Off-label use of lung sealants: the need for evidence-based guidelines and adequate indications for use
Review Article

Off-label use of lung sealants: the need for evidence-based guidelines and adequate indications for use

Bob P. Hermans, Wilson W. L. Li, Stefan M. van der Heide, Ad F. T. M. Verhagen

Department of Cardio-thoracic Surgery, Radboud University Medical Center, Nijmegen, The Netherlands

Contributions: (I) Conception and design: BP Hermans, WWL Li; (II) Administrative support: BP Hermans; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: BP Hermans; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Bob P. Hermans, MD, PhD. Department of Cardio-thoracic Surgery, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. Email: Bob.Hermans@Radboudumc.nl.

Abstract: Prolonged pulmonary air leakage remains a significant challenge in thoracic surgery, and is associated with a more complicated post-operative course. Lung sealants may provide a solution, but the evidence for their effectiveness is heterogenous and head-to-head comparisons between sealants are lacking. While there are some consensus guidelines discussing when an air leak should be treated, there are no practice guidelines and specific sealant choice is left to surgeon experience. This review addresses the evidence gaps in this field. First, an overview of previously tested sealants is provided, illustrating that several sealants may be considered off-label. For example, a polyethylene glycol spray (Coseal®) or a human serum albumin and polyethylene glycol spray (Progel®) are only indicated in addition to sutures or staples, limiting usability on superficial parenchymal lesions. Off-label use may be concerning due to unknown risk of adverse events, and lead to legal challenges for the prescribing physician. The role of manufacturers with regard to off-label use is discussed. To close the gap in evidence, this review provides several recommendations for evidence generation, including clinical trial design, network meta-analysis, and ex-vivo human lung testing. Until high quality evidence is available, we propose forming consensus-driven practice guidelines to support thoracic surgeons in choosing lung sealants.

Keywords: Air leakage; lung cancer; lung sealant; guidelines

Submitted Jun 19, 2025. Accepted for publication Sep 10, 2025. Published online Nov 24, 2025.

doi: 10.21037/jtd-2025-1230

Introduction

Thoracic surgeons are often faced with the consequences of prolonged air leakage (PAL, defined as air leak >5 days) (1). PAL occurs in about one in ten cases after lung resection and leads to increased risk of infections (empyema 8.2% vs. 0%), reoperations (4.6% vs. 0.85%), longer hospital stay (4 days longer) and higher mortality (odds ratio 1.9) (2-5). Pre-emptive treatment of intra-operative air leaks (IALs, defined as any air leak during surgery as diagnosed by water submersion test or mechanical ventilator test) with lung sealants offers a conceptually sound solution, but evidence in literature is heterogenous, leading to vague recommendations such as: ‘systematic use is not recommended’ or ‘recommended according to surgeon experience’ (6,7). As of now there are several key questions that require further scrutinization: When is an IAL significant? When should sealants be considered? What sealants should be used?

Mini-review structured approach

A structured literature search is performed by one author (B.P.H.) according to Appendix 1. We looked for systematic reviews, meta-analysis, consensus documents or evidence-based guideline documents. A total of 843 articles were screened, identifying 6 systematic reviews, 3 consensus articles and 2 evidence-based guideline documents (6-16). An overview of all included studies in the systematic reviews is collected (N=38), plus an additional unpublished trial (N=1), and a network chart is made of the subset of randomized clinical trials (RCTs) that tested commercially available sealants in the European Union (EU) market (N=25). For these sealants, the instructions for use were gathered and an overview table is made summarizing indications for use and notable contra-indications.

When should sealants be used?

Expert consensus highlight that sealants should not be used prophylactically (e.g., on staple lines) but only with IAL. Cardillo et al. performed a Delphi consensus survey among 46 Italian experts, describing several situations in which sealants may be used [e.g., 150–300 mL/min IAL, chronic obstructive pulmonary disease (COPD)] (13). Similarly, Brunelli et al. polled 258 European Society of Thoracic Surgery (ESTS) members, and recommended sealant use only in high risk cases with IAL (12). However, the current pre-operative risk scores have a high number of false positives (17). Singhal et al. (2010) discussed in their expert review that use in high risk subgroups is based on gut feeling rather than actual data, since analysis in high-risk subgroups is incomplete (15). Zaraca performed Delphi consensus rounds among 32 experts from various countries, suggesting that moderate IAL in high-risk patients (100–400 mL/min) or severe (>400 mL/min) IAL should be treated. Unfortunately, there was no consensus whether or not to use sealants in these situations (14). Based on experimental and clinical data, Rice et al. (2010) also did not recommend routine prophylactic use of various sealants in their evidence-based approach (16).

It is worth noting that no standardized mechanical ventilator parameters are defined for testing IAL size, while these can have a profound impact (18,19). It remains to be investigated which type of standardization (positive end-expiratory pressure, volume versus pressure control, respiratory rate, inspiratory:expiratory ratio) and measurements (absolute air leak values versus proportion of tidal volume) has the best predictive value of post-operative air leak (19,20).

What sealants should be used?

For sealant selection, data from RCTs should be considered, but meta-analyses in this field often perform pooled analyses of various sealants with differing mechanisms of action (7,8,10). Only TachoSil® has been evaluated separately, compared to standard treatment (9). BioGlue® was discussed in a separate systematic review for prevention of PAL and management of broncho-pleural fistula (BPF), but no meta-analysis was performed (11). A network meta-analysis might be useful, but the number of head-to-head comparisons is limited (Figure 1A) (6,7,10). So, it is challenging to establish evidence-based guidelines on the optimal use of sealants (12). An overview of systematic reviews and meta-analysis is shown in Table 1.

Figure 1 Network graph of tested lung sealants and recommendations for future studies. (A) Network graph showing the number of randomized comparisons of commercially available sealants. (B) Example flow-chart for a randomized clinical trial into lung sealants for prevention of pulmonary air leakage [adapted from (21)].

Table 1

Summary of evidence from systematic reviews and meta-analysis

Author, year Sealants analyzed Total sample size Summary statistic
Belda-Sanchis, 2010 (7) 7 sealants; 16 RCTs 873 intervention; 771 control 12 RCTs significant reduction air leaks; 3 RCTs significant reduction LOS
Malapert, 2010 (8) 8 sealants/buttress; 13 RCTs 1,335 intervention; 1,335 control PAL >7 days: OR =0.55 (95% CI: 0.39–0.79)
Tsilimigras, 2017 (11) 1 sealant (BioGlue); 2 RCTs; 1 pilot; 1 retrospective 106 intervention; 109 control NR
McGuire, 2018 (10) 10 sealants; 21 RCTs 1,292 intervention; 1,245 control PAL: OR =0.55 (95% CI: 0.35–0.87) (12 trials);
LOS: OR =−0.96 (95% CI: −1.74 to −0.18) (9 trials)
Zhou, 2019 (9) 1 sealant (TachoSil); 6 RCTs 465 intervention; 456 control PAL >7 days: RR =0.57 (95% CI: 0.35–0.92) (4 trials);
LOS: WMD =−1.89 days (95% CI: −2.42 to −1.35) (6 trials)
Aprile, 2023 (6) 8 sealants; 10 RCTs; 5 retrospective 1,248 intervention; 1,190 control NR

CI, confidence interval; LOS, length of stay; NR, not reported; OR, odds radio; PAL, prolonged air leak; RCT, randomized clinical trial; WMD, weighted mean difference.

Off-label use of lung sealants

The guideline gap is particularly concerning given that several sealants evaluated in trials do not have broad indications for practical use, and are mainly intended for hemostatic use. While the precise indications for each agent might vary as a result of different regulations, clinical use should (partially) be considered off-label (22). Polymeric spray sealants such as Coseal® or Progel® are indicated on IAL, but only as an adjunct to sutures or staplers. This limits their use on frequently occurring and difficult to suture superficial parenchymal injuries (e.g., due to dissection of fissure or adhesiolysis). Remarkably, Coseal® is even contra-indicated on decorticated lung areas. Currently, the sealant with the broadest indication is Hemopatch®, but with limited clinical evidence. In a single unpublished trial with Hemopatch® versus TachoSil® similar outcomes were found (EudraCT nr. 2017-003931-12). Notable contra-indications for various sealants include prevention of BPF and use in contaminated or infection cases (Table 2).

Table 2

Overview of indications for use and notable contra-indications of lung sealants that were tested in clinical studies

Name Main components IFU ref.‡ Indications Notable contra-indications and precautions Lung sealing indication
BioGlue® Bovine serum albumin, glutaraldehyde CE; L09418.001; 06-2023§ Adjunct to standard methods in cardiac, vascular, dural and pulmonary tissue No substitute for sutures or staplers; not in infection, caution in contaminated areas; no sufficient data for use on BPF; excessive use can cause residual air space and atelectasis Only as adjunct to standard methods
CoSeal® PEGs CE; 04-2012§ Adjunctive hemostasis in vascular reconstructions; enforcement of suture/staple lines in lung resection; prevent adhesions after cardiac or laparotomic/laparoscopic surgery Not on bronchial stump, during bronchial sleeve resections or sealing decorticated areas; not if pleural adhesions are desired; not in contaminated pulmonary resection Only as enforcement of suture/staple lines
Hemopatch® NHS-PEG coated bovine collagen pad CE; M000483; 03-2017§ Sealing of bleeding, leakage, body fluids or air when conventional techniques are ineffective or impractical Not in presence of infection; no substitute for conventional procedures for hemostasis and sealing Not as substitute for conventional procedures, but can be used in case impractical
Progel® Human serum albumin, PEG crosslinker UK; M-00443; 07-2018§ Sealing of visible air leaks after standard pleural closure Not on main stem or lobar bronchi; not on any other surface then visceral pleura (e.g. gelatin sponges); safety and efficacy not established in contaminated pulmonary resections, active infection, spontaneous pneumothorax, non-resective injuries, congenital or acquired defects, FEV <40% Only as enforcement of suture/staple lines
TachoSil® Human fibrinogen/thrombin coated equine collagen pad EMA; 05-2024 Supportive treatment for hemostasis, promote tissue sealing, suture support in vascular surgery where standard techniques are insufficient None related to lung sealing Tissue sealing where standard techniques are insufficient
Tisseel® Human fibrinogen, synthetic aprotinin, human thrombin BE; 01-2022§ Hemostasis; tissue sealing, among others of lung and pleura None related to lung sealing Tissue sealing
Beriplast® P Human fibrinogen, factor XIII (human), aprotinin (bovine)/human thrombin, calcium chloride GER; 03-2024†† Supportive hemostasis when standard techniques are inadequate; tissue adhesive to promote adhesion/sealing or as suture reinforcement None related to lung sealing To promote sealing
Vivostat Autologous fibrin sealant CE; Ver. 10, 05-2021†† Fibrin sealants have a wide range of uses including hemostasis, tissue sealing (fluid or air), tissue gluing None related to lung sealing Tissue sealing

†, commercially available devices included in reviews (6-11), and unpublished data of Hemopatch®; ‡, this table is not meant as a substitute for the instruction for use provided by the manufacturer; §, up-to-date version obtained from manufacturer; , most recent version from EMA website; ††, up-to-date version obtained from website of manufacturer. BE, Belgium; BPF, broncho-pleural fistula; CE, Conformité Européene; EMA, European Medicine Agency; FDA, Food and Drug administration; FEV, forced expiratory volume; GER, Germany; IFU, instruction for use; NHS, N-hydroxysuccimide; PEG, polyethylene glycol; UK, United Kingdom.

Off-label use of medical devices poses potential legal challenges for the prescribing physician, since they are accountable for potential adverse effects (23). According to the position paper of The European Association of Medical devices Notified Bodies (published after the new EU-MDR 2017/745 directive), off-label use can be ethically acceptable if there is an unmet clinical need lacking good approved alternatives. This requires clinicians to ensure that they are both making informed decisions when considering such use, although the risks may not be fully understood, and obtaining informed consent from patients (24). But, there also is an explicit responsibility for manufacturers to identify off-label use, and take measures to extend the indications for use by initiating clinical studies for formal conformity assessment (23,25).

Off-label use may be especially concerning due to unknown risk of adverse events. Current meta-analysis does not indicate that lung sealants are associated with increased complications (e.g., atelectasis, hematothorax, pneumonia) (8-10), but cautious interpretation is required. For example, a 2010 meta-analysis described a pooled odds ratio of 2.2 for empyema with a very wide 95%-confidence interval of 0.57 to 8.5 (8).

Regarding the required indications for use, we believe sealants should be indicated for both primary and secondary use to meet the varied demands of lung surgery. Primary use involves standalone application, such as sealing superficial parenchymal lesions during fissure dissection or adhesiolysis, where both patches and sprays may be suitable, though sprays are often more practical in video-assisted procedures (12). Secondary use refers to sealants as adjuncts to sutures or staples, reinforcing them or sealing suture-hole leakage. For this, spray sealants may be preferable due to their ability to mechanically interlock with suture holes (26).

Closing the gap in lung sealant evidence

Considering the above, there is a need for better evidence to support guideline formulation. As of now, it seems there is more of an emphasis on research into hemostatic agents, but basic and clinical research into the aerostatic properties of already available agents seems to lack behind. Ultimately, we need prospective randomized head-to-head comparative clinical trials and (network) meta-analysis (27).

In our opinion, high quality clinical trials should follow the following principles (21). High-risk patients (based on risk scores, e.g., Bordeaux model), for PAL should be selected to reduce the required sample size (17). Minimally invasive procedures should be included to reflect clinical practice, since application of sealants requires a different technique for open versus video-assisted procedures which can influence outcomes. Blinding should be applied to post-operative follow-up, and chest tube removal should be standardized using digital systems by using quantitative cut-off points for drain removal. These quantitative cut-off points can also be used in the analysis to verify that adherence to drain removal protocol was comparable in both intervention and control groups. New lung sealants should be compared to gold standards (e.g., TachoSil®), and traditional intra-operative techniques such as pleural tenting, pleurodesis and staple line buttresses should also be considered (1,9). Cost-effectiveness should be assessed as well (28). Power calculations should use PAL incidence as primary outcome. A study flow-chart example is provided in Figure 1B (21).

However, due to the high costs of clinical trials, there may be an important role for preclinical models using human tissue (29). Parenchymal lesions in healthy animal lungs likely provide limited translational value due to intrinsic sealing and high tissue density compared to emphysematous lungs (30,31). Recent research also demonstrates differences in visceral pleura biomechanics between species, which should be taken into account when designing human-specific sealants (29). In addition, biomechanics may differ in various disease states (emphysema/cancer/fibrosis), which may require dynamic formulations (29,32). The development of realistic ex-vivo human lung perfusion models for iterative testing of mechanical properties can play an important role in comparative research for lung sealants (29,33). For this, tight collaborations with transplant programs are required to attain non-transplantable human lungs.

Conclusions

While the prospects of well-designed comparative trials and network meta-analyses are valuable, they don’t currently support thoracic surgeons in making intraoperative decisions: when and which sealant to use. Especially since the use of several sealants in common clinical scenario’s is considered off-label, a set of professional guidelines is warranted. We propose forming a multidisciplinary panel to synthesize current evidence and expert opinion into practical guidelines, similar to the Delphi approaches by Brunelli, Zaraca, and Cardillo (12-14). Ultimately, however, the development of effective sealants that demonstrably reduce PAL remains essential (12).

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1230/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1230/coif). W.W.L.L. and A.F.T.M.V. received payments from Johnson & Johnson, Bristol-Myer Squibb, Merck Sharp and Dohme, which all payments were made to the institution. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Hermans BP, Li WWL, van der Heide SM, Verhagen AFTM. Off-label use of lung sealants: the need for evidence-based guidelines and adequate indications for use. J Thorac Dis 2025;17(11):10551-10557. doi: 10.21037/jtd-2025-1230

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