Chemistry: analytical and immunological testing – Oxygen containing – Inorganic carbon compounds
Reexamination Certificate
2001-03-13
2003-04-01
Warden, Jill (Department: 1743)
Chemistry: analytical and immunological testing
Oxygen containing
Inorganic carbon compounds
C436S146000, C436S145000, C422S080000, C422S090000, C422S082070
Reexamination Certificate
active
06541268
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a sensor for the partial pressure of carbon dioxide (pCO
2
) in particular in vivo or ex vivo, e.g. in or on the surfaces of body tissues or organs, in blood or in the airflow from the lungs, and to a method of measuring pCO
2
.
DESCRIPTION OF THE RELATED ART
Ischemia, localized diminution in blood flow, is the most prevalent cause of death in the western world. Thus for example myocardial infarction, cerebral infarction and other conditions characterised by hypoperfusion to one or more organs are major factors in mortality.
Reperfusion, reversal of ischemia, is frequently possible if an ischemia is detected in time. Thus early detection of ischemia followed by appropriate chemical treatment (e.g. with an agent such as streptokinase, urokinase or t-PA which serves to lyse thrombi or emboli) or surgical intervention can save the affected organ as well as the patient's life.
While the heart may be monitored continuously for ischemias using an electrocardiograph (ECG), other organs may become severely ischemic and incur irreversible damage before any symptom is detected. Indeed many organs are “silent” when it comes to ischemia. The phenomenon of silent myocardial infarction is now well recognised. Furthermore, liver and kidney may be severely ischemic without alerting symptoms before the organ damage is irreversible.
It is known that there is a distinct correlation between pCO
2
in or on the surface of an organ and the presence of an ischemia in that organ. During tissue metabolic acidosis, e.g. during the anaerobic metabolism that occurs in an ischemia in any organ or tissue, large quantities of carbon dioxide are formed. CO
2
is in practical terms freely cell-membrane permeable and since in the ischemia blood flow to transport away the CO
2
is absent or restricted, CO
2
build up in the ischemic tissue will occur and pCO
2
in or on the ischemic tissue will increase. Generally, in the healthy body, the maximum pCO
2
in blood (venous blood) is 7-10 kPa and the maximum PCO
2
in healthy (aerobic) tissue is some 1-6 kPa higher, although the maxima may vary from organ to organ, e.g. 8-12 kPa for kidney, 7-11 kPa for liver, 8-12 kPa for intestinal serosa, and 12-19 kPa for intestinal mucosa. Where oxygen supply falls below the critical oxygen delivery level, PC
0
2
values measured in the tissue may rise by 3 to 10 times and the elevated PCO
2
levels give a clear indication of anaerobic metabolism and hence, if appropriate, of ischemia.
Sensors for pCO
2
are available: however these are generally bulky, often involve relatively complex glass electrodes, routinely do not give stable reproducible readings (i.e. suffer problems of drift), and are sufficiently expensive as to mandate reuse and thus the need to be repeatedly sterilized.
DE-A-2911343 and U.S. Pat. No. 4,324,256 disclose an electrode device for transcutaneous pCO
2
measurment with a pH-sensitive measuring electrode in contact with a bicarbonate electrolyte.
There is thus a need for simple, small, and preferably disposable, sensors which can be used generally to determine pCO
2
, e.g. in order to detect ischemias.
SUMMARY OF THE INVENTION
We have now developed a simple sensor particularly suitable for pCO
2
measurement, especially as part of a technique for monitoring for ischemias.
Viewed from one aspect therefore the invention provides a carbon dioxide sensor comprising a closed chamber having as a wall portion thereof a substantially water-tight, carbon dioxide-permeable membrane and containing two electrodes, said chamber containing a film of substantially electrolyte-free liquid capable of simultaneously contacting said membrane and both of said electrodes.
By substantially electrolyte-free, it is meant that the liquid has an osmolality no greater than that at 37° C. of an aqueous 5 mM sodium chloride solution, preferably no more than that of a 500 &mgr;M sodium chloride solution, more especially no more than that of a 10
−5
to 10
−6
M HCl solution.
Viewed from an alternative aspect the invention provides a carbon dioxide sensor comprising a first electrode, a second electrode, a carbon dioxide permeable membrane, a liquid in electrical contact with said first and second electrodes and said membrane, means for applying an alternating electrical potential to said first and second electrodes whereby to cause an alternating current in said liquid, and means for generating a signal indicative of the conductance of said liquid, wherein said liquid is reactive with carbon dioxide to alter its conductance and wherein said electrical potential has a frequency of 20 to 10000 Hz, preferably 100 to 4000 Hz.
Viewed from a still further aspect the invention provides a carbon dioxide sensor comprising a first electrode, a second electrode, a carbon dioxide permeable membrane, a liquid in electrical contact with said first and second electrodes and said membrane, and wall means which together with said membrane and said electrodes define a chamber enclosing said liquid such that in the electrical path between said electrodes through said liquid the electrical resistance of said liquid at each of said electrodes is less than in a portion of said liquid in contact with said membrane. This increased electrical resistance relative to the resistance at the electrodes may be achieved by restricting the cross sectional area of the electrical path through the liquid between the electrodes at a zone in which the liquid is in contact with the membrane, e.g. by decreasing the depth of the liquid for a part of the path between the electrodes, and/or by ensuring a relatively large area of contact between each electrode and the liquid.
Preferably the liquid in contact with the electrodes is aqueous and especially preferably it is water, substantially electrolyte-free as defined above. Other solvents that react with CO
2
to increase or decrease their conductance, e.g. by the production or neutralization of ions, may likewise be used. In practice, however, deionized or distilled water with or without the addition of a strong acid (e.g. HCl) to a concentration of 0.1 to 100 &mgr;M, preferably 0.5 to 50 &mgr;M, more especially about 1 &mgr;M, has been found to function particularly well. The function of this small addition of acid is generally to maintain the pH of the liquid at 6 or below to avoid significant contributions to conductance by hydroxyl ions and to maintain the linearity of the measurements of PCO
2
.
The sensors of the invention are provided with or are connectable to an electrical power source arranged to apply an alternating electrical potential across the electrodes with a frequency of 20 to 10000 Hz, preferably 50 to 4000 Hz, more especially 100 to 1200 Hz. At frequencies below 20 Hz, the sensitivity of pCO
2
determination is lower due to electropolarization and moreover the instrument response time becomes overly slow, while at frequencies above 10 kHz sensitivity is again less due to stray capacitance effects.
For particularly high accuracy, the potential or current across the electrodes (and hence the resistance or conductance of the liquid between the electrodes) is determined using a lock-in amplifier set to the same frequency as that of the voltage generator.
Furthermore it is preferred to incorporate in the sensor, or in a sensor-plus-detector system, a passive high pass filter (e.g. a capacitor and a resistor) to screen out current with a frequency less than 20 Hz, preferably less than 150 Hz.
The power source may be an AC power source or alternatively a DC source in conjunction with an oscillator, i.e. a combination which together constitutes an AC power source.
The power supply is preferably such that the maximum current density through the liquid at the electrodes is no more than 50 A/m
2
, preferably no more than 30 A/m
2
, more preferably no more than 20 A/m
2
, in particular no more than 10 A/m
2
, and most preferably about 1 A/m
2
or below. Higher current density values of 20 A/m
2
or greater should only be used at the higher frequencies,
Mirtaheri Peyman
Tonnessen Tor Inge
Alertis Medical AS
Cantor & Colburn LLP
Siefke Sam P.
Warden Jill
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