To compare echocardiographic measures of biventricular function and pulmonary artery size in infants with congenital diaphragmatic hernia (CDH) and normal controls, and examine their correlation, if any, with outcomes in CDH.
We included consecutive neonates (<1 month old) with CDH and term controls without structural heart defects. Clinical and outcomes data were recorded and echocardiograms evaluated for right ventricular (RV) and left ventricular (LV) myocardial performance index (MPI), cardiac output index (CI) and McGoon index, among others. Statistical analyses (SPSS version 17, SPSS, Chicago, IL, USA) included between-group comparisons, using analysis of variance and χ 2-test and binary regression, with significance set at P<0.05.
Infants with CDH (n=34) were comparable with controls (n=35) in their age, weight, gestational age and gender. CDH was left sided in 24 (70%) neonates. Extracorporeal membrane oxygenation (ECMO) was required in 15 (45%) neonates; 18 (53%) infants survived. MPIs, CI and eccentricity index in systole were significantly worse in the CDH group, compared with controls and among CDH infants who died, compared with survivors. Infants with CDH who died or needed ECMO had significantly impaired MPIs and CI than survivors. On regression analyses, LV CI and MPIs were independently associated with mortality.
Infants with CDH had significantly impaired ventricular function and pulmonary hypertension, compared with controls. In the CDH group, LV dysfunction was associated with death and adverse outcomes. Further studies incorporating echocardiographic indices as prognostic markers of CDH are warranted.
Congenital diaphragmatic hernia (CDH) remains a condition with significant mortality, despite the use of intensive life-sustaining technologies, such as extracorporeal membrane oxygenation (ECMO).1 Pulmonary hypertension (PHT) is an intrinsic part of the pathophysiology of CDH, and is thought to be secondary to reversible pulmonary vasoreactivity as well as a fixed component of pulmonary vascular hypoplasia.2 PHT causes an increase in right ventricular (RV) after load, progressively impairing RV function. RV dysfunction and dilation, in turn lead to left ventricular (LV) dysfunction, potentially contributing to adverse clinical outcomes.3 In fact, RV dysfunction is considered the major determinant of illness severity in infants with primary PHT.4 Accurate detection of PHT, using the traditional echocardiographic tricuspid regurgitation method of measurement of pulmonary artery pressures, is possible in only 70% cases.5 Besides, an assessment of its severity has been shown to be imprecise and unreliable in young children. Furthermore, the complex geometry of the right ventricle has precluded objective quantification of its function by traditional measures, such as ejection or shortening fraction.6
In recent years, the myocardial performance or Tei index has emerged as an objective reproducible measure of global systolic and diastolic RV and LV function, which is relatively independent of preload and after load.7, 8 Myocardial performance index (MPI) has been shown to predict outcome in adults with idiopathic pulmonary artery hypertension.9 Dyer et al.10 found a strong correlation between MPI (r=0.94) and mean pulmonary artery pressures on cardiac catheterization, and response to treatment among 12 children with idiopathic PHT. In infants with persistent PHT of the newborn, low LV output was demonstrated in about 60% and decreased LV size, and output to correlate with the need for advanced therapies.11, 12
Limited previous studies on small populations of infants with CDH have evaluated one or a few of the traditional echocardiographic measures of pulmonary artery size and pressure estimates. Some of the studies have demonstrated a correlation between pulmonary artery size, surrogates for size of pulmonary vascular bed and outcome.13, 14, 15 MPI has not been previously evaluated as a prognostic marker in this population. In this study, we sought to evaluate biventricular function, pulmonary artery size and PHT, using sophisticated echocardiographic parameters such as RV and LV MPI in infants with CDH, in comparison with normal controls. We hypothesized that infants with CDH would have impaired biventricular function and PHT, compared with controls. We further hypothesized that among infants with CDH, small pulmonary artery size, elevated RV systolic pressures and biventricular especially LV dysfunction would correlate with outcomes.
This was a retrospective analysis of medical records and echocardiograms performed for clinical indications. Our study population included consecutive infants with a diagnosis of (A) CDH admitted to Children's Hospital of Michigan neonatal intensive care unit within the first month of life between 1 January 2002 and 31 March 2008, and (B) an equal number of normal term (>37 weeks gestation) neonates (<1 month age) on whom an echocardiogram was performed for clinical evaluation of a murmur. The study cohort was identified using the electronic neonatal intensive care unit discharge database with the search words ‘congenital diaphragmatic hernia’. Infants who did not have an echocardiogram or who had a congenital structural heart lesion other than a patent ductus arteriosus or a patent foramen ovale were excluded from the study. The control group was identified (during the same period) using the electronic echocardiographic database of the Division of Cardiology. Infants who required oxygen, ventilation or hemodynamic support, or were diagnosed with a structural heart defect (except patent ductus arteriosus or patent foramen ovale), were excluded from the control group. The study and waiver of parental consent were approved by the Human Investigation Committee of Wayne State University.
Medical records were reviewed to obtain demographic data for both groups of infants, and details of the neonatal course and outcomes until discharge for infants with CDH. The size of the defect was assessed from the operative notes as ‘agenesis’ if the diaphragm or most of the diaphragm was absent (findings of absent or missing rim of diaphragm or repair requiring ‘suturing the patch to the ribs’), without agenesis but requiring patch closure and defects that were repaired by primary closure.16 The initial echocardiogram performed on each infant was reviewed by a single investigator (SA), who was blinded to outcomes data. At our center, all echocardiograms are performed by certified echocardiographic technicians or pediatric cardiology fellows or attendings using a Phillips sono 5500 machine (Phillips Healthcare, Andover, MA, USA) and an 8- or 12-MHz probe. Measures obtained included (A) cardiac output (right and left sided), (B) systolic function (shortening fraction), (C) global cardiac function (right and LV MPI), (E) RV systolic pressure estimate from tricuspid regurgitation jet, (F) other indicators of PHT such as bowing of the interventricular septum (eccentricity index), (G) pulmonary artery size relative to descending aorta size.
Shortening fraction was calculated from standard parasternal short axis M-mode measurements. MPI was calculated using the standard formula: isovolumic contraction time + isovolumic relaxation time divided by the ventricular ejection time. RV MPI was calculated from tricuspid valve inflow and pulmonary valve outflow pulse Dopplers. Time from cessation to the beginning of tricuspid inflow (a) and the RV ejection time (b) were measured and RV MPI calculated as (a–b)/b (Figure 1a).8 The RV inflow (a) interval was recorded from the apical four chamber view with a continuous wave Doppler signal aligned to the tip of tricuspid valve leaflets as the duration of regurgitation. The RV ejection time (b) was obtained from the parasternal long or short axis view with pulse wave Doppler placed at the level of pulmonary valve. These two measurements were obtained in different cycles with similar heart rates. Similarly, LV MPI was calculated using pulse Doppler at the junction of aortic and mitral valves in the apical five chamber view. The left sided MPI was obtained from a single cardiac cycle. Maximum left and right pulmonary artery diameters were measured at the site of origin (from the main pulmonary artery) in the suprasternal or high parasternal views. Descending aorta dimensions were measured at the level of diaphragm on the subcostal view. The McGoon index was taken as a validated measure of pulmonary artery size and calculated as the sum of the diameter of pulmonary arteries at the site of origin indexed to descending aorta. The eccentricity index in diastole and systole were calculated as the ratio of diameters in parasternal short axis at the level of papillary muscle as depicted below. LV end-diastolic eccentricity index, a measure of the displacement of interventricular septum, was measured in the parasternal mid-papillary short-axis view at both end-systole and end-diastole, using the method of Ryan et al. as D1/D2, where D1 is the diameter of the LV parallel to the interventricular septum (anterior to inferior wall) and D2 is the diameter perpendicular to and bisecting the interventricular septum (septum to posterolateral wall; Figure 1b).17 The left and RV output is calculated using method described by Sholler et al.18 In short, the left sided flow velocity time integral is obtained by placing the pulse wave Doppler at the aortic valve level in apical five chamber view. The heart rate was measured from the beginning of one ejection cycle to the beginning of next ejection cycle. The internal diameter of LV outflow tract is measured from the parasternal long axis at the end of systole. The RV outflow is similarly measured by pulse wave recording of the flow at the level of pulmonary valve in the parasternal long axis view. The velocity time integral from at least five consecutive cardiac cycles was obtained. The diameter of the pulmonary valve annulus was obtained at end systole from the same parasternal view. RV systolic pressure was estimated using continuous-wave Doppler from the apical four-chamber view, incorporating modified Bernoulli equation.
Demographic data and echocardiographic indices in the study and control groups of infants were presented as mean (s.d.) or median and (interquartile ranges). A χ2-test, analysis of variance and the non-parametric Wilcoxon test (for skewed data) were used to compare these measures between groups. Binary regression analyses was carried out to evaluate the association between clinical and echocardiographic variables and mortality. Significance was taken as a P-value of <0.05. Statistical analyses was conducted using SPSS software version 17 (SPSS).
Our study cohort comprised 34 infants with CDH and 35 term controls. Table 1 describes baseline demographic characteristics of the two groups. In the CDH group, an antenatal diagnosis of CDH was available in 20 (59%) infants. CDH was left sided in 24 (70%) infants and right sided in the remaining 10 (30%). Among infants with CDH, 28 (82.4%) underwent surgical repair at a mean age of 8.4±1.4 (median 6) days. The diaphragmatic defect was categorized as ‘agenesis’ in 7 (25%) cases, ‘without agenesis requiring patch closure in 8 (29%) and ‘small defects repaired by primary closure’ 13 (46%) cases. In all, 15 (44.2%) infants underwent ECMO, 19 (56%) required inhaled nitric oxide and 18 (53%) survived to discharge.
Among infants with CDH, those who died (n=16) had a significantly higher antenatal diagnosis (84 versus 27%) and surgical repair rates (72 versus 100%) compared with survivors (n=18). The sidedness of the hernias (73 and 72%) was not significantly different in CDH survivors and CDH infants who died. Table 2 compares echocardiographic measures in three groups: controls, CDH infants who died and those who survived. On a three-way comparison, LV cardiac index (CI), MPI, both LV and RV and eccentricity index in systole were significantly different between controls and CDH survivors, between CDH survivors and CDH infants who died and between controls and CDH infants who died. In addition, the eccentricity index in diastole was significantly higher in controls, compared with CDH infants who died. The McGoon index, a reflection of the pulmonary artery size indexed to descending aorta size was comparable in the three groups. No echocardiographic evidence of hypoplasia to cardiac structures was found in any infant with left sided CDH.
When a similar comparison was conducted between infants who survived (n=13) versus those who died or required ECMO (n=21), again RV and LV MPI, LV CI and systolic and diastolic eccentricity indices were all significantly worse in the death/ECMO group (Table 3). Figure 2 depicts a box plot of LV and RV MPI in three groups of infants: controls, CDH survivors and CDH who died.
Finally, we performed a binary regression analysis with death as an outcome, using gestational age, sidedness of hernia, antenatal diagnosis, right and left sided CI and MPI and eccentricity indices. Significant associations with mortality in CDH were observed with antenatal diagnosis (P=0.001), lower LV CI (P=0.005), impaired right and left sided MPI (P=0.006 and 0.01 respectively) and eccentricity index in systole (P=0.01).
Our results demonstrate that infants with CDH have a lower mean LV cardiac output, global biventricular dysfunction and PHT, compared with controls. Among infants with CDH, impaired global ventricular function, as reflected by higher mean right and left myocardial performance indices, lower left-sided cardiac output index and PHT was observed in those who died as well as those who died or required ECMO, compared with survivors. MPI is considered normal at 0.3±0.03, that is, if the ratio of the sum of isovolumic contraction and relaxation times to the ventricular ejection time is a third.18 The CDH population had a significantly impaired MPI with a mean value >0.5. On binary regression, risk of mortality in CDH was significantly associated with lower LV CI, elevated right and left sided MPI and PHT.
The few previous studies on the utility of echocardiographic measures in the CDH population have focused mainly on pulmonary artery size and pressure. Okazaki et al.14 evaluated 28 left-sided CDH infants and demonstrated that pulmonary artery diameters on day 0 and left pulmonary artery flow were prognostic. Mean left and right pulmonary artery diameters and their ratios were significantly smaller among infants who died compared with those who survived and did not need nitric oxide. Another study involving 47 infants with a 74% survival found that 49% had normal pulmonary artery pressure estimates within the first 3 weeks of life, all of whom survived.2 Persistent systemic or suprasystemic pressures, unrelieved by treatment was noted in 17%, all of whom died. Systemic pulmonary artery pressures were associated with decreased survival at all time points (week 1, 3 and 6), when compared with normal pressure infants. Hasegawa et al.13 studied nine infants within 24 h of birth and showed that a low left to right main pulmonary artery dimension ratio <1 predicted persistent fetal circulation and pulmonary hypoplasia. Of those with persistent fetal circulation, three out of five died, whereas one of those without persistent fetal circulation died.11 Suda et al.15 reviewed echocardiograms of 40 neonates with CDH and found that non-survivors had significantly smaller diameters of right and left hilar pulmonary arteries and a lower McGoon index, which relates pulmonary artery size with the descending artery size. Left ventricle ejection fraction was also lower in those who died. The authors acknowledged that a third of survivors with larger combined hilar pulmonary artery size required ‘aggressive treatment’ including ECMO and that apart from size alone, pulmonary vasoconstriction may have a pathogenic part in CDH. Vuletin et al.,19 in a recent retrospective chart review of 19 left CDH infants, demonstrated a significant negative correlation between prenatal magnetic resonance imaging-based PHT index and the McGoon index and postnatal PHT at 3 weeks of age. These studies underscore a probable, although imperfect correlation between echocardiographic measures of PHT and outcome in infants with CDH. Our results are consistent with these data.
It is only recently that MPI has emerged as an objective measure of global ventricular function. In adults, RV MPI has been shown to be significantly impaired in those with RV pressure overload and further that this leads to LV dysfunction.20 Eidem et al.7 have demonstrated the utility of MPI for assessing RV function among infants with congenital heart disease. In a single case–control study, RV MPI was measured in 16 infants with PHT, including 9 with CDH and 28 controls. RV MPI was found to be significantly elevated in the PHT group but correlated poorly with pulmonary artery pressures.
To our knowledge, this is the first study to evaluate a comprehensive echocardiographic profile of the anatomy and function of the pulmonary vasculature, as well as right and left sides of the heart in the CDH population of infants. These data provide new insights into the presence, nature and severity of cardiac dysfunction in this population. Our data are from a single center over a relatively limited time period, during which management practices were consistent. It is encouraging to find that non-invasive, widely available objective echocardiographic measures were independently associated with outcomes. For an individual infant, a detailed echocardiogram, incorporating all these parameters, in addition to currently used clinical data, may be the critical first step to timely and targeted interventions to improve contractility or reduce PHT. Further prospective trials on the impact of this approach on clinical outcomes are warranted.
We recognize the limitations of our study. The effect, if any, of high ventilatory support, high frequency oscillation, pressors and nitric oxide on the echocardiographic parameters are unclear and have not been accounted for. Our sample size was small, although in line with other similar studies. The timing of the echocardiograms, which were ordered for clinical purposes at a mean age of 4.6 days was somewhat delayed and after institution of therapies. Nonetheless, our results validating the predictive ability of newer echocardiographic indices of PHT and function in infants with CDH are exciting, potentially important data on which to base further prospective studies.