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Ann Thorac Surg 2002;73:1727-1731
© 2002 The Society of Thoracic Surgeons


Original article: general thoracic

Predictors and treatment of persistent air leaks

Robert J. Cerfolio, MD, FACS*a, Cynthia Sale Bass, CRNPa, Amanda Harrison Pask, RNa, Charles R. Katholi, PhDa

a Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA

* Address reprint requests to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd, THT 712, Birmingham, AL 35294, USA
e-mail: Robert.cerfolio{at}ccc.uab.edu

Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8–10, 2001.


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
Background. Air leaks prolong hospital stay.

Methods. A prospective algorithm was applied to patients. If patients were ready for discharge but still had an air leak, a Heimlich valve was placed and they were discharged. If the leak was still present after 2 weeks, the tube was clamped for a day and removed.

Results. There were 669 patients. Factors that predicted a persistent air leak were FEV1% of less than 79% (p = 0.006), history of steroid use (p = 0.002), male gender (p = 0.05), and having a lobectomy (p = 0.01). Types of air leaks on day 1 that eventually required a Heimlich valve were expiratory leaks (p = 0.02), leaks that were an expiratory 4 or more (p < 0.0001), and the presence of a pneumothorax concomitant with an air leak (p < 0.0001). Thirty-three patients were placed on a Heimlich valve, and 6 patients had a pneumothorax or subcutaneous emphysema develop; all patients had an expiratory 5 leak or larger (p < 0.0001). Thirty-three patients went home on a valve. Seventeen patients had leaks that resolved by 1 week, 6 by 2 weeks, and the remaining 9 had their tubes removed without problems.

Conclusions. Steroid use, male gender, a large leak, a leak with a pneumothorax, and having a lobectomy are all risk factors for a persistent leak. Discharge on a Heimlich valve is safe and effective for patients with a persistent leak unless the leak is an expiratory 5 or more. Once home on a valve, most air leaks will seal in 2 weeks; if not, chest tubes can be safely removed regardless of the size of the leak or the presence of a pneumothorax.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
Air leaks continue to be the most common complication after pulmonary resection. In this article, predictors and a type of treatment for air leaks is evaluated. Previous randomized trials [1, 2] have shown that water seal is not only safe for patients with air leaks, but it is also superior to wall suction for stopping air leaks. However, despite the use of early water seal and a whole host of intraoperative techniques to help prevent air leaks, many patients still come out of the operating room with leaks. Even more frustrating is the fact that a significant number of these patients have persistent leaks. It is difficult to predict who these patients will be. In this article, risk factors for having a persistent air leak are identified. The results of a prospective algorithm to treat the problem of persistent air leaks are presented.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
Since January 1, 1999, an algorithm was applied to all patients who underwent elective pulmonary resections. All patients had routine preoperative evaluations before undergoing operations. This included pulmonary function testing, arterial blood gas, computed tomographic scan of the chest, positron emission tomographic scan, complete history, physical examination, and other appropriate tests. Patients who had lung cancer underwent either segmentectomy or lobectomy. Metastasectomy was performed by wedge resection if possible. If needed, however, segmentectomy or lobectomy was performed. Patients with lung cancer had complete thoracic lymphadenectomy.

Before chest closure, warm water was instilled in the chest. The lung was re-inflated and air leaks were pinpointed and sutured. Postoperatively, a previously described classification for air leaks was used [1, 2]. This classification system determines whether air leaks are expiratory, forced expiratory, inspiratory, or continuous. The type of leak is determined by asking the patient to take deep breaths in and out. If there is an air leak seen in the air leak meter, which is housed within the drainage system and used on all patients in this trial (Sahara S-1100 Pleur-evac Chest Drainage System; Genzyme Biosurgical, Cambridge, MA), then its size is determined. Leaks are measured from 1 (the smallest) to 7 (the largest). Patients’ air leaks were scored daily on rounds by the surgeon in this series (RJC) and by his primary clinical nurse practitioner (CSB).

Algorithm chest tube management
Chest tubes were managed as previously described [3]. In general, patients who underwent lobectomy received two chest tubes and those who had segmentectomy or wedge resection received one. All patients had their chest tubes placed on -20 cm of suction on the day of the operation. The tubes were converted to water seal on the morning of postoperative day (POD) 1. Patients remained on water seal unless they had an enlarging pneumothorax develop that was symptomatic or an enlarging subcutaneous emphysema develop. Pneumothoraces without subcutaneous emphysema were observed unless the patient became symptomatic with documentation of hypoxia. Hypoxia was defined as a consistent decrease in oxygen saturation by pulse oximeter of at least 5%. One chest tube was taken out on POD 2, and the last tube was taken out on POD 3 if the drainage was less than 450 mL, and if there was no air leak. If the patient had an air leak, only one chest tube was removed before POD 4. The tube that had the larger air leak was left in, and the other tube was removed; this technique is called serial chest tube clamping. If the patient had an air leak that was still present on the morning of POD 4, it was defined as a persistent air leak. The remaining chest tube was placed to a Heimlich valve. Patients and their families had Heimlich valve teaching on POD 4. The patient was then observed in the hospital for 24 hours. If by the morning of POD 5 there was no new or enlarging pneumothorax, or new subcutaneous emphysema by chest roentgenogram or physical exam, the patient was discharged. Patients were discharged with the Heimlich valve attached to a Foley leg bag with several holes cut in the top of the bag [4]. This allows air to escape and prevents fluids from spilling onto the patient’s clothing.

Once discharged, patients were then managed as outpatients. They were placed on Keflex (Cephalexin, Lily, Indianapolis, IN) while the chest tube was present. They were instructed on how to check and see if they still had a leak. The bag was taken off the Heimlich valve and the end of the valve was placed in a cup of water. Deep coughs were given. If the leak was gone, the tube was removed. If the leak continued, patients informed us.

If patients still had an air leak after 2 weeks, they returned to the clinic. In the clinic, air leaks were again reevaluated by submerging the end of the Heimlich valve under a cup of water. If a bubble was present with expiration or with a cough, the patient was admitted into the hospital that day and a clamp was placed on their chest tube. Chest roentgenograms were performed in the clinic before clamping, and the next morning after being clamped for a minimum of 12 hours. If the chest roentgenogram showed no new or expanding pneumothorax, or no new subcutaneous emphysema from the previous day, the chest tube was removed. Tubes were removed irrespective of the size of the leak or the presence of a pneumothorax.

All data are reported with median and ranges. Bi-variable comparisons were made using a Kruskal-Wallis test or a {chi}2 test, or both, with a Fisher’s exact test if needed. Multivariable analysis was performed using logistic regressions.


    Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
There were 669 patients with 410 men (66%). Five hundred fifty three patients (83%) had a significant past medical history. Sixty-seven patients (10%) had a past medical history consistent with insulin-dependent diabetes, 40 patients (6%) had a history of steroid use of more than 10 mg of prednisone per day for at least 4 weeks before the operation, and 48 patients (8%) had a past surgical history of a previous ipsilateral thoracotomy. Types of pulmonary resections were wedge resection in 337 patients (50%), segmentectomy in 24 (4%), and lobectomy in 308 (46%). The percentage of patients with air leaks on each POD is shown in Figure 1.



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Fig 1. Percentage of patients with air leaks on each postoperative day (POD).

 
Multivariable analysis was performed in an attempt to identify predictors of having an air leak on POD 4. Variables were analyzed including patient demographics (such as gender and age), past medical history (such as medicines, previous operations, previous illnesses, syndromes, or conditions), and operative findings and techniques (such as presence of adhesion, types of fissures, types of resection). Statistically significant variables found to be predictors of having a persistent leak were a forced expiratory volume 1% of less than 79 (p = 0.006), a maximum voluntary ventilation percent of less than 75 (p = 0.01), a history of steroid use (p = 0.002), male gender (p = 0.05), and having a lobectomy (p = 0.01). A lobectomy was also found to be an independent predictor of having a persistent leak (p = 0.001). Interestingly, the type of the air leak also predicted the need for a Heimlich valve. Air leaks on POD 1 that eventually required a Heimlich valve were expiratory leaks (p = 0.02), air leaks that scored an expiratory 4 or more (p < 0.0001), and the presence of a pneumothorax concomitant with an air leak (p < 0.0001).

As shown in Figure 1, 55 patients (8%) had an air leak on POD 4. All were placed on a Heimlich valve. Twenty-two patients’ air leaks resolved by the next day, which left 33 patients (5%; 27 men, 6 women) who still had an air leak. Not all tolerated the Heimlich valve initially. Six patients had a pneumothorax or enlarging subcutaneous emphysema develop. Subcutaneous emphysema was heralded by a change in voice in 3 patients. All of these patients had a higher pitched voice, and all had expiratory air leaks that were five or more on the classification system. They were returned to a drainage system with underwater seal and a chest roentgenogram was performed. In 2 of these 6 patients, water seal was enough to eliminate the pneumothorax or the subcutaneous emphysema, or both. However, in 4 patients suction was required. In 2 patients, -10 cm of suction was enough to relieve the pneumothorax or subcutaneous emphysema, or both. Two patients required -20 cm of suction to relieve the problem. All patients were then eventually placed back onto a Heimlich valve when air leakage was less then an expiratory 4. These 6 patients were all eventually discharged on the Heimlich valve by POD 11.

Results on Heimlich valve at home
Thirty-three total patients were eventually discharged home with the Heimlich valve. After 1 week at home on a Heimlich valve, 17 patients’ air leaks resolved. By 2 weeks, 6 more patient’s air leaks had resolved. One patient’s chest tube was removed accidentally when it got caught in a car door, and she suffered no sequela when it came out. The remaining 9 patients still had an air leak despite being home on a Heimlich valve for 2 weeks. All of these patients returned to the clinic, had the air leak confirmed, and were then readmitted to the hospital. They underwent provocative chest tube clamping [1, 2] as previously described. All 9 patients tolerated clamping. None had subcutaneous emphysema develop, and none had any change in their morning chest roentgenogram the next day. All had their chest tubes removed. The first 5 patients in this series were watched in the hospital for 24 hours and went home the next day. The remaining 4 patients went home that day.

Significant complications occurred in only the 1 patient who accidentally caught his chest tube in the car door; his chest tube was removed. He had had the tube in for 12 days. He tolerated this without any sequela, despite the fact that he had an air leak when he checked it earlier that day. However, 22 of the 33 patients related that the tube and Heimlich valve were "bothersome." Complaints by survey included leaking of fluid around the chest tube site, the chest tube pulling on their skin, and disruption of normal sleep patterns. Follow-up was completed in all 9 patients with a median duration of 7 months (range, 4 months–2 years). None had an air leak or a pneumothorax on follow-up chest roentgenogram develop.


    Comment
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
In this review, several predictors for the development of a persistent air leak were identified. These included patient characteristics consistent with poor wound healing, such as the preoperative use of steroids. Other patient characteristics were pulmonary function tests consistent with emphysema, such as a low FEV1% and a low maximum voluntary ventilation percent. These findings were not surprising and are consistent with other reports. Abolhoda and colleagues [5] showed that a forced expiratory volume in 1 second/forced vital capacity ratio of less than 50% was associated with prolonged air leaks and Brunelli and colleagues [6] described the association of air leaks with a low FEV1%. However, some previously identified risk factors that were not statistically significant in our series included preoperative radiation, preoperative chemotherapy, the DLCO%, a previous ipsilateral thoracotomy, the presence of adhesions, the status of fissures, or the type of lobectomy. These results may be due to some intraoperative techniques that were used in this series, such as the use of fissure-less operations.

Lobectomy was more likely to cause a persistent air leak than a wedge resection or a segmentectomy. This is probably because of the fact that there is more pulmonary parenchyma resected with a lobectomy, and hence there is a smaller chance for apposition of the visceral pleura and parietal pleura.

If a surgeon has a preoperative awareness that a patient is at increased risk of having a persistent air leak, the surgeon may be able to take extra measures during the operation to help prevent them. These measures might include the use of buttressed stapled lines with bovine pericardium (Bio-Vascular Dry Peri-Strips, Minneapolis, MN) [7], the use of pleural tents for upper lobectomy [8], the use of pneumoperitoneum after lower lobectomy [9], and the use of Focal Seal (Genzyme, Biosurgery, Cambridge, MA) [11]. Future research is needed to help determine if these measures are cost effective, safe, and useful, and if so, in which patients.

Despite all of these new techniques and careful intraoperative inspection for leaks before closing, 5% of patients still have an air leak by the time they are ready for discharge. A Heimlich valve seems to be a safe and effective tool that allows patients to go home with a leak. However, it cannot be used on everyone. If the air leak is larger than an expiratory 5, the patient will most likely have a pneumothorax or new subcutaneous emphysema develop, oftentimes heralded by a high-pitched voice. If this occurs, the patient should be reconnected to a drainage system with an underwater seal. If the pneumothorax or subcutaneous air is still present on water seal, then the least amount of suction needed to return the patient to his previous state before the Heimlich valve should be applied. The Heimlich valve will be successful later when the air leak is less than an expiratory 5.

Once discharged, the Heimlich valve is fairly well tolerated by most patients with few complications. Although there were no empyemas in this series, we have experienced 2 patients who did have this problem develop. For this reason, we prefer to use oral antibiotics while the patient has the chest tube in place. There are no data to support this practice, but it is our preference. Despite the overall excellent results, and the high-resolution rate of air leaks at home on a Heimlich valve, the indwelling tube and drainage system is annoying to many patients. As Wain and colleagues [10] stated, the Heimlich valve may be great for the surgeon (because the patient is discharged home), but it may not be so great for the patient. Therefore, the best treatment for air leaks remains to be prevention. Yet, when given the choice, most patients are thrilled to have the valve because it allows them to go home.

Once home, most leaks will stop on the Heimlich valve. For those patients who continue to have an air leak even after being home for 2 weeks on a Heimlich valve, their chest tubes can be safely removed. This is true even if the patient also has a pneumothorax. It seems unusual to remove a chest tube when there is a leak [11] and a concomitant pneumothorax, but in patients who have had a thoracotomy, a pulmonary resection, and have been home on a Heimlich valve for 2 weeks, it seems very safe. This technique, first described by Kirshner [12] in 1992, seems to be clinically true irrespective of the size of the air leak and irrespective of the size of the pneumothorax. It probably works because pleural adhesions form, which compartmentalize the pleural space. These adhesions probably prevent the lung from collapsing further and prevent a tension pneumothorax. Although the lung is still leaking, the air introduced into the pleural space with each breath or cough does not seem to collapse the rest of the lung and seems to be of no sequela.

In conclusion, several factors seem to predict a persistent air leak; these include patient factors such as being a male, having poor pulmonary function tests, and other characteristics that predict or are associated with poor wound healing. A lobectomy is more likely to lead to a persistent air leak than a wedge resection or a segmentectomy. The classification system for air leaks previously described is extremely useful clinically. It allows one to predict the natural history of air leaks. When a patient has an air leak that is an expiratory 4 on POD 1, it will not seal by POD 4 irrespective of chest tube management. Armed with this information, one is able to warn patients and their families early in their hospital care. They can receive early education and preparation for going home on the Heimlich valve. This helps the surgeon provide a better product for the patient. Air leaks that are an expiratory 5 or more will fail a Heimlich valve.

Once patients are successfully converted to a Heimlich valve (successful being defined as the nondevelopment of a new or enlarging pneumothorax or subcutaneous emphysema), they can be discharged home. The chest tube and valve are safe at home, and the method is effective in sealing persistent air leaks as an outpatient. However, the chest tube, Heimlich valve, and drainage system is bothersome to most patients. If air leaks persist after 2 weeks on a Heimlich valve, the chest tube can be removed irrespective of the size of the air leak or irrespective of the presence of a pneumothorax.


    Discussion
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 
DR THOMAS D’AMICO (Durham, NC): We should all be grateful to you for spending so much time and effort in providing evidence about a very important daily management issue that is practiced so empirically, I am sure, across the country, and to provide some data about what to do and when to do it. I share your enthusiasm about using water seal in virtually every patient, but I do not use Heimlich valves very often. I have three specific questions for you regarding your excellent series.

Number 1: In patients that I operate on, especially thoracoscopic lobectomy patients with a forced expiratory volume in one second (FEV1) of less than 35%, and in all the lung volume reductions, I create a pleural tent, and my impression is that it has improved the hospital stay; and it is rare to see a patient with thoracoscopic lobectomy or lung volume reduction stay longer than a week now due to air leaks. I wonder if you have any experience with either open or thoracoscopic pleural tents for the patients that you have identified as high risk?

Number 2: I know you mentioned it in the introduction, but what is the diagnostic breakdown for your wedge resections, because they did comprise approximately 50% of your series.

Last, perhaps you could share with us how you discern whether air coming out of the air leak chamber is a true air leak or whether it is a space that is an ex-vacuo pneumothorax, or does that even matter to you in your algorithm and your staging system?

Once again, I am sure your father is proud to have his name used in this staging system, and I enjoyed your article.

DR CERFOLIO: I appreciate your kind comments. I will take your questions in reverse order, because the question about the air leak is critical. There are times when a fellow resident or medical students—and we teach this classification system to them all literally in a few minutes as new members are always joining our team every week or so (it is so user friendly and very easy to learn)—the resident may say "I see an E1 leak," but my nurse practitioner Cyndi, who has seen thousands of these, will go by and she will report an E2 or an E3. Or there are times they say they see an FEV1, a forced expiratory of 1, and really what they are seeing is a little residual bubble. When you go to seal quickly on postoperative day 1 like I do, patients can have a little bit of air left in their residual space. When you ask them to cough, the first cough may yield a little bubble that goes through the air leak meter, but then with subsequent deep coughing it will not. This is not an air leak.

We are extremely rigid in how we define this. We have them take their biggest breath in and their biggest breath out. If there is no cough, they then take deep coughs to rule out a forced expiratory. There are patients with no leak who have a fixed space problem (a pneumothorax that will not resolve despite patent functioning chest tubes on high suction—the lung will just not expand to fill the entire pleural space). Fixed spaces like these are very common. I get the tubes out if there are no air leaks. These spaces do not get infected. They fill with fluid. We do not treat the patients with antibiotics, we send them home. The quicker you get your tube out the less likely you are to iatrogenically infect it. It will fill up with noninfected fluid if you just get the tubes out. However, if they have an air leak and a pneumothorax, that is a problem because the critical element for healing of leaks—apposition of the visceral and parietal pleural—is lacking.

That leads me to your first question, the use of pleural tents. I divide the pleural space into two different compartments (one is superior and the other is inferior). I treat the inferior space with a pneumoperitoneum. It is important to note that I do this open. Several surgeons have called me about this and have had problems with air embolism because they have done it with a Veres needle. We make a small 1–2 cm incision in the diaphragm; make sure we see the liver so no air is put into the liver; put a red rubber catheter in. We published an article on that after bilobectomy and presented it at the AATS a few years ago. It showed decreased air leaks and length of stay.

Pleural tents help control the superior or upper pleural space. I do use them routinely in lung volume reduction. I have tried to critically look at that and decide when it is actually needed. It adds some time (10 minutes) to the procedure and it can bleed afterwards. I do not think the routine patient who undergoes upper lobectomy needs one. I try to measure the space after the lung is re-inflated. If there is 5 cm between the fully inflated lower lobe or middle lobe (after an upper lobectomy) and the apical chest wall, and I did not have to go extra-pleurally to resect the tumor, then I perform a pleural tent. I have not been able to prove that this is right or wrong. It has been very hard for me to try to bring science to that particular issue, but I think a pleural tent is great when it looks like you are going to have a space problem and if you have residual leaks that you cannot stop. If there are no leaks and the patient has no risk factors to develop a leak after the operating room, then I do not do one.

Your second question was about the diagnoses of the patients who underwent wedge resection. They were all done for metastasectomy. We don’t do wedge resection for lung cancer. Even the patient with an FEV 1% and a DLCO% that starts off less than 20% can undergo a segmentectomy. I believe it is a better operation. We do preoperative rehabilitation, incentive spirometry teaching, etc, prior to surgery. I do not have the exact breakdown of each cell type, but basically they were done for renal cell carcinoma, colon cancer, breast cancer, sarcoma, and the least were for melanoma.

DR TODD DEMMY (Columbia, MO): A lot of my questions were already discussed except for one. How does chest tube position in these patients influence the air leak? If you put a position chest tube high in a residual apical space after upper lobectomy, you are more likely to have a "bladder phenomenon" where a patient can cough and simulate an air leak. Do you do anything special with your chest tube position at the end of your thoracotomy to minimize this?

DR CERFOLIO: We place the tubes in the apex of the chest. We are very rigid because we are studying it, and I will give a quick answer. For upper lobes we put in two tubes, one anterior and one posterior, but all the way in the apex. I cut a hole, a small hole so the tube does not kink, in the posterior tube in its most inferior part for drainage. For middle lobes I place one chest tube in the apex, and for lower lobes we place two tubes. A right angle chest tube in the posterior-inferior position and another tube all the way up in the apex. I think it is critical for every operation to have an anterior chest tube that goes all the way up into the apex, and it seems to control the space very, very well. I am unaware of this "bladder phenomenon" that you mentioned, except for what I said earlier about residual. Perhaps you are describing what we call a "momentum swing" in their air leak chamber. This means with each breath in and out the fluid in the air leak reservoir seems to swing into the air leak chamber. This simulates a leak in some rare patients. If you add more fluid to the chamber, you can tell if they have a real leak or not. Thank you.


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Discussion
 References
 

  1. Cerfolio R.J., Tummala R.P., Holman W.L., et al. A prospective algorithm for the management of air leaks after pulmonary resection. Ann Thorac Surg 1998;66:1726-1731.[Abstract/Free Full Text]
  2. Cerfolio R.J., Bass C., Katholi C.R. A prospective randomized trial compares suction versus water seal for air leaks. Ann Thorac Surg 2001;71:1613-1617.[Abstract/Free Full Text]
  3. Cerfolio R.J., Pickens A., Bass C., Katholi C.R. Fast tracking pulmonary resection. J Thorac Cardiovasc Surg 2001;122:318-324.[Abstract/Free Full Text]
  4. Cerfolio R.J. A new portable chest drainage device. Ann Thorac Surg 2000;69:998-1001.[Abstract/Free Full Text]
  5. Albolhoda A., Liu D., Brooks A., et al. Prolonged air leaks following radical upper lobectomy: an analysis of incidence and possible risk factors. Chest 1998;113:1507-1510.[Abstract/Free Full Text]
  6. Brunelli A., Al Refai M., Muti M., et al. Pleural tent after upper lobectomy: a prospective randomized study. Ann Thorac Surg 2000;69:1722-1724.[Abstract/Free Full Text]
  7. Miller J.I., Landreneau R.J., Wright C.E., et al. A comparative study of buttressed versus nonbuttressed staple line in pulmonary resections. Ann Thorac Surg 2001;71:319-323.[Abstract/Free Full Text]
  8. Okur E., Kir A., Halezeroglu S., et al. A pleural tenting following upper lobectomies or bilobectomies of the lung to prevent residual space and prolonged air leak. Eur J Cardiothoracic Surg 2001:1012-1015.
  9. Cerfolio R.J., Holman W.L., Katholil C.R. Pneumoperitoneum after concomitant resection of the right middle and lower lobes (bilobectomy). Ann Thorac Surg 2000;70:942-947.[Abstract/Free Full Text]
  10. Wain J.C., Kaiser L.R., Johnstone D.W., et al. Trial of a novel synthetic sealant in preventing air leaks after lung resection. Ann Thorac Surg 2001;71:1623-1629.[Abstract/Free Full Text]
  11. Kato R., Kobayahi T., Watanabe M., et al. Can the chest tube draining the pleural cavity with persistent air leakage be removed?. Thorac Cardiovasc Surg 1992;40:292-296.[Medline]
  12. Kirshner P.A. Provacative clamping and removal of chest tubes despite persistent air leak. Ann Thorac Surg 1992;53:740-741.[Medline]



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