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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200310-1483OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1006-1013, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200310-1483OC

Original Article

Pulmonary Vascular Effects of Inhaled Nitric Oxide and Oxygen Tension in Bronchopulmonary Dysplasia

Peter M. Mourani, D. Dunbar Ivy, Dexiang Gao and Steven H. Abman

Divisions of Critical Care, Cardiology, and Pulmonary Medicine, The Pediatric Heart-Lung Center, Department of Pediatrics, The Children's Hospital and University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Peter M. Mourani, M.D., Department of Pediatrics, Division of Critical Care, The Children's Hospital, 1056 East 19th Avenue B530, Denver, CO 80218. E-mail: Peter.Mourani{at}UCHSC.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pulmonary hypertension contributes significantly to morbidity and mortality in bronchopulmonary dysplasia (BPD), but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, we studied the acute effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) were 34 ± 3 mm Hg and 0.42 ± 0.07, respectively. In response to hypoxia, PAP and PVR/SVR increased by 50 ± 8% and 82 ± 14%, respectively (p < 0.01). Hyperoxia decreased PVR/SVR by 28 ± 9% (p = 0.05). The addition of iNO treatment (20–40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 ± 5% (p < 0.01) and 45 ± 6% (p < 0.05) from baseline values, respectively, achieving near normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.

Key Words: bronchopulmonary dysplasia • cardiac catheterization • nitric oxide • pulmonary hypertension • pulmonary vascular reactivity

Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows ventilator and oxygen therapy for neonatal respiratory distress shortly after birth (1, 2). Patients with BPD can develop severe airways disease and abnormalities of lung function that can persist throughout childhood (3–7). In fact, a significant number of children and adolescents with BPD suffer from recurrent respiratory infections, airway hyperresponsiveness, and exercise intolerance. Although many studies of long-term outcomes have focused on serial changes in lung mechanics and airway function, abnormalities of the pulmonary circulation, including the development of pulmonary hypertension, also contribute to the late morbidity and mortality of BPD (8–10).

In addition to marked vasoconstriction due to acute hypoxia, the pulmonary circulation in BPD is further characterized by altered lung structure and growth. BPD has been described as an arrest of lung development, characterized by histologic evidence of reduced numbers of both alveoli and intraacinar arteries (11–15). The reduction in vessel number along with alveolar hypoxia contributes to pulmonary arterial structural remodeling by medial hypertrophy and abnormal extension of muscle to arteries in the periphery. Intimal proliferation and adventitial thickening may further reduce the cross-sectional area of the pulmonary vascular bed. Although most studies describing the pathologic aspects of BPD come from autopsy data, it is reasonable to assume similar changes occur in some survivors of BPD who exhibit clinical symptoms of pulmonary hypertension and cor pulmonale (16). However, the physiology of the pulmonary circulation in patients with BPD with pulmonary hypertension beyond early childhood, including the relative roles of high pulmonary vascular tone versus the effects of decreased growth (vessel density) and structure (smooth muscle hypertrophy and adventitial thickening), have not been studied. Cardiac catheterization has been used to study the pulmonary vascular tone and reactivity of patients with BPD in response to oxygen (10, 13, 17, 18), calcium channel blockers (19, 20), prostacyclin (13), and hydralazine (10), but most of these studies were performed in small numbers of patients over a decade ago in children generally less than 3 years of age, and only a few children up to age 6 are described in the current literature (21).

Although pulmonary hypertension is associated with higher risk of morbidity and mortality in patients with BPD, therapeutic strategies are uncertain. Supplemental oxygen has been the standard therapy for patients with BPD with intermittent or chronic hypoxia, although controversies exist in the literature regarding its use (22–24). Calcium channel blockers benefit some patients with pulmonary hypertension due to other etiologies, and have been suggested as chronic therapy for patients with BPD and pulmonary hypertension, but have not been proven to provide long-term benefit (18, 19, 25, 26). Inhaled nitric oxide (iNO) improves oxygenation in patients with BPD (27), and may decrease the incidence of chronic lung disease and death in premature infants with respiratory distress syndrome (28). The acute response to iNO has been used to predict the response to chronic therapy with calcium channel blockers (29, 30) and to guide treatment (31) in patients with primary pulmonary hypertension. It has even been suggested that iNO may be useful for long-term therapy of pulmonary hypertension (32–34). However, the direct hemodynamic effects of iNO therapy and its potential therapeutic role have not been assessed in patients with BPD.

To test the hypothesis that high vascular tone contributes to pulmonary hypertension in BPD and to determine pulmonary vascular reactivity in children with BPD, we studied the acute effects of changes in oxygen tension, inhaled NO, and calcium channel blockers in patients with BPD who underwent cardiac catheterization for clinical indications. We report that pulmonary hypertension in children with BPD remains responsive to changes in oxygen tension, and that combined treatment with oxygen and iNO decreases pulmonary artery pressures to near-normal levels. These findings suggest that tone contributes significantly to late pulmonary hypertension, and may suggest that chronic therapy with iNO and oxygen may be a useful treatment strategy in selected patients with BPD and pulmonary hypertension.

Some of the results of this study has been reported previously in the form of an abstract (35).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
We reviewed the medical records of all patients with a diagnosis of BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension from January 1995 through April 2003. Approval for review of the medical records was granted by the local institutional review board. In our institution, cardiac catheterization is reserved for patients with BPD who have persistent signs of severe cardiorespiratory disease and are suspected of having significant pulmonary hypertension, to: assess the severity of pulmonary hypertension; to exclude or document the severity of associated anatomic cardiac lesions; to define the presence of aorto-pulmonary collateral vessels, pulmonary venous obstruction, or left heart dysfunction; and to assess pulmonary vascular reactivity in patients who fail to respond to oxygen therapy alone.

The diagnosis of BPD was based on the following criteria: respiratory distress requiring mechanical ventilation during the first days of life, clinical evidence of respiratory distress and oxygen dependency persisting beyond one month of age, and presence of radiographic evidence of BPD as evidenced by hyperexpansion with alternating areas of atelectasis and focal emphysema (1, 2). Patients with other risk factors for pulmonary hypertension (including Down Syndrome, congenital diaphragmatic hernia, or anatomic congenital heart disease other than atrial septal defect and a history of patent ductus arteriosis) were excluded from analysis to more directly explore the pulmonary circulation in BPD without complicating factors. Patients who underwent cardiac catheterization during an acute illness or who required continuous vasoactive infusions were also excluded.

The patient characteristics identified included gestational age, birth weight, sex, duration of mechanical ventilation at birth, and duration of oxygen requirement. Patient data relevant to each catheterization, including the age at the time of catheterization, as well as the respiratory and medication requirements at the time of study were also collected. The chest X-rays, computed tomography (CT) scans, pulmonary function tests, and pulmonary artery wedge angiograms were reviewed as available.

Cardiac Catheterization
Patients received general anesthesia or were sedated with midazolam and fentanyl or meperidine at the discretion of the cardiologist performing the procedure. Patients who were receiving chronic therapy with nifedipine (half-life is approximately 2 hours) were instructed to not take scheduled doses on the day of the study to independently assess the effects of each study condition. Vascular access was obtained by the femoral approach via Seldinger technique. Cardiac output was measured by thermodilution in patients without intracardiac shunts. In patients with intracardiac shunts, the method of Fick was used. Oxygen consumption was measured at baseline conditions, and this value was used during oxygen, nitric oxide, and calcium channel blocker treatment.

Data for ten outcome variables were collected as available from the medical record, including mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), mean aortic/systemic arterial pressure (AoP), right atrial pressure (RAP), cardiac index (CI), pulmonary vascular resistance index (PVRI), systemic vascular resistance index (SVRI), pulmonary to systemic vascular resistance ratio (PVR/SVR), and arterial PCO2 and PO2. Pulmonary and systemic vascular resistances were indexed for body surface area and expressed as PVRI and SVRI, respectively, in Wood units (U · m2).

Study Design
We evaluated pulmonary hemodynamics during normoxia (baseline) and during exposure to acute hypoxia and to different vasodilators, including hyperoxia, hyperoxia plus inhaled nitric oxide (iNO), and calcium channel blockers (CCB). Patients were selected for analysis if hemodynamic evaluations were performed under at least one these conditions in addition baseline measurements. Patients were evaluated in Denver, Colorado (altitude 1,600 m). Because the studies were performed at altitude, PaO2 levels rather than FIO2 levels were targeted to assess changes in oxygen tension (below 55 mm Hg for hypoxia; between 55 and 120 mm Hg for normoxia; above 120 mm Hg for hyperoxia). Blood gases and/or saturations were monitored while the FIO2 was titrated to reach the targeted PaO2. The effects of iNO were assessed in addition to oxygen therapy to achieve maximal pulmonary vasodilatation. Baseline hemodynamic parameters were measured in normoxic conditions, while patients were breathing room air or supplemental oxygen at the same level as used for their chronic therapy (oxygen required to maintain saturation greater than 92%). For patients who required only nighttime oxygen, baseline measurements were performed in room air conditions.

Measurements recorded during hypoxic conditions were performed while oxygen-dependent patients were breathing room air (eight catheterizations), or non–oxygen-dependent patients were breathing 16% oxygen (seven catheterizations). The hemodynamic response to hyperoxia was measured while patients were breathing supplemental oxygen as delivered by nasal cannula, face mask, head hood, or through a mechanical ventilation circuit to achieve arterial PO2 in excess of 120 mm Hg. Inhaled NO was added to oxygen therapy, delivered continuously or by pulsed nasal cannula, as previously described (36) to assess the acute hemodynamic response to hyperoxia + iNO. In two patients, measurements were recorded while breathing hyperoxia + iNO, but not during hyperoxia alone. Diltiazem or nifedipine were only administered to children who were reactive to oxygen and iNO as defined by a 20% or greater decrease in PAP from room air conditions. Diltiazem (0.25 mg/kg, intravenously) or nifedipine (0.125 mg/kg, sublingually) was administered while monitoring systemic blood pressure. CCB were administered to patients while they were breathing supplemental oxygen to avoid hypoxemia during acute administration. All patients were allowed to equilibrate in each study period for at least 10–15 minutes before hemodynamics were measured. In cases where pulmonary hemodynamics were assessed in multiple conditions, patients were equilibrated in baseline conditions between study interventions.

Statistical Analysis
Summary statistics are presented as the mean ± 1 SEM except where specifically noted. Each of the ten outcomes was assessed under the five study conditions (baseline, hypoxia, hyperoxia, hyperoxia + iNO, and CCB) in a linear mixed model, which handles the correlation among the observations within the same subjects. Multiple comparisons between the five study conditions were performed with Bonferroni correction. For the analysis a p value <= 0.05 corrected for the multiple comparisons was considered significant. The degree of the patients' response to each of the four study conditions in reference to their own baseline measurements were analyzed using two-sample paired t tests. This was done for each of the ten outcome variables. More stringent criteria for significance was applied due to the increased number of comparisons (four) such that a corrected p value <= 0.05 (actual p value <= 0.0125) was considered significant. Subsequent analyses were conducted using two-sample t tests for means, comparing the responses to each of the four study interventions from patients less than 5 years old to the results from patients greater than 5 years old. The results from each of these subgroups were also compared with the responses from the whole study group. Five years of age was chosen as the separation point because the majority of hemodynamic information about patients with BPD in the literature was obtained from patients at or below this age (10, 13, 17–21). Correlation analyses were performed to assess the relationship between baseline PAP and the degree of change in response to the four test conditions. In addition, the relationship between the changes in PAP in response to hyperoxia + iNO and CCB were assessed to evaluate whether the response to iNO may be predictive of the response to CCB. Statistical analyses were performed using the SAS 8.2 (SAS Institute Inc., Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifteen patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension met the initial criteria for this study. We excluded two patients with BPD and structural congenital heart disease, and one patient with congenital diaphragmatic hernia. Two patients with BPD were also excluded because measurements were only obtained during baseline conditions without assessment of vasoreactivity to hypoxia or vasodilator agents. The remaining 10 patients underwent a total of 17 catheterizations. The data from two catheterizations were excluded because the patients were either acutely ill or receiving continuous intravenous vasodilators. As a result, the hemodynamic data from 15 cardiac catheterizations performed in 10 patients were analyzed.

A summary of the study patients is presented in Table 1 (a more detailed list of individual characteristics is available in the online supplement). For all but three of the catheterizations, patients required chronic treatment with supplemental oxygen. Five patients were treated with nighttime oxygen alone, and three patients required chronic mechanical ventilation at the time of study. Medications at cardiac catheterization included diuretic therapy (six catheterizations), digoxin (two catheterizations), calcium channel blockers (three catheterizations), inhaled bronchodilators (nine catheterizations), inhaled steroids (six catheterizations), systemic steroids (two catheterizations), ranitidine (three catheterizations), and metcolpramide (one catheterization).


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  		TABLE 1. Patient characteristics

 
Three patients underwent patent ductus arteriosis ligation in the newborn period, and one patient at 6 months of age. Two patients had previously undergone surgical repair of an atrial septal defect before their cardiac catheterizations. Two patients had an existing atrial septal defect at the time of the evaluation; one of these patients also had significant aorto-pulmonary collateral vessels that required placement of occluding coils at the time of the catheterization.

Chest X-rays were available for review in 9 of the 10 patients, and showed areas of hyperinflation with variable degrees of patchy atelectasis. Three patients were noted to have prominent great vessels, and three patients had decreased peripheral vascular markings. CT scans were available for seven patients and demonstrated heterogeneous regions of hyperinflation with infiltrates or atelectasis in each film. Other abnormalities noted were cardiomegaly (3), abnormal pulmonary vessels (4), and interstitial prominence (3). On review of pulmonary artery wedge angiograms, pruning of peripheral pulmonary vessels was noted in 9 of the 15 studies. Collateral vessels were identified in four patients, but only one required intervention by placement of an occluding coil. Pulmonary function tests were available for five patients, all showing significant airway obstruction with FEV1 ranging from 34 to 75% of predicted. Three of the five had significant hyperresponsiveness defined by at least a 20% improvement in FEV1 after inhaled albuterol administration.

Hemodynamic measurements were recorded at baseline (15 catheterizations), during hypoxia (11 catheterizations), during hyperoxia (12 catheterizations), during hyperoxia + iNO (11 catheterizations), and after CCB administration (9 catheterizations). Mean values for each of the ten outcome variables measured during each of the study conditions are presented in Table 2 (a more detailed summary of individual responses is available in the online supplement). The mean arterial PO2 at baseline was 79.6 ± 5.8 mm Hg, and the mean arterial PCO2 was 36.7 ± 1.9 mm Hg. The mean AoP for the group was within the range of normal (71 ± 5 mm Hg). The mean PAP (34 ± 3 mm Hg), PVRI (6.4 ± 1.0 U · m2), and PVR/SVR (0.42 ± 0.07) were elevated in comparison to established normal age appropriate values (37–40).


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  		TABLE 2. Hemodynamic data

 
Reactivity Testing
Individual and mean responses for both PAP and PVR/SVR to the four study conditions compared with baseline are presented in Figures 1 and 2. Of the 11 catheterizations during which hypoxia testing took place, arterial PO2 decreased by an average of 43% or 37.4 ± 5.9 mm Hg (p < 0.01) from each patient's baseline values. Hypoxia increased PAP by an average of 50% above baseline values, rising by 15.5 ± 3.0 mm Hg (p < 0.01), and increased by at least 20% in all but one patient (Figure 1A). In comparison, PAP increased by an average of 13% or 2.2 mm Hg above baseline in historic control subjects (37). PVRI and PVR/SVR increased by 3.77 ± 1.09 U · m2 (p < 0.05) and 0.22 ± 0.05 (p < 0.01), respectively, representing changes of 65% and 82% above baseline. All but one patient had at least a 25% increase in PVR/SVR above baseline values (Figure 2A). Other hemodynamic parameters, including CI, AoP, SVR, and SVRI, did not change during hypoxemia.



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  		Figure 1. Individual effects of (A) hypoxia, (B) hyperoxia, (C) hyperoxia + iNO, and (D) CCB on mean pulmonary artery pressure (PAP) compared with normoxic baseline measurements. For patients assessed in each condition, the mean PAP increased in response to hypoxia and decreased in response to hyperoxia + iNO from their normoxic baseline values. No significant change was observed in mean PAP in response to either oxygen alone or CCB. *p < 0.01 versus baseline measurements; paired t test analysis corrected for multiple comparisons. Light dashed lines represent measurements made in individual patients. The solid line displays mean values for the study group. The heavy dashed line demonstrates the response to hypoxia of a previously published group of six age-appropriate control subjects (37).

 


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  		Figure 2. Individual effects of (A) hypoxia, (B) hyperoxia, (C) hyperoxia + iNO, and (D) CCB on the pulmonary to systemic vascular resistance ratio (PVR/SVR) compared with normoxic baseline measurements. For patients assessed in each condition, the mean PVR/SVR increased in response to hypoxia and decreased in response to hyperoxia and hyperoxia + iNO from their normoxic baseline values. No significant change was observed in mean PVR/SVR in response to CCB. *p < 0.01, {dagger}p <= 0.05 versus baseline measurements; paired t test analysis corrected for multiple comparisons. Light dashed lines represent measurements made in individual patients. The solid line displays mean values for the study group.

 
The response to hyperoxia was assessed during 12 catheterizations. In these patients, hyperoxia decreased PAP from each patient's baseline value by an average of 17% and by at least 20% in 4 of 12 catheterizations, but this was not statistically significant (Figure 1B). Treatment with hyperoxia + iNO (n = 11 catheterizations) decreased PAP by an average of 29% (p < 0.01), producing at least a 20% decrease in 8 of 11 catheterizations (Figure 1C). Treatment with CCB (n = 9 catheterizations) decreased PAP by 20% in 2 of 9 patients, but did not produce significant changes in PAP measurements for the group (Figure 1D). Although PVR/SVR decreased in response to hyperoxia and hyperoxia + iNO, no effect was seen with CCB treatment (Figures 2B–2D). PVR/SVR decreased by an average 28% (p = 0.05) with hyperoxia and by an average of 45% (p < 0.05) with hyperoxia + iNO. Six of twelve patients achieved at least a 20% reduction in PVR/SVR during hyperoxia, whereas ten of eleven patients had at least a 25% reduction in response to hyperoxia + iNO. Although the mean AoP of the 9 catheterizations where reactivity testing to CCB took place was significantly lower than the mean AoP of all patients measured at baseline (Table 2), individual responses to CCB showed an average decrease of 8% in AoP after CCB administration, and this was not significant. However, it was noted that two patients exhibited clinically adverse hemodynamic effects in response to CCB. In one patient, PAP increased by 10%, AoP declined by 10%, and CI decreased by 40%. The other patient experienced a 28% decrease in AoP and a 15% drop in CI while having no effect on PAP. These effects occurred in the absence of hypoxemia, and both of these patients had favorable responses to hyperoxia + iNO. With the exception of PO2, there were no significant changes in the other outcome variables in response to hyperoxia, hyperoxia + iNO, or CCB.

The correlation coefficient for the relationship between each patient's baseline PAP and their response to hypoxia was 0.62 (p < 0.05). There were significant correlations between baseline PAP and the response to hyperoxia (r = 0.61, p = 0.03) and for hyperoxia + iNO (r = 0.71, p= 0.015) (Figure 3). In contrast, the response to CCB was not correlated to baseline PAP (r = 0.29, p > 0.05) nor to the PAP response of hyperoxia + iNO (r = 0.6, p > 0.05).



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  		Figure 3. Relationships between baseline mean pulmonary artery pressure (PAP) measurements and the degree of change in PAP in response to hypoxia (upper panel) and hyperoxia + iNO (lower panel).

 
Pulmonary Vascular Reactivity of Older Children
Eight catheterizations were performed in five patients older than 5 years. Changes in pulmonary hemodynamics were assessed in response to hypoxia in seven catheterizations, to hyperoxia in six catheterizations, to hyperoxia + iNO in six catheterizations, and to CCB in four catheterizations. The median age at catheterization for this group was 10 years (range, 5–26 years). Mean PAP for the group of older patients (30.6 ± 3.1 mm Hg) was not significantly lower than that of children less than 5 years of age (38.1 ± 4.0 mm Hg; p > 0.05) (Figure 4). There were no differences between the groups in any of the other outcome variables at baseline.



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  		Figure 4. Mean pulmonary artery pressures (PAP) in young (open bars) and older patients (filled bars) in response to four different conditions. Young Patients = patients less than 5 years old (n = 7 catheterizations); Older Patients = patients greater than 5 years of old (n = 8 catheterizations). There were no significant differences in these measurements between the groups.

 
In response to hypoxia, all of the older patients had at least a 20% increase in PAP and PVR/SVR above baseline values. Hyperoxia + iNO increased arterial PO2 (266 ± 38 mm Hg) and decreased PAP by an average of 37% compared with baseline (p < 0.05), with PAP declining in all patients by at least 20% from baseline, and all but two patients achieving a PAP <= 20 mm Hg. PVRI and PVR/SVR decreased 44% and 55%, respectively (p < 0.05). There were no significant hemodynamic changes in response to either hyperoxia alone or CCB for patients in this group. For patients over 5 years of age, the responses to the study conditions were not significantly different from the responses in patients under 5 years of age or to the study group as a whole. One patient had five catheterizations performed over time due to prolonged oxygen requirement and persistent signs of pulmonary hypertension (Figure 5). This patient was treated with nifedipine for approximately 4 years, encompassing the data of the first two catheterizations shown. Although this patient demonstrated progressive improvement in baseline pulmonary artery pressures and the degree of vasoreactivity to acute hypoxia, the response to hypoxia remained abnormal.



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  		Figure 5. Mean pulmonary artery pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) measurements under baseline (open bars) and hypoxic conditions (filled bars) in a single patient with BPD from three separate cardiac catheterizations.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We report that pulmonary vascular reactivity to changes in oxygen tension and iNO persists into adolescence in selected patients with BPD and pulmonary hypertension. All but one patient (6 months old) exhibited increased mean pulmonary artery pressure by more than 20% in response to acute hypoxia, suggesting that the risk for pulmonary vasoconstriction due to hypoxia persists in older patients with BPD. Although acute hyperoxia caused modest pulmonary vasodilatation above normoxic baseline values, we found that iNO augmented the vasodilator response of oxygen, and that the combination of supplemental oxygen and iNO often reduced mean pulmonary arterial pressure to near normal values for age. In contrast, calcium channel blockers failed to consistently improve pulmonary hemodynamics in normoxic patients, and caused adverse effects in two patients. These findings demonstrate that although structural remodeling and dysmorphic vascular growth can contribute to pulmonary hypertension in patients with BPD (8, 9, 11, 15), increased pulmonary vascular tone and heightened vasoreactivity persist in older patients with BPD. In addition, although past reports have examined the effects of iNO on gas exchange in severe BPD (27), its effects on pulmonary vascular tone have not been evaluated. We found that iNO enhanced the pulmonary vasodilator response to hyperoxia in patients with BPD, and that this was in striking contrast with the lack of response to acute CCB testing in normoxic patients.

Some of the patients included in this study represent the oldest patients with BPD and pulmonary hypertension described in the literature (10, 13, 17–21). Previously, a study conducted by Berman and coworkers, examining the long-term outcome of patients with BPD, contained the oldest patients whose pulmonary hemodynamics have been described (21). Four of these patients, all being treated with chronic oxygen therapy, were evaluated between the ages of 5 and 6, exhibiting improved but persistent pulmonary hypertension in comparison to their prior catheterizations. All remained responsive to oxygen (at least a 20% decrease in PAP compared with room air). In the present study, all seven catheterizations performed in patients greater than 5 years of age, in whom hypoxia testing took place, demonstrated persistent abnormal hypoxic pulmonary vasoconstrictor responses. Interestingly, two patients, both of whom were treated with CCB based on their initial hemodynamic evaluation, underwent repeat reactivity testing demonstrating interval declines of baseline PAP. Whether the interval improvement represents the natural course of this disease, a response to the treatment regimen, or both, is uncertain.

Previous studies have reported acute beneficial effects of oxygen supplementation in patients who were hypoxemic while breathing room air (10, 17, 18). A past study suggested that achieving a PO2 greater than 55 to 60 mm Hg or oxygen saturations greater than 92% blunted the hypoxia-induced rise in PAP in infants with BPD (18). We report that there was little further decrease in PAP with higher levels of oxygen supplementation that achieve oxygen tension greater than 70 mm Hg. The avoidance of hypoxia through the use of supplemental oxygen has been the standard therapy for patients with BPD and pulmonary hypertension, and our results support its continued use. Indeed, most patients in this study were receiving some form of oxygen therapy at the time of their catheterizations. Although oxygen therapy appears to improve the quality of life in many patients with BPD and may help improve pulmonary vascular disease over time, some patients continue to have elevated baseline pulmonary artery pressures and clinical symptoms of pulmonary hypertension, suggesting the potential need for additional or alternate treatment strategies.

Despite the lack of evidence showing long-term benefit, calcium channel blockers have become the most commonly recommended second line therapy for pulmonary hypertension in patients with BPD based on two studies assessing the acute response to CCB in patients with BPD (19, 20, 25, 26). In both studies, nifedipine acutely lowered PAP and PVR in children with BPD and pulmonary hypertension. However, patients were hypoxemic during their evaluation, and in one study the effects of nifedipine on PAP were not different from the effects of supplemental oxygen alone (19). CCB can blunt the normal hypoxic pulmonary vasoconstrictor response, which may explain why CCB have been shown to improve PAP in patients with hypoxemia. However, this effect may worsen /Q matching and induce hypoxemia as well. In the present study, all patients remained well oxygenated through their evaluation with CBB, and acute responses to CCB were limited.

Reactivity testing with iNO has been used in patients with pulmonary hypertension to predict survival and direct therapy, but has not been evaluated in patients with BPD with pulmonary hypertension. Studies in patients with primary pulmonary hypertension suggest that the acute response to iNO can predict acute and chronic responses to CCB (29, 30). Our data showed poor correlation between the acute responses to iNO and CCB. Although it is possible that the doses of CCB used were subtherapeutic, two patients who had favorable responses to oxygen plus iNO had adverse hemodynamic effects in response to CCB, and these responses were not predictable. In contrast, several other patients in this study were treated with CCB based on reactivity testing. Two such patients had subsequent evaluation with cardiac catheterization and had interval improvements in baseline pulmonary pressures. Therefore, CCB may be a useful therapy in these patients, but due to the potential risk for adverse hemodynamic effects, we recommend treatment with CCB not be instituted without first determining the clinical response during catheterization.

Past studies have shown that iNO is an effective pulmonary vasodilator in children with pulmonary hypertension with congenital heart disease, adult respiratory distress syndrome, persistent pulmonary hypertension of the newborn, and other clinical settings (41–47). Although we did not directly compare responses of children with different causes of pulmonary hypertension, the degree of fall in PAP and PVR/SVR in the patients with BPD is similar to published data (41–44). Despite radiologic evidence of structural abnormalities and pruning of the pulmonary vessels on angiogram, the fact that most of the patients studied have persistent vasoconstriction in response to hypoxia and near normalization (< 25 mm Hg) of pulmonary pressures in response to oxygen plus iNO suggests that the pulmonary circulation in BPD is characterized by increased vascular tone and abnormal vasoreactivity. A recent prospective randomized trial of iNO therapy in premature infants with respiratory distress syndrome showed that it decreased the incidence of chronic lung disease and death (28). Whether long-term iNO therapy can improve pulmonary hypertension and lung disease in patients with established BPD is unknown, but deserves further study. Methods of administration and safety of long-term iNO use has been assessed in patients with pulmonary hypertension of other etiologies (32–34), and should be explored with this patient population as well.

There are several potential limitations to this study. First, patients with BPD and pulmonary hypertension who are evaluated by cardiac catheterization represent a highly selected patient population, which makes it difficult to achieve sufficient numbers to fully compare young and old patients. Selection criteria for enrollment in this study were intentionally strict to isolate the impact of BPD disease on pulmonary hypertension. In addition, certain patients had more than one catheterization. These factors may have created a selection bias and therefore limited the ability to generalize the results. Second, these patients represent a spectrum of BPD disease with varying birth weights, gestational ages, surfactant administration, and neonatal complications. Such differences may explain discrepancies among the responses to the study interventions, but despite these differences the results were fairly consistent. Third, the conditions in which patients were evaluated, although quite similar, could not be kept exactly consistent, and not all patients were evaluated during all conditions. The fact that some patients were evaluated under general anesthesia while others were studied during conscious sedation could have impacted baseline hemodynamics and vasoreactivity. Conscious sedation in patients with chronic lung disease can predispose patients to hypoventilation, negatively impacting pulmonary hemodynamic measurements. Patients in this study were closely monitored to ensure patients were normocarbic, but a few of patients did have transient elevations of arterial PCO2 during their evaluation.

In summary, we found that pulmonary hypertension in children with BPD can persist into adolescence, and that in addition to structural pulmonary vascular disease, vascular tone continues to contribute to high PAP in these patients. Furthermore, we have demonstrated that pulmonary vascular bed remains responsive to changes in oxygen tension, and that iNO can acutely and selectively lower PAP and PVR in patients with BPD. We speculate that oxygen supplementation to maintain normal oxygenation and avoid hypoxemia may be an effective long-term clinical strategy, but that marked hyperoxia is unlikely to cause further improvement in pulmonary hypertension. CCB may be useful adjunctive therapy for patients who fail to respond to oxygen therapy alone, but potential for adverse effects should limit its use to patients whose response has been assessed during catheterization. Inhaled NO is useful for assessing pulmonary vascular tone and reactivity in BPD, but does not predict the response to CCB. Inhaled NO holds promise as long-term therapy for patients with BPD and pulmonary hypertension not responsive to oxygen therapy and/or CCB, and further studies are indicated to determine whether chronic treatment with iNO can alter the long-term course of this disease.


   FOOTNOTES
 
This study was supported by The Children's Hospital Research Institute, the Pediatric General Clinical Research Center at the University of Colorado Health Sciences Center, MO1-RR00069, General Clinical Research Centers Program, NCRR, NIH, and NIH SCOR HL57144.

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: P.M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.D.I. received financial support for speaking at conferences sponsored by Actelion and for serving on the advisory board for CoTherix, INO Therapeutics, and GlaxoSmithKline; D.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.H.A. is currently a Scientific Advisor to INO Therapeutics and his clinical research is partially supported by a grant from INO Therapeutics, and he has previously served as a consultant to Pfizer, but is not currently serving.

Received in original form October 31, 2003; accepted in final form June 4, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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