Right Ventricular Function in Preterm and Term Neonates: Reference Values for Right Ventricle Areas and Fractional Area of Change Philip T. Levy, MD, Brittney Dioneda, Mark R. Holland, PhD, Timothy J. Sekarski, RDCS, Caroline K. Lee, MD, Amit Mathur, MD, W. Todd Cade, PT, PhD, Alison G. Cahill, MD, MSCI, Aaron Hamvas, MD, and Gautam K. Singh, MD, St Louis, Missouri; Morristown, New Jersey; and Chicago, Illinois
Background: Right ventricular (RV) fractional area of change (FAC) is a quantitative two-dimensional echocardiographic measurement of RV function. RV FAC expresses the percentage change in the RV chamber area between end-diastole (RV end-diastolic area [RVEDA]) to end-systole (RV end-systolic area [RVESA]). The objectives of this study were to determine the maturational (age- and weight-related) changes in RV FAC and RV areas and to establish reference values in healthy preterm and term neonates. Methods: A prospective longitudinal study was conducted in 115 preterm infants (23–28 weeks’ gestational age at birth, 500–1,500 g). RV FAC was measured at 24 hours of age, 72 hours of age, and 32 and 36 weeks’ postmenstrual age (PMA). The maturational patterns of RVEDA, RVESA, and RV FAC were compared with those in 60 healthy full-term infants in a cross-sectional study ($37 weeks, 3.5 6 1 kg), who underwent echocardiography at birth (n = 25) and 1 month of age (n = 35). RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and FAC was calculated using the formula 100 [(RVEDA RVESA)/RVEDA)]. Premature infants who developed chronic lung disease or had clinically and hemodynamically significant patent ductus arteriosus were excluded (n = 55) from the reference values. Intra- and interobserver reproducibility analysis was performed. Results: RV FAC ranged from 26% at birth to 35% by 36 weeks’ PMA in preterm infants (n = 60) and increased almost 2 times faster in the first month of age compared with healthy term infants (n = 60). Similarly, RVEDA and RVESA increased throughout maturation in both term and preterm infants. RV FAC and RV areas were correlated with weight (r = 0.81, P < .001) but were independent of gestational age at birth (r = 0.3, P = .45). RVEDA and RVESA were correlated with PMA in weeks (r = 0.81, P < .001). RV FAC trended lower in preterm infants with bronchopulmonary dysplasia (P = .04) but was not correlated with size of patent ductus arteriosus (P = .56). There was no difference in RV FAC based on gender or need for mechanical ventilation. Conclusions: This study establishes reference values of RV areas (RVEDA and RVESA) and RV FAC in healthy term and preterm infants and tracks their maturational changes during postnatal development. These measures increase from birth to 36 weeks’ PMA, and this is reflective of the postnatal cardiac growth as a contributor to the maturation of cardiac function These measures are also linearly associated with increasing weight throughout maturation. This study suggests that two-dimensional RV FAC can be used as a complementary modality to assess global RV systolic function in neonates and facilitates its incorporation into clinical pediatric and neonatal guidelines. (J Am Soc Echocardiogr 2015;28:559-69.) Keywords: Right ventricle, Fractional area of change, Cardiac function, Neonates, Prematurity
Right ventricular (RV) performance is an important determinant of clinical status and long-term outcome in preterm and term neonates with cardiopulmonary pathology.1,2 RV mechanics begin to undergo maturational changes in the early postnatal period that have long-
term influence on cardiac function.1 Preterm birth is associated with global alterations in myocardial structure and function by adult age, including smaller RV size and greater RV mass than normal. Intuitively, alterations in RV function in the first months of age may
From the Washington University School of Medicine, St Louis, Missouri (P.T.L., B.D., T.J.S., C.K.L., A.M., W.T.C., A.G.C., G.K.S.); Goryeb Children’s Hospital, Atlantic Health System, Morristown, New Jersey (P.T.L.); Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (M.R.H.); and Northwestern University Feinberg School of Medicine, Chicago, Illinois (A.H.).
doctoral Mentored Training Program in Clinical Investigation (NIH UL1 TR000448), and the Thrasher Research Fund.
This study was supported by grants from the Premature and Respiratory Outcomes Program (NIH 1U01 HL1014650, U01 HL101794), NIH R21 HL106417, a Pediatric Physician Scientist Training Grant (NIH 5 T32 HD043010-09), the Post-
0894-7317/$36.00
Reprint requests: Philip T. Levy, MD, Washington University School of Medicine, One Children’s Place, Campus Box 8116-NWT, St Louis, MO 63110 (E-mail: [email protected]).
Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.01.024
559
560 Levy et al
serve as a sensitive marker of altered hemodynamics, as well BPD = Bronchopulmonary as of the onset of clinical and subdysplasia clinical cardiorespiratory dysfunction.1,3-5 Therefore, EF = Ejection fraction early assessment of RV FAC = Fractional area of performance, in healthy and change critically ill preterm infants, is essential for the surveillance in LPA = Left pulmonary artery the early neonatal period.6 MPI = Myocardial Recent pediatric and neonatal performance index echocardiographic guidelines MRI = Magnetic resonance recommend performing quantiimaging tative measurements of RV systolic function using at least one PDA = Patent ductus of the following echocardioarteriosus graphic measures: (1) RV fracPMA = Postmenstrual age tional area of change (FAC), (2) tricuspid annular plane systolic RV = Right ventricular excursion (TAPSE), or (3) RV RVEDA = Right ventricular myocardial performance index end-diastolic area (MPI).7-10 Normal values for RVESA = Right ventricular TAPSE and RV MPI have end-systolic area previously been established in separate studies of healthy TAPSE = Tricuspid annular children, neonates, and preterm plane systolic excursion infants, but, there are no reference normal data in children or neonates for RV FAC.6,7,11-13 The structural and functional organization of the right ventricle has a complex three-dimensional myofiber arrangement.12 The dominant longitudinal shortening of the right ventricle provides the major contribution to RV ejection fraction (EF) and stroke volume during systole, and there is a strong association between RV FAC measured by echocardiography and RV EF determined by magnetic resonance imaging (MRI).14-17 RV FAC that describes this longitudinal shortening on a global level may provide a sensitive measure of RV function in neonates. RV FAC as an echocardiographic tool to assess RV systolic function has been applied in adults15,17-19 children, and neonates.16,20,21 However, the reference values for the controls cohorts for the pediatric studies refer to those for adults.5,10,15,17,18,22 The use of RV FAC in children and neonates requires knowledge of the range of normal values specific to these patient populations as well as the variations due to maturational changes before routine clinical applications of RV FAC can be implemented in neonates.23 Therefore, the aims of this study were to determine the maturational (age- and weight-related) changes of RV area and RV FAC in preterm infants, compare the evolution with term infants, and establish normal reference values in both preterm and term neonates. Abbreviations
METHODS Study Population Preterm Infants. One hundred fifteen preterm infants (born between 23-0/7 and 28-6/7 weeks’ gestation) were prospectively enrolled from among infants participating in the Premature and Respiratory Outcomes Program (ClinicalTrials.gov identifier NCT01435187). All the infants were enrolled at Washington University/St Louis Children’s Hospital neonatal intensive care unit
Journal of the American Society of Echocardiography May 2015
between August 2011 and August 2013. All 115 preterm infants underwent echocardiography at 32 and 36 weeks’ postmenstrual age (PMA). The timings of the echocardiographic studies at 32 and 36 weeks’ PMA were carefully selected to avoid the early postnatal period of clinical and cardiopulmonary instability and early mortality associated with extreme preterm birth. Choosing to study all infants at a common PMA optimizes the determination of the impact of gestational and chronological age on cardiac function at a specific developmental stage and allows the analysis of measures by postgestational weeks from birth.24 To evaluate the pattern of longitudinal maturation by gestational age at birth and birth weight, 30 of the 115 infants underwent echocardiography at two additional time points, 24 and 72 hours of age. In these 30 infants, we tracked the maturational patterns at 24 hours of age, 72 hours of age, 32 weeks’ PMA, and 36 weeks PMA. Available patient clinical and demographic characteristics were obtained at each time point and are summarized in Table 1. Inclusion criteria included preterm infants born between 23-0/7 and 28-6/7 weeks’ gestational age and alive at 1 year of age. Infants with any suspected congenital anomalies of the airways, congenital heart disease (except hemodynamically insignificant ventricular or atrial septal defects), intrauterine growth restriction, or small size for gestational age were excluded from the study. Infants with qualitative RV or left ventricular systolic dysfunction and/or echocardiographic signs of pulmonary hypertension (i.e., unusual degree of RV hypertrophy, flat septum, or elevated tricuspid regurgitation velocity) were also excluded from the reference values. Patients with clinically and hemodynamically significant patent ductus arteriosus (PDA), defined as moderate to large PDA, were excluded from the reference values.25 We used the relationship of the PDA to left pulmonary artery (LPA) to define size and clinical significance (large = PDA/LPA ratio $ 1, moderate = PDA/LPA ratio < 1 but $ 0.5, and small = PDA/LPA ratio < 0.5). Spontaneous closure of the PDA in extremely low gestational age neonates may not occur in the first week of life, and this delayed closure may be a physiologic consequence of increased pulmonary vascular resistance from pulmonary immaturity.25 Infants with moderate to large PDA based on its relationship to the LPA have a 15 times greater likelihood of requiring treatment for clinically and hemodynamically significant PDA than those with small PDA.25 We therefore excluded infants with moderate to large PDA in the first 4 days of age and any size PDA at 32 and 36 weeks’ PMA from the reference values. Only infants with ‘‘respiratory healthiness’’ were included for analysis.7,26 In the first few months of age, the definition of ‘‘respiratory healthiness’’ may become difficult as a large majority of premature infants present with acute respiratory failure after birth and often require some sort of respiratory support up to 36 weeks’ PMA. Respiratory disease syndrome and the need for mechanical ventilation are common in preterm birth in the early postnatal period. Moderate and severe bronchopulmonary dysplasia (BPD), defined as the need for persistent supplemental oxygen support at 36 weeks’ PMA, is recognized as the most significant respiratory consequence of premature birth in the late postnatal period.26,27 Therefore, infants with any need for oxygen supplementation at 36 weeks’ PMA, classified as moderate or severe BPD, were excluded from the reference values.26 We assessed for the contributions of mechanical ventilation and respiratory disease syndrome, as well as BPD, as defined by the 2001 National Institutes of Health (NIH) BPD workshop (Appendix 1), in a subanalysis from birth through 36 weeks’ PMA. Healthy Term Infants. RV areas and RV FAC were acquired in 60 healthy full-term infants enrolled as a control cohort from the St Louis
Levy et al 561
Journal of the American Society of Echocardiography Volume 28 Number 5
Table 1 Demographic and clinical characteristics of premature infants Timing of echocardiography
24 h of age
72 h of age
32 wk PMA
36 wk PMA
Infants recruited at each time point
30
30
115
115
Infants included in reference values*
20
20
60
60
27 6 1
27 6 1
26 6 2
26 6 2
915 6 118
915 6 118
899 6 218
899 6 218
Gestational age at birth Weight at birth Weight at examination Male/female
9/11
9/11
27/33
27/33
Antenatal steroids
17/20
17/20
53/60
53/60
Surfactant
20/20
20/20
60/60
60/60
858 6 111
814 6 140
1,400 6 238
2,192 6 297
52 6 7
48 6 11
52 6 9
50 6 9
17/30
14/30
1/115
0/115
No/mild
21/30
21/30
60/115
60/115
Moderate/severe*
9/30
9/30
55/115
55/115
Respiratory Weight (kg) at echocardiography RR (breaths/min) Invasive mechanical ventilation BPD
Cardiovascular PDA
27/30
23/30
19/115
11/115
Small
17
13
13
8
Moderate*
6
5
5
3
Large*
4
5
1
0
HR (beats/min)
159 6 14
164 6 12
148 6 16
146 6 11
SBP (mm Hg)
50 6 10
59 6 10
73 6 10
80 6 9
DBP (mm Hg)
33 6 7
37 6 9
42 6 9
46 6 10
MAP (mm Hg)
39 6 7
44 6 8
49 6 14
55 6 14
DBP, Diastolic blood pressure; HR, heart rate; MAP, mean arterial blood pressure; RR, respiratory rate; SBP, systolic blood pressure. Data are expressed as mean 6 SD or as numbers. All demographic and clinical characteristics are from the infants included in the reference values. *Infants with moderate or large PDA at 24 or 72 hours of age, or any size PDA at 32 or 36 weeks’ PMA, were excluded from the reference values. Infants requiring respiratory support at 36 weeks’ PMA, classified as moderate or severe BPD, were also excluded from the reference values.
Children’s Hospital newborn nurseries. These infants were enrolled from a control group from the Premature and Respiratory Outcomes Program and from a control cohort enrolled through the Maternal Lipid Metabolism and Neonatal Heart Function in Diabetes study (ClinicalTrials.gov identifier NCT01346527). Twenty-five infants underwent echocardiography at birth (5 6 3 days) and 35 separate infants at 1 month of age (30 6 7 days). Infants were included from each study if they were $37 weeks’ gestational age at birth. Patients were excluded if they required oxygen supplementation or respiratory support in the first month of age, had abnormal findings on chest radiography, or were diagnosed with congenital heart defects other than PDA or patent foramen ovale. We compared the maturational patterns from birth to 1 month of age with the observed patterns in preterm infants. We obtained informed written consent from all parents in each study, and the institutional review board of Washington University approved the studies. Echocardiographic Analysis of FAC Standard echocardiograms were acquired in the resting state without sedation by one designated experienced primary pediatric cardiac sonographer (T.J.S.) Two-dimensional, real-time, grayscale im-
ages were acquired by a commercially available ultrasound imaging system (Vivid 7 or 9; GE Medical Systems, Milwaukee, WI). The images were obtained using a transducer centered frequency phased-array probe (ranging between 7.5 and 12 MHz) and optimized to visualize the myocardial walls. Two-dimensional images were acquired from the RV-focused apical four-chamber view using a previously published protocol for RV image acquisition and data analysis.9,24 The image data were digitally stored for three cardiac cycles in cine loop format for offline analysis by vendor-customized semiautomated software analysis program (EchoPAC version 110.0.x; GE Medical Systems). RVend-systolic area (RVESA) and RVend-diastolic area (RVEDA) were measured in the RV-focused apical four-chamber view. Beats with similar RR intervals were used to minimize errors in calculation.2 RVESA and RVEDA were measured at the frames just before tricuspid valve opening and just after the valve closure, respectively.5,10 A ‘‘sail sign’’ was traced from the (1) septal side of the tricuspid annular plane (septal-tricuspid annular hinge point) to the (2) apical-septal point and then to the (3) RV free wall side of the tricuspid annular plane (lateral-tricuspid annular hinge point).24,28 The trabeculations were included in the RV area measurements to avoid underestimating the areas.9,12,29 RV endocardial areas were delineated for three consecutive cardiac
562 Levy et al
Journal of the American Society of Echocardiography May 2015
Figure 1 Calculation of RV FAC. This is an example of how to generate and calculate RV FAC. RV FAC was obtained by tracing the RV endocardium in (A) end-systole (RVESA) and (B) end-diastole (RVEDA). For RVESA and RVEDA, a ‘‘sail sign’’ was traced from the (1) septal side of the tricuspid annular plane (septal-tricuspid annular hinge point) to the (2) apical-septal point and then to the (3) RV free wall side (RVFW) of the tricuspid annular plane (lateral-tricuspid annular hinge point).24,28 Care was taken to include the trabeculations in the measurements of the area by tracing RVEDA and RVESA between RV trabeculations and the compact layer of the ventricle.9,12,29 RVESA and RVEDA were measured at the frames just before tricuspid valve opening and just after the valve closure, respectively.5,10 Fractional area of change = 100 [RVEDA (cm2) RVESA (cm2]/RVEDA (cm2).
Table 2 Change in RV areas and FAC in the first month of age Birth
Full-term infants
1 mo
Slope of change
P
(n = 25)
(n = 35)
RVEDA (cm2)
3.7 6 0.7
4.8 6 0.6
0.38
Background: Right ventricular (RV) fractional area of change (FAC) is a quantitative two-dimensional echocardiographic measurement of RV function. RV FAC expresses the percentage change in the RV chamber area between end-diastole (RV end-diastolic area [RVEDA]) to end-systole (RV end-systolic area [RVESA]). The objectives of this study were to determine the maturational (age- and weight-related) changes in RV FAC and RV areas and to establish reference values in healthy preterm and term neonates. Methods: A prospective longitudinal study was conducted in 115 preterm infants (23–28 weeks’ gestational age at birth, 500–1,500 g). RV FAC was measured at 24 hours of age, 72 hours of age, and 32 and 36 weeks’ postmenstrual age (PMA). The maturational patterns of RVEDA, RVESA, and RV FAC were compared with those in 60 healthy full-term infants in a cross-sectional study ($37 weeks, 3.5 6 1 kg), who underwent echocardiography at birth (n = 25) and 1 month of age (n = 35). RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and FAC was calculated using the formula 100 [(RVEDA RVESA)/RVEDA)]. Premature infants who developed chronic lung disease or had clinically and hemodynamically significant patent ductus arteriosus were excluded (n = 55) from the reference values. Intra- and interobserver reproducibility analysis was performed. Results: RV FAC ranged from 26% at birth to 35% by 36 weeks’ PMA in preterm infants (n = 60) and increased almost 2 times faster in the first month of age compared with healthy term infants (n = 60). Similarly, RVEDA and RVESA increased throughout maturation in both term and preterm infants. RV FAC and RV areas were correlated with weight (r = 0.81, P < .001) but were independent of gestational age at birth (r = 0.3, P = .45). RVEDA and RVESA were correlated with PMA in weeks (r = 0.81, P < .001). RV FAC trended lower in preterm infants with bronchopulmonary dysplasia (P = .04) but was not correlated with size of patent ductus arteriosus (P = .56). There was no difference in RV FAC based on gender or need for mechanical ventilation. Conclusions: This study establishes reference values of RV areas (RVEDA and RVESA) and RV FAC in healthy term and preterm infants and tracks their maturational changes during postnatal development. These measures increase from birth to 36 weeks’ PMA, and this is reflective of the postnatal cardiac growth as a contributor to the maturation of cardiac function These measures are also linearly associated with increasing weight throughout maturation. This study suggests that two-dimensional RV FAC can be used as a complementary modality to assess global RV systolic function in neonates and facilitates its incorporation into clinical pediatric and neonatal guidelines. (J Am Soc Echocardiogr 2015;28:559-69.) Keywords: Right ventricle, Fractional area of change, Cardiac function, Neonates, Prematurity
Right ventricular (RV) performance is an important determinant of clinical status and long-term outcome in preterm and term neonates with cardiopulmonary pathology.1,2 RV mechanics begin to undergo maturational changes in the early postnatal period that have long-
term influence on cardiac function.1 Preterm birth is associated with global alterations in myocardial structure and function by adult age, including smaller RV size and greater RV mass than normal. Intuitively, alterations in RV function in the first months of age may
From the Washington University School of Medicine, St Louis, Missouri (P.T.L., B.D., T.J.S., C.K.L., A.M., W.T.C., A.G.C., G.K.S.); Goryeb Children’s Hospital, Atlantic Health System, Morristown, New Jersey (P.T.L.); Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (M.R.H.); and Northwestern University Feinberg School of Medicine, Chicago, Illinois (A.H.).
doctoral Mentored Training Program in Clinical Investigation (NIH UL1 TR000448), and the Thrasher Research Fund.
This study was supported by grants from the Premature and Respiratory Outcomes Program (NIH 1U01 HL1014650, U01 HL101794), NIH R21 HL106417, a Pediatric Physician Scientist Training Grant (NIH 5 T32 HD043010-09), the Post-
0894-7317/$36.00
Reprint requests: Philip T. Levy, MD, Washington University School of Medicine, One Children’s Place, Campus Box 8116-NWT, St Louis, MO 63110 (E-mail: [email protected]).
Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.01.024
559
560 Levy et al
serve as a sensitive marker of altered hemodynamics, as well BPD = Bronchopulmonary as of the onset of clinical and subdysplasia clinical cardiorespiratory dysfunction.1,3-5 Therefore, EF = Ejection fraction early assessment of RV FAC = Fractional area of performance, in healthy and change critically ill preterm infants, is essential for the surveillance in LPA = Left pulmonary artery the early neonatal period.6 MPI = Myocardial Recent pediatric and neonatal performance index echocardiographic guidelines MRI = Magnetic resonance recommend performing quantiimaging tative measurements of RV systolic function using at least one PDA = Patent ductus of the following echocardioarteriosus graphic measures: (1) RV fracPMA = Postmenstrual age tional area of change (FAC), (2) tricuspid annular plane systolic RV = Right ventricular excursion (TAPSE), or (3) RV RVEDA = Right ventricular myocardial performance index end-diastolic area (MPI).7-10 Normal values for RVESA = Right ventricular TAPSE and RV MPI have end-systolic area previously been established in separate studies of healthy TAPSE = Tricuspid annular children, neonates, and preterm plane systolic excursion infants, but, there are no reference normal data in children or neonates for RV FAC.6,7,11-13 The structural and functional organization of the right ventricle has a complex three-dimensional myofiber arrangement.12 The dominant longitudinal shortening of the right ventricle provides the major contribution to RV ejection fraction (EF) and stroke volume during systole, and there is a strong association between RV FAC measured by echocardiography and RV EF determined by magnetic resonance imaging (MRI).14-17 RV FAC that describes this longitudinal shortening on a global level may provide a sensitive measure of RV function in neonates. RV FAC as an echocardiographic tool to assess RV systolic function has been applied in adults15,17-19 children, and neonates.16,20,21 However, the reference values for the controls cohorts for the pediatric studies refer to those for adults.5,10,15,17,18,22 The use of RV FAC in children and neonates requires knowledge of the range of normal values specific to these patient populations as well as the variations due to maturational changes before routine clinical applications of RV FAC can be implemented in neonates.23 Therefore, the aims of this study were to determine the maturational (age- and weight-related) changes of RV area and RV FAC in preterm infants, compare the evolution with term infants, and establish normal reference values in both preterm and term neonates. Abbreviations
METHODS Study Population Preterm Infants. One hundred fifteen preterm infants (born between 23-0/7 and 28-6/7 weeks’ gestation) were prospectively enrolled from among infants participating in the Premature and Respiratory Outcomes Program (ClinicalTrials.gov identifier NCT01435187). All the infants were enrolled at Washington University/St Louis Children’s Hospital neonatal intensive care unit
Journal of the American Society of Echocardiography May 2015
between August 2011 and August 2013. All 115 preterm infants underwent echocardiography at 32 and 36 weeks’ postmenstrual age (PMA). The timings of the echocardiographic studies at 32 and 36 weeks’ PMA were carefully selected to avoid the early postnatal period of clinical and cardiopulmonary instability and early mortality associated with extreme preterm birth. Choosing to study all infants at a common PMA optimizes the determination of the impact of gestational and chronological age on cardiac function at a specific developmental stage and allows the analysis of measures by postgestational weeks from birth.24 To evaluate the pattern of longitudinal maturation by gestational age at birth and birth weight, 30 of the 115 infants underwent echocardiography at two additional time points, 24 and 72 hours of age. In these 30 infants, we tracked the maturational patterns at 24 hours of age, 72 hours of age, 32 weeks’ PMA, and 36 weeks PMA. Available patient clinical and demographic characteristics were obtained at each time point and are summarized in Table 1. Inclusion criteria included preterm infants born between 23-0/7 and 28-6/7 weeks’ gestational age and alive at 1 year of age. Infants with any suspected congenital anomalies of the airways, congenital heart disease (except hemodynamically insignificant ventricular or atrial septal defects), intrauterine growth restriction, or small size for gestational age were excluded from the study. Infants with qualitative RV or left ventricular systolic dysfunction and/or echocardiographic signs of pulmonary hypertension (i.e., unusual degree of RV hypertrophy, flat septum, or elevated tricuspid regurgitation velocity) were also excluded from the reference values. Patients with clinically and hemodynamically significant patent ductus arteriosus (PDA), defined as moderate to large PDA, were excluded from the reference values.25 We used the relationship of the PDA to left pulmonary artery (LPA) to define size and clinical significance (large = PDA/LPA ratio $ 1, moderate = PDA/LPA ratio < 1 but $ 0.5, and small = PDA/LPA ratio < 0.5). Spontaneous closure of the PDA in extremely low gestational age neonates may not occur in the first week of life, and this delayed closure may be a physiologic consequence of increased pulmonary vascular resistance from pulmonary immaturity.25 Infants with moderate to large PDA based on its relationship to the LPA have a 15 times greater likelihood of requiring treatment for clinically and hemodynamically significant PDA than those with small PDA.25 We therefore excluded infants with moderate to large PDA in the first 4 days of age and any size PDA at 32 and 36 weeks’ PMA from the reference values. Only infants with ‘‘respiratory healthiness’’ were included for analysis.7,26 In the first few months of age, the definition of ‘‘respiratory healthiness’’ may become difficult as a large majority of premature infants present with acute respiratory failure after birth and often require some sort of respiratory support up to 36 weeks’ PMA. Respiratory disease syndrome and the need for mechanical ventilation are common in preterm birth in the early postnatal period. Moderate and severe bronchopulmonary dysplasia (BPD), defined as the need for persistent supplemental oxygen support at 36 weeks’ PMA, is recognized as the most significant respiratory consequence of premature birth in the late postnatal period.26,27 Therefore, infants with any need for oxygen supplementation at 36 weeks’ PMA, classified as moderate or severe BPD, were excluded from the reference values.26 We assessed for the contributions of mechanical ventilation and respiratory disease syndrome, as well as BPD, as defined by the 2001 National Institutes of Health (NIH) BPD workshop (Appendix 1), in a subanalysis from birth through 36 weeks’ PMA. Healthy Term Infants. RV areas and RV FAC were acquired in 60 healthy full-term infants enrolled as a control cohort from the St Louis
Levy et al 561
Journal of the American Society of Echocardiography Volume 28 Number 5
Table 1 Demographic and clinical characteristics of premature infants Timing of echocardiography
24 h of age
72 h of age
32 wk PMA
36 wk PMA
Infants recruited at each time point
30
30
115
115
Infants included in reference values*
20
20
60
60
27 6 1
27 6 1
26 6 2
26 6 2
915 6 118
915 6 118
899 6 218
899 6 218
Gestational age at birth Weight at birth Weight at examination Male/female
9/11
9/11
27/33
27/33
Antenatal steroids
17/20
17/20
53/60
53/60
Surfactant
20/20
20/20
60/60
60/60
858 6 111
814 6 140
1,400 6 238
2,192 6 297
52 6 7
48 6 11
52 6 9
50 6 9
17/30
14/30
1/115
0/115
No/mild
21/30
21/30
60/115
60/115
Moderate/severe*
9/30
9/30
55/115
55/115
Respiratory Weight (kg) at echocardiography RR (breaths/min) Invasive mechanical ventilation BPD
Cardiovascular PDA
27/30
23/30
19/115
11/115
Small
17
13
13
8
Moderate*
6
5
5
3
Large*
4
5
1
0
HR (beats/min)
159 6 14
164 6 12
148 6 16
146 6 11
SBP (mm Hg)
50 6 10
59 6 10
73 6 10
80 6 9
DBP (mm Hg)
33 6 7
37 6 9
42 6 9
46 6 10
MAP (mm Hg)
39 6 7
44 6 8
49 6 14
55 6 14
DBP, Diastolic blood pressure; HR, heart rate; MAP, mean arterial blood pressure; RR, respiratory rate; SBP, systolic blood pressure. Data are expressed as mean 6 SD or as numbers. All demographic and clinical characteristics are from the infants included in the reference values. *Infants with moderate or large PDA at 24 or 72 hours of age, or any size PDA at 32 or 36 weeks’ PMA, were excluded from the reference values. Infants requiring respiratory support at 36 weeks’ PMA, classified as moderate or severe BPD, were also excluded from the reference values.
Children’s Hospital newborn nurseries. These infants were enrolled from a control group from the Premature and Respiratory Outcomes Program and from a control cohort enrolled through the Maternal Lipid Metabolism and Neonatal Heart Function in Diabetes study (ClinicalTrials.gov identifier NCT01346527). Twenty-five infants underwent echocardiography at birth (5 6 3 days) and 35 separate infants at 1 month of age (30 6 7 days). Infants were included from each study if they were $37 weeks’ gestational age at birth. Patients were excluded if they required oxygen supplementation or respiratory support in the first month of age, had abnormal findings on chest radiography, or were diagnosed with congenital heart defects other than PDA or patent foramen ovale. We compared the maturational patterns from birth to 1 month of age with the observed patterns in preterm infants. We obtained informed written consent from all parents in each study, and the institutional review board of Washington University approved the studies. Echocardiographic Analysis of FAC Standard echocardiograms were acquired in the resting state without sedation by one designated experienced primary pediatric cardiac sonographer (T.J.S.) Two-dimensional, real-time, grayscale im-
ages were acquired by a commercially available ultrasound imaging system (Vivid 7 or 9; GE Medical Systems, Milwaukee, WI). The images were obtained using a transducer centered frequency phased-array probe (ranging between 7.5 and 12 MHz) and optimized to visualize the myocardial walls. Two-dimensional images were acquired from the RV-focused apical four-chamber view using a previously published protocol for RV image acquisition and data analysis.9,24 The image data were digitally stored for three cardiac cycles in cine loop format for offline analysis by vendor-customized semiautomated software analysis program (EchoPAC version 110.0.x; GE Medical Systems). RVend-systolic area (RVESA) and RVend-diastolic area (RVEDA) were measured in the RV-focused apical four-chamber view. Beats with similar RR intervals were used to minimize errors in calculation.2 RVESA and RVEDA were measured at the frames just before tricuspid valve opening and just after the valve closure, respectively.5,10 A ‘‘sail sign’’ was traced from the (1) septal side of the tricuspid annular plane (septal-tricuspid annular hinge point) to the (2) apical-septal point and then to the (3) RV free wall side of the tricuspid annular plane (lateral-tricuspid annular hinge point).24,28 The trabeculations were included in the RV area measurements to avoid underestimating the areas.9,12,29 RV endocardial areas were delineated for three consecutive cardiac
562 Levy et al
Journal of the American Society of Echocardiography May 2015
Figure 1 Calculation of RV FAC. This is an example of how to generate and calculate RV FAC. RV FAC was obtained by tracing the RV endocardium in (A) end-systole (RVESA) and (B) end-diastole (RVEDA). For RVESA and RVEDA, a ‘‘sail sign’’ was traced from the (1) septal side of the tricuspid annular plane (septal-tricuspid annular hinge point) to the (2) apical-septal point and then to the (3) RV free wall side (RVFW) of the tricuspid annular plane (lateral-tricuspid annular hinge point).24,28 Care was taken to include the trabeculations in the measurements of the area by tracing RVEDA and RVESA between RV trabeculations and the compact layer of the ventricle.9,12,29 RVESA and RVEDA were measured at the frames just before tricuspid valve opening and just after the valve closure, respectively.5,10 Fractional area of change = 100 [RVEDA (cm2) RVESA (cm2]/RVEDA (cm2).
Table 2 Change in RV areas and FAC in the first month of age Birth
Full-term infants
1 mo
Slope of change
P
(n = 25)
(n = 35)
RVEDA (cm2)
3.7 6 0.7
4.8 6 0.6
0.38
