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Applications of Inhaled Nitric Oxide Following Cardiac Operations
MEDICAL/SURGICAL CONSIDERATIONS
temic vasorelaxation. Because the half-life of cGMP is less than one minute, the vasodilating action of NO is stopped when inhaled NO is withdrawn from the breathing circuit. Thus the pharmacologic effects of NO are eliminated with cessation of the drug (1). Inhaled NO is considered an experimental drug by the Federal Drug Administration (FDA). As such, it may not be purchased for clinical use without an Investigational New Drug number issued to an investigator by the FDA. Further, its use requires approval of a local Investigational Review Board. Inhaled NO is typically administered in concentrations of 1 to 80 ppm. Because it is potentially toxic to lung tissue, the concentration of administered inhaled NO (and its product of oxidation, NO2) must be monitored by chemiluminescence. When closely monitored, inhaled NO may be used safely. It may be prudent to “scavenge” the exhaled gas from patients treated with inhaled NO, but recent data suggest that the exposure of hospital personnel to NO or its metabolites from such patients is minimal (2,3). The pulmonary vasoconstricting effects of cardiopulmonary bypass are well recognized. Following cardiopulmonary bypass, increased pulmonary vascular tone may be due to increased levels of circulating or local vasoconstricting agonists. Recent data suggest that pulmonary vascular endothelial cell dysfunction may contribute to pulmonary vasoconstriction following cardiopulmonary bypass; impairment of endothelium-dependent pulmonary vasorelaxation has recently been described following cardiopulmonary bypass (4). Inhaled NO achieves pulmonary vascular smooth relaxation independently of the endothelium and may offer a mechanistic advantage for use as a pulmonary vasodilator following cardiopulmonary bypass. There are few data regarding the effect of inhaled NO in the pulmonary circulation in adult cardiac surgical patients. In a recent study of patients undergoing aortocoronary bypass surgery, inhaled NO (20 and 40 ppm) produced a consistent reduction in pulmonary arterial pressure and PVR without change in systemic arterial pressure or systemic vascular resistance (SVR) (5). Mean pulmonary arterial pressure (MPAP) was lowered from 29 6 1 to 21 6 1 mm Hg by inhaled NO; systemic mean arterial pressure remained unchanged during inhalation of NO at 75 6 3 mm Hg. PVR was lowered from 343 6 30 to 233 6 25 dyne z sec z cm25 during inhalation of NO with no change in SVR. This pulmonary vasodilation produced a significant reduction in transpulmonary gradient as well as RV stroke work index. No greater pulmonary vasodilation was achieved by NO 40 ppm over NO 20 ppm. All hemodynamic variables returned to baseline after cessation of inhaled NO.
BRIEF REVIEW
Applications of Inhaled Nitric Oxide Following Cardiac Operations David A. Fullerton, MD, Cardiothoracic Surgery, Northwestern University Medical School, Chicago, Illinois ncreased pulmonary vascular resistance (PVR) may greatly complicate the perioperative management of cardiac surgical patients. Since PVR is the primary clinical determinant of right ventricular (RV) afterload, increased PVR may result in RV afterload-mismatch, compromising cardiac output. Pharmacologic agents which are currently used as pulmonary vasodilators in cardiac surgical patients include sodium nitroprusside, nitroglycerin, dobutamine, phosphodiesterase (PDE) inhibitors, and prostaglandin E1 (PGE1). Unfortunately, these intravenous vasodilators produce nonselective vasodilation of both the pulmonary and systemic circulations. Nonselective vasodilation may be hazardous in patients with increased PVR; significant hypotension may result if the degree of systemic vasodilation exceeds that of the pulmonary vasodilation. Such hypotension may impair coronary arterial perfusion pressure to such an extent as to produce RV ischemia and failure.
I
Nitric Oxide Mechanisms of Action Inhaled nitric oxide (NO) is a relatively new therapy which holds promise for the control of PVR in cardiac surgical patients. Recent studies have demonstrated that inhaled NO may be used as an effective pulmonary vasodilator in patients following cardiopulmonary bypass. Because its vasodilating actions are clinically focused in the pulmonary circulation and have no effect in the systemic circulation, it offers particular advantage in cardiac surgical patients. Once inhaled into the alveolus, NO readily diffuses across the alveolar-capillary membrane to relax pulmonary vascular smooth muscle by stimulating the production of guanosine 39, 59-cyclic monophosphate (cGMP). As it diffuses into the blood vessel lumen, it is immediately bound to hemoglobin and inactivated; the affinity of hemoglobin for NO is 3,000 times greater than for oxygen. In binding the NO, the hemoglobin is converted to nitrosyl hemoglobin and then to methemoglobin. Methemoglobin is then converted to nitrates and nitrites by methemoglobin reductase found in erythrocytes. It is estimated that most of the circulating nitrates and nitrites found in blood are derived from the metabolism of endogenous NO. By binding to hemoglobin, the vasodilating actions of inhaled NO are limited to the pulmonary circulation without producing unwanted sys-
Potential Indications Valvular heart disease is the most common reason for pulmonary hypertension among adult cardiac surgical patients;
ACC CURRENT JOURNAL REVIEW September/October 1997 © 1997 by the American College of Cardiology Published by Elsevier Science Inc.
50
1062-1458/97/$17.00 PII S1062-1458(97)00082-2
MEDICAL/SURGICAL CONSIDERATIONS
produced significant pulmonary vasodilation, thereby converting nonresponding patients into responders. PVR and MPAP were significantly reduced and cardiac output was increased without change in systemic mean arterial pressure (7). Such combined therapy may be particularly valuable in patients with right heart dysfunction secondary to pulmonary hypertension by effectively lowering right ventricular afterload.
it produces remodeling of the pulmonary vascular bed. Unlike cardiac surgical patients who have pulmonary hypertension solely on the basis of pulmonary vasoconstriction (such as patients undergoing aortocoronary bypass grafting), at least three pathophysiologic mechanisms contribute to the pulmonary hypertension seen in long-standing aortic or mitral valvular disease: 1) increased left atrial (LA) pressure transmitted retrograde into the arterial circulation; 2) vascular remodeling of the pulmonary vasculature in response to chronic obstruction to pulmonary venous drainage (“fixed component”); and 3) pulmonary arterial vasoconstriction (“reactive component”). Thus, control of PVR in such patients may be a vexing problem. Once the elevated LA pressure is relieved by valve replacement, increased PVR does not immediately return to normal; several days to weeks may be required. For this reason, perioperative pulmonary vasodilator therapy is most often required in patients undergoing valve surgery and it is in this group of patients that inhaled NO would theoretically be most useful. Unfortunately, the efficacy of inhaled NO as a pulmonary vasodilator appears to be less in cardiac surgical patients with pulmonary hypertension from valvular heart disease than in patients undergoing aortocoronary bypass grafting. In patients undergoing aortocoronary artery bypass grafting, inhaled NO (40 ppm) produced a 24% decrease in MPAP (33 6 1 to 25 6 1 mm Hg), a 36% decrease in PVR (375 6 30 to 250 6 30 dyne z sec z cm25), and no change in systemic arterial blood pressure. On the other hand, patients with pulmonary hypertension from valvular heart disease did not respond to inhaled NO: MPAP was 39 6 3 and PVR was 620 6 30 before, during and after NO (6).
Nitric Oxide in the Evaluation for Heart Transplant Increased PVR (.6 Wood U) is a strong relative contraindication to cardiac transplantation. Therefore, potential heart transplant recipients must be carefully evaluated to determine if elevated pulmonary arterial pressure may be lowered with vasodilator therapy. Such pharmacological provocation is typically performed in the cardiac catheterization suite using sodium nitroprusside or PGE1 infusion. Inhaled NO (up to 80 ppm) has likewise been shown to lower pulmonary arterial pressure and PVR without producing systemic vasodilation. But because most patients under consideration for heart transplantation have severe left ventricular (LV) dysfunction, a selective reduction in RV afterload produced by lowering PVR may increase the preload of the left ventricle (left atrial pressure) in a patient unable to increase LV output. This may produce an unwanted elevation in LA pressure (8). Until further data are available, the routine use of inhaled NO to determine the reactivity of the pulmonary circulation in patients under consideration for heart transplantation may be inadvisable. In the postoperative period following heart transplantation, RV failure secondary to increased PVR continues to account for a large percentage of early deaths. Inhaled NO has been used to effectively lower RV afterload (PVR) and optimize RV function in patients with RV dysfunction following orthotopic heart transplantation. When directly compared to other pulmonary vasodilators following heart transplantation, the reduction in pulmonary arterial pressure and PVR produced by inhaled NO was comparable to that produced by IV infusions of sodium nitroprusside, PGE1 and prostacyclin. Unlike IV vasodilators, inhaled NO “selectively” lowered PVR without producing systemic vasodilation. It may therefore be particularly well suited as a pulmonary vasodilator in the postoperative heart transplant patient.
Nitric Oxide in Cardiac Surgery Patients As noted, the intracellular mediator of the vasodilating actions of NO is cGMP. Although the mechanism by which cGMP effects pulmonary vascular smooth muscle relaxation is unclear, pulmonary vascular tone is assumed to be closely related to intracellular levels of pulmonary vascular smooth muscle cGMP. In turn, the net concentration of cGMP within pulmonary vascular smooth muscle is determined by the balance of its production by guanylate cyclase and degradation by PDE. In cardiac surgical patients whose pulmonary hypertension failed to respond to inhaled NO, the effectiveness of inhaled NO was increased by using a twopronged approach: (1) stimulating cGMP production with inhaled NO plus (2) preventing the breakdown of cGMP by inhibiting PDE (dipyridamole). In a study of 10 cardiac surgical patients with pulmonary hypertension from aortic and/or mitral valvular disease (MPAP $ 30 mm Hg) studied in the operating room after valve replacement, neither inhaled NO alone (40 ppm) nor dipyridamole (0.2 mg/kg IV) alone lowered PVR or pulmonary artery pressure. However, the combination of inhaled NO plus dipyridamole effectively
Nitric Oxide in Pediatric Surgical Patients Secondary pulmonary hypertension most commonly complicates the perioperative management of pediatric cardiac surgical patients undergoing surgical correction of congenital heart disease (CHD). This pulmonary hypertension is derived in large part from the structural changes induced by excessive pulmonary blood flow (“fixed component”). However, pulmonary vasoconstriction may also contribute to
ACC CURRENT JOURNAL REVIEW September/October 1997
51
MEDICAL/SURGICAL CONSIDERATIONS
apparent that some patients may not respond to inhaled NO therapy. Future research efforts should be focused upon the identification of those patients who may not respond to NO in order that appropriate management may be devised.
pulmonary hypertension (“reactive component”). Recent data in laboratory animal models as well as in children with CHD suggest that dysfunction of the vascular endothelium is produced with chronic excessive pulmonary blood flow. Such dysfunction may contribute to pulmonary hypertension. Inhaled NO has been shown to successfully lower PVR when given to patients in the cardiac catheterization laboratory prior to correction of congenital heart defects suggesting that at least prior to surgical correction, the “reactive” component of the pulmonary hypertension in these patients may be successfully attenuated by a combination of oxygen and NO therapy (9). Further, inhaled NO has been administered to 17 patients with refractory pulmonary hypertension in the early postoperative period following correction of congenital heart lesions. The procedures included repair of total anomalous pulmonary venous return (6), complete atrial ventricular septal defect (4), ventricular septal defect (3), truncus arteriosus (2), ventricular septal defect and interrupted aortic arch (1), and LA obstruction following a Senning operation (1). Inhaled NO lowered pulmonary arterial pressure in 12 of these 17 patients; 5 (30%) of these patients did not respond to inhaled NO. Prior to administration of inhaled NO (20 to 40 ppm), the ratio of MPAP to mean aortic pressure was 0.75. Among the patients who did respond, inhaled NO successfully lowered this ratio to 0.5 where it remained for 12 hours during inhaled NO therapy. However, administration of inhaled NO was associated with a significant decrease in mean systemic arterial blood pressure in 4 of these 17 patients (24%) (10).
REFERENCES 1. Fullerton DA, McIntyre RC Jr. Inhaled nitric oxide: Therapeutic applications in cardiothoracic surgery. Ann Thorac Surg 1996;61:1856 –1864. 2. Wessel DL, Adatia I, Thompson JE, Hickey PR. Delivery and monitoring of inhaled nitric oxide in patients with pulmonary hypertension. Crit Care Med 1994;22:930 – 8. 3. Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH. Nitric oxide and the lung. Am J Resp Crit Care Med 1994;149:1375– 80. 4. Wessel DL, Adatia I, Giglia TM, et al. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation 1993;88:2128 –38. 5. Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr. Effective control of pulmonary vascular resistance with inhaled nitric oxide following cardiac operation. J Thorac Cardiovasc Surg 1996;111:753– 63. 6. Fullerton DA, Jaggers J, Wollmering M, Piedalue F, Grover FL, McIntyre RC Jr. Variable response to inhaled nitric oxide after cardiac surgery. Ann Thorac Surg 1997;63:1251– 6. 7. Fullerton DA, Jaggers J, Piedalue F, Grover FL, McIntyre RC. Effective control of refractory pulmonary hypertension after cardiac surgery. J Thorac Cardiovasc Surg 1997;113:363– 8. 8. Kierler-Jensen N, Ricksten S-E, Stenqvist O, et al. Inhaled nitric oxide in the evaluation of heart-transplant candidates with elevated pulmonary vascular resistance. J Heart Lung Transplant 1994;13:366 –75. 9. Robert JD Jr, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation 1993;87:447–53. 10. Journais D, Pouard P, Mauriat P, Malhe`re T, Vouhe´ P, Safran D. Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects. J Thorac Cardiovasc Surg 1994;107:1129 –35.
Summary In summary, inhaled NO holds promise as a valuable therapeutic tool to be used in the management of pulmonary hypertension following cardiac operations. However, it is
Address correspondence and reprint requests to David A. Fullerton, MD, Cardiothoracic Surgery, Northwestern University Medical School, Suite 1030 Wesley Pavilion, 251 East Chicago Avenue, Chicago, IL, 60611.
ACC CURRENT JOURNAL REVIEW September/October 1997
52
temic vasorelaxation. Because the half-life of cGMP is less than one minute, the vasodilating action of NO is stopped when inhaled NO is withdrawn from the breathing circuit. Thus the pharmacologic effects of NO are eliminated with cessation of the drug (1). Inhaled NO is considered an experimental drug by the Federal Drug Administration (FDA). As such, it may not be purchased for clinical use without an Investigational New Drug number issued to an investigator by the FDA. Further, its use requires approval of a local Investigational Review Board. Inhaled NO is typically administered in concentrations of 1 to 80 ppm. Because it is potentially toxic to lung tissue, the concentration of administered inhaled NO (and its product of oxidation, NO2) must be monitored by chemiluminescence. When closely monitored, inhaled NO may be used safely. It may be prudent to “scavenge” the exhaled gas from patients treated with inhaled NO, but recent data suggest that the exposure of hospital personnel to NO or its metabolites from such patients is minimal (2,3). The pulmonary vasoconstricting effects of cardiopulmonary bypass are well recognized. Following cardiopulmonary bypass, increased pulmonary vascular tone may be due to increased levels of circulating or local vasoconstricting agonists. Recent data suggest that pulmonary vascular endothelial cell dysfunction may contribute to pulmonary vasoconstriction following cardiopulmonary bypass; impairment of endothelium-dependent pulmonary vasorelaxation has recently been described following cardiopulmonary bypass (4). Inhaled NO achieves pulmonary vascular smooth relaxation independently of the endothelium and may offer a mechanistic advantage for use as a pulmonary vasodilator following cardiopulmonary bypass. There are few data regarding the effect of inhaled NO in the pulmonary circulation in adult cardiac surgical patients. In a recent study of patients undergoing aortocoronary bypass surgery, inhaled NO (20 and 40 ppm) produced a consistent reduction in pulmonary arterial pressure and PVR without change in systemic arterial pressure or systemic vascular resistance (SVR) (5). Mean pulmonary arterial pressure (MPAP) was lowered from 29 6 1 to 21 6 1 mm Hg by inhaled NO; systemic mean arterial pressure remained unchanged during inhalation of NO at 75 6 3 mm Hg. PVR was lowered from 343 6 30 to 233 6 25 dyne z sec z cm25 during inhalation of NO with no change in SVR. This pulmonary vasodilation produced a significant reduction in transpulmonary gradient as well as RV stroke work index. No greater pulmonary vasodilation was achieved by NO 40 ppm over NO 20 ppm. All hemodynamic variables returned to baseline after cessation of inhaled NO.
BRIEF REVIEW
Applications of Inhaled Nitric Oxide Following Cardiac Operations David A. Fullerton, MD, Cardiothoracic Surgery, Northwestern University Medical School, Chicago, Illinois ncreased pulmonary vascular resistance (PVR) may greatly complicate the perioperative management of cardiac surgical patients. Since PVR is the primary clinical determinant of right ventricular (RV) afterload, increased PVR may result in RV afterload-mismatch, compromising cardiac output. Pharmacologic agents which are currently used as pulmonary vasodilators in cardiac surgical patients include sodium nitroprusside, nitroglycerin, dobutamine, phosphodiesterase (PDE) inhibitors, and prostaglandin E1 (PGE1). Unfortunately, these intravenous vasodilators produce nonselective vasodilation of both the pulmonary and systemic circulations. Nonselective vasodilation may be hazardous in patients with increased PVR; significant hypotension may result if the degree of systemic vasodilation exceeds that of the pulmonary vasodilation. Such hypotension may impair coronary arterial perfusion pressure to such an extent as to produce RV ischemia and failure.
I
Nitric Oxide Mechanisms of Action Inhaled nitric oxide (NO) is a relatively new therapy which holds promise for the control of PVR in cardiac surgical patients. Recent studies have demonstrated that inhaled NO may be used as an effective pulmonary vasodilator in patients following cardiopulmonary bypass. Because its vasodilating actions are clinically focused in the pulmonary circulation and have no effect in the systemic circulation, it offers particular advantage in cardiac surgical patients. Once inhaled into the alveolus, NO readily diffuses across the alveolar-capillary membrane to relax pulmonary vascular smooth muscle by stimulating the production of guanosine 39, 59-cyclic monophosphate (cGMP). As it diffuses into the blood vessel lumen, it is immediately bound to hemoglobin and inactivated; the affinity of hemoglobin for NO is 3,000 times greater than for oxygen. In binding the NO, the hemoglobin is converted to nitrosyl hemoglobin and then to methemoglobin. Methemoglobin is then converted to nitrates and nitrites by methemoglobin reductase found in erythrocytes. It is estimated that most of the circulating nitrates and nitrites found in blood are derived from the metabolism of endogenous NO. By binding to hemoglobin, the vasodilating actions of inhaled NO are limited to the pulmonary circulation without producing unwanted sys-
Potential Indications Valvular heart disease is the most common reason for pulmonary hypertension among adult cardiac surgical patients;
ACC CURRENT JOURNAL REVIEW September/October 1997 © 1997 by the American College of Cardiology Published by Elsevier Science Inc.
50
1062-1458/97/$17.00 PII S1062-1458(97)00082-2
MEDICAL/SURGICAL CONSIDERATIONS
produced significant pulmonary vasodilation, thereby converting nonresponding patients into responders. PVR and MPAP were significantly reduced and cardiac output was increased without change in systemic mean arterial pressure (7). Such combined therapy may be particularly valuable in patients with right heart dysfunction secondary to pulmonary hypertension by effectively lowering right ventricular afterload.
it produces remodeling of the pulmonary vascular bed. Unlike cardiac surgical patients who have pulmonary hypertension solely on the basis of pulmonary vasoconstriction (such as patients undergoing aortocoronary bypass grafting), at least three pathophysiologic mechanisms contribute to the pulmonary hypertension seen in long-standing aortic or mitral valvular disease: 1) increased left atrial (LA) pressure transmitted retrograde into the arterial circulation; 2) vascular remodeling of the pulmonary vasculature in response to chronic obstruction to pulmonary venous drainage (“fixed component”); and 3) pulmonary arterial vasoconstriction (“reactive component”). Thus, control of PVR in such patients may be a vexing problem. Once the elevated LA pressure is relieved by valve replacement, increased PVR does not immediately return to normal; several days to weeks may be required. For this reason, perioperative pulmonary vasodilator therapy is most often required in patients undergoing valve surgery and it is in this group of patients that inhaled NO would theoretically be most useful. Unfortunately, the efficacy of inhaled NO as a pulmonary vasodilator appears to be less in cardiac surgical patients with pulmonary hypertension from valvular heart disease than in patients undergoing aortocoronary bypass grafting. In patients undergoing aortocoronary artery bypass grafting, inhaled NO (40 ppm) produced a 24% decrease in MPAP (33 6 1 to 25 6 1 mm Hg), a 36% decrease in PVR (375 6 30 to 250 6 30 dyne z sec z cm25), and no change in systemic arterial blood pressure. On the other hand, patients with pulmonary hypertension from valvular heart disease did not respond to inhaled NO: MPAP was 39 6 3 and PVR was 620 6 30 before, during and after NO (6).
Nitric Oxide in the Evaluation for Heart Transplant Increased PVR (.6 Wood U) is a strong relative contraindication to cardiac transplantation. Therefore, potential heart transplant recipients must be carefully evaluated to determine if elevated pulmonary arterial pressure may be lowered with vasodilator therapy. Such pharmacological provocation is typically performed in the cardiac catheterization suite using sodium nitroprusside or PGE1 infusion. Inhaled NO (up to 80 ppm) has likewise been shown to lower pulmonary arterial pressure and PVR without producing systemic vasodilation. But because most patients under consideration for heart transplantation have severe left ventricular (LV) dysfunction, a selective reduction in RV afterload produced by lowering PVR may increase the preload of the left ventricle (left atrial pressure) in a patient unable to increase LV output. This may produce an unwanted elevation in LA pressure (8). Until further data are available, the routine use of inhaled NO to determine the reactivity of the pulmonary circulation in patients under consideration for heart transplantation may be inadvisable. In the postoperative period following heart transplantation, RV failure secondary to increased PVR continues to account for a large percentage of early deaths. Inhaled NO has been used to effectively lower RV afterload (PVR) and optimize RV function in patients with RV dysfunction following orthotopic heart transplantation. When directly compared to other pulmonary vasodilators following heart transplantation, the reduction in pulmonary arterial pressure and PVR produced by inhaled NO was comparable to that produced by IV infusions of sodium nitroprusside, PGE1 and prostacyclin. Unlike IV vasodilators, inhaled NO “selectively” lowered PVR without producing systemic vasodilation. It may therefore be particularly well suited as a pulmonary vasodilator in the postoperative heart transplant patient.
Nitric Oxide in Cardiac Surgery Patients As noted, the intracellular mediator of the vasodilating actions of NO is cGMP. Although the mechanism by which cGMP effects pulmonary vascular smooth muscle relaxation is unclear, pulmonary vascular tone is assumed to be closely related to intracellular levels of pulmonary vascular smooth muscle cGMP. In turn, the net concentration of cGMP within pulmonary vascular smooth muscle is determined by the balance of its production by guanylate cyclase and degradation by PDE. In cardiac surgical patients whose pulmonary hypertension failed to respond to inhaled NO, the effectiveness of inhaled NO was increased by using a twopronged approach: (1) stimulating cGMP production with inhaled NO plus (2) preventing the breakdown of cGMP by inhibiting PDE (dipyridamole). In a study of 10 cardiac surgical patients with pulmonary hypertension from aortic and/or mitral valvular disease (MPAP $ 30 mm Hg) studied in the operating room after valve replacement, neither inhaled NO alone (40 ppm) nor dipyridamole (0.2 mg/kg IV) alone lowered PVR or pulmonary artery pressure. However, the combination of inhaled NO plus dipyridamole effectively
Nitric Oxide in Pediatric Surgical Patients Secondary pulmonary hypertension most commonly complicates the perioperative management of pediatric cardiac surgical patients undergoing surgical correction of congenital heart disease (CHD). This pulmonary hypertension is derived in large part from the structural changes induced by excessive pulmonary blood flow (“fixed component”). However, pulmonary vasoconstriction may also contribute to
ACC CURRENT JOURNAL REVIEW September/October 1997
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MEDICAL/SURGICAL CONSIDERATIONS
apparent that some patients may not respond to inhaled NO therapy. Future research efforts should be focused upon the identification of those patients who may not respond to NO in order that appropriate management may be devised.
pulmonary hypertension (“reactive component”). Recent data in laboratory animal models as well as in children with CHD suggest that dysfunction of the vascular endothelium is produced with chronic excessive pulmonary blood flow. Such dysfunction may contribute to pulmonary hypertension. Inhaled NO has been shown to successfully lower PVR when given to patients in the cardiac catheterization laboratory prior to correction of congenital heart defects suggesting that at least prior to surgical correction, the “reactive” component of the pulmonary hypertension in these patients may be successfully attenuated by a combination of oxygen and NO therapy (9). Further, inhaled NO has been administered to 17 patients with refractory pulmonary hypertension in the early postoperative period following correction of congenital heart lesions. The procedures included repair of total anomalous pulmonary venous return (6), complete atrial ventricular septal defect (4), ventricular septal defect (3), truncus arteriosus (2), ventricular septal defect and interrupted aortic arch (1), and LA obstruction following a Senning operation (1). Inhaled NO lowered pulmonary arterial pressure in 12 of these 17 patients; 5 (30%) of these patients did not respond to inhaled NO. Prior to administration of inhaled NO (20 to 40 ppm), the ratio of MPAP to mean aortic pressure was 0.75. Among the patients who did respond, inhaled NO successfully lowered this ratio to 0.5 where it remained for 12 hours during inhaled NO therapy. However, administration of inhaled NO was associated with a significant decrease in mean systemic arterial blood pressure in 4 of these 17 patients (24%) (10).
REFERENCES 1. Fullerton DA, McIntyre RC Jr. Inhaled nitric oxide: Therapeutic applications in cardiothoracic surgery. Ann Thorac Surg 1996;61:1856 –1864. 2. Wessel DL, Adatia I, Thompson JE, Hickey PR. Delivery and monitoring of inhaled nitric oxide in patients with pulmonary hypertension. Crit Care Med 1994;22:930 – 8. 3. Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH. Nitric oxide and the lung. Am J Resp Crit Care Med 1994;149:1375– 80. 4. Wessel DL, Adatia I, Giglia TM, et al. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation 1993;88:2128 –38. 5. Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr. Effective control of pulmonary vascular resistance with inhaled nitric oxide following cardiac operation. J Thorac Cardiovasc Surg 1996;111:753– 63. 6. Fullerton DA, Jaggers J, Wollmering M, Piedalue F, Grover FL, McIntyre RC Jr. Variable response to inhaled nitric oxide after cardiac surgery. Ann Thorac Surg 1997;63:1251– 6. 7. Fullerton DA, Jaggers J, Piedalue F, Grover FL, McIntyre RC. Effective control of refractory pulmonary hypertension after cardiac surgery. J Thorac Cardiovasc Surg 1997;113:363– 8. 8. Kierler-Jensen N, Ricksten S-E, Stenqvist O, et al. Inhaled nitric oxide in the evaluation of heart-transplant candidates with elevated pulmonary vascular resistance. J Heart Lung Transplant 1994;13:366 –75. 9. Robert JD Jr, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation 1993;87:447–53. 10. Journais D, Pouard P, Mauriat P, Malhe`re T, Vouhe´ P, Safran D. Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects. J Thorac Cardiovasc Surg 1994;107:1129 –35.
Summary In summary, inhaled NO holds promise as a valuable therapeutic tool to be used in the management of pulmonary hypertension following cardiac operations. However, it is
Address correspondence and reprint requests to David A. Fullerton, MD, Cardiothoracic Surgery, Northwestern University Medical School, Suite 1030 Wesley Pavilion, 251 East Chicago Avenue, Chicago, IL, 60611.
ACC CURRENT JOURNAL REVIEW September/October 1997
52