NL7906967A - LIQUID AMPULLE FILLING AND AMPULES FILLED THERE WITH AND METHOD FOR PREPARING THEREOF. - Google Patents

Description

«-" Λ Λ a j * INSTEDMENTATIQN LABORATORY S.p.A., Milan, Italy

Liquid ampoule filling and ampoules filled therewith, and a method for preparing them

The invention relates to a liquid ampoule filling and ampoules filled therewith for the quality control of hemogas analyzers.

Hemogas analyzers are instruments with which the pH, 5 P_ and ΡΛ in blood can be measured using electrodes, and CO2 02 has been widely used in recent years *

For accurate diagnosis it is required that the measurement results of the gas analysis of blood be accurate because even small deviations can be significant, especially since the pH, P ^ 10 and PQ often have to be determined in acute and intensive therapy.

It is therefore clear that there is a need for a quality control in the hemogas analysis.

A suitable means for equilibrating a liquid with a gas is the tonometer with reference whole blood, if possible from the same sample as analyzed. A proportional portion of whole blood is balanced with a gas mixture of known and P_. By introducing a blood standard thus obtained into the hemo-CO2 O2 gas analyzer, an accurate control of the instrument 20 with respect to the P and Prt is possible.

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The advantages of this method can mainly be attributed to the fact that the control can be performed with whole blood, eliminating possible differences arising from the liquid composition.

25 Nevertheless, inconveniences such as the time required to carry out the operation, the need to have carefully analyzed gas mixtures, the cost of the necessary instruments, and the manual execution of the operation stand for the routine 7906967 *, 2 «application of this method in the way.

Moreover, with whole blood equilibrated with gas in the tonometer it is possible to control the P ^ but not the pH. The latter determination is usually performed with phosphate-5 buffer solutions prepared according to the specification of the

United States National Bureau of Standard (NBS).

Therefore, there is a need for a system to perform the quality control in the gas analysis of blood simply, quickly, and adequately without the use of special methods.

It is well known that gas-balanced buffers in ampoules are the most suitable and practical for performing routine check of hemogas analyzers. The use of such ampoules is very simple. The ampoules are kept for 10 sec. shaken 15 and after breaking open, the content is sucked up by the hemogas analyzer

A contents for such ampoules are described in U.S. Pat. No. 4,001,142. This is based on triethanolamine. However, the ionic strength is not sufficiently close to that of whole blood. Moreover, the use of such a buffer entails a different situation from that which arises with the phosphate buffer used for pH calibration.

According to the invention, a gas-equilibrated phosphate buffer solution with a particular pH, P 2 and PQ 2 is provided as an ampoule filling, which has excellent stability at temperatures of 4.2S and 37 ° C *

The invention further provides a method of preparation by which an excellent agreement can be achieved within a single batch and between different batches of buffez solution, that is to say, the values within a batch of a production and between batches of 30 different resins are very close to each other. ampoules are filled with three different solutions, each representing a different clinical value for the acid-base balance, namely normal, acidosis and alkalosis.

The buffer solution of the invention contains equi-molecular amounts of sodium or potassium monohydrogen phosphate or 7906967 f sodium sodium or potassium dihydrogen phosphate, sodium hydrogen carbonate and sodium chloride. The total concentration of phosphate is preferably 50 mmol / l.

The buffer solution according to the invention meets the following requirements: recommendation by the NBS as standard for the pH standardization in hemogas analyzers and performance of the quality control with a buffer of the same type as for calibration. Furthermore, with the buffer according to the invention more accurately than with other buffers, incorrect response of the pH electrode is demonstrated. In addition, the buffer in ampoules is stable for more than 2 years at a temperature between 4 and 37 ° C, which is not the case for other types of buffers such as Tris (hydroxymethyl aminomethane and triethanolamine).

The molar concentration of bicarbonate added in the above three different solutions is different. The bicarbonate concentration and dissolved COg are equilibrated. By using this balance and changing the bicarbonate concentration and percentage of CO 2 in the gas mixture at the appropriate time when adjusting the liquid-gas balance, pairs of values for the pH and corresponding to the above three different clinical CO2 values are obtained.

To this end, the change of the pH with the hydrogen carbonate concentration at certain P 2 values was investigated taking into account the variation in equilibrium due to the difference in temperature when setting the gas-liquid equilibrium (25 ° C ) and when reading the instrument (37 ° C). On the basis of this, it appeared possible to determine the optimal ratio of hydrogen carbonate concentration and percentage of CO in the gas mixture for each of the three clinical values to obtain the desired pairs of values for pH and.

In order to obtain the values for the ΡΛ corresponding to each of the ° 2 30 clinical values, the change of the P ^ with the percentage of oxygen in the gas mixture used to adjust the gas-liquid equilibrium was investigated. Account was also taken of the fact that the solution and the gas were equilibrated at a temperature of 25 ° C and that the instrument was read at a temperature of 37 ° C.

7906967 * * ’4

The sodium chloride is added to the phosphate buffer in an amount selected so that the summed hydrogen carbonate concentration and sodium chloride concentration are constant and preferably, for the three clinical values, equal to 60 nanol / l. This achieves that the molarity of the finished solutions with the different three clinical values for the acid-base equilibrium is constant. Preferably, the molarity is 110mmol / l, which value corresponds to an ionic strength of about 0.16 and thus very closely approximates the ionic strength of whole blood. This final concentration was chosen not only because of the similarity to whole blood, but also because 0.16 has been found to be the optimal ionic strength at which the hemogas analyzer operates on the pH line.

The buffer medium may be deionized water or a mixture of deionized water and about 30% glycerol.

Due to the presence of 30% glycerol, the buffer solution is given a viscosity and a diffusion potential equal to that of whole blood, and the same oxygen tension. Therefore, a glycerol-containing whole blood buffer solution comes close to the "Blood gas Factor", that is, the difference in electrode response between a gas-20 mixture and a liquid equilibrated therewith.

To prevent contamination during preparation, an antibacterial agent can be added to the buffer solution.

A suitable bactericide is sodium trichlorophenate. Other bactericides such as quaternary ammonium salts have been found to have drawbacks with respect to pH and Pn.

° 2

Dyes can be used to visualize the course of the buffer solution in the instrument and to indicate the difference between the solutions of different clinical values. Suitable dyes are Red E 123 (FD&C Red No. 2) and Red E 124 (Food Red 30 No. 7) and Yellow E 102 (FD&C Yellow No. 5). By mixing the dye E 102 with the dyes E 123 or E 124 in certain proportions, an orange color of the desired intensity is obtained. The choice of the aforementioned dyes is based on the solubility and lightfastness as well as on the compatibility with the buffer solution.

35 In U.S. Pat. No. 4,001,142 7906967 "I vt." 5 m indicate a method in which the balance between the buffer solution and the gas mixture is set directly in the ampoules. According to the present method, this is done in a so-called tonometer before the ampoules are filled.

5 The tonometer can be a cylindrical container of different sizes according to the required capacity. The tonometer can be internally equipped with a mixer to achieve complete homogeneity in the liquid-gas system, a gas supply and diffusion device as small bubbles in the solution to adjust the equilibrium 10, and control devices of the temperature, pH.

and, further means may be provided for transporting the gas-equilibrated liquid to the ampoule filling machine.

The temperature in the tonometer is usually kept constant at 25 ° C using a coolant circulation system. The temperature of 25 ° C has been chosen at various temperatures after numerous investigations, and is based on careful considerations. First, this temperature is closest to room temperature so that temperature changes in the transport of the gas equilibrated liquid from the tonometer to the ampoule filling machine are avoided or reduced as far as possible. And when the ampoules are kept at a temperature between 20 and 30 ° C, it is not necessary to bring the temperature to 25 ° C in order to obtain practically identical results as with an ampoule previously at a temperature of 25 ° C 25 has been brought. As a result, the feasibility with the product according to the invention is considerably simplified.

The pressure in the tonometer is kept constant at atmospheric.

The gas mixture of oxygen, nitrogen and carbon dioxide which is equilibrated with the buffer solution is supplied from a gas cylinder with a capacity of 40 l and at a maximum pressure of 150 atmospheres. At the outlet of the cylinder, the gas pressure is reduced to desired pressure after which the gas is passed through a flow meter to determine the desired flow rate and then to a humidifier maintained at a temperature of 25 ° C.

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The gas is metered from the humidifier to the tonometer.

The time required to equilibrate 5 L of buffer solution with gas is approximately 4 hours at a gas flow rate of 0.5 L / min.

The ampoules are filled with the gas-equilibrated solutions in automatic filling machines. The ampoules can be pre-rinsed with the same gas mixture as that with which the solutions are equilibrated. Filling can also be carried out in an atmosphere of the same gas mixture and the ampoule can be stored under the same gas mixture until closed. Thus, the gas-equilibrated solution can be prevented from being contaminated by air.

Ampoules not containing glycerol can be sterilized in an autoclave at a temperature of 120 ° C for 1 hour.

Example I

Acid-base balance: normal.

A solution for quality control in hemogas analysis with an average pH of 7.35, an average of 5.98 kPa (45 mm of mercury) and an average P_ of 11,990 kPa (90 mm of mercury) was prepared from the following components:

Deionized water up to 1000 ml glycerol 300 ml sodium and potassium phosphate 50 mmol / 1 sodium hydrogen carbonate 36 mmol / 1 25 sodium chloride 24 mmol / 1 sodium trichlorophenate 0.1 g / 1 gas mixture: 5.00% COi »12.3% 02 * remainder N ^.

First, a mixture of water and glycerol was prepared. The phosphates, the hydrogen carbonate, sodium chloride and trichlorophenate were dissolved therein. The solution was filtered through a 0.22 µm aperture filter and then charged into a tonometer and equilibrated therein with a gas mixture at a temperature of 25 ° C. Then 1 ml ampoules with the gas equilibrated solution filled and then closed. The ampoules were analyzed in a hemogas analyzer and the pH, P1 and P1. were determined at 37 ° C.

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Example II

Acid-base balance: alkalose *

There was a solution? prepared for the quality control in the hemogas analysis with a mean pH of 7.55, mean 5 2.660 kPa (20 now mercury) and mean P_ of 19.285 kPa (145 mm CO2 2 mercury) from the following ingredients:

Deionized water up to 1000 ml glycerol 300 ml sodium and potassium phosphate 50 mmol / 1 10 sodium hydrogen carbonate 28 nmol / 1 sodium chloride 32 nuol / 1 sodium trichlorophenaar 0.1 g / 1 gas mixture: 2.27 «CX> 2, 21.15« 02, rest Nj.

The preparation was carried out in the same manner as in Example I.

Example lil

Acid-base balance: acidosis.

A quality control solution in the hemogas analysis was prepared with an average pH of 7.20, average P ^ of 20 of 9.310 kPa (70 mm mercury) and average ΡΛ of 7.960 kPa (60 now mercury) ° 2 from the following ingredients :

Deionized water up to 1000 ml glycerol 300 ml sodium and potassium phosphate 50 mmol / 1 25 sodium hydrogen carbonate 34 mmol / 1 sodium chloride 26 mmol / 1 sodium trichlorophenate 0.1 g / 1

Gas mixture: 7.8% CO2, 6.8% 02, residue N2 <

The preparation was carried out in the same manner as in Example I.

7906967

Claims (25)

1. A solution as an ampoule filling with three different clinical values for the acid-base equilibrium, namely normal, acidosis and alkalose, intended for quality control of hemogas analyzers, with the solution containing water, a phosphate, sodium hydrogen carbonate, sodium chloride, dissolved carbon diocyde, contains oxygen and nitrogen, and optionally also glycerol, a colorant and / or a bactericide. Solution according to claim 1, characterized in that the solution contains glycerol at a concentration of 30%. Solution according to claim * and / or 2. characterized in that the solution contains a bactericide consisting of sodium trichlorophenate or another phenol derivative. Solution according to any one of claims 1 to 3, characterized in that the phosphate buffer consists of 25 mmole / l sodium or potassium monohydrogen phosphate or 25 mmole / l sodium or potassium dihydrogen phosphate. Solution according to any one of the preceding claims, characterized in that the amounts of sodium hydrogen carbonate and sodium chloride are chosen such that the sum of their concentrations is equal to 60 mmol / l. 20 Solution according to any one of the preceding claims, characterized in that the solution contains a dye consisting of Red E 123 (FD&C Red Ho. 2) or E 124 (Food Red Ho. 7) and Yellow E 102 (FD & c Ho. 5 ), each at a concentration of 60 mg / 1, or an orange mixture of Yellow E 102 (40 mg / 1) and Red E123 or E 124 (20 mg / 1). Solution according to any one of claims 1 to 5, characterized in that the solution contains no dye. Solution according to any one of claims 1-6, characterized in that the solution does not contain glycerol. Solution according to claim 8, characterized in that the solution does not contain any colorant. Solution with a clinical value for the acid-base equilibrium normal, intended for the quality control of hemogas analyzers, characterized in that the solution is water, 30% glycerol, 50 mmol / 1 phosphate buffer, 36 mmol / 1 sodium hydrogen carbonate and 24 mmol / 1 contains sodium chloride, and optionally a bactericide, for example sodium 7906967 »trichlorophenate or another phenol derivative and optionally a coloring agent, for example Red E 123» Red E 124 or Yellow E 102 »or a mixture of Yellow E 102 and Red E 123 or E 124 »which solution is equilibrated with a gas mixture consisting of 5% 0% CO 2 12% 3 and for the 5 residue nitrogen» and has a pH of 7 35-7.40. 11. Solution with a clinical value for the acid-base equilibrium acidosis intended for the quality control of hemogas analyzers »characterized in that the solution is water, 30% glycerol, 50 beautiful / 1 phosphate buffer, 34 mmol / 1 sodium hydrogen carbonate» 26 mmol / 1 sodium chloride, and optionally a bactericide, for example sodium trichlorophenate or another phenol derivative and optionally a coloring agent, for example Red E 123, Red E 124 or Yellow E 102 or a mixture of Yellow E 102 and Red E 123 or Red E 124, which solution is equilibrated with a gas mixture consisting of 7.8% CO 2, 6.8% and the balance nitrogen, and 15 which has a pH of 7.12-7.22. Solution with a clinical value for the alkaline acid-base equilibrium, for the quality control of hemogas analyzers, characterized in that the solution is water, 30% glycerol, 50 mmol / 1 phosphate buffer, 28 mmol / 1 sodium bicarbonate and 32 mmol / l sodium chloride, and optionally a bactericide, for example sodium trichloro phenate or another phenol derivative and optionally a coloring agent, for example Red E123, Red E 124 or Yellow E 102 or a mixture of Yellow E 102 and Red E 123 or Red E 124, which solution is equilibrated with a gas mixture consisting of 2.27% CO2, 21.15% and the balance nitrogen, and which has a pH of 7.50-7.65. Solution according to claim 10, characterized in that the solution does not contain any colorant. Solution according to claim 11. characterized in. that the solution does not contain any colorant. Solution according to claim 12, characterized in that the solution contains no dye. 16. Solution with a clinical value for the acid-base equilibrium normal, existed for the quality control of hemogas analyzers, characterized in that the solution was water, 50 nmol phosphate-35 buffer, 41 mmol sodium hydrogen carbonate and 19 mmol sodium chloride 7906967 Si-V r, and optionally a bactericide, for example sodium trichlorophenate or another phenol derivative and optionally a dye, for example, RED E 123 or Yellow E 102 or a mixture thereof, which solution is equilibrated with a gas mixture consisting of 5.07% COi, 11.79% 0 ^ and 5 for the balance nitrogen, and which has a pB of 7.34-7.41. 17 * Solution with a clinical value for the acid-base equilibrium acidosis, intended for the quality control of hemogas analyzers, characterized in that the solution contains water, 50 mmol / 1 phosphate buffer, 37 mmol / 1 sodium hydrogen carbonate and 23 mmol / 1 contains sodium chloride 10, and optionally a bactericide, for example sodium trichlorophenate or another phenol derivative and optionally a coloring agent, for example, Yellow E 102 or Red E 123 or a mixture thereof, which solution is equilibrated with a gas mixture consisting of 7.89% CO2. 6.17% c> 2 and the balance nitrogen and which has a pH of 7.15-7.25. 18. A solution with a clinical value for the alkaline acid-base balance, intended for the quality control of hemogas analyzers, characterized in that the solution is water, 50 mmol / 1 phosphate buffer, 39 mmol / 1 sodium hydrogen carbonate and 21 mmol / 1 contains sodium chloride, and optionally a bactericide, for example sodium trichlorophenate 20 or another phenol derivative and optionally a coloring agent, for example Red E 123 or Yellow E 102 or a mixture thereof, which solution is equilibrated with a gas mixture consisting of 2.25% CO 2, 19.4% and the balance nitrogen and which has a pH of 7.55-7.65. Solution according to claim 16, characterized in that the solution does not contain any dye. Solution according to claim 17, characterized in that the solution contains no dye. Solution according to claim 18, characterized in that the solution contains no dye. Method for preparing solutions with three different clinical values for the acid-base equilibrium, namely normal, acidosis and alkalose, intended for the quality control of hemo-gas analyzers, characterized in that a solution of a phosphate buffer in water or a mixture of water and glycerol having a composition according to any one of the preceding claims is prepared, the buffer solution is filtered, for example, through a filter with 0.22 micron gingen, and equilibrated with a gas mixture of carbon dioxide, oxygen and nitrogen, at a controlled temperature in a so-called tonometer, provided with an electrode system for controlling the temperature, pH, P_ and P_ during equilibrium of the solution a> 2 «2 with the gas mixture, and further of means to transfer the gas-balanced solution to an ampoule filling machine with the gas-balanced solution discharge, which filling machine is provided with means to prevent contamination of the gas-equilibrated solution with air, after which the closed ampoules are optionally sterilized, for example in an autoclave. A method according to claim 22, characterized in that the temperature in the tonometer at which the solution is equilibrated with the gas is 25 ° C. Ampoules filled with a solution according to any one of claims 1-21 or prepared according to the method according to claim 22 and / or 23. 25. Solution, ampoules filled with a solution and method of preparing a solution as described in the description and examples. 7906967