Home SVCC                                                  Area: English - Español - Português

Inhaled Vasodilators in Congenital
Heart Disease and Elevated
Pulmonary Vascular Resistance

Maurice Beghetti, MD

Pediatric Cardiology Unit, Department of Pediatrics,
Hôpital des Enfants, University of Geneva, Switzerland

   The assessment of pulmonary vascular reactivity plays an important role in the management of chronic pulmonary hypertension. In children with heart disease and significantly increased pulmonary blood, flow progressive pulmonary vessel wall damage can lead to medial and intimal changes, smooth muscle cell hypertrophy and hyperplasia and finally fibrosis and obliteration. Surgical correction is no longer indicated when fixed pulmonary vascular disease is diagnosed, as it will carry an unacceptably high operative risk or will continue to progress despite surgical repair. The patient will then dye of right ventricular failure. The increase in muscularity carries potential for vasoconstriction; therefore elevated pulmonary vascular resistance encountered at all stages of increased muscularity may in part be due to this reversible vasoconstriction.

   Different diagnostic techniques are offered to evaluate the degree and progression of pulmonary vascular disease.

   Heath and Edwards have first described morphologic criteria for pulmonary vascular disease based on lung biopsies. Rabinovitch, then described a morphometric method which evaluates the extension of muscle into usually non muscularized peripheral arteries. Despite reports showing a good correlation of biopsy with postoperative hemodynamics, the predictive value of lung biopsies remains controversial. Indeed lesions may be unequally distributed within the lungs, and thus the degree of pulmonary vascular disease may be misinterpreted. Moreover, this static description does not take into account the dynamics of the pulmonary vascular bed. In addition, open lung biopsy is required, as a transbronchial route does not offer adequate material, and this is not without risk. The pulmonary wedge angiogram is another technique described by Rabinovitch et al. to evaluate pulmonary vascular disease. Standard catheterization and assessment of pulmonary vascular reactivity remains the test performed in most cardiac centers to assess operability, even if there are some limitations such as difficulties in measurement of cardiac output and failure to take into consideration the pulsatile nature of the pulmonary circulation. New techniques using intravascular ultrasound and assessing the pulsatility and distensibility of the pulmonary arteries may offer new insights in the assessment of pulmonary vascular disease in the future.

   Limits of pulmonary vascular resistance and pulmonary to systemic resistance ratio allowing surgical repair are somewhat different from center to center. Children with pulmonary vascular resistance > 3.5 U all had decreased alveolar to artery ratio. This lesion is considered to precede obliterative disease, but possibly identifies patients whose pulmonary vascular disease could progress despite corrective surgery. Bush et al observed that vascular resistance > 6 Wood U*m2 bears no direct correlation with a Heath-Edwards grading, but is associated with a poor prognosis whatever the lung morphology. At our institution, children with congenital heart disease, left to right shunt and pulmonary hypertension are considered to be straightforward candidates for surgical repair as long as Rp/Rs is < 0.3; for values higher than that we perform a vasodilatory testing with inhaled vasodilators to assess the reactivity of the pulmonary vascular bed.

   Since the early 60's, where high percentage inspired oxygen was recognized as a pulmonary vasodilator in congenital heart disease, 100% oxygen has been used to assess pulmonary vascular reactivity routinely. Conclusions based on this test only however were not considered sufficient. Other agents such as tolazoline, prostacyclin or calcium channel blockers, have been used but they all vasodilate the systemic vascular bed as well. As they require an intravenous administration, their results may be confounded by changes in systemic hemodynamics and intrapulmonary shunts. The use of a selective pulmonary vasodilator such as inhaled nitric oxide offers the clinician important advantages in the investigation of pulmonary vascular reactivity.

   Several studies have been performed to assess the effect of inhaled nitric oxide on pulmonary vascular resistance in congenital heart disease.

   First, Roberts et al studied the effect of 20 and 80 ppm inhaled nitric oxide in 10 patients with congenital heart disease. The maximum reduction in pulmonary vascular resistance was obtained with the highest dose. There was an additive effect when a high dose of inspired oxygen was delivered simultaneously. Winberg et al showed, in addition, that children with a normal pulmonary vascular tone did not respond to nitric oxide. Day et al failed to demonstrate an increased response to 60 ppm as compared to 12 ppm.

   Our group studied the effect of 35 ppm nitric oxide in children with long-standing pulmonary hypertension and congenital heart disease. Characteristics baseline hemodynamics, and response to 35 ppm inhaled NO of all children are summarized in Table 1.

   Individual changes in pulmonary vascular resistance and Rp/Rs with NO inhalation are shown in the Figure 1.

   We showed that the decline of the selective response to nitric oxide seems to parallel the progression of established vascular disease and thus may be helpful for the selection of patients for corrective surgery. Our observation supports the hypothesis that NO may safely allow the preoperative identification of children with limited pulmonary vascular reactivity. The reliability of the criteria used to decide on operability, whether hemodynamic or morphologic, largely depend on the experience gathered in a given center. In this study, operability was based on whether vasodilation brought the Rp/Rs to 0.3. This index has the advantage of being independent of oxygen consumption. A value <0.3 has been shown to correlate with good long-term outcome and is accepted as an indicator of reversible pulmonary vascular disease in children with ventricular septal defects.

   Atz et al studied the effects of nitric oxide and high levels of inspired oxygen. Inhalation of 80 ppm nitric oxide and 100% oxygen produced a similar degree of pulmonary vasodilation. In addition the combination of both vasodilators provides additional pulmonary vasodilation and may identify patients who would not respond to each substance alone.

   Our group compared the effects of 20 ppm nitric oxide and aerosolized iloprost (25ng/Kg/min). We concluded that in children with pulmonary hypertension and congenital heart disease both inhaled nitric oxide and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance The combination, however, failed to prove more potent than either substance alone (Figure 2).

   In this study, are also measured the second messenger responsible for the vasodilator effect, i.e. cGMP for nitric oxide and cAMP for iloprost. Plasma cGMP-levels increased by 97% from 17.6±11.9 nmol/l (baseline 1) to 34.7±21.4 nmol/l during iNO (p<0.01), and normalized to baseline values after iNO was discontinued. During combined iNO and iloprost inhalation cGMP increased from 17.4±14.1 nmol/l (on iloprost alone) to 36.1±15.2 nmol/l (p<0.001). Plasma cAMP-levels remained stable under iNO (baseline 55.7±22.9 nmol/l; iNO 54.0±21.8 nmol/l). During iloprost for 10 min. cAMP increased by 20% from 54.0±21.8 nmol/l to 65.1±21.2 nmol/l (p<0.05) and remained elevated at 66.0±19.85 nmol/l during combined iNO and iloprost inhalation (p<0.05, vs baseline and iNO) (Table 2).

   In children with pulmonary hypertension and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an selective increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Although aerosolized iloprost may be an alternative to iNO for acute testing of vascular reactivity and for postoperative treatment of acute PHT, it may prove to be more useful for prolonged treatment of pulmonary hypertension.

   Severe pulmonary vascular changes have been found in patients with right ventricular failure after heart transplantation. Therefore, the preoperative assessment of the degree of vasoconstriction versus fixed obliterative disease is crucial in the decision to transplant the heart alone or to proceed with heart and lung transplantation. There are several reports of the effects of inhaled nitric oxide in patients with elevated pulmonary vascular resistance before transplantation. Nitric oxide produces selective pulmonary vasodilation without systemic hypotension which is a common limiting feature of intravenous prostacyclin and sodium nitroprusside. Inhaled nitric oxide provides an effective assessment of pulmonary vascular resistance before cardiac transplantation.

   Inhaled vasodilators are simple to deliver either by mask, ventilator or aerosol. They are selective for the pulmonary circulation and free of side effects when used as a trial of vasoreactivity over short period of times (15-30 minutes). There is now very good evidence that inhaled vasodilators are a useful diagnostic tool to evaluate pulmonary vasoreactivity and tailor management decisions in patients with congenital heart disease and elevated pulmonary vascular resistance. In our experience it seems that the selective response to inhaled vasodilators parralels the progression of established vascular disease and thus may help in selecting patients for operation.


1. Berner M, Beghetti M, Spahr-Schopfer I, Oberhansli I, Friedli B. Inhaled nitric oxide to test the vasodilator capacity of the pulmonary vascular bed in children with long-standing pulmonary hypertension and congenital heart disease. Am J Cardiol. 1996;77:532-535.

2. Roberts JD, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation. 1993;87:447-453

3. Adatia I, Perry S, Landzberg M, Moore P, Thompson JE, Wessel DL. Inhaled nitric oxide and hemodynamic evaluation of patients with pulmonary hypertension before transplantation. J Am Coll Cardiol. 1995;25:1652-1664.

4. Rabinovitch M, Haworth SG, Castaneda AR, Nadas AS, Reid LM. Lung biopsy in congenital heart disease: A morphometric approach to pulmonary vascular disease. Circulation. 1978;58:1107-1122.

5. Rabinovitch M, Keane JF, Norwood WI, Castaneda AR, Reid L. Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation. 1984;69:655-667.

6. Wilson NJ, Sear MD, Taylor GP, Leblanc JG, Sandor GS. The clinical value and risks of lung biopsy in children with congenital heart disease. J Thorac Cardiovasc Surg. 1990;99:460-468.

7. Rabinovitch M, Keane JF, Fellows KE, Castaneda AR, Reid L. Quantitative analysis of the pulmonary wedge angiograms in congenital heart defects. Circulation. 1981;63:152-164.

8. Ivy DD, Neish SR, Knudson OA, Nihill MR, Schaffer MS, Tyson RW, Abman SH, Shaffer EM, Valdes-Cruz L. Intravascular ultrasonic characteristics and vasoreactivity of the pulmonary vasculature in children with pulmonary hypertension. Am J Cardiol. 1998;81:740-748.

9. Lock JE, Einzig S, Bass JL, Moller JH. The pulmonary vascular response to oxygen and its influence on operative results in children with ventricular septal defect. Pediatr Cardiol. 1982;3:41-46.

10. Houde C, Bohn DJ, Freedom RM, Rabinovitch M. Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators. Br Heart J. 1993;70:461-468.

11. Winberg P, Lundell BPW, Gustafsson LE. Effect of inhaled nitric oxide on raised pulmonary vascular resistance in children with congenital heart disease. Br Heart J. 1994;71:282-286.

12. Day RW, Lynch JM, Shaddy RE, Osmond GS. Pulmonary vasodilatory effects of 12 and 60 parts per million inhaled nitric oxide in children with ventricular septal defect. Am J Cardiol. 1995;75:196-198.

13. Atz AM, Adatia I, Lock JE, Wessel DL. Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol. 1999;33:813-819.

14. Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli B, Beghetti M. Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease. Vasodilator capacity and cellular mechanisms. Circulation 2001; 103: 544-548

15. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprussiate is useful in defining a high risk group. Am J Coll Cardiol. 1992;19:48-54.

16. Heath D, Edwards JE: The pathology of hypertensive pulmonary vascular disease. Circulation 1958; 28: 533-47



Your questions, contributions and commentaries will be answered
by the lecturer or experts on the subject in the Pediatric Cardiology list.
Please fill in the form (in Spanish, Portuguese or English) and press the "Send" button.

or commentary
Name and Surname:
E-Mail address:


2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
Dr. Raúl Bretal
Scientific Committee
Dr. Armando Pacher
Technical Committee - CETIFAC

Copyright© 1999-2001 Argentine Federation of Cardiology
All rights reserved


This company contributed to the Congress: