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Changes in pulmonary artery pressure during early transitional circulation in healthy full-term newborns
Ultrasonics 56 (2015) 524–529
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Ultrasonics journal homepage: www.elsevier.com/locate/ultras
Changes in pulmonary artery pressure during early transitional circulation in healthy full-term newborns Qian Hu a,1, Wei D. Ren a,⇑, Jian Mao b, Juan Li b, Wei Qiao a, Wen J. Bi a, Yang J. Xiao a, Ying Zhan a, Min Xu a, Chun X. Liu b, Lu Sun a, Lian Tang a, Jing Zhang a a b
Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China Department of Neonatology, Shengjing Hospital of China Medical University, Shenyang, China
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 20 September 2014 Accepted 2 October 2014 Available online 17 October 2014 Keywords: Pulmonary artery systolic pressure Tricuspid regurgitation Ductal Doppler Neonate Reference value
a b s t r a c t Background: Although pulmonary artery systolic pressures (PASPs) are frequently measured in newborn infants using the tricuspid regurgitant jet velocity or ductal Doppler velocity, little is known about the reference range in the general population. Methods: This was a retrospective study of 296 neonates less than 14 days of age who were evaluated using echocardiography. Patients included in this study did not have clinical or acquired cardiac disease. PASP was estimated using the ductal Doppler velocity and/or the tricuspid regurgitant jet velocity and the Bernoulli equation. Results: The majority of the definite right-to-left through the ductus arteriosus was limited to the first 6 h after birth, and the majority of the left-to-right shunt was limited to 10 h after birth. After 10 h, 24 infants with Doppler color-flow imaging revealed a very small and transient jet. The percentage of measurable tricuspid regurgitation was 91% after 24 h. Multivariable regression analysis found that there was a significant correlation between neonatal age and PASP (determined from tricuspid regurgitant jet velocity and Bernoulli equation: r2 = 0.748, P < 0.0001; and from ductal Doppler velocity: r2 = 0.179, P < 0.001). The upper 95% limit for PASP measured in healthy neonates younger than 14 days was 39.1 mmHg. Conclusions: The ductal Doppler velocity is measured more easily for monitoring PASP than tricuspid regurgitant jet velocity in newborns soon after birth; however, in neonates older than 24 h, the tricuspid regurgitant jet velocity is easier for measurement. Age is an independent impact factor of PASP in the neonates. And PASP values gradually decreased to less than 39.1 mmHg by 14 days after birth. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction There have been recent important advances in our understanding of the regulation of fetal and newborn pulmonary circulation, both of which have a complex and varied physiology [1]. And that pulmonary artery systolic pressures (PASPs) are frequently assessed in newborn infants using tricuspid regurgitant jet velocities [2,3] or ductal Doppler velocities [4]. The studies suggest a gradual drop in PASP with increasing age, but the wide-range of variation and the small sample sizes cannot permit adequate appraisal of the rate of decline. So it is necessary to describe
normal changes in PASP during the early neonatal period to diagnose whether pulmonary arterial hypertension is present. Patent ductus arteriosus (PDA) [5] and tricuspid regurgitation (TR) [6] are frequently found in neonates, and echocardiographic measurements of the Doppler flow velocity across the PDA and the tricuspid regurgitant jet velocity have been shown to yield accurate values for PASP [7–9]. So, the aim of this study was to use echocardiography to determine the changes in PASP during the transitional circulation in healthy neonates and determine normal values for PASP. 2. Methods
⇑ Corresponding author at: Department of Ultrasound, Shengjing Hospital of China Medical University, No. 36, San Hao Street, He Ping District, Shenyang City, Liaoning Province 110004, China. Fax: +86 024 22867316. E-mail address: [email protected] (W.D. Ren). 1 Present address: Dalian Municipal Central Hospital, Dalian, China. http://dx.doi.org/10.1016/j.ultras.2014.10.005 0041-624X/Ó 2014 Elsevier B.V. All rights reserved.
2.1. Study participants From a clinical echocardiography database recorded at the Shengjing Hospital between September 1, 2011 and August 31, 2013, we collected subjects of healthy full-term infants
Q. Hu et al. / Ultrasonics 56 (2015) 524–529
(38 weeks 6 Gestational Age < 42 weeks, 2500 g 6 Birth Weight 6 4000 g) less than 14 days of age with normal transthoracic echocardiography study. Normality was defined by (1) normal left and right ventricular function and dimensions, (2) normal left and right atrial dimensions, (3) absence of valvular stenosis, (4) absence of significant valvular insufficiency, and (5) absence of coronary artery dilatation [10]. Infants included in the study did not have perinatal asphyxia or require oxygen, and had a technically adequate 2-dimensional and Doppler echocardiographic evaluation. Finally, 296 healthy full-term newborns delivered vaginally were selected for study. Most were outpatients referred for evaluation of a heart murmur which was found to be innocent on clinical, electrocardiographic, and radiological grounds. The others were inpatients in whom cardiac examination was performed to exclude patients with congenital or acquired heart disease. Weight, age, sex, gestational age, apgar scores and blood pressure were recorded for each subject. 2.2. Doppler echocardiography Images of the Doppler echocardiography were all collected from a clinical echocardiography database and from the same doctor. Measurements were performed using a Philips iE33 Ultrasound System with an S5-1 transducer, and included determination of the ductal blood flow velocity and tricuspid regurgitant jet velocity using pulse- or continuous-wave Doppler. The aortic valve velocity was determined using pulsed-wave Doppler.
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sex, gestational age and age was estimated by determining the Spearman correlation coefficient for each variable and univariate analysis. Multiple linear regression analysis was used to assess the relationship of PASP as the dependent variable with age and other covariates. Absolute agreement and reliability of PDA- and TR-based measurements of PASP were evaluated on the basis of an intraclass correlation coefficient (ICC). Standard linear regression analysis was used for comparison of PASP values derived from ductal and tricuspid regurgitant Doppler velocities. Analysis of covariance was performed to evaluate the significance of PASP values calculated from transductal and maximal TR Doppler velocities and obtained from differences in catheterization. A Bland–Altman [14] difference plot was used to analyze the agreement between intraobserver (and interobserver) variabilities of PASP. Statistical significance (2 sided) was judged at P < 0.05. 3. Results 3.1. Characteristics of the participants Table 1 shows the characteristics of the study population. There were 296 healthy full-term newborns (136 boys and 160 girls; weight 2.5 kg to 4.0 kg, mean, 3.31 ± 0.33 kg) with ages ranging from 32 min to 14 days (mean, 68.13 ± 73.56 h) at the time they underwent echocardiography. 3.2. Echocardiographic assessment
2.3. Determination of the PASP 2.3.1. Determining the PASP across the patent ductus arteriosus The peak instantaneous pressure gradient across the PDA at peak systole (reflected by peak Doppler velocity at the point in time corresponding to peak systole) was obtained from superimposing the ductal Doppler spectral display above the corresponding aortic Doppler recording with identical RR intervals [4]. PASP at each study in all neonates with ductal flow was, therefore, calculated by subtracting or adding the appropriate ductal Doppler velocity (converted to millimeters of mercury) to the systolic blood pressure. For bidirectional ductal shunting: PASP = blood pressure +4V2 (V = Velocity, arrow indicates the velocity) (Fig. 1A); for unidirectional left to right shunting: PASP = blood pressure-4V2 (V = Velocity, arrow shows the velocity) (Fig. 1B). 2.3.2. Determining the PASP across the tricuspid regurgitant jet velocity The estimation of PASP was based on Bernoulli equation (PASP = 4V2 + right atrial pressure, where V is maximal systolic velocity of the regurgitant jet) if there is no pulmonary stenosis. A continuous holosystolic envelope was taken into account for evaluation of the pressure gradient. If a tricuspid regurgitant jet could be obtained only by color Doppler, it was considered ‘‘detectable’’, otherwise ‘‘measurable’’. The PASP, which equal to the sum of right atrial pressure and systolic transtricuspid gradient in the absence of right ventricular outflow obstruction. The pressure of the right atrium was assumed to be 0 mmHg [11–13] (Fig. 1C). Data were analyzed by two expert researchers for interobserver agreement and by the one of them for intraobserver agreement assessment. 2.4. Statistical methods Continuous variables are expressed as the mean value ± SD, or as median value plus interquartile range, when a normal distribution was not found. The assumption of normality was tested using a percent–percent (P–P) plot. The association of PASP with weight,
Ductal Doppler shunts. The percentage of infants with different ductal flow patterns were shown in Table 2. It was clearly that a definite right-to-left shunt through the ductus arteriosus was obtained in 101 of the 296 infants. The majority of these were limited to the first 6 h after birth (Two of these infants had unidirectional flow 1.5 and 2 h after birth, however, they had low systemic pressure.). A definite left-to-right shunt from the ductus was seen in 22 of the 296 babies. The majority of these were limited to 10 h after birth. After 10 h, 24 infants with Doppler colorflow imaging revealed a very small and transient jet. Our data show similar values and similar changes with the best available data which obtained from the neonatal cardiac catheterization before 6 h after birth (P > 0.13). According to the multiple linear regression analysis, age was independent impact factor of a reduced PASP (t = 4.14, P < 0.001). Furthermore, There was a significant correlation between PASP and age (determined from ductal Doppler velocity: r2 = 0.179, P < 0.001). A p-p plot indicated that the PASP values were not normally distributed. Based on these statistical analyses, the Reference value of PASP from ductal Doppler velocity less than 6 h of age was determined (Table 3). The estimated upper 95% limit of PASP measured in healthy neonates was 75.3 mmHg younger than 6 h after birth. Tricuspid regurgitation Evidence of TR was seen in all 296 infants, but only 200 of these (68%) had measurable TR. The regurgitant tricuspid observation in the 296 infants with detectable and measurable regurgitation were contained in Table 4. In this study, the proportion of measurable TR increased from 39% before the first 24 h of age to 91% after 24 h. Multiple linear regression found that neonatal age independently affected the PASP (t = 24.232, P < 0.0001). There are no correlations between PASP and weight (t = 1.686, P = 0.093), and sex (t = 0.210, P = 0.834), and gestational age (t = 0.755, P = 0.451). And a significant correlation between PASP and age (determined from tricuspid regurgitant jet velocity and Bernoulli equation: r2 = 0.748, P < 0.0001) have been found. Fig. 3 shows the relationship between PASP and age. Furthermore, Our data show similar values and similar pattern falling with time that obtained from the neonatal cardiac catheterization before
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Q. Hu et al. / Ultrasonics 56 (2015) 524–529
Fig. 1. Presentation of systolic pulmonary artery pressure (PASP) calculated. (A) Bidirectional ductal shunting (PASP = blood pressure + 4v2), where v = velocity. Arrows indicate the point where ductal Doppler velocity corresponding to peak systolic was measured. (B) Pure left to right shunting (PASP = blood pressure-4v2). (C) Tricuspid regurgitation (PASP = 4v2 + RAP), where RAP = pressure of the right atrium. The Doppler signal continues throughout the whole of systole and the maximal velocity can easily be measured (⁄). Table 1 Clinical characteristic of patients included in this study. Clinical parameter
Value
Number of patients Gender of babies Boy Girl Mean weight (kg) Gestational age (w) Age (h) Blood pressure (mmHg) Systolic Diastolic Mean Delivery
296 136 160 3.31 ± 0.33 39.72 ± 0.95 68.13 ± 73.56 68.63 ± 10.90 36.25 ± 11.01 47.21 ± 11.64 All were vaginal birth
Data are expressed as mean ± SD; w: week.
3 days of age, and there were no significant differences between these two groups (P > 0.2). Based on p–p plot, we obtained the Reference values of PASP from maximal TR velocity of neonates less than 14 days of age (Table 5). The upper 95% limit for PASP measured in healthy infants younger than 14 days was 39.1 mmHg. Bland–Altman plot regression showed the 95% limits of agreement for inter- and intraobserver measurements were not significantly different ( 0.2 to 4.4% vs. 0.1 to 3.6%, respectively) (Fig. 4A and B).
3.3. Relation between ductal Doppler-derived PASP and pulmonary artery pressure calculated from TR Doppler jet In this study, we selected the subjects that have TR and PDA at the same time, compared PASP obtained from superimposing the ductal Doppler spectral with PASP calculated from TR Doppler velocity. For PDA- and TR-based measurements of PASP absolute agreement was almost perfect (ICC = 0.952). PASP calculated from ductal Doppler velocities (added to or subtracted from systolic blood pressure) correlated significantly with PASP calculated from TR Doppler velocity (in millimeters of mercury) which included an assumed right atrial pressure of 10 mmHg (r = 0.71, P < 0.001) (Fig. 2). The effect of using different values for estimates of right atrial pressure (0, 5, and 10 mmHg, respectively) on the preceding regression was calculated. There was no significant variation in slope (0.84–0.85), whereas the y intercept appeared more variation (10–18.5). 4. Discussion These are the first neonates-derived data showing that pulmonary artery systolic pressure (PASP) decrease with age from the general community. In this study of 296 echocardiographic normals
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Q. Hu et al. / Ultrasonics 56 (2015) 524–529 Table 2 The percentage of infants with different ductal flow patterns.
No (%) right-to-left shunt No (%) high velocity left-to-right No (%) small and transient jet
0 < age (h) 6 6 (n = 97)
6 < age (h) 6 10 (n = 19)
10 < age (h) 6 24 (n = 31)
95(98%) 2(2%) 0
5(26%) 14(74%) 0
1(3%) 6(19%) 24(77%)
h, hour; n, number of infants.
Table 3 PASP calculated from superimposing the ductal Doppler spectral in 97 healthy neonates. Age (h)
Minimum
Maximum
Mean
P5
P50
P95
P99
0–6
41.00
89.00
62.62 ± 7.58
52.90
62.00
75.30
89.00
Data are mean ± SD; h, hour; PASP: pulmonary arterial systolic pressure.
Table 4 The percentage of babies with tricuspid regurgitation.
No (%) detectable TR No (%) measurable TR
0 < age (h) 6 6 (n = 97)
6 < age (h) 6 10 (n = 19)
10 < age (h) 6 24 (n = 31)
1 < age (d) 6 2 (n = 22)
97 (100%) 36 (37%)
19 (100%) 4 (21%)
31 (100%) 12 (39%)
22 (100%) 20 (91%)
h, hour; d, day; n, number of infants.
Fig. 2. Correlation between pulmonary arterial systolic pressure (PASP) obtained from superimposing the ductal Doppler spectral and the PASP calculated from tricuspid regurgitant (TR) Doppler velocity at the same time in the same infants.
studied nearly 2 years, we observed the major fall in PASP takes place during the first 24 h after birth and a gradual decrease occurs during the first 14 days of life. Importantly, decreasing PASP was associated with increased age independently. 4.1. Patent ductus arteriosus and PASP In our study, almost all patent ductus (DA) were closed within 24 h after birth. The pattern of flow through the ductus arteriosus was bidirectional in some of the early studies. This pattern is primarily accounted for by a sharp decrease in the diastolic pressure and a more gradual decrease in the systolic pressure [15]. And this finding of shunting is seen when PASP is equal to or slightly greater than systemic pressure which is compatible with high early postnatal pulmonary artery pressures [16]. In our study, majority bidirectional shunting can persist for as 6 h. Right-to-left shunts through the ductus arteriosus were not commonly observed. This has also been found in previous study [17]. But it is different from the findings of previous study that [18,19]
Fig. 3. Derived PASP from tricuspid regurgitant jet velocity and the Bernoulli equation in 200 healthy neonates.
indicate shunts in this direction are common in crying infants up to 72 h of age. In the later studies, with the falling of pressure, the flow direction was entirely left-to-right and remains so up to 10 h after birth throughout the cardiac cycle. And then the shunt finally either becomes small or disappears entirely. This observation together with the previous studies used different methods indicated that the eventual functional closure of the ductus arteriosus occurs between 10 h and 96 h of age [19–22]. This is the first study to show a Reference value of PASP calculated from ductal Doppler velocity in neonates age before 6 h. Among infants less than 6 h of age, 95% had a PASP <75.3 mmHg. And this calculated PASP have correlated well with data from neonatal cardiac catheterisation that 95% had a PASP <72 mmHg. Furthermore, with an estimated right atrial pressure of 10 mmHg added to the pressure gradient between the right ventricle and the right atrium, a significant positive linear correlation was found
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Table 5 Derived PASP from tricuspid regurgitant jet velocity and the Bernoulli equation in 200 healthy neonates. Age (d)
Minimum
Maximum
Mean
P5
P50
P95
P99
0–1 1–3 3–7 7–14
40.10 33.00 31.50 30.50
62.60 57.50 55.00 44.00
50.55 ± 4.05 41.80 ± 3.75 37.80 ± 3.30 33.08 ± 2.53
40.73 34.16 32.93 30.50
50.80 41.95 37.90 32.20
57.12 46.51 40.97 39.14
62.60 57.50 55.00 44.00
Data are mean ± SD; h, hour; PASP: pulmonary arterial systolic pressure.
the year 1964, despite the increase in the proportion of detachable TR (P > 0.2). The calculation of PASP by Doppler techniques requires a measurable TR jet. Not all babies had TR that was measurable on Doppler before 24 h of age. There were only 52(35%) of 147 infants had measurable TR. This finding was consistent with previous studies that only 7(37%) of 19 newborns had measurable tricuspid regurgitation [25]. After 24 h of age, measurable tricuspid regurgitant flow has been found in 91% of measurements in neonates. 4.3. Correlations of PASP In our study, age was found to be correlated well with PASP among echocardiographic normals. Although previous studies of small groups of patients have also reported an association between age and PASP [3,4], they had not established significance by multiple linear regression analysis to rule out the influence of body weight and others. 4.4. Indirect and direct method of measurement of PASP
Fig. 4. (A) Bland–Altman plot to show the mean difference and 95% limits of agreement between interobserver. (B) Bland–Altman plot to show the mean difference and 95% limits of agreement between intraobserver.
between ductal- and tricuspid regurgitation (TR)-estimated PASP. This has also been shown in previous studies [17,23] comparing catheter- and Doppler-derived pulmonary artery pressures. Therefore, it would show that PASP can be accurately obtained from such ductal Doppler velocities.
4.2. Detection of TR and recording of PASP In the first 6 h of age, there were 37% infants with measurable TR and 100% babies with detectable TR in 97 neonates. Because pulsed-Doppler echocardiography can often miss a small or eccentric jet from TR, whereas Doppler color-flow imaging is sensitive enough to detect these jets [24]. In our study, the proportion of echocardiographic normal infants could be detected increased from 72.7% in 1995 to 100% in 2013. It is unlikely that the detectable TR has increased, we due to this change to improvements in instrument and recording techniques. The PASP has not changed significantly from the neonatal cardiac catheterization showed in
According to an indirect method of assessment, we found that PASP in neonates born at full term falls rapidly over the first 24 h of life. And it is consistent with previous studies, both those using Doppler assessment [25] and those using direct measurement [15]. We also found that two different Doppler techniques used to calculate PASP have correlated well and that the PASP were consistent with data (the data we used were obtained in 1964 by Emmanouilides et al. who catheterised 51 healthy unsedated term babies, and the data are the acknowledged best available data on pulmonary arterial pressure in neonates) from neonatal cardiac catheterization [15]. After that, we found a gradual reduction in PASP until 14 days of age. A few echocardiographic and Doppler studies found a more faster decrease in pulmonary artery pressure until days 4 and 5 but used indirect signs: acceleration time of pulmonary flow velocity pattern [3,26,27] Two other groups of authors using TR Doppler velocity examined 56 and 20 full-term infants, respectively [2,3]. They showed a similar decrease in PASP but lower absolute values than our evaluation. From our studies and others, it is clear that there is a considerable variation in the rate of decline of pulmonary arterial pressure in the first two weeks of life. A greater number of measurements will be necessary before it may be stated at which day of life the majority of normal infants arrive at the mature level of pressure. 4.5. Reference intervals for PASP Attempts to determine the Reference values for PASP of neonates have proven difficult, and many strategies have been used. Previous studies of selected normals or control groups for other echocardiographic studies were usually small. The commonly used normal values for neonatal PASP have been derived from adult normals. For convenient use in clinic, we have therefore summarized approximated normal ranges of PASP for a complete population
Q. Hu et al. / Ultrasonics 56 (2015) 524–529
of healthy full-term infants. A small decrease in most measurements was seen over time. This has not been shown in health full-term infants. Reference ranges need to take these changes into account, and further work on this change of measurements is needs. Similar values for PASP have been shown in previous studies based on echocardiographic. In a study of 56 subjects from birth to 4 days old, Schmitz [3] et al. reported PASP less than 30 mmHg. Aldudak and Kervancioglu [2] found PASP less than 24.9 mmHg among 20 subjects from birth to 5 days of age. But our data of PASP values gradually decreases to less than 39.1 mmHg by 14 days after birth. We attribute this in the large numbers in our study. Furthermore, through analysis of covariance which performed to detect significance differences between PASP calculated from maximal TR and obtained from catheterization [15], there were no significant differences between the two groups. 4.6. Study limitations A major disadvantage is that we were only able to estimate pulmonary arterial pressure in babies with measurable tricuspid regurgitation and a patent ductus arteriosus with diameters greater than 3 mm [28]. 5. Conclusions In normal full-term neonates, the PSAP decreased rapidly during the first 24 h of life, and then decreased gradually. Ductal Doppler velocities can be reliably used to monitor PASP in newborns younger than 6 h. After 24 h, assessment of tricuspid regurgitant jet velocity can be used. And among neonates with a normal Doppler echocardiography, 95% had a PASP <39.1 mmHg by 14 days after birth. References [1] Y. Gao, J.U. Raj, Regulation of the pulmonary circulation in the fetus and newborn, Physiol. Rev. 90 (4) (2010) 1291–1335. [2] B. Aldudak, M. Kervancioglu, Effect of mode of delivery on postnatal decline in pulmonary artery pressure, Saudi Med. J. 32 (6) (2011) 579–583. [3] A.J. Schmitz, Color Doppler echocardiographic evaluation of tricuspid regurgitation and systolic pulmonary artery pressure in the full-term and preterm newborn, Angiology 48 (8) (1997) 725–734. [4] N.N. Musewe, Doppler echocardiographic measurement of pulmonary artery pressure from ductal Doppler velocities in the newborn, J. Am. Coll. Cardiol. 15 (2) (1990) 446–456. [5] K.M. Felipe, Y. Shi-Joon, M. Luc, H. Ashley, Assessment of ductal blood flow in newborns with obstructive left heart lesions by cardiovascular magnetic resonance, J. Cardiovasc. Magn. Reson. 15 (1) (2013) 45.
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[6] L. Duangmanee, J. Tipawan, C. Prakul, D. Kritvikrom, S. Jarupim, N. Apichart, Heart murmur in the first week of life: Siriraj Hospital, J. Med. Assoc. Thai. 88 (Sup8) (2005) 163–168. [7] C.S. Lam, Age-associated increases in pulmonary artery systolic pressure in the general population, Circulation 119 (20) (2009) 2663–2670. [8] A. Grossman, Pulmonary artery pressure in young healthy subjects, J. Am. Soc. Echocardiogr. 25 (3) (2012) 357–360. [9] J.R. Skinner, R.J. Boys, E.N. Hey, S. Hunter, Estimation of pulmonary arterial pressure in the newborn: study of the repeatability of four Doppler echocardiographic techniques, Pediatr. Cardiol. 17 (1996) 360–369. [10] A.E. Weyman, Principles and Practice of Echocardiography, 2nd ed., Lea & Febiger, Malvern, Pa, 1982. [11] E.D. Burnard, L.S. James, Atrial pressures and cardiac size in the newborn infant, J. Pediatr. 62 (1963) 815–826. [12] W. Blankenship, J. Lind, R.A. Arcilla, Atrial pressures and pulmonary circulation time in the newborn infant, Acta Paediatr. Scand. 54 (1965) 446–456. [13] M.Y. Young, D. Cottom, Arterial and venous blood pressure responses during a reduction in blood volume and hypoxia and hypercapnia in infants during the first two days of life, Pediatrics 37 (1966) 733–742. [14] J.M. Bland, D.G. Altman, Statistical methods for assessing agreement between two methods of clinical measurement, The Lancet. 1 (8476) (1986) 307–310. [15] G.C. Emmanouilides, Pulmonary arterial pressure changes in human newborn infants from birth to 3 days of age, J. Pediatr. 65 (1964) 327–333. [16] N.N. Musewe, J.F. Smallhorn, L.N. Benson, P.E. Burrows, R.M. Freedom, Validation of Doppler-derived pulmonary arterial pressure in patients with ductus arteriosus under different haemodynamic states, Circulation 76 (25) (1987) 1081–1091. [17] A.J. Moss, G. Emmanouilides, E.R. Duffie, Closure of the ductus arteriosus in the newborn infant, Pediatrics 7 (32) (1963) 25–30. [18] F.L. Eldridge, H.N. Hultgren, M.E. Wigmore, The physiologic closure of the ductus arteriosus in newborn infants: a preliminary report, Science 119 (1954) 731. [19] F.L. Eldridge, H.N. Hultgren, M.E. Wigmore, The physiologic closure of the ductus arteriosus in the newborn infant, J. Clin. Invest. 34 (1955) 987. [20] R. Gentile, G. Stevenson, T. Dooley, Pulsed Doppler echocardiographic determination of time of ductal closure in normal newborn infants, J. Pediatr. 98 (1981) 443–448. [21] A.M. Rudolph, J.E. Drorbaugh, P.A.M. Auld, A.J. Rudolph, A.S. Nadas, C.A. Smith, J.P. Hubbell, Studies on the circulation in the neonatal period, Pediatrics 27 (1961) 551–566. [22] A.M. Rudolph. Fetal circulation and cardiovascular adjustments after birth, in Rudolph’s Pediatrics, 21st ed., Norwalk, CT, Appleton & Lange, 2003, pp. 1309– 1313. [23] S. Hiraishi, Y. Horiguchi, H. Misawa, Noninvasive Doppler echocardiographic evaluation of shunt flow dynamics of the ductus arteriosus, Circulation 75 (1987) 1146–1153. [24] L.R. San, Clinical guide practice. Patent ductus arteriosus, Rev. Med. Inst. Mex Segur. Soc. 50 (4) (2012) 453–463. [25] J.R. Skinner, Non-invasive assessment of pulmonary arterial pressure in healthy neonates, Arch. Dis. Child. 66 (4 Spec No) (1991) 386–390. [26] T. Hosono, Right ventricular flow dynamics in the early neonatal period assessed by pulsed Doppler echocardiography (abstract), J. Cardiol. 17 (1987) 895–905. [27] N.J. Evans, N.J. Archer, Postnatal circulatory adaptation in healthy term and preterm neonates, Arch. Dis. Child. 65 (1990) 24–26. [28] A.R. Snider, The ductus arteriosus: a window for assessment of pulmonary artery pressures?, J Am. Coll. Cardiol. 15 (2) (1990) 457–458.
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Ultrasonics journal homepage: www.elsevier.com/locate/ultras
Changes in pulmonary artery pressure during early transitional circulation in healthy full-term newborns Qian Hu a,1, Wei D. Ren a,⇑, Jian Mao b, Juan Li b, Wei Qiao a, Wen J. Bi a, Yang J. Xiao a, Ying Zhan a, Min Xu a, Chun X. Liu b, Lu Sun a, Lian Tang a, Jing Zhang a a b
Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China Department of Neonatology, Shengjing Hospital of China Medical University, Shenyang, China
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 20 September 2014 Accepted 2 October 2014 Available online 17 October 2014 Keywords: Pulmonary artery systolic pressure Tricuspid regurgitation Ductal Doppler Neonate Reference value
a b s t r a c t Background: Although pulmonary artery systolic pressures (PASPs) are frequently measured in newborn infants using the tricuspid regurgitant jet velocity or ductal Doppler velocity, little is known about the reference range in the general population. Methods: This was a retrospective study of 296 neonates less than 14 days of age who were evaluated using echocardiography. Patients included in this study did not have clinical or acquired cardiac disease. PASP was estimated using the ductal Doppler velocity and/or the tricuspid regurgitant jet velocity and the Bernoulli equation. Results: The majority of the definite right-to-left through the ductus arteriosus was limited to the first 6 h after birth, and the majority of the left-to-right shunt was limited to 10 h after birth. After 10 h, 24 infants with Doppler color-flow imaging revealed a very small and transient jet. The percentage of measurable tricuspid regurgitation was 91% after 24 h. Multivariable regression analysis found that there was a significant correlation between neonatal age and PASP (determined from tricuspid regurgitant jet velocity and Bernoulli equation: r2 = 0.748, P < 0.0001; and from ductal Doppler velocity: r2 = 0.179, P < 0.001). The upper 95% limit for PASP measured in healthy neonates younger than 14 days was 39.1 mmHg. Conclusions: The ductal Doppler velocity is measured more easily for monitoring PASP than tricuspid regurgitant jet velocity in newborns soon after birth; however, in neonates older than 24 h, the tricuspid regurgitant jet velocity is easier for measurement. Age is an independent impact factor of PASP in the neonates. And PASP values gradually decreased to less than 39.1 mmHg by 14 days after birth. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction There have been recent important advances in our understanding of the regulation of fetal and newborn pulmonary circulation, both of which have a complex and varied physiology [1]. And that pulmonary artery systolic pressures (PASPs) are frequently assessed in newborn infants using tricuspid regurgitant jet velocities [2,3] or ductal Doppler velocities [4]. The studies suggest a gradual drop in PASP with increasing age, but the wide-range of variation and the small sample sizes cannot permit adequate appraisal of the rate of decline. So it is necessary to describe
normal changes in PASP during the early neonatal period to diagnose whether pulmonary arterial hypertension is present. Patent ductus arteriosus (PDA) [5] and tricuspid regurgitation (TR) [6] are frequently found in neonates, and echocardiographic measurements of the Doppler flow velocity across the PDA and the tricuspid regurgitant jet velocity have been shown to yield accurate values for PASP [7–9]. So, the aim of this study was to use echocardiography to determine the changes in PASP during the transitional circulation in healthy neonates and determine normal values for PASP. 2. Methods
⇑ Corresponding author at: Department of Ultrasound, Shengjing Hospital of China Medical University, No. 36, San Hao Street, He Ping District, Shenyang City, Liaoning Province 110004, China. Fax: +86 024 22867316. E-mail address: [email protected] (W.D. Ren). 1 Present address: Dalian Municipal Central Hospital, Dalian, China. http://dx.doi.org/10.1016/j.ultras.2014.10.005 0041-624X/Ó 2014 Elsevier B.V. All rights reserved.
2.1. Study participants From a clinical echocardiography database recorded at the Shengjing Hospital between September 1, 2011 and August 31, 2013, we collected subjects of healthy full-term infants
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(38 weeks 6 Gestational Age < 42 weeks, 2500 g 6 Birth Weight 6 4000 g) less than 14 days of age with normal transthoracic echocardiography study. Normality was defined by (1) normal left and right ventricular function and dimensions, (2) normal left and right atrial dimensions, (3) absence of valvular stenosis, (4) absence of significant valvular insufficiency, and (5) absence of coronary artery dilatation [10]. Infants included in the study did not have perinatal asphyxia or require oxygen, and had a technically adequate 2-dimensional and Doppler echocardiographic evaluation. Finally, 296 healthy full-term newborns delivered vaginally were selected for study. Most were outpatients referred for evaluation of a heart murmur which was found to be innocent on clinical, electrocardiographic, and radiological grounds. The others were inpatients in whom cardiac examination was performed to exclude patients with congenital or acquired heart disease. Weight, age, sex, gestational age, apgar scores and blood pressure were recorded for each subject. 2.2. Doppler echocardiography Images of the Doppler echocardiography were all collected from a clinical echocardiography database and from the same doctor. Measurements were performed using a Philips iE33 Ultrasound System with an S5-1 transducer, and included determination of the ductal blood flow velocity and tricuspid regurgitant jet velocity using pulse- or continuous-wave Doppler. The aortic valve velocity was determined using pulsed-wave Doppler.
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sex, gestational age and age was estimated by determining the Spearman correlation coefficient for each variable and univariate analysis. Multiple linear regression analysis was used to assess the relationship of PASP as the dependent variable with age and other covariates. Absolute agreement and reliability of PDA- and TR-based measurements of PASP were evaluated on the basis of an intraclass correlation coefficient (ICC). Standard linear regression analysis was used for comparison of PASP values derived from ductal and tricuspid regurgitant Doppler velocities. Analysis of covariance was performed to evaluate the significance of PASP values calculated from transductal and maximal TR Doppler velocities and obtained from differences in catheterization. A Bland–Altman [14] difference plot was used to analyze the agreement between intraobserver (and interobserver) variabilities of PASP. Statistical significance (2 sided) was judged at P < 0.05. 3. Results 3.1. Characteristics of the participants Table 1 shows the characteristics of the study population. There were 296 healthy full-term newborns (136 boys and 160 girls; weight 2.5 kg to 4.0 kg, mean, 3.31 ± 0.33 kg) with ages ranging from 32 min to 14 days (mean, 68.13 ± 73.56 h) at the time they underwent echocardiography. 3.2. Echocardiographic assessment
2.3. Determination of the PASP 2.3.1. Determining the PASP across the patent ductus arteriosus The peak instantaneous pressure gradient across the PDA at peak systole (reflected by peak Doppler velocity at the point in time corresponding to peak systole) was obtained from superimposing the ductal Doppler spectral display above the corresponding aortic Doppler recording with identical RR intervals [4]. PASP at each study in all neonates with ductal flow was, therefore, calculated by subtracting or adding the appropriate ductal Doppler velocity (converted to millimeters of mercury) to the systolic blood pressure. For bidirectional ductal shunting: PASP = blood pressure +4V2 (V = Velocity, arrow indicates the velocity) (Fig. 1A); for unidirectional left to right shunting: PASP = blood pressure-4V2 (V = Velocity, arrow shows the velocity) (Fig. 1B). 2.3.2. Determining the PASP across the tricuspid regurgitant jet velocity The estimation of PASP was based on Bernoulli equation (PASP = 4V2 + right atrial pressure, where V is maximal systolic velocity of the regurgitant jet) if there is no pulmonary stenosis. A continuous holosystolic envelope was taken into account for evaluation of the pressure gradient. If a tricuspid regurgitant jet could be obtained only by color Doppler, it was considered ‘‘detectable’’, otherwise ‘‘measurable’’. The PASP, which equal to the sum of right atrial pressure and systolic transtricuspid gradient in the absence of right ventricular outflow obstruction. The pressure of the right atrium was assumed to be 0 mmHg [11–13] (Fig. 1C). Data were analyzed by two expert researchers for interobserver agreement and by the one of them for intraobserver agreement assessment. 2.4. Statistical methods Continuous variables are expressed as the mean value ± SD, or as median value plus interquartile range, when a normal distribution was not found. The assumption of normality was tested using a percent–percent (P–P) plot. The association of PASP with weight,
Ductal Doppler shunts. The percentage of infants with different ductal flow patterns were shown in Table 2. It was clearly that a definite right-to-left shunt through the ductus arteriosus was obtained in 101 of the 296 infants. The majority of these were limited to the first 6 h after birth (Two of these infants had unidirectional flow 1.5 and 2 h after birth, however, they had low systemic pressure.). A definite left-to-right shunt from the ductus was seen in 22 of the 296 babies. The majority of these were limited to 10 h after birth. After 10 h, 24 infants with Doppler colorflow imaging revealed a very small and transient jet. Our data show similar values and similar changes with the best available data which obtained from the neonatal cardiac catheterization before 6 h after birth (P > 0.13). According to the multiple linear regression analysis, age was independent impact factor of a reduced PASP (t = 4.14, P < 0.001). Furthermore, There was a significant correlation between PASP and age (determined from ductal Doppler velocity: r2 = 0.179, P < 0.001). A p-p plot indicated that the PASP values were not normally distributed. Based on these statistical analyses, the Reference value of PASP from ductal Doppler velocity less than 6 h of age was determined (Table 3). The estimated upper 95% limit of PASP measured in healthy neonates was 75.3 mmHg younger than 6 h after birth. Tricuspid regurgitation Evidence of TR was seen in all 296 infants, but only 200 of these (68%) had measurable TR. The regurgitant tricuspid observation in the 296 infants with detectable and measurable regurgitation were contained in Table 4. In this study, the proportion of measurable TR increased from 39% before the first 24 h of age to 91% after 24 h. Multiple linear regression found that neonatal age independently affected the PASP (t = 24.232, P < 0.0001). There are no correlations between PASP and weight (t = 1.686, P = 0.093), and sex (t = 0.210, P = 0.834), and gestational age (t = 0.755, P = 0.451). And a significant correlation between PASP and age (determined from tricuspid regurgitant jet velocity and Bernoulli equation: r2 = 0.748, P < 0.0001) have been found. Fig. 3 shows the relationship between PASP and age. Furthermore, Our data show similar values and similar pattern falling with time that obtained from the neonatal cardiac catheterization before
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Fig. 1. Presentation of systolic pulmonary artery pressure (PASP) calculated. (A) Bidirectional ductal shunting (PASP = blood pressure + 4v2), where v = velocity. Arrows indicate the point where ductal Doppler velocity corresponding to peak systolic was measured. (B) Pure left to right shunting (PASP = blood pressure-4v2). (C) Tricuspid regurgitation (PASP = 4v2 + RAP), where RAP = pressure of the right atrium. The Doppler signal continues throughout the whole of systole and the maximal velocity can easily be measured (⁄). Table 1 Clinical characteristic of patients included in this study. Clinical parameter
Value
Number of patients Gender of babies Boy Girl Mean weight (kg) Gestational age (w) Age (h) Blood pressure (mmHg) Systolic Diastolic Mean Delivery
296 136 160 3.31 ± 0.33 39.72 ± 0.95 68.13 ± 73.56 68.63 ± 10.90 36.25 ± 11.01 47.21 ± 11.64 All were vaginal birth
Data are expressed as mean ± SD; w: week.
3 days of age, and there were no significant differences between these two groups (P > 0.2). Based on p–p plot, we obtained the Reference values of PASP from maximal TR velocity of neonates less than 14 days of age (Table 5). The upper 95% limit for PASP measured in healthy infants younger than 14 days was 39.1 mmHg. Bland–Altman plot regression showed the 95% limits of agreement for inter- and intraobserver measurements were not significantly different ( 0.2 to 4.4% vs. 0.1 to 3.6%, respectively) (Fig. 4A and B).
3.3. Relation between ductal Doppler-derived PASP and pulmonary artery pressure calculated from TR Doppler jet In this study, we selected the subjects that have TR and PDA at the same time, compared PASP obtained from superimposing the ductal Doppler spectral with PASP calculated from TR Doppler velocity. For PDA- and TR-based measurements of PASP absolute agreement was almost perfect (ICC = 0.952). PASP calculated from ductal Doppler velocities (added to or subtracted from systolic blood pressure) correlated significantly with PASP calculated from TR Doppler velocity (in millimeters of mercury) which included an assumed right atrial pressure of 10 mmHg (r = 0.71, P < 0.001) (Fig. 2). The effect of using different values for estimates of right atrial pressure (0, 5, and 10 mmHg, respectively) on the preceding regression was calculated. There was no significant variation in slope (0.84–0.85), whereas the y intercept appeared more variation (10–18.5). 4. Discussion These are the first neonates-derived data showing that pulmonary artery systolic pressure (PASP) decrease with age from the general community. In this study of 296 echocardiographic normals
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Q. Hu et al. / Ultrasonics 56 (2015) 524–529 Table 2 The percentage of infants with different ductal flow patterns.
No (%) right-to-left shunt No (%) high velocity left-to-right No (%) small and transient jet
0 < age (h) 6 6 (n = 97)
6 < age (h) 6 10 (n = 19)
10 < age (h) 6 24 (n = 31)
95(98%) 2(2%) 0
5(26%) 14(74%) 0
1(3%) 6(19%) 24(77%)
h, hour; n, number of infants.
Table 3 PASP calculated from superimposing the ductal Doppler spectral in 97 healthy neonates. Age (h)
Minimum
Maximum
Mean
P5
P50
P95
P99
0–6
41.00
89.00
62.62 ± 7.58
52.90
62.00
75.30
89.00
Data are mean ± SD; h, hour; PASP: pulmonary arterial systolic pressure.
Table 4 The percentage of babies with tricuspid regurgitation.
No (%) detectable TR No (%) measurable TR
0 < age (h) 6 6 (n = 97)
6 < age (h) 6 10 (n = 19)
10 < age (h) 6 24 (n = 31)
1 < age (d) 6 2 (n = 22)
97 (100%) 36 (37%)
19 (100%) 4 (21%)
31 (100%) 12 (39%)
22 (100%) 20 (91%)
h, hour; d, day; n, number of infants.
Fig. 2. Correlation between pulmonary arterial systolic pressure (PASP) obtained from superimposing the ductal Doppler spectral and the PASP calculated from tricuspid regurgitant (TR) Doppler velocity at the same time in the same infants.
studied nearly 2 years, we observed the major fall in PASP takes place during the first 24 h after birth and a gradual decrease occurs during the first 14 days of life. Importantly, decreasing PASP was associated with increased age independently. 4.1. Patent ductus arteriosus and PASP In our study, almost all patent ductus (DA) were closed within 24 h after birth. The pattern of flow through the ductus arteriosus was bidirectional in some of the early studies. This pattern is primarily accounted for by a sharp decrease in the diastolic pressure and a more gradual decrease in the systolic pressure [15]. And this finding of shunting is seen when PASP is equal to or slightly greater than systemic pressure which is compatible with high early postnatal pulmonary artery pressures [16]. In our study, majority bidirectional shunting can persist for as 6 h. Right-to-left shunts through the ductus arteriosus were not commonly observed. This has also been found in previous study [17]. But it is different from the findings of previous study that [18,19]
Fig. 3. Derived PASP from tricuspid regurgitant jet velocity and the Bernoulli equation in 200 healthy neonates.
indicate shunts in this direction are common in crying infants up to 72 h of age. In the later studies, with the falling of pressure, the flow direction was entirely left-to-right and remains so up to 10 h after birth throughout the cardiac cycle. And then the shunt finally either becomes small or disappears entirely. This observation together with the previous studies used different methods indicated that the eventual functional closure of the ductus arteriosus occurs between 10 h and 96 h of age [19–22]. This is the first study to show a Reference value of PASP calculated from ductal Doppler velocity in neonates age before 6 h. Among infants less than 6 h of age, 95% had a PASP <75.3 mmHg. And this calculated PASP have correlated well with data from neonatal cardiac catheterisation that 95% had a PASP <72 mmHg. Furthermore, with an estimated right atrial pressure of 10 mmHg added to the pressure gradient between the right ventricle and the right atrium, a significant positive linear correlation was found
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Table 5 Derived PASP from tricuspid regurgitant jet velocity and the Bernoulli equation in 200 healthy neonates. Age (d)
Minimum
Maximum
Mean
P5
P50
P95
P99
0–1 1–3 3–7 7–14
40.10 33.00 31.50 30.50
62.60 57.50 55.00 44.00
50.55 ± 4.05 41.80 ± 3.75 37.80 ± 3.30 33.08 ± 2.53
40.73 34.16 32.93 30.50
50.80 41.95 37.90 32.20
57.12 46.51 40.97 39.14
62.60 57.50 55.00 44.00
Data are mean ± SD; h, hour; PASP: pulmonary arterial systolic pressure.
the year 1964, despite the increase in the proportion of detachable TR (P > 0.2). The calculation of PASP by Doppler techniques requires a measurable TR jet. Not all babies had TR that was measurable on Doppler before 24 h of age. There were only 52(35%) of 147 infants had measurable TR. This finding was consistent with previous studies that only 7(37%) of 19 newborns had measurable tricuspid regurgitation [25]. After 24 h of age, measurable tricuspid regurgitant flow has been found in 91% of measurements in neonates. 4.3. Correlations of PASP In our study, age was found to be correlated well with PASP among echocardiographic normals. Although previous studies of small groups of patients have also reported an association between age and PASP [3,4], they had not established significance by multiple linear regression analysis to rule out the influence of body weight and others. 4.4. Indirect and direct method of measurement of PASP
Fig. 4. (A) Bland–Altman plot to show the mean difference and 95% limits of agreement between interobserver. (B) Bland–Altman plot to show the mean difference and 95% limits of agreement between intraobserver.
between ductal- and tricuspid regurgitation (TR)-estimated PASP. This has also been shown in previous studies [17,23] comparing catheter- and Doppler-derived pulmonary artery pressures. Therefore, it would show that PASP can be accurately obtained from such ductal Doppler velocities.
4.2. Detection of TR and recording of PASP In the first 6 h of age, there were 37% infants with measurable TR and 100% babies with detectable TR in 97 neonates. Because pulsed-Doppler echocardiography can often miss a small or eccentric jet from TR, whereas Doppler color-flow imaging is sensitive enough to detect these jets [24]. In our study, the proportion of echocardiographic normal infants could be detected increased from 72.7% in 1995 to 100% in 2013. It is unlikely that the detectable TR has increased, we due to this change to improvements in instrument and recording techniques. The PASP has not changed significantly from the neonatal cardiac catheterization showed in
According to an indirect method of assessment, we found that PASP in neonates born at full term falls rapidly over the first 24 h of life. And it is consistent with previous studies, both those using Doppler assessment [25] and those using direct measurement [15]. We also found that two different Doppler techniques used to calculate PASP have correlated well and that the PASP were consistent with data (the data we used were obtained in 1964 by Emmanouilides et al. who catheterised 51 healthy unsedated term babies, and the data are the acknowledged best available data on pulmonary arterial pressure in neonates) from neonatal cardiac catheterization [15]. After that, we found a gradual reduction in PASP until 14 days of age. A few echocardiographic and Doppler studies found a more faster decrease in pulmonary artery pressure until days 4 and 5 but used indirect signs: acceleration time of pulmonary flow velocity pattern [3,26,27] Two other groups of authors using TR Doppler velocity examined 56 and 20 full-term infants, respectively [2,3]. They showed a similar decrease in PASP but lower absolute values than our evaluation. From our studies and others, it is clear that there is a considerable variation in the rate of decline of pulmonary arterial pressure in the first two weeks of life. A greater number of measurements will be necessary before it may be stated at which day of life the majority of normal infants arrive at the mature level of pressure. 4.5. Reference intervals for PASP Attempts to determine the Reference values for PASP of neonates have proven difficult, and many strategies have been used. Previous studies of selected normals or control groups for other echocardiographic studies were usually small. The commonly used normal values for neonatal PASP have been derived from adult normals. For convenient use in clinic, we have therefore summarized approximated normal ranges of PASP for a complete population
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of healthy full-term infants. A small decrease in most measurements was seen over time. This has not been shown in health full-term infants. Reference ranges need to take these changes into account, and further work on this change of measurements is needs. Similar values for PASP have been shown in previous studies based on echocardiographic. In a study of 56 subjects from birth to 4 days old, Schmitz [3] et al. reported PASP less than 30 mmHg. Aldudak and Kervancioglu [2] found PASP less than 24.9 mmHg among 20 subjects from birth to 5 days of age. But our data of PASP values gradually decreases to less than 39.1 mmHg by 14 days after birth. We attribute this in the large numbers in our study. Furthermore, through analysis of covariance which performed to detect significance differences between PASP calculated from maximal TR and obtained from catheterization [15], there were no significant differences between the two groups. 4.6. Study limitations A major disadvantage is that we were only able to estimate pulmonary arterial pressure in babies with measurable tricuspid regurgitation and a patent ductus arteriosus with diameters greater than 3 mm [28]. 5. Conclusions In normal full-term neonates, the PSAP decreased rapidly during the first 24 h of life, and then decreased gradually. Ductal Doppler velocities can be reliably used to monitor PASP in newborns younger than 6 h. After 24 h, assessment of tricuspid regurgitant jet velocity can be used. And among neonates with a normal Doppler echocardiography, 95% had a PASP <39.1 mmHg by 14 days after birth. References [1] Y. Gao, J.U. Raj, Regulation of the pulmonary circulation in the fetus and newborn, Physiol. Rev. 90 (4) (2010) 1291–1335. [2] B. Aldudak, M. Kervancioglu, Effect of mode of delivery on postnatal decline in pulmonary artery pressure, Saudi Med. J. 32 (6) (2011) 579–583. [3] A.J. Schmitz, Color Doppler echocardiographic evaluation of tricuspid regurgitation and systolic pulmonary artery pressure in the full-term and preterm newborn, Angiology 48 (8) (1997) 725–734. [4] N.N. Musewe, Doppler echocardiographic measurement of pulmonary artery pressure from ductal Doppler velocities in the newborn, J. Am. Coll. Cardiol. 15 (2) (1990) 446–456. [5] K.M. Felipe, Y. Shi-Joon, M. Luc, H. Ashley, Assessment of ductal blood flow in newborns with obstructive left heart lesions by cardiovascular magnetic resonance, J. Cardiovasc. Magn. Reson. 15 (1) (2013) 45.
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