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Ann Thorac Surg 1997;63:1251-1256
© 1997 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, Department of Surgery, Northwestern University Medical School, Chicago, Illinois, and Department of Surgery, The University of Colorado, Denver, Colorado
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Methods. The effect of inhaled NO (40 ppm) on pulmonary hemodynamics in patients with pulmonary hypertension (mean pulmonary artery pressure 
30 mm Hg) was studied in the operating room after cardiac operation. Fifteen patients with valvular heart disease comprised the study group; 25 patients undergoing aortocoronary bypass grafting were controls.
Results. In patients undergoing aortocoronary bypass grafting, inhaled NO produced a 24% decrease in mean pulmonary artery pressure (33 ± 1 to 25 ± 1 mm Hg; p < 0.05), a 36% decrease in pulmonary vascular resistance (375 ± 30 to 250 ± 30 dyne•s•cm-5; p < 0.05), 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: mean pulmonary artery pressure was 39 ± 3 mm Hg and pulmonary vascular resistance was 620 ± 30 dyne•s•cm-5 before, during, and after NO.
Conclusions. Among cardiac surgical patients with pulmonary hypertension, the response to inhaled NO is variable. Despite the promise of inhaled NO as a pulmonary vasodilator in cardiac surgical patients, these data suggest that alternative therapies are needed to control pulmonary hypertension in patients with pulmonary hypertension from valvular heart disease.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Pulmonary hypertension secondary to increased pulmonary vascular resistance (PVR) may greatly complicate the perioperative management of cardiac surgical patients. Because PVR is the primary clinical determinant of right ventricular afterload, increased PVR may result in right ventricular afterload mismatch, compromising cardiac output. Most pharmacologic agents currently used as pulmonary vasodilators are administered intravenously and produce vasodilation of both the systemic and pulmonary circulations. Such nonselective vasodilation may be hazardous in patients with increased PVR [1, 2]; marked hypotension may result if the degree of systemic vasodilation exceeds that of pulmonary vasodilation.
Inhaled nitric oxide (NO) is a promising therapy for control of pulmonary hypertension [3]. It has been shown to produce a significant reduction in both pulmonary arterial pressure and PVR without reduction of systemic arterial pressure or systemic vascular resistance in patients after a cardiac operation. Therefore, it may be clinically valuable as a "selective" pulmonary vasodilator in cardiac surgical patients [4]. Mechanistically, inhaled NO diffuses from the alveolus into the subjacent pulmonary vascular smooth muscle. Within pulmonary vascular smooth muscle cells, NO acts to lower PVR by stimulating guanylate cyclase in pulmonary vascular smooth muscle to produce guanosine 3',5'-cyclic monophosphate, which in turn produces vascular smooth muscle relaxation by mechanisms that are yet unclear [5]. The net concentration of cyclic guanosine 3',5'-monophosphate within pulmonary vascular smooth muscle is determined by the balance of its production by guanylate cyclase and degradation by phosphodiesterase.
Valvular heart disease is the most common reason for pulmonary hypertension among adult cardiac surgical patients; it produces remodeling of the pulmonary vascular bed. Unlike cardiac surgical patients who have pulmonary hypertension solely on the basis of pulmonary vasoconstriction, the increased PVR in cardiac surgical patients with pulmonary hypertension secondary to valvular heart disease is derived from both pulmonary vasoconstriction ("reactive component") and pulmonary vascular remodeling ("fixed component") [6]. Because of such pulmonary vascular remodeling, we hypothesized that the effectiveness of inhaled NO in lowering PVR is reduced in cardiac surgical patients with valvular heart disease.
The purpose of this study was to examine the effect of inhaled NO on pulmonary hemodynamics in cardiac surgical patients with pulmonary hypertension with and without valvular heart disease. The results of this study demonstrate that the response to inhaled NO after cardiac surgery is variable; patients with pulmonary hypertension secondary to valvular heart disease failed to respond to inhaled NO.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Administration of Inhaled NO |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Protocol for Data Collection |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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30 mm Hg] after cardiopulmonary bypass. Two groups of patients with pulmonary hypertension were studied: those undergoing operation for valvular heart disease and those undergoing aortocoronary bypass. The group of patients with pulmonary hypertension secondary to valvular heart disease consisted of 15 consecutive patients who underwent the following surgical procedures: aortic valve replacement (n = 4), mitral valve replacement (n = 8), and aortic and mitral valve replacement (n = 3). The group of patients with pulmonary hypertension but without valvular heart disease consisted of 25 consecutive patients with three-vessel coronary artery disease undergoing aortocoronary bypass. All 25 patients had complete coronary artery revascularization including reversed saphenous vein grafts to the right coronary artery system.
Patients received preoperative medication comprising morphine sulfate, 0.1 mg/kg, and scopolamine hydrobromide, 0.4 mg, intramuscularly 1 hour prior to arrival in the operating room. Ongoing drug therapy for concomitant medical problems was continued as deemed appropriate by the attending anesthesiologist.
Each patient was monitored with a five-lead electrocardiogram, a radial artery line, and a pulmonary artery thermodilution oximetric catheter (Abbot Laboratories, Chicago, IL) introduced through the right internal jugular vein. To accurately measure pulmonary venous outflow pressure (left atrial pressure) for determination of PVR, a left atrial pressure-monitoring catheter was introduced into the left atrium through the right superior pulmonary vein after the patient had been weaned from cardiopulmonary bypass. The left atrial pressure catheter was subsequently removed after completion of data collection and prior to chest closure. The anesthesia technique consisted of a high-dose narcotic (fentanyl) and a relaxant (vecuronium bromide) supplemented with intravenous midazolam hydrochloride. Inhalational anesthetic agents were administered only during cardiopulmonary bypass.
Data were collected in the operating room beginning approximately 20 minutes after completion of cardiopulmonary bypass but prior to chest closure. After weaning from bypass and after protamine sulfate administration, all patients were in hemodynamically stable condition and demonstrated normal coagulation. No patient required cardiac pacing, antiarrhythmic therapy, or inotropic or vasoactive drug administration. No inhalational anesthetics were given from the time of cessation of cardiopulmonary bypass during the period of data collection.
The protocol for collection of data proceeded as follows: Tidal volume was set at approximately 10 mL/kg, and respiratory rate was adjusted to establish an arterial carbon dioxide tension of approximately 40 mm Hg and an arterial pH of approximately 7.40 [7]. To avoid changes in pulmonary hemodynamics secondary to changes in ventilatory patterns, ventilator settings were not altered during the study period. Fraction of inspired oxygen was maintained at a mean of 0.97 (range, 0.94 to 0.99), and no patient had application of positive end-expiratory pressure during the study period. Arterial oxygen tension was maintained greater than 275 mm Hg throughout the study period to avoid any influence of hypoxemia on pulmonary vascular tone. Arterial and mixed venous blood gas samples were obtained at each point of data collection. The hemodynamic variables measured and recorded were heart rate, mean systemic arterial blood pressure, MPAP, central venous pressure, left atrial pressure, and thermodilution cardiac output (mean of three values). These allowed mathematical derivation of PVR and systemic vascular resistance, cardiac index, right ventricular stroke work index, and transpulmonary gradient.
After placement of the left atrial pressure line and with the patient in a hemodynamic steady-state, baseline hemodynamic variables were determined. Then, NO 40 ppm was added to the ventilatory circuit. After 15 minutes of inhaled NO 40 ppm, hemodynamic variables were determined. The inhaled NO was then stopped. After 15 minutes, hemodynamic data after inhalation of NO were collected. The left atrial pressure line was removed under direct vision, and its insertion site in the right superior pulmonary vein was determined to be hemostatic. Methemoglobin level was determined before and after data collection.
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Statistical Analysis |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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. All patients undergoing aortocoronary bypass and 11 of the 15 patients undergoing valve operations had a history of cigarette smoking. None, however, demonstrated clinical or radiographic evidence of major chronic pulmonary disease.
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lists the arterial and mixed venous blood gas values along with the hemodynamic variables determined at each point of data collection. There were no significant changes in arterial pH, arterial oxygen tension, or arterial carbon dioxide tension throughout the study period. Likewise, there were no significant changes in heart rate, central venous pressure, or left atrial pressure throughout the period of data collection. Methemoglobin level was 2.1 ± 0.1 ppm before and after NO administration in the group with valvular heart disease and 2.4 ± 0.2 ppm before and after NO administration in the group undergoing aortocoronary bypass grafting.
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). This reduction in MPAP was produced without change in pulmonary artery flow (cardiac output) or pulmonary venous outflow pressure (left atrial pressure), findings suggesting that inhaled NO lowered pulmonary artery pressure by pulmonary vasorelaxation (see Table 2
). In fact, inhaled NO lowered the transpulmonary gradient from 23 ± 1 to 14 ± 1 mm Hg (a 39% reduction) (p < 0.05) (see Table 2). In turn, this pulmonary vasodilation produced a 36% decrease in PVR (from 375 ± 30 to 240 ± 30 dynes•s•cm-5) (p < 0.05) (Fig 2). There was no change in systemic arterial blood pressure (see Table 2).
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, inhaled NO had no effect on MPAP patients with valvular heart disease: MPAP was 39 ± 3 mm Hg before, during, and after inhaled NO (see Fig 1). Likewise, inhaled NO had no effect on PVR, which was 620 ± 30 dyne•s•cm-5 before, during and after inhaled NO (Fig 2). |
Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Pulmonary hypertension in cardiac surgical patients without valvular heart disease, unlike patients with valvular heart disease, results primarily from pulmonary vasoconstriction; the pulmonary vasoconstrictive effects of cardiopulmonary bypass are well recognized. In most adult patients undergoing cardiac operation who have pulmonary hypertension, it is present on the basis of mitral or aortic valve disease. At least three pathophysiologic mechanisms contribute to the pulmonary hypertension seen in long-standing aortic or mitral valve disease: (1) increased left atrial 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") [6]. Once the elevated left atrial pressure is relieved by valve replacement, increased PVR does not immediately return to normal; several days to weeks may be necessary [8]. For this reason, perioperative pulmonary vasodilator therapy is most often required in patients undergoing valve operation, and it is in this group of patients that inhaled NO would theoretically be most useful. However, the results of the present study suggest that inhaled NO may be ineffective in such patients.
Patients undergoing a cardiac surgical procedure offered an excellent opportunity to examine the influence of inhaled NO on PVR. Each cohort of patients in the present study represented a homogeneous group for study. Control of many variables that affect PVR was available in these patients. Surgical access allowed accurate measurement of pulmonary venous outflow pressure (left atrial pressure) for calculation of PVR. The anesthetized, mechanically ventilated patient allowed for maintenance of a constant rate of ventilation and tidal volume to avoid mechanical alterations in PVR [9]. Further, arterial oxygen tension could be well controlled, and changes in acid-base status avoided.
A standard cardiac anesthesia technique was employed in the present study. Intravenous anesthetic agents were administered only before cardiopulmonary bypass, and inhalational anesthetic agents were not given after cessation of cardiopulmonary bypass until after the period of data collection. Therefore, any influence of anesthesia on PVR was assumed to have been held constant during the period of data collection. Although the anesthesia technique may or may not influence the response of the pulmonary vasculature to inhaled NO, the influence was held constant during the period of data collection. Further, the same anesthesia technique was employed in both groups of patients. In addition, to optimize clinical relevance, patients were examined early postoperatively.
The present study was designed to examine the acute effects of inhaled NO administration. Therefore, one may not draw conclusions regarding the effects of prolonged exposure. The concentration of inhaled NO used in the present study, 40 ppm, has previously been shown to have significant pulmonary vasodilating actions in cardiac surgical patients [4] and was therefore used in this study. Although patients with valvular heart disease in the present study failed to respond to a concentration of 40 ppm, it is possible that such patients may respond to a higher concentration of inhaled NO.
However, inhaled NO is a potentially toxic gas, and its toxicity is directly related to the concentration of inhaled NO: inhalation of greater than 1,000 ppm has been shown to cause acute lung injury in laboratory animals [10]. In humans, NO is believed to cause silo-filler's disease [11]. Therefore, prolonged administration of inhaled NO requires chemiluminescence monitoring to accurately measure both the concentration of inhaled NO and the exhaled concentration of its toxic metabolite, NO2. Blood samples are also required to measure the level of methemoglobin concentration. During the brief administration of inhaled NO in the present study, there were no changes in NO2 or methemoglobin. Adatia and associates [12], however, did report methemoglobin levels as high as 9% in children receiving 80 ppm of inhaled NO. Administration of greater than 40 ppm therefore carries some risk, which must be acknowledged. Despite these potential toxicities, prolonged administration of inhaled NO to patients with adult respiratory distress syndrome in concentrations up to 80 ppm and for duration up to 53 days has not been found to produce lung toxicity [13]. Nonetheless, a brief trial of inhaled NO has been reported to precipitate pulmonary edema in a patient with stable heart failure [14]. Of particular concern in cardiac surgical patients is the possibility that inhaled NO may depress myocardial contractility. Although no changes in cardiac output were found with inhaled NO in our study, further investigation is required to determine the influence of inhaled NO on cardiac function.
Because pulmonary hypertension in patients undergoing cardiac operation for valvular heart disease is derived from both "reactive" and "fixed" components, control of PVR in such patients can be a vexing problem. In 6 patients studied up to 24 hours after mitral valve replacement for mitral stenosis, Girard and colleagues [15] reported only a modest reduction in MPAP by inhaled NO (40 ppm). The present study examined patients in the immediate postoperative period to optimize clinical relevance. However, the possibility must be recognized that the efficacy of inhaled NO may be greater several days after valve replacement, and this was not examined here. From a clinical standpoint, however, effective pulmonary vasorelaxation is most commonly needed in the early postoperative period. For that reason, this study examined the effect of inhaled NO immediately after cardiac operation.
Nonetheless, prior studies have demonstrated that the "reactive" component of PVR can be modulated in the immediate postoperative period and pulmonary vasodilation achieved in patients undergoing aortic or mitral valve replacement or both by changes in acid-base status [16] and by intravenous administration of adenosine [17]. The pulmonary vasodilating actions of inhaled NO are mediated by guanosine 3',5'-cyclic monophosphate, whereas those of adenosine are mediated by adenosine 3',5'-cyclic monophosphate; the intracellular mechanisms by which acid-base status affects pulmonary vascular smooth muscle tone are unknown. The results of the present study suggest that the intracellular mechanisms by which inhaled NO produces pulmonary vasorelaxation are intact in cardiac surgical patients with pulmonary hypertension without valvular heart disease, but these mechanisms are impaired in patients with valvular heart disease. It is tempting to speculate that pulmonary vascular remodeling produces impairment of specific intracellular mechanisms and that this may help explain why some pulmonary vasodilating agents are effective in patients with pulmonary hypertension secondary to valvular heart disease, and other agents are not.
In summary, the response to inhaled NO is variable among cardiac surgical patients with pulmonary hypertension. Despite the promise of inhaled NO as a pulmonary vasodilator, the results of the present study suggest alternative therapies are needed to control pulmonary hypertension in patients with pulmonary hypertension from valvular heart disease.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Fullerton, Division of Cardiothoracic Surgery, Northwestern University Medical School, Suite 1030 Wesley Pavilion, 251 E Chicago Ave, Chicago, IL 60611. (e-mail: dfullert{at}nmh.org).
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals
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TopFootnotesAbstractIntroductionMaterial and MethodsAdministration of Inhaled NOProtocol for Data CollectionStatistical AnalysisResultsCommentAcknowledgmentsReferences |
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