Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Inorganic standards or controls
Reexamination Certificate
2000-12-04
2003-07-29
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Inorganic standards or controls
C436S008000, C436S149000, C436S150000, C252S408100
Reexamination Certificate
active
06599746
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention is directed to a calibration fluid for a calibration of a sensor for measuring a blood value, an application of the fluid and a method for the production of the fluid.
EP 0 657 030 B1 discloses a calibration fluid for a calibration of a sensor for measuring a blood value that comprises a biocompatible electrolyte that, for example, is composed of a Ringer, Ringer Lactate or Ringer Acetate infusion solution and a biocompatible carbon dioxide source that is added to this solution, this generating bicarbonate ions (HCO
3
−ions
) in a specific concentration and carbon dioxide (CO
2
) with a specific partial pressure pCO
2
in the solution.
The compositions of biocompatible electrolytes employed as infusion solutions can be derived from the product descriptions of the various pharmaceutical companies such as, for example, Pharmacia, Braun, Fresenius, Baxter, etc. The composition of blood or blood plasma in view of the pH value, carbon dioxide partial pressure pCO
2
and concentrations of the ions contained in the blood is described, for example, in Koryta, “Medical and Biological Applications of Electrochemical Devices”, John Wiley & Sons, 1980, page 82.
Given a specific example of the calibration fluid according to EP 0 657 030 B1 (see page 4, lines 2-7 therein), the fluid is composed of 500 ml Ringer Lactate solution to which 10 ml of 8.4% NaHCO
3
are added as carbon dioxide source. The added quantity of NaHCO
3
corresponds to approximately 20 mmol/l that is contained in the Ringer lactate solution and temporarily stabilizes the unstable pH value of such a solution.
HCO
3
−
ions are not contained in traditional physiological electrolytes such as Ringer solutions but are contained in blood plasma. The normal physiological concentration of the HCO
3
−
ions in blood plasma lies at 24 mmol/l and can fluctuate within a concentration range containing this concentration value that is still viewed as being physiologically normal.
Given the specific example of the calibration fluid according to EP 0 657 030 B1, the 20 mmol/l NaHCO
3
added to the original electrolyte free of HCO
3
−
ions generate HCO
3
−
ions in the electrolyte in a concentration that still lies in the normal physiological range of the concentration of the HCO
3
−
ions in blood plasma at 37° C.
In the specific example of the calibration fluid according to EP 0 657 030 B1, the concentration of the HCO
3
−
ions at 37° C. is so high that this fluid—according to the known Henderson-Hasselbalch equation (see, for example, Muller-Plathe, “Säure-Basen-Haushalt und Blutgase”, Thieme Verlag, 1982, for example page 32)—has a pH value of 7.95 at this temperature and a value of the pCO
2
of 1.2·10
3
Pa (=9 mmHg), these values remaining stable, for example, over a time span of 18 hours.
The pH value of the fluid can be lowered to approximately 7.1 by adding another agent for regulating the pH value, for example sodium or potassium phosphate, so that it is possible to hold the pCO
2
to more than 7.33·10
3
Pa (=55 mmHg). In this case, however, there is no longer a fluid according to the preamble of claim 1, since the concentration of the HCO
3
−
ions does not lie in the normal physiological range of this concentration, for example in the range 24 mmol/l±5 mmol/l.
The normal physiological pH value of blood, which is recited as 7.41 at 37° C. in many medical textbooks, falls into the pH range between 7.1 and 7.95.
Biocompatible or, respectively, physiological electrolytes such as Ringer solutions are often stored in plastic bags and are air-saturated. At 22° C. and 760·(4/3)·10
2
Pa (760 mmHg) air pressure, a partial pressure composition for this electrolyte derives as
155·(4/3)·10
2
Pa (155 mmHg) pO
2
585·(4/3)·10
2
Pa (585 mmHg) pN
2
20·(4/3)·10
2
Pa (20 mmHg) pH
2
O, i.e.
760·(4/3)·10
2
Pa (760 mmHg).
overall
pO
2
is thereby the partial pressure of the oxygen, pN
2
is the partial pressure of the nitrogen and pH
2
O is the partial pressure of water.
By adding the 20 mmol/l NaHCO
3
to such an electrolyte, 9·(4/3)·10
2
Pa (9 mmHg) pCO
2
is added to the sum of these partial pressures or—given the presence of the inorganic phosphate buffer—55·(4/3)·10
2
Pa (55 mmHg) pCO
2
is added thereto. The atmospheric pressure that is respectively present and bears on the fluid is thereby exceeded, and an exhalation of gases of the fluid, i.e. a bubble formation in the fluid, can occur.
Physiological electrolytes such as Ringer solutions exhibit an ion intensity that is usually equal to the normal physiological ion intensity of blood, this lying at 155 mmol/l and potentially fluctuating within an ion intensity range containing this ion intensity value that is still considered physiologically normal.
The addition of the 20 mmol/l NaHCO
3
to such an electrolyte raises the ion intensity of the calibration fluid resulting therefrom by 20 mmol/l to non-physiological values that, for example, lie between 165 mmol/l and 185 mmol/l.
In physiological electrolytes such as Ringer solutions, moreover, the concentration of Na
+
ions is usually selected equal to the normal physiological concentration of the blood, this lying at 140 mmol/l. The addition of the 20 mmol/l NaHCO
3
to the electrolyte increases the concentration of the Na
+
ions in the calibration fluid resulting therefrom from the normal 140 mmol/l to non-physiological 160 mmol/l.
Moreover, physiological electrolytes such as Ringer solutions comprise an osmolarity that is selected equal to the normal physiological osmolarity of blood plasma, this lying at 295 mosmol/l and potentially fluctuating within an osmolarity range containing this osmolarity value that is still considered physiologically normal.
The addition of the 20 mmol/l NaHCO
3
to such an electrolyte raises the osmolarity of the calibration fluid resulting therefrom by 2·20 mosmol/l=40 mosmol/l to non-physiological values that, for example, lie between 315 mosmol/l and 355 mosmol/l.
The known calibration fluid can be infused, and sensors for measuring the pCO
2
of blood can be calibrated with this fluid not only in vitro but also in vivo.
SUMMARY OF THE INVENTION
An object of the invention is to offer calibration fluid that enables a calibration of the sensor with a precision that is higher compared to the known calibration fluid.
This object is achieved by the calibration fluid compose of a bio-compatible electrolyte that at 37° C. has a concentration of bicarbonate ions that lies in a range of 24 mmol/l±5 mmol/l, a pH value that lies in a pH range within 5 through 9 and contains a value of 7.41; and an ion intensity that lies in a range of 155 mmol/l±10 mmol/l.
The normal physiological range of the concentration of bicarbonate ions blood plasma falls in the range of 25 mmol/l±5 mmol/l of the concentration of the bicarbonate ions indicated in claim 1, and the normal physiological range of the ion intensity (ionic strength) of the blood falls in the recited range of 155 mmol/l±10 mmol/l, and it can be expedient to select a value lying optimally close to 155 mmol/l for the concentration of the bicarbonate ions and to select a value lying optimally close to 155 mmol/l for the ion intensity.
The specific example of a calibration fluid known from EP 0 657 030 B1 and the inventive calibration fluid differ essentially in that the ion intensity in the known calibration fluid—differing from the inventive calibration fluid—does not lie in the range of 155 mmol/l±10 mmol/l but outside this range.
The inventive calibration fluid is based on the perception resulting from Nernst's equation (see Koryta, pages 13 ff) that, given potentiometric determination of the unknown pH value and/or of an unknown concentration of an ion type of a fluid such as, for example, blood with the assistance of a fluid having a known pH value and/or of a known concentration of this ion type—the concentrations of the two fluids can only be directly compared to one another and a cor
Baker & Botts LLP
Wallenhorst Maureen M.
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