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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 8  |  Page : 309-316

The single chest tube versus double chest tube application after pulmonary lobectomy: A systematic review and meta-analysis


Department of Thoracic Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, China

Date of Web Publication22-Feb-2017

Correspondence Address:
Changhong Liu
Department of Thoracic Surgery, The Second Hospital of Dalian Medical University, Dalian
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.200743

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 > Abstract 

Objective: Draining of the chest cavity with two chest tubes after pulmonary lobectomy is a common practice. The objective of this study was to evaluate whether using two tubes after a pulmonary lobectomy is more effective than using a single tube.
Patients and Methods: We performed a meta-analysis of five randomized studies that compared the single chest tube with double chest tube application after pulmonary lobectomy. The primary end-point was amount of drainage and duration of chest tube drainage. The secondary end-points were the patient's numbers of new drain insertion after operation, hospital stay after operation, the patient's numbers of subcutaneous emphysema after operation, the patient's numbers of residual pleural air space, pain score, the number of patients who need thoracentesis, and cost.
Results: Five randomized controlled trials totaling 502 patients were included. Meta-analysis results are as follows: There were statistically significant differences in amount of drainage (risk ratio [RR] = –0.15; 95% confidence interval [CI] = –3.17, –0.12, P = 0. 03), duration of chest tube drainage (RR = –0.43; 95% CI = –0.57, –0.19, P = 0.02), pain score (P < 0.05). Compared with patients receiving the double chest tube group, there were no statistically significant differences between the two groups with regard to the patient's numbers of new drain insertion after operation.
Conclusion: Compared with the double chest tube, the single chest tube significantly decreases amount of drainage, duration of chest tube drainage, pain score, the number of patients who need thoracentesis, and cost. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample, multicenter, randomized, controlled trials.

Keywords: Double chest tube, meta-analysis, pulmonary lobectomy, single chest tube, systematic review


How to cite this article:
Zhang X, Lv D, Li M, Sun G, Liu C. The single chest tube versus double chest tube application after pulmonary lobectomy: A systematic review and meta-analysis. J Can Res Ther 2016;12:309-16

How to cite this URL:
Zhang X, Lv D, Li M, Sun G, Liu C. The single chest tube versus double chest tube application after pulmonary lobectomy: A systematic review and meta-analysis. J Can Res Ther [serial online] 2016 [cited 2017 Mar 26];12:309-16. Available from: http://www.cancerjournal.net/text.asp?2016/12/8/309/200743


 > Introduction Top


In recent year, the incidence of the lung diseases is increasing, especially the lung cancer. Inadequate re-expansion of the residual lung is one of the most important causes of morbidity following lung resection and may instigate postsurgical hemothorax, persistent air leak, or atelectasis. To expand postoperative residual lungs, drainage of the pleural space after pulmonary lobectomy is generally performed using two chest tubes: one is placed into the posterior and basilar region to drain fluid, while the other is directed toward the apex for removing the air from the chest. It has been assumed that a complete control on fluid and air in the pleural space could only be maintained by inserting two chest tubes.[1],[2]

Theoretically, using a single chest tube causes less pain and discomfort during the postoperative period and is more economical in terms of time and costs more than the classical two-drain approach. Less pain in the postoperative period may improve the patient's capability to perform respiratory exercises, aid bronchial toilet, and thereby, facilitate better lung expansion and decrease the rate of complication.[3]

Therefore, we undertook this meta-analysis to assess whether using two tubes after a pulmonary lobectomy is more effective than using a single tube. The main objective of this meta-analysis, based on individual patient data, is to compare the single chest tube with double chest tube after pulmonary lobectomy, with a statistical power much higher than each trial. Data regarding the chest tube application were collected and analyzed.


 > Patients and Methods Top


Inclusion criteria

Types of studies

All randomized controlled clinical trials (irrespective of language or publication status) comparing the single chest tubes to double chest tube application after pulmonary lobectomy were considered eligible for the meta-analysis. Abstracts or unpublished data were included only if sufficient information on interventions and outcomes was available and if the final results were confirmed by contact with the first author.

Types of participants

The following randomized controlled trials (RCTs) were included:

  1. Trials comprising patients who were scheduled to undergo the pulmonary lobectomy or bilobectomy operation with mediastinal nodal dissection
  2. Trials of the single chest tube and double chest tube application after pulmonary lobectomy
  3. Trials in which the primary outcome measure was amount of drainage and duration of chest tube drainage. The secondary outcome measures were the patient's numbers of new drain insertion, hospital stay after operation, the patient's numbers of subcutaneous emphysema, the patient's numbers of residual pleural air space, pain score, and the number of patients who need thoracentesis.


Exclusion criteria

  1. Patients who were scheduled to undergo a pneumonectomy, wedge resection, and nonresectable thoracotomy
  2. Patients in whom postoperative massive air leakage or massive bleeding.


Literature search

The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed, EMBASE, ISI databases, and Chinese Biomedical Literature Database were searched for RCTs comparing the single chest tube with the double chest tube after pulmonary lobectomy without language restriction. Moreover, Google Scholar and reference lists of all the included studies were searched for additional reports. Contact with the authors was initiated by E-mail or telephone if any information was not available. The search strategies used the following major terms: “pulmonary lobectomy (mesh),” “pulmonary lobectomy OR lung lobectomy OR pulmonary lobectomies,” “chest tube OR chest drain.”

Data extraction and quality assessment

The search strategy described was used to obtain titles and abstracts of RCTs that were relevant to this review. Two reviewers independently assessed the titles and abstracts of all identified trials to confirm fulfillment of inclusion criteria; data abstraction was performed independently by two reviewers. Any difference of opinion or disagreement that arose in the course of search, data abstraction, quality assessment, or other related work between the two investigators was resolved by mutual discussions.

The risk of bias of the included RCTs was assessed according to the Cochrane Handbook 5.0.2 by two reviewers independently and was judged using the following criteria: sequence generation; allocation sequence concealment; blinding of participants, incomplete outcome data; free of selective reporting; and free of other bias.[4],[5] Each entry was definitively judged by an answer (yes/no/unclear): “Yes” indicates low risk of bias, “No” indicates high risk of bias, and “Unclear” indicates unclear or unknown risk of bias.[4] Disagreements were resolved by referring to the third reviewer until consensus was reached. If any information was unavailable, contact with the authors was initiated through E-mail or telephone.

Statistical analysis

The statistical analysis was conducted using the Cochrane software RevMan 5.1.[4] The risk ratios (RRs) with 95% confidence interval (CI) for dichotomous variables and standardized mean difference with 95% CI for continuous variables were calculated using the fixed-effects model or random-effects model.[6] Heterogeneity between studies was assessed by the Chi-square test with statistical significanceat P < 0.10. I2 was calculated to measure the quantity of heterogeneity, with I2 > 50% indicating significant heterogeneity.[7] The meta-analysis was conducted using the fixed-effects model if there was no statistically significant heterogeneity (P ≥ 0.10, I2 < 50%); otherwise, the possible reasons were explored or the random-effects model was used for the significant heterogeneity (P < 0.10, I2 > 50%).

Sensitivity analysis was carried out by omitting poor quality studies that have a high risk of bias. Intention-to-treat analysis was not performed because of insufficient information about loss to follow-up in treatment and control groups. The patient numbers of subcutaneous emphysema after operation, pain score, the number of patients who need thoracentesis, and cost were assessed with descriptive analysis. The funnel plot was not used due to the limited number of RCTs.


 > Results Top


Description of studies

The flowchart of literature screening is presented in [Figure 1]. According to the established search strategy used, a total of 921 potentially relevant literature items were identified in the databases of the 921 items searched, 224 duplicate studies were excluded by endnote software. After screening the titles and abstracts of the remaining 697 studies, 684 irrelevant studies were excluded, leaving 13 studies for further assessment. After the full-text review of the 13 studies, we excluded 8 of them. Therefore, five trials that fulfilled the inclusion criteria were included.[8],[9],[10],[11],[12]
Figure 1: The flowchart of literature screening

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Characteristics of included studies

The characteristics of included studies are shown in [Table 1]; two trials [11],[12] were performed in China, other trails [8],[9],[10] were performed in Spain, Japan, and Turkey. Both groups were well matched at baseline from the information in all of the trials.
Table 1: The characteristics of included studies

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Risk of bias in included studies

The risk of bias in the included trials is summarized in [Table 2]. All trials were randomized, one [8] of which was randomized by computer-generated numbers, one [9] of which was randomized by consecutive, one [10] of which was randomized by block-randomization, one [12] of which was randomized by hospital order, allocation concealment was not reported in any trial. Blinding was reported in only one trial: one trial [8] did not use blinding.
Table 2: Risk of bias in included studies

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Meta-analysis results

Amount of drainage

The amount of drainage was reported in four trials;[8],[9],[10],[12] the random-effects model was used to perform meta-analysis because there was significant heterogeneity between trials (I2 = 98%, P < 0.1); the meta-analysis result of amount of drainage showed that there was a significant difference between the two groups (RR = –0.15; 95% CI = –3.17, –0.12, P = 0. 03) [Figure 2].
Figure 2: The meta-analysis of amount of drainage

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Duration of chest tube drainage

The duration of chest tube drainage was reported in four trials;[8],[9],[10],[11],[12] the random-effects model was used to perform meta-analysis because there was significant heterogeneity between trials (I2 = 74%, P < 0.1); the meta-analysis showed that duration of chest tube drainage was significant difference between the two groups (RR = –0. 43; 95% CI = –0.57, –0.19, P = 0.02) [Figure 3].
Figure 3: The meta-analysis of duration of chest tube drainage

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The patient's numbers of new drain insertion after operation

The patient's numbers of the new drain after operation were reported in four Trials;[8],[9],[11] the fixed-effects model was used to perform meta-analysis because there was no significant heterogeneity between trials (I2 = 0%, P > 0.1); the meta-analysis result of the patient's numbers of new drain insertion after operation showed that there was no significant difference between the two groups (RR = 0.42; 95% CI = 0.10, 1.78, P = 0. 24) [Figure 4].
Figure 4: The meta-analysis of the patient's numbers of new drain insertion after operation

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Hospital stay after operation

The hospital stay after operation was reported in four trials;[8],[9],[12] the fixed-effects model was used to perform meta-analysis because there was no significant heterogeneity between trials (I2 = 0%, P > 0.1); the meta-analysis showed that hospital stay after operation had no significant difference between the two groups (RR = –0.20; 95% CI =–0.41, 0.01, P = 0.06) [Figure 5].
Figure 5: The meta-analysis of hospital stay after operation

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The patient numbers of residual pleural air space

The patient's numbers of the residual pleural air space were reported in two trials;[8],[9] the fixed-effects model was used to perform meta-analysis because there was no significant heterogeneity between trials (I2 = 0%, P > 0.1); the meta-analysis result of the patient's numbers of residual pleural air space showed that there was no significant difference between the two groups (RR = 0. 74; 95% CI = 0.33, 1.67, P = 0.47) [Figure 6].
Figure 6: The meta-analysis of the patient's numbers of residual pleural air space

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The patient's numbers of subcutaneous emphysema after operation

The patient's numbers of the subcutaneous emphysema were reported in two trials;[8],[12] Gómez-Caro et al.[8] reported that there was no patient who has subcutaneous emphysema after operation in the single chest tube group and there were six patients who has subcutaneous emphysema after operation in the double chest tube group; there was no significant difference (P > 0.05). Zhou and Na [12] reported that there were thirty patients who have subcutaneous emphysema after operation in the single chest tube group and there were twenty patients who has subcutaneous emphysema after operation in the double chest tube group; there was no significant difference (P > 0.05).

Pain score

Three trails [8],[9],[10] investigated the pain score. Gómez-Caro et al.[8] reported that all patients were asked to complete questionnaires collecting information in relation to pain control and a pain score was registered twice daily (numerical verbal pain score); there was no significant difference (P > 0.05) between the single and double chest tube group in terms of pain score registered (single chest tube group 2.3 ± 1.2 vs. double chest tube group 2.2 ± 0.9); in both groups, the most painful day was the 2nd day after surgery. Okur et al.[9] report that the degree of pain was recorded using the visual analog scale (VAS) before administering the analgesia; the VAS is a 10 cm horizontal line that is labeled “no pain” at one end and “worst pain imaginable” at the other; the patients in the single tube group experienced slightly less pain both in the early and late postoperative periods; the mean VAS score on the 2nd postoperative day was 4. 28 ± 0.21 in the single tube group and 5.10 ± 0.23 in the double tube group (P < 0.05); the mean VAS score on the 2nd postoperative week was 1.48 ± 0. 13 in the single tube group and 2.00 ± 0. 17 in the double tube group (P < 0.05). Tanaka et al.[10] report that the pain score was evaluated by a VAS, the degree of pain was evaluated by the maximum pain score from immediately after the operation until discharge; there was no statistically significant difference (P > 0. 05) in the maximum pain score (4.57 ± 3.23 in the single tube group vs. 3.92 ± 3.08 in the double tube group).

The number of patients who need thoracentesis

The number of patients who need thoracentesis was reported in two trials;[10],[11] Tanaka et al.[10] reported that there were no patients who needed thoracentesis because of the residual lung expansion appropriately in both groups. Huang and Yongfeng [11] reported that there were two patients who needed thoracentesis in the single chest tube group and six patients who needed thoracentesis in the double chest tube group.

Cost

Only one trail [8] reports the cost, the amount of cost-saving in the single chest tube group was 212.67 ± 7.6₰ (mean ± standard deviation [SD]) compared to the double chest tube group (additional sutures, dressing pads, stitch cutters, removal packs, gloves).


 > Discussion Top


The inadequate expansion of the residual lung after pulmonary lobectomy is one of the most important causes of complications after major anatomical resections;[13] adequate re-expansion is an important factor that helps avoid hypoxemia, atelectasis, and acute respiratory insufficiency. Therefore, to avoid this problem, most literature and experts recommend that double chest drains are inserted after pulmonary lobectomy, one drain in the apical position for the drainage of air and the other in the basal position for the drainage of blood and exudate. However, the pleural cavity is not a fixed space; after lobectomy, expansion of the remaining lung, mediastinal shift, and elevation of the diaphragm would obliterate any space and squeeze out any residual fluid or air through an optimally placed drain. Further clearance occurs with changes in posture and to a much lesser extent though pleural resorption.

In recent years, many thoracic surgeons have adopted one chest tube as the thoracic drainage after pulmonary lobectomy; several reports have been published comparing the use of one chest tube with the use of two chest tubes for thoracic drainage after pulmonary lobectomy;[14],[15],[16] these reports find that there were no significant differences in the postoperative complications, and a single drain is as effective as an approach using two drains, that it is significantly more economical, reduces hospitalization times, reduces postoperative pain more quickly, and reduces pleural fluid loss.

The pain was also relieving for patient after pulmonary lobectomy with one drain, effective pain control is of fundamental importance if one is to avoid respiratory complications such as sputum retention [17] and it allows patients to undergo their respiratory rehabilitation more comfortably,[3] it is mandatory in our opinion that patients are kept as comfortable as possible during the postoperative course;[18] early mobilization and less oxygen support are likely to accelerate the recovery of patients undergoing a thoracic procedure [19] and reduce the incidence of sputum retention.[17]

The amount of the single chest tube drainage is less than the amount of the double chest tube drainage; there might be few possible reasons for the decreased fluid drainage in the single-tube group; first, the duration of drainage in the single tube group is shorter than that in the double tube group, increased pleural secretion in double tube group may be explained by greater pleural fluid secretion from the pleura due to higher irritation caused by two tubes; second, technologically superior instruments are being used in lung resection operations, such as linear stapler for incomplete fissures, sealing materials for parenchymal air leaks, or other advanced materials for hemostasis, air leaks, and bleeding, are observed to a lesser extent after lung resections than they were two or three decades ago. This may also be another reason why only one chest tube should be used after pulmonary lobectomy.

This meta-analysis was based on five RCTs that included 502 patients. All patients in both groups were reported to be well matched for age, sex, and type of tumor.

Randomization was performed in all trials. However, of the five included studies, four trials [8],[9],[10],[11],[12] mention the adequate sequence generation, it can produce selective bias; allocation concealment was not reported in the five trials,[8],[9],[10],[11],[12] which might lead to unclear risk of selection bias, because it was possible for those responsible for recruiting the participants to alter their assignment if allocation was concealed.

Blinding was reported in only one trial,[9] which might cause a high risk of performance bias or detection bias. Future research should clearly spell out how to implement blinding. Although a comprehensive literature search was conducted, some published and unpublished trials might have been missed, which would lead to nonpublication bias. Publication bias might exist. No trials were multicenter; the pharmacogenomic difference could exist among different countries. Future study should pay attention to the impact of geographic differences. We still need more high-quality, multicenter, randomized, controlled trials from other countries and regions.

The meta-analysis result shows that in the pain score, Gómez-Caro et al.[8] reported that there was no significant difference (P > 0.05) between the single and double chest tube group in terms of pain score registered (single chest tube group 2.3 ± 1.2 vs. double chest tube group 2.2 ± 0.9); in both groups, the most painful day was the 2nd day after surgery. Okur et al.[9] report that the mean VAS score on the 2nd postoperative day was 4.28 ± 0.21 in the single tube group and 5.10 ± 0.23 in the double tube group (P < 0.05); the mean VAS score on the 2nd postoperative week was 1.48 ± 0.13 in the single tube group and 2.00 ± 0.17 in the double tube group (P < 0. 05). Tanaka et al.[10] report that there was no statistically significant difference (P > 0.05) in the maximum pain score (4.57 ± 3.23 in the single tube group vs. 3.92 ± 3.08 in the double tube group). In patients who need thoracentesis, Tanaka et al.[10] reported that there were no patients who needed thoracentesis in both groups. Huang and Yongfeng [11] reported that there were two patients who needed thoracentesis in the single chest tube group and six patients who needed thoracentesis in the double chest tube group. In Cost, Gómez-Caro et al.[8] report the cost, the amount of cost-saving in the single chest tube group was 212.67 ± 7.6₰ (mean ± SD) compared to the double chest tube group. The meta-analysis showed that there were statistically significant differences in amount of drainage (RR = –0.15; 95% CI =–3.17, –0.12, P = 0.03), duration of chest tube drainage (RR = –0.43; 95% CI –0.57, –0.19, P = 0.02) between the single chest tube group and double chest tube group.

The meta-analysis result shows that in the patient's numbers of subcutaneous emphysema, Gómez-Caro et al.[8] reported that there was no patient who has subcutaneous emphysema after operation in the single chest tube group and there were six patients who has subcutaneous emphysema after operation in the double chest tube group; there was no significant difference (P > 0.05). Zhou and Na [12] reported that there were thirty patients who have subcutaneous emphysema after operation in the single chest tube group and there were twenty patients who has subcutaneous emphysema after operation in the double chest tube group; there was no significant difference (P > 0.05).

With regard to the patient's numbers of new drain insertion after operation (RR = 0. 42; 95% CI = 0.10, 1.78, P = 0.24), hospital stay after operation (RR = –0.20; 95% CI –0.41, 0.01, P = 0.06), the patient's numbers of residual pleural air space (RR = 0.74; 95% CI = 0. 33, 1.67, P = 0.47), there was no significant difference between the two groups.

Limitations and implications for RCTs and meta-analysis in review, some limitations should be considered and some improvements should be made for further studies. (1) In five trials, the type of the chest tube and the method of the pulmonary lobectomy are different, the meta-analysis result may be influenced. (2) This review is limited by the methodological quality of the included RCTs. Some information is insufficient to permit defined judgment. Although every attempt was made to contact the authors of the included trials through E-mail or telephone, it is also recommended that additional RCTs be performed and reported according to the CONSORT statement which offers a standard way to improve the quality of research. (3) Currently, there are few data to compare the single and double chest tube application in patients after pulmonary lobectomy. Therefore, additional RCTs should be conducted in these specific subgroups. (4) Rigorous test design should be conducted before test to reduce bias. (5) In five trials, the amount of the drainage (<50–250 ml) is different when the chest tube was removed; the meta-analysis result may be influenced.


 > Conclusion Top


The meta-analysis result showed that using the single chest tube after operation offered, the same clinically meaningful and statistically improvement in the patients numbers of new drain insertion after operation, the hospital stay after operation, the patient numbers of residual pleural air space, and the patient's numbers of subcutaneous emphysema after operation in patients after pulmonary lobectomy, but the single chest tube significantly decreases amount of drainage, duration of chest tube drainage, pain score, the number of patients who need thoracentesis, and cost, compared with patients receiving the double chest tube. Hence, patients with the single chest tube may be more suitable for patients after pulmonary lobectomy. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample, multicenter, randomized, controlled trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Fell SC, Kirby TJ. Technical aspects of lobectomy. In: Shields TW, Locicero J, Ponn RB, Rusch VW, editors. General Thoracic Surgery. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 433-57.  Back to cited text no. 1
    
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Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.1. The Cochrane Collaboration. Available from: http://www.cochrane-handbook.org. [Last updated on 2011 Mar].  Back to cited text no. 4
    
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Higgins JP, Altman DG. Assessing risk of bias in included studies. In: Julian P, Higgins SG, editors. Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: John Wiley and Sons; 2008. p. 187-241.  Back to cited text no. 5
    
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Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 2000;19:3127-31.  Back to cited text no. 6
    
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Gómez-Caro A, Roca MJ, Torres J, Cascales P, Terol E, Castañer J, et al. Successful use of a single chest drain postlobectomy instead of two classical drains: A randomized study. Eur J Cardiothorac Surg 2006;29:562-6.  Back to cited text no. 8
    
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Okur E, Baysungur V, Tezel C, Sevilgen G, Ergene G, Gokce M, et al. Comparison of the single or double chest tube applications after pulmonary lobectomies. Eur J Cardiothorac Surg 2009;35:32-5.  Back to cited text no. 9
    
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Tanaka M, Sagawa M, Usuda K, Machida Y, Ueno M, Motono N, et al. Postoperative drainage with one chest tube is appropriate for pulmonary lobectomy: A randomized trial. Tohoku J Exp Med 2014;232:55-61.  Back to cited text no. 10
    
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Huang M, Yongfeng MA. Clinical observation of single multi-side hole chest drainage tuble after pulmonary lobectomy. Med Theory Pract 2013;26:2987-8.  Back to cited text no. 11
    
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Zhou H, Na YU. Comparison of the effect of two kinds of chest drainage method after pulmonary lobectomy. J Mod Nurs 2011;17:3881-2.  Back to cited text no. 12
    
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Kim EA, Lee KS, Shim YM, Kim J, Kim K, Kim TS, et al. Radiographic and CT findings in complications following pulmonary resection. Radiographics 2002;22:67-86.  Back to cited text no. 13
    
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Alex J, Ansari J, Bahalkar P, Agarwala S, Rehman MU, Saleh A, et al. Comparison of the immediate postoperative outcome of using the conventional two drains versus a single drain after lobectomy. Ann Thorac Surg 2003;76:1046-9.  Back to cited text no. 14
    
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Kejriwal NK, Newman MA. Use of a single silastic chest drain following thoracotomy: Initial evaluation. ANZ J Surg 2005;75:710-2.  Back to cited text no. 15
    
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Icard P, Chautard J, Zhang X, Juanico M, Bichi S, Lerochais JP, et al. A single 24F Blake drain after wedge resection or lobectomy: A study on 100 consecutive cases. Eur J Cardiothorac Surg 2006;30:649-51.  Back to cited text no. 16
    
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Bonde P, McManus K, McAnespie M, McGuigan J. Lung surgery: Identifying the subgroup at risk for sputum retention. Eur J Cardiothorac Surg 2002;22:18-22.  Back to cited text no. 17
    
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Savage C, McQuitty C, Wang D, Zwischenberger JB. Postthoracotomy pain management. Chest Surg Clin N Am 2002;12:251-63.  Back to cited text no. 18
    
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Nomori H, Horio H, Suemasu K. Early removal of chest drainage tubes and oxygen support after a lobectomy for lung cancer facilitates earlier recovery of the 6-minute walking distance. Surg Today 2001;31:395-9.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]



 

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