Abstract OBJECTIVES This substudy of the colchicine for prevention of perioperative atrial fibrillation (COP-AF) pilot trial seeks to assess the effect of colchicine administration on the volume of postoperative pleural drainage, duration of chest tube in situ and length of stay following lung resection. METHODS Between April 2014 and April 2015, 100 patients undergoing lung resection at 2 tertiary care centres participated in a pilot blinded randomized trial comparing perioperative twice daily 0.6 mg of colchicine orally (n = 49) or placebo (n = 51) twice daily for 10 days. The primary outcome was total pleural drainage volume, which was recorded in 8-h intervals for the first 2 postoperative days per standardized protocol. RESULTS Only 1 patient did not complete the trial. The mean volume of pleural drainage at 40-h mark postoperation was significantly less in the colchicine group (550.9 ml) compared with the placebo group (741.3 ml, P = 0.039). Compared with the placebo group, the colchicine group showed significantly less mean pleural drainage on postoperative Day 2 (583.8 vs 763.3 ml, P = 0.039) and beyond. There were no differences in mean time to chest tube removal (6.8 days for the colchicine group vs 5.9 days for the placebo group, P = 0.585) and mean hospital length of stay (7.4 vs 6.9 days, P = 0.641). CONCLUSIONS Oral colchicine is potentially effective in diminishing the amount of pleural drainage following lung resection and can be considered in patients at high risk of large postoperative pleural effusion. A full-scale, prospective placebo-controlled randomized trial is needed to assess the clinical significance of perioperative colchicine administration following oncological lung resection. Pleural effusion, Pilot randomized controlled trial, Lung resection, Colchicine, Chest tube INTRODUCTION The management of pleural drains after thoracic surgery remains largely experience based with substantial variability among surgeons . Recently, focus has been placed on establishing evidence-based guidelines regarding postoperative chest tube management [2–8]. With the advent of fast-track surgery [9–11], renewed emphasis has been placed on early chest tube removal, with associated benefits of decreasing postoperative pain, attenuating the risk of infection and improving mobility and rehabilitation . Predictors of prolonged postoperative chest tube duration include the presence of an air leak and excessive pleural fluid drainage. Some authors have attributed pleural drainage as ‘the most common cause of delayed discharge and chest tube removal in the United States’ . To date, there remains no consensus as to the maximal permissible amount of drainage before chest tube removal following pulmonary resection. Despite the impact of pleural drainage on the duration of chest tube insertions and length of hospital stay, there is a paucity of research assessing the different variables that increase post-lung resection drainage, including the extent of resection and the quality of the pleural lining. No research has evaluated the effectiveness of different interventions in reducing pleural effusion in dedicated thoracic surgery patients. In the setting of cardiac surgery, randomized controlled trials have suggested that postoperative colchicine decreases the rates of pericardial and pleural effusions as well as decreasing the incidence of pericarditis and post-pericardiotomy syndrome [14–16]. Colchicine functions by inhibiting leucocyte migration leading to suppression of the inflammatory response . Data from 5 clinical trials (including a total of 1323 patients) demonstrated the safety of colchicine in the postoperative setting [15–16, 18, 19]. The purpose of this substudy of the colchicine for prevention of perioperative atrial fibrillation (COP-AF) pilot trial was to evaluate the effectiveness of colchicine in decreasing post-lung resection pleural drainage and its impact on chest tube duration and in-hospital length of stay. METHODS The COP-AF (colchicine for prevention of perioperative atrial fibrillation in patients undergoing lung resection surgery: a pilot randomized controlled study) pilot trial was a multicentre trial conducted by the Population Health Research Institute (PHRI) at McMaster University, specifically evaluating the feasibility of conducting a full-scale trial assessing the efficacy and safety of colchicine versus placebo in the prevention of perioperative atrial fibrillation. The results of the COP-AF feasibility pilot trial will be published separately. This substudy reflects a joint effort between the Division of Thoracic Surgery and the PHRI. It is important to note that some of the inclusion/exclusion criteria and logistical parameters reflect the collaborative effort of this project with a dual research focus. In this trial, patients, health care providers, data collectors and outcome adjudicators were blinded to treatment allocation. Between April 2014 and April 2015, patients were recruited for study participation at 2 tertiary care thoracic surgery centres: St. Joseph’s Healthcare Hamilton, McMaster University, Hamilton, and Health Sciences Centre, Winnipeg. Inclusion criteria included age 55 years or older, sinus rhythm, resectable primary or secondary lung cancer and consenting to participate in the trial. Subjects were excluded if they demonstrated any of the following characteristics: atrial fibrillation/flutter just before surgery, intolerance to colchicine, myelodysplastic disorders, renal impairment (estimated glomerular filtration rate <30 ml/min/1.73 m2), current treatment with colchicine and those unable to take oral medication for >24 h following surgery. Eligible patients were randomized in a 1:1 ratio to either colchicine or placebo by an interactive Web-based randomization system. Patients in the treatment arm received colchicine 0.6 mg, and those in the control arm received placebo, twice daily for a total of 10 days. The first dose was given within 4 h before surgery, and the second dose was administered between 18:00 and 23:59 on the day of surgery. If a patient was discharged from hospital prior to the completion of their course, they were given a package containing colchicine 0.6 mg or placebo tablets to complete a 10-day course. At the completion of surgical resection, one or two 28-Fr surgical chest tubes were inserted into the pleural space. The choice of the number of chest tubes was at the discretion of the operating surgeon. If 2 chest tubes were placed, 1 was an anteriorly located curved tube placed along the diaphragm, and the other was a straight tube placed posteriorly to the apex of the chest. Total pleural fluid measurements were made using the Thopaz digital chest drainage system (Medela, McHenry, IL, USA) or the traditional pleurovac analogue system (Atrium®; Medical Corporation, Merrimack, NH, USA) and were recorded in 8-h intervals by designated thoracic surgery nurses following the initial postoperative 24 h. With the exception of pneumonectomy cases, chest tubes were placed on −20 cmH2O for the first 24 h following surgery. Following that point, suction was stopped, and the chest tube was placed on water seal, unless a significant air leak existed (defined as >40 ml/min for 8 h or longer on the digital drainage system or air bubble with tidal breathing on the pleurovac system). In the absence of an air leak on the 2nd postoperative day, chest tubes were removed when pleural drainage was less than 350 ml per 24 h or less than 150 ml during the preceding 8 h. Following pneumonectomy, a single chest tube was placed and attached to a pleurovac off suction (mimicking a balanced drainage system). In the absence of bleeding or mediastinal instability, the chest tube was removed on the 1st postoperative day under sterile precautions and accordingly the measured drainage quantities reflect a total duration of 24–36 h based on the timing of chest tube removal. All patients were seen in outpatient follow-up at 30 days or were contacted by phone. The primary outcome of interest in this substudy was the total chest tube drainage volume within the first 2 postoperative days. Secondary outcomes included in situ chest tube duration and in-hospital length of stay. All other outcomes are reported separately in the COP-AF pilot trial publication. A cut-off of 48 h was established for assessing drainage based on the premise that the majority of patient would have their chest tubes removed by that point in adherence to our usual clinical practice patterns. This fixed time point analysis allows for a complete assessment of pleural fluid volume for each patient in the study. Data were collected prospectively and analysed using an intention-to-treat approach in which patients were analysed in the groups to which they were randomized using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA). Continuous data were presented using means (standard deviation) or medians (range) and analysed using the Student’s t-test (for parametric data) or the Mann–Whitney U-test (for non-parametric data). Categorical data were reported as proportions and analysed using the χ2 or the Fisher’s exact test (for cell sizes <5). Univariate analysis was utilized to compare baseline characteristics between the 2 treatment arms. Statistical significance was set at P < 0.05. RESULTS Of 205 eligible patients approached for study participation, 100 participants were randomized to perioperative colchicine administration (n = 49) or placebo (n = 51). One patient randomized to the placebo arm did not undergo surgery and therefore did not receive any treatment. Therefore, the final analysis related to chest tube drainage and duration included 49 patients in the colchicine arm and 50 patients in the placebo group. There was no loss to follow-up in either intervention arm (Fig. 1). Figure 1: View largeDownload slide The CONSORT diagram. Figure 1: View largeDownload slide The CONSORT diagram. Table 1 reports the baseline characteristics, which were similar between the 2 groups except for 3 variables: female gender (68.8% in the colchicine group vs 43.1% in the placebo group, P = 0.010), prevalence of coronary artery disease (10.2% in the colchicine group vs 29.4% in the placebo group, P = 0.016) and the proportion of patients with hypertension (42.9% in the colchicine group vs 66.7% in the placebo group, P = 0.017). Procedure-specific comparisons did not yield any difference between the 2 groups (Table 2). In assessing the entire cohort as a whole, 73.2% of patients underwent lobar resection (4 pneumonectomies, 3 bilobectomies and 64 lobectomies), with 13 patients undergoing segmentectomy and an equal number having a non-anatomical wedge resection. Half of the overall procedures were conducted using minimally invasive surgical approaches, either via video-assisted thoracoscopic surgery or via robotic-assisted surgery. This proportion was maintained within the 2 treatment arms (48.5% in the colchicine arm vs 50.0% in the placebo arm, P = 0.763). No repeat procedures were required for any patient in either group. Table 1: Patient characteristics Overall Colchicine Placebo P-value n % n % n % Demographics Age, mean (SD) 100 68.6 (7.4) 49 68.9 (7.5) 51 68.3 (7.4) 0.67 Gender, female 55 55.6 33 68.8 22 43.1 0.010 Medical history Atrial fibrillation/atrial flutter 0 0.0 0 0.0 0 0.0 Stroke/transient ischaemic attack 10 10.0 7 14.3 3 5.9 0.20 Congestive heart failure 1 1.0 1 2.0 0 0.0 0.49 Deep vein thrombosis/pulmonary embolus 6 6.0 3 6.1 3 5.9 1.00 Coronary artery disease 20 20.0 5 10.2 15 29.4 0.016 Cardiac arrest 0 0.0 0 0.0 0 0.0 Peripheral vascular disease 6 6.0 3 6.1 3 5.9 1.000 Diabetes on treatment 17 17.0 8 16.3 9 17.6 0.86 Hypertension 55 55.0 21 42.9 34 66.7 0.017 Chronic obstructive pulmonary disease 48 48.0 23 46.9 25 49.0 0.84 Interstitial lung disease 2 2.0 2 4.1 0 0.0 0.24 Home oxygen therapy 0 0.0 0 0.0 0 0.0 Secondary malignancy 7 7.0 3 6.1 4 7.8 1.00 History of tobacco use 88 88.0 43 87.8 45 88.2 0.94 Overall Colchicine Placebo P-value n % n % n % Demographics Age, mean (SD) 100 68.6 (7.4) 49 68.9 (7.5) 51 68.3 (7.4) 0.67 Gender, female 55 55.6 33 68.8 22 43.1 0.010 Medical history Atrial fibrillation/atrial flutter 0 0.0 0 0.0 0 0.0 Stroke/transient ischaemic attack 10 10.0 7 14.3 3 5.9 0.20 Congestive heart failure 1 1.0 1 2.0 0 0.0 0.49 Deep vein thrombosis/pulmonary embolus 6 6.0 3 6.1 3 5.9 1.00 Coronary artery disease 20 20.0 5 10.2 15 29.4 0.016 Cardiac arrest 0 0.0 0 0.0 0 0.0 Peripheral vascular disease 6 6.0 3 6.1 3 5.9 1.000 Diabetes on treatment 17 17.0 8 16.3 9 17.6 0.86 Hypertension 55 55.0 21 42.9 34 66.7 0.017 Chronic obstructive pulmonary disease 48 48.0 23 46.9 25 49.0 0.84 Interstitial lung disease 2 2.0 2 4.1 0 0.0 0.24 Home oxygen therapy 0 0.0 0 0.0 0 0.0 Secondary malignancy 7 7.0 3 6.1 4 7.8 1.00 History of tobacco use 88 88.0 43 87.8 45 88.2 0.94 Table 2: Operative details Overall Colchicine Placebo P-value n % n % n % Resection type 0.37 Pneumonectomy 4 4.0 3 6.1 1 2.0 Bilobectomy 4 4.0 1 2.0 3 5.9 Lobectomy 65 65.0 31 63.3 34 66.7 Segmentectomy 13 13.0 5 10.2 8 15.7 Wedge 13 13.0 9 18.4 4 7.8 Other 1 1.0 0 0.0 1 2.0 Resection classification 0.54 Lobar 73 73.7 35 71.4 38 76.0 Sublobar 26 26.3 14 28.6 12 24.0 Resection approach 0.69 Open 50 51.0 26 53.1 24 49.0 Video-assisted thoracoscopic surgery 39 39.8 19 38.8 20 40.8 Robotic 9 9.2 4 8.2 5 10.2 Resection approach simplified 0.35 Open 50 51.0 26 53.1 24 49.0 Minimally invasive 48 49.0 23 46.9 25 51.0 Overall Colchicine Placebo P-value n % n % n % Resection type 0.37 Pneumonectomy 4 4.0 3 6.1 1 2.0 Bilobectomy 4 4.0 1 2.0 3 5.9 Lobectomy 65 65.0 31 63.3 34 66.7 Segmentectomy 13 13.0 5 10.2 8 15.7 Wedge 13 13.0 9 18.4 4 7.8 Other 1 1.0 0 0.0 1 2.0 Resection classification 0.54 Lobar 73 73.7 35 71.4 38 76.0 Sublobar 26 26.3 14 28.6 12 24.0 Resection approach 0.69 Open 50 51.0 26 53.1 24 49.0 Video-assisted thoracoscopic surgery 39 39.8 19 38.8 20 40.8 Robotic 9 9.2 4 8.2 5 10.2 Resection approach simplified 0.35 Open 50 51.0 26 53.1 24 49.0 Minimally invasive 48 49.0 23 46.9 25 51.0 Table 3: Outcome measures n with data n with missing data Overall mean (SD) Colchicine mean (SD) Placebo mean (SD) P-value Length of stay (days) 99 0 7.1 (4.4) 7.4 (5.3) 6.9 (3.3) 0.64 Volume drained at 1 h (ml) 71 28 126.1 (124.7) 92.9 (81.5) 156.6 (148.9) 0.008 Volume drained at 24 h (ml) 98 1 296.6 (235.5) 244.3 (164.0) 349.0 (282.2) 0.062 Volume drained at 32 h (ml) 73 26 478.8 (287.4) 391.8 (216.7) 563.5 (323.5) 0.028 Volume drained at 40 h (ml) 68 31 651.7 (352.5) 550.9 (230.1) 741.3 (416.4) 0.039 Volume drained at 48 h (ml) 83 16 676.8 (401.5) 583.8 (318.2) 763.3 (452.6) 0.039 Time to chest tube removal (days) 99 0 6.4 (5.8) 6.8 (6.9) 5.9 (4.5) 0.59 n with data n with missing data Overall mean (SD) Colchicine mean (SD) Placebo mean (SD) P-value Length of stay (days) 99 0 7.1 (4.4) 7.4 (5.3) 6.9 (3.3) 0.64 Volume drained at 1 h (ml) 71 28 126.1 (124.7) 92.9 (81.5) 156.6 (148.9) 0.008 Volume drained at 24 h (ml) 98 1 296.6 (235.5) 244.3 (164.0) 349.0 (282.2) 0.062 Volume drained at 32 h (ml) 73 26 478.8 (287.4) 391.8 (216.7) 563.5 (323.5) 0.028 Volume drained at 40 h (ml) 68 31 651.7 (352.5) 550.9 (230.1) 741.3 (416.4) 0.039 Volume drained at 48 h (ml) 83 16 676.8 (401.5) 583.8 (318.2) 763.3 (452.6) 0.039 Time to chest tube removal (days) 99 0 6.4 (5.8) 6.8 (6.9) 5.9 (4.5) 0.59 With no difference in treatment adherence, the mean total amount of pleural drainage at 48 h was significantly less in the colchicine arm when compared with the placebo [583.8 (318.2) ml vs 763.3 (452.6) ml, P = 0.039]. The difference in overall drainage was not present at the 24-h mark (244.3 ml with colchicine vs 349.0 ml with placebo, P = 0.062) but was evident starting at the 32-h mark and onwards (Fig. 2). Despite the overall difference in pleural drainage, this did not translate to a decrease in the mean time to chest tube removal between the 2 groups [i.e. 6.8 days in the colchicine arm and 5.9 days in those receiving placebo (P = 0.585)]. There was also no difference in the mean length of stay in hospital [7.4 (5.3) days in the colchicine group vs 6.9 (3.3) days in the placebo group, P = 0.641]. Figure 2: View largeDownload slide Distribution of chest tube drainage (ml) over time. Post-op: postoperative. Figure 2: View largeDownload slide Distribution of chest tube drainage (ml) over time. Post-op: postoperative. DISCUSSION This prospective randomized blinded pilot study demonstrated that perioperative colchicine administration decreases the volume of pleural drainage following oncological lung resection. Despite a significant difference in the total quantity of pleural effusion, this did not translate to a difference in the chest tube duration. Several reports utilizing different drainage volume cut-offs have been published—each reporting successful chest tube removal at higher volumes. One of the earliest reports was by Cerfolio and Bryant  in 2008, who reported on 2077 patients undergoing 8608 non-pneumonectomy pulmonary resections. This study demonstrated that 18% of patients were discharged earlier using a threshold of 450 ml/day for chest tube removal. This was not associated with an increased rate of hospital readmission or reintervention in the pleural space. Only 0.55% of patients were readmitted for recurrent symptomatic effusion . As the initial trial validating the safety of early chest tube removal, this served as a catalyst for other trials. Nonetheless, as a retrospective single-centre analysis, the external validity is limited—good patient outcomes could be attributed to reasons other than liberal chest tube removal at higher pleural drainage volume. In 2013, Zhang et al.  conducted a prospective randomized single-blinded trial of 70 patients randomized to early chest tube removal at a volume of 300 ml/day versus traditional management (threshold of 100 ml/day). Duration of chest tube placement and length of stay were significantly shorter in the 300 ml/day group. There was, however, no difference in the rates of post-removal pleural effusion, postoperative complications or the need for thoracentesis (4.9% vs 0%) between the 2 groups. Interestingly, however, the early removal group had a 9.8% incidence of reaccumulation of pleural fluid when compared with 0% in the traditional group . Using the fast-track post-video-assisted thoracoscopic surgery, Bjerregaard et al.  removed the chest tubes with a drainage threshold of 500 ml/day. Their retrospective cohort analysis of 599 patients identified a post-chest tube removal pleural space reintervention rate of 2.8% and was not associated with the time of chest tube removal. The findings of this trial were, however, limited by its retrospective nature and the fact that all operations were conducted using video-assisted thoracoscopic surgery (which is known to cause less pleural inflammation and subsequently effusion). None of these trials evaluated the factors that were associated with increased postoperative pleural drainage or means by which to mitigate them. Our trial is the first thoracic surgery study attempting to intervene by decreasing the volume of pleural drainage following lung resection using pharmacotherapy. Previous work in the cardiac surgery population has proved the efficacy of perioperative colchicine in decreasing postoperative pericarditis and post-pericardiotomy syndrome. Traction for postoperative treatment with colchicine began with the study by Finkelstein et al.  in 2002, which demonstrated that post-pericardiotomy syndrome in 10.6% of patients receiving cholchicine vs 21.9% of patients in the control group (P < 0.135). The colchicine for the prevention of the post-pericardiotomy syndrome (COPPS) randomized trial later depicted a significant reduction in the incidence of post-pericardiotomy syndrome at 12 months with colchicine (8.9% in the colchicine arm vs 21.1% in the placebo group, P = 0.002, number needed to treat = 8) . The same study group demonstrated that colchicine significantly reduced the incidence of pericardial and pleural effusion post-cardiac surgery, which were identified on echocardiography or chest X-ray (19.4% vs 31.7%, respectively, P = 0.011, with a relative risk reduction of 38.8%), and had minimal associated side effects . In addition to the different surgical procedures and patient population, some other difference between our trial and the aforementioned studies exist. Namely, in the COPPS trial, patients were treated with colchicine starting on the 3rd postoperative day, with no preoperative dose administered. In addition, the duration of treatment was substantially longer than our protocol, with patients receiving treatment for a total of 30 days after surgery. Finally, an important distinction in outcome analysis needs to be made. While our data quantified the volume of pleural drainage, the COPPS and Finkelstein trials dichotomized the variable—reporting on the incidence of effusion using transthoracic echocardiography. By providing specific volume of drainage in the immediate postoperative period, our study allowed for continuous assessment of the effects of colchicine over time, with the possibility of establishing a plateau effect time period when treatment could potentially be stopped. In addition, volume assessment provides details important to the determination of clinical relevance. The amount of postoperative pleural effusion production following lung resection is greater than that following cardiac surgery. Possible mechanisms explaining this phenomenon include direct disruption of the pleural membrane, surgical lung manipulation and the relative loss of lung volume leading to a post-resection pleural space with limited apposition of the visceral and parietal pleura. Colchicine treatment could therefore potentially have a greater role in the thoracic surgery population. The potential mechanism by which colchicine diminishes pleural effusion formation relates to its anti-inflammatory effects. By inhibiting leucocyte migration and disrupting kinin formation, colchicine impedes the inflammatory cascade and possibly decreases the consequent effects on pleural permeability and diminishes the amount of pleural fluid formation. The safety of colchicine has been proved in several clinical trials encompassing over 1300 patients. No serious side effects were reported, with the most common complaints being gastrointestinal symptoms and diarrhoea (which resolved after drug discontinuation). A collaborative effort by the European Society of Thoracic Surgeons (ESTS), American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS) and General Thoracic Surgical Club (GTSC) led to the publication of a consensus document promoting an evidence-based approach to the management of the pleural space . The committee highlighted the need for more thorough analysis assessing pertinent risk factors for increased postoperative pleural drainage and for dynamic measurement of quantity and character of pleural fluid, as well as the rate of reintervention following chest tube removal. The most critical aspect of postoperative pleural space management is the identification of patients/procedures at greatest risk of developing large-volume effusion. Colchicine treatment would likely have the greatest impact in such a population group. Recently, Hristova et al.  attempted to develop an aggregate risk score identifying patients at higher risk of developing LVE (defined as pleural drainage >400 ml/day) on the 2nd postoperative day. In this retrospective analysis of 229 consecutive patients undergoing lobectomy, the authors identified a large-volume effusion rate of 23%. Large pleural effusion was associated with a longer mean chest duration (6.5 vs 4.5 days, P < 0.001) and longer mean postoperative length of stay (6.9 days vs 5.5 days, P < 0.001). Using stepwise logistic regression, an aggregate score predicting large-volume effusion risk was created and identified the following predictors of large postoperative pleural drainage: patient age >70 years, lower lobectomy and the presence of COPD. Such a composite score can be valuable, identifying parameters for differential chest tube management based on a patient’s individual risk. Moreover, it can also serve as a means of identifying which patients would benefit the most from colchicine administration in the perioperative setting. Limitations Although this serves as the first prospective study evaluating the effectiveness in decreasing post-lung resection pleural drainage, our trial has several limitations. First, the small sample size of a pilot trial identifies the need for caution in the interpretation of our primary result. Increased sample size would also allow for sensitivity analysis, assessing the impact of different surgical techniques on rate of pleural effusion and identifying a potential subgroup of patients with greatest benefit from colchicine administration. Second, there was a differential distribution of some baseline characteristics between the 2 groups, despite the fact that central randomization was undertaken. The differences in gender, prevalence of coronary artery disease and hypertension were, however, unlikely to have substantial consequences on pleural drainage and would not be expected to serve as confounders to our analysis. There was no difference between the treatment arms with regard to other potentially more impactful parameters. We did not evaluate the rate of post-discharge pleural effusion or reintervention following chest tube removal. These variables are important and will be included as secondary outcomes in the full-scale trial. Finally, the lack of difference in the length of stay or duration of chest tube in situ between the 2 groups could be explained by the advent of robotic surgery at our institution, which coincided with the timing of this trial. Initially, robotic lung resections (accounting for 9% of this study cohort) were associated with higher rates of air leaks and accordingly chest tube duration. As a minimally invasive novel technique, the initial learning curve could account for these discordant findings. CONCLUSION Perioperative short-term administration of colchicine following oncological lung resection was associated with significantly decreased volume of pleural drainage on the 2nd postoperative day. The anti-inflammatory effects of colchicine hold promise as a means to decrease the amount of pleural fluid produced after thoracic surgery. The use of this treatment approach can potentially be considered in patients at high risk of large postoperative pleural effusion. Funding This work was supported by a March 2013 Canadian Institute for Health Research Operating Grant and the April 2013 Physicians Services Incorporated Foundation Health Research Grant. Conflict of interest: none declared. REFERENCES 1 Zhang Y, Li H, Hu B, Li T, Miao JB, You B et al. A prospective randomized single-blind control study of volume threshold for chest tube removal following lobectomy. 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European Journal of Cardio-Thoracic Surgery – Oxford University Press
Published: Apr 1, 2018
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