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Does Preoperative Hookwire Localization Influence Postoperative Acute and Chronic Pain After Video-Assisted Thoracoscopic Surgery: A Prospective Cohort Study

Authors Kong L, Gao L , Zhang H, Wang X, Zhang J

Received 25 August 2022

Accepted for publication 24 December 2022

Published 5 January 2023 Volume 2023:16 Pages 21—32

DOI https://doi.org/10.2147/JPR.S387543

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Jinlei Li



Lingchao Kong,1,2,* Lingling Gao,1,2,* Hong Zhang,1,2 Xin Wang,1,2 Jun Zhang1,2

1Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jun Zhang, Department of Anesthesiology, Shanghai Cancer Center, Fudan University and Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong’An Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86-21-64175590, Fax +86-21-64174774, Email [email protected]

Purpose: This study aimed to investigate whether preoperative computerized tomography-guided hookwire localization-associated pain could affect acute and chronic postsurgical pain (CPSP) in patients undergoing video-assisted thoracoscopic surgery (VATS).
Methods: We enrolled 161 adult patients who underwent elective VATS; sixty-nine patients experienced hookwire localization (Group A) and 69 did not (Group B). Group A was further subdivided into the multiple localization group (n=35, Group Amultiple) and the single localization group (n=34, Group Asingle) according to the number of hookwires. The numerical rating scale (NRS) was used preoperatively, during recovery at the post-anesthesia care unit (PACU), and the first two days, 3 and 6 months postoperatively. Furthermore, multivariate regression analysis was used to identify the risk factors associated with CPSP. The postoperative adverse events, length of hospital stay, and satisfaction in pain management were also recorded.
Results: The incidence and severity of acute postoperative pain were similar between Group A and Group B (p > 0.05). The incidence (56.5% vs 30.4%, p = 0.002) and the NRS scores (2.0 [2.0– 3.0] vs 1.0 [1.0– 2.0], p = 0.011) for CPSP were significantly higher in Group A than in Group B at 3 months postoperatively. On subgroup analysis, compared with Group Asingle, the intensity of CPSP (2.0 [2.0– 3.0] vs 2.0 [1.0– 2.0], p = 0.005) in Group Amultiple was slightly higher at 3 months postoperatively. Conversely, the CPSP incidence (60.0% vs 29.4%, p = 0.011) was significantly higher at 6 months postoperatively in Group Amultiple. The multivariate regression analysis further validated hookwire localization as a risk factor for CPSP (odds ratio: 6.199, 95% confidence interval 2.049– 18.749, p = 0.001). Patient satisfaction relating to pain management at 3 months postoperatively was lower in Group A (p = 0.034).
Conclusion: The preoperative pain stress of hookwire localization increased the incidence and intensity of CPSP rather than acute pain at 3 months postoperatively, especially in patients with multiple hookwires.

Keywords: chronic postsurgical pain, postoperative acute pain, hookwire localization, video-assisted thoracoscopic surgery, lung cancer

Introduction

Postoperative pain after thoracic surgery affects the quality of a patient’s recovery and its management remains a major clinical challenge. The suboptimal control of acute pain after thoracotomy or video-assisted thoracoscopic surgery (VATS) is associated with chronic postsurgical pain (CPSP). CPSP, defined by pain intensity and pain-related functional interferences, is a common post-thoracotomy complication. The incidence of CPSP in thoracic surgery varies from 14% to 83% depending on the type of surgery or the definition of CPSP.1–4 CPSP can lead to increased postoperative complications, long-term disability, reduced quality of life, and increased healthcare spending.5 The development of CPSP is considered a multifactorial process. Numerous studies have investigated the risk factors associated with “pain chronification” after thoracic surgery. Moreover, pre-existing pain is one of these risk factors contributing to the development of CPSP.6 A recent meta-analysis reported that the pooled unadjusted odds ratios (ORs) for the development of CPSP were 2.43 for preoperative pain at the surgical site, 1.75 for preoperative pain elsewhere, and 3.95 for preoperative pain at an unspecified site.7 Considering this, pre-existing pain is not only associated with severe postoperative acute pain,8 but also with CPSP.9 Furthermore, pre-existing pain is usually of a chronic nature before surgery.10–12 Importantly, whether preoperative acute pain stress influence the incidence and intensity of CPSP are unknown.

The excision of lung nodules during thoracoscopic surgery is popular under the concept of enhanced recovery after surgery. Lung nodules within lung parenchyma judged too small or too far from the pleural surface must be localized preoperatively. The percutaneous placement of spring hookwires is widely used to localize small pulmonary nodules under computerized tomography (CT) guidance before VATS.11,12 This aims to assist thoracic surgeons to quickly identifying the targeted lesions during thoracoscopic resections. Although local anesthesia is used, hookwire localization-associated pain remains a concern in the clinical setting.13 The extent and mechanism of preoperative pain stress caused by CT-guided hookwire localization and its effects on postoperative acute and chronic pain have not been previously reported.

In this prospective observational cohort study, we aimed to determine whether the acute pain stress from preoperative CT-guided hookwire localization influences the incidence and intensity of postoperative acute and chronic pain after VATS at a single cancer center.

Materials and Methods

Patients and Groups

Consecutive patients, aged 18–75 years, indicated for VATS for lung cancer under general anesthesia and assessed with the American Society of Anesthesiologists (ASA) physical status of I–II, were recruited from the Fudan University Shanghai Cancer Center (FUSCC) from August to December 2021. The study was completed in July 2022. Exclusion criteria included severe cardiac and lung diseases, history of chronic pain or painkillers or psychotropic drugs usage within 3 months before surgery, severe anxiety or depression, and preoperative chemotherapy and radiation therapy. This study was approved by the Institutional Review Board of FUSCC (Number: 2107238–15) and written informed consent was obtained from all trial participants. The trial was registered after patient enrollment at clinicaltrials.gov (NCT05478460, Principal investigator: Jun Zhang, link to trial registry: https://register.clinicaltrials.gov/, Date of registration: May 30, 2022).

The patients were assigned into two groups (Group A: preoperative hookwire localization and Group B: without preoperative hookwire localization). Patients in Group A underwent CT-guided hookwire localization 1 hour before VATS on the day of surgery. In brief, the patient was placed on a CT table in a suitable position (supine, prone, lateral) according to the location of the pulmonary nodule(s) to obtain the shortest needle insertion route for their initial CT scan. Local anesthesia of the skin and planned puncture tract was performed by a radiologist using 1% lidocaine. Then, a needle was advanced using a technique identical to that for CT-guided biopsies, and a hookwire or multiple hookwires (20 G ×120 mm, PAJUNK®, Geisingen, Germany) were inserted into or close to the pulmonary nodule(s). The localizations were deemed successful in all patients who were able to hold his/her breath. Patients who did not undergo preoperative hookwire localization (Group B) had the same preoperative preparation as patients in Group A other than the localization.

Anesthetic Management

Anesthesia and perioperative management were identical for both groups. Standard monitoring was performed including electrocardiogram (ECG), invasive blood pressure, pulse oxygen saturation (SpO2), and end-tidal carbon dioxide partial pressure (PetCO2) during the surgical procedures. Bispect ral index (BIS) monitoring (Version XP, Covidien plc, Dublin, Ireland) was used intraoperatively to maintain the appropriate depth of anesthesia. Specifically, 1 mg midazolam, propofol targeted controlled infusion (TCI) at 3–4 μg/mL (Marsh mode), 0.03 μg/kg sufentanil, and 0.6 mg/kg rocuronium, were used for anesthetic induction, and endotracheal intubation. The correct placement of a double-lumen tube was confirmed by fiber bronchoscopy. Propofol TCI at 2–4 μg/mL, and remifentanil TCI 1–2 ng/mL (Minto mode) were used intraoperatively to maintain the loss of consciousness and analgesia. Intermit rocuronium was administered for immobility. The intraoperative hemodynamics was kept stable Changes in blood pressure and heart rate generally were kept within 20% of the preoperative levels. One-lung ventilation was performed before VATS to secure the collapse of the independent lung. The patients were delivered to PACU for further monitoring and postoperative management following surgery. Subsequently, patients were transferred to the ward when the Steward score was >4.

Surgical Procedure

VATS procedure for lung cancer was performed in the lateral position. The types of surgical procedures included lobectomy, segmentectomy, and wedge resection. The single-port, two-port, or three-port VATS and location of the chest wall incision were selected to remove lung cancer by an experienced thoracic surgeon group according to the clinical features of the patient’s lesion. Lymph node excision was performed as necessary. The length of incisions was identical and the resected tissues were extracted from a disposable incision protector placed at the port. At the end of the surgery, a chest tube was placed for postoperative thoracic drainage. During the insertion of the chest drain, injury to the intercostal nerves was cautiously avoided. The draining chest tube was removed once significant air leakage was not detected for more than 24 hours and the total amount of pleural effusion was less than 200 mL per day.

Postoperative Pain Control

A patient-controlled intravenous analgesic (PCIA) pump was used by all patients after surgery. The analgesia formula included 100 ug sufentanil and 200 mg flurbiprofen diluted in 200 mL with normal saline. The settings of the PCIA pump were managed by a dedicated Acute Pain Service team. The pump settings included a background infusion at 4 mL/h and a patient-controlled bolus at 4 mL/time, with a lockout interval of 20 min. In patients with a persistent numerical rating scale (NRS) score of >5 for 1 hour, intravenous oxycodone (30 mg) was provided as rescue analgesia.

Pre- and Postoperative Pain Evaluations

Acute Pain Evaluation

The NRS was used for evaluating pre- and postoperative pain. The pain intensity was classified as no pain (NRS = 0), mild pain (NRS = 1–3), moderate pain (NRS = 4–6), and severe pain (NRS = 7–10). The preoperative pain was assessed following the hookwire localization procedure when the patient was in the waiting area, whereas acute postoperative pain was assessed in the PACU, 24 and 48 hours postoperatively in the ward. Patients were requested to report their pain scores both at rest and on coughing.

CPSP Evaluation

Telephone follow-up interviews were performed to assess chronic pain 3 and 6 months after VATS. The incidence and intensity of pain were assessed based on the following questions:

  1. Have you experienced any pain along the scar after surgery, and was the pain different from what you experienced one day before the surgery?
  2. Is there any other cause for the pain (eg, recurrence of a malignant tumor or chronic wound infection)?
  3. Has the pain persisted for at least 3 (or 6) months?
  4. Please breathe deeply and cough twice. Then, rate your chest pain on the NRS from 0–10 (0: no pain and 10: worst possible pain).

We defined CPSP in the same way as Macrae.14 Pain score of ≥1 at surgical sites measured by an 11-point NRS was diagnosed as CPSP.15 In particular, the following were considered: 1) pain that developed after surgery; 2) other etiologies have been excluded; 3) the exacerbation of pre-existing chronic pain has been ruled out; and 4) pain that persisted for at least 3 (or 6) months after VATS.

Demographic characteristics and clinical data including preoperative anxiety and depression status, intraoperative opioids consumption, surgical duration, and postoperative nausea (PON) and vomiting (POV), shoulder-back pain, the length of hospital stay, satisfaction of pain management, were collected. The patient’s satisfaction for pain management was rated with a 5-point Likert scale (1 = very unsatisfied, 5 = very satisfied). The status of anxiety and depression were evaluated by the Hamilton anxiety scale (HAMA-14)16 and the Hamilton depression scale (HAMD-17),17 respectively.

Statistical Analysis

Sample Size Calculation

From our preliminary results, the NRS score at 3 months postoperatively (POM3) was 2.5±1.2 in patients with preoperative hookwire localization, and 1.8±0.8 in those without preoperative hookwire localization, respectively. There was a 0.7 difference between the two groups, with a variance of 1.2. Considering a statistical power of 90% and a two-sided α significance level of 0.05, a sample size of 62 patients in each arm was required to test our hypothesis. A dropout rate of 10% was included. In total, 69 patients were required for each group and a total of 138 patients were needed for our study.

Data normality was tested using the Kolmogorov–Smirnov test. Categorical variables were presented as numbers (percentage) or proportions, and continuous variables were presented as mean ± standard deviation (SD), or median (interquartile ranges, IQR), depending on the data distribution (normal distribution or not). The continuous variables were analyzed using the independent t-test for variables with a normal distribution and the Mann–Whitney U-test for variables that did not demonstrate a normal distribution. Pearson χ2 test or Fisher exact test for categorical variables was used to compare between two groups. Multivariate logistic regression analysis was used to identify the risk factors that were predictive of CPSP after VATS. Statistical significance was defined as p<0.05. Statistical analyses were performed using SPSS 19.0 (SPSS, Inc., Chicago, IL, USA).

Results

This study recruited 161 patients. All cases of one or multiple hookwires were successful. Of the 161 patients, 23 patients withdrew from the study due to various reasons: 11 cases were changed to thoracotomy, two required re-operation during the first 3 months postoperatively, five required repeat thoracic catheter insertion during hospitalization, two experienced chest infection, and three were lost to follow-up. Hence, 138 patients were included in the final analysis (Figure 1). Of the 138 patients, 69 underwent hookwire localization (Group A) and 69 did not (Group B). None of the patients required a preoperative drain for pneumothorax. Small pulmonary nodules (SPNs) in both groups of patients were successfully removed thoracoscopically. The demographic characteristics and clinical data are summarized in Table 1. The two groups were comparable in terms of age, gender, body mass index (BMI), ASA classification, age-adjusted Charlson Comorbidity Index (aCCI), previous surgical history, preoperative Hamilton anxiety scale and Hamilton depression scale (HAMA/MAMD) scores, type of lung surgery, duration of chest drainage, and postoperative length of stay. Notably, the SPNs were located more in the left lung in Group A than in Group B (p = 0.013), and there were more ports for VATS in Group B than in Group A (p = 0.025). Moreover, the duration of surgery and anesthesia was longer in Group B than in Group A (91.5±40.8 vs 73.8±38.1, p = 0.009; 125.5±41.6 vs 109.3±38.1, p = 0.019, respectively). Furthermore, there was no significant difference in the intraoperative consumption of sufentanil and remifentanil between the two groups (Supplementary Table 1).

Table 1 Demographic Data and Clinical Characteristics

Figure 1 The study flowchart.

Abbreviation: NRS, Numeric Rating Scale.

Acute Pre- and Postoperative Pain

In Group A, the incidence of acute pain after hookwire localization was 95.65% (66/69). These patients generally experienced mild-moderate pain. The NRS score was 2.0 (1.0, 2.0) at rest, and 3.5 (2.0, 5.0) on coughing (Table 2). Half of the patients (33/66) reported mild pain and the other half (33/66) indicated moderate pain.

Table 2 The Incidence and Intensity (NRS) of Perioperative Acute Pain

The Intensity of acute postoperative pain both at rest (PACU: p = 0.239, postoperative day (POD)1: p = 0.531, POD2: p = 0.797) and on coughing (PACU: p = 0.250, POD1: p = 0.066, POD2: p = 0.157) were comparable in the PACU and at POD1 and POD2 between two groups (Table 2). Correspondingly, the sufentanil consumption was similar for both the groups at POD1 and POD2. However, at POD1, the patients in Group A (2.0 [1.0–6.0]) utilized the PCIA more times than the patients in Group B (1.0 [1.0–4.0], p = 0.045, Supplementary Table 1). This suggests that patients who underwent preoperative hookwire localization may have more severe acute postoperative pain shortly after VATS.

CPSP

The incidence of CPSP 3 months after surgery in Group A (56.5%, 95% confidence interval (CI): 44.5–68.5%) was higher than in Group B (30.4%, 95% CI: 19.3%–41.6%, p = 0.002) (Figure 2). Furthermore, the NRS score 3 months after surgery in Group A (2.0 [2.0–3.0]) was higher than that in Group B (1.0 [1.0–2.0], p = 0.011), indicating that more patients who underwent preoperative hookwire localization experienced serious CPSP 3 months postoperatively. In contrast, at 6 months postoperatively, these differences in the incidence (44.9%, 95% CI: 37.9–57.0% vs 30.4% 95% CI: 19.3%–41.6%, p = 0.079) and intensity (2.0 [2.0–2.0] vs 2.0 [1.0, 2.0], p = 0.214) of CPSP between two groups were no longer statistically significant (Table 3). Furthermore, the dosages and durations of oral analgesic drugs at 3 months postoperatively (Supplementary Table 3) and 6 months postoperatively (Supplementary Table 4) were similar between the two groups.

Table 3 The Incidence and Intensity (NRS) of Chronic Postsurgical Pain (CPSP)

Figure 2 The incidences of chronic postsurgical pain (CPSP). (A) The comparison of CPSP between patients with preoperative hookwire localization (Group A) and those without hookwire localization (Group B); (B) The comparison of CPSP between multiple hookwires localization (Group Amultiple) and single hookwire localization (Group Asingle). *p<0.05, **p<0.01.

To identify whether the number of hookwire influenced acute and chronic postoperative pain, we further subdivided the patients in Group A into Group Asingle (n = 34) and Group Amultiple(n = 35). After hookwire localization, 32/34 (94.1%) of patients in Group Asingle 32/34 (94.1%) and 34/35 (97.1%) of patients in Group Amultiple reported pain. When the patients were in the waiting area, the NRS score at rest was similar between the two subgroups, whereas the NRS score on coughing was significantly higher in Group Amultiple (4.0 [3.0–6.0]) than in Group Asingle (3.0 [2.0–4.0], p = 0.037). In contrast, there was no difference in pain intensity at the PACU, and at POD1 and POD2 between the two subgroups (Table 4). Moreover, the incidence of CPSP at POM3 was 62.9% (95% CI: 46.0–79.7%) in Group Amultiple, and 50.0% (95% CI: 32.3–67.7%) in Group Asingle, whereas the incidence of CPSP at POM6 was 60.0% (95% CI: 42.9–77.6%) in Group Amultiple, and 29.4% (95% CI:13.3–45.5%) in Group Asingle (Figure 2). The results demonstrated that the CPSP incidence in Group Amultiple was significantly higher at POM6 (p = 0.011) but not at POM3 (p = 0.281) than Group Asingle. On the contrary, the intensity of CPSP at POM3 (2.0 [2.0–3.0] vs 2.0 [1.0–2.0], p = 0.005) was higher in Group Amultiple than in Group Asingle but not at POM6 (2.0 [1.0–2.0] vs 2.0 [2.0–2.0], p = 0.330) (Table 4).

Table 4 The Incidence and Intensity (NRS) of Postoperative Acute and Chronic Pain in Subgroups

Postoperative Adverse Events and Satisfaction Rating

The study also evaluated the incidence of postoperative adverse events including postoperative nausea and vomiting (PONV), and shoulder-back pain, and the patient’s satisfaction rating for pain management (Supplementary Table 2). The occurrences of PON (46.4% vs 30.4%, p = 0.081), POV (27.5% vs 20.3%, p = 0.318), shoulder-back pain (20.3% vs 18.8%, p = 0.830), and the satisfaction rating for pain management (4.3±0.7 vs 4.4±0.7, p = 0.336) on discharge were not different between Group A and Group B. However, the satisfaction rating for pain management 3 months after surgery was lower in Group A (4.6±0.5) than in Group B (4.8±0.3, p = 0.034). At 6 months postoperatively, the satisfaction rating for pain management was similar between Group A (4.8±0.4) and Group B (4.9±0.3, p = 0.106).

Risk Factors Associated with CPSP

The multivariate regression analysis showed that preoperative hookwire localization (OR: 6.199, 95% CI: 2.049–18.749, p = 0.001) and surgical history (OR: 0.383, 95% CI: 0.151–0.698, p = 0.042) were associated with the development of CPSP (Table 5), whereas the lung tumor location, number of ports, and VATS surgery duration and anesthesia duration, were not associated with CPSP. The results further suggest that hookwire localization-associated acute pain can lead to CPSP following VATS. Interestingly, preoperative surgical history without chronic pain may be a protective factor for CPSP after VATS.

Table 5 Multivariate Logistic Regression Analysis of Factors Affecting Incidence of CPSP at Postoperative Third Month

Discussion

Chronic postsurgical pain severely impairs patients’ health and their quality of life. The risk factors for CPSP include intraoperative nerve injury, surgery duration, pre-existing pain, younger age, female sex, genetic predisposition, psychological vulnerability, and severity of acute postoperative pain.6 Although chronic preoperative pain enhanced the susceptibility to surgically induced pain,12 the effects of preoperative hookwire localization-related pain on chronic postoperative pain after VATS have not been reported previously. In this study, we found that hookwire localization caused mild-moderate pain before surgery in most patients undergoing VATS, and that this pain seemed to have limited influence on acute postoperative pain. However, a higher incidence and intensity of CPSP were noted in patients with hookwire localization when compared with those without hookwire localization at 3 months postoperatively but not at 6 months postoperatively. The subgroup analysis showed that multiple hookwires localization induced a higher intensity of CPSP at 3 months postoperatively and a higher incidence of CPSP at 6 months postoperatively than single hookwire localization. These findings suggest that acute preoperative pain at the surgical site may influence chronic postoperative pain, thereby posing a challenge for optimal perioperative pain management in this surgical population.

CPSP, also known as persistent postsurgical pain, is defined as chronic pain that develops or increases in intensity after a surgical procedure or tissue injury, and persists at least 3 months after the surgery or tissue trauma in the International Classification of Diseases-11 (ICD-11).18 CPSP after thoracic surgery is relatively common, and the incidence rate is as high as 65%.19 A meta-analysis of prospective studies reported that the incidence of CPSP at 3 and 6 months after thoracotomy was 57% and 47%, respectively,20 whereas the incidence of CPSP after VATS varied greatly from 7.7% to 44.0%,1,18,21–23 depending on the perioperative pain control and the number of ports. Notably, the definition of CPSP also influences the incidence. Previous studies reported that pain cut-offs of NRS >0, ≥3, or ≥4, used to define CPSP, produced rates of 37.5%, 9.7%, and 5.7%, respectively, in non-cardiac surgery.24 The incidence of CPSP in the present study is relatively high. This may be because we used pain cut-offs of NRS ≥1. A large retrospective study on thoracic surgery reported that around 1/3 of patients suffering from CPSP reported moderate or severe chronic pain, but only 3% of patients with CPSP sought active analgesic therapy.1 In the present study, the incidence of CPSP in patients with and without hookwire localization was 56.5% and 30.4%, respectively, and the incidence was higher (62.9%) in patients undergoing multiple hookwires localization. Nevertheless, most of the patients in our study reported mild-to-moderate pain intensities. Similar to previous studies, the incidence of CPSP after VATS also decreased over time in our study. These findings suggest that preoperative hookwire localization can influence the incidence of CPSP after VATS.

The removal of lung nodules by means of VATS is often helpful. Nevertheless, it is impossible to locate these lesions intraoperatively without the aid of preoperative localization techniques. The CT-guided hookwire localization prior to surgical resection is one of these techniques. Its complications include pain, pneumothorax (most are insignificant), hemorrhage, and hemoptysis. Other methods for preoperative localization of lung nodules include coil positioning, dye injection, and radionuclide location. These localization techniques yield similarly successful targeting rates and may have fewer complications.25,26 However, they may lead to a higher localization-associated pain score when compared with that of hookwire localization.27,28 The patients undergoing hookwire localization usually report moderate to severe postoperative chest pain,29,30 which results from the irritation or injury of the pleural tissues caused by the retained hookwires. In our study, most of the patients with hookwire localization reported mild-moderate pain before VATS, which restricted their activities (reduced activities to reduce pain and prevent dislodgement or migration of hookwire(s)). Simultaneous preoperative multiple hookwires localization may induce a higher incidence and a higher intensity of preoperative pain stress compared with single hookwire localization.31 Our result also revealed that patients with multiple hookwires localization experienced a higher pain intensity on coughing than those with single hookwire localization preoperatively. Nevertheless, the incidence of hookwire localization-associated pain between the two subgroups did not demonstrate a statistically significant difference. Furthermore, the number of hookwire also did not influence the incidence and intensity of early acute postoperative pain. Chronic preoperative pain is associated with an increased incidence of CPSP and prolonged opioid use,10–12 Interestingly, we found, for the first time, that not only hookwire localization but also the number of hookwires may influence the development of CPSP more than acute postoperative pain. Our finding suggests that preoperative pain stress from hookwire localization may trigger a mechanism underlying acute preoperative pain transition to CPSP.

There are numerous treatment options for CPSP prevention. However, none of them is optimal as the mechanisms underlying the transition from acute pain to CPSP remain unclear.32 Limited studies have reported on how preoperative pain, especially acute pain, increases the incidence of CPSP at the surgical site. Recent studies have indicated that preoperative inflammatory markers may be associated with the development of CPSP. Preoperative dysregulation of circulating microRNAs and long non-coding RNA (lncRNA) related to the inflammatory processes may serve as predictive biomarkers of pain outcome after surgery.33,34 The hookwire localization may trigger releases of inflammatory mediators. In this study, we did not measure preoperative serum levels of inflammatory cytokines. The hookwire localization and related pain are preoperative stress which may cause prolongation of postsurgical pain.35 The latest experimental studies showed that preoperative stress-induced expression of the transcription factor CCAAT/enhancer-binding protein β in spinal microglia may contribute to CPSP.36 Conversely, perioperative activation of spinal α7 nAChR in microglia-alleviated preoperative stress-induced prolongation of postsurgical pain.37 These preclinical data suggest that priming the proinflammatory activation of microglia may play a key role in the preoperative stress-induced prolongation of postsurgical pain. Since local anesthesia at puncture sites does not abolish pleuritic pain, preoperative control of hookwire localization-related pain with preoperative use of nonsteroidal anti-inflammatory drugs may improve CPSP after VATS. In the future, this hypothesis needs further clinical validation.

There are several confounders to our findings. In this study, the duration of surgery and anesthesia and the number of ports influenced the incidence of CPSP. The longer surgery duration is recognized as a predictor of CPSP.5 However, in our study, the patients without hookwire localization (Group B) had longer surgical and anesthetic times than those with hookwire localization (Group A). Meanwhile, the patients in Group B had fewer ports for the VATS procedures than those in Group A. Previous studies demonstrated that the use of multiple ports can lead to a higher acute postoperative pain intensity and a higher incidence of CPSP than the use of a single port.23,38,39 However, there is no difference in the early acute postoperative pain scores between patients with multiple ports and those with a single port.40 Overall, uniport VATS may have a small clinical benefit in reducing postoperative pain, considering the majority of studies reported on the first 72 h following surgery. In our study, the patients with hookwire localization utilized the patient-controlled analgesic pump more frequently on POD1, indicating a higher opioid use. Conversely, the patients with hookwire localization had a shorter surgical time and fewer numbers of port, but at 3 months postoperatively, they reported a higher incidence and intensity of CPSP. The multivariate linear regression analysis also confirmed that preoperative hookwire localization was associated with an increased risk of CPSP after VATS. Combined with an increased risk of CPSP in patients with multiple hookwire localization, these results further support that preoperative hookwire localization-related pain may promote the development of CPSP.

This study has several limitations. First, this is an observational cohort study but not a randomized control study. Whether hookwire localization was performed or not was determined by thoracic surgeons according to the surgical indications. Therefore, the baseline clinical characteristics between the two groups demonstrated some differences. For example, the patients with hookwire localization had a higher proportion of lung edge resection and fewer ports for VATS. The results remained valid after controlling for confounders in the multivariate linear regression analysis. Second, the subgroup analysis compared the effects between preoperative single hookwire and multiple hookwire localization-related pain on the incidence and intensity of CPSP but these were not the primary endpoints of this study. Furthermore, the sample size may be not large enough for the desired statistical power. Finally, background infusion of PCIA was used during postoperative pain management. This is considered unsafe and may result in oversedation and ventilatory impairment due to opioid overdose. Our rationale for providing a background infusion was because the intensity of acute postoperative pain after VATS is commonly severe. Nevertheless, this may overestimate opioid consumption.

Conclusion

Hookwire localization induces mild-moderate preoperative pain, and importantly, this pain stress increases the risk of CPSP after VATS. Moreover, multiple hookwire localization may lead to worse CPSP. Greater attention should be paid to hookwire localization-associated pain. Management of the prior pain state may be helpful for the prevention and management of pain and the transition from acute to chronic pain.33 Since the mechanism underlying hookwire localization-associated CPSP is unknown, clinically effective therapy that provides an overall improved outcome for the patients should be investigated.

Data Sharing Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Files can be emailed to anyone that concerned.

Ethics Approval and Informed Consent

This study was approved by the Ethics Committee of the Fudan University Shanghai Cancer Center, with the ethics number:2107238-15. The trial was registered after patient enrollment at clinicaltrials.gov (NCT05478460). Patients provided written consent. All methods were carried out in accordance with Declaration of Helsinki.

Acknowledgments

This study was supported by Shanghai Municipal Natural Science Foundation (to Jun Zhang, No.22Y11904200). Thanks are also given to surgeons in Department of thoracic surgery for their help on data collection.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Funding

This work was funded by a grant from the Shanghai Science and Technology Committee (No.20Y11906200). The funder was not involved in the design, conduct, or publication of this work.

Disclosure

The authors report no conflicts of interest in this work.

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