Transcript Poster - Research - Vanderbilt University

Non-invasive Continuous Blood Pressure Measurement in Mice
Andrew
1
McClellan ,
Laura
1
Miller ,
Sachin
2
Paranjape , Andre’ Diedrich,
M.D.,
1,2
Ph.D.
1Department
of Biomedical Engineering, Vanderbilt University,
2Autonomic Dysfunction Center, Department of Medicine, Vanderbilt University Medical Center; Nashville, Tennessee
Current devices for BP measurement in mice:
--Inflatable tail cuff with photo-sensor: uses Korotkoff method, not continuous measurements
--Implantable catheter/RF transmitter: highly invasive, expensive, time-consuming
--Arterial line: invasive, cumbersome, time-consuming
Objective:
We aim to adopt the Penaz method3 for continuous BP measurement at the mouse tail. The Penaz
method has been successfully implemented with measurement at the human finger (Finapres™),
so we will investigate whether the method can be used with mouse physiology, where heart rates
can be between 500-700 bpm, and blood pressures can be between 70-200mmHg. We will use a
mouse tail cuff with photo-sensor that is currently used to measure single systolic and diastolic BP
values.
Theory:
To non-invasively measure blood pressure waveforms the Penaz, or volume clamp, method was
used. With this method, the amount of pressure applied to the artery that is needed to maintain the
mean arterial volume is the blood pressure waveform. This calls for dynamic pulsatile unloading of
the arteries. Thus, during systole, when the blood pressure increases, arteries will slightly expand
due to their elasticity. To maintain a constant arterial volume, a pressure is applied equal to that of
the intra-arterial pressure. Likewise, during diastole, when blood pressure decreases, the applied
pressure is lessened. By measuring the applied pressure necessary to maintain a constant arterial
volume, a blood pressure waveform can be obtained.
Figure 1. Top: tail cuff with photo-sensor
Bottom: mouse restrained in tail cuff, speaker valve.
Figure 2.
Continuous blood pressure
measurement system.
Speaker Valve
Computer/DAQ
Harvard Plethysmogram
& Pressure Monitor
Results:
Voltage to Pressure Calibration Curve
WinDAQ
Figure 5a. Left:
calibration curve
from input voltage
to speaker to cuffapplied pressure.
y = 0.0006x
R2 = 1
0.1
0.09
Tail Cuff with
Photosensor
Analog Circuit
invert and
amplify
0.08
offset and
amplify power
Speaker
Valve
0.07
Voltage (v)
--Several transgenic and gene knockout mouse models have been developed to study human
diseases, with research relying on clinical measurements of blood pressure (BP) regulation:
--Hypertension
--Disorders of the cardiovascular system
--Dysfunctions of the autonomic nervous system (orthostatic intolerance, multiple system
atrophy, neurally-mediated syncope)
--Diabetes
--Spectral analysis techniques in the frequency domain have been used to assess the function of
blood pressure regulation and autonomic nervous system function using data from clinical tests:1,2
--Pharmacological baroreflex and hemodynamic response tests
--Behavorial studies
--Exercise and food studies
**Continuous beat-to-beat sampling of blood pressure is required, reporting a blood pressure
waveform as a function of time (vs. single systolic/diastolic values)
pressure signal
plethysmogram
Pressure
Source
0.06
Figure 5b. Right:
Change in
constant cuffapplied pressure
with change in DC
voltage offset.
0.05
0.04
0.03
0.02
Figure 3. Continuous blood pressure measurement system schematic.
0.01
0
0
Methodology:
 Plethysmogram is a measure of optical impedance
-- Obtained from tail cuff with photo-sensor (Figure 1)
-- Blood pressure α blood volume
-- Blood volume α optical impedance
-- Optical impedance α voltage
-- voltage α pressure applied by tail cuff
Need
Implementation
Plethysmogram
Harvard Rat
Blood Pressure
Monitor
Tail cuff
Pressure Meter
Signal Inversion
Adjustable Gain
Inverting Amplifier w/
potentiometer (LM741)
Power Amplification
LM386-4
Pressure Source
Voltage to Pressure
Transduction
Lab air source
 Speaker valve transduces voltage to pressure (Figure 1)
Data Acquisition
-- increase in voltage = increased displacement of speaker diaphragm
-- increase in displacement of speaker diaphragm = increase in leak occlusion
-- increase in leak occlusion = increase in pressure in cuff
Speaker Valve
WinDAQ
 Analog circuit alters the plethysmographic signal and controls the speaker (Figure 4)
--adjustable offset
- used to alter DC offset = non-oscillatory cuff pressure
- controlled by adjusting the supply voltage to the power amplifier
(LM386-4 self centers output to ½ supply voltage)
--inversion
- need in increase in cuff pressure for an increase in arterial volume
- increase in arterial volume = increase optical impedance = decrease in plethysmogram
- since the speaker valve increases pressure with increasing voltage, must invert
plethysmographic signal
-- adjustable gain
- plethysmogram must be scaled to create large enough fluctuations in pressure to maintain
constant arterial volume
- must be adjustable because the magnitude of pressure oscillations will vary between subjects
and over time within subjects
-gain and inversion accomplished with an inverting amplifier (LM741)
 Open-loop mode
-- sets up system: centers cuff pressure oscillations around mean arterial pressure
-- set cuff-applied pressure to mean arterial pressure
-- Marey's Law – plethysmographic signal will be maximal at mean arterial pressure (Figure 6)
-- increase pressure until plethysmographic signal is maximal
 Closed-loop mode
-- measures continuous BP: creates dynamic, pulsatile unloading of the arterial wall
-- applied pressure already set at mean arterial pressure
-- allow plethysmographic signal to control pressure oscillations
-- scale plethysmographic signal until the unadulterated plethysmographic signal is minimal
-- pressure fluctuations created by the inverted and amplified plethysmographic signal equal the intraarterial blood pressure waveform.
20
40
60
80
100
120
140
160
Pressure (mmHg)
Figure 6. Demonstration of Maney’s Law. When
cuff-applied pressure (top) reached the mouse’s
mean arterial pressure, the plethysmographic
signal (bottom) reached its maximum and then
diminished when the vessel became fully occluded.
Change in Cuff Applied Pressure vs. DC Offset
210
200
Change in Pressure (mmHg)
Introduction:
y = 20.305x + 150.41
R2 = 0.9606
190
180
170
160
150
140
130
0
0.5
1
1.5
2
2.5
3
Change in Voltage (V)
Figure 7. Cuff-applied pressure over time as the circuit
gain was decreased.
Pressure amplitude changed
proportionally to change in gain.
1 mmHg
Figure 8. Simulated plethysmographic signal (10Hz, 22mVp-p, shown in red) and cuff-applied pressure (grey) vs
time. Cuff-applied pressure is 1 mmHg. Time scale is 20ms/div.
Figure 9. Incomplete arterial unloading. Plethysmographic signal from mouse (red) and cuff-applied pressure (grey)
vs. time. Cuff-applied pressure was not enough to provide constant volume to the artery and completely diminish
plethysmographic signal, however it was decreased suggesting partial arterial unloading. Time scale is 20ms/div.
Conclusions:
--The open-loop mode of our system was achieved. Marey’s Law was demonstrated with our
system, as we were able to center the cuff pressure around a mouse’s mean arterial pressure
according to the appearance of the maximum plethysmographic signal (Figure 6a). We were
also able to alter the speaker offset for voltage centering, where a change DC voltage offset
resulted in a proportional change in constant pressure (Figure 5b).
--The concept of the closed loop mode was demonstrated. The system was able to roughly
regulate cuff-applied pressure with the inversion of the plethysomographic signal at its same
frequency, as described by the Penaz Method (i.e. counteracting the blood pressure to achieve
constant arterial volume) (Figure 8). The amplitude of the cuff-applied pressure could be
controlled by changing the gain in the circuit (Figure 6b).
--However, the maximum mechanical oscillations produced by the speaker valve were only
enough to produce oscillatory changes in the cuff-applied with a magnitude of 1 mmHg. Without
pressure changes of the same value as the mean arterial pressure of a mouse, complete arterial
unloading could not be achieved. However, the plethysmographic signal was decreased during
measurement, suggesting partial arterial unloading. Additionally, the shape of the pressure
wave, as transduced by the speaker valve, was altered.
Analog Circuit
--The Penaz Method, successful in humans, has potential for adaptation to mouse physiology
and would be a safer, more cost effective, and more ethical way to obtain continuous blood
pressure measurements.
Power Supply
Recommendations:
Pressure Monitor
Tail Cuff
Figure 4.
Analog circuit to modify
(invert, amplify, offset) the
plethysmographic signal
for output to the speaker
valve.
-- The major shortcoming of the system lies in the transduction from voltage to pressure with the
speaker. A higher wattage power amplifier and speaker could produce more sufficient
mechanical oscillations in the speaker. Other types of valves such as a solenoid, could also be
viable alternatives.
References:
1. Iellamo F, et al.:(1996) Evaluation of reproducibility of spontaneous baroreflex sensitivity at rest and during laboratory tests J. Hypertension 1996; 4: 1099-1104
2. Dawson SL, et al.:(1997) The reproducibility of cardiac baroreceptor activity assessed non-invasively by spectral and sequence techniques Clin. Auton. Research; 7: 279-84
3. Penaz, J. (1973) Photoelectric measurement of blood pressure, volume and flow in the finger. Digest. 10th Int. Conf. Med. Biol. Eng. Dresden, 104