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J Thorac Cardiovasc Surg 1996;111:913-919
© 1996 Mosby, Inc.
CARDIAC AND PULMONARY REPLACEMENT |
From the Divisions of Cardiothoracic Surgery, Cardiothoracic Anesthesiology, and Pulmonary Medicine, Washington University School of Medicine, St. Louis, Mo.
Received for publication June 21, 1995 Revisions requested Sept. 26, 1995; revisions received Jan. 3, 1996 Accepted for publication Jan. 5, 1996. Address for reprints: G. Alexander Patterson, MD, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes Hospital Plaza, Suite 3108, Queeny Tower, St. Louis, MO 63110.
Abstract
Objective: Early severe graft dysfunction, as manifested by hypoxia and pulmonary hypertension, occurs in 10% to 20% of lung transplant recipients. We retrospectively investigated whether inhaled nitric oxide would reduce human lung allograft dysfunction by comparing postoperative hemodynamic data, gas exchange, and outcome in lung transplant recipients with early graft dysfunction treated with or without nitric oxide.
Method: Among 243 adult lung transplant procedures, there were 32 patients (13.2%) in whom immediate severe allograft dysfunction developed (arterial oxygen tension/inspired oxygen concentration ratio <150). Group 1 (n = 17) included patients who underwent transplantation before nitric oxide became available in our center and were treated conventionally. Group 2 (n = 15) included those treated with nitric oxide as soon as severe allograft dysfunction was diagnosed. Duration of nitric oxide therapy (20 to 60 ppm) was 15 to 217 hours (average 84 hours).
Results: In group 2, nitric oxide lowered mean pulmonary artery pressure from 30 ± 2 to 26 ± 2 mm Hg (p < 0.05), improved the ratio of arterial oxygen tension to inspired oxygen fraction from 88 ± 10 to 153 ± 30 (p < 0.05) within 1 hour, and caused a sustained improvement in these parameters during extended therapy. Mean arterial pressure and cardiac index were unchanged during nitric oxide therapy. Transient methemoglobinemia (>6%) developed in two patients. However, no complications were associated with nitric oxide use. Duration of mechanical ventilation was 17 ± 5 days in group 1 and 12 ± 3 days in group 2. Four patients had airway complications in group 1, whereas no airway complication was encountered in group 2. Mortality was 24% (4/17) in group 1 and 7% (1/15) in group 2.
Conclusion: Nitric oxide improves oxygenation and decreases pulmonary artery pressure without systemic circulatory effects in patients with severe allograft dysfunction. Furthermore, in these patients, nitric oxide may shorten postoperative mechanical ventilation time and reduce airway complications and mortality. (J THORAC CARDIOVASC SURG 1996;111:913-9)
Despite improved preservation methods and perioperative management, severe allograft dysfunction occurs in 10% to 20% of lung transplant recipients.
1,2 Its associated severe hypoxia, pulmonary hypertension, and lung edema complicate postoperative management. Nitric oxide was reported to be an important endothelium-derived relaxing factor in 1987. 3 Rossaint and colleagues 4 reported in 1993 that extended treatment with inhaled nitric oxide for patients with severe adult respiratory distress syndrome reduces the pulmonary artery pressure without producing systemic vasodilatation and increases arterial oxygenation by improving ventilation-perfusion matching. We 5 recently tested the effect of short periods of nitric oxide inhalation on hemodynamics and arterial oxygenation in patients after bilateral lung transplantation. Nitric oxide dramatically improved the arterial oxygen tension/inspired oxygen fraction (Pao2/Fio2) ratio and lowered the mean pulmonary artery pressure in patients with impaired oxygenation. We 6 recently demonstrated that nitric oxide markedly improved posttransplantation gas exchange in canine lung allografts stored for 18 hours. The purpose of this report was to compare the effects of inhaled nitric oxide with conventional therapy in a group of lung transplant recipients with severe allograft dysfunction.
Patients and methods
Between September 1988 and December 1994, 243 consecutive single (n = 111) and bilateral sequential single (n = 132) lung transplants were performed at Barnes Hospital. En bloc double lung transplants (n = 8) performed in our early experience were not included in this study. Thirty-two patients (13.2%) had immediate severe allograft dysfunction, as manifested by a Pao2/Fio2 ratio less than 150. These 32 patients were divided into two groups. Group 1 (n = 17) included patients having lung transplantation before January 1993 (when inhaled nitric oxide became available in our institution) and treated conventionally. Group 2 (n = 15) included those patients having lung transplantation after February 1993 and treated with inhaled nitric oxide as soon as severe allograft dysfunction was diagnosed. These two groups were compared in regard to requirement for extracorporeal membrane oxygenation (ECMO), days requiring mechanical ventilation, airway complications, and mortality. In group 2, the effect of inhaled nitric oxide was evaluated by the changes of systemic and pulmonary hemodynamics and arterial blood gases measured before and during nitric oxide treatment.
Donor lungs were harvested by the technique we 7 have previously described. All donors were pretreated with systemic heparin and the pulmonary artery bed was flushed with modified Euro-Collins solution after prostaglandin E1 (500 µg) administration. All transplant operations were performed by means of previously described techniques. 8 Cardiopulmonary bypass was used in all patients with pulmonary hypertension and in other patients as dictated by inadequate gas exchange or hemodynamics during transplantation. 9
Routine clinical monitoring of the patients included a radial arterial line and a 7.5F Swan-Ganz catheter (Baxter Healthcare Corp., Irvine, Calif.) positioned into the pulmonary artery through the internal jugular vein. Systemic, pulmonary artery, pulmonary wedge, and central venous pressures were recorded. Cardiac output was determined by the thermodilution method.
Postoperative sedation included intravenous fentanyl citrate and midazolam. Vecuronium bromide was given when indicated. Inotropic support, vasodilators, and diuretics were used as necessary to maximize hemodynamic stability and graft function. Prostaglandin E1 (0.01 to 0.03 µg/kg per minute) was administered routinely from 1989 unless significant hypotension was encountered. All patients received mechanical ventilation in the volume-controlled mode with the application of positive end-expiratory pressure (5 to 15 cm H2O). Ventilator settings were adjusted to provide adequate oxygenation as measured by Pao2 and adequate ventilation as measured by arterial pH and carbon dioxide tension. Standard immunosuppression consisted of cyclosporine, azathioprine, steroid, and antilymphocyte antibody as reported previously. 10
Nitric oxide was supplied from Scott Specialty Gases (Plumsteadville, Pa.) in cylinders containing nitric oxide in nitrogen in a concentration of 2200 ppm. The delivery system consisted of a reducing valve and a flowmeter. The nitric oxide gas mixture (1/8 to 1/4 L/min) was delivered into the inspiratory port of the ventilator. The concentration of nitric oxide was continuously measured from a sampling line at the Y connector attached to the endotracheal tube; a chemiluminescence device (model 42A, Thermoenvironmental Instruments, Franklin, Mass.) that was calibrated before each use with a calibration gas of known 25 ± 1 ppm nitric oxide in nitrogen (Scott Specialty Gases) was used to obtain these measurements. The flow was adjusted according to the concentration measured by the analyzer. The starting dose of inhaled nitric oxide was 40 to 60 ppm and the gas was gradually weaned to 20 ppm. It was continued until its cessation did not cause deterioration in oxygenation or pulmonary artery pressure. Methemoglobin levels were measured every 2 to 6 hours with a Co-Oximeter (model 2500, Ciba-Corning, Medfield, Mass.) by means of a multiple wave-length spectrophotometric method. When methemoglobinemia (>6%) was noticed, 1 gm of ascorbic acid was given intravenously and the dose of nitric oxide was reduced.
Informed consent was obtained from all patients for nitric oxide administration and the protocol for nitric oxide use was approved by the Human Studies Committee of Washington University.
All data are presented as the mean ± the standard error of the mean. Significance was sought between the two groups with use of a 
2 test for nonparametric data and Student's t test for parametric data. Repeated-measures analysis of variance was used to test the effect of nitric oxide on systemic and pulmonary hemodynamics and also on arterial blood gas analysis. Statistical significance was determined at a p value of 0.05.
Results
Demographic results (Table I)
Recipient age, recipient sex, donor age, donor Pao2, procedure, total ischemic time, use of cardiopulmonary bypass during transplant procedures, and initial Pao2 (Fio2 = 1.0) after reperfusion were not significantly different between the two groups.
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Table II)
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Four patients in group 1 had airway complications. Early fatal bronchial dehiscence occurred in two patients, one of whom underwent retransplantation without success, and late bronchial stenosis occurred in two patients. In contrast, no airway complication was encountered in group 2.
Hospital mortality was four of 17 (24%) in group 1 and one of 15 (7%) in group 2. Causes of death in group 1 were airway dehiscence in two patients, severe allograft dysfunction in one, and sepsis in one patient. One patient in group 2 died of severe allograft dysfunction.
Requirement of ECMO, duration of mechanical ventilation, airway complication, and hospital mortality did not reach statistical significance between the two groups.
Effect of inhaled nitric oxide
Nitric oxide treatment was initiated in the operating room in four patients and on arrival at the intensive care unit in five patients. In the remaining six patients, nitric oxide was initiated 1 to 10 hours after they arrived in the intensive care unit because of progressive allograft dysfunction. Duration of nitric oxide therapy was 15 to 217 hours (average 84 hours).
The effect of nitric oxide on hemodynamics and arterial blood gases was evaluated by comparing the data obtained during nitric oxide therapy and those obtained immediately before nitric oxide therapy was initiated (baseline value). Data were obtained from 13 patients treated with inhaled nitric oxide, excluding two patients who required ECMO immediately after transplantation. Because the duration of nitric oxide therapy was different in each case, statistical analysis was performed on the data obtained during the first 8 hours (Table III). Nitric oxide administration resulted in rapid improvement of arterial oxygenation and pulmonary artery pressure without affecting systemic pressure or cardiac index and caused a sustained improvement in these parameters during extended therapy (Figs. 1 and 2).
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Discussion
Early severe allograft dysfunction, as manifested by allograft edema, pulmonary hypertension, and decreased arterial oxygenation, develops in 10% to 20% of lung transplant recipients. 1,2 This dysfunction has been known as pulmonary reimplantation response. 11 Ischemia-reperfusion injury is thought to be the major cause of this phenomena. 12 A number of strategies have been developed in an attempt to reduce early allograft dysfunction, for example, use of oxygen-derived radical scavengers, 13 pentoxifylline, 14 and prostaglandin E1. 15 However, 13% of deaths occurred within 90 days after transplantation and were still attributable to severe allograft dysfunction at the moment according to the St. Louis International Lung Transplant Registry (Pohl MS, personal communication).
Endothelial dysfunction may play a central role in pulmonary hypertension. Acetylcholine relaxes preconstricted vascular smooth muscle by binding to muscarinic receptors on the endothelial cell, causing the release of a potent vasodilating substance called endothelium-derived relaxing factor. 16 In 1987, nitric oxide was reported to be an important endothelium-derived relaxing factor. 3 Nitric oxide is thought to diffuse from the endothelium to adjacent smooth muscle and produce relaxation through a cyclic guanosine monophosphate–dependent pathway. The vascular response to acetylcholine is altered in a number of conditions, such as chronic obstructive lung disease, 17 pulmonary hypertension after cardiopulmonary bypass, 18 and lung transplantation 19,20 wherein significant endothelial nitric oxide production is inadequate. However, vasodilatation may be elicited by inhaled nitric oxide, an endothelium-independent smooth muscle relaxant.
We previously tested the effects of short periods of nitric oxide inhalation (40 to 60 ppm) and systemic prostaglandin E1 (0.03 to 0.06 mg/kg per minute) on hemodynamics and arterial oxygenation in patients after bilateral lung transplantation. 5 In patients with impaired oxygenation, nitric oxide improved Pao2/Fio2 ratio and lowered mean pulmonary artery pressure without systemic circulatory effects. In contrast, prostaglandin E1 did not improve oxygenation and lowered systemic arterial pressure. Interestingly, in patients without impaired oxygenation, nitric oxide was of no benefit and paradoxically worsened oxygenation. We have also demonstrated the beneficial effects of inhaled nitric oxide on allograft dysfunction owing to reperfusion injury in a canine single lung transplant model. 6
On the basis of this experience and several reports on nitric oxide treatment for pulmonary hypertension 21-23 and adult respiratory distress syndrome, 4 extended inhaled nitric oxide treatment has been given to the 15 lung transplant recipients with severe allograft dysfunction since February 1993. Inhaled nitric oxide rapidly improved oxygenation and decreased pulmonary artery pressure without systemic circulatory effects. It should also be noted that inhaled nitric oxide does not cause tachyphylaxis. Because nitric oxide, an endothelium-independent smooth muscle relaxant, is delivered via the airway, pulmonary blood flow is redistributed away from nonventilated regions of the lungs and toward ventilated regions, thereby improving the matching of ventilation and perfusion. Another beneficial effect may be derived from a potential antineutrophil effect of nitric oxide. Our previous canine study demonstrated that preserved lung allografts treated with inhaled nitric oxide had decreased myeloperoxidase activity, indicating decreased neutrophil sequestration in comparison with that of untreated allografts.
Patients with severe lung allograft dysfunction usually require prolonged mechanical ventilation. We 24 have recently reported that prolonged mechanical ventilation is associated with an increased incidence of airway complications. Whether this increase is due to mechanical ventilation itself or to the parenchymal injury necessitating mechanical ventilation is not known. Our observations suggest that inhaled nitric oxide may shorten the time required for mechanical ventilation in patients with severe allograft dysfunction. Interestingly, four patients treated without nitric oxide had airway complications, two of which proved fatal. In contrast, no airway complications were noted when nitric oxide was used.
ECMO has been used when conventional measures for treatment of severe allograft dysfunction proved unsuccessful. 25 In our entire experience of 243 patients undergoing lung transplantation, only six patients required ECMO. Four of them survived and were discharged from the hospital. We have avoided the use of ECMO as much as possible because of the potential complications of bleeding, infection, and renal insufficiency. We speculate that at least two more patients would have required ECMO had nitric oxide not been available. On the other hand, one patient required ECMO 24 hours after transplantation because of progressive allograft dysfunction despite nitric oxide therapy. This patient's lung never recovered. Our current strategy is to use nitric oxide as the first therapeutic intervention in the presence of severe allograft dysfunction and to reserve ECMO for subsequent treatment failures or for circumstances in which euvolemic hemodynamic instability proves refractory to management with standard pressor and inotropic agents.
The absence of systemic vasodilatation with inhaled nitric oxide was confirmed in this study. The lack of systemic effects results from the rapid inactivation of nitric oxide by hemoglobin in red blood cells. 18 The reaction of hemoglobin and nitric oxide forms nitrosyl hemoglobin and subsequently methemoglobin. 26 Intravenously infused vasodilators such as prostaglandin E1, on the other hand, cause both pulmonary and systemic vasodilatation. 5,15 The dose of a vasodilator agent is limited by concomitant dilatation of the systemic vasculature, leading to systemic arterial hypotension.
The therapeutic importance of our data on inhaled nitric oxide is evident but must be considered in conjunction with possible toxic effects. Nitric oxide can be converted by oxidation to nitric dioxide and other toxic agents such as peroxynitrite, resulting in lung injury. 27 Formation of methemoglobin may decrease oxygen delivery. There is indirect evidence that nitric oxide may be directly related to allograft rejection. In a rat left lung allograft model we 28 have recently demonstrated that inhibition of nitric oxide synthase by aminoguanidine markedly delayed the onset and decreased the severity of lung allograft rejection. Little evidence for nitric oxide toxicity exists with exposures less than 100 ppm in normal rats 27 and rabbits. 29 In fact, in our experience we observe no complications associated with extended nitric oxide inhalation for up to 217 hours. Transient mild methemoglobinemia occurred in two patients and was successfully treated with ascorbic acid administration. We did not encounter any episodes of intractable acute rejection.
In summary, this study demonstrates that inhaled nitric oxide improves gas exchange and decreases pulmonary artery pressure in patients with early allograft dysfunction. It also suggests that inhaled nitric oxide may shorten postoperative mechanical ventilation time, reduce airway complications, and reduce mortality in patients with severe lung allograft dysfunction.
Appendix: Discussion
Dr. Paul F. Waters (Los Angeles, Calif.)
We in our program have also encountered severe early graft dysfunction that leaves us helplessly watching the patient become hypoxemic and hypotensive, with very few therapeutic modalities other than ECMO. We have seen an excellent therapeutic response to nitric oxide in some cases and have found it to be ineffective in others. Have any of your patients been unresponsive to nitric oxide therapy?
Dr. Date
We had one patient who did not respond to nitric oxide treatment. This patient required ECMO 24 hours after the initiation of nitric oxide, but the lung never recovered. This patient probably should have been treated with ECMO earlier. However, we do not know how to distinguish between patients who should be treated with ECMO from the beginning and those who should be treated with nitric oxide when the graft dysfunction is very severe.
Dr. Waters
Is your use of nitric oxide now still a reactive process or are you using it prophylactically in patients in whom the risk is particularly high, for instance, patients with Eisenmenger-type pulmonary vascular disease or those with primary pulmonary hypertension?
Dr. Date
We have actually tested more than 50 patients with a short course of nitric oxide. Only the patients with graft dysfunction as manifested by Pao2/Fio2 ratios less than 150 responded well, which means oxygenation was improved. However, nitric oxide had an adverse effect in patients who did not have graft dysfunction, which means oxygenation became worse. Therefore, we use nitric oxide only for the patient with graft dysfunction as manifested by a Pao2/Fio2 ratio less than 150.
Dr. Waters
I see. I noticed that some of your patients with pulmonary vascular disease had single lung transplants and some had double lung transplants. What were the particular reasons why one patient would receive one operation and another the other?
Dr. Date
Currently, if both lungs are available, we use bilateral lung transplantation for this group of patients. However, donor shortage is a big problem. If single lung transplantation is the only option for that patient, then we use that option. However, the primary choice for us is double lung transplantation at this time.
Dr. Waters
Are you saying that there is no particular stratification, that the type of treatment depends on whether there is a double lung block available?
Dr. Date
The quality of the lung also has an impact. If we do a single lung transplantation, the lung has to be perfect and the lung has to be close to the center. The ischemic time should be shorter than for bilateral lung transplantation, because the patient who receives a single lung transplant for pulmonary hypertension has a difficult course.
Dr. Waters
My final question relates to any thoughts that you might have on the etiology of this severe graft dysfunction. Do you think it is an immunologic process, a reperfusion injury, a combination?
Dr. Date
We have investigated the effect of nitric oxide using a canine left single lung transplant model, and we found that by administering nitric oxide we could reduce myeloperoxidase activity. Therefore, maybe one of the causes of this reimplantation phenomenon is neutrophil activation, and nitric oxide may be working on this phenomenon.
Dr. Waters
Have you used leukocyte depletion at all in reperfusion?
Dr. Date
No, not yet.
Dr. Robert C. Robbins (Stanford, Calif.)
I agree with Dr. Waters' comments about primary pulmonary hypertension and your comments about the use of double lung transplantation. I think that is the best operation.
In patients with primary pulmonary hypertension, have you observed that if you do the operations without cardiopulmonary bypass dysfunction is worse in the lung that is implanted first, probably related to reperfusion injury?
Dr. Date
We have to use cardiopulmonary bypass for transplant operations in patients with pulmonary hypertension. If we do not, the patient cannot tolerate the pneumonectomy. Therefore, we electively use cardiopulmonary bypass for all patients with pulmonary hypertension. With regard to bilateral lung transplantation in this group of patients, function in the first transplanted lung is usually poorer than that of the second transplanted lung, even though the second lung has a longer ischemic time. The probable reason is hyperperfusion to the first transplanted lung during the second lung implantation, as you mentioned.
Acknowledgments
We acknowledge the assistance of Mary Ann Kelly in preparation of the manuscript and statistical advice from Richard B. Schuessler, PhD.
Footnotes
Read at the Twenty-first Annual Meeting of The Western Thoracic Surgical Association, Coeur d'Alene, Idaho, June 21-24, 1995. 
J THORAC CARDIOVASC SURG 1996;111:913-9
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S. M. Arcasoy and R. M. Kotloff Lung Transplantation N. Engl. J. Med., April 8, 1999; 340(14): 1081 - 1091. [Full Text] [PDF]
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L. T. Eriksson, R. Roscher, R. Ingemansson, and S. Steen Cardiovascular effects of induced hypothermia after lung transplantation Ann. Thorac. Surg., March 1, 1999; 67(3): 804 - 809. [Abstract] [Full Text] [PDF]
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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]
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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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S. C. Body and S. K. Shernan The Utility of Nitric Oxide in the Postoperative Period Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 1998; 2(1): 4 - 30. [Abstract] [PDF]
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R. C. King, O. A. R. Binns, R. C. Kanithanon, P. E. Parrino, T. B. Reece, J. D. Maliszewskyj, K. S. Shockey, C. G. Tribble, and I. L. Kron Acellular Low-Potassium Dextran Preserves Pulmonary Function After 48 Hours of Ischemia Ann. Thorac. Surg., September 1, 1997; 64(3): 795 - 800. [Abstract] [Full Text]
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T. Mizuta, Y. Fujii, M. Minami, S. Tanaka, T. Utsumi, H. Kosaka, R. Shirakura, and H. Matsuda INCREASED NITRIC OXIDE LEVELS IN EXHALED AIR OF RAT LUNG ALLOGRAFTS J. Thorac. Cardiovasc. Surg., May 1, 1997; 113(5): 830 - 835. [Abstract] [Full Text]
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S. Fujino, I. Nagahiro, A. N. Triantafillou, C. H. R. Boasquevisque, M. Yano, J. D. Cooper, and G. A. Patterson Inhaled Nitric Oxide at the Time of Harvest Improves Early Lung Allograft Function Ann. Thorac. Surg., May 1, 1997; 63(5): 1383 - 1389. [Abstract] [Full Text]
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R. C. King, O. A. R. Binns, R. C. Kanithanon, J. T. Cope, R. L. Chun, K. S. Shockey, C. G. Tribble, and I. L. Kron Low-Dose Sodium Nitroprusside Reduces Pulmonary Reperfusion Injury Ann. Thorac. Surg., May 1, 1997; 63(5): 1398 - 1404. [Abstract] [Full Text]
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M. Yamashita, R. A. Schmid, S. Fujino, J. D. Cooper, and G. A. Patterson NICORANDIL, A POTENT ADENOSINE TRIPHOSPHATE-SENSITIVE POTASSIUM-CHANNEL OPENER, AMELIORATES LUNG ALLOGRAFT REPERFUSION INJURY J. Thorac. Cardiovasc. Surg., November 1, 1996; 112(5): 1307 - 1314. [Abstract] [Full Text]
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M. Yamashita, R. A. Schmid, K. Ando, J. D. Cooper, and G. A. Patterson Nitroprusside Ameliorates Lung Allograft Reperfusion Injury Ann. Thorac. Surg., September 1, 1996; 62(3): 791 - 796. [Abstract] [Full Text]
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R. J. Novick, K. E. Gehman, I. S. Ali, and J. Lee Lung Preservation: The Importance of Endothelial and Alveolar Type II Cell Integrity Ann. Thorac. Surg., July 1, 1996; 62(1): 302 - 314. [Abstract] [Full Text]
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