• 
• 

Three Part Question

In [adult patients undergoing lung resection], does [intraoperative use of surgical adhesives] reduce the [incidence and length of postoperative air leaks]?

Clinical Scenario

You have just completed a right upper lobectomy in a 67 year old smoker for non-small cell carcinoma. He had multiple adhesions and an incomplete fissure and on testing there were many air leaks. A colleague has been trying out a spray-on glue to reduce air leaks and thus you ask for this glue to be brought into theatre and apply it liberally. The air leak stops on day one, the drains are all removed on day 3 and he is discharged on day 5. You wonder whether you should use this glue for all your lobectomy patients and thus resolve to look this up in the literature.

Search Strategy

Medline 1950 to Jan 2007 using the OVID interface
[exp lung neoplasms/ OR lung neoplasm.mp/ OR lung carcinoma.mp OR lung cancer.mp OR pneumonectom$.mp OR lobectom$.mp OR lung resection.mp OR pulmonary resection$.mp OR Thoracotom$.mp] AND [exp Tissue Adhesives/ OR tissue adhesive.mp OR exp Fibrin Tissue Adhesive/ OR sealant.mp OR vivostat.mp OR fibrin glu$.mp OR TachoComb.mp OR bioglue.mp OR focalseal.mp]

Search Outcome

A total of 261 papers were identified using the reported search of which 12 represented best evidence on the subject. These studies are summarised below

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Tansley et al, 2006 UK	52 patients undergoing lung resection were randomised- 25 to treatment group and 25 to control group. Test Substance : Bioglue (Glutaraldehyde/ BSA)	Randomized Controlled Trial (level 1b)	Air leak duration	Air leak duration 1 vs 4d(med; S)	Small numbers Single blinded study with 3 surgeons- no blinding post op therefore possible bias regarding LOS Bioglue is a glutaraldehyde albumin adhesive
			Chest drainage	Length of drainage 4 vs 5d (med; S)
			Hospital Stay	Length of stay 6 vs 7d (med; S)
Serra-Mitjans et al, 2006 Spain	Systematic review of 12 studies from 1966 to 2004	Systematic Review (level 1a)	Air leak duration, hospital stay, Chest drain removal	8 trials showed significantly less air leak in treatment groups.	Includes all major RCTs up to time of publication Concluded that sealants may have benefits in reducing post op air leaks but cannot be recommended for routine use at present.
Porte et al, 2001 France	120 pts undergoing lung resection randomised n= 59:61 treatment: controls Test Substance : Polyethylene glycol (focalseal) 'Selective' trial; only patients with sig. air leak at the end of operation were eligible. Pts followed up at 6 months.	PRCT (level 1b)	Air Leaks after treatment	Air leak duration 34 vs 63h (mn;SD)	2 surgeons Drains kept in minimum of 6d in spite of AL status which must affect LOS results N=4 (6.8%) of treatment group developed empyema Synthetic (PEG) lung sealant used (Focalseal)
			Secondary outcomes included time of chest drainage and hospital stay	Length of drainage 6d Length of stay 9.2 vs 8.6d (mn;NS)
Wain et al, 2001 USA	172 pts undergoing lung resection randomised 2:1 treatment:control (n= 117, n=55) Test Substance : Polyethylene glycol (focalseal) Non-selective study i.e. pts with no intraoperative AL were randomised into the treatment and control groups Pts followed up at 6 months.	PRCT (level 1b)	Primary endpoint was proportion of pts remaining leak free post op.	Air leak duration 31 vs 52h (mn;SD)	5 Centres, 10 surgeons Non blinded study 46 pts with no operative air leak were randomised (30 in treatment group; 16 in control group) A standardised post-op protocol was not instituted- authors feel this is one reason why length of stay and chest drainage were not affected. 3% of treatment group developed empyema PEG sealant which does not require light polymerisation used (Focalseal-L)
			Secondary outcomes included time of chest drainage and hospital stay	Length of drainage 4.5 vs 5.2d(mn;NS) Length of stay 7.4 vs 10.1d(mn;NS)
Lang et al, 2004 Hungary	189 pts randomised, 96 in treatment group, 93 in control group Test Substance : Fibrin/ Collagen (Tachocomb)	PRCT (level 1b)	Incidence of Air leak post lobectomy. Safety of Tachocomb. Efficacy for treatment of air leak	Air Leak duration 1.9 vs 2.7d(mn; SD). Length of drainage NA. Length of Stay NA	5 centres in 4 countries Non selective study Non blinded study Did not measure LOS/ LODrainage Tachocomb is a collagen fleece patch coated with fibrin
Fabian et al, 2003 USA	100 patients randomly assigned (50+50) to receive fibrin sealant Vivostat) and control groups. Test Substance : Fibrin glue (vivostat ) Non selective study	PRCT (level 1b)	Rate of air leak on Day 0 till drain out.	Air leak duration 1.1 vs 3.1d(mn;SD)	Operations performed by residents under supervision No post op drain management protocol given.
			Pleural drainage	Length of drainage 3.5 vs 5 (mn;SD)
			Time to drain removal
			Length of stay	Length of stay 4.6 vs 4.9d(mn;NS)
Belboul et al, 2004, France	Pts underwent 3 month follow up appointment with CT scan. Test Substance : Autologous fibrin glue Forty pts (20+20) 'Selective' study, all randomised pts had ALs	PRCT (level 1b)	% pts free of air leak at day 4&6 empyema Time to drain removal	%Air leak at closure 8 vs. 16 (SD) Air leak duration NA Length of drainage 1 vs 2d (med;NS) Length of stay 4 vs 4.5d (med;NS)	Small numbers. Single centre with 4 surgeons. Blinded post op observers. Criteria for drain removal not given.
Allen et al, 2004 USA	148 pts undergoing lung resection randomised 2:1 into treatment and controls (n= 95, n=53 respectively) Test Substance : Polyethylene glycol (focalseal) Selective study i.e. only pts with intraoperative Air leak randomised. 1 month follow up period to assess morbidity	PRCT (level 1b)	Primary endpoint was proportion of pts remaining leak free post op.	Air leak duration 2 vs. 2d (med;NS) Length of drainage 6.8 vs. 6.2 (med;NS) Length of stay 6 vs 7d (med;SD)	5 Centres, 10 surgeons Non blinded study PEG sealant which does not require light polymerisation used (Focalseal-L)
Macchiarini et al, 1999, France	24 patients randomised, 13 to treatment arm and 11 to control. Test Substance : fibrin glue 'Non-selective' trial	PRCT (level 1b)	Persistence of Air leaks intra- and post-operatively	Air leak duration 1.9 vs. 2.4 (NS)	Small numbers Empyema in 3.8% of treatment arm
			Time to drain removal	Length of drainage 6.1 vs. 6.9 (NS)
			Hospital stay and costs	Length of stay 13 vs. 14 (NS)
Wong et al, 1997, UK	66 patients undergoing lung resection or decortication. 33 randomised patients had fibrin glue sprayed on lung surface pre chest closure. 33 were controls. Test Substance : fibrin glue Selective study	PRCT (level 1b)	Air leak	Air leak duration 4 vs. 5d (med; NS)	Single surgeon Post op observations not stated whether blinded. Fibrin glue
			Intercostal drainage	Length of drainage 6 vs. 6d (med; NS)
			In hospital stay	Length of Stay 8 vs. 9d (med;NS)
Mouritzen et al, 1993, Denmark	114 patients undergoing lung resection (n=63) and pneumonectomies (n=51). 2 groups, surgery alone (n=59) and surgery + fibrin (n=55) Test Substance : fibrin glue	PRCT (level 1b)	Airway pressure tolerance	Airway Pressure tolerance 81% improvement with Fibrin, p<0.01	Lots of pneumonectomy patients
			Incidence of patients with air leak	Incidence of Air leak 66% vs. 39% , p<0.02
			No of days with air leak	Time of air leak; NS
Fleisher et al, 1990, UK	28 patients (14+14) undergoing lobectomy randomised to treatment + controls Test Substance : fibrin glue Non-selective trial	PRCT (level 1b)	Air Leak duration	Air leak duration 3.2 vs. 3.3d (mn;NS)	Small numbers
			Intercostal drainage	Length of drainage 6.1 vs. 5.9 (mn;NS)
			In hospital stay	Length of Stay 9.8 vs. 11.5 (mn;NS)

Comment(s)

A total of 12 papers (11 trials and 1 systematic review) have been cited in the comparison table. Apart from Tansley et al, all were included in the comprehensive Cochrane Systematic Review written by Serra-Mitjans et al. Most trials looked at 3 primary outcomes: Air Leak duration, Length of time of intercostal drainage, Length of hospital stay. 7 trials use fibrin based sealants, 3 trials use polyethylene- glycol based sealants, and 1 trial uses a glutaraldehyde based sealant. The basic conclusions are: 6 trials found a significant reduction in the duration of air leak after use of a sealant as compared to controls[Tansley,Porte, Wain, Lang, Fabian, Belboul], however 5 trials found the difference to be non-significant[Allen, Macchiarini, Wong, Mouritzen, Fleisher]. Only 2 trials found a significant reduction in the time of intercostal drainage compared to controls[Tansley, Fabian] , 6 trials found the difference to be non-significant[Wain, Belboul, Allen, Wong, Fleisher]. Only 2 trials found length of hospital stay to be significantly shorter in groups treated with sealant compared to their controls[Tansley, Allen], whilst 7 trials found a non-significant difference[Porte, Wain, Fabian, Belboul, Macchiarini, Wain, Fleisher]. We conclude that there is weak evidence that sealants may reduce the duration of air leaks following lung resection surgery but it is unlikely their use influences the length of time of intercostal drainage or length of hospital stay for the patient. However there are several points which need clarification when looking at these trials in detail. Further work will be needed to answer the question definitively. Some of the issues which need addressing are as follows: 1. The outcome measures. The majority of trials did not define management of intercostal drains post-operatively. This is highly variable between institutions. Also blinding of observers post-operatively was not always clearly stated. Therefore using time of drainage as an outcome measure and subsequently length of hospital stay as another primary outcome measure (as this must depend on time of drainage) seems flawed. The only definitive outcome measure which can be reliably used when comparing results between studies is post-operative air leak duration. 2. The sealant properties. There were 7 trials using fibrin based sealants, 3 trials using polyethylene- glycol based sealants and one trial using a glutaraldehyde based sealant. Of the 7 studies using fibrin based sealants, post-operative air leak duration was significantly reduced in 3 trials but made no difference in the remaining 4. Of the 3 studies using polyethylene-glycol based sealants, 2 found a significant reduction in post-operative air leak duration compared to a single trial which found it made no difference. The single trial using a glutaraldehyde based sealant found a significant reduction in post-operative air leak duration it its treatment group as opposed to its controls. Therefore the type of sealant used will influence the results. More work needs to be performed to define this more clearly. 3. The mode of application of sealants e.g. sprays vs. syringe 'spot' application Practicalities of usage have to be considered. E.g. light wands, autologous blood, collagen fleece, time added to surgery etc. General problems with the set up of these trials, e.g. learning curve/ experience of surgeon; single vs. multicentre studies; no. of patients recruited etc.

Clinical Bottom Line

We conclude that 6 of the identified randomized trials found a significant reduction in air leak duration, but 5 found no significant difference. In contrast to significant reductions in air leak, only 2 studies identified a reduction in time to chest drain removal. Also only 2 studies found a significant reduction in length of stay. There are multiple issues surrounding these studies ranging from identifying the optimal glue and delivery system, dealing with the learning curve of surgeons and robust protocols for chest drain removal to selection of patients suitable for surgical adhesive usage. Thus routine usage of surgical adhesive for all operations cannot yet be recommended, although there is a wide range of adhesives available to surgeons which may be useful in selected situations.

References

1. Tansley P, Al-Mulhim F, Lim E, Ladas G, Goldstraw P. A prospective, randomized, controlled trial of the effectiveness of BioGlue in treating alveolar air leaks. Journal of Thoracic & Cardiovascular Surgery 132(1):105-12, 2006.
2. Serra-Mitjans M, Belda-Sanchis J, Rami-Porta R. Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer.[update of Cochrane Database Syst Rev. 2001;(4):CD003051; PMID: 11687173]. [Review] Cochrane Database of Systematic Reviews (3):CD003051, 2005.
3. Porte HL, Jany T, Akkad R, Conti M, Gillet PA, Guidat A, Wurtz AJ. Randomized controlled trial of a synthetic sealant for preventing alveolar air leaks after lobectomy. Annals of Thoracic Surgery 71(5):1618-22, 2001.
4. Wain JC, Kaiser LR, Johnstone DW, Yang SC, Wright CD, Friedberg JS, Feins RH, Heitmiller RF, Mathisen DJ, Selwyn MR. Trial of a novel synthetic sealant in preventing air leaks after lung resection. Annals of Thoracic Surgery 71(5):1623-8; discussion 1628-9, 2001.
5. Lang G, Csekeo A, Stamatis G, Lampl L, 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. European Journal of Cardio-Thoracic Surgery 25(2):160-6, 2004.
6. Fabian T, Federico JA, Ponn RB. Fibrin glue in pulmonary resection: a prospective, randomized, blinded study. Annals of Thoracic Surgery 75(5):1587-92, 2003.
7. Belboul A, Dernevik L, Aljassim O, Skrbic B, Radberg G, Roberts D. The effect of autologous fibrin sealant (Vivostat) on morbidity after pulmonary lobectomy: a prospective randomised, blinded study. European Journal of Cardio-Thoracic Surgery 26(6):1187-91, 2004.
8. Allen MS, Wood DE, Hawkinson RW, Harpole DH, McKenna RJ, Walsh GL, Vallieres E, Miller DL, Nichols FC, III, Smythe WR, Davis RD, Group MSSS. Prospective randomized study evaluating a biodegradable polymeric sealant for sealing intraoperative air leaks that occur during pulmonary resection. Annals of Thoracic Surgery 77(5):1792-801, 2004.
9. Macchiarini P, Wain J, Almy S, Dartevelle P. Experimental and clinical evaluation of a new synthetic, absorbable sealant to reduce air leaks in thoracic operations. Journal of Thoracic & Cardiovascular Surgery 117(4):751-8, 1999.
10. Wong K, Goldstraw P. Effect of fibrin glue in the reduction of postthoracotomy alveolar air leak. Annals of Thoracic Surgery 64(4):979-81, 1997.
11. Mouritzen C, Dromer M, Keinecke HO. The effect of fibrin glueing to seal bronchial and alveolar leakages after pulmonary resections and decortications. European Journal of Cardio-Thoracic Surgery 7(2):75-80, 1993.
12. Fleisher AG, Evans KG, Nelems B, Finley RJ. Effect of routine fibrin glue use on the duration of air leaks after lobectomy. Annals of Thoracic Surgery 49(1):133-4, 1990.