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Lung volume reduction surgery in an emphysema model

Institution: University of California, Irvine
Investigator(s): Matthew Brenner, M.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0158 Award: $404,139
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Emphysema is a severe and debilitating lung disease that results from smoking cigarettes. Patients with emphysema suffer from destruction of the lung tissue with symptoms of severe shortness of breath. The symptoms can progress to complete debilitation and death. Medical treatment of emphysema has little affect on disease symptoms. Recently, new surgical techniques have been described to improve breathing function and symptoms in patients with severe emphysema. This surgery is called lung volume reduction surgery (LVRS). Animal studies are needed in order to improve LVRS surgery as well as to facilitate determining which patients should be treated with this procedure. We have developed an animal model of emphysema that is very similar to human emphysema. We have also developed LVRS surgical techniques and lung function measurement methods. We plan to study the ways of improving LVRS using this animal model.

LVRS improves lung function by reducing the size of over-inflated lungs that result from emphysema. The exact effects of the volume reduction surgery on lung function are not known, nor is it known how to determine the optimal amount of lung tissue to remove during surgery. We will try to answer the following questions in this study: 1) Is long -term improvement best if both sides are operated upon simultaneously, or would it be better to operate on one side, then operate on the other side at a later time when symptoms recur? 2) Is it better to perform a single incision in the middle of the chest, or is it better to use small videoscopes and make small cuts on both sides? 3) What type of lung disease is associated with the best response to treatment? 4) Is it better to use staples alone to reduce the size of the lung, or should staples and lasers be used together, 5) How much tissue should be removed at the time of surgery?

We will attempt to answer these questions by performing lung volume reduction surgery on rabbits with severe emphysema. We will measure their lung function before and after the surgery using the different techniques described. The findings from this study should help improve surgical treatment up for patients with severe emphysema. In addition, some patients with severe emphysema and lung cancer cannot be operated on to cure their cancers because their lung function is too poor. By improving lung function with LVRS, many of these patients could then undergo surgery to cure their lung cancer.

Final Report
Objectives: Emphysema is a devastating lung disease in which lung tissue degenerates. There is no effective medical treatment for more than 1 million patients suffering from emphysema. Surgical treatments for patients with emphysema using lung stapling or lasers have been described. These procedures have shown promise for treatment of severely disabled patients with emphysema in recent clinical trials and is the focus of an ongoing National Emphysema Treatment Trial (NETT). However, these procedures remain high risk, long term efficacy is unproven, and at the end of the NETT, optimal surgical techniques will remain undefined. There is presently no scientific method for studying optimal surgical treatment approaches other than clinical studies on patients. With funding from the TRDRP, we have been studying animal model methods with the goal of improving effectiveness of lung volume reduction surgery and providing models for future studies. We developed rabbit models of diffuse emphysema and began investigations with the following specific aims: 1) To demonstrate the value of rabbit models of emphysema for investigation of LVRS. 2) To determine relationships between volume of tissue removed and physiologic response in emphysema, and to use these relationships to develop intraoperative methods for determining the optimal extent of resection. 3) To determine the effects of tissue removal on airway conductance, lung elastic recoil, and upstream segment resistance. 4) To directly compare response from surgical volume reduction to mixed laser/staple volume reduction procedures.

Significant Findings from Work To Date: We focused on these first 4 specific aims through this study period. A number of important findings have resulted. Improved animal emphysema models with moderately severe emphysema were described. However, we continue to work toward development of more severe degrees of disease. With regard to the LVRS surgical procedures, identifiable peak response regions for surgical lung tissue volume removal were found. Unfavorable responses were seen with removal of too little or too much lung tissue, Certain physiologic variables (DLCO, pulmonary artery pressures, and cardiac output) tolerated smaller lung resection than other measures (peak flows, recoil). Therefore, improvements in one variable must be weighed against deterioration in other variables as increasing volumes of tissue are removed. There may be distinction between optimal and maximal (limiting) resections. Intraoperative pulmonary artery pressures and cardiac output measurements may serve as clinical indicators of maximal resection limits. We are continuing to investigate the potential value of PA pressure measurement enhancement with intraoperative inotropic stimulation. We are continuing rapid ventilatory stress measurements to detect rate related trapping of air in the lungs that may be indicator of optimal resection. We have shown that elastic recoil increases significantly, maximal flow increase, chest wall effects are minimal, and increased airway support is less significant than recoil effects. We have completed studies that appeared to show marginally increased benefit from combining laser and staple lung volume reduction procedures together compared to staple procedures alone. However, there are increased complications from the combined procedure that may outweigh the marginal benefits. Finally, we have been working with techniques to increase the severity of the emphysema in the model itself using multiple elastase exposures, pulmonary function based dosing regimens, and physiologic selection criteria analogous to those used in humans. These findings have been presented at conferences and have resulted in a number of presentations and publications.

Implications For Reducing Human and Economic Costs of Tobacco Related Disease In California: The findings from this study have already demonstrated important principles of what limits the amount of tissue that can be removed during LVRS, given some indications of potential methods for intraoperatively determining how much tissue to remove, and should improve surgical and laser lung treatment techniques for emphysema. We will continue these investigations with the support of a new 3 year CTRDRP renewal grant. The results of these studies should be directly beneficial to lung volume reduction in humans and this model should be widely applicable for future studies in this rapidly expanding field. Such advances may provide significant relief for patients with severe tobacco related emphysema in California and elsewhere.
Publications

Intraoperative cardiac output may predict survival with Staple Lung Volume Reduction surgery in rabbit emphysema model
Periodical: Surgical Forum Index Medicus:
Authors: Serna D, Powell LL, Brenner M, McKenna R, Fischel R, Chen JC ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Volume Reduction Surgery in severe emphysema
Periodical: Surgical Forum Index Medicus:
Authors: Powell LL, Serna D, Brenner M, et al ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Pulmonary vascular resistance increased after lung volume reduction surgery in rabbits with more severe emphysema
Periodical: Journal of Surgical Research Index Medicus:
Authors: Powell LL, Serna D, Brenner M, et al ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Compliance and FRC after staple vs. combine stape/free-beam Holmium Laser lung reduction surgery in a rabbin emphysema model
Periodical: Annals of Thoracic Surgery Index Medicus:
Authors: Serna D, Powell LL, Brenner M, et al ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Diffusing capacity limitations of the extent of lung volum reduction surgery in an animal model of emphysema
Periodical: Journal of Thoracic and Cardiovascular Surgery Index Medicus:
Authors: Chen JC, Serna DL, Powell LL, et al ART
Yr: 1999 Vol: 117 Nbr: Abs: Pg: 728-735

Effect of lung volume reduction surgery on pulmonary diffusing capacity in a rabbit model of emphysema
Periodical: Journal of Surgical Research Index Medicus:
Authors: Chen J, Brenner M, Huh J, et al ART
Yr: 1998 Vol: 78 Nbr: Abs: Pg: 155-160

The effect of lung volume reduction surgery in a rabbit model of bullous lung disease
Periodical: Journal of Investigative Surgery Index Medicus:
Authors: Brenner M, Kafie F, Yoong B, et al ART
Yr: 1998 Vol: 11 Nbr: Abs: Pg: 281-288

Rate of FEV1 change following lung volume reduction surgery
Periodical: Chest Index Medicus:
Authors: Brenner M, McKenna RJ, Gelb RF, Fischel RJ, Wilson AF ART
Yr: 1998 Vol: 113 Nbr: Abs: Pg:

Changes in pulmonary physiology after lung volume reduction surgery in rabbits with moderate and severe emphysema
Periodical: Surgical Forum Index Medicus:
Authors: Powell LL, Serna D, Brenner M, et al ART
Yr: 1998 Vol: XLIX Nbr: Abs: Pg: 266-268

Changes in pulmonary physiology after lung volume reduction surgery in a rabbit model of obstructive diffuse emphysema
Periodical: Journal of Thoracic and Cardiovascular Surgery Index Medicus:
Authors: Huh J, Brenner M, Chen JC, et al ART
Yr: 1998 Vol: 115 Nbr: Abs: Pg: 328-335