EP0305429A1

EP0305429A1 - Clinical gas monitoring

Info

Publication number: EP0305429A1
Application number: EP19880901884
Authority: EP
Inventors: Robert Martin Pettigrew; Karen Margaret Montgomery Ness; Andrew Ramsey Hopkins
Original assignee: Scientific Generics Ltd
Current assignee: Scientific Generics Ltd
Priority date: 1987-02-25
Filing date: 1988-02-24
Publication date: 1989-03-08
Also published as: AU1343488A; WO1988006725A1

Abstract

Le procédé et l'appareil sont destinés à être employés dans le contrôle de gaz pour utilisation clinique. Dans un premier mode de réalisation servant à contrôler la composition de gaz d'anesthésie, ledit appareil comprend (a) un conduit définissant un canal d'écoulement pour le courant de gaz en écoulement, (b) une tête de détecteur disposée dans ledit conduit et comprenant une surface active, et (c) une fenêtre optiquement transparente ménagée dans la paroi dudit conduit adjacente à la tête de détecteur et destinée à permettre un rayonnement optimal depuis une source extérieure qui vient heurter cette surface active en passant à travers ladite fenêtre et destinée à permettre la sortie du rayonnement émis par ladite surface active, laquelle est une surface capable de supporter une résonance de plasmon. Afin de pouvoir effectuer des analyses de gaz sanguin extracorporelles et in vitro, ledit appareil comprend une cellule destinée à recevoir un échantillon de sang à analyser et incorporant dans ou sur l'une de ses surfaces une membrane perméable au gaz et, en contact avec la surface de cette membrane à distance du volume collecteur de ladite cellule, une surface active capable de supporter une résonance de plasmon.The method and apparatus are intended for use in the control of gases for clinical use. In a first embodiment for controlling the composition of anesthesia gas, said apparatus comprises (a) a conduit defining a flow channel for the flow of flowing gas, (b) a detector head disposed in said conduit and comprising an active surface, and (c) an optically transparent window formed in the wall of said duct adjacent to the detector head and intended to allow optimal radiation from an external source which strikes this active surface while passing through said window and intended to allow the exit of the radiation emitted by said active surface, which is a surface capable of supporting a plasmon resonance. In order to be able to carry out extracorporeal and in vitro blood gas analyzes, said apparatus comprises a cell intended to receive a blood sample to be analyzed and incorporating in or on one of its surfaces a membrane permeable to gas and, in contact with the surface of this membrane remote from the collecting volume of said cell, an active surface capable of supporting a plasmon resonance.

Description

CLINICAL GAS MONITORING

This invention relates to clinical gas monitoring and, more particularly, is concerned with anaesthetic gas monitoring and blood gas monitoring by a technique utilising Kaman spectroscopy.

Vibrational spectroscopy has been employed for many years to study the structure and bonding of molecules. As each bond has its own, characteristic frequency, vibrational spectra and molecular structure are related. In this way, compositional analysis can be carried out by inspecting the vibrational spectrum of a sample and comparing it with the spectra of known compounds.

The two main techniques employed are infrared absorption and Raman spectroscopy. In the first case, a wavelength tunable or broadband light source is used to illuminate the specimen, and the wavelengths at which energy is absorbed are recorded. In Kaman spectroscopy, a fixed wavelength source is employed, and the spectrum of emitted radiation recorded; the maxima in the emission spectrum represent the difference in energy between the incoming light quanta and the vibrational energy of the molecular bonds in the sample.

In general, vibrational energy levels lie in the infrared, and this represents a disadvantage for infrared absorption spectroscopy. Ideally one requires a tunable or broadband source of IK radiation. Although this is clearly possible using thermal radiation, in general power levels are low, and detectors with the required sensitivity are expensive.

With Kaman spectroscopy, however, one can illuminate the sample in the visible waveband, for example using a fixed frequency laser, and generate an emitted spectrum, shifted to the red, representative of the sample composition.

The major disadvantage to Kaman scattering is that it is a weak process, relying on a non-linear interaction between the source radiation and the sample. In the past this has meant that even for concentrated samples under ideal conditions photon counting and photomultiplier tubes have to be employed to detect the emitted radiation. Kemote detection, when the sample volume may be small, or dilute, has therefore been impractical. In the technique we propose, a method of compositional analysis utilises the enhancement of the efficiency of generation of the Kaman spectrum by using a configuration in which a surface plasmon is excited in an appropriate surface layer and the Kaman spectrum is simultaneously generated. It is known that when a surface plasmon is excited, the electric field associated with the electromagnetic wave is highly enhanced (by a factor of 10 3 to 104). This means that it will interact with high efficiency with molecules in close proximity to the surface; the excitation efficiency of the Kaman spectrum is much higher than would be the case without the surface plasmon phenomenon. In addition, excited molecules in close proximity to a metal surface can radiate light by co-operating with the metal surface; the 'image' of the molecular dipoles acts with the molecules themselves to form a 'phased array' of emitters. This emission can interact with the surface plasmon resonances of the metal surface so that the light is emitted in known, calculable directions. Thus the collection efficiency of the Kaman spectrum is enhanced.

One aspect of the present invention is particularly concerned with a sensor head specifically designed for use in monitoring of anaesthetic gases. The sensor is potentially integratable with gas lines. The option of continuous monitoring during surgery is available.

There is a requirement during surgery where the patient receives a general anaesthetic, to monitor the concentrations of both inhaled and exhaled gases. Anaesthetic gases used are usually nitrous oxide (NO) , halothane and other ether-like materials. These are used either individually or more usually in combination. Additionally oxygen is provided and carbon dioxide (CO_) is occasionally given to stimulate respiration. Exhaled gases to be monitored are oxygen and more importantly carbon dioxide. Current operating theatre procedure includes the use of separate tubes for inhaled and exhaled gases which have a two-way valved junction as close to the patient as possible to minimise dead space. Disposable circuits are generally used. Continuous monitoring of exhaled CO_ is currently available using for example the Datex Normocap equipment as supplied by Vickers Medical, a Division of Vickers pic, located at Basingstoke, England. Flow control is manually supervised by the anaesthetist using perception of other conditions such as patient responses in addition to gas concentration measurements.

The first aspect of the present invention utilises surface plasmon enhanced Kaman spectroscopy in the monitoring of anaesthetic gases. Equipment for this purpose based on conventional Kamam spectroscopy has been developed by Biomaterials International Inc. (BID of

Salt Lake City, Utah, USA. This equipment, however, has a number of drawbacks which arise essentially as a result of the very low signal level available with conventional

Kaman spectroscopy. We have devised a technique for improving the signal level by .. a surface plasmon technique. More particularly, according to one aspect of the present invention there is provided an apparatus for monitoring the concentration of two or more predetermined gases in a flowing gas stream, which comprises (a) a conduit defining a flow channel for said flowing gas stream, (b) located within said conduit, a sensor head comprising an active surface; and (c) an optically transparent window in the wall of said conduit adjacent to said sensor head to permit optical radiation from an external source to impinge upon said active surface through said window and to permit egress of radiation emitted by said active surface; wherein said active surface is a surface capable of supporting a plasmon resonance.

The use of surface plasmon enhancement ameliorates the problems associated with low signals, e.g. the BII instrument uses an air-cooled argon ion laser to provide a sufficiently high intensity light source to ensure measurable signals; this is not required in order to put the present invention into practice. Additionally, the present invention incorporates a number of other features such as compatibility with anaesthetic gas lines.

Preferably, the active surface is a metal-coated grating surface or a metal-coated surface of a triangular prism. Advantageously, the sensor head includes a heating element close to the active surface in order to permit control of the prevailing temperature at which the active surface functions. This may be important, for example, in order to avoid condensation of liquids or vapours on the active surface.

In a second aspect, the present invention is concerned with a sensor head designed specifically for use in monitoring of blood gas analytes in samples taken from a patient for n vitro analysis. The sensor is capable of both identification of gases and continuous measurement of their concentration. In a third aspect, the present invention is concerned with a sensor head designed specifically for use in monitoring of blood gas analytes in an extracorporeal circuit.

In blood gas analysis, one is usually concerned with the measurement of 0_ and CO,, partial pressures in both arterial and veinous flow, although the technique of the present invention may also be applicable to the detection of other analytes. Current techniques are based on either electrochemical (potentiometric or amperometric) or optical sensors. For example, the Cardiomet 4000 system manufactured by Biomedical Sensors Limited of High Wycombe, England combines pO measurement using an electrochemical sensor based on a Clark electrode with pCO_? and pH measurement based on the optical absorption properties of chemical dyes. Electrochemical sensors suffer from some problems associated with their complexity and fragility which makes for example miniaturisation of the sensors difficult.

There have been recent developments in electrochemical sensors, such as the use of ion selective field effect transistors (ISFETS). However the productionisation of such systems has riot yet been fully addressed.

In addition to optical sensors based on absorption and fluorescence, fibre optic sensors, either extrinsic or intrinsic, can be developed for application in blood gas analysis. The problem with such intrinsic sensors is the identification of a transduction mechanism appropriate to the particular parameter which is to be sensed. According to a second aspect of the present invention, there is provided an apparatus for determining blood gas concentrations, which comprises a cell adapted to receive a blood sample for analysis, said cell incorporating in or on one surface thereof a gas-permeable membrane and, in contact with that surface of said membrane remote from the receptive volume of said cell, an active surface which is capable of supporting a plasmon resonance.

According to a third aspect of the present invention, there is provided apparatus for determining blood gas concentration, which comprises (a) a sensor head including a body portion supporting and/or containing an active surface capable of supporting a plasmon resonance; (b) contiguous with said active surface, a gas-permeable membrane; and (c) an optical connection capable of transmitting a light input to said active surface and capable of transmitting a light output away from said active surface.

The present invention utilises a single optical technique for the monitoring of a number of blood gases e.g. p0₂ and pCO». The technique is also applicable to the detection and measurement of other blood gas analytes. Its simplicity compared with electrochemical sensors and versatility to monitor a plurality of analytes make it an attractive alternative sensor technology. The present invention provides ' a method of analysis which utilises enhancement of the efficiency of

Kaman spectrum generation in a configuration in which a surface plasmon resonance is generated in an appropriate surface layer and the Kaman spectrum is generated simultaneously.

The invention will be described hereinafter, by way of example, with reference to the accompanying drawings, in which:

FIGURE 1 illustrates schematically the working method of the invention.

FIGURES 2a and 2b illustrate schematically two embodiments ot the active surface used in the invention;

FIGURE 2c illustrates schematically the production of a Kaman spectrum; FIGURE 3 illustrates a preferred feature relating to the sensor head;

FIGURE 4 illustrates the location of the sensor head in a conduit defining a flow path for the flowing gas stream; FIGURE 5 illustrates a flow line for a patient breathing an anaesthetic gas mixture, the flow line including apparatus in accordance with the invention;

FIGURE 6 illustrates two arrangements of sample cell in accordance with the invention; FIGURE 7 illustrates part of a sample cell in accordance with this invention; and FIGURE 8 illustrates schematically one embodiment of the present invention for use in extracorporeal blood gas analysis.

Referring now to the drawings, the general layout is as shown in Figure 1. A sensor head 1 supports an active surface 2 which, in this embodiment, is in the form of a grating. A source 3 of coherent radiation, e.g. a laser operating in the visible or near infra-red, produces a collimated beam lambda, _.which is directed at the active surface 2 at an angle of incidence theta.. Surface plasmon enhanced Raman emission occurs and the emitted rays lambda are detected by a detection system 4. In the presence of a material, e.g. a specific gas, whose presence is to be detected, the enhanced Raman emission is affected in a specific and detectable manner; in this way, the detection and measurement of the Kaman emission is used to give a qualitative and/or quantitative indication of the presence of the material. The sensor itself comprises a metal coated substrate which may be part either of a prism (also known as Kretchmann or Otto geometry) or of a grating assembly. These arrangements are shown schematically in Figure 2. As shown in Figure 2c, the metal grating has a dielectric constant E„ while the dielectric medium onto which the metal layer is deposited has a dielectric constant E.. Surface plasmon generation can occur at the metal dielectric interface E. , E . The wavelength and angle of incidence of the illumination source, and the pitch, depth and groove shape of the grating (if used) are chosen to ensure efficient surface plasmon generation at the interface. This configuration, in which surface plasmon and Raman spectrum are generated simultaneously, provides enhancement of the efficiency of Kaman spectrum generation. in Figure 2a, the sensor head comprises a prism which carries a metal film 2 on one surface; the film 2 communicates directly with a conduit C through which the material undergoing analysis is passed. The arrangement of Figure 2b is different in that the active metal film 2 is spaced from the prism by a narrow gap (e.g. of 1 micrometre or less) which forms part of the conduit C. The sensor head structure itself preferably has the following features:

The substrate 1 is heated, e.g. by resistance heating element 5, to eliminate condensation of the gas being monitored (see Figure 3). ^Gas flow is controlled over the surface and feedback may be used to control the flow. As shown in Figure 4, a gas to be analysed may be fed through a line 6 to a chamber 7 containing the sensor head 1. Gas leaves chamber 7 by output line 8. Valves 9 and 10 are disposed upstream and downstream, respectively, of chamber 7 and may be used as part of a feedback loop (not shown).

The sensor is capable of recognition and concentration measurement of a number of gases simultaneously. One mode of operation would involve the sensor being integrated as far downstream as possible such as is shown in Figure 5. Here, a patient breathes through a mask (not shown) which is supplied by a tube 11 which contains a sensor head 1 of this invention. Inhaled gas (which may be an anaesthetic gas mixture) is admitted to tube 11 via tube 12 and valve 14, while exhaled gas is vented to the atmosphere via valve 14 and tube 13. This allows monitoring of both inhaled and exhaled gases in synchronisation with the patient's breathing. To operate in this mode, a level of intelligence and turning logic would be required in the control of the detection system. Alternatively a sensor could be used in each of the inhaled and exhaled gas lines. A sensor incorporated in the gas line would fit into the instrument allowing positioning with respect to light source and detection systems via some form of clip-in positioning. Since it is known that tubing used for anaesthetic gas delivery is usually disposable, one mode of operation of the sensor could involve a disposable sensor unit fully integrated during manufacture with the tubing by, for example, moulding. This would avoid additional connectors from tubing to sensor.

The sensor assembly illustrated in Figures 6 and 7 is intended for use in in vitro blood gas analysis and is capable of sensing the presence and relative concentrations of a number of gases simultaneously. Since the sensor is to be used to monitor the gaseous content of a liquid (blood) sample, a unique feature of the invention is a membrane structure 18 which prevents the liquid sample from coming into direct contact with the Kaman active surface but which allows the flow of gaseous constituents from the blood sample across the membrane into the sensing region close to the surface. This is illustrated in Figure 7. The spacing between the membrane and the sensing surface may be very small. In one advantageous embodiment of this invention the cell containing the blood sample and the sensing surface can be integrated into a single component as shown in Figures 6a and 6b. These show a sample cell 15 which may be, for example, a polycarbonate moulding and would be a disposable unit. In Figure 6a, the membrane 18 fits over a prism 16 coated with a metal film 17; in Figure 6b, the membrane 18 is positioned on top of a metal grating 17. The entire unit would locate into the measuring instrument to ensure appropriate illumination and detection geometries.

The sensor is compatible with carousel techniques conventionally used for iri vitro analysis of a large number of blood samples.

The sensor of Figure 8 is intended for use in the extracorporeal analysis of blood gas concentrations and is capable of sensing the presence and relative concentrations of a number of gases simultaneously. For extra-corporeal blood gas analysis, it is a unique feature of the system that the sensor assembly itself (1) is remote from the illumination and detection systems. These may be housed in a main surface plasmon enhanced Kaman spectroscopic (SPEKS) instrument 19, while the sensor 1 forms part of an extracorporeal blood circuit, the required optical connection between the two being made by an optical fibre light delivery and collection system 20. This is shown in schematic form in Figure 8. The sensor itself may be a miniaturised grating or prism assembly, as described above with respect to the other embodiments of the invention. A membrane structure is also required to prevent direct contact between the blood and the sensing structure but allowing a flow of blood gases into the sensing region close to the sensing structure.

The sensor may be connected with the system controlling the flow in the extracorporeal circuit and the measurements generated may be used for on-line control of such a system.

Continuous monitoring of the blood gas concentrations is available via the SPEKS technique.

Highly efficient surface plasmon generation can occur at a metal-dielectric interface when the momentum of the incident radiation and the surface plasmon are matched. This does not occur under normal circumstances, since the surface plasmon momentum is always less than that of light. However momentum matching can be achieved by a number of techniques: i) Metal coated Prism ATK (attenuated total internal reflection) , also known as Otto or Kretchmann geometry configuration as shown in Figures 2a and

2b. At a particular angle of incidence, the momentum of the evanescent wave matches the surface plasmon mode ensuring efficient surface plasmon generation. ii) Use of a metal coated grating to ensure momentum matching (Figure 2c). The wavelength and angle of incidence of the illumination source and the grating pitch, depth and groove shape are chosen to ensure efficient surface plasmon generation at the interface. Illumination from the dielectric side of the grating is possible if the metal coating is sufficiently thin (< 10's nm) to allow penetration of the enhanced electric field into the material to be sensed. iii) It is known that under optimised conditions of physical parameters efficient^" surface plasmon generation can occur when a colloidal suspension of metalised spheres is illuminated. The dimensions of the spheres should be comparable with the wavelength of light.

It will be appreciated that components shown in the drawings are not drawn to scale; the enlargement of certain items whose dimensions are of the order of the wavelength of light is necessary for clarity.

Claims

Claims:

1. A method of determining the presence or concentration of one or more gaseous components in a fluid solution or mixture of clinical significance, which comprises bringing said fluid solution or mixture into close proximity to or contact with an active surface which is capable of supporting plasmon resonance so that the gaseous components(s) of interest are capable of interacting with said surface; illuminating the active surface with optical radiation of predetermined wavelength and at a predetermined angle of incidence; and observing radiation emitted from said active surface.

2. A method according to claim 1, wherein said fluid solution or mixture is the gaseous mixture in a flow line connecting a patient to a source of an anaesthetic gas mixture.

3. A method according to claim 1, wherein said fluid solution or mixture is blood.

4. Apparatus for monitoring the concentration of two or more predetermined gases in a flowing gas stream, which comprises (a) a conduit defining a flow channel for said flowing gas stream, (b) located within said conduit, a sensor head comprising an active surface; and (c) an optically transparent window in the wall of said conduit adjacent to said sensor head to permit optical radiation from an external source to impinge upon said active surface through said window and to permit egress of radiation emitted by said active surface; wherein said active surface is a surface capable of supporting a plasmon resonance.

5. Apparatus for determining blood gas concentrations, which comprises a cell adapted to receive a blood sample for analysis, said cell incorporating in or on one surface thereof a gas-permeable membrane and, in contact with that surface of said membrane remote from the receptive volume of said cell, an active surface which is capable of supporting a plasmon resonance.

6. Apparatus for determining blood gas concentration, which comprises (a) a sensor head including a body portion supporting and/or containing an active surface capable of supporting a plasmon resonance; (b) contiguous with said active surface, a gas-permeable membrane; and (c) an optical connection capable of transmitting a light input to said active surface and capable of transmitting a light o.utput away from said active surface.