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
  • 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 generally to the calibration of analysis equipment. More specifically, the present invention relates to calibration reagents including dissolved gases therein. Most specifically, the present invention relates to reagents for calibrating blood gas analysis systems.
• Automated chemical analyses are rapidly supplanting manual techniques, particularly in the health care field.
• the rapid and accurate analysis of blood chemistry is particularly important in operating rooms, critical care facilities and clinical environments.
• Calibration is typically carried out by the use of reagents which are facsimiles of the materials being analyzed and which include known quantities of the target analytes therein.
• equipment for blood gas analysis is typically calibrated by utilizing a blood facsimile which includes known concentrations of dissolved oxygen and carbon dioxide therein and which may further include bicarbonate, calcium, sodium and potassium ions, as well as other ionic species and organic species such as glucose.
• concentration of a given gas in a liquid will vary depending upon the ambient temperature and pressure conditions to which the liquid is exposed. Furthermore, atmospheric gases can dissolve into the liquid thereby changing the concentration of particular species therein.
• One approach to the problem of providing accurate calibration reagents for blood gas analysis equipment involves the on site preparation of the reagents by the tono etery of liquid with a known concentration of gas. In this process, a gas is bubbled through a liquid under controlled conditions? the concentration of gases in the reagent may be calculated after compensating for temperature and barometric pressure, and the solution is ready for use in a calibration procedure. Solutions thus prepared must be used very promptly since their gas concentration can change rapidly.
• Another approach to the problem of calibration solutions involves the use of previously prepared solutions which are stored in a flexible, relatively gas-impermeable package having zero headspace. By zero headspace is meant that the liquid occupies the entirety of the package and there is no free gas therein.
• solutions of this type are packaged at total gas pressures substantially less than atmospheric ' and at elevated temperatures.
• One package of this type is disclosed in U.S. Patent No. 4,116,336 of Sorensen et al.
• the reagent described therein is a blood facsimile which is packaged in a laminate foil-polymer bag, at a total gas pressure of less than 600 and preferably 500-550, mmHg at 37 ° C.
• a major problem encountered with the flexible bag approach is that the package is responsive to ambient temperature and pressure changes and hence storage at high altitudes, air transport or thermal cycling can cause outgassing and bubble formation.
• the total gas pressure is kept substantially below atmospheric, typically in the range of 500-550 mmHg. This very low pressure gives rise to various problems.
• the low pressure within the bag facilitates the diffusion of ambient atmospheric gases therethrough, hence causing a change in the composition of the reagent during storage.
• great care is taken in selecting gas-impermeable packaging materials, it has been found very difficult to provide a total barrier to diffusion.
• filling of the bags at low dissolved gas pressures necessitates additional care and increases the cost of production.
• the present invention provides an improved calibration reagent and method for its preparation.
• the reagent comprises a liquid, such as a blood facsimile, having one or more gaseous materials dissolved therein.
• the calibration reagent is prepared at total dissolved gas pressures which are near, or only slightly below, atmospheric; however, it is resistant to bubble formation during storage» The reagent retains its stated composition during storage at high altitudes and at temperature extremes.
• the reagent comprises a liquid vehicle having a known concentration of a first gaseous material dissolved in the vehicle and further including helium dissolved therein. Helium has the unique property of being more soluble in warm liquid than in cold liquid.
• the first gaseous material may comprise oxygen or carbon dioxide and in particular embodiments, the reagent may include a plurality of gaseous materials dissolved therein.
• the reagent may comprise a calibration reagent for a blood gas analyzer and in such instance the reagent may include oxygen in a range of concentrations sufficient to create a partial pressure of 50-300 mmHg.
• the reagent may also include a range of concentrations of carbon dioxide sufficient to produce a partial pressure of 10-100 mmHg therein.
• the reagent may include dissolved ionic materials such as bicarbonate ion, sodium ion, potassium ion and the like.
• the reagent is preferably supplied in a flexible package having zero head space.
• the package is fabricated from a material having a low permeability to gases and particularly from a material having a higher permeability for helium than for oxygen, carbon dioxide and nitrogen.
• FIGURE 1 is a graph depicting the pressure of dissolved gas in reagent package of the present invention as a function of storage time
• FIGURE 2 is a cross sectional view of a flexible package of calibration reagent structured in accord with the principles of the present invention.
• the calibration reagents of the present invention include a liquid vehicle together with a known concentration of one or more gaseous materials therein and further include helium dissolved in the vehicle.
• the calibration reagents retain their compositional integrity over relatively long periods of time and are not detrimentally affected by changes in pressure or temperature during storage.
• Helium is an extremely inert substance which is generally not included in reagents for chemical analyses; however, helium manifests unique properties and the present invention recognizes that these properties make helium an advantageous additive for stabilizing the compositional integrity of solutions having gases dissolved therein. Because of its inertness to all commonly encountered reagents, helium will not adversely interfere with calibration or analytical procedures. Helium also possesses unique solubility properties.
• helium is more soluble in hot water than in cold water.
• ⁇ " c. cold
• 10.5 cc of helium dissolves in 1 liter of hot (50 ° C.) water.
• helium has a very low solubility in water and hence relatively small amounts of dissolved helium can create a relatively large partial pressure.
• helium has an extremely high mobility and is far more volatile than any other gases present in calibration reagents. All of these unique properties of helium synergistically interact to stabilize dissolved-gas- containing calibration reagents toward compositional change.
• Bubble formation occurs in a liquid when the total pressure of the gases dissolved therein exceeds the atmospheric pressure. Bubble formation can occur in - 1 - calibration reagents when they are heated since most gases become less soluble in hot liquids. Since helium is more soluble in warm liquids than in cold liquids, inclusion of helium in a gas-containing calibration reagent tends to inhibit bubble formation at elevated temperatures. As the reagent is warmed, there is tendency for most dissolved gases to increase their partial pressures and if the total gas pressure becomes to high, bubble formation will occur; however, if helium is included in the reagent, it will decrease its partial pressure as the temperature increases thereby preventing bubble formation.
• helium has a very low solubility in aqueous based liquids further operates to its advantage since relatively small amounts of dissolved helium will exert a fairly large partial pressure; hence, the effects of helium are magnified by its low solubility. ' If the ambient pressure becomes sufficiently low so as to be less than the total dissolved gas pressure in the liquid, bubble formation will still occur; however, the generation of an extremely small helium bubble will significantly lower the total pressure of dissolved gas thereby precluding further bubble formation. Thus it will be seen that helium tends to inhibit bubble formation by decreasing the total pressure of dissolved gases in a calibration liquid as the temperature increases and further acts to mitigate the effects of any possible bubble formation that may occur.
• the very high mobility of helium still further enhances the stability of gas-containing calibration reagents.
• the permeability of a large number of materials to helium is far higher than it is for most other gases.
• a typical calibration reagent such as one which might be employed for a blood gas analyzer
• a partial pressure of oxygen which is generally no more than 300 mm Hg and a partial pressure of carbon dioxide which usually does not exceed 100 mm Hg.
• the remainder of the atmosphere was made up of nitrogen and the total gas pressure was usually kept below 550 mm Hg to avoid bubble formation.
• FIG. 1 illustrates this phenomenon. Shown in the figure is a graph depicting pressure of the dissolved gases as a function of time. Curve A depicts the total gas pressure in a calibration reagent which includes helium and a known concentration of dissolved oxygen.
• the reagent is contained in a package which has a higher permeability for helium than for oxygen or nitrogen. It will be noted that the total gas pressure manifests an initial drop followed by a slow rise. This corresponds to helium leaking out of the package and being replaced by nitrogen which leaks in. The two processes occur simultaneously, but the rate of helium leakage is faster.
• the low point on Curve A represents the depletion of helium and the slow rise in total gas pressure is attributable to continued inward diffusion of nitrogen.
• the package is initially filled at a total gas pressure which is near atmospheric and because of the solubility properties of helium, bubble formation is initially inhibited. As the total gas pressure decreases, the tendency to bubble formation is further inhibited.
• Curve B represents the concentration of dissolved oxygen and throughout the entire process it will be noted that the concentration is essentially stable. Since the concentration of oxygen in the solution is approximately that of a solution equilibrated with ambient air, and since the package has a low permeability to oxygen, leakage of oxygen into or out of the package is fairly minimal. The time scale for diffusion of the helium and nitrogen will depend upon the permeability of the package, the nature of the reagent and the actual pressure of the gases.
• the calibration reagent of the present invention is most advantageously packaged in a flexible package having zero head space.
• zero head space is meant that a liquid entirely fills the package without any bubbles or voids.
• FIG 2 there is shown, in cross section, one particular reagent package 20 structured in accord with the principles of the present invention.
• the package is fabricated from a relatively low gas permeability material comprising a laminate of metallic foil 22 interposed between layers of thermo plastic polymer 24,26.
• the packet is fabricated by laminating the interior layers 26 of polymeric material by a heat sealing process so as to provide a packet which contains the calibration reagent 28 of the present invention therein.
• the reagent of the present invention may be packaged in other manners than as is shown herein.
• the packaging may be totally, or partially rigid, with zero head space.
• the calibration reagents include other species such as known concentrations of potassium, calcium, bicarbonate, sodium and other such ions. Additionally, the reagent will preferably include a buffer to establish a stable pH, and may include other species such as glucose or colorimetric standards. The specific quantities of each of the foregoing species present in the solution will depend upon a particular applications and the particular equipment being calibrated. The following examples detail some specific compositions of calibration reagent for a blood- gas analyzer and the methods by which they are manufactured.
• This calibration reagent was prepared to approximate a blood sample and is intended for use in calibrating a carbon dioxide sensor.
• the solution is water based and Table 1 hereinbelow sets forth the concentrations of the dry and liquid components of the solution.
• the calibration solution was prepared by dissolving the ingredients of Table 1 in distilled water. The solution thus prepared was heated to 37C. and tonometered at 700 mm
• the solution was analyzed and found to have the following properties: pH 6.890 - 6.910; pressure of C0 2 , 63-67 mmHg; pressure 0 2 , O.OmmHg; potassium concentration as measured by a Radiometer brand analyzer 1.8 -1.9 mmol/1; potassium ion concentration as measured by a Nova brand analyzer 1.83 -1.98 mmol/1 and a calcium ion concentration of .18 - .22 mmol/1.
• a second calibration solution was prepared which included both oxygen and carbon dioxide therein.
• the liquid and solid components of the calibration solution are set forth in Table 2.
• the ingredients set forth in the table were dissolved in distilled water, pH was adjusted to approximately 7.3 by the use of 1.0 N HCl and the resultant solution was tonometered with a gas mixture comprising 21% 0 2 and 6.3% C0 2 in helium. Tonometring was carried out at 37 * C. and 700 mm Hg absolute pressure. As in the preceding example, the resultant tonometered solution was sealed in an air tight, zero head space package.

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• 1993
  • 1993-04-16 CA CA 2118424 patent/CA2118424A1/en not_active Abandoned
  • 1993-04-16 WO PCT/US1993/003603 patent/WO1993021533A1/en not_active Application Discontinuation
  • 1993-04-16 JP JP5518632A patent/JPH07505953A/ja active Pending
  • 1993-04-16 EP EP93912284A patent/EP0639277A4/de not_active Withdrawn
  • 1993-04-16 AU AU42890/93A patent/AU4289093A/en not_active Abandoned

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