Improved application technique of albumin-glutaraldehyde glue for repair of superficial lung defects
Bures et al. Journal of Cardiothoracic Surgery
Improved application technique of albumin-glutaraldehyde glue for repair of superficial lung defects
Maximilian Bures 4
Patrick Zardo 3
Florian Länger 2
Ruoyu Zhang 0 1
0 Department of Thoracic Surgery, Center for Pneumology and Thoracic Surgery, Schillerhoehe Hospital , Solitudestr. 18, Gerlingen , Germany
1 Department of Thoracic Surgery, Center for Pneumology and Thoracic Surgery, Chest Hospital Schillerhoehe, Teaching hospital of the University of Tuebingen , Gerlingen , Germany
2 Department of Pathology, Hannover Medical School , Carl-Neuberg Str. 1, 30625 Hannover , Germany
3 Department of Cardiac and Thoracic Surgery, Otto-von-Guericke University Magdeburg , Magdeburg , Germany
4 Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School , Hannover , Germany
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Methode: Der kaudale Lappen der frisch entnommenen Schweinlungen (n = 20) wurde intubiert und beatmet. Eine
pleurale Läsion (40 × 25 mm) wurde erstellt und AAL mit steigendem inspiratorischem Tidalvolumen (TVi) untersucht.
Die Lungenlappen wurden randomisiert mit Standardverfahren (Kontrollgruppe) oder mit der rahmengestützten
Technik appliziert (Versuchsgruppe), wobei ein quadratischer Silikonrahmen um die Läsion platziert wurde. Nach
Applikation von Albumin-Glutaraldehyd-Kleber wurde AAL auf die gleiche Weise gemessen bis zur Auftritt von
Kleberbruch. Zur Untersuchung der Elastizität des Klebers wurde die Länge der pleuralen Läsion gemessen.
Ergebnis: Die oberflächliche pleurale Läsion führte bei aufsteigendem TVi zum Anstieg von AAL. Vor der Applikation
des Klebers war AAL vergleichbar in den beiden Gruppen. Applikationsfehler trat bei einem Test in der Kontrolgruppe
auf. Bei TVi = 400, 500, 600 und 700 ml führte der Albumin-Glutaraldehyd-Kleber zur kompletten Versieglung jeweils in
10, 10, 9 und 8 Lungen in der Versuchsgruppe, und 9, 7, 6 und 4 Lungen in der Kontrolgruppe. Der mittlere Bruchdruck
war signifikant höher in Versuchsgruppe (41.0 ± 1.0 vs. 37.5 ± 4.2 cmH2O, p = 0.0195). Allerdings bestand kein Unterschied
an Dehnung der versiegelten pleuralen Läsion in den beiden Gruppen (1.0 ± 0.4 vs. 1.5 ± 1.7 mm, p = 0.3772).
Schlussfolgerung: Unsere in vitro Versuche zeigten, dass die rahmengestützte Applikationstechnik unkontrolliertes
Abfließen des flüssigen Klebers effektiv verhindern und die Abdichtungswirksamkeit vom Albumin-Glutaraldehyd-Kleber
verbessern kann. Wir empfehlen weitere Untersuchungen dieser Applikationstechnik in gut gestalteten, kontrollierten
Superficial parenchymal lung defects are common
sequelae of lung surgery, particularly in patients with firm
pleural adhesions or incomplete fissures. They result in
alveolar air leaks (AAL), which are associated with
prolonged chest tube duration and hospital stay as well as
higher postoperative morbidity [1–3]. In the past decade
surgical sealants have been increasingly used in treating
AAL as adjuncts to conventional surgical closing
techniques . One of the most commonly used sealants is
BioGlue™ (CryoLife Europa Ltd., Surrey, UK), which is
composed of bovine serum albumin and glutaraldehyde
. Its clinical benefits for treating AAL have been
proven in various clinical trials [6–8]. In addition, our
previous in vitro experiment has confirmed the high
sealing efficacy of BioGlue™, which is superior in
resisting higher ventilation pressure .
BioGlue™ is delivered in liquid form, which makes it
prone to unintentional run-off. Reported consequences
include among others a blocked leaflet after mechanical
aortic valve replacement resulting in a high transvalvular
gradient . Our personal experience in lung surgery
confirms that BioGlue™ run-off after sealing superficial
lung defects is almost inevitable and leads to hardened
strands often far away from the original lesion site.
These unintentional run-offs decrease the amount of
sealant on the lesion which might reduce its sealing
efficacy. Moreover, due to the rigid nature of hardened
BioGlue™, overflowing sealant might impair expansion of
adjacent lung parenchyma.
In the present study we used an established in vitro
lung model to examine whether a special application
technique based on a silicone frame that is placed
Lungs of German landrace pigs were freshly excised in a
local slaughterhouse. Within two hours following
harvest, the lungs were dissected along the trachea until the
tracheal bifurcation was reached. The caudal lobe was
selectively intubated, ventilated and immersed in water
to ensure impermeability. After connection to the
ventilation machine (Evita, Dräger, Lübeck, Germany), the
caudal lobe was ventilated in volume-controlled mode
with a PEEP of 5 cmH2O, an I:E ratio of 1:2 and a
frequency of 12/min. The caudal lobe was fully inflated
when inspiratory tidal volume (TVi) ≥ 400 mL.
Overinflation of the lobe was observed with TVi ≥ 800 mL. A
superficial parenchymal lesion was created in a
previously marked area of 40 × 25 mm on the inflated caudal
lobe with gentle pressure from a small drill with a
roughened conic head, working from the margins
towards the lesions center. Marker spots were then applied
to the cranial and caudal edge of the lesion. Starting
ventilation at TVi = 300 ml, TVi was increased by
100 ml in steps until a maximal inspiratory pressure
(Pmax) of 40 cmH2O was reached. Following each
increase in TVi, the expiratory tidal volume (TVe),
resistance, compliance, as well as Pmax, mean inspiratory
pressure (Pmean) and plateau inspiratory pressure
(Pplat) were recorded after five cycles. AAL was
calculated as the difference between TVi and TVe.
Lung lobes were randomly selected and subjected to
either a standard technique sealing in accordance with
CryoLife guidelines (control group, n = 10) or a modified
technique relying on placement of a square silicone frame
around the lesion site (study group, n = 10). Standard
sealant application consists in carefully meandering along the
lesion surface and, in accordance with user guidelines,
respecting a safety margin of 1 cm to all sides. For our
modified technique, a silicone frame (transparent silicone
60 ± 5 Shore, Erik’s NordOst GmbH, Hannover, Germany)
customized to allow for the mentioned safety margin, was
placed around the lesion on the inflated lower lobe (Fig. 1).
Afterwards glue was applied within frame borders in the
same meandering fashion. In both groups a period of 60 s
was awaited until the glue hardened and full sealant
adhesion was achieved (Fig. 2). In this experiment the sealant
was applied exclusively in 2 ml syringes, using only one
sample for each lesion.
The caudal lobe was then ventilated again with TVi
rising slowly from 100 ml. Commencing at TVi = 400 ml
the same parameters as prior were recorded,
continuously screening for bubbles under water application. The
distance between marker spots was measured with each
increase for the evaluation of elasticity. Air leak was
assessed through air bubble observation by two
independent investigators. Any disagreement would be
arbitrated by a third investigator. Sealing was considered
successful, when no bubble was visible under
submersion after five cycles of ventilation. This corresponds to
grade 0 on the Macchiarini scale . Sealing failure was
determined once air bubbles were observed (grade 1 or
higher). In the moment of sealant failure Pmax was
recorded as burst pressure. Sealant failure was furthermore
categorized into adhesive or cohesive failure. Adhesive
failure was considered if the sealant failure occurred at
the interface between sealant and parenchymal defect.
Cohesive failure was defined as failure within the sealant.
When cohesive or adhesive failure was observed before
Fig. 2 Applied BioGlue™ within the borders of the silicone frame
The normality of variables was tested using the
Kolmogorov-Smirnov one-sample-test. Descriptive statistics are
presented as mean ± standard deviation in case of normal
distribution. Multiple linear regression was used to
determine the ventilation parameters’ correlation with AAL.
Statistical significance was assumed if p < 0.05. All
statistical analysis was performed using SPSS (version 16.0 for
Windows; SPSS Inc., Chicago, Illinois, USA).
Following a set of four pilot tests for our modified
technique, a total of 20 consecutive tests were undertaken by
means of the standard and frame application techniques
in a randomized manner (see the Additional file 1).
AAL prior to glue application were comparable in
both groups (Table 1). Application error occured once
during standard application. At TVi = 400, 500, 600, 700
and 800 ml, BioGlue™ achieved sealing in 10, 10, 9, 8
and 8 lobes in the study group, while 9, 7, 6, 4 and 2
lobes were sealed in the control group, respectively. Even
in over-inflated lobes (TVi = 900 ml), superficial defects
were still sealed in four tests in our study group, while
only one lobe remained sealed in the control group.
Sealing rates of both groups are presented in Fig. 3.
Table 1 Air leak assessment before sealant application
Study group (n = 10)
Control group (n = 10)
TVi inspired tidal volume
Fig. 3 Sealing rates of BioGlue™ in study and control group
Difference in sealing rate between both groups reached
statistical significance at TVi = 800 ml (80 % vs. 20 %,
p = 0.0121).
Mean burst pressure was significantly higher in the
study group than in the control group (41.0 ± 1.0 cmH2O
versus 37.5 ± 4.2 cmH2O, p = 0.0195). Both groups
exhibited only cohesive sealant failures. Concerning
elasticity, there was no difference in expansion of the
covered defect between both application techniques
(1.0 ± 0.4 vs. 1.5 ± 1.7 mm, p = 0.3772).
As a highly effective sealant, BioGlue™ is regularly
implemented in cardiovascular surgery for hemostasis . In
lung surgery it has gained widespread acceptance as an
adjunct in treating AAL in recent years . A major
drawback of its application in liquid form on the surface of
inflated lung tissue is sealant run-off, which in turn may
impair sealing efficacy and trap surrounding parenchyma.
Recently our group has developed a special application
technique which basically consists in placing a silicone
frame around the lesion site to prevent sealant run-off
(frame technique). The present in vitro experiment was
aimed to examine whether this special applicaiton
technique might improve the sealing efficacy of BioGlue™.
To assess sealing efficacy we used an established in
vitro lung model in the present study, which has been
proven reliable in the previous experiments [9, 12]. In a
randomized order BioGlue™ was applied onto
standardized superfical lung defects by means of the standard
technique according to the usage guide or the frame
technique. The testing results of the standard application
technique demonstrated a high sealing efficacy of
BioGlue™ in treating AAL. The mean burst pressure was
very close to the upper limit of the commonly applied
ventilation pressure (40 cmH2O). However, when a
silicone frame was placed around lesion site, run-off of the
liquid sealant could be prevented and the sealing efficacy
presented as sealing rate and burst pressure was
significantly improved. In majour lung resection, division of
incomplete fissures is often inevitable and causes
superficial parenchymal lung defects and postoperative
prolonged air leaks despite meticulous surgical technique.
In many cases, the defect is not horizontal, rendering
adaequate applicaion of BioGlue™ difficult. According to
our results, it is reasonable to speculate that the
frameassisted application technique might facilitate sealing air
leaks in this specific setting. Nevertheless, the potential
clinical benefits and practical implications of this special
application technique require confirmation from
welldesigned randomized clinical trials.
In the present in vitro experiment we used a square
silicone frame to test the special application technique. The
measurement of the lesion’s length before and after sealant
application indicated that the silicone frame did not alter
the elasticity of the underlying lung tissue. Despite the
wide use of silicone in surgical practice, caution should be
taken for potential side effects of this non-absorbable
material. While concern has been arised about the chronic
foreign body reactions and potential risk for
carcinogenesis associated with silicone implants [13, 14], there have
been report that implanted silicone may even be a
protective factor concerning the development of carcinoma .
Taken together, the potential side effects of the present
application technique deserves further investigation.
As video-assisted thoracic surgery (VATS) has been
widely adopted and practiced in lung surgery in the last
two decades, air leak sealing by means of topical sealant
application through trocars has becomen a feasible
approach . A ample body of evidence demonstrates that
prolonged air leaks are still one of the major complications
after VATS major lung resections and limit the clinical
benefits of this minimally invasive approach . As liquid
sealant BioGlue™ can also be applied thoracoscopically
using a delivery tip extention. In this aspect, the present
study might stimulate further investigation and improve
the air leak management during VATS procedures.
One of the limitations of the present experiment is the
certain inevitable variation in the size of tested procine
lobes. To minimize this confounding feature, the lungs
were harvested from the pigs in almost the same weight.
As all lobes were fully inflated with a TVi of 400 ml, no
significant differences were noted in this regard. In
addition, the randomization of the application
techniques might also contribute in reducing this bias. The
authors recognize that the sealant applications were not
blinded for the assessment of air tightness and the
measurement of the lesion’s length in the present experiment.
I t may have resulted in information bias, which was
certainly minimized by randomization of the application
techniques. Finally, the observation bias might have
arisen due to the inevitable subjectiveness in the
judgment of air bubbles, even though it was performed by
two investigators independently. Nevertheless, the
statistic analysis revealed significant results in favor to the
application technique with silicone frame. We believe that
our investigation is a further step to improve the
application of fluid glue and useful to prevent prolonged
postoperative air leaks after lung resection. Future
efforts will need to be directed both towards assessing the
effectiveness of the frame-assisted application technique
in well designed clinical trails and towards examination
of absorbable materials as frame.
Our in vitro tests indicated that application by means of
the frame technique prevents glue run-off and improve
the sealing efficacy of BioGlue™. The implications of this
special application technique should be further analyzed
in well-designed, controlled clinical trials.
Additional file 1: Results of individual tests. (XLS 63 kb)
AAL: Alveolar air leak; PEEP: Positive end-expiratory pressure; Pmax: Maximal
inspiratory pressure; Pmean: Mean inspiratory pressure; Pplat: Plateau
inspiratory pressure; TVe: Expiratory tidal volume; TVi: Inspired tidal volume
The BioGlue™ samples used for this study were provided by CryoLife Europa,
Ltd.. Special thanks to Mr. Stefan Pingel for his support in this regard. We
also acknowledge support by Deutsche Forschungsgemeinschaft and Open
Access Publishing Fund of University of Tübingen.
Availability of data and materials
Please contact authors for data requests.
MB carried out the conception and design of the study, in vitro tests,
acquisition of data, analysis and interpretation of the data, statistical analysis
as well as drafting of the manuscript. PZ participated in acquisition, analysis
and interpretation of the data, critical revision of the manuscript and
supervision of the study. FL participated in histological examination. RZ
participated in the conception and design of the study, acquisition and
interpretation of the data, drafting and critical revision of the manuscript.
All authors read and approved the final manuscript.
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