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Cardiovascular Engineering and Technology, Vol. 13, No. 2, April 2022 ( 2021) pp. 279–290 ENGINEERING
https://doi.org/10.1007/s13239-021-00575-2 SOCIETY

Original Article

Simulating Radial Pressure Waveforms with a Mock Circulatory Flow

Loop to Characterize Hemodynamic Monitoring Systems
ANNA PACKY,1,2 GAVIN A. D’SOUZA,1 MASOUD FARAHMAND,1 LUKE HERBERTSON,1 and CHRISTOPHER G.
SCULLY 3
1
Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, U.S. Food and Drug
Administration, Silver Spring, MD, USA; 2University of Maryland, College Park, MD, USA; and 3Center for Devices and
Radiological Health, Office of Science and Engineering Laboratories, U.S. Food and Drug Administration, Bldg. 62 Rm 1129,
10903 New Hampshire Ave., Silver Spring, MD 20993, USA
(Received 22 February 2021; accepted 15 August 2021; published online 1 September 2021)

Associate Editor Igor Efimov oversaw the review of this article.

Abstract device testing applications to hemodynamic monitoring

Purpose—Mock circulatory loops (MCLs) can reproducibly
generate physiologically relevant pressures and flows for
cardiovascular device testing. These systems have been
extensively used to characterize the performance of thera-
peutic cardiac devices, but historically MCLs have had
limited use for assessing patient monitoring systems. Here,
we adapted an MCL to include peripheral components and
evaluated its utility for qualitative and quantitative benchtop
testing of hemodynamic monitoring devices.
Methods—An MCL was designed to simulate three physio-
logical hemodynamic states: normovolemia, cardiogenic
shock, and hyperdynamic circulation. The system was
assessed for stability in pressure and flow values over time,
repeatability, waveform morphology, and systemic-periph-
eral pressure relationships.
Results—For each condition, cardiac output was controlled
to the nearest 0.2 L/min, and flow rate and mean arterial
pressure remained stable and repeatable over a 60-s period
(n = 5, standard deviation of ± 0.1 L/min
and ± 0.84 mmHg, respectively). Transfer function analyses
showed that the systemic-peripheral relationships could be
adequately manipulated. The results from this MCL were
comparable to those from other published MCLs and
computational simulations. However, resolving current lim-
itations of the system would further improve its utility. Three
pulse contour analysis algorithms were applied to the
pressure and flow data from the MCL to demonstrate the
potential role of MCLs in characterizing hemodynamic
monitoring systems.
Conclusion—Overall, the development of robust analysis
methods in conjunction with modified MCLs can expand
Address correspondence to Christopher G. Scully, Center for
Devices and Radiological Health, Office of Science and Engineering
Laboratories, U.S. Food and Drug Administration, Bldg. 62 Rm
1129, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.
Electronic mail: Christopher.Scully@fda.hhs.gov
279
1869-408X/22/0400-0279/0  2021 This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply
systems. Properly validated MCLs can create a stable and
reproducible environment for testing patient monitoring
systems over their entire operating ranges prior to clinical
use.
Keywords—Hemodynamic monitoring devices, Cardiac de-
vice testing, Pulse contour analysis, Cardiovascular flow
circuit.
INTRODUCTION
Hemodynamic monitoring devices employ tech-
niques such as pulse contour analysis of radial artery
pressure waveforms to provide continuous information
about the hemodynamics of a patient in a minimally
invasive manner.3 Testing hemodynamic measure-
ments has generally involved evaluating device mea-
surements against more invasive reference
measurements such as triplicate thermodilution mea-
surements of cardiac output (CO) using central ca-
theters, which have their own uncertainties and
limitations31,7 and are declining in use, limiting patient
populations for testing.9,36 In addition, the use of
minimally invasive, continuous monitoring devices
often involves characterizing rapid changes in CO and
associated parameters to understand patient responses
to treatment, which may occur more quickly than the
time it takes to perform successive thermodilution
measurements.1 The differences in physiological
responses among patients makes it difficult to assess
280 PACKY et al.
device reproducibility and to compare diagnostic re-
sults between devices in a clinical setting.30
A mock circulatory loop (MCL) is a useful tool for
simulating cardiovascular hemodynamics on the
bench. Different pathophysiologic conditions, repre-
senting a range of disease states and patient popula-
tions, can be evaluated in a pre-clinical setting using an
MCL. Academic researchers and device manufacturers
have utilized MCLs for evaluating the hemodynamics
of implantable cardiovascular devices4,22 prior to
conducting more expensive animal studies and clinical
trials. Also, MCLs have been used for years to char-
acterize the fluid dynamics within therapeutic cardio-
vascular devices, including mechanical circulatory
support devices, heart valves, vascular conduits and
grafts, and catheters.10–27 Further, the efficacy of using
hemodynamic indices for diagnosing cardiovascular
diseases including vascular and valvular stenosis, an-
eurysms, and congenital heart defects has been evalu-
ated using MCLs.17–2 Experimental studies using
MCLs have led to the optimization of device designs
and the determination of appropriate performance
parameters over the full operating range of the device
in a well-controlled environment, which may not be
attainable through animal studies or clinical trials.
Thus, MCLs enable the evaluation of certain devices
earlier in their total product life cycle, leading to design
improvements and a better understanding of perfor-
mance and limitations before more costly clinical trials.
In recent years, MCLs have been modified to
incorporate peripheral vascular components for simu-
lating arterial pressure waveforms.42,14 Hemodynamic
monitoring devices can be connected to these circuits
and algorithms can be applied28 to estimate invasive,
central hemodynamic parameters from measured
pressure signals that are representative of in vivo radial
artery pressure. Therefore, it is critical to fully char-
acterize peripheral pressure waveforms within an MCL
and then correlate them to the cardiac hemodynamics
to demonstrate the utility of using MCLs for evaluat-
ing hemodynamic monitoring devices. The focus of
this work is to investigate if an MCL with peripheral
vascular components provides central-peripheral
pressure relationships across a range of hemodynamic
states that can then be used for generating represen-
tative radial pressure waveforms for hemodynamic
monitoring device testing. A controllable MCL can
help evaluate how well a medical device can monitor
changes in flow and pressure values. This can poten-
tially expand the role of MCLs in medical device
testing.
We describe an MCL with peripheral vascular
components and provide a characterization of the
central-peripheral pressure relationships. The MCL
offers many adjustable settings to achieve target car-
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diac hemodynamics and peripheral pressure wave-
forms. This allows us to set known changes in
hemodynamics under a range of physiologically rele-
vant conditions towards designing test methods for
evaluating how monitoring devices can track those
changes. We characterized our MCL to assess the
overall controllability across the desired functional
range. This process includes: (1) characterizing the
system to mimic the hemodynamics over a range of
clinically relevant cardiac states; (2) assessing the
repeatability and stability of the pressure and flow
values, as well as its ability to resolve small changes in
flow; and (3) qualitatively and quantitatively evaluat-
ing the arterial pressure waveform characteristics for
three hemodynamic states. We then applied three pulse
contour analysis algorithms for measuring CO to the
peripheral pressure waveforms to demonstrate the
potential for non-clinical characterization of hemody-
namic monitors during known changes in flow and
pressure using an MCL.
MATERIALS AND METHODS
Design of Mock Circulatory Loop
An MCL was first designed to create physiologic
pressure and flow waveforms. This system consists of
physical components that mimic the left ventricular
function, as well as the systemic and peripheral circu-
lations comprised of arteries and veins. A block dia-
gram of the MCL is shown in Fig. 1, and images of the
physical MCL are shown in the Supplementary
Information as Figure S1. A description of the sys-
temic loop is provided first followed by a description of
the peripheral loop.
Deionized water is circulated through the MCL
using a piston pump [ViVitro Labs, Victoria, BC,
Canada] that is fluid-coupled to a suspended silicone-
based mock ventricular sac. This causes the ventricular
sac to expand and contract during each beat of the
pump. The wall motion of the ventricular sac is con-
trolled by the inputted piston waveform, beat rate, and
amplitude of piston motion. The ventricular sac mo-
tion causes the artificial (bi-leaflet mechanical) heart
valves [St. Jude Medical Regent Valve, St. Jude Med-
ical, Inc., St. Paul, MN], to open and close, which al-
lows fluid to be ejected unidirectionally from the left
ventricle into the systemic part of the MCL during
systole. Source compliance, which simulates the left
ventricular viscoelastic behavior, was controlled by
manually adjusting the air volume in the source com-
pliance chamber using a syringe. The baseline com-
pliance level was defined as complete unloading of the
ventricular sac. Source compliance on the piston pump
 Simulating Radial Pressure Waveforms 281

FIGURE 1. Block diagram of the mock cardiovascular flow circuit. Arrows represent the flow direction of the systemic loop (grey)
and the peripheral loop (black). The atrial, ventricular, and venous chambers contain water for circulation through the system. All
other block units can be modified to simulate different types of flows. *Pressure measurement location. °Flow measurement
location.

was set before the test by adding 60 mL of air to the
working fluid which surrounds the outside of the
ventricular sac. Distal to the ventricle, fluid passes
through the aortic root and ascending aorta, and then
through tubing representative of the systemic circula-
tion, where the flow rate and aortic pressure are
recorded. Two air-filled (passive) compliance chambers
are connected to the aortic root and ascending aorta to
simulate the compliance of the respective vessels. A
third air-filled (passive) compliance chamber is placed
in-line in the mock descending aorta to simulate the
systemic vascular compliance. All the air-filled com-
pliance chambers were manually controlled using a
syringe for adjusting and setting the volume of air in
the chamber to simulate the compliance effect.
Mechanical resistance, simulating the systemic vascu-
lar resistance, is applied before the systemic loop re-
turns to the large venous reservoir using an
electronically activated ball valve. The ball valve en-
ables a set amount of mechanical resistance (measured
as the % occlusion of the tubing cross-section) to be
applied using a specific voltage value (0.0–10.0 Volts),
thus allowing for easy repeatability between experi-
ments and when re-setting the system. Fluid from the
large venous reservoir is then circulated back into the
left atrial chamber to complete the systemic loop.
The peripheral loop branches off the systemic loop
at the mock descending aorta proximal to the systemic
compliance chamber. Peripheral vascular compliance
is simulated using anatomically representative tubing
durometers, diameters, and lengths. Peripheral vascu-
lar resistance is simulated using a manually controlled
screw compressor tubing clamp. Repeatability with the
screw clamp between experiments and when re-setting
the system was achieved by approximating the distance
between the clamp jaws using a caliper. Although this
technique of manual adjustment is not highly accurate
in terms of repeatability, the set point for the screw
clamp was influenced primarily by the desired flow
split between the peripheral and systemic loops. Fluid
from the peripheral loop circulates back into the sys-
temic loop after the venous reservoir. Since the MCL is
an open-loop system consisting of a venous reservoir
and atrial chamber open to atmosphere (Figs. 1 and
S1), the transient pressure pulse in the proximal and
distal regions of the venous reservoir are similar. Thus,
attaching the peripheral loop after the venous reservoir
in the MCL (instead of the anatomically accurate
proximal position) is not expected to alter the patho-
physiologic hemodynamics of the peripheral circula-
tion. Supplementary Table S1 includes details of the
MCL components including tubing dimensions and
material properties.
Two flow sensors and four pressure transducers
were used in the MCL to monitor hemodynamics at
the locations identified in Fig. 1. Aortic and peripheral
loop flow rates were measured simultaneously using
ultrasound Doppler clamp-on flow sensors [ME11PXL
(aorta) and ME5PXL (peripheral), Transonic Systems,
Inc., Ithaca, NY] in the mock descending aorta and in
the representative radial artery, respectively. The two
flow sensors were coupled to a flow meter [T402,
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282 PACKY et al.
Transonic Systems, Inc., Ithaca, NY], which recorded
and displayed the instantaneous flow rate (in mL/min
or L/min). Left ventricular and left atrial pressures
were measured with disposable pressure transducers
[Utah Medical Products Inc., Midvale, Utah] and sent
to an amplifier module [Bus 21097, ViVitro Labs,
Victoria, BC, Canada]. The aortic and peripheral
pressures were measured using invasive pressure ca-
theters [SPR-350, Millar Instruments, Houston, TX]
coupled to an amplifier [PCU-2000 Pressure Control
Unit, Millar Instruments, Houston, TX]. The periph-
eral pressure measurement was made 0.83 m distal to
the aorta. All pressure and flow signals were acquired
using a data acquisition system [NI-9205, National
Instruments, Austin, TX] at a sampling rate of 1000
Hz, and an in-house software control program was
developed to modify, display, and analyze the hemo-
dynamic signals.
Experimental Design
The MCL was used to simulate three different
physiologic hemodynamic states for demonstrating the
versatility of the system: normovolemia, cardiogenic
shock, and hyperdynamic. The representative hemo-
dynamic states were based on average physiologic
ranges found in the literature.40,23 The nominal nor-
movolemic state was defined here to have a beat rate of
75 beats per minute (BPM), CO of 5 L/min, and mean
arterial pressure (MAP; defined as the time-averaged
aortic pressure) between 90 and 100 mmHg. The flow
rate was varied by ± 1 L/min from the nominal flow
for the normovolemic state. For the cardiogenic shock
state, beat rate was set to 90 BPM, CO to 3 ± 1 L/min,
and MAP was less than 70 mmHg.38 For the hyper-
dynamic state, beat rate was set to 120 BPM, CO to
8 ± 2 L/min, and MAP was between 65 and 70
mmHg.28–32
The system variables, including the peripheral and
systemic resistances, beat rate, and the gain applied to
the piston waveform, were adjusted to generate the
three hemodynamic states. The systemic vascular
resistance, set using the ball valve, was empirically
derived for each hemodynamic state. The peripheral
vascular resistance was set to achieve a peripheral loop
flow rate equating to approximately 3% of the total
CO to achieve a consistent target for adjusting
peripheral resistance in each state, based on an initial
baseline position of the screw clamp (i.e., distance
between clamp jaws) used in the peripheral loop. The
clamp position was kept constant as the flow rate was
varied for each hemodynamic state. This provided
peripheral flow rates during the normovolemic state
from ~120 to 170 mL/min, which is on the order of
measured radial artery volume flows.25,21
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Prior to testing, a verification step was performed to
ensure that the MCL could replicate a normal physi-
ologic condition, with pressures of 120/80 mmHg and
a CO of 5 L/min. Additionally, the fluid height levels
were set for each compliance chamber, and any resid-
ual air removed from the flow loop. To set each
hemodynamic state, the resistances, beat rate, piston
waveform, and gain were first adjusted to produce the
nominal flow setting for that state. Then, MAP was set
to the desired level by adjusting the systemic resistance
produced by the ball valve. Next, the gain on the pis-
ton pump was manually adjusted to achieve the target
CO. For each hemodynamic state, all measurements
were recorded at the nominal flow for 60 seconds,
followed by data acquisition over a range of flow rates.
Specifically, COs of ± 1 L/min of the nominal nor-
movolemic and cardiogenic shock conditions were
produced with steps of ± 0.2 L/min, and of ± 2 L/min
of the hyperdynamic state with steps of ± 0.4 L/min,
as shown in Fig. 2, by adjusting the gain of the piston
pump.
Data Analysis
Pressure and flow data were analyzed using MA-
TLAB [MathWorks, Natick, MA]. A low-pass filter
with a cut-off frequency of 50 Hz was applied to the
pressure and flow waveforms, which were subsequently
down-sampled to 128 Hz. Individual beat cycles were
detected using a previously reported pressure pulse
beat detector.35,16 All measurements were calculated
for each beat cycle and averaged across the 60-second
acquisition period. Stroke volume (SV) from the ven-
tricular sac was calculated using the average flow of a
60-second acquisition period divided by the beat rate.
Systemic vascular resistance (SVR) was calculated as
FIGURE 2. The flow rate was manipulated for each
hemodynamic state across a range of 61 L min21 from the
nominal flow rate (62 L min21 for the hyperdynamic state) in
0.2 L min21 increments (0.4 L min21 for the hyperdynamic
state). Each measurement step was captured for 60 seconds.
The first three steps were performed at the nominal, low, then
high flow rates done for each state. The total number of
completed steps for each state was 25.
 Simulating Radial Pressure Waveforms
the mean pressure drop from the aorta to the left at-
rium divided by CO.
Stability of the pressure and flow values over time
and repeatability of the MCL were determined for each
hemodynamic state. Stability was assessed by fitting a
linear line to the recorded pressure and flow values
over an acquisition period using the nominal level for
each hemodynamic state and assessing the slope. We
used the data from the 5 nominal positions for each
hemodynamic state (see Fig. 2) to evaluate the
repeatability by determining the variation in the pump
gain required to achieve the same flow rates and
pressures across the 5 replicate trials.
Discrete Fourier transforms were calculated for the
pressure signals following linear detrending to identify
the harmonics present in the generated waveforms. The
relationship between aortic and peripheral pressure
waveforms was evaluated by estimating the transfer
function using a Hamming window (length of 1024
samples with 512 samples overlapping). Transfer
function data are reported for each hemodynamic state
as mean ± standard deviation across each 60-second
acquisition period.
Characterizing Hemodynamic Monitoring Algorithms
Three pulse contour analysis algorithms were
applied to the radial pressure waveforms recorded for
each hemodynamic state: Liljestrand-Zander (CO =
k * (SBP  DBP)/(SBP + DBP) * HR), Pulse Pres-
sure (CO = k *R (SBP  DBP) * HR), and Systolic
Area (CO ¼ k  ABPðtÞdt  HR), where SBP and
DBP refer to systolic and diastolic blood pressure, HR
to heart rate, and ABP to arterial blood pressure
waveform.35 Each method requires a calibration value
‘k’. This was determined for each of the three states
from the initial settings by dividing the uncalibrated
value from each algorithm by the reference flow rate,
and then the algorithms were applied to measure CO at
each subsequent step in the experimental protocol de-
scribed above and compared to the reference systemic
flow measurement.
RESULTS
Hemodynamic States
Each hemodynamic state was studied over a range
of flow rates, pressures, and beat rates, Table 1. For
each hemodynamic state, controllable changes to flow
and pressure were produced by adjusting the piston
gain, as shown in Figure 3 for the normovolemic state.
Table 1 shows the full range of the system using the
lowest, nominal and highest settings of each hemody-
283
namic state. The difference between the overall mini-
mum and maximum (range) values of mean aortic and
peripheral pressures across experiments were 76 and 74
mmHg, respectively. The average SVR range was 1012
dyn s cm-5. The overall mean aortic flow rate range
across experiments (difference between maximum and
minimum flow rate achieved) was 7.9 L/min and the
mean peripheral flow rate range was 0.2 L/min. The
gain settings were set between 19.7% and 59.4% to
achieve the desired flow rates for the three hemody-
namic states, and the ball valve position was set at
62%, 64%, and 46% occlusion for the normovolemic,
cardiogenic shock, and hyperdynamic states, respec-
tively. The peripheral flow was approximately 3% of
the CO for each hemodynamic state (Table 1), and it
did not vary substantially across the flow rate steps
within each hemodynamic state (0.4, 0.5, and 0.4%
ratio differences for the normovolemic, cardiogenic
shock, and hyperdynamic states, respectively). The
large achievable flow rate range demonstrates the
ability to simulate many physiologic conditions with
this MCL.
Flow rate was adjusted through a 22-step protocol
of 0.2 L/min increments for each hemodynamic state
(0.4 L/min for the hyperdynamic state). The mean and
standard deviation of the CO at each step are shown in
Fig. 4. For cardiogenic shock, we observed increased
variability in the measured flow within each one-min-
ute step as the flow rate was increased (Fig. 4d). The
average coefficient of variation across steps for both
the hyperdynamic and cardiogenic shock states was
2.2%, as a percentage of the mean value. The nor-
movolemic state, which was the middle condition in
terms of CO, showed a lower average coefficient of
variation of 1.3%. The hyperdynamic state had a
higher standard deviation in beat-to-beat CO values at
each step compared to the normovolemic and cardio-
genic shock states (Fig. 4d). Overall, the maximum
coefficient of variation observed across any step for
any test condition was 5.4%, which occurred at the
highest flow rate of the cardiogenic shock state.
Stability of Pressure and Flow Values and Repeatability
The normovolemic and hyperdynamic states
showed a slight decrease in MAP of 1.8 mmHg and 0.6
mmHg, respectively, over the 60-second period. This
decrease is small in comparison to the absolute values
of the MAP (~94 and 60 mmHg, respectively, Tables 1
and 2) for those specific states. The MAP of the car-
diogenic shock state was stable over the test duration.
Mean flow rates were stable for each condition over
the 60-second duration.
The repeatability of the MCL at the different
hemodynamic states is characterized in Table 2. The
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284 PACKY et al.

TABLE 1. Range of the system capabilities for each hemodynamic state.

Normovolemic Cardiogenic shock Hyperdynamic

High Nominal Low High Nominal Low High Nominal Low

HR (BPM) 75 75 75 90 90 90 120 120 120

CO (L/min) 5.98 5.03 4.02 3.97 2.98 2.04 9.92 8.05 5.97
PF (L/min) 0.17 0.14 0.12 0.11 0.08 0.07 0.28 0.24 0.20
PTF (%) 2.79 2.83 2.92 2.69 2.80 3.20 2.86 2.95 3.29
SV (mL) 79.7 67.0 53.6 44.1 33.1 22.7 82.7 67.1 49.8
ABP (mmHg)
Diastolic 95.3 73.4 55.5 69.7 50.4 38.0 55.7 44.3 35.4
Mean 121.0 94.0 71.2 84.1 60.7 45.0 76.2 60.5 47.3
Systolic 152.2 119.3 90.4 103.2 75.3 56.1 108.1 84.7 65.9
PP 56.9 45.9 34.9 33.5 24.8 18.1 52.3 40.3 30.6
PBP (mmHg)
Diastolic 91.7 70.4 53.3 67.0 48.4 36.6 55.6 43.7 34.5
Mean 117.8 91.5 69.3 81.8 59.0 43.8 74.0 58.8 45.5
Systolic 156.3 122.8 93.1 108.1 78.5 58.1 113.0 88.6 67.8
PP 64.6 52.4 39.7 41.1 30.2 21.5 57.1 44.4 32.6
AtP (mmHg)
Mean 8.5 9.4 9.9 11.1 11.8 12.1 9.8 10.4 10.5
VBP (mmHg)
Mean  66.6 53.9 42.1 48.6 37.1 30.0 62.3 48.6 36.7
s
SVR dyncm 5 1505.0 1346.2 1219.1 1471.2 1312.6 1288.4 535.7 498.1 492.5

HR heart rate, CO cardiac output, PF peripheral flow, PTF percent of total flow through peripheral loop, SV stroke volume, ABP aortic blood
pressure, PP pulse pressure, PBP peripheral blood pressure, AtP atrial blood pressure, VBP ventricular blood pressure, SVR systemic
vascular resistance.

normovolemic and hyperdynamic flow rates varied by

roughly 1% for the 5 repeated trials. While the MCL is
repeatable and stable for the operating ranges tested
here, there may be increased variability in both CO
and MAP when the piston gain is further increased.
The gain values of the normovolemic and hyperdy-
namic states are nearly double that of the cardiogenic
shock state, resulting in higher standard deviations in
both CO and MAP for these two states. Repeatability
testing involved returning to the same state after
increasing and decreasing the flow. During the hyper-
dynamic trials, air was added to the compliance
chambers, which may have contributed to the vari-
ability among replicate tests.

FIGURE 3. 10 second segment traces for the peripheral (a)
pressure and (b) flow waveforms at the nominal, low, and high
flow settings for the normovolemic state. Each setting was
run for 60 seconds and the dashed vertical lines indicate that
the waveforms were truncated to only display the first 10
seconds for each setting.
standard deviation of the MAP across the 5 repeated
trials when flow was set at the nominal value (see
Fig. 2) was within 1 mmHg for each state, and the
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Waveform Assessment
The systemic and peripheral pressure waveforms
resembled physiologic arterial waveforms, which in-
clude characteristics such as a steep rise during systole
and a more prominent dicrotic notch in the peripheral
waveform (Fig. 5). The dicrotic notch is more evident
in the peripheral pressure waveforms in comparison to
the systemic pressure waveforms, especially for the
cardiogenic shock and hyperdynamic states. The pulse
morphology remains similar at each flow rate step for
each state, seen in both Figs. 3 and 5. Figure 6 shows
the Fourier transform of the peripheral pressure
 Simulating Radial Pressure Waveforms 285

FIGURE 4. Aortic flow rates at each step for the (a) normovolemic (b) cardiogenic shock, and (c) hyperdynamic states. (d) The
mean cardiac output (CO) compared to the standard deviation of the cardiac output in L/min for each hemodynamic state. NV
normovolemic, CS cardiogenic shock, HD hyperdynamic.

TABLE 2. Repeatability of the flow loop at each of the

hemodynamic states at the nominal flow level (Mean 6 changes for each of the three hemodynamic states
Standard Deviation). (Fig. 8). Pulse Pressure and Systolic Area methods
demonstrate reasonable tracking of changes in the
Repeatability
reference systemic flow with some undershoot/over-
Gain (%) CO (L/min) MAP (mmHg) shoot of changes that varies based on the hemody-
namic state, but the Liljestrand-Zander method is not
Normovolemic 48.1 ± 0.00 5.0 ± 0.07 93.98 ± 0.81
Cardiogenic shock 26.0 ± 0.00 3.0 ± 0.04 60.89 ± 0.15
able to track the changes.
Hyperdynamic 47.6 ± 0.88 8.1 ± 0.07 60.60 ± 0.84

DISCUSSION

waveforms at the initial nominal step for each hemo-
dynamic state. Information content decays at higher
frequencies, with a modulus of < 1 mmHg above 7
Hz.
The systemic-peripheral transfer functions show
increasing amplification at the peripheral location
from 0 to approximately 5 Hz, after which the ampli-
fication decreases (Fig. 7a). The amplitude varied
across hemodynamic states with the cardiogenic shock
state exhibiting the highest amplitude and the hyper-
dynamic state having the lowest amplitude at most
frequencies. The phase delay showed less variability
(Fig. 7b) compared to reported aortic-radial pressure
transfer functions, which showed phase delays up to -8
radians by 10 Hz.20
Application of Cardiac Output Algorithms
After calibration at the baseline step, the pulse
contour analysis algorithms generally tracked CO
Hemodynamic monitoring devices can continuously
measure critical cardiovascular parameters by analyz-
ing the peripheral pressure waveforms. However, it can
be challenging to collect adequate reference measure-
ments for repeatably and precisely evaluating these
parameters. It is also difficult to understand how dif-
ferent confounding factors affect the performance of
hemodynamic monitoring devices. Non-clinical test
methods can potentially provide repeatable conditions
for assessing safety and performance aspects of
hemodynamic monitoring devices that are difficult to
determine and isolate through clinical studies. MCLs
provide potential means for augmenting or reducing
the amount of invasive and expensive animal and
human testing that is often required for medical device
development. The focus of MCL development has
historically been for assessing cardiac devices such as
ventricular assist devices and heart valves27,37–11;
therefore, the modules necessary for modeling the ra-
dial arterial pressure waveforms are not included in
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FIGURE 5. Pressure waveforms for the hemodynamic states. The nominal waveform for each state is a solid black line, the low is
a dashed-dotted line, and the high is a dashed line. (a) Aortic pressure at normovolemic state, (b) peripheral pressure at
normovolemic state, (c) aortic pressure at cardiogenic shock state, (d) peripheral pressure at cardiogenic shock state, (e) aortic
pressure at hyperdynamic state, and (f) peripheral pressure at hyperdynamic state.

this generation of MCLs. Recently, researchers devel-
oped an MCL platform capable of generating radial
arterial waveforms.42 However, the ability of MCLs to
simulate radial arterial pressure remains limited. The
challenges include difficulties in achieving a realistic
transfer function between systemic arterial pressure
and radial pressure under various hemodynamic states
as well as achieving a framework capable of producing
a broad range of flow rates under different hemody-
namic conditions for assessing the performance of
hemodynamic monitoring systems. In this work, we
adapted an MCL that was previously used only for
cardiac device testing (e.g., ventricular assist devices,
heart valves) to include peripheral components. The
adapted MCL was used to generate and acquire
peripheral pressure waveforms to assess hemodynamic
monitoring devices under known conditions and set
changes to those conditions, something that cannot be
feasibly performed in clinical studies. Our results show
that the flow loop can produce a wide range of phys-
iologic conditions to simulate different clinical sce-
narios.
Pulse contour analysis uses a peripherally recorded
arterial pressure waveform to continuously estimate
hemodynamic parameters such as CO in real-time.
Advantages of these devices include their ability to
identify and monitor changes in CO that are indicative
of how a patient responds to therapy, or that estimate
responsiveness such as through dynamic indices
including stroke volume variation.44 These applica-
tions measure small changes in CO over short time
scales compared to traditional reference measure-
ments. In this respect, intermittent reference measure-
ments can offer only limited information about the
time-varying hemodynamic behavior. Non-clinical
testing tools such as MCLs have the potential to allow
us to better understand properties of monitoring sys-
tems such as the response to a known change of CO

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 Simulating Radial Pressure Waveforms
FIGURE 6. Frequency spectra of peripheral pressure
waveforms in the MCL for the (a) normovolemic, (b)
cardiogenic shock, and (c) hyperdynamic states.
over specified time-scales or the limit of resolution (i.e.,
minimum detectable change). Thus, in this study, we
tested the feasibility of generating and characterizing
different physiological waveforms on the bench using
an MCL.
We applied three different pulse contour analysis
algorithms to the recorded peripheral pressure data to
demonstrate how the MCL could be used for charac-
terizing pressure-derived CO measurement devices.
For this testing, the piston beat rate and systemic
resistance and compliance were kept constant so that
only the ability to track changes in flow rate was tested.
This is in contrast to pre-clinical animal or clinical
testing where it is not feasible to directly manipulate
only a single characteristic. Two of the approaches,
Pulse Pressure and Systolic Area, were able to track
changes in CO in the MCL for each of the three
hemodynamic states with some overshoot and
undershoot that varied between the different hemody-
namic states. The third approach, Liljestrand-Zander,
was not able to track flow changes in the MCL within
each hemodynamic state. The Liljestrand-Zander
287
FIGURE 7.. Systemic-peripheral pressure transfer functions
for the hemodynamic states, showing (a) amplitude and (b)
phase difference. Note: step 24 of the normovloemic state was
not included due to a synchronous recording error between
the pressure and flow measurements. NV normovolemic, CS
cardiogenic shock, HD hyperdynamic.
approach was developed considering non-linear arte-
rial compliance-pressure relationships, which the cur-
rent design of the MCL does not address. This may be
one reason for the lack of tracking performance in the
current study.34
While we presented an initial iteration of the MCL
here, additional optimization, refinement, and charac-
terization of the flow loop is needed to incorporate
such a loop into hemodynamic monitoring device
testing. Historically, MCLs have been used for char-
acterizing the hemodynamic performance of cardio-
vascular devices where indices such as pressure, flow
rate, velocity, and shear stress within the device are
evaluated under patient- and disease-specific condi-
tions. For hemodynamic monitoring device testing,
this type of characterization can be expanded to con-
sider not only the physiologic range, but also to
encompass the limits of resolution of the system and
the pressure waveform properties. Pulse contour
analysis devices estimate CO, a central flow measure-
ment, based on peripheral pressure waveforms.
Therefore, the flow loop should provide physiologi-
cally relevant aortic-peripheral pressure relationships
and pressure-flow relationships. We demonstrated
systemic-peripheral transfer functions from the MCL
similar up to ~6 Hz to aortic-radial transfer functions
in clinical reports.13 A lack of branching and associ-
ated wave reflections in both the aortic and peripheral
waveforms could explain why the current MCL setup
does not follow the trends of clinical and computa-
BIOMEDICAL
ENGINEERING
SOCIETY
288 PACKY et al.
FIGURE 8. Estimated cardiac output values from three pulse
contour analysis algorithms for the (a) normovolemic, (b)
cardiogenic shock, and (c) hyperdynamic conditions.
tional models past this point. This may be caused by an
insufficient representation of the human anatomy in
the MCL, including limited branching and viscoelastic
properties of the arteries, which could lead to damp-
ened pulse wave reflections and fewer higher frequency
components in the waveforms. Another study that
utilized an MCL42 defined a sophisticated representa-
tion of the radial pulse waveform based on the com-
parisons of early and late systolic pressure, as well as
the dicrotic notch location for the average middle-aged
person. While the analyses of the current MCL does
not specifically look at these factors, our analysis is
done using a larger range of factors, including a wide
range of hemodynamic parameters, morphology of the
waveforms, and relationships between systemic-pe-
ripheral pressures and flows.
While our results showed that our MCL could
simulate a wide range of physiologic conditions, was
relatively stable and repeatable, was controllable for
small changes in flow rate, and provided pressure
waveforms with realistic morphology, there are several
limitations to the study. One such limitation is the use
of deionized water as the test fluid to rapidly design
BIOMEDICAL
ENGINEERING
SOCIETY
our system. The MCL would better mimic the clinical
setting if a water-glycerin solution5 that more closely
mimics the viscosity of blood is used instead. A second
limitation is that while we could control the flow rate,
this needed to be done by manually adjusting a gain
knob, which limits the type of automated testing pro-
cedures that could be implemented. For example,
manual adjustments to the gain make it difficult to
have precise timing for evaluating temporal response
of hemodynamic monitoring systems. However, a
system which provides the flexibility of manipulating
the stroke volume directly is still advantageous over
animal or clinical testing, for which precise and
repeatable manipulations of pressures, flows, and
vascular properties (e.g., resistance) cannot be assured.
A third limitation is related to the mock aortic cham-
ber in our current design, which is anatomically inac-
curate causing a pressure drop of 10 mmHg due to the
presence of a 90-degree bend. For our study purposes,
we measured the aortic pressure at a location directly
distal to this bend. Future design iterations of the
MCL will need to include an anatomically accurate
mock aorta. A fourth limitation is the previous men-
tioned lack of non-linear relationship between arterial
compliance and pressure, which can affect the testing
of certain algorithms as shown in Fig. 8. These limi-
tations can be improved upon through future design
changes to the MCL. One limitation of MCLs, in
general, relates to the difficulty in replicating vascular
properties including compliance and resistance, and
manipulating them over time. While testing with
benchtop MCLs provides advantages such as having
the ability to reproducibly test extreme operating
conditions in a well-controlled environment, this type
of bench testing can be enhanced by coupling the
physical flow loops with computational models to
further incorporate physiologic changes.24,18
In summary, an MCL was developed and utilized to
generate a range of physiologic conditions represented
by three unique hemodynamic states. The MCL
hemodynamics were adjusted using 0.2 L/min incre-
ments to execute an experimental protocol which
accounts for subtle increases and decreases in CO. The
MCL generated consistent and repeatable results over
a 60-second period and multiple trials. Using a versa-
tile MCL, several hemodynamic measurements and
waveform characteristics compared favorably with
data published in the literature. We were able to apply
multiple pulse contour analysis algorithms to pressure
waveforms recorded from the MCL to compare the
estimated CO to reference flow values under known
conditions. Future improvements to the MCL would
allow for more comprehensive testing of these and
other hemodynamic states, while accounting for dif-
ferent patient populations and cardiac dysfunctions.
 Simulating Radial Pressure Waveforms 289
3
Overall, this initial study provides valuable insight Boisson, M., M. Poignard, B. Pontier, O. Mimoz, B. De-
towards development of MCLs as non-clinical testing baene, and D. Frasca. Cardiac output monitoring with
thermodilution pulse-contour analysis vs. non-invasive
tools for evaluating hemodynamic monitoring devices.
pulse-contour analysis. Anaesthesia. 74(6):735–740, 2019.
4
Broda, C., P. Smith, Y. Wang, O. Frazier, W. Dreyer, I.
Adachi, et al. Hemodynamic improvement with applica-
SUPPLEMENTARY INFORMATION tion of mechanical circulatory support in heart failure with
preserved ejection fraction in a mock circulation loop. J.
Heart Lung Transpl. 38(4):S373, 2019.
The online version contains supplementary material 5
Brookshier, K. A., and J. M. Tarbell. Evaluation of a
available at https://doi.org/10.1007/s13239-021-00575- transparent blood analog fluid: aqueous xanthan gum/
2. glycerin. Biorheology. 30(2):107–116, 1993. https://doi.org/
10.3233/bir-1993-30202.
6
Chang, T.-I., K.-H. Hsu, C.-W. Luo, J.-H. Yen, P.-C. Lu,
and C.-I. Chang. In vitro study of trileaflet polytetrafluo-
ACKNOWLEDGMENTS roethylene conduit and its valve-in-valve transformation.
The authors would like to acknowledge Dr. Sungtae Interact Cardiovasc Thorac Surg. 30(3):408–416, 2020. h
ttps://doi.org/10.1093/icvts/ivz274.
Shin for his work in developing the in-house software 7
Critchley, L. A., and J. A. Critchley. A meta-analysis of
for controlling the MCL. studies using bias and precision statistics to compare car-
diac output measurement techniques. J. Clin. Monit.
Comput. 15(2):85–91, 1999.
8
DISCLAIMER Della Rocca, G., M. G. Costa, P. Chiarandini, G. Bertossi,
M. Lugano, L. Pompei, et al. Arterial pulse cardiac output
The mention of commercial products, their sources, agreement with thermodilution in patients in hyperdy-
or their use in connection with material reported herein namic conditions. J. Cardiothorac. Vasc. Anesth.
22(5):681–687, 2008.
is not to be construed as either an actual or implied 9
Doshi, R., K. Patel, P. Patel, and P. M. Meraj. Trends in
endorsement of such products by the Department of the utilization and in-hospital mortality associated with
Health and Human Services. This article reflects the pulmonary artery catheter use for cardiogenic shock hos-
research conducted by the authors and should not be pitalizations. Indian Heart J. 70(Suppl 3):S496, 2018.
10
construed to represent FDA’s views, guidance, or D’Souza, G. A., R. K. Banerjee, and M. D. Taylor. Eval-
uation of pulmonary artery stenosis in congenital heart
policies. disease patients using functional diagnostic parameters: an
in vitro study. J Biomech. 81:58–67, 2018. https://doi.org/
10.1016/j.jbiomech.2018.09.014.
11
CONFLICT OF INTEREST Ferrari, G., C. De Lazzari, R. Mimmo, G. Tosti, D. Am-
brosi, and K. Gorczynska. A computer controlled mock
Anna Packy, Gavin D’Souza, Masoud Farahmand, circulatory system for mono-and biventricular assist device
Luke Herbertson, and Christopher Scully declare that testing. Int. J. Artif. Organs. 21(1):26–36, 1998.
12
they have no conflict of interest. Figliola, R. S., A. Giardini, T. Conover, T. A. Camp, G.
Biglino, J. Chiulli, et al. In vitro simulation and validation
DATA AVAILABILITY of the circulation with congenital heart defects. Prog
Pediatr Cardiol. 30(1–2):71–80, 2010. https://doi.org/10.10
Electronic data reported in this study will be made 16/j.ppedcard.2010.09.009.
13
available upon request. Gallagher, D., A. Adji, and M. F. O’Rourke. Validation of
the Transfer Function Technique for Generating Central
from Peripheral Upper Limb Pressure Waveform. Oxford:
CODE AVAILABILITY Oxford University Press, 2004.
14
Code used in this study will be made available upon Gehron, J., J. Zirbes, M. Bongert, S. Schäfer, M. Fiebich,
G. Krombach, et al. Development and validation of a life-
request. sized mock circulatory loop of the human circulation for
fluid-mechanical studies. Asaio J. 65(8):788–797, 2019.
15
REFERENCES Glynn, J., H. Song, B. Hull, S. Withers, J. Gelow, J. Mudd,
et al. The oregonheart total artificial heart: design and
1
Beurton, A., J.-L. Teboul, F. Gavelli, F. A. Gonzalez, V. performance on a mock circulatory loop. Artif Organs.
Girotto, L. Galarza, et al. The effects of passive leg raising 41(10):904–910, 2017. https://doi.org/10.1111/aor.12959.
16
may be detected by the plethysmographic oxygen satura- Goldberger, A. L., L. A. Amaral, L. Glass, J. M. Haus-
tion signal in critically ill patients. Crit. Care. 23(1):19, dorff, P. C. Ivanov, R. G. Mark, et al. PhysioBank,
2019. PhysioToolkit, and PhysioNet: components of a new
2
Biglino, G., A. Giardini, C. Baker, R. S. Figliola, T.-Y. research resource for complex physiologic signals. Circu-
Hsia, A. M. Taylor, et al. In vitro study of the Norwood lation. 101(23):e215–e220, 2000.
17
palliation: a patient-specific mock circulatory system. Gregory, S. D., J. P. Pauls, E. L. Wu, A. Stephens, U.
ASAIO J. 58(1):25–31, 2012. https://doi.org/10.1097/MA Steinseifer, G. Tansley, et al. An advanced mock circula-
T.0b013e3182396847. tion loop for in vitro cardiovascular device evaluation.

BIOMEDICAL
ENGINEERING
SOCIETY
290 PACKY et al.
Artif Organs. 44(6):E238–E250, 2020. https://doi.org/10.1
111/aor.13636.
18
Hang, T., A. Giardini, G. Biglino, T. Conover, and R. S.
Figliola. In vitro validation of a multiscale patient-specific
Norwood Palliation model. Asaio J. 62(3):317–324, 2016.
19
Jiang, X., S. R. Srinivasan, E. Urbina, and G. S. Berenson.
Hyperdynamic circulation and cardiovascular risk in chil-
dren and adolescents: the Bogalusa Heart Study. Circula-
tion. 91(4):1101–1106, 1995.
20
Karamanoglu, M., M. O’rourke, A. Avolio, and R. Kelly.
An analysis of the relationship between central aortic and
peripheral upper limb pressure waves in man. Eur. Heart J.
14(2):160–167, 1993.
21
Kim, S., J. Lee, W. Kim, J. Sun, M. Kwon, and H. Kil.
Evaluation of radial and ulnar blood flow after radial ar-
tery cannulation with 20-and 22-gauge cannulae using du-
plex Doppler ultrasound. Anaesthesia. 67(10):1138–1145,
2012.
22
Koenig, S. C., G. M. Pantalos, K. J. Gillars, D. L. Ewert,
K. N. Litwak, and S. W. Etoch. Hemodynamic and pres-
sure–volume responses to continuous and pulsatile ven-
tricular assist in an adult mock circulation. ASAIO J.
50(1):15–24, 2004.
23
Kroeker, E. J., and E. H. Wood. Comparison of simulta-
neously recorded central and peripheral arterial pressure
pulses during rest, exercise and tilted position in man. Circ.
Res. 3(6):623–632, 1955.
24
Kung, E., M. Farahmand, and A. Gupta. A hybrid
experimental-computational modeling framework for car-
diovascular device testing. J. Biomech. Eng. 141(5):051012,
2019.
25
Masengu, A., J. McDaid, A. P. Maxwell, and J. B. Hanko.
Preoperative radial artery volume flow is predictive of
arteriovenous fistula outcomes. J. Vasc. Surg. 63(2):429–
435, 2016.
26
Meess, K., R. Izzo, M. Dryjski, R. Curl, L. Harris, M.
Springer, et al. 3D Printed Abdominal Aortic Aneurysm
Phantom for Image Guided Surgical Planning with a Pa-
tient Specific Fenestrated Endovascular Graft System.
SPIE Medical Imaging: SPIE, 2017.
27
Pantalos, G. M., S. C. Koenig, K. J. Gillars, G. A. Girid-
haran, and D. L. Ewert. Characterization of an adult mock
circulation for testing cardiac support devices. ASAIO J.
50(1):37–46, 2004. https://doi.org/10.1097/01.mat.0000104
818.70726.e6.
28
Persona, P., E. Saraceni, F. Facchin, E. Petranzan, M.
Parotto, F. Baratto, et al. Pulse contour analysis of arterial
waveform in a high fidelity human patient simulator. J.
Clin. Monitor. Comput. 32(4):677–681, 2018.
29
Petrou, A., M. Granegger, M. Meboldt, and Daners M.
Schmid. A versatile hybrid mock circulation for hydraulic
investigations of active and passive cardiovascular im-
plants. ASAIO J. 65(5):495–502, 2019. https://doi.org/10.
1097/mat.0000000000000851.
30
Ramsingh, D., B. Alexander, and M. Cannesson. Clinical
review: does it matter which hemodynamic monitoring
system is used? Crit. Care. 17(2):208, 2013.
31
Robin, E., M. Costecalde, G. Lebuffe, and B. Vallet.
Clinical relevance of data from the pulmonary artery ca-
theter. Crit. Care. 10(3):1–10, 2006.
BIOMEDICAL
ENGINEERING
SOCIETY
32
Rzheutskaya, R.E. Characteristics of hemodynamic disor-
ders in patients with severe traumatic brain injury. Crit
Care Res Pract. 2012;2012:606179. https://doi.org/10.1155/
2012/606179.
33
Shehab, S., S. M. Allida, P. J. Newton, D. Robson, P. S.
Macdonald, P. M. Davidson, et al. Valvular regurgitation
in a biventricular mock circulatory loop. Asaio J.
65(6):551–557, 2019.
34
Sun, J. X., A. T. Reisner, M. Saeed, T. Heldt, and R. G.
Mark. The cardiac output from blood pressure algorithms
trial. Crit Care Med. 37(1):72–80, 2009. https://doi.org/10.
1097/CCM.0b013e3181930174.
35
Sun, J, A. Reisner, M. Saeed, and R. Mark. Estimating
cardiac output from arterial blood pressure waveforms: a
critical evaluation using the MIMIC II database. Comput.
Cardiol. 295–298, IEEE, 2005. https://doi.org/10.1109/CI
C.2005.1588095.
36
Teboul, J.-L., M. Cecconi, and T. W. Scheeren. Is there still
a place for the Swan-Ganz catheter? New York: Springer,
2018.
37
Trusty, P. M., M. Tree, D. Vincent, J. P. Naber, K. Maher,
A. P. Yoganathan, et al. In vitro examination of the Ven-
triFlo true pulse pump for failing Fontan support. Artif
Organs. 43(2):181–188, 2019. https://doi.org/10.1111/aor.1
3301.
38
Vahdatpour, C., D. Collins, and S. Goldberg. Cardiogenic
shock. J. Am. Heart Assoc.8(8):e011991, 2019. https://doi.
org/10.1161/JAHA.119.011991.
39
Villanueva, C., A. Albillos, J. Genescà, J. G. Abraldes, J. L.
Calleja, C. Aracil, et al. Development of hyperdynamic
circulation and response to b-blockers in compensated
cirrhosis with portal hypertension. Hepatology. 63(1):197–
206, 2016.
40
Vincent, J.-L., A. Rhodes, A. Perel, G. S. Martin, G. Della
Rocca, B. Vallet, et al. Clinical review: update on hemo-
dynamic monitoring-a consensus of 16. Crit. Care. 15(4):1–
8, 2011.
41
Wu, C., S. M. Retta, R. A. Robinson, B. A. Herman, and
L. W. Grossman. A novel study of mechanical heart valve
cavitation in a pressurized pulsatile duplicator. ASAIO J.
55(5):445–451, 2009. https://doi.org/10.1097/MAT.0b013e
3181b4c44f.
42
Yang, T.-H., J. U. Kim, Y.-M. Kim, J.-H. Koo, and S.-Y.
Woo. A new blood pulsation simulator platform incorpo-
rating cardiovascular physiology for evaluating radial pulse
waveform. J. Healthc. Eng. 2019;2019:4938063. https://doi.
org/10.1155/2019/4938063.
43
Young, E., J.-F. Chen, O. Dong, S. Gao, A. Massiello, and
K. Fukamachi. Transcatheter heart valve with variable
geometric configuration. Vitro Evaluat. Artif Organs.
35(12):1151–1159, 2011. https://doi.org/10.1111/j.1525-159
4.2011.01331.x.
44
Zhang, Z., B. Lu, X. Sheng, and N. Jin. Accuracy of stroke
volume variation in predicting fluid responsiveness: a sys-
tematic review and meta-analysis. J. Anesth. 25(6):904–916,
2011.
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