1. Field of the Invention
This invention relates to an apparatus which enables the study of gas content in, and interactions with, biologic and other media, e.g., blood.
2. Description of the Prior Art
Numerous methods exist to measure gas partial pressures and gas tensions in liquids (except inert, toxic and anaesthetic gases which are more difficult), but measurement of gas content (i.e., the total amount of gas present) is more difficult. Content is a function of the partial pressure of the gas, its solubility in the material and any reactions with the material. Most methods calculate content from knowledge of the gas partial pressure, the temperature and solubility of the gas in the material being studied. In many cases however, accurate solubility data is not available and this is especially true when considering inert, toxic and anaesthetic gases. In addition, biologic and other specimens are seldom of pure, known or fixed composition. Tissue specimens are always composed of a mixture of cell types. All this could invalidate assumptions about solubility coefficients. The new apparatus enables measurement of solubilities by providing a means of saturating the material with gas and then the means to remove the contained gas permitting measurement of the amount dissolved. All this is done without the need of transfers from one container to another.
Furthermore, the design of the apparatus in the form of a modified syringe enables blood or fluid specimens to be directly aspirated from the patient with no intermediate containment vessel. This prevents any gas loss and therefore reduces errors, permitting highly accurate and reliable research to be undertaken. The apparatus is easily disassembled and sterilized for repeated use with contaminated or potentially infectious materials. The apparatus may be constructed of materials carefully chosen so as not to interact in any way with the gas or liquid under study.
An area of major importance is the determination of dissolved gases in blood, both those naturally-occurring, e.g., oxygen, carbon dioxide and nitrogen and those added for purposes of anaesthesia, e.g., isoflurane, halothane and nitrous oxide, or those used when diving under increased pressures (nitrogen, helium).
General anaesthesia has been accomplished by inhalation of the anaesthetic gas by the patient. The anaesthetic gases used are normally found, after application, as dissolved gas in the blood stream of the patient. It is extremely important that the level of the anaesthetic gas in the blood stream of a patient be rapidly and accurately determined particularly during any surgical operation.
The percentage of carbon dioxide or oxygen in the blood stream is a function of the adequacy of ventilation and the cardiovascular, respiratory and metabolic function of the patient who is under anaesthesia. It may also be a function of the level of anaesthetic gas in the blood stream, although the level of anaesthetic gas cannot be measured directly. For these and other reasons it is important to determine in vivo the level of gases dissolved in the blood stream.
Most present methods for determining the level of anaesthetic gas in the blood stream are based primarily on determining its partial pressure in gas in the lung or in the breathing system. Many physiologic dysfunctions occur which may result in these measurements not accurately representing anaesthetic gas in the blood or brain. Other gases, including carbon dioxide and oxygen are also commonly measured in respiratory gas but in this case it is possible to take samples of blood periodically and, through electrochemical laboratory analysis, determine the partial pressure or the partial pressures or percentages of the gases under consideration in the blood stream at a remote location from the patient.
The determination of naturally-occurring blood gases is also important for clinical analysis. In particular, the determination of carbon dioxide (CO.sub.2) and oxygen (O.sub.2) tensions in whole blood and blood serum are among the most frequently performed analysis in a clinical laboratory. Due to the great importance of these analysis, a number of techniques have been developed and are presently being used to determine CO.sub.2 and O.sub.2 concentration.
A knowledge of the tension of each of the gases in the human blood stream is a valuable medical diagnostic tool. A means for continually monitoring the arterial system and analyzing the blood stream gases of one or more patients, for example, in a post-operative intensive care unit, would be an extremely valuable tool for determining the condition of patients' respiratory systems and would provide an early warning of possible malfunctioning.
At the present time, the analysis of the blood stream gases is made by withdrawing an arterial or venous blood sample and, without exposing the sample to the atmosphere, expose the blood to oxygen and carbon dioxide electrodes which measure gas tension electrochemically. The mass spectrometer is not used for such routine measurements at the present time but has the advantage that virtually any gas can be easily identified and measured.
In one present method used to determine the in vivo measurement of oxygen (pO.sub.2) in blood, an arterial needle which encloses an electrode assembly surrounded by a polyethylene membrane is inserted into a vein or artery. The dissolved oxygen in the blood diffuses through the membrane into an electrolytic solution and is reduced at a platinum cathode. The current produced is proportional to the oxygen content and is converted into a meter reading. However, this method has not found wide use because it is prone to many technical problems.
Numerous biomedical and other fields require knowledge of gas solubility and gas volumes in biological fluids or tissues. This is important in research in diving and aviation medicine, anaesthesia, toxicology and biochemistry. Although as mentioned above methods are available for measuring oxygen and carbon dioxide in blood and other fluids, it is more difficult to measure inert, poisonous, or anaesthetic gases or to measure gas production from various biological reactions. Existing methods for the determination of gas content in blood involve the use of the Van Slyke apparatus [using the method of D. D. Van Slyke which was published in the Journal of Biological Chemistry, Vol. 61, page 523 (1924)], vacuum extraction, gas chromatography, volumetric analysis or some combination of these preceding. In the basic Van Slyke method, blood serum and acid are mixed in a closed volume and the carbon dioxide in the blood is extracted from the blood by application of vacuum. The extracted carbon dioxide is then measured volumetrically or manometrically. When the vacuum is drawn, other blood gases are released from the serum in addition to the carbon dioxide. This requires that a base, such as sodium hydroxide, be added in order to separate the carbon dioxide from the other released gases. After this, the volumetric measurement is performed by known techniques. Few advances have been made on this methodology since 1924, with the result that gas content is seldom performed except with the above method.
Another disadvantage of most prior art techniques for measuring blood gases concerns the use of a vacuum when the reagent and blood react to release the gases to be detected. Use of a vacuum means that species other than the gas to be measured (e.g., CO.sub.2) will be released. For instance, O.sub.2, N.sub.2, etc. will be released from the blood and will contaminate the sample measurement where it is desired to measure CO.sub.2. Chemical methods are required to remove unwanted gases. However, use of these methods introduces further time-consuming procedures and other possible errors including solution or adsorption of other gases by the chemicals and unknown solubility of gases in the chemicals. It would therefore be described to provide a method which can measure numerous gases simultaneously without the need to separate one from another.
Still another disadvantage of the use of vacuum relates to the possibility of leakage and lack of vacuum tightness. In vacuum systems, errors generally occur because apparatus, e.g., valves and stopcocks, develop leaks. Since the vacuum apparatus is designed to operate reliably only when reproducibly good vacuum is provided, such techniques are critically dependent on the reliability of components which are themselves subject to numerous problems. Consequently, it is important to provide a technique which suffers only minimal interference from dissolved gases in the blood other than the species which is to be measured.
In general, such prior art methods using vacuum for measuring blood gases contain certain "non-equilibrium" features which lead to errors. The application of vacuum extracts gas from the blood which is partly reabsorbed by the blood when the vacuum is removed. Potential errors include leaks when working with high vacuums. The use of lesser vacuums can result in incomplete extraction. Leaks also occur when multiple transfers of samples between different reaction or measurement chambers are necessary. Such leaks may go undetected, especially when nitrogen or other atmospheric gases are being measured and the detection system is not gas-specific. Other problems include uncertainty that all gas has been extracted by a vacuum, inadequate control of temperature or ambient pressure and the need to make numerous assumptions or apply correction factors. In addition, many of the existing methods are highly dependent on the skill and technique of the experimenter and may suffer from inter- and intra-observer variation which is not appreciated.
In gas chromatography, the released gases are typically carried in a gas stream over a chromatographic column and then through a detector. The gas stream used as the carrier is usually He, or some other gas having a different thermal conductivity than the gases which are to be measured. The column has different affinities for each gas in the mixture and acts to separate the different gases from one another. The detector usually comprises a hot filament wire whose resistance changes in accordance with the thermal conductivity of the gas which is in contact with the wire. Since the thermal conductivities of the gases to be measured are different from the carrier gas, and since the gases have been separated in a known order, each of the transient peaks of the detector response can be associated with one of the gases to be measured. These transient responses are usually plotted on a recorder, since the measurement is a dynamic one done in accordance with the flow of gases, rather than a stationary gas measurement. The integral under the response curve or the peak height of the response curve is then a measure of the gas content in the blood sample.
While there have been numerous publications relating to gas chromatography for the determination of, for instance, CO.sub.2 in blood serum, this technique has not found wide application in routine laboratory measurements. The technique is complex, requiring a significant amount of apparatus including a chromatography column, together with recording equipment. Additionally, the method is very time consuming. Part of the time consumption is due to the burdens placed on the operator of the apparatus, who has to inject the blood sample, and then wait until the sample passes through the column and the detector. The operator then has to relate the recorder output to the signal from a calibration sample, all of which is time consuming and which can lead to human error. The time involved means that results will seldom be available in time for them to be clinically useful. In this situation, gas chromatography cannot compete with electrochemical means of determining respiratory gases, or with the non-invasive methods of pulse oximetry or analysis of exhaled gases with infrared or mass spectrometry equipment.
In addition to the disadvantages noted above, gas chromatography requires the use of a separation column which is damaged by the direct injection of blood specimens. This necessitates the use of a pre-column which can be discarded as required. Also, usually high temperatures are required in the gas chromatography resulting in vaporization of the liquid and pyrolysis of biologic and other material with the possibility of producing gases in the process perhaps including the gas it is sought to study. Gas chromatography also requires a carrier gas stream. This is a dynamic measurement rather than a static measurement, and is consequently more complex and is thought to be less reliable. With such a dynamic process, constant flow rates are required and transient responses have to be quickly recorded in order to provide accurate results. While our method using mass spectrometry also employs intermittent use of a carrier gas the flow rate merely affects the rate of washout of the gases under study and does not alter the final result. In addition it would be desirable to provide a technique which measures all gases simultaneously rather than one at a time.
In addition to the above disadvantages, using gas chromatography the carrier gas has to be a gas having a different thermal conductivity than the gas species to be detected, in order that the measurement of the detected gas species is not altered by the presence of the carrier gas. It is for this reason that gases, e.g., He, which has a significantly different thermal conductivity than air, O.sub.2, N.sub.2, etc., are used.
Canadian Patent No. 1,097,101 patented Mar. 10, 1981 by D. P. Friswell et al. provided an automatic liquid sample-injecting apparatus for liquid chromatography. Such automatic liquid sample-injecting apparatus used a conduit, e.g. a hypodermic needle or pipette to suck liquid from a sample source and transfer it to an injector valve apparatus. The apparatus was equipped with a seal adapted to exert a radial thrust or wiping action on the conduit. Conduit working means included both a drip-proof means to supply a non-contaminating solvent for washing the exterior of the needle and means to remove such solvent, all without interfering with the use of the needle in a series of automatic injections.
Canadian Patent No. 1,121,177 patented Apr. 6, 1982 by G. Sisti et al. provided an apparatus for feeding carrier gas to gas-chromatographic columns. The apparatus included a pressure regulator to introduce gas at constant pressure and a rate regulator to introduce gas at constant flow rate, between the gas source and a fitting to the injector The regulators were positioned in parallel. A switch was provided for alternatively connecting either the pressure regulator during the injection of the sample or samples into the column, or the flow rate regulator during the subsequent processing stage inside the gas-chromatographic column.
Canadian Patent No. 1,138,226 patented Dec. 28, 1982 by J. F. Muldoon provided an improvement with respect to electronic instrumentation associated with gas chromatography systems. The patent system included a gas processor for producing a time varying signal which was related to the constituents of the gas mixture. A converter sampled the time varying signal and converted it to digital form for providing a sampled data signal. A rate of change estimator provided a rate of change signal. The estimator includes recursive digital feedback means coupled to an output of the estimator and also to the converter. In this manner, past time value signals of the estimated rate of change signal and of the sampled data signal were produced. The estimator further comprised means for combining the past time value signals with the sampled data signal for producing the estimated rate of change signal. Although this invention improved gas chromatography methods it did not improve the sample handling problems which exist when measuring gases contained in liquid.
U.S. Pat. No. 2,987,912 patented Jun. 13, 1961 by J. G. Jacobson provided a method for the determination of the amount of a gas dissolved in a liquid. The first steps in the patented method involved flushing the vessel with a neutral gas in a closed system and measuring the amount of the dissolved gas with a measuring means. The vessel was then filled to a predetermined level with the liquid to provide a constant ratio of-gas to liquid, while retaining the neutral gas in the system. The neutral gas was then circulated in the system in highly dispersed state through the liquid to extract dissolved gas from the liquid. The amount of gas dissolved in the liquid was indicated by the change in response of the measuring means after a predetermined length of time of circulation substantially shorter than needed for reaching equilibrium between the gas dissolved in the liquid and the extracted gas.
U.S. Pat. No. 3,518,982 patented Jul. 7, 1970 by R. S. Timmins et al., provided a device and method for monitoring gases in the blood stream. The patented method included the insertion of a catheter having a membrane of a material which was permeable to the gas to be measured in the blood stream. The membrane employed in the catheter had a significant rate of diffusion for at least one gaseous component of the blood stream which is to be analyzed. A gas stream of known composition and pressure, called a flush gas, was then introduced into the catheter and isolated in the chamber. Depending upon the partial pressure differences of the gaseous components on either side of the membrane wall, diffusion through the membrane occurred, which caused the normal pressure within the chamber to change with time. This pressure change was related to the concentration of the gases in the flush gas and in the blood stream to be analyzed. The pressure in the chamber at a given time was then determined, the number of pressure determinations made being at least equal to the number of gas components (n) to be analyzed in the blood stream, which components have a significant rate of diffusion through the membrane wall of the catheter. Similar pressure determinations at a given time with additional flush gases of known composition and pressure were made to obtain a series of (n+1) pressure determinations. From these pressure determinations, the value of the actual characteristic mass transport function of the gas to be analyzed could then be determined. That value was termed the "calibration factor". This calibration factor for the patient and catheter was then employed to determine the quantitative level of the dissolved gases in the blood stream continuously or intermittently.
U.S. Pat. No. 3,564,901 patented Feb. 27, 1971 by G. H. Megrue provided a system and technique for gas analysis. In the patented technique, a microgram quantity of material from predetermined meteoritic regions was volatilized in a high vacuum. The gases released from these regions were isotopically analyzed to determine their identity and abundance at each of the predetermined regions.
U.S. Pat. No. 3,710,778 patented Jan. 16, 1973 by F. L. Cornelius provided a blood gas sensor amplifier and testing system. The invention included an amplifier for processing the output signal from an in vivo sensor for the partial pressure of gas in blood. Means were provided for displaying the signal in terms of partial pressure of the gas in millimeters of mercury.
U.S. Pat. No. 3,922,904 patented Dec. 2, 1975 by D. D. Williams et al. provided a method and apparatus for detecting dissolved gases in a liquid. The method included the first step of flowing a carrier gas for displacing the dissolved gas from the liquid over a flowing body of the liquid in a confined cylindrical zone. Films of the liquid were continuously lifted into and across the flowing carrier gas to effect displacement of the dissolved gas from the liquid and to effect formation of a mixture of the carrier gas and displaced dissolved gas. The mixed gas was flowed through an operating thermal conductivity cell to relate the thermal conductivity of the mixed gas to that of the carrier gas.
U.S. Pat. No. 3,964,864 patented Jun. 22, 1976 by H. Dahms provided for a method and apparatus for the determination of CO.sub.2, or O.sub.2 in body fluids, e.g., blood. The technique for such determination included the first step of reacting the sample and a reagent in a vessel to release CO.sub.2 into a gas space filled with air at atmospheric pressure to produce a mixture of the released CO.sub.2 and air. The gas space had a volume greater than the volume of sample in the vessel. At least a portion of the mixture in the gas space was transferred to a detector by adding a displacing liquid to the vessel. The concentration of the transferred gas mixture in the detector was then measured.
U.S. Pat. No. 4,117,727 patented Oct. 3, 1978 by D. P. Friswell provided a bubble sensor for use in liquid chromatography. A sample conduit or loop which was already filled with liquid eluent communicated with the bore of a needle. The opening of the needle bore was immersed in a liquid sample so that the sample may be backfilled into the sample loop by the withdrawal of the syringe which communicated with the sample loop. After the liquid sample had been drawn into the sample conduit, the needle was lifted from the sample source and moved toward a final position in which the sample conduit was placed in parallel with a primary conduit, so that the pump which pumped the liquid eluent drove the sample from the opening toward the chromatographic column. As the needle was being raised toward this position, it was stopped at an intermediate position in which the orifice was sealed. In this condition, the liquid sample was within the sample conduit which was part of a closed space between the orifice and the syringe. The syringe was driven a small distance to reduce the volume of that space by a predetermined, programmed increment. The pressure before and after the change in the space was compared to indicate the presence or absence of a bubble in the sample.
U.S. Pat. No. 4,187,856 patented Feb. 12, 1980 by L. G. Hall et al., provided a method for analyzing various gases in the blood stream. According to the patentee, the catheter provided with a blood-blocking membrane at its distal end was equipped with a very small tube throughout its lumen which terminated in the area of the membrane. A "carrier" gas, e.g., helium, was introduced through the tube and against the interior surface of the membrane where it mixed with the blood gases passing through the membrane. The blood gases thus mixed with the carrier gas was under a small pressure and passed by viscous flow at a relatively high speed through the tubing interconnecting the catheter with the sampling input leak of the mass spectrometer. Problems with this procedure, however, may include denaturation of proteins and blood components blocking the membrane, difficulties with calibration and diffusion of carrier gas into the blood stream.
U.S. Pat. No. 4,270,381 patented Jun. 2, 1981 by D. E. Demaray provided a procedure for the measurement of gaseous products produced by microbial samples. Each sample module provided a closed reaction vessel communicating with a liquid reservoir from which displaced liquid passed to a vertical measuring column. The displaced liquid activated a float which moved a marker responsive to volume of gas produced in the reaction vessel. Plural sample modules were combined so that markers of all moved in a parallel direction upon a recording sheet moved perpendicularly thereto to provide a record of gas formation at a function of time.
U.S. Pat. No. 4,235,095 patented Nov. 25, 1980 by L. N. Liebermann provided a device for detecting gas bubbles in liquid. The detector included a pair of electromechanical transducers for disposition on a fluid-filled conduit in an acoustically-coupled relationship. An adjustable gain driving amplifier responsive to the electrical output of one transducer drove the other transducer. An automatic gain control circuit automatically adjusted the gain of the driving amplifier to maintain the system on the margin of oscillation. An indicating circuit detected modulation of the driving signal. Bubbles passing through the conduit increased the gain required to maintain the system on the margin of oscillation, and were detected as modulations of the driving signal.
U.S. Pat. No. 4,330,385 patented May 18, 1982 by R. M. Arthur et al. provided dissolved oxygen measurement instrument. The instrument included an enclosure which was partially submerged. Liquid from the main body was continuously circulated through the enclosure and an entrapped volume of air was continuously circulated through the enclosure. The amount of oxygen in this entrapped air was continuously measured by an oxygen concentration sensor which was disposed in the path of the circulating air. This provided an indirect measurement of the amount of dissolved oxygen in the liquid without actually bringing the sensor into contact with the liquid.
U.S. Pat. No. 4,468,948 patented Sep. 4, 1984 by T. Nakayama provided a method and apparatus for measuring the concentration of a gas in a liquid. The method involved passing a carrier gas through a liquid-repellent porous partition tubing, immersed in a liquid, having continuous minute channels extending through the tubing wall. The gaseous volatile substance, which passed from the liquid into the carrier gas through the continuous minute channels, was introduced into a gas detector while the flow rate and the pressure of the carrier gas were controlled by simultaneously operating both a carrier gas control means and a choking means.
U.S. Pat. No. 4,550,590 patented Nov. 5, 1988 by J. Kesson provided a method and apparatus for monitoring the concentration of gas in a liquid. The apparatus included a semi-permeable diaphragm across the face of which the liquid flowed. Gas contained in the liquid permeated through the diaphragm into a chamber and the pressure within the chamber was measured. This pressure was representative of the concentration of gas in the liquid.
U.S. Pat. No. 4,702,102 patented Oct. 27, 1987 by D. Hammerton provided an apparatus for the direct readout of gas dissolved in a liquid. The apparatus included a gas permeable tube or membrane closed at one end, and having its other end connected to a pressure sensor. The gas permeable tube was mounted on the apparatus housing such that it could be immersed in the liquid to be measured. During the measurement process, if the liquid contained less dissolved gas than -the equilibrium quantity at atmospheric pressure, it absorbed gas from within the gas permeable tube thereby changing the internal tube-gas pressure. The percentage of dissolved gas was related to the extent of gas absorption by the liquid and the resulting internal tube-gas pressure after gas absorption was substantially complete. Rapid measurement of the percentage of dissolved gas was achieved by altering the combined internal volume of the gas permeable tube and the pressure sensor to produce an optimum minimum internal volume within the combined internal volumes.
U.S. Pat. No. 4,862,729 patented Sep. 5, 1989 by K. Toda et al. provided a method for measuring the amount of gas contained in a liquid. The method included the step of introducing a liquid material into a vacuum measuring chamber. The volume of the measuring chamber was changed to provide two different liquid pressures of the liquid material in the measuring chamber. The different pressures were then detected to measure the amount of gas on the basis of Boyle's law. The apparatus included a cylindrical measuring chamber with an inlet part connecting the measuring chamber to a sample source. A valve was provided including means for closing the measuring chamber from the inlet part. A piston was fitted into the measuring chamber. A first means was provided for moving the piston a predetermined distance in the measuring chamber, the means comprising at least two cylindrical ports separated by a seal member on the piston, the cylinder ports being positioned so that the first means effected movement of the piston over the length of the measuring chamber. A pressure gauge was connected to the measuring chamber. A second means was provided for moving the piston a predetermined distance in the measuring chamber. Means were provided for detecting the location of the valve means and the piston.
U.S. Pat. No. 4,944,178 patented Jul. 31, 1990 by Y. Inoue et al. provided an apparatus and method for measuring dissolved gas in oil. In the patented method, air was blown into an oil sample through a bubble generator. Bubbles were passed through the oil sample to extract dissolved gas therefrom. A resulting air-extracted gas mixture was contacted by a gas sensor for detecting and measuring the dissolved gas. The mixture was recirculated through the oil sample.
U.S. Pat. No. 4,944,191 patented Jul. 31, 1990 by J. Pastrone et al. provided a detector to determine whether a gas is present in a liquid delivery conduit. The detector was an ultrasonic sound generator and receiver which were spaced from each other so as to receive a projecting portion of a cassette in which a liquid-carrying passage was defined by a flexible membrane. The liquid-carrying passage in the projecting portion fit between the ultrasonic sound generator and receiver, with opposite sides of the flexible membrane being in contact with the sound generator and sound receiver. The sound generator and sound receiver each included a substrate having a layer of conducting material. Two electrically isolated regions Were defined on the conductive layer and a piezo-electric chip was electrically connected between the two regions. An electrical signal applied between the first and second regions excited the piezoelectric chip on the sound generator, causing it to generate an ultrasonic signal, which was transmitted through the liquid carrying passage. If liquid was present in the passage, the amplitude of the ultrasonic sound signal received by the piezoelectric chip on the sound receiver was substantially greater than when liquid was absent in the passage. The ultrasonic detector thus produced a signal indicative of liquid in the liquid carrying passage.
U.S. Pat. No. 5,062,292 patented Nov. 5, 1991 by M. Kanba et al. provided device for measuring a gas dissolved in an oil. The device included a sample container for containing a sample oil. An air bubble generator extracted the gas dissolved in the oil. A gas container contained the gas and a gas sensor detected the gas charged in the gas container. Gas measuring means was provided for measuring a concentration of the gas in response to a signal dispatched from the gas sensor. A pump supplied air to the air bubble generator.