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Eur J Cardiothorac Surg 2007;31:198-202. doi:10.1016/j.ejcts.2006.11.033
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Efficiency of fleece-bound sealing (TachoSil^®) of air leaks in lung surgery: a prospective randomised trial

^a Division of Thoracic and Hyperbaric Surgery, University Medical School, Graz, Austria
^b Institute for Medical Informatics, Statistics, and Documentation, University Medical School, Graz, Austria

Received 18 September 2006; received in revised form 21 November 2006; accepted 24 November 2006.

^_* Corresponding author. Tel.: +43 345273178; fax: +43 3163854679. (Email: udo{at}anegg.net).

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: Persistent air leakage following pulmonary resection is a major limiting factor for discharge from hospital. The aim of this study was to evaluate the sealing capacity of TachoSil^® for the closure of alveolar air leaks following parenchymal resections and to determine its effect on time to chest drain removal and duration of hospitalisation. Methods: A total of 173 patients undergoing lobectomy or segmentectomy were enrolled in a single-centre, randomised study to compare the efficacy of TachoSil^® with standard treatment. Alveolar air leaks were evaluated intraoperatively by submersion of the resection site in saline and were graded according to the Macchiarini scale as 0 (no bubbles), 1 (single bubbles), 2 (stream of bubbles), 3 (coalescent bubbles). Patients with grade 1 or 2 air leaks were randomised to TachoSil^® or standard treatment. Grade 3 patients received standard treatment until the air leak was downgraded to grade 1 or 2 at which point they were randomised. Patients with grade 0 leakage were excluded. The primary efficacy endpoints of the study were postoperative quantification of air leakage on postoperative days 1 and 2. Other efficacy measurements included mean time to chest drain removal and mean time to hospital discharge. Results: The mean intraoperative post-treatment air leakage was significantly lower in the TachoSil^® group (153.32 ml/min, range: 10–450 ml/min) compared with the standard treatment group (251.04 ml/min, range: 15–970 ml/min; P = 0.009). The significant difference in air leakage volume observed intraoperatively post-treatment was maintained postoperatively. TachoSil^® showed a trend towards reduced incidence of postoperative leakage when measured >48 h or >7 days after surgery (30.7% vs 38.96% and 24% vs 32.46%, respectively). The mean times to chest drain removal and to hospital discharge were significantly reduced following the use of TachoSil^® (5.1 days vs 6.3 days, P = 0.022 and 6.2 days vs 7.7 days, P = 0.01, respectively). Conclusions: The use of TachoSil^® following pulmonary resection resulted in a reduction in air leakage compared with standard techniques. This reduction in air leakage resulted in a significant reduction in both the time to chest drain removal and the period of hospitalisation.

Key Words: Air leakage • Lung tissue sealing • TachoSil^®

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
The incidence of intraoperative pulmonary air leakage during lung surgery is reported to be as high as 70% [1]. Persistent air leakage, lasting longer than 7 days, occurs in 15–25% of patients and is a major limiting factor for discharge from hospital due to the need for prolonged chest tube drainage [2].

Standard therapy for treating air leaks after lung resection involves surgical stapling or suturing techniques and electrocautery. Approaches to decrease the intensity and duration of air leaks include the use of a variety of sealants, such as fibrin glue [3–5], synthetic polyethyleneglycol-based materials [1,6,7] and collagen patches coated with fibrinogen and thrombin [8]. A recent systematic review evaluating the effectiveness of sealants in preventing or reducing postoperative air leaks after pulmonary resection for lung cancer concluded that while surgical sealants seem to reduce postoperative air leaks, they had no effect on length of hospitalisation and that some may even increase the risk of infectious complications [2].

A recent study that investigated the efficacy and safety of a fixed combination of a collagen patch coated with human fibrinogen and thrombin (TachoComb^®) over conventional treatment suggested that there was no additional value of added sealant if air tightness was achieved with standard techniques [8]. However, significant reductions in intraoperative air leakage, as well as in the intensity and duration of postoperative leakage, were demonstrated for a subgroup of patients with established air leakage at randomisation. The aim of this study was to compare the air sealing capacity of TachoSil^® (TS) with approved routine surgical procedures for the closure of alveolar air leaks following parenchymal resection in a large group of patients with proven intraoperative air leakage and to determine whether there was any effect on time to chest drain removal and duration of hospitalisation.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
2.1 Study design
This was a randomised, prospective, open-label, parallel group study carried out at a single centre. The study was conducted according to the ethical principles of the Declaration of Helsinki and in accordance with Good Clinical Practice. The trial population comprised patients undergoing lobectomy (n = 148) or segmentectomy (n = 25) (limited resection in case of reduced functional operability) for non-small cell lung cancer performed through anterolateral or posterolateral thoracotomy. Complete mediastinal lymph node dissection was performed in all patients. Clinical (preoperative) tumour stage was according to the International Union against Cancer (UICC) I and II. Neoadjuvant radio-chemotherapy was an exclusion criterion. Patients undergoing video-assisted thoracoscopic lobectomies as well as lobectomies for non-malignant reasons were excluded from the study. The schedule for inclusion was determined by the patient's admission to hospital. Interlobal fissure was divided using routine procedures, most commonly by employing stapling devices and/or electrocautery. Bronchial stump closure was uniformly performed using commercially available stapling devices.

Randomisation, on the basis of the use of close envelopes containing notes reading either ‘A’ for Tachosil^® or ‘B’ for conventional treatment, was performed intraoperatively according to the following criteria: parenchymal leakage was evaluated intraoperatively by submersion of the resection site in saline and reventilation of the lung, applying a peak pressure of 25 cm H₂O. Leakage was graded according to the Macchiarini scale as 0 (no leakage), 1 (single bubbles), 2 (stream of bubbles), 3 (coalescent bubbles) [9]. Patients with grade 1 or 2 leakage were randomised to TachoSil^® or standard treatment (ST). Patients with grade 3 leakage underwent further surgery using conventional procedures including parenchymal suturing (pledget-reinforced PDS 4.0), stapling or electrocautery followed by another submersion test until the leakage was downgraded. Patients with grade 1 or 2 leakage were then randomised. Patients with grade 0 leakage were excluded from the study.

2.1.1 TachoSil^® group
TachoSil^®, supplied as ready-to-use patches, was applied to the leakage area with an overlap of 1 cm width if more than one patch was required. Patch sizes used were 9.5 cm x 4.8 cm x 0.5 cm or 4.8 cm x 4.8 cm x 0.5 cm.

2.1.2 Standard treatment group
Standard treatment included the use of pledget-reinforced PDS 4.0 sutures with absorbable patches or staples, according to the degree of air leakage. When leakage occurred adjacent to the lobar margin, stapling devices provided satisfactory tissue closure. Additionally, electrocautery was applied in the outer range of the leaking site in order to thermally shrink the treated area.

All patients received two drainage tubes, one of which was removed on the first or second postoperative day. In all cases the tubes were connected to a Buelau drainage system to which continuous suction limited with 12 cm H₂O was applied.

The first chest tube was removed when there was no more clinical evidence of air leakage and routine chest X-ray showed no major pneumothorax. In addition, the volume of drained fluids was required to be less than 200 ml during the preceding 24-h period. Removal of the second chest tube was scheduled when the leakage volume was less than 20 ml/min and the drainage quantity less than 200 ml/24 h.

2.2 Measurement of air leakage volume
The first intraoperative spirometric measurement was performed by the anaesthetist immediately after the submersion test and prior to treatment, the second intraoperative measurement followed treatment of air fistulae.

Postoperatively, air leakage volume (ml/min) was measured using a digital mass airflow sensor device (AIRFIX^®) connected to the chest drain-suction unit. Details concerning this device, and the applicability of this technique as a standard quantification tool for air leakage are reported elsewhere [10]. Postoperative measurements of volume were made in the morning of postoperative days 1 and 2.

In patients with persistent air leakage (>7 days) regular measurements were performed every second day.

2.3 Efficacy parameters
The primary efficacy endpoints of the study were postoperative quantification of air leakage on postoperative days 1 and 2. Other efficacy measurements included mean time to chest drain removal and mean time to hospital discharge.

2.4 Statistics
The statistical method used was the t-test for independent samples. A P value <0.05 was considered to be significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
A total of 173 patients were screened for inclusion in the study; 21 patients without intraoperative leakage (grade 0) were excluded. Initially, grade 3 leakage was detected in 43 patients, all of whom were to be downstaged to grade 1 or 2 following surgical fistula management. Prior to randomisation, grade 1 leakage was found in 29 and grade 2 leakage in 123 patients. A total of 152 patients with grade 1 or 2 leakage were randomised; 75 to the TS group and 77 to the ST group.

The baseline characteristics of the patients in the TS and ST groups were comparable (Table 1 ). The surgical variables were similar for the two treatment groups; no statistical significance could be detected in regard to the baseline characteristics. The mean consumption of sutures in the ST group was 2.8 (range: 1–5).

Post-treatment, air leakage was detected in all patients in both treatment groups. The mean intraoperative post-treatment air leakage was significantly lower in the TS group (153.32 ml/min, range: 10–450 ml/min) compared with the ST group (251.04 ml/min, range: 15–970 ml/min; P = 0.009) (Fig. 1 ).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Intraoperative and postoperative air leakage volume on days 1 and 2.

On postoperative day 1 air leakage was detected in 47/75 patients (62.67%) in the TS group and in 53/77 patients (69.64%) in the ST group (P = 0.331). On postoperative day 2 air leakage was detected in 22/75 (30.26%) and in 30/77 (38.96%) of patients in the TS and ST groups, respectively (P = 0.234).

3.3 Duration of air leakage
Air leakage present after >48 h was detected in 23/75 (30.7%) and in 30/77 (38.96%) patients in the TS and ST groups, respectively (P = 0.234). On day 3 the mean leakage in the TS group was 68.63 ml/min (range: 40–150 ml/min) compared with 87.46 ml/min (range: 30–240 ml/min) in the ST group.

Persistent air leakage (for >7 days) was detected in 18/75 (24%) and in 25/77 (32.46%) patients in the TS and ST groups, respectively (P = 0.282). On day 8, the mean leakage in the 18 patients in the TS group was 44.65 ml/min (range: 25–80 ml/min) whereas it was 67.21 ml/min (range: 30–125 ml/min) in the ST group (Fig. 2 ).

View larger version (16K): [in this window] [in a new window]   Fig. 2. Percentage of patients with air leakage >48 h and persistent air leakage >7 days.

View larger version (15K): [in this window] [in a new window]   Fig. 3. Mean time to drainage removal and to hospital discharge.

Postoperative follow-up was continued by screening for tumour relapse by computerised tomography scan every 6 months. No clinical differences have been observed between the two groups to date.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Postoperative air leakage is a common problem following lung resection [1]. Standard techniques do not result in adequate sealing in the majority of patients [2]. As a result, these patients require prolonged chest tube drainage time, putting them at increased risk of pleural infections, pulmonary embolism, respiratory distress and associated pain. Persistent air leak is the most common reason for prolonged hospital stay [2,11].

Previously, the ability of TachoSil^® to reduce intraoperative leakage as well as to reduce the intensity and duration of postoperative leakage was demonstrated in a small subgroup of patients with established air leakage. Since no benefit of prophylactic use of the sealant was demonstrated, the present study was designed to exclude patients in whom complete sealing had been achieved using standard techniques. A total of 21 patients (12%) were excluded on this basis, consistent with the high incidence of intraoperative leakage following standard procedures reported by others [1].

In this selected population of patients with established intraoperative air leakage, we demonstrated significant reductions in air leakage volume on postoperative days 1 and 2 using TachoSil^®. This represented reductions approaching 50%. Furthermore, the use of TachoSil^® showed a trend towards a reduction in the proportion of patients with leakage after >48 h or >7 days as well as a reduction in the mean leakage volumes at these times. The mean duration of air leakage is also influenced to a great extent by an underlying pulmonary disease (mostly by chronic obstructive pulmonary disease and emphysema), by concomitant cardiovascular disease, by the type of suction device used and by the algorithm for appropriate drain management [12].

Importantly, the benefits of TachoSil^® translated to significant reductions in time to chest drain removal and time to hospital discharge. According to the postoperative documentation in both groups, no significant difference in complication rate was detected. However, the fact that the patients in the Tachosil^® group could have their chest tubes removed and thereby enabling them to be discharged from hospital more than 1 day earlier accounts for a significant reduction in pain and is more convenient for the patient. Regarding the portion of patients with persistent air leaks, use of Tachosil^® accomplished a statistical trend in reduction of leakage and frequency (Fig. 2). However, only a minor portion of patients is affected by this complication and the vast majority still benefit from the effects of Tachosil^® as described above. Given the beneficial effects of TachoSil^® on reducing air leakage volume and the frequency of postoperative leakage this reduced period of hospitalisation is perhaps not surprising, since patients need to remain under clinical observation during the time of chest drainage. To our knowledge, this is the only randomised trial of sealants to demonstrate benefits in both time to drain removal and hospital discharge. The previous trial by Lang et al. [8] did not include these clinically relevant endpoints. In one randomised trial which compared a fibrin glue and thrombin solution with standard treatment, time to drain removal was reduced from 5 to 3.5 days [3], with no impact on time to hospital discharge. In another trial of a polymeric biodegradable sealant with human serum albumin, length of stay was reduced by 1 day compared with standard treatment [13].

TachoSil^®, a fixed combination of a collagen patch coated with human fibrinogen and thrombin, was developed to achieve both haemostatic and tissue sealant effects, and was originally used for haemostasis in liver surgery, particularly in case of parenchymal bleeding not amenable to the usual surgical procedures [14]. It has also found application for the sealing of lymphatic fistulas during lymphadenectomy [15] as well as in kidney resection surgery [16]. Its high degree of elasticity when moistened makes it particularly suitable for sealing pulmonary parenchymatous tissue [17]. The safety of TachoSil^® has been established in both lung and liver resection surgery [8,14].

The method used to determine air volume in this study has advantages over the semi-quantitative methods routinely used that are based on the relative intensity of air bubbles appearing in the water reservoir of the drainage system. The AIRFIX^® system provides simple and reliable digital bedside quantification of air leaks while remaining compatible with standard thoracic drainage systems. Its application in the diagnosis and management of postoperative air leaks was recently reported [10].

In conclusion, the results of this study demonstrate that the use of TachoSil^® following pulmonary resection resulted in a reduction in air leakage compared with standard techniques. This reduction in air leakage volume resulted in a significant shortening of drainage period and time to discharge. Advantages of reducing the time to drainage tube removal may include more rapid mobilisation as well as a reduction in the pain associated with thoracic drainage [18]. Although this relatively small-scale study did not include a formal cost-saving analysis or show any significant differences in postoperative complications the reduction in time to chest drain removal and period of hospitalisation would have obvious cost saving benefits. However, further studies in larger patient populations are still necessary to investigate these issues.

	Acknowledgments

 
No source of funding was involved in this work.

	Footnotes

 
^\#9734; The results were presented in part at the European Society of Thoracic Surgeons, 12–13 May 2006, Romania.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 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): Udo Anegg Alfred Maier Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anegg, U. Articles by Smolle-Jüttner, F. Search for Related Content PubMed PubMed Citation Articles by Anegg, U. Articles by Smolle-Jüttner, F. Related Collections Lung - cancer Trachea and bronchi