U.S. patent application number 11/774229 was filed with the patent office on 2008-01-31 for system for repetitive measurements of cardiac output in freely moving individuals.
This patent application is currently assigned to Alfred E. Mann Institute for Biomedical Engineering at the University of Southern Californ. Invention is credited to Cesar Blanco, Daniel P. Holschneider, Jean-Michel I. Maarek, Frances Richmond.
Application Number | 20080027298 11/774229 |
Document ID | / |
Family ID | 38987226 |
Filed Date | 2008-01-31 |
United States Patent
Application |
20080027298 |
Kind Code |
A1 |
Blanco; Cesar ; et
al. |
January 31, 2008 |
System for Repetitive Measurements of Cardiac Output in Freely
Moving Individuals
Abstract
A system for evaluating the cardiovascular system parameters
using indicator dilution and non-invasive or minimally invasive
detection and calibration methods are disclosed. Intravascular
indicators are stimulated, and emissions patterns detected for
computation of cardiac output, cardiac index, blood volume and
other indicators of cardiovascular health.
Inventors: |
Blanco; Cesar; (Los Angeles,
CA) ; Richmond; Frances; (South Pasadena, CA)
; Holschneider; Daniel P.; (Los Angeles, CA) ;
Maarek; Jean-Michel I.; (Rancho Palos Verdes, CA) |
Correspondence
Address: |
MCDERMOTT WILL & EMERY LLP
2049 CENTURY PARK EAST
38th Floor
LOS ANGELES
CA
90067-3208
US
|
Assignee: |
Alfred E. Mann Institute for
Biomedical Engineering at the University of Southern
Californ
|
Family ID: |
38987226 |
Appl. No.: |
11/774229 |
Filed: |
July 6, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10847480 |
May 17, 2004 |
|
|
|
11774229 |
Jul 6, 2007 |
|
|
|
10153387 |
May 21, 2002 |
6757554 |
|
|
10847480 |
May 17, 2004 |
|
|
|
60292580 |
May 22, 2001 |
|
|
|
Current U.S.
Class: |
600/317 ;
600/526 |
Current CPC
Class: |
A61B 2503/40 20130101;
A61B 5/0275 20130101; A61B 2560/0223 20130101; A61B 5/0261
20130101 |
Class at
Publication: |
600/317 ;
600/526 |
International
Class: |
A61B 5/02 20060101
A61B005/02 |
Claims
1) A cardiac output system for repetitive cardiac output measuring
of a freely moving individual comprising: a) a dye calibration and
delivery system (CDS) configured to be worn by the individual
comprising: i. a calibration station configured to hold at least
one calibration cartridge and to draw blood from the individual;
and ii. a dye delivery station configured to hold at least one dye
delivery cartridge and to administer a predetermined amount of dye
to the individual's blood stream.
2) The system of claim 1 further comprising hardware and software
configured to control the calibration station and the dye delivery
station.
3) The system of claim 1, wherein the at least one cartridge is
configured to contain a plurality of separately sealed chambers
having different contents.
4) The system of claim 3, wherein the contents include any one of
dye, sterile water or sterile saline.
5) The system of claim 1, wherein the at least one cartridge is
configured to be of a transparent material.
6) The system of claim 1, wherein the calibration station includes
at least one element that is configured to illuminate the dye
within the calibration cartridge.
7) The system of claim 1, wherein the calibration station includes
at least one element configured to sense fluorescence intensity
transmitted from or reflected by the dye.
8) The system of claim 7, wherein the CDS is calibrated remotely by
an external device based on the sensed fluorescence intensity.
9) The system of claim 8, wherein the CDS administers the dye to
the individual based on received commands from the external
device.
10) The system of claim 1, wherein the CDS is configured to
administer the dye at predetermined times.
11) The system of claim 1, wherein the dye is administered
repetitively based on the individual's measured heart rate.
12) The system of claim 1, wherein the dye is administered while
the individual is on an exercise equipment.
13) The system of claim 1, wherein the CDS is configured to
administer a predetermined amount of dye to the individual based on
the individual's weight.
14) The system of claim 1, wherein the dye is indocyanine green
(ICG).
15) The system of claim 1, wherein the CDS is configured to draw
blood and/or administer dye to the individual through plurality of
onboard attached IV lines.
16) The system of claim 1, wherein the calibration station is
further configured to retain at least one final calibration
cartridge.
17) The system of claim 16, wherein the CDS is configured to draw a
final blood sample from the individual into the final calibration
cartridge.
18) The system of claim 17, wherein the CDS is configured to
transmit to the external device data related to the concentration
of the dye in the final calibration cartridge.
19) The system of claim 17, wherein the CDS is configured to
transmit to the external device data related to blood volume within
the individual's cardiovascular system based on the concentration
of the dye in the blood sample.
20) The system of claim 17, wherein the CDS is configured to draw a
final blood sample at the end of the repetitive cardiac output
measuring process.
21) The system of claim 8, wherein the CDS is configured to
communicate to the external device through a dongle.
22) The system of claim 1, wherein the CDS is configured to
communicate with an any one of PDA, laptop or desktop computer.
23) A cardiac output system for repetitive cardiac output measuring
of a freely moving individual comprising: a) a dye calibration and
delivery system (CDS) configured to be worn by the individual
comprising: i. a calibration station configured to hold at least
one calibration cartridge and to draw blood from the individual;
and ii. a dye delivery station configured to hold at least one dye
delivery cartridge and to administer a predetermined amount of dye
to the individual's blood stream; b) a sensing device configured to
be worn by the individual comprising: i. at least one illumination
source configured to rest against the individual's skin and to
excite the administered dye in the blood stream; and ii. at least
one photodetector configured to rest against the individual's skin
and to detect fluorescence intensity reflected from or transmitted
by the illuminated dye; and c) an external device configured to
wirelessly communicate with at least the CDS and the sensing
device, and to determine the cardiac output of the individual based
on the detected fluorescence intensity and the information
indicative of the concentration of the dye in the blood that was
drawn from the individual.
24) The system of claim 23 further comprises hardware and software
configured to operate the system and devices a-c.
25) The system of claim 23, wherein the system further includes a
dye mixing station configured to hold the calibration and/or dye
delivery cartridges.
26) The system of claim 25, wherein the cartridges are configured
to contain a plurality of separately sealed chambers having
different contents.
27) The system of claim 26, wherein the contents include any one of
dye, sterile water or sterile saline.
28) The system of claim 27, wherein the mixing station is
configured to automatically mix the contents of the cartridges by
an ultrasonic process.
29) The system of claim 25, wherein the cartridges are configured
to be of a transparent material.
30) The system of claim 23, wherein the calibration station
includes at least one element that is configured to illuminate the
calibration cartridge having a dye concentration and sense the
fluorescence intensity transmitted from or reflected by the
dye.
31) The system of claim 30, wherein the external device is
configured to calibrate the system based on the sensed fluorescence
intensity.
32) The system of claim 23, wherein the external device is
configured to enable the CDS remotely to administer the dye to the
individual.
33) The system of claim 32, wherein the CDS is configured to
administer the dye at predetermined times.
34) The system of claim 33, wherein the dye is administered
repetitively based on the individual's measured heart rate.
35) The system of claim 34, wherein the dye is administered while
the individual is on an exercise equipment.
36) The system of claim 32, wherein the CDS is configured to
administer a predetermined amount of dye to the individual based on
the individual's weight.
37) The system of claim 23, wherein the dye is indocyanine green
(ICG).
38) The system of claim 23, wherein the CDS is configured to draw
blood and/or administer dye to the individual through plurality of
onboard attached IV lines.
39) The system of claim 23, wherein the sensing device is
configured to detect fluorescence intensity reflected from or
transmitted by the administered dye for a predetermined
duration.
40) The system of claim 23, wherein the calibration station is
further configured to retain at least one final calibration
cartridge.
41) The system of claim 40, wherein the CDS is configured to draw a
final blood sample from the individual into the final calibration
cartridge.
42) The system of claim 41, wherein the external device is
configured to determine the concentration of the dye in the blood
sample of the final calibration cartridge.
43) The system of claim 42, wherein the external device configured
to determine the blood volume within the individual's
cardiovascular system based on the concentration of the dye in the
blood sample.
44) The system of claim 41, wherein the CDS is configured to draw a
final blood sample at the end of a repetitive cardiac output
measuring process.
45) The system of claim 23, wherein the external device is
configured to communicate with the CDS and the sensing device
through a dongle.
46) The system of claim 45, wherein the external device is any one
of PDA, laptop or desktop computer.
47) A computer readable medium having computer-executable
instructions to cause a computer or computer-based system to
repetitively measure cardiac output of a freely moving individual
comprising: a) calibrating and dye delivery of a calibration and
delivery system (CDS) that is worn by the individual comprising: i.
drawing blood from the individual into a calibration cartridge
having a dye concentration; and ii. administering a predetermined
amount of dye to the individual's blood stream; b) sensing
fluorescence intensity from the administered by a sensing device
that is worn by the individual comprising: i. illuminating the
administered dye in the blood stream of the individual; and ii.
detecting the fluorescence intensity reflected from or transmitted
by the illuminated dye; and c) determining the cardiac output of
the individual by an external device that communicates wirelessly
with at least the CDS and the sensing device, based on the detected
fluorescence intensity and the information indicative of the
concentration of the dye in the blood that was drawn from the
individual.
48) The computer-readable medium of claim 47, wherein the
calibration includes illuminating the calibration cartridge and
sensing the fluorescence intensity transmitted from or reflected by
the dye.
49) The computer-readable medium of claim 47, wherein the
determining of the cardiac output is based on remotely enabling the
CDS to administer the dye to the individual.
50) The computer-readable medium of claim 47, wherein the
administering of the dye is enabled at predetermined times.
51) The computer-readable medium of claim 49, wherein the
administering of the dye is enabled repetitively based on the
individual's measured heart rate.
52) The computer-readable medium of claim 50, wherein the
administering of the dye is enabled while the individual is on an
exercise equipment.
53) The computer-readable medium of claim 47, wherein the
predetermined amount of dye is calculated based on the individual's
weight.
54) The computer-readable medium of claim 47, wherein the detecting
of the fluorescence intensity lasts for a predetermined
duration.
55) The computer-readable medium of claim 47 further includes
drawing of a final blood sample from the individual into a final
calibration cartridge to determine the concentration of the dye in
the blood sample.
56) The computer-readable medium of claim 55, wherein the
determining of the cardiac output is to determine the blood volume
from the concentration of the dye in the blood sample.
57) The computer-readable medium of claim 55, wherein the final
drawing of blood from the individual is enabled at the end of a
repetitive cardiac output measuring process.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/847,480, filed May 17, 2004, entitled
"Measurement of Cardiac Output and Blood Volume by Non-Invasive
Detection of Indicator Dilution;" which is Continuation of U.S.
patent application Ser. No. 10/153,387, filed May 21, 2002 (now
U.S. Pat. No. 6,757,554, issued Jun. 29, 2004) entitled
"Measurement of Cardiac Output and Blood Volume by Non-Invasive
Detection of Indicator Dilution." This application also relates to
U.S. patent application Ser. No. 11/625,184 filed Jan. 19, 2007
entitled "Method and Apparatus for Measurement of Cardiac Output
and Blood Volume by Non-Invasive Detection of Indicator Dilution";
U.S. patent application Ser. No. 11/744,147 filed May 3, 2007
entitled "Method for Dye Injection for The Transcutaneous
Measurement of Cardiac Output"; and U.S. patent Ser. No. 11/744,157
filed May 3, 2007 entitled "Method and Apparatus for Measurement of
Cardiac Output and Blood Volume By Noninvasive Detection of
Indicator Dilution for Hemodialysis." The content of all of these
applications is incorporated herein by reference.
1. FIELD OF THE INVENTION
[0002] This invention pertains to the detection of parameters of
cardiovascular system of a subject.
2. GENERAL BACKGROUND AND STATE OF THE ART
[0003] Cardiac output is a central part of the hemodynamic
assessment in patients having heart disease, acute hemodynamic
compromise or undergoing cardiac surgery, for example. Cardiac
output is a measure of the heart's effectiveness at circulating
blood throughout the circulatory system. Specifically, cardiac
output (measured in L/min) is the volume of blood expelled by the
heart per beat (stroke volume) multiplied by the heart rate. An
abnormal cardiac output is at least one indicator of cardiovascular
disease.
[0004] The current standard method for measuring cardiac output is
the thermodilution technique (Darovic, G. O. Hemodynamic
monitoring: invasive and noninvasive clinical application. 2nd Ed.
W. B. Saunders, 1995). Generally, the technique involves injecting
a thermal indicator (cold or heat) into the right side of the heart
and detecting a change in temperature caused as the indicator flows
into the pulmonary artery.
[0005] Typically, the thermodilution technique involves inserting a
flow-directed balloon catheter (such as a Swan-Ganz catheter) into
a central vein (basilic, internal jugular or subclavian) and
guiding it through the right atrium and ventricle to the pulmonary
artery. The balloon catheter is typically equipped with a
thermistor near its tip for detecting changes in blood temperature.
A rapid injection of a bolus of chilled glucose solution (through a
port in the catheter located in the vena cava near the right
atrium) results in a temperature change in the pulmonary artery
detected with the thermistor. The measured temperature change is
analyzed with an external electronic device to compute the cardiac
output. The algorithm implemented in this computation is typically
a variant of the Stewart-Hamilton technique and is based on the
theory of indicator mixing in stirred flowing media (Geddes L A,
Cardiovascular devices and measurements. John Wiley & Sons.
1984).
[0006] Thermodilution measurements of cardiac output are
disadvantageous for several reasons. First, placement of the
thermodilution balloon catheter is an expensive and invasive
technique requiring a sterile surgical field. Second, the catheter
left in place has severe risks to the patient such as local
infections, septicemia, bleeding, embolization, catheter-induced
damage of the carotid, subclavian and pulmonary arteries, catheter
retention, pneumothorax, dysrrhythmias including ventricular
fibrillation, perforation of the atrium or ventricle, tamponade,
damage to the tricuspid values, knotting of the catheter, catheter
transection and endocarditis. Third, only specially trained
physicians can insert the balloon catheter for thermodilution
cardiac output. Last, thermodilution measurements of the cardiac
output are too invasive to be performed in small children and
infants.
[0007] Another method used for measuring cardiac output is the dye
indicator dilution technique. In this technique, a known volume and
concentration of indicator is injected into the circulatory flow.
At a downstream point, a blood sample is removed and the
concentration of the indicator determined. The indicator
concentration typically peaks rapidly due to first pass mixing of
the indicator and then decreases rapidly as mixing proceeds in the
total blood volume (.about.10 seconds; first pass concentration
curve). Further, indicator concentration slowly diminishes as the
indicator is metabolized and removed from the circulatory system by
the liver and/or kidneys (time depending upon the indicator used).
Thus, a concentration curve can be developed reflecting the
concentration of the indicator over time. The theory of indicator
dilution predicts that the area under the first pass concentration
curve is inversely proportional to the cardiac output.
[0008] Historically, indicator dilution techniques have involved
injecting a bolus of inert dye (such as indocyanine green) into a
vein and removing blood samples to detect the concentration of dye
in the blood over time. For example, blood samples are withdrawn
from a peripheral artery at a constant rate with a pump. The blood
samples are passed into an optical sensing cell in which the
concentration of dye in the blood is measured. The measurement of
dye concentration is based on changes in optical absorbance of the
blood sample at several wavelengths.
[0009] Dye-dilution measurements of cardiac output have been found
to be disadvantageous for several reasons. First, arterial blood
withdrawal is time consuming, labor intensive and depletes the
patient of valuable blood. Second, the instruments used to measure
dye concentrations (densitometer) must be calibrated with samples
of the patient's own blood containing known concentrations of the
dye. This calibration process can be very laborious and time
consuming in the context of the laboratory where several samples
must be run on a daily basis. Further, technical difficulties arise
in extracting the dye concentration from the optical absorbance
measurements of the blood samples.
[0010] A variation on the dye-dilution technique is implemented in
the Nihon Kohden pulse dye densitometer. In this technique, blood
absorbance changes are detected through the skin with an optical
probe using a variation of pulse oximetry principles. This
variation improves on the prior technique by eliminating the
necessity for repeated blood withdrawal. However, as described
above, this technique remains limited by the difficulty of
separating absorbance changes due to the dye concentration changes
from absorbance changes due to changes in blood oxygen saturation
or blood content in the volume of tissue interrogated by the
optical probe. This method is also expensive in requiring large
amounts of dye to create noticeable changes in absorbance and a
light source producing two different wavelengths of light for
measuring light absorption by the dye and hemoglobin
differentially. Even so, the high background levels of absorption
in the circulatory system make this technique inaccurate. Finally,
where repeat measurements are desired, long intervals must ensue
for the high levels of the indicator to clear from the blood
stream. Thus, this technique is inconvenient for patients
undergoing testing and practitioners awaiting results to begin or
alter treatment.
[0011] Other approaches for measuring cardiac output exist which
are not based on indicator dilution principles. These include
ultrasound Doppler, ultrasound imaging, and the Fick principle
applied to oxygen consumption or carbon dioxide production and
electric impedance plethysmography (Darovic, supra). However, these
techniques have specific limitations. For instance, the ultrasound
techniques (Doppler and imaging) require assumptions on the
three-dimensional shape of the imaged structures to produce cardiac
output values from velocity or dimension measurements.
[0012] Blood volume measures the amount of blood present in the
cardiovascular system. Blood volume is also a diagnostic measure
that is relevant to assessing the health of a patient. In many
situations, such as during or after surgery, traumatic accident or
in disease states, it is desirable to restore a patient's blood
volume to normal as quickly as possible. Blood volume has typically
been measured indirectly by evaluating multiple parameters (such as
blood pressure, hematocrit, etc.). However, these measures are not
as accurate or reliable as direct methods of measuring blood
volume.
[0013] Blood volume has been directly measured using indicator
dilution techniques (Geddes, supra). Briefly, a known amount of an
indicator is injected into the circulatory system. After injection,
a period of time is allowed to pass such that the indicator is
distributed throughout the blood, but without clearance of the
indicator from the body. After the equilibration period, a blood
sample is drawn which contains the indicator diluted within the
blood. The blood volume can then be calculated by dividing the
amount of indicator injected by the concentration of indicator in
the blood sample (for a more detailed description see U.S. Pat. No.
6,299,583 incorporated by reference). However, to date, the
dilution techniques for determining blood volume are
disadvantageous because they are limited to infrequent measurement
due to the use of indicators that clear slowly from the blood.
[0014] Thus, it would be desirable to have a non-invasive, cost
effective, accurate and sensitive technique for measuring
cardiovascular parameters, such as cardiac output and blood
volume.
SUMMARY
[0015] The present cardiovascular measurement devices and methods
assess cardiovascular parameters within the circulatory system
using indicator dilution techniques. Cardiovascular parameters are
any measures of the function or health of a subject's
cardiovascular system.
[0016] In one aspect of the present cardiovascular measurement
devices and methods, a non-invasive method for determining
cardiovascular parameters is described. In particular, a
non-invasive fluorescent dye indicator dilution method is used to
evaluate cardiovascular parameters. The method may be minimally
invasive, requiring only a single peripheral, intravenous line for
indicator injection into the circulatory system of the patient.
Further, a blood draw may not be required for calibration of the
system. Further, cardiovascular parameters may be evaluated by
measuring physiological parameters relevant to assessing the
function of the heart and circulatory system. Such parameters
include, but are not limited to cardiac output and blood
volume.
[0017] Such minimally invasive procedures are advantageous over
other methods of evaluating the cardiovascular system. First,
complications and patient discomfort caused by the procedures are
reduced. Second, such practical and minimally invasive procedures
are within the technical ability of most doctors and nursing staff,
thus, specialized training is not required. Third, these minimally
invasive methods may be performed at a patient's bedside or on an
outpatient basis. Finally, methods may be used on a broader patient
population, including patients whose low risk factors may not
justify the use of central arterial measurements of cardiovascular
parameters.
[0018] In another aspect of the cardiovascular measurement devices
and methods, these methods may be utilized to evaluate the
cardiovascular parameters of a patient at a given moment in time,
or repeatedly over a selected period of time. The dosages of
indicators and other aspects of the method can be selected such
that rapid, serial measurements of cardiovascular parameters may be
made. These methods can be well suited to monitoring patients
having cardiac insufficiency or being exposed to pharmacological
intervention over time. Further, the non-invasive methods may be
used to evaluate a patient's cardiovascular parameters in a basal
state and when the patient is exposed to conditions which may alter
some cardiovascular parameters. Such conditions may include, but
are not limited to changes in physical or emotional conditions,
exposure to biologically active agents or surgery. For example,
embodiments of the cardiovascular measurement devices and methods
can be used for cardiac output monitoring before, during, or after
kidney dialysis; cardiac output monitoring under shock conditions
(such as, for example, septic shock, anaphylactic shock,
cardiogenic shock, neurogenic shock, hypovolemic shock); cardiac
output monitoring during stress tests to better understand the
heart's ability to increase blood supply to the heart and body
while exercising or under other conditions requiring additional
blood flow through the heart; cardiac output monitoring before,
during, and after chemotherapy treatment to monitor fluid
equilibrium in the body; and cardiac output measurements for
athletes needing to understand how their cardiac performance to
improve their athletic performance.
[0019] In another aspect of the cardiovascular measurement devices
and methods, modifications of the method may be undertaken to
improve the measurement of cardiovascular parameters. Such
modifications may include altering the placement of a photodetector
relative to the patient or increasing blood flow to the detection
area of the patient's body.
[0020] In yet another aspect of the cardiovascular measurement
devices and methods, the non-invasive method of assessing
cardiovascular parameters utilizes detection of indicator emission,
which is fluorescence, as opposed to indicator absorption. Further,
indicator emission may be detected in a transmission mode and/or
reflection mode such that a broader range of patient tissues may
serve as detection sites for evaluating cardiovascular parameters,
as compared to other methods. Measurement of indicator emission can
be more accurate than measurements obtained by other methods, as
indicator emission can be detected directly and independent of the
absorption properties of whole blood.
[0021] In a further aspect of the cardiovascular measurement
devices and methods, a system for the non-invasive or minimally
invasive assessment of cardiovascular parameters is described. In
particular, such a system may include an illumination source for
exciting the indicator, a photodetector for sensing emission of
electromagnetic radiation from the indicator and a computing system
for receiving emission data, tracking data over time and
calculating cardiovascular parameters using the data.
[0022] In another aspect of the cardiovascular measurement devices
and methods, the methods and system described herein may be used to
assess cardiovascular parameters of a variety of subjects. In some
embodiments, the methodology can be modified to examine animals or
animal models of cardiovascular disease, such as cardiomyopathies.
The methodology of the present invention is advantageous for
studying animals, such as transgenic rodents whose small size
prohibits the use of current methods using invasive procedures. The
present cardiovascular measurement devices and methods are also
advantageous in not requiring anesthesia which can effect cardiac
output measurements.
[0023] In yet another aspect of the cardiovascular measurement
devices and methods, a noninvasive calibration system can be used
to determine the concentration of circulating indicator dye. In
some embodiments, the concentration of circulating indicator dye
can be determined from the ratio of emergent fluorescent light to
transmitted and/or reflected excitation light.
[0024] In another aspect of cardiovascular measurement devices and
methods, a noninvasive, mobile, self-contained, stand alone system
can be used to repetitively perform the cardiac output measurements
in freely moving individuals. The device will be worn by the
individual and it will communicate remotely with a
PDA/laptop/desktop computer through a wireless dongle. This will
further assist the individual to freely move about during the
cardiac output measurements.
[0025] In other embodiments, the methodology can be modified for
clinical application to human patients. The present cardiovascular
measurement devices and methods may be used on all human subjects,
including adults, juveniles, children and neonates. The present
invention is especially well suited for application to children,
and particularly neonates. As above, the present technique is
advantageous over other methods at least in that it is not limited
in application by the size constraints of the miniaturized
vasculature relative to adult subjects.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 is a diagrammatic depiction of an example of one
embodiment of the system of the present invention.
[0027] FIG. 2 is a fluorescence intensity curve generated using one
embodiment of the present invention.
[0028] FIG. 3 is a diagrammatic depiction of an example of one
embodiment of the present invention having a photodetector
positioned on the ear skin surface.
[0029] FIG. 4 is a diagrammatic depiction of a user interface of a
cardiac output computer program useful in conjunction with this
invention. The interface may depict information regarding values
measured and converted from fluorescence to concentration, and
parameters of the curve fit for the values obtained using the
method or system.
[0030] FIG. 5 is a depiction of a decay of fluorescence intensity
curve as a function of time following injection of a 1 mg dose of
indocyanine green (ICG) in an experimental animal.
[0031] FIG. 6 is a depiction of a calibration curve for blood ICG
concentration as a function of transcutaneous ICG fluorescence.
[0032] FIG. 7 is a depiction of cardiac output and aortic velocity
measurements during one representative experiment.
[0033] FIG. 8 is a depiction of cardiac output measurements derived
from sites on the ear surface and on the exposed femoral artery
during one experiment.
[0034] FIG. 9 is a flow chart depicting one method of the present
invention.
[0035] FIG. 10 illustrates a fluorescence intensity curve that
includes an extrapolation that intercepts the point on the curve at
which the fluorescence is indicative of the concentration of the
indicator when mixed throughout the volume of blood of the
subject.
[0036] FIGS. 11A-11D are graphs showing calculated transmission and
fluorescence signals at 784 nm and 830 nm for different ICG
concentrations and hemoglobin contents when absorption coefficients
are the same at these two wavelengths.
[0037] FIGS. 12A-12D are graphs showing transmission and
fluorescence signals at 784 nm and 830 nm for different ICG
concentrations and hemoglobin contents when absorption coefficients
vary with wavelength and an additional absorber is included.
[0038] FIG. 13 is a diagrammatic depiction of an alternative
embodiment of cardiac output system for repetitive cardiac output
measuring of an individual.
[0039] FIG. 14 is an exemplary depiction of a dye delivery
cartridge used in the system of FIG. 13.
[0040] FIG. 15 is an exemplary depiction of a calibration cartridge
used in the system of FIG. 13.
[0041] FIG. 16 is an exemplary depiction of a final calibration
cartridge used in the system of FIG. 13.
[0042] FIG. 17 is flow chart depicting the repetitive cardiac
output process of the system of FIG. 13.
[0043] FIG. 18 is a flow chart depicting the CDS initialization
process of FIG. 17.
[0044] FIG. 19 is a flow chart depicting the preparation process of
the dye delivery cartridge of FIG. 17.
[0045] FIG. 20 is a flow chart depicting the preparation process of
dye calibration cartridge of FIG. 17.
[0046] FIG. 21 is a flow chart depicting the IV lines installation
procedure of FIG. 17.
[0047] FIG. 22 is a flow chart depicting the CDS calibration
process of FIG. 17.
[0048] FIG. 23 is a flow chart depicting the cardiac output
monitoring process of FIG. 17.
DETAILED DESCRIPTION
[0049] The method and system of the present invention are for the
evaluation of cardiovascular parameters of a subject using an
indicator dilution technique.
[0050] The method of this invention generally involves the
injection of a selected amount of indicator into the bloodstream of
the subject (FIG. 9). Preferably, the indicator is illuminated
using a first wavelength of excitation light selected to cause the
indicator to fluoresce and emit a second wavelength of light. A
photodetector is placed near the subject for the detection of the
intensity of the emitted second wavelength of light, which is
proportional to the concentration of the indicator circulating
within the circulatory system. The photodetector transmits this
intensity information to a computing system, which records and
preferably maps the intensity curve of the indicator detected over
time.
[0051] Typically, the indicator concentration values increase to a
peak rapidly after injection of the indicator. Then, the
concentration values decrease rapidly, then more steadily as the
indicator is mixed throughout the body circulatory system and
metabolized over time. A microprocessor driven computation then can
calculate from the concentration curve, the patient's cardiac
output and/or blood volume values. Additionally, values can be
generalized repeatedly using this method, at intervals of about
every 2-5 minutes.
[0052] Indicators. The indicators useful in this invention are
preferably inert and biocompatible in that they do not alter
cardiovascular parameters, such as heart rate. Further, the
indicator is preferably a substance that once injected, does not
diffuse out of the vasculature of the cardiovascular system. Also,
the indicator is preferably selected to be one which is metabolized
within the body at a rate such that repeated measures using this
method may be conducted at intervals of about 2-5 minutes. It is
also desirable that the background levels of circulating indicator
be cleared between intervals, although measurements may be taken
when background levels are not zero. Finally, the indicator can be
selected to be detectable by the photodetector system selected.
[0053] In one embodiment, a non-invasive dye indicator dilution
method may be used to evaluate cardiovascular function. Many
different dye indicators may be used within the scope of this
invention. Preferably, the dye indicator is fluorescent having an
excitation wavelength and an emission wavelength in the near
infrared spectrum, preferably about 750 nm to about 1000 nm, and
more preferably about 750 nm to about 850 nm.
[0054] Most preferably, the indicator used is indocyanine green
(ICG; purchased for example from Akorn, Decatur or Sigma, St.
Louis, Mo.; commercial names:
[0055] Diagnogreen.COPYRGT., ICGreen.COPYRGT.,
Infracyanine.COPYRGT., Pulsion.COPYRGT.). ICG has been previously
been used to study the microcirculation of the eye, the digestive
system and liver function (Desmettre, T., J. M. Devoisselle, and S.
Mordon. Fluorescence properties and metabolic features of
indocyanine green (ICG) as related to angiography. Surv Opthalmol
45, 15-27, 2000). ICG fluoresces intensely when excited at near
infrared wavelengths. In the context of this invention, ICG in
blood plasma has a peak fluorescence of about 810 to 830 nm with an
optimal excitation wavelength of about 780 nm (Hollins, supra;
Dorshow, supra). ICG may be advantageous for use in this invention
in remains intravascular because it is protein bound. ICG breaks
down quickly in aqueous solution, and metabolites are not
fluorescent, minimizing recirculation artifact and reducing the
time period between which measurements can be made. The wavelength
of emission of ICG is also within the optical window (750-1000 nm)
in which living tissues are relatively transparent to light.
[0056] Other biocompatible fluorescent dyes such as fluorescein and
rhodamine would also be suitable in this invention. Fluorescein in
blood plasma has a peak fluorescence of about 518.+-.10 nm with an
optimal excitation wavelength of about 488 nm (Hollins, supra;
Dorshow, supra). Rhodamine in blood plasma has a peak fluorescence
of about 640.+-.10 nm with an optimal excitation wavelength of
about 510 nm.
[0057] Indicator dosage. The dosage of indicator is preferably
selected such that an amount used is non-toxic to the subject, is
present in the circulatory system for an amount of time adequate to
establish an indicator concentration curve, but is metabolized in
an amount of time such that repeated measurements can be conducted
at intervals of about 2-5 minutes apart. Further, the indicator is
preferably administered to the subject by injection into a
vein.
[0058] A dosage of about 0.015 mg/kg is preferable in that this
dose leads to peak blood concentrations below 0.002 mg/ml. In this
concentration range, the measurement of the circulating indicator
concentration is linearly related to the intensity of the emission
wavelength detected. For example, in a laboratory animal model,
about 0.045 mg can be injected into a 3 kg rabbit (blood volume=200
ml) such that the average circulating concentration is about
0.00023 mg/ml whole blood.
[0059] Dye dilution techniques have been applied in humans in other
methods and systems using indocyanine green as a dye. Living
tissues of humans and animals are relatively transparent for near
infrared wavelengths of light which allows for transmission of
light across several mm of tissue and transcutaneous detection of
the fluorescence emission of ICG. The use of dosages in the ranges
stated above is additionally suitable for human use.
[0060] Illumination Source. The illumination sources useful in this
invention are preferably selected to produce an excitation
wavelength in the near infrared spectrum, preferably about 750 nm
to about 1000 nm, and more preferably about 750 to about 850 nm.
This selection is advantageous in at least that most tissues are
relatively transparent to wavelengths in this range. Thus, in some
embodiments, an indicator in the blood stream is excited
transcutaneously and indicator emissions detected transcutaneously.
Further, blood constituents do not fluoresce at these wavelengths,
thus there is no other contributor to the measured fluorescence
emission signal. Therefore, this method is advantageous in that at
least the sensitivity of detection in this method is improved over
other methods, which measure indicator absorption, as opposed to
emission.
[0061] However, it is within the scope of the invention to use
other wavelengths of light, for example in the blue-green or
ultraviolet range as some tissues are relatively transparent even
at these wavelengths. Selection of the illumination source,
therefore, can depend in part on the indicator selected and the
tissue from which detection will be made. Preferably, the
illumination source is selected to result in the peak emission
wavelength of the indicator.
[0062] Examples of illumination sources which may be used in this
invention include, but are not limited to lamps, light emitting
diodes (LEDs), lasers or diode lasers.
[0063] In some embodiments, modifications to the system or
illumination source may be altered to further to maximize the
sensitivity or accuracy of the system for measuring indicator
concentration. For example, in some embodiments, the excitation
wavelength produced by the illumination source will be steady.
Alternatively, the excitation wavelength produced by the
illumination source can be modulated to allow for a lock-in
detection technique.
[0064] For example, the illumination source may emit light in a
periodic varying pattern having a fixed frequency and the emission
recorded by the photodetector read at the same frequency to improve
the accuracy of the readings. The periodic varying pattern and
frequency can be selected to improve noise-rejection and should be
selected to be compatible with the rest of the instrumentation
(such as the light source and photodetector).
[0065] The illumination source may be adapted to target a detection
area of the subject's tissue from which emission wavelength
intensity will be recorded. In some embodiments, the illumination
source may comprise an optic fiber for directing the excitation
light to the detection area. In some embodiments, the illumination
source may comprise mirrors, filters and/or lenses for directing
the excitation light to the detection area.
[0066] Detection Areas. The target detection area is that location
of a subject's tissue which is exposed to the excitation wavelength
of light and/or from which the emission wavelength light intensity
output will be measured.
[0067] Preferably, the method of detection is non-invasive. In
these embodiments, a detection area is selected such that a
photodetector can be placed in proximity to the detection area and
emission wavelength light intensity measured. Preferably, the
photodetector is placed transdermally to at least one blood vessel,
but more preferably a highly vascularized tissue area. Examples of
detection areas include, but are not limited to fingers, auricles
of the ears, nostrils and areas having non-keratinized epithelium
(such as the nasal mucosa or inner cheek). In alternative
embodiments, the method of detection is minimally invasive. For
example, the photodetector can be placed subdermally (within or
beneath the epidermis) and proximate to at least one blood vessel
or in a perivascular position.
[0068] In yet alternative embodiments, the method of detection is
minimally invasive. For example, the photodetector can be placed
intravascularly to detect indicator emissions, such as within an
artery. In such embodiments, an external probe for emitting and
receiving light may not be needed. For example, in some embodiments
the probe may include a fiber optic located within an intravascular
catheter. Specifically, the device may include an intravascular
catheter made of biocompatible plastic material which contains,
embedded in the catheter wall, an optical fiber 412 that ends at or
near the tip 416 of the catheter. For example, the catheter may
have a diameter of 100 .mu.m or less. The fiber optic can be used
to optically sense the presence and concentration of endogenous
substances in the blood or exogenous substances injected or infused
in the blood stream through the catheter lumen or another catheter.
A fiber optic connector 414 at the proximal external end of the
fiber optic connects the fiber to an external monitor. In use, the
needle of an injection syringe can be inserted through the catheter
lumen and used to inject the indicator material (meanwhile the
catheter may be allowed to remain within the vein or artery). The
injection needle may be withdrawn from the catheter after
injection. After the indicator has been injected and the indicator
has had sufficient time to circulate through the cardiovascular
system, light from a light source can be directed to the blood and
circulated indicator via the optical fiber embedded in the
catheter. The optical fiber of the catheter may also be used to
receive light from the indicator and transmit the light to the
monitor. In alternative embodiments, the catheter may include a
plurality of optical fibers for transmitting and/or receiving light
used to obtain measure parameters of interest of the cardiovascular
system. Catheters that include optical fibers are described in U.S.
Pat. Nos. 4,730,622 to Cohen and 5,217,456 to Narciso, the entire
contents of each of which are incorporated by reference. In
addition, other sensing devices and mechanisms may be included in
the intravascular probe.
[0069] Additionally, the detection area may be arterialized during
indicator emission detection. Examples of conditions resulting in
detection area arterializations include, but are not limited to
heating or exposure to biologically active agents which effect
sympathetic system blockade (such as lidocaine).
[0070] Photodetector. The detection of indicator emissions can be
achieved by optical methods known in the art. Measurement of
indicator concentration can be made by administering a detectable
amount of a dye indicator and using non-invasive, minimally
invasive, or intravascular procedures, preferably for continuous
detection. The photodetector may be positioned proximately to the
detection area of the subject. The photodetector may be positioned
distally or proximately to the site of the illumination source.
[0071] Fluorescent light is emitted from the indicator with the
same intensity for all directions (isotropy). Consequently, in some
embodiments, the emission of the dye can be detected both in
"transmission mode" when the excitation light and the photodetector
are on opposite sides of the illuminated tissue and in "reflection
mode" when the excitation and the photodetector are on the same
side of the tissue. This is advantageous over other methods at
least in that the excitation light and emitted light can be input
and detected from any site on the body surface and not only
optically thin structures.
[0072] Photodetectors which are useful in this invention are those
selected to detect the quantities and light wavelengths
(electromagnetic radiation) emitted from the selected indicator.
Photodetectors having sensitivity to various ranges of wavelengths
of light are well known in the art.
[0073] In some embodiments, modifications to the system are made to
further enhance the sensitivity or accuracy of the system for
measuring indicator concentration. For example in some embodiments,
the detection system can incorporate a lock-in detection technique.
For example, the excitation light may be modulated at a specific
frequency and a lock-in amplifier can be used to amplify the output
of the photodetector only at that frequency. This feature is
advantageous in at least that it further improves the sensitivity
of the system by reducing signal to noise and allows detection of
very small amounts of fluorescence emission.
[0074] In some embodiments a photomultiplier tube is utilized as or
operably connected with another photodetector to enhance the
sensitivity of the system. Finally, in some embodiments, additional
features, such as filters, may be utilized to minimize the
background of the emission signals detected. For example, a filter
may be selected which corresponds to the peak wavelength range or
around the peak wavelength range of the indicator emission.
[0075] The detected electromagnetic radiation is converted into
electrical signals by a photoelectric transducing device which is
integral to or independent of the photodetector. These electrical
signals are transmitted to a microprocessor which records the
intensity of the indicator emissions as correlated to the
electrical signal for any one time point or over time. (For an
example of such a device see U.S. Pat. No. 5,766,125, herein
incorporated by reference.)
[0076] System Calibration.
[0077] A) Minimally Invasive Calibration
[0078] The method may be minimally invasive in requiring only a
single peripheral blood draw from the circulatory system to be
taken for calibration purposes. In this invention, indicator
concentration is preferably being measured continuously and
non-invasively using a photodetector. However, one blood sample
from the subject may be withdrawn for calibration of the actual
levels of circulating indicator with the indicator levels detected
by the system. For example, a blood sample may be drawn from the
subject at a selected time after the administration of the
indicator into the blood stream. The blood sample may then be
evaluated for the concentration of indicator present by comparison
with a calibration panel of samples having known indicator
concentrations. Evaluation of the indicator concentration may be
made spectrophotometrically or by any other means known in the art.
Where the subject blood concentration of indicator falls within a
range of about 0.001 to about 0.002 mg/ml, the
concentration-fluorescence curve is linear and it crosses the
origin of the axes, the fluorescence is zero when the concentration
is zero. Therefore a single measurement point suffices to define
the calibration curve, and no further blood samples need be
taken.
[0079] B) Noninvasive Calibration
[0080] In another embodiment no blood draw is required for
calibration of this system. It is noted that the fluorescence of
some indicators, such as ICG, does not substantially vary from
patient to patient and that the skin characteristics are relatively
constant for large classes of patients. Thus, the fluorescence in
the blood of the patient measured from a given site on the body
surface can be converted in an absolute measurement of ICG
concentration, once the curve of indicator concentration vs.
fluorescence is defined for that site of measurement.
[0081] In an exemplary embodiment using noninvasive calibration,
the concentration of a fluorescent indicator (ICG) injected in the
bloodstream can be determined without taking a blood sample. A
probe (including or connected to one or several photodetectors, as
described above) can measure the intensity of fluorescent light
emitted by the ICG indicator when illuminated by a light source in
or near the skin. The probe can also measure the intensity of the
light from that source that is reflected by or transmitted through
the illumination skin site. Since the ratio of emergent fluorescent
light to transmitted excitation light is directly proportional to
ICG concentration (see FIGS. 11A-D, FIGS. 12A-12D, and Example 3
below), the concentration of ICG can be determined from the ratio
of emergent fluorescent light to transmitted excitation light. For
example, the graph in FIG. 11C shows that ICG concentration is
directly proportional to the ratio of fluorescent light to
transmitted excitation light. In another example illustrated by the
graph of FIG. 12C, ICG remains directly proportional to the ratio
of fluorescent light to transmitted excitation light even when
factoring the variations of absorption properties for hemoglobin
(Hb) and ICG with wavelength and the absorption by bloodless
tissue. While the slopes of the lines in FIG. 12C vary slightly
depending upon hemoglobin content, the differences between the
light ratios are relatively small. The ratios may be normalized by
creating a table of coefficients that take into account various
factors that may affect the light ratios (such as absorption by
bloodless tissue, hemoglobin content, path length, skin color,
moisture on skin surfaces, body hair, and other factors known to
those skilled in the art).
[0082] The probe used to transmit and receive light may include a
single optical fiber, multiple optical fibers for transmitting
and/or receiving light, or other configuration known to those
skilled in the art. The excitation light that is received and used
in the ratio against fluorescence may be reflected and/or
transmitted light. For example, in one embodiment, the light
transmitter and receiver can be on the same skin surface so that
the receiver can receive light reflected from the tissue. In such
an embodiment, the receiving and transmitting element are the same
optical fiber (See Diamond et al., "Quantification of fluorophore
concentration in tissue-simulating media by fluorescence
measurements with a single optical fiber;" Applied Optics, Vol. 42,
No. 13, May 2003; the contents of which are incorporated herein by
reference). In other embodiments, they may be different optical
fibers (or other devices known to those skilled in the art). In
such embodiments, the various optical fibers may be spatially
positioned in relation to each other to optimize measurement, as
described in Weersink et al. (See Weersink et al., "Noninvasive
measurement of fluorophore concentration in turbid media with a
simple fluorescence/reflectance ratio technique;" Applied Optics,
Vol. 40, No. 34, December 2001; and U.S. Pat. No. 6,219,566 to
Weersink et al.; the contents of both of which are incorporated
herein by reference). In another embodiment, the transmitter and
receiver are positioned substantially opposite each other to allow
transmission of the light (such as forward scattering) from the
transmitter, through the tissue, and out of the tissue to the
receiver on the other side of the tissue.
[0083] These methods and systems may be utilized to measure several
cardiovascular parameters. Once the system has been calibrated to
the subject (where necessary) and the indicator emissions detected
and recorded over time, the computing system may be used to
calculate cardiovascular parameters including cardiac output and
blood volume.
[0084] Cardiac output calculations. In some embodiments, the
cardiac output is calculated using equations which inversely
correlate the area under the first pass indicator emission curve
(magnitude of intensity curve) with cardiac output. Cardiac output
is typically expressed as averages (L/min). The general methods
have been previously described (Geddes, supra, herein incorporated
by reference).
[0085] Classically, the descending limb of the curve is plotted
semi-logarithmically to identify the end of the first pass of
indicator. For example, the descending limb of the curve may be
extrapolated down to 1% of the maximum height of the curve. The
curve can then be completed by plotting values for times preceding
the end time. Finally, the area under this corrected curve is
established and divided by the length (time) to render a mean
height. This mean height is converted to mean concentration after
calibration of the detector. The narrower the curve, the higher the
cardiac output; the wider the curve, the lower the cardiac output.
Several variations of this calculation method are found, including
methods that fit a model equation to the ascending and descending
portions of the indicator concentration curve.
[0086] Depending upon the indicator type and dosage selected, the
curve may not return to zero after the end of the first pass due to
a residual concentration of indicator recirculation in the system.
Subsequent calculations of cardiac output from the curve may then
account for this recirculation artifact by correcting for the
background emissions, prior to calculating the area under the
curve.
[0087] Sequential measurements of a cardiovascular circulatory
parameter, such as cardiac output or blood volume, may be taken.
Each measurement may be preceded by the administration of an
indicator to the cardiovascular system. Each measurement may be
separated by a time period during which the indicator that was
previously administered is substantially eliminated from the
circulatory system, for instance by metabolic processes.
[0088] To obtain a measurement in absolute physical units, e.g., in
liters per minute for cardiac output or liters for blood volume, a
blood sample may be taken after each administration of the
indicator for calibration purposes, as explained in more detail
above.
[0089] Another approach may be to take a blood sample only after
the first administration of the indicator and to use this blood
sample for calibration purposes during each subsequent
administration of the indicator and measurement of its resulting
fluorescence. However, the operating characteristics of the test
equipment may shift during these tests. The optical properties of
the tissue being illuminated may also change. The positioning of
the illumination source and/or the photo detector may also change.
All these changes can introduce errors in the computation of the
parameter in absolute physical units when the computations are
based on a blood sample that was taken before the changes
occurred.
[0090] These errors may be minimized by measuring the changes that
occur after the blood sample is taken and by then adjusting the
measured fluorescence intensity to compensate for these measured
changes. This may be accomplished by measuring the intensity of the
illumination light after it is transmitted through or reflected by
the tissue through which the administered indicator passes. This
illumination intensity measurement may be made shortly before,
during or shortly after each administration of the indicator. The
computations of the cardiovascular parameter that are made during
tests subsequent to the first test (when the calibrating blood
sample was taken) may then be adjusted in accordance with
variations in these illumination intensity measurements.
[0091] For example, the computation of the cardiovascular parameter
that is made following the second administration of the indicator
may be multiplied by the ratio of the illumination intensity
measurement made prior to the first administration of the indicator
to the illumination intensity measurement made prior to the second
administration of the indicator. If the illumination intensity
between the first and second measurements doubles, for example,
application of this formula may result in a halving of the
computation. Other functional relationships between the measured
cardiovascular parameter and the illumination intensity
measurements may also be implemented.
[0092] Any equipment may be used to make the illumination intensity
measurements. In one embodiment, the photo detector that detects
the fluorescence intensity may also be used to make the
illumination intensity measurements. The optical filter that
removes light at the illumination frequency may be removed during
the illumination intensity measurements. The leakage of the
illumination thought this filter may instead be measured and used
as the information for the computation.
[0093] Another approach to minimizing the number of needed blood
samples for a sequence of tests is to take advantage of the known
relationship between the amount of indicator that is injected, the
volume of blood in the circulatory system and the resulting
concentration of the indicator in that blood.
[0094] One step in this approach is to determine the volume of
blood in the cardiovascular circulatory system using any technique,
such as a tracer dilution technique, applied for instance with the
Evans Blue dye. The concentration of the indicator after it is
administered and mixed throughout the total blood volume, with no
offset for metabolic elimination, may then be computed by dividing
the amount of the indicator that is administered by the volume of
the blood.
[0095] The theoretical magnitude of the intensity of the
fluorescence from the indicator after the indicator is mixed
throughout the total blood volume, without having been metabolized
or otherwise eliminated from the circulatory system, may then be
determined from the fluorescence curve. FIG. 10 illustrates one way
that this may be done, the intensity of the fluorescence of an
administered indicator will often rise quickly after the injection,
as illustrated by a sharply rising portion 1001. The intensity may
then decay slowly, as illustrated by a slowly falling portion 1003.
A portion of the curve 1004 during the slow decay may be
extrapolated until it intercepts a point 1005 on the fast rising
portion. The level of the intensity of the fluorescence at the
point 1005 may represent the concentration of the indicator after
it is administered and mixed throughout the total blood volume,
with no offset for metabolic elimination, i.e., the concentration
of the indicator that was computed above.
[0096] Based on this extrapolated point, a conversion factor may
then be determined that converts the measured intensity of the
fluorescence to the concentration of the indicator in the
cardiovascular system. The conversion factor may be determined by
equating it to the ratio of the concentration of the indicator that
was calculated above to the measurement of the intensity of the
fluorescence at the intercepted point. The concentration of the
indicator at other points on the fluorescence intensity curve shown
in FIG. 10 may then be computed by multiplying the measured
fluorescence intensity value by the conversion factor.
[0097] Subsequent administrations of indicator may be made and
measured to monitor the cardiovascular parameter over short or long
periods of time. The same computational process as is described
above may be used each time to determine the absolute physical
value of the desired cardiovascular parameter without having to
again take a blood sample. The process may also intrinsically
compensate for changes between measurements, other than changes in
blood volume, such as changes in the operating characteristics of
the test equipment, the optical properties of the tissue being
illuminated, and/or the positioning of the illumination source
and/or the photo detector.
[0098] All of the foregoing computations, as well as others, may be
automatically performed by a computing system. The computing system
may include any type of hardware and/or software.
[0099] Results obtained using this system can be normalized for
comparison between subjects by expressing cardiac output as a
function of weight (CO/body weight (L/min/kg)) or as a function of
surface area (cardiac index=CO/body surface area
(L/min/m.sup.2)).
[0100] Blood volume calculations. In some embodiments, blood volume
may be measured independently or in addition to the cardiac output.
General methods of measuring blood volume are known in the art. In
some embodiments, circulating blood volume may be measured using a
low dose of indicator which is allowed to mix within the
circulatory system for a period of time selected for adequate
mixing, but inadequate or the indicator to be completely
metabolized. The circulating blood volume may then be calculated by
back extrapolating to the instant of injection the slow metabolic
disappearance phase of the concentration curve detected over time
(Bloomfield, D. A. Dye curves: The theory and practice of indicator
dilution. University Park Press, 1974). Alternative methods of
calculation include, but are not limited to those described in U.S.
Pat. No. 5,999,841, 6,230,035 or 5,776,125, herein incorporated by
reference. This method and system may be used to examine the
general cardiovascular health of a subject. In one embodiment, the
method may be undertaken one time, such that one cardiac output and
or blood volume measurement would be obtained. In other
embodiments, the method may be undertaken to obtain repeated or
continuous measurements of cardiovascular parameters over time.
Further, repeated measures may be taken in conditions where the
cardiovascular system is challenged such that a subject's basal and
challenged cardiovascular parameters can be compared. Challenges
which may be utilized to alter the cardiovascular system include,
but are not limited to exercise, treatment with biologically active
agent which alter heart function (such as epinephrine),
parasympathetic stimulation (such as vagal stimulation), injection
of liquids increasing blood volume (such as colloidal plasma
substitutes) or exposure to enhanced levels of respiratory
gases.
[0101] A schematic of one embodiment of a system 10 useful in the
present invention is shown in FIG. 1. The system comprises an
illumination source 12 here a 775 nm laser selected to emit an
excitation wavelength of light 14 which maximally excites ICG, the
indicator selected. Here the illumination source 12 is positioned
proximately to the subject 16, such that the excitation wavelength
of light 14 is shone transdermally onto the indicator circulating
in the bloodstream. The system also comprises a photodetector 20
placed in proximity to the subject's skin surface 18 for detection
of the indicator emission wavelength 22. Optionally, a filter 24
may be used for isolating the peak wavelength at which the
indicator emits, being about 830 nm. Finally, the photodetector 20
is operably connected to a microprocessor 26 for storing the
electronic signals transmitted from the photodetector 20 over time,
and generating the indicator concentration curve (FIG. 2).
Optionally, the microprocessor 26 may regulate the illumination
source to coordinate the excitation and detection of emissions from
the indicator, for example using a modulation technique. The
microprocessor may also comprise software programs for analyzing
the output obtained from the detector 20 such that the information
could be converted into values of cardiac output or blood volume,
for example and/or displayed in the form of a user interface.
[0102] In order to demonstrate the utility of the invention, a
non-invasive indicator detection system 10 of the invention was
used to repeatedly monitor cardiac output. With reference to FIG.
1, a fiber optic 12b transmitted light from illumination source 12a
to the subject's skin 18. A second fiber optic 20b, positioned near
the skin 18 transmitted the emitted light to a photodetector 20.
The indicator was intravenously injected. A body portion which
included blood vessels near the surface of the skin was irradiated
with a laser. A characteristic fluorescence intensity/concentration
curve was obtained upon excitation with laser light at about 775 nm
and detection of the fluorescence at about 830 nm. From this
information cardiac output and blood volume for the subject was
calculated.
[0103] The system used for this method may comprise a variety of
additional components for accomplishing the aims of this invention.
For example, non-invasive detection is described for monitoring of
indicators within the circulatory system of the patient.
Modifications of the detectors to accommodate to various regions of
the patient's body or to provide thermal, electrical or chemical
stimulation to the body are envisioned within the scope of this
invention. Also, calibration of the system may be automated by a
computing system, such that a blood sample is drawn from the
patient after administration of the indicator, concentration
detected and compared with known standards and/or the emission
curve. Also, software may be used in conjunction with the
microprocessor to aid in altering parameters of any of the
components of the system or effectuating the calculations of the
cardiovascular parameters being measured. Further, software may be
used to display these results to a user by way of a digital
display, personal computer or the like.
A System of Repetitive Measurements of Cardiac Output in Freely
Moving individual
[0104] During check ups and related procedures, physicians may
benefit from observing the cardiac output data of the patient at
different times while the patient is performing an exercise routine
(i.e. jogging on a treadmill). Therefore, a repeated cardiac output
measurement routine is performed on the patient at different heart
rates. For example, the first cardiac output of the patient may be
measured when the patient is at rest and then at the median and
near maximum effort while on the exercise equipment. It may be very
inconvenient for the patient to freely move around and perform a
given exercise while being wired to a machine. In an alternative
embodiment of the present cardiac output systems and methods, the
system may comprise a repetitive cardiac output measuring system to
collect data from a freely moving individual, such as the exemplary
system depicted in FIG. 13. The system may use a method of dye
dilution to monitor cardiac output performance in
individuals/patients. The system includes two major components. The
first component would be worn by the individual as an arm or
forearm band/bracelet, and referred to as a calibration and
delivery system (or "CDS") 100. The second component may include a
sensing device that transmits and receives light of different
intensity that may also be worn by the individual, wherein the
transmitting and the receiving elements of the device rest against
the individual's skin. In an exemplary embodiment, the component
may be placed against the individual's ear to target the ear lobe,
as depicted by the ear lobe sensor (or "ELS") 111 in FIG. 13.
Communication between the CDS and the ELS may either be through a
hard wired or a wireless configuration. In either setup the CDS may
communicate bidirectionally and wirelessly with a remote external
device such as a PDA/laptop/desktop computer 115 through a wireless
dongle 112. In the hard wired configuration the CDS may provide
power and data storage to the ELS. The CDS may also provide a
communication link between the ELS and the dongle 112. In the
wireless configuration the ELS would own its power source (i.e.
Battery 123) and may communicate directly and wirelessly with the
remote dongle.
[0105] The CDS may include circuitry and processing section 101 to
control its functions. As depicted in FIG. 13 the CDS may contain
the calibration and delivery docking stations 102 and 105,
respectively. Theses stations may hold the removable calibration
and dye delivery docks 104 and 106, respectively, in place. The
calibration dock 104 may hold the calibration cartridge 109 onboard
and the dye delivery dock 106 may hold the dye delivery
cartridge(s) 107.
[0106] The exemplary system of FIG. 13 further includes a dye
mixing station 114 external to the CDS for preparing the dye
delivery cartridge(s) 107 prior to loading on the removable dye
delivery dock 106. The mixing station may be equipped with slots
113 to hold cartridge(s). Turing to FIG. 14, a dye delivery
cartridge 107 is shown that includes separately sealed chambers
116, 117, and 118 having the dye, sterile water and the sterile
saline, respectively. Each of the dye delivery cartridge(s) may be
made of a transparent material (i.e. transparent plastic). The area
of the cartridge 107 covering the delivery dye may be opaque to
block light from reaching the dye. The mixing station may
sequentially break the seals in between the chambers, wherein the
dye 116 and the sterile water 117 may get mixed first and then the
mixture of the two may be mixed with the sterile saline 118.
[0107] Turning to FIG. 15, a calibration cartridge 109 is depicted
that includes sealed chambers 119, 120, and 121 holding the dye,
sterile water and an empty chamber "under vacuum", respectively,
and may be made of a transparent material as in the dye delivery
cartridge. The mixing station 114 may will be configured to break
the seals and sequentially mix the dye 119 and the sterile water
120 first, and then the "under vacuum" chamber 121 may be exposed
to the mixture. In addition to the calibration cartridge 109, the
calibration dock 104 may be loaded with a final calibration
cartridge 110 as depicted in FIG. 16. The final calibration
cartridge 110 may include one chamber that may be under vacuum and
may be used at the end of a typical repetitive cardiac output
procedure to draw final blood sample from the individual. The drawn
sample, having some concentration of the dye present, may be used
to determine the blood volume within the individual's
cardiovascular system based on the concentration of the dye.
[0108] Both the calibration and dye delivery docks 104 and 106 may
contain holders within them for special cartridges that may be
attached to valve controlled flow systems that may allow the
cartridges to be filled with blood or eject their contents (e.g.
through a peristaltic mechanism) into the blood stream.
[0109] Referring back to FIG. 13, the electronics 101 of the CDS
may provide for bidirectional communication between the cardiac
output signals with the ELS and the dongle 112 as well as control
programming of the other hardware such as dye delivery dock. The
detected fluorescence intensity signal from the ELS 111 that is
attached to the individual's ear may be relayed to the dongle 112
through the CDS in the hardwired mode. The signal from the ELS at
different dye delivery times may be received by the dongle. The
dongle may interpret the received signals to determine the cardiac
output of the individual. The data may then be communicated to the
external computer for filing or to generate a corresponding profile
of the measured cardiac output data of the Individual.
[0110] The ELS may include a light emitting element 122 and
receiving elements 124 (e.g. a laser diode and a photosensor). The
transmitting and receiving elements could either be positioned at
opposite sides in transmission mode (as shown with opposite views
shown in FIG. 13) or at the same side for reflection mode
detection.
[0111] FIG. 17 depicts an exemplary embodiment of repetitive
measurement of cardiac output in freely moving individuals using
the system of FIG. 13. The process begins by initializing the CDS
with the patient's data. This process is shown in FIG. 18. The
computer may make a communication link with the CDS through the
wireless dongle 112 of FIG. 13. The dongle may contain all the
COMPS software necessary for CDS operations, data collection, data
interpretation, and maintaining individual's records. The CDS may
be in communication with the ELS in the hardwired mode. Based on
the weight of the individual the required amount of dye (i.e. ICG)
will be determined and filled in each of the dye delivery
cartridges.
[0112] Returning to FIG. 17, the miniature dye delivery cartridge
is prepared, as shown in the block diagram of FIG. 19. Upon
determining the appropriate dye amount for each dye delivery
cartridge, the cartridge may be loaded on the mixing station 114.
As discussed previously, the chambers of the dye delivery cartridge
107 may be mixed in sequence. The mixed cartridge may be
transported back to the dye delivery dock of the CDS.
[0113] Next, the miniature dye calibration cartridge may be placed
on the mixing station 114. The calibration cartridge may also be
mixed accordingly in the sequence, as discussed above, and
transported to the calibration dye delivery dock.
[0114] Turing back to FIG. 17, the CDS and the ELS may be placed on
the individual. The CDS may have the calibration and dye delivery
docks 104 and 106, respectively, on board having their cartridges
loaded.
[0115] Next the IV lines may be attached to the individual/patient.
The system may have IV-1 and IV-2 lines to communicate the
dye/blood between the individual and the CDS. As shown in the block
diagram of FIG. 21 the IV-1 line first end may be attached to the
calibration dock port and the other end may be inserted to the
individual's vein (i.e. medial cubital vein). Accordingly, the IV-2
line first end may be attached to dye delivery dock port and the
opposite end may be inserted to the individual's vein (i.e.
superficial dorsal vein of the hand).
[0116] The next step in FIG. 17 is the dye calibration step,
wherein the dye in the exemplary embodiment is ICG. FIG. 22 depicts
the block diagram of the dye calibration routine. Here the
calibration cartridge that was previously loaded into the
calibration dock may be used to calibrate the dye fluorescence and
it's concentration in the blood sample. The calibration station 131
in CDS may include flaps (not shown) that may act as a fastening
gate that holds the calibration dock in the station 131. The
calibration docking station may also include plurality of
photodetectors 103 located on the bottom of the calibration docking
station. The photodetectors may be positioned under the calibration
dock and configured to illuminate the transparent calibration and
final calibration cartridges placed in the calibration dock. In the
exemplary embodiment of the CDS, the photodetectors may be
positioned side by side as shown in the station 102.
[0117] The flaps placed over the calibration cartridges may include
a plurality of light emitting devices such as diodes (LEDs), lasers
or diode lasers (not shown). The light emitting elements on the
flaps may be positioned directly opposite to the photodetectors in
the station. The emitting elements may also be positioned side by
side on the flaps directly across the opposing photodetectors 103.
The exact location of the light emitting elements and the
corresponding photodetectors are not limited to the present
exemplary configuration. Their location within the calibration
station can easily be interchanged or they may be installed on the
side wall of the station rather than at top and bottom. The
emitting elements and photodetectors may even be installed on the
same side (such as the bottom of the station 102) in the reflection
mode calibration.
[0118] The calibration step of FIG. 22 may be initiated by drawing
a blood sample from the individual through the IV-1 line setup
above into the "under vacuum" chamber of the calibration cartridge,
which will be mixed with the previously mixed dye. The
corresponding light emitting element located over the cartridge may
illuminate the mixture and the photodetector may receive the
transmitted/reflected fluorescence. Upon receiving the signals the
CDS transmits the signals to the external dongle for
interpretation.
[0119] Once the calibration of the dye and its concentration
measurement in the blood sample are complete, the next step in FIG.
17 is to initiate the repetitive cardiac output measurement process
for the individual. This step is depicted in the routine of the
block diagram of FIG. 23.
[0120] The dye delivery station starts delivering the dye using the
first dye delivery cartridge to the individual's cardiovascular
system through the IV-2 line. A predetermined time is set to let
the dye concentration reach the target area. The patient's earlobe
serves as the target area in this exemplary embodiment. Once the
dye has reached the target area, the ELS initiates the transmitting
of a predetermined wavelength of light by the transmitting element
122 to the earlobe. The receiver element 124 of the ELS detects the
transmitted/reflected fluorescence light from the earlobe. The ELS
reads the received signal for a predetermined time once enabled.
The signal from the ELS is communicated to the CDS and is further
communicated by the CDS to the external dongle 112 of the system of
FIG. 13. The dongle may interpret the received signal from the CDS
and maintain individual's record. This first dye delivery step may
preferably be initiated when the individual is at rest having
normal pulse rate.
[0121] The next dye injection to the individual's cardiovascular
system may be delayed by some time to allow the previously injected
dye in the cardiovascular system to be cleared from the
circulation. In the exemplary embodiment approximately an
approximately five minute wait time may be sufficient to inject the
dye from the second dye delivery cartridge. Various wait times may
be used in different embodiments. The second dye injection step may
be initiated after the individual has reached a higher pulse rate,
such as when the heart rate is elevated by 20%. Again as in the
first injection, the dongle may receive the fluorescence signal and
perform interpretation of the signal to generate the cardiac output
value.
[0122] In some embodiments, a third dye concentration may be
injected from the delivery dock. The wait time for this injection
may be longer than that of the second dye injection due to the
presence of more concentration of dye present in individual's
cardiovascular system and the time for it to be cleared. In this
embodiment a 15 minute wait time may be sufficient before
administering the third injection. This step may preferably be
initiated when the pulse rate of the individual has elevated even
higher (for example by 80%).
[0123] The repetitive cardiac output measuring process above is not
necessarily limited to any type of dye, the wait time before each
injection, or the target pulse rate at which the individual is
injected with the dye. A skilled practitioner in this field could
use the most appropriate dye, wait time and pulse rate for a given
application.
[0124] The external dongle 114 receiving the signals from the CDS
may be able to interpret the cardiac output data and relay them to
the external computer to generate a profile of the received
data.
[0125] In addition to the above repetitive cardiac output measuring
process of FIG. 17, after the final injection of dye to the
individual a final blood sample may be drawn from the individual
into the final cartridge of the calibration dock 104. The
corresponding light emitting element on the flaps (not shown) and
the photodetector 103 may be enabled. The transmitted/reflected
signal may be processed by the CDS and sent to the external dongle.
Through this last step the total blood volume of the individual may
also be calculated.
[0126] The communication and control of the system of FIG. 13 could
be accomplished by computer software. The dye release to the
individual may either be through initiation of an operator manually
or automatically by the system. In automatic dye delivery mode the
dye delivery timing may be programmed into the CDS.
[0127] The operation of the system of FIG. 13 is not in any way
limited to the exemplary embodiment of FIGS. 17-23. The system can
operate in more than one way. Various modifications to this
embodiment will be readily apparent to those skilled in the art,
and the principles defined herein may be applied to other
embodiments without departing from the spirit or scope of the
system of FIG. 13.
[0128] The following examples further illustrate exemplary
embodiments of the invention, which are not intended to be
limiting.
EXAMPLE 1
[0129] Experimental system and method. An implementation of the
system and method of this invention was tested in rats. The
excitation source was a 775 nm pulsed diode laser and the
fluorescence was detected with a detector being a photomultiplier
(PMT) with extended response in the near-infrared range of the
spectrum (FIG. 1). Optic fibers were placed in close contact with
the skin of the animal's ear for the excitation and detection of
the indicator within the blood stream. After injection of a
100.quadrature.l bolus of ICG (0.0075 mg/ml) into the jugular vein
of a rat, the fluorescence intensity trace (indicator concentration
recording) was measured transcutaneously at the level of the rat's
ear using reflection mode detection of emissions (FIG. 2).
[0130] Calculation of blood volume and cardiac output. The initial
rapid rise and rapid decay segments of the fluorescence intensity
trace represent the first pass of the fluorescent indicator in the
arterial vasculature of the animal. Such a waveform is
characteristic of indicator dilution techniques. This portion of
the recording is analyzed with one of several known algorithms
(i.e. Stewart Hamilton technique) to compute the "area under the
curve" of the fluorescence intensity trace while excluding the
recirculation artifact. Here, the initial portion of the
fluorescence trace y(t) was fitted with a model equation
y(t)=y.sub.0t.sup..quadrature.exp(-.quadrature.t) which
approximates both the rising and descending segments of the trace.
This equation derived from a "tank-in-series" representation of the
cardiovascular system has been found fit well the experimental
indicator dilution recordings. The numerical parameters of the fit
were determined from the approximation procedure, and then the
"area under the curve" was computed by numeric integration and used
to find the cardiac output with the known formula: Q = m .intg. 0
.infin. .times. C .function. ( t ) .times. d t = amount .times.
.times. injected area .times. .times. under .times. .times. the
.times. .times. curve ##EQU1##
[0131] Back extrapolation of the slow decay segment of the
fluorescence intensity trace to the instant when ICG is first
detected in the blood (time 0) yields the estimated concentration
of ICG mixed in the whole circulating blood volume. By dividing the
amount of injected ICG by this extrapolated ICG concentration at
time 0, the circulating blood volume was computed.
[0132] Calibration methods. Indicator concentration C(t) was
computed from the fluorescence y(t) using one of two calibration
methods. Transcutaneous in vivo fluorescence was calibrated with
respect to absolute blood concentrations of ICG, using a few blood
samples withdrawn from a peripheral artery after bolus dye
injection of ICG. The blood samples were placed in a fluorescence
cell and inserted in a tabletop fluorometer for measurement of
their fluorescence emission. The fluorescence readings were
converted into ICG concentrations using a standard calibration
curve established by measuring with the tabletop fluorometer the
fluorescence of blood samples containing known concentrations of
ICG.
[0133] An alternative calibration procedure which avoids blood loss
uses a syringe outfitted with a light excitation--fluorescence
detection assembly. The syringe assembly was calibrated once before
the cardiac output measurements by measuring ICG fluorescence in
the syringe for different concentrations of ICG dye in blood
contained in the barrel of the syringe. During the measurement of
cardiac output, a blood sample was pulled in the syringe during the
slow decay phase of the fluorescence trace that is the phase during
which recirculating dye is homogeneously mixed in the whole blood
volume and is being slowly metabolized. The fluorescence of that
sample was converted to concentration using the syringe calibration
curve and then related to the transcutaneous fluorescence reading.
So long as the ICG concentrations in blood remain sufficiently low
(<0.001 mg/ml), a linear relationship can be used to relate
fluorescence intensity to concentration.
[0134] Either one of these calibration methods can be developed on
a reference group of subjects to produce a calibration nomogram
that would serve for all other subjects with similar physical
characteristics (i.e., adults, small children etc.). This is
advantageous over prior methods at least in that an additional
independent measurement of the blood hemoglobin concentration for
computation of the light absorption due to hemoglobin is not
required.
EXAMPLE 2
A. A Sample Method and System for Measuring Cardiac Output and
Blood Volume
[0135] Experiments have been performed in New Zealand White rabbits
(2.8-3.5 Kg) anesthetized with halothane and artificially
ventilated with an oxygen-enriched gas mixture (FiO2.about.0.4) to
achieve a SaO2 above 99% and an end-tidal CO2 between 28 and 32 mm
Hg (FIG. 4). The left femoral artery was cannulated for measurement
of the arterial blood pressure throughout the procedure. A small
catheter was positioned in the left brachial vein to inject the
indicator, ICG. Body temperature was maintained with a heat
lamp.
[0136] Excitation of the ICG fluorescence was achieved with a 780
nm laser (LD head: Microlaser systems SRT-F780s-12) whose output
was sinusoidally modulated at 2.8 KHz by modulation of the diode
current at the level of the laser diode driver diode (LD Driver:
Microlaser Systems CP 200) and operably connected to a
thermoelectric controller (Microlaser Systems: CT15W). The
near-infrared light output was forwarded to the animal preparation
with a fiber optic bundle terminated by a waterproof
excitation-detection probe. The fluorescence emitted by the dye in
the subcutaneous vasculature was detected by the probe and directed
to an 830 nm interferential filter (Optosigma 079-2230) which
passed the fluorescence emission at 830.+-.10 nm and rejected the
retro-reflected excitation light at 780 nm. The fluorescence
intensity was measured with a photomultiplier tube (PMT; such as
Hamamatsu H7732-10MOD) connected to a lock-in amplifier (Stanford
Research SR 510) for phase-sensitive detection of the fluorescence
emission at the reference frequency of the modulated excitation
light. The output of the lock-in amplifier was displayed on a
digital storage oscilloscope and transferred to a computer for
storage and analysis.
[0137] In most experiments, one excitation-detection probe was
positioned on the surface of the ear arterialized by local heating.
In some studies, the laser emission beam was separated in two beams
with a beam splitter and directed to two measurement sites (ear
skin and exposed right femoral artery). Two detection systems
(PMT+lock in amplifier) were used for measurement of the
fluorescence dilution traces from the two sites. In all
experiments, a complete record of all experimental measurements
(one or two fluorescence traces, arterial blood pressure, end-tidal
CO2, Doppler flow velocity) was displayed on line and stored for
reference.
[0138] Calculations. A LabView program was used to control the
oscilloscope used for sampling the fluorescence dilution curves,
transfer the data from the oscilloscope to a personal computer and
analyze the curves online for estimation of the cardiac output and
circulating blood volume. As shown on the program user interface
(FIG. 5), the measured fluorescence dilution trace (a) is converted
to ICG blood (b) using the calibration parameters estimated as
described in the next section of this application and fitted to a
model: C(t)=C.sub.0t.sup..alpha.exp(-.beta.t).
[0139] The model fit is performed from the time point for which the
fluorescent ICG is first detected to a point on the decaying
portion of the trace that precedes the appearance of recirculating
indicator (identified from the characteristic hump after the
initial peak in the experimental trace). The model equation is used
to estimate the "area under the curve" for the indicator dilution
trace. The theory of indicator dilution technique predicts that the
area under the concentration curve is inversely proportional to the
cardiac output (Q): m/.sup..infin..sub.0.intg. C(t)dt.
[0140] Where m is the mass amount of injected indicator and c(t) is
the concentration of indicator in the arterial blood at time t. The
program also fits the slow decaying phase of the measurement to a
single exponential to derive the circulating blood volume from the
value of the exponential fit at the time of injection. For the
experimental ICG trace shown in FIG. 4, the estimated cardiac
output is 509 ml/min and the circulating blood volume is 184 ml, in
the expected range for a 3 Kg rabbit. This computer program is
advantageous in that it improved the ability to verify that the
experimental measurements are proceeding as planned or to correct
without delay any measurement error or experimental
malfunction.
[0141] Indicator dosage. In this experiment is was found that a
dose of about 0.045 mg injected ICG was optimal in this animal to
allow for detection of an intense fluorescence dilution curve and
at the same time rapid metabolic disposal of the ICG. Further, with
this small dose cardiac function measurements could be performed at
about intervals of 4 minutes or less.
[0142] Detector placement. Defined fluorescence readings were
obtained by positioning the detection probe above the skin surface
proximate to an artery or above tissue, such as the ear or the paw
arterialized by local heating.
B. Calibration of Transcutaneous Indicator Intensity and
Circulating Indicator Concentration
[0143] Calibration of the transcutaneous fluorescence intensity
measured at the level of the animals' ear as a function of ICG
concentration in blood was performed as follows. A high dose of ICG
(1 mg) was injected intravenously and equilibrated homogeneously
with the animal's total blood volume in about a one minute period.
At equilibrium, the blood ICG concentration resulting from this
high dose is several times larger than the peak ICG concentration
observed during the low dose ICG injections (0.045 mg) used to
measure the cardiac output. In this way, a calibration curve was
created that accommodated the full range of ICG concentrations
observed during the cardiac function measurements.
[0144] As the liver metabolizes ICG, the blood ICG concentration
decreases back to 0 in about 20 minutes. During that time period, 5
to 8 blood samples (1.5 ml) were withdrawn from the femoral artery
and placed in a pre-calibrated blood cuvette. The fluorescence
intensity of the blood in the cuvette was converted to a
measurement of concentration using the known standard curve of
fluorescence intensity versus ICG concentration established for the
cuvette. ICG fluorescence was measured at the level of the ear at
the exact time of the blood sample withdrawal. Because ICG is
homogeneously equilibrated in the animal's blood volume, when the
blood samples are withdrawn, the fluorescence intensity measured at
the level of the ear corresponds directly to the ICG blood
concentration at the time of the measurement and therefore the ICG
concentration determined from the cuvette reading. As this example
shows, transcutaneous ICG fluorescence is proportional to blood ICG
concentration such that a single blood withdrawal can suffice to
find the proportionality factor between the two quantities.
[0145] As shown in FIG. 5, the transcutaneous ear fluorescence
intensity (in V) as a function of time (in s) after the high dose
(1 mg) ICG injection during the calibration sequence. FIG. 5 shows
the characteristic first order exponential decay of ICG in blood as
the dye is being metabolized. FIG. 6 shows the ICG concentration
(in mg/ml) as a function of the in vivo fluorescence for the same
example and the same time points. For the range of concentrations
used in these studies, ICG concentration and transcutaneous
fluorescence were linearly related. The calibration line passes
through the origin of the axes since there is no measured
fluorescence when the ICG blood concentration is 0.
[0146] Thus, a simple proportionality factor exists between blood
ICG concentration and transcutaneous fluorescence. This feature of
the fluorescence dilution technique measuring light emission is
advantageous over the conventional dye dilution technique based on
ICG absorption which requires light absorption caused by ICG to be
separated from light absorption by tissue and blood. After the
proportionality factor is determined, ICG fluorescence dilution
profiles can only then are converted into concentration
measurements for computation of the cardiac output using the
indicator-dilution equation.
[0147] Results of cardiac output measurements. Calibrated cardiac
output readings have been obtained in 8 animals (body wt:
3.0.+-.0.2 Kg). The following table lists the values during
baseline conditions. The values are presented as the mean .+-.
standard deviation of three consecutive measurements obtained
within a 15 min period. TABLE-US-00001 TABLE 1 Exp. Cardiac output
(ml/min) 1 530 .+-. 15 2 500 .+-. 17 3 370 .+-. 12 4 434 .+-. 16 5
481 .+-. 6
[0148] The average for the five experiments (463 ml/min) is in
order of reported cardiac outputs (260-675 ml/min) measured with
ultrasound or thermodilution techniques in anesthetized rabbits
(Preckel et al. Effect of dantrolene in an in vivo and in vitro
model of myocardial reperfusion injury. Acta Anaesthesiol Scand,
44, 194-201, 2000. Fok et al. Oxygen consumption by lungs with
acute and chronic injury in a rabbit model. Intensive Care Med,
27,1532-1538, 2001). Basal cardiac output varies greatly with
experimental conditions such as type of anesthetic, duration and
depth of anesthesia, leading to the wide range of values found in
the literature. In this example, the variability (standard
deviation/mean) of the calculated cardiac output with fluorescence
dilution is .about.3% for any triplicate set of measurements which
compares favorably with the reported variability for the
thermodilution technique (.about.5-10%).
C. Comparison of Measurements Obtained by Fluorescence Dilution
Cardiac Output Method Via Transcutaneous Measurement and
Subcutaneous Measurement
[0149] Experimental methodology. The experimental preparation
described in the preceding section (Example 2) includes two
measurement sites for the fluorescence dilution traces: a
transcutaneous site at the level of the ear central bundle of blood
vessels and the exposed femoral artery. The ear vasculature is
arterialized by local heating. With this preparation, the cardiac
output estimates obtained from the peripheral non-invasive
(transcutaneous) measurement site were compared with estimates
obtained by interrogating a major artery.
[0150] The intensity of the fluorescence signal at the level of the
exposed femoral artery during the slow metabolic disappearance
phase of the injected ICG is compared to the calibrated ear
fluorescence measurement to derive a calibration coefficient
(arterial ICG fluorescence into ICG blood concentration). In this
way cardiac output estimates expressed in ml/min were derived from
the two sites.
[0151] Results. FIG. 8 shows the time course of the cardiac output
measurements obtained from the ear site and from the exposed
femoral artery in a representative experiment during control
conditions (C), intense then mild vagal stimulation (S,I and S,M),
and post-stimulation hyperemia (H). Near-identical estimates of the
cardiac output are obtained from the two sites during all phases of
the study.
[0152] The relationship between cardiac output derived from
measurement of the fluorescence dilution curve at the level of the
skin surface (COskin, in ml/min) and at the level of the exposed
femoral artery (COfem, in ml/min) was investigated. The linear
relationships between the two measures are summarized in the table
below: TABLE-US-00002 TABLE 2 Regression Number Exp. Linear
regression Coef. measurements 1 COskin = 0.65(.+-.0.11) * 0.81 22
COfem + 145.0 (.+-.54.0) 2 COskin = 1.01(.+-.0.06) * 0.96 27 COfem
+ 2.0 (.+-.22.0) 3 COskin = 1.05(.+-.0.14) * 0.91 13 COfem - 56.0
(.+-.54.0)
[0153] The two measures of fluorescence cardiac output are tightly
correlated. In the last two experiments, the slope of the
regression line is not statistically different from 1.0 and the
ordinate is not different from 0.0 indicating that the two
measurements are identical. These observations suggest that
fluorescence dilution cardiac output can be reliably measured
transcutaneously and from a peripheral site of measurement that has
been arterialized by local application of heat. Attenuation of the
excitation light and ICG fluorescence emission by the skin does not
prevent the measurement of well-defined dye dilution traces that
can be analyzed to derive the cardiac output.
[0154] While the specification describes particular embodiments of
the present invention, those of ordinary skill can devise
variations of the present invention without departing from the
inventive concept.
D. Comparison of Measurements Obtained by Fluorescence Dilution
Cardiac Output Method and Doppler Flow Velocity Technique
[0155] Experimental methodology. The present method was compared
with an ultrasonic Doppler velocity probe method to record cardiac
output measurements. In this example the above procedure was
modified in that, the animal's chest was opened with a median
incision of the sternum and a 6 mm 20 MHz Doppler velocity probe
was gently passed around the ascending aorta and tightened into a
loop that fits snuggly around the aorta.
[0156] For detection of the fluorescent detection of the indicator,
two illumination+detection fiber optic probes were used: one probe
was placed on or above the ear middle vessel bundle and the other
probe was placed in proximity to the dissected left femoral artery.
Local heating to 42 degrees centigrade arterialized the ear
vasculature.
[0157] In this example, two maneuvers were used to change the
cardiac output from its control level: vagal stimulation, which
reduces the cardiac output, and saline infusion, which increases
the circulating volume and cardiac output. The right vagal nerve
was dissected to position a stimulating electrode. Stimulation of
the distal vagus results in a more or less intense decrease of the
heart rate that depends on the stimulation frequency and voltage (1
ms pulses, 3 to 6 V, 10 to 30 Hz). The cardiac output and aortic
flow velocity also decrease during vagal stimulation even though
less markedly than the heart rate decreases because the stroke
volume increases. Saline infusion at a rate of 15-20 ml/min
markedly increases the cardiac output. FIG. 7 shows the time course
of the cardiac output and aortic velocity measurements in one
experiment including control conditions (C), intense then mild
vagal stimulation (S,I and S,M), and saline infusion (I).
[0158] Results. There is consistent tracking of the Doppler aortic
velocity by the fluorescence dilution cardiac output measurement.
The relationship between fluorescence dilution cardiac output and
aortic Doppler flow velocity was investigated in four rabbits. The
linear relationships between fluorescence dilution cardiac output
(CO, in ml/min) and aortic flow velocity signal (VAor, not
calibrated, in Volts) are summarized in the table: TABLE-US-00003
TABLE 3 Regression Exp. Linear regression Coef. Measurements 1 CO =
789(.+-.123) * VAor + 166 0.79 27 (.+-.34) 2 CO = 607(.+-.62) *
VAor + 50(.+-.32) 0.90 24 3 CO = 614(.+-.64) * VAor - 45(.+-.38)
0.90 27 4 CO = 654(.+-.41) * VAor - 3(.+-.29) 0.97 18
[0159] This data indicates that the fluorescence dilution cardiac
output is highly correlated with aortic flow velocity as indicated
by the elevated regression coefficient (.gtoreq.0.9 in 3
experiments). Further, the slopes of the linear regression lines
between fluorescence dilution cardiac output and aortic flow
velocity are similar and statistically not different in the four
studies. This suggests a constant relationship between the two
variables across experiments. The ordinates of regression lines are
not different from 0 in the last three experimental studies, which
suggests absence of bias between the two measures of aortic
flow.
[0160] The results above establish that fluorescence dilution
cardiac output measured transcutaneously tracks the Doppler flow
velocity measured in the ascending aorta.
EXAMPLE 3
Comparison with Thermodilution Method
[0161] Experimental methodology. Other experiments were performed
in New Zealand White rabbits using the methodology described for
the preceding example 2. In addition, a 4 F thermodilution balloon
catheter was inserted into the right femoral vein and advanced
until the thermistor reached the main pulmonary artery. Correct
placement of the catheter tip was verified visually through the
thoracotomy. The catheter was connected to a cardiac output
computer to measure the thermodilution cardiac output. Cardiac
output measurements were obtained with the present method
(CO.sub.ICG) and the comparison thermodilution method (CO.sub.TD)
during baseline conditions, reduced flow conditions resulting from
vagal stimulation, and increased flow conditions resulting from
blood volume expansion with saline.
[0162] Results. Average values of CO.sub.ICG and CO.sub.TD measured
in baseline conditions in the 10 animals were 412 (.+-.13) ml/min
and 366 (.+-.11) ml/min, respectively, in the expected range for
anesthetized rabbits. In each animal, CO.sub.ICG was linearly
related to CO.sub.TD as shown on the following table 4. The slope
of the regression line (range: 0.74-1.25) was not different from
1.0 in 8 studies. In the combined data from all 10 studies the
linear relationship between CO.sub.ICG and CO.sub.TD had a slope
(0.95.+-.0.03) not different from 1.0 and an ordinate (77.+-.10
ml/min) that was slightly >0. TABLE-US-00004 TABLE 4 Experiment
EQUATION N R 1 CO.sub.ICG = 094.sup..dagger.(.+-.0.08) CO.sub.TD +
84(.+-.23) 21 0.94 2 CO.sub.ICG = 1.25.sup..dagger.(.+-.0.17)
CO.sub.TD - 0*(.+-.39) 17 0.88 3 CO.sub.ICG = 0.74(.+-.0.11)
CO.sub.TD + 122(.+-.26) 20 0.85 4 CO.sub.ICG =
0.90.sup..dagger.(.+-.0.05) CO.sub.TD + 98(.+-.15) 11 0.99 5
CO.sub.ICG = 1.08.sup..dagger.(.+-.0.11) CO.sub.TD + 84(.+-.47) 14
0.94 6 CO.sub.ICG = 1.07.sup..dagger.(.+-.0.09) CO.sub.TD +
16*(.+-.33) 14 0.96 7 CO.sub.ICG = 1.15(.+-.0.06) CO.sub.TD +
29*(.+-.25) 12 0.99 8 CO.sub.ICG = 0.82.sup..dagger.(.+-.0.09)
CO.sub.TD + 83(.+-.37) 12 0.94 9 CO.sub.ICG =
0.88.sup..dagger.(.+-.0.12) CO.sub.TD + 98*(.+-.62) 16 0.89 10
CO.sub.ICG = 1.05.sup..dagger.(.+-.0.08) CO.sub.TD - 20*(.+-.33) 15
0.97 All CO.sub.ICG = 0.95.sup..dagger.(.+-.0.03) CO.sub.TD +
74(.+-.10) 152 0.94
[0163] These studies further established that cardiac output
CO.sub.ICG measured with the present method is linearly related to
thermodilution cardiac output CO.sub.TD. The slope of the
regression line between these variables was near 1.0 for most
experiments, as well as for the grouped data from all
experiments.
EXAMPLE 4
A. Noninvasive Calibration
[0164] One embodiment of the calibration system includes a method
to determine non-invasively transcutaneously the concentration of a
fluorescent indicator injected in the bloodstream by measuring the
intensity of the fluorescence light emitted by the indicator when
illuminated by a light source in or near the skin and the intensity
of the light from that source reflected by or transmitted through
the illuminated skin site.
[0165] In the pulse dye densitometer (Cardiac output and
circulating blood volume analysis by pulse dye densitometry. Iijima
T. et al. Journal of Clinical Monitoring, 13, 81-89, 1997,
incorporated herein in its entirety by reference), light absorption
is measured at two wavelengths: 805 nm where ICG absorption is near
maximum and 890 nm where ICG absorption is very small. Assuming at
first that tissue absorption of light is only due to blood
hemoglobin and ICG, the ratio C.sub.ICG/C.sub.Hb can be expressed
as a function of the ratio .PSI. of the optical densities measured
at 805 nm and 890 nm, C ICG / C Hb = E Hb , 805 - .PSI. .times.
.times. E Hb , 890 .PSI. .times. .times. E ICG , 890 - E ICG , 805
##EQU2##
[0166] where E represents the absorption coefficient from Beer's
Law. The latter is expressed as I.sub.x=I.sub.0 e.sup.-E.C.x with
C=concentration, E=absorption coefficient, x=pathlength in
substance. Note that if we assume that E.sub.ICG,890=0, the ratio
of the concentrations C.sub.ICG/C.sub.Hb is linearly related to the
ratio of the optical densities measured at two wavelengths.
[0167] Taking into account scattering and absorption by other
material beside ICG and Hb, the developers of the pulse dye
densitometer established that the ratio of the optical density
changes between before and after ICG administration at 805 nm and
890 nm could be expressed as a function of the ratio
C.sub.ICG/C.sub.Hb.
[0168] ICG fluorescence is proportional to the absorption of light
by ICG at the wavelength of excitation (805 nm in the model above
or 784 nm in our studies). Therefore, we hypothesized that the
ratio C.sub.ICG/C.sub.Hb can be derived from the ratio of the
change in light signal measured at the wavelength of emission
(related to ICG fluorescence) to the light signal measured at the
wavelength of excitation (related to ICG and Hb absorption).
[0169] We considered a model of light propagation in tissue, which
at first assumed that only hemoglobin and ICG were absorbers (See
Table 5 below). The absorption coefficients of ICG and Hb were
derived from the literature and considered to be independent of
wavelength. We then added a dependence of the absorption
coefficients on wavelength and tissue absorption in the model to
investigate the effect of these factors. TABLE-US-00005 TABLE 5 1-D
model of light propagation and fluorescence generation ##STR1##
##STR2##
[0170] The following data and assumptions were applied to the model
of Table 5: .mu..sub.a,ICG=38.1 .mu.l.mu.g.sup.-1mm.sup.-1 for
wavelength .lamda.=784 nm
.mu..sub.a,HbO2.about..mu..sub.a,Hb=0.0026
.mu.l.mu.g.sup.-1mm.sup.-1 for wavelength .lamda.=784 nm [0171]
Initially, we assume that the absorption coefficients have the same
values at 830 nm (fluorescence) and at 784 nm (incident excitation
light). C.sub.Hb=12-18 gdl.sup.-1=120-180
.quadrature.g/.quadrature.l in blood C.sub.ICGmax=0.005
.quadrature.g/.quadrature.l in blood
[0172] Tissue assumed to contain 10% blood
[0173] Quantum yield of ICG fluorescence=0.04
[0174] Transmission calculated through 40 mm tissue in 0.02 mm
increment
[0175] We modeled transmission and fluorescence signals at 784 nm
and 830 nm for different ICG concentrations and hemoglobin contents
when absorption coefficients are the same, and the results are
illustrated in the graphs of FIGS. 11A-11D. For this simple model,
the transmitted excitation light decreases nonlinearly as a
function of ICG concentration in the model and the curve varies
with the hemoglobin content (see FIG. 11A). Also the emergent
fluorescence light increases nonlinearly with ICG concentration
(inner filter effect), and the curve varies with hemoglobin content
(see FIG. 11B). Thus, the fluorescence signal varies markedly if
there is more or less absorption by blood in the tissue.
[0176] However, the ratio (emergent fluorescence light/transmitted
excitation light) is proportional to the ICG concentration and
independent of the hemoglobin content of the tissue (see FIG. 11C).
Therefore, by measuring the ratio and if the relationship is known,
the ICG concentration can be estimated. Also, the ratio (emergent
fluorescence light y/transmitted excitation light x) is
proportional to the ratio (ICG concentration/Hb concentration) but
in this case the slope varies with the hemoglobin content of the
tissue (see FIG. 11D). In an alternative embodiment of the
calibration system, the concentration of Hb may be obtained from a
blood sample, and this concentration value can be used to determine
the ratio of ICG value to Hb value, which can then be used with the
ratio of transmitted excitation light to fluorescence light to
determine the concentration of ICG for calibration.
[0177] We also modeled transmission and fluorescence signals and at
784 nm and 830 nm for different ICG concentrations and hemoglobin
contents when absorption coefficients are the different and an
additional absorber is included, and the results are illustrated in
the graphs of FIGS. 12A-12D.
[0178] Absorption by ICG is actually slightly more elevated at 784
nm (excitation) than it is at 830 nm (fluorescence peak). In
contrast oxy-hemoglobin absorption is less at 784 nm (excitation)
than it is at 830 nm. In addition to blood hemoglobin and ICG,
bloodless tissue absorbs to a certain extent. We determined various
values from the literature: .mu..sub.a,ICG=38.1
.mu.l.mu.g.sup.-1mm.sup.-1 for wavelength .lamda.=784 nm
.mu.a,HbO2.about..mu..sub.a,Hb=0.0026 .mu.l.mu.g.sup.-1mm.sup.-1
for wavelength .lamda.=784 nm .mu..sub.a,ICG=34.1
.mu.l.mu.g.sup.-1-mm.sup.-1 for wavelength .lamda.=830 nm
.mu..sub.a,HbO2.about..mu..sub.a,Hb=0.0035
.mu.l.mu.g.sup.-1mm.sup.-1 for wavelength .lamda.=830 nm
.mu.a,tissue=0.1mm.sup.-1 independent of wavelength in the range
784-830 nm. C.sub.Hb=12-18 gdl.sup.-1=12-180 .mu.g/.mu.l in blood
C.sub.ICGmax=0.005 .mu.g/.mu.l in blood
[0179] Tissue assumed to contain 10% blood
[0180] Quantum yield of ICG fluorescence=0.04
[0181] Transmission calculated through 40 mm tissue in 0.02 mm
increment
[0182] For this more complete model, the magnitude of the
transmitted excitation light and emergent fluorescent lights are
markedly decreased when compared to the first model primarily
because of the absorption by bloodless tissue. Both signals follow
the pattern found for the simple model. In particular, the emergent
fluorescence light increases nonlinearly with ICG concentration
(inner filter effect) and the curve varies with hemoglobin
content.
[0183] As before the ratio (emergent fluorescence light/transmitted
excitation light) is proportional to the ICG concentration (See
FIG. 12C). While the slope is dependent on the hemoglobin content,
there are only small differences between the four levels of
hemoglobin considered. This suggests that by measuring the ratio of
the fluorescence/transmitted light, the ICG concentration can be
estimated once the linear relationship is determined and possibly
including a factor that accounts for the hemoglobin content.
[0184] While these models do not consider tissue scattering, the
latter is often assumed to increase the pathlength of light in
tissue by a fixed proportionality factor: the pathlength factor
(about 3.6 for human forearm, see Measurement of hemoglobin flow
and blood flow by near-infrared spectroscopy. Edwards A. D. et
al.--J. Appl. Physiol. 75, 1884-1889, 1993, the entire contents of
which are incorporated herein by reference). This suggests that the
model analysis above would likely remain valid even in the presence
of scattering.
[0185] Other biocompatible fluorescent dyes such as fluorescein and
rhodamine would also be suitable in the noninvasive calibration of
the example 4 above. Fluorescein in blood plasma has a peak
fluorescence of about 518.+-.10 nm with an optimal excitation
wavelength of about 488 nm (Hollins, supra; Dorshow, supra).
Rhodamine in blood plasma has a peak fluorescence of about
640.+-.10 nm with an optimal excitation wavelength of about 510
nm.
[0186] The previous description of the disclosed embodiments is
provided to enable any person skilled in the art to make or use the
cardiac output monitor devices, methods and systems. Various
modifications to these embodiments will be readily apparent to
those skilled in the art, and the generic principles defined herein
may be applied to other embodiments without departing from the
spirit or scope of the devices, methods and systems described
herein. Thus, the cardiac output devices, methods and systems are
not intended to be limited to the embodiments shown herein but are
to be accorded the widest scope consistent with the principles and
novel features disclosed herein.
* * * * *