Ann Thorac Surg 1996;62:874-877
© 1996 The Society of Thoracic Surgeons
Case Report
Adenosine for Refractory Pulmonary Hypertension
David A. Fullerton, MD,
James Jaggers, MD,
Stephen D. Jones, MD,
James M. Brown, MD,
Robert C. McIntyre, Jr, MD
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado
Accepted for publication March 26, 1996.
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Abstract
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We report 2 patients with refractory acute pulmonary hypertension. In both, a central venous infusion of adenosine into the circulation effectively lowered pulmonary arterial pressure when standard treatment measures had failed, and reversed the clinical state of shock by achieving pulmonary vasodilatation. We conclude that adenosine may help lower pulmonary arterial pressure without lowering systemic arterial pressure in the setting of acute pulmonary hypertension when standard measures have failed.
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Introduction
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An acute increase in pulmonary vascular resistance, or pulmonary hypertensive crisis, may produce such high right ventricular afterload that the right ventricle is unable to pump blood through the lungs into the left heart, precipitating right ventricular failure, systemic hypotension, and death. With the exception of inhaled nitric oxide (an experimental drug), the currently available pharmacologic agents used for pulmonary vasodilation dilate both the systemic and pulmonary circulations. Such nonselective vasodilation is extremely hazardous in patients with increased pulmonary vascular resistance; life-threatening hypotension results if the degree of systemic vasodilation exceeds that of the pulmonary vasodilation [1].
Adenosine may offer a therapeutic advantage as a pulmonary vasodilator. It is cleared from the blood via the lungs by adenosine deaminase, found in vascular endothelial cells and erythrocytes; its plasma half-life is less than 10 seconds [2, 3]. Its vasodilatory action may therefore be focused in the pulmonary circulation without producing unwanted systemic hypotension. We report 2 patients in whom acute life-threatening pulmonary hypertension was refractory to conventional therapy but successfully treated with adenosine.
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Case Reports
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Patient 1
A 62-year-old man underwent a left pneumonectomy for squamous cell carcinoma of the lung. Pulmonary arterial pressure (PAP) was 38/26 mm Hg immediately after pneumonectomy. On the fifth postoperative day he required reintubation for hypotension and respiratory distress from aspiration. At that time the PAP was 75/45 mm Hg, the pulmonary capillary wedge pressure was 10 mm Hg, the radial arterial pressure was 80/40 mm Hg, and the cardiac index was 1.6 L • min-1 • m-2. An echocardiogram showed right ventricular dilatation, attributed to very high PAP. An electrocardiogram showed no evidence of ischemia. A radionuclide ventilation-perfusion scan showed low ventilation and perfusion, probably due to pulmonary embolism. Efforts to vasodilate the pulmonary circulation were made with an intravenous infusion of prostaglandin E1 (0.1 µg • kg-1 • min-1), then milrinone (0.5 µg • kg-1 • min-1), and then isoproterenol (0.1 µg • kg-1 • min-1). Each agent produced significant systemic hypotension without any decrease in PAP; their administration was stopped. Inhaled nitric oxide was given at 80 ppm, then 40 ppm without hemodynamic effect. At this point the patient was in severe right heart failure (central venous pressure, 24 mm Hg), was anuric, and had metabolic acidosis (serum lactate, 11.9 mmol/L); his arterial blood gas sample revealed an arterial oxygen tension of 64 mm Hg (inspired oxygen fraction of 0.96), arterial carbon dioxide tension of 43 mm Hg, and pH of 7.19.
A central venous infusion of adenosine (Fujisawa, Tokyo, Japan) was begun (50 µg • kg-1 • min-1) with an immediate decrease in mean PAP from 56 to 36 mm Hg and an immediate increase in cardiac index, systemic arterial pressure, and mixed venous oxygen saturation (from 41% to 59%) (Fig 1
). The patient soon began making urine, and the metabolic acidosis resolved. After 1 hour, the adenosine infusion was temporarily stopped to determine whether the hemodynamic improvement was indeed attributable to the adenosine. As shown in Figure 1, while the adenosine infusion was stopped, the patient's mean PAP quickly rose from 35 to 52 mm Hg, his cardiac index fell from 2.6 to 1.8 L • min-1 • m-2 and his systemic mean arterial pressure fell from 69 to 42 mm Hg. Once the adenosine infusion was resumed (25 µg • kg-1 • min-1), mean PAP again decreased from 52 to 32 mm Hg, the cardiac index increased from 1.8 to 2.5 L • min-1 • m-2, and systemic mean arterial pressure increased from 42 to 68 mm Hg.
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Fig 1. . Hemodynamic response to adenosine infusion in patient 1. Infusion of adenosine (50 µg • kg-1 • min-1) produced a decrease in mean pulmonary arterial pressure and an increase in mean systemic arterial pressure and cardiac index. Temporary cessation of the adenosine infusion was associated with reversal of these hemodynamic changes. Resumption of the adenosine (25 µg • kg-1 • min-1) promptly lowered mean pulmonary arterial pressure and increased mean systemic arterial pressure and cardiac index.
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The adenosine infusion was continued for 62 hours, during which time the patient's condition steadily improved; his mean PAP stabilized at 36 mm Hg with a systemic arterial pressure of 115/70 mm Hg and a pulmonary capillary wedge pressure of 8 mm Hg. At the time of this report he was stable and being weaned from mechanical ventilation.
Patient 2
A 39-year-old man underwent mitral valve replacement for critical mitral stenosis. His preoperative PAP was 46/30 mm Hg. With each attempt to wean him from cardiopulmonary bypass, his mean PAP quickly rose to at least 60 mm Hg with a pulmonary capillary wedge pressure of 12 mm Hg. Repeated attempts to wean him from cardiopulmonary bypass resulted in right ventricular distention and failure. As with patient 1, a combination of therapies was used in an effort to lower pulmonary vascular resistance, including an alkalemic arterial pH and an arterial oxygen tension of at least 150 mm Hg. Infusions of pulmonary vasodilators were cumulatively added: amrinone (10 µg • kg-1 • min-1), isoproterenol (0.3 to 0.5 µg • kg-1 • min-1), prostaglandin E1 (0.1 µg • kg-1 • min-1), and nitroprusside (1 to 2 µg • kg-1 • min-1). These in combination failed to lower PAP, but did lower mean systemic arterial pressure to 45 to 50 mm Hg. To counteract the systemic vasodilation of these agents, epinephrine and norepinephrine were infused into the left atrium while the pulmonary vasodilators were infused into the central venous circulation. Again, the patient could not be weaned from bypass. An intrapulmonary arterial balloon pump was inserted via a synthetic tube graft sewn to the main pulmonary artery; even this did not allow separation from cardiopulmonary bypass.
Finally, adenosine was infused into the central venous circulation (50 µg • kg-1 • min-1). The addition of adenosine effectively lowered pulmonary vascular resistance: systemic mean arterial pressure rose from 36 to 66 mm Hg and mean PAP decreased from 57 to 29 mm Hg. These were associated with an increase in mixed venous oxygen saturation from 32% to 55%. With improvement in right ventricular function, the patient was successfully separated from cardiopulmonary bypass. The adenosine infusion was continued for 56 hours postoperatively (50 µg • kg-1 • min-1) in combination with the other vasoactive agents. The intrapulmonary arterial balloon pump was removed on the second postoperative day; thereafter, the adenosine infusion was weaned off, followed by successful weaning of all pharmacologic agents. The patient was discharged to home on postoperative day 20. Two weeks after hospital discharge he was walking 6.4 km twice daily. He remains asymptomatic 6 months after the operation.
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Comment
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The patients described in this report had acute life-threatening pulmonary vasoconstriction from disparate causes; in patient 2 it was exacerbated by the pulmonary vasoconstricting influences of cardiopulmonary bypass. Conventional vasodilator therapy produced systemic hypotension without pulmonary vasodilation in both patients; inhaled nitric oxide alone (up to 80 ppm) failed to achieve pulmonary vasodilatation in patient 1. Infusion of adenosine into the central venous circulation effectively lowered PAP without decreasing systemic arterial pressure. This in turn increased cardiac index, reversing the clinical state of shock. Refractory acute pulmonary hypertension is uncommon among adult cardiothoracic surgical patients, but usually fatal. The patients in the present report were in extremis and failed to respond to all other available pulmonary vasodilator therapy; adenosine was infused as a last-ditch effort.
Because the patients in this report were critically ill, other agents were not withdrawn when adenosine infusion was started. Therefore, one may not draw conclusions about the effects of adenosine alone versus its effects in combination with other pharmacologic agents on the pulmonary circulation in acute pulmonary hypertensive crisis. But at least in combination with other agents, pulmonary vasorelaxation was achieved after the initiation of adenosine treatment when other therapies failed. As demonstrated in Figure 1
, temporary withdrawal of adenosine resulted in recurrence of severe pulmonary hypertension, which was reversed by restarting the adenosine infusion.
It is unclear why the addition of adenosine achieved pulmonary vasorelaxation when other pulmonary vasodilators did not. However, the intracellular mechanisms by which pulmonary vasodilators produce relaxation of pulmonary vascular smooth muscle may be dysfunctional in acute pulmonary vascular injury [4, 5]. It is tempting to speculate that the intracellular mechanisms by which adenosine produces pulmonary vascular smooth muscle relaxation remain intact in acute lung injury while the mechanisms of other pulmonary vasodilators are impaired. The vast majority of patients with acute pulmonary hypertension respond to conventional therapeutic measures. However, the present report illustrates that adenosine may be useful in situations when other pulmonary vasodilators are ineffective. Adenosine is another agent that may be added to the armamentarium used to treat acute pulmonary hypertension.
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Acknowledgments
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Supported by National Institutes of Health grant R29HL49398.
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Footnotes
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Address reprint requests to Dr Fullerton, Cardiothoracic Surgery, Box C-310, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262.
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References
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- Packer M, Greenberg B, Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Engl J Med 1982;306:1326–31.
- Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983;93:21–6.[Medline]
- Utterback DB, Staples ED, White SE, Hill JA, Belardinelli L. Basis for the selective reduction of pulmonary vascular resistance in humans during infusion of adenosine. J Appl Physiol 1994;76:724–30.[Abstract/Free Full Text]
- Fullerton DA, McIntyre RC Jr, Hahn AR, et al. Dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury. Am J Physiol 1995;268:L1029–35.[Abstract/Free Full Text]
- McIntyre RC Jr, Harken AH, Fullerton DA. Mechanisms of pulmonary vasomotor function in normal and injured lung. Surgery 1994;115:272–5.[Medline]
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Abstract
Introduction
