| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1995;59:28-32
© 1995 The Society of Thoracic Surgeons
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Lung transplantation is emerging around the world as a treatment option for children with end-stage lung disease. Of particular interest is the performance of lung transplantation in infants with severe pulmonary hypoplasia [1]. Severe pulmonary hypoplasia in the neonatal period is secondary to congenital diaphragmatic hernia, oligohydramnios-induced pulmonary hypoplasia, or congenital cystic adenomatoid malformation of the lung. In infants with these malformations that result in severe pulmonary hypoplasia, there are currently no viable treatment options other than lung transplantation [2]. It has been speculated that lung transplantation may only be needed to serve as a temporary measure in infants with severe pulmonary hypoplasia due to congenital diaphragmatic hernia [3]. In these patients, the transplant would need to function only until the hypoplastic native lung has developed sufficiently to support respiratory function.
Rejection continues to be a major problem in patients who undergo lung transplantation, due to the high antigenicity of lung tissue. Lung transplants have been shown to be associated with more episodes of rejection than any other transplanted organ [4]. It is thought, however, that neonates who undergo transplantation have a distinct advantage over older patients in that they are victims of fewer rejection episodes and require less immunosuppression therapy [3]. Despite this immune privilege, pediatric patients with lung transplants are still subject to suffering acute and chronic rejection [5, 6]. A long-term immunosuppression regimen also has deleterious effects on the growing child.
It has been shown that survivors of diaphragmatic hernia experience nearly normal pulmonary function over time [7–10]. In the ideal scenario, the transplanted lung would function until the native lung grows, thus averting the adverse effects of long-term immunosuppression therapy. If a patient with severe pulmonary hypoplasia due to congenital diaphragmatic hernia undergoes transplantation, will the native lung develop normal function in the face of a immunosuppressed state and chronic rejection? This study was designed to answer this question by evaluating the development and function of the contralateral, native lung of an infant swine that has undergone lung transplantation and subsequent rejection of the transplanted lung.
|
Material and Methods |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Three animal groups were studied. The first was the control group (n = 4). These animals did not undergo transplantation and did not receive any immunosuppressive drugs. They were matched with the second group by age and size. The second group was the study group (n = 5). All study animals underwent left whole lung transplantation according to the method described previously by our group [14, 15]. The third group underwent unilateral pneumonectomy without transplantation.
All transplantations were performed by the same surgeons using a consistent surgical technique and method of preservation (ice-cold, heparinized physiologic normal saline solution). All animals, both recipients and donors, were of similar age (8 ± 0.5 weeks) and body weight (10.5 ± 0.8 kg).
Immunosuppression and Postoperative Care
On the day before transplantation, recipient animals received cyclosporine (18 mg • kg-1 • day-1, given orally; Sandoz Pharmaceutical, East Hanover, NJ), which was continued daily until sacrifice. The animals also received methylprednisolone (500 mg intravenously) at the time of transplantation and daily for 5 days, as well as azathioprine (1 mg/kg intravenously) at the time of transplantation and daily until sacrifice. Acute rejection was diagnosed when tachypnea, fever, lethargy, and dry cough occurred. These episodes were treated empirically with intramuscularly administered methylprednisolone (500 mg daily) for 3 days. Chest roentgenograms were obtained at 7 days and monthly thereafter. The 5 study animals all went on to suffer chronic rejection of the transplanted lung. At 10 months of age, both the control and study groups underwent evaluation of pulmonary hemodynamics, functional residual capacity, and airway mechanics under the same anesthetic. At the completion of these measurements, the lungs were harvested through a median sternotomy and weighed. A small piece of lung was excised from the posterior lower lobe in all the animals for calculation of the wet-to-dry lung weight ratio. The rest of the lung was preserved with 10% buffered formalin solution. The animals were euthanized with a lethal dose of pentobarbital.
Calculation of Pulmonary Vascular Resistance
The control and study group animals were anesthetized with ketamine (10 mg/kg) and intubated, and final chest roentgenograms were obtained. The animals were maintained with intermittently administered intravenous pentobarbital and ventilated mechanically (15 mL/kg tidal volume, 12 breaths/min, inspired oxygen fraction of 1.0). Carotid artery and pulmonary artery catheters were placed through a cutdown access to the carotid artery and internal jugular vein after a tracheostomy tube was inserted. Arterial and pulmonary arterial pressures were continuously transduced and cardiac outputs were measured in triplicate using a thermistor-tipped Swan-Ganz catheter. The pulmonary capillary wedge and left atrial pressures were also measured. The pulmonary vascular resistance (PVR) was calculated using the following formula: PVR = (mPAP - PCWP) 80/CO, where CO is the cardiac output, PCWP is the pulmonary capillary wedge pressure, and mPAP is the mean pulmonary artery pressure.
Calculation of Functional Residual Capacity
The left lungs in the control animals were isolated in vivo by placing intrabronchial balloon catheters, under bronchoscopic control, to occlude the left mainstem bronchus. The functional residual capacity of the right lung was then calculated using the helium dilution technique [16]. The functional residual capacities of the right lung were obtained in the study animals using the same technique, but without the need to isolate the left lung because of its absence, which was confirmed by bronchoscopic evaluation.
Calculation of Airway Mechanics
With the animals anesthetized and mechanically ventilated, as already described, airflow and transrespiratory pressure were measured at the tracheostomy tube using a Fleisch pneumotachometer (no. 2, linear to 3,000 mL/s with a dead space of 40 mL; OEM, Richmond, VA) and two differential pressure transducers (MP45-1; Validyne Engineering, Northridge, CA). The signals were digitized at a rate of 15 ms with a data acquisition system (AII Devices, San Rafael, CA) and stored on diskettes (Apple IIE; Apple Computers, Cupertino, CA). These instruments were calibrated immediately before every experiment.
Gas flow and transrespiratory pressure were recorded over ten ventilated breaths. Pressure-volume loops were constructed for each breath by hand-editing the three points of zero flow with a manual cursor and text editor. Dynamic pulmonary compliance was calculated as the slope of the line of best fit through the origin and apex of the pressure-volume relationship. In every case, this was reported as the mean of at least ten breaths with a breath-to-breath coefficient of variability of less than 10%. Dynamic airway resistance was calculated from measurements of the total (inspiratory and expiratory) pressure change at 50% tidal volume, divided by the absolute value of the flow at that volume.
Studies of Gas Exchange
Arterial blood for determination of the blood gas values was drawn from controls with the left hilar structures clamped. Arterial blood specimens were drawn from the study animals without the need for left hilar clamping because of the left pulmonary artery obliteration. Samples were analyzed by a blood gas instrument (model 158; Dow Corning).
Morphologic Analysis
At the end of the study, the right lungs of the control and study group animals were harvested after systemic heparinization had been carried out. The lungs were placed so as to allow dependent drainage of all intravascular fluid. The lungs were fixed with 10% buffered formalin that was instilled through the airways at a constant pressure of 25 cm H2O for 1 hour. The lungs were then immersed in the buffered formalin and tissue blocks were taken from the periphery. The most peripheral lung tissue was studied in all lungs because there the airway dimensions are more uniform and not subject to the effects of dichotomous branching. The tissue blocks were embedded in paraffin, and 5-µm sections were cut and stained with hematoxylin-eosin. The cross-sectional surface areas of at least 50 alveoli and 25 noncartilaginous airways per lung were measured by tracing the alveoli and airway perimeters on a video monitor with a manual cursor (Zeiss Orthoplan; Carl Zeiss, Thornwood, NY). The values were then calculated by a software program on a computer (International Business Machines). These measurements were obtained by a person blinded as to whether the lung specimen was from a control or a study animal. Mean cross-sectional airway and alveolar areas were determined for each lung, and consequently for each group.
Statistical Analysis
All values are reported as the mean ± standard error of the mean. Student's t test was used to compare paired samples. A p value of less than or equal to 0.05 was taken to indicate significant difference between the values.
|
Results |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Lung Volumes and Airway Mechanics
The functional residual capacity and dynamic airway compliance and resistance values are shown in Table 1
. There was no statistically significant difference between the study group animals and the control animals in terms of these values.
|
. There was a statistically significant increase in the pulmonary vascular resistance in the study animals. The arterial oxygen tension in the study animals was also significantly higher than that in the control animals. However, there were no significant differences in the cardiac outputs between the study and control animals throughout the terminal period of the study.
|
Morphologic Findings
The cross-sectional areas of alveoli and noncartilaginous airways are given in Table 3. The sample size of the study group in this table is 4 because one of the lungs was found to be inadequately preserved. The lungs had no gross evidence of emphysema. The histologic specimens also did not exhibit signs of emphysema. Histologic examination of the chronically rejected lung remnants revealed evidence of fibrotic tissue with no recognizable alveoli, airways, or vasculature. There was also no evidence of infection in the rejected lungs.
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Functional residual capacity (the volume of the lung at the end of normal respiration) is a gross measure of functional lung volume, and it tended to be higher in the study animals. Although this difference was not statistically significant, it does suggest a degree of compensatory functional growth. Although the peripheral vascular resistance was significantly greater in the study animals, the airway resistance was not, nor was the native lungs' ability to oxygenate blood impaired. The native right lung of the study animals was clearly able to oxygenate the blood better than the right lung of the controls with the left hilar structures clamped.
The significant increase in the dry lung weight of the study animals represents convincing evidence that the native left lung experienced compensatory growth. This increase in weight was not due to an increase in the extravascular water content, given that the wet-to-dry weight ratios did not differ between the study and control lungs. Another indication of compensatory growth in our study animals was the significantly greater cross-sectional surface areas of the alveoli and terminal airways.
Shortcomings of this model need to be mentioned. First, the findings yielded by animal studies are difficult to extrapolate to the human setting. Therefore, correlative clinical studies must be conducted for this purpose. Second, the native right lung of the animals receiving transplants has no degree of pulmonary hypoplasia. Because of this, it was thought that this lung at the time of transplantation could support the animal by itself. For this reason, we performed left lung pneumonectomies in four 8-week-old pigs, resulting in a mortality of 75% shortly after extubation. The death that occurred in the pneumonectomy controls was prevented by left lung transplantation in the study animals. An additional pitfall of our study is the small sample size permitted in this resource intensive experiment. A small sample size limits our certainty regarding the magnitude of the difference seen between groups and values. In addition, the absence of significance may not accurately indicate that there are no clinically important differences.
Lung transplantation in neonates with severe lung hypoplasia is an option for infants who otherwise would have no chance at survival. A lung transplant may only be needed as a bridge to allow the native lung time to develop and function by itself. Our data support the hypothesis that the development and function of the native contralateral lung may be nearly normal, even in the face of chronic rejection of the transplanted lung and an immunosuppressed state.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Address reprint requests to Dr Kron, Department of Surgery, University of Virginia Health Sciences Center, Box 181-95, Charlottesville, VA 22908.
|
References |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. Lee, E. N. Mendeloff, C. Huddleston, S. C. Sweet, and M. de la Morena Bilateral lung transplantation for pulmonary hypoplasia caused by congenital diaphragmatic hernia J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 295 - 297. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
