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Eur J Cardiothorac Surg 2004;26:1187-1191
© 2004 Elsevier Science NL

The effect of autologous fibrin sealant (Vivostat®) on morbidity after pulmonary lobectomy: a prospective randomised, blinded study

Ali Belboul*, Leif Dernevik, Obaid Aljassim, Biljana Skrbic, Göran Rådberg, Donald Roberts

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Göteborg 413 45, Sweden

Received 5 June 2004; received in revised form 13 August 2004; accepted 15 August 2004.

* Corresponding author. Tel.: +46 31 3421556; fax: +46 31 417991. (E-mail: ali.belboul{at}hjl.gu.se).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Objective: Postoperative air leakage is the most frequent complication after pulmonary surgery. The development of modern surgical techniques has been influenced strongly by the need to manage air leakage effectively during pulmonary resection. This study evaluated the effect of using an autologous fibrin sealant (Vivostat®) during lobectomy on morbidity following surgery. Methods: This was a prospective, blinded, randomised clinical study. Patients undergoing lobectomy were enrolled into two groups (Vivostat or non-treatment control, 20 per group). Air leakage was measured over a 1-h period (using a mechanical suction pump) on the day of operation, and both air leakage and bleeding/exudation (drainage volume) were recorded every morning postoperatively until the chest tubes were removed. Personnel recording these parameters were blinded to the intervention received. Results: Compared with the control group, mean bleeding/exudate volumes were significantly reduced in the Vivostat group (day 1, 370 vs. 525ml; total, 424 vs. 782ml; both P<0.001), and drains were inserted for a shorter time (medians, 1 vs. 2 days, P=0.07). Significantly fewer patients had air leakage at any time in the Vivostat group (40 vs. 80%, P=0.02), and air leakage volumes were significantly lower compared with the control group (median differences: day of surgery: 0.6l/min, P=0.01; total 0.8l/min, P=0.03). Postoperative hospitalisation time was shorter in the Vivostat group than in the control group but the difference was not significant (0.5 days, P=0.12). Conclusions: Vivostat fibrin sealant significantly reduces post-surgical air leakage and drainage volumes following lobectomy in pulmonary surgery and is suitable for routine use in this procedure.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Prolonged postoperative air leaks are a major cause of morbidity after pulmonary resection [1] and lead to prolonged chest tube drainage time, which is associated with pain and immobilisation. This puts the patients at an increased risk for development of pneumothorax, infections and bronchopleural fistulae and, consequently, a prolonged hospital stay, which increases healthcare costs. Advances in surgical techniques, including the use of stapling devices, have minimised, but not abolished, air leakage during pulmonary surgery.

A variety of complementary natural and synthetic materials have been tried to overcome such complications including fibrin sealants, collagen fleece, and synthetic glues, with mixed results. Irrespective of their efficacy, they cannot replace an exact and precise surgical technique. Nevertheless, they can be very helpful or even life saving in situations where air leakage cannot be assured by classic means. There is no consensus as to the best surgical technique, but there has been a consistent trend towards the use of fibrin glue material to reduce air leakage after pulmonary resection. Which glue to use, depends on several factors, including availability, haemostatic efficacy, mechanical properties, effects on wound healing, tissue cellular response, surgeons' experience and the possibility of transmission of blood–borne diseases.

The Vivostat® System (Vivolution A/S, Denmark) is a medical device for the perioperative preparation and application of an autologous fibrin sealant in the operating theatre. The system is fully automated and microprocessor-controlled, and is made up of three components: an automated processor unit, an automated applicator unit, and a disposable, single-patient-use unit, which includes a Preparation set, into which 120ml of blood is donated, and a Spraypen applicator [2,3]. Although, animal studies have suggested that Vivostat is effective at reducing air leakage following pulmonary resection [4], clinical studies with Vivostat in pulmonary surgery have not been published previously. The present study evaluated the use of Vivostat as an adjunct in pulmonary surgery. Postoperative air leakage, chest tube drainage and hospitalisation time were used as indicators of postoperative morbidity.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
This prospective study was carried out at the Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Göteborg between January 2002 and December 2003. Forty consecutive adult patients with lung tumours only limited to one lobe with no established nodal disease preoperatively undergoing elective lobectomy were enrolled. Patients were excluded if the operation required wedge resection, lung biopsies and thoracoscopic resections. Four thoracic surgeons carried out resections using standard dissection and stapling techniques according to the surgeon's standard practice. All patients had intra- and post-operative thoracal epidural analgesia (TEDA). The presence of emphysema and pleural adhesions were not reasons for patients exclusions.

At the end of the operation and before closing the chest, the lung was ventilated under positive end expiratory pressure and warm saline was installed into the chest cavity to test for air leaks. The operating surgeon then corrected any leaks surgically until satisfied that no more could be done. The patients were then assigned (20 per group) to either the control or Vivostat groups by opening a sealed envelope that contained the randomisation code (allocated by a computer generated random sequence). Patients assigned to the control group underwent no additional interventions. Patients assigned to the Vivostat group donated 120ml of blood and Vivostat fibrin sealant, which was prepared according to the manufacturer's instructions for use. Vivostat was applied over the entire areas of risk for air leaks and bleeding (all areas of dissection) with the lung deflated and without ventilation. After 5min, the lung was ventilated and the chest closed with two drains set at 10–15cmH2O.

The following variables were measured and recorded daily until discharged from hospital: rate of air leak on the day of the operation, and daily thereafter in the morning until chest drains were removed; time to chest tube removal; 24-h and chest-tube drainage (bleeding/exudation) volume at removal of chest tube, duration of TEDA treatment and postoperative length of hospital stay. Postoperative haemoglobin and leucucocyte counts were also recorded. The rate of air leakage was assessed by a mechanical suction pump and was expressed in litres per minute. The personnel recording these parameters were blinded to the intervention received. Adverse events were monitored throughout the patients hospital stay. Postoperative air leakage, chest tube drainage and hospitalisation time were used as indicators of postoperative morbidity.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
The data for each variable and within each randomised group were tested for significant deviation from a normal distribution using the Kolmogorov–Smirnov test. Two-tailed t-tests (normally distributed data) or Mann–Whitney U-test (non-normally distributed data) were used for evaluating the significance of differences between group means or medians, as appropriate. The significance of any proportional differences in attributes (e.g. with or without air leakage) were evaluated using the Fisher's Exact Test (two groups). Statistical analysis was carried out using SPSS software, version 12.0.1 (SPSS Inc., USA).


   4. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
4.1. Patient characteristics
Both groups were similar with regard to demographic and baseline characteristics (Table 1). The mean age for the total study population was 64 (standard deviation 11) years and 29 patients (72.5%) were smokers. There was an indication of a possible difference with regard to their forced expiratory flow in 1s (FEV1); however, examination of the individual patient data indicated no apparent relationship between baseline FEV1 values and any of the performance variables. The patients general condition were considered to be normal risks for lobectomy. In the control group, there was 1 patient with emphysema and another one with pleural adhesions. In the Vivostat group, 1 patient needed decortication for releasing atelectatic lung parenchyma and another one had combined adherences with emphysema. None of the patients in this study underwent additional bullectomy as the emphysematous changes were generalised with minimal bullae formation.


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  		Table 1. Baseline demographics
 
4.2. Patient withdrawals and adverse effects
No patients were withdrawn from the study and no adverse effects were recorded during the study. Postoperatively, patients in the control group had significantly lower haemoglobin concentration than the Vivostat group. Postoperative leucocyte levels were similar in both groups.

4.3. Performance variables
The results for each of the performance variables for both randomised groups are summarised in Table 2. Use of Vivostat was associated with a mean 255ml lower drainage volume in the 24-h postoperative period, and a mean lower total drainage volume of 382ml compared with the control group. These differences were highly statistically significant (both P<0.001).


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  		Table 2. Postoperative morbidity variables
 
The number of patients without an air leak immediately postoperatively (day 0), was significantly greater (16 patients, 80%) in the Vivostat group compared to the control group (8 patients, 40%) (P=0.02). Of the patients without air leakage recorded on the day of the operation, four in the Vivostat group and one in the control group had air leaks recorded on the first postoperative day. The proportions of patients without air leakage on any day were 12 in the Vivostat group and seven in the control group (60 vs. 35%, P=0.21) (Fig. 1). The median air-leak rate was significantly lower in the Vivostat group compared with the control group on the day of operation (differences in medians 0.5l/min; P=0.01) and averaged over the period of chest-tube drainage (differences in medians 0.6l/min). Although median durations of chest-tube drainage and hospitalisation times were shorter in the Vivostat group compared with control groups (1 and 0.5 days, respectively), the differences were not statistically significant. There was less need for postoperative TEDA in the Vivostat group although the difference was not significant (medians: 2 vs. 3 days, P=0.07).



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  		Fig. 1. Daily air-leak volumes in individual patients during the study.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
Thoracic surgery of the lung frequently involves various grades of pulmonary resection and sometimes decortication, which leads to haemorrhage and air leaks. Meticulous attention to haemostasis during surgery can reduce blood loss. Effective techniques for reducing air leakage are still to be perfected, however, a variety of natural and synthetic materials are available for the purpose, including fibrin sealants, collagen fleece, synthetic glue and stapling [5–8].

Use of fibrin sealants has been shown to reduce complications of air leakage, such as bronchopleural fistulae, the formation of pleural adhesions, pneumothorax, and secondary infections [9–11]. Conventional fibrin sealants utilise components prepared from pooled human plasma (fibrinogen, thrombin) and, sometimes, animal-derived components (e.g. bovine aprotinin or thrombin). These carry a potential risk of transmitting human- or animal-borne infectious materials (e.g. viruses such as hepatitis B and C, human T-cell leukaemia, human immunodeficiency virus type 1 (HIV-1), or prions responsible for diseases such as Creutzfeldt–Jakob disease (CJD) or bovine spongiform encephalopathy (BSE)). There are additional concerns of antigenic reactions to foreign proteins and of thrombotic effects from high concentrations of added thrombin [12]. An autologous fibrin sealant free from added thrombin, such as Vivostat, provides a definite means of preventing these potential adverse effects.

In this study, we have demonstrated that the adjunctive use of Vivostat autologous fibrin sealant during lobectomy significantly reduces postoperative air leakage, both in terms of the rate of air leakage per patient and the proportion of patients experiencing air leakage, and the amount of postoperative bleeding/exudation. The majority of drainage fluid, at least in the first 24h, is due to bleeding. Vivostat use reduced this volume over the first 24h by 155ml, and by 358ml overall, more than compensating for the 120ml of blood donated by the patient for preparation of the fibrin sealant. Slightly higher haemoglobin levels were recorded in the Vivostat group postoperatively, although we could not confirm that this was a direct consequence of the reduced blood loss achieved with Vivostat. Reductions in bleeding and air leakage would be expected to reduce the need for chest-tube drainage and the need for hospitalisation. Although results for these parameters favoured Vivostat, no statistically significant differences were found. Reducing hospitalisation time is associated with considerable cost benefits, thus, a larger study may be justified to establish if there is a significant meaningful benefit for Vivostat in this regard.

Previous studies of the effects of fibrin sealants in pulmonary surgery have given inconsistent results with regard to air leakage and the duration of chest-tube drainage. Wong and Goldstraw [13], in a randomised trial of 66 patients with alveolar air leaks following pulmonary surgery, identified a non-significant but shorter duration of chest-tube drainage (6 vs. 9 days) and hospitalisation (6 vs. 8 days) for fibrin sealant (sprayed) and untreated controls, respectively. Fleischer et al. [14] were also unable to identify a significant effect of fibrin sealant in reducing the duration of chest-tube drain insertion (6.0 vs. 5.9 days) and hospitalisation (9.8 vs. 11.5), or in the duration of air leakage (2.3 vs. 3.3 day) for fibrin sealant versus controls, respectively, in a 28-patient lobectomy study. Gagarine et al. [15], in a retrospective study of 360 patients, of whom 102 received fibrin sealant during surgery, did identify a significant reduction of 1.4 days in duration of chest-tube intubation with fibrin sealant compared with control, but did not find any significant difference in the proportion of patients with extended air leaks (>7 days) or in the length of hospital stay (6.3 vs. 7.7 days, respectively). Finally, in a case-control study of 100 patients undergoing precision resections for lung metastases [16], more complications were significant benefits of fibrin sealant were found in comparison with cauterisation for duration air leakage (2.7 vs. 7.8 days, P<0.001), drain insertion (4.5 vs. 9.5, P<0.001) and hospital stay (6.5 vs. 11.5 days, P<0.001), and there were more adverse effects with cauterisation (28 vs. 2%, P<0.001). In the above studies, duration of hospitalisation (median 4.5 days) and duration of drainage (median 2 days) in the control groups were markedly longer than our study (median 4.5 days); suggesting differences in postoperative patient-management procedures. The relatively short period of hospitalisation in our study reduces the likelihood of finding a significant difference between treatment groups.

We believe our study was the first randomised clinical study to measure air leakage intraoperatively while patients were still on the respirator, and, postoperatively, by a flowmeter in the mechanical electrical suction device, with repeated measurements until the removal of the chest tube. This enabled the amount of air leakage, as well as the chest-tube drainage fluid to be quantified. In this way, despite the relatively small group sizes (20 per group), we were able to demonstrate a significant benefit for Vivostat over control in postoperative morbidity.

For some time we have used Vivostat routinely in cardiac surgery for redo-operations, aortic dissections and other high-risk bleeders, as well using Vivostat perioperatively in patients undergoing thoracoscopic procedures to control air leaks and bleeding. The morbidity benefits shown for Vivostat in this randomised, blinded study provides good justification for its routine use as a tissue sealant for pulmonary lobectomies.


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

  1. Lang G, Csekeö A, Stamatis G, Lampl G, Hagman L, Marta GM, Mueller MR, Klepetko W. Efficacy and safety of topical application of human fibrinogen/thrombin-coated collagen patch (TachoComb) for treatment of air leakage after standard lobectomy. Eur J Cardiothorac Surg 2004;25:160-166.[Abstract/Free Full Text]
  2. Kjaergard HK, Axelsen P. Effectiveness of autologous fibrin sealant in experimental lung surgery. Eur Surg Res 1996;28:162-166.
  3. Kjaergard HK, Trumbull HR. Vivostat system autologous fibrin sealant: preliminary study in elective coronary bypass grafting. Ann Thorac Surg 1998;66:482-486.[Abstract/Free Full Text]
  4. Kjaergard HK, Pedersen JH, Krasnik M, Weis-Fogh US, Fleron H, Griffin HE. Prevention of air leakage by spraying Vivostat fibrin sealant after lung resection in pigs. Chest 2000;117(4):1124-1127.[Abstract/Free Full Text]
  5. Gibble JW, Ness PM. Fibrin glue: the perfect operative sealant?. Transfusion 1990;30:741-747.[CrossRef][Medline]
  6. Strausberg RL, Link RP. Protein-based medical adhesives. Trends Biotechnol 1990;8:53-57.[CrossRef][Medline]
  7. Reiter D. Methods and materials for wound management. Otolaryngol Head Neck Surg 1994;110:550-556.[CrossRef][Medline]
  8. Donkerwolcke M, Burny F, Muster D. Tissues and bone adhesives—historical aspects. Biomaterials 1998;19:1461-1466.[CrossRef][Medline]
  9. Mouritzen C, Drömer M, Keinecke H-O. The effect of fibrin gluing to seal bronchial and alveolar leakages after pulmonary resections and decortications. Eur J Cardiothorac Surg 1993;7:75-80.[Abstract]
  10. York EL, Lewall DB, Hirji M, Gelfand ET, Modry DL. Endoscopic diagnosis and treatment of postoperative bronchopleural fistula. Chest 1990;97:1390-1392.[Abstract/Free Full Text]
  11. Petsas T, Siamblis D, Giannakenas C, Tepetes K, Dougenis D, Spiropoulos K, Fezoulis I, Dimopoulos I. Fibrin glue for sealing the needle-track in fine-needle percutaneous lung biopsy using a coaxial system: part II-clinical study. Cardiovasc Intervent Radiol 1995;18:378-382.[CrossRef][Medline]
  12. Cederholm-Williams. Fibrin Glue. Br Med J 1994;308:570.
  13. Wong K, Goldstraw P. Effect of fibrin glue in the reduction of postthoracotomy alveolar air leak. Ann Thorac Surg 1997;64:979-981.[Abstract/Free Full Text]
  14. Fleisher AG, Evans KG, Nelems B, Finley RJ. Effect of routine fibrin glue use on the duration of air leaks after lobectomy. Ann Thorac Surg 1990;49:133-134.[Abstract]
  15. Gagarine A, Urschel JD, Miller JD, Bennett WF, Young JE. Effect of fibrin glue on air leak and length of hospital stay after pulmonary lobectomy. J Cardiovasc Surg (Torino) 2003;44:771-773.[Medline]
  16. Brega Massone PP, Magnani B, Conti B, Lequaglie C, Cataldo I. Cauterization versus fibrin glue for aerostasis in precision resection for secondary lung tumors. Ann Surg Oncol 2003;10:441-446.[CrossRef][Medline]



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