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Doppler echocardiographic evaluation of pulmonary vascular resistance in children with congenital heart disease
Doppler Echocardiographic Evaluation of Pulmonary Vascular Resistance in Children with Congenital Heart Disease Makram ~ Ebeid, MD, FACC, Peter L. Ferret, MD, FACC, Brad Robinson, MD, FACC, Norman Weatherby, PhD, and Henry Gelband, MD, FACC, Miami, Florida
Noninvasive assessment of pulmonary vascular resistance has not been well defined. Cardiac catheterization findings in 33 patients with congenital heart disease (mean age 1.4 years) were compared with Doppler echocardiographic parameters. The right ventricular pre-ejection period (RVPEP), ejection time (RVET), and the ratio RVPEP/RVET correlated better with pulmonary vascular resistance than with pulmonary artery pressure. A highly significant correlation with a small standard error of estimate (SEE) was demonstrated between pulmonary vascular resistance and a newly derived parameter RVPEP/velocity time integral (VTI) [ r = 0.87, p < 0.0001, SEE = 2]. An
R V P E P / V T I value of <0.4 seconds/meter (M) was able to select patients with pulmonary vascular resistance <3 Wood U n i t . M 2, even in the presence of pulmonary artery hypertension caused by increased pulmonary blood flow, with 97% accuracy (100% sensitivity, and 92% specificity). An R V P E P / V T I value of 0.4 to 0.6 seconds/M identified patients with pulmonary vascular resistance between 3 to 7.5 Wood Unit - M 2 with 91% accuracy, and a value of >0.6 seco n d s / M selected patients with total pulmonary vascular resistance _>7.5 Wood Unit - M 2 with 94% accuracy. (J Am Soc Echocardiogr 1996;9:822-31.)
A c c u r a t e noninvasive assessment of pulmonary artery systolic pressure in the presence o f ventricular septal defect, tricuspid regurgitation, or aortic to pulmonary artery shunts has been established using the peak velocity as estimated by Doppler echocardiography. 1-6 Some studies used the right ventricular relaxation time and acceleration time 7 to derive nomograms and formulas of varying complexity to estimate the pulmonary artery pressure. Most Doppler echocardiographic studies attempting to assess pulmonary artery hypertension did not address whether the pulmonary artery hypertension was the result o f increased pulmonary blood flow or increased pulmonary vascular resistance. Invasive procedures usually are required t o resolve that issue, This study is designed to explore the possibility that combining Doppler echocardiographic measurements o f the pulmonary blood flow and time intervals o f the right ventricle can determine the cause o f the pulmonary artery hypertension, whether it results from in-
creased pulmonary blood flow or from increased pulmonary vascular resistance.
From the Division of Cardiology, Department of Pediatrics, and the Department of Epidemiologyand Public Health, Universityof Miami School of Medicine. Reprint requests: Makram IL Ebeid, MD, Cleveland Clinic Foundation, Department of Pediatric Cardiology, M40, 9500 Euclid Avenue, Cleveland, OH 44195-0001. Copyright © 1996 by the AmericanSociety of Echocardiography. 0894-7317/96 $5.00 + 0 27/1/73928 822
METHODS Study Patients Patients with congenital heart disease who underwent medically indicated cardiac catheterization in conjunction with echocardiographic evaluation were included in this study. Patients who met any of the following conditions were excluded: right ventricular outflow tract obstruction, oxygen therapy during data acquiring, complete right bundle branch block, or inadequate Doppler recordings.
Hemodynamic Measurements Hemodynamic measurements and calculations were obtained in the cardiac catheterization laboratory using established techniques. The flow was calculated us!ng Fick's principle. The pulmonary artcriolar and total resistance were calculated as previously described. 8-~°Briefly, pulmonary arteriolar (or vascular) resistance = (mean pulmonary artery pressure- left atrial pressure)/pulmonary blood flow, and total resistance = mean pulmonary artery pressure/pulmonary blood flow. Pulmonary artery wedge pressure was used if left atrial pressure was not available. 9 Resistance is expressed in Wood units • M 2. Patients were divided into four groups. Group I included patients with pulmonary arteriolar resistance <3 Wood units • M 2, normal pulmonary artery systolic pressure <35 mm Hg, and
Journal of the AmericanSocietyof Echocardiography Volume 9 Number 6
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F i g u r e 1 Doppler findings in the four groups of patients expressed as mean + SD. The RYTEP/VTI ratio is significantly diffcrent in the four groups of patients with minimal overlap (compare with the other Dopplcr measurcments). Thc RVPEP/VTI ratio is able to discriminate between patients with pulmonary artery hypertension caused by increased pulmonary blood flow (Group II) and patients with pulmonary artery hypertension caused by increased pulmonary vascular resistance (Groups III and IV). Abbreviations as in Table 1.
pulmonary artcry mean prcssurc <20 mm Hg. 8'9 Group II consisted of patients with puhnonary artery hypertension (defined as pulmonary artcry systolic pressure _>35 mm H g or pulmonary artcry mean pressure >_20 mm Hg) 9'~° but normal pulmonary arteriolar resistance <3 Wood units • M 2. Group I I I included patients with pulmonary artery hypertension and moderately increased pulmonary vascular resistance be~veen 3 and 7.5 Wood units • M 2.
Group IV included patients with markedly increased pulmonary resistance (puhnonary arteriolar resistance >7.5 Wood units - M 2) and elevated pulmonary artery pressure. Determining the pulmonary vascular resistance for values >12 Wood units • M 2 has no clinical value and the estimation of the resistance at this level can be inaccurate. Thus data of those patients were considered together as previously used in similar clinical situations, s'~1,,2
824
Journal of the American Society of Echocardiography November-December 1996
E b e i d et al.
Table 1
H e m o d y n a m i c a n d Doppler findings
Patient No.
Group I 1 2 3 4 5 6 7 8 9 10 11 Mean + 8D Group II 12 13 14 15 16 17 18 19 20 21 Mean _+SD p value vs Group I Group I I I 22 23 24 25 Mean + SD p value vs Group I Group I V 26 27 28 29 30 31 32 33 Mean +- 8D p value vs Group I
PASP
PADP
PAMP
TPR
13 16 18 24 30 20 22 31 30 6 30 22 +- 6
6 7 10 12 9 6 10 10 12 10 12 9 _+2
i0 10 12 16 20 10 15 17 20 15 17 14 + 4
3.4 1.6 1.6 3.4 1.5 1.6 2.7 2.5 0.8 1.8 4.5 2+1
32 51 70 38 32 50 48 65 62 52 48 +_ 13 <0.0001
15 18 30 18 14 20 20 22 26 20 20 +__5 <0.0001
22 32 46 26 24 30 30 32 43 35 31 + 8 <0.00001
60 80 55 60 63 + 11 <0~0001
20 30 20 24 23 + 5 <0.0001
94 100 105 108 110 89 48 140 95+26 <0.0001
40 55 55 55 70 30 22 55 45+16 <0.0001
PAR
RVPEP
RVET
2.4 1.4 0.9 2.4 0.8 N/A 1.1 N/A 0.4 1 1.3 1 +- 0.7
0.071 0.06 0.064 0.072 0.07 0.039 0.071 0.057 0.063 0.053 0.069 0.062 + 0.1
0.281 0.26 0.298 0.239 0.269 0.236 0.317 0.22 0.285 0.186 0.215 0.25 + 0.04
1.4 2.6 3.4 1 3.3 1.5 1.45 1.19 3.3 2.4 2 +- 1 NS
0.8 2.2 2.9 0.7 1.5 1.1 0.78 0.9 2.9 1.7 1 +- 0.9 NS
0.73 0.05 0.06 0.069 0.097 0.043 0.063 0.058 0.058 0.055 0.06 + 0.01 N8
0.241 0.204 0.203 0.198 0.279 0.227 0.188 0.231 , 0.21 0.22 0.22 + 0.03 <0.04
38 50 34 42 41 +- 7 <0.0001
5.3 6 3.9 5.2 5+ 1 <0.001
4.9 5.6 3 4 4+1 <0.0001
0.082 0.085 0.087 0.073 0.08 + 0.01 <0.005
0,219 0.231 0.19 0.193 0.21 +- 0.02 <0.05
62 72 72 66 80 61 36 84 65+_15 <0.0001
9.7 10.6 ->15 >__15 _>15 10.5 ->15 11.3 13+2 <0.0001
8.1 8.9 ->12 ->12 ->12 9.5 8 10 10+_1 <0.0001
0.064 0.097 0.098 0.107 0.091 0.076 0.065 0.088 0.084+-0.02 <0.003
0.186 0.266 0.198 0.23 0.179
0.197 0.135 0.17 0.19+-0.04 <0.01
The pressure is measured in mm Hg; the resistance in Wood Units • M 2. Doppler parameters are measured in sec, meter, or see/meter. Findings denoted c are corrected for heart rate. AcT, acceleration time; N/A, not available; NS, not significant; PADP,pulmonary artery diastolic pressure; PAMP, pulmonary artery mean pressure; PAR, pulmonary arteriolar resistance; PASP,pulmonary artery systolic pressure; RVET, right ventricular ejection time; RVPEP,right ventricular pre-ejection period; TPR, total pulmonary vascular resistance; VT/', velocity time integral.
Doppler Echocardiography D o p p l e r echocardiographic m e a s u r e m c n t s wcre o b t a i n e d within 6 h o u r s o f the time o f cardiac cathcterization using a commercially available machine (Toshiba m o d e l S S H 1 6 0 A ; Toshiba America Medical Systems, Inc., Carrolton, Tex.). O n e 28-year-old patient, w h o h a d a vcntricular scptal defect, E i s e n m e n g e r syndrome, a n d pulm o n a r y vascular resistance >12 W o o d units • M 2, under-
w e n t the echocardiographic evaluation 1 week after the cardiac catheterization. Simultaneous electrocardiogram tracing a n d Doppler echocardiographic m e a s u r e m e n t s were o b t a i n e d at a recording speed of 100 m m / s e c o n d in 25 patients (8 patients were r e c o r d e d at 50 m m / s e c o n d ) . U s i n g a S M H z or a 3.5 M H z phased array transducer to acquire the best image a n d D o p p l e r signal, the left parasternal s h o r t axis view was used. A pulsed wave D o p p -
Journal of the American Society of Echocardiography Volume 9 Number 6
RVETc
E b e i d et al.
VTI
VTIc
AcT
0.33 0.34 0.38 0.32 0.31 0.34 0.37 0.33 0.38 0.31 0.31 0.34 + 0.03
0.18 0.19 0.2 0.18 0.19 0.18 0.28 0.17 0.31 0,26 0.21 0.21 + 0.05
0.21 0.25 0.26 0.24 0,22 0.26 0.33 0.26 0.41 0.43 0.31 0.28 -+ 0.07
0.138 0.091 0.145 N/A 0.113 0.105 0.143 N/A 0.125 0.044 0.061 0.1 + 0.04
0.37 0.35 0.32 0.32 0.36 0.35 0,3 0.34 0.32 0.33 0.34 + 0.02 NS
0.34 0.2 0.27 0.35 0.58 0.33 0.22 0.34 0.16 0.36 0.29 -+ 0,12 <0.02
0.53 0.34 0.43 0.56 0.76 0.5 0.35 0.49 0.24 0.54 0.45 + 0.144 <0.002
0.33 0.34 0.22 0.27 0,29 + 0.06 <0.05
0.15 0.21 0.28 0.15 0.19 + 0.06 NS
0.3 0.32 0.24 0.29 0.24 0.28 0.21 0.26 0.27 + 0.04 <0.0005
0.14 0.16 0.16 0.14 0.13 0.13 0.08 0.15 0,133 + 0.03 <0.001
AT/ET
RVPEP/ET
RVPEP/VTI
Heart Rate
0.16 0.119 0.187 N/A 0.13 0.153 0,167 N/A 0.165 0.07 0.091 0.132 + 0.04
0.49 0.35 0.49 N/A 0.42 0.45 0.45 N/A 0.44 0.23 0.29 0.39 + 0.09
0.25 0.23 0.22 0.3 0.26 0.17 0.22 0.26 0.22 0.28 0.33 0.26 + 0.04
0.39 0.32 0.32 0.4 0.36 0.22 0.25 0.33 0.2 0.21 0.33 0.30 + 0.07
81 103 100 106 80 126 82 140 105 158 132
N/A 0.065 0.069 0.078 N/A 0.075 0.064 N/A 0.061 0.073 0.07 + 0.006 <0.02
N/A 0.11 0.109 0.122 N/A 0.114 0.103 N/A 0.094 0.11 0.11 + 0.09 NS
N/A 0.32 0.34 0.39 N/A 0.33 0.34 N/A 0.29 0.34 0.33 + 0,03 NS
0.3 0.25 0.3 0.35 0.35 0.19 0.34 0.25 0.28 0.25 0.28 + 0.05 NS
0.21 0.25 0.22 0.2 0.17 0.13 0.29 0.17 0.37 0.15 0.21 -+ 0.07 <0.02
146 172 150 148 103 138 153 125 137 135
0.23 0.31 0.31 0.22 0.26 + 0.05 NS
0.064 0.043 0.074 0.061 0.06 + 0.013 <0.05
0,096 0.063 0.083 0.09 0.08 + 0.014 <0.03
0.29 0.2 0.38 0.33 0.29 + 0.08 NS
0.36 0.47 0.45 0.39 0.46 + 0.05 <0.0001
0,54 0.41 0.31 0.49 0.43 _-+0.1 <0.02
137 129 74 130
0.21 0.19 0.2 0.18 0.17 0.19 0.12 0.22 0.18 + 0.03 <0.002
0.035 N/A 0.073 0.065 0.05 0.062 0,084 0.052 0.06 + 0.02 <0.01
0.052 N/A 0.09 0.079 0.067 0.089 0.128 0.078 0.08 + 0.02 <0.01
0.18 N/A 0.38 0.27 0.28 0.31 0.62 0.31 0.32 + 0.14 NS
0.25 0.36 0.49 0.47 0.51 0,39 0.48 0.52 0,42 _+0.09 <0.0001
0.48 0.61 0.61 0.76 0.7 0.58 0.84 0.6 0.64 + 0.11 <0.0001
132 85 93 92 104 125 137 133
ler sample v o l u m e was positioned u n d e r two-dimensional echocardiographic guidance distal to the p u l m o n a r y leaflets in the middle o f the main p u l m o n a r y artery. Care was taken to p r o d u c e clean waveforms depicting an a b r u p t waveform deflection at the o n s e t o f the flow, a systolic waveform with discernible peak, a n d crisp r e t u r n o f the waveform to baseline at the e n d o f flow? ~ M e a s u r e m e n t s included the right ventricular pre-ejection period (RVPEP), r i g h t ventricular ejection time (RVET), acceleration time (ACT), velocity rime integral (VTI), a n d the ratios A c T / R V E T , R V P E P / E T , a n d R V P E P / V T I . T h e R V P E P was m e a s u r e d from the b e g i n n i n g o f the QRS wave to the o p e n i n g o f the p u l m o n a r y valve. T h e A c T was defined as the time from o n s e t o f flow to the peak velocity.
AcTc
825
T h e R V E T was m e a s u r e d from the o p e n i n g to the closure o f the p u l m o n a r y v a l v e Y 17 T h e V T I was o b t a i n e d in meters by digitizing the signal envelope with the aid o f a c o m p u t e r p r o g r a m ) 7-19 M e a s u r e m e n t s o f at least three cardiac cycles 2° were o b t a i n e d a n d averaged. D o p p l e r measurements were examined before a n d after correcting for h e a r t rate by dividing the m e a s u r e m e n t s with the square r o o t o f the preceding R to R i n t e r v a l ) 5"~9
Data Analyisis
Data o f the four groups are expressed as m e a n + SD and c o m p a r e d using S t u d e n t ' s ~test. A p value o f <0.05 was considered significant. Sensitivity and specificity were cal-
826
Journal of the American Society of Echocardiography November-December 1996
E b e i d et al.
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Figure 2 Linear regression relation between PAR values and RVPEP/VTI ratio in all the patients. Dotted lines indicate the 95% confidence limits. (RVPEP/VTI, right ventricular pre-ejection period/velocity time integral; PAR, pulmonary arteriolar resistance.)
culated as the percentage of patients in each group selected (or excluded) correctly by the Doppler echocardiographic parameter suggested. The relationship between Doppler echocardiographic and hemodynamic measurements also was evaluated by simple linear regression. In addition, this relationship was examined in the subgroups of patients without extracardiac shunts (patent ductus arteriosus) and those without left-sided obstructive lesions (mitral stenosis or coarctation of the aorta). Subsequently, multiple regression analysis was performed. A Doppler variable was considered to have an independent and important contribution if the regression coefficient was significantly different from zero. Variables would be deleted from the regression model if the relationship, adjusted for the number of predictors, remained at a significant and a high level (defined as R~ >.7).
tricular canal (n = 6). One patient had an atrioventticular canal and a patent dnctus arteriosus, 3 patients had a patent ductus arteriosus, I had ventricular septal defect with coarctation o f the aorta, 1 had total anomalous pulmonary venous return and an atrial septal defect, 2 had coarctation o f the aorta, 1 had coarctation o f the aorta with aortic stenosis, and 1 had mitral stenosis. The left atrial or pulmonary artery wedge pressure was not measured in 2 patients (numbers 6 and 8) whose total pulmonary resistance was <2.5 Wood units • M 2. These patients were excluded from the linear regression analysis o f the pulmonary arteriolar resistance.
HEMODYNAMIC FINDINGS RESULTS D e m o g r a p h i c Data Forty-nine patients underwent cardiac catheterization and concomitant echocardiographic evaluation during the study period. Thirty-three patients (16 male, 17 female) with congenital heart disease met the inclusion criteria. Their ages ranged from 10 days to 28 years (mean 1.4 years). Twenty-three patients had intracardiac shunts consisting ofventricular septal defect (n = 16), atrial septal defect (n = 1), and atrioven-
Group I included 11 patients with normal pulmonary artery pressure (mean systolic pressure o f 22 + 6 mm Hg) + and pulmonary arteriolar resistance of l - 0.7 Wood units. M 2 (Table 1). Group II included 10 patients with no significant change in pulmonary vascular resistance (mean pulmonary resistance of 1 + 0.9 Wood units • M 2) but with pulmonary artery hypertension 8 as a result o f increased pulmonary blood flow (mean pulmonary artery systolic pressure o f 48 4-- 13 mm H g and a mean pres-
Journal o f the American Society o f Echocardiography Volume 9 N u m b e r 6
Ebeid et al. 827
Table 2 Linearregression correlations between Doppler and hemodynamic findings PAR RVPEP/VTI RVPEP/ET RVPEP RVPEPc VTI VTIc RVET RVETc AcT AcTc AcT/ET *p < 0.0001, ]'p < 0.001, :~p < 0.05.
TPR
PASP
PAMP
r = 0.88*
r= 0.91"
r= 0.64
r= 0.68*
S E E = 1.9
S E = 1.9
SEE = 26
SEE = 16
r = 0.79*
r = 0.80*
r = 0.73*
r = 0.75*
SEE = 2.5
SEE = 2.8
SEE = 23
S E E = 15
r = 0.67*
r = 0.55~
r = 0.48z~
r = 0.51~
SEE = 3
SEE = 3.9
SEE = 28.9
SEE = 18.9
r = 0.67*
r = 0.65*
r = 0.66]
r = 0.68*
SEE = 3
SEE = 3.6
SEE = 25
SEE = 16
r = 0,58]"
r = 0.55].
r = 0.35~c
r = 0.37~
SEE = 3.4
SEE = 4
SEE = 30.9
SEE = 20.5
r = 0.61"
r = 0.56]"
N S [p = 0.52,
r = 0.37~
SEE = 3
SEE = 4
r = 0.34, SEE = 31]
SEE = 20.5
r = 0,46:~
r = 0.45:~
r = 0.49:~
r = 0.49:~
SEE = 3.7
SEE = 4.2
SEE = 28.7
SEE = 19.2
r = 0.64"
r = 0.71"
r = 0.56]"
r = 0.59]"
SEE = 3.2
SEE = 3.4
SEE = 27
S E E = 18
r = 0.43~
r = 0.41:[:
r = 0.62~
r = 0.6:~
S E E = 3.9
SEE = 4.5
SEE = 26.4
SEE = 17.7
r = 0.5].
r = 0.47~
r = 0.7*
r = 0.69*
SEE = 3.6
SEE = 4.4
SEE = 24
SEE = 16.3
NS
NS
NS
NS
SEE,standard
error o f estimate; remaining abbreviations as in Table 1.
sure of 31 _+8 mm Hg, both significantlyhigher than Group I; p < 0.0001). Group III included 4 patients with pulmonary arteriolar resistance of 4 + 1 Wood units • M z (p < 0.0002 versus either Group I or II), pulmonary artery systolic pressure of 63 + 11 mm Hg, and a mean pressure of 41 + 7 mm Hg (both significantly different from Group I but not different from Group II). Group IV (n = 8) included patients with pulmonary artery hypertension and markedly elevated pulmonary vascular resistance (mean l0 + 1 Wood units- M2).
spectively). The value was significantly lower in patients with pulmonary artery hypertension caused by increased pulmonary blood flow if there was no associated rise in the pulmonary vascular resistancc (Group II; p = 0.01). With the increase in pulmonary vascular resistance, the RVPEP/VTI value increased significantly in Groups III and IV.
Linear Regression Relationship Between Doppler and Hemodynamic Findings
Measurement of the RVPEP/ET was not different in the two groups with pulmonary arteriolar resistance <3 Wood Units M 2 (Groups I and II), even when the patients had pulmonary artery hypertension (Group II). The RVPEP/ET value was significantlyhigher in groups with elevated pulmonary vascular resistance (Groups III and IV).
The linear regression relationship between the Doppler and the hemodynamic results arc presented in Table 2. Among the different Doppler echocardiographic parameters tested, the ratio RVPEP/VTI had the strongest correlation with pulmonary arteriolar resistance (r= 0.88; p < 0.0001). The relationship is defined by the equation pulmonary arteriolar resistance (Wood Units • M 2) = -2.8 + 17.8 RVPEP/VTI (seconds/M). The SEE was the smallest, 1.9 Wood units • M 2 (Figure 2). This relationship remained strong after exclusion of patients with leftsided obstructive lesions (r = 0.89, SEE = 1.7 Wood units • M z, p < 0.0001 ) or extracardiac shunts (patent ductus arteriosus, r = 0.85, SEE = 1.9, p < 0.0001) (Figure 3).
Right Ventricular Pre-ejection Period/Velocity
Sensitivity and Specificity of RVPEP/VTI
Doppler Findings in the Four Groups The rcsults of the Doppler studies are presented in Table 1 and Figure 1.
Right Ventricular Pre-ejection Period/Ejection Time (RVPEP/ET)
Time Integral (RvPEP/VTI) The value of RVPEP/VTI was significantly different in all of the four groups (Figure 1). In Groups I and II, the value was low, less than 0.4 scconds/M (0.3 + 0.07 seconds/M and 0.21 _+0.07 see/M, re-
The sensitivity and specificity of RVPEP/VTI in the different groups ranged between 75% and 100%, with an overall accuracy between 91% and 97% (Table 3). With exclusion of patients with patent ductus arteriosus or left-sided obstructive lesions, the
Journal of the American Society of Echocardiography
828 Ebeid et al.
November-December1996
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Figure 3 Linear regression relation between PAR values and RVPEP/VTI ratio after excluding patients with left-sided obstructive lesions (A) or patent ductus arteriosus (B). Dotted lines indicate the 95% confidence limits. Abbreviations as in Figure 2.
accuracy of this parameter remained high (between 89% and 100%).
DISCUSSION Right ventticular systolic time intervals measured by M-mode echocardiography have been used to assess the pulmonary artery hypertension with contradictory results. 4'16'21-23 M-mode echocardiography cannot incorporate the pulmonary blood flow in the measurement, thus the distinction between pulmonary artery hypertension on the basis of increased pulmonary blood flow as opposed to pulmonary vascular resistance using M-mode echocardiography is considered difficult and inaccurate, z2 Most Doppler echocardiographic studies addressing pulmonary artery hypertension did not determine whether this was caused by increased pulmonary blood flow or pulmonary vascular resistance. Cooper et a132 and Ritter et al. 24 concluded that the specific Doppler echocardiographic parameters tested were not accurate enough to evaluate the responsiveness of the pulmonary vascular bed to pulmonary vasodilators. The current study tests the linear relationship between the pulmonary vascular resistance and newly derived, as well as conventional, Doppler echocardiographic measurements. It also compares these Doppler echocardiographic findings in patients with pulmonary artery hypertension caused by increased
pulmonary blood flow as opposed to increased pulmonary vascular resistance. The decrease in acceleration t i m e a4-16,25-2s o r AcT/RVET 14'27 was proposed to be indicative of pulmonary artery hypertension or increased pulmonary vascular resistance. We, and others, 6'~2'29 found that the AcT value with or without heart rate correction, or the ratio AcT/RVET 4"6"12"13'15"29 was a weak predictor of pulmonary artery pressure or resistance (Table 2 and Figure 1). Although the AcT value decreased with increasing pulmonary pressure and resistance, it could not distinguish between patients with pulmonary hypertension caused by increased flow (Group II) as opposed to patients with pulmonary hypertension caused by increased resistance (Group III). The change was not reflective of the degree of pulmonary vascular disease (Groups III and IV). The AcT/ET value in patients with markedly elevated resistance (Group IV) approached normal values, similar to previous findings? °
The Right Ventricular Pre-ejection Period (RVPEP), Ejection Time (ET), and RVPEP/ET The RVPEP and RVPEP/ET, ~6'31 as determined by M-mode echocardiography, have been shown to be elevated and the RVET value to be decreased in patients with pulmonary artery hypertension.16a~ Selection of healthy subjects from a patient population with pulmonary artery hypertension using these parameters, with and without heart rate correction, was
Journal of the American Society of Echocardiography Volume 9 Number 6
E b e i d et al.
829
Table 3 Ability of RVPEP/VTI to predict PAR RVPEp/ArrI value
_<.4 sec./M
0.41-0.6 sec./M
>0.6 sec.M
Predictd PAR
<3 Wood.M2
3-7.5 Wood.Mz
->7.5 Wood.M2
Sensitivity Specificity Accuracy (all patients) Accuracy (after excluding leftsided obstructive lesions) Accuracy (after excluding extracardiac shunts)
%
N
%
N
%
N
100 92 97 96
(21/21) (11/12) (32/33) (27/28)
75 93 91 89
(3/4) (27/29) (30/33) (25/28)
75 100 94 93
(6/8) 28/25) Sl/S3) 26/28)
100
(29/29)
93
(27/29)
93
27/29)
The number in parentheses represents the actual number of patients. RVPEP/VTI,right ventricular pre-ejection period/velocity time integral; PAR,pulmonary arteriolar resistance.
reported to be poor, 23 with low sensitivity and specificity ranging from 31% to 58%.is The change in the RVPEP/ET value was noted only when the pulmonary hypertension was caused by increased resistance and not flow (Figure 1). This change was not reflective of the degree of pulmonary vascular disease (no difference between Groups III and IV). This study demonstrates that these parameters, as measured by Doppler, are unreliable to determine the cause or the degree of the pulmonary hypertension, with a large overlap between the different groups (Table 1 and Figure 1). Velocity Time Integral (VTI) To our knowlcdge, the relationship of the VTI t o the pulmonary vascular resistance has not been previously examined. Because the VTI is proportional to the forward flow in the pulmonary artery, I7-~9'32 we found an inverse linear relationship between the VTI and pulmonary vascular resistance. The VTI value increased in cases of pulmonary hypertension if the latter was associated with pulmonary arteriolar resistance <3 Wood units • M2; that is, if the pulmonary hypertension was caused by increased pulmonary blood flow (Group II). However, the VTI value decreased in patients with pulmonary hypertension if the latter Was the result of increased pulmonary resistance (Table 1, Groups III and IV). In this study, a new concept to assess the pulmonary vascular resistance, namely the ratio RVPEP/VTI,is proposed. Among the different Doppler parameters tested, the RVPEP/VTI ratio has the strongest linear relationship with the pulmonary arteriolar resistance (Figure 2), with a correlation of 0.88 (p < 0.0001), and a small SEE (1.9 Wood units.M2). The RVPEP/VTI ratio proved to be a significant predictor of pulmonary vascular resistance (Table 4, Model 1) even when the RVPEP and VTI values were statistically controlled (Model 2). The ratio was able to dis-
criminate between patients with pulmonary artery hypertension on the basis of increased pulmonary blood flow (Group II) as opposed to increased pulmonary vascular resistance (Groups III and IV; Figure 1). The difference between patients with pulmonary resistance <3 Wood units • M 2 (Groups I and II) and those with pulmonary vascular resistance _>3 Wood Units • M 2 (Groups III and IV) is the highest with the least overlap (Figure 1 and Table 1). The accuracy of this ratio in selecting patients in the different groups is _>91% (Table 3). With the exclusion of patients with left-sided obstructive lesions (coarctation of the aorta or mitral stenosis), the relationship remains highly significant (r = 0.89, p < 0.0001, SEE = 1.7) (Table 3 and Figure 3A). The presence of extracardiac shunts such as patent ductus arteriosus can influence the measurement of the VTI. All of our patients who had patent ductus arteriosus had evidence of minimal shunting at the ductal level, detected by both echocardiography and catheterization data (three had pulmonary vascular disease with elevated pulmonary resistance at or near systemic levels, and one had a small patent ductus arteriosus in addition to the primary lesion of the atrioventricular canal defect). After exclusion of these patients, the relationship between the RVPEP/;VTI ratio and the pulmonary vascular resistance proved to be equally strong, with similar accuracy in selecting patients with and without elevated pulmonary vascular resistance (93% to 100%; Table 3), and with a highly significant linear regression relationship (Figure 3B). These findings were similar for total pulmonary resistance (Tables 1 and 2). Thus RVPEP/VTI was influenced by the change in either total or arteriolar resistance. Heart Rate Correction When a single Doppler parameter such as the RVPEP or RVET is used, the need for heart rate correction
830
Journal of the AmericanSocietyof Echocardiography November-December 1996
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Table 4
Multivariate analysis of determinants o f the pulmonary vascular resistance
Variable
Model 1 Interccpt RVPEP/VTI Model 2 Intercept RVPEP/VTI RVPEP VTI
Coefficient
-3 18.3
Standard
error
0.83 1.9
t value
SE
R2
2,1
0.75
-3.6 9.6
-<0.0011" <0.00001" 2
-7 17.7 49 3.5
2.3 4.9 38 7.5
-3 3.6 1.3 .47
p value
0.77 <_0.0053 _<0.0012" 0.2 0.64
The ratio RVPEP/VTI independently is an excellentdeterminant of the tot~ilpulmonary vascularresistance. *Statisticallysignificantvalues. Abbreviationsas in Table 1.
should be considered. Different formulas or nomograms have been used for that purpose in some studies ls'19'22 but not in o t h e r s . 12'1<2a It was demonstrated, however, that the heart rate correction is not needed when a ratio such as the RVPEP/ET is u s e d . ls'21 The VTI value is equal to the product of the RVET and the mean velocity, ~8'19 and no heart rate correction is needed for the latter, thus by using the ratio RVPEP/VTI the need for heart rate correction, with its controversy, 18 is eliminated. Study Limitations In this study the number of patients in Groups III and IV is relatively small. This is expected because intervention is usually done before the patients reach this stage. The high statistical significance and the strong correlation of the measurement compensate for the lack of a large number of patients in the high resistance groups. Another limitation is the presence of a time difference o f a few hours between obtaining the hemodynamic and echocardiographic data. It is possible that some change took place in the resistance during that period. Given the strong correlation and significant differences among the groups, it is unlikely that this change is significant enough to affect the accuracy of this measurement. In addition, this parameter is not intended to provide an exact value for the pulmonary vascular resistance. A range of clinically useful values for the resistance, however, can be estimated (Figure 2) and the selection of patients with and without pulmonary vascular disease is possible (Table 1 and Figure 1), especially when used in conjunction with other available modalities.
CONCLUSION
The pre-ejection period corrected for stroke volume as reflected by the ratio RVPEP/VTI is a newly derived parameter that is superior to other conventional Doppler parameters in selecting patients with and without increased pulmonary vascular resistance.
We thank Dan Murphy, M D , at the Cleveland Clinic Foundation for reviewing the manuscript and rendering valuable advice and Diane McMullen for typing this manuscript.
REFERENCES 1. Currie PJ, Seward JB, Chan KL, et al. Continuous-wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 125 patients. J Am Coil Cardiol 1985;6:750-6. 2. Marx GR, Alien HD, Goldberg SI. Doppler echocardiographic estimation of systolic pulmonary artery pressure in patients with aortic-pulmonary shunts. J Am Coll Cardiol 1986;7:880-5. 3. Schiller NB. Pulmonary artery pressure estimation by Doppler and two-dimensional echocardiography. Cardiol Clin
1990;8:277-87. 4. Stevenson JG. Comparison of several noninvasive methods for estimation of pulmonary artery pressure. J Am Soc Echocardiogr 1989;2:157-71. 5. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppl_er ultrasound in patients with tricuspid incompetence. Circulation 1984;70:657-62. 6. Zellers T, Gutgesell HE Noninvasive estimation of pulmonary artery pressure. J Pediatr 1989;114:735-74. 7. Mirrakhimov MM, Tenenbaum AM, Moldotashev fig,, Zlatkovsky ML. New approaches to noninvasive assessment of pulmonary artery pressure. Clin Cardiol 1992;i5:811-6. 8. Grossman W. Blood flow measurement: The cardiac output. In: Grossman W, Balm D, eds. Cardiac catheterization, angiography and intervention. 4th ed. Philadelphia: Lea and Febiger, 1991:108-10, 144-5,148. 9. Lock J-. Helnodynamic evaluation of congenital heart disease. In: Lock J, Keane J, Fellows K, eds. Diagnostic and interventional catheterization in congenital heart disease. Boston: Mardnus Nijhoff Publishing, 1988;37, 39, 57-8. 10. Vargo TA. Cardiac catheterization-hemodynamic measurements. In: Garson A, Bricker JT, McNamara D, eds. The science and practice of pediatric cardiology. Philadelphia: Lea and Febiger, 1990:916, 931-3. 11. Askenazi J, Ahnberg DS, Korngold E, LaFarge CG, Malitz DL, Treves S. Quantitative radionuclide angiography: detection and quantitation of left to right shunts. Am J Cardiol 1976;37:382-7 12. Cooper MJ, Tyndale M, Silverman, NH. Evaluation of the responsiveness of elevated pulinonary vascular resistance in children by Doppler echocardiography. J Am Coil Cardiol 1988;12:470-5.
Journal of the AmericanSocietyof Echocardiography Volume 9 Number 6
13. Stevenson JG, Kawabori I, Guntheroth WG. Non-invasive estimation of peak pulmonary artery pressure by M-mode echocardiography. J Am Coil Cardiol 1984;4:1021-7. 14. Kitabatake A, Inoue M, Asao M, et al. Noninvasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983;68:302-9. 15. Kosturakis D, Goldberg S, Allen H, Loeber C. Doppler echocardiographic prediction of pulmonary arterial hypertension in congenital heart disease. Am J Cardio11984;53:1110-5. 16. Feigenbaum H. Echocardiography. 4th. ed. Philadelphia: Lea and Febiger, 1986:218-20. 17. Murphy D. Doppler echocardiography. In: Garson A, Bricker JT, McNamara D, eds. The science and practice of pediatric cardiology. Philadelphia: Lea and Febiger, 1990:7934. 18. Goldberg SJ, Allen HD, Marx GR, Donnerstein RL. Flow computation in Doppler echocardiography. Philadelphia: Lea and Febiger, 1988:153-8, 170-1. 19. Snider AR, Serwer GA. Methods for obtaining quantitative information from the echocardiographic examination. In: Echocardiography in pediatric heart disease. Chicago: Year Book Medical Publishers, 1990:82, 84, l l 0 . 20. Kristensen BO, Goldberg SJ. Number of cardiac cycles required to accurately determine mean velocity of blood flow in the ascending aorta and pulmonary trunk. Am J Cardiol 1987;60:746-7. 21. Hirschfeld S, Meyer R, Schwartz DC, Korfhagen J, Kaplan S. Echocardiographic assessment of pulmonary artery pressure and pulmonary vascular resistance. Circulation 1975;52:64250. 22. Riggs T, Hirschfeld S, Borkat G, Knoke J, Liebman J. Assessment of the pulmonary vascular bed by echocardiographic right ventricular systolic time intervals. Circulation 1978;57: 939-47. 23. Silverman NH, Snider AR, Rudolph AM. Evaluation of pulmonary hypertension by M-mode echocardiography in chil-
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28. 29.
30.
31.
32.
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dren with ventricularseptal defect. Circulation 1980;61:112532. Ritter SB, Cooper RS, Golinko RK. Non-invasive assessment of pulmonary hypertension and pulmonary vascular reactivity in congenital heart disease: pulsed Doppler application. J Cardiovasc Ultrason 1986;5:213-21. ChaJ~ KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coil Cardiol 1987;9:54944. Dabestani A, Mahan G, Gardin JM, et al. Evaluation of pulmonary artery pressure and resistance by pulsed Doppler echoeardiography. Am J Cardiol 1987;59:662-8. Martin-Duran R, Larman M, Trugeda A, et al. Comparison of Doppler-determined elevated pulmonary arterial pressure with pressure measure at cardiac catheterization. Am J Cardiol 1986;57:859-63. Missri JC. Evaluation of pulmonary hypertension by Doppler eehocardiography. J Cadiovasc Uhrason 1988;7:277-81. Nanna M, Lin SL, Tak T, et al. Inaccuracy of Doppler estimates of pulmonary artery pressure using flow acceleration time. Can J Cardiol 1990;6:19-23. Friedman DM, Bierman FZ, Barst R. Gated pulsed Doppler evaluation of idiopathic pulmonary artery hypertension in children. Am J Cardiol 1986;58:369-70. Spooner EW, Perry BL, Stern AiM, Sigmann J. Estimation of puhnonary/systemic resistance ratios from echocardiographic systolic time intervals in young patients with congenital heart disease. Am J Cardiol I978;42:810-6. Goldberg SJ, Sahn DJ, Allen HD, Valdes-Cruz LM, Hoenecke H, Carnahan Y. Evaluation of pulmonary and systemic blood flow by two-dimensional Doppler echocardiography using fast Fourier transform spectral analysis. Am J Cardioi 1982;50:1394-400.
Noninvasive assessment of pulmonary vascular resistance has not been well defined. Cardiac catheterization findings in 33 patients with congenital heart disease (mean age 1.4 years) were compared with Doppler echocardiographic parameters. The right ventricular pre-ejection period (RVPEP), ejection time (RVET), and the ratio RVPEP/RVET correlated better with pulmonary vascular resistance than with pulmonary artery pressure. A highly significant correlation with a small standard error of estimate (SEE) was demonstrated between pulmonary vascular resistance and a newly derived parameter RVPEP/velocity time integral (VTI) [ r = 0.87, p < 0.0001, SEE = 2]. An
R V P E P / V T I value of <0.4 seconds/meter (M) was able to select patients with pulmonary vascular resistance <3 Wood U n i t . M 2, even in the presence of pulmonary artery hypertension caused by increased pulmonary blood flow, with 97% accuracy (100% sensitivity, and 92% specificity). An R V P E P / V T I value of 0.4 to 0.6 seconds/M identified patients with pulmonary vascular resistance between 3 to 7.5 Wood Unit - M 2 with 91% accuracy, and a value of >0.6 seco n d s / M selected patients with total pulmonary vascular resistance _>7.5 Wood Unit - M 2 with 94% accuracy. (J Am Soc Echocardiogr 1996;9:822-31.)
A c c u r a t e noninvasive assessment of pulmonary artery systolic pressure in the presence o f ventricular septal defect, tricuspid regurgitation, or aortic to pulmonary artery shunts has been established using the peak velocity as estimated by Doppler echocardiography. 1-6 Some studies used the right ventricular relaxation time and acceleration time 7 to derive nomograms and formulas of varying complexity to estimate the pulmonary artery pressure. Most Doppler echocardiographic studies attempting to assess pulmonary artery hypertension did not address whether the pulmonary artery hypertension was the result o f increased pulmonary blood flow or increased pulmonary vascular resistance. Invasive procedures usually are required t o resolve that issue, This study is designed to explore the possibility that combining Doppler echocardiographic measurements o f the pulmonary blood flow and time intervals o f the right ventricle can determine the cause o f the pulmonary artery hypertension, whether it results from in-
creased pulmonary blood flow or from increased pulmonary vascular resistance.
From the Division of Cardiology, Department of Pediatrics, and the Department of Epidemiologyand Public Health, Universityof Miami School of Medicine. Reprint requests: Makram IL Ebeid, MD, Cleveland Clinic Foundation, Department of Pediatric Cardiology, M40, 9500 Euclid Avenue, Cleveland, OH 44195-0001. Copyright © 1996 by the AmericanSociety of Echocardiography. 0894-7317/96 $5.00 + 0 27/1/73928 822
METHODS Study Patients Patients with congenital heart disease who underwent medically indicated cardiac catheterization in conjunction with echocardiographic evaluation were included in this study. Patients who met any of the following conditions were excluded: right ventricular outflow tract obstruction, oxygen therapy during data acquiring, complete right bundle branch block, or inadequate Doppler recordings.
Hemodynamic Measurements Hemodynamic measurements and calculations were obtained in the cardiac catheterization laboratory using established techniques. The flow was calculated us!ng Fick's principle. The pulmonary artcriolar and total resistance were calculated as previously described. 8-~°Briefly, pulmonary arteriolar (or vascular) resistance = (mean pulmonary artery pressure- left atrial pressure)/pulmonary blood flow, and total resistance = mean pulmonary artery pressure/pulmonary blood flow. Pulmonary artery wedge pressure was used if left atrial pressure was not available. 9 Resistance is expressed in Wood units • M 2. Patients were divided into four groups. Group I included patients with pulmonary arteriolar resistance <3 Wood units • M 2, normal pulmonary artery systolic pressure <35 mm Hg, and
Journal of the AmericanSocietyof Echocardiography Volume 9 Number 6
0.7-~
Ebeid et al.
p <.0001
p<.0005
f
[
0.6 q
823
p<,O002
,
1
p<.O02 p<.02 p<.OO5 [
II ..q-
I ( - - 1
m
o.5~
i p<,O02
p<.04
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VTic
p<.001
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rp <.0001
0.8
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p <.02
F
p<.0001 E
p<.003
°°i
t
I
0.4
0.2
RVPEP/ET
•
RVPEP/VTI
Group I
.~
Group II
Group III
[]
Group IV
F i g u r e 1 Doppler findings in the four groups of patients expressed as mean + SD. The RYTEP/VTI ratio is significantly diffcrent in the four groups of patients with minimal overlap (compare with the other Dopplcr measurcments). Thc RVPEP/VTI ratio is able to discriminate between patients with pulmonary artery hypertension caused by increased pulmonary blood flow (Group II) and patients with pulmonary artery hypertension caused by increased pulmonary vascular resistance (Groups III and IV). Abbreviations as in Table 1.
pulmonary artcry mean prcssurc <20 mm Hg. 8'9 Group II consisted of patients with puhnonary artery hypertension (defined as pulmonary artcry systolic pressure _>35 mm H g or pulmonary artcry mean pressure >_20 mm Hg) 9'~° but normal pulmonary arteriolar resistance <3 Wood units • M 2. Group I I I included patients with pulmonary artery hypertension and moderately increased pulmonary vascular resistance be~veen 3 and 7.5 Wood units • M 2.
Group IV included patients with markedly increased pulmonary resistance (puhnonary arteriolar resistance >7.5 Wood units - M 2) and elevated pulmonary artery pressure. Determining the pulmonary vascular resistance for values >12 Wood units • M 2 has no clinical value and the estimation of the resistance at this level can be inaccurate. Thus data of those patients were considered together as previously used in similar clinical situations, s'~1,,2
824
Journal of the American Society of Echocardiography November-December 1996
E b e i d et al.
Table 1
H e m o d y n a m i c a n d Doppler findings
Patient No.
Group I 1 2 3 4 5 6 7 8 9 10 11 Mean + 8D Group II 12 13 14 15 16 17 18 19 20 21 Mean _+SD p value vs Group I Group I I I 22 23 24 25 Mean + SD p value vs Group I Group I V 26 27 28 29 30 31 32 33 Mean +- 8D p value vs Group I
PASP
PADP
PAMP
TPR
13 16 18 24 30 20 22 31 30 6 30 22 +- 6
6 7 10 12 9 6 10 10 12 10 12 9 _+2
i0 10 12 16 20 10 15 17 20 15 17 14 + 4
3.4 1.6 1.6 3.4 1.5 1.6 2.7 2.5 0.8 1.8 4.5 2+1
32 51 70 38 32 50 48 65 62 52 48 +_ 13 <0.0001
15 18 30 18 14 20 20 22 26 20 20 +__5 <0.0001
22 32 46 26 24 30 30 32 43 35 31 + 8 <0.00001
60 80 55 60 63 + 11 <0~0001
20 30 20 24 23 + 5 <0.0001
94 100 105 108 110 89 48 140 95+26 <0.0001
40 55 55 55 70 30 22 55 45+16 <0.0001
PAR
RVPEP
RVET
2.4 1.4 0.9 2.4 0.8 N/A 1.1 N/A 0.4 1 1.3 1 +- 0.7
0.071 0.06 0.064 0.072 0.07 0.039 0.071 0.057 0.063 0.053 0.069 0.062 + 0.1
0.281 0.26 0.298 0.239 0.269 0.236 0.317 0.22 0.285 0.186 0.215 0.25 + 0.04
1.4 2.6 3.4 1 3.3 1.5 1.45 1.19 3.3 2.4 2 +- 1 NS
0.8 2.2 2.9 0.7 1.5 1.1 0.78 0.9 2.9 1.7 1 +- 0.9 NS
0.73 0.05 0.06 0.069 0.097 0.043 0.063 0.058 0.058 0.055 0.06 + 0.01 N8
0.241 0.204 0.203 0.198 0.279 0.227 0.188 0.231 , 0.21 0.22 0.22 + 0.03 <0.04
38 50 34 42 41 +- 7 <0.0001
5.3 6 3.9 5.2 5+ 1 <0.001
4.9 5.6 3 4 4+1 <0.0001
0.082 0.085 0.087 0.073 0.08 + 0.01 <0.005
0,219 0.231 0.19 0.193 0.21 +- 0.02 <0.05
62 72 72 66 80 61 36 84 65+_15 <0.0001
9.7 10.6 ->15 >__15 _>15 10.5 ->15 11.3 13+2 <0.0001
8.1 8.9 ->12 ->12 ->12 9.5 8 10 10+_1 <0.0001
0.064 0.097 0.098 0.107 0.091 0.076 0.065 0.088 0.084+-0.02 <0.003
0.186 0.266 0.198 0.23 0.179
0.197 0.135 0.17 0.19+-0.04 <0.01
The pressure is measured in mm Hg; the resistance in Wood Units • M 2. Doppler parameters are measured in sec, meter, or see/meter. Findings denoted c are corrected for heart rate. AcT, acceleration time; N/A, not available; NS, not significant; PADP,pulmonary artery diastolic pressure; PAMP, pulmonary artery mean pressure; PAR, pulmonary arteriolar resistance; PASP,pulmonary artery systolic pressure; RVET, right ventricular ejection time; RVPEP,right ventricular pre-ejection period; TPR, total pulmonary vascular resistance; VT/', velocity time integral.
Doppler Echocardiography D o p p l e r echocardiographic m e a s u r e m c n t s wcre o b t a i n e d within 6 h o u r s o f the time o f cardiac cathcterization using a commercially available machine (Toshiba m o d e l S S H 1 6 0 A ; Toshiba America Medical Systems, Inc., Carrolton, Tex.). O n e 28-year-old patient, w h o h a d a vcntricular scptal defect, E i s e n m e n g e r syndrome, a n d pulm o n a r y vascular resistance >12 W o o d units • M 2, under-
w e n t the echocardiographic evaluation 1 week after the cardiac catheterization. Simultaneous electrocardiogram tracing a n d Doppler echocardiographic m e a s u r e m e n t s were o b t a i n e d at a recording speed of 100 m m / s e c o n d in 25 patients (8 patients were r e c o r d e d at 50 m m / s e c o n d ) . U s i n g a S M H z or a 3.5 M H z phased array transducer to acquire the best image a n d D o p p l e r signal, the left parasternal s h o r t axis view was used. A pulsed wave D o p p -
Journal of the American Society of Echocardiography Volume 9 Number 6
RVETc
E b e i d et al.
VTI
VTIc
AcT
0.33 0.34 0.38 0.32 0.31 0.34 0.37 0.33 0.38 0.31 0.31 0.34 + 0.03
0.18 0.19 0.2 0.18 0.19 0.18 0.28 0.17 0.31 0,26 0.21 0.21 + 0.05
0.21 0.25 0.26 0.24 0,22 0.26 0.33 0.26 0.41 0.43 0.31 0.28 -+ 0.07
0.138 0.091 0.145 N/A 0.113 0.105 0.143 N/A 0.125 0.044 0.061 0.1 + 0.04
0.37 0.35 0.32 0.32 0.36 0.35 0,3 0.34 0.32 0.33 0.34 + 0.02 NS
0.34 0.2 0.27 0.35 0.58 0.33 0.22 0.34 0.16 0.36 0.29 -+ 0,12 <0.02
0.53 0.34 0.43 0.56 0.76 0.5 0.35 0.49 0.24 0.54 0.45 + 0.144 <0.002
0.33 0.34 0.22 0.27 0,29 + 0.06 <0.05
0.15 0.21 0.28 0.15 0.19 + 0.06 NS
0.3 0.32 0.24 0.29 0.24 0.28 0.21 0.26 0.27 + 0.04 <0.0005
0.14 0.16 0.16 0.14 0.13 0.13 0.08 0.15 0,133 + 0.03 <0.001
AT/ET
RVPEP/ET
RVPEP/VTI
Heart Rate
0.16 0.119 0.187 N/A 0.13 0.153 0,167 N/A 0.165 0.07 0.091 0.132 + 0.04
0.49 0.35 0.49 N/A 0.42 0.45 0.45 N/A 0.44 0.23 0.29 0.39 + 0.09
0.25 0.23 0.22 0.3 0.26 0.17 0.22 0.26 0.22 0.28 0.33 0.26 + 0.04
0.39 0.32 0.32 0.4 0.36 0.22 0.25 0.33 0.2 0.21 0.33 0.30 + 0.07
81 103 100 106 80 126 82 140 105 158 132
N/A 0.065 0.069 0.078 N/A 0.075 0.064 N/A 0.061 0.073 0.07 + 0.006 <0.02
N/A 0.11 0.109 0.122 N/A 0.114 0.103 N/A 0.094 0.11 0.11 + 0.09 NS
N/A 0.32 0.34 0.39 N/A 0.33 0.34 N/A 0.29 0.34 0.33 + 0,03 NS
0.3 0.25 0.3 0.35 0.35 0.19 0.34 0.25 0.28 0.25 0.28 + 0.05 NS
0.21 0.25 0.22 0.2 0.17 0.13 0.29 0.17 0.37 0.15 0.21 -+ 0.07 <0.02
146 172 150 148 103 138 153 125 137 135
0.23 0.31 0.31 0.22 0.26 + 0.05 NS
0.064 0.043 0.074 0.061 0.06 + 0.013 <0.05
0,096 0.063 0.083 0.09 0.08 + 0.014 <0.03
0.29 0.2 0.38 0.33 0.29 + 0.08 NS
0.36 0.47 0.45 0.39 0.46 + 0.05 <0.0001
0,54 0.41 0.31 0.49 0.43 _-+0.1 <0.02
137 129 74 130
0.21 0.19 0.2 0.18 0.17 0.19 0.12 0.22 0.18 + 0.03 <0.002
0.035 N/A 0.073 0.065 0.05 0.062 0,084 0.052 0.06 + 0.02 <0.01
0.052 N/A 0.09 0.079 0.067 0.089 0.128 0.078 0.08 + 0.02 <0.01
0.18 N/A 0.38 0.27 0.28 0.31 0.62 0.31 0.32 + 0.14 NS
0.25 0.36 0.49 0.47 0.51 0,39 0.48 0.52 0,42 _+0.09 <0.0001
0.48 0.61 0.61 0.76 0.7 0.58 0.84 0.6 0.64 + 0.11 <0.0001
132 85 93 92 104 125 137 133
ler sample v o l u m e was positioned u n d e r two-dimensional echocardiographic guidance distal to the p u l m o n a r y leaflets in the middle o f the main p u l m o n a r y artery. Care was taken to p r o d u c e clean waveforms depicting an a b r u p t waveform deflection at the o n s e t o f the flow, a systolic waveform with discernible peak, a n d crisp r e t u r n o f the waveform to baseline at the e n d o f flow? ~ M e a s u r e m e n t s included the right ventricular pre-ejection period (RVPEP), r i g h t ventricular ejection time (RVET), acceleration time (ACT), velocity rime integral (VTI), a n d the ratios A c T / R V E T , R V P E P / E T , a n d R V P E P / V T I . T h e R V P E P was m e a s u r e d from the b e g i n n i n g o f the QRS wave to the o p e n i n g o f the p u l m o n a r y valve. T h e A c T was defined as the time from o n s e t o f flow to the peak velocity.
AcTc
825
T h e R V E T was m e a s u r e d from the o p e n i n g to the closure o f the p u l m o n a r y v a l v e Y 17 T h e V T I was o b t a i n e d in meters by digitizing the signal envelope with the aid o f a c o m p u t e r p r o g r a m ) 7-19 M e a s u r e m e n t s o f at least three cardiac cycles 2° were o b t a i n e d a n d averaged. D o p p l e r measurements were examined before a n d after correcting for h e a r t rate by dividing the m e a s u r e m e n t s with the square r o o t o f the preceding R to R i n t e r v a l ) 5"~9
Data Analyisis
Data o f the four groups are expressed as m e a n + SD and c o m p a r e d using S t u d e n t ' s ~test. A p value o f <0.05 was considered significant. Sensitivity and specificity were cal-
826
Journal of the American Society of Echocardiography November-December 1996
E b e i d et al.
>1,1
~"
~ /~/
//
~r(I / / ? / /// N/1 / // /ll7 ///
10
1/ i I ! /
y=-2.8+17.8x
/
r=.88
/ !
SEE=I.9 p<.O001
i1~1 / ~ 0 J 0
,
,
~
I
,
,
0.2
,
I
0,4
,
p , l , , ~ , , I 0.6
0.8
1
RVPEP/VTI
Figure 2 Linear regression relation between PAR values and RVPEP/VTI ratio in all the patients. Dotted lines indicate the 95% confidence limits. (RVPEP/VTI, right ventricular pre-ejection period/velocity time integral; PAR, pulmonary arteriolar resistance.)
culated as the percentage of patients in each group selected (or excluded) correctly by the Doppler echocardiographic parameter suggested. The relationship between Doppler echocardiographic and hemodynamic measurements also was evaluated by simple linear regression. In addition, this relationship was examined in the subgroups of patients without extracardiac shunts (patent ductus arteriosus) and those without left-sided obstructive lesions (mitral stenosis or coarctation of the aorta). Subsequently, multiple regression analysis was performed. A Doppler variable was considered to have an independent and important contribution if the regression coefficient was significantly different from zero. Variables would be deleted from the regression model if the relationship, adjusted for the number of predictors, remained at a significant and a high level (defined as R~ >.7).
tricular canal (n = 6). One patient had an atrioventticular canal and a patent dnctus arteriosus, 3 patients had a patent ductus arteriosus, I had ventricular septal defect with coarctation o f the aorta, 1 had total anomalous pulmonary venous return and an atrial septal defect, 2 had coarctation o f the aorta, 1 had coarctation o f the aorta with aortic stenosis, and 1 had mitral stenosis. The left atrial or pulmonary artery wedge pressure was not measured in 2 patients (numbers 6 and 8) whose total pulmonary resistance was <2.5 Wood units • M 2. These patients were excluded from the linear regression analysis o f the pulmonary arteriolar resistance.
HEMODYNAMIC FINDINGS RESULTS D e m o g r a p h i c Data Forty-nine patients underwent cardiac catheterization and concomitant echocardiographic evaluation during the study period. Thirty-three patients (16 male, 17 female) with congenital heart disease met the inclusion criteria. Their ages ranged from 10 days to 28 years (mean 1.4 years). Twenty-three patients had intracardiac shunts consisting ofventricular septal defect (n = 16), atrial septal defect (n = 1), and atrioven-
Group I included 11 patients with normal pulmonary artery pressure (mean systolic pressure o f 22 + 6 mm Hg) + and pulmonary arteriolar resistance of l - 0.7 Wood units. M 2 (Table 1). Group II included 10 patients with no significant change in pulmonary vascular resistance (mean pulmonary resistance of 1 + 0.9 Wood units • M 2) but with pulmonary artery hypertension 8 as a result o f increased pulmonary blood flow (mean pulmonary artery systolic pressure o f 48 4-- 13 mm H g and a mean pres-
Journal o f the American Society o f Echocardiography Volume 9 N u m b e r 6
Ebeid et al. 827
Table 2 Linearregression correlations between Doppler and hemodynamic findings PAR RVPEP/VTI RVPEP/ET RVPEP RVPEPc VTI VTIc RVET RVETc AcT AcTc AcT/ET *p < 0.0001, ]'p < 0.001, :~p < 0.05.
TPR
PASP
PAMP
r = 0.88*
r= 0.91"
r= 0.64
r= 0.68*
S E E = 1.9
S E = 1.9
SEE = 26
SEE = 16
r = 0.79*
r = 0.80*
r = 0.73*
r = 0.75*
SEE = 2.5
SEE = 2.8
SEE = 23
S E E = 15
r = 0.67*
r = 0.55~
r = 0.48z~
r = 0.51~
SEE = 3
SEE = 3.9
SEE = 28.9
SEE = 18.9
r = 0.67*
r = 0.65*
r = 0.66]
r = 0.68*
SEE = 3
SEE = 3.6
SEE = 25
SEE = 16
r = 0,58]"
r = 0.55].
r = 0.35~c
r = 0.37~
SEE = 3.4
SEE = 4
SEE = 30.9
SEE = 20.5
r = 0.61"
r = 0.56]"
N S [p = 0.52,
r = 0.37~
SEE = 3
SEE = 4
r = 0.34, SEE = 31]
SEE = 20.5
r = 0,46:~
r = 0.45:~
r = 0.49:~
r = 0.49:~
SEE = 3.7
SEE = 4.2
SEE = 28.7
SEE = 19.2
r = 0.64"
r = 0.71"
r = 0.56]"
r = 0.59]"
SEE = 3.2
SEE = 3.4
SEE = 27
S E E = 18
r = 0.43~
r = 0.41:[:
r = 0.62~
r = 0.6:~
S E E = 3.9
SEE = 4.5
SEE = 26.4
SEE = 17.7
r = 0.5].
r = 0.47~
r = 0.7*
r = 0.69*
SEE = 3.6
SEE = 4.4
SEE = 24
SEE = 16.3
NS
NS
NS
NS
SEE,standard
error o f estimate; remaining abbreviations as in Table 1.
sure of 31 _+8 mm Hg, both significantlyhigher than Group I; p < 0.0001). Group III included 4 patients with pulmonary arteriolar resistance of 4 + 1 Wood units • M z (p < 0.0002 versus either Group I or II), pulmonary artery systolic pressure of 63 + 11 mm Hg, and a mean pressure of 41 + 7 mm Hg (both significantly different from Group I but not different from Group II). Group IV (n = 8) included patients with pulmonary artery hypertension and markedly elevated pulmonary vascular resistance (mean l0 + 1 Wood units- M2).
spectively). The value was significantly lower in patients with pulmonary artery hypertension caused by increased pulmonary blood flow if there was no associated rise in the pulmonary vascular resistancc (Group II; p = 0.01). With the increase in pulmonary vascular resistance, the RVPEP/VTI value increased significantly in Groups III and IV.
Linear Regression Relationship Between Doppler and Hemodynamic Findings
Measurement of the RVPEP/ET was not different in the two groups with pulmonary arteriolar resistance <3 Wood Units M 2 (Groups I and II), even when the patients had pulmonary artery hypertension (Group II). The RVPEP/ET value was significantlyhigher in groups with elevated pulmonary vascular resistance (Groups III and IV).
The linear regression relationship between the Doppler and the hemodynamic results arc presented in Table 2. Among the different Doppler echocardiographic parameters tested, the ratio RVPEP/VTI had the strongest correlation with pulmonary arteriolar resistance (r= 0.88; p < 0.0001). The relationship is defined by the equation pulmonary arteriolar resistance (Wood Units • M 2) = -2.8 + 17.8 RVPEP/VTI (seconds/M). The SEE was the smallest, 1.9 Wood units • M 2 (Figure 2). This relationship remained strong after exclusion of patients with leftsided obstructive lesions (r = 0.89, SEE = 1.7 Wood units • M z, p < 0.0001 ) or extracardiac shunts (patent ductus arteriosus, r = 0.85, SEE = 1.9, p < 0.0001) (Figure 3).
Right Ventricular Pre-ejection Period/Velocity
Sensitivity and Specificity of RVPEP/VTI
Doppler Findings in the Four Groups The rcsults of the Doppler studies are presented in Table 1 and Figure 1.
Right Ventricular Pre-ejection Period/Ejection Time (RVPEP/ET)
Time Integral (RvPEP/VTI) The value of RVPEP/VTI was significantly different in all of the four groups (Figure 1). In Groups I and II, the value was low, less than 0.4 scconds/M (0.3 + 0.07 seconds/M and 0.21 _+0.07 see/M, re-
The sensitivity and specificity of RVPEP/VTI in the different groups ranged between 75% and 100%, with an overall accuracy between 91% and 97% (Table 3). With exclusion of patients with patent ductus arteriosus or left-sided obstructive lesions, the
Journal of the American Society of Echocardiography
828 Ebeid et al.
November-December1996
>_12 [A]
~ /t~/
,7// / p l // I/I I/I I ~/// ///"
/~?/
/ I/i II I/ Ix I///
,o 8
t~,
y=-3+lg.4x
!
6 I
,
i
1
0.2
,
i
i
I
~
i
i
0.4
I
0.6
i
i
i
I
0.8
RVPEP/VTI
.85
,
SEE=1.9 p <.oo01
I ~1 ~"~
~//~.~.1~ ~ i
r =
I
_.~1./ ~///
/
0
y=-2,4+16.2X
,~ /~//'/
p<.O001 I
~/// I / /~ ///~ /
4
r=.89 SEE=1,7
///
[B]
/
/ 10
>12
0 i
i
i
I
0.2
,
,
i
I
0.4
=
i
i
I
i
i
0.6
i
I
0.8
i
i
,
I
1
RVPEP/VTI
Figure 3 Linear regression relation between PAR values and RVPEP/VTI ratio after excluding patients with left-sided obstructive lesions (A) or patent ductus arteriosus (B). Dotted lines indicate the 95% confidence limits. Abbreviations as in Figure 2.
accuracy of this parameter remained high (between 89% and 100%).
DISCUSSION Right ventticular systolic time intervals measured by M-mode echocardiography have been used to assess the pulmonary artery hypertension with contradictory results. 4'16'21-23 M-mode echocardiography cannot incorporate the pulmonary blood flow in the measurement, thus the distinction between pulmonary artery hypertension on the basis of increased pulmonary blood flow as opposed to pulmonary vascular resistance using M-mode echocardiography is considered difficult and inaccurate, z2 Most Doppler echocardiographic studies addressing pulmonary artery hypertension did not determine whether this was caused by increased pulmonary blood flow or pulmonary vascular resistance. Cooper et a132 and Ritter et al. 24 concluded that the specific Doppler echocardiographic parameters tested were not accurate enough to evaluate the responsiveness of the pulmonary vascular bed to pulmonary vasodilators. The current study tests the linear relationship between the pulmonary vascular resistance and newly derived, as well as conventional, Doppler echocardiographic measurements. It also compares these Doppler echocardiographic findings in patients with pulmonary artery hypertension caused by increased
pulmonary blood flow as opposed to increased pulmonary vascular resistance. The decrease in acceleration t i m e a4-16,25-2s o r AcT/RVET 14'27 was proposed to be indicative of pulmonary artery hypertension or increased pulmonary vascular resistance. We, and others, 6'~2'29 found that the AcT value with or without heart rate correction, or the ratio AcT/RVET 4"6"12"13'15"29 was a weak predictor of pulmonary artery pressure or resistance (Table 2 and Figure 1). Although the AcT value decreased with increasing pulmonary pressure and resistance, it could not distinguish between patients with pulmonary hypertension caused by increased flow (Group II) as opposed to patients with pulmonary hypertension caused by increased resistance (Group III). The change was not reflective of the degree of pulmonary vascular disease (Groups III and IV). The AcT/ET value in patients with markedly elevated resistance (Group IV) approached normal values, similar to previous findings? °
The Right Ventricular Pre-ejection Period (RVPEP), Ejection Time (ET), and RVPEP/ET The RVPEP and RVPEP/ET, ~6'31 as determined by M-mode echocardiography, have been shown to be elevated and the RVET value to be decreased in patients with pulmonary artery hypertension.16a~ Selection of healthy subjects from a patient population with pulmonary artery hypertension using these parameters, with and without heart rate correction, was
Journal of the American Society of Echocardiography Volume 9 Number 6
E b e i d et al.
829
Table 3 Ability of RVPEP/VTI to predict PAR RVPEp/ArrI value
_<.4 sec./M
0.41-0.6 sec./M
>0.6 sec.M
Predictd PAR
<3 Wood.M2
3-7.5 Wood.Mz
->7.5 Wood.M2
Sensitivity Specificity Accuracy (all patients) Accuracy (after excluding leftsided obstructive lesions) Accuracy (after excluding extracardiac shunts)
%
N
%
N
%
N
100 92 97 96
(21/21) (11/12) (32/33) (27/28)
75 93 91 89
(3/4) (27/29) (30/33) (25/28)
75 100 94 93
(6/8) 28/25) Sl/S3) 26/28)
100
(29/29)
93
(27/29)
93
27/29)
The number in parentheses represents the actual number of patients. RVPEP/VTI,right ventricular pre-ejection period/velocity time integral; PAR,pulmonary arteriolar resistance.
reported to be poor, 23 with low sensitivity and specificity ranging from 31% to 58%.is The change in the RVPEP/ET value was noted only when the pulmonary hypertension was caused by increased resistance and not flow (Figure 1). This change was not reflective of the degree of pulmonary vascular disease (no difference between Groups III and IV). This study demonstrates that these parameters, as measured by Doppler, are unreliable to determine the cause or the degree of the pulmonary hypertension, with a large overlap between the different groups (Table 1 and Figure 1). Velocity Time Integral (VTI) To our knowlcdge, the relationship of the VTI t o the pulmonary vascular resistance has not been previously examined. Because the VTI is proportional to the forward flow in the pulmonary artery, I7-~9'32 we found an inverse linear relationship between the VTI and pulmonary vascular resistance. The VTI value increased in cases of pulmonary hypertension if the latter was associated with pulmonary arteriolar resistance <3 Wood units • M2; that is, if the pulmonary hypertension was caused by increased pulmonary blood flow (Group II). However, the VTI value decreased in patients with pulmonary hypertension if the latter Was the result of increased pulmonary resistance (Table 1, Groups III and IV). In this study, a new concept to assess the pulmonary vascular resistance, namely the ratio RVPEP/VTI,is proposed. Among the different Doppler parameters tested, the RVPEP/VTI ratio has the strongest linear relationship with the pulmonary arteriolar resistance (Figure 2), with a correlation of 0.88 (p < 0.0001), and a small SEE (1.9 Wood units.M2). The RVPEP/VTI ratio proved to be a significant predictor of pulmonary vascular resistance (Table 4, Model 1) even when the RVPEP and VTI values were statistically controlled (Model 2). The ratio was able to dis-
criminate between patients with pulmonary artery hypertension on the basis of increased pulmonary blood flow (Group II) as opposed to increased pulmonary vascular resistance (Groups III and IV; Figure 1). The difference between patients with pulmonary resistance <3 Wood units • M 2 (Groups I and II) and those with pulmonary vascular resistance _>3 Wood Units • M 2 (Groups III and IV) is the highest with the least overlap (Figure 1 and Table 1). The accuracy of this ratio in selecting patients in the different groups is _>91% (Table 3). With the exclusion of patients with left-sided obstructive lesions (coarctation of the aorta or mitral stenosis), the relationship remains highly significant (r = 0.89, p < 0.0001, SEE = 1.7) (Table 3 and Figure 3A). The presence of extracardiac shunts such as patent ductus arteriosus can influence the measurement of the VTI. All of our patients who had patent ductus arteriosus had evidence of minimal shunting at the ductal level, detected by both echocardiography and catheterization data (three had pulmonary vascular disease with elevated pulmonary resistance at or near systemic levels, and one had a small patent ductus arteriosus in addition to the primary lesion of the atrioventricular canal defect). After exclusion of these patients, the relationship between the RVPEP/;VTI ratio and the pulmonary vascular resistance proved to be equally strong, with similar accuracy in selecting patients with and without elevated pulmonary vascular resistance (93% to 100%; Table 3), and with a highly significant linear regression relationship (Figure 3B). These findings were similar for total pulmonary resistance (Tables 1 and 2). Thus RVPEP/VTI was influenced by the change in either total or arteriolar resistance. Heart Rate Correction When a single Doppler parameter such as the RVPEP or RVET is used, the need for heart rate correction
830
Journal of the AmericanSocietyof Echocardiography November-December 1996
Ebeid et al.
Table 4
Multivariate analysis of determinants o f the pulmonary vascular resistance
Variable
Model 1 Interccpt RVPEP/VTI Model 2 Intercept RVPEP/VTI RVPEP VTI
Coefficient
-3 18.3
Standard
error
0.83 1.9
t value
SE
R2
2,1
0.75
-3.6 9.6
-<0.0011" <0.00001" 2
-7 17.7 49 3.5
2.3 4.9 38 7.5
-3 3.6 1.3 .47
p value
0.77 <_0.0053 _<0.0012" 0.2 0.64
The ratio RVPEP/VTI independently is an excellentdeterminant of the tot~ilpulmonary vascularresistance. *Statisticallysignificantvalues. Abbreviationsas in Table 1.
should be considered. Different formulas or nomograms have been used for that purpose in some studies ls'19'22 but not in o t h e r s . 12'1<2a It was demonstrated, however, that the heart rate correction is not needed when a ratio such as the RVPEP/ET is u s e d . ls'21 The VTI value is equal to the product of the RVET and the mean velocity, ~8'19 and no heart rate correction is needed for the latter, thus by using the ratio RVPEP/VTI the need for heart rate correction, with its controversy, 18 is eliminated. Study Limitations In this study the number of patients in Groups III and IV is relatively small. This is expected because intervention is usually done before the patients reach this stage. The high statistical significance and the strong correlation of the measurement compensate for the lack of a large number of patients in the high resistance groups. Another limitation is the presence of a time difference o f a few hours between obtaining the hemodynamic and echocardiographic data. It is possible that some change took place in the resistance during that period. Given the strong correlation and significant differences among the groups, it is unlikely that this change is significant enough to affect the accuracy of this measurement. In addition, this parameter is not intended to provide an exact value for the pulmonary vascular resistance. A range of clinically useful values for the resistance, however, can be estimated (Figure 2) and the selection of patients with and without pulmonary vascular disease is possible (Table 1 and Figure 1), especially when used in conjunction with other available modalities.
CONCLUSION
The pre-ejection period corrected for stroke volume as reflected by the ratio RVPEP/VTI is a newly derived parameter that is superior to other conventional Doppler parameters in selecting patients with and without increased pulmonary vascular resistance.
We thank Dan Murphy, M D , at the Cleveland Clinic Foundation for reviewing the manuscript and rendering valuable advice and Diane McMullen for typing this manuscript.
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