Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Blood gas standard or control
Reexamination Certificate
2000-08-16
2003-10-14
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Blood gas standard or control
C436S008000, C436S009000, C436S014000, C436S015000, C436S016000, C436S068000, C422S105000, C422S105000
Reexamination Certificate
active
06632675
ABSTRACT:
FIELD OF THE INVENTION
This invention relates primarily to the field of clinical reference solutions—quality control reagents and calibrators. More specifically it relates to methods of preparing multi-analyte reference solutions that have stable oxygen partial pressure (pO
2
) in zero headspace containers, preferably in flexible foil laminate containers. The solutions are stable at room temperature and have long shelf and use lives.
BACKGROUND OF THE INVENTION
Clinical laboratories employ a variety of instrument systems for the analysis of patient samples. For example, pH/blood gas instruments measure blood pH, pCO
2
and pO
2
. CO-Oximeter instruments typically measure the total hemoglobin concentration (tHb), and the hemoglobin fractions—oxyhemoglobin (O
2
Hb), carboxyhemoglobin (COHb), methemoglobin (MetHb), reduced hemoglobin (HHb) and sulfhemoglobin (SHb)(collectively referred to as “CO-Ox fractions”). Ion selective electrode (ISE) instruments measure the content of blood electrolytes, such as, Na
+
, Cl
−
, Ca
++
, K
+
, Mg
++
and Li
+
. Also, a variety of other parameters such as, metabolites, e.g., glucose, lactate, creatinine and urea, can be measured in clinical laboratories by related instrument systems.
Instrument systems currently available may combine the measurement of blood pH, gases, electrolytes, various metabolites, and CO-Ox fractions in one instrument for a comprehensive testing of the properties of blood. For example, all such analytes are measured by the Rapidlab™ 865 critical care diagnostics system from Chiron Diagnostics Corporation [Medfield, Mass. (USA)].
A calibrator is used to set the response level of the sensors. A control is used to verify the accuracy and reliability of such an instrumentation system.
A control is a solution having a known concentration of an analyte or analytes contained in the same, or a similar matrix in which the samples to be analyzed exist. The assay results from the control product are compared to the expected assay results to assure that the assay technique is performing as expected.
Commercial blood gas analysis systems have been available since the 1960s. The earliest reference-materials were gas mixtures in pressurized cylinders, and those materials are still commonly used. In the 1970s, the development of liquid reference solutions began, leading to products in which reagents have been equilibrated with precision gas mixtures and packaged in flexible containers with zero headspace, requiring either refrigeration to maintain stability or the resort to calculations to compensate for the expected pO
2
changes during storage.
Most quality control materials for such analyzers consist of tonometered aqueous solutions (a solution containing dissolved gases) in glass ampules. The typical gas headspace above the liquid in those ampules provides a reserve of oxygen against any potential oxygen-consuming reactions which may occur within the solution during the shelf life of the product.
In the absence of a gas headspace within their containers, reference solutions for oxygen determinations are particularly difficult to make and maintain stable. The inventors determined that the sources of said instability could be several.
First, the instability may be due to reactivity between the dissolved oxygen and the other components of the calibrator or quality control reagent. The other components might either react with the dissolved oxygen, reducing its concentration, or, alternatively, the other components may react with each other to generate oxygen, thus also changing the oxygen concentration. Second, the solution might be contaminated with microorganisms which, due to their metabolism, might change the oxygen content. Third, the oxygen might permeate through, or react with, the packaging material, also affecting the oxygen content of the reference material.
Reference materials that are manufactured for distribution in commerce must be made to withstand the various conditions encountered in the distribution chain and must be sufficiently stable to provide good performance within the time frame in which they are expected to be used by the customer, which is usually at least about six months, preferably for about nine months, and more preferably approximately 1 year for the typical calibrating or quality control solution distributed to commercial laboratories and hospitals. In addition, reference solutions, as with other reagents, should be packaged in containers which are easy to handle, convenient to use and which meet other design requirements of their intended usage. This is particularly true of reagents which are used in conjunction with various analytical instruments.
The users of instruments which determine the oxygen partial pressure of blood and other body fluids have a need for such reference materials and would benefit from liquid materials over the more conventional precision gas mixtures in cylinders with regulators. Liquid reference solutions are inherently less expensive, safer, and eajier to manipulate than high-pressure gas tanks.
Although reference solutions used in instruments measuring pO
2
have been made in the past, they have suffered from being unstable and having expensive, complicated, or unreliable means to access their contents. Some reference solutions, when used on analytical instruments, have extended their usefulness by allowing the instrument to calculate the expected oxygen level, said level being calculable from the age of the product, given the fact that the rate of decrease in oxygen level can be predicted based on historic performance [Conlon et al.,
Clin. Chem
., 42: 6—Abstract S281 (1996)]. Several developers have included inner layers of plastic materials selected because of their heat sealability (e.g., U.S. Pat. No. 5,405,510—Betts) or low gas permeability (U.S. Pat. No. 4,116,336—Sorensen) or gas tightness (U.S. Pat. No. 4,163,734—Sorensen). Some have disclosed that the inner layer should be inert, but have not provided enablement as to how to select such an inner layer (U.S. Pat. No. 4,643,976—Hoskins) and/or weren't capable of maintaining oxygen at a precise level appropriate for blood gas purposes.
Most blood gas/electrolyte/metabolite/CO-Oximetry/hematocrit quality controls (QCs) on the market today are provided in glass ampules which must be manually broken and manually presented to the analyzer. Rüther, H., U.S. Pat. No. 5,628,353 (issued May 13, 1997) describes an automated device which breaks open glass ampules by forcing a metal tube with thick walls and a small inner diameter, into the bottom of an ampule, and then aspirates the contents of the ampule into an analyzer. Such an automated ampule breaker is mechanically complex, requiring moving parts that are subject to wear and risk of failure, and could be subject to jamming and clogging from small bits of broken ampule glass.
In the 1980s, Kevin J. Sullivan disclosed an alternative to glass ampules—the first commercial product with a blood gas reagent in a flexible, zero headspace package [U.S. Pat. Nos. 4,266,941; 4,375,743; and 4,470,520]. Coated aluminum tubes were filled with 40-50 mL of blood gas QC solutions without any headspace. The tubes were enclosed in pressurized cans, to prevent outgassing and to supply a source of force to cause the QC solutions to flow into the sample path of a blood gas analyzer. One container of Sullivan's packaging design replaced about 30 glass ampules. Sullivan's packaging relieved the user of the task of opening many glass ampules and of the attendent risks of broken glass. The disadvantages of Sullivan's packaging included a need to refrigerate, a shelf life of less than a year, a menu of only three analytes, and the complexity and cost of a spring-loaded valve.
The instant invention not only overcomes the limitations of glass ampules, such as sensitivity of gas values to room temperature due to the headspace above the liquid, and complications resulting from the sharp edges which form upon brea
Conlon Dennis R.
Green Robert B.
Rannikko Minna A.
Sullivan Kevin J.
Bayer Corporation
Reed Dianne E.
Reed & Eberle LLP
Wallenhorst Maureen M.
Wu Louis L.
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