U.S. patent application number 15/201424 was filed with the patent office on 2016-10-27 for methods and systems for measuring and using the oxidation-reduction potential of a biological sample.
The applicant listed for this patent is Aytu BioScience, Inc.. Invention is credited to David Bar-Or, Raphael Bar-Or, Leonard T. Rael.
Application Number | 20160313279 15/201424 |
Document ID | / |
Family ID | 50484353 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160313279 |
Kind Code |
A1 |
Bar-Or; Raphael ; et
al. |
October 27, 2016 |
METHODS AND SYSTEMS FOR MEASURING AND USING THE OXIDATION-REDUCTION
POTENTIAL OF A BIOLOGICAL SAMPLE
Abstract
Methods and systems for measuring and using the
oxidation-reduction characteristics of a biological sample are
provided. The system generally includes a test strip and a readout
device. A fluid sample is placed in the test strip, and the test
strip is in turn operatively connected to the readout device. The
readout device provides a controlled current that is sent across
the fluid in the sample chamber. In addition, the readout device
identifies an inflection point or transition time at which the
voltage between contacts of the test strip is changing at the
highest rate. The oxidation-reduction capacity of the sample is
taken as the integral of the current profile from the time at which
current begins to be supplied to the sample to the identified
transition time.
Inventors: |
Bar-Or; Raphael; (Denver,
CO) ; Bar-Or; David; (Englewood, CO) ; Rael;
Leonard T.; (Centennial, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Aytu BioScience, Inc. |
Englewood |
CO |
US |
|
|
Family ID: |
50484353 |
Appl. No.: |
15/201424 |
Filed: |
July 2, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14061436 |
Oct 23, 2013 |
9410913 |
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15201424 |
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61717511 |
Oct 23, 2012 |
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61868983 |
Aug 22, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 35/16 20130101;
G01N 27/26 20130101; G01N 33/48707 20130101; G01N 33/49 20130101;
G01N 33/48 20130101; G01N 27/4161 20130101; G01N 2800/7009
20130101; G01N 27/4168 20130101 |
International
Class: |
G01N 27/416 20060101
G01N027/416; G01N 33/487 20060101 G01N033/487; G01N 33/49 20060101
G01N033/49 |
Claims
1. A readout device, comprising: a plurality of readout contacts;
an analog front end, including: a current supply; an electrometer,
wherein the current supply is operable to provide a current to
first and second contacts of the plurality of readout contacts, and
wherein the electrometer is operable to read a voltage potential
between the second contact and a third contact of the readout
contacts.
2. The device of claim 1, further comprising: a controller; an
analog to digital converter, wherein the analog to digital
converter connects the electrometer to the controller; a digital to
analog converter, wherein the digital to analog converter connects
the controller to the current supply.
3. The device of claim 2, wherein the controller is operable to
determine an inflection point in the voltage potential, and is
further operable to determine a quantity of the charge supplied
between a first time and the inflection point.
4. The device of claim 3, further comprising: a user interface,
wherein the user interface includes a user output, and wherein the
user output provides a cORP value derived from the determined
quantity of the charge supplied between the first time and the
inflection point.
5. The device of claim 4, further comprising: a connector, wherein
the connector is operative to receive a test strip containing a
fluid sample, wherein the readout contacts are included in the
connector, and wherein the readout contacts are placed in operative
contact with leads of a test strip.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 14/061,436, filed Oct. 23, 2013, which claims the benefit
of U.S. Provisional Patent Application Ser. No. 61/717,511, filed
Oct. 23, 2012, and U.S. Provisional Patent Application Ser. No.
61/868,983, filed Aug. 22, 2013, the entire disclosures of which
are hereby incorporated herein by reference.
FIELD
[0002] The present invention relates to methods and apparatuses for
measuring the oxidation-reduction potential of a fluid sample and
methods of using the same.
BACKGROUND
[0003] Whole blood and blood products, such as plasma and serum,
have oxidation-reduction potentials (ORP). Clinically the ORP of
blood, plasma and serum provides the oxidative status of an animal.
More particularly, the ORP of blood, plasma and serum is related to
health and disease.
[0004] An oxidation-reduction system, or redox system, involves the
transfer of electrons from a reductant to an oxidant according to
the following equation:
oxidant+ne.sup.-reductant (1)
where ne.sup.- equals the number of electrons transferred. At
equilibrium, the redox potential (E), or oxidation-reduction
potential (ORP), is calculated according to the Nernst-Peters
equation:
E(ORP)=E.sub.o-RT/nF ln [reductant]/[oxidant] (2)
where R (gas constant), T (temperature in degrees Kelvin) and F
(Faraday constant) are constants. E.sub.o is the standard potential
of a redox system measured with respect to a hydrogen electrode,
which is arbitrarily assigned an E.sub.o of 0 volts, and n is the
number of electrons transferred. Therefore, ORP is dependent on the
total concentrations of reductants and oxidants, and ORP is an
integrated measure of the balance between total oxidants and
reductants in a particular system. As such, ORP provides a measure
of the overall oxidative status of a body fluid or tissue of a
patient.
[0005] Oxidative stress is caused by a higher production of
reactive oxygen and reactive nitrogen species or a decrease in
endogenous protective antioxidative capacity. Oxidative stress has
been related to various diseases and aging, and it has been found
to occur in all types of critical illnesses. See, e.g., Veglia et
al., Biomarkers, 11(6): 562-573 (2006); Roth et al., Current
Opinion in Clinical Nutrition and Metabolic Care, 7:161-168 (2004);
U.S. Pat. No. 5,290,519 and U.S. Patent Publication No.
2005/0142613. Several investigations have shown a close association
between the oxidative status of a critically ill patient and the
patient's outcome. See Roth et al., Current Opinion in Clinical
Nutrition and Metabolic Care, 7:161-168 (2004).
[0006] Oxidative stress in patients has been evaluated by measuring
various individual markers. See, e.g., Veglia et al., Biomarkers,
11(6): 562-573 (2006); Roth et al., Current Opinion in Clinical
Nutrition and Metabolic Care, 7:161-168 (2004); U.S. Pat. No.
5,290,519 and U.S. Patent Publication No. 2005/0142613. However,
such measurements are often unreliable and provide conflicting and
variable measurements of the oxidative status of a patient. See
Veglia et al., Biomarkers, 11(6): 562-573 (2006); Roth et al.,
Current Opinion in Clinical Nutrition and Metabolic Care, 7:161-168
(2004). The measurement of multiple markers which are then used to
provide a score or other assessment of the overall oxidative status
of a patient has been developed to overcome the problems of using
measurements of single markers. See Veglia et al., Biomarkers,
11(6): 562-573 (2006); Roth et al., Current Opinion in Clinical
Nutrition and Metabolic Care, 7:161-168 (2004). Although such
approaches are more reliable and sensitive than measurements of a
single marker, they are complex and time consuming. Thus, there is
a need for a simpler and faster method for reliably measuring the
overall oxidative status of a patient.
[0007] The oxidation/reduction potential can be measured
electrochemically. Electrochemical devices for measuring ORP of
blood and blood products typically require large sample volumes
(that is, ten to hundreds of milliliters) and long equilibrium
periods. Furthermore, the electrochemical devices have large, bulky
electrodes that require cleaning between sample measurements. Such
electrochemical devices are poorly suited for routine clinical
diagnostic testing. It has been suggested to use electrodes that
have undergone treatment to prevent biofouling. However, such
devices necessarily involve complex manufacturing techniques.
Moreover, conventional electrochemical devices have not provided a
format that is convenient for use in a clinical setting.
[0008] The oxidative and radical characteristics of human blood
plasma and its blood components (such as low density lipoproteins,
serum albumin, and amino acids) can also be determined from photo
chemiluminescence, with and without thermo-initiated free radical
generation. A photo chemiluminescent system generally includes a
free radical generator and a detector that measures
chemiluminometric changes in the presence of an antioxidant. More
specifically, the blood plasma sample (or one of its components)
containing an amount of antioxidant is contacted and reacted with a
known amount of free radicals. The free radicals remaining after
contacting the blood plasma sample are determined
chemiluminometrically. This type of measurement and detection
system is not suitable for rapid, large scale measurements of blood
plasma samples in a clinical setting for assessing or monitoring
human or animal health.
[0009] There remains a need for improved methods and devices for
measuring the oxidation-reduction characteristics of biological
samples. Further, there is a need for use of such improved methods
and devices in novel applications.
SUMMARY
[0010] Embodiments of the present invention are directed to solving
these and other problems and disadvantages of the prior art, and
provide systems and methods for measuring oxidation-reduction
potential (ORP) characteristics (i.e., static oxidation-reduction
potential (sORP) and/or the oxidation-reduction potential capacity
(cORP)) of a fluid. Moreover, the measured ORP can provide
information regarding the status of a subject rapidly and
conveniently in a clinical and/or emergent setting.
[0011] Systems in accordance with embodiments of the present
disclosure generally include a test strip with a reference cell, a
sample chamber, and a plurality of electrodes. The sample chamber
is configured to receive a fluid sample. The system additionally
includes a readout device with contacts for interconnection to the
electrodes of a test strip, a test signal power supply, and an
electrometer. The readout device can additionally include memory
and a processor operable to execute programming code stored in the
memory to operate the power supply and record a voltage sensed by
the electrometer over time.
[0012] More particularly, a system for identifying an oxidative
capacity of a fluid in accordance with embodiments of the present
disclosure can include:
[0013] a fluid sample;
[0014] a test strip, including: [0015] a reference cell; [0016] a
sample chamber; [0017] a counter electrode, wherein a first portion
of the counter electrode extends into the sample chamber; [0018] a
working electrode, wherein a first portion of the working electrode
extends into the sample chamber; [0019] a reference electrode,
wherein the reference electrode is in electrical contact with the
reference cell;
[0020] a readout device, including: [0021] a first contact; [0022]
a second contact; [0023] a third contact; [0024] a test signal
power supply, wherein a first terminal of the test signal power
supply is electrically connected to the first contact, and wherein
a second terminal of the test signal power supply is electrically
connected to the second contact; [0025] an electrometer, wherein a
first input of the electrometer is electrically connected to the
second contact, and wherein a second input of the electrometer is
electrically connected to the third contact; [0026] memory; [0027]
a processor, wherein with the first contact electrically connected
to the counter electrode, the second contact electrically connected
to the working electrode, and the third contact electrically
connected to the reference electrode, and with the fluid sample in
the sample chamber, the processor is operable to execute
programming code stored in the memory to:
[0028] operate the test signal power supply to supply a current
across the sample chamber between the counter electrode and the
working electrode for at least a first period of time;
[0029] during the first period of time, monitor the voltage sensed
by the electrometer;
[0030] identify an inflection point in the voltage sensed by the
electrometer;
[0031] record the time at which the inflection point is
identified.
[0032] The processor can also operate to integrate the current
between a start time and the time at which the inflection point is
reached to obtain an oxidation-reduction capacity of the fluid
sample. Alternatively or in addition, the processor can operate the
test signal power supply to supply the current at a static first
level for a first time segment, and after the first time segment,
operate the test signal power supply to supply the current at a
rising level for at least a second time segment.
[0033] The system can additionally include a readout device
incorporating an output device, wherein the obtained
oxidation-reduction capacity of the fluid sample is output to a
user by the output device. The output can be provided in units of
Coulombs.sup.-1.
[0034] Methods in accordance with embodiments of the present
disclosure include techniques for obtaining ORP characteristics of
a fluid sample. The disclosed methods include applying a current to
a fluid sample, and measuring a voltage across that fluid sample
over a period of time while the current is applied. An inflection
or transition point, such as a point at which the voltage is
changing the fastest, can be identified. The quantity of current
applied between the first period of time and the inflection point
can then be integrated to obtain a value with units of Coulombs
that is indicative of an oxidation-reduction capacity of the fluid
sample. The determined value can then be output, for example for
diagnostic or other purposes.
[0035] In accordance with embodiments of the present disclosure, a
method for measuring oxidation-reduction potential capacity is
disclosed that includes:
[0036] applying a current to a fluid sample;
[0037] measuring a voltage across the fluid sample over a first
period of time, while applying the current to the fluid sample;
[0038] integrating the applied current over the first period of
time to obtain a value indicative of an oxidation reduction
capacity.
[0039] The current can be applied to the fluid sample between a
counter electrode and a working electrode, and the voltage across
the fluid sample can be measured between a reference electrode and
the working electrode.
[0040] In accordance with at least some embodiments of the method,
the current applied to the fluid sample is varied over time.
[0041] The inflection point in the measured voltage can be
identified. In addition, the first period of time over which the
current is integrated can end at a time at which the inflection
point is identified.
[0042] The current can be held constant during at least a first
segment of the first period of time, and the current can be varied
during at least a second segment of the first period of time.
[0043] The first segment of the first period of time can follow the
second segment of the first period of time. Moreover, the current
can be increased at a linear rate during the second segment of the
first period of time. Alternatively, the current can be increased
at an exponential rate during the second segment of the first
period of time. As yet another alternative, the current can be
increased according to a step function during the second segment of
the first period of time.
[0044] According to at least some embodiments, the inflection point
is the point at which the rate of change in the measured voltage is
at a local maximum.
[0045] In accordance with still other embodiments, a readout device
is provided that includes a plurality of readout contacts, and an
analog front end. The analog front end includes a current supply
and an electrometer. The current supply is operable to provide a
current to first and second contacts of the plurality of readout
contacts. The electrometer is operable to read a voltage potential
between the second contact and the third contact of the readout
contacts.
[0046] The readout device can further include a controller and an
analog to digital converter that connects the electrometer to the
controller. In addition, the readout device can include a digital
to analog converter that connects the controller to the current
supply.
[0047] The controller can operate to determine an inflection point
in the voltage potential, and to determine a quantity of charge
supplied between a first time and the inflection point.
[0048] A user interface can be provided that includes a user
output. The user output can provide an oxidation reduction
potential capacity value that is derived from the determined
quantity of the charge supplied between the first time and the
inflection point.
[0049] A connector that is operative to receive a test strip
containing a fluid sample can also be included in the readout
device. The connector includes the readout contacts, and places the
readout contacts in operative contact with leads of the test
strip.
[0050] Additional features and advantages of embodiments of the
present disclosure will become more readily apparent from the
following detailed description, particularly when taken together
with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1 depicts components of a system for measuring the
oxidation-reduction potential capacity of a fluid in accordance
with embodiments of the present invention;
[0052] FIG. 2 illustrates components of a readout device in
accordance with embodiments of the present disclosure;
[0053] FIG. 3 illustrates further aspects of a readout device in
accordance with embodiments of the present disclosure;
[0054] FIG. 4 depicts a test strip in accordance with embodiments
of the present invention;
[0055] FIG. 5 is a flowchart depicting aspects of a method for
measuring oxidation-reduction potential capacity in accordance with
embodiments of the present disclosure; and
[0056] FIG. 6 is a graph depicting a supplied current and a
measured potential difference over time.
DETAILED DESCRIPTION
[0057] Embodiments of the present invention provide systems and
methods for measuring oxidation-reduction potential (ORP)
characteristics (i.e., static oxidation-reduction potential (sORP)
and/or oxidation-reduction capacity (cORP)) of a fluid that are
suitable for rapid, routine clinical diagnostic testing and methods
of using the system to evaluate or monitor the status of a subject.
The system generally includes a test strip and a readout device.
More particularly, embodiments of the present invention can
determine the ORP characteristics of a body fluid of a patient in a
convenient and timely manner. A biological sample of a patient that
can be used in the method of invention can be any body fluid.
Suitable body fluids include a blood sample (e.g., whole blood,
serum or plasma), urine, saliva, cerebrospinal fluid, tears, semen,
vaginal secretions, amniotic fluid and cord blood. Also, lavages,
tissue homogenates and cell lysates can be utilized and, as used
herein, "body fluid" includes such preparations. Preferably, the
body fluid is blood, plasma, serum or cerebrospinal fluid. For head
injuries, the body fluid is most preferably cerebrospinal fluid or
plasma. In cases other than head injuries, the body fluid is most
preferably plasma.
[0058] The test strip generally includes a substrate, a reference
cell, a counter electrode, a working electrode, a reference
electrode, and a sample chamber. In general, by placing a fluid
sample in the sample chamber, an electrical connection is
established between the reference cell, the counter electrode, the
working electrode, and the reference electrode. The test strip can
then be connected to a readout device, for the determination of a
static ORP value and an ORP capacity value.
[0059] The readout device generally includes contacts to
electrically interconnect the readout device to the various
electrodes included in the test strip. In accordance with
embodiments of the present disclosure, the readout device includes
an analog front end. The analog front end generally functions to
provide a controlled current that can be sent across the fluid in
the sample chamber through an electrical connection to the counter
electrode and the working electrode. In addition, the analog front
end is operable to generate a voltage signal that represents the
potential difference between the reference electrode and the
working electrode. An analog to digital (ADC) converter is provided
to convert the voltage signal representing the reference electrode
to working electrode potential difference to a digital signal. A
digital to analog converter (DAC) is provided to convert a digital
control signal to analog signals in connection with the provision
of the controlled current to the test strip. A controller
interfaces with the ADC and the DAC. Moreover, the controller can
include or comprise a processor that implements programming code
controlling various functions of the readout device, including but
not limited to controlling the current supply to the test strip,
and processing the potential difference measurement signal. The
controller can operate in association with memory. In addition, the
readout device includes a user interface, and a power supply.
[0060] FIG. 1 depicts components of a system 100 for measuring the
oxidation-reduction potential (ORP) value, including but not
limited to the static oxidation-reduction value (sORP) and/or the
oxidation-reduction capacity value (cORP), of a fluid sample in
accordance with embodiments of the present disclosure. As used
herein, the sORP is a measured potential difference or voltage
across a fluid sample such as a measured potential difference or
voltage across a fluid sample placed in a test strip that includes
a reference cell as described herein. The cORP as used herein is a
measure of the quantity of charge provided to a fluid sample over a
defined period such as can be measured in a test strip as described
herein. Accordingly, the cORP can be viewed as the capacity of a
fluid sample to absorb an electrical charge supplied as a current
over some defined period. For example, the period can be defined by
a start point corresponding to the initiation of current supply to
a sample and an endpoint such as an inflection point or a midpoint
between a first and a second inflection point. In general, the
system 100 includes a readout device 104, which can implement a
galvanometer, and a test strip 108. The readout device 104 includes
a connector or readout aperture 112 for electrically
interconnecting readout contacts 116 of the readout device 104 to
electrode contacts 120 provided as part of the test strip 108. The
readout device 104 can also incorporate a user interface 124, which
can include a user output 126, such as a display, and a user input
128, such as a keypad. In accordance with still other embodiments,
the user interface 124 can comprise an integrated component, such
as a touch screen interface. In addition to providing contacts 120
for interconnecting the test strip 108 to the readout device 104,
the test strip 108 includes a sample chamber aperture 132 formed in
a test strip overlay 136, to receive a fluid sample in connection
with the determination of an ORP value of that fluid sample.
[0061] FIG. 2 illustrates additional components and features of a
readout device 104 in accordance with embodiments of the present
disclosure. As shown, the readout contacts 116 are interconnected
to an analog front end 220. As described in greater detail
elsewhere herein, the analog front end 220 generally functions to
provide a controlled current that is passed between a counter
electrode and a working electrode of the test strip 108. In
addition, the analog front end 220 functions to provide a voltage
signal representing a potential difference between a reference
electrode and the working electrode of the test strip 108. In
accordance with still further embodiments, the analog front end 220
can include a strip detect circuit, to provide a signal indicating
the interconnection of a test strip 108 to the readout device
104.
[0062] The analog front end 220 generally receives control signals
from a digital to analog (DAC) converter 224. Signals output by the
analog front end 220 are generally provided to an analog to digital
converter (ADC) 228. The DAC 224 and ADC 228 are in turn connected
to a controller 232. The controller 232 may comprise a processor
that is operable to execute instructions stored in memory as part
of the controller 232, or as a separate memory device 236. For
example, the processor, executing instructions stored in memory
236, can implement a process according to which the current
supplied to the test strip 108 is controlled. In addition, the
controller 232 can execute instructions stored in memory 236 to
record the quantity of current supplied to the test strip 108, to
detect an inflection point in the voltage potential between
electrodes of the test strip 108, and to calculate an ORP capacity.
The memory 236 can also function as storage for data, including but
not limited to intermediate and/or final ORP values. The controller
232, for example, can comprise a general purpose programmable
processor or controller or a specially configured application
integrated circuit (ASIC).
[0063] The user interface 124 generally operates to provide user
input to the controller 232. In addition, the user interface 124
can operate to display information to a user, including but not
limited to the status of the readout device 104 or of the system
100 generally, a sORP value, and a cORP value.
[0064] The readout device 104 also generally includes a power
supply 240. Although not shown in the figure, the power supply 240
is generally interconnected to power consuming devices via a power
supply bus. The power supply 240 may be associated with a battery
or other energy storage device, and/or line power.
[0065] With reference now to FIG. 3, additional features of a
system 100 in accordance with embodiments of the present disclosure
are depicted. More particularly, details of the analog front end
220 and of the electrical circuit associated with the test strip
108 are depicted. As shown, the readout contacts 116 interconnect
to the electrode leads or contacts 120, to electrically connect the
analog front end 220 to the test strip 108. In the illustrated
embodiment, the analog front end 220 includes a test strip sense
circuit 304. The test strip sense circuit 304 includes a test strip
detection supply lead 308 and a test strip detection input lead
312. In general, when a suitable test strip 108 is operatively
connected to the readout device 104, continuity between the test
strip detect supply lead 308 and the test strip detection input
lead 312 is established, allowing a test strip detect signal
indicating that a test strip 108 is present to be passed between
the supply 308 and the input 312 leads. Moreover, a test strip 108
can incorporate a resistor or other component to modify the test
strip detect signal, to indicate to the readout device 104
characteristics of the particular test strip 108 that has been
interconnected to the readout device 104, such as the voltage value
of a reference cell incorporated into the test strip 108. In
response to sensing the presence of a test strip 108, the readout
device 104 can operate to provide an interrogation signal in the
form of a controlled current to the test strip 108.
[0066] The current is provided by the readout device 104 to the
sample chamber 132 of the test strip 108 via a counter electrode
lead 316 and a working electrode lead 320. More particularly, the
current may be supplied to the counter electrode lead 316 from the
output of a current follower 324, while the working electrode 320
can be provided as an input to that current follower 324. In
addition, a set of current range select resistors 328 and
associated switches 332 can be controlled by the DAC 224, as
directed by the controller 232, for example depending on the
characteristics of the interconnected test strip 108. In addition,
the DAC 224, as directed by the controller 232, can control the
input to the current follower 324 to in turn control the amount of
current supplied to the test strip 108 by the current electrode
lead 316. The DAC 224, as directed by the controller 232, can also
operate various switches and/or amplifiers to control the operating
mode of the analog front end 220.
[0067] The analog front end 220 additionally includes an
electrometer 336 that receives a first input signal from a
reference electrode lead 340 and a second input signal from the
working electrode lead 320. The output from the electrometer 336
generally represents the potential difference between the reference
electrode lead 340 and the working electrode lead 320. The signal
output by the electrometer 336 can be amplified in a gain circuit
344, and output to the ADC 228.
[0068] FIG. 4 depicts aspects of a test strip 108 in accordance
with embodiments of the present invention. More particularly, the
view presented by FIG. 4 shows the test strip 108 with the test
strip overlay 136 removed. In general, the test strip 108 includes
a working electrode 404, a reference electrode 408, and a counter
electrode 412. In addition, the test strip 108 includes a reference
cell 416. By placing a fluid sample within a sample chamber region
420, the working electrode 404, the reference electrode 408, the
counter electrode 412, and the reference cell 416 are placed in
electrical contact with one another. Moreover, by placing the
electrode contacts 120 corresponding to the counter electrode 412,
the working electrode 404 and the reference electrode 408 in
contact with the readout contacts 116 corresponding to the counter
electrode lead 316, the working electrode lead 320, and the
reference electrode lead 340 respectively, the test strip 108 is
operatively connected to the readout device 104. Accordingly, a
supply current provided to the test strip 104 can be sent across
the fluid sample, between the counter electrode 412 and the working
electrode 404 by the readout device 104. Moreover, the potential
difference between the reference electrode 408 and the working
electrode 404 can be sensed by the readout device 104. In
accordance with further embodiments of the present disclosure, the
test strip 108 can include a test strip detect circuit 424, that
includes an input 428 and an output 432. The test strip detect
circuit 424 can, in addition to the input 428 and the output 432,
include a resistor or other component for modifying a test strip
sense signal provided by the readout device 104, to indicate to the
readout device 104 an identification of the test strip 108.
[0069] To measure the cORP or antioxidant reserve, the sample is
titrated with a linearly increasing oxidizing current between a
counter and working electrode to exhaust the relevant antioxidants
at the working electrode while monitoring the voltage between the
working and reference electrodes. The result is a time vs voltage
curve and a time vs current curve. The time versus voltage curve is
used to find an inflection point where the voltage is changing the
fastest (antioxidants are exhausted so system tries to find a new
equilibrium). The time at maximum velocity (i.e., at the inflection
point) is referred to as the transition time. The capacity or cORP
is then the integral of the current profile from the beginning to
the transition time with units of uC.
[0070] Calculation of the transition time may be accomplished
several ways including noise filtration, curve fitting and standard
numerical differentiation techniques. Usually the unfiltered
numerical derivative is noisy, making finding maxima difficult or
unreliable. To that end one technique is to curve fit the time
versus voltage profile with a polynomial (5th-7th order is usually
sufficient) and directly differentiating the resulting polynomial
analytically. This approach has the advantage of very smooth
derivatives making the determination of the transition time robust
as long as the fit is good.
[0071] FIG. 5 is a flowchart illustrating aspects of the operation
of a system 100 for determining the ORP, including but not limited
to the cORP, of a fluid sample in accordance with embodiments of
the present invention. In general, the method includes obtaining a
fluid sample and placing the fluid sample in the sample chamber 420
of a test strip 108 (step 504). At step 508, the test strip 108 is
connected to the readout device 104 (step 508). In general, while
the readout device 104 is in an on or standby mode, an electrical
signal may be output by the test strip detection output lead 308.
By connecting a suitable test strip 108 to a readout device 104,
continuity between the test strip detect output lead 308 and the
test strip detect input lead 312 is established. In addition, the
signal received at the test strip detect input lead 312 can provide
an indication of characteristics of the test strip 108, which can
in turn be used to control aspects (e.g., a current range) of a
current supplied to the test strip 108. Such characteristics can
include but are not limited to the type and composition of the test
strip electrodes 404, 408 and 412, and the potential of the
reference cell 416.
[0072] At step 512, a current can be supplied by the readout device
104 to the counter electrode 412 of the test strip 108. More
particularly, a current can be passed between the counter electrode
412 and the working electrode 404 by the counter electrode lead 316
and the working electrode lead 320. In accordance with embodiments
of the present disclosure, the current that is supplied to the test
strip 108 is controlled by the controller 232 of the readout device
104. More particularly, the current can be provided for at least a
first segment of time at a selected, steady state level. The first
segment of time can be a fixed time period. Alternatively, the
first segment of time can expire once a determination has been made
that the potential difference sensed by the readout device 104
between the reference electrode 408 and the working electrode 404
has a rate of change that is less than some selected amount. In
accordance with still other embodiments, a combination of
parameters may be applied to determine the time period over which
the current is supplied at a steady state. Moreover, in accordance
with other embodiments, no current is supplied during the first
period of time (i.e. the supplied current during the first segment
of time is zero). As can be appreciated by one of skill in the art
after consideration of the present disclosure, while no current is
supplied and while the rate of change of that potential difference
is zero or less than some selected amount, the potential difference
measured by the readout device 104 between the reference electrode
408 and the working electrode 404 is equal to the sORP of the fluid
sample.
[0073] After the first segment of time has expired, the current can
be supplied at an increasing rate (step 516). For example, the
amount can be increased linearly, as a step function,
exponentially, according to a combination of different profiles, or
in any other fashion. For instance, the current can be increased
linearly from 0 amps at a specified rate until an endpoint is
reached. As another example, the amount can be stepped from 0 amps
to some non-zero value, and that non-zero value can be provided at
a steady rate for some period of time, or can be provided at an
increasing rate according to some function. At step 520, a
determination can be made as to whether an inflection point in the
potential difference monitored between the reference electrode 408
and the working electrode 404 has been detected. More particularly,
the reference electrode lead 340 and the working electrode lead 320
connect the reference electrode 408 and the working electrode 404
respectively to the electrometer 336, which outputs a signal
representing the potential difference between the reference 408 and
the working 404 electrodes. The analog to digital converter 228
then converts the signal representing the potential difference
between the reference 408 and working 404 electrodes to a digital
signal that is provided to the controller 232. If an inflection
point has been detected, the readout device 104, and in particular
the controller 232, can record the time from which current was
first supplied to the time at which the inflection point is
reached. In addition, the controller 232 can integrate the current
signal to determine an amount of charge that has been supplied to
the fluid sample up to the time at which the inflection point is
reached (step 524). In accordance with embodiments of the present
disclosure, a first inflection point (e.g., a point at which the
voltage measured across a fluid sample while a current is being
supplied is at a local maximum rate of change) is used as the point
at which integration of the current is stopped. However, multiple
inflection points can be observed in the measured voltage.
Accordingly, rather than using the first observed inflection point
as the end point for integration, a subsequent inflection point can
be used. As yet another example, a time determined with reference
to multiple inflection points, such as a midpoint between two
observed inflection points or an average time of multiple observed
inflection points can be used as the end point of the integration
for purposes of determining the cORP of a fluid sample. At step
528, the determined quantity of charge or a value derived from the
determined quantity of charge can be output to a user as an ORP
capacity (cORP) value for the fluid sample, for example through the
output device 128 facility of a user interface 124 provided as part
of or interconnected to a readout device 104. For example, the cORP
value can be defined as one over the quantity of charge. The
process can then end.
[0074] FIG. 6 depicts the current, shown as line 604, supplied by a
readout device 104 to an interconnected test strip 108 over time.
In addition, sample measured potential difference values 608a-c for
different exemplary samples are depicted. As can be understood by
one of skill in the art after consideration of the present
disclosure, although three potential difference values 608 are
shown, a current 604 is provided to only one fluid sample during
determination of an ORP value. As can also be appreciated by one of
skill in the art after consideration of the present disclosure, the
ramped portion of the current 604 is shown sloping in a downward
direction, because it depicts an oxidizing current. In addition, it
can be appreciated that the area between the current curve 604 and
a current value of zero for a selected period of time represents a
quantity of charge provided to a fluid sample held in a test strip
108. Accordingly, this quantity of charge can be used to provide a
measurement of the ORP capacity (cORP) of the fluid sample.
Moreover, the voltage curves 608 represent a static ORP (sORP)
value of a respective fluid sample at different points in time. The
area under the current curve 604 (which is above the curve 604,
between that curve and a current of zero in FIG. 6) that is used to
determine the cORP can have a start point at a first point in time
and an end point at a second point in time. As an example, the
start point for integration of the current 604 can be selected as a
point at which the observed sORP signal or reading has stabilized.
For instance, in the example of FIG. 6, the potential difference
values have stabilized after about 50 seconds have elapsed.
Moreover, in this example no current is being supplied to the
sample by the readout device 104 during the first segment of time
leading up to the start point at which current is supplied. That
start point can also correspond to the time at which the current
604 begins to be applied at an increasing rate. In accordance with
embodiments of the present disclosure, where a curve 608 reaches an
inflection point, for example the point at which the rate of change
in the measured potential difference is at a maximum (i.e., a point
of maximum slope), the integration of the current signal 604 is
stopped. For example, looking at curve 608b, an inflection point
can be seen at about 200 seconds, and integration of the current
604 can thus be performed during the period beginning at 50 seconds
and ending at 200 seconds. Alternatively, the integration of the
current signal 604 can be stopped after some predetermined period
of time. As yet another alternative, the integration of the current
signal 604 can be stopped at the earlier of the observation of an
inflection point or the expiration of a predetermined period of
time.
[0075] As can be appreciated by one of skill in the art after
consideration of the present disclosure, the measurement of the
sORP value can be in units of Volts, and the integration of the
current signal or value 604 therefore gives a value representing a
quantity of charge in Coulombs. cORP values, as a measure of a
quantity of charge, is expressed herein as one over the quantity of
charge in Coulombs. In particular, by taking the inverse of the
observed quantity of charge, a more normal distribution is
obtained, facilitating the application of parametric statistics to
observed ORP values. As used herein, the terms ORP capacity,
inverse capacity levels, inverse capacity ORP or ICL are all
equivalent to cORP as defined above. It will be appreciated that
expression of cORP as one over a quantity of charge encompasses
alternative equivalent expressions.
[0076] As noted above, higher than normal values of sORP are
indicative of oxidative stress and are considered to be a negative
indication for the subject being evaluated. cORP is a measure of a
subject's capacity to withstand oxidative insult. Thus, it is a
positive indication for a subject to have a normal or higher
capacity to withstand oxidative insult. Since cORP is defined as
the inverse of the quantity of charge to reach a voltage inflection
point, a higher cORP value is indicative of a lesser capacity to
withstand oxidative insult, and likewise, a lower cORP value is
indicative of a greater capacity to withstand oxidative insult.
[0077] The present invention includes embodiments for monitoring or
evaluating the health of patients having a variety of conditions by
determining the ORP characteristics of a biological sample of the
patient. Typically, the ORP characteristics of the patient are
compared to an ORP characteristic reference value or values that
are relevant to that patient. As used herein, a reference value can
be an ORP characteristic of the patient from a time when the
patient did not have the condition in question (i.e., when he/she
was healthy) or from an earlier time period when the patient had
the condition in question (for purposes of monitoring or evaluating
the condition or treatment thereof). Such reference values are
referred to as self reference values. For example, reference values
can also include initial, maximum and ending reference values, such
as when ORP characteristics are evaluated over a time frame such as
when a patient is being admitted to a medical facility (initial),
during a stay at a medical facility (maximum), and at a time when a
patient is being considered for transfer, discharge, or other
disposition (ending). Alternatively, a reference value can be an
ORP characteristic of a relevant healthy population (e.g., a
population that is matched in one or more characteristics of
species, age, sex, ethnicity, etc.). Such reference values are
referred to as normal reference values. Further, a reference value
can be an ORP characteristic of a relevant population similarly
situated as the patient (e.g., a population having the same or
similar condition as the patient for which the patient is being
treated and preferably, one that is also matched in one or more
characteristics of species, age, sex, ethnicity, etc.). Such a
reference value is referred to as a condition specific reference
value. For example, a condition specific reference value can be a
cancer reference value or a neurodegenerative reference value.
[0078] As used herein, a subject is any individual for whom a
biological sample is being tested for an ORP characteristic. The
term subject can include patient if the subject is an individual
being treated by a medical professional. The terms subject and
patient can refer to any animal, including humans and non-human
animals, such as companion animals (e.g., cats, dogs, horses, etc.)
and livestock animals (i.e., animals kept for food purposes such as
cows, goats, chickens, etc.). Preferred subjects include mammals
and most preferably include humans.
[0079] In various embodiments of the invention, the ORP
characteristics of a biological sample of a subject are measured.
The measurement of the ORP characteristics of a biological sample
can done at multiple time points. The frequency of such
measurements will depend on the condition being evaluated. For
example, urgent conditions such as sepsis can employ more frequent
testing of an individual. In contrast, chronic conditions such as
neurodegenerative conditions can employ longer term testing
intervals. As such, for example, testing can be done every 30
minutes, hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12
hours, 18 hours, or day for more urgent conditions. Alternatively,
testing can be done every day, 2 days, 3 days, 4 days, 5 days, 6
days, week, 2 weeks, 3 weeks, month, 2 months, 3 months, 4 months,
5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11
months, or year for more chronic conditions.
[0080] In various embodiments of the invention, the ORP
characteristics of a biological sample of a subject are measured
for purposes of diagnosing, evaluating or monitoring a subject for
a specific condition. In such embodiments, the methods can include
identifying in the subject a risk factor, such as a lifestyle or
genetic risk factor, for the specific condition and/or a symptom of
the specific condition.
[0081] Readmission
[0082] In one embodiment of the invention, a patient is evaluated
for ORP characteristics prior to discharge from a medical facility
to determine if the patient, who is at the medical facility for a
disease or condition, is or is not at risk of early readmission to
a medical facility for the disease or condition or complications
thereof. Any patient in a medical facility can be evaluated
according to the invention. It is particularly important, however,
that patients known to be at high risk of early readmission be
evaluated prior to discharge. Such patients include patients who
(i) required a prolonged period of intensive care or mechanical
ventilation, (ii) suffered a stroke, (iii) suffer from
cardiovascular diseases (e.g., heart disease, coronary artery
disease, myocardial infarction, acute coronary syndrome or heart
failure), (iv) have cancer, (v) suffer from pulmonary or
respiratory disorders (e.g., pneumonia and other respiratory
infections (especially patients who have suffered from
complications of pneumonia), chronic obstructive pulmonary disease
(COPD), dyspnea, pleural effusion, or hypoxia), (vi) suffer from
gastrointestinal disorders, (vii) suffer from sensory disturbances
(e.g., pain, fever, vertigo, or sleep apnea), (viii) suffer from
renal, urinary or prostate disorders, (ix) suffer from skin
disorders or wound infections, (x) suffer from HIV/AIDS, (xi) have
diabetes, or (xii) suffer from any other serious illness.
[0083] Preferably, a patient is evaluated for a risk of early
readmission during the 48 hours, 36 hours, 24 hours and/or 12 hours
prior to expected discharge. Early readmission generally refers to
readmission within one week, two weeks, three weeks, 30 days, 45
days, 60 days, 75 days or 90 days from the day of discharge.
[0084] Medical facilities can include, without limitation
hospitals, nursing homes, residential treatment center, skilled
nursing facilities, and geriatric care facilities.
[0085] This embodiment of the invention includes evaluating a
subject who is in a medical facility for treatment of a disease or
condition before discharge to determine whether the subject is at
risk of readmission to the medical facility for the disease or
condition, or complications thereof. A biological sample of the
subject is tested for an ORP characteristic which is compared to a
readmission reference value to determine the discharge status of
the subject. Then a discharge decision for the subject is made
based on the discharge status of the subject.
[0086] For example, ORP characteristic values of a patient that are
significantly elevated compared to the ORP characteristic values of
an individual or population that was not readmitted within a
relevant time frame indicates that the patient is at risk of early
readmission. Similarly, ORP characteristic values of a patient that
are not significantly lower compared to the ORP characteristic
values of an individual or population that was readmitted within a
relevant time frame indicates that the patient is at risk of early
readmission. If the patient is at risk for early readmission, the
patient's discharge can be postponed or additional treatment after
discharge can be prescribed. Such additional treatment after
discharge may include referral to extended stay care or early
disease management programs at home. These programs can reduce
early readmission rates and often include nurse contact within 24
hours after discharge and frequent home check-ups for proper
medication compliance and rehabilitation treatments. ORP values
that are statistically the same as or lower than that of controls
indicates that the patient is not at risk of early readmission.
[0087] Diabetes
[0088] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring a subject with diabetes
mellitus that includes measuring the ORP characteristics of a
biological sample from the subject. The ORP characteristics are
compared with the ORP characteristics of a diabetes reference value
to evaluate whether they are significantly different and to
determine the diabetes status of the subject. The subject is
treated based on the diabetes status.
[0089] ORP characteristics of the subject may be used to diagnose,
evaluate and/or monitor the progress of diabetes in the subject or
the development of diabetic complications in the subject or the
regulation of blood sugar levels in the subject over time, i.e.,
the effective compliance of the subject with prescribed diabetic
treatments. Such treatments can include insulin administration,
oral hypoglycemic agents, exercise, and/or a diabetic diet.
[0090] Elevated ORP characteristics of a subject are indicative of
rapidly progressing diabetes or diabetic complications in the
subject and can indicate a need to change or increase anti-diabetic
therapies or implement additional therapies, including but not
limited to antioxidant therapy.
[0091] In order to determine the trend of ORP characteristics in a
diabetic subject over time, without limitation, the ORP
characteristics of the subject may be checked every 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11 or 12 months after the initial determination of
the disease or condition for a period of years or indefinitely, in
order to compare and determine a trend in the ORP characteristics
of the subject or to assess the status of the subject at a given
point in time. If the diabetic subject is admitted to an emergency
or hospital care unit, the subject may be monitored at frequent
intervals over the entire period of stay prior to discharge and in
some embodiments, the change in the ORP characteristics may be at
least one factor considered in determining the appropriate
discharge date.
[0092] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, serum, and cerebrospinal fluid (CSF) in a convenient
and timely manner. The ORP of the subject may also be obtained from
a tissue of the subject including, but not limited to, pancreatic,
ocular or kidney tissue.
[0093] Sepsis
[0094] Another embodiment of the invention provides methods of
diagnosing, evaluating or monitoring sepsis in a subject that
includes measuring the ORP characteristics of a biological sample
from a subject that has been diagnosed with, or is suspected of
having septicemia/bacteremia potentially leading to inflammation,
septic shock and multiple organ dysfunction syndrome/failure, and
death. The ORP characteristics of the subject are compared with the
ORP characteristics of a reference value, such as that of a
biological sample from another subject or group of sepsis patients,
to determine the sepsis status of the subject. Alternatively or
additionally, it may be determined if the ORP of the subject has
increased or decreased compared to a prior ORP characteristics
measurement obtained from the same subject. The subject is then
treated based on the determined sepsis status.
[0095] In one embodiment, ORP characteristics of the subject that
are statistically similar to or greater than the ORP
characteristics of sepsis patient(s) is diagnostic of sepsis in the
subject tested. The ORP value(s) may be used to supplement other
diagnostic markers of sepsis in the subject such as one or more of
white blood cell count, blood cultures, blood pressure, heart rate,
temperature, or chest X-ray.
[0096] Similarly, an increase in the ORP characteristics of the
subject over time is indicative of the progressive development or
worsening of severe infection to sepsis and/or septic shock and/or
multiple organ failure. Similarly, an increase in the ORP of the
subject over time may also indicate a failure of sepsis treatment
measures in a subject diagnosed with sepsis, especially the failure
of antibiotic and/or anti-oxidant therapy in the sepsis patient. In
order to determine the trend of the ORP characteristics in the
subject over time, without limitation, the ORP characteristics
value of the subject may be checked every 30 minutes, 1 hour, 2
hours, 3 hours, 4 hours, 5 hours or 6 hours after the initial
determination in order to compare and determine a trend in the ORP
characteristics of the subject.
[0097] The ORP of the subject may be obtained from a biological
sample of the subject, including but not limited to blood, plasma,
and serum, in a convenient and timely manner. The ORP of the
subject may also be obtained from a tissue of the subject,
including but not limited to, tissues of the skeletal muscles,
liver and/or lung.
[0098] In related embodiments, the subject may present with signs
and symptoms of sepsis or septic shock or may have been previously
diagnosed with sepsis and the subject's ORP value(s) may be used to
monitor and/or guide a therapy such as antibiotic therapy, fluid
resuscitation, vasopressors or anti-oxidant therapy. In these
embodiments, the ORP value of the subject may be checked every 30
minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours
after the initial determination in order to compare and determine a
trend in the ORP value of the patient. An increase in the ORP
values of the subject over the time period of the treatment for
sepsis is indicative of inadequate or insufficient or inappropriate
antibiotic therapy and/or anti-oxidant therapy and may indicate a
need to increase the dose and/or the dosing frequency of the
antibiotic therapy and/or anti-oxidant therapy or the need to
discontinue the current antibiotic therapy and/or anti-oxidant
therapy and switch to another antibiotic therapy and/or
anti-oxidant therapy. An ORP value of the subject that is
decreasing over the time period of the treatment for sepsis is
indicative of a successful antibiotic therapy and/or anti-oxidant
therapy in the subject.
[0099] Stroke
[0100] Another embodiment of the invention provides methods of
diagnosing, evaluating or monitoring a subject having or suspected
of having a stroke that includes measuring ORP characteristics of a
biological sample from a subject that is suspected of having a
stroke, and then evaluating if the ORP characteristics are
significantly different than the ORP characteristics of a reference
value such as a biological sample from another subject or group of
subjects known to be having a stroke to determine the stroke status
of the subject. Alternatively or additionally, it may be determined
if the ORP characteristics have increased or decreased compared to
a prior ORP characteristics measurement obtained from the same
subject. The subject is then treated based on the stroke
status.
[0101] In one embodiment, the ORP characteristics measurement are
taken in addition to other patient diagnostic criteria such as one
or more of vital signs, ECG, blood sugar level, CT scan (CAT Scan,
Computed axial tomography), MRI (Magnetic resonance imaging, MR),
MRA (Magnetic resonance angiogram), Cerebral arteriogram (Cerebral
angiogram, Digital subtraction angiography), PT (Prothrombin time)
or PTT (Partial thromboplastin time), in order to diagnose stroke
and/or rule out such diagnoses as drug overdose,
hyper/hypoglycemia, seizure, head trauma, intracranial mass,
migraine, meningitis, encephalitis, cardiac and arrest ischemia.
Additionally, the ORP characteristics measurement may be used alone
or in conjunction with the other diagnostic criteria described
above to evaluate the use of fibrinolytic therapy or other acute
interventions.
[0102] In these emergency care situations, ORP characteristics of
the subject that are statistically similar to or greater than the
ORP characteristics of a subject or group of subjects diagnosed
with stroke is indicative of a stroke in the subject and may
indicate use of fibrinolytic therapy in the subject and/or
admission to a hospital care unit. Alternatively, ORP
characteristics of the subject that are statistically similar to a
subject or group of "normal" subjects that are not affected by
stroke is indicative of other sources of neurological distress and
may suggest no intervention with fibrinolytic therapy in the
subject.
[0103] An increase in the ORP characteristics of the subject over
time following initial presentation of the subject may be
indicative of developing brain damage in the stroke patient. In
order to determine the trend of the ORP characteristics in the
subject over time, without limitation, the ORP characteristics
value of the subject may be checked every 1, 2, 3, 4, 5, 6, 7, 8,
9, or 10 minutes after the initial determination for a period of 1,
2, 3, or 4 hours, in order to compare and determine a trend in the
ORP characteristics value of the subject. If the subject is
admitted to a hospital care unit, the subject may be monitored at
frequent intervals over the entire period of stay prior to
discharge and in some embodiments, the change in the ORP
characteristics values may be at least one factor considered in
determining the appropriate discharge date.
[0104] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, serum, and cerebrospinal fluid (CSF) in a convenient
and timely manner. The ORP characteristics of the subject may also
be obtained from a tissue of the subject, including but not limited
to, brain tissue biopsy.
[0105] Cardiovascular Diseases
[0106] Atherosclerosis and its related cardiovascular morbidity and
mortality, underlie many chronic diseases. Most atherosclerotic
patients have multiple cardiovascular risk factors, which
potentiate each other, causing a huge burden on health systems.
Oxidative stress has a major role in the pathogenesis of
atherosclerosis.
[0107] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring a cardiovascular disease,
disorder, or condition in a subject that includes measuring the ORP
characteristics of a biological sample from a subject that has been
diagnosed with, or is suspected of having or developing a
cardiovascular disease, disorder or condition, and then evaluating
if the ORP characteristics are significantly different than a
reference value such as the ORP characteristics of a biological
sample from another subject or group of subjects known to be free
of the cardiovascular disease, disorder or condition. Alternatively
or additionally, it may be determined if the ORP characteristics
have increased or decreased compared to a prior ORP characteristics
measurement obtained from the same subject. The subject is then
treated based on the cardiovascular disease status. Suitable
treatments can include thrombolytic therapy, angioplasty, cardiac
catheterization, or treatment of reperfusion injury.
[0108] In one embodiment, the cardiovascular disease is a disorder
such as heart failure, atherosclerosis, ischemic heart disease,
myocardial hypertrophy, hypertension, hypercholesterolemia,
hyperlipidemia, sinus node dysfunction and related rhythm
abnormalities, especially atrial fibrillation, type 2 diabetes,
renal failure with varying degrees of insufficiency; chronic kidney
disease (CKD) not on renal replacement therapy (RRT); continuous
ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD).
[0109] In such disorders, ORP characteristics of the subject that
are significantly greater than the ORP characteristics of subjects
known to be free of cardiovascular disease and/or atherosclerosis
is indicative of the development or worsening of cardiovascular
disease and/or atherosclerosis in the subject. Similarly, an
increase in the ORP characteristics of the subject over time is
indicative of the development or worsening of cardiovascular
disease and/or atherosclerosis in the subject. In order to
determine the trend of the ORP characteristics in the subject over
time, without limitation, the ORP characteristics value of the
subject may be checked every 1, 2, 3, 4, 5, or 6 months after the
initial determination in order to compare and determine a trend in
the ORP characteristics value of the patient.
[0110] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, and serum, in a convenient and timely manner. The
ORP characteristics of the subject may also be obtained from a
tissue of the subject, including but not limited to, tissues of the
myocardium (e.g., epicardium, endocardium, base, apex) and/or
tissues of the immune system (e.g., peripheral polymorphonuclear
leukocytes (PMNLs)).
[0111] In a related embodiment, a subject may present with chest
pain and the ORP characteristics of the subject are obtained and
compared to an ORP characteristics value from subjects undergoing
cardiac arrest and/or subjects known to be "normal" or free of
cardiovascular disease. An ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from subjects undergoing cardiac arrest is
indicative of a patient experiencing or at elevated risk of
developing cardiac arrest. In this circumstance, the subject may be
admitted to a hospital or care unit, or processed for further
evaluation that may include obtaining and evaluating an EKG from
the subject and/or enzyme levels associated with cardiac arrest,
such as troponin (types cTnI and/or cTnT) creatine kinase, and
myoglobin. The ORP characteristics value of the subject may be
checked every 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5
hours or 6 hours after the initial determination in order to
compare and determine a trend in the ORP characteristics value of
the patient.
[0112] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from "normal" subjects is indicative of a patient at no or
low risk of cardiac arrest. In this circumstance, the subject may
be discharged or otherwise released from any further evaluation.
Similarly, the ORP characteristics value of such subject may be
checked every 1 to 6 hours after the initial determination in order
to compare and determine a trend in the ORP characteristics value
of the patient.
[0113] Athletics
[0114] Another embodiment of the invention provides methods of
evaluating or monitoring athletic performance in a subject that
includes measuring the ORP characteristics of a biological sample
from a subject athlete, and then evaluating if the ORP
characteristics are significantly different than the ORP
characteristics of a reference value such as biological sample from
the subject athlete at an earlier time point during a training
program. Alternatively or additionally, the ORP characteristics of
the subject may be compared to the ORP characteristics of a target
population. The subject athlete is then treated by preparing a
training program based on the measured ORP characteristics. For
example, such a training program can include a new or modified
program, which can include more or less rigorous training
requirements than the athlete is currently performing and/or
modified nutrition and/or supplementation. The training program can
then be executed by the athlete.
[0115] The method is suitable for any athlete or individual
engaging in athletic endeavors. More particularly the athlete can
be an endurance athlete or a strength athlete and can be male or
female. The type of athletic endeavor can be resistance exercise,
including acute heavy resistance exercise. Such exercise can be
weightlifting, sprinting, field events, football, martial arts,
wrestling, or boxing. The exercise can also be endurance exercise,
such as running, cycling, swimming, hiking, triathalon, softball,
baseball, soccer, basketball, hockey, football, rugby, tennis, and
lacrosse.
[0116] In order to determine the trend of the ORP characteristics
in the subject over time, without limitation, the ORP
characteristics value of the subject may be checked during a
training program, such as every 1, 2, 3, or 4 weeks or every 1, 2,
3, 4, 5, or 6 months to compare and determine a trend in the ORP
characteristics value of the athlete.
[0117] ORP characteristic testing may be used alone or in
conjunction with other athletic/athlete testing and evaluation
methodologies, such as VO.sub.2 maximum, anaerobic threshold test,
Wingate test, critical power, resting metabolic rate, body
composition, speed testing, power testing, strength testing,
flexibility testing, muscle biopsy, fast twitch fiber test, slow
twitch fiber test, and ACTN3 genetic testing.
[0118] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to design training regimens that may be optimally designed for
the subject.
[0119] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to identify risk factors or potential hazards for
participation in athletic activities. Such risk factors may include
identification of increased chance of injury to the subject.
[0120] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to monitor recovery time and progress following a sports
injury. In one such embodiment, ORP characteristic values may help
to determine the presence of, and/or recovery from, a concussion in
the subject. In another such embodiment, ORP characteristic values
are obtained during the subject's recovery time and the values are
used to determine the fitness and extent of recovery of the athlete
to return to the athletic performance.
[0121] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to provide prognostic information about the likely performance
of a subject in an athletic event or performance. In some
embodiments, ORP characteristic value comparisons with ORP
characteristic values of other athletes may be indicative of the
subject's performance in specific sports events such as
power/sprinter athletic events or athletic events requiring
endurance.
[0122] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to provide information about the performance of a subject
during an athletic event to maximize the subject's performance
during the event or to minimize risk or harm to the subject during
the event.
[0123] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to help design workout or practice regimens for athletes based
on the ORP characteristic values obtained during or shortly after
the participation in the athletic event.
[0124] In certain embodiments, ORP characteristic values and
comparison with ORP characteristic values of other athletes may be
used to provide a feedback or a monitoring mechanism to establish a
baseline to measure progress from earlier training periods and/or
cycles to subsequent training periods.
[0125] Neurodegenerative Disorders
[0126] Reactive oxygen species (ROS) and oxidative damage are
important factors in the processes involved in neurodegenerative
disorders. Reduction of the antioxidant defenses can lead to an
increase in the oxidation of critical proteins in neurons in the
brain, particularly in Alzheimer's disease.
[0127] Another embodiment of the present invention provides methods
of diagnosing, evaluating or monitoring a neurodegenerative
disease, disorder, or condition in a subject that includes
measuring the ORP characteristics of a biological sample from a
subject that has been diagnosed with, or is suspected of having or
developing a neurodegenerative disease, disorder or condition, and
then evaluating if the ORP characteristics are significantly
different than the ORP characteristics of a reference value such as
a biological sample from another subject or group of subjects known
to be free of the neurodegenerative disease, disorder or condition
to determine the neurodegenerative disorder status of the subject.
Alternatively or additionally, it may be determined if the ORP
characteristics from the subject have increased or decreased
compared to a prior ORP characteristics measurement obtained from
the same subject. The subject is then treated based on the
neurodegenerative disorder status.
[0128] The neurodegenerative disease may be a disease or disorder
such as Parkinson's Disease (PD), Parkinsonian-like syndromes such
as Amyotrophic Lateral Sclerosis (ALS) and Progressive Supranuclear
Palsy (PSP), Alzheimer's Disease (AD) and poly Q disorders such as
Huntington's disease. In such disorders, an elevation in the ORP
characteristics of the subject over the ORP characteristics of
subjects known to be free of neurological disorder is indicative of
the development or worsening of a neurological disorder in the
subject. Similarly, an increase in the ORP characteristics of the
subject over time is indicative of the development or worsening of
neurological disorder in the subject. In order to determine the
trend of the ORP characteristics in the subject over time, without
limitation, the ORP characteristics value of the subject may be
evaluated every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months
after the initial determination in order to compare and determine a
trend in the ORP characteristics value of the patient.
[0129] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, and serum, in a convenient and timely manner. The
ORP characteristics of the subject may also be obtained from a
tissue of the subject, including but not limited to, tissues of the
central nervous system (e.g., cerebrospinal fluid, brain or spinal
tissues).
[0130] ORP characteristics of a subject that are statistically
similar to, or less than, the ORP characteristics value from
"normal" subjects is indicative of a patient at no or low risk of
developing a neurological disorder. In this circumstance, further
evaluation of the subject can be discontinued. Alternatively, an
ORP characteristics value of the subject that is statistically
similar to, or greater than, the ORP characteristics value from
subjects having a neurological disorder, is indicative of a subject
at moderate or elevated risk of developing a neurological disorder.
Such a subject can be recommended for further evaluation and/or
repeated or regular evaluation of ORP characteristics values to
evaluate or monitor potential progress in developing a neurological
disorder. Such a patient may also be recommended for administration
of antioxidant therapy, such as administration of a cocktail of
multiple antioxidants, psychological treatment for cognitive
disorders and/or anti-inflammatory agents beneficial in the
prevention of neurodegenerative disease.
[0131] Evaluation of Patients in Critical Care Setting
[0132] Critically ill patients suffer from oxidative stress as
critical illness can drastically increase the production of
reactive oxygen or nitrogen species while these patients have
reduced plasma and intracellular levels of antioxidants and free
electron scavengers or cofactors, and decreased activity of the
enzymatic system involved in detoxification of reactive oxygen or
nitrogen species. The pro-oxidant/antioxidant balance is of
functional relevance during critical illness because it is involved
in the pathogenesis of multiple organ failure. Thus, there is a
significant relationship between oxidative stress and severity in
critically ill patients.
[0133] A further embodiment of the invention provides methods of
diagnosing, evaluating or monitoring critically ill patients and
the severity of their condition by measuring the ORP
characteristics of a biological sample from such a patient and then
evaluating if the ORP characteristics are significantly different
than the ORP characteristics of a reference value such as a
biological sample from a normal population or from a critically ill
population to determine the critically ill status of the patient.
The patient is then treated based on the critically ill status.
[0134] In one embodiment, the ORP characteristics of a subject are
obtained upon intensive care unit (ICU) admission and in order to
determine the trend of the ORP characteristics in the subject over
time, without limitation, the ORP characteristics value of the
subject may be checked every 30 minutes, 1 hour, 2 hours, 3 hours,
4 hours, 5 hours or 6 hours or on a daily or weekly basis after the
initial determination in order to compare and determine a trend in
the ORP characteristics of the subject. These ORP evaluations may
be used in conjunction with other markers of oxidative
stress/capacity such as monitoring of dietary intake of antioxidant
vitamins (A, C and E) Sequential Organ Failure Assessment scores,
Acute Physiology and Chronic Health Evaluation (APACHE) II scores,
specific biological markers of oxidative stress such as lipid
peroxides, carbonyl groups, which represent damage to lipids and
proteins, and evaluation of the endogenous antioxidants bilirubin,
total proteins and uric acid.
[0135] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from "normal" or non-critically ill subjects is indicative of
a critical care patient at no or reduced risk of deterioration in
condition and/or organ failure. Such subjects may be discharged
from the critical care setting and may be prescribed different or
reduced antioxidant and/or other therapies with the expectation of
improved health and positive medical outcome.
[0136] Alternatively, an ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from critical care subjects or who shows
significantly greater or persistent worsening in ORP
characteristics values, is indicative of a subject at elevated risk
of sustained requirements for critical care therapies, or poor
medical prognosis or mortality. Such subject may be recommended for
further evaluation and/or repeated or regular evaluation of ORP
characteristics values and/or administration of one or more
antioxidant therapies. In addition, such subjects can be
administered fluid resuscitation or have their vital signs
monitored
[0137] Cancer
[0138] Oxidative stress, chronic inflammation, and cancer are
closely linked. Mechanisms by which oxidative stress leads to
chronic inflammation, which in turn can mediate chronic diseases
such as cancer include the activation of a variety of transcription
factors (including NF-.kappa.B, AP-1, p53, HIF-1.alpha.,
PPAR-.gamma., .beta.-catenin/Wnt) leading to the expression of
growth factors, inflammatory cytokines, chemokines, cell cycle
regulatory molecules, and anti-inflammatory molecules, which may
lead to the transformation of normal cells, and effect tumor cell
survival, proliferation, chemoresistance, radioresistance,
invasion, angiogenesis and stem cell survival.
[0139] Another embodiment of the invention is a method of
diagnosing, evaluating and/or monitoring cancer in a subject by
measuring the ORP characteristics of a biological sample from such
a subject and then evaluating if the ORP characteristics are
significantly different than the ORP characteristics of a reference
value such as a biological sample from a normal population or from
a cancer population to determine the cancer status of the subject.
The subject is then treated based on the cancer status. In various
embodiments, the cancer can be any type of cancer, including a
solid tumor, a leukemia or lymphoma or a metastatic disease. In
such cancer, ORP characteristics of the subject that are
significantly greater than the ORP characteristics of subjects
known to be cancer free is indicative of the presence or worsening
of a cancer in the subject. Similarly, an increase in the ORP
characteristics of a cancer patient over time is indicative of the
development or worsening of the cancer and potentially the
development of metastatic disease. In order to determine the trend
of the ORP characteristics in such patient over time, the ORP
characteristics value of the subject may be checked every 1 to 6
months after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
patient.
[0140] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, and serum. The ORP characteristics of the subject
may also be obtained from a tissue of the subject, including but
not limited to, organ tissues or tumor biopsies.
[0141] Thus, in one embodiment, a subject suspected of having a
cancer may be evaluated for ORP characteristics values indicative
of cancer in the subject or in a specific tissue of the subject. An
ORP characteristics value of the subject that is statistically
similar to, or less than, the ORP characteristics value from
subjects known to be cancer free or "normal" is indicative of a
subject that is cancer free or such value may be used to rule out a
cancer diagnosis, either alone or in conjunction with other
diagnostic procedures. An ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from subjects known to have cancer, and a
specific cancer type, or grade is indicative of a subject that has
cancer or such value may be used to determine the type of cancer in
the subject or the tumor grade. The ORP characteristics values of
such subject may be checked regularly after the initial
determination in order to re-evaluate the initial cancer diagnosis
or to continue or evaluate or monitor tumor grade in a cancer
patient.
[0142] In a related embodiment, a patient diagnosed with a cancer
and undergoing anti-cancer therapy may be regularly monitored by
evaluation of ORP characteristics values indicative of successful
or unsuccessful anti-cancer therapy. An ORP characteristics value
of the subject that is statistically similar to, or less than, the
ORP characteristics value from subjects known to be cancer free or
successfully responsive to certain cancer therapies is indicative
of a patient responding to a cancer therapy and/or having a
positive prognosis for cancer survival or remission. Likewise, an
ORP characteristics value of the subject that is statistically
similar to, or less than, the ORP characteristics value from prior
ORP characteristics values of the same subject prior to or earlier
in treatment is indicative of a patient responding to a cancer
therapy and/or having a positive prognosis for cancer survival or
remission. In these circumstances, the subject may be continued on
the same anti-cancer therapy or even discontinued from therapy. The
ORP characteristics values of such subject may be checked, without
limitation, every 1, 2, 3, 4, 5, or 6 months after the initial
determination in order to evaluate the prolonged survival and
monitor reoccurrence of a cancer in the subject or the development
of a metastatic disease.
[0143] Alternatively, an ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from subjects known to have the same cancer
or to have progressed to a higher grade tumor or to have succumbed
to cancer, is indicative of a cancer patient that is not responding
to a specific cancer therapy and/or having a negative or poor
prognosis for cancer survival or remission. In this circumstance,
the subject may be discontinued on an anti-cancer therapy or
recommended for a change in anti-cancer therapy, such as the
addition of an additional anti-cancer therapy or change to a
different anti-cancer therapy. Anti-cancer therapies can include
without limitation surgery, chemotherapy, and radiation.
[0144] Obesity/Metabolic Syndrome
[0145] Obesity induces systemic oxidative stress and increased
oxidative stress in accumulated fat and has been linked with
dysregulation of adipocytokines and development of metabolic
syndrome.
[0146] Another embodiment of the invention is a method of
diagnosing, evaluating and/or monitoring obesity in a subject as
well as monitoring progress in a weight loss regimen, which may
include diet and/or exercise regimens by measuring the ORP
characteristics of a biological sample from such a subject and then
evaluating if the ORP characteristics are significantly different
than the ORP characteristics of a reference value such as a
biological sample from a normal population or from an obese
population to determine the obesity and/or metabolic syndrome
status of the subject. The subject is then treated based on the
obesity and/or metabolic syndrome status of the subject. In these
methods, an increase in the ORP characteristics of the subject over
the ORP characteristics of subjects of normal or average body mass
index (BMI) is indicative of the presence or worsening of the
obesity in the subject. Alternatively, or in addition, an increase
in the ORP characteristics of the subject over the ORP
characteristics of other obese subjects having a similar or greater
BMI than the tested subject, is indicative of the presence or
worsening of the obesity in the subject.
[0147] Similarly, an increase in the ORP characteristics of an
obese subject over time is indicative of the progression or
worsening of the obesity or metabolic syndrome in the subject. In
order to determine the trend of the ORP characteristics in such
subjects over time, without limitation, the ORP characteristics
value of the subject may be checked every 1, 2, 3, 4, 5, or 6 weeks
or every 1, 2, 3, 4, 5, or 6 months after the initial determination
in order to compare and determine a trend in the ORP
characteristics value of the subject.
[0148] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, and serum. The ORP characteristics of the subject
may also be obtained from a tissue of the subject, including but
not limited to, fat tissue biopsies.
[0149] In one embodiment, an obese subject undertaking a weight
loss regimen may be evaluated for ORP characteristics values
indicative of increasing obesity or progressive weight loss in the
subject in a specific tissue of the subject. An ORP characteristics
value of the subject that is statistically similar to, or less
than, the ORP characteristics value from subjects with normal or
low BMI is indicative of a subject that is progressing to weight
loss, either alone or in conjunction with other diagnostic
procedures. An ORP characteristics value of the subject that is
statistically similar to, or greater than, the ORP characteristics
value from other obese subjects is indicative of a subject that is
not progressing to weight loss or is gaining weight or progressing
to the development or worsening of metabolic syndrome. The ORP
characteristics values of such subject may be evaluated regularly
after the initial determination in order to re-evaluate the initial
evaluation of weight loss or disease progression.
[0150] In a related embodiment, an obese subject undergoing a
weight loss regimen may be regularly monitored by evaluation of the
subject's ORP characteristics values compared with ORP
characteristics values indicative of successful or unsuccessful
weight loss regimen(s). An ORP characteristics value of the subject
that is statistically similar to, or less than, the ORP
characteristics value from subjects having a normal or lower BMI
compared with the subject, or ORP characteristics values of
subjects successfully reducing weight in a weight loss regimen is
indicative of a subject successfully losing weight and/or having a
positive prognosis for losing or maintaining weight or overcoming
metabolic syndrome. In this circumstance, the subject may be
continued on the same anti-obesity regimen or even discontinued
from a regimen. Without limitation, the ORP characteristics values
of such subject may be checked every 1, 2, 3, 4, 5, or 6 weeks
every 1, 2, 3, 4, 5, or 6 months after the initial determination in
order to evaluate the subject's progress and/or disease
prognosis.
[0151] Alternatively, an ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from obese subjects having the same or
greater BMI as the subject tested is indicative of a subject that
is not responding to a specific weight loss regimen and/or having a
negative or poor prognosis for developing or worsening metabolic
syndrome. In this circumstance, the subject may be discontinued on
the weight loss regimen or recommended for a change in the weight
loss regimen, such as the addition of additional weight-loss
therapies or change to a different weight loss regimen.
[0152] Hemodialysis
[0153] Dialysis is associated with an increased generation of
oxidants, which play an important part in the development of
atherogenesis and inflammation.
[0154] One embodiment of the invention is a method of monitoring
hemodialysis in a subject as well as monitoring the need for iron
replacement therapy in a dialysis patient by measuring the ORP
characteristics of a biological sample from such a subject and then
evaluating if the ORP characteristics are significantly different
than the ORP characteristics of a reference value such as a
biological sample from a normal population or from a dialysis
population to determine the hemodialysis status of the subject. The
subject is then treated based on the hemodialysis status of the
subject. In these methods, an increase in the ORP characteristics
of the patient over the ORP characteristics of patients of normal
kidney function is indicative of the need for reduction in the
frequency of dialysis or reduced iron replacement therapy.
[0155] In order to determine the trend of the ORP characteristics
in the subject over time, without limitation, the ORP
characteristics value of the subject may be checked after every
hemodialysis treatment in order to compare and determine a trend in
the ORP characteristics of the subject.
[0156] Brain Injury
[0157] Brain tissue is particularly vulnerable to oxidative damage
because of its high rate of metabolic activity, accompanied by
intensive production of reactive oxygen metabolites, relatively low
antioxidant capacity, low repair mechanism activities, the
non-replicating nature of neuronal cells, and the high membrane
surface-to-cytoplasm ratio. The high concentrations of
polyunsaturated fatty acids in the membrane lipids of the brain are
the source for lipid peroxidation in which initiating free radicals
can precipitate destruction of adjacent lipid molecules. The brain
also contains high levels of transition metals, such as iron, which
are located in specific sites in the brain (e.g., substantia nigra)
and are capable of catalyzing the production of highly toxic
radicals via the metal-mediated Haber-Weiss reaction.
[0158] The physiological response to brain injury is extremely
complex and involves the activation of an overlapping network of
humoral, tissue, and cellular pathways. The initiating injury
triggers the release of endogenous mediators, which initiate a
cascade of molecular, cellular, and tissue responses resulting in
delayed tissue edema, necrosis, and impaired function. It has been
suggested that the initial events in blunt head trauma lead to a
final common pathway of neuronal death involving loss of cellular
calcium homeostasis, production of free radicals, and tissue
acidosis (Siesjo B K, Agardh C D & Begtsson F. (1989) Free
radicals and brain damage. Cerbrovasc Brain Metab Rev 1: 165-211).
A number of therapeutic approaches, based on intervention by
scavenging ROS, have been attempted both in experimental models and
in the clinical setting, but a practical and effective method of
identifying and/or monitoring the oxidative status of a patient
that has suffered a brain injury or is suspected of sustaining a
brain injury is needed.
[0159] Another embodiment of the invention provides methods of
diagnosing, evaluating or monitoring a brain injury in a subject
that includes measuring the ORP characteristics of a biological
sample from a subject that has been diagnosed with, or is suspected
of having or developing a brain injury, and then evaluating if the
ORP characteristics are significantly different than the ORP
characteristics of a reference value such as the same biological
sample from another subject or group of subjects having no brain
injury, disorder or condition to determine the brain injury status
of the subject. The subject is then treated based on the brain
injury status of the subject. Alternatively or additionally, it may
be determined if the ORP characteristics have increased or
decreased compared to a prior ORP characteristics measurement
obtained from the same subject. In a specific embodiment, this may
include comparison to an ORP characteristics measurement obtained
from the same subject taken before the suspected or confirmed brain
injury occurred.
[0160] In one embodiment, the brain injury is a traumatic brain
injury causing damage to the brain resulting from events such as
external mechanical force, rapid head acceleration or deceleration,
impact, blast waves, or penetration of the head by a
projectile.
[0161] In such injuries, an increase in the ORP characteristics of
the subject over the ORP characteristics of subjects known to be
free of brain injury is indicative of the development or worsening
of the injury or subsequent functional impairments in the subject.
Similarly, an increase in the ORP characteristics of the subject
over time is indicative of the development or worsening of brain
injury in the subject. In order to determine the trend of the ORP
characteristics in the subject over time, without limitation, the
ORP characteristics value of the subject may be checked every 1, 2,
3, 4, 5, or 6 days or weeks after the initial determination in
order to compare and determine a trend in the ORP characteristics
value of the patient.
[0162] The ORP characteristics of the subject may be obtained from
a body fluid of the subject, including but not limited to blood,
plasma, cerebrospinal fluid (CSF) and serum, in a convenient and
timely manner. The ORP characteristics of the subject may also be
obtained from a tissue of the subject, including but not limited
to, tissues of the brain.
[0163] In a related embodiment, the subject may present with
symptoms of head injury, such as dizziness, nausea, vomiting, loss
of consciousness, headache, vomiting, nausea, lack of motor
coordination, difficulty balancing, lightheadedness, blurred
vision, tinnitus, fatigue or lethargy, changes in sleep patterns,
behavioral or mood changes, confusion, trouble with memory,
concentration, or attention, and the ORP characteristics of the
subject are obtained and compared to an ORP characteristics value
from one or more subjects known to have undergone head injury
and/or subjects known to be "normal" or free of head injury. An ORP
characteristics value of the subject that is statistically similar
to, or greater than, the ORP characteristics value from subjects
known to have sustained head injury is indicative of a patient
experiencing or at elevated risk of developing permanent neural
injury or functional deficits. In this circumstance, the subject
may be admitted to a hospital or care unit, or processed for
further evaluation that may include obtaining and evaluating brain
scans. Possible treatments for brain injury include medication
(e.g., pain relievers, diuretics, anti-seizure drugs or
coma-inducing drugs), surgery (e.g., removing clotted blood,
repairing skull fractures, or opening a window in the skull),
rehabilitation (e.g., physiatry, occupational therapy, physical
therapy, speech and language pathology, or neuropsychology). The
ORP characteristics value of the subject may be checked every 1 to
6 hours after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
subject.
[0164] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from "normal" subjects is indicative of a subject lacking a
brain injury at no or low risk of further brain damage. In this
circumstance, the subject may be discharged or otherwise released
from any further evaluation. Similarly, the ORP characteristics
value of such subject may be checked every 1 to 6 hours after the
initial determination in order to compare and determine a trend in
the ORP characteristics value of the patient.
[0165] Pregnancy/Fetal Health
[0166] Pregnancy is a prolonged state of oxidative stress arising
from increased placental mitochondrial activity and production of
reactive oxygen species. Excessive production of ROS may occur at
certain windows in placental development and in pathologic
pregnancies, such as those complicated by preeclampsia and/or IUGR,
overpowering antioxidant defenses, with deleterious outcome. For
example, in the first trimester, establishment of blood flow into
the intervillous space is associated with a burst of oxidative
stress. The inability to mount an effective antioxidant defense
against this may result in early pregnancy loss. Oxidative stress
peaks by the second trimester of pregnancy, ending what appears to
be a vulnerable period for fetal health and gestational progress.
In late gestation, increased oxidative stress may be seen in
pregnancies complicated by diabetes, IUGR, and preeclampsia.
[0167] Another embodiment of this invention is a method of
diagnosing, evaluating and/or monitoring pregnancy in a subject as
well as monitoring progress in fetal development or risk by
measuring the ORP characteristics of a biological sample from such
a subject and then evaluating if the ORP characteristics are
significantly different than the ORP characteristics of a reference
value, such as a biological sample from a non-pregnant population
or from a pregnant population to determine the pregnancy and/or
fetal development status of the subject. The subject is then
treated based on the pregnancy and/or fetal development status. In
these methods, an increase in the ORP characteristics of the
subject over the ORP characteristics of non-pregnant subjects is
indicative of the presence of pregnancy in the subject.
Alternatively, or in addition, an increase in the ORP
characteristics of the subject over the ORP characteristics of a
reference value from pregnant subjects known to have normal
pregnancy of the same gestational period, is indicative of a
potential developing maternal or fetal risk or high-risk pregnancy
in the subject.
[0168] In order to determine the trend of the ORP characteristics
in such subjects over time, without limitation, the ORP
characteristics value of the subject may be checked every 1, 2, 3,
4, 5, or 6 days or weeks after the initial determination in order
to compare and determine a trend in the ORP characteristics value
of the subject.
[0169] The ORP characteristics of the subject may be obtained from
a body fluid of the subject, including but not limited to blood,
plasma, amniotic fluids, and serum. The ORP characteristics of the
subject may also be obtained from a tissue of the subject,
including but not limited to, placental or fetal tissues.
[0170] Thus, in one embodiment, a pregnant subject may be evaluated
for ORP characteristics values indicative of abnormal pregnancy or
increased fetal risk in the subject.
[0171] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from subjects known to have a normal pregnancy of the same
gestational period is indicative of a subject that is progressing
with normal pregnancy. An ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from subjects known to have a normal
pregnancy of the same gestational period is indicative of a subject
that is not progressing to normal pregnancy or may be progressing
to abnormal pregnancy, including preeclampsia or eclampsia,
gestational diabetes, or may be at elevated risk of miscarriage or
fetal death.
[0172] The ORP characteristics values of such subject may be
checked regularly after the initial determination in order to
re-evaluate the initial evaluation of normal pregnancy or abnormal
pregnancy or fetal development or developmental progression. In a
related embodiment, a pregnant subject may be regularly monitored
by evaluation of the subject's ORP characteristics values compared
with ORP characteristics values indicative of normal fetal
development. An ORP characteristics value of the subject that is
progressing statistically to an ORP characteristics value that is
similar to, or greater than, the ORP characteristics value from
subjects having a normal pregnancy compared with the subject, is
indicative of a subject that may be progressing to unhealthy or
abnormal pregnancy.
[0173] The ORP characteristics values of such subject may be
checked, without limitation, every 1, 2, 3, 4, 5, or 6 weeks or
every 1, 2, 3, 4, 5, or 6 months after the initial determination in
order to evaluate the subject's pregnancy progress and/or disease
prognosis.
[0174] In some embodiments, subjects found to have elevated ORP
characteristics indicative of abnormal or high-risk pregnancy are
administered an antioxidant regimen and/or a regimen of avoidance
of iron excess to ameliorate maternal and early fetal damage.
[0175] Respiratory Distress
[0176] Respiratory distress, including acute respiratory distress
syndrome (ARDS), is a lung condition that leads to low oxygen
levels in the blood that can be life threatening. Respiratory
distress is typically experienced in subjects with a respiratory
disorder, such as pneumonia, sepsis, severe bleeding caused by
injury, chest or head injury, breathing harmful fumes, or inhaling
vomited stomach contents.
[0177] Another embodiment of this invention is a method of
diagnosing, evaluating and/or monitoring respiratory distress in a
subject by measuring the ORP characteristics of a biological sample
from such a subject and then evaluating if the ORP characteristics
are significantly different than the ORP characteristics of a
reference value, such as a biological sample from a population at
risk for respiratory distress or from a patient having a
respiratory disorder to determine the respiratory distress status
of the subject. The subject is then treated based on the
respiratory distress status. In these methods, an increase in the
ORP characteristics of the subject compared to the ORP
characteristics of a healthy or normal subject is indicative of the
presence of respiratory distress in the subject. Alternatively, or
in addition, progressively increasing ORP characteristics in a
subject with a respiratory disorder may be indicative of developing
acute respiratory distress syndrome in the subject. Alternatively,
the ORP characteristics of the subject may be compared to the ORP
characteristics of a healthy or normal subject to rule out
respiratory distress in subject experiencing low blood pressure,
confusion, and extreme tiredness or other symptoms of respiratory
distress.
[0178] Subjects who develop respiratory distress often are
hospitalized for other health problems. Thus, one embodiment is
monitoring the ORP characteristics of a hospitalized patient to
identify developing respiratory distress before an acute
respiratory distress syndrome is experienced.
[0179] In certain embodiments, a subject having an ORP
characteristics value indicative of respiratory distress may be
administered oxygen therapy, steroids or mechanical
ventilation.
[0180] In order to determine the trend of the ORP characteristics
in such subjects over time, without limitation, the ORP value of
the subject may be checked every 1, 2, 3, 4, 5, or 6 minutes, hours
or days after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
subject.
[0181] The ORP characteristics of the subject may be obtained from
a body fluid of the subject, including but not limited to blood,
plasma, saliva, mucus, respiratory aspirates or other lung fluids,
breath condensates, and serum. The ORP characteristics of the
subject may also be obtained from a tissue of the subject,
including but not limited to, lung tissues.
[0182] Childhood Health
[0183] Reactive oxygen species (ROS) play a crucial role in the
initiation and progression of various diseases in children and
adolescents and therefore, the evaluation of oxidative stress in
pediatric diseases is an important concern.
[0184] Another embodiment of this invention is a method of
diagnosing, evaluating and/or monitoring newborn or adolescent
health in a child as well as monitoring progress in fetal
development or risk by measuring the ORP characteristics of a
biological sample from a child and then evaluating if the ORP
characteristics are significantly different than the ORP
characteristics of a reference value, such as a biological sample
from a healthy child or from a child having a known disease state,
to determine the childhood health status of the subject. The
subject is then treated based on the childhood health status. Such
treatment can include identification of a specific disease of the
child. In these methods, an increase in the ORP characteristics of
the child over the ORP characteristics value of healthy children is
indicative of the presence of a disease state or developing disease
state in the child. Alternatively, or in addition, an ORP
characteristics value of the child similar to the ORP
characteristics of a reference value from a healthy child of
similar age, may be used to rule out a present or developing
disease state in the child. Such developing disease states may
include cancer, diabetes and respiratory diseases.
[0185] In order to determine the trend of the ORP characteristics
in a child over time, without limitation, the ORP characteristics
value of the child may be checked every 1, 2, 3, 4, 5, or 6 days or
weeks after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
child.
[0186] The ORP characteristics of the child may be obtained from a
body fluid of the subject, including but not limited to blood,
plasma, serum, saliva, tears, mucus, pulmonary fluids and urine.
The ORP characteristics of the child may also be obtained from a
tissue of the child, including but not limited to, skin or
hair.
[0187] Frailty
[0188] Frailty has been thought of as a global measure of one's
susceptibility to disease and death; it can also be thought of
one's vulnerability to stressors. While varied, frailty has been
measured using a combination of the following factors: physical
ability, self-reported health, co-morbidities, physiology and
psychology. These commonly measured factors have been shown to be
associated with a high risk of death and hospitalization, as well
as a high use of health care. One of the main limitations of
assessing frailty is the lack of a quick, easy-to-use,
point-of-care method. Although there are measures of frailty that
can be considered quick and easy to administer, they are not as
strongly associated with poor outcomes, or rely on a more
subjective assessment as compared to the Clinical Frailty Scale of
the Canadian Study of Health and Aging (CSHA) or the Fried scale
(Frailty in Older Adults: Evidence for a Phenotype. J Gerontol A
Biol Sci Med Sci, 56(3), M146-157 (2001)).
[0189] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring a subject for frailty that
includes measuring the ORP characteristics of a biological sample
from a subject that has been diagnosed with, or is suspected of
having or developing frailty, and then evaluating if the ORP
characteristics are significantly different than a reference value
such as the ORP characteristics of a biological sample from another
subject or group of subjects known to be frail or known to be fit
to determine the frailty status of the subject. The subject is then
treated based on the frailty status. Alternatively or additionally,
it may be determined if the ORP characteristics have increased or
decreased compared to a prior ORP characteristics measurement
obtained from the same subject. The ORP characteristics of the
subject may be obtained from a biological sample of the subject,
including but not limited to blood, plasma, and serum, in a
convenient and timely manner.
[0190] In such conditions, ORP characteristics of the subject that
are significantly greater than the ORP characteristics of subjects
known to be fit is indicative of the presence, development or
worsening of frailty in the subject. Similarly, an increase in the
ORP characteristics of the subject over time is indicative of the
development or worsening of frailty in the subject. In order to
determine the trend of the ORP characteristics in the subject over
time, without limitation, the ORP characteristics value of the
subject may be checked every 1, 2, 3, 4, 5, or 6 weeks or months
after the initial determination in order to compare and determine a
trend in the ORP characteristics value of the patient. Patients who
are frail can be treated by maintaining or increasing food intake,
resistance exercise, balance exercise, reducing social isolation
and controlling geriatric health issues (e.g., depression, impaired
vision and hearing, and decreased mobility).
[0191] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from fit subjects is indicative of a patient at no or low
risk of frailty. In this circumstance, the subject may be released
from any further evaluation.
[0192] Determination of ORP characteristics values for subjects at
differing levels of frailty can be achieved by evaluating the ORP
values for subjects at different grades on the CHSA Clinical
Frailty Scale from Grade 1 (Very Fit) to Grade 7 (Severely Frail)
or on the Fried scale of Grade 0 (robust), Grade 1 or 2
(intermediate or pre-frail), or Grade 3, 4 or 5 (frail).
[0193] Allergy
[0194] There is ample evidence that allergic disorders, such as
asthma, rhinitis, and atopic dermatitis, are mediated by oxidative
stress. Asthma affects 5% to 10% of the population and in
asthmatics, oxidative stress occurs not only as a result of
inflammation but also from environmental exposure to air pollution.
Excessive exposure to reactive oxygen and nitrogen species is the
hallmark of oxidative stress and leads to damage of proteins,
lipids, and DNA.
[0195] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring an allergic disorder in a
subject that includes measuring the ORP characteristics of a
biological sample from a subject that has been diagnosed with, or
is suspected of having an allergic disorder, and then evaluating if
the ORP characteristics are significantly different than a
reference value, such as the ORP characteristics of a biological
sample from another subject or group of subjects known to be free
of allergic disorders, to determine the allergic disorder status of
the subject. Alternatively or additionally, it may be determined if
the ORP characteristics have increased or decreased compared to a
prior ORP characteristics measurement obtained from the same
subject. The subject is then treated based on the allergic disorder
status.
[0196] In such allergic disorders, ORP characteristics of the
subject that are significantly greater than the ORP characteristics
of subjects without an allergic disorder is indicative of allergic
reaction or progressing allergic disorder in the subject.
Similarly, an increase in the ORP characteristics of the subject
over time is indicative of the progression of the allergic disorder
in the subject and may also indicate a failure of a treatment for
the allergic disorder.
[0197] In order to determine the trend of the ORP characteristics
in the subject over time, without limitation, the ORP
characteristics value of the subject may be checked every 1, 2, 3,
4, 5, or 6 days, weeks or months after the initial determination in
order to compare and determine a trend in the ORP characteristics
value of the patient.
[0198] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, saliva, mucus and serum, in a convenient and timely
manner. The ORP characteristics of the subject may also be obtained
from a tissue of the subject, including lung tissues.
[0199] In a related embodiment, a subject may present with symptoms
of allergic reaction and the ORP characteristics of the subject are
obtained and compared to an ORP characteristics value from subjects
having an allergic disorder and/or subjects known to be free of
allergic disorders. An ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from subjects having an allergic disorder is
indicative of a patient having an acute allergic reaction or
progression or escalation of an allergic disorder in the subject.
In this circumstance, the subject may be treated for an allergic
disorder. For example, the subject can be treated by administration
of antihistamines, decongestants, steroids, bronchodilators,
anti-leukotrienes, or antibody-based therapy or immunotherapy. The
ORP characteristics value of the subject may be checked, without
limitation, every 1, 2, 3, 4, 5, or 6 hours, days or weeks after
the initial treatment in order to compare and determine a trend in
the ORP characteristics value of the patient that may be indicative
of effective treatment or progression of the allergic reaction. In
these instances, the subject may be treated for allergic reaction
or disorder. Additionally, therapeutic interventions that decrease
exposure to environmental reactive oxygen species or augment
endogenous antioxidant defenses might be beneficial as adjunctive
therapies for allergic respiratory disorders.
[0200] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from subjects known to be free of an allergic disorder is
indicative of a patient that is not experiencing an allergic
reaction or having a progressive allergic disorder. In this
circumstance, the subject may be released from any further
evaluation without treatment for allergic reaction or disorder, or
the ORP characteristics value may be used to rule out allergy in
the patient. Similarly, the ORP characteristics value of such
subject may be checked, without limitation, every 1, 2, 3, 4, 5, or
6 hours or days after the initial determination in order to compare
and determine a trend in the ORP characteristics value of the
patient, which may reveal the presence of an allergic disorder or
the confirmation that the subject is not experiencing an allergic
reaction.
[0201] Banked Blood Products
[0202] After it is donated, human blood begins to lose the ability
to facilitate the transfer of oxygen from red blood cells to
tissues. Studies have demonstrated that recipients who receive
blood transfusions have higher incidences of lung infection, heart
attack, heart failure, stroke and even death. It has been shown
that banked blood is not the same as blood in the body, as it lacks
nitric oxide in red blood cells that opens up blood vessels to
facilitate the transfer of oxygen from red blood cells to tissues.
It has also been shown that adding this gas back to stored blood
products before transfusion appears to restore red blood cells'
ability to transfer oxygen to tissues.
[0203] Another embodiment of this invention is a method of
assessing and/or monitoring the quality of a banked blood product
by measuring the ORP characteristics of the banked blood product
and then evaluating if the ORP characteristics are significantly
different than the ORP characteristics of a reference value, such
as a blood sample from a healthy child or adult or from a similar
banked blood product known to retain the ability to transfer oxygen
to tissues to determine the status of the banked blood product. The
banked blood product is then administered to a recipient in need of
such treatment or discarded. If the banked blood product is
administered, it may be administered in conjunction with a reducing
agent (e.g., vitamin C). If administered in conjunction with a
reducing agent, the banked blood product may be admixed with a
reducing agent prior to administration to the recipient.
Alternatively or additionally, the banked blood product may be
administered concurrently but separately with a reducing agent to
the recipient. If admixed with or administered concurrently with a
reducing agent, the ORP characteristics of the banked blood product
may be evaluated to determine the amount of a reducing agent to be
mixed with the banked blood product or administered to the
recipient of the banked blood product.
[0204] The ORP characteristics of the banked blood product may be
assessed at the time of collecting the banked blood product from a
donor or any time thereafter, up to the time of administering the
banked blood product to a recipient or discarding the banked blood
product. The ORP characteristics of the banked blood product may
also be continually assessed for a time period during the storage
of the product, including a period extending throughout the entire
period of storage of the product.
[0205] Anesthesia
[0206] Anesthetics may cause oxidative and metabolic stress during
administration of anesthesia, such as during surgery, especially
coronary surgery, and extracorporeal circulation, leading to organ
damage and poor outcome. One embodiment of the invention provides
methods of evaluating or monitoring a subject's oxidative stress
during administration of anesthesia by assessing the ORP
characteristics of a biological sample from the subject and then
evaluating if the ORP characteristics are significantly different
than the ORP characteristics of a reference value such as the same
biological sample from another subject or group of subjects having
undergone the same or similar procedure to determine the anesthesia
status of the subject. The subject is then treated based on the
anesthesia status of the subject. Alternatively or additionally, it
may be determined if the ORP characteristics have increased or
decreased compared to a prior ORP characteristics measurement
obtained from the same subject. In a specific embodiment, this may
include comparison to an ORP characteristics measurement obtained
from the same subject taken before onset of the administration of
anesthesia.
[0207] The ORP characteristics value of the subject may be obtained
from a body fluid of the subject, including but not limited to
blood, plasma, serum, saliva, lung fluids, and breath condensates.
The ORP characteristics of the subject may also be obtained from a
tissue of the subject, including but not limited to, a tissue of
the lung or other organ of the subject.
[0208] In order to determine the trend of the ORP characteristics
in such subjects over time, without limitation, the ORP value of
the subject may be checked every 1, 2, 3, 4, 5, or 6 minutes after
the initial determination in order to compare and determine a trend
in the ORP characteristics value of the subject.
[0209] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from normal subjects (i.e., not receiving anesthesia) is
indicative of a subject that is stable undergoing administration of
anesthesia and not in need of emergency measures or adjustment of
anesthetic administration during the procedure.
[0210] Alternatively, an ORP characteristics value of the subject
that is statistically similar to, or greater than, the ORP
characteristics value from normal subjects or who shows
significantly greater or persistent worsening in ORP
characteristics values during administration of anesthesia, is
indicative of a subject at elevated risk of oxidative stress, organ
damage and poor outcome. Such subject may be treated by adjustment
(e.g., titration) to the anesthesia administration or the
administration of one or more antioxidant therapies.
[0211] Infection
[0212] Oxidative stress, primarily due to increased generation of
reactive oxygen species (ROS) and reactive nitrogen species (RNS),
is a feature of many viral and bacterial infections. ROS and RNS
modulate the permissiveness of cells to viral replication, regulate
host inflammatory and immune responses, and cause oxidative damage
to host tissues.
[0213] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring an infection in a subject that
includes measuring the ORP characteristics of a biological sample
from a subject that has been diagnosed with, or is suspected of
having an infection, and then evaluating if the ORP characteristics
are significantly different than a reference value such as the ORP
characteristics of a biological sample from another subject or
group of subjects known to be free of infection to determine the
infection status of the subject. Alternatively or additionally, it
may be determined if the ORP characteristics have increased or
decreased compared to a prior ORP characteristics measurement
obtained from the same subject. The subject is then treated based
on the infection status.
[0214] In one embodiment, the infection is a viral infection,
including RNA viruses, such as influenza viruses, DNA viruses, such
as hepatitis B virus, and retroviruses, such as human
immunodeficiency virus (HIV).
[0215] In another embodiment, the infection is a bacterial
infection. Some bacterial infections give rise to oxidative stress
in the host when inflammatory cells that express inducible nitric
oxide synthase are triggered in an inflammatory process thereby
exaggerating the oxidative stress encountered following the
bacterial infection.
[0216] In such infections, ORP characteristics of the subject that
are significantly greater than the ORP characteristics of subjects
known to be free of infection are indicative of infection or
progressing infection in the subject. Similarly, an increase in the
ORP characteristics of the subject over time is indicative of the
progression of the infection in the subject and may also indicate a
failure of an anti-infective treatment applied to the subject. In
order to determine the trend of the ORP characteristics in the
subject over time, without limitation, the ORP characteristics
value of the subject may be checked every 1, 2, 3, 4, 5, or 6 days
or months after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
patient.
[0217] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, saliva, mucus and serum, in a convenient and timely
manner. The ORP characteristics of the subject may also be obtained
from a tissue of the subject, including, an infected tissue or
organ.
[0218] In a related embodiment, a subject may present with symptoms
of infection and the ORP characteristics of the subject are
obtained and compared to an ORP characteristics value from subjects
having an infection and/or subjects known to be free of the
infection. An ORP characteristics value of the subject that is
statistically similar to, or greater than, the ORP characteristics
value from subjects having an infection is indicative of a patient
having an infection or progression of an infection in the subject.
In this circumstance, the subject may be treated for an infection,
for example by the administration of antibiotics, anti-fungal
medication or anti-viral medication. The ORP characteristics value
of the subject may be checked every 1, 2, 3, 4, 5, or 6 hours or
days after the initial treatment in order to compare and determine
a trend in the ORP characteristics value of the patient that may be
indicative of effective treatment or progression of the
infection.
[0219] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from subjects known to be free of an infection is indicative
of a patient that is not infected. In this circumstance, the
subject may be released from any further evaluation without an
anti-infective treatment, or the ORP characteristics value may be
used to rule out infection in the patient. Similarly, the ORP
characteristics value of such subject may be checked, without
limitation, every 1, 2, 3, 4, 5, or 6 hours or days after the
initial determination in order to compare and determine a trend in
the ORP characteristics value of the patient, which may reveal the
presence of an infection or the confirmation that the subject is
free of infection.
[0220] Trauma
[0221] Trauma encompasses a physiological wound caused by an
external source. Unintentional and intentional traumatic injuries
were the fifth and seventh leading causes of worldwide mortalities,
in the 2002 World Health Organization estimates of causes of death
by rate. Excessive production of reactive oxygen species due to
excitotoxicity and exhaustion of the endogenous antioxidant system
may follow traumatic injury in a subject. This oxidative stress in
turn induces peroxidation of cellular and vascular structures,
protein oxidation, cleavage of DNA, and inhibition of the
mitochondrial electron transport chain.
[0222] Another embodiment of the invention provides methods of
diagnosing, evaluating or monitoring a traumatic injury in a
subject that includes measuring the ORP characteristics of a
biological sample from a subject that has or is suspected of having
experienced a traumatic injury, and then evaluating if the ORP
characteristics are significantly different than the ORP
characteristics of a reference value such as the same biological
sample from another subject or group of subjects that have not
experienced a traumatic injury to determine the brain injury status
of the subject to determine the trauma status of the patient. The
subject is then treated based on the trauma status of the subject.
Alternatively or additionally, it may be determined if the ORP
characteristics have increased or decreased compared to a prior ORP
characteristics measurement obtained from the same subject. In a
specific embodiment, this may include comparison to an ORP
characteristics measurement obtained from the same subject taken
before the suspected or confirmed traumatic injury occurred.
[0223] The trauma may include, for example, blunt trauma, traumatic
asphyxia, penetrating trauma, chest trauma, abdominal trauma,
facial trauma, geriatric trauma, pediatric trauma, polytrauma,
blast injury, head injury, spinal cord injury, psychological
trauma, and orthopedic trauma, such as bone break or fracture.
[0224] In such injuries, an increase in the ORP characteristics of
the subject over the ORP characteristics of subjects known to be
free of traumatic injury is indicative of the development or
worsening of the injury or poor prognosis of the subject.
Similarly, an increase in the ORP characteristics of the subject
over time is indicative of the development or worsening of injury
in the subject. In order to determine the trend of the ORP
characteristics in the subject over time, the ORP characteristics
value of the subject may be checked every 1 to 6 minutes or days
after the initial determination in order to compare and determine a
trend in the ORP characteristics value of the patient.
[0225] The ORP characteristics of the subject may be obtained from
a body fluid of the subject, including but not limited to blood,
plasma, cerebrospinal fluid (CSF) and serum, in a convenient and
timely manner. The ORP characteristics of the subject may also be
obtained from a tissue of the subject, including but not limited
to, skin, muscle or bone tissues or tissue from an injured organ.
Similarly, the ORP characteristics value of such subject may be
checked, without limitation, every 1, 2, 3, 4, 5, or 6 hours after
the initial determination in order to compare and determine a trend
in the ORP characteristics value of the patient.
[0226] The ORP characteristics of the subject are obtained and
compared to an ORP characteristics value from one or more subjects
known to have undergone similar trauma and/or subjects known to be
normal or lacking a traumatic injury. An ORP characteristics value
of the subject that is statistically similar to, or greater than,
the ORP characteristics value from subjects known to have sustained
a traumatic injury is indicative of a patient experiencing or at
elevated risk of developing further injury or death or poor
prognosis for recovery from traumatic injury. In this circumstance,
the subject may be admitted to a hospital or emergency care unit,
administered fluid resuscitation, or vasopressors.
[0227] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from "normal" subjects is indicative of a subject that is
recovering from a traumatic injury or has a good prognosis for
recovery from the traumatic injury and is at lowered risk of death
following the traumatic injury. In this circumstance, the subject
may be discharged or treated for the injury and discharged without
further evaluation.
[0228] A related embodiment is a method of predicting or prognosing
traumatic orthopedic injury in a subject, including stratification
of patients following injury, such as hip fracture in an elderly
patient, that includes measuring the ORP characteristics of a
biological sample from a subject that is at risk of a traumatic
injury, and then evaluating if the ORP characteristics are
significantly different than the ORP characteristics of a reference
value such as the same biological sample from another subject or
group of subjects that are not considered to be at risk of
experiencing a traumatic injury to determine the trauma injury risk
status of the subject.
[0229] An ORP characteristics value of the subject that is
statistically similar to, or greater than, the ORP characteristics
value from a subject known to have sustained a traumatic orthopedic
injury is indicative of a patient at elevated risk of sustaining a
traumatic orthopedic injury or is at risk of poor prognosis for
recovery from traumatic orthopedic injury. In this circumstance,
the subject may be administered antioxidant therapy, or admitted to
a medical facility or long term care facility, or provided measures
to reduce the risk of experiencing a traumatic orthopedic injury or
associated comorbidities.
[0230] An ORP characteristics value of the subject that is
statistically similar to, or less than, the ORP characteristics
value from normal subjects not considered to be at risk of a
traumatic orthopedic injury is indicative of a subject that is at
low risk of experiencing a traumatic orthopedic injury or has a
good prognosis for recovery from a traumatic orthopedic injury and
is at lowered risk of death following a traumatic orthopedic
injury. In this circumstance, the subject may be discharged from a
medical facility or removed from further observation.
[0231] Pyloric Stenosis
[0232] Pyloric stenosis is a narrowing of the opening from the
stomach to the duodenum due to enlargement of the muscle
surrounding the pylorus, leading to projectile non-bilious
vomiting. It most often occurs in the first few months of life,
when it is referred to as infantile hypertrophic pyloric
stenosis.
[0233] Another embodiment of the invention provides methods of
diagnosing, evaluating or monitoring pyloric stenosis in a subject,
especially a child subject, that includes measuring the ORP
characteristics of a biological sample from the subject that has
been diagnosed with, or is suspected of having or developing
pyloric stenosis, and then evaluating if the ORP characteristics
are significantly different than a reference value, such as the ORP
characteristics of a biological sample from another subject or
group of subjects known to have pyloric stenosis to determine the
pyloric stenosis status of the subject. Alternatively or
additionally, it may be determined if the ORP characteristics have
increased or decreased compared to a prior ORP characteristics
measurement obtained from the same subject. The subject is then
treated based on the pyloric stenosis status or diagnosis.
Treatment may include the administration of intravenous and/or oral
atropine to the subject, or surgery (pyloromyotomy).
[0234] Following such diagnosis, ORP characteristics of the subject
that are significantly greater than the ORP characteristics of
normal subjects known to be free of pyloric stenosis is indicative
of the development or worsening of pyloric stenosis and dehydration
and metabolic alkalosis in the subject. Similarly, an increase in
the ORP characteristics of the subject over time is indicative of
the development or worsening of pyloric stenosis in the subject. In
order to determine the trend of the ORP characteristics in the
subject over time, the ORP characteristics value of the subject may
be checked, without limitation, every 1, 2, 3, 4, 5, or 6 minutes
or days after the initial determination in order to compare and
determine a trend in the ORP characteristics value of the
patient.
[0235] The ORP characteristics of the subject may be obtained from
a biological sample of the subject, including but not limited to
blood, plasma, serum, saliva, tears, and mucus in a convenient and
timely manner. The ORP characteristics of the subject may also be
obtained from a tissue of the subject, including but not limited
to, tissues of the digestive tract.
[0236] Medical Care Staging
[0237] The treatment capacity of certain specialty areas of a
medical care facility may become overcrowded or may be
under-utilized when patients are not appropriately and timely moved
from one area to another depending on their medical condition and
health status. For example, the emergency department in a hospital
may become overcrowded when sick patients who have been evaluated
by an emergency physician and admitted to a hospital, are left
waiting for an inpatient hospital bed to become available.
Alternatively, the full resources of the intensive care unit (ICU)
in a hospital may be under-utilized if patients appropriately in
need of such intensive care are not admitted and transferred from
the emergency room to the intensive care unit. Further, discharge
disposition decisions are important for appropriate utilization of
medical facilities (e.g., hospitals), long term care facilities and
skilled nursing facilities.
[0238] Another embodiment of this invention provides methods of
diagnosing, evaluating or monitoring a patient within a medical
care facility to determine the most appropriate transfer or
discharge decision for the patient. In one embodiment, a patient is
evaluated for ORP characteristics during diagnosis or treatment in
one department or section of a medical care facility, such as a
hospital or skilled nursing facility. A biological sample of the
patient is tested for an ORP characteristic which is compared to a
medical care staging reference value to determine the medical care
staging status of the patient. Then a transfer decision for the
patient is made based on the medical care staging status of the
patient. The patient may be admitted to the medical facility,
transferred from one department or unit of the facility to a
different department or unit within the same facility, transferred
from one department or unit of the facility to a different
department or unit at a separate facility, not admitted to the
medical facility or discharged from the medical care facility
(e.g., discharged to home, a long term care facility, or a skilled
nursing facility).
[0239] For example, ORP characteristic values of a patient in the
emergency room department of a hospital that are significantly
elevated compared to the ORP characteristic values of an individual
or population of patients admitted to an intensive care unit of a
medical care facility may be transferred from the emergency room to
the intensive care unit. Alternatively, ORP characteristic values
of a patient in the emergency room department of a hospital that
are normal, or below the ORP characteristic values of an individual
or population of patients admitted to an intensive care unit of a
medical care facility, may be sent home from the emergency room
and/or not transferred to the intensive care unit.
[0240] Similarly, ORP characteristic values of a patient in an
intensive care unit of a medical care facility that are normal, or
below the ORP characteristic values of an individual or population
of patients in an intensive care unit of a medical care facility,
may be transferred from the intensive care unit to another medical
step down unit. Alternatively, ORP characteristic values of a
patient in another department of a medical facility, such as a
coronary care unit, that are significantly elevated compared to the
ORP characteristic values of an individual or population of
patients in that department or similar to the ORP characteristic
values of an individual or population of patients admitted to an
intensive care unit of a medical care facility, the patient may be
transferred to the intensive care unit.
[0241] Such patient(s) may be evaluated for medical care staging
ORP characteristic values at any time during their treatment at the
facility in order to assess the need or ability to transfer to a
different medical department.
[0242] Medical facilities may include, without limitation,
hospitals, nursing homes, residential treatment centers, skilled
nursing facilities, and geriatric care facilities.
[0243] Clinical Trials
[0244] Inclusion and exclusion criteria are the conditions that
must be met in order to participate in a clinical trial, or the
standards used to determine whether a person may be allowed to
participate in a clinical trial. Important criteria used to
determine a subject's appropriateness for clinical trial
participation include the age, sex, stage of a disease (if any),
treatment history, and other medical conditions of the potential
study participant. In addition, the conduct of clinical trials
involves the use of endpoints for example to determine therapeutic
efficacy of a treatment being evaluated.
[0245] Another embodiment of this invention provides methods of
evaluating or monitoring a subject enrolled in or under
consideration for enrollment in a clinical trial. A biological
sample of the subject is tested for an ORP characteristic which is
compared to a clinical trial ORP reference value to determine the
clinical trial status of the subject. The subject is then included
in (or enrolled) or excluded (or withdrawn) from a clinical trial
based on the trial status of the subject. Alternatively, the
subject is assessed for therapeutic efficacy as part of the
trial.
[0246] Subjects may be evaluated for clinical trial ORP
characteristics at any time during their evaluation for, or
enrollment in, a clinical trial in order to assess the inclusion or
exclusion from the trial. Alternatively, subjects can be evaluated
during a clinical trial as part of the trial.
[0247] For example, a subject being considered for inclusion in a
clinical trial having ORP characteristic values that are
significantly elevated compared to the ORP characteristic values of
a normal individual or population of such subjects can be excluded
or withdrawn from the clinical trial. Alternatively, ORP
characteristic values of such a subject that are normal, or below
the ORP characteristic values of an individual or population of
patients included in such a clinical trial can be included or
enrolled in the clinical trial.
[0248] As a further example, a subject in a clinical trial having
ORP characteristic values as an endpoint in the trial can be
evaluated in the trial as having met the endpoint. For example, the
endpoint can be lowered or normal ORP values as an indicator of
therapeutic efficacy of a treatment being tested. Alternatively,
high ORP characteristic values can be endpoint of the time or
amount of chemotherapy to be administered as a marker of induced
toxicity.
[0249] Insurance Underwriting
[0250] When buying insurance, such as life insurance or disability
insurance, a subject is typically required to undergo a medical
exam for insurance underwriting purposes. When underwriting an
insurance policy, insurers use mathematical and statistical methods
to assess risk and measure the costs of alternative strategies with
regard to the design, funding, accounting, administration, and
maintenance or redesign of insurance plans, pension plans and
annuities. Medical tests conducted by insurance companies on
prospective policyholders often include analysis of blood and urine
samples, and measurement of height, weight, blood pressure and
pulse rate. The blood tests routinely screen for elevated blood
sugar levels, abnormal liver and kidney functions, HIV, cocaine and
cotinine. The results of these tests and measurements are compared
to morbidity data to determine whether to insure the subject, and
if so, how much to charge the subject.
[0251] Another embodiment of this invention provides methods of
evaluating or monitoring a subject enrolled in, or under
consideration for, enrollment in an insurance plan. A biological
sample of the subject is tested for an ORP characteristic which is
compared to an insurance ORP reference value to determine the
insurable status of the subject. The subject is then included or
enrolled in an insurance plan based on the insurable status of the
subject and the rate or cost of the insurance is based on the
insurable status of the subject. Alternatively, the subject is then
excluded from an insurance plan based on the insurable status of
the subject.
[0252] For example, a subject being considered for insurance having
ORP characteristic values that are significantly elevated compared
to the ORP characteristic values of an individual or population
that is otherwise actuarially similar to the subject being
considered can be denied insurance or be provided insurance at a
higher rate or cost than individuals that are otherwise actuarially
similar to the subject being considered. Alternatively, ORP
characteristic values of such a subject being considered for
insurance that are normal, or below the ORP characteristic values
of an individual or population that is otherwise actuarially
similar to the subject being considered can be provided insurance
coverage. Alternatively, ORP characteristic values of such a
subject being considered for insurance that are actuarially similar
to the ORP characteristic values of an individual or population
that is considered to have an elevated insurance risk can be denied
coverage or provided insurance coverage at elevated cost.
[0253] Subjects may be evaluated for inclusion or exclusion using
an insurance ORP reference value at any time during their
evaluation for, or enrollment in, an insurance or pension plan in
order to assess the inclusion or exclusion from the plan.
[0254] In each of these embodiments, the ORP value from the subject
is preferably obtained by applying a current to a biological sample
(a fluid or tissue sample) obtained from the subject and measuring
a voltage across the sample over a period of time. The measured
voltage is integrated over the period of time to obtain a value
indicative of an oxidation reduction capacity (ORP).
[0255] Accordingly, the present invention has been described with
some degree of particularity directed to the exemplary embodiments
of the present invention. It should be appreciated though that
modifications or changes may be made to the exemplary embodiments
of the present invention without departing from the inventive
concepts contained herein.
EXAMPLES
Example 1
[0256] This example evaluates methods of the present invention for
use as a trauma frailty index by analysis of hip fracture patients.
In particular, this example explores the use of oxidation reduction
potential (ORP) and anti oxidant reserves (capacity) as biomarkers
for a trauma frailty index. There are no measures available to
rapidly assess trauma patient frailty. Widely-accepted measures,
such as deficit accumulation calculations or self-reported surveys,
are impractical within fast-paced trauma departments.
[0257] The Charlson Comorbidity Index (CCI) is a validated measure
of comorbidities that provides insight to frailty. Oxidative stress
occurs when the body produces too many damaging free radicals,
causing or exacerbating disease. Oxidative stress measures were
compared to the CCI to predict patient disposition and
mortality.
[0258] Trauma patients were examined with traumatic hip fractures
aged 65 and above, admitted between Jan. 1, 2010 and Jun. 30, 2012.
Oxidative stress capacity levels were measured through use of a
diagnostic oxidation reduction potential diagnostic system. ORP
plasma samples were taken at admission (within 48 hours of
admission) and discharge (within 48 hours of discharge).
Differences between admission and discharge ORP were also
calculated. Covariates included age-adjusted CCI values,
comorbidity counts, and injury severity score (ISS). Outcome
variables included patient disposition and mortality. Statistical
analysis included Pearson correlations, generalized linear models
and stepwise multivariate linear regression.
[0259] Patients with a non-fall or a non femoral injury or were
transferred from an outside facility were excluded. 153 patients
aged 65 and above with a traumatic hip fracture admitted to an
ACS-verified, Level I trauma center were included in the analysis.
Data were collected from a trauma registry.
[0260] Of 153 patients, 47% were above 85 years, 71% were female.
The mean age-adjusted CCI was 5.4; median values for comorbidities
and ISS were 2.0 and 9.0, respectively. 83% of patients were
discharged to a skilled nursing facility (SNF), 10% went home, 5%
went to hospice or rehabilitation, and 2% died. ORP capacity levels
were not normally distributed, thus inverse capacity levels (ICL)
was calculated (1/ORP capacity level). Admission ICL was correlated
with comorbidity count (p<0.05), and discharge ICL was
correlated with both age-adjusted CCI (p<0.05) and comorbidity
counts (p<0.05). When measuring by percentiles, admission ICL
was positively correlated with age (p=0.05) and comorbidity count
(p<0.05); discharge ICL was correlated with comorbidity count
(p=0.05). Patients with higher age-adjusted CCI or higher age were
also more likely to have a sizeable increase in ICL (p<0.05 for
both results). When examining outcomes, a lower ICL at admission
reached a near-significant association with disposition to a SNF
(p=0.09), and a larger change in ICL was also associated with
discharge to SNF (p<0.05). The low number of deaths (n=3)
prohibited analysis on mortality.
[0261] The association between discharge ORP and categorical
covariates is shown below in Table 1:
TABLE-US-00001 TABLE 1 Association Between Discharge ORP and
Categorical Covariates Static ORP Inverse Capacity ORP Age 65-84 (n
= 75) 185.1 2.6 Age .gtoreq. 85 (n = 56) 186.8 2.8 p value 0.63
0.46 Male (n = 38) 186 2.8 Female (n = 93) 185.8 2.7 p value 0.95
0.49 Age-adjusted CCI < 6 (n = 75) 184.2 2.6 Age-adjusted CCI
.gtoreq. 6 (n = 55) 187.4 2.9 p value 0.37 0.04 ISS < 16 (n =
129) 185.3 2.7 ISS .gtoreq. 16 (n = 2) 218.4 3.5 p value 0.10
<0.001 Normal VS 186.6 2.7 Abnormal VS 172.6 2.1 p value 0.34
0.22
[0262] A higher ISS and a higher CCI were associated with a higher
inverse capacity ORP
[0263] The association between ORP and discharge disposition is
shown below in Table 2:
TABLE-US-00002 TABLE 2 Association Between ORP and Discharge
Disposition home/rehab SNF (n = 20) (n = 147) p value Admission
Static ORP 168.4 (27.7) 164.9 (23.2) 0.60 Admission Inverse
Capacity 2.4 (1.0) 2.0 (0.9) 0.09 ORP Discharge Static ORP 179.2
(17.9) 186.2 (19.6) 0.17 Discharge Inverse Capacity 2.6 (0.8) 2.7
(0.8) 0.70 ORP Change in Static ORP 10.7 (29.4) 22.2 (21.8) 0.18
Change in Inverse Capacity 0.0 (1.0 0.7 (0.8) 0.03 ORP Mean
(SD)
Skilled nursing facility (SNF) is a worse hospital disposition than
home, nursing home, or a rehabilitation facility. A lower admission
inverse capacity ORP was associated with disposition to SNF. A
larger change in inverse capacity ORP was associated with discharge
to SNF.
[0264] When clinicians consider the degree of frailty in older
patients, treatment response, discharge options and end-of-life
decisions may improve. This example demonstrates that the ICL
increased with age-adjusted CCI and comorbidities, and changes in
ICL values were associated with patient discharge. This example
supports measuring oxidative stress capacity levels as a quick
measure of frailty in trauma patients.
Example 2
[0265] This example demonstrates the use of ORP in adult patients
with isolated Traumatic Brain Injury (TBI). The objective of this
preliminary study was to examine the association between ORP, as
measured by a device of the present invention, and various
in-hospital patient outcomes in an isolated traumatic brain injury
population.
[0266] A five-year prospective, observational cohort study was
conducted at two Level I Trauma Centers in the United States, and
included all admitted trauma patients who were at least 18 years
old, suffered an isolated traumatic brain injury and provided their
signed, informed consent. Plasma samples were collected in 2 mL
sodium heparin tubes, and aliquoted into 0.2 mL volumes for ORP
analysis. All samples were collected within 48 hours of injury or
discharge. All ORP operators were blinded to the patients' clinical
information. Each sample was tested using a system of the invention
in duplicate. ORP duplicate tests reading more than 10 mV different
were retested; samples of retests showing more than a 10 mV
difference were excluded.
[0267] Static ORP (sORP) and inverse capacity ORP (cORP) were
collected from the system, and the first, last, maximum and the
change from first to last ORP values were analyzed. Student's
T-tests, correlational analyses, and multivariate logistic
regression were used to examine the association between ORP and
various outcomes, including abbreviated injury severity (AIS) score
of the head, in-hospital mortality, and discharge to a skilled
nursing facility (SNF). All deaths were excluded from length of
stay and complication analyses. Due to the investigative nature of
this study, an alpha of 0.10 was used for all analyses.
[0268] There were 645 patients included in this study. A majority
were <65 years (69%), male (61%), and the median head AIS was 3.
There were a total of 11 deaths in the study, and 56 patients were
discharged to a skilled nursing facility (SNF).
[0269] The results showed that after adjustment, a 20 mV increase
in the first sORP were associated with a significant increase in
the odds of in-hospital death (OR: 4.24, 95% CI: 1.2-15.3), being
discharged to a SNF (OR: 1.28, 95% CI: 1.00-1.63), and significant
decrease in the odds of having a complication (OR: 0.75, 95% CI:
0.63-0.89). After adjustment, a 20 mV increase in the last sORP and
the maximum sORP were associated with significantly increased odds
of being discharged to a SNF (OR: 2.28, 95% CI: 1.52-3.41; OR:
1.59, 95% CI: 1.20-2.09).
[0270] After adjustment, a 1-unit increase in the first inverse
cORP were associated with significantly increased odds of being
discharged to a SNF (OR: 1.97, 95% CI: 1.25-3.11), and a
significantly decreased odds of having a complication (OR: 0.76,
95% CI: 0.61-0.94). After adjustment, a 1-unit increase in the last
inverse cORP was associated with a significant increase in the odds
of in-hospital mortality (OR: 5.05, 95% CI: 1.20-21.30), and a
1-unit increase in the maximum inverse cORP was associated with a
significant increase in the odds of being discharged to a SNF (OR:
1.66, 95% CI: 1.21-2.28).
[0271] This investigative study demonstrates that deleterious
changes in sORP and cORP are associated with poor patient outcomes.
The ability of the redox system of the invention provides a useful
point-of-care measure of ORP. Dichotomization points for sORP and
inverse cORP will provide physicians with a useful guide for
ascertaining the risk of certain patient outcomes.
Example 3
[0272] This example demonstrates the utility of monitoring sORP and
cORP as a measure of frailty in an elderly population. Frailty can
be consistently assessed through a Frailty Index, and increases in
oxidative stress are associated with frailty. Therefore, ORP levels
are associated with Frailty Index scores. This example will
demonstrate the level of agreement between ORP-derived frailty and
Frailty Index-derived frailty.
[0273] RedoxSYS.TM. is a small, portable reader that provides
quantitative measurements of sORP and cORP. An ORP sensor is
inserted into RedoxSYS.TM. and a plasma sample is added to the
application spot. The test starts when the sample fills the
reference electrode thereby completing the electrochemical circuit.
After testing is complete, the reader displays the test
results.
[0274] The percent agreement between ORP values and a Frailty Index
is examined in two phases: the derivation phase and the validation
phase. In the derivation phase, ranges of ORP values that best
discriminate Frailty Index categories of non-frail or frail are
derived from an initial population of 100 elderly subjects. The
validation phase tests a second, separate population of 100 elderly
subjects, and examines the percent agreement between the Frailty
Index-assigned frailty and the ORP-assigned frailty. The FRAIL
scale, the CSHA Clinical Frailty Scale, and the Charlson
Comorbidity Index (CCI) are also examined. Each block of 100
patients is block-recruited in the following manner: 50 patients
aged 65-84 and 50 patients aged 85 or older.
[0275] Once it has been determined that the subject meets the study
enrollment criteria and written informed consent has been obtained,
the following information is collected: [0276] Demographics,
medical history (including comorbidities, previous procedures, and
vitamin usage). [0277] Frailty Index (incorporated in patient
survey, Table 4) [0278] FRAIL Scale (incorporated in patient
survey, Table 4) [0279] CSHA Clinical Frailty Scale (Table 5)
[0280] A whole blood sample (.about.10 mL) is drawn into a
sodium-heparinized anti-coagulated whole blood Vacutainer tube upon
enrollment. The whole blood sample is analyzed at each site for
sORP and cORP on RedoxSYS.TM. within two hours. The results of the
RedoxSYS.TM. test are blinded to the medical team providing patient
care and are not used for patient management.
[0281] In the first phase of the study, 100 elderly patients are
examined. A receiver operator curve (ROC) is fit against ORP values
and frailty to determine ORP dichotomization values for
discriminating "frail" and "not frail." Frailty is assigned as
follows: Frailty Index Score 0.0 to 0.35 is considered "not frail",
while >0.35 is considered "frail".
[0282] In the second phase of the study, a second set of 100
elderly patients is categorized into "frail" and "not frail"
categories based on their Frailty Index scores, as well as their
ORP values (based on the ORP frailty cutoff value from the first
phase of the study). Both the positive percent agreement and
negative percent agreement is calculated for the ORP and Frailty
Index-assigned categories.
[0283] The positive percent agreement is calculated as follows (see
Table 3 below): TP/(TP+FN). The negative percent agreement is
calculated as follows: TN/(TN+FP). A two-sided test, testing that
the negative and positive percent agreements are not different from
a proportion of 0.50 is done and the corresponding 95% confidence
intervals and P-values are calculated.
TABLE-US-00003 TABLE 3 Frailty Index Not Frail Frail ORP Not Frail
True Negative (TN) False Negative (FN) Frail False Positive (FP)
True Positive (TP)
[0284] Pearson correlation is used to examine the correlation
between ORP and comorbidities, as follows: [0285] CCI (defined
continuously) [0286] a-CCI (defined continuously) [0287] Number of
comorbidities present (defined continuously) Pearson correlation is
used to examine the correlation between ORP and the FRAIL scale and
the CSHA Clinical Frailty Scale, as follows: [0288] FRAIL scale
(defined continuously) [0289] CSHA Clinical Frailty Scale (defined
continuously) Poisson regression and linear regression is used to
examine the association between ORP and comorbidities, as follows:
[0290] CCI (defined continuously) [0291] a-CCI (defined
continuously) [0292] Number of comorbidities present (defined
continuously) [0293] Student's t-tests and logistic regression with
crude and adjusted odds ratios (and 95% confidence intervals) is
used to examine the association between ORP and comorbidities, as
follows: [0294] CCI.gtoreq.5 [0295] CCI.gtoreq.3 [0296] upper
quartile of CCI (75.sup.th percentile) [0297] presence of any
comorbidity (0 vs. .gtoreq.1 comorbidity)
[0298] The percent positive agreement and percent negative
agreement is used to examine the agreement between ORP and
comorbidities, ORP and the FRAIL scale, and ORP and the CSHA
Clinical Frailty Scale as follows: [0299] The FRAIL scale
(Frail=3-5, Not frail=0-2) [0300] The CSHA Clinical Frailty Scale
(Frail=5-7, Not frail=0-4) [0301] CCI.gtoreq.5 [0302] CCI.gtoreq.3
[0303] upper quartile of CCI (75th percentile) [0304] presence of
any comorbidity (0 vs. .gtoreq.1 comorbidity)
[0305] Linear regression models are built for chronological age and
Frailty Index Score. These models are used to output the calculated
age ("biological age") for each participant based on their Frailty
Index Score. Each participant's biological age is then subtracted
from their chronological age. If the resulting value is negative,
then the model indicates that that participant is expected to be
older based on their Frailty Index Score; these patients are
labeled as being frail. If after subtracting the biological age
from the chronological age, the value is positive or zero, then the
model indicates that that participant is expected to be younger or
as old based on their Frailty Index Score; these patients are
labeled as being non-frail. Using this new frailty categorization
scheme, ORP cutoff values are determined that discriminate frail
from non-frail using first phase data, and agreement levels are
assessed using second phase data.
TABLE-US-00004 TABLE 4 Patient Survey Difficulty with: 1. Arthritis
Yes No 2. Bladder/bowels Yes No 3. Cooking Yes No 4. Dementia Yes
No 5. Dressing Yes No 6. Ear Yes No 7. Eating Yes No 8. Fatigue Yes
No 9. Feet Yes No 10. Getting in or out bed Yes No 11. Going out
Yes No 12. Hearing Yes No 13. Light housework Yes No 14. Managing
money Yes No 15. Self-rated health Yes No 16. Shopping Yes No 17.
Taking a bath Yes No 18. Taking medicine Yes No 19. Teeth Yes No
20. Using the telephone Yes No 21. Using the toilet Yes No 22.
Vision Yes No 23. Walking around Yes No History of: 1. Broken bones
Yes No 2. Broken hip Yes No 3. Diabetes Yes No 4. Flu Yes No 5.
Glaucoma Yes No 6. Heart attack Yes No 7. Hypertension Yes No 8.
Parkinson's disease Yes No 9. Stomach problems Yes No 10. Stroke
Yes No 11. Recent loss of weight Yes No 12. How much did the
patient lose? (lbs) 13. Patient's current weight? (lbs) Can the
patient: 14. Climb one flight of stairs? Yes No 15. Walk one block?
Yes No 16. What is the patient's current housing situation? a. Home
b. Nursing Home c. Other:
TABLE-US-00005 TABLE 5 CHSA Clinical Frailty Scale The clinician
will grade each patient based on their own understanding of the
following scale. 1 - Very fit. Robust, active, energetic,
well-motivated and fit. These people exercise regularly and are in
the most fit group for their age. 2 - Well. Without active diseases
but less fit that people in category 1. 3 - Well, with treated
comorbid disease. Disease symptoms are well- controlled compared to
those in category 4. 4 - Apparently vulnerable. Although not
frankly dependent, these people commonly complain of being "slowed
up" or have disease symptoms. 5 - Mildly frail. With limited
dependence on others for instrumental activities of daily living. 6
- Moderately frail. Help is needed with both instrumental and non-
instrumental activities of daily living. 7 - Severely frail.
Completely dependent on others for activities of daily living, or
terminally ill.
[0306] The results of this Example show that measurement of sORP
and cORP is useful in assessing frailty in an elderly population,
and discriminating between frail and non-frail individuals. ORP
measurements are also useful in identifying frailty comorbidities
and determining differences between chronological age and
biological age.
[0307] The foregoing examples of the present invention have been
presented for purposes of illustration and description.
Furthermore, these examples are not intended to limit the invention
to the form disclosed herein. Consequently, variations and
modifications commensurate with the teachings of the description of
the invention, and the skill or knowledge of the relevant art, are
within the scope of the present invention. The specific embodiments
described in the examples provided herein are intended to further
explain the best mode known for practicing the invention and to
enable others skilled in the art to utilize the invention in such,
or other, embodiments and with various modifications required by
the particular applications or uses of the present invention. It is
intended that the appended claims be construed to include
alternative embodiments to the extent permitted by the prior
art.
* * * * *