Patent Document

This is a continuation of application Ser. No. 08/252,383, filed Jun. 1, 1994, and now U.S. Pat. No. 5,422,278 issued Jun. 6, 1995, which is a continuation of application Ser. No. 08/004,211, filed Jan. 13, 1993, and now abandoned, which is a continuation of application Ser. No. 07/794,693, filed on Nov. 18, 1991, now abandoned which is a continuation of application Ser. No. 07/628,990, filed on Dec. 17, 1990, now abandoned, which is a continuation of application Ser. No. 07/511,824, filed on Apr. 16, 1990, now abandoned, which is a continuation of application Ser. No. 07/361,836, filed on June 1, 1989, now abandoned, which is a continuation of Ser. No. 07/121,499, filed on Nov. 17, 1987, now abandoned. 
    
    
     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 capable of 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 anaesthetics. Blood gases, such as carbon dioxide and oxygen, 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 one type of ion in the presence of other ions in the bodily fluids. To obtain accurate measurements, a set of calibration solutions are used to calibrate the electrodes. 
     In addition to calibration, the tests run on clinical chemical analyzers are verified by specific control solutions. Under ideal conditions, control materials used in the verification of instrumentation performance should have essentially the same constituents as those present in the fluid which is to be subjected to analysis. 
     Most blood gas instruments are currently calibrated using a buffer for the pH and humidified gases for carbon dioxide and oxygen. Some instruments tonometer buffer inside the instrument and use this liquid for equilibration. Blood gas instruments that also measure electrolytes have separate solutions for calibration and control of the ion selective electrodes. The electrolyte calibrator and control solutions do not currently contain all the blood gas parameters. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention relates to calibrating and control solutions for instrumentation which measures both blood gas and electrolytes and a method of using such solutions with blood gas instruments. This invention relates to aqueous solutions containing buffers and electrolytes adjusted to specific levels for calibration or quality control blood gas instruments. In particular, the present invention relates to a novel blood gas-electrolyte instrument control solution having three levels. The three levels simulate three different patient conditions: one normal and two abnormal. Level one has low electrolyte parameters, acidosis pH and gas parameters which represent respiratory acidosis, i.e. low O 2  and high CO 2  concentrations. Level two has normal conditions in all parameters. Level three has high electrolyte parameters, alkalosis pH, and gas parameters which represent respiratory alkalosis, i.e. low CO 2  and high O 2  concentrations. 
     Additionally, the present invention relates to a novel blood gas electrolyte instrument calibrating solution that contains parameters necessary for the calibration of both blood gas and ion selective electrode instrumentation. In particular, the present calibrating solution contains two levels having the necessary parameters. Level one has normal pH, pCO 2  and pO 2  and electrolytes. Level two is the zero oxygen calibrator. It has physiologically high concentrations of CO 2 , physiologically low electrolyte levels and zero O 2 . 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The blood gas-electrolyte calibrating solutions of this invention are prepared by conventional manufacturing techniques using readily available materials. A typical calibrating solution with the contemplation of this invention is prepared by simply combining in appropriate relative proportions buffer, electrolytes, and other standard auxiliary reagents. 
     EXAMPLE I 
     A Diamond Sensor System GEM 6 Blood Gas Electrolyte monitor is calibrated with a calibrating solution having two levels. The calibrating solution is comprised of an aqueous biological buffer with a preservative, electrolytes, and blood gas components. A detergent is added for use as a wetting agent. 
     Level one has normal pH, pCO 2 , pO 2 . Sulfate ions are used to keep the calcium in solution. Level two is the &#34;O&#34; calibrator. It has low pH, physiologically high concentrations of CO 2  and zero O 2  and physiologically low electrolyte levels. The O 2  is kept at zero, even in the presence of room air, with sufficient sulfite and nitrogen. 
     
                       TABLE I______________________________________           LEVEL 1 LEVEL 2______________________________________NaCL (mMol/L)     --        46CaCl.sub.2 (mMol/L)             3.8       0.3KCL (mMol/L)      6.9       2.2Sulfite (mMol/L)  --        40Sulfate (mMol/L)  26        --CO.sub.2 (mmHg)   35        65O.sub.2 (mmHg)    115-170   0MOPS (mMol/L)     100       100pH (37° C.)             7.4       6.9Na.sup.+ (mMol/L) 135       150K.sup.+ (mMol/L)  6.0       2Ca.sup.2+ (mMol/L)             2.0       0.2CL.sup.- (mMol/L) 120       80Ionic Strength mMol/L             160       160______________________________________ 
    
     Table I lists the composition of the two levels of the blood gas electrolyte calibrating solution together with concentrations and pH values. The pH of the solution is adjusted and sodium bicarbonate is added to reach the desired carbon dioxide level. Albumin may be added if a protein matrix is desired. 
     The electrolytes used in this control solution may be: sodium, potassium, calicum, and chloride. Lithium is not added to the calibrating solutions or controls for the DSS GEM 6 instrument due to interference with the sensors, although, with other instruments lithium may be used. The buffer used is designed to give the appropriate pH value by combining the acid and salt forms. This buffer was selected due to the very small temperature effect demonstrated by the buffer. Various solutions having the above discussed levels can be prepared for as many calibration points as necessary for the instrumentation. Most instrumentation use a one or two point calibration for sloping electrodes. 
     The final solution is sterile filtered and is stored in gas tight containers without a gaseous headspace. In the final container no further equilibrium with gases will take place and the final solution is therefore not affected by pressure and temperature. 
     The addition of calcium as an electrolyte and bicarbonate as a buffer for pH and carbon dioxide, creates conditions for the formation of calcium carbonate. Calcium carbonate is an insoluble precipitate, which will eventually remove all the calcium from solution and therefore make the calcium no longer measurable as an ion. To prevent this from occurring sulfate ions are added which protect the calcium ion from contact with the carbonate ion. This protection is necessary when high levels of both calcium and carbon dioxide are desired. 
     The level I solution is tonometered with 100% nitrogen until the oxygen level is less than 10 mmHg. Sulfite ions are then added to scavenge the remaining oxygen. The sulfite is added in excess so that residual sulfite is available to scavenge oxygen that may contact the solution. This enables the solution to maintain a zero oxygen value. The bicarbonate is then added to create the desired pCO 2  value. 
     The solutions are then tonometered using the appropriate gases needed to reach the requested oxygen and carbon dioxide values (the final solutions are sterile filtered and stored in gas tight containers without headspace). No further equilibrium with gases takes place and the final solution is not affected by pressure and temperature. The solution is stable in the final container and is ready for use with a blood gas/electrolyte analyzer. 
     EXAMPLE II 
     The blood gas-electrolyte controls of this invention are prepared by conventional manufacturing techniques using readily available materials. A typical control within the contemplation of this invention is prepared by simply combining in appropriate relative proportions, buffer, electrolytes, foaming agent and other standard auxiliary reagents and chemicals; the pH and concentration of dissolved carbon dioxide thereof being adjusted to the appropriate value, depending on the natures, the control, an aliquot thereof placed in a sealable receptacle: the receptacle flushed with gas: and the receptacle sealed so as to create a headspace above control fluids which is occupied by the gas. Albumin may be added if a protein matrix is desired. Glycine is added to bind a portion of the calcium to provide a total calcium value that reflects normal values for Level II and abnormal values for Levels I and III. The glycine also prevents precipitation of the remaining ionized calcium. 
     The performance of a Diamond Sensor Gem 6 Blood Gas-Electrolyte monitor is verified using a blood gas-electrolyte control. The controls are comprised of three levels: normal and two abnormal conditions. Level one, an abnormal control, having low electrolyte levels, acidosis pH and gas levels which represent respiratory, acidosis, level two, normal parameters and level three, high levels of electrolytes, alkalosis pH and gas levels which represent respiratory alkalosis, were formed in the presence of the biological buffer N-2-hydroxyethylpiperazine-N&#39;-2&#39;ethanesulfonic acid. This buffer was selected due to the temperature effect demonstrated by the buffer. The temperature coefficient (change in pKa per degree C.=0.014), enables the control to indicate a malfunction of the instrument temperature regulation. The material is packaged in glass ampules which have been flushed with the appropriate gases. This ampule must be shaken prior to use in a blood gas-electrolyte analyzer. The shaking equilibrates the gas with the liquid and also creates a foam layer. The foam layer will protect the solution from contamination with room air gases for 4 minutes after opening the ampule. 
     
                       TABLE II______________________________________       LEVEL 1 LEVEL 2    LEVEL 3______________________________________NaCL (mMol/L) 41        48         79CaCl.sub.2 (mMol/L)         2.1       2.9        3.4KCL (mMol/L)  2.5       4.2        6.8Glycine (mMol/L)         639       599        532O.sub.2 (mmHg)         40        100        150CO.sub.2 (mmHg)         60        40         13HEPES (mMol/L)         50        50         50pH (37° C.)         7.16      7.4        7.6Na.sup.+ (mMol/L)         120       138        150K.sup.+ (mMol/L)         2.5       4          6.8Ca.sup.2+ (mMol/L)         0.9       1.15       1.5Total Ca (mg/dl)         8.5       11.5       13.5CL.sup.- (mMol/L)         86        102        116Ionic Strength mMol/L         160       160        160______________________________________ 
    
     Table II lists the composition of the three levels of the blood gas-electrolyte control solution together with concentrations and pH values. 
     The calibrator and control solutions are currently used to calibrate and control the Diamond Sensor Systems GEM-6 blood gas electrolyte monitor. The two level calibrator solutions are used to perform two calibration points on the instrumentation. The calibration points at 37 C. are: 
     
         ______________________________________      LOWPARAMETER* CALIBRATOR    HIGH CALIBRATOR______________________________________pH         6.9 ± 0.02 7.4 ± 0.02pCO.sub.2  65 mmHg ± 3.0                    35 mmHg ± 3.0pO.sub.2   0 mmHg ± 5.0                    115 ± 5.0K.sup.+    2.0 mM/L ± 0.3                    6.0 mM/L ± 0.3Ca.sup.++  0.2 mM/L ± 0.1                    2.0 mM/L ± 0.1______________________________________ *Stated values are at atmospheric pressure, temperature coefficient of pH = -.01 pH unit/C. 
    
     EXAMPLE III 
     The control formulations by typical blood gas electrolyte instrumentation. Table III shows the results of some of these tests. 
     
                       TABLE III______________________________________Typical Values ExpectedAqueous Blood Gas/Electrolyte Control                              ExpectedParameter    Level   Instrument  Mean  Range 1SD______________________________________pH       I       Il 1303     7.16  7.14-7.28                                     0.002pH       I       Corning 178 7.17  7.15-7.19                                     0.006pH       I       NOVA Stat   7.15  7.13-7.17                                     0.001pH       II      Il 1303     7.39  7.37-7.41                                     0.004pH       II      Corning 178 7.41  7.39-7.43                                     0.002pH       II      NOVA Stat   7.40  7.36-7.42                                     0.006pH       III     Il 1303     7.63  7.62-7.65                                     0.002pH       III     Corning 178 7.63  7.61-7.65                                     0.001pH       III     NOVA Stat   7.64  7.62-7.66                                     0.003pCO.sub.2 mmHg    I       Il 1303     64    59-69  1.0pCO.sub.2 mmHg    I       Corning 178 67    62-72  2.8pCO.sub.2 mmHg    I       NOVA Stat   66    61-71  1.0pCO.sub.2 mmHg    II      Il 1303     36    32-40  0.2pCO.sub.2 mmHg    II      Corning 178 36    32-40  0.4pCO.sub.2 mmHg    II      NOVA Stat   36    32-40  0.8pCO.sub.2 mmHg    III     Il 1303     11.0   9-13  0.1pCO.sub.2 mmHg    III     Corning 178 8.0    6-10  0.1pCO.sub.2 mmHg    III     NOVA Stat   11.0   9-13  0.1pO.sub.2 mmHg    I       Il 1303     42    34-50  1.4pO.sub.2 mmHg    I       Corning 178 41    33-49  2.0pO.sub.2 mmHg    I       NOVA Stat   42    34-50  1.3pO.sub.2 mmHg    II      Il 1303     104    96-112                                     2.0pO.sub.2 mmHg    II      Corning 178 106    98-114                                     3.0pO.sub.2 mmHg    II      NOVA Stat   102    94-110                                     3.9pO.sub.2 mmHg    III     Il 1303     180   172-188                                     2.5pO.sub.2 mmHg    III     Corning 178 183   175-191                                     3.1pO.sub.2 mmHg    III     NOVA Stat   189   183-199                                     2.5Sodium   III     NOVA 6      139   134-144                                     0.8mM/LSodium   III     NOVA Stat   141   136-146                                     1.0mM/LSodium   III     NOVA 10     144   139-149                                     1.0mM/LPotassium    I       NOVA 6      2.4   2.1-2.7                                     0.1mM/LPotassium    I       NOVA Stat   2.5   2.2-2.8                                     0.1mM/LPotassium    I       NOVA 10     2.4   2.1-2.7                                     0.1mM/LPotassium    II      NOVA 6      4.0   3.7-4.3                                     0.1mM/LPotassium    II      NOVA Stat   3.8   3.5-4.1                                     0.1mM/LPotassium    II      NOVA 10     3.8   3.5-4.1                                     0.1mM/LPotassium    III     NOVA 6      6.4   6.1-6.7                                     0.1mM/LPotassium    III     NOVA Stat   6.9   6.6-7.2                                     0.1mM/LPotassium    III     NOVA 10     0.65  6.2-6.8                                     0.1mM/LiCa mM/L I       NOVA 6      0.8   0.6-1.0                                     0.1iCa mM/L I       NOVA Stat   0.8   0.6-1.0                                     0.1iCa mM/L II      NOVA 6      1.1   0.9-1.3                                     0.1iCa mM/L II      NOVA Stat   1.1   0.9-1.3                                     0.1iCa mM/L III     NOVA 6      1.6   1.4-1.8                                     0.1iCa mM/L III     NOVA Stat   1.6   1.4-1.8                                     0.1Chloride I       NOVA Stat   96    93-99  0.4mM/LChloride I       NOVA 10     96    93-99  0.2mM/LChloride II      NOVA Stat   108   104-112                                     1.0mM/LChloride II      NOVA 10     108   104-112                                     0.1mM/LChloride III     NOVA Stat   124   120-128                                     0.3mM/LChloride III     NOVA 10     124   121-129                                     0.1mM/LTotal Ca I       NOVA 10     0.9   0.7-1.1                                     0.2mg/LTotal Ca II      NOVA 10     1.0   0.8-2.2                                     0.2mg/LTotal Ca III     NOVA 10     1.8   1.6-2.0                                     0.2mg/LLithium  I       Corning Flame                        0.6   0.4-0.8                                     0.3mM/LLithium  II      Corning Flame                        1.7   1.5-1.1                                     0.3mM/LLithium  III     Corning Flame                        3.0   2.8-3.2                                     0.3mM/L______________________________________ 
    
     While these calibrating and control systems are particularly advantageous in biological fluid analysis systems such as Diamond Sensor Systems GEM-6 it will be apparent that other biological fluid analysis systems can use the presently described calibrating and control solutions. Therefore, while particular embodiments of the invention have been shown and described, various modifications will be apparent to those skilled in the art and therefore is not intended that the invention be limited to the disclosed embodiments or to details thereof and departures may be made there from within the spirit and scope of the invention.

Technology Category: 4