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Abstract
Background and objectives Pain management makes an important contribution to good respiratory care and early recovery after thoracic surgery. Although the development of video-assisted thoracoscopic surgery (VATS) has led to improved patient outcomes, chest tube removal could be distressful experience for many patients. The aim of this trial was to test whether the addition of lidocaine cream would have a significant impact on the pain treatment during chest tube removal from patients who had undergone VATS for lung cancer.
Methods This clinical trial was a double-blind randomized study. Forty patients with histologically confirmed lung cancer amenable to lobectomy/segmentectomy were enrolled. All patients had standard perioperative care. Patients were randomly assigned to receive either epidural anesthesia plus placebo cream (placebo, Group P) or epidural anesthesia plus 7% lidocaine cream cutaneously around the chest tube insertion site and on the skin over the tube’s course 20 min (Group L) before chest drain removal.
Results Visual analog scale (VAS) scores were higher in Group P (median 5, IQR, 3.25-8) than in Group L (median 2, IQR, 1-3). Pain intensities measured using a PainVision system were also higher in Group P (median 296.7, IQR, 216.9–563.5) than Group L (median 41.2, IQR, 11.8–97.0). VAS scores and the pain intensity associated with chest drain removal were significantly lower in Group L than Group P (p=0.0002 vs p<0.0001).
Conclusion Analgesia using lidocaine cream is a very simple way to reduce the pain of chest tube removal after VATS.
Trial registration number UMIN000013824.
- acute pain
- pain measurement
- postoperative pain
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Introduction
Pain management after thoracic surgery is very important because it facilitates deep breathing, coughing, and early ambulation, which are critical for good respiratory care and early recovery.1
Uncontrolled acute perioperative pain and related surgical stress responses are strongly associated with poor outcomes after thoracotomy and are predictive of chronic pain development.1 2 Video-assisted thoracoscopic surgery (VATS) has enabled chest incisions to be minimized, which has led to improved patient outcomes. However, postoperative chest tube placement continues to be associated with the need for in-hospital management3 and is one of the most important factors leading to persistent chest pain after VATS. During the process of chest tube removal, separating the chest tube from adherent tissues causes acute pain4 and is described an excruciating experience by patients.5 The conventional method usually utilizes an anchoring suture, a purse-string suture, and skin stapler for wound closure after the chest tube is removed. Although this method is reliable, clipping with a stapler or suturing can be painful and may require good anesthesia technique to reduce pain.6 7
Use of local anesthetics such as subcutaneous lidocaine injection is the most common method used to alleviate the pain caused by chest tube removal. Lidocaine acts through non-selective blockade of sodium channels (allosteric coupling to the voltage sensors) on small damaged or dysfunctional pain fibers at the site of application.8 9 However, the subcutaneous injection itself also causes sharp pain and a sense of discomfort in the patients, and patient’s response to the medication can vary so that complete pain relief may not be achieved.
Lidocaine plaster/cream/patch is used commonly and is recommended as a first-line treatment for neuropathic pain treatment.9 The rationale is that pain is transmitted to the central nervous system by afferent nociceptive fibers, and transmission can be interrupted by local application of blocking drugs with no (or extremely limited) systemic effect. Importantly, plaster/cream/patch also eliminates the risk of needle stick injuries and the pain of anesthetic injections. Compared with placebo, lidocaine plaster reduces allodynia and neuropathic symptoms in patients with painful peripheral neuropathy.10 11 A small randomized clinical study demonstrated that postoperative application of a topical anesthetic cream to chest tube sites in cardiovascular/thoracic surgery patients 3 hours before chest tube removal is more effective than intravenous morphine for blunting the pain elicited by the tube removal.12 One of the small clinical study’s limitations was that neither epidural nor intercostal analgesia was used. We therefore performed this study in patients who underwent VATS with general anesthesia and postoperative epidural analgesia to determine if lidocaine cream would reduce pain ratings more than placebo cream during chest tube removal.
The aim of the present study was to use a visual analog scale (VAS) and the PainVision system to test whether the addition of lidocaine cream would have a significant impact on the pain treatment even in the presence of postoperative epidural analgesia during chest tube removal in patients who had undergone VATS for lung cancer.
Methods
Study design
This clinical trial was a single center, double-blind randomized study performed in Akita, Japan. This study was registered at the University Hospital Medical Information Network (UMIN) (http://www.umin.ac.jp/ctr/index.htm).
Patients population
Patients with histologically confirmed non-small cell lung cancer amenable to surgical resection with curative intent were eligible to participate in this study. All participants were chemotherapy/radiation-naïve and >20 years of age, with an Eastern Cooperative Oncology Group performance status of 0–1 and adequate hematological, hepatic, and renal function. Exclusion criteria included: (1) central nervous system metastasis with symptoms; (2) a history of stroke or diabetes mellitus; (3) taking opioids at baseline; (4) localized chest infection; (5) allergy to local anesthesia; (6) neuropathy at enrollment. No patients with an American Society of Anesthesiologists physical status classification greater than III were included. Patients who had undergone radical lung cancer surgery were enrolled in the study between October 2017 and February 2019. Randomization was carried out preoperatively, just after full registration, using a simple random allocation method (figure 1). First, the person in charge of biostatistics in the central administration office generated random digit numbers that were allocated sequentially to 20 envelopes in the placebo arm and 20 envelopes in the treatment arm of the study. Thereafter, the 20 envelopes in each arm were reordered such that the independently generated random digit numbers were placed in ascending order in each arm. They were then allocated to the consecutively enrolled patients. Referring to an earlier study in this field,12 a sample size of 20 in each group (ie, a total sample size of 40, assuming equal group sizes) was required to achieve a power of 80% at a 5% (two sided) level of significance for detecting a true difference between means in the test group and a reference group for pain rating of 1.7 units, assuming a pooled SD of 1.9 units. The patients’ characteristics are listed in table 1.
Patient characteristics and comparisons between the two groups
Flowchart of participants’ recruitment.
General anesthesia and surgery
All patients had standard preoperative and intraoperative care. A thoracic epidural catheter (T5-T8) was placed before induction of general anesthesia. The paramedian approach was used in all patients, and the epidural space was identified using the loss-of-resistance technique, after which the epidural catheter was inserted. A continuous infusion at 4 mL/hour of 0.2% levobupivacaine with fentanyl 0.002 mg/mL was administered intraoperatively and postoperatively. On postoperative day (POD) 2, this was switched to 0.2% ropivacaine patient-controlled epidural analgesia. General anesthesia was induced using propofol 1.5–2 mg/kg and remifentanil 0.2–0.4 µg/kg/min. Anesthesia was maintained with 1%–2% sevoflurane and oxygen in air after tracheal intubation with a left-sided double-lumen endobronchial tube (Mallinckrodt’s Broncho-Cath 32–37 Fr, Mallinckrodt Medical Ltd, Athlone, Ireland). These lung cancer patients were treated using VATS (8–15 cm wound) segmentectomy or lobectomy plus systematic nodal dissection. Standard surgical techniques for rib retraction and chest tube (24Fr. Thoracic UK Catheter, NIPRO, Japan) placement were applied at the seventh or eighth intercostal space.
Postoperative analgesia
Patients were randomly assigned to either a placebo group (Group P, n=20) or a lidocaine cream group (Group L, n=20) for chest drain removal. Patients in Group P received a continuous infusion of 0.2% ropivacaine at a rate of 2–6 mL/h via epidural catheter beginning on POD 2. Patients in the Group L received the ropivacaine infusion plus 7% lidocaine cream 100 g, which was composed of lidocaine 7 g, carboxyvinyl polymer (Carbopol 934 p) 1 g, lauromacrogol (NIKKOL BL-2) 2 g, 10% sodium hydroxide solution 1 mL, and sterile purified water 89 mL. Adjustment of the infusion rate and bolus dose (3 mL, lockout time 30 min) was allowed if the patient complained of wound pain (VAS>4). Twenty minutes before chest tube removal, the lidocaine cream or a placebo cream was placed around the chest tube insertion site and on the skin over the tube’s course (figure 2A), after which the cream was covered with an occlusive dressing.
The experiments were carried out with patients in a lateral position. A pair of gold-plated surface electrodes were placed just beside the site of chest tube removal. (A) For chest tube removal, 7% lidocaine cream was placed around the chest tube insertion site and on the skin over the tube’s course. (B) Measurements using PainVision, a system for quantitative analysis of perception and pain. VATS, video-assisted thoracoscopic surgery.
Technique for chest tube removal and chest drain wound closure
The chest drain tube (24Fr. Thoracic UK Catheter) was inserted and an anchoring suture was placed using 2–0 nylon. A purse-string suture was placed around the chest tube, whirled around, and to with the chest tube (figure 2A). When the chest tube was to be removed, the anchoring suture was cut-off and the purse string suture was tied as the chest tube was withdrawn.
Visual analog scale
Pain severity was measured using a 100 mm VAS, where 0 represented no pain and 100 represented the worst pain imaginable. The VAS score was obtained from all patients within 10 min after chest drain tube removal.
Pain intensity assessed using the PainVision system
Pain intensity was measured objectively using the PainVision system (PS-2100, Nipro Corporation, Osaka, Japan) (figure 2B).13 First, sensors transmitting an electric current were attached on the forearm. The painless current perception threshold, which indicated the pain threshold of each subject, was measured twice, and the mean values were used as the measurements before chest drain tube removal. Second, the pain-compatible electrical current was measured. A gradually increasing pulsed current was applied within 5 min after the chest drain was removed and the drain wound was closed using 2–0 nylon, which had been placed intraoperatively. When the pain caused by the chest drain removal and the painless electric stimulation were considered equal, that current was defined as the pain-compatible electrical current. The pain-compatible electrical current was measured twice, and the mean values were used as the measurements. On the basis of these measurements,13 14 pain intensity was calculated using the following equation:
Pain intensity
=100×(pain-compatible electrical current−current perception threshold)/current perception threshold.
The VAS score was obtained immediately after the PainVision procedure and assessed at the same time point.
Statistical analyses
Group data are expressed as means±SD. Continuous data were compared using unpaired t-tests, and categorical data were compared using the χ2 test with continuity correction or Fisher’s exact test when applicable. Differences between the measured VAS scores and measured pain intensities in Groups P and L were examined using the Wilcoxon/Kruskal-Wallis test. Correlation between VAS scores and pain intensities was assessed with the Spearman rank correlation coefficient. All statistical analyses were performed using JMP IN 11.0.0 (SAS Institute, Cary, NC, USA). A two-sided p value less than 0.05 was considered significant.
Results
We evaluated chest drain tube removal from 40 patients who underwent radical segmentectomy or lobectomy plus systematic lymph node dissection for lung cancer, and who completed the study protocol. No patients withdrew from the study. There were no differences in age, weight, type of thoracic surgery, or chest tube location and duration between Groups P and L. VAS scores for postoperative wound pain on POD 1–7 did not significantly difference between the two groups (online supplementary figure 1).
Supplemental material
The VAS score during the chest drain removal was greater in patients (Group P) receiving only epidural anesthesia than in those (Group L) receiving the epidural plus lidocaine cream (median (IQR), 5 (3.25–8) vs 2 (1–3)1–3; p=0.0002). The pain intensity measured using the PainVision system was also greater in Group P than in Group L (median (IQR), 296.7 (216.9–563.5) vs 41.2 (1.8–97.0); p<0.0001). Both VAS scores and the measured pain intensities were significantly lower during chest drain removal in Group L than Group P (figure 3). There was a statistically significant correlation between these two scales (r=0.698, p<0.001).
Pain severity for chest drain removal. The enrolled patients were randomly divided to receive epidural anesthesia alone (placebo, Group P, n=20) or epidural anesthesia plus 7% lidocaine cream (Group L, n=20) for chest drain tube removal. (A) Visual analog scale (B) the pain intensity measured with the PainVision system VAS and pain intensities associated with chest drain removal were significantly lower in Group L than Group P (p=0.0002 and p<0.0001). *p<0.01, statistically significant difference. VAS, visual analog scale.
To determine whether there were differences in reported pain between men and women, the groups were subdivided based on gender. For men, VAS scores were significantly higher in Group P than Group L (median (IQR), 5 (5–8)5–8 vs 2 (2–3)2 3; p=0.0020). Likewise, the pain intensity measured using PainVision was higher in Group P than Group L (median (IQR), 285 (285–555.3) vs 44.5 (45.7–92.6); p=0.0001). For women, VAS score tended to be higher in Group P than Group L, but the difference was not significant (median (IQR), 5 (4–8)4–8 vs 2 (1–4.75); p=0.635). On the other hand, pain intensity measured using the PainVision system was significantly higher in Group P than Group L (median (IQR), 379.9 (180.6–856.6) vs 37.25 (9.85–165.2); p=0.0161, figure 4). Table 2 summarizes the differences compared between both groups.
Summary of the differences in the VAS scores and the pain intensity between both groups
The difference of pain severity in the gender. When the patients in each group were subdivided based on gender, the VAS scores for men, but not women (p=0.635), were significantly lower in Group L than Group P. The pain intensities measured using PainVision were lower in Group L than Group P for both men and women. *p<0.01, statistically significant difference. VAS, visual analog scale.
Discussion
In the present study, we demonstrated that during chest drain tube removal after VATS in patients with lung cancer, epidural anesthesia plus lidocaine cream is more effective than epidural anesthesia alone for controlling pain. We evaluated each patient’s pain experience using both VAS scores and measurements of pain intensity made using the PainVision system. No new toxicities or analgesia-related AEs, including drain site infection, were reported for lidocaine cream in the present study. Additionally, the pain intensity measured using PainVision correlated well with the VAS score, which is the conventional pain assessment for chest tube removal.
PainVision is a system for quantitative analysis of pain perception and is used for evaluation of pain in pain clinics and in clinical anesthesia practice.13 15 16 The system gives patients a painless alternative sensory stimulus equivalent to pain (mainly by stimulating Aβ and Aδ sensory nerve fibers) and measures the stimulus intensity.15 16 The PainVision system promises to be useful for quantitative assessment of perioperative pain, for post-thoracotomy pain syndrome due to intercostal nerve damage, and for sharp pain caused by chest drain tube removal. Pain intensity measured using the PainVision system was in good agreement with the VAS score in each patient in both Group P and Group L. Although acute pain is a sensation associated with subjective factors and is difficult to assess quantitatively or statistically using methods such as VAS or the face pain rating scale, our study demonstrated that the PainVision system could adequately and objectively measure the acute pain associated with chest tube removal.
Various biological and psychosocial factors, including gender-specific hormones, endogenous opioid systems, genotypes, pain coping strategies, and stereotypical gender roles, may contribute to gender differences in responses to pharmacological pain treatments.17 In the present study, investigation of gender differences revealed a significant difference between both women and men when measuring the pain intensity with the PainVision system. Although the small number of patients is a limitation in the present study, when we subdivided the participants based on gender, there is no significant difference between the VAS scores of women in Groups P and L, though a significant difference was detected using the PainVision system. This suggests the PainVision system may be a clinically important tool for quantitative assessment of perioperative pain.
The advantages of local treatment of pain over systemic treatment are numerous. With local routes, the therapeutic effect extends only to the locally affected area. While the oral/injection route is the method most frequently used for postoperative pain treatment, it puts the patient at risk of adverse effects. Older patients often take drugs (eg, gabapentinoids, opioid agonists, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and Na+ channel blockers), which can lead to adverse systemic effects and adverse drug-drug interactions.9 The advantage of local anesthesia is the possibility of its combination with systemic treatment so as to achieve an additive or synergistic effect without systemic drug interaction or additional side effects.18 In addition to its efficacy and safety, local anesthesia with lidocaine cream is simple and easy to administer and shows good patient compliance. With injected local anesthetic, the patient experiences the initial discomfort of the sting of the needle. But complete pain relief may be achieved with lidocaine cream, which eliminates the necessity for an injection.
This study has some limitations. First, lidocaine cream requires considerable time to take effect, which detracts from its utility as a method of pain reduction.19 In the present study, the cream was applied to the patients 20 min before removing their chest tube. What’s more, caution is needed because there is a small risk of systemic distribution of lidocaine due to accidental mucosal absorption, which can lead to severely adverse effects. Side effects of lidocaine cream are usually mild local skin reactions, such as edema, pallor, and erythema. Systemic toxicity from a topical anesthetic cream rarely occurs in adults. If systemic toxicity does occur, however, severe complications, including methemoglobinemia, central nervous system toxicity, and cardiotoxicity may be encountered, especially in infants and children.20 Possible factors contributing to the development of systemic toxicity include application of an excessive amount of anesthetic, large application area, prolonged application time, diseased/inflamed skin, age younger than 3 months, prematurity, and concomitant use of a methemoglobin-inducing agent.
Second, although the conventional methods used with patients in the present study secures the chest tube in position and prevents air or pleural fluid from entering the pleural space during the removal process, a disadvantage is the unsightly scar left after with the closing purse-string suture is removed. Moreover, a dressing is required for the chest tube removal site, and remaining suture material must be removed at a subsequent outpatient visit. Some methods of wound closure using knotless suture material,7 21 a two-layer method with triclosan-coated sutures,22 or the “Roman sandal” modified method using an alpha shape made up of cross-wires23 at the chest tube site have also been reported for general thoracic surgery. Advantages of these new suturing methods include quicker performance during both instillation and removal of the drain, no need for stitch removal at follow-up, good wound healing, and excellent cosmetic results without infection. Our analgesia method with addition of lidocaine cream can also be applied to these new methods for chest drain removal.
The local anesthetic effects of lidocaine cream are detectable at a depth of <5 mm after 120 min.24 In all of our patients, the cream was applied for 20 min prior to chest tube removal. Third important limitation of this study is that the effects of different application times on the efficacy of the lidocaine cream were not tested. The 20-min waiting period after lidocaine cream application was a small inconvenience to the patients as well as the surgeons and other members of the medical staff. In addition, although intercostal nerve block has been used extensively for analgesia after thoracic surgery, we made no comparison with intercostal nerve block in the present study.25
Fourth, our study was unable to quantify the amount of epidural local anesthetic and opioid consumed between groups. This limitation may lead to weaken our conclusion that the differences in analgesia were solely a result of lidocaine cream.
Although the lidocaine cream is not sterile, it does not support bacterial growth. Not only do local anesthetics serve as agents for pain control, they possess antimicrobial activity as well. Local anesthetics at concentrations typically used in clinical settings (eg, bupivacaine 0.125%–0.75%; lidocaine 1%–3%) inhibit growth of numerous bacteria and fungi under various conditions.26 Importantly, no evidence of infection was detected at the chest drain site of any patient in Group L 24 or 48 hours after tube removal or at the 1-month follow-up.
In summary, our results show that analgesia achieved with lidocaine cream reduces the pain caused by chest drain tube removal in patients who undergo a segmentectomy/lobectomy. We suggest that local analgesia with lidocaine cream could be recommended as a simple and effective means of managing pain associated with post-VATS chest tube removal and improving the comfort of surgical patients without increasing management difficulty or postoperative complications.
Acknowledgments
The authors are grateful to Professor Akiteru Goto (Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine) and Professor Hiroshi Nanjo (Clinical Pathology, Akita University Hospital) for suggesting pathological diagnoses.
References
Footnotes
Contributors SW collected and analyzed the data. KI analyzed the data and wrote the paper. TK, YS, ST, IM, NK, MA, TM, HI, YS, and SM helped to collect the data. KN suggested the statistical analysis. TN and YM designed and supervised the research. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Written informed consent was obtained from each patient before enrollment.
Ethics approval The study was carried out in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by the institutional review boards at Akita University Hospital (approval number/ID 1122).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.