Can Ultrasound-Guided Continuous Paravertebral Block Reduce the Incidence of Chronic Postsurgical Pain in Patients with Thoracoscopic Lung Cancer Surgery? A Randomized Controlled Trial

Background Thoracoscopic lung cancer surgery is accompanied by severe pain. Both continuous paravertebral block (CPVB) and continuous wound infiltration (CWI) are widely used for perioperative analgesia in thoracoscopic surgery. However, the effects of these different methods on chronic postsurgical pain (CPSP) are still unknown. Patients and Methods. This prospective randomized controlled trial assessed the eligibility of 113 patients. Ninety-seven patients who met the inclusion criteria were randomly divided into a CPVB group and a CWI group, and 80 patients were analyzed in the final study. The primary outcome measures were the incidence and intensity of chronic postsurgical pain (CPSP) at 3, 6, and 9 months after surgery. The secondary outcome measures were the numerical rating scale (NRS) score of rest and activity at 12, 18, and 24 hours and on the 2nd, 3rd, and 7th days postoperatively; the Barthel Activities of Daily Living (ADL) score of activity levels on the 1st, 2nd, 3rd, and 7th days postoperatively; and the long-term quality of the life score at 3, 6, and 9 months postoperatively. Results The incidence of chronic postsurgical pain in the CWI group was significantly higher than that in the CPVB group at 3, 6, and 9 months after surgery (all P < 0.05). The intensity of chronic postsurgical pain was significantly decreased in the CPVB group at 3, 6, and 9 months after surgery (P < 0.05). NRS-R and NRS-A scores were significantly decreased in the CPVB group within the first week after thoracoscopic surgery (P < 0.001). ADL scores were increased in the CPVB group within 3 days postoperatively. However, there were no differences in the ADL score on the 7th postoperative day or the long-term quality of the life score at 3, 6, and 9 months postoperatively. Conclusion Continuous ultrasound-guided paravertebral block reduced the intensity of acute pain within 7 days postoperatively and reduced the incidence of chronic pain at 3, 6, and 9 months after surgery, but there was no significant advantage in long-term quality of life. This trial is registered with ChiCTR2000038505.


Introduction
Lung cancer is the most common malignant tumor in the world, and surgery has been the main treatment option until now [1].However, some patients may also experience chronic postsurgical pain (CPSP) due to surgical incisions, expander compression, drainage tube depression, and rib and nerve injury [2].It has been reported that the incidence of CPSP in patients after lung cancer surgery is 25%-75% [3].Te defnition of chronic postsurgical pain (CPSP) in the International Association for the Study of Pain (IPSP) is pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e., at least 3 months after surgery or tissue trauma.Te pain is either localized to the surgical feld or the area of injury, projected to the innervation territory of a nerve situated in this area, or referred to a dermatome [4].Due to the psychological distress and disability caused by CPSP, it has a great negative impact on quality of life.Terefore, it has become an important problem for patients who receive lung cancer surgery.
Multimodal analgesia strategies are recommended for the management of pain [5].Nerve block and local anesthetic analgesia are common techniques combined with opioids that aim to reduce short-term pain in thoracic surgery [6,7].Previous guidelines pointed out that the European Society of Anesthesia recommends continuous wound infltration analgesia for postoperative pain management after lung cancer surgery.Because it is an efective, low-cost, proven, and safe analgesic technique, it is also easy to perform [8,9].However, with the development of ultrasound technology, paravertebral block has gradually become a new choice for perioperative analgesia in thoracoscopic surgery, with a high success rate and a low rate of serious complications [10,11].
Both analgesic techniques have advantages, but the comparative impact of these techniques on CPSP functional recovery and quality of life after patients receive thoracoscopic surgery has not been explored to date.Terefore, our study aims to compare the efcacy of ultrasound-guided continuous paravertebral block (CPVB) and continuous wound infltration (CWI) on the incidence and intensity of CPSP and long-term quality of life after thoracoscopic lung cancer surgery.

Te Study Design and
Participants.Tis prospective randomized clinical trial was conducted after obtaining approval from the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=61825ChiCTR2000038505) and approved by the Ethics Committee of the First Afliated Hospital of Chongqing Medical University (IRB: 2020-407).Tis study was performed at the First Afliated Hospital of Chongqing Medical University in accordance with the Consolidated Standards of Reporting Trials Statement for Reporting Trials August 2020 to January 2021.Written informed consent was obtained from each patient before recruitment.

Inclusion Criteria.
Patients with lung cancer undergoing elective thoracoscopic surgery, age over 18 years, BMI 18-40 kg/m2, and American Society of Anesthesiologists (ASAs) physical status II-III were enrolled in this study.

Inclusion Criteria for Chronic Postsurgical Pain.
Pain that occurs or increases after surgery or tissue injury lasts at least three months and is limited to the surgical or injury site.

Exclusion Criteria.
Contraindications to CPVB included allergies to local anesthetics, infection, or coagulopathy; allergic constitution; severe cardiovascular or hepatorenal insufciency; coagulation system disease; morbid obesity (BMI >40 kg/m 2 ); history of chronic pain; presence of neuropsychiatric diseases; and inability to comply with the study protocol for any reason.Other causes of pain, including infection, malignancy, and preexisting pain, were excluded.

Randomization and Blinding.
Te computer random number method generated a total of 113 random numbers (ranging from 1 to 113).Te frst 56 numbers were assigned to the CPVB group, and the remaining 57 digits were assigned to the CWI group.Patients ranked the numbers sequentially according to the experiment, and statistical analysis was fnally performed based on the grouped information.Surgeries were performed by the same group of surgeons.Te patients, data collector, and care team were blinded, while the anesthesiologists and surgeons were unblinded participants who were not otherwise involved in the study.

Anesthesia Procedure.
After patient arrival at the operation room, an intravenous sodium lactate Ringer's solution infusion was initiated and a radial artery catheter was placed.Standard monitoring, including evaluation of pulse oxygen saturation (SpO 2 ), end-tidal carbon dioxide partial pressure (PETCO 2 ), bispectral index monitoring (BIS), 3-lead electrocardiography, body temperature (T), and urine output, was performed.Anesthesia and operations were performed after a safety check.Midazolam (0.04 g/kg), sufentanil (0.5 g/kg), propofol (1.5 mg/kg), and vecuronium (0.1 mg/kg) were administered for induction.Intubation was performed using a double-lumen endobronchial tube, and the ipsilateral lung was defated during the procedure.Te lungs were ventilated with VC-IPPV set at Vt 5-8 mL/kg, I/E ratio of 1 : 2, and a respiratory rate sufcient to maintain PETCO 2 at 35-45 mmHg.Te target BIS value was maintained at 40-60.General anesthesia was maintained by infusion of propofol, sufentanil, and sevofurane.Small doses of noradrenaline were used to maintain the invasive arterial blood pressure (IBP) and the heart rate (HR) at a normal stage.

Ultrasound-Guided CPVB.
In the CPVB group, ultrasound-guided CPVB was performed with the patient in the lateral position by the same anesthesiologist at the end of the operation.After identifying the paravertebral space of the proposed level of the intercostal skin incision, a 20-gauge catheter (B.Braun Melsungen AG, 34209 Melsungen, Germany) was inserted 2-3 cm into the paravertebral space by using an out-of-plane approach with an 18-gauge Tuohy cannula needle.When there was no blood or cerebrospinal fuid refux after suction, a bolus of 1-2 ml of saline solution was injected through the PVB catheter to confrm the correct position, and then, 15 ml of 0.33% ropivacaine was given (Figure 1).Within 48 hours, continuous paravertebral patientcontrolled analgesia (PCA) was administered (a capacity of 300 mL, including 1% ropivacaine 600 mg, fentanyl 0.5 mg, saline 230 ml; a background dose of 5 ml/h, a bolus dose of 5 ml, and a lock-out time of 45 minutes).
Before skin closure, the same surgeon placed two multiperforated wound catheters (PAINfusor ® , Baxter, Maurepas, France) between the serratus anterior and the intercostal external in the CWI group.Te catheter was inserted three to four centimeters from the incision and sutured to the skin (Figure 2(A)).Catheter permeability was tested before a bolus injection of 10 mL of 0.33% ropivacaine.Ten, the catheters were connected to a disposable postoperative local anesthesia analgesia device (TJPS060-2-250-5) containing 300 ml of 0.2% ropivacaine and a background dose of 5 mL/h (Figure 2(B)).Te catheters were removed after 48 hours by the surgical team.

Pain Research and Management
After the surgery, acupuncture hypoalgesia and hypothermia tests were used to confrm whether the dermatomal level of sensory blockade had reached the fourth thoracic vertebra by 4 hours postoperatively, and patients with failed blockade were excluded.For rescue analgesia, dezocine (10 mg) was given intravenously immediately when NRS exceeded 4 in the resting state.

Outcome Measures
3.1.Te Main Outcome Measures.Te incidence of CPSP was assessed by the number of positive cases of CPSP (NRS ≥ 1 and 3 months postoperatively).Te intensity of CPSP can be indirectly assessed by the scores of the efects of pain on daily life and the level of pain treatment measures [12].Te patient's initial pain the day after surgery was referred to as postoperative pain.Te pain felt in the frst week after surgery was referred to as persistent postoperative pain.Finally, chronic pain was defned as lasting more than three months after surgery.
Te efect of pain on daily life had four grades: grade A (no efect), grade B (mild efect), grade C (moderate efect), and grade D (severe efect).
Te level of pain treatment measures had four grades: grade A (no treatment measures), grade B (rest or reduced activity), grade C (self-medication), and grade D (treatment at a hospital).

Te Secondary Outcome Measures. Secondary outcome measures were as follows: (1) general information of the patients;
(2) the NRS score for rest and activity at 12, 18, and 24 hours as well as 2, 3, and 7 days postoperatively; (3) the Barthel Activities of Daily Living (ADL) score for the activity level at 1 st , 2 nd , 3 rd , and 7 th day postoperatively: this scale comprises 10 basic daily activities (bowel control, bladder control, feeding, toileting, bathing, dressing, grooming, walking, stair climbing, and chair-to-bed/bed-to-chair transfer), with each item scored as 0 � need complete help, 1 � need some help, or 2 � need no help [13].(4) Te long-term quality of the life score at 3, 6, and 9 months postoperatively: long-term quality of life was assessed by the 12-item Short-Form Health Survey (SF-12), which is a 12-item (domain) questionnaire.Two summary components were constructed to summarize the physical and mental components (PCS and MCS, respectively).Te scale was explained to the patients by a research doctor who  Pain Research and Management was unaware of the group allocation.( 5) Postoperative-related data included additional analgesic requirement, patient satisfaction with postoperative analgesia (if patients had an NRS score of <2, the postoperative analgesia was considered satisfactory), adverse efects after surgery, length of ICU stay, time of chest tube removal, time of tracheal tube removal, and length of hospital stay.
Te patients were divided into two groups according to whether the NRS-R score was ≥2 on the frst day after the operation.Te incidence of CPSP in the two groups was followed up at 3, 6, and 9 months after surgery.
All patients were interviewed by telephone at 3, 6, and 9 months after surgery to collect postoperative data.

Sample Size Calculation
Sample size calculation was performed using PASS 15.0 (Stata Corp. LP, College Station, Texas, USA), which relied on the chronic pain incidence at 3 months after surgery.According to our preliminary results of 38 cases (19 cases in the CPVB group and 19 cases in the CWI group), we found that the incidence of CPSP at 3 months was approximately 10.5% in the CPVB group and 42.1% in the CWI group.Using a two-proportion test with a power of 90% (α � 0.05), the minimal sample size needed to be 39 patients in each group to detect diferences between the two groups.Considering a 20% dropout rate, we ultimately included a total of 113 patients.

Statistical Analysis
All statistical analyses were performed using the Statistical Package for the Social Sciences version 26.0 (SPSS Inc., Chicago, USA).Parametric variables were compared by an independent t test and are reported as the mean (standard deviation).Nonparametric variables were compared using the Mann-Whitney U test and are reported as medians (interquartile ranges (IQRs)).Categorical variables are listed as a ratio or as the numbers and percentage, and the differences between two groups were analyzed by Fisher's exact test or the chi-squared test for trends.All comparisons were two-tailed, and a P value <0.05 was considered statistically signifcant.

Patient Characteristics.
Between August 2020 and January 2021, 113 patients with lung cancer undergoing elective thoracoscopic surgery were enrolled in our study.Seven patients were excluded for the following reasons: history of chronic pain (n � 4), neuropsychiatric diseases (n � 1), morbid obesity (BMI >40 kg/m 2 ) (n � 1), and conversion to thoracotomy (n � 1).Furthermore, nine patients refused to participate.Seventeen patients were excluded from the fnal analysis because of mechanical obstruction of the PCA device (n � 2), catheter displacement (n � 1), death due to cancer metastasis (n � 1), suspected drug allergy (n � 1), and loss of follow-up (n � 12).Consequently, data were analyzed for 40 patients in each group.Figure 3 shows the Consolidated Standards of Reporting Trials fow diagram.Both groups of patients were comparable in terms of surgical and demographic data (Table 1).

Te Incidence and Intensity of CPSP.
Te CPSP incidence is shown in Figure 4. Te CPSP incidence was signifcantly higher in the CWI group (42.5% vs. 20% P � 0.030) than in the CPVB group at the 3 rd month postoperatively; the CPSP incidence was signifcantly higher in the CWI group (35.0% vs. 15.0%P � 0.039) than in the CPVB group at the 6 th month postoperatively, while at the 9 th month, the incidence of CPSP was signifcantly (25.0% vs. 7.5% P � 0.034) higher in the CWI group than in the CPVB group.Te intensity of CPSP, the impact score of pain on daily life (3 rd month postoperatively, P � 0.021; 6 th month postoperatively, P � 0.048; 9 th month postoperatively, P � 0.048), and the pain treatment measures (3 rd month postoperatively, P � 0.014; 6 th month postoperatively, P � 0.030; 9 th month postoperatively, P � 0.041) in the CPVB group were signifcantly lower than those in the CWI group (Table 2).

Pain Management within 7 Days after Surgery.
Acute pain scores at rest are shown in Figure 5. Te NRS-A scores of patients in the CPVB group were lower than those in the CWI group at the 6th, 12th, and 18th hours and the 1st, 2nd, 3rd, and 7th days after surgery (the CPVB group vs. the CWI group: F = 41.044,P < 0.001; F = 55.290,P < 0.001).

Postoperative-Related Data.
During the 48-hour postoperative period, the CPVB group used signifcantly less rescue analgesia (2/40 vs. 13/40, P � 0.002) and had higher analgesia satisfaction (33/40 vs. 15/40, P � 0.001).Te incidence of adverse events such as respiratory depression and urinary retention was similar in the two groups (P > 0.050).However, there was a signifcant reduction in the incidence of postoperative nausea and vomiting in the CPVB group compared with those in the CWI group (1/40 vs. 11/40, P � 0.002).Te length of ICU stay, time of chest tube removal, time of tracheal tube removal, and length of hospital stay were comparable between the two groups (Table 6).

Discussion
Our study revealed that CPVB can signifcantly reduce the chronic pain incidence and intensity at 3, 6, and 9 months after surgery and provide better acute pain relief up to 7 days after surgery when compared to local anesthetic continuous infusion but had no efect on long-term quality of life in patients with lung cancer.Our results may still promote the innovation of the postoperative analgesia mode of thoracic surgery and provide patients with better analgesia and faster rehabilitation quality after surgery.Te complexity of postoperative pain can be caused by a variety of factors, including the operative wound, muscle splitting, chest tube stimulation, and visceral pain; the complexity of pain generators necessitates multimodal postoperative analgesia [14].For the control of postoperative pain, ultrasound-guided PVB is considered to be an alternative to TEA, which is regarded as the gold standard for postoperative analgesia in thoracic surgery [15].Judging by the NRS scores at rest and activity during the 1st week after thoracoscopic surgery, our study proved that CPVB provided better acute pain relief as well as reduced the consumption of remedial analgesics, as has been reported in literature [2].PVB is a technique in which a local anesthetic is injected into the thoracic paravertebral space containing the intercostal nerves, the sympathetic chain, and the dorsal rami of the spinal nerves.Terefore, PVB can produce ipsilateral sensory, motor, and sympathetic nerve blockade [16].Te injected local anesthetic may difuse upward and downward along the paravertebral space.A single injection could produce anesthesia at 4-5 spinal levels, covering a wide plane [17].In contrast, the local anesthetic continuous infusion of a wound cannot produce such a broad analgesic plane, which may be the reason why CPVB is superior to local anesthetic continuous infusion of a wound.In addition, the study found diferences in the Barthel ADL scores on the 1st, 2nd, 3rd, and 7th postoperative days between the two groups.Tis may be related to the patients' perception of pain.Patients in the CPVB group experienced lower postoperative pain, which increased their ability to perform autonomous activities and accelerated their postoperative recovery.

Pain Research and Management
Several studies have demonstrated that acute pain intensity is the strongest predictor of chronic pain [18][19][20][21].In 1994, Katz et al. frst showed that acute pain intensity within 24 hours postoperatively predicted chronic pain at 1.5 years after the operation in a prospective study [18].Kampe et al. also reported that higher pain scores during the frst fve postoperative days seem to be the strongest risk factors for the development of chronic pain [19].Our study also showed that the management of acute pain has a signifcant efect on the development of chronic pain.Patients with more severe acute pain (NRS ≥ 2 on the frst postoperative day) were more likely to experience chronic pain.Acute pain in the early stages after surgery is thought to cause neuroplastic changes in the dorsal horn of the spinal cord, while pain can also cause sensitivity of the central nervous system and abnormalities in neurotransmitters among neurons, transforming acute postoperative pain into CPSP [22].Strengthening the management of acute pain is of great signifcance to prevent the occurrence of CPSP.Te highly efective analgesia provided by CPVB not only prevented acute pain but also provided aferent nerve block for several days after the operation to ensure that neuroplasticity was prevented, thereby avoiding the occurrence of chronic pain to a signifcant extent [23].
Te reported prevalence of chronic pain after thoracic surgery is quite variable, ranging from 14.3 to 90% [24][25][26].Our fndings that show almost 20% of patients in the CPVB group and 42.5% in the CWI group were still reporting pain at 3 months postoperatively and that 7.5% of patients in the CPVB group and 25% of patients in the CWI group were still in pain at 9 months are consistent with the reported literature [25,26].In both groups, the chronic pain incidence decreased with time, and there were signifcant diferences in the incidence of CPSP at 3, 6, and 9 months after the operation.In addition, at 3, 6, and 9 months postoperatively, the impact scores for the efects of pain on daily life and treatment measures were signifcantly decreased in the CPVB group compared with those in the CWI group.It is suggested that CPVB can not only reduce the incidence of CPSP but also reduce the intensity of CPSP.Tis is similar to the fndings in previous studies.A meta-analysis showed that PVB can effectively prevent chronic pain after breast surgery, reducing the incidence of such a pain [27].Borys et al. reported that patients who received PVB had a lower CPSP incidence and experienced a lower CPSP intensity at 6 months postoperatively than did control patients and patients receiving ketamine administration [24].Te explanation for the lower incidence of chronic pain in the PVB groups in these studies may be that PVB, which can not only produce a very dense aferent blockade of sensory information but also completely block transmission within the sympathetic chain, reduces central sensitization, thereby leading to less CPSP [28,29].
Severe persistent postsurgical pain mandates the liberal use of painkillers, including opiates, which itself increases the risk of chronic pain emergence [30].Te related mechanisms may be extensive tissue damage due to opiate use and opioidinduced hyperalgesia after prolonged and high-dose use of opioids [31].Te results of the present study suggest that patients in the CPVB group used less rescue analgesia and exhibited less postoperative opioid use, which was also one of the reasons why the incidence of CPSP in the CPVB group was lower than that in the CWI group.Tere was a signifcant reduction in the incidence of postoperative nausea and vomiting in the CPVB group compared with that in the CWI group (1/40 vs. 11/40, P � 0.002), which may be related to the amount of rescue analgesics used.
To evaluate the long-term postoperative quality of life of patients with lung cancer undergoing thoracoscopic surgery, SF-12 was selected as the evaluation tool in this study.SF-12  was developed and validated as a generic short-form instrument for measuring health-related quality of life.Te tool has been widely applied to assess important quality of life domains in medical studies [32].In the present study, the two groups were comparable regarding SF-12 scores.It is suggested that compared with continuous local-anesthetic infusion into wounds, continuous PVB does not afect the long-term quality of life of lung cancer patients undergoing thoracoscopic surgery.Tis was comparable to the fndings of the Chiu et al. trial, in which it was found that the quality of life at 1 year after breast cancer surgery was similar in the two groups as assessed by SF-12 [33].Our study did not determine the baseline quality of life for all patients.Terefore, it could not be concluded whether CPSP impaired the patients' quality of life.
7.1.Limitations.Some limitations of this study need to be considered.First, the sample size of our study (a singlecenter investigation) is slightly small, which may have biased the research results.Second, there was no blank control group in our clinical study because our local ethics committee believes that it is immoral to use normal saline for PVB or wound infltration.Tird, we failed to assess the nature of the postoperative chronic pain, that is, whether it was purely nociceptive pain or neuropathic pain.Fourth, all subjects in this study were given a 15 ml anesthetic load dose when they received paravertebral nerve block, but there was no signifcant diference in BMI between the two groups, so the average local anesthetic dose received by patients did not difer between the groups.Fifth, the paravertebral nerve block and catheter placement were performed after surgery, primarily to match the timing of analgesia in the CWI group and to minimize bias between groups due to the diferent timing of analgesia.Sixth, we did not collect more information about the patients' environment and behavior, which may have infuenced the development of chronic pain.As a result, intraoperative drug infusion into the paravertebral space was not considered.However, despite such faws, this study may still provide new insights into pain management in patients undergoing thoracic surgery.

Conclusion
Ultrasound-guided CPVB can reduce the number of patients receiving remedial analgesics after thoracoscopic surgery, promote the quality of early postoperative rehabilitation, and reduce the incidence and intensity of CPSP within 9 months after thoracoscopic surgery by better acute pain control, but there was no signifcant advantage in the longterm quality of life within 9 months postoperatively.

Figure 2 :
Figure 2: Te position of the multiperforated wound catheters (A); the catheters were connected to a disposable postoperative local anesthesia analgesia device (B).
Figure 3: Patient fow diagram.CPVB, continuous paravertebral block; CWI, continuous wound infltration.Continuous variables with a normal distribution are presented as the mean ± standard deviation (SD), nonparametric variables are reported as the median (interquartile range (IQR)), and categorical variables are presented as n (%).CPVB, continuous paravertebral block; CWI, continuous wound infltration; ASA, American Society of Anesthesiologists; BMI: body mass index.Pain Research and Management

Table 4 :
Long-term quality of the life score at 3, 6, and 9 months postoperatively.Continuous variables with a normal distribution are presented as the mean ± standard deviation (SD).CPVB, continuous paravertebral block; CWI, continuous wound infltration; SF-12, 12-item Short-Form Health Survey; PCS, physical health summary; MCS, mental health summary.

Table 5 :
Te relationship between patients with NRS-R ≥ 2 on the frst postoperative day and the incidence of chronic pain at 3, 6, and 9 months postoperatively.