WO1997044657A1 - Blood gas/electrolyte calibrator and method for use - Google Patents

Blood gas/electrolyte calibrator and method for use Download PDF

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Publication number
WO1997044657A1
WO1997044657A1 PCT/US1997/008581 US9708581W WO9744657A1 WO 1997044657 A1 WO1997044657 A1 WO 1997044657A1 US 9708581 W US9708581 W US 9708581W WO 9744657 A1 WO9744657 A1 WO 9744657A1
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Prior art keywords
ion
calcium
solution
acetate
calibrator
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Application number
PCT/US1997/008581
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French (fr)
Inventor
Ronald E. Betts
Original Assignee
Sendx Medical, Inc.
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Publication date
Application filed by Sendx Medical, Inc. filed Critical Sendx Medical, Inc.
Priority to AU31357/97A priority Critical patent/AU3135797A/en
Publication of WO1997044657A1 publication Critical patent/WO1997044657A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/492—Determining multiple analytes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/84—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving inorganic compounds or pH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2496/00—Reference solutions for assays of biological material
    • G01N2496/70—Blood gas control solutios containing dissolved oxygen, bicarbonate and the like

Definitions

  • This invention relates to aqueous solutions containing buffers and electrolytes adjusted to specific levels for calibration or quality control of chemical analyzers.
  • this invention relates to a solution which has the specific parameters for the calibration and quality control of both blood gas and ion selective electrode instrumentation.
  • Analytical devices for determining various parameters in whole blood with the aid of ion-selective electrodes have been used in intensive care units and in the field of anesthetics.
  • Various blood chemistries such as carbon dioxide, pH, K + , Na + , and Ca ++ , can be measured using ion selective electrodes.
  • An ion selective electrode consists of an electrochemical half-cell (an internal electrolyte solution and an internal reference electrode) and a sensing membrane. These types of electrodes are used to measure a specific ion in the presence of other ions in bodily fluids, such as whole blood.
  • a set of calibration solutions are used to calibrate the electrodes.
  • control solutions are used with clinical chemical analyzers to verify the accuracy of tests run.
  • control solutions used to verify performance of medical instruments should have essentially the same constituents as those present in the fluid that is subjected to analysis.
  • the present invention relates to calibrating and control solutions for instrumentation that measures both blood gas and electrolytes, and to a method of using such solutions in instruments that measure blood gases and electrolytes.
  • this invention relates to a method for stabilizing free calcium ions in blood gas/electrolyte instrument control solutions containing bicarbonate as a buffer for pH and/or source of carbon dioxide and calcium as an electrolyte.
  • Precipitation of calcium carbonate in the calibrator or control solution is prevented by addition of protecting species, usually ions, which protect the calcium cations from contact with the carbonate ions.
  • the preferred protecting species is acetate.
  • the method of this invention for stabilizing free calcium ion solutions used as controls with or to calibrate instruments that measure blood gases and electrolytes is practiced in solutions prepared by conventional manufacturing techniques using readily available materials.
  • solutions made by the method of this invention can be used either as standard controls to verify the accuracy of results or to calibrate the instruments, for convenience both types of solutions are referred to herein as "calibrator solutions.”
  • a typical calibrator solution within the contemplation of this invention is prepared by simply combining in appropriate relative proportions a buffer, electrolytes, and other standard auxiliary reagents, such as a detergent used as a wetting agent.
  • the approximate pH of the solution is provided by combining the acid and salt forms of the buffer used, normally to a pH of about 7.0 to 7.4.
  • the solution is tonometered with oxygen and CO 2 mixed with nitrogen or other suitable gas to produce the desired level of oxygen, CO 2 , and pH for the solution.
  • the electrolytes used in the control solution are generally selected from sodium (Na + and/or NaCL), potassium (K + and/or KC1), calcium (Ca +2 and/or CaCl 2 ), and chloride. Lithium can also be added.
  • Table I contains a list representative of compounds that can be added to calibrator solutions in the method of this invention as protecting species, or as a source of protecting species, to prevent the combination of free calcium ions with carbonate ion in formation of calcium carbonate.
  • the amount of the protecting species added depends on the levels of both calcium and carbon dioxide desired in the calibrator solution, and can readily be determined by one skilled in the art.
  • the calcium ions are preferably protected by addition to the calibrator solution of acetate ion as the protecting species, most preferably, in the form of sodium acetate.
  • Various solutions can be prepared for as many calibration points as necessary for the instrumentation.
  • the amount of calcium in a solution can also be assayed by adding incremental amounts of the protecting species of the invention to a solution containing an unknown amount of calcium and determining the amount of protecting species corresponding to the point at which formation of calcium carbonate is detected. From this information, the amount of calcium ion in the solution can be calculated using known methods of analytical chemistry.
  • the calibrator solution is generally filtered, placed into gas tight containers, such as laminate bags of aluminum foil, and stored in the containers without a gaseous headspace, so that in the final container no further equilibrium with gases will take place.
  • gas tight containers such as laminate bags of aluminum foil
  • the final solution is not affected by changes in temperature or pressure.

Abstract

Free calcium ion is maintained in an aqueous calibration solution for maintaining quality control in a blood gas/electrolyte analyzer, which solution contains calcium and sodium bicarbonate, by addition of sufficient of a protecting species, preferably acetate ion, to prevent formation of calcium carbonate in the solution.

Description

BLOOD GAS/ELECTROLYTE CALIBRATOR AND METHOD FOR USE
Field of the Invention This invention relates to aqueous solutions containing buffers and electrolytes adjusted to specific levels for calibration or quality control of chemical analyzers. In particular, this invention relates to a solution which has the specific parameters for the calibration and quality control of both blood gas and ion selective electrode instrumentation. Background of the Invention
Analytical devices for determining various parameters in whole blood with the aid of ion-selective electrodes have been used in intensive care units and in the field of anesthetics. Various blood chemistries, such as carbon dioxide, pH, K+, Na+, and Ca++, can be measured using ion selective electrodes. An ion selective electrode consists of an electrochemical half-cell (an internal electrolyte solution and an internal reference electrode) and a sensing membrane. These types of electrodes are used to measure a specific ion in the presence of other ions in bodily fluids, such as whole blood. To obtain accurate measurements, a set of calibration solutions are used to calibrate the electrodes.
In addition to calibration solutions, specific control solutions are used with clinical chemical analyzers to verify the accuracy of tests run. Under ideal conditions, control solutions used to verify performance of medical instruments should have essentially the same constituents as those present in the fluid that is subjected to analysis.
Most blood gas instruments are currently calibrated using a buffer for the pH, and are tonometered with humidified gases for carbon dioxide and oxygen. Blood gas instruments that also measure electrolytes, such as K+, Na+, and Ca++, require solutions for calibration and control of the ion selective electrodes.
For instrumentation systems which measure both blood gas and ionized calcium along with other electrolytes (such as Na, K, Li and Cl), a single control solution is needed. To date this has been accomplished in aqueous solutions by incorporating soluble salts of the desired electrolytes into the buffered aqueous solution, which has been tonometered with carbon dioxide and oxygen to provide the pH, pCO2, and pQ control values needed for quality control of blood gas analyzers.
If soluble calcium salts are used in such a solution, it is very difficult to stabilize the calcium ions in solution in a satisfactory manner due to the tendency of free ionic calcium to combine with anions and precipitate out of solution. This phenomenon is exacerbated at low temperature.
Summary of the Invention
The present invention relates to calibrating and control solutions for instrumentation that measures both blood gas and electrolytes, and to a method of using such solutions in instruments that measure blood gases and electrolytes. In particular, this invention relates to a method for stabilizing free calcium ions in blood gas/electrolyte instrument control solutions containing bicarbonate as a buffer for pH and/or source of carbon dioxide and calcium as an electrolyte. Precipitation of calcium carbonate in the calibrator or control solution is prevented by addition of protecting species, usually ions, which protect the calcium cations from contact with the carbonate ions. The preferred protecting species is acetate.
Description of the Preferred Embodiments
The method of this invention for stabilizing free calcium ion solutions used as controls with or to calibrate instruments that measure blood gases and electrolytes is practiced in solutions prepared by conventional manufacturing techniques using readily available materials. Although the solutions made by the method of this invention can be used either as standard controls to verify the accuracy of results or to calibrate the instruments, for convenience both types of solutions are referred to herein as "calibrator solutions."
A typical calibrator solution within the contemplation of this invention is prepared by simply combining in appropriate relative proportions a buffer, electrolytes, and other standard auxiliary reagents, such as a detergent used as a wetting agent. The approximate pH of the solution is provided by combining the acid and salt forms of the buffer used, normally to a pH of about 7.0 to 7.4. Next the solution is tonometered with oxygen and CO2 mixed with nitrogen or other suitable gas to produce the desired level of oxygen, CO2, and pH for the solution.
The electrolytes used in the control solution are generally selected from sodium (Na+ and/or NaCL), potassium (K+ and/or KC1), calcium (Ca+2 and/or CaCl2), and chloride. Lithium can also be added.
The combination in calibrator solutions of calcium, as an electrolyte, and bicarbonate as a buffer for pH as well as a source of carbon dioxide, creates conditions for the formation of calcium carbonate, an almost insoluble precipitate. Due to the conditions of equilibrium in calibrator solutions employing calcium and bicarbonate, eventually the calcium will be removed from solution in the form of calcium carbonate. At relatively low temperatures, which may be encountered during storage or use of calibrator solutions, the equilibrium conditions are more favorable for precipitation of calcium carbonate than at body temperature. In the method of this invention calcium cations are protected by addition of protecting species, such as protecting ions, or a source of such ions, which protect calcium from contact with carbonate ions in the calibrator solutions.
Table I contains a list representative of compounds that can be added to calibrator solutions in the method of this invention as protecting species, or as a source of protecting species, to prevent the combination of free calcium ions with carbonate ion in formation of calcium carbonate.
TABLE 1 acetate propionate butyrate aliphatic carboxylic acids having the formula CH3(CH2)xCOOH where x = 3 to 18, and preferably 3 to 16, and salts thereof
The amount of the protecting species added depends on the levels of both calcium and carbon dioxide desired in the calibrator solution, and can readily be determined by one skilled in the art. When a salt is added as the source of an ionic protecting species, care must be taken that the counter cation in the salt, i.e. Na+ or K+, does not raise the amount of the counter ion in the calibrator solution outside the calibration range. In the practice of this invention, the calcium ions are preferably protected by addition to the calibrator solution of acetate ion as the protecting species, most preferably, in the form of sodium acetate. Various solutions can be prepared for as many calibration points as necessary for the instrumentation. Most instruments use one or two points of calibration, a low point and a high point, for sloping electrodes. Generally, in the method of this invention, sufficient protecting species, for example acetate ion, is added to a low point calibrator solution to maintain the level of calcium cation therein at about 1.2 mM/L of solution, and sufficient protecting species is added to the high point calibrator solution to maintain the calcium cation therein at about 4.1 mM/L of solution. A representative example of low point and high point calibrator solutions made in accordance with the method of this invention for establishing two calibration points at 37°C is provided in Table 2 below: TABLE 2
PARAMETER LOW Ca++ CALIBRATOR HIGH Ca++ CALIBRATOR
KC1 3.5 mM 8.9 mM
NaCl 108 mM 86 mM NaC2H3O2 10 mM lO mM
NaHCO3 20 mM 20 mM
NaMOPS 12.6 mM 12.6 mM
MOPS 4.1 mM 14.1 mM
CaCl2 1.6 mM 4.9 mM CO2 35 mmHg 65 mmHg
O2 155 mmHg 155 mmHg
Glutaraldehyde ≤ 1%* ≤ l%*
* = weight percent
As one skilled in the art will appreciate, the amount of calcium in a solution, such as a calibrator solution, can also be assayed by adding incremental amounts of the protecting species of the invention to a solution containing an unknown amount of calcium and determining the the amount of protecting species corresponding to the point at which formation of calcium carbonate is detected. From this information, the amount of calcium ion in the solution can be calculated using known methods of analytical chemistry.
In preparation, the calibrator solution is generally filtered, placed into gas tight containers, such as laminate bags of aluminum foil, and stored in the containers without a gaseous headspace, so that in the final container no further equilibrium with gases will take place. By this means, the final solution is not affected by changes in temperature or pressure. The following examples illustrate the manner in which the invention can be practiced. It is understood, however, that the examples are for the puφose of illustration, and the invention is not to be regarded as limited to any of the specific materials or conditions therein.
EXAMPLE 1
To compare the efficacy of acetate ion for preventing precipitation of calcium ion from solution, a parallel experiment was conducted using identical aqueous solutions, except that the protecting species added to Solution 1 was 26 mmol/1 of sulfate ion in the form of sodium sulfate; whereas the protecting species added to Solution 2 was 10 mmol/1 of acetate ion in the form of sodium acetate. The two solutions were stored at
5°C and the concentrations of Na+, K+, Ca+2, and Cl were monitored over a period of about two months. The results of this experiment are summarized in Table 2 below.
TABLE 2 Control Aqueous Solution With Sulfate*
Figure imgf000009_0001
* Concentration of ions is in mM/L
As shown by the results summarized in Table 2, the concentration of Ca+2 remained substantially constant over the course of two months even under refrigeration when acetate was used as the protecting species. The foregoing description of the invention is exemplary for purposes of illustration and explanation. It should be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the following claims are intended to be interpreted to embrace all such modifications.

Claims

What is claimed is:
1. A method to include calcium ion in a calibrator solution for a blood gas/electrolyte instrument wherein either a bicarbonate buffer or carbon dioxide is also present in the solution comprising combining in a calibrator solution calcium and sufficient of a protecting species selected from the group consisting of acetate, propionate, and butyrate ions, and carboxylic acids having the formula CH3(CH2)xCOOH, wherein x is an integer from 3 to 18, and salts thereof, to prevent the formation of calcium carbonate therein.
2. The method of claim 1 wherein the protecting species is acetate ion. 3. The method of claim 2 wherein the acetate ion is added in the form of sodium or potassium acetate.
4. The method of claim 1 wherein the acetate ion is added in the form of sodium acetate.
5. A method for assaying for calcium ion comprising a) combining in a calibrator solution calcium and sufficient incremental amounts of a protecting species selected from the group consisting of acetate, propionate, and butyrate ions, and carboxylic acids having the formula CH3(CH2)xCOOH, wherein x is an integer from 3 to 18, and salts thereof, to detect the amount of protecting species corresponding to the point at which precipitation of calcium carbonate is initiated and b) determining from the amount of protecting species the concentration of calcium ion in the solution.
AMENDED CLAIMS
[received by the International Bureau on 16 September 1997 (16.09.97); original claims 1, 4 and 5 amended; remaining claims unchanged (1 page)]
1. A method to include calcium ion in a calibrator solution for a blood gas/electrolyte instrument wherein either a bicarbonate buffer or carbon dioxide is also present in the solution comprising combining in a calibrator solution calcium and sufficient of a protecting species selected from the group consisting of acetate ion, propionate ion, butyrate ion, carboxylic acids having the formula CH3(CH2)xCOOH, wherein x is an integer from 3 to 18, and salts thereof, to prevent the formation of calcium carbonate therein.
2. The method of claim 1 wherein the protecting species is acetate ion.
3. The method of claim 2 wherein the acetate ion is added in the form of sodium or potassium acetate.
4. The method of claim 2 wherein the acetate ion is added in the form of sodium acetate.
5. A method for assaying for calcium ion comprising a) combining in a calibrator solution calcium and sufficient incremental amounts of a species selected from the group consisting of acetate ion, propionate ion, butyrate ion, carboxylic acids having the formula CH3(CH2)xCOOH, wherein x is an integer from 3 to 18, and salts thereof, to detect the amount of said species corresponding to the point at which precipitation of calcium carbonate is initiated and b) determining from the amount of said species the concentration of calcium ion in the solution.
PCT/US1997/008581 1996-05-20 1997-05-19 Blood gas/electrolyte calibrator and method for use WO1997044657A1 (en)

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US08/650,622 1996-05-20

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4945062A (en) * 1988-06-15 1990-07-31 Bionostics Incorporated Control for blood gas/calcium analysis instrumentation
US5296217A (en) * 1992-06-15 1994-03-22 Indiana University Foundation Methods for preventing dental calculus in domestic animals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4945062A (en) * 1988-06-15 1990-07-31 Bionostics Incorporated Control for blood gas/calcium analysis instrumentation
US5296217A (en) * 1992-06-15 1994-03-22 Indiana University Foundation Methods for preventing dental calculus in domestic animals

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