Factors related to post‐thoracotomy pain following robotic‐assisted thoracic surgery

Robotic‐assisted thoracic surgery (RATS) is a minimally invasive procedure; however, some patients experience persistent postoperative pain. This study aimed to investigate factors related to postoperative pain following RATS.

Post-thoracotomy pain (PTP) is a long-term, distressing complication in patients undergoing thoracotomy and minimally invasive surgery for thoracic disease.PTP syndrome (PTPS) is defined by the International Association for the Study of Pain as the pain that recurs along a thoracotomy scar for at least 2 months after the surgical procedure. 1Moreover, the mechanisms underlying chronic postsurgical pain, including PTP, are complex.However, many pain syndromes are neuropathic and result from changes in the nervous system following injury. 2The process of neuropathic pain initiation following intercostal nerve injury begins with Schwann cells and infiltrating macrophages, which degenerate distally to the site of nerve injury and produce local and systemic mediators that drive pain signals.Furthermore, a neuroma at the site of injury is a source of spontaneous ectopic excitability of the sensory fibers. 3Microscopy of the intercostal nerve specimens from patients with PTPS revealed fibrosis, hyalinization of the epineurium and perineurium, intense hyperemia of blood capillaries, and interstitial edema.The negative impact on wound healing is considered key component of the development of intense chronic pain. 40][11][12] In the latter, two studies indicated that chronic pain after robotic-assisted thoracic surgery (RATS) is more severe compared with that of video-assisted thoracoscopic surgery (VATS). 13,14owever, another study reported no significant differences between RATS and VATS. 12Risk factors for chronic pain include age, 11 female sex, 15,16 preoperative anxiety, 17 acute postoperative pain, [18][19][20] more extensive surgical procedure, 19 surgical approach, and thoracotomy. 11,21lthough RATS is increasingly adopted owing to its usefulness, the incidence of pain and its risk factors have not been sufficiently investigated.We aimed to investigate the incidence of postoperative persistent pain and the risk factors associated with RATS for lung cancer.

| PATIENTS AND METHODS
This study was approved by the Institutional Review Board of Fukuoka University Hospital (No. U22-08-004).Consecutive patients who underwent RATS lobectomy or segmentectomy between May 2019 and December 2022 were included.Patients who underwent preoperative pain control for any condition or underwent chest wall resection were excluded.Six senior residents or more experienced physicians performed pulmonary resection.

| Procedures
A four-arm technique was used to perform the RATS.The ports were placed as follows: a 4-cm utility incision without a rib spreading on the sixth intercostal space (ICS) on the anterior axillary line, which was used as a robotic port and assistant; a port on the eighth ICS in the middle axillary line with a 30 camera, and two ports on the eighth ICS, approximately 8-cm away from each dorsal side.All robotic surgeries were performed using the da Vinci Xi Surgical System (Intuitive, Sunnyvale, CA, USA).All patients underwent intercostal nerve block with bupivacaine at each port at the end of surgery.

| Pain assessment and control modalities
Most patients were managed using epidural anesthesia or intravenous patient-controlled analgesia (IV-PCA) for 1-3 days postoperatively.Patients in both groups received oral nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen starting on postoperative day 1, with weak oral opioids (tramadol) added as needed.Patients with intercostal neuralgia received an additional dose of pregabalin or mirogabalin, and each drug was discontinued when required.The daily dose per body weight did not differ between the patients.All patients were assessed for pain at the outpatient visit approximately 2-3 weeks after discharge.Patients who required analgesics received them for 2-4 weeks.Patients who required further analgesics visited the outpatient clinic and received appropriate treatment.The patients were divided into two groups, PTP and non-PTP, according to the duration of postoperative analgesia.The PTP group included patients who had received analgesics, including NSAIDs, acetaminophen, weak opioids (tramadol), pregabalin, and mirogabalin, for postoperative pain for at least 2 months.

| Data collection
A retrospective review of 145 patients who underwent lobectomy or segmentectomy for primary lung cancer was performed to identify factors associated with PTP.After excluding patients who underwent preoperative pain management for any condition or chest wall resection, 138 patients were eligible for inclusion.All patients were observed for at least 6 months after surgery.
Preoperative characteristics, including age, sex, height, body mass index (BMI), smoking status, and major comorbidities, including history of other malignancies within 5 years, cardiovascular disease, cerebrovascular disease, diabetes, chronic obstructive pulmonary disease, pulmonary fibrosis, autoimmune disorder, smoking status, tumor location, and clinical Stage (cStage) were collected.Diabetes was defined as the condition requiring oral medication or insulin.Width of the eighth ICS in the midaxillary line, the most dorsal width of the eighth ICS, transverse length of the thorax at the level of the eighth ICS in the middle axillary line, anteroposterior length of the thorax at the level of the eighth ICS in the middle axillary line, and the angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the midaxillary line and the secondary carina, which indicates the assumed angle formed by the chest wall and the robotic arm, are shown in Figure 1A-C, respectively.These measurements were taken using preoperative computed tomography (CT).Perioperative outcomes, including operative duration, blood loss, conversion to thoracotomy rate, postoperative complications, chest tube duration, postoperative stay, epidural anesthesia, IV-PCA, and adjuvant chemotherapy were collected.The postoperative complications included air leakage (>7 days), pneumonia, bronchopleural fistula, empyema, reintubation, atrial or ventricular arrhythmia, and delirium.

| Statistical analysis
An independent t-test was used to compare age, height, BMI, operative duration, blood loss, number of chest tube days, duration of postoperative oral analgesia, width of the eighth ICS in the midaxillary line, most dorsal width of the eighth ICS, transverse length of the thorax at the level of the eighth ICS in the middle axillary line, anteroposterior length of the thorax at the level of the eighth ICS in the middle axillary line, and the angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the midaxillary line and the secondary carina between the two groups.The chi-square test was used to compare sex comorbidities, smoking status, lobes affected, procedures, cStage, complications, epidural anesthesia, IV-PCA, adjuvant chemotherapy, opioid, and pregabalin or mirogabalin use between the two groups.
Multivariate analysis was used to evaluate factors related to PTP.The variables included height, age, sex, and the transverse length of the thorax at the level of the eighth ICS on the midaxillary line.Logistic analysis was used for multivariate analysis, and the factors to be analyzed were those with a p-value <.05 and two factors (age <65 years and female sex) reported previously. 11,15,16cute postoperative pain is a known risk factor but was omitted because of insufficient records of the Numerical Rating Scale or other objective indicators of acute pain in this study.Statistical significance was determined if the p-value was <.05.Pearson correlation coefficients were calculated to assess the correlation between patient height and eighth ICS width, transverse length of the thorax at the level of eighth ICS in the middle axillary line, anteroposterior length of the thorax at the level of eighth ICS in the middle axillary line, and the angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the middle axillary line and the secondary carina.Receiver operating characteristic (ROC) curves and the AUC were used to assess the performance of height in predicting PTP.The optimal cutoff for height was derived from the ROC curve, with the shortest distance to sensitivity and specificity.All analyses were conducted using Bell Curve for Excel (version 4.02; Social Survey Research Information Co., Ltd.).

| Duration of analgesic's use
Of the 138 patients, 81 (58.7%) received analgesics within 30 days of surgery.Following pain assessment approximately 1 month postoperatively, 45 (32.6%) patients received analgesics for at least 60 days.

| Thorax and ICS width
There were significant differences in transverse length of the thorax at the eighth ICS in the middle axillary line between two groups (median length; 270.5 vs. 260.5 mm, p = .016)(Table 2).However, there were no significant differences in the width of eighth ICS in the middle axillary line, width of the most dorsal eighth ICS, anteroposterior length of the thorax, and the angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the middle axillary line and secondary carina.

| Postoperative outcome
There were no differences in operative duration, chest tube placement duration, or complications between the two groups.An epidural catheter or IV-PCA with fentanyl was used for several days postoperatively in both groups (Table 3).
In multivariate analysis, height was correlated with PTP (p = .009,odds ratio [OR] = 0.907, 95% confidence interval [CI], 0.843-0.976)(Table 5).However, age, sex, and the transverse length of the thorax at the eighth ICS in the midaxillary line were not correlated with PTP.

| Correlations of height and ICS, thorax
Height was correlated with transverse length of the chest (r = .407,p < .001, Figure 2C), anteroposterior length of the chest (r = .294,p < .001, Figure 2D), and width of the eighth ICS in the middle axillary line (r = .210,p = .013,Figure 2A) using Pearson correlation coefficients, but not with width of the most dorsal eighth ICS (r = À.017, p = .838,Figure 2B) and angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the middle axillary line and the secondary carina (r = À.082, p = .334,Figure 2E).Note: The transverse and anteroposterior lengths of the thorax were measured at the level of eighth intercostal space (ICS) in the middle axillary line (Figure 1A,B).The angles formed by the horizontal axis and the line connecting the second carina and the eighth ICS in the middle axillary line (degrees) are shown in Figure 1C.Abbreviation: PTP, post-thoracotomy pain.

| DISCUSSION
[11][12] Kwon et al. 12 reported that the incidence of chronic pain after RATS was 34.6%.In the present study, 32.6% of the patients received analgesics for at least 2 months, which is comparable to that in the literature.Previous studies have assessed postoperative pain at several time points.PTPS is defined as pain that recurs or persists along a thoracotomy scar for at least 2 months after the surgical procedure.In the present study, patients with persistent pain were defined as those who received analgesics for at least 2 months after surgery.Similarly, of the patients who received analgesics for at least 2 months after uniportal VATS during the same period at our institution, 5 (5.9%) of 84 patients received analgesics.The RATS group had more patients with postoperative persistent pain than the uniportal VATS group.Several studies have indicated that needle VATS with 2-3-mm thin instruments had less postoperative pain, including residual neuralgia, than conventional VATS. 22,23These reports also suggest that the Note: The transverse length of the thorax was measured at the level of eighth intercostal space (ICS) along the middle axillary line.Values in bold are significant at p < .05.Abbreviations: CI, confidence interval; PTP, post-thoracotomy pain.
relationship between port size and ICS or chest wall loading causes pain.In particular, an excessive load on the chest wall is a possible cause of postoperative pain in robotic surgery.An extremely inclined arm often results in the lifting of the superior and pressing of the inferior chest wall, which causes a notable load on the chest wall and pinches the intercostal nerves.Moreover, the dorsal ICS is narrow and provides opportunities for orthogonal movement of the instrument to the ribs, placing stress on the chest wall and intercostal nerves.Bleeding in the port incision is often observed, mostly in the dorsal port.This also suggests that the ports in narrow ICS and the orthogonal movement of the instrument increase the load on the chest wall.Univariate analysis showed that patient height and transverse length of the thorax were significantly shorter in the PTP group, and multivariate analysis showed significant differences only in height as a risk factor for PTP.Therefore, we investigated the relationship between height and the eighth ICS width, and the thorax.Contrary to our expectations, the width of the most dorsal eighth ICS did not correlate with height.This may be owing to an increase in rib width with height.The transverse length of the thorax was the most strongly correlated factor with height, followed by the anteroposterior length of the thorax.This suggests that the depth of the thoracic cavity plays a role in pain and that a shallow thoracic cavity results in a greater load on the chest wall.
The shorter transverse and anteroposterior lengths of the thorax may indicate that the range of motion of the ribs attached to the spine and sternum is more limited, which may result in excessive load on the chest wall by robotic arm movement.The eighth ICS width in the middle axillary line also correlated with height.The shallow thoracic cavity and narrower eighth ICS in the middle axillary line lead to pain; therefore, short stature is a surrogate for these factors.On the other hand, RATS could lead to an extremely inclined arm and increased pain in patients with taller stature and narrower chests; however, no such results were observed in the present study.One possible reason for this is that patients with a taller stature and narrower thorax have a rib inclination closer to the craniocaudal line and robotic arm movement more parallel to the rib and ICS, which may reduce pain.RATS with various port placements have also been reported.Well-known port placements include those reported by Cerfolio et al. 24 and Ninan and Dylewski. 25he former reported a complete portal robotic lobectomy using four arms with an assistant port.The port placement for the robotic arm follows one ICS: the seventh for upper and middle lobectomies and the eighth for lower lobectomies.Ninan and Dylewski 25 reported a complete portal robotic lobectomy using three arms, with an assistant port at the tip of the 11th rib (the chest was accessed through the eighth ICS).The robotic camera port was placed in the fifth to sixth ICS over the midfissure area.Two additional ports were placed anteriorly and posteriorly within the same ICS.The port placement reported by Ninan and Dylewski 25 is more cranial and uses a 0 camera, which means that the arms are not extremely flat and may exert less load on the chest wall.We recently investigated whether placing ports anteriorly or superiorly reduces postoperative pain in RATS.However, for patients with short stature, there are limitations to the port set that allows sufficient working space.To ensure this and achieve some distance between the remote center and the target, the port needs to be placed caudally.However, further research is required to confirm this hypothesis.
Female sex has been reported to be a risk factor for chronic pain.In this study, the proportion of female in the PTP group was higher than that in the non-PTP group.However, sex was not a significant risk factor in the multivariate analysis.This may be owing to the confounding effects of female sex and height.In our analysis, female were shorter than male (female vs. male, median: 153 cm vs 166.8 cm, p < .001),and 98% of all female were shorter than 165 cm, the cutoff value indicated by the predict PTP ROC analysis.
This retrospective study had some limitations.First, although the assessment of analgesia provides insights, it may not accurately reflect postoperative pain owing to insufficiently recorded pain scores.Therefore, patients were divided into two groups based on the duration of analgesia.However, several studies have reported the use of analgesics as an indicator of pain. 26,27Second, there were insufficient records of acute pain assessment and psychological evaluation such as anxiety in this study.It is desirable to assess not only postoperative pain but also the quality of life using the European Organization for Research and Treatment of Cancer QLG Core Questionnaire (EORTC QLQ-C30) and other methods.Therefore, prospective studies are required to verify these results.

1
Measurement of the thorax length and assumed angle formed by robotic arm and chest wall on preoperative CT. (A) Transverse length of the thorax at the level of eighth intercostal space (ICS) in the middle axillary line.(B) Anteroposterior length of the thorax at the level of the eighth ICS in the middle axillary line.(C) Angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the midaxillary line and the secondary carina.

F I G U R E 2
Correlation between height and intercostal space (ICS) width and thorax.(A) Width of eighth ICS in the middle axillary line.(B) The most dorsal width of the eighth ICS.(C) Transverse length of the chest at the level of eighth ICS in the midaxillary line.(D) Anteroposterior length of the chest at the level of the eighth ICS in the middle axillary line.(E) The angle formed by the horizontal axis at the eighth ICS in the middle axillary line and the line connecting the eighth ICS in the midaxillary line and the secondary carina.Scatterplot and correlation between patient height and ICS width and thorax.
T A B L E 3Note: Values in bold are significant at p < .05.Abbreviations: BPF, bronchpleural fistula; IV-PCA, intravenous patient-controlled analgesia; PTP, postthoracotomy pain.T A B L E 4 Postoperative oral analgesics (to 60 days after surgery).Note: Values in bold are significant at p < .05.Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs; PTP, post-thoracotomy pain.T A B L E 5 Factors associated with PTP-multivariable analysis (p-values).