1656 JACC Vol. 25, No. 7 June 1995:1656-64 HEART TRANSPLANTATION Inhaled Nitric Oxide and Hemodynamic Evaluation of Patients With Pulmonary Hypertension Before Transplantation IAN ADATIA, FRCPC, STANTON PERRY, MD, MICHAEL LANDZBERG, MD, PHILIP MOORE, MD, JOHN E. THOMPSON, RRT, DAVID L. WESSEL, MD Boston, Massachusetts Objectives. We investigated the effect of inhaled nitric oxide and infused acetylcholine in patients with pulmonary hypertension undergoing cardiac catheterization before cardiopulmonary transplantation. Background. The fate of patients under consideration for transplantation of the heart or lungs, or both, is influenced by the evaluation of their pulmonary vascular reactivity. Methods. We evaluated 11 patients who were classified into two groups on the basis of mean left atrial pressure >15 mm Hg (group I, n = 6) or _<15 mm Hg (group II, n = 5). All patients inhaled nitric oxide at 80 ppm. This was preceded by an infusion of 10 -6 tool/liter of acetylcholine in seven consecutive patients (n = 3 in group I, n = 4 in group If). Results. In group I, inhaled nitric oxide decreased pulmonary artery pressure from (mean --- SE) 71 -+ 13 to 59 +- 10 mm Hg (p < 0.05), pulmonary vascular resistance from 14.9 +- 3.8 to 7.6 --- 1.7 Um 2 (p < 0.05) and intrapulmonary shunt fraction from 17.8 + 3.6% to 12.7 + 2.1% (p < 0.05). Left atrial pressure tended to increase from 27 +- 4 to 32 -+ 5 mm Hg (p = 0.07). In group II pulmonary vascular resistance decreased in response to nitric oxide from 36.4 -+ 9.0 to 31.1 +- 7.9 Um 2 (p < 0.05). Cardiac index, systemic pressure and resistance did not change in either group. Seven patients who received acetylcholine had no significant alteration in pulmonary hemodynamic variables. Conclusions. These preliminary observations suggest that nitric oxide is a potent pulmonary vasodilator with minimal systemic effects. It may be useful in discriminating patients needing combined heart and lung transplantation from those requiring exchange of the heart alone. (J Am CoU Cardiol 1995;25:1656-64) The fate of patients under consideration for transplantation of the heart or lungs, or both, is influenced by the evaluation of their pulmonary vascular reactivity. Successful reduction of an elevated pulmonary vascular resistance may delay the need for transplantation or permit exchange of the heart alone (1-3). Pulmonary hypertension was established as an adverse prog- nostic factor for cardiac transplantation in early reports (4) and remains a significant risk factor for early death despite contin- ued improvement in survival of high risk patients (5,6). Cur- rent pulmonary vascular assessment often relies on intrave- nously infused vasodilators. Their administration is not without hazard, and the hemodynamic results may be confounded by changes in cardiac output, systemic hypotension and hypox- emia secondary to increased intrapulmonary shunting (7). In contrast, the inhalation of nitric oxide has been shown to vasodilate the human pulmonary vascular bed with minimal systemic effects and without increasing intrapulmonary shunt- ing (8-14). The systemic effects of inhaled nitric oxide are limited by its avid affinity for, and subsequent inactivation by, From the Departments of Cardiology and Respiratory Therapy, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Manuscript received March 7, 1994; revised manuscript received January 11, 1995, accepted January 19, 1995. Address for corresoondence: Dr. David L. Wessel, Cardiac ICU Office, Children's Hospital, 300 Longwood Avenue, Farley 653, Boston, Massachusetts 02115, hemoglobin (15). Evidence is accumulating that the production of nitric oxide from L-arginine by the endothelial cell mediates vessel tone through a cyclic guanosine monophosphate (cGMP)-dependent mechanism in both the systemic and pul- monary circulations (16-19). The vascular response to acetylcholine, an endothelium- dependent vasodilator (20), is regarded as a measure of endothelial cell integrity and has been documented to be abnormal in a number of vascular diseases (21,22). The pulmonary vascular response to acetylcholine may be abnor- mal after cardiopulmonary bypass (9) and in patients with congestive heart failure and secondary pulmonary hyperten- sion (23). If decreased production of endogenous nitric oxide is responsible for vasoconstriction in patients with pulmonary hypertension rather than obliteration of the pulmonary vascu- lature, then administration of nitric oxide might achieve pul- monary vasodilation. Therefore, we investigated the effects of nitric oxide inhalation and acetylcholine infusion on the hemo- dynamic variables and gas exchange in patients with pulmonary hypertension undergoing cardiac catheterization as part of their assessment before consideration for cardiopulmonary transplantation. Methods Patients. We evaluated 11 patients (median age 13 years, range 0.7 to 27) with pulmonary hypertension (mean [_SE] ©1995 by the American College of Cardiology 0735-1097/95/$9.50 0735-1097(95)00048-9
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`JACC Vol. 25, No. 7 ADATIA Err AL. 1657 June 1995:1656-64 NITRIC OXIDE IN PULMONARY HYPERTENSION Table 1. Pretransplantation Diagnoses of Patients Age Pt No./Gender (yr) Diagnosis 1/M 2 Shone syndrome variant 2/F 8 Shone syndrome variant 3/F 9 Idiopathic restrictive cardiomyopathy 4/F 13 Ventricular failure after Senning procedure for TGA and VSD Adriamycin-induced cardiotoxicity Shone syndrome variant; severe MR Primary pulmonary hypertension (right to left atrial shunt) Cystic fibrosis Eisenmenger complex with small VSD Eisenmenger complex with ASD Eisenmenger complex with VSD and pulmonary artery band 5/M 20 6/F 26 7/M 0.7 8/F 11 9/17 14 10/F 23 11/M 27 ASD (VSD) = atrial (ventricular) septal defect; F = female; M = male; MR = mitral regurgitation; Pt = patient; TGA = transposition of the great arteries. pulmonary artery pressure 71.6 + 8.4 mm Hg) who underwent cardiac catheterization to assess their pulmonary vascular resistance and reactivity as part of their pretransplant manage- ment (Table 1). The patients were classified into two groups on the basis of a mean left atrial pressure >15 mm Hg (group I) or -<15 mm Hg (group II) and coinciding with whether they were combined heart and lung or lung transplant candidates, respectively. Thus, group I had an elevated mean left atrial pressure (27.0 _+ 4.2 mm Hg) and treatment options potentially restricted to combined heart and lung transplantation. In contrast, group II had a low mean atrial pressure (7.2 + 1.3 mm Hg), and these patients were considered candidates for lung transplantation. The difference in left atrial pressure was significant (p < 0.05). The only other difference in the mea- sured baseline variables between the groups was a higher right atrial pressure in group I. There was a tendency for group I to have a higher partial pressure of arterial oxygen (Pao2) (p = 0.05) and lower pulmonary vascular resistance (Table 2). Group I: high left atrial pressure. Group I included six patients (Patients 1 to 6) with an elevated pulmonary vascular resistance (mean 14.9 + 3.8 Um 2) and transpulmonary gradi- ent (mean 44.7 _+ 12.2 mm Hg) in the setting of severe left ventricular failure despite optimal medical management with digoxin, diuretic drugs and, when appropriate, maximal after- load reduction therapy. Patients 1, 2, and 6 were diagnosed as having Shone syndrome variants. Patients 1 and 2 had an elevated end- diastolic pressure, mild mitral stenosis (previous mitral valve replacement in Patient 1) and moderate left ventricular out- flow tract obstruction. Patient 6 had undergone mitral valve replacement (twice) and aortic valve replacement. In addition, a ventricular septal defect and aortic coarctation were repaired in infancy. Her predominant lesion was severe perivalvar mitral regurgitation not amenable to surgical correction. Two other patients had acquired cardiomyopathies (idiopathic in Patient 3 and secondary to adriamycin treatment for leukemia 12 years earlier in Patient 5). Patient 4 had right ventricular (systemic ventricular) failure after a Senning procedure with ventricular septal defect closure for transposition of the great arteries in infancy. Subsequently, she had undergone tricuspid valve (systemic atrioventricular valve) replacement. Group II: low left atrial pressure. Group II included five patients (Patients 7 to 11) who had pulmonary hypertension with an elevated pulmonary vascular resistance (mean 36.4 +_ 9.0 Um z) but with preserved ventricular function. Two patients had primary lung pathology (Patient 7 had primary pulmonary hypertension; Patient 8 had cystic fibrosis). Three patients had pulmonary hypertension associated with congenital intracar- diac shunts and had developed the Eisenmenger complex. Patient 9 had a large ventricular septal defect in infancy but had developed progressive elevation of pulmonary vascular resistance despite spontaneous reduction in the size of the defect. Patient 10 had an atrial septal defect with reversed shunting, and Patient 11 had a large ventricular septal defect and developed pulmonary vascular disease after an inadequate pulmonary artery band placed in infancy. These three patients were considered for lung transplantation with primary cardiac repair (24). Hemodynamie assessment. Seven consecutive patients were investigated with both acetylcholine and nitric oxide (Patients 1, 3, 4, 7, 8, 10 and 11), and four patients received nitric oxide gas alone (Patients 2, 5, 6 and 9) because we had discontinued the use of acetylcholine as a pulmonary vasodi- lator at the time of their assessment. During cardiac catheter- ization but before angiography, hemodynamic measurements were recorded at baseline, during a 2-rain infusion of acetyl- choline, 15 rain after return to a steady baseline and after 15 rain of nitric oxide inhalation (80 ppm). In two patients we recorded hemodynamic variables at 40 as well as 80 ppm. In addition to receiving nitric oxide preoperatively, Patient 4 was studied after heart transplantation. The hemodynamic variables recorded were heart rate, systemic and pulmonary arterial pressures, right and left atrial pressures, arterial and venous blood gases and oxygen satura- tion. In six patients (Patients 1 to 3, 5, 6 and 8) without tricuspid or pulmonary regurgitation or intracardiac shunting, cardiac output was measured by thermodilution, and left atrial pressure from pulmonary artery wedge pressures. In four patients with intracardiac shunts (Patients 7 and 9 to 11) and one with pulmonary regurgitation (Patient 4), the systemic and pulmonary blood flows were estimated using the Fick principle. Oxygen consumption was measured (Waters Inc., model MM20). Oxygen saturation was measured by co-oximetry in blood drawn from systemic artery, pulmonary artery, systemic vein and pulmonary vein or left atrium. All preoperative studies were conducted with the patients awake and breathing spontaneously but sedated with midazolam and morphine. The postoperative study in Patient 4 was conducted during mechan- ical ventilation. Delivery and monitoring of nitric oxide. The details of nitric oxide gas preparation, delivery and monitoring have
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`1658 ADATIA ET AL. JACC Vol. 25, No. 7 NITRIC OXIDE IN PULMONARY HYPERTENSION June 1995:1656-64 Table 2. Hemodynamic Response to Inhaled Nitric Oxide Group I: Patients With High Left Atrial Pressure CI BP PAp (liters/min PAWp/LAp RAp SVRI PVRI HR Pao 2 TPG Qs/Qt Pt No. (ram Hg) (mm Hg) per m 2) (mm Hg) (ram Hg) (Urn 2) (Um 2) (beats/min) (ram Hg) (mm Hg) (%) 5 6 Mean _+. SE 1 Baseline 69 92 3.4 16 NO 80 ppm 72 84 4.7 26 2 Baseline 80 120 2.9 32 NO 80 ppm 100 90 3.4 45 3 Baseline 74 56 3.1 26 NO 80 ppm 66 40 3.1 26 4 Baseline 67 45 2,6 22 NO 40 ppm 70 37 2.4 22 NO 80 ppm 67 35 2.4 22 Baseline 75 37 2.0 21 NO 80 ppm 75 34 2.1 24 Baseline 65 80 3.4 45 NO 80 ppm 70 70 4.0 50 Baseline 72 -+ 2 72 _+ 13 2.9 _+ 0.2 27 _+ NO 80ppm 75+-5 59_+I0 3.3+-0.4 32_+ 10 17.4 22.4 148 65 76 26.8 10 13.2 12.3 148 76 58 19.7 18 21.4 30.3 130 53 88 25.6 18 24.1 13.2 100 84 45 17.5 10 20.6 9.7 85 96 30 10.7 10 18.1 4.5 80 89 14 8.2 8 22.7 8.8 61 90 23 13.5 5 27.1 6.3 73 NA 15 NA 5 25.8 5.4 73 96 13 12.2 14 30.5 8.0 75 102 16 6.2 14 29.0 4.8 70 100 10 6.1 40 7.4 10.3 83 107 35 23.8 40 7.5 5.0 111 327 20 12.7 17 -+ 5 20.0 -+ 3.1 14.9 +- 3.8 97 + 14 86 -+ 9 45 -+ 12 17.8 -+ 3.6 16 + 5 19.6 -+ 8.2 7.6 -+ 1.7 97 -+ 12 129 + 40 27 -+ 8 12.7 -+ 2.1 Group II: Patients With Low Left Atrial Pressure CI PBFI BP PAp (liters/min (liters/min PAWp/LAp RAp SVRI PVRI HR Pao 2 TPG Pt No. (ram Hg) (mm Hg) per m e) per m z) (mm Hg) (mm Hg) (Urn 2) (Urn 2) (beats/rain) (mm Hg) (mm Hg) 7 Baseline 56 80 2.7 1.9 7 6 18.5 38.4 152 46 73 NO 80 ppm 57 82 3.0 2.1 7 6 17.0 35.7 153 48 75 8 Baseline 100 30 3.5 3.5 12 7 26.6 5.1 80 NA 18 NO 80 ppm 95 27 3.5 3.5 13 7 25.1 4.0 80 NA 14 9 Baseline 75 80 2.3 1.6 6 6 30.0 46.3 79 58 74 NO 40 ppm 75 80 2.1 1.7 7 6 32.9 42.9 80 NA 73 NO 80 ppm 75 74 2.3 1.8 6 6 30.0 37.8 83 62 68 10 Baseline 116 66 2.4 1.9 4 4 46.7 32.6 142 57.0 62 NO 80 ppm 116 66 3.2 2.3 6 5 34.7 26.1 156 57.0 60 11 Baseline 107 102 2.7 1.6 7 7 37.0 59.4 75 41 95 NO 80 ppm 105 100 2.9 1.8 7 7 33.8 51.7 75 42 93 Mean _+ SE Baseline 91 -+ 11 72 _+ 12 2.7 _+ 0.2 2.1 _+ 0.4 7 -+ 2 6 _+ 1 31.8 _+ 4.8 36.4 --- 9.0 106 _+ 17 51 _+ 4 64 _+ 13 NO 80ppm 90-+11 70-+12 3.0+-0.2 2.3+0.3 8_+1 6_+1 28.1_+3.3 31.1 +7.9 109_+18 52_+4 62+13 Baseline = before nitric oxide (NO); BP = mean systemic arterial pressure; CI = cardiac index; HR = heart rate; LAp = left atrial pressure; NA = not available; Pao 2 = systemic arterial oxygen tension; PAp = mean pulmonary artery pressure; PAWp = pulmonary artery wedge pressure; PBFI = pulmonary blood flow index; Pt = patient; PVRI = pulmonary vascular resistance index; QdQt = intrapulmonary shunt fraction; RAp = fight atrial pressure; SVRI = systemic vascular resistance index; TPG = transpulmonary gradient. been reported elsewhere (9,25). In brief, nitric oxide gas (Scott Specialty Gases) of medical grade quality and conforming to Food and Drug Administration guidelines was supplied in tanks in a concentration of 800 ppm. Pure nitrogen and nitric oxide were fed separately into a Bird (Bird Products Corpora- tion) low flow blender at 50 psi. This blender controlled the proportion of nitric oxide and nitrogen mixture that flowed into a second Bird blender, where it was blended with oxygen. The fraction of inspired oxygen delivered to the patient could thus be adjusted (between 0.21 and 0.97) independently of the nitric oxide. The gas flow distal to the oxygen blender was controlled by a standard oxygen flowmeter. This gas mixture was delivered to the patient through a one-way inspiratory valve to a face mask. An in-line oxygen analyzer was positioned between the flowmeter and the face mask. The mask was hand held by an investigator to fit snugly over the patient's face. The expiratory gases from the patient circuit were scavenged by a reservoir bag and regulated wall suction. Nitric oxide and nitrogen dioxide levels were monitored by chemiluminescence. A sampling port at the airway permitted a volume of inspira- tory gas mixture to flow to the analyzer (Thermoenvironmental Instruments Chemiluminescence, model 42H). Methemoglobin levels were measured after nitric oxide inhalation with a co-oximeter (CIBA-Corning, model 2500) using a multiwavelength spectrophotometric method. Acetylcholine. Acetylcholine was diluted in 5% dextrose to yield a concentration of 10 .6 mol/ml and infused into the pulmonary artery at a rate (in ml/min) equal to the baseline pulmonary blood flow (in liters/rain), to achieve a final con- centration in the pulmonary circulation of 10 6 mol/liter for all
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`JACC Vol. 25, No. 7 ADATIA ET AL. 1659 June 1995:1656-64 NITRIC OXIDE IN PULMONARY HYPERTENSION Table 3. Hemodynamic Response to 10 6 mol/liter of Acetylcholine Infused Over 2 min Group I: Patients With High Left Atrial Pressure CI BP PAp (liters/mfu PAWp/LAp RAp SVRI PVRI HR Pao 2 TPG QJQt Pt No. (mm Hg) (mm Hg) per m 2) (mm Hg) (mm Hg) (Um 2) (Urn 2) (beats/min) (mm Hg) (mm Hg) (%) 1 Baseline 65 91 4.0 15 10 13.8 19.0 146 65 76 NA ACh 60 91 4.3 15 10 11.6 17.7 146 67 76 NA 3 Baseline 62 52 3.1 19 10 16.8 10.6 85 92 33 11.0 ACh 66 52 3.0 18 10 18.7 11.3 90 83 34 18.0 4 Baseline 58 36 2.2 . 16 7 23.2 9.1 61 94 20 11.7 ACh 55 33 2.2 16 6 22.3 7.7 60 90 17 11.8 Mean _+ SE Baseline 62 _+ 2 60 _+ 16 3.1 _+ 0.5 17 _+ 1 9 -+ 9 17.9 +_ 2.8 12.9 _+ 3.1 97 _+ 25 84 _+ 9 43 + 17 11.4 _+ 0.4 ACh 60 _+ 3 59 -+ 17 3.2 _+ 0.6 16 + 1 9 +_ 1 17.5 + 3.1 12.2 _+ 2.9 99 -+ 25 80 _+ 7 42 _+ 18 14.9 _+ 3.1 Group II: Patients With Low Left Atrial Pressure CI PBFI BP PAp (titers/min (liters/min PAWp/LAp RAp SVRI PVRI HR Pao 2 TPG Pt No. (mm Hg) (mm Hg) per m 2) per m 2) (mm Hg) (ram Hg) (Urn 2) (Um 2) (beats/min) (mm Hg) (ram Hg) 7 Baseline 58 86 2.3 1.4 6 6 22.6 57.1 165 42 80 ACh 58 88 2.8 1.5 6 6 18.4 54.7 165 41 82 8 Baseline 104 31 4.2 4.2 13 7 23.1 4.3 101 NA 18 ACh 103 27 4.0 4.0 12 7 24.0 3.8 90 NA 15 10 Baseline 118 70 3.2 2.1 6 4 35.6 30.5 146 60 64 ACh 116 66 2.9 2.1 7 4 38.6 28.1 146 61 59 11 Baseline 105 101 2.7 2.3 7 8 35.9 40.9 75 43 94 ACh 105 101 2.6 2.2 7 7 37.7 42.7 75 43 94 Mean _+ SE Baseline 96 + 13 72 _+ 15 3.1 _+ 0.4 2.5 _+ 0.6 8 -+ 2 6 _+ 1 28.7 _+ 4.1 33.2 _+ 11.1 122 _+ 21 48 _+ 5 64 _+ 17 ACh 96 _+ 13 71 _+ 16 3.1 _+ 0.4 2.5 _+ 0.5 8 _+ 1 6 +_ 1 29.2 _+ 5.4 32.3 _+ 11.0 119 + 22 48 _+ 6 63 + 17 ACh = after acetylcholine infusion; Baseline = before acetylcholine; BP = mean systemic arterial pressure; CI - cardiac index; HR = heart rate; LAp = left atrial pressure; NA = not available; Pa% - systemic arterial oxygen tension; PAp = mean pulmonary artery pressure; PAWp - pulmonary artery wedge pressure; PBFI = pulmonary blood flow index; Pt = patient; PVRI = pulmonary vascular resistance index; Qs/Qt = intrapulmonary shunt fraction; RAp right atrial pressure; SVRI = systemic vascular resistance index; TPG = transpulmonary gradient. patients, independent of differences in pulmonary blood flow. In earlier studies this dose of acetylcholine had reliably caused pulmonary vasodilation with minimal systemic effects in chil- dren with congenital heart disease undergoing preoperative cardiac catheterization (9). Statistical analysis and calculations. The change in the hemodynamic variables between baseline and in response to acetylcholine and nitric oxide was compared with a nonpara- metric test for repeated measures (Friedman), and when differences were found, a Wilcoxon signed-rank test was used. A p value <0.05 was considered significant. The differences between groups I and II were analyzed using a Mann-Whitney U Test. Standard equations were used to calculate systemic and pulmonary vascular resistances and were indexed to body surface area. To calculate the intrapulmonary shunt fraction (Qs/Qt) in patients with high left atrial pressure, we applied the equation as described by Riley and Cournand (26). Ethical approval and informed consent. The investigation was approved by the Children's Hospital Investigational Re- view Board and reported to the Food and Drug Administra- tion. Written informed consent was obtained from the patients or their parents. Results Individual patient responses to inhaled nitric oxide and aeetylcholine are displayed in Tables 2 and 3, respectively. Effect of nitric oxide. Nitric oxide in group I (patients with an elevated left atrial pressure). Group I patients displayed marked pulmonary vascular reactivity in response to nitric oxide. Pulmonary artery pressure decreased from 71.7 _+ 12.9 to 58.8 _+ 10.4 mm Hg (p < 0.05); pulmonary vascular resistance decreased from 14.9 +_ 3.8 to 7.6 _+ 1.7 Um 2 (p < 0.05); and transpulmonary gradient was reduced from 44.7 _+ 12.2 to 26.7 _+ 8.1 mm Hg (p < 0.05) (Table 2). The intrapulmonary shunt fraction decreased from 17.8 _+ 3.6% to 12.7 _+ 2.1% (p < 0.05). There was a tendency for left atrial pressure to increase (27.0 _+ 4.2 to 32.2 _+ 4.9 mm Hg, p = 0.07). Cardiac index was 2.9 _+ 0.2 liters/rain per m 2 at baseline and 3.3 _+ 0.4 liters/rain per m 2 with nitric oxide. Systemic vascular resistance index and blood pressure did not change with nitric oxide. All six patients had a baseline pulmonary vascular resistance ->8 Um 2, thereby potentially eliminating transplantation of the heart alone. However, four patients responded to inhaled nitric oxide with a reduction in pulmonary artery pressure that reduced pulmonary vascular resistance <6.0 Um 2 and in three
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`1660 ADATIA ET AL. JACC Vol. 25, No. 7 NITRIC OXIDE IN PULMONARY HYPERTENSION June 1995:1656-64 patients transpulmonary gradient <15 mm Hg such that their transplantation status was altered from combined heart and lung transplantation to heart transplantation alone. Two of these patients (Patients 3 and 4) underwent successful cardiac transplantation with a low pulmonary vascular resistance in the postoperative period. Three days after cardiac transplantation, Patient 4 had a pulmonary artery pressure of 41 mm Hg and pulmonary vascular resistance of 5.5 Um 2, identical to that predicted by the preoperative assessment with nitric oxide. There was a further reduction in pulmonary artery pressure to 36 mm Hg and in pulmonary vascular resistance to 4.2 Um 2 in response to inhaling nitric oxide for 15 min. Patient 3 had a mean pulmonary artery pressure in the immediate postoperative period of 25 mm Hg, with a pulmo- nary vascular resistance of 3.5 Um 2. One month after trans- plantation, mean pulmonary artery pressure was 26 mm Hg and pulmonary vascular resistance 6.2 Um 2. Patient 3 died 2 months after cardiac transplantation and after hospital dis- charge of acute graft rejection. There were three additional deaths. Patient 1 died after heart and lung transplantation, Patient 2 during an intercur- rent pneumonia while awaiting a heart and lung donation and Patient 6 while awaiting a donor heart. Patient 5 is awaiting cardiac transplantation. Important increases in left atrial pressure and cardiac index were confined to Patients 1, 2, and 6, who carried the diagnosis of Shone syndrome variants. All three patients had a suprasys- temic pulmonary artery pressure but no intracardiac shunt. In patients 1 and 2, left atrial pressure returned toward baseline at 18 and 33 mm Hg, respectively, 15 min after discontinuing the inhalation of nitric oxide. Nitric oxide in group II (patients with a low left atrial pressure). Although there was a statistically significant de- crease in pulmonary vascular resistance from 36.4 + 9.0 to 31.1 + 7.9 Um 2 (p < 0.05), the changes in pulmonary hemodynamic variables were not clinically important (Table 2). There was a tendency for pulmonary artery pressure to decrease and for pulmonary blood flow to increase. Only Patient 8 with cystic fibrosis responded to nitric oxide with a 10% decline in pulmonary artery pressure and a 21% decline in pulmonary vascular resistance. Patient 8 underwent lung transplantation, and the four other group II patients are awaiting transplantation. Effect of aeetyleholine. In the seven patients who received acetylcholine, there was no overall significant alteration in pulmonary hemodynamic variables. The decrease in pulmo- nary vascular resistance was significantly less than that with nitric oxide (p < 0.05) (Table 3). Acetylcholine in group I (patients with a high left atrial pressure). Three of six patients received acetylcholine. No patient responded with a larger decrease in pulmonary artery pressure or pulmonary vascular resistance than that with nitric oxide. Acetylcholine did not change pulmonary artery pressure in two patients (Patients 1 and 3), but pulmonary vascular resistance increased by 6.5% in Patient 3 and decreased by 7% in Patient 1, associated with changes in cardiac index. Patient 4 responded with an 8% decrease in pulmonary artery pressure and a 15% decrease in pulmonary vascular resistance without a change in cardiac index. Acetylcholine in group II (patients with a low left atrial pressure). Four of five patients received acetylcholine. Patient 8 with cystic fibrosis responded with a 13% decrease in pulmonary artery pressure and a 12% decrease in pulmonary vascular resistance. Patient 11 responded with a small increase in pulmonary vascular resistance (4.5%) accompanied by a small decrease in pulmonary blood flow (4.5%). Differences between groups I and II. The difference in the responses of patients with a high versus low left atrial pressure is evident from Table 2. The percent change in pulmonary artery pressure (p < 0.05), pulmonary vascular resistance (p < 0.01) and transpulmonary gradient (p < 0.01) were signifi- cantly greater with nitric oxide in group I than group II. Pathologic findings. Pathologic examination of the heart in three of the patients who died (Patients 1, 2, and 6) confirmed the clinical diagnosis and demonstrated very hypertrophied left atrial and ventricular walls with extensive endocardial fibro- elastosis. Vascular histologic examination of the lungs in Patients 1 and 2 demonstrated changes of grades 3 to 4 and grade 2 in Patient 6 according to the classification of Heath and Edwards (27). Left ventricular cavity size was reduced in Patients 1 and 2. Nitrogen dioxide and methemoglobin. Nitrogen dioxide levels remained <1 ppm throughout exposure to nitric oxide in all patients. Methemoglobin levels ranged from 0% to 0.9% (mean 0.4 +_ 0.1%, normal reference range 0% to 5%). Discussion General findings. This preliminary evaluation suggests that nitric oxide was effective in lowering pulmonary artery pressure and pulmonary vascular resistance without important systemic effects in a small group of patients undergoing assessment of pulmonary vascular reactivity as a prelude to cardiopulmonary transplantation. The response was most clinically important in the group of patients with ventricular failure and left atrial hypertension. On the basis of the response to nitric oxide, four patients were reclassified to receive heart transplantation alone, and two did so with low pulmonary vascular resistance in the postoperative period. In the two patients in whom the challenge with inhaled nitric oxide failed to lower pulmonary vascular resistance adequately, histologic examination of the explanted lungs confirmed severe pulmonary vascular disease. We suggest that nitric oxide may be useful in further discrim- inating between those patients needing combined cardiopul- monary transplantation and those for whom cardiac replace- ment alone is sufficient. In contrast to assessment of pulmonary vascular reactivity with intravenous vasodilators, use of inhaled nitric oxide minimizes confounding variables, such as systemic vasodilation and concomitant changes in cardiac output, and simplifies the interpretation of changes in pulmonary vascular resistance (11,28,29). However, because we did not compare endothelium-independent intravenous vasodilators, such as
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`JACC Vol. 25, No. 7 ADATIA ET AL. 1661 June 1995:1656-64 NITRIC OXIDE IN PULMONARY HYPERTENSION prostacyclin or sodium nitroprusside, with inhaled nitric oxide, we cannot exclude the possibility that the response to these agents would have been similar in our patients. Although 7 of the 11 patients in the present study had congenital heart disease with pulmonary hypertension, they differ from patients reported previously because of the ad- vanced nature of their pulmonary hypertension (8,9). Nitric oxide and heart versus heart and lung transplanta- tion. Elevated pulmonary vascular resistance is regarded as a risk factor before cardiac transplantation (1,30), manifested primarily by an increased risk of postoperative right ventricular failure (4-6,31). Patients with pulmonary and left atrial hyper- tension often have a reversible component to their pulmonary hypertension if the underlying cause can be relieved (32). Therefore, assessment of the reversibility and quantification of • the pulmonary vascular disease are important before trans- plantation. Limited numbers of donor organs further dictate that accurate assessment of the lowest achievable pulmonary vascular resistance be made, thereby limiting combined heart and lung transplantations and ensuring more effective distri- bution and proper use of scarce resources. Patients with left atrial hypertension may have a high calculated pulmonary vascular resistance because the cardiac index is low, the pulmonary vasculature is constricted, or there is fixed pulmonary vascular obstructive disease with a reduc- tion in recruitable lung vessels. Preoperative assessment may be aimed at increasing cardiac output with drugs such as dobutamine or combining vasodilation and an increase in cardiac output with drugs such as nitroprusside or prostacydin. The use of catecholamines or systemic vasodilators is not without risk, especially in patients with left ventricular outflow tract obstruction, as in two of our patients, or in patients with increased susceptibility to arrhythmias. The use of vasodilators is often limited because of systemic hypotension or an increase in intrapulmonary shunt resulting in hypoxemia, which further confounds assessment of pulmonary vasoconstriction (2,3,28). Nitric oxide produced a decrease in pulmonary artery pressure and pulmonary vascular resistance and a decrease in intrapul- monary shunt fraction without important changes in heart rate, systemic vascular resistance, systemic blood pressure or cardiac output. This is concordant with findings in other related studies (9 -14,29). The effect of nitric oxide in the three patients with the diagnosis of Shone syndrome variant was interesting. Both patients had suprasystemic right ventricular pressure and responded to nitric oxide not only with marked reduction in pulmonary artery pressure and resistance, but also with a substantial increase in cardiac output associated with an ele- vation in left atrial pressure. One might postulate that when right ventricular pressure is suprasystemic, reductions in after- load result in an increase in cardiac output because of reduced left ventricular deformation and improved right ventricular perfusion and performance. The increased cardiac output may then cause an increase in left atrial pressure if there is either mitral stenosis or a noncompliant left atrium and ventricle. Indeed, Wood et al. (33) made the insightful observation that in patients with mitral stenosis, symptoms of pulmonary edema were rare among those with the highest pulmonary vascular resistances, which led them to show that lowering pulmonary vascular resistance in such patients could lead to an increase in left atrial pressure and cardiac output. This was most marked in our patients with end-stage Shone disease and congenitally small, noncompliant left atria and ventricles. Kieler-Jensen et al. (28) reported an increase in pulmonary artery wedge pressure after inhalation of nitric oxide in adult patients with acquired cardiomyopathies. We did not witness such an eleva- tion in left atrial pressure after a trial of nitric oxide in other patients (25). The hemodynamic effects of nitric oxide are quickly reversed when it is withdrawn (8,11,14,28,34), thus limiting any lasting adverse sequelae. Nevertheless, precipita- tion of pulmonary edema was reported after a trial of nitric oxide (35) and highlights the need for careful observation and intensive monitoring during its administration. In Patient 4, nitric oxide further reduced postoperative pulmonary artery pressure and pulmonary vascular resistance. Nitric oxide has been used with success in the postoperative cardiac patient (9,10) and after cardiac transplantation to support a patient with transient right ventricular failure (36). Patients with pulmonary hypertension and transient graft dysfunction after lung transplantation have benefited from prolonged treatment with nitric oxide (14). Nitric oxide may prove to be a useful addition to the pharmacologic support of patients with elevated pulmonary vascular resistance and poor right ventricular function after heart transplantation. Clinical effects of nitric oxide. The striking response of the pulmonary circulation to nitric oxide in patients with pulmo- nary venous hypertension is evident from other publis