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Ann Thorac Surg 1996;61:1118-1123
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Adenosine Effectively Controls Pulmonary Hypertension After Cardiac Operations

Department of Surgery, University of Colorado Health Sciences Center and the Department of Veterans Affairs Medical Center, Denver, Colorado

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Pulmonary hypertension secondary to increased pulmonary vascular resistance may greatly complicate the perioperative management of patients having cardiac operations. Adenosine may have a therapeutic role as a selective pulmonary vasodilator. The purpose of this study was to examine the pulmonary hemodynamic effects of a central venous infusion of adenosine in cardiac operative patients with pulmonary hypertension.

Methods. Ten cardiac patients with pulmonary hypertension (age, 62 ± 6 years) were studied in the operating room under general anesthesia after weaning from cardiopulmonary bypass. Cardiac output, pulmonary vascular resistance, systemic vascular resistance, mean pulmonary arterial pressure, and mean systemic arterial pressure were determined before, during, and after central venous infusion of adenosine (50 µg • kg^-1 • min^-1) for 15 minutes. Statistical analysis was by analysis of variance, and significance was accepted at p < 0.05.

Results. Adenosine produced significant pulmonary vasodilation. Mean pulmonary arterial pressure was lowered from 36 ± 1 to 28 ± 2 mm Hg (p < 0.05), and pulmonary vascular resistance was lowered from 560 ± 30 to 260 ± 30 dynes • s • cm^-5 (p < 0.05) during adenosine administration. At the same time, cardiac output rose from 4.0 ± 0.6 to 6.2 L/min (p < 0.05). Pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output returned to baseline after the adenosine infusion was stopped. There was no change in systemic mean arterial pressure during adenosine infusion.

Conclusions. Adenosine may be used clinically as a selective pulmonary vasodilating agent to optimize pulmonary hemodynamic indices without adverse systemic hemodynamic effects in patients with pulmonary hypertension having cardiac operations. It may be particularly valuable in patients with right heart dysfunction by selectively lowering right ventricular afterload.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1123.

Pulmonary hypertension secondary to increased pulmonary vascular resistance (PVR) may greatly complicate the perioperative management of patients having cardiac operations. Because PVR is the primary clinical determinant of right ventricular afterload, increased PVR may result in right ventricular afterload mismatch, compromising cardiac output. With the exception of inhaled nitric oxide, which is currently an experimental drug, pharmacologic agents that are currently used as pulmonary vasodilators produce vasodilation of both the systemic and pulmonary circulations. Such nonselective vasodilation may be hazardous in patients with increased PVR [1]; life-threatening hypotension may result if the degree of systemic vasodilation exceeds that of pulmonary vasodilation.

For editorial comment, see page 1051.

The principal intracellular mechanisms of pulmonary vasodilating agents are ultimately mediated through either guanosine 3',5'-cyclic monophosphate or adenosine 3',5'-cyclic monophosphate [2, 3]. Nitrovasodilators such as sodium nitroprusside, nitroglycerin, and inhaled nitric oxide relax pulmonary vascular smooth muscle by activating pulmonary vascular smooth muscle guanylate cyclase to generate cyclic guanosine monophosphate. On the other hand, agents such as adenosine, which are mediated through cyclic adenosine monophosphate, do so by activating membrane receptors on the pulmonary vascular smooth muscle cell, leading to activation of adenylate cyclase and generation of cyclic adenosine monophosphate.

Adenosine is an endogenous nucleoside; its role as a vasodilator in the coronary and other circulations is well recognized [4]. It is cleared rapidly from the circulation by adenosine deaminase, found in vascular endothelial cells and erythrocytes; its plasma half-life is less than 10 seconds [5]. Adenosine has been shown to vasodilate both the canine [6] and feline [7] pulmonary circulations. In laboratory animal lung preparations [8] and in humans [9], adenosine is largely cleared by a single pass through the lung. Adenosine has been shown to relax isolated human pulmonary arterial rings through an adenosine A₂ receptor–mediated mechanism [10].

In patients with primary pulmonary hypertension, infusion of adenosine has been shown to lower pulmonary arterial pressure and PVR [11, 12]. In cardiac operative patients without pulmonary hypertension, we have previously demonstrated that a central venous infusion of adenosine produced a significant reduction of pulmonary arterial pressure and PVR without changes in systemic vascular resistance or systemic arterial pressure [13]. We therefore hypothesized that adenosine produces pulmonary vasodilation in cardiac operative patients with pulmonary hypertension without producing unwanted systemic hemodynamic effects.

The purpose of this study was to examine the effects of a central venous infusion of adenosine on pulmonary and systemic hemodynamic indices in patients with pulmonary hypertension after cardiac operations. The results of this study demonstrated that adenosine effectively lowered pulmonary arterial pressure and PVR and increased cardiac output without producing a reduction in systemic arterial pressure.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This protocol was approved by the Human Subjects Review Committee of the University of Colorado Health Sciences Center and the Research and Development Committee, Human Subjects Subcommittee of the Denver Veterans Affairs Medical Center. Informed consent was obtained from each participant.

Protocol for Data Collection
Ten consecutive patients with pulmonary hypertension (mean pulmonary artery pressure 30 mm Hg or greater) having cardiac operations participated in this study. The patients underwent the following surgical procedures: aortic valve replacement for aortic stenosis (n = 1), aortic valve replacement for aortic insufficiency (n = 3), mitral valve replacement for mitral stenosis (n = 2), mitral valve replacement for mitral insufficiency (n = 2), and aortocoronary bypass grafting for three-vessel coronary artery disease (n = 2). All patients had a left ventricular ejection fraction of greater than 0.40 as determined by contrast ventriculography. All patients undergoing aortocoronary bypass grafting had complete coronary artery revascularization, including reversed saphenous vein grafts to the right coronary artery system.

Patients received preoperative medication with morphine sulfate 0.1 mg/kg and scopolamine 0.4 mg intramuscularly 1 hour before 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 measure pulmonary venous outflow pressure (left atrial pressure) accurately for determination of PVR, we introduced a left atrial pressure–monitoring catheter 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 before chest closure. The anesthetic technique consisted of a high-dose narcotic (fentanyl) and relaxant (vecuronium) supplemented with intravenous midazolam. 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 before chest closure. After weaning from bypass and administration of protamine, all patients were hemodynamically stable and demonstrated normal coagulation. No patients required cardiac pacing, antiarrhythmic therapy, or inotropic or vasoactive drug administration. No inhalational anesthetic agents were administered from the time of cessation of cardiopulmonary bypass during the period of data collection.

Data collection proceeded as follows. Tidal volume was set at approximately 10 mL/kg, and respiratory rate was adjusted to establish an arterial partial pressure of carbon dioxide of approximately 40 mm Hg and an arterial pH of approximately 7.40 [14]. To avoid changes in pulmonary hemodynamic indices secondary to changes in ventilatory patterns, we kept ventilator settings constant 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 at any point during the study. Arterial partial pressure of oxygen (pO₂) was therefore maintained greater than 250 mm Hg throughout the study 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, systemic mean arterial blood pressure, mean pulmonary arterial pressure, central venous pressure, left atrial pressure, and cardiac output by the thermodilution method (mean of three values). These allowed mathematic calculation of pulmonary and systemic vascular resistance, transpulmonary gradient, and intrapulmonary shunt fraction using standard formulas.

After placement of the left atrial pressure line and with the patient in a hemodynamic steady state, we measured baseline hemodynamic variables. Then, a continuous infusion of adenosine (Fujisawa, Tokyo, Japan) was begun through the central venous circulation at a dose of 50 µg • kg ^-1 • min ^-1. After 15 minutes of adenosine infusion, hemodynamic variables were determined. The adenosine infusion was stopped; after 15 minutes, hemodynamic variables were determined again. The left atrial pressure line was then removed under direct vision, and its insertion site in the right superior pulmonary vein was determined to be hemostatic.

Statistical Analysis
Statistical analyses were performed with a MacIntosh Quadra 650 Computer (Apple Computer, Inc, Cupertina, CA) and StatView software (Brain Power, Inc, Calabasas, CA). Data are presented as mean ± one standard error of the mean. Statistical evaluation used standard analysis of variance in conjunction with the Student-Newman-Keuls multiple comparisons procedure. Two-sided statistical evaluation was used. A p value of less than 0.05 was accepted as statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The study population comprised 10 patients (6 male, 4 female) with a mean age of 62 ± 6 years. All patients had a history of cigarette smoking; however, none demonstrated clinical or radiographic evidence of important chronic pulmonary disease. As determined by preoperative pulmonary function studies, all patients had a forced expiratory volume at 1 second of at least 1.5 L/min. All patients had pulmonary hypertension preoperatively, as determined in the cardiac catheterization suite approximately 1 week before operation. The systolic pulmonary artery pressure was 68 ± 5 mm Hg, and the mean pulmonary artery pressure was 39 ± 3 mm Hg. Aortic cross-clamp time was 89 ± 15 minutes, cardiopulmonary bypass time was 126 ± 18 minutes, tidal volume was 10 mL/kg, and respiratory rate was 12 breaths/min.

Table 1 lists the arterial and mixed venous blood gas values along with the hemodynamic variables determined at each point of data collection. There were no changes in arterial pH, arterial pO₂, or arterial partial pressure of carbon dioxide throughout the study period. Likewise, there were no significant changes in heart rate, central venous pressure, or left atrial pressure during data collection.

View larger version (14K): [in this window] [in a new window]   Fig 1. . Effect of adenosine infusion on pulmonary and systemic arterial pressures. Mean pulmonary arterial pressure (MPAP; closed circles) was significantly reduced while there was no change in mean systemic arterial pressure (MAP; open circles). (*p < 0.05 versus before and after adenosine infusion.)

The pulmonary vasorelaxation produced by adenosine resulted in a significant reduction in PVR. As shown in Figure 2, PVR was 540 ± 35 dynes • s • cm^-5 before adenosine infusion and was lowered significantly to 245 ± 36 dynes • s • cm^-5 (p < 0.05). After adenosine administration, PVR returned to 515 ± 38 dynes • s • cm^-5 (p < 0.05 versus during infusion; not different from before infusion).

View larger version (12K): [in this window] [in a new window]   Fig 2. . Effect of adenosine infusion on pulmonary vascular resistance (PVR) and cardiac output. Cardiac output rose significantly as pulmonary vascular resistance was significantly reduced. (*p < 0.05 versus before and after adenosine infusion.)

Despite producing significant pulmonary vasorelaxation, adenosine infusion did not appear to interfere with pulmonary ventilation-perfusion matching. As shown in Table 1, no change in arterial pO₂ occurred during adenosine infusion despite notable pulmonary vasorelaxation. Likewise, no change in intrapulmonary shunt fraction occurred as a result of this pulmonary vasorelaxation. As shown in Table 1, intrapulmonary shunt fraction was 15% ± 4% before adenosine infusion, 16% ± 3% during the infusion, and 15% ± 4% after cessation of adenosine infusion.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The results of this study demonstrated that after cardiac operation, a central venous infusion of adenosine in patients with pulmonary hypertension produced a significant reduction in mean pulmonary arterial pressure, transpulmonary gradient, and PVR without changing systemic arterial blood pressure. This pulmonary vasodilation was associated with a significant increase in cardiac output and was achieved without an increase in the intrapulmonary shunt fraction or a decrease in arterial pO₂. In the present study, we examined the hemodynamic effects of an adenosine infusion over a relatively short period; one may not draw conclusions regarding the influence of an adenosine infusion for a prolonged period of time. Further, this study examined the effects of a single dose of adenosine (50 µg • kg^-1 •min^-1) and did not address the question of the effects of smaller or larger doses.

As in the present study, the majority of adult patients undergoing cardiac operation who have pulmonary hypertension have it on the basis of mitral or aortic valvular disease. Three pathophysiologic mechanisms contribute to the pulmonary hypertension seen in long-standing aortic or mitral valvular 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'') [15]. 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 required. The pulmonary vasoconstrictive effects of cardiopulmonary bypass are well recognized, and patients with chronic pulmonary vascular structural changes may have an exaggerated response to vasoconstricting agonists. The results of the present study suggest that the ''reactive'' component of the increased PVR in such patients can be modulated effectively with adenosine.

Patients undergoing cardiac operations offered an opportunity to examine the influence of adenosine on PVR. Control of many variables that affect pulmonary hemodynamic indices was available in this select group of patients. Operative access allowed accurate measurement of pulmonary venous outflow pressure (left atrial pressure) for calculation of PVR. The anesthetized, mechanically ventilated patient allowed maintenance of a constant rate of ventilation and tidal volume to avoid mechanical alterations of PVR. Furthermore, arterial pO₂ could be well controlled and changes in acid-base status were avoided.

The use of adenosine as a pulmonary vasodilating agent is based on the knowledge that adenosine is metabolized by adenosine deaminase, found in vascular endothelial cells and in erythrocytes. In this way, adenosine may produce pulmonary vasorelaxation and be metabolized during passage through the lungs before reaching the systemic circulation. In isolated rabbit lung preparations, adenosine is largely cleared in a single pass through the lung; the clearance was increased when the isolated lungs were perfused with blood [8]. In humans, the pulmonary clearance of adenosine is concentration dependent; when adenosine is infused in low concentrations, its clearance is nearly complete, but infusion at higher concentrations does produce systemic vasodilation. When infused into humans at 75 µg • kg^-1 • min^-1, approximately 80% of adenosine was extracted during passage through the pulmonary circulation, and the extraction ratio fell slightly at higher infusion concentrations [9]. In human volunteers, infusion of adenosine in higher doses than used in the present study-70 to 100 µg • kg^-1 • min^-1-has been shown to reduce both pulmonary and systemic vascular resistances as well as mean arterial pressure with a compensatory increase in heart rate [16–18]. In patients with primary pulmonary hypertension, infusion of adenosine (0.1 to 50 µg • kg^-1 • min^-1) lowered PVR and increased cardiac output without a fall in systemic arterial pressure [11]. Adenosine has been used intraoperatively in large doses (100 µg • kg^-1 • min^-1) to produce deliberate, controlled systemic hypotension during neurosurgical [19] and peripheral vascular surgical procedures [20]. In cardiac operative patients without pulmonary hypertension, adenosine infused at 50 µg • kg^-1 • min^-1 produced a significant reduction in mean pulmonary arterial pressure and PVR without a change in systemic arterial pressure or resistance [13]. Because cardiac output rose during adenosine infusion in the present study, the calculated value of systemic vascular resistance fell, although mean arterial pressure was unchanged (see Table 1). Whether the adenosine was cleared from the blood before acting in the systemic circulation and the reduction in systemic vascular resistance was secondary to an increased cardiac output, or whether a reduction in systemic vascular resistance was counteracted by enhanced cardiac output, is unknown. It would appear, however, that adenosine preferentially vasodilated the pulmonary circulation, as the ratio of PVR to systemic vascular resistance fell significantly during adenosine infusion (see Table 1).

Several pharmacologic agents have been used as pulmonary vasodilators in cardiac operations, including nitroglycerin, sodium nitroprusside, inhaled nitric oxide, prostaglandin E₁, amrinone, isoproterenol, and nifedipine. With the exception of inhaled nitric oxide, which is currently an experimental drug, all of these agents clinically produce vasodilation of both the systemic and pulmonary vascular beds [21]. In patients with increased PVR, such nonselective vasodilation may be hazardous; significant hypotension may result if the reduction of systemic vascular resistance is greater than the reduction in PVR [1]. Such hypotension may in fact be life-threatening if the systemic arterial pressure is low enough to decrease coronary arterial perfusion pressure, resulting in right ventricular ischemia and failure [22]. Further, the clinical effectiveness of intravenous pulmonary vasodilators is often limited by the fact that they increase intrapulmonary shunt fraction and thereby lower arterial pO₂.

Adenosine may offer several advantages as a pulmonary vasodilating agent in cardiac operations. At a dose of 50 µg • kg^-1 •min^-1, pulmonary vasodilation was achieved without a change in heart rate or in intrapulmonary shunt fraction. It must be acknowledged that the patients in the current study did not have adult respiratory distress syndrome; it is unknown whether such patients may have an increase in intrapulmonary shunt fraction with adenosine infusion. Infusion of this dose of adenosine produced no change in mean systemic arterial pressure. Therefore, the results of the current study suggest that the vasodilating actions of adenosine may be clinically focused upon the pulmonary vascular bed without an unwanted reduction in systemic arterial pressure or an increase in intrapulmonary shunt fraction. In this way, adenosine may be used as a ''selective'' pulmonary vasodilator after cardiac operations.

Continuous infusion of adenosine has been reported to produce an increase in pulmonary capillary wedge pressure [23]. Although this finding was initially thought to represent a negative inotropic effect of adenosine, Nussbacher and colleagues [24] have demonstrated recently that any increase in left atrial pressure resulting from adenosine infusion is the result of vascular loading (increased blood through the lungs into the left atrium) rather than a negative inotropic effect. In the present study, left atrial pressure was measured directly and was unchanged by adenosine infusion. Likewise, cardiac output increased significantly during adenosine infusion. However, if the left ventricle is unable to accommodate the increased preload produced by adenosine infusion, one might observe an increase in left atrial pressure.

In summary, adenosine produced a significant reduction in mean pulmonary arterial pressure and PVR in patients with pulmonary hypertension undergoing cardiac operations. This pulmonary vasorelaxation was produced with an increase in cardiac output without reducing systemic arterial pressure. We conclude that adenosine may be clinically useful to vasodilate the pulmonary circulation preferentially in cardiac operations. It may be particularly valuable in patients with right heart dysfunction by achieving a preferential reduction in right ventricular afterload, thereby optimizing right heart function.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported by National Institutes of Health grant R29HL49398.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Forty-second Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9–11, 1995.

Address reprint requests to Dr Fullerton, Cardiothoracic Surgery, University of Colorado Health Sciences Center, Box C-310, 4200 E Ninth Ave, Denver, CO 80262.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): David A. Fullerton Stephen D. Jones Frederick L. Grover Robert C. McIntyre, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fullerton, D. A. Articles by McIntyre, R. C. Search for Related Content PubMed PubMed Citation Articles by Fullerton, D. A. Articles by McIntyre, R. C., Jr Related Collections Related Articles