Ultrasound in Med. & Biol., Vol. 46, No. 10, pp. 27112716, 2020
Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved.
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https://doi.org/10.1016/j.ultrasmedbio.2020.06.019

 Original Contribution
FEASIBILITY OF NON-INVASIVE PULSE PRESSURE MEASUREMENT USING THE
PHASED-TRACKING METHODTAGEDPSHUSAKU KOBORI,* JUN MUROTSUKI,y SHIMPEI WATANABE,z HIDEYUKI HASEGAWA,x HIROSHI KANAI,{NOBUO YAEGASHI,* and MASATOSHI SAITO*TAGEDNE* Department of Obstetrics and Gynecology, Tohoku University, Sendai, Miyagi, Japan; y Department of Maternal and Fetal
Medicine, Tohoku University Graduate School of Medicine, Miyagi Children’s Hospital, Sendai, Miyagi, Japan; z Department ofPediatrics, Tohoku University, Sendai, Miyagi, Japan; x Graduate School of Science and Engineering, Toyama University, Toyama,
Japan; and { Department of Electronic Engineering, Tohoku University Graduate School of Engineering, Sendai, Miyagi, Japan(Received 25 June 2019; revised 25 June 2020; in final from 26 June 2020)

Abstract—Phased tracking (PT) is a high-precision ultrasonic technology that enables measurements of pulsepressure (PP). The aim of this study was to verify the accuracy of estimated PP using PT. Estimated PPs werecompared with measured PPs in three sheep fetuses that were connected to an artificial placenta system. Similarly, estimated and measured PPs of 30 human neonates were compared. PP was calculated using the WaterHammer equation (PP = r £ PWV (pulse wave velocity) £ DU). PWV was estimated by measuring the transit
times of pulse waves at two sites along the aorta using the PT method, and DU was obtained by subtracting enddiastolic velocity from peak systolic velocity. The correlation between the estimated and measured PPs of the
sheep fetuses was strong (r = 0.95, p ˂ 0.01), as was the case with the human neonates (r = 0.88, p ˂ 0.05). It can beconcluded from the results of this study that PT may be a non-invasive alternative method used to predict PP.
(E-mail: masa_saito_lizard@yahoo.co.jp) © 2020 World Federation for Ultrasound in Medicine & Biology. All
rights reserved.
Key Words: Ultrasound, Sheep, Fetal, Neonate.

be 20 mm (Struijk et al. 2013). However, the issue
remains that regardless of the method used, it is difficult
to capture small changes in fetal blood vessel walls.
Strujik et al. (2013) previously attempted to measure fetal pulse pressure (PP) using the echo tracking
method. The basic principles of echo tracking technology include first determining the echo radiofrequency(RF) signals of the vessel wall, which contain both theamplitude and original phase information, and then automatically tracking vessel wall movement via the phasetrajectory tracking method. However, this method istechnically limited in measuring the movement of fetal
blood vessels, and therefore, the PP values that are
obtained may vary. Kanai et al. (1996, 1997) developed
a different ultrasonic tracking system, called the phasedtracking (PT) method, which can accurately trace finemovements with a significantly high spatial resolution of
0.5 mm. Miyashita et al. (2015) reported that this PT
method more accurately monitored fetal blood vessels
and measurement of fetal PP. However, in previous studies (Struijk et al. 2013; Miyashita et al. 2015), no attempt

INTRODUCTION
Through measurement of fetal blood pressure (BP), it
becomes possible to better understand the condition of
the pathologic fetus in more detail. However, at present,
it is not possible to measure fetal BP non-invasively.
Additionally, because fetal blood vessels are small, it
may not be possible to accurately monitor the movementof fetal blood vessels through conventional ultrasonography. A previous study revealed that the diameter of theaorta in human fetuses at 2040 wk of gestation
changed by approximately 300500 mm depending on
the pressure exerted by the pulse waves (Miyashita et al.
2015). To determine the pulse wave velocity (PWV)
accurately, the transition of the fetal blood vessel wall
must be measured with an accuracy of a few micrometers. The distance resolution (5 MHz) of the M-mode
used in obstetrics is approximately 300 mm. The distanceresolution of the echo tracking method has been found to
Address correspondence to: Masatoshi Saito, Department of
Obstetrics and Gynecology, Tohoku University, Sendai, Miyagi 9808574, Japan. E-mail: masa_saito_lizard@yahoo.co.jp

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was made to compare the measured fetal PP values withthe values estimated using the PT method, and thus, theaccuracy of the PT method remains uncertain.
The objective of this study was to evaluate the accuracy of the PT method in measuring sheep fetal PP
through comparisons of measured versus estimated PP
values in sheep fetuses and human neonates.
METHODS
Accuracy of the PT method in sheep fetus
All procedures involving animals were approved by
the Animal Care and Use Committee of the Tohoku University School of Medicine (Sendai, Japan). Suffolk
ewes (n = 5, term at 147 d) underwent laparotomy at gestational days 90 and 137 under artificial ventilation andanesthesia with 1.5% isoflurane. Sheep fetuses born at
137 d were considered almost term fetuses, while thoseborn at 90 d are preterm. We examined whether the PP
measurement method using ultrasound is valid for bothterm and preterm sheep fetuses. A polyvinyl cannula (8Fr, Duraflo II, Edwards Lifesciences, Irvine, CA, USA)was inserted into the two umbilical arteries of each sheep
fetus delivered from the ewes, while a second polyvinyl
cannula (12 Fr, Argyle Trocar catheter; Covidien, Dublin, Ireland) was inserted into the umbilical vein. The
cannulas were connected to an artificial placenta (AP)system (Miura et al. 2016). As illustrated in Figure 1, theAP system consists of two outflow tubes: a flow tube andmembranous oxygenator. Appropriate oxygenation is
supplied through the membranous oxygenator. The AP
system uses the fetal heart pump to circulate the blood in
the tubes. A catheter was inserted into the internal
carotid artery of the sheep fetuses to measure central
arterial pressure. In addition, a superior vena cava catheter was inserted into the internal jugular vein of the sheep
fetuses for central venous delivery of nutrition. The
sheep fetuses were placed in a bag containing artificial
amniotic fluid. Lipo-prostaglandin E1 was used to prevent closure of the ductus arteriosus. Non-invasive PP
measurements of the sheep fetuses were performed threetimes for a total of 10 min every 8 h until 72 h after introduction of the AP system. Afterward, the measured andestimated PP values were compared.
Accuracy of the PT method in human neonates
The human study protocol was approved by theinstitutional ethics committee. Measurements were performed after obtaining written informed consent fromthe participants at the Department of Maternal and Fetal
Medicine of Miyagi Children’s Hospital (Sendai, Japan).
Thirty normal neonates were enrolled in the study from
April 2017 to April 2018. No maternal complications
were observed. Non-invasive PP measurement by

Fig. 1. Layout of the AP system. The AP system consists of
two outflow tubes: an inflow tube and a membranous oxygenator. Two tubes were connected to the umbilical arteries, andone tube was connected to the umbilical vein. The AP systemused the fetal heart pump to circulate the blood in the tubes.
Appropriate oxygenation was supplied through the membranous oxygenator. Blood flowed through the two umbilicalarteries and two outflow tubes to the membranous oxygenator.
The blood was oxygenated in the membranous oxygenator andsent systemically through an inflow tube and an umbilical vein.
The SVC catheter was inserted into the internal jugular vein of
the sheep fetus for central venous delivery of nutrition.
AP = artificial placenta: SVC = superior vena cava; Ao = aorta;
UC = umbilical cord.

ultrasound was performed after giving milk to the newborn infants at postpartum hour 12. The median gestational age was 37.6 (range: 3639) wk. Ideally, acatheter should have been inserted into the inferior aortaof the newborn to measure the PP to compare with theaortic PP measured by the ultrasound. However, thecatheter is not usually inserted into the inferior aorta of anormal healthy newborn, in clinical practice, so in thiscase the PP was measured using ultrasound and wascompared with the PP measured with an oscillometricelectronic sphygmomanometer. A BP cuff was applied
to the left upper arm to measure PP. Estimated PP was
calculated by measuring PWV and blood flow velocity
at the descending aorta of the neonates. The measured
and estimated PP values were then compared.
Ultrasonic PT method and PP measurement
An ultrasonic beam scanned different directions at aframe rate of 500 Hz using the Prosound F75 PremierFeasibility of Noninvasive Pulse Pressure Measurements  S. KOBORI et al.

Ultrasound Processor (Hitachi-ALOKA, Tokyo, Japan)
with a 5-MHz convex array probe (Hitachi). The RF signals
from the beam were applied perpendicularly to the descending aorta at the diaphragm level. The RF signal of each scanline was captured for 24 s. The fine motions of the vessel
wall in each beam obtained from the RF signals were analyzed offline using PT. In conventional ultrasonographic
techniques, deviations of a point of interest that are smaller
than the wavelength cannot generally be detected because
they are measured based on the amplitude of the reflected
waves. For this reason, the minimum wavelength measured
by a probe (5 MHz) that is often used for obstetric examinations is said to be approximately 300 mm. The measurement
principle of the PT method is different from that of conventional methods. For example, in the PT approach, an ultrasonic pulse is transmitted from the ultrasound probe andreflected by the aortic wall with a slight movement. By thetime it returns to the probe, a phase delay has occurred in
the ultrasound pulse because of propagation length. By
detecting the phase difference between two ultrasonic pulsesthat are continuously transmitted and received, it is possible
to estimate the displacements of a point of interest that aresmaller than the wavelength with a distance measurement
precision of 0.5 mm (Ozawa et al. 2015).
Aortic PPs of the sheep fetuses and human newborns were estimated using the PWV and blood flow
velocity change (DU) of the descending aorta. All
motions of the proximal and distal borders of the lumenof the descending aorta in sheep fetuses and human newborns were analyzed at each point using the PT method.
PWV was estimated using measurements of the pulse
wave’s transit time at two sites along the aorta using the
PT method. The transit time of the pulse wave travelingfrom the proximal site to the distal site through the arterial wall was analyzed and defined as the peak-to-peakinterval in the systolic phase (Fig. 2). PWV was obtainedby dividing the distance between the two sites by thetransit time of the pulse waves. DU was measured withthe pulse Doppler method using the same ultrasonographic probe at the same level as the descending aorta.
The beam-to-flow angle of the ultrasound beam was kept
as low as possible (<30˚). RF signals and DU were tomeasured separately. DU is obtained by subtracting enddiastolic velocity from peak systolic velocity. The sample volume was set to 2 mm to measure blood flow andthe sample gate, which is located just at the center of theblood vessel. According to the WaterHammer
equation (Gary 2015), the relationship between thechanges in pressure DP and velocity DU is obtained asPPðDP ÞðPaÞ ¼ r g=cm3  PWVðm=sÞ  DU ðm=sÞ
where r is blood density, and DU is the blood flow
velocity change. The equation assumes that blood

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Fig. 2. Ultrasonic measurement using the phased-tracking method
was performed at 90˚ on fetal blood vessels. The RF signals were
captured simultaneously from different directions. All motions of
the proximal (A point) and distal (B point) borders of the lumen of
the fetal descending aorta were analyzed using the phased-tracking
method at each point, and the time delay was measured. Pulse
wave velocity was obtained by dividing the distance between theanalyzed points by the time delay of the pulse wave.

density is a constant value (1.05 g/mL) that is independent of gestational age. PP is obtained by subtracting diastolic BP from systolic blood pressure. Similarly, DU is
obtained by subtracting end-diastolic velocity from peaksystolic velocity. The WaterHammer equation is a
result of applying the conservation of mass and momentum to the wave. It indicates that the pressure and velocity waveforms in the arteries are not independent of eachother as is often thought. In the context of the unidirectional wave, there is a simple linear relationship betweenr and U. In the WaterHammer formula, the unit ofpressure is expressed in Pascals, so it becomes necessary
to multiply the right side of the equation by 7.51 to convert to millimeters of mercury.
PP ðmmHg Þ¼ r  PWV  DU ðg=cm3  m=s  m=sÞ ¼ r  PWV  DU ð1000kg=m3  m2 =s2 Þ¼ r  PWV  DU ð1000N=m2 Þ ¼ r  PWV  DU ð1000PaÞ
¼ r  PWV  DU ð7:51mmHg Þ

For example, the DU of the descending aorta
obtained with the Doppler method is 0.8 (m/s), and thePWV obtained with the PT method is 4 (m/s). In thiscase, PP (mm Hg) is 1.05 £ 0.8 £ 4 £ 7.51 = 25.23.

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Volume 46, Number 10, 2020

All ultrasonic examinations were performed by one
examiner. The intra-rater reliability of the measured values of the sheep fetuses and human neonates was evaluated accordingly.
Statistical analysis
Reported values are presented as the group mean (range). Statistical analyses were performed using IBM
SPSS Software for Windows, Version 20.0 (IBM Corp.,
Armonk, NY, USA). To compare the two groups,
median differences were tested for significance using theMannWhitney U-test. Spearman’s correlation coefficient was used to determine the strength of the links
between the two data sets. Intra-rater reliability was
examined using intra-class correlation coefficient (ICC)
and was considered moderate to good if ICC was
between 0.50 and 0.75 and good to excellent if ICC was
between 0.75 and 1.00. A p value <0.05 was considered
to indicate statistical significance.

RESULTS
Accuracy of the PT method: Sheep fetus
Cardiac arrest occurred in two of the five fetuses(40%) involved in the study before the introduction of
the AP system. The estimated and measured PP valuesof sheep fetuses born on days 137 (n = 1) and 90 (n = 2)of the gestational period were compared. Of the sheep
fetuses born on day 90 of the gestational period, one
died within 8 h, and the other died within 36 h. The
sheep fetus born on day 137 of the gestational period
died in 32 h. An analysis of the non-invasive PP measurements was possible 60 of 89 times. Measurement failures were caused by disappearance of the descending
aorta from the screen because of a large fetal body movement. The correlation between the estimated and measured PP values was highly significant (y = 1.03x,
R = 0.95, p < 0.01) (Fig. 3). The measurement error of
the estimated PP was within §3 mm Hg for almost allmeasurements. The ICC (95% confidence interval [CI])was 0.987 (0.9770.992).
Accuracy of the PT method in human neonates
Non-invasive PP measurements were performed forall 30 neonates. There were no maternal complications.
Three newborns (3/30) were considered small for gestational age. The median birth weight was 2460 (range:
21203120) g. The correlation between the estimatedand measured PP values was strong (y = 0.86x, R = 0.88,
p < 0.05) (Fig. 4). The ICC (95% CI) was 0.928(0.8480.966). However, the estimated PP value wasslightly lower than the measured PP value.

Fig. 3. Correlation between the estimated and measured PP
values of sheep fetuses (term at 147 d) at gestational days 137(n = 1) and 90 (n = 2). Estimated PP was measured by ultrasound. Measured PP was measured with the catheter. It appears
that the PPs of 90-d fetuses were significantly lower than thePPs of the 137-d fetus. The PPs of the 137-d fetus ranged from2040 mm Hg over its 32-h lifetime, and this provided most of
the points on the graph. The others are clustered in in a 5+ mm
Hg range. PP = pulse pressure.

Fig. 4. Correlation between estimated and measured pulsepressure values of human fetuses.

DISCUSSION
The results from this study indicate that there was astrong correlation between the estimated and measured
PP values of sheep fetuses and human neonates. It was
confirmed that PP measurement using ultrasound washighly accurate. This study is the first of its kind as there
are currently no studies comparing measured and estimated PP values in sheep fetuses or neonates.
Struijik et al. (2013) previously measured the rate ofchange in the diameter of the descending aorta of the
fetus using the echo tracking method and calculated fetal
PP using the MoensKorteweg equation. However, it
was technically difficult to obtain the rate of change inFeasibility of Noninvasive Pulse Pressure Measurements  S. KOBORI et al.

the diameter of blood vessels using the echo tracking
method. Miyashita et al. (2015) measured the change indiameter of the descending aorta of the fetus using the
PT method and calculated the fetal PP value using the
MoensKorteweg equation. Although the accuracy ofthe measurement had improved, it was higher than theassumed PP value (Johnson et al. 2000). In previous
studies (Langewouters et al. 1984), when pressure wasapplied to the aorta, the aortic diameter exhibited no linear change in pressure. This may have been owing to theerror caused by diameter-dependent estimates from the
MoensKorteweg equation. The present study used theWaterHammer formula to calculate the PP value
wherein the PP value is calculated only from the PWV
and blood flow velocity of the descending aorta. In the
WaterHammer equation, the change in pressure as it
occurs when a water flow is blocked by a valve can becalculated from the change in blood flow velocity. Similarly to blood vessels, the change in BP that occurs when
the blood flow generated during systole is resisted by the
peripheral narrow blood vessels is calculated as
the change in blood flow velocity. According to theWaterHammer formula, the PP can be measured bysubtracting the lowest blood flow velocity from the highest blood flow velocity and multiplying that value by thedensity and change in PWV. Although the conventional
method may have involved more complex measurements
and calculations, the WaterHammer formula was simple and made it possible to measure the PP value in ashorter time (Struijk et al. 2013; Miyashita et al. 2015).
The PP values measured with ultrasound in this study
were considered more reproducible than those in previous reports doing the same.
It was concluded that the sheep model may be superior to the human neonate model because the arterial catheter is inserted into the aorta through the internal carotid
artery for BP measurements. Non-invasive PP measurements can be performed in conformity to the insertion site.
In this experiment, the estimated and measured PP valuesof the sheep fetuses were approximately the same. It has
been widely recognized that aortic BP more accuratelyreflects the hemodynamic status of adult patients thanperipheral BP and, thus, is used as the most reliable hemodynamic parameter (Gary 2015). The method proposed inthis study is a non-invasive technique used to measure thecentral BP of a fetus; therefore, it is considered that theresults obtained with this method most accurately reflect
the hemodynamic status of a fetus.
In this experiment, the measured PP value of the brachial artery of a newborn strongly correlated to the estimatedPP value of the descending aorta, but the estimated PP values were lower by approximately 4 mm Hg. It has beenargued that, in adults, BP is higher in the brachial artery thanin the central artery because of differences in vessel

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diameters (Learoyd and Taylor 1965). It can also be inferredthat the differences in our results between estimated andmeasured PP values were owing to the same cause. For
adults, there exists an algorithm to convert peripheral arterialpressure into central arterial pressure (Munir et al. 2008).
According to the algorithm, a value obtained by multiplying
the PP of the brachial artery by 0.79 can be approximated to
the PP of the central artery. In this study, the value obtainedby multiplying the PP of the brachial artery measured using
the oscillometric method by 0.79 strongly agreed with thevalue obtained by multiplying the PP of the central artery
measured using ultrasound (y = 1.06x, r = 0.89, p < 0.01).
In the study described here, we chose to conduct theexperiment on a sheep fetus because it had a circulation
pattern similar to that of a human fetus (Schrauben et al.
2019). Initially it was hypothesized that the accuracy of
the PT methods would depend largely on the size of the
fetal blood vessels, and therefore, the PPs of sheep
fetuses were measured on days 90 and 137 of the gestational period. The human newborns were selected on thebasis of whose blood vessels were small enough to illustrate that PP measurements can be applied to “fine andtiny” blood vessels of the human fetus.
Although there are two umbilical veins in a sheep
fetus, one umbilical vein was ligated to achieve the same
circulation as a human fetus in this study. Ligation of
one umbilical vein is thought to increase the internalpressure of the catheter in the artificial placenta. We
compared measured PPs with estimated PPs in the central artery, and we thought that ligation of the umbilicalvein did not affect this study.
Because the pulse Doppler method has an angle correction function, it is possible to measure from any angle.
Because the phase-tracking method does not have an angle
correction function, it is necessary to measure perpendicularly to the blood vessel. If measured obliquely, the delay
time calculated will be too large, and the PWV will bemeasured smaller than it actually is. Moreover, the wall displacement detected by ultrasound becomes small, and theaccuracy of measurement becomes low.
This method can be applied only to the normal cardiovascular system. For example, if there was a stenosis ofblood vessels or regurgitation in the human fetus, PP could
not be measured correctly. In this study, a sheep newborn
was connected to the AP rather than a sheep fetus. Afterdelivery of the sheep by cesarean section, it was possible toinsert a catheter into the carotid artery of the sheep, returnit into the uterus of the maternal sheep and perform ultrasound measurements from the abdominal wall of the maternal sheep. At first, this model was used to take ultrasoundmeasurements from the abdominal wall of the maternal
sheep, but it was not realistic to do so because the sheep
moved violently. Therefore, research was conducted using
sheep that were connected to an AP. It remains to be seen

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to what extent PP reflects fetal well-being. A multi-institutional joint research program is currently being conducted
to measure fetal PP in human fetuses for conditions such as
anemia, twin-to-twin transfusion syndrome and intrauterine
growth retardation in comparison with those in healthy
newborns. It is thought that the results of this joint research
will elucidate fetal pathologies of these fatal conditions in amore comprehensive way from the viewpoint of PP.
CONCLUSIONS
The results of this study indicate that there is astrong correlation between the estimated and measured
PPs of sheep fetuses. This was also the case with humanneonates. It was confirmed that PP measurement using
the ultrasound technique is highly accurate.
Conflict of interest disclosure—None of the authors have a conflict ofinterest.

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