Ann Thorac Surg 2003;75:1587-1592
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Fibrin glue in pulmonary resection: a prospective, randomized, blinded study
Thomas Fabian, MDa,
John A. Federico, MDa,
Ronald B. Ponn, MDa*
a Department of Surgery, The Hospital of St. Raphael, New Haven, Connecticut, USA
Accepted for publication December 4, 2002.
* Address reprint requests to Dr Ponn, General Thoracic Surgeons of CT, 330 Orchard St, New Haven, CT 06511, USA.
e-mail: rbponn{at}aol.com
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Abstract
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BACKGROUND: In contrast to the rare large-airway bronchopleural fistulas after lung resection, peripheral or alveolar air leaks (AAL) are very common, often prolong hospital stay, increase utilization of resources, and on occasion result in significant morbidity. Various adjuncts have been used in attempts to reduce AAL. One of these, the topical application of fibrin glue, has to date failed to demonstrate efficacy in small clinical trials. This study reexamines the role of fibrin glue in routine lobar and wedge pulmonary resections.
METHODS: Of 113 patients enrolled, 13 became ineligible because of intraoperative findings. The remaining 100 patients were randomly assigned to one of two groups at the conclusion of lung resection, regardless of the presence or absence of identifiable air leak. The control group received no additional intervention. The experimental group underwent application of 5 mL of fibrin glue delivered by a pressurized, aerosolized spraying mechanism. Postoperatively a blinded clinical observer recorded outcomes including the incidence and duration of AAL, prolonged AAL (PAAL), the volume of pleural drainage, the time to tube removal, and the postoperative length of stay (LOS), as well as any complications related to treatment.
RESULTS: Both groups were comparable with regard to demographics, diagnoses, and procedures. Statistically significant reductions were found in the experimental group in the overall incidence of AAL (34% versus 68%, p = 0.001), mean duration of AAL (1.1 versus 3.1 days, p = 0.005), mean time to chest tube removal (3.5 versus 5.0 days, p = 0.02), and the incidence of PAAL (2% versus 16%, p = 0.015). There was no significant difference in the volume of chest tube drainage or LOS (4.6 days glue and 4.9 days control, p = 0.318). There were no complications related to the use of fibrin glue.
CONCLUSIONS: Aerosolized fibrin glue appears to be safe and effective in reducing AAL. The overall incidence of AAL was reduced by 50% and PAAL occurred in only 1 treated patient (2% versus the usually reported 15%). Further studies with this and other methods are required to delineate routine versus selective use, to compare methods, and clarify cost benefit.
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Introduction
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Alveolar air leak (AAL) after pulmonary resection may be associated with an increase in morbidity and a prolonged length of hospital stay. Although most leaks seal within a few days, prolonged AAL represents at the very least a nuisance to both the patient and the thoracic surgeon and increases the utilization of inpatient and outpatient resources. Many methods of minimizing this complication have been tried with mixed results. Despite the use of various techniques the overall incidence of AAL remains higher than 60% in the early postoperative period and prolonged alveolar air leak (PAAL), defined as air leaks lasting more than 7 days, occur in more than 15% of patients and may increase hospital length of stay (LOS) by more than 5 days [1].
The primary approach to AAL is based on careful surgical technique and the liberal use of stapling devices when dealing with fissures. With the goal of further reducing this problem, newer approaches have been described. The use of waterseal rather than suction may reduce the duration of AAL [2, 3]. Buttressing of staple lines with bovine pericardial strips or polytetrafluoroethylene sleeves achieved popularity in dealing with the rarified parenchymal tissue of patients undergoing lung volume reduction surgery and has also been applied to routine lobectomy [4–6]. Direct sealants in the form of fibrin glue [7, 8], synthetic gels and polymers [9–11], and adherent patches [12] have also been tested.
Fibrin glue simulates the final step in the clotting cascade. This sealant consists of two components usually derived from human donors—a concentrate of fibrinogen and other procoagulants reconstituted in aprotinin solution and a thrombin-calcium solution. The two components are mixed at the time of application by various delivery systems. Because of variable reported results using fibrin glue to lessen AAL, the present study was designed to evaluate its efficacy when delivered with a simple fine mist, pressurized aerosol system.
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Material and methods
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The study was approved by the Human Investigation Committee of our institution. Patients undergoing planned open anatomic resection or wedge resection were eligible for enrollment. Prospectively thoracoscopic resections, lung biopsies in immunocompromised patients and others with diffuse lung disease (most of whom fell into the thoracoscopic group), and operations on women of pregnancy age were not included. Enrolled study patients were excluded intraoperatively when the resection was extended to pneumonectomy or sleeve resection or when no resection was performed. There were no exclusion criteria based on clinical stage, medical history, laboratory data, or pulmonary function. Patients were invited to participate after explanation of the purpose and potential risks and benefits and were required to sign informed consent.
All procedures were performed by residents under the direct supervision of one of two thoracic surgeons. All resections were carried out using standard dissection and stapling techniques. At the conclusion of the resection patients were randomly assigned in the operating room to control or treatment groups in a 1:1 ratio, regardless of identifiable air leak, by opening a sealed envelope. Patients assigned to the control group underwent no additional interventions. Patients assigned to the experimental group were treated with an application of 5 mL of fibrin glue using the HemaMyst system (Hemacure Corporation, Sarasota, FL). This device provides a fine aerosolized mist spray of fibrin glue under pressure (Fig 1).
Application is controlled by a foot pedal and can be stopped and restarted without the problem of the glue congealing. This method allows precise coverage of large surfaces using small amounts of glue components. After pleural irrigation the lung was partially reinflated. Raw and stapled lung surfaces were sprayed with a portion of the fibrin glue. The quantity was left to the surgeon’s discretion. This spray was followed by the application of fibrin glue to the mediastinal lymph node bed when applicable and then spraying the remainder of fibrin glue on the dissected or stapled lung and bronchial stump. The lung was then left unventilated until completion of placement of the paracostal sutures. One or two chest drains were placed according to the surgeon’s standard practice. Preparation of the glue components was accomplished in about 5 minutes. Mist application took 1 minute or less.
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Fig 1. HemaMyst fibrin glue application system. Pressure control (upper left); foot pedal (upper right); syringe system (lower left) to which catheters of various lengths can be attached for glue application; fine mist spray (lower right) from pressurized system.
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All pleural drains were connected to -20 cm suction in the initial postoperative period. Upon arrival in the recovery room each patient was assessed by the blinded observer for the presence or absence of air leak and the volume of chest tube drainage. A repeat assessment was performed 4 hours later. During the subsequent 48 hours the blinded observer recorded these data every 8 hours. Thereafter the same observer recorded the presence or absence of air leak each morning until the chest tube was removed. The duration the chest tube was in place and the length of hospital stay were also recorded. Overall management was not determined by the study protocol. Conversion to waterseal versus suction, timing of tube removal, placement of Heimlich (Becton Dickinson, Franklin Lakes, NJ) or Pneumostat (Atrium Medical, Nashua, NH) valves, and discharge of patients with valved tubes in place were determined by our usual practice. For study purposes patients discharged with valves were followed up until the time of outpatient chest tube removal.
The data were analyzed using the software Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL) system. Quantitative variables were analyzed using a Student’s t test. Qualitative variables were evaluated with the 
2 test and Fisher’s exact test.
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Results
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During a 1-year period (January to December 2001) 187 patients were eligible for enrollment, 113 of whom agreed to participate. The most common reason for not participating was concern about the informed consent clause that noted the potential for blood-born disease transmission. Thirteen enrolled patients were withdrawn intraoperatively because of extension to pneumonectomy or bronchoplastic lobectomy [11] or because of nonresective thoracotomy [2]. This left 50 patients randomized to the control group and 50 to the experimental group. The two groups were comparable in age, sex, comorbidity, smoking history, procedure, and diagnosis (Table 1).
Table 2
summarizes the outcome data. The 68% overall incidence of AAL in the control group was significantly higher than the 34% incidence in the fibrin glue cohort (p = 0.001). The mean duration of air leak in the control group (3.1 days, range, 0 to 19) was significantly (p = 0.005) higher than that of the fibrin glue patients (1.1 days, range, 0 to 10). Chest tubes were removed earlier in patients treated with glue (postoperative day 3.5 versus 5.0, p = 0.02). Most importantly, the incidence of PAAL was significantly lower in the treated patients than in the control group, 2% versus 16% (p = 0.015). Table 3
summarizes the clinical details of the PAAL cases. The incidence of PAAL in the control group is similar to that reported in the literature [1] whereas PAAL occurred in only 1 of 50 fibrin glue patients. The duration of PAAL ranged from 8 to 19 days in the untreated patients and was 10 days in the single fibrin glue case.
No significant differences between groups were noted in the volume of chest tube drainage, the proportion of patients discharged with chest tubes and valves in place, or the mean postoperative hospital LOS (control 4.9 days, fibrin glue 4.6). With respect to general clinical course, there was no operative mortality. All patients were extubated in the operating room. No patient required blood transfusion. Two patients in the experimental group had chest tubes replaced after removal. No patients in the control group required reinsertion. Of the 2 patients requiring reinsertion, 1 chest tube was replaced due to acute respiratory distress shortly after chest tube removal. After insertion no air leak was noted and the patient was diagnosed by computed tomography with a pulmonary embolism. The second patient required tube reinsertion in the office for a persistent symptomatic apical air space 3 days after initial removal. The drain was removed 4 days later. One patient in the control group required placement of a Pleurx catheter (Denver Biomedical, Denver, CO) on postoperative day 13 for unexplained, nonchylous persistently high volume drainage. The Pleurx catheter was removed in the office 8 days later. No patients had empyema or wound infections.
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Comment
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Peripheral AAL is much more common and less ominous than bronchial stump fistulas. With the exception of very large AAL or association with a significant residual postresection space, most AAL are benign and resolve with time and appropriate drain management. Placement of additional drains and various means of pleurodesis may be required on occasion. The need for repeat operation, however, is vanishingly small. Nonetheless the frequency of AAL makes them a clinical issue because of prolongation of hospital stay, patient discomfort and anxiety, increased utilization of inpatient and outpatient resources, and occasional septic or respiratory problems. Although it has been shown that many patients with AAL can be discharged with vented tubes [13, 14] many surgeons have not adopted this approach. Therefore methods to decrease the incidence of AAL and especially PAAL are worthy of investigation and comparison. Overall AAL occurs in a majority of cases, 60% or more, and PAAL in 15% to 25%. Risk factors for PAAL have variably been reported to include male sex, postoperative pneumothorax/space, severe emphysema, incomplete fissures, and upper lobectomy [1, 18]. Prolonged AAL is often the only morbidity associated with lung resection and the only reason for prolonged LOS [18].
Postoperative measures to limit the duration of AAL include early conversion to waterseal [2, 3], instillation of talc or other sclerosing/sealing agent including autologous blood [15] through the chest drains, endobronchial occlusion of small feeding airways [16], and thoracoscopic application of fibrin glue [17]. Adjunctive intraoperative maneuvers include space reduction by formation of an apical pleural "tent" [19], induction of pneumoperitoneum [20], diaphragmatic relocation [21], electrocautery or laser [22] on lung parenchyma, staple line buttressing [4–6], and the application of topical agents.
Among topical agents, recent attention has focused on synthetic bioresorbable systems [10, 11, 23]. Table 4 summarizes recent reports. The sealant is a water-soluble polyethylene glycol gel and is applied in a three-step process. First a primer is applied, followed by the sealant. Photopolymerization is accomplished with a xenon light wand. Marchiarini and associates [23] reported a study in pigs in which sealant was successful in closing parenchymal staple lines and bronchial stumps. They followed this with a randomized clinical series that included 15 sealant patients and 11 controls. All intraoperative leaks were sealed in the treatment group versus in only 18% of controls. Some treatment patients developed leaks subsequently but the overall leak-free postoperative course was significantly higher with sealant use (77% versus 9%). Time to tube removal and LOS were not different. There was one empyema in the treated patients, necessitating completion pneumonectomy. Wain and associates [11] reported a favorable experience with this method in a four-center randomized trial including 172 patients. They noted a significant difference in the absence of AAL at the conclusion of operation in favor of the sealant group (92% versus 29% control). Despite the development of AAL at some point postoperatively in a high proportion of sealant patients, the overall incidence of AAL was significantly less in the treated group (61% versus 89% control). The mean duration of AAL was also less in the sealant cohort. There was, however, no significant difference in the time to chest tube removal or in postoperative LOS. Alveolar air leak persisted at 7 days in 2.5% of treated cases and 7% of controls. Porte and associates [10] also reported a randomized trial. In contrast to the previous series, only patients with AAL at the conclusion of lobectomy were included. There were 59 treatment patients and 61 controls. There was a significant decrease in intraoperative AAL after sealant application (38.5% versus 59.9% control), percentage of patients free of air leak at 4 days (87.2% versus 58.5%control), and mean time to last observable AAL (33.7 versus 63.2 hours control). Alveolar air leak at day 6 did not differ significantly, however, and was quite high (86.9% sealant versus 78% control) nor was there a shorter LOS. Empyema with drainage of infected sealant was noted in 4 patients and benign space problems were seen in more of the treated cases. Although the authors suggest that sealant may act as a foreign body leading to infection, the differences were not statistically significant. This series is difficult to evaluate because of an unusual practice of removing all chest tubes on postoperative day 6 regardless of the presence or absence of AAL. Also a very high proportion of patients required additional drainage after tube removal (12 of 59 sealant, 13 of 61 control). Other sealants showing promise in animal models include a biologic hydrogel glue [9] and collagen membrane polyglycolic acid patches [12].
There is greater experience with fibrin glue. Fibrin glue has been shown experimentally to increase closure line strength and to reduce air leaks [24, 25]. Several nonrandomized series have also suggested efficacy in clinical use [26–28]. We are aware of only two previous randomized human trials in pulmonary surgery reported in the English literature. Both studies failed to show benefit in either routine [8] or selective [7] use. In addition, Porte and associates [10] refer to a randomized clinical study that they reported in the French literature that showed no benefit. Fleisher and associates [8] randomized 28 lobectomies over a 7-month period, 14 controls and 14 treated with 2 mL of fibrin glue using a two-syringe system, regardless of the presence or absence of AAL. They found similar duration of AAL (mean, 3.2 days for glue versus 3.3 for controls) and time to tube removal (mean, 6.0 days fibrin glue versus 5.9 days controls). Also the mean LOS was equally long in both groups (9.8 days for glue and 11.5 for controls). Wong and Goldstraw [7] randomized 66 patients judged to have a moderate to severe intraoperative AAL and used 5 mL of glue. There was no difference in the duration of air leak (mean, 4 days control and 5 days glue), time to drain removal (mean, 6 days for both), and LOS (9 and 8 days, respectively, for control and glue patients).
The present study represents the largest randomized trial of fibrin glue in pulmonary resection and is the only trial using a blinded observer. Our finding of reduced incidence of AAL and PAAL as well as earlier time to drain removal in treated patients, in contrast to earlier studies, may be related to the amount of product applied and to the method of application. We used 5 mL in all cases. In addition we believe that the pressurized mist system is superior to the two-syringe technique in which manual pressure is the sole driving force. The pressurized system yields a fine spray that allows precise application of a smooth layer of glue to the target areas. The ability to stop and resume the application without congealing of the components is a great advantage that allows application of additional layers where deemed necessary. Although postoperative LOS was comparable between the two groups, our LOS represents one of the shortest reported in the literature. We agree with Cerfolio [29] questioning why LOS remains high despite shorter duration of air leak achieved by various approaches.
A potential shortcoming of our series is that decisions regarding tube management and patient discharge were not set by the study protocol and were not blinded to the attending surgeons. It may be argued, however, that this is a better means of evaluating sealants than a strict protocol that changes routine patterns of care. The main area in which this issue might bias the results is in the recording of time to cessation of air leak and tube removal in patients discharged with valves; there were only 9 such cases and they were seen at least every third day. Another criticism might be that the degree of AAL was not quantified [29]. However, AAL quantification is not at present the standard of care, remains unproven in terms of clinical decision-making and its introduction in this experience would be a change in our current practice pattern, thus adding another variable.
A general concern with fibrin glue is transmission of blood-borne diseases. We are not aware of any instances of this problem. One recent study [30] showed 20% transmission of human parvovirus B19, a usually innocuous virus but a potential pathogen in immunocompromised hosts. The use of a rapidly prepared autologous fibrin glue, reported experimentally [31], would address this issue.
In summary we report a randomized experience using aerosolized fibrin glue in lung resection. The method is simple and effective. Further studies with synthetic sealants, patches, fibrin glue, and autologous agents are needed. In addition to efficacy, cost analysis will have to be assessed. Although LOS is an important factor in cost, use of outpatient resources also plays a role. As we found no difference in drainage, a lesser quantity of glue applied only to lung parenchyma may reduce cost. The cost of fibrin glue varies between $70 and $90 per cc. Routine versus selective use of glue also needs clarification. We have begun a randomized study confined to patients with intraoperative AAL.Table 4
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Abstract
Introduction
