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Reference Values and Calculation of z-Scores of Echocardiographic Measurements of the Normal Pediatric Right Ventricle
Reference Values and Calculation of z-Scores of Echocardiographic Measurements of the Normal Pediatric Right Ventricle Martin Koestenberger, MDa,*, Bert Nagel, MDa, William Ravekes, MDb, Alexander Avian, PhDc, Ante Burmas, MDa, Gernot Grangl, MDa, Gerhard Cvirn, PhDd, and Andreas Gamillscheg, MDa Determination of right ventricular (RV) size and function has gained more interest in recent years in adults and children, especially in patients with congenital heart disease. Data on normal RV size parameters in children are scant. The aim of this study was to investigate growth-related changes in RV internal dimensions in a healthy pediatric cohort and the predictive value of RV parameters in identifying enlarged right ventricles in children with secundum-type atrial septal defects (ASD). A prospective study was conducted in a group of 576 healthy children (aged 1 day to 18 years) and 37 children (aged 1.4 to 17.7 years) with moderate-sized to large ASDs. The effects of age, body length, body weight, and body surface area were determined on the following RV parameters: end-diastolic basal diameter, end-diastolic midcavity diameter, end-diastolic length, end-systolic length, end-diastolic area, and end-systolic area. The predictive value of normal values stratified for age, body weight, body length, and body surface area was tested in children with ASDs. RV end-diastolic basal diameter, end-diastolic midcavity diameter, end-diastolic length, end-systolic length, end-diastolic area, and end-systolic area showed positive correlations with age, body length, body surface area, and body weight. In this population, RV z scores showed high specificity for detecting patients with ASDs, with sensitivity up to 89%, especially in children <8 years of age. In conclusion, the normal ranges of pediatric RV internal dimensions are provided. The z scores of these RV parameters were also calculated. Normal RV z scores might be important predictors in identifying enlarged right ventricles in patients with ASDs. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:1590e1598) The importance of right ventricular (RV) internal dimensions has increasingly been recognized in pediatric and adult heart disease. Enlarged RV dimensions can provide relevant hints for the diagnosis of congenital heart defects (CHDs), such as atrial septal defect (ASD), and have been shown to be a major diagnostic criterion for arrhythmogenic RV dysplasia.1,2 RV volume and/or pressure overloading conditions after cardiac surgery for CHDs can cause remodeling and dysfunction of the right ventricle.3e6 Therefore, accurate assessment of RV size and function is critically important for guiding treatment and follow-up in a number of cardiovascular conditions. Reference values of various RV diameters for the adult population are
a Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Graz, Austria; bDivision of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; cInstitute for Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria; and dInstitute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria. Manuscript received June 23, 2014; revised manuscript received and accepted August 5, 2014. See page 1597 for disclosure information. *Corresponding author: Tel: þ43-316-385-84276; fax: þ43-316-38513682. E-mail address: [email protected] (M. Koestenberger).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.08.028
available.7,8 On the basis of RV guidelines,7 2-dimensional (2D) echocardiographic measurements from the apical 4-chamber view were described to be useful for the assessment of RV size: RV end-diastolic basal diameter (RVEDb-d), RV end-diastolic midcavity diameter (RVEDm-d), RV enddiastolic length (RVEDL), RV end-diastolic area (RVEDa), and RV end-systolic area (RVESa). These parameters are easy to determine and therefore may be used as noninvasive measurements to study RV size and performance also in children.9 In the pediatric age group, the influence of growing age, body length (BL), body weight (BW), and body surface area (BSA) on RV internal dimensions has not been appropriately analyzed to date. The first aim of our prospective study was to determine the normal z-score values for the RV variables RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, correlated with age, BL, BW, and BSA. The second aim of our study was to determine if using upper reference values (z score > 2) for these variables accurately predicted enlarged right ventricles in children with moderatesized to large ASDs. Methods The healthy study group consisted of 576 pediatric patients (328 male, 248 female). Only subjects whose echocardiographic results were judged normal by one of our staff pediatric cardiologists were included. The study group www.ajconline.org
Miscellaneous/Reference Values of Pediatric Right Ventricle
Figure 1. RV measurements in end-diastole and end-systole in the apical 4-chamber view. (A) The RVEDb-d was measured as the distance between the RV free wall and septum, just distal to the tricuspid annulus. The RVEDm-d is measured in the middle third of the right ventricle at the level of the left ventricular papillary muscles. RVEDb-d and RVEDm-d were measured from the leading edge to the leading edge of the endocardial signals. The measurements of RVEDb-d, RVEDm-d, RVEDL, and RVEDa were performed at end-diastole, which was defined as the frame closest to the onset of the R wave of the electrocardiogram. RVEDa was measured by outlining the endocardial borders of the right ventricle in end-diastole in the apical 4-chamber view. The major axis of the right ventricle was defined as the distance between the RV apex and the midpoint of the tricuspid valve annulus. (B) The measurements of RVESL and RVESa were performed at end-systole, which was defined as the time frame preceding tricuspid valve opening, showing the minimal RV area (in most instances the time of the end of the T wave). RVESa was measured by outlining the endocardial borders of the right ventricle in end-systole in the apical 4-chamber view.
encompassed neonates to adolescents (aged 1 day to 18 years, BW 2.8 to 98.0 kg, BSA 0.20 to 2.23 m2), including 46 neonates and 64 infants. All patients with CHDs or acquired heart disease, chest and thoracic spine deformities, or chromosomal syndromes were excluded from analysis. Patients were examined in a rest state. Infants were allowed to be bottle fed during the examination. The ASD study group consisted of 37 patients (16 male, 21 female; median age 6.2 years, range 1.4 to 17.7) with unrepaired isolated secundum-type ASDs with moderate to large left-to-right shunting at the atrial level and signs of RV volume overload. The ASD size in our patients ranged from 6 to 16 mm on transthoracic examination. Our patients with
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ASD had normal RV systolic pressure as assessed by tricuspid regurgitation velocity (calculated from the modified Bernoulli equation). Echocardiography was performed using a commercially available echocardiographic system (Sonos iE33; Philips Medical Systems, Andover, Massachusetts) using transducers of 5-1, 8-3, and 12-4 MHz depending on patient size and weight. Images were recorded digitally and later analyzed by one of the investigators (M.K.) using off-line software (Xcelera Echo; Philips Medical Systems, Eindhoven, the Netherlands). Echocardiographic images were considered to be of sufficient technical quality only if the entire endocardial surface of the RV cavity could be clearly visualized in the apical 4-chamber view. The apical 4-chamber view was orientated to obtain the maximum dimension of the right ventricle. From this view, the lateral side of the right ventricle and the right side of the interventricular septum lie parallel to the ultrasound beam. Optimal RV images were selected for measurement of the American Society of Echocardiographyerecommended 2D RV parameters.7 The following parameters were recorded: the RVEDa and RVESa were measured by outlining the endocardial borders of the right ventricle in end-diastole and end-systole in the apical 4-chamber view. RVEDb-d was measured as the distance between the RV free wall and septum, just distal to the tricuspid annulus. RVEDm-d was measured in the middle third of the right ventricle at the level of the left ventricular papillary muscles,7 measured in the apical 4-chamber view. The major axis of the right ventricle was defined as the distance between the RV apex and the midpoint of the tricuspid valve annulus in systole (RVESL) and diastole (RVEDL). Measurements of RVEDb-d, RVEDm-d, RVEDL, and RVEDa were performed at end-diastole, which was defined as the frame closest to the onset of the R wave of the electrocardiogram. RVEDb-d and RVEDm-d were measured from the leading edge to the leading edge of the endocardial signals. Measurements of RVESL and RVESa were performed at end-systole, which was defined as the time frame preceding tricuspid valve opening, showing the minimal RV area (in most instances, the time of the end of the T wave). To minimize variability, a strict institutional protocol for image acquisition for the measurement of RV dimensions was used. Age, BW, BL, and BSA were measured at the time of echocardiography, and BSA was calculated using the Mosteller formula.10 The echocardiographic measurement of the various RV internal dimensions is shown in Figure 1. All data were measured from 3 well-trained observers (M.K., B.N., and A.B.) from 3 to 5 consecutive beats and averaged as previously recommended.7 For data analysis, SPSS version 20 (SPSS, Inc., Chicago, Illinois) was used. Reliability of both the interobserver and intraobserver measurements was analyzed by using a random-effects model analysis of variance (intraclass correlation coefficient [ICC]). Intraobserver reliability was high for all measured parameters (RVEDb-d ICC 0.97, 95% confidence interval [CI] 0.93 to 0.98; RVEDm-d ICC 0.98, 95% CI 0.95 to 0.99; RVEDL ICC 0.97, 95% CI 0.93 to 0.99; RVEDa ICC 0.99, 95% CI 0.98 to 1.00; RVESL ICC 0.98, 95% CI 0.96 to 0.99; RVESa ICC 0.99, 95% CI 0.97 to 0.99). Interobserver reliability was high for all measured
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Figure 2. Age versus mean value of RV dimension parameters 2 SDs (z). The mean is represented by the black solid line. The 2z lines are represented by the black broken line. Healthy subjects are denoted by circles and patients with ASD by diamonds. Mean and 2z results from regression analysis of healthy subjects. (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (E) RVEDa, and (F) RVESa: mean and 2z are shown independent of gender. (D) RVESL genderspecific means and 2z are shown (male: blue; female: red).
parameters (RVEDm-d ICC 0.94, 95% CI 0.88 to 0.97; RVEDL ICC 0.96, 95% CI 0.91 to 0.98; RVEDa ICC 0.99, 95% CI 0.98 to 1.00; RVESL ICC 0.96, 95% CI 0.91 to 0.98; RVESa ICC 0.98, 95% CI 0.96 to 0.99), except for RVEDb-d (ICC 0.88, 95% CI 0.73 to 0.94). Data are presented as mean 2 SDs. After plotting the data from healthy children and adolescents, we compared linear, quadratic, cubic, and logarithmic models. If the more complex model did not result in significant improvement in the correlation coefficient, the simpler model was used. Data were examined for heteroscedasticity to determine whether the SD of the residuals varied across the range of values for the independent variable. When significant heteroscedasticity was detected, weighted least square methods were used. The resulting residuals (differences between
observed data and predicted values from the model) were examined and tests for normality were applied to determine whether they conformed to a normal distribution. Examination of residuals was crucial for the development of z scores that would accurately predict the normal ranges. To test the final models, their ability to identify children with ASDs was analyzed. Therefore, sensitivity, specificity, negative predictive value, and positive predictive value for a cut-off score of þ2 SDs was calculated. Furthermore receiver-operating characteristic curves were plotted, and the best cut-off score was computed. This study complies with all institutional guidelines related to patient confidentiality and research ethics, including institutional review board approval (26-328 ex 13/14) of the Ethics Board of the Medical University of Graz.
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Figure 3. BL versus mean value of RV dimension parameters 2 SDs (z). The mean is represented by the black solid line. The 2z lines are represented by the black broken line. Healthy subjects are denoted by black circles and patients with ASD by green diamonds. Mean and 2z results from regression analysis of healthy subjects for (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (D) RVESL, (E) RVEDa, and (F) RVESa are shown.
Results All investigated RV variables, RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, increased from neonates to adolescents in a nonlinear way. The RVEDb-d RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa data are shown in Figures 2 and 3, listed in Tables 1e3, and shown in Supplementary Figures A and B. Because of the strong collinearity of BSA and age, separate models for age and BSA were calculated. For RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, age, BL, BW, and BSA were significant determinants (p <0.0001), with R2 values ranging from 0.79 to 0.90. For all RV dimension parameters, gender was a significant predictor (p <0.01), but adding gender resulted in only a minor increase of explained variance (p <0.001) for all models. Therefore, only for RVESL with age, gender-
specific z scores are presented, showing similar RVESL values for female and male neonates and higher RVESL values for male compared with female adolescents (Figure 2). Heteroscedasticity was observed in all models. Regression equations results are listed in Table 1. Age- and BL-related z scores for RV dimension parameters are listed in Tables 2 and 3. Additionally, BW- and BSA-related z scores for RV dimension parameters are listed in Supplementary Tables A and B. In our 37 patients with moderate-sized to large secundum ASDs (median age 6.2 years, range 1.4 to 17.7), the median age-specific RVEDb-d z score was 3.3, the median age-specific RVEDm-d z score was 2.1, the median age-specific RVEDL z-score was 1.7, the median agespecific RVESL z score was 2.6, the median age-specific RVEDa z-score was 3.0, and the median age-specific
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Table 1 Regression models for RV dimension parameters with age, BW, BL, and BSA Regression Model
BSA BW BL age BSA BW BL
(m2) (kg) (cm) (years) (m2) (kg) (cm)
e (aþb*ln(BSA)) e (aþb*ln(weight)) e (aþb*body length .5) e (aþb*age .5) e (aþb *ln(BSA)) e (aþb*ln(weight)) e (aþb*ln(body length))
ˇ
576 575 575 576 576 575 575 576 576 575 575 576 576 575 575 576 248 328 574 574 575 576 575 575 576
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
female male
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ESa
e (aþb*age .5) e (aþb*ln(BSA)) aþb*weight .5 aþb*body length e (aþb*age .5) e (aþb*ln(BSA)) e (aþb*ln(weight)) aþb*body length aþb*age .5 e (aþb*ln(BSA)) a b*weight .5 aþb*body length (aþb*age .5) 2 e (aþb*ln(BSA)) e (aþb*ln(weight)) e (aþb*ln(body length)) e (aþb*age .5) ˇ
ESL
(years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years)
ˇ
EDa
age BSA BW BL age BSA BW BL age BSA BW BL age BSA BW BL age
ˇ
EDL
ˇ
EDm-d
ˇ
EDb-d
Model estimates b
R2
n
intercept (a)
(b)
0.28 0.99 0.70 0.41 0.15 0.87 -0.30 0.35 2.03 1.60 1.14 0.53 1.47 2.42 0.09 -5.48 0.39 0.45 1.30 0.02 -0.76 0.42 1.87 -0.50 -6.19
0.25 0.48 0.37 0.02 0.25 0.49 0.35 0.02 1.10 0.52 0.71 0.04 0.70 0.98 0.70 1.63 0.50 0.50 0.54 0.38 0.18 0.50 1.00 0.71 1-67
0.79 0.85 0.81 0.81 0.79 0.81 0.81 0.81 0.86 0.86 0.86 0.87 0.88 0.90 0.90 0.89 0.84 0.85 0.85 0.85 0.85 0.84 0.88 0.88 0.87
For each RV dimension parameters regression models, number of subjects used to build the model (n), explained variance (R2), and the model estimates (a, b) for construction estimated mean values with the predictors age, BSA, BW, and BL are shown. Table 2 Age related z-scores for RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa are shown RVEDb-d z-Score
month
year
1 2 3 4-6 7-12 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RVEDm-d z-Score
RVEDL z-Score
RVEDa z-Score
RVESL z-Score
RVESa z-Score
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
1.0 1.0 1.1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.7
1.4 1.4 1.5 15 1.6 1.8 2.0 2.1 2.2 2.4 2.5 2.6 2.7 2.8 2.9 3.1 3.2 3.3 3.4 3.5 3.6 3.7
2.0 2.0 2.1 2.2 2.3 2.5 2.7 2.9 3.1 3.3 3.4 3.6 3.7 3.9 4.0 4.2 4.3 4.5 4.6 4.8 4.9 5.1
0.9 0.9 0.9 1.0 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.4
1.2 1.3 1.3 1.4 1.4 1.6 1.7 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3
1.7 1.8 1.9 1.9 2.0 2.2 2.4 2.6 2.8 2.9 3.0 3.2 3.3 3.5 3.6 3.7 3.9 4.0 4.1 4.2 4.4 4.5
1.2 1.4 1.5 1.6 1.9 2.3 2.6 2.9 3.2 3.4 3.6 3.8 4.0 4.1 4.3 4.5 4.6 4.7 4.9 5.0 5.1 5.3
2.3 2.4 2.5 2.7 3.0 3.4 3.8 4.1 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 5.9 6.1 6.2 6.4 6.5 6.6
3.3 3.5 3.6 3.8 4.1 4.5 4.9 5.3 5.6 5.8 6.1 6.3 6.5 6.7 6.9 7.1 7.2 7.4 7.6 7.7 7.9 8.0
1.0 1.2 1.4 1.6 2.1 2.8 3.7 4.5 5.2 5.9 6.6 7.2 7.9 8.5 9.1 9.7 10.4 11.0 11.6 12.1 12.7 13.3
2.6 2.9 3.2 3.6 4.3 5.4 6.6 7.7 8.7 9.7 10.6 11.4 12.3 13.1 13.9 14.7 15.5 16.3 17.1 17.8 18.6 19.3
4.9 5.4 5.7 6.3 7.3 8.8 10.4 11.8 13.1 14.3 15.5 16.6 17.7 18.8 19.8 20.8 21.8 22.7 23.7 24.6 25.5 26.4
1.3 1.3 1.3 1.4 1.5 1.7 1.8 2.0 2.1 2.3 2.4 2.5 2.6 2.8 2.9 3.0 3.1 3.2 3.4 3.5 3.6 3.7
1.7 1.8 1.9 1.9 2.1 2.3 2.5 2.7 2.9 3.1 3.3 3.4 3.6 3.8 3.9 4.1 4.2 4.4 4.6 4.7 4.9 5.0
2.4 2.5 2.6 2.7 2.8 3.1 3.4 3.7 4.0 4.2 4.4 4.7 4.9 5.1 5.3 5.5 5.8 6.0 6.2 6.4 6.6 6.8
1.3 1.3 1.4 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.8 2.9 3.1 3.2 3.4 3.5 3.6 3.8 3.9 4.1
1.8 1.8 1.9 2.0 2.1 2.3 2.6 2.8 3.0 3.2 3.4 3.6 3.8 3.9 4.1 4.3 4.5 4.6 4.8 5.0 5.2 5.4
2.5 2.6 2.6 2.7 2.9 3.2 3.6 3.8 4.1 4.4 4.6 4.8 5.1 5.3 5.5 5.8 6.0 6.2 6.4 6.7 6.9 7.1
The values in the table are shown as follows: For each age group the estimated mean and 2 z-scores according to the regression analysis of the RV parameters EDb-d, EDm-d, EDL, ESL, EDa, and ESa are shown. The range 2 z-scores represent the expectable normal intervals of deviation for a certainty level of 95%. EDa ¼ end-diastolic area; EDb-d ¼ end-diastolic basal diameter; EDL ¼ end-diastolic length; EDm-d ¼ end-diastolic mid-cavity diameter; ESa ¼ endsystolic area; ESL ¼ end-systolic length.
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Table 3 Body length (BL) related z-scores for RVEBb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa are shown BL (cm)
50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190
RVEDb-d z-Score
RVEDm-d z-Score
RVEDL z-Score
RVEDa z-Score
RVESL z-Score
RVESa z-Score
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
0.7 0.8 0.9 1.0 1.0 1.1 1.2 1.3 1.4 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.2 2.2 2.3 2.4 2.5 2.6 2.6 2.7 2.8 2.9 3.0
1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9
1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.8 2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8
0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 1.2 1.2 1.3 1.4 1.5 1.5 1.6 1.7 1.8 1.8 1.9 2.0 2.0 2.1 2.2 2.3 2.3 2.4 2.5 2.6 2.6
1.2 1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.6 2.7 2.8 2.9 3.0 3.0 3.1 3.2 3.3 3.4 3.4
1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3
1.3 1.5 1.6 1.8 1.9 2.1 2.3 2.4 2.6 2.8 2.9 3.1 3.3 3.4 3.6 3.7 3.9 4.1 4.2 4.4 4.6 4.7 4.9 5.1 5.2 5.4 5.6 5.7 5.9
2.3 2.5 2.6 2.8 3.0 3.2 3.3 3.5 3.7 3.9 4.0 4.2 4.4 4.6 4.8 4.9 5.1 5.3 5.5 5.6 5.8 6.0 6.2 6.3 6.5 6.7 6.9 7.0 7.2
3.3 3.5 3.7 3.9 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.5 5.7 5.9 6.1 6.3 6.5 6.7 6.9 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.3 8.5
1.5 1.8 2.1 2.4 2.7 3.0 3.4 3.7 4.1 4.5 4.9 5.4 5.8 6.3 6.7 7.2 7.7 8.2 8.8 9.3 9.8 10.4 11.0 11.6 12.2 12.8 13.5 14.1 14.8
2.5 2.9 3.3 3.8 4.3 4.8 5.3 5.9 6.4 7.0 7.7 8.3 8.9 9.6 10.3 11.0 11.7 12.5 13.3 14.0 14.8 15.6 16.5 17.3 18.2 19.1 20.0 20.9 21.8
4.0 4.7 5.4 6.1 6.8 7.6 8.4 9.2 10.1 11.0 11.9 12.8 13.8 14.8 15.8 16.8 17.9 19.0 20.1 21.2 22.3 23.5 24.7 25.9 27.1 28.4 29.6 30.9 32.2
1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.9 3.0 3.1 3.2 3.3 3.5 3.6 3.7 3.9 4.0 4.1 4.3
1.7 1.8 1.9 2.0 2.1 2.2 2.4 2.5 2.6 2.7 2.8 3.0 3.1 3.2 3.4 3.5 3.7 3.8 4.0 4.1 4.3 4.4 4.6 4.8 4.9 5.1 5.3 5.5 5.6
2.3 2.4 2.6 2.7 2.9 3.0 3.2 3.3 3.5 3.7 3.8 4.0 4.2 4.4 4.5 4.7 4.9 5.1 5.3 5.5 5.7 5.9 6.1 6.3 6.5 6.7 7.0 7.2 7.4
0.8 1.0 1.1 1.3 1.5 1.6 1.8 2.0 2.2 2.5 2.7 2.9 3.2 3.4 3.7 3.9 4.2 4.5 4.8 5.1 5.4 5.7 6.0 6.4 6.7 7.0 7.4 7.8 8.1
1.4 1.6 1.9 2.2 2.4 2.7 3.1 3.4 3.7 4.1 4.4 4.8 5.2 5.6 6.0 6.4 6.8 7.3 7.7 8.2 8.7 9.2 9.7 10.2 10.7 11.2 11.8 12.3 12.9
2.4 2.8 3.2 3.6 4.1 4.6 5.1 5.6 6.1 6.7 7.3 7.9 8.5 9.1 9.8 10.4 11.1 11.8 12.5 13.2 14.0 14.7 15.5 16.3 17.1 17.9 18.7 19.6 20.4
The values in the table are shown as follows: For each BL group the estimated mean and 2 z-soeres according to the regression analysis of the RV parameters EDb-d, EDm-d, EDL, E5L, EDa, and ESa are shown. The range 2 z-scores represent the expectable normal intervals of deviation for a certainty level of 95%. BL ¼ Body length; EDa ¼ end-diastolic area; EDb-d ¼ end-diastolic basal diameter; EDL ¼ end-diastolic length; EDm-d ¼ end-diastolic mid-cavity diameter; ESa ¼ end-systolic area; ESL ¼ end-systolic length.
RVESa z score was 4.0, respectively. Younger children had the highest age-specific RVEDb-d, RVEDm-d, RVESL, RVEDa, and RVESa z scores. With increased age, these z scores decreased in our patients with ASD (r < 0.37, p <0.024; Figure 2). Age-specific z scores came closer to the mean of our healthy children in patients with ASDs >8 years of age. Similar developments were observed in BL-, BW-, and BSA-specific z scores (Figure 3, Supplementary Figures A and B). To investigate the ability of RV internal dimension upper normal reference ranges in detecting children with ASDs, we used as a cut-off point a z score of >2. For age-specific z scores, the best results were obtained for RVESa. Thirty-three of 37 patients with ASDs were identified as having enlarged right ventricles. The smallest number of identified patients was observed with RVEDL age-specific z scores (12 of 37). When using a cut-off point of z score >2 for BSA, BW, or BL, up to 84% of our patients with ASDs were identified as having enlarged right ventricles. Overall, a visual inspection of the changes in RV dimensional values suggests that these values are increased especially in children <8 years of age. No statistically significant gender differences in RV parameters were seen in our patients
with ASDs. Specificity ranged from 89% (age-specific RVESa z score) to 99% (age-specific RVEDL z score), as listed in Table 4. Using the best cut-off point according to receiver-operating characteristic curve analysis (>2.21), the specificity of age-specific RVESa z scores could be increased up to 91% with sensitivity of 89%. For agespecific RVEDL z score, sensitivity could be increased from 32% to 76%, with a decrease in specificity from 99% to 82% using a cut-off point of <0.96 (Figure 4). Discussion Our study was undertaken to obtain normal RV internal dimensions values in a healthy pediatric study group. Our secondary aim was to see if those normal values could accurately predict RV dilatation in patients with moderate to large ASDs. It is important to create age-related normal values for children because pediatric cardiologists, unlike their adult colleagues, need to have measurements indexed to age, BL, BW, and BSA because of the variability of age-dependent growth. Quantitative assessments of dilated RV dimensions using 2D echocardiography in children cannot be done without first having age-related normative
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Table 4 Impact of reference values on the detection of enlarged RVs in a children with moderate-sized to large ASDs Sensitivity
Cut Off: > 2z
NPV
PPV
98% 98% 98% 98% 97% 97% 97% 95% 96% 97% 97% 97% 99% 99% 99% 99% 98% 98% 98% 98% 99% 99% 99% 99%
49% 57% 65% 68% 37% 43% 44% 32% 71% 50% 49% 58% 48% 43% 41% 43% 40% 42% 44% 38% 33% 42% 43% 36%
Specificity RVEDb-d
RVEDm-d
RVEDL
RVEDa
RVESL
RYESa
Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL
68% 65% 65% 62% 54% 49% 46% 22% 32% 54% 51% 49% 84% 81% 81% 78% 65% 65% 65% 65% 89% 84% 84% 84%
95% 97% 98% 98% 94% 96% 96% 97% 99% 97% 97% 98% 94% 93% 92% 93% 94% 94% 95% 93% 89% 93% 93% 91%
For each RV dimension parameters sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the parameters age, BSA, BW, and BL are shown.
data. The right ventricle is hard to image using 2D echocardiography because of its complex geometry, with separate outflow and inflow portions, a main body that is crescentic and truncated, and the variable trabecular pattern of the free wall.11 The most easily and reproducible measurements of RV internal parameters come from the apical 4-chamber view. As part of its guidelines on chamber quantification, the American Society of Echocardiography published recommendations for the RV assessment in adults.7 Three parameters were recommended as a minimum for the assessment of RV size: RVEDb-d, RVEDm-d, and RVEDL. D’Oronzio et al12 retrospectively studied the influence of age, gender, and BSA in a healthy adult population on RV size and function measurements. They found that gender and BSA were significant determinants of RV size and function. The American Society of Echocardiography published recommendations for quantification methods during the performance of pediatric echocardiography, with the RV internal dimension parameters described to be useful but normative data to be missing.9 Before determining RV internal parameters in children with various forms of CHDs, sufficient quantitative pediatric reference data from echocardiographically normal patients from infants to adolescents are required. We found that pediatric values of RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa increased with age, BL, BW, and BSA. As
expected, the normal values for all RV internal parameters in our older adolescents are similar to adult RV diameter normal reference data.7 Clinically relevant difference of the RV internal parameter values between male and female subjects were only seen in age-specific RVESL values. This gender difference between female and male subjects was detected at >10 years of age and therefore might be due to puberty associated growing differences in size and weight. Awareness of the role of the right ventricle in various cardiovascular diseases is increasing.13e18 In some cases, therapeutic decisions may depend on progression of RV dilatation or a change in systolic RV function. RV diastolic area measurement was shown to be highly reproducible during patient selection for transcatheter pulmonary valve replacement and also to correlate closely with RV end-diastolic volume measured on magnetic resonance imaging.17 The findings were in agreement with the statements of Greutmann et al14,15 that 2D echocardiography holds promise for identifying and quantifying the degree of RV dilatation in patients with volume-loading conditions. Fontana et al19 investigated RV dimensions in 43 healthy children and in 20 children with ASDs. They found that the RV short-axis dimensions were significantly higher in children with ASDs compared with normal children.19 Recently, end-systolic RV volume has been shown to be increased in patients with ASD when compared with controls.20 We obtained the best agespecific z scores for RVESa and RVEDa, suggesting that area measurements might be better to predict enlarged right ventricles in pediatric patients with ASDs. Our younger children with ASDs had the highest age-specific z scores. With increased age, those z scores decrease. There is a higher mean variation of normal values in our healthy adolescents, and therefore RV enlargement seems to be less prominent with increasing age. The anterior and retrosternal position of the right ventricle, however, limits the ability of 2D echocardiography to image it accurately, because of the inability of ultrasound to image through air or bone. It has been known that the longitudinal diameter of the right ventricle is often foreshortened on 2D echocardiography because of an inability to image from the true cardiac apex.21 Another limitation of RV imaging by transthoracic echocardiography is the result of a lack of fixed reference points to ensure optimization of the right ventricle. As a result, the imager can image the right ventricle through various cut planes. Therefore, guidelines describe the essential need to adjust the apical 4-chamber to acquire an RV-focused view.7 It was possible to identify enlarged right ventricles in our patients with ASDs with RV parameter z scores, especially in children <8 years of age. With increasing age, BSA, BW, and BL z scores of our patients with ASDs drew near to normal values but were still higher compared with healthy patients. These data may be useful to guide decision making in patients with ASDs for timing interventional or surgical closure. Being able to identify and quantify the amount of RV dilatation from a quick 4-chamber view may also be helpful in patients in whom detailed examination of the atrial septum from subxiphoid imaging is not possible.
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Figure 4. Receiver-operating characteristic (ROC) curves of age-specific z scores for RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa. Predictive performance of age-specific z scores of (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (D) RVESL, (E) RVEDa, and (F) RVESa for patients with ASD. The ROC curve is a graphic plot of the true-positive rate (sensitivity) versus the false-positive rate (1 specificity) for the detection of patients with ASD.
Disclosures The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2014.08.028. 1. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H,
Kilner P, Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR, Walma E; Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC); Association for European Paediatric Cardiology (AEPC); ESC Committee for Practice Guidelines (CPG). ESC guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31: 2915e2957. 2. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular
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4.
5.
6. 7.
8. 9.
10. 11.
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cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010;121:1533e1541. Grapsa J, O’Regan DP, Pavlopoulos H, Durighel G, Dawson D, Nihoyannopoulos P. Right ventricular remodeling in pulmonary arterial hypertension with three-dimensional echocardiography: comparison with cardiac magnetic resonance imaging. Eur J Echocardiogr 2010;11:64e73. Khoo NS, Young A, Occleshaw C, Cowan B, Zeng IS, Gentles TL. Assessments of right ventricular volume and function using threedimensional echocardiography in older children and adults with congenital heart disease: comparison with cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2009;22:1279e1288. van der Zwaan HB, Geleijnse ML, McGhie JS, McGhie JS, Boersma E, Helbing WA, Meijboom FJ, Roos-Hesselink JW. Right ventricular quantification in clinical practice: two-dimensional vs. threedimensional echocardiography compared with cardiac magnetic resonance imaging. Eur J Echocardiogr 2011;12:656e664. Vonk Noordegraaf A, Galiè N. The role of the right ventricle in pulmonary arterial hypertension. Eur Respir Rev 2011;20:243e253. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685e713. Willis J, Augustine D, Shah R, Stevens C, Easaw J. Right ventricular normal measurements: time to index? J Am Soc Echocardiogr 2012;25: 1259e1267. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, Lai WW, Geva T. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010;23:465e495. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. Foale R, Stefanini L, Rickards A, Somerville J. Left and right ventricular morphology in complex congenital heart disease defined by two dimensional echocardiography. Am J Cardiol 1982;49:93e99.
12. D’Oronzio U, Senn O, Biaggi P, Gruner C, Jenni R, Tanner FC, Greutmann M. Right heart assessment by echocardiography: gender and body size matters. J Am Soc Echocardiogr 2012;25:1251e1258. 13. Davlouros PA, Niwa K, Webb G, Gatzoulis MA. The right ventricle in congenital heart disease. Heart 2006;92(Suppl 1):i27ei38. 14. Greutmann M, Tobler D, Biaggi P, Mah ML, Crean A, Wald RM, Silversides CK, Oechslin EN. Echocardiography for assessment of regional and global right ventricular systolic function in adults with repaired tetralogy of Fallot. Int J Cardiol 2012;157:53e58. 15. Greutmann M, Tobler D, Biaggi P, Mah ML, Crean A, Oechslin EN, Silversides CK. Echocardiography for assessment of right ventricular volumes revisited: a cardiac magnetic resonance comparison study in adults with repaired tetralogy of Fallot. J Am Soc Echocardiogr 2010;23:905e911. 16. Chaowalit N, Durongpisitkul K, Krittayaphong R, Komoltri C, Jakrapanichakul D, Phrudprisan S. Echocardiography as a simple initial tool to assess right ventricular dimensions in patients with repaired tetralogy of Fallot before undergoing pulmonary valve replacement: comparison with cardiovascular magnetic resonance imaging. Echocardiography 2012;29:1239e1246. 17. Brown DW, McElhinney DB, Araoz PA, Zahn EM, Vincent JA, Cheatham JP, Jones TK, Hellenbrand WE, O’Leary PW. Reliability and accuracy of echocardiographic right heart evaluation in the U.S. Melody Valve Investigational Trial. J Am Soc Echocardiogr 2012;25: 383e392. 18. Tonelli AR, Conci D, Tamarappoo BK, Newman J, Dweik RA. Prognostic value of echocardiographic changes in patients with pulmonary arterial hypertension receiving parenteral prostacyclin therapy. J Am Soc Echocardiogr 2014;27:733e741. 19. Fontana GP, Kirkman J, DiSessa T, Hagan A, Hiriashi S, Isabel-Jones J, Friedman WF. Evaluation of right ventricular and right atrial size in children with atrial septal defect using two-dimensional apex echocardiography. J Clin Ultrasound 1982;10:385e390. 20. De Koning WB, van Osch-Gevers LM, Robbers-Visser D, van Domburg RT, Bogers AJ, Helbing WA. Enlarged right ventricular size at 11 years’ follow-up after closure of secundum-type atrial septal defect in children. Cardiol Young 2013;23:7e13. 21. Lang RM, Mor-Avi V, Sugeng L, Nieman PS, Sahn DJ. Threedimensional echocardiography: the benefits of the additional dimension. J Am Coll Cardiol 2006;48:2053e2069.
a Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Graz, Austria; bDivision of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; cInstitute for Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria; and dInstitute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria. Manuscript received June 23, 2014; revised manuscript received and accepted August 5, 2014. See page 1597 for disclosure information. *Corresponding author: Tel: þ43-316-385-84276; fax: þ43-316-38513682. E-mail address: [email protected] (M. Koestenberger).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.08.028
available.7,8 On the basis of RV guidelines,7 2-dimensional (2D) echocardiographic measurements from the apical 4-chamber view were described to be useful for the assessment of RV size: RV end-diastolic basal diameter (RVEDb-d), RV end-diastolic midcavity diameter (RVEDm-d), RV enddiastolic length (RVEDL), RV end-diastolic area (RVEDa), and RV end-systolic area (RVESa). These parameters are easy to determine and therefore may be used as noninvasive measurements to study RV size and performance also in children.9 In the pediatric age group, the influence of growing age, body length (BL), body weight (BW), and body surface area (BSA) on RV internal dimensions has not been appropriately analyzed to date. The first aim of our prospective study was to determine the normal z-score values for the RV variables RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, correlated with age, BL, BW, and BSA. The second aim of our study was to determine if using upper reference values (z score > 2) for these variables accurately predicted enlarged right ventricles in children with moderatesized to large ASDs. Methods The healthy study group consisted of 576 pediatric patients (328 male, 248 female). Only subjects whose echocardiographic results were judged normal by one of our staff pediatric cardiologists were included. The study group www.ajconline.org
Miscellaneous/Reference Values of Pediatric Right Ventricle
Figure 1. RV measurements in end-diastole and end-systole in the apical 4-chamber view. (A) The RVEDb-d was measured as the distance between the RV free wall and septum, just distal to the tricuspid annulus. The RVEDm-d is measured in the middle third of the right ventricle at the level of the left ventricular papillary muscles. RVEDb-d and RVEDm-d were measured from the leading edge to the leading edge of the endocardial signals. The measurements of RVEDb-d, RVEDm-d, RVEDL, and RVEDa were performed at end-diastole, which was defined as the frame closest to the onset of the R wave of the electrocardiogram. RVEDa was measured by outlining the endocardial borders of the right ventricle in end-diastole in the apical 4-chamber view. The major axis of the right ventricle was defined as the distance between the RV apex and the midpoint of the tricuspid valve annulus. (B) The measurements of RVESL and RVESa were performed at end-systole, which was defined as the time frame preceding tricuspid valve opening, showing the minimal RV area (in most instances the time of the end of the T wave). RVESa was measured by outlining the endocardial borders of the right ventricle in end-systole in the apical 4-chamber view.
encompassed neonates to adolescents (aged 1 day to 18 years, BW 2.8 to 98.0 kg, BSA 0.20 to 2.23 m2), including 46 neonates and 64 infants. All patients with CHDs or acquired heart disease, chest and thoracic spine deformities, or chromosomal syndromes were excluded from analysis. Patients were examined in a rest state. Infants were allowed to be bottle fed during the examination. The ASD study group consisted of 37 patients (16 male, 21 female; median age 6.2 years, range 1.4 to 17.7) with unrepaired isolated secundum-type ASDs with moderate to large left-to-right shunting at the atrial level and signs of RV volume overload. The ASD size in our patients ranged from 6 to 16 mm on transthoracic examination. Our patients with
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ASD had normal RV systolic pressure as assessed by tricuspid regurgitation velocity (calculated from the modified Bernoulli equation). Echocardiography was performed using a commercially available echocardiographic system (Sonos iE33; Philips Medical Systems, Andover, Massachusetts) using transducers of 5-1, 8-3, and 12-4 MHz depending on patient size and weight. Images were recorded digitally and later analyzed by one of the investigators (M.K.) using off-line software (Xcelera Echo; Philips Medical Systems, Eindhoven, the Netherlands). Echocardiographic images were considered to be of sufficient technical quality only if the entire endocardial surface of the RV cavity could be clearly visualized in the apical 4-chamber view. The apical 4-chamber view was orientated to obtain the maximum dimension of the right ventricle. From this view, the lateral side of the right ventricle and the right side of the interventricular septum lie parallel to the ultrasound beam. Optimal RV images were selected for measurement of the American Society of Echocardiographyerecommended 2D RV parameters.7 The following parameters were recorded: the RVEDa and RVESa were measured by outlining the endocardial borders of the right ventricle in end-diastole and end-systole in the apical 4-chamber view. RVEDb-d was measured as the distance between the RV free wall and septum, just distal to the tricuspid annulus. RVEDm-d was measured in the middle third of the right ventricle at the level of the left ventricular papillary muscles,7 measured in the apical 4-chamber view. The major axis of the right ventricle was defined as the distance between the RV apex and the midpoint of the tricuspid valve annulus in systole (RVESL) and diastole (RVEDL). Measurements of RVEDb-d, RVEDm-d, RVEDL, and RVEDa were performed at end-diastole, which was defined as the frame closest to the onset of the R wave of the electrocardiogram. RVEDb-d and RVEDm-d were measured from the leading edge to the leading edge of the endocardial signals. Measurements of RVESL and RVESa were performed at end-systole, which was defined as the time frame preceding tricuspid valve opening, showing the minimal RV area (in most instances, the time of the end of the T wave). To minimize variability, a strict institutional protocol for image acquisition for the measurement of RV dimensions was used. Age, BW, BL, and BSA were measured at the time of echocardiography, and BSA was calculated using the Mosteller formula.10 The echocardiographic measurement of the various RV internal dimensions is shown in Figure 1. All data were measured from 3 well-trained observers (M.K., B.N., and A.B.) from 3 to 5 consecutive beats and averaged as previously recommended.7 For data analysis, SPSS version 20 (SPSS, Inc., Chicago, Illinois) was used. Reliability of both the interobserver and intraobserver measurements was analyzed by using a random-effects model analysis of variance (intraclass correlation coefficient [ICC]). Intraobserver reliability was high for all measured parameters (RVEDb-d ICC 0.97, 95% confidence interval [CI] 0.93 to 0.98; RVEDm-d ICC 0.98, 95% CI 0.95 to 0.99; RVEDL ICC 0.97, 95% CI 0.93 to 0.99; RVEDa ICC 0.99, 95% CI 0.98 to 1.00; RVESL ICC 0.98, 95% CI 0.96 to 0.99; RVESa ICC 0.99, 95% CI 0.97 to 0.99). Interobserver reliability was high for all measured
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Figure 2. Age versus mean value of RV dimension parameters 2 SDs (z). The mean is represented by the black solid line. The 2z lines are represented by the black broken line. Healthy subjects are denoted by circles and patients with ASD by diamonds. Mean and 2z results from regression analysis of healthy subjects. (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (E) RVEDa, and (F) RVESa: mean and 2z are shown independent of gender. (D) RVESL genderspecific means and 2z are shown (male: blue; female: red).
parameters (RVEDm-d ICC 0.94, 95% CI 0.88 to 0.97; RVEDL ICC 0.96, 95% CI 0.91 to 0.98; RVEDa ICC 0.99, 95% CI 0.98 to 1.00; RVESL ICC 0.96, 95% CI 0.91 to 0.98; RVESa ICC 0.98, 95% CI 0.96 to 0.99), except for RVEDb-d (ICC 0.88, 95% CI 0.73 to 0.94). Data are presented as mean 2 SDs. After plotting the data from healthy children and adolescents, we compared linear, quadratic, cubic, and logarithmic models. If the more complex model did not result in significant improvement in the correlation coefficient, the simpler model was used. Data were examined for heteroscedasticity to determine whether the SD of the residuals varied across the range of values for the independent variable. When significant heteroscedasticity was detected, weighted least square methods were used. The resulting residuals (differences between
observed data and predicted values from the model) were examined and tests for normality were applied to determine whether they conformed to a normal distribution. Examination of residuals was crucial for the development of z scores that would accurately predict the normal ranges. To test the final models, their ability to identify children with ASDs was analyzed. Therefore, sensitivity, specificity, negative predictive value, and positive predictive value for a cut-off score of þ2 SDs was calculated. Furthermore receiver-operating characteristic curves were plotted, and the best cut-off score was computed. This study complies with all institutional guidelines related to patient confidentiality and research ethics, including institutional review board approval (26-328 ex 13/14) of the Ethics Board of the Medical University of Graz.
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Figure 3. BL versus mean value of RV dimension parameters 2 SDs (z). The mean is represented by the black solid line. The 2z lines are represented by the black broken line. Healthy subjects are denoted by black circles and patients with ASD by green diamonds. Mean and 2z results from regression analysis of healthy subjects for (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (D) RVESL, (E) RVEDa, and (F) RVESa are shown.
Results All investigated RV variables, RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, increased from neonates to adolescents in a nonlinear way. The RVEDb-d RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa data are shown in Figures 2 and 3, listed in Tables 1e3, and shown in Supplementary Figures A and B. Because of the strong collinearity of BSA and age, separate models for age and BSA were calculated. For RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa, age, BL, BW, and BSA were significant determinants (p <0.0001), with R2 values ranging from 0.79 to 0.90. For all RV dimension parameters, gender was a significant predictor (p <0.01), but adding gender resulted in only a minor increase of explained variance (p <0.001) for all models. Therefore, only for RVESL with age, gender-
specific z scores are presented, showing similar RVESL values for female and male neonates and higher RVESL values for male compared with female adolescents (Figure 2). Heteroscedasticity was observed in all models. Regression equations results are listed in Table 1. Age- and BL-related z scores for RV dimension parameters are listed in Tables 2 and 3. Additionally, BW- and BSA-related z scores for RV dimension parameters are listed in Supplementary Tables A and B. In our 37 patients with moderate-sized to large secundum ASDs (median age 6.2 years, range 1.4 to 17.7), the median age-specific RVEDb-d z score was 3.3, the median age-specific RVEDm-d z score was 2.1, the median age-specific RVEDL z-score was 1.7, the median agespecific RVESL z score was 2.6, the median age-specific RVEDa z-score was 3.0, and the median age-specific
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Table 1 Regression models for RV dimension parameters with age, BW, BL, and BSA Regression Model
BSA BW BL age BSA BW BL
(m2) (kg) (cm) (years) (m2) (kg) (cm)
e (aþb*ln(BSA)) e (aþb*ln(weight)) e (aþb*body length .5) e (aþb*age .5) e (aþb *ln(BSA)) e (aþb*ln(weight)) e (aþb*ln(body length))
ˇ
576 575 575 576 576 575 575 576 576 575 575 576 576 575 575 576 248 328 574 574 575 576 575 575 576
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
female male
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ˇ
ESa
e (aþb*age .5) e (aþb*ln(BSA)) aþb*weight .5 aþb*body length e (aþb*age .5) e (aþb*ln(BSA)) e (aþb*ln(weight)) aþb*body length aþb*age .5 e (aþb*ln(BSA)) a b*weight .5 aþb*body length (aþb*age .5) 2 e (aþb*ln(BSA)) e (aþb*ln(weight)) e (aþb*ln(body length)) e (aþb*age .5) ˇ
ESL
(years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years) (m2) (kg) (cm) (years)
ˇ
EDa
age BSA BW BL age BSA BW BL age BSA BW BL age BSA BW BL age
ˇ
EDL
ˇ
EDm-d
ˇ
EDb-d
Model estimates b
R2
n
intercept (a)
(b)
0.28 0.99 0.70 0.41 0.15 0.87 -0.30 0.35 2.03 1.60 1.14 0.53 1.47 2.42 0.09 -5.48 0.39 0.45 1.30 0.02 -0.76 0.42 1.87 -0.50 -6.19
0.25 0.48 0.37 0.02 0.25 0.49 0.35 0.02 1.10 0.52 0.71 0.04 0.70 0.98 0.70 1.63 0.50 0.50 0.54 0.38 0.18 0.50 1.00 0.71 1-67
0.79 0.85 0.81 0.81 0.79 0.81 0.81 0.81 0.86 0.86 0.86 0.87 0.88 0.90 0.90 0.89 0.84 0.85 0.85 0.85 0.85 0.84 0.88 0.88 0.87
For each RV dimension parameters regression models, number of subjects used to build the model (n), explained variance (R2), and the model estimates (a, b) for construction estimated mean values with the predictors age, BSA, BW, and BL are shown. Table 2 Age related z-scores for RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa are shown RVEDb-d z-Score
month
year
1 2 3 4-6 7-12 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RVEDm-d z-Score
RVEDL z-Score
RVEDa z-Score
RVESL z-Score
RVESa z-Score
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
1.0 1.0 1.1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.7
1.4 1.4 1.5 15 1.6 1.8 2.0 2.1 2.2 2.4 2.5 2.6 2.7 2.8 2.9 3.1 3.2 3.3 3.4 3.5 3.6 3.7
2.0 2.0 2.1 2.2 2.3 2.5 2.7 2.9 3.1 3.3 3.4 3.6 3.7 3.9 4.0 4.2 4.3 4.5 4.6 4.8 4.9 5.1
0.9 0.9 0.9 1.0 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.4
1.2 1.3 1.3 1.4 1.4 1.6 1.7 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3
1.7 1.8 1.9 1.9 2.0 2.2 2.4 2.6 2.8 2.9 3.0 3.2 3.3 3.5 3.6 3.7 3.9 4.0 4.1 4.2 4.4 4.5
1.2 1.4 1.5 1.6 1.9 2.3 2.6 2.9 3.2 3.4 3.6 3.8 4.0 4.1 4.3 4.5 4.6 4.7 4.9 5.0 5.1 5.3
2.3 2.4 2.5 2.7 3.0 3.4 3.8 4.1 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 5.9 6.1 6.2 6.4 6.5 6.6
3.3 3.5 3.6 3.8 4.1 4.5 4.9 5.3 5.6 5.8 6.1 6.3 6.5 6.7 6.9 7.1 7.2 7.4 7.6 7.7 7.9 8.0
1.0 1.2 1.4 1.6 2.1 2.8 3.7 4.5 5.2 5.9 6.6 7.2 7.9 8.5 9.1 9.7 10.4 11.0 11.6 12.1 12.7 13.3
2.6 2.9 3.2 3.6 4.3 5.4 6.6 7.7 8.7 9.7 10.6 11.4 12.3 13.1 13.9 14.7 15.5 16.3 17.1 17.8 18.6 19.3
4.9 5.4 5.7 6.3 7.3 8.8 10.4 11.8 13.1 14.3 15.5 16.6 17.7 18.8 19.8 20.8 21.8 22.7 23.7 24.6 25.5 26.4
1.3 1.3 1.3 1.4 1.5 1.7 1.8 2.0 2.1 2.3 2.4 2.5 2.6 2.8 2.9 3.0 3.1 3.2 3.4 3.5 3.6 3.7
1.7 1.8 1.9 1.9 2.1 2.3 2.5 2.7 2.9 3.1 3.3 3.4 3.6 3.8 3.9 4.1 4.2 4.4 4.6 4.7 4.9 5.0
2.4 2.5 2.6 2.7 2.8 3.1 3.4 3.7 4.0 4.2 4.4 4.7 4.9 5.1 5.3 5.5 5.8 6.0 6.2 6.4 6.6 6.8
1.3 1.3 1.4 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.8 2.9 3.1 3.2 3.4 3.5 3.6 3.8 3.9 4.1
1.8 1.8 1.9 2.0 2.1 2.3 2.6 2.8 3.0 3.2 3.4 3.6 3.8 3.9 4.1 4.3 4.5 4.6 4.8 5.0 5.2 5.4
2.5 2.6 2.6 2.7 2.9 3.2 3.6 3.8 4.1 4.4 4.6 4.8 5.1 5.3 5.5 5.8 6.0 6.2 6.4 6.7 6.9 7.1
The values in the table are shown as follows: For each age group the estimated mean and 2 z-scores according to the regression analysis of the RV parameters EDb-d, EDm-d, EDL, ESL, EDa, and ESa are shown. The range 2 z-scores represent the expectable normal intervals of deviation for a certainty level of 95%. EDa ¼ end-diastolic area; EDb-d ¼ end-diastolic basal diameter; EDL ¼ end-diastolic length; EDm-d ¼ end-diastolic mid-cavity diameter; ESa ¼ endsystolic area; ESL ¼ end-systolic length.
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Table 3 Body length (BL) related z-scores for RVEBb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa are shown BL (cm)
50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190
RVEDb-d z-Score
RVEDm-d z-Score
RVEDL z-Score
RVEDa z-Score
RVESL z-Score
RVESa z-Score
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
2
0
2
0.7 0.8 0.9 1.0 1.0 1.1 1.2 1.3 1.4 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.2 2.2 2.3 2.4 2.5 2.6 2.6 2.7 2.8 2.9 3.0
1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9
1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.8 2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8
0.6 0.7 0.7 0.8 0.9 1.0 1.0 1.1 1.2 1.2 1.3 1.4 1.5 1.5 1.6 1.7 1.8 1.8 1.9 2.0 2.0 2.1 2.2 2.3 2.3 2.4 2.5 2.6 2.6
1.2 1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.1 2.2 2.3 2.4 2.5 2.6 2.6 2.7 2.8 2.9 3.0 3.0 3.1 3.2 3.3 3.4 3.4
1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3
1.3 1.5 1.6 1.8 1.9 2.1 2.3 2.4 2.6 2.8 2.9 3.1 3.3 3.4 3.6 3.7 3.9 4.1 4.2 4.4 4.6 4.7 4.9 5.1 5.2 5.4 5.6 5.7 5.9
2.3 2.5 2.6 2.8 3.0 3.2 3.3 3.5 3.7 3.9 4.0 4.2 4.4 4.6 4.8 4.9 5.1 5.3 5.5 5.6 5.8 6.0 6.2 6.3 6.5 6.7 6.9 7.0 7.2
3.3 3.5 3.7 3.9 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.5 5.7 5.9 6.1 6.3 6.5 6.7 6.9 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.3 8.5
1.5 1.8 2.1 2.4 2.7 3.0 3.4 3.7 4.1 4.5 4.9 5.4 5.8 6.3 6.7 7.2 7.7 8.2 8.8 9.3 9.8 10.4 11.0 11.6 12.2 12.8 13.5 14.1 14.8
2.5 2.9 3.3 3.8 4.3 4.8 5.3 5.9 6.4 7.0 7.7 8.3 8.9 9.6 10.3 11.0 11.7 12.5 13.3 14.0 14.8 15.6 16.5 17.3 18.2 19.1 20.0 20.9 21.8
4.0 4.7 5.4 6.1 6.8 7.6 8.4 9.2 10.1 11.0 11.9 12.8 13.8 14.8 15.8 16.8 17.9 19.0 20.1 21.2 22.3 23.5 24.7 25.9 27.1 28.4 29.6 30.9 32.2
1.2 1.3 1.4 1.5 1.6 1.7 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.9 3.0 3.1 3.2 3.3 3.5 3.6 3.7 3.9 4.0 4.1 4.3
1.7 1.8 1.9 2.0 2.1 2.2 2.4 2.5 2.6 2.7 2.8 3.0 3.1 3.2 3.4 3.5 3.7 3.8 4.0 4.1 4.3 4.4 4.6 4.8 4.9 5.1 5.3 5.5 5.6
2.3 2.4 2.6 2.7 2.9 3.0 3.2 3.3 3.5 3.7 3.8 4.0 4.2 4.4 4.5 4.7 4.9 5.1 5.3 5.5 5.7 5.9 6.1 6.3 6.5 6.7 7.0 7.2 7.4
0.8 1.0 1.1 1.3 1.5 1.6 1.8 2.0 2.2 2.5 2.7 2.9 3.2 3.4 3.7 3.9 4.2 4.5 4.8 5.1 5.4 5.7 6.0 6.4 6.7 7.0 7.4 7.8 8.1
1.4 1.6 1.9 2.2 2.4 2.7 3.1 3.4 3.7 4.1 4.4 4.8 5.2 5.6 6.0 6.4 6.8 7.3 7.7 8.2 8.7 9.2 9.7 10.2 10.7 11.2 11.8 12.3 12.9
2.4 2.8 3.2 3.6 4.1 4.6 5.1 5.6 6.1 6.7 7.3 7.9 8.5 9.1 9.8 10.4 11.1 11.8 12.5 13.2 14.0 14.7 15.5 16.3 17.1 17.9 18.7 19.6 20.4
The values in the table are shown as follows: For each BL group the estimated mean and 2 z-soeres according to the regression analysis of the RV parameters EDb-d, EDm-d, EDL, E5L, EDa, and ESa are shown. The range 2 z-scores represent the expectable normal intervals of deviation for a certainty level of 95%. BL ¼ Body length; EDa ¼ end-diastolic area; EDb-d ¼ end-diastolic basal diameter; EDL ¼ end-diastolic length; EDm-d ¼ end-diastolic mid-cavity diameter; ESa ¼ end-systolic area; ESL ¼ end-systolic length.
RVESa z score was 4.0, respectively. Younger children had the highest age-specific RVEDb-d, RVEDm-d, RVESL, RVEDa, and RVESa z scores. With increased age, these z scores decreased in our patients with ASD (r < 0.37, p <0.024; Figure 2). Age-specific z scores came closer to the mean of our healthy children in patients with ASDs >8 years of age. Similar developments were observed in BL-, BW-, and BSA-specific z scores (Figure 3, Supplementary Figures A and B). To investigate the ability of RV internal dimension upper normal reference ranges in detecting children with ASDs, we used as a cut-off point a z score of >2. For age-specific z scores, the best results were obtained for RVESa. Thirty-three of 37 patients with ASDs were identified as having enlarged right ventricles. The smallest number of identified patients was observed with RVEDL age-specific z scores (12 of 37). When using a cut-off point of z score >2 for BSA, BW, or BL, up to 84% of our patients with ASDs were identified as having enlarged right ventricles. Overall, a visual inspection of the changes in RV dimensional values suggests that these values are increased especially in children <8 years of age. No statistically significant gender differences in RV parameters were seen in our patients
with ASDs. Specificity ranged from 89% (age-specific RVESa z score) to 99% (age-specific RVEDL z score), as listed in Table 4. Using the best cut-off point according to receiver-operating characteristic curve analysis (>2.21), the specificity of age-specific RVESa z scores could be increased up to 91% with sensitivity of 89%. For agespecific RVEDL z score, sensitivity could be increased from 32% to 76%, with a decrease in specificity from 99% to 82% using a cut-off point of <0.96 (Figure 4). Discussion Our study was undertaken to obtain normal RV internal dimensions values in a healthy pediatric study group. Our secondary aim was to see if those normal values could accurately predict RV dilatation in patients with moderate to large ASDs. It is important to create age-related normal values for children because pediatric cardiologists, unlike their adult colleagues, need to have measurements indexed to age, BL, BW, and BSA because of the variability of age-dependent growth. Quantitative assessments of dilated RV dimensions using 2D echocardiography in children cannot be done without first having age-related normative
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Table 4 Impact of reference values on the detection of enlarged RVs in a children with moderate-sized to large ASDs Sensitivity
Cut Off: > 2z
NPV
PPV
98% 98% 98% 98% 97% 97% 97% 95% 96% 97% 97% 97% 99% 99% 99% 99% 98% 98% 98% 98% 99% 99% 99% 99%
49% 57% 65% 68% 37% 43% 44% 32% 71% 50% 49% 58% 48% 43% 41% 43% 40% 42% 44% 38% 33% 42% 43% 36%
Specificity RVEDb-d
RVEDm-d
RVEDL
RVEDa
RVESL
RYESa
Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL Age BSA BW BL
68% 65% 65% 62% 54% 49% 46% 22% 32% 54% 51% 49% 84% 81% 81% 78% 65% 65% 65% 65% 89% 84% 84% 84%
95% 97% 98% 98% 94% 96% 96% 97% 99% 97% 97% 98% 94% 93% 92% 93% 94% 94% 95% 93% 89% 93% 93% 91%
For each RV dimension parameters sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the parameters age, BSA, BW, and BL are shown.
data. The right ventricle is hard to image using 2D echocardiography because of its complex geometry, with separate outflow and inflow portions, a main body that is crescentic and truncated, and the variable trabecular pattern of the free wall.11 The most easily and reproducible measurements of RV internal parameters come from the apical 4-chamber view. As part of its guidelines on chamber quantification, the American Society of Echocardiography published recommendations for the RV assessment in adults.7 Three parameters were recommended as a minimum for the assessment of RV size: RVEDb-d, RVEDm-d, and RVEDL. D’Oronzio et al12 retrospectively studied the influence of age, gender, and BSA in a healthy adult population on RV size and function measurements. They found that gender and BSA were significant determinants of RV size and function. The American Society of Echocardiography published recommendations for quantification methods during the performance of pediatric echocardiography, with the RV internal dimension parameters described to be useful but normative data to be missing.9 Before determining RV internal parameters in children with various forms of CHDs, sufficient quantitative pediatric reference data from echocardiographically normal patients from infants to adolescents are required. We found that pediatric values of RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa increased with age, BL, BW, and BSA. As
expected, the normal values for all RV internal parameters in our older adolescents are similar to adult RV diameter normal reference data.7 Clinically relevant difference of the RV internal parameter values between male and female subjects were only seen in age-specific RVESL values. This gender difference between female and male subjects was detected at >10 years of age and therefore might be due to puberty associated growing differences in size and weight. Awareness of the role of the right ventricle in various cardiovascular diseases is increasing.13e18 In some cases, therapeutic decisions may depend on progression of RV dilatation or a change in systolic RV function. RV diastolic area measurement was shown to be highly reproducible during patient selection for transcatheter pulmonary valve replacement and also to correlate closely with RV end-diastolic volume measured on magnetic resonance imaging.17 The findings were in agreement with the statements of Greutmann et al14,15 that 2D echocardiography holds promise for identifying and quantifying the degree of RV dilatation in patients with volume-loading conditions. Fontana et al19 investigated RV dimensions in 43 healthy children and in 20 children with ASDs. They found that the RV short-axis dimensions were significantly higher in children with ASDs compared with normal children.19 Recently, end-systolic RV volume has been shown to be increased in patients with ASD when compared with controls.20 We obtained the best agespecific z scores for RVESa and RVEDa, suggesting that area measurements might be better to predict enlarged right ventricles in pediatric patients with ASDs. Our younger children with ASDs had the highest age-specific z scores. With increased age, those z scores decrease. There is a higher mean variation of normal values in our healthy adolescents, and therefore RV enlargement seems to be less prominent with increasing age. The anterior and retrosternal position of the right ventricle, however, limits the ability of 2D echocardiography to image it accurately, because of the inability of ultrasound to image through air or bone. It has been known that the longitudinal diameter of the right ventricle is often foreshortened on 2D echocardiography because of an inability to image from the true cardiac apex.21 Another limitation of RV imaging by transthoracic echocardiography is the result of a lack of fixed reference points to ensure optimization of the right ventricle. As a result, the imager can image the right ventricle through various cut planes. Therefore, guidelines describe the essential need to adjust the apical 4-chamber to acquire an RV-focused view.7 It was possible to identify enlarged right ventricles in our patients with ASDs with RV parameter z scores, especially in children <8 years of age. With increasing age, BSA, BW, and BL z scores of our patients with ASDs drew near to normal values but were still higher compared with healthy patients. These data may be useful to guide decision making in patients with ASDs for timing interventional or surgical closure. Being able to identify and quantify the amount of RV dilatation from a quick 4-chamber view may also be helpful in patients in whom detailed examination of the atrial septum from subxiphoid imaging is not possible.
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Figure 4. Receiver-operating characteristic (ROC) curves of age-specific z scores for RVEDb-d, RVEDm-d, RVEDL, RVESL, RVEDa, and RVESa. Predictive performance of age-specific z scores of (A) RVEDb-d, (B) RVEDm-d, (C) RVEDL, (D) RVESL, (E) RVEDa, and (F) RVESa for patients with ASD. The ROC curve is a graphic plot of the true-positive rate (sensitivity) versus the false-positive rate (1 specificity) for the detection of patients with ASD.
Disclosures The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2014.08.028. 1. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H,
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