Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/02—Inhalators with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
  • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
  • A61B5/0813—Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
  • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
  • A61M2016/0015—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors
  • A61M2016/0018—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical
  • A61M2016/0021—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical with a proportional output signal, e.g. from a thermistor

Definitions

• This invention relates to a device (hereinafter an "applicator") suitable for the delivery of a fluid bolus, e.g. a bolus of a liquid or gas; optionally containing an entrained discontinuous phase, for example solid particles, liquid droplets, vesicles (e.g. micelles, liposomes, microbubbles, microballoons, etc) and the like.
• a fluid bolus e.g. a bolus of a liquid or gas
• an entrained discontinuous phase for example solid particles, liquid droplets, vesicles (e.g. micelles, liposomes, microbubbles, microballoons, etc) and the like.
• the applicator is suitable for the delivery of a gas bolus into the respiratory system of a human or an air-breathing animal (e.g. mammal, reptile or bird) .
• the applicator is suitable for the delivery of a bolus of a hyperpolarized gas
• MRI magnetic resonance imaging
• the nuclei responsible for the signal are protons, generally water protons.
• the strength of the MR signal is proportional to the population difference (the polarization) between the different nuclear spin states of the imaging nuclei and this in turn is governed by a Boltzmann distribution and is dependent on the magnetic field and temperature.
• N ⁇ is the population for nuclei in one spin state ⁇ (e.g. +%) ;
• N ⁇ is the population for nuclei in the other spin state ⁇ (e.g. -%) ; y is the magnetogyric ratio for the nucleus; i is Planck's constant divided by "2 ⁇ ; k is Boltzmann's constant;
• B c is the magnetic field (or magnetic flux density) ;
• T is temperature in Kelvin; and ⁇ is the magnetic core dipole moment .
• 3 He has a nuclear spin I of 4 and this can be used as the imaging nuclei in MRI (see for example US-A-5642625 , US-A- 5612103, US-A-5545396, 095/27438, 097/37239, Song et al. J. Mag. Res. A 115: 127-130 (1995) and Middleton et al. Mag. Res. Med. 3_3_: 271-275 (1995)).
• a bolus of hyperpolarized 3 He is delivered into the respiratory tract of the subject, e.g. into the trachea, lungs, and alveolar space, and an MR signal from the 3 He is used to generate an image of the lungs. Since the natural occurrance of 3 He elsewhere in the body is negligible, there is negligible signal from regions in the body other than the respiratory tract .
• Helium atoms have different properties to the oxygen and nitrogen molecules that make up the majority of the air that the subject normally breathes, e.g. in terms of ability to diffuse, and if the 3 He bolus is not to distribute in the respiratory tract significantly differently from air, it is desirable to ensure that it makes up only a relatively small proportion of the total breath intake .
• the invention provides an apparatus for fluid administration comprising: a variable volume fluid reservoir and a fluid conduit leading therefrom to a fluid outlet, a first fluid inlet and a second fluid inlet; a first detector arranged to detect fluid flow between said conduit and said reservoir; a first valve arranged to permit or prevent fluid flow from said first inlet through said conduit into said reservoir; a second valve which in a first setting permits fluid flow from said second inlet through said conduit to said outlet and prevents fluid flow from said reservoir through said conduit to said outlet and in a second setting permits fluid flow from said reservoir through said conduit to said outlet and prevents fluid flow from said second inlet through said conduit to said outlet; a second detector arranged to detect fluid flow into said conduit from said second inlet; and an activator arranged to control the operation of said first and second valves.
• the apparatus of the invention is primarily intended for the delivery of hyperpolarized gases into the respiratory tract of a subject and will be described in that context below, it is also suitable for the bolus delivery of other one or more phase fluids, e.g. liquids, solid-in-liquid suspensions, gas-in-liquid dispersions, aerosols, gases, gas mixtures, powder-in-gas dispersions, etc. as mentioned above.
• phase fluids e.g. liquids, solid-in-liquid suspensions, gas-in-liquid dispersions, aerosols, gases, gas mixtures, powder-in-gas dispersions, etc.
• liquids will simply be referred to as gases and liquid flow and liquid inlets, etc. will be referred to as gas flow and gas inlets, etc.
• Fig. 1 of the accompanying drawings illustrates this for two different gases in schematic form.
• a hose (1) is initially filled with a first type of gas (2) , such as air.
• a second gas type (3) e.g. hyperpolarized 3 He
• the original type of gas (4) e.g. hyperpolarized 3 He
• this gas sequence passes unmixed into the lungs, provided that no intermixing takes place due to turbulence, or due to excessively high flow velocities.
• a defined volume of gas to be placed in a specific part of the lung .
• the applicator of the invention is desirably equipped with a third valve which serves to prevent gas flow back to the second valve from the outlet, e.g. by directing it to a second outlet (e.g. a vent) or to a second reservoir, for example for the collection of 3 He for reuse .
• a third valve which serves to prevent gas flow back to the second valve from the outlet, e.g. by directing it to a second outlet (e.g. a vent) or to a second reservoir, for example for the collection of 3 He for reuse .
• This third valve is preferably arranged to operate to prevent such flow back when the subject exhales and may be controlled by the activator or may be a passive valve operated automatically by the reversal of gas flow at the outlet.
• the second -valve may have a third setting in which gas flow from the outlet is prevented from passing to the first reservoir or to the second inlet and is directed instead to a second outlet or to a second reservoir; in this arrangement the third valve is unnecessary.
• the first reservoir may be any variable volume reservoir, e.g. a barrel with a movable piston (ie. as in a syringe), a flexible sack, a bellows, etc.
• a movable piston ie. as in a syringe
• a flexible sack e.g. a syringe
• a bellows e.g. a folding bellows for example made of plastic, preferably a helium tight film or a plastic coated with such a film
• gas flow into or out of the expandable container will cause a corresponding gas flow through the venting aperture and thus allow the gas flow in and out of the expandable container to be detected and measured indirectly.
• gas flow into the second inlet is from a respirator.
• the gas flow from the respirator should be redirected to exert pressure on the exterior of the variable volume reservoir so that the gas flow from that reservoir to the subject should be at the same pressure as the earlier/later gas flow from the respirator to the subject.
• the applicator should include a detector, e.g. a differential pressure detector, that will detect when the variable volume reservoir has reached its minimum volume whereupon the second valve may be returned to its first setting.
• the conduit should be provided with a further (third) inlet and a further (fourth) valve arranged to prevent or permit gas flow from the third inlet through the conduit and into the variable volume reservoir. Operation of the applicator so as to administer this further fluid via the variable volume reservoir may be equivalent to operation to administer fluid from the first inlet and the activator is preferably arranged to control the fourth valve too.
• the operation of the activator in the applicator of the invention is preferably controlled by a controller (e.g. a computer) in response to signals from the detectors and to the settings input by the operator, e.g. desired bolus size and placement.
• a controller e.g. a computer
• the invention provides a device for the exact application of gaseous substances transported in the gas into the lungs and respiratory tracts, which is provided with the following:
• a metering device (230,231) connected to the first inlet (203) for the metered administration of the volume to be applied of the first gaseous substance;
• a switchover valve (240) connected on the one hand with the metering device (230,231) and the second inlet (301,305), and, on the other, with the outlet (241,243), for the optional connection of the outlet (241,243) with the second inlet (301,305) in a first valve setting, and with the metering device (230,231) in a second valve setting;
• the metering device (230,231) having an expandable container (231) connected to the first inlet (203) and arranged in a housing (230) which is provided with at least one venting aperture (235,236) to which a further measuring device (232,244) is connected for measuring the gas which flows out of the housing (230) during expansion of the container (231) and/or flows into the housing (230) during contraction of the container (231) ; and
• control unit (220) connected to the two measuring devices (304,232,244) and the switchover valve
• valves, conduits etc. of the applicator are preferably so constructed that linear flow of the gases following the second valve prevails, ie. to avoid turbulence which would diffuse the bolus, mixing the different gas types.
• the applicator desirably is arranged to permit different bolus volumes, and to permit placement of the bolus at any desired part of the entire breath intake. Moreover it preferably will be arranged to permit a single application or a sequence of applications in which, for example, the bolus volume, the bolus placement, the respiration volume, etc. may be varied. Furthermore, it is desirable for the applicator to be arranged to permit administration of gas boli of either a single gas or a gas mixture, e.g. a mixture of a hyperpolarised gas such as 3 He with a gas which does not shorten the relaxation times of the hyperpolarised gas, e.g. a gas such as nitrogen. In such a case, the non- relaxing gas (e.g. N 2 ) will generally be filled into the variable volume reservoir first and then mixed with a selected quantity of hyperpolarised 3 He immediately after. A long bolus of diluted 3 He may then be administered, e.g. for gas flow studies.
• a single gas or a gas mixture
• the operation of the applicator ie . the production of a gas sequence through the outlet, should not noticeably interfere with or appreciably interrupt the subject's respiration.
• the gases used e.g. 3 He
• the applicator is preferably arranged for their recovery.
• Respirators can control the respiration by pressure control or flow control; ie . in respiration form (3), during inhalation, either the pressure or the gas flow is regulated. While with spontaneous respiration the volume of the air inhaled varies from time to time, with volume-controlled respiration by means of a respirator the same respiration gas volume is always introduced. All these forms of respiration can be used with the invention described here.
• the 3 He polarisation can, however, be raised to values close to 1 , at ambient temperature and with low magnetic fields of the order of magnitude of mT; i.e. well above the Boltzmann equilibrium polarisation.
• the process is known as "optical pumping" , and the physical principles, as well as the technical realisation, are described by Colegrove et al . Phys . Rev. 132 : 2561-2572 (1963), Walters et al . Phys. Rev. Lett. 8 . : 439-442 (1962), Schearer et al . Phys. Rev. Lett. 1_0: 108-110 (1963), Eckert et al . Nucl . Instr. & Meth.
• Ferromagnetic substances distort homogeneous magnetic fields, and lead to gradients which are very much stronger. These should therefore preferably be avoided as materials for the construction of an applicator.
• Non-ferromagnetic substances such as, for example, plastics, titanium, or glass, leave the magnetic field undistorted, and are in principle suitable. They differ, however, in their wall relaxation properties if used as gas container materials. To preserve 3 He polarisation over lengthy periods of time, special glass containers which leave relaxation times ⁇ 1 ranging from hours to days are preferred (see Heil et al . , supra) . Valves which come into contact with hyperpolarised gases are preferably made of titanium (see Becker et al . (1994) supra).
• Plastics may be used but are of limited suitability as 3 He may be able to penetrate their porous structures and become depolarised in them. Typical relaxation times are in the minute range. However, in the nuclear spin tomograph itself all moving parts will normally be made of plastic, because moving metal parts have proved to cause interference with nuclear resonance tomography.
• paramagnetic impurities including gaseous oxygen
• paramagnetic impurities including gaseous oxygen
• [0 2 ] is the oxygen density in Amagat units in the 3 He gas (see Saam et al . , Phys. Rev. A 52: 862-865 (1995)).
• relatively thick conduit etc. walls may be desired so that oxygen may be expelled, for example by flushing with nitrogen gas.
• all the component parts of the applicator are of non-magnetic materials, especially non-metallic materials, more preferably electrically non-conductive materials, e.g. plastics.
• Moving parts particularly are desirably made of plastics.
• the measuring device which determines the quantity of gas which flows into or out of the housing of the metering device at contraction and expansion respectively preferably comprises a flowmeter connected to a venting aperture of the housing, and a differential pressure gauge connected to a ventillation aperture of the housing, which measures the differential pressure between the interior of the housing and the outlet of the applicator.
• the switchover valve (the second valve) may then be switched over in response to the measured value .
• the applicator of the invention can be arranged within a nuclear spin tomograph. (Appropriate selection of materials in this regard has already been commented upon above) .
• the dead space in the apparatus especially between first inlet and variable volume reservoir and between that reservoir and the outlet, is minimised. This assists in reducing unnecessary loss in polarisation by time delay or wall contact.
• the invention provides a method of magnetic resonance imaging in which a fluid (preferably gaseous, especially a hyperpolarised gas) MR imaging agent is administered in a bolus to a subject and a MR image (preferably a non proton MR image) of at least a part of said subject into which said agent distributes is generated, characterised in that said fluid is administered using an apparatus according to the invention, the fluid preferably being administered into the respiratory system of the subject.
• a fluid preferably gaseous, especially a hyperpolarised gas
• MR image preferably a non proton MR image
• Imaging according to the method of the invention may be performed conventionally.
• the bolus administration conveniently takes up 2 to 100%, more preferably 5 to 30% in time of the breath intake, and may be positioned at any stage of that intake.
• the gas administered, if hyperpolarised is preferably polarised to a value of P of at least 5%, preferably at least 10%.
• Fig. 1 is a schematic representation of a gas bolus arranged between two other gas flows in a hose;
• Fig. 2 is a schematic view of an applicator according to the invention.
• Fig. 3 is a schematic view of the applicator of Fig. 2 in the operating position in which air is being fed to the subject patient;
• Fig. 4 is a schematic view of the applicator of Fig. 2 in the operating position in which the subject patient is being supplied with the bolus of gas, e.g. hyperpolarised 3 He;
• the bolus of gas e.g. hyperpolarised 3 He;
• Fig. 5 is a scehmatic view of an alternative applicator, equivalent to that of Fig. 3 but with a passively-actuated non-return valve to -prevent the backflow of air into the outlet of the applicator;
• Fig. 6 is a schematic view of a further applicator in the same operating position as that of Figure 4 ;
• Fig. 7 is a graph showing 3 He concentration in three simulated breaths.
• Fig. 8 is a graph showing 3 He concentration in four simulated breaths .
• Fig. 2 shows with (10) an overview of the equipment modules which are used for the application of 3 He boli.
• the person (101) to be examined lies in the field of the nuclear spin tomograph (102) .
• His respiration air passes via a hose (301) to the applicator (20) , which conveys it onwards to the patient.
• the exhaled air can be recovered via the line (302) .
• the intake air can be provided from a respirator (30) under controlled conditions; this also allows for special oxygen densities to be adjusted in the respiration air.
• special gases In the event of it being intended that special gases should be recovered after respiration, they can be collected, for example, in a bag (303) .
• the special gas boli are inserted into the respiration air by the applicator (20) which is placed within the nuclear spin tomograph, close to the patient's head. The result of this is that, except for unavoidable dead volumes in the respiration hoses, further dead volumes can be avoided.
• the reservoir (201-203) of hyperpolarised 3 He is considered here to be part of the applicator (20) .
• the gas is hyperpolarised externally, and is located in the container (201) , which has been filled at the supplier or manufacturer.
• the container (201) consists, for example, of a glass cell with a valve (202) , and can be connected via a connection flange (203) to the applicator (20) .
• Fig. 3 shows a schematic diagram of the applicator
• all the cross-sections conveying respiration gas are preferably designed with a relatively large cross-section surface area corresponding to the area of a circle of a diameter of, for example 22 mm. This permits a laminar current in flows of up to 560 ml/s.
• the patient Before the application of the desired gas bolus, the patient inhales via the line (301/305) , the valve
• the bellows (231) are located in a housing (230) . With the switchover valve in the switched-over position (relative to the representation of the valve (240) in Fig. 3, displaced to the right) , the bellows are connected to the line (305) . If the applicator (20) is connected to a respirator, then in this case the housing (230) is subjected to the preliminary pressure of the respiration air from the respirator. As a consequence, the bellows (231) are pressed empty, and the gas volume originally filled into it via the line (206) , valve (240) , and line (241) is conducted to the patient.
• the differential pressure sensor (244) is connected via the line (242) to a ventilating aperture (235) in the housing (230) .
• the exhaled air preferably should not flow back into the applicator.
• a respirator When a respirator is being used, it monitors the inhalation and exhalation phase, and allows gas to pass freely via the line (301) accordingly, or opens a valve (not shown) at the end of the line (302) .
• the line (241) and (302) For this operating mode, it is sufficient for the line (241) and (302) to be connected directly to the mouth by means of Y-piece, and for the gas to be applied via a mouthpiece .
• the patient normally sucks air in via the line (301) and (305) , the valve (240) , and the line (241) .
• a passively-actuated valve (245) (Fig. 5) is accordingly used. At exhalation, this blocks the line (241) and clears the line (302) .
• the patient sucks the bellows (231) empty after the valve (240) is switched over. In this case, too, a pressure differential at the differential pressure sensor (244) causes valve (240) to switch back.
• Fig. 5 a passively-actuated valve (245)
• an applicator is shown which is provided with passively activated valves (310) and (311) in the respirator line (301) and the exhalation line (302) .
• This can be done by using a Y-piece in combination with these valves and in this way possible relaxation of hyperpolarised gas by the commercially " available valves such as valve (245) of Fig. 5 may be avoided.
• a flowmeter (304) is inserted into the inspiration branch (lines 301,305).
• the filling of the bellows (231) is effected during the expiration phase either from external gas cylinders via the line (211) or from the 3 He tank (201) , the valve (202) of which has been opened after being flanged on. Gas is filled into the bellows (231) , previously pressed empty, via the computer-controlled valves (212) and (204) respectively.
• the quantity is determined in accordance with the bolus quantity which is to be applied.
• the gas flow is adjusted by means of metering valves (213) and (205) respectively, in such a way that the gas quantity conveyed is filled into the bellows (231) , e.g. in about 0.5 seconds.
• the setting of the metering valve (205) is determined in accordance with the preliminary pressure in the line (211) or in the tank (201) (in relation to atmospheric pressure) , which in the case of nitrogen is usually 4 bar, and in the case of 3 He 2 to 0 bar, depending on how much gas remains in the tank (201) .
• Temporal delays due to valve switching times may be compensated for as the switching times of the valves can be determined in advance from known gas flows, and the valves may be actuated early, by the known delay times. This means, in particular, that the moment of administration of the bolus can be effected with a precision of within 20 ms, which restricts the uncertainty of pre- inhaled gas quantities at an assumed respiration flow of 500 ml/s to less than ⁇ q ⁇ 500 ml/s. 20 ms, ie. less than 10 ml. It should be noted that in all cases the gas from the dead volume in line (241) between the valve (240) and the patient must be pre- inhaled before the bolus which is to be applied reaches the patient. Accordingly, the applicator (20) can to advantage be located directly next to the patient ' s head. The dead volume in the line (241) may then be as little as 60 ml in the embodiment described.
• valves, metering valves, and flowmeters used may, as far as possible, be conventional commercial components.
• the valves (204) and (233) in this embodiment may be hydraulically operated, and adapted to the required dimensions, and may be manufactured from appropriate selected materials.
• the valve (240) is conveniently hydraulically actuated, and advantageously designed in such a way that, during the switchover phase, all the inlets and outlets are connected. This then ensures that the gas flow to the patient will not be interrupted when the valve is switched.
• Fig. 7 shows how sharp and how placeable the boli produced using the applicator may be.
• Three simulated breath intakes, (a) , (b) and (c) , with 3 He bolus placement at different points in the breath intakes were generated and the 3 He content of the gas leaving the outlet (mouthpiece) was measured indirectly by adding carbon dioxide to the respirator air and measuring the C0 2 content of the gas at the mouthpiece using a conventional C0 2 meter.
• the 3 He contents for the three simulated breaths are shown superimposed.
• Fig. 8 shows how the bolus size (duration) may be varied.

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Citations (10)

• 1998
  • 1998-11-13 IL IL13611698A patent/IL136116A0/xx unknown
  • 1998-11-13 CA CA002309996A patent/CA2309996A1/en not_active Abandoned
  • 1998-11-13 HU HU0100529A patent/HUP0100529A2/hu unknown
  • 1998-11-13 AU AU18743/99A patent/AU1874399A/en not_active Abandoned
  • 1998-11-13 WO PCT/EP1998/007516 patent/WO1999025243A1/en not_active Application Discontinuation
  • 1998-11-13 JP JP2000520685A patent/JP2001522681A/ja active Pending
  • 1998-11-13 CN CN98811897.1A patent/CN1281345A/zh active Pending
  • 1998-11-13 BR BR9814968-7A patent/BR9814968A/pt not_active Application Discontinuation
  • 1998-11-13 PL PL98340503A patent/PL340503A1/xx unknown
  • 1998-11-13 EP EP98963495A patent/EP1030594A1/en not_active Withdrawn
• 2000
  • 2000-05-12 NO NO20002478A patent/NO20002478L/no not_active Application Discontinuation

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