Doppler echocardiography is a noninvasive test that is commonly used to screen for PH and to help guide management. Cardiac catheterization, the standard method for assessing pulmonary vascular disease, is a much more invasive test and has been reserved for patients for whom noninvasive assessments are considered inadequate and for assessment of acute vasoreactivity, to guide long-term therapy. Previous studies in adults and children evaluated the ability of echocardiography to diagnose and to determine the severity of PH,^5–12 but few studies in infants compared directly the echocardiographic estimates of systolic PA pressure (sPAP) derived from the tricuspid regurgitant jet velocity (TRJV) with direct measurements obtained through cardiac catheterization,^7,12 and no study concentrated on infants and young children with CLD.

In addition, most of the previous studies assessed the validity of echocardiographic measurements performed simultaneously with cardiac catheterization measurements, showing good correlation between sPAP estimated with echocardiography and the value measured with cardiac catheterization.^5–7,9–12 Although performing simultaneous echocardiographic measurements during cardiac catheterization is the best study design to evaluate the validity and capability of echocardiographic measurements, this approach does not mirror the use of echocardiography in clinical practice, where echocardiographic interpretation serves as the basis for the decision to refer patients for cardiac catheterization (often performed days to weeks later) and guides therapy. Questions remain regarding whether echocardiography identifies correctly patients who should undergo cardiac catheterization and whether it provides sufficient information for effective monitoring of patients with established PH without cardiac catheterization, especially children with CLD.

In our institution, cardiac catheterization is reserved for patients with CLD who have persistent signs of severe cardiorespiratory disease and are suspected of having significant PH after optimal management of their CLD and associated morbidities, to assess the severity of PH; to exclude or to document the severity of associated anatomic cardiac lesions; to define the presence of systemic/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. In addition, patients being treated for PH with vasodilator therapy are referred for cardiac catheterization when clinical improvement is in doubt or echocardiographic measurements fail to provide adequate hemodynamic assessment.

In the present study, we sought to determine the effectiveness of echocardiography, as used in clinical practice, to predict the presence and severity of PH in a population of children <2 years of age with CLD attributable to BPD, CDH, or pulmonary hypoplasia who sub-sequently underwent cardiac catheterization. Our objectives were to determine how often the sPAP can be estimated with echocardiography by using the TRJV, whether the sPAP estimated with echocardiography predicts accurately PH severity, as measured during subsequent cardiac catheterization, whether other qualitative echocardiographic signs of PH predict the presence of PH in the absence of a measurable TRJV, and ultimately whether echocardiographic results are of sufficient reliability to diagnose and to manage PH without cardiac catheterization.

Clinical characteristics of the study patients are presented in Table 1. The median interval between echocardiography and cardiac catheterization was 4 days (range: 0–57 days), and all except 4 studies were performed within 30 days. No patients were studied more than twice. Patients in 23 (74%) of the studies had a history of shunt lesions (including patent ductus arteriosus), 3 of whom had undergone atrial septal defect closure and 5 surgical patent ductus arteriosus closure. In 16 (52%) of the paired studies, patients were receiving specific PH therapy at the time of the studies.

The major hemodynamic findings from the echocardiographic and cardiac catheterization studies are presented in Table 2. The TRJV was detectable in only 19 of the 31 echocardiographic studies, allowing estimation of sPAP for 61% of the patients. The cutoff value of 40 mm Hg for echocardiography-estimated sPAP predicted correctly the presence or absence of PH, as determined with cardiac catheterization (mPAP of >25 mm Hg), in 15 of 19 studies. Cardiac catheterization diagnosed PH in 23 (74%) of the 31 studies. The mPAP determined with cardiac catheterization for patients in whom a TRJV was detected was 38 ± 13 mm Hg, which was greater than the mPAP (30 ± 6 mm Hg) for patients without a detectable TRJV (P = .03).

PH was diagnosed with cardiac catheterization in 16 (84%) of 19 studies in which a TRJV was detected and in 7 (58%) of 12 studies in which TRJV was not detected (P = .10). The ability to estimate sPAP with echocardiography was similar for patients who were receiving PH therapy (10 of 15 patients) and those who were not (9 of 16 patients). Estimations of sPAP with echocardiography were possible for 10 of 18 patients who had shunt lesions. A measurable TRJV was detected in 3 of 7 studies in which the shunt flow was reported as bidirectional, in 1 of 2 studies with right-to-left shunts, and in 6 of 9 studies with left-to-right shunts. All cardiac shunts detected with echocardiography were verified with cardiac catheterization. The pulmonary flow/systemic flow ratio was >1.2 (median: 1.00; range: 0.54–2.23) in 5 of the 18 studies in which a shunt was detected. Aortopulmonary collateral vessels were found in 14 (45%) of the cardiac catheterization studies, 3 of which were deemed clinically significant and large enough to require mechanical occlusion with coils during cardiac catheterization.

There was poor correlation between sPAP values estimated with echocardiography and those measured with cardiac catheterization (r = 0.19; P = .43) (Fig 1). To study the potential effect on the data of the length of time between echocardiographic and cardiac catheterization studies, the subset of patients for whom the interval between echocardiography and cardiac catheterization was ≤10 days (n = 12) was analyzed separately. Despite the shorter time interval, the correlation between sPAP values measured with echocardiography and cardiac catheterization remained poor (r = −0.26; P = .42). The use of other measurements, such as sPAP/sBP, yielded similarly poor correlations between echocardiography and cardiac catheterization (r = 0.18; P = .5). Mean sPAP estimated with echocardiography (65 ± 24 mm Hg) was not statistically different from mean sPAP measured during cardiac catheterization (51 ± 16 mm Hg; P = .13) (Table 2). When echocardiographic estimates of sPAP were grouped according to the severity of PH, as determined with cardiac catheterization, there was no difference in mean sPAP determined with echocardiography between the groups (Fig 2). Echocardiography-estimated sPAP overestimated and underestimated the severity of PH, as determined with cardiac catheterization, correctly identifying PH severity in only 9 of the 19 studies (Fig 3). Of the 3 studies that did not show PH with echocardiography, 1 patient had mild/moderate PH and 1 had severe PH with cardiac catheterization. Both of the children with PH for whom echocardiography indicated no PH had been diagnosed as having PH during previous cardiac catheterization. One child had BPD and was hospitalized with mechanical ventilation and nitric oxide therapy. The other (severe PH) had CDH and was not hospitalized but was being treated chronically with epoprostenol and nasally administered nitric oxide. The intervals between echocardiography and cardiac catheterization for these patients were 3 and 2 days, respectively. Both patients had all of the assessed qualitative echocardiographic findings of PH. Estimated sPAP misclassified 6 patients with mild/moderate PH, as determined with cardiac catheterization, as having severe PH and misclassified 2 patients (1 as having mild/moderate PH and 1 severe PH) who did not have PH, as determined with cardiac catheterization; the time intervals between echocardiography and cardiac catheterization for the latter 2 patients were 1 and 11 days, respectively. Both patients were hospitalized and undergoing mechanical ventilation. Other than sedation level (both received general anesthesia during cardiac catheterization), there were no significant differences in their condition or support at the times of the 2 studies. Both had qualitative findings of PH with echocardiography.

To determine whether the addition of estimated values of RAP to the measured TRJV improved the accuracy of echocardiographic estimates of sPAP, sPAP values were recalculated by adding progressive estimates of RAP (5, 7.5, and 10 mm Hg). The ability of echocardiography-estimated sPAP to predict correctly the severity of PH, as determined with cardiac catheterization, decreased when any of the adjustments for RAP were used (data not shown). The mean RAP measured with cardiac catheterization for the entire study group was 8.13 ± 2.4 mm Hg; for the group in which sPAP could be estimated with echocardiography, the value was 8.16 ± 2.0 mm Hg.

Echocardiographic estimates of sPAP (without adjustment for RAP) were greater than the 40 mm Hg cutoff value for the diagnosis of PH in 16 (84%) of the 19 studies. The actual prevalence of PH in this group, based on the standard definition of mPAP of >25 mm Hg determined with cardiac catheterization, was 74%. The sensitivity, specificity, and positive and negative predictive values of estimated sPAP in diagnosing PH were 88% (95% CI: 64%–97%), 33% (95% CI: 6%–79%), 88% (95% CI: 64%–97%), and 33% (95% CI: 6%–79%), respectively (Table 3).

As applied in clinical practice, echocardiography is used to determine the presence and severity of PH or to monitor patients with known PH. For older patients with PH, serial determinations of functional class and exercise capacity and routine right heart catheterization are recommended to guide therapy.¹⁴ The inability to assess functional class and exercise capacity in young children and the reluctance of many physicians to perform right heart catheterizations in these children further complicate decision-making regarding the management of PH in CLD. Therefore, practitioners have relied more on echocardiographic findings in this population, not only to screen and to diagnose PH but also to monitor disease progression and to assess responses to therapy. Confusing this issue further is the lack of a data-derived definition of PH and a known basal level of PA pressure above which predictable consequences occur. Therefore, defining the levels of PA pressure to identify the presence and severity of PH and to guide therapy remains uncertain.¹⁴ We chose to use the commonly accepted cutoff value of mPAP of >25 mm Hg, as determined with cardiac catheterization, to define PH.¹⁵ Although echocardiography-estimated sPAP of >35 mm Hg has been used to define PH, we used the more-conservative cutoff value of >40 mm Hg to eliminate possible false-positive results.¹⁶

Estimated sPAP derived from the TRJV has become one of the most often used echocardiographic findings for evaluation of PH in adults with heart disease or idiopathic PA hypertension.^5–8 Those studies showed excellent correlation coefficients (r = 0.93–0.97), in comparison with the standard cardiac catheterization measurements. Such studies are extremely limited for children <2 years of age and have been performed only in patients with congenital heart disease.^{7, 12} Those studies evaluated echocardiography and cardiac catheterization performed simultaneously under the same hemodynamic conditions, eliminating differences in sedation level, oxygenation, and ventilator support and significant time intervals between studies. Although previous studies of children with PH showed better correlation between echocardiography-estimated sPAP and the cardiac catheterization measurement, previous studies represent the best possible performance of echocardiography under ideal conditions, not as applied in routine clinical practice as in the present study.

Although the time interval between echocardiography and cardiac catheterization can be considered a limitation of this study, a strength of the current study is evaluation of these tests as actually applied in clinical practice. Patients included in this study received similar levels of support and treatment at the times of echocardiography and cardiac catheterization. There were no detectable differences in medications or fluid status between the studies. In comparison with echocardiography, however, patients were treated longer by the time cardiac catheterization was performed. Whether the additional treatment time could alter hemodynamic factors to a significant degree is unclear. Although the time interval between studies ranged from 0 days to 57 days, when the data were reanalyzed to reduce the interval between echocardiography and cardiac catheterization to ≤10 days, the correlation and accuracy between the measurements did not improve. Another factor that might have contributed to the differing results is that fact that most patients who did not require mechanical ventilatory support at baseline were evaluated with cardiac catheterization under general anesthesia. Although an effort was made to maintain the preexisting goals for oxygenation and ventilation, subtle changes in gas exchange during anesthesia with mechanical ventilation and differing levels of oxygen supplementation could have led to changes in the assessed hemodynamic variables. Differences in the sedation levels of patients undergoing echocardiography and cardiac catheterization might further limit the comparability of the assessed hemodynamic values. In clinical decision-making, however, echocardiography and cardiac catheterization are generally interpreted with little regard to the level of sedation and its subsequent effect on hemodynamic factors. We chose to define the severity of PH on the basis of the pulmonary/systemic pressure ratio, rather than absolute PA pressure, to limit the potential impact of sedation on hemodynamic factors.

A few studies specifically evaluated echocardiography-estimated sPAP in adults with CLD, most with chronic obstructive pulmonary disease.^17–19 Those studies reported smaller proportions of patients in whom a TRJV could be measured and lower correlation coefficients between echocardiography-estimated sPAP and cardiac catheterization measurements, compared with adults with primary PH or heart disease. Echocardiography-estimated sPAP in that population also had poor accuracy.^18,20 Echocardiography was able to detect a measurable TRJV in 61% of our patients, but estimates of sPAP had both poor correlation and poor accuracy for determining PH severity, compared with values measured with subsequent cardiac catheterization. The ability to estimate sPAP in this study was greater than that reported in a study of premature infants with established CLD (31%), in which 79% of studies revealed PH.²¹ It has been postulated that factors associated with CLD, specifically marked pulmonary hyperinflation, expansion of the thoracic cage, and alteration of the position of the heart, adversely affect the ability to detect and to measure TRJV.¹⁸ These mechanisms may also apply to children with CLD, especially infants with BPD and those requiring mechanical ventilation. It was also reported that tricuspid regurgitation is not always present, even in neonates with systemic pressure-level PA pressures,²² which was confirmed in this study.

The ability to estimate sPAP accurately through echocardiography depends on the quality of the tricuspid regurgitant jet. Doppler recording of the frequency spectrum of a tricuspid regurgitation jet optimally shows a smooth, sharply demarcated envelope. In some patients, however, this frequency spectrum is incomplete and its envelope is poorly demarcated. Such inadequate signals may not allow reliable measurement of the spectrum's peak velocity, yielding imprecise estimates of sPAP. Clinical documentation of the quality of the envelope from which the TRJV is measured may be lacking or may not be well understood by noncardiologists, limiting proper interpretation of the estimated sPAP. We recommend close communication with the consulting cardiologist to determine the reliability of the tricuspid regurgitant jet envelope and the subsequently estimated sPAP.

Because the tricuspid regurgitant jet is not always present or measurable, qualitative echocardiographic measures of PH, such as right atrial enlargement, right ventricular hypertrophy, right ventricular dilation, PA dilation, and septal flattening, have been used as non-invasive screening tools. These measurements, with the exception of PA dilation, seem to have good sensitivity and positive predictive value for diagnosing PH in children with CLD, but specificity and negative predictive value are poor. Furthermore, for patients in whom a tricuspid regurgitant jet was not measurable, qualitative measures were less reliable, which suggests that the ability to estimate sPAP may influence the subjective assessment of these parameters. Several studies have used right ventricular outflow patterns or time intervals obtained with echocardiography to estimate PA pressures and to diagnose PH in children,^11,23–28 with limited success, especially in children with CLD.^26,28

Interestingly, 68% of children in this study had a history of a shunt lesion, and shunt lesions, primarily atrial shunts, were detected in 58% of the patients. Whether the presence of shunt lesions contributed to the decision to evaluate these patients with cardiac catheterization, accelerated changes of pulmonary vascular disease, or both, is unclear. Although there is limited evidence to describe accurately the prevalence of shunt lesions in neonatal patients with CLD,²⁹ the observations of this study raise the possibility that patients with CLD who have shunt lesions may be at increased risk for pulmonary vascular disease and PH. Additional studies on the impact of left-to-right shunt lesions in children with CLD, as well as early treatment for pulmonary overcirculation, should be evaluated.