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Ann Thorac Surg 1996;62:1759-1764
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Rebound Pulmonary Hypertension After Inhalation of Nitric Oxide

Cardiac Intensive Care Unit and Department of Cardiology, Children's Hospital, and Departments of Pediatrics and Anesthesia, Harvard Medical School, Boston, Massachusetts

Accepted for publication June 20, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. We describe the hemodynamic response to initiation and withdrawal of inhaled nitric oxide (NO) in infants with pulmonary hypertension after surgical repair of total anomalous pulmonary venous connection.

Methods. Between January 1, 1992, and January 1, 1995, 20 patients underwent repair of total anomalous pulmonary venous connection. Nine patients had postoperative pulmonary hypertension and received a 15-minute trial of inhaled NO at 80 parts per million. Five of these patients received prolonged treatment with NO at 20 parts per million or less.

Results. Mean pulmonary artery pressure decreased from 35.6 ± 2.4 to 23.7 ± 2.0 mm Hg (mean ± standard error of the mean) (p = 0.008), and pulmonary vascular resistance decreased from 11.5 ± 2.0 to 6.4 ± 1.0 U•m² (p = 0.03). After prolonged treatment with NO, pulmonary artery pressure increased transiently in all patients when NO was discontinued.

Conclusions. After operative repair of total anomalous pulmonary venous connection, inhaled NO selectively vasodilated all patients with pulmonary hypertension. Withdrawal of NO after prolonged inhalation was associated with transient rebound pulmonary hypertension that dissipated within 60 minutes. Appreciation of rebound pulmonary hypertension may have important implications for patients with pulmonary hypertensive disorders when interruption of NO inhalation is necessary or when withdrawal of NO is planned.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Inhaled nitric oxide (NO) is a selective pulmonary vasodilator in a variety of experimental and clinical circumstances. Since 1992, NO has been reported to lower pulmonary vascular resistance or improve systemic oxygenation in several pulmonary hypertensive disorders of childhood, including persistent pulmonary hypertension of the newborn [1, 2], acute respiratory failure [3], and congenital heart disease [4–6]. The response of pulmonary artery pressure to vasodilators is rarely measured directly in newborns, especially in patients with persistent pulmonary hypertension of the newborn or other forms of neonatal respiratory failure.

Infants with total anomalous pulmonary venous connection (TAPVC) frequently have obstruction of the pulmonary venous pathway. When pulmonary venous return is obstructed preoperatively, pulmonary hypertension is severe and requires urgent surgical relief. Pulmonary hypertension persists with ill-defined frequency and poorly described duration after successful anatomic repair [7–9]. Death may occur suddenly in the early postoperative course and is thought to be secondary to pulmonary hypertensive crises [10]. Increased neonatal pulmonary vasoreactivity, endothelial injury induced by cardiopulmonary bypass [5], and intrauterine anatomic changes in the pulmonary vascular bed in this disease [11] contribute to postoperative pulmonary hypertension.

We hypothesized that infants with anatomically obstructed TAPVC would have a high rate of postoperative pulmonary hypertension and that their pulmonary vascular bed could be selectively dilated with inhaled NO. Our aim was to define the incidence of postoperative pulmonary hypertension in infants with TAPVC and to describe the hemodynamic effects of initiation and withdrawal of inhaled NO in postoperative patients with pulmonary hypertension. In this study, we quantified the initial and sustained response to inhaled NO and documented a transient reboundlike phenomenon during termination of NO therapy after extended use.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
Between January 1, 1992, and January 1, 1995, 20 patients with isolated TAPVC presented to Children's Hospital for operative repair. Anomalous pulmonary venous drainage was supracardiac in 9 patients, infracardiac in 8, to the coronary sinus in 2, and mixed in 1. All infants had repair during cardiopulmonary bypass using deep hypothermic circulatory arrest. Postoperatively, 9 of 20 patients demonstrated pulmonary hypertension, defined as a mean pulmonary artery pressure (mPAP) of 25 mm Hg or greater and a transpulmonary pressure gradient of 15 mm Hg or greater or pulmonary vascular resistance of 3 U•m² or more.

Patients with postoperative pulmonary hypertension were given inhaled NO at 80 parts per million (ppm). Written informed consent was obtained from the parents of all patients under a protocol approved by the Clinical Investigation Committee of Children's Hospital. The clinical characteristics of these patients are summarized in Table 1. All infants were mechanically ventilated, maintaining a moderate respiratory alkalosis. Patients were paralyzed with metocurine or vecuronium and were sedated with a continuous infusion of fentanyl during the first postoperative night. All patients received dopamine infusions; 2 patients received low-dose epinephrine, 2 were supported with isoproterenol, and 1 was given amrinone.

Prolonged Therapy
We elected to use prolonged NO therapy if, after a favorable response to NO, mPAP returned to 35 mm Hg or higher or cardiac index was less than 2.5 L • min^-1 • m^-2 after completion of the 15-minute trial. We reintroduced NO at 20 ppm in 5 patients. Nitric oxide was weaned once each day to 10 ppm, and withdrawn from 10 ppm if mPAP remained less than systemic. If during weaning, mPAP increased to systemic levels, NO was reintroduced at the prior dose. During withdrawal of NO, hemodynamic variables were measured continuously and displayed graphically each minute.

Delivery and Monitoring of Nitric Oxide
Our NO delivery system has been described previously [12]. We used NO gas (Scott Specialty Gases, Plumsteadville, PA) of medical grade quality that conformed to Food and Drug Administration standards. Nitric oxide, nitrogen dioxide, and inspired oxygen were monitored continuously from a sampling port at the airway (Thermoenvironmental Instruments Chemiluminescence model 42H, Franklin, MA). Ventilation indices were kept constant throughout the initial 80-ppm trial. Methemoglobin levels were measured after the 15-minute trial in all patients by co-oximetry (model 2500; CIBA-Corning, Medfield, MA), and every 12 hours in those receiving prolonged therapy.

Statistical Analysis
Standard equations were used to calculate pulmonary vascular and systemic vascular resistances and intrapulmonary shunt fraction (Qs/Qt). Vascular resistances were corrected for body surface area (U•m²). A paired nonparametric test (Wilcoxon signed rank test) was used to compare hemodynamic variables at baseline and after 15 minutes of inhaled NO. A value of p less than 0.05 was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The hemodynamic changes after the 15-minute trial of NO are displayed in Table 2. Nitric oxide decreased mPAP in all 9 patients (35.6 ± 2.4 to 23.7 ± 2.0 mm Hg; p = 0.008), for a 32% ± 5% reduction (Fig 1). Pulmonary vascular resistance decreased by 41% ± 7% in all 6 patients in whom it could be calculated (11.5 ± 2.0 to 6.4 ± 1.0 U•m²; p = 0.03) (Fig 2). There were no significant changes in right or left atrial pressure heart rate, cardiac index, systemic blood pressure, or systemic vascular resistance. There was no effect on pH (7.49 ± 0.02 to 7.50 ± 0.02), systemic arterial carbon dioxide tension (34 ± 2 to 34 ± 2 mm Hg), systemic arterial oxygen tension (159 ± 21 to 165 ± 26 mm Hg), arterial oxygen saturation (99% ± 1% to 99% ± 1%), or calculated intrapulmonary shunt fraction (Qs/Qt) (0.14 ± 0.03 to 0.14 ± 0.03).

View larger version (19K): [in this window] [in a new window]   Fig 1. . Effect of a 15-minute trial of inhaled nitric oxide (NO) on mean pulmonary artery (PA) pressure. Mean pulmonary artery pressure decreased in all patients. Open circles = changes for the group (mean ± standard error). p = 0.008 compared with baseline values.

View larger version (16K): [in this window] [in a new window]   Fig 2. . Effect of a 15-minute trial of inhaled nitric oxide (NO) on pulmonary vascular resistance (PVR). Values decreased in all patients. Open circles = changes for the group (mean ± standard error). p = 0.03 compared with baseline values.

View larger version (37K): [in this window] [in a new window]   Fig 3. . Bedside tracings of pulmonary artery (PA) pressure in mm Hg, showing systolic (Sys), mean, and diastolic (Dia), for each patient (Pt) receiving prolonged nitric oxide therapy plotted against time. Cursor = time of nitric oxide withdrawal; pulmonary artery pressures at time of withdrawal are displayed to the right of each tracing. In each patient a transient increase is seen, which dissipates without reinstitution of nitric oxide.

Toxicity
Nitrogen dioxide levels were measured continuously and remained less than 1 ppm among patients receiving continuous NO therapy. Methemoglobin levels were measured every 12 hours during prolonged NO therapy and remained less than 2%.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Pulmonary hypertension occurred commonly among infants after repair of TAPVC and was present in 88% of patients with an infradiaphragmatic drainage pattern. Inhaled NO significantly and selectively decreased pulmonary artery pressure in all hypertensive patients. The average reduction in pulmonary vascular resistance was 41%. Although the effect of inhaled NO on hemodynamic indices has been reported after operations for congenital heart disease [4–6, 13], this study describes the acute and prolonged hemodynamic effects of NO in a single, homogeneous population at substantial risk for postoperative pulmonary hypertension. The striking and uniform response to NO seen in this patient population may reflect a variety of predisposing factors. Increased responsiveness to NO seen in pediatric patients with pulmonary venous hypertension may result from pulmonary vasorelaxation at a combination of precapillary and postcapillary vessels [14, 15]. Effects of cardiopulmonary bypass may render the pulmonary vasculature more labile [5] and thus more responsive to vasodilators in general. Prolonged use of NO in this small group of patients was not associated with methemoglobinemia, readily identifiable pulmonary toxicity, or tachyphylaxis.

Rebound Pulmonary Hypertension
We observed a reboundlike phenomenon in the pulmonary artery pressure with NO as it was withdrawn. After several hours (12 to 72) of postoperative treatment and recovery, NO could be discontinued, but a transient increase in mPAP was always observed. During the first minutes after final NO withdrawal, pulmonary artery pressure rose moderately without an impact on systemic hemodynamic indices and then declined to low levels. These changes were complete within 1 hour of withdrawal and were not attributable to any change in ventilation or pharmacologic support.

Rebound pulmonary hypertension is common to vasodilators after chronic use. After abrupt withdrawal of nitroprusside (an NO donor), a transient rebound in pulmonary artery pressure occurs [16]. Negative feedback inhibition by exogenous NO has been postulated to account for this observation. Negative feedback inhibition has been demonstrated to exist for inducible [17] and endothelial [18] NO synthase in vitro. Nitric oxide donor agents inhibit endothelial NO biosynthesis in bovine arterial ring preparations by an apparent negative feedback process on endothelial NO synthase. Arterial rings recovered responsiveness to endothelium-dependent relaxing agents within 30 to 40 minutes of withdrawing the NO donor agent, similar in timing to the slow spontaneous decrease in mPAP that we observed [19]. Decreased endogenous production of exhaled NO in smokers could also support a negative feedback theory [20].

Alternatively, inhaled NO may play an unknown role in the modulation of endogenous pulmonary vasoconstrictors. Pulmonary vasodilation achieved by the delivery of large doses of exogenous NO could provoke secondary production or activation of vasoconstrictors (eg, endothelin or thromboxane) or reduction in vasodilators (eg, atrial natriuretic peptide or prostacyclin). With the short half-life of NO, abrupt discontinuation could allow a brief period of unopposed vasoconstriction until stimulation of endogenous vasodilators or until a change in the stimulus for vasoconstriction achieved a new balance of vasomotor tone. A third alternative is that exposure to exogenous NO altered the membrane receptor conformation in vascular smooth muscle, which reconfigured within 30 to 60 minutes after NO was withdrawn.

Treatment with NO may be needlessly prolonged if clinicians are unaware that a moderate increase in pulmonary artery pressure upon withdrawal may be transient and well tolerated if the underlying pathologic process has improved. Appreciation of the abrupt rebound and slow recovery allowed discontinuation of NO in our patients after a median treatment period of 28 hours, compared with 9.5 days in the work by Beghetti and associates [21]. During weaning of NO, if mild elevations in pulmonary artery pressure are seen without instability of systemic hemodynamic indices, it seems prudent to continue careful observation without reinstitution of NO. Dose-response testing for inhaled NO should be undertaken during the initial exposure to NO, as information obtained during weaning may reflect rebound effects and not the true dose-response relation.

If the underlying pulmonary hypertensive process has not resolved, then the tendency for an abrupt increase in pulmonary artery pressure may be hazardous if NO therapy must be withdrawn or interrupted. For example, one should continue to provide a source of NO when suctioning or changing NO tanks because abrupt discontinuation can result in cardiovascular collapse [22]. If withdrawal of NO is necessary before resolution of the pathologic process, hemodynamic instability may be expected. If an unstable patient with pulmonary hypertension is stabilized with NO before transfer to a specialized center for further management, NO should be available during patient transport.

Limitations
During a period of 3 years, only 5 patients with TAPVC qualified for extended treatment with NO. Insufficient numbers of patients limit meaningful outcome analysis. It appears that a randomized trial examining discrete outcome variables for a single rare disease such as TAPVC may be beyond the scope of a single institution. Furthermore, in the absence of control patients with TAPVC, we cannot exclude the possibility that postoperative pulmonary hypertension resolves completely and spontaneously within 6 to 12 hours without associated morbidity. However, the rapid onset of action of NO allows patients to serve as their own controls for analysis of the hemodynamic effect. Reports in the medical literature suggest that there may be clinical value in reducing pulmonary artery pressure if it approaches systemic pressure during recovery from cardiopulmonary bypass and deep hypothermic circulatory arrest [23].

This study did not investigate the dose-response relation between NO and reduction in pulmonary artery pressure. Although some have seen continued reduction in pulmonary vascular resistance with doses of NO up to 80 ppm [4], other investigators have shown that doses less than 10 ppm may be equally efficacious [13]. Our investigation did not examine the lowest effective dose, nor did it provide information about the optimal method of weaning from NO. It is possible that alternative strategies of weaning NO more slowly, use of doses less than 10 ppm, or concomitant use of intravenous nitrates (NO donors) during withdrawal would modify or eliminate the rebound pulmonary hypertension that we describe.

Summary
Pulmonary hypertension is associated with the postoperative course of infants with TAPVC, particularly those with infracardiac or obstructed drainage. Inhaled NO selectively reduced pulmonary artery pressure and pulmonary vascular resistance in patients with postoperative pulmonary hypertension and was used as prolonged therapy in 5 patients. Withdrawal from prolonged inhalation of NO resulted in transient rebound pulmonary hypertension that dissipated uneventfully within 60 minutes. Appreciation of rebound pulmonary hypertension and its spontaneous resolution may have important implications in the management of patients who require prolonged NO treatment.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank the cardiac surgeons at Children's Hospital whose technical skill made this study possible: Richard A Jonas, John E. Mayer, Frank L. Hanley, Redmond P. Burke, and Pedro J. del Nido. We are grateful to Aldo R. Castañeda for his critical review of the manuscript.

This study was supported in part by a grant-in-aid award from Children's Hospital.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Wessel, Cardiac ICU Office, Children's Hospital, 300 Longwood Ave, Farley 653, Boston, MA 02115.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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