Effects of Serratus Anterior Plane Block on Early Recovery from Thoracoscopic Lung Resection: A Randomized, Blinded, Placebo-controlled Trial

The Institutional Review Board at Memorial Sloan Kettering Cancer Center (New York, New York) approved the study protocol (Institutional Review Board No. 19-470) on December 18, 2019, and all patients gave written informed consent before inclusion in the trial. The trial was registered before patient enrollment at ClinicalTrials.gov (NCT04238455; principal investigator: Jacob Jackson, M.D.; date of registration: January 23, 2020). Patients were enrolled from February 4, 2020, to June 28, 2022. The study followed Consolidated Standards of Reporting Trials guidelines.

Patients who were 18 yr or older, weighed 50 kg or more, and were scheduled to undergo elective unilateral minimally invasive anatomic lung resection were eligible for the study. Patients who underwent wedge resection(s) in addition to their primary segmentectomy or lobectomy were eligible according to their primary procedure, as were segmentectomy patients who underwent multiple segmentectomies (trisegmentectomy; n = 1) or lobectomy patients who underwent an additional lobectomy (bilobectomy; n = 1). No enrolled patients underwent pneumonectomy. Exclusion criteria were a history of ipsilateral thoracic surgery, a history of anaphylaxis or contraindication to local anesthetics, chronic sustained-release opioid use for more than 2 weeks’ duration during the 30 days before surgery, significant cognitive impairment or documented psychologic impairment, pregnancy, and American Society of Anesthesiologists Physical Status greater than III.

Randomization using the Memorial Sloan Kettering Clinical Research Database was performed intraoperatively, at the time of removal of the surgical specimen from the patient, to avoid postrandomization exclusions. Patients were randomized to either the serratus anterior plane block group or the placebo group, with a 1:1 allocation ratio. Randomization was stratified by segmentectomy or lobectomy and by video-assisted thoracoscopic surgery or robotic-assisted thoracoscopic surgery. Only the investigational pharmacists involved in the study had access to the patient allocation in the Clinical Research Database; they prepared blinded syringes for the anesthesiologist who administered the study block. The patient, surgeon, anesthesiologist, nurses, investigators performing patient assessment after surgery, and study statistician were blinded to treatment group allocation. Group allocation was concealed until the trial was closed to accrual and the final patient had finished the study period of 30 days from the day of surgery.

Patients with an Apfel score of 3 or greater (1 point each for female sex, nonsmoker, history of postoperative nausea and vomiting, and use of postoperative opioids) or a history of severe postoperative nausea or vomiting were administered the antiemetic aprepitant, a substance P/neurokinin-1 receptor antagonist, during the preoperative period as part of the institutional enhanced recovery pathway for nausea and vomiting prophylaxis. All patients received 4 mg intravenous dexamethasone intraoperatively, also for nausea and vomiting prophylaxis. The anesthetic management and other aspects of perioperative care were performed in a routine manner, including standard monitoring, induction of general anesthesia with propofol, maintenance of general anesthesia with sevoflurane, neuromuscular blockade with rocuronium or vecuronium, lung isolation with a left-sided double-lumen tube, and placement of a radial arterial line. Fentanyl, dexmedetomidine, acetaminophen, and ketorolac were administered intraoperatively; however, ketamine and opioids other than fentanyl were not permitted intraoperatively for study patients. Wound infiltration with local anesthetic by the surgical team was also not permitted. Video-assisted thoracoscopic surgery was conducted with three ports; robotic-assisted thoracoscopic surgery was conducted with five ports. All patients received a single 18-French chest tube. Anesthesiologist investigators who were blinded to group allocation performed the serratus anterior plane block or sham block postoperatively, as described below. In the postanesthesia care unit (PACU), patients recovered in accordance with the institutional enhanced recovery pathway. There were no study restrictions on medications, including analgesics, or interventions used to aid in the recovery process. Our institutional enhanced recovery analgesic regimen for the postoperative phase consisted of intravenous and oral opioids, intravenous and oral acetaminophen, intravenous ketorolac, and lidocaine patches placed on the ipsilateral chest wall near the chest tube. Patients who took gabapentinoids at home were allowed to continue them postoperatively.

After the completion of the lung resection, the surgical team followed their existing practice of performing internal intercostal nerve blocks under thoracoscopic visualization. The intercostal nerve blocks were standardized to 3 ml bupivacaine 0.25% injected in the fifth through the eighth intercostal spaces (six intercostal spaces) for a total volume of 18 ml and a total dose of 45 mg. All study patients received internal intercostal nerve blocks.

Serratus anterior plane block was performed by the anesthesiology team after closure of the skin incisions but before the patient’s emergence from general anesthesia. The patient was already in the lateral decubitus position from the procedure and had been prepped and draped in a sterile fashion. Sonographic landmarks were identified along the posterior axillary line, including the latissimus dorsi muscle, serratus anterior muscle, intercostal muscles, ribs, and pleura. A 22-gauge, 50-mm echogenic block needle (SonoBlock II, Pajunk Medical Systems, USA) was advanced under ultrasound guidance (Sonosite S2; Fujifilm Sonosite, USA) and in plane with a parasagitally positioned linear 13-6 MHz ultrasound transducer (L25 transducer; Fujifilm Sonosite) at the level of the nipple line until the fifth rib was contacted. In the fascial plane deep to the serratus anterior muscle, 20 ml bupivacaine 0.25% with 2 mg dexamethasone and 50 μg clonidine was injected (serratus anterior plane block group). Aspiration at 5-ml intervals was performed to avoid intravascular injection. A second injection of 20 ml identical injectate was performed using the same technique at the eighth rib, just cephalad to the chest tube site. The total doses administered were 100 mg bupivacaine 0.25%, 4 mg dexamethasone, and 100 μg clonidine for each patient in the study group. For patients in the placebo group, the syringes contained normal saline. The total volume injected in both groups was 40 ml. The serratus anterior plane block procedure was tailored to be performed in approximately 5 min. Afterward, the anesthesiology team emerged the patient from general anesthesia, extubated the patient, and transported the patient to the PACU when stable.

The primary outcome was cumulative intravenous morphine equivalents during the first 24 h after arrival to the PACU. Secondary outcomes were cumulative intravenous morphine equivalents during the first 48 h after arrival to the PACU and 11-point numerical rating scale pain scores, where 0 indicates “no pain” and 10 indicates “the worst pain imaginable.” Pain scores were measured at rest and during cough as part of routine nursing assessments at the following timepoints: every 2 h postoperatively until 12 h and then at 24 h, 36 h, and 48 h, if the patient had not yet been discharged from the hospital. For incentive spirometry, the highest achieved volume, to the nearest 250 ml, during a maximal inspiratory maneuver was measured as the best of three attempts, with patients sitting upright, using a handheld volumetric incentive spirometer (Vyaire AirLife, Cardinal Health, USA). Measurements were recorded preoperatively on the day of surgery (baseline) and again on postoperative days 1 and 2, unless the patient had already been discharged from the hospital. The incidence of nausea and vomiting was ascertained by in-person interview on postoperative days 1 and 2; the administration of a rescue antiemetic (e.g., ondansetron) during the first 48 h postoperatively was considered a positive incidence of nausea, regardless of the patient response at the time of the interview with research staff. The Quality of Recovery–15 (QoR-15) questionnaire²³  was administered at the time of research consent (baseline, usually within 1 week before surgery) and on postoperative day 7, either in person or by telephone interview with research staff. Three attempts were made to contact patients via telephone for the postoperative assessment before the patient was deemed to be unreachable. Although it was not prespecified as a secondary outcome, length of hospital stay was also collected for all patients from hospital records and was compared between the two groups. Other analyzed measures included the use of postoperative nonopioid analgesics during the first 48 h postoperatively and the occurrence of serious adverse events within 30 days of the procedure.

The sample size calculation was based on the primary outcome, using the ratio of means. This choice was motivated by the relevance of the hypothesis as a percentage reduction in intravenous morphine equivalents with serratus anterior plane block (ratio of two means), rather than the difference of two actual amounts in their original scale (difference of two means), and addresses the right-skewed distribution of opioid requirements.²⁴  Existing literature supported a hypothesized ratio of 0.65 of study group to placebo group mean postoperative intravenous morphine equivalents.¹⁴  Assuming a two-sided α of 0.05, a total sample size of 92 evaluable patients would yield 80% power to detect a ratio of 0.65 of study group to placebo group mean intravenous morphine equivalents (i.e., a mean opioid reduction of 35%), with a coefficient of variation of 0.85. The sample size calculation was conducted using the East 6 program (Cytel, USA).

The primary outcome was analyzed using a linear regression model for log-transformed postoperative opioid consumption in morphine milligram equivalents during the first 24 h after arrival in the PACU, including group assignment and stratification factors. Pain scores recorded over time were analyzed using mixed-effects linear regression models, with patient-level random effects and fixed effects of group assignment, stratification factors, and timepoint of measurement. Postoperative inspiratory volume on incentive spirometry at the patient level was analyzed using linear regression, with group assignment, stratification factors, and adjustment for baseline volume as covariates. The odds of postoperative nausea and vomiting between the two groups were quantified using logistic regression, with group assignment and stratification factors. The change in global QoR-15 score (postoperative day 7 minus baseline) was summarized for each patient and compared between the two groups using linear regression, with group assignment and stratification factors. All major comparisons between the groups were performed according to the intention-to-treat principle. Although it was not prespecified in the protocol, a sensitivity analysis of the primary outcome and of the secondary outcome of cumulative postoperative intravenous morphine equivalents during the first 48 h postoperatively was also performed. All statistical tests were two-sided, and P < 0.05 was considered to indicate statistical significance. Statistical analyses were conducted using Stata 18.0 (StataCorp, USA) and R 4.1.2 (R Core Team, Austria).

A total of 99 patients were consented to the study (fig. 1). Four patients who were consented chose to withdraw before surgery and randomization. Two patients who were consented could not be randomized for other reasons: one patient’s surgical case was delayed late into the evening, when research staff were no longer available, and one patient underwent surgery during the height of the COVID-19 pandemic, when research workflows were disrupted. The remaining 93 patients were enrolled and randomized. Of the 47 patients in the placebo group, 1 patient could not be included for analysis because of bleeding upon arrival to the PACU, which required immediate return to the operating room for thoracotomy. Data on 92 patients were included in the final analysis (46 patients per group). Within the study group, logistic errors occurred for two patients: one patient did not receive any block because of a technical issue with the randomization software that prevented timely creation of the block syringes by the investigational pharmacy, and one patient received a sham block with normal saline because of an error by the investigational pharmacy (summarized in fig. 1). Therefore, in the sensitivity analysis, two patients who experienced logistic errors were analyzed with the placebo group instead of the serratus anterior plane block group (fig. 1) to reflect an as-treated analysis. Demographic data, comorbid conditions, and operative details for these study subjects are detailed in table 1.

In the intention-to-treat analysis of the primary outcome, median (interquartile range) cumulative 24 h intravenous morphine equivalents was not significantly different between the groups after adjustment for stratification factors (serratus anterior plane block, 10.6 [5.0 to 27.1] mg; placebo, 18.8 [9.9 to 29.6] mg; a reduction of 32% [ratio, 0.68 (95% CI, 0.44 to 1.06)]; P = 0.085; table 2). The cumulative 48-h postoperative intravenous morphine equivalents was also not significantly different between the groups after adjustment for stratification factors (serratus anterior plane block, 16.3 [6.3 to 38.8] mg; placebo, 26.7 [14.6 to 37.3] mg; a reduction of 35% [model-based ratio, 0.65 (95% CI, 0.41 to 1.03)]; P = 0.068; table 2). In the sensitivity analysis, using the as-treated approach, cumulative 24-h intravenous morphine equivalents was lower in the serratus anterior plane block group after adjustment for stratification factors (serratus anterior plane block, 10.0 [5.0 to 27.2] mg; placebo, 19.9 [10.4 to 29.0] mg; a reduction of 36% [ratio, 0.64 (95% CI, 0.41 to 1.00)]; P = 0.048; table 2). The cumulative 48-h postoperative intravenous morphine equivalents was also lower in the serratus anterior plane block group after adjustment for stratification factors (serratus anterior plane block, 15.6 [5.6 to 38.3] mg; placebo, 26.8 [14.7 to 38.6] mg; a reduction of 40% [ratio, 0.60 (95% CI, 0.38 to 0.97)]; P = 0.036; table 2).

Median pain scores at rest or with cough were not significantly different between groups when compared at any of the timepoints. Using a composite of all available pain scores, pain scores at rest were lower over time in the serratus anterior plane block group, but the difference was not statistically significant (coefficient, –0.22 [95% CI, –0.59 to 0.14]; P = 0.2; fig. 2A). Composite pain scores with cough were lower in the serratus anterior plane block group (coefficient, –0.41 [95% CI, –0.81 to –0.01]; P = 0.044; fig. 2B). Of note, no patients were discharged within the first 24 h postoperatively. Four patients were discharged within the first 48 h postoperatively, three of whom were in the serratus anterior plane block group.

After surgery, the decrease in inspiratory volume on incentive spirometry from baseline was similar between the groups after adjustment for stratification factors and baseline value (postoperative day 1: coefficient, 80 [95% CI, –116 to 276]; P = 0.4; postoperative day 2: coefficient, 84 [95% CI, –125 to 292]; P = 0.4; table 3). The odds of experiencing postoperative nausea and/or vomiting on postoperative days 1 and 2 were not statistically significantly different between the groups (odds ratio, 1.2 [95% CI, 0.35 to 3.91]; P = 0.8; table 3), nor were QoR-15 global scores statistically significantly different on postoperative day 7, after adjustment for stratification factors and baseline score (coefficient, 3.7 [95% CI, –2.10 to 9.45]; P = 0.2; table 3). The length of hospital stay was shorter in the serratus anterior plane block group by 25%, but this difference was not statistically significant (ratio, 0.75 [95% CI, 0.53 to 1.05]; P = 0.1; table 3). The use of nonopioid analgesics during the first 48 h postoperatively was similar between the groups (table 4). Serious adverse events within 30 days of the procedure in the placebo group included one case each of urosepsis requiring intensive care unit (ICU) admission, splenic laceration requiring embolization, and possible ethanol withdrawal syndrome concurrent with pneumonia leading to ICU admission. One patient in the placebo group presented to an outside hospital for possible transient ischemic attack in the setting of new-onset atrial fibrillation. In the serratus anterior plane block group, serious adverse events within 30 days of the procedure included one case of pneumothorax after discharge requiring return to the hospital for chest tube placement. Two patients developed pneumonia, one of whom required ICU admission; the other patient was diagnosed after hospital discharge and required readmission. There were no complications directly associated with serratus anterior plane block or sham block in the trial.

Incorporation of serratus anterior plane block into a multimodal analgesia treatment plan for patients undergoing minimally invasive anatomic lung resection was not associated with a significant reduction in the primary outcome of intravenous morphine equivalents in the first 24 h postoperatively. Despite a 44% reduction in median intravenous morphine equivalents in the serratus anterior plane block group, and a 32% reduction after adjustment for stratification factors, the difference was not statistically significant between groups. Interestingly, the sensitivity analysis did reveal a 50% reduction in median intravenous morphine equivalents, and a 36% reduction after adjustment for stratification factors, which was statistically significant as per our hypothesis. When assessing the intravenous morphine equivalents reduction during the first 48 h postoperatively, there was a similar reduction in the serratus anterior plane block group that was not statistically significant except in the sensitivity analysis. The other notable finding was a statistically significant reduction in composite pain with cough score in the serratus anterior plane block group, despite similar results between groups at individual timepoints for both pain at rest and pain with cough scores.

In our study, serratus anterior plane block had several favorable features. Serratus anterior plane block has previously been shown to have minimal risks,^13–15  and the technique did not result in any block-related complications in the current study. On average, the block was performed in less than 5 min, concurrent with the patient’s emergence from general anesthesia and with the patient already in the lateral decubitus position. Because of its ease of administration, serratus anterior plane block had a short learning curve at our institution, even among anesthesiologists with no previous formal training in ultrasound or regional anesthesia. Additionally, serratus anterior plane block is better visualized than deeper blocks in patients with a large body habitus and more likely to be safe to perform in situations where a deeper block may be considered too risky (e.g., because of anticoagulation or bleeding diathesis concerns). Together, these qualities may recommend serratus anterior plane block over other fascial plane blocks of the chest for patients undergoing minimally invasive thoracic surgery without a thoracic epidural.

The serratus anterior plane block technique used in this study was informed by the existing literature. In the original description by Blanco et al.,¹¹  superficial serratus anterior plane block (i.e., injection in the fascial plane superficial to the serratus anterior muscle) had a longer duration and greater area of sensory loss on the hemithorax than injection deep to the serratus anterior muscle when evaluated in four healthy volunteers. However, in a cadaveric study by Biswas et al.,²⁵  a deep injection technique was shown to provide a comparable injectate spread to a superficial injection technique. Furthermore, the same study showed that a double-injection technique (40 ml vs. 20 ml) doubled the area of injectate spread.²⁵  A retrospective review of patients with postmastectomy pain²⁶  and a retrospective cohort study of patients who underwent ambulatory breast cancer surgery²⁷  also suggested that injection in the fascial plane deep to the serratus anterior muscle was as effective as superficial injection. In our experience, the superficial plane can be difficult to identify at the level of the eighth rib because of the thinner latissimus dorsi and serratus anterior muscle bodies when moving caudally along the posterior axillary line. Also, the deep injection technique is easier to perform because of tactile feedback from contacting the rib with the block needle. We located the injections in the posterior axillary line, instead of the midaxillary line, because of the posterior location of a port for robotic-assisted procedures and our own experience with patient discomfort at this location after receipt of serratus anterior plane block in the midaxillary line. The adjuvants used in the block were added to improve the quality of the block and to extend the duration. Clonidine is an α-2 receptor agonist commonly used for this purpose,²⁸  and dexamethasone is a corticosteroid that has been used specifically to prolong and enhance serratus anterior plane block in patients undergoing video-assisted thoracoscopic surgery.²⁹  The decision to perform the block postoperatively allowed us to minimize disruptions to workflow, avoid delaying surgery start time, perform intraoperative randomization, and synchronize the timing of serratus anterior plane block for all study patients.

The strengths of this study are (1) the clearly defined and randomized patient population (with stratification to procedure type and approach), (2) the inclusion of a sham block control, and (3) the analysis of patient-centered outcome measures. First, previous studies of serratus anterior plane block have included diverse types of thoracic procedures (e.g., lung resection, esophagectomy, lung volume reduction) and varying degrees of lung resection, from wedge resection to pneumonectomy, without discrimination. In this study, we not only focused on a discrete group of patients undergoing minimally invasive lung resection but also used stratification methods to ensure balance across important clinical factors in our trial cohorts. Second, a sham control group reduced bias regarding treatment allocation and the assessment of subjective outcomes modified by treatment. The purpose of the sham block control was to preserve adequate blinding of the study patient, the investigators, and the care providers, all of whom could have noticed the block injection sites or other unforeseen differences between the study groups. In addition, from a physiologic standpoint, a sham block helped eliminate any confounding effect that needling or stretch of the fascial plane from the injectate may have had on sensation in the hemithorax. Finally, in addition to analgesic outcomes, we analyzed a baseline and a postoperative QoR-15 assessment. The QoR-15 score is internationally recognized as a valid, extensive, and yet efficient means of assessing patients’ quality of recovery after surgery, covering measures of physical and mental well-being.^29,30  Although previous studies of serratus anterior plane block have used quality of recovery as the primary outcome measure, we were less optimistic about finding a significant difference between groups who were both receiving “usual care” according to an enhanced recovery pathway and elected to analyze quality of recovery as a secondary outcome. At least one previous study failed to use a baseline QoR-15 score as a reference, and as such, this may explain discrepancies in the effect of serratus anterior plane block on QoR-15 scores in the existing literature.²²  Interestingly, Kim et al.¹⁵  found that serratus anterior plane block was associated with quality of recovery in patients undergoing video-assisted thoracoscopic surgery; however, they used the long-version QoR-40 assessment and performed the assessment earlier in the recovery period (at 24 h instead of 7 days after surgery).

Our study has several limitations. First, the study population was from a single center. Despite a large catchment area, the patient population was not diverse in terms of age or race. Second, the study was powered to detect a difference only in the primary outcome, leaving the study underpowered to detect differences in the secondary outcomes. Larger, more-tailored studies may be required to further elucidate the effects of serratus anterior plane block on respiratory function, postoperative nausea and vomiting, and other early recovery outcomes. Third, we were limited in our ability to collect some secondary outcome data points later during recovery. However, we navigated these issues with statistical methods that accounted for the numerous collected data points and attempted to mitigate the effect of missing data points.

In conclusion, serratus anterior plane block did not result in a significant reduction in postoperative opioid consumption when added to a multimodal regimen for acute pain management after thoracoscopic anatomic lung resection. Serratus anterior plane block was associated with a statistically significant reduction in composite pain with cough score. The sensitivity as-treated analysis showed a significant and modest clinical reduction in the primary outcome that warrants further investigation.

The authors thank David B. Sewell, M.A., M.F.A. (Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York), for his help with preparation of the manuscript.

This study was supported, in part, by the National Institutes of Health (Bethesda, Maryland)/National Cancer Institute (Bethesda, Maryland; Cancer Support Grant P30 CA008748).

Dr. Park serves as a consultant for Intuitive Surgical (Orange, Connecticut), Ceevra (San Francisco, California), Medtronic (Minneapolis, Minnesota), and Becton Dickinson (Franklin Lakes, New Jersey). Dr. Jones is a member of the advisory council for AstraZeneca (Cambridge, United Kingdom) and the advisory committee for MORE Health (San Mateo, California), has been a speaker for DAVA Oncology (Plano, Texas), and receives research grant support from Merck (Rahway, New Jersey). The other authors declare no competing interests.

Full protocol available at: jacksoj1@mskcc.org. Raw data available at: jacksoj1@mskcc.org.