Chemistry: analytical and immunological testing – Blood gas
Reexamination Certificate
2001-08-22
2003-12-16
Snay, Jeffrey (Department: 1743)
Chemistry: analytical and immunological testing
Blood gas
C436S136000, C436S138000, C436S172000, C422S082070, C422S082080, C422S091000
Reexamination Certificate
active
06664111
ABSTRACT:
FIELD OF THE INVENTIONS
This invention broadly relates to devices for sensing and determining the concentration of oxygen or an oxygen-related analyte in a medium. More specifically, this invention relates to sensing elements for sensing and sensor systems for determining blood or tissue oxygen concentrations.
BACKGROUND OF THE INVENTION
Oftentimes during surgical procedures, a number of blood analytes are monitored in real time. For example, during open-heart surgery, the surgeon and other members of the surgical team often monitor blood pH, as well as the concentration of various blood gases, such as O
2
and CO
2
. It is also of interest to monitor these analytes in patients for extended periods of time before or after surgery. Furthermore, it is oftentimes desirable to monitor these analytes in critically ill patients in an intensive care unit. It may also be desirable to monitor other blood analytes, such as glucose, in critically ill patients.
Because of their unique properties, fluorescence-based sensing elements have been employed in sensor systems designed for real time monitoring of blood analytes including pH, CO
2
O
2
and K
+
. The sensing element comprises a sensor film and a substrate for holding the sensor film and bringing it into contact with the patient's blood. Typically, the sensor film comprises a fluorescent substance that is distributed in a polymeric matrix that is permeable to the analyte of interest (e.g. O
2
and CO
2
sensors). Alternatively, the fluorescent substance is anchored to a polymeric film that is contacted with the analyte of interest (e.g. pH and K
+
sensors).
For in vivo applications, the sensor film may be disposed on the tip of an optical fiber and then inserted into an arterial catheter or into a needle for insertion into the tissue of the patient, as disclosed in Lubbers et al U.S. Pat. No. Re 31,879, and Maxwell U.S. Pat. No. 4,830,013. For ex vivo and extracorporeal applications, the sensor film may be disposed on a carrier disk and incorporated into a disposable flow through cassette, which is then placed in an arterial line circuit or an extracorporeal blood loop as shown in Cooper U.S. Pat. No. 4,640,820. Each of these patents is incorporated by reference in its entirety herein.
When exposed to light at a proper wavelength, the fluorescent substances (referred to hereinafter as “fluorophores”) absorb energy and are driven from their ground state energy level into an excited state energy level. Fluorophores are unstable in their excited states and fluoresce (radiative decay) or give off thermal energy (non-radiative decay) as they return to their ground state. The fluorescence intensity, I, represents the intensity of the emission given off by the fluorophore as it returns to the ground state. The fluorescence lifetime, &tgr;, represents the average amount of time the fluorophore remains in its excited state prior to returning to the ground state.
Fluorescence based oxygen sensing elements work on the principle that oxygen molecules can collisionally quench the excited state of a fluorophore. When the fluorophore is excited in the presence of oxygen molecules, collisional interactions between the excited state and the oxygen molecule introduce a new mechanism for non-radiative decay, resulting in a decrease in both the fluorescence intensity and the excited state lifetime. Thus, blood gas monitoring systems which employ fluorescence based oxygen sensing elements have been designed to monitor oxygen-related changes in fluorescence intensity or excited state lifetime of the fluorophore.
The relationship between the fluorescence intensities and lifetimes in the absence (I
o
, &tgr;
o
) and presence (I, &tgr;) of oxygen is described by the Stern-Volmer equation:
I
0
I
=
τ
0
τ
=
k
q
[
O
2
]
k
em
+
k
nro
=
1
+
k
q
τ
0
[
O
2
]
=
1
+
ak
q
τ
0
p
O
2
=
1
+
K
SV
p
O
2
Equation
1
where [O
2
] is the concentration of oxygen in the sensing element; pO
2
is the partial pressure of oxygen in the medium being sensed; a is the solubility constant for oxygen in the sensing element which equals [O
2
]/pO
2
; k
q
is the bimolecular quenching constant in the sensing element; k
em
represents the rate constant for radiative decay; k
nro
represents the rate constant for non-radiative decay in the absence of oxygen; and K
SV
is the Stern-Volmer quenching constant.
Relative fluorescence intensities (I
o
/I) or relative fluorescence lifetimes &tgr;
o
/&tgr; are measured experimentally. Ideally, a plot of I
o
/I or &tgr;
o
/&tgr; against pO
2
should give a straight line with a slope of K
SV
=ak
q
&tgr;
o
and an intercept of unity. A calibration curve can be made of intensity versus concentration, and from this the concentration of the quenching species in the medium can be determined.
When a disposable flow-through cassette containing a sensor disk is clipped into the optics head of a blood gas-monitoring device, there are several factors that can lead to variability in the intensity of the fluorescent return signal that is given off by the sensing element and detected by the sensor system detector. Similarly, when a fiber optic probe having a sensor film at the distal end of the fiber is inserted into an arterial catheter or into tissue, there are several factors that can lead to variability in the intensity of the fluorescent return signal. In both configurations, these sources of variability include optical coupling efficiencies throughout the optical train, optical coupling to the cassette or fiber optic probe, lamp intensity, concentration of the fluorophore in the sensing element, and thickness of the sensing element. Even after the sensor system has been calibrated, return signal intensities can drift as a result of fiber bending, fluctuations in lamp intensity, temperature dependent changes in optical coupling efficiencies or the detection electronics, and photo-bleaching of the fluorophore. The effects of fiber bending and photo-bleaching are particularly pronounced in fiber optic probes.
A well recognized advantage of using fluorescence lifetime to determine oxygen concentration is that fluorescence lifetime is insensitive to variations in sensor film thickness, optical coupling efficiencies, fiber bending, and fluctuations in lamp intensity. The two most common techniques for measuring fluorescence lifetimes are the pulse method and the phase modulation method. In the pulse method, the fluorophore is excited by a brief pulse of light, and the decay of fluorescence is determined. In the phase modulation method, the fluorophore is excited by a light beam that is preferably sinusoidally amplitude modulated at a radial frequency &ohgr;=2&pgr;f, where f is the frequency in cycles per second. The fluorescence emission from the fluorophore is a forced response to this excitation signal, and is therefore amplitude modulated at the same radial frequency &ohgr; as the excitation signal. However, because of the finite lifetime of the fluorophore in the excited state, the emission is phase shifted by an angle &thgr; with respect to the excitation signal. Furthermore, the amplitude or intensity of the emission is less modulated (demodulated) by an amount m with respect to the excitation signal. The lifetime of the fluorophore can be calculated in a known manner from measurements of the phase shift (tan &thgr;=&ohgr;&tgr;) and the demodulation factor (m=(1+&ohgr;
2
&tgr;
2
)
−1/2
).
By measuring the phase shift, one can determine the fluorescence lifetime and therefore the analyte concentration. The Stern-Volmer slope is determined by measuring the phase shift and plotting the equation
τ
0
τ
=
tan
θ
0
tan
θ
=
1
+
K
SV
p
O
2
Equation
2
This approach still requires measurement of a reference signal from the light source or from the driver electronics, and this reference signal must be used t
Alvarez, Jr. Daniel
Bentsen James G.
Knudson Orlin B.
Roberts Ralph R.
Rude Michael J.
3M Innovative Properties Company
Lown Jean A.
Snay Jeffrey
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