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Ann Thorac Surg 2004;77:1028-1032
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

Sealing of the mediastinum with a local hemostyptic agent reduces chest tube duration after complete mediastinal lymph node dissection for stage I and II non–small cell lung carcinoma

^a Department of Cardiothoracic Surgery, University of Vienna Medical School, Vienna, Austria
^b Department of General Surgery, University of Vienna Medical School, Vienna, Austria

Accepted for publication August 28, 2003.

^* Address reprint requests to Dr Mueller, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
e-mail: michael-rolf.mueller{at}akh-wien.ac.at

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
BACKGROUND: We assessed the impact of coverage of the mediastinum with a local hemostyptic agent as well as the impact of perioperative thromboembolic prophylaxis on cumulative chest drain volume and on the duration of chest tubes after surgical resection with complete mediastinal lymph node dissection for stage I or II non–small cell lung cancer.

METHODS: In a prospective, randomized two-by-two factorial design, 80 patients with clinical stage I or II non–small cell lung cancer were allocated to one of two surgical therapy arms (TachoComb or conventional surgical hemostasis) and one of two anticoagulation arms (enoxaparin 4,000 IU or dalteparin 5,000 IU). Primary end point was cumulative chest drain volume; secondary end point was duration of chest tubes. Additionally clinical data were obtained.

RESULTS: Comparison of the surgical arms revealed significantly lower cumulative chest drain volumes and thereby an earlier chest tube removal in the TachoComb group (p = 0.045). With regard to thromboembolic prophylaxis, a significantly earlier chest tube removal was found for patients treated with dalteparin (p = 0.039). Analysis of the interaction of surgical and anticoagulation treatment revealed the combined use of TachoComb and dalteparin was superior to other combinations (cumulative chest drain volumes 498 ± 67 mL versus 1,000 ± 88 mL, 924 ± 87 mL, and 895 ± 118 mL; p = 0.008; mean duration of chest tubes 1.78 ± 0.15 days versus 2.96 ± 0.21 days, 2.93 ± 0.17 days, and 3.06 ± 0.27 days; p = 0.019).

CONCLUSIONS: The combined use of a local hemostyptic agent and dalteparin seems superior as compared with other regimens of hemostasis and thromboembolic prophylaxis in patients undergoing surgical resection and complete mediastinal lymph node dissection for stage I and II non–small cell lung cancer with regard to cumulative chest drain volume as well as duration of chest tubes.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
The optimal algorithm for removal of chest tubes after major lung resections is still a matter of ongoing discussion. Water-seal systems or applying wall suction to the tubes are the most frequently used regimens [1–4]. The mean time to removal of chest tubes, determined by the presence of air leaks and the cumulative chest drain volume, is variable and depends on the decision of the individual surgeon [1, 5–7]. However, cumulative chest drain volume depends on several factors such as the surgical access used, the volume of resected lung tissue, and the compliance of the chest wall, mediastinum, and diaphragm. We hypothesized that postoperative chest drain volume is also associated with the extent of mediastinal lymph node dissection after surgical resection for non–small cell lung cancer (NSCLC). Excessive drain volumes in general prohibit early chest tube removal, adversely affect postoperative mobilization, and increase pain load, morbidity, and in-hospital stay as well as costs.

Local hemostyptic agents have proven to be beneficial in various surgical conditions [8–12]. Collagen fleece patches coated with coagulation factors like fibrinogen, thrombin, and aprotinin (TachoComb, Nycomed, Linz, Austria) mimic the last step of the coagulation cascade. All coagulation and fibrinolytic factors are produced and secreted by lymphatic endothelial cells and are involved in the sealing of lymphatic capillaries [13]. Local hemostyptic agents may therefore reduce postoperative secretion from lymphatic fistulas caused by mediastinal lymph node dissection.

Even though low molecular weight heparins (LMWHs) have become the standard for thromboembolic prophylaxis in most European countries and Canada, it was not until recently that LMWHs were approved for use in the United States. Physical methods and unfractionated heparin remain the preferred prophylactic modalities, but LMWHs have gained rapid acceptance since their approval for use for thromboembolic prophylaxis in North America [14, 15]. The rationale for the direct comparison of dalteparin and enoxaparin resulted from an intuitive clinical observation by our staff nurses. They believed that patients treated with enoxaparin had a marked delay in chest tube removal because of increased chest tube volumes. At the beginning we could not understand this observation and thereby initiated the presented study to put this impression on a rational basis. Furthermore, as thromboembolic prophylaxis modulates plasmatic coagulation and fibrinolysis, it may affect the efficacy of the local hemostyptic agent.

Therefore, the aim of this study was to assess the impact of coverage of the mediastinum with a local hemostyptic agent as well as the impact of perioperative thromboembolic prophylaxis on cumulative chest drain volume and on the duration of chest tubes after surgical resection and complete mediastinal lymph node dissection for stage I and II NSCLC.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patients
Between January 2001 and June 2002, 80 patients with stage I or II NSCLC were included in the study protocol. Primary exclusion criteria were clinical stages higher than II, disorders of primary or secondary hemostasis, and infectious diseases. Written informed consent was obtained in all patients. Preoperative staging was by computed tomographic scanning of the chest as well as the brain, and by upper abdominal sonography as well as by bone scintigraphy. Mediastinal lymphatic disease was excluded by negative 18-fluoro-deoxyglucose positron emission tomography scan. In patients with hypermetabolic nodes in the mediastinum, cervical mediastinoscopy was performed to exclude N2 disease. Patients with adequate lung function, defined as a predicted forced expired volume in 1 second of at least 1 L after surgery, were projected for lobectomy along with complete mediastinal lymph node dissection.

Study design
In this randomized study we used a two-by-two factorial design. The study protocol was approved by the institutional review board. A computer-generated random list assigned each patient to one of two surgical therapy arms (TachoComb or conventional surgical hemostasis) and one of two anticoagulation arms (enoxaparin 4,000 IU or dalteparin 5,000 IU).

The two results of randomization for each patient were stored in separate sealed envelopes in an additional sealed envelope. If a patient was recruited for the study, the envelope containing randomization data concerning anticoagulation was broken and thromboembolic prophylaxis was initiated the evening before surgery. In case of secondary exclusion criteria during surgery (massive pleural adhesions, massive hemorrhage, extended resection, major air leakage at final water submersion test) patients were excluded (n = 15). After completion of lobectomy and complete mediastinal lymph node dissection the second envelope was broken and the result concerning surgical treatment of the mediastinal dissection area was announced to the surgical team.

Surgical technique
All surgical procedures were performed by one single surgeon (M.R.M.) in a standardized technique: anterolateral thoracotomy without rib resection was performed through the fourth intercostal space. Stapling devices were used for the central vessels; small arterial vessels were closed using vascular clips. Mediastinal lymph node dissection was carried out en bloc when possible, resulting in a complete ipsilateral mediastinal lymph node dissection including paratracheal, paraaortic, hilar, infracarinal, and paraesophageal groups [16]. Surgical clips to close lymph vessels were not used. After thorough surgical hemostasis and rinsing of the pleural cavity with warm saline solution, TachoComb was moistened for a few seconds and carefully placed onto the dry mediastinal dissection areas. In the control group, meticulous conventional surgical hemostasis was carried out. Prevention of air leaks included water submersion test during an inspiratory hold of 30 mm Hg provided by the anesthesiologist and, in some cases, control by suturing. Two soft chest tubes were positioned, a ventral 24F one and a dorsal 24F right-angle tube, and the chest was closed in layers using resorbable suture material. Chest tubes were connected to closed disposable water-sealed systems (Pleurevac, Genzyme Biosurgery, Cambridge, MA) with the dry suction control adjusted at 15 cm H₂O. Postoperative anticoagulation was maintained 8 hours postoperatively and then every other 24 hours. Chest tube volumes were recorded exactly every 24 hours after closure of the chest as well as the cumulative chest tube volume at the time of removal. Removal of chest tubes was done following a standardized protocol, when no forced expiratory air leaks were detectable at coughing (tubes still at a suction of 15 cm H₂O) and total fluid volume was equal or less than 200 mL during the last 24 hours. Patients were routinely discharged from the surgical ward the day after they had their drains removed. Primary end point was cumulative chest drain volume; secondary end point was duration of chest tubes. Data are given as mean ± standard deviation.

Laboratory examinations
Variables of primary and secondary hemostasis (prothrombin time, activated partial thromboplastin time, fibrinogen level, and platelet count) were investigated the day before surgery and on day 3 after surgery.

Statistical analysis
After testing for normality of distribution, continuous variables were compared using two-way analysis of variance. Categorical variables were compared using the ^2.test. Owing to the factorial design, a test for interaction (TachoComb and perioperative anticoagulation) was used [17]. A p value less than 0.05 was considered significant, two-sided. Statistical analysis was performed with SPSS 11.0 statistical software (SPSS, Inc, Chicago, IL).

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Clinical results
Mean age of patients was 64.7 years (range, 44 to 81 years). Seventy-two percent of patients were male. No major adverse events (death, neurologic injury, severe infection, or chylothorax) were observed. No patient had extended chest tube duration because of persistent air leaks. Two units of TachoComb were used in each patient.

Comparison of laboratory characteristics
Concerning laboratory characteristics of patients (variables of primary and secondary hemostasis), no significant differences were found among the four study groups.

Local hemostyptic agent versus conventional surgical hemostasis
Mean chest drain volume at day 3 (96 versus 157 mL; p = 0.045) and mean duration of chest tubes (2.53 versus 2.97 days; p = 0.046) were significantly lower when TachoComb was used (Table 1).

View larger version (21K): [in this window] [in a new window]   Fig 1. Course of chest drain volumes. Postoperative chest drain volumes according to the interaction of the local hemostyptic agent and thromboembolic prophylaxis. (* = statistically significant.)

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

The time to removal of chest tubes is determined by two factors, air leakage and cumulative chest drain volume. Air leakage exceeding the first postoperative day is rarely observed, which is in accordance with several reports in the literature [2, 5, 6]. We generally use water-sealed systems, which allow adjusting the routinely applied wall suction to exactly the negative pressure aimed at. Suction is generally not fixed to a certain negative pressure, but adjusted to the current situation in a way that bubbles are seen just at expiration and forced expiration. To achieve similar conditions in all patients for this study we decided to use a fixed suction of 15 cm H₂O, which was maintained until removal of chest tubes. In this study all patients were meticulously checked for intraoperative air leaks by repeated water submersions tests to exclude prolonged chest tube duration caused by persistent air leaks.

Cumulative chest drain volume substantially determines the duration of chest tubes and thereby contributes to postoperative morbidity and costs of thoracic surgery. Lobectomy for lung cancer generally implements mediastinal lymphadenectomy; however, the degree to which the mediastinal lymph nodes should be sought and the extent of their removal remain controversial. Current surgical practice varies from sampling and systematic sampling to complete mediastinal lymph node dissection [16]. However, mediastinal dissection—for staging or treatment purposes—implies the opening of lymphatic vessels and may thereby affect cumulative chest drain volume. Meticulous surgical techniques on the one hand may help to counteract excessive drain volume; on the other hand, sealing of opened lymphatic vessels by local hemostyptic agents may provide another rationale that has not been demonstrated in controlled studies to date.

Routinely applied measures to prevent pulmonary emboli are compression stockings as well as physical therapy at the earliest time possible. However, the use of LMWH is an accepted standard to reduce the risk of perioperative thromboembolic complications after surgery [14, 15]. Our additional rationale for this strategy was that the mean age of our patient cohort is rather high, that patients suffer from active cancer, and finally that patients are immobilized for 2 days because of chest tubes as well as postthoracotomy pain. The kind of anticoagulation protocol used might by itself affect closure of microvessels and may further interact with local hemostatics. Analysis of the interaction of the local hemostyptic agent and the type of LMWH used yielded the combination of TachoComb with dalteparin to be superior to the other three regimens used with regard to cumulative chest drain volume as well as with regard to duration of chest tubes. Inasmuch as this study is a single surgeon's series, these results cannot be explained by surgeon-specific factors such as a different extent of mediastinal dissection. Management and time of removal of chest tubes were clearly defined and not subjected to individual influences.

The local hemostyptic agent per se seems to be effective in reducing cumulative chest drain volume as well as the duration of chest tubes after surgical resection and complete mediastinal lymph node dissection for stage I or II NSCLC. However, potential drawbacks of the local hemostyptic agent such as the potential allergic effect of aprotinin have to be kept in mind. In recent reports addressing this issue, conflicting evidence exists whether reexposure to aprotinin is safe or not [18, 19]. However, these reports have always applied aprotinin systemically but not topically. It remains speculative whether topical application contributes to attenuated immunologic responses or not. In our personal clinical experience we did not observe any systemic reactions in patients after repeated exposure to aprotinin, neither in general thoracic nor in open heart surgery.

How far may differences between both anticoagulants used in this study (enoxaparin and dalteparin) further influence the observed effect? Both substances belong to the group of LMWHs and are produced from unfractionated heparin using different preparation methods; hence they slightly differ in molecular weight [20, 21]. Anti-factor Xa activity of dalteparin and enoxaparin is nearly the same (approximately 90 U/mg), and clinical effectiveness in prophylaxis of thromboembolism therefore identical [22]. The LMWHs release tissue factor pathway inhibitor, which neutralizes the endogenic tissue factor, by this inhibiting also tissue factor–mediated activation of platelets and macrophages. Enoxaparin leads to a 10% higher release of tissue factor pathway inhibitor as compared with dalteparin [23]. Enoxaparin has a slightly longer half-life (129 to 180 hours versus 119 to 139 hours), which might cause accumulation at repeated application. Although both LMWHs are strong inactivators of platelet-bound factor X, enoxaparin has the higher anti-Xa to anti-IIa ratio as compared with dalteparin (2.7 versus 2) [4]. These pharmacologic differences may serve as an explanation for the isolated positive effects of dalteparin as compared with enoxaparin in our study.

Limitations of the study
The small patient number may expose this study to a type I error. Additionally it may seem to be unfortunate that we attempted to study two variables simultaneously in a relatively small series. However, because development of this study came from an intuitive observation of our staff nurses, we initially concentrated on thrombosis prophylaxis as a determinant for postoperative pleural secretion. The mediastinal wound was considered the main source of chest tube output. Introducing effective countermeasures by the use of a local hemostyptic agent raised the academic discussion on interactions between local hemostatic and systemic fibrinolytic measures.

Conclusions
We therefore conclude that the combined use of a local hemostyptic agent and dalteparin appears to be superior as compared with other regimens of hemostasis and thromboembolic prophylaxis in patients after surgical resection and complete mediastinal lymph node dissection for stage I and II NSCLC with regard to cumulative chest drain volume as well as duration of chest tubes.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We thank Daniela Dunkler, MS (statistician), for the statistical analysis of this work.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Martin Czerny Tatjana Fleck Walter Klepetko Ernst Wolner Michael Rolf Mueller Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Czerny, M. Articles by Mueller, M. R. Search for Related Content PubMed PubMed Citation Articles by Czerny, M. Articles by Mueller, M. R. Related Collections Lung - other