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EXPERIMENTAL STUDY

Validation of a digital color Doppler flow measurement method for pulmonary regurgitant volumes and regurgitant fractions in an in vitro model and in a chronic animal model of postoperative repaired tetralogy of Fallot

Yoshiki Mori, MD^*, Timothy Irvine, MD^*, Michael Jones, MD, Rosemary A. Rusk, MD^*, Quynh Pham, MS^*, Antoinette Kenny, MD and David J. Sahn, MD, FACC^*

^* Oregon Health Sciences University, Portland, Oregon, USA
the Laboratory of Animal Medicine and Surgery, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
Freeman Hospital, Newcastle upon Tyne, United Kingdom

Manuscript received January 10, 1999; revised manuscript received August 29, 2000, accepted October 4, 2000.

Reprint requests and correspondence: Dr. Michael Jones, Laboratory of Animal Medicine and Surgery, National Heart, Lung and Blood Institute, 9000 Rockville Place, Building 14E, Room 1074A, Bethesda, Maryland 20892

	Abstract

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OBJECTIVES

The purpose of this study was to validate a digital color Doppler (DCD) automated cardiac flow measurement method for quantifying pulmonary regurgitation (PR) in an in vitro and a chronic animal model of the right ventricular outflow tract of postoperative tetralogy of Fallot (TOF).

BACKGROUND

There has been no reliable ultrasound method that can accurately quantitate PR.

METHODS

We developed an in vitro model of mild pulmonary stenosis and wide-open PR that mimics the patterns of flow seen in patients with postoperative TOF. Thirteen different forward and regurgitant stroke volumes (RSVs) across the noncircular shaped cross-sectional outflow tract flow area were estimated using the DCD method in two orthogonal planes. In six sheep with surgically created PR, 24 different hemodynamic states with PR strictly quantified by electromagnetic probes were also studied.

RESULTS

The RSVs and regurgitant fractions (RFs) obtained by the DCD method using average values from two orthogonal planes correlated well with reference values (RSV: r = 0.99, mean difference = 0.02 ± 0.39 ml/beat for in vitro model; r = 0.97, mean differences = 1.79 ± 1.84 ml/beat for animal model, RF: r = 0.98, mean difference = –1.10 ± 4.34% for in vitro model; r = 0.94, mean difference = 2.73 ± 6.75% for animal model). However, the DCD method using a single plane had limited accuracy for estimating pulmonary RFs and RSVs.

CONCLUSIONS

The DCD method using average values from two orthogonal planes provides accurate estimation of RSVs and RFs and should have clinical importance for serially quantifying PR in patients with postoperative TOF.

Abbreviations and Acronyms   ACM = automated cardiac flow measurement   DCD = digital color Doppler   EM = electromagnetic flow   FSV = forward stroke volume   MPA = main pulmonary artery   PR = pulmonary regurgitation   RF = regurgitant fraction   RSV = regurgitant stroke volume   RVOT = right ventricular outflow tract   TOF = tetralogy of Fallot

The noninvasive techniques that are presently used in quantifying PR include a pulsed Doppler method (1,4) and a velocity encoded magnetic resonance imaging (5). However, the quantitative pulsed Doppler method requires meticulous care in measuring the area of flow tract, and the pulsed Doppler method assumes a flat velocity profile during forward and reverse flow as well as a constant flow area, assumptions which are rarely correct (6–9). The high cost, long acquisition time and nonportability of magnetic resonance imaging instrumentation limit the use of this technique in clinical practice.

Recently, a technique has been developed for automated cardiac flow measurement (ACM) based on spatiotemporal integration of digital color Doppler (DCD) velocities, which provides accurate estimates of cardiac output in in vitro studies (10–13) and in clinical setting (14,15). We hypothesized that: 1) the DCD method could estimate the amount of PR and 2) the DCD cardiac output measurement method using average values from two orthogonal planes could improve the accuracy of quantifying PR. To test this hypothesis, we performed the DCD studies for forward and reversed flow using two orthogonal planes for determining pulmonary regurgitant volumes (RSVs) and regurgitant fractions (RFs) in an in vitro model mimicking postoperative TOF without peripheral pulmonary stenosis and in a chronic animal model.

	Methods

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In vitro flow model of the right ventricular outflow tract (RVOT) after repair of TOF.   Our repaired TOF model consisted of a rubber tube and a more compliant latex tube 18-mm in diameter. The rubber tube and the compliant latex tube were modeled to simulate the RVOT and main pulmonary artery (MPA), respectively. At the outlet of the rubber tube, a restricting ring with a 10-mm inner diameter was inserted so as to produce mild stenosis mimicking a pulmonary annulus with no valve function. An external constrictor also was placed around the end of the rubber tube to alter its shape from circular to a more clinically relevant ovoid geometry. The diameter of major axis and minor axis of ovoid is about 21 mm and 15 mm, respectively (Fig. 1). A solution of water mixed with 1% cornstarch was used as fluid medium to improve echocardiography reflectivity. The repaired TOF model was connected to a computer controlled programmable pulsatile pump (UHDC flow system, Model PFS A-3-1-G-1, London, Ontario, Canada). A fixed pump rate of 50 beats/min was used. Five different sinusoidal waveforms were used to obtain different RFs. For each waveform, different forward and reversed stroke volumes were obtained by changing peak flow rate and the waveform program for the pump. Instantaneous forward and reversed flow were measured by an ultrasonic probe (Model 16 NB272, Transonic system Inc, Ithaca, New York) and T201-2-channel ultrasonic blood flow meter (Model T 106X, Transonic System Inc., Ithaca, New York) and were recorded at 25 mm/s on chart paper. The forward stroke volume (FSV) per beat and RSV per beat were obtained by planimetry of the flow signal recordings on the strip chart paper to yield as reference values. Regurgitant fraction was calculated as the ratio of the RSV per beat to the FSV per beat. Three consecutive cardiac cycles were measured and averaged. Thirteen different FSVs and RSVs were examined.

View larger version (27K): [in this window] [in a new window]   Figure 1 The repaired tetralogy of Fallot model used in this in vitro model. See details in text. MPA = main pulmonary artery; PA = pulmonary artery; RVOT = right ventricular outflow tract.

To obtain pulmonary RSV and RF, two electromagnetic flow (EM) probes (model EP455, Carolina Medical Electronics, Inc., King, North Carolina) were placed, one around the pulmonary artery just above the pulmonary valve and the second around the skeletonized ascending aorta distal to the coronary ostia and proximal to the brachiocephalic trunk. Both flow probes were connected to flow meters (model FM501, Carolina Medical Electronics) and interfaced to the physiological recorder (Gould ES 2000, Cleveland, Ohio). All hemodynamic data were recorded at a paper speeds of 250 mm/s. Four consecutive cardiac cycles were analyzed for each hemodynamic determination as describe elsewhere (16,17).

For determination of pulmonary and aortic flow volumes, the integrals of instantaneous pulmonary and aortic flows over time were determined by planimetry of the flow signal recordings. The problem of the zero baseline drift was managed as previously described (18) so that the baseline value for the pulmonary flow recordings was adjusted until the forward minus the reversed pulmonary flow volumes equaled the aortic forward flow volumes. The RF was calculated as diastolic, reverse pulmonary flow volume per minute divided by forward pulmonary flow volume per minute.

A total of 24 stable hemodynamic states were obtained in the six sheep by altering preload or afterload using blood transfusion, sodium nitroprusside and angiotensin II (Peptide Institute Inc., provided by Tanabe Seiyaku Co., Osaka, Japan).

Acquisition of two orthogonal planes.   Color Doppler imaging was performed with a Toshiba Power Vision SSA-380A (Toshiba Corp., Tokyo, Japan) equipped with software for ACM. The principle of the ACM as a DCD method is described in detail elsewhere (10,12–14,15). A 5MHz omniplane transesophageal probe was placed in a water bath adjacent to the RVOT portion of our model to image parallel to flow. Color Doppler image loops were obtained in the two orthogonal planes corresponding to major and minor axes of the RVOT lumen (Fig. 1 and 2). The transducer was located and fixed about 2.5 cm away from the "pulmonary annulus," and the central Doppler beam was oriented parallel to flow.

View larger version (60K): [in this window] [in a new window]   Figure 2 Examples of selected two-dimensional color Doppler images in the in vitro model. Image for measurement of forward stroke volume with flow coming towards the transducer in a horizontal plane corresponding to the major axis (top). Images for measurement of regurgitant stroke volume with flow going away from the transducer in a horizontal plane (middle) and in a paired orthogonal plane corresponding to the minor axis (bottom). The sampling rectangular box is below (or above) proximal to the flow convergence region for measuring the forward and regurgitant stroke volume. Note that the velocity profile of prestenotic flow is not flat, and the distance of velocity profile for regurgitant flow in the major axis is larger than it is in the minor axis.

View larger version (62K): [in this window] [in a new window]   Figure 3 Examples of selected two-dimensional color Doppler images in the animal model. Images for measurement of forward stroke volume with flow going away from the transducer in an oblique outflow view corresponding to the horizontal plane (top left) and in a long axis view corresponding to the paired orthogonal plane (bottom left). Images for measurement of regurgitant volume with flow coming towards the transducer in the oblique outflow view (top right) and in the long axis view (bottom right) at the same diastolic phase. Note that the distance of the velocity profile for the RV forward flow in the oblique outflow view is larger than it is in the long axis view. Although the diameter of velocity profile for the regurgitant flow is similar, the shape of the velocity profile is different between two planes. AO = aorta; PA = pulmonary artery; RVOT = right ventricular outflow tract.

Interobserver variability.   To evaluate the effect of interobserver variability on measurement of FSV and RSV, two investigators independently performed measurements on 10 randomly selected flow conditions in our in vitro model. The two independent investigators were blinded to the flow rates of the images selected or the reference flow meter data.

Statistical analysis.   Data are expressed as mean ± standard deviation. Correlation between the DCD computed data and reference data were assessed by simple and multiple linear regression analyses (19). Agreement between the DCD computed data and reference data was tested according to the Bland-Altman method (20). The DCD computed data were compared with the references using paired Student t test. For comparison of mean difference (DCD data-reference data) between three different planes, analysis of variance with Scheffé F test was used. A value of p < 0.05 was considered statistically significant.

	Results

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In vitro study.   Peak pressure gradients across the pulmonary annulus determined by continuous wave Doppler ranged from 10 to 25 mm Hg (average, 14 ± 6 mm Hg), and the pulmonary RFs obtained by flow meter covered the ranges of mild to severe regurgitation from 10% to 71% (average, 41 ± 19%).

Correlation and mean difference between the DCD method in two orthogonal planes and flow meter method for measuring FSVs, RSVs and RFs are shown in Table 1 and Figure 4. The simple regression analysis showed that the FSVs and RSVs derived by the DCD method in either plane and those using an average of two orthogonal planes correlated well with the references (Table 1). In the horizontal plane corresponding to the major axis, the DCD method overestimated the actual FSVs (mean degree of overestimation = 139 ± 12%, p < 0.0001) and RSVs (mean degree of overestimation = 129 ± 20%, p = 0.0005), but in the paired orthogonal plane corresponding to the minor axis, this method underestimated the actual FSVs (mean degree of underestimation = 68 ± 11%, p < 0.0001) and RSVs (mean degree of underestimation = 68 ± 14%, p = 0.0007). However, there was no significant difference in the FSVs and RSVs between the DCD computed data using the average of two orthogonal planes and reference data (p = 0.16 for the FSV and p = 0.84 for the RSV). As a result, these measurements of the pulmonary RFs by the DCD method agreed with the references using all implementation methods (the major, the minor axis and the average of two orthogonal planes) (Fig. 4, Table 1). None of the RFs obtained by three different implementations were significantly different from the references (p = 0.15 for the major axis, p = 0.72 for the minor axis and p = 0.84 for the average of two orthogonal planes), and the mean difference of RFs was also not different between three different planes (p = 0.43).

View larger version (26K): [in this window] [in a new window]   Figure 4 Regression (A) and agreement (B) between regurgitant fractions by the DCD method and those by the flow meter in an in vitro study. In the major axis (A1 and B1), in the minor axis (A2 and B2) and using the average values from two orthogonal planes (A3 and B3). DCD = digital color Doppler.

Animal study.   Peak velocities across the pulmonary annulus determined by continuous wave Doppler ranged from 0.6 to 3.1 m/s (average, 1.4 ± 0.6 m/s). One sheep had mild, but significant, pulmonary stenosis in which the peak pressure gradients across the pulmonary annulus determined by continuous wave Doppler ranged from 16 to 36 mm Hg (average, 31 ± 6 mm Hg). Pulmonary RFs obtained by the EM method were within clinically relevant ranges from 9.8% to 75% (average, 37 ± 18%). Heart rate ranged from 88 to 136 beats/min (average, 104 ± 12 beats/min).

Correlation and mean difference between the DCD method in two orthogonal planes and the EM method for measuring FSVs, RSVs and RFs are shown in Table 2 and Figure 5. Multiple regression analysis showed that the FSVs and RSVs derived by the DCD method in a single plane correlated with those obtained by the EM method (Table 2). In the oblique outflow view, the DCD method overestimated the actual FSVs (mean degree of overestimation = 148 ± 21%, p < 0.0001), but in the long axis view corresponding to the orthogonal plane, this method underestimated the actual FSVs (mean degree of underestimation = 74 ± 12%, p < 0.0001). The DCD method significantly overestimated the actual RSVs in either plane (mean degree of overestimation = 136 ± 64% for the oblique outflow view, p = 0.006 and mean degree of overestimation = 132 ± 66% for the long axis view, p = 0.04). As a result of these measurements, the RFs obtained by the DCD method using either single plane also correlated with reference data but with wide variability, especially in the long axis view (Fig. 5). In the oblique outflow view, the DCD method underestimated actual RFs (mean degree of underestimation = 90 ± 35%, p = 0.0009), but in the long axis view, it overestimated actual RFs (mean degree of overestimation = 191 ± 126%, p < 0.0001) (Table 2).

View larger version (28K): [in this window] [in a new window]   Figure 5 Regression (A) and agreement (B) between regurgitant fractions by the DCD method and references in an animal model. In the oblique outflow view (A1 and B1), in the long axis view (A2 and B2) and using average values from two orthogonal planes (A3 and B3). DCD = digital color Doppler; EM = electromagnetic flow.

Interobserver variability.   There was good agreement between the two independent observers’ determinations of RSVs (r = 0.98, p < 0.0001, mean absolute difference = 0.06 ± 0.71 ml/beat) and RFs (r = 0.93, p < 0.0001, mean absolute difference = 1.11 ± 5.59%) for the in vitro data.

	Discussion

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Advantages of a DCD method.   The DCD method we used has several advantages over the pulsed Doppler method for quantifying PR. First, since the area of flow is computed directly, it does not require a separate step and separate views to measure the size of vessel or the area of the flow tract, which is a major source of error in the pulsed Doppler method (6,7). The DCD method accounts for the dynamically changing vessel size and flow profile through frame by frame temporal integration during the systolic phase or diastolic phase of flow. We demonstrated that RSVs and RFs could be accurately estimated even in the presence of mild pulmonary stenosis by this method, although it was necessary to use two orthogonal planes in the case of noncircular geometry, such as in our model. Another advantage of this DCD method is that it is easy and quick to implement.

Advantages of the DCD method for calculating regurgitant volumes using the average of two orthogonal planes.   Although the DCD method does not assume either a flat flow profile or constant flow area, it does assume a circular shaped flow area and an axial symmetry of the spatial flow profile (10,12–14,15). Noncircular geometry may be present in the RVOT or MPA in postoperative patients with TOF as in our model. Our study demonstrated that the DCD method using the average of two orthogonal planes could mitigate the limitations of assuming axial symmetry of flow area and velocity profile, providing accurate estimation of pulmonary RSVs and RFs. In our in vitro model, the DCD method using a single plane overestimated the actual FSVs and RSVs, and the paired orthogonal plane underestimated them. As a result, the DCD method that used the average of two orthogonal planes estimated more accurately the actual FSVs and RSVs than it did by using a single plane. In our animal model, the DCD method using a single plane corresponding to the oblique outflow view overestimated FSVs, and the paired orthogonal plane corresponding to the long axis view underestimated them. Both single planes (oblique outflow view and long axis view) methods overestimated the actual RSVs. As a result, the DCD method using the average of two orthogonal planes yielded a better estimate of the actual FSVs, RSV and RFs than it did using the single plane, although it slightly overestimated the actual FSVs and RSVs. In our in vitro model, the shape of the cross-sectional flow area of the MPA was ovoid, and the spatial velocity distribution of the regurgitant flow in the ovoid flow area was almost uniform with the regurgitant orifice located in the center of the tube mimicking the pulmonary annulus. In fact, although the diameters were different, the shape of velocity profiles of regurgitant flow was almost similar in two orthogonal planes in our in vitro model (Fig. 2). In contrast, in our animal model, the cross-sectional flow area of the MPA was different from that in the in vitro model: near circular as opposed to ovoid. The spatial velocity distribution of the regurgitant flow, however, was different in the in vivo model both as a result of variable orifice position and MPA curvature. The diameters of the velocity profiles of the regurgitant flow were similar in the oblique outflow view and the long axis view at the same phase of diastole, but the shapes of the velocity profiles were different (Fig. 3). In addition, although the shapes of the cross-sectional flow area of the RVOT and MPA were the same in our vitro model, they differed substantially in our animal model (Fig. 3) and would probably differ substantially in patients. In the in vivo study, the reason for overestimation in RSVs obtained by either single plane, and in RSVs and FSVs obtained by the average of two orthogonal planes, may be related to the difficulty in obtaining exact orthogonal planes and, in particular, in not identifying the actual minor axis. Recently, in preliminary studies, we have demonstrated that the three-dimensional DCD method without geometric assumption so as to calculate the flow volumes should be more objective and less susceptible to error (21).

Study limitations.   Some patients with repaired TOF may have peripheral pulmonary stenosis, not simulated in this study. In vitro and clinical studies have shown the effect of color gain settings, wall filters, frame rates and pulse repetition frequency on any color Doppler method (10,12–14,15). In clinical settings, it may not always be possible to have the high quality images we had, and it may be difficult to image parallel to flow as we did in our in vitro model. The DCD algorithm as implemented is relatively tolerant of mild degrees of misalignment of the Doppler beam orientation with flow direction (14). Fortunately, the angle between forward and regurgitant flow direction in the RVOT and Doppler beam orientation can be minimized by appropriate transducer position from the oblique outflow view (subcostal or parasternal) or long axis view of RVOT in patients.

Conclusions.   Our study has demonstrated in our models of postoperative TOF that the DCD method is potentially clinically useful for quantifying pulmonary RSVs and RFs.

	Acknowledgments

 
The authors thank Judy Schultheis for her assistance with the preparation of the manuscript.

	References

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