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Ann Thorac Surg 2004;77:1792-1801
© 2004 The Society of Thoracic Surgeons
a Division of General Thoracic Surgery, Mayo Clinic, Rochester, Minnesota, USA
b Division of Cardiothoracic Surgery, University of Washington, Seattle, Washington, 3M Corporation, St. Paul, Minnesota, Duke University Medical Center, Durham, North Carolina, Cedars Sinai Medical Center, Los Angeles, California, and M.D. Anderson Cancer Center, Houston, Texas, USA
Accepted for publication October 10, 2003.
* Address reprint requests to Dr Allen, Division of General Thoracic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
e-mail: allen.mark{at}mayo.edu
Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.
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Abstract |
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METHODS: In a multicenter prospective randomized trial, 161 patients with a median age of 67 years old (range 18–85 years old), were randomized in a 2:1 ratio to receive sealant or control for at least one significant air leak (
2.0 mm in size) after pulmonary resection. In the sealant group, all significant air leaks underwent attempted repair by standard methods (sutures, staples, or cautery) prior to the application of sealant. The control group underwent only standard methods. Blood was analyzed for immunologic response. Patients were followed up 1 month after surgery.
RESULTS: Intraoperative air leaks were sealed in 77% of the sealant group compared with 16% in the control group (p < 0.001). The sealant group had significantly fewer patients with postoperative air leaks compared with the control group (65% vs 86%, p = 0.005). Median length of hospitalization was 6 days (range, 3–23 days) for the sealant group compared with 7 days (range 4–38 days) for controls (p = 0.028). There was no difference in mortality, morbidity, duration of chest tubes, or immune responses between the two groups.
CONCLUSIONS: This study demonstrates the effectiveness of a biodegradable polymer when used as an adjunct to standard closure methods for sealing significant intraoperative air leaks that develop from pulmonary surgery. Use of the sealant led to a reduction in postoperative air leaks, which may have decreased the length of hospitalization.
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Introduction |
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Various materials have been developed to seal the lung. Fibrin-based sealants have been reported to be ineffective in controlling air leaks by several authors [4–7]. "Bioglue" (Cryolife, Inc, Kennesaw, GA), a protein-based polymer that has been approved in Europe, but not in the United States, as a lung sealant may control air leaks. However, this product is inflexible and does not allow the lung to expand and contract. "FocalSeal-L" (Genzyme, Cambridge, MA), a relatively new product, is a synthetic material used to seal intraoperative air leaks. This product has been approved by the FDA for this indication and has been found to be effective, but is cumbersome to use because it requires application of several layers and light activation to polymerize. It has also been reported to potentially increase the rate of postoperative empyema [8, 9].
Recently, a new polymeric biodegradable sealant has been developed that does not require light for activation. The sealant is produced by combining a polyethylene-glycol-based cross linker, functionalized with succinate groups ([PEG-(SS)2]), with human serum albumin-USP just prior to usage (U.S. Patent No. 5583114). Once mixed, the sealant polymerizes to form a clear, flexible hydro-gel matrix that adheres to the lung tissue within 20 to 30 seconds. After application, the material forms a flexible seal over the surface of the air leak that can withstand 30 mm Hg air pressure within 2 minutes of application and a maximum burst pressure of greater than 90 mm Hg in less than 10 minutes. The polymer is biodegradable and is completely reabsorbed from the lung surface by 1 month after surgery [10, 11].
The purpose of this multiinstitutional randomized trial is to evaluate the safety and effectiveness of this new tissue sealant to seal air leaks caused by pulmonary surgery.
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Material and methods |
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2.0 mm in diameter) at the completion of the pulmonary resection. Exclusion criteria included pregnancy, breast feeding, known sensitivity to human albumin, participation in the National Emphysema Therapeutic Trial (NETT) or other trials not approved by the sponsor, or the presence of a significant clinical disease or condition that might complicate the surgery and make it difficult to evaluate the safety and effectiveness of the sealant. The study was performed at five academic institutions: Mayo Clinic, Rochester, MN; Duke University, Raleigh-Durham, NC; Cedar Sinai Medical Center, Los Angeles, CA; Washington University, Seattle, WA; and M. D. Anderson Cancer Center, Houston, TX. There were ten board-certified general thoracic surgeons who participated in the trial. Each investigator underwent training in preparation and use of the sealant prior to the start of the study.
The primary endpoint was the proportion of patients who remained air leak free following surgery through the 1-month follow-up period or duration of hospitalization, whichever was longer. The presence of air leaks during hospitalization was monitored by daily observation of the water seal chamber. Secondary measures of effectiveness included: the proportion of intraoperative air leaks in each group that were sealed or reduced as demonstrated by the air leak test prior to completion of surgery; the proportion of patients in each group that was free of air leaks immediately following surgery in the recovery room; duration of postoperative air leak (POAL); chest tube duration; and length of hospitalization.
The primary measure of safety was the incidence of adverse events related to the sealant that were reported during hospitalization and through the 1-month follow-up period. Changes in cellular and humoral immune response were monitored in the sealant and control patients. T-cell function was evaluated by lymphocyte proliferation assay (LPA) performed on blood samples drawn preoperatively and at 1-month follow-up [12–14]. To assess if there was a humoral response to sealant, an enzyme-linked immunoabsorbent assay (ELISA) was performed on serum collected preoperatively and at 1-month follow-up [15–17].
This was an open-label, randomized (2:1), stratified, controlled multicenter trial. The required sample size was 156 patients. It was anticipated that 220 patients needed to be enrolled in order to randomize 174 patients who met the final intraoperative criteria for air leaks. Extra patients were enrolled to account for patients who were lost to follow-up or discontinued the study. Randomization was stratified by percent predicted preoperative forced expiratory volume in 1 second (FEV1%), separating patients with FEV1% greater than 40% from those with FEV1% equal to or less than 40% [18]. Separate randomizations were prepared for each surgeon.
Only patients who met initial eligibility requirements and were found to have at least one IOAL, with a bubble size equal to or greater than 2.0 mm, were randomized. After all pulmonary resections were completed, air leaks were identified by filling the chest cavity with saline, submerging the lung and inflating to 20 to 25 cm H2O pressure and looking for air bubbles. If a patient met the IOAL criteria ( 2.0-mm bubbles), air leaks were attempted to be closed with standard methods of air leak closure, such as suturing and stapling. After standard methods had been applied, the patients were then randomized to either no further treatment (control) or application of sealant (sealant). Patients randomized to control had already had sutures and/or staples used in an attempt to control their IOAL and proceeded directly to the second air leak test; no other sealants were used. Patients randomized to sealant had up to three applications of sealant placed on each air leak. Sealant was not applied prophylactically to areas of the lung that were not leaking air at the time of surgery. After application of the sealant to each of the identified air leaks, ventilation to the treated lung was suspended for 2 minutes to allow the sealant to reach its optimal strength and then the second leak test was performed after all air leaks had been attempted to be sealed. If air leaks were observed in either group after the second leak test, investigators were permitted to use additional surgical techniques (ie, pleural tent, phrenic nerve crush) to control the pleural space (Fig 1).
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Chest tubes were placed on 20 to 25 cm H2O suction for 24 hours, after which they were placed to H2O seal at the discretion of each investigator. Chest tubes were removed when the following occurred: there was no air leak; the lung had expanded sufficiently, or in the investigator's opinion, there was no significant increase in the size of a pneumothorax that would prevent removal; and drainage was less than 5.0 mL/kg per 24 hours or less than 2.5 mL/kg per 12 hours [19]. Duration of POAL was measured from the day of surgery until the postoperative day when an air leak was no longer observed. Air leaks were assessed by qualified hospital staff, including investigators, nurse study coordinators, physician assistants, and residents. If there were multiple readings at a designated air leak assessment time and a discrepancy was observed between readings, the investigator's assessment was utilized. Chest roentgenograms were obtained preoperatively, within 6 hours of surgery, within 24 hours prior to and after chest tube removal; and at 1-month follow-up. After chest tube removal, all patients were monitored for clinical evidence of a pneumothorax or empyema.
Some patients who had a prolonged air leak were discharged from the hospital with the chest tube connected to a Heimlich valve [20]. When this occurred, the patient was asked to return weekly for air leak assessment until the chest tube was removed. Chest tube duration was measured from the day of surgery to the day the last chest tube was removed.
Patients were followed up at 1 month and questioned about complications since discharge from the hospital. They also had a physical exam, chest roentgenogram, immunologic testing (LPA and ELISA), and blood tests including complete blood count, platelet count, blood urea nitrogen, creatinine, alkaline phosphatase, and serum glutaminate amino transferase.
The sample size was based on a 2:1 randomization scheme, statistical power of 80%, and two-sided alpha level of 0.05 to detect a 25% difference in the proportion of patients with postoperative air leaks. The sample size was sufficient to obtain information regarding relative incidence of adverse event rates in both groups. The demographics and clinical characteristics were compared using Wilcoxon rank sum tests for continuous variables and Fisher's exact tests for categoric responses [21, 22]. The portion of patients without a postoperative air leak in each group was compared using a logistical model for binary outcomes. Stepwise logistic regression analysis was performed to identify and adjust for any differences in prognostic variables and to assess the association with the probability of success in preventing POAL. Secondary endpoints were compared by Wilcoxon rank sum tests and Fisher's exact tests. The incidence of complications between sealant and control groups was compared using the Fisher's Exact tests. Changes in laboratory tests and vital signs were analyzed for within group differences using Wilcoxon signed-rank tests and for between group differences using Wilcoxon rank sum tests. To compare results of the LPA test for cell-mediated immunity and ELISA tests for serum antibodies between the sealant and control group, 95% confidence limits were established based on results obtained from control patients. Postsurgical tests results for sealant and control were compared to these limits to identify any positive responses to either assay. A p value of 0.05 or less was considered statistically significant.
This study was conducted in compliance with the United States Code of Federal Regulations (CFR), 21 CFR Part 812, Investigational Device Exemptions, Part 56, Institutional Review Boards, Part 50, Protection of Human Subjects, and the ethical principles that have their origin in the Declaration of Helsinki. Institutional review boards at each institution approved the study prior to initiation of the study. Informed consent was obtained in writing from all patients.
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Results |
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Investigators required only one application of sealant to close most air leaks. For each air leak closure attempted, a single application of sealant was used in 125 (59.5%) of the IOAL, two applications for 70 (33.3%), three applications for 9 (4.3%), and was not specified for 4 (1.9%) of the IOAL. In 1 patient, the investigator deviated from the protocol and did not attempt to close two of the three air leaks with sealant. The median application time was 2 minutes per application and 6 minutes per patient for all air leaks. The median volume of sealant used was 4 mL/patient. No patient had additional methods used to control air leaks after the second leak test.
Primary endpoint
The percent of patients who remained leak free following surgery through the 1-month follow-up was 35% (36/103) in the sealant group compared with 14% (8/58) in the control group. This statistically significant difference (p = 0.005) was observed at all five investigating sites and ranged from 21% to 54% in the sealant group and ranged from 0% to 25% for the control group (Fig 3).
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The size of the air leak was associated with the sealant's ability to seal it. For air leaks equal to or less than 5.0 mm, 84% (128/152) were sealed compared with 17% (12/71) in the controls. For air leaks greater than 5.0 mm, 58% (33/57) were stopped by sealant compared with only 14% (5/37) in the control group. The source of air leak also affected the percentage sealed (Table 4). An air leak from a torn lung was the least likely to be sealed.
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Late air leaks (those that first appeared on or after postoperative day 2) occurred in 8% of patients (8/103) in the sealant group and in 2% of patients (1/58) in the control group. This difference was not statistically significant (p = 0.151). The incidence of prolonged air leaks (> 7 days) was not different between the two groups: 14% (14/103) in sealant patients compared with 12% (7/58) in the control group (p = 0.813).
The duration of chest tube drainage was similar in both groups. The sealant group had their chest tube in for a median of 6.8 days (range 2–42 days), whereas the control group had a chest tube in for a median of 6.2 days (range 3–22, p = 0.679). Similarly, cumulative drainage from the chest tube did not differ significantly between the two groups. The median total cumulative drainage was 960 mL for patients in the sealant group and 1360 mL in the control group (p = 0.117).
The median length of hospitalization was shorter for patients in the sealant group. Median hospitalization for the sealant group was 6 days, whereas for the control it was 7 days. This difference was statistically significant (p = 0.028). If patients who died during their hospitalization are included as censored observations, the difference remained statistically significant (p = 0.04). There were 27 patients who were hospitalized greater than 10 days, 14/103 (14%) in the sealant group and 13/58 (22%) in the control group. Prolonged air leaks that resulted in hospitalization greater than 10 days occurred in 5 patients (5%) in the sealant group and in 2 patients (3%) in the control group (p = 1.000).
The frequency of adverse events was similar in the sealant and control groups. Most of the common adverse events were anticipated problems that normally occur after pulmonary resection, including fever, nausea, confusion, constipation and dyspnea, and were generally of mild to moderate severity. Atrial fibrillation occurred in 11.7% of the sealant patients and 12.2% of the control patients (p = 1.000). There was no statistical difference in the frequency of any adverse event between the two groups; although, there was a higher incidence of pneumonia in the control group (12%) than in the sealant group (5%). None of the complications were thought to be related to the sealant. No patient developed an empyema, and only 1 patient required a chest tube for a recurrent pneumothorax. This patient had previously been treated with radiation therapy, chemotherapy, and underwent a redo thoracotomy to resect metastatic osteogenic sarcoma. Multiple air leaks were present, and application of sealant decreased the size of the leak but did not stop them completely. The patient was discharged from the hospital on postoperative day 4 but developed a pneumothorax requiring a chest tube on postoperative day 20.
Operative mortality was 4.9% (5/103) in the sealant group, and it was 6.9% (4/58) in the control group (p = 0.723). None of the deaths were considered related to use of the sealant. The cause of death in 5 patients in the sealant group was adult respiratory distress syndrome in 3, pneumonia in 1 and pulmonary embolism in 1. In the control group, the cause of death was cardiac arrhythmia in 2 patients, pneumonia and anoxic brain injury in 1 patient each.
There were no significant differences between the two groups when comparing laboratory values at any period during the study (ie, preoperative, at discharge or at the 1 month follow-up). There were no significant changes observed between control and sealant patients in either their humoral or cellular immune response to the sealant as detected by ELISA and LPA, respectively, indicating the lack of immune response to the sealant. One patient in each group had a postoperative ELISA consistent with the formation of sealant antibodies; however, in each patient, the preoperative serum also revealed a high value, indicating that their serum contained antibodies that cross-reacted with the sealant and that the high postoperative values were not related to sealant exposure.
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Comment |
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This sealant is less complicated to use than others currently available [23]. No heating, stirring or priming is required, nor is a supplemental light source necessary to activate the polymerization process. The materials are easily assembled from the sterile kit and can be applied to the surface of the lung to seal air leaks within a few minutes of opening the kit. Our trial revealed that it only took a median of 6 minutes per patient to significantly reduce or eliminate air leaks. The material can be applied to any surface of the lung, but is easier when the surface is level to minimize runoff. The sealant can be applied to the lung next to the pulmonary artery without fear of damage.
The sealant has also been demonstrated to be safe. With the exception of the pneumothorax that occurred 20 days postoperatively, there were no adverse events that were considered to be related to the sealant and the incidence of adverse events between the two groups was similar. We did not see any immune response from the product, although we did exclude patients with known prior sensitivity to human albumin. No patient developed an empyema. Porte and colleagues [9] reported that 4 of 59 patients who received Advaseal (Ethicon, Somerville, NJ), a synthetic surgical lung sealant, developed infections in the pleural space and a chest tube was required for drainage. In study by Wain and coworkers [8] using FocalSeal-L (Genzyme, Cambridge, MA), they reported four empyemas in 125 patients treated. This was not a statistically significant increase over the control group. The mechanism for these empyemas is unknown, but the polyethylene-glycol-based product may trap bacteria and lead to a higher incidence of empyema. Because the sealant we used is completely reabsorbed within 30 days, we do not feel we missed any late empyemas that may have developed. Although the sealant contains a human blood component, it is derived from plasma collected according to methods specified by the FDA and is FDA licensed. These methods have been designed to minimize the risk of transmitting the hepatitis or human immunodeficiency virus (HIV) and other blood-born pathogens. The product is sterile, which further reduces the risk of microbial contamination.
Our study design differed from other randomized trials [8, 9] because we did not include patients without significant intraoperative air leaks. Furthermore, we did not apply sealant to potential sites of air leaks prophylactically, but rather only to areas that were leaking air. Thus, our rate of 35% for completely eliminating postoperative air leaks only includes patients who had significant ( 2.0 mm) IOAL. In Wain and coworkers' report [8], 24% of the treatment group had no IOAL, yet only 39% of treated patients remained leak free until hospital discharge. In 72 patients of our sealant group who had their IOAL sealed, 31 patients (43%) remained sealed throughout the 1-month follow-up. The differences in the rates between the two studies are difficult to compare because of the differences in study design.
Most of the air leaks we treated resulted from dissection in the fissures between the lungs. The sealant was most effective sealing an air leak from this location. We were able to seal 81.4% of leaks that originated from the fissures. Success was less in other areas, especially when the leak was from a tear in the lung. The leaks from a torn lung tended to be larger that other types of leaks. Although we could not prove it statistically, larger leaks did seem to be more difficult to seal, as would be expected.
Our data demonstrated a shorter hospitalization for patients who had sealant applied compared with controls. However, we did not observe any difference in chest tube duration. These two seemingly incongruous findings may be because patients with air leaks are usually kept in the hospital for observation another day after the chest tube is removed, whereas if the chest tube is kept in just for high drainage, patients can be sent home immediately after removal of the chest tube. Another explanation for this finding may be that more Heimlich valves were used in sealant patients (10%) than controls (2%), even though this difference was not statistically significant. Patients who were discharged with a Heimlich valve in place were seen every week, so their chest tube may have stayed in well after the air leaked stopped, compared with an in-patient who would typically have their chest tube removed the day after the air leak stopped. Another explanation may be that our measurement was not sensitive enough because we only measured chest tube duration by days and not by hours. It is possible that a difference in chest tube removal could have been found if the actual time of chest tube removal had been measured. To clearly answer this question another study should be performed with length of stay as the primary endpoint.
This study took place at several institutions, which introduced the potential for different standards of care. Although efforts were made to standardize procedures at all sites, bias may have persisted. The randomization by surgeon should have minimized these difficulties. The study was not blinded because it is not possible to spray a control substance on the lung that would be indistinguishable from the sealant. Even though it was not possible to blind the surgeons to the test material, specific chest tube management criteria were established prior to enrollment to minimize the potential for bias in patient care practices. In addition, all patients were randomized after standard methods of air leak closure had been applied to eliminate the potential for any bias that may have been introduced when applying standard methods of air leak closure had the investigator known that patient would be receiving the sealant.
The ideal sealant to stop air leaks from the lung should be easy to apply, bond rapidly, and adhere sufficiently to withstand the pressure of forceful coughing and breathing, yet allow the lung to expand and contract while adhering to the visceral pleura. The material must be nontoxic and easily biodegradable. Finally, it must not be too expensive to manufacture. The ideal sealant does not exist; however, the sealant examined in this study seems to have some desirable properties. It is nontoxic and relatively easy to apply. It adheres to the lung well, yet remains flexible to allow the lung to expand. Although effective in controlling air leaks, the sealant is not perfect. We await further enhancements in material technology to develop the perfect sealant.
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Discussion |
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DR ALLEN: As I mentioned in the beginning, this product is currently undergoing FDA review, and it has to go through a final FDA review. Hopefully, it will be available sometime around the time of the AATS meeting or the early summer this coming year.
DR LESLIE KOHMAN (Syracuse, NY): If your chest tube duration was not different and your length of stay was a day shorter in the sealant group, how can you explain that, and if the air leak was really short, how come the chest tubes all stayed in for 6 days? Does this stuff cause more drainage or were people reluctant to take out the tubes when there was still a fair amount of drainage? Your 5 cc/kg for 24 hours is roughly equivalent to what Dr Cerfolio recommends, but might be more than many people are comfortable with.
DR ALLEN: I think the discrepancy between the length of time the chest tubes are left in and the days in the hospital comes from the fact that we only measured the day the chest tube came out. We did not keep track of the number of hours the chest tube was in. So maybe our measurement was not sensitive enough to pick up a difference in the two groups.
I do not really have an explanation as to why the chest tubes were left in so long, but when you take the control versus the sealant there is almost absolutely no difference between the two groups. So it is hard to imagine that sealant would cause some sort of excess drainage from the chest tube.
DR JEAN DESLAURIERS (St. Foy, Quebec, Canada): Mark, do you consider that this study is a positive study, based only on duration of hospitalization? If you consider the amount of money that this product is likely to cost, do you consider that we have gained something?
I have the other two questions. The first one is, how do you measure a 2-mm air leak? I would think that it would be difficult to differentiate between a 1.5-mm and a 2-mm size air leak when there is bubbling from many sites.
Secondly, you said there were no significant differences in complications, but I thought that I noted more pneumonia in the sealant group than in the control group. I have always thought these products may, in some way, prevent lung reexpansion and perhaps it is a factor contributing to higher incidence of pneumonias.
DR ALLEN: I think the question whether this study is positive or negative goes to the way that the trial was set up. What we were looking for is to see what proportion of patients were air leak free through their entire follow-up course. We had a positive result. I think most of the investigators would say that in the operating room when you spray this material on an air leak, it stops the air leak. It does not work all the time, it is not perfect, and, as you can see from the data, there are still a fair number of people who have an air leak. So, it cannot stop all the air leaks, but it does a good job of closing those air leaks that develop into fissure when you do a lobectomy.
To measure the air leak size, we did a dunk test. We filled the chest with saline, and then the anesthesiologist would inflate the lung and we'd look for bubbles. We did our best to try to estimate the size of the bubbles. We did not want to use the sealant on insignificant little air leaks, so we chose 2.0 mm as the minimum size. We then graded the sizes of the air leaks as best we could.
There was no statistically significant difference in the incidence of pneumonia in the two groups. The sealant does not constrict the lungs. It is a very pliable membrane that is formed, and it allows the lung to expand and contract with ventilation.
DR RICHARD FEINS (Rochester, NY): Mark, at least one of the other products that purports to do this same thing does leave an abnormality on the x-ray until the material resorbs. Does this product do the same thing?
DR ALLEN: No, you cannot see it on x-ray at all. It is completely invisible on the x-ray.
DR CAMERON D. WRIGHT (Boston, MA): Nice presentation, Mark. As you know, we looked at another product as well, and it seems to me that this product has the same problem that that product has, namely that it does not work in a reliable fashion. We all want a completely reliable sealant, and the key slide I thought was the fact that the rate of sealing went down from 80% in the operating room (OR) to only about 40% in the recovery room, and thus the product is unreliable. You can't take out your chest tubes quickly because it doesn't 100% of the time seal your air leaks, and that seems to be the real problem with your product.
DR ALLEN: I agree. In the operating room, you put the sealant on the air leaks; you do not see any more air leaks but by the time you get to the recovery room, for whatever reason there are more air leaks. We would like something that you could put on the lung that would allowthe chest tubes to be taken out almost immediately.
DR DOUGLAS E. WOOD (Seattle, WA): Mark, if it's all right, I was going to make a comment about Jean's question, because certainly this study was not powered for secondary outcome measures. The study was powered for primary outcome measures. So this certainly warrants a larger study to see if whether this air leak benefit transmits to a shortened hospitalization, as is suggested, but I don't think one can rely on just this study.
And actually, the pneumonia incidence was the opposite of what was said. The incidence of pneumonia was higher in the control group, not in the sealant group. I don't want there to be a misunderstanding about that. It was the control group that had the higher incidence of pneumonia.
DR JOSEPH SHRAGER (Philadelphia, PA): Could I just raise one more practical problem which hasn't been raised? The problem I have with these devices or these materials are that you can't really tell intraoperatively what air leak is going to last 10 minutes and what air leak is going to last 10 days by just looking at it. At least I can't. So then you are left with the option of either putting this stuff on every patient you do, essentially, or putting it on none of them. I have opted not to use it on any of them, even though I have been at two centers that tested this sort of stuff, because to use it on all patients becomes exorbitantly expensive.
So what is really needed, I think, is some way to grade air leaks intraoperatively to know which ones are likely to persist, allowing us to decide which ones to use these products on. I don't think anybody has been able to come up with that yet, although Rob Cerfolio has taken a good stab at it. So after doing this study, is it your feeling you are going to use this product on all patients or no patients? I mean, you can't use this product on any patients right now, but theoretically if it were approved for clinical use?
DR ALLEN: I will use it on patients who have a defined number of air leaks in the operating room. In the redo patients who have thousands of air leaks, you cannot really spray multiple applications over the whole lung. However, in those patients who had a lobectomy and have had pulmonary functions, you have got a pretty good idea those are the ones who are at risk for a prolonged air leak, and I think those are the patients who will be helped. If it saves a couple of days in the hospital, it will clearly be cost effective. I agree, we still have to figure out where to use it and as we gain more experience, hopefully we will determine that.
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