring treatment with electrolytes and magnesium. In 2 patients (infiltration group), dexamethasone was not given, and 1 patient received clonidine 60 µg (infiltration group) and 1 received ketamine 10 mg (PECS group). In 1 patient, the surgeon added epinephrine (for hemostasis) to the surgical injectate and infiltrated at commencement of surgery. In 2 patients (1 in each group), the surgeons commented on poor operating conditions potentially related to the preoperative PECS injection.

DISCUSSION

PECS II block was not superior to local anesthetic infiltration by surgeon having no impact on patient-reported QoR 24 hours postoperatively. This finding applied to the global QoR score and its separate domains. We performed a sensitivity analysis adjusting for differences in baseline QoR-15 scores (PECS group, 135; infiltration, 139), and this did not alter our conclusions. In both groups, the QoR-15 score decreased as expected from the postoperative period compared to the preoperative period. The median difference between groups was −2 and intuitively this appears unimportant given a maximum global QoR score (best recovery) of 150. The difference in QoR-15 that patients consider important has been estimated as 8.8 Because the 95% CI for the median difference was −9 to 5, we consider it unlikely that a clinically important difference in QoR-15 exists between groups. QoR-15 has been recommended as 1 of 6 standardized end points for use in perioperative clinical trials that evaluate patient comfort and pain after surgery.13 QoR-15 has undergone extensive psychometric testing (validity, reliability, consistency, and responsiveness) and it performed well in all dimensions, taking on average 2.5 minutes to complete.4

At both 24 hours and 3 months postoperatively, the Brief Pain Inventory global score and its pain subscale were not different. At 3 months, the Brief Pain Inventory global score and pain subscale were 0 in both groups, Although 15 patients reported pain localized to the breast, no patients were taking potent opioids, so likely persistent postsurgical pain was not significant in our study cohort.

The methodology of an early trial evaluating PECS block was criticized for being unblinded and not including an appropriate therapy for the control group (eg, local anesthetic infiltration).2,14 In this current trial, we ensured blinding of participants and personnel through the use of a sham intervention with injection of 0.9% saline and other steps taken to conceal group allocation. We also provided local anesthetic infiltration for the control group. Our results that PECS II block does not improve QoR are consistent with Kamiya et al15 who reported from a placebo-controlled trial that PECS II block improved pain scores 6 hours, but not the QoR-40 score measured 24 hours postoperatively. A double-blind placebo-controlled trial by Versyck et al16 reported that PECS II block reduced early postoperative opioid consumption; however, local infiltration by the surgeon was not used, and, therefore, patients were denied the potential benefit of this technique. A double-blind controlled trial by Cros et al17 reported that PECS I block when combined with multimodal analgesia and surgical infiltration did not reduce pain scores after minor breast surgery; however, the use of PECS I block makes this study difficult to compare to our trial.

PECS II block requires the local anesthetic to be injected close to the surgical field and the injectate may interfere with surgical dissection required for axillary dissection and lymph node location. Two patients were withdrawn from the study because of this concern, and in 2 further patients, the surgeons commented on poor operating conditions related to the PECS block. Other blocks suitable for breast surgery include paravertebral, erector spinae, and serratus plane blocks, and these techniques appropriately involve injection of local anesthetic remote from the surgical field. Future research should evaluate all regional analgesia techniques reported for breast surgery; however, substantial time is required to complete traditional parallel 2-arm trials. Therefore, we recommend novel study designs, for example, multiple arm Bayesian adaptive trial methods because these designs may accelerate discovery in regional anesthesia by sharing controls (eg, local anesthetic infiltration), allocating more patients to effective arms and stopping earlier for either success or futility.18 Further advantages can occur when a platform trial is established to study multiple interventions under one master protocol. These novel study designs are particularly suitable when multiple competing therapies (thoracic interfascial plane blocks) are available for one condition (breast surgery).

This study has limitations. Loss of eligible patients because of resource/logistical issues and recruitment to alternative trials may have introduced selection bias. As recommended, the protocol could have been explicit in identifying potential scenarios where patients may not receive the study intervention postrandomization.19 The surgical cohort comprised 12 patients from 104 who had mastectomy, with the remainder having tissue-preserving surgery reflecting our current practice. The results of this trial do not necessarily apply to patients having mastectomy and other more invasive surgeries for breast cancer. Participants in the infiltration group were administered local anesthetic postsurgical trauma compared to preoperative timing in the PECS group, which potentially may have favored the latter group. We did not include nonsteroidal anti-inflammatory drugs in our analgesic regimen over concerns about the acceptance of these drugs by a significant proportion of our participants, surgeons, and physicians. Finally, our perioperative analgesic regimen varied according to recruiting hospital because of varying availability of the intended study drug tapentadol.

CONCLUSIONS

In this randomized clinical trial, PECS II block was not superior to local infiltration by the surgeon for improving QoR of patients having mostly minor surgery for breast cancer.

ACKNOWLEDGMENTS

The authors acknowledge substantial support from Jonathan Termaat, research assistant from Waikato Hospital, Hamilton, New Zealand. Dr Christopher Scarff and Michael Henderson from St Vincent’s Hospital Melbourne and Peter MacCallum Cancer Centre, Victoria, Australia provided administrative support. Dr Seamus O’Flahaerty from St Vincent’s Hospital Melbourne provided support for postoperative follow-up. Dr Roman Kluger provided administrative support and statistical advice. The authors thank the surgeons responsible for care of study participants for supporting this study.

DISCLOSURES

Name: Michael J. Barrington, PhD.

Contribution: This author helped conceive, design, and implement the study protocol at St Vincent’s Hospital, Melbourne; develop grant content; submit protocol to Ethics and Governance; maintain consistent protocol implementation across 3 centers, and database and data integrity; prepare and critically revise the drafts; and approve and submit the final manuscript.

Name: Gloria J. Seah, FANZCA.

Contribution: This author helped design the protocol, write and submit grant application, submit protocol to Ethics and Governance, implement the study at Peter MacCallum Cancer Centre, and approve the final manuscript.

Name: Robert Gotmaker, MBiostat.

Contribution: This author helped analyze and prepare the data, critically revise the drafts, and approve the final manuscript.

Name: Daniel Lim, MPharmPrac.

Contribution: This author helped conceive and design the protocol, acquire the data, provide administrative and technical support, and approve the final manuscript.

Name: Kelly Byrne, FANZCA.

Contribution: This author helped design the protocol, submit the protocol to Ethics and Governance, and prepare and approve the final manuscript.

This manuscript was handled by: Richard C. Prielipp, MD, MBA.

FOOTNOTES

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