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Ann Thorac Surg 1997;63:1398-1404
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Low-Dose Sodium Nitroprusside Reduces Pulmonary Reperfusion Injury

Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia

	Abstract

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
Background. Reperfusion injury is a significant cause of early allograft dysfunction after lung transplantation. We hypothesized that direct pulmonary arterial infusion of an intravascular nitric oxide donor, sodium nitroprusside (SNP), would ameliorate pulmonary reperfusion injury more effectively than inhaled nitric oxide without causing profound systemic hypotension.

Methods. Using an isolated, ventilated, whole-blood-perfused rabbit lung model, we studied the effects of both inhaled and intravascular nitric oxide during lung reperfusion. Group I (control) lungs (New Zealand White rabbits, 3 to 3.5 kg) were harvested en bloc, flushed with Euro-Collins solution, and then stored inflated for 18 hours at 4°C. Lungs were then reperfused with whole blood and ventilated with 60% oxygen for 30 minutes. Groups II, III, and IV received pulmonary arterial infusions of SNP at 0.2, 1.0, and 5.0 µg•kg^-1•min^-1, respectively, whereas group V was ventilated with 60% oxygen and nitric oxide at 80 ppm during reperfusion.

Results. Pulmonary arterial infusions of SNP even at 0.2 µg•kg^-1•min^-1 (group II) showed significant improvements in pulmonary artery pressure (31.35 ± 0.8 versus 40.37 ± 3.3 mm Hg; p < 0.05) and pulmonary vascular resistance (38,946 ± 1,269 versus 52,727 ± 3,421 dynes•s/cm^-5; p < 0.05) when compared with control (group I) lungs after 30 minutes of reperfusion. Infusions of SNP at 1.0 µg•kg^-1•min^-1 (group III) showed additional significant improvements in dynamic airway compliance (1.98 ± 0.10 versus 1.46 ± 0.02 mL/mm Hg; p < 0.05), venous-arterial oxygenation gradient (116.00 ± 24.4 versus 34.43 ± 2.5 mm Hg; p < 0.05), and wet-to-dry ratio (6.9 ± 0.9 versus 9.1 ± 2.2; p < 0.05) when compared with control (group I) lungs. Lungs that received inhaled nitric oxide at 80 ppm (group V) were significantly more compliant (1.82 ± 0.13 versus 1.46 ± 0.02 mL/mm Hg; p < 0.05) than control (group I) lungs.

Conclusions. Pulmonary arterial infusion of low-dose SNP during lung reperfusion significantly improves pulmonary hemodynamics, oxygenation, compliance, and edema formation. These effects were achieved at doses of SNP that did not cause profound systemic hypotension. Direct intravascular infusion of SNP via pulmonary arterial catheters could potentially abate reperfusion injury immediately after allograft implantation.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
See also page 1404.

Pulmonary transplantation remains the definitive therapy for selected patients with end-stage lung disease. Despite its relative clinical success, lung transplantation numbers have plateaued in recent years due to inadequate donor organ availability and an incomplete understanding of pulmonary ischemia-reperfusion injury. Only 10% to 25% of multiorgan donors have lungs that are thought to be suitable for donation [1, 2]. Of these, as many as 20% of transplanted pulmonary allografts will experience severe graft dysfunction immediately after implantation [3]. Iatrogenic volume overload, inapparent preimplantation donor allograft injury, and inadequate organ preservation all contribute to subsequent pulmonary ischemia-reperfusion injury and early allograft dysfunction. Pharmacologic and biologic manipulations aimed at limiting pulmonary ischemia-reperfusion injury would not only optimize early allograft function, but could possibly allow for the salvage of otherwise "marginal" organs.

The exact cellular and biochemical mechanisms contributing to pulmonary ischemia-reperfusion injury are becoming better understood. It is apparent that the process of pulmonary ischemia-reperfusion injury is multifactorial [4]. Neutrophil [5–7] and cytokine [8, 9] mediated cellular injury are believed to play an important role in pulmonary allograft dysfunction. Likewise, the importance of adequate vascular endothelial cell [10, 11] and type II pneumocyte [12–14] preservation has been demonstrated. Recent attention has focused on the importance of maintaining the metabolic integrity of the vascular endothelium and its ability to produce nitric oxide (NO), otherwise known as endothelium-derived relaxing factor.

Nitric oxide production by the pulmonary vascular endothelium is believed to play a critical role in preserving pulmonary vascular hemodynamics and gas exchange. Nitric oxide is produced from the conversion of L-arginine to L-citrulline by a constitutive isoform of nitric oxide synthase, ecNOS. Once it is produced, NO rapidly diffuses into the adjacent smooth muscle layer in a paracrine fashion to serve as a potent vasodilator [15]. Inside the smooth muscle cell, NO subsequently activates guanylate cyclase converting guanosine triphosphate to cyclic guanosine monophosphate and preventing the release of Ca²⁺ from the sarcoplasmic reticulum. Nitric oxide also interacts at the blood-endothelial interface to prevent the adhesion of both platelets and neutrophils to the normal vascular endothelium. Once in direct contact with the blood, NO is rapidly stabilized and inactivated by binding with the heme group of hemoglobin.

Administration of ventilated NO at concentrations between 5 and 80 ppm has been shown to improve pulmonary hemodynamics and oxygenation in both animal and human subjects without causing systemic vasodilatation [16]. Clinically, inhaled NO has decreased ventilation-perfusion mismatch, improved oxygenation, and decreased pulmonary artery (PA) hypertension in patients with both acute lung injury and early allograft dysfunction after pulmonary transplantation [3]. Recent studies have demonstrated the effectiveness of ventilated NO in improving oxygenation and pulmonary vascular hemodynamics during reperfusion after prolonged allograft storage [17]. However, others believe that the administration of inhaled NO at the time of immediate reperfusion may actually exacerbate lung injury due to free radical formation [18].

Intravascular infusions of NO donors such as sodium nitroprusside (SNP) have been shown to be effective at decreasing PA hypertension more effectively than inhaled NO administration [19]. Others have shown intravenous NO donors such as nitroglycerin and SNP to be effective in decreasing PA pressure but undesirable because of significant systemic vascular effects [20, 21]. Intravascular SNP is not rapidly inactivated by the blood, and systemic hypotension could result despite directed intrapulmonary arterial infusion. We hypothesized that direct PA infusions of low doses of SNP (0.2 to 1.0 µg•kg^-1•min^-1) would ameliorate pulmonary reperfusion injury more effectively than inhaled NO (80 ppm) without causing profound systemic hypotension in an isolated, ventilated, whole-blood-perfused rabbit lung model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
Lung-Heart Block Harvesting
Using the following experimental model previously described by our laboratory [7], we randomized 36 adult New Zealand white rabbits of either sex (3.0 to 3.5 kg) to five experimental groups. Each rabbit was anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (5 mg/kg). Tracheal intubation was performed via a tracheostomy and followed by paralysis with metocurine (0.2 mg/kg, intravenously). Mechanical ventilation was instituted (Ventilator RSP1002; Kent Scientific Corporation, Litchfield, CT) using room air with a tidal volume of 12 mL/kg and a rate of 20 breaths/min.

A median sternotomy and thymectomy were then performed. The superior and inferior venae cavae were loosely encircled with ligatures, and the pericardium was opened. Both the PA and the aorta were dissected free and similarly encircled. A pursestring suture was then placed in the free wall of the right ventricle, and the rabbit was heparinized (500 U/kg, intravenously). After injection of 30 µg of prostaglandin E₁ (Alprostadil; Upjohn Company, Kalamazoo, MI) directly into the PA, the venae cavae were ligated, thus initiating the 18-hour ischemic period.

The PA was then cannulated through a right ventriculotomy in the center of the pursestring and both the right ventricular and PA ligatures were tied around the cannula. After the left ventricle was vented through a left ventriculotomy and the aorta was ligated, 50 mL/kg of Euro-Collins solution at 4°C was infused into the PA from a height of 30 cm. Topical cooling was achieved with cold saline slush. During PA flush, the left atrium was cannulated through the left ventriculotomy and a second pursestring tied around the cannula. A second catheter was placed in the left atrium to directly transduce LA pressures. After the PA flush, the inflow and outflow cannulas were clamped. Care was taken to leave the pleurae intact until the completion of the flush to avoid parenchymal injury. The lungs were stored inflated by clamping the tracheal tube at end-inspiration. The lung-heart block was then excised, immersed in cold 0.9% saline solution, and stored at 4°C for 18 hours.

All experimental protocols were reviewed and approved by an institutional animal use committee. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

	Assessment of Lung Function

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
After 18 hours of storage at 4°C the lung-heart block was suspended by a force transducer in a warm, humidified tissue chamber. Ventilation was reestablished with a 60% O₂/room air gas mixture at a tidal volume of 12 mL/kg and a respiratory rate of 20 breaths/min. The lungs were reperfused with homologous fresh whole venous blood from a main reservoir. A second venous blood reservoir was used to determine single-pass oxygenation at 10, 20, and 30 minutes after initiation of reperfusion. Blood was harvested from a single rabbit for each experiment. The inflow and outflow cannulas were then connected to the blood-primed perfusion circuit with care taken to avoid the introduction of air. The perfusion circuit (Kent Scientific Corporation, Litchfield, CT) was designed to recirculate 150 mL of warmed blood through a 270-µm blood filter (2C7600; Baxter, Deerfield, IL) using a roller pump (7521-40; Cole Palmer Instrument Company, Chicago, IL) at a rate of 60 mL/min. A 270-µm blood filter was chosen so as not to affect leukocyte or platelet counts. Continuous recording of PA pressure, left atrial pressure, lung weight, airway flow, and airway pressure was facilitated by using a dynamic data acquisition program (Workbench PC; Strawberry Tree, Inc, Sunnydale, CA) run on a personal computer (470A; Compaq Prolinea, Houston, TX). This program automatically calculated and displayed pulmonary vascular resistance, tidal volume, and dynamic airway compliance. The left atrial pressure was maintained within the physiologic range (4 to 8 mm Hg) by adjusting the height of a small outflow reservoir in the circuit. Pulmonary venous blood samples were collected for blood gas analysis (Corning 178 pH/Blood Gas Analyzer) at 10, 20, and 30 minutes after the start of reperfusion. At each sampling interval inflow from the main reservoir was interrupted and the circuit was filled with venous blood from the second inflow reservoir. Thirty milliliters of venous blood was passed through the pulmonary vasculature at each interval to ensure accurate measurement of pulmonary venous oxygen content. Oxygen contact with exposed blood surfaces inside the reservoir containers was minimized by the continuous infusion of 100% nitrogen. After 30 minutes of reperfusion, specimens of lung tissue were acquired for weight analysis. Wet-to-dry ratios were calculated after passive desiccation at room temperature to a stable dry weight.

	Experimental Protocol

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
All lungs were flushed with Euro-Collins solution and reperfused at a physiologic flow rate of 60 mL/min for 30 minutes. Five experimental groups were defined as follows: group I lungs served as controls (n = 7) and were reperfused without intervention after 18 hours of storage, group II lungs (n = 8) received a continuous infusion of SNP at 0.2 µg•kg^-1•min^-1 administered through the PA cannula throughout reperfusion, group III lungs (n = 7) received a similar infusion of SNP at a rate of 1.0 µg•kg^-1•min^-1 during reperfusion, and group IV lungs (n = 7) received an infusion of SNP at a rate of 5.0 µg•kg^-1•min^-1. All infusions were administered by a syringe infusion pump (model 22; Harvard Apparatus, South Natick, MA). A fifth experimental group, group V lungs (n = 7), underwent reperfusion while being ventilated with a mixture of 60% oxygen, 80 ppm NO, and room air. A 10 to 100 ppm NO sensor (EIT Sensor Stik, Exton, PA) was placed in line from the ventilator to ensure the accurate administration of the NO gas. Data were recorded every 15 seconds and analyzed at the end of the 30-minute reperfusion period. Oxygenation data were obtained and analyzed at 10-minute intervals. All values are expressed as the mean ± the standard error of the mean. Statistical analysis was performed by analysis of variance to compare the experimental groups. Differences were considered statistically significant if the p value was less than 0.05.

	Measuring Mean Arterial Pressure

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
Seven adult New Zealand white rabbits of either sex (3.0 to 3.5 kg) were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (5 mg/kg). Tracheal intubation was performed via a tracheostomy and followed by paralysis with metocurine (0.2 mg/kg, intravenously). Mechanical ventilation was instituted (Ventilator RSP1002; Kent Scientific Corporation) using room air with a tidal volume of 12 mL/kg and a rate of 20 breaths/min. An 18-gauge intravenous catheter was inserted directly into the right femoral artery via femoral cutdown to facilitate monitoring of systemic arterial pressure. A stepwise infusion of SNP was administered via ear vein by a syringe infusion pump (Model 22; Harvard Apparatus) at the following doses: 0.20, 0.40, 0.80, 0.16, 0.32, and 0.64 µg•kg^-1•min^-1. A continuous recording of mean arterial pressure was facilitated by using a dynamic data acquisition program (Workbench PC; Strawberry Tree, Inc) run on a personal computer (470A; Compaq Prolinea). All animals were then euthanized by pentobarbital overdose and withdrawal of ventilatory support. Once the raw data were analyzed, linear regression analysis was performed to determine the dose of SNP that resulted in lowering the mean arterial pressure by 10 mm Hg.

	Results

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
Hemodynamics
There was a significant reduction in both PA pressure (Fig 1) and pulmonary vascular resistance (Fig 2) for all of the SNP groups (groups II, III, and IV) when compared with control (group I) after 30 minutes of reperfusion. Pulmonary arterial infusions of SNP at 0.2, 1.0, and 5.0 µg•kg^-1•min^-1 resulted in significant reductions of pulmonary artery pressure (31.35 ± 0.8, 30.32 ± 0.3, and 30.93 ± 1.3 mm Hg, respectively, versus 40.37 ± 3.3 mm Hg; p < 0.05) and pulmonary vascular resistance (38,946 ± 1,269, 38,568 ± 1,360, and 40,316 ± 2,458 dynes•s/cm^-5, respectively, versus 52,727 ± 3,421 dynes•s/cm^-5; p < 0.05) when compared with control (group I) lungs. There were no statistically significant differences in pulmonary hemodynamics between lungs ventilated with 80 ppm NO (group V) and control (group I) or SNP-reperfused lungs (groups II, III, and IV) (Table 1).

View larger version (61K): [in this window] [in a new window]   Fig 1. . Pulmonary artery pressure at 30 minutes of reperfusion. (NO = nitric oxide; SNP = sodium nitroprusside.)

View larger version (66K): [in this window] [in a new window]   Fig 2. . Pulmonary vascular resistance at 30 minutes of reperfusion. (NO = nitric oxide; SNP = sodium nitroprusside.)

	Dynamic Airway Compliance

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

View larger version (63K): [in this window] [in a new window]   Fig 3. . Dynamic airway compliance at 30 minutes of reperfusion. (NO = nitric oxide; SNP = sodium nitroprusside.)

	Venous-Arterial Oxygen Gradient

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

View larger version (58K): [in this window] [in a new window]   Fig 4. . Venous-arterial (V-A) oxygenation gradients at 30 minutes of reperfusion. (NO = nitric oxide; SNP = sodium nitroprusside.)

	Wet-to-Dry Ratios

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

View larger version (58K): [in this window] [in a new window]   Fig 5. . Wet-to-dry weight ratios after 2 weeks of passive dessication at room temperature. All dry weights were measured on three separate occasions to determine steady state. (NO = nitric oxide; SNP = sodium nitroprusside.)

	Mean Arterial Pressure

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

View larger version (25K): [in this window] [in a new window]   Fig 6. . Linear regression analysis of mean arterial pressure (MAP) of adult New Zealand white rabbits (n = 7). Notice a drop in MAP by 10 mm Hg occurs at a sodium nitroprusside infusion of 1.35 µg•kg-1•min-1.

	Comment

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

There are several mechanisms that are thought to play a role in NO's ability to diminish pulmonary hypertension and improve alveolar-capillary gas exchange. Nitric oxide is a potent vasodilator that has the ability to counteract hypoxic vasoconstriction through a direct effect on pulmonary vascular smooth muscle [16]. Additionally, NO is able to prevent both platelet and neutrophil adherence to the intact vascular endothelium [15]. This action serves to decrease the extravasation of leukocytes into the lung's parenchyma and attenuates the cytokine cascade in an attempt to maintain microvascular impermeability.

Results thus far have shown decreased pulmonary hypertension and improved oxygenation [17, 22]. However, some believe that the use of inhaled NO during the immediate reperfusion period may lead to free radical formation and cellular damage, thereby limiting the usefulness of this therapeutic modality [23]. Alternatively, the inability to salvage a severely damaged organ may not be a function of peroxynitrate formation, but perhaps could be a reflection of the biochemical properties of inhaled NO. Severely damaged organs may prevent inhaled NO from gaining access to the vascular endothelium due to the production of excessive amounts of interstitial edema. Due to the lipophilic nature of NO, it is not rapidly diffusible in water. Therefore, its effects are limited to those cells that communicate via direct contact. This characteristic seems to limit the effects of inhaled NO on the pericapillary vessels. Intravascular NO donation overcomes this barrier by linking NO to a carrier compound. This characteristic allows intravascular NO donors to access the entire pulmonary vasculature and produce a profound decrease in PA pressure and edema formation by decreasing excessive hydrostatic forces [19].

Intravascular infusions of NO donors such as SNP have been shown to be effective at decreasing PA hypertension. Others have shown intravenous NO donors such as nitroglycerin and SNP to be effective in decreasing PA pressure, but undesirable because of significant systemic vasodilatation [20, 21]. Use of a low-dose, directed, PA infusion of an NO donor (SNP) could potentially have a profound effect on pulmonary hemodynamics and oxygenation while minimizing the risk of systemic hypotension.

Our results confirm the ability of an intravascular NO donor (SNP) to decrease ischemia-reperfusion injury in an isolated, ventilated rabbit lung model. Directed PA infusions of 1.0 µg•kg^-1•min^-1 appeared to have the greatest significant effects on improving pulmonary hemodynamics, dynamic airway compliance, and oxygenation, and reducing lung edema formation. However, infusions of as little as 0.2 µg•kg^-1•min^-1 of SNP showed significant improvements in hemodynamics and appeared more effective than inhaled NO at increasing pulmonary oxygenation and preventing edema formation. These improvements in reperfusion injury were achieved at doses of SNP that were found to decrease mean arterial pressures by less than 7.5 mm Hg (10% decrease from baseline) in normal subjects. Extrapolation of these data to the population awaiting lung transplantation remains to be investigated.

Inhaled NO at 80 ppm significantly increased dynamic airway compliance without significantly decreasing edema formation. Perhaps this phenomenon can be attributed to inhaled NO's ability to directly relax airway smooth muscle. Interestingly enough, infusion of SNP at 1.0 µg•kg^-1•min^-1 appeared to increase dynamic airway compliance more effectively than inhaled NO. This finding could be principally a result of decreased edema formation, or perhaps a combination of decreased edema formation and the ability of endovascularly liberated NO to readily traverse the capillary and alveolar cell layers to directly relax bronchial smooth muscle.

Some have argued that the absolute dose of NO is greater with SNP administration than with inhaled NO therapy. In our model we delivered inhaled NO at 80 ppm using a minute volume of 0.7 L at 1 atmosphere and 293 degrees kelvin. This calculates to 2.33 x 10^-6 moles/min of inhaled NO using the ideal gas law. An infusion of 1.0 µg•kg^-1•min^-1 SNP provides a dose of 4 µg/min in a 3.0- to 4.0-kg subject. The molecular weight of SNP is approximately 262 g/mole, giving a delivery of 1.53 x 10^-8 moles/min of NO. Therefore, the total contribution of NO from SNP infusion is approximately 100-fold less than that achieved with inhaled NO. The relative dose may be smaller for inhaled NO due to incomplete diffusion and limited endothelial and smooth muscle contact when compared with intravascular SNP administration.

In summary, PA infusions of SNP decreases reperfusion injury by significantly improving pulmonary hemodynamics, oxygenation, and dynamic airway compliance while significantly decreasing pulmonary edema formation. These results are achieved at doses of SNP that do not appear to cause significant systemic hypotension in normal subjects. Sodium nitroprusside at 1.0 µg•kg^-1•min^-1 appears to ameliorate reperfusion injury better than inhaled NO at 80 ppm. The applicability of these findings to a survival model of pulmonary transplantation remains to be investigated.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
This work was supported by the National Institutes of Health under R01 grant HL 48242 and National Research Service Award fellowship F32HL09328-02. The technical advice and support of Anthony J. Herring is acknowledged.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 
Presented at the Forty-third Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 7–9, 1996.

Address reprint requests to Dr Kron, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Box 310, Charlottesville, VA 22908.

	References

Top Footnotes Abstract Introduction Material and Methods Assessment of Lung Function Experimental Protocol Measuring Mean Arterial Pressure Results Dynamic Airway Compliance Venous-Arterial Oxygen Gradient Wet-to-Dry Ratios Mean Arterial Pressure Comment Acknowledgments References

 

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				S. C. Clark, C. Sudarshan, J. Roughan, P. A. Flecknell, and J. H. Dark MODULATION OF REPERFUSION INJURY AFTER SINGLE LUNG TRANSPLANTATION BY PENTOXIFYLLINE, INOSITOL POLYANIONS, AND SIN-1 J. Thorac. Cardiovasc. Surg., March 1, 1999; 117(3): 556 - 564. [Abstract] [Full Text] [PDF]

				R. C. King, V. E. Laubach, R. C. Kanithanon, A. M. Kron, P. E. Parrino, K. S. Shockey, C. G. Tribble, and I. L. Kron Preservation with 8-bromo-cyclic GMP improves pulmonary function after prolonged ischemia Ann. Thorac. Surg., November 1, 1998; 66(5): 1732 - 1738. [Abstract] [Full Text] [PDF]

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