JP2001522681A - Fluid administration device - Google Patents

Abstract

(57) The present invention provides a variable volume fluid reservoir, a fluid conduit leading from the reservoir to a fluid outlet, a first fluid inlet, a second fluid inlet, the conduit and the reservoir. A first detector arranged to detect fluid flow between the first inlet and the first inlet through the conduit and into or out of the reservoir. A first valve and, in a first setting, allowing fluid to flow from the second inlet through the conduit to the outlet, and from the reservoir to the outlet through the conduit. A second setting to allow fluid to flow from the reservoir through the conduit to the outlet and to prevent the fluid from flowing from the second inlet to the outlet through the conduit. A second valve for preventing fluid from flowing into said second inlet; A fluid detector comprising a second detector arranged to detect the flow of fluid from the conduit to the conduit and a driver arranged to control the operation of the first and second valves. I do.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention provides a fluid mass (eg, such as solid particles, liquid droplets, vesicles (eg, micelles, liposomes, microbubbles, microballoons, etc.), and the like, which is selectively arranged. The present invention relates to a device suitable for delivering a liquid or gaseous mass (hereinafter referred to as an "applicator"), in particular for the respiration of humans or air-breathing animals (e.g. mammals, reptiles or birds). Suitable for delivering a gas mass to the system, and more particularly, the applicator is suitable for delivering a hyperpolarized gas mass.

In magnetic resonance imaging (MRI), an image of a subject under observation is generated using nuclear magnetic resonance signals from nuclei having non-zero nuclear spins in the subject. Conventional M
In RI, the nuclei involved in the signal ("imaging nuclei") are protons, generally water protons. The strength of the MR signal is proportional to the number difference (polarization) between the various nuclear spin states of the imaging nucleus, while this is governed by the Boltzmann distribution and depends on the magnetic field and temperature. The equilibrium polarization P ₀ for the I = 1/2 contrast nucleus is expressed by the following equation.

[0003]

(Equation 1)

The above equation is

[0005]

(Equation 2)

Is approximated by Here, Nα is the number of nuclei in one spin state α (eg, + ／), Nβ is the number of nuclei in another spin state β (eg, − ／), and Y is the magnetic property of the nuclei. Rotation ratio,

[0007]

[Outside 1]

Is the Planck constant divided by 2π, k is the Boltzmann constant, B ₀ is the magnetic field (or magnetic flux density), T is the Kelvin temperature, and μ is the magnetic core dipole moment.

In recent years, it has been found that the intensity of the MR signal can be increased by polarizing (hyperpolarizing) the contrast nucleus to a polarization value higher than the equilibrium value at the magnetic field strength and the operating temperature of the MR imaging apparatus. Was.

[0010] One way to accomplish hyperpolarization, ³ the He optical pumping (eg a, Schearer et al, Phys Rev. Letters 10:. 108-110 (1963), and Eckert et al., N
ucl. Instr. and Methods A320 : 53-65 (1992)). ³ He is a nuclear spin I is 1/2, can be used as contrast nuclei in MRI (e.g., US-A-5642625, US -A-5612103, US-A-5545396, WO95 / 27438, WO97
/ 37239, Song et al., J. Mag. Res.A 115 : 127-130 (1995) and Middleton et al., Mag.
Res. Med. 33 : 271-275 (1995)).

[0011] In general, ³ in the He MRI, hyperpolarized ³ He mass subject respiratory (e.g., trachea, lung, and alveolar spaces) is delivered to the raw image MR signal is high from ³ He Used to generate Since ³ He, which occurs naturally elsewhere in the body, is negligible, signals from regions of the body other than the respiratory system are negligible.

Helium atoms have different properties, for example, in their ability to diffuse with respect to the oxygen and nitrogen molecules that make up the majority of the air normally breathed by a subject. Therefore, where the distribution of the ³ He mass in the respiratory system is not very different from that of air, it is desirable that the ³ He mass constitute a relatively low proportion of the total respiratory intake.

[0013] Further, if the ³ He mass can be delivered at different stages of respiratory intake, it is possible to generate MR images that emphasize different parts of the respiratory system (eg, alveolar space or trachea).

Further, it would be advantageous to be able to produce and supply an amount of hyperpolarized gas well in excess of that required to produce a single image, and thus use a source of hyperpolarized gas that contains a very large amount of gas. It is desirable to be able to form a gas mass of a reproducible size. A high level of reproducibility with regard to mass size and placement is desired for histological clinical studies and protocols.

Therefore, there is a need for a device that can deliver a desired amount of hyperpolarized ³ He mass at a desired point in time of respiratory ingestion so that the subject can inhale.

According to one aspect, the invention includes a variable volume fluid reservoir, a fluid conduit leading from the reservoir to a fluid outlet, a first fluid inlet, a second fluid inlet, the fluid conduit and the fluid conduit. A first detector arranged to detect fluid flow to and from a reservoir; and allowing or preventing fluid from flowing from the first inlet through the conduit to the reservoir. A first valve, arranged in a first setting, to allow fluid to flow from the second inlet through the conduit to the outlet, and from the reservoir through the conduit. Preventing fluid from flowing to the outlet, and in a second setting, allowing fluid to flow from the reservoir through the conduit to the outlet and from the second inlet through the conduit A second blocking fluid from flowing to said outlet A valve, a second detector arranged to detect fluid flow from the second inlet to the conduit, and a driver arranged to control the operation of the first and second valves. A fluid administration device is provided.

The device “applicator” of the present invention is primarily intended for delivering hyperpolarized gas to the respiratory system of a subject, and is described below in this regard. Deliver a mass of at least one other fluid phase (eg, liquid, solid-in-liquid suspension, gas-in-liquid dispersion, aerosol, gas, gas mixture, powder-in-gas dispersion, etc.), as described above. Also suitable for However, hereinafter, such a "liquid" is simply called a gas, and the flow of the liquid and the liquid inlet are called the flow of the gas and the gas inlet.

The main purpose of the applicator of the present invention is to introduce different gases during inhalation. In this case, mixtures of different types of gases should be avoided as much as possible. FIG. 1 of the accompanying drawings schematically shows the case where two different gases are used. The hose (1) is initially filled with a first type of gas (2), such as air.
This is followed by a second gas type (3) (eg, hyperpolarized ³ He) and then filled with a first type of gas (4). As the contents of the hose are inhaled during breathing, this gas sequence passes through the lungs without mixing. However, it is assumed that mixing does not occur due to turbulent flow or excessively high flow velocity. Thus, depending on the location and amount of gas mass (3) in the hose, it is possible to place a predetermined amount of gas in a specific part of the lung.

[0019] The applicator of the present invention provides, for example, a gas flow through a second outlet (eg, a vent),
Alternatively, a third valve is desirably provided which prevents gas flow from returning to the second valve by directing it to a second reservoir for collecting ³ He for reuse.

The third valve is preferably arranged to prevent such reversion when the subject exhales, is controlled by a driver or the gas flow is reversed at the outlet A passive valve that sometimes operates automatically may be used. Alternatively, the second valve prevents gas flow from the outlet from passing to the first storage or the second inlet,
Alternatively, it may have a third setting to direct the gas flow to the second outlet or the second reservoir. In this arrangement, a third valve is not required.

The first reservoir may be any variable volume reservoir, for example, a cylinder with a movable piston (ie, as in a syringe), a flexible pouch, a bellows, or the like. But,
In a particularly advantageous embodiment, the first reservoir is an extensible container (eg, a plastic, preferably a helium blocking membrane) disposed within a rigid container with a vent to which the first detector is mounted. Or a foldable bellows made of plastic coated with such a membrane. Gas flows into and out of the extensible container cause corresponding gas flows through the vents to indirectly detect and measure gas flows in and out of the extensible container. It becomes possible to do.

In a particularly preferred embodiment of the applicator, the gas flow to the second inlet is from a respirator. In this embodiment, when the second valve is in the second setting, the flow of gas from the respirator is altered to provide pressure outside the variable volume storage, and the flow of gas from the storage to the subject. Is preferably at the same pressure as the gas flow before / after from the respirator to the subject. The applicator reaches the minimum capacity of the variable capacity storage,
A detector (eg, a pressure difference detector) that detects when the second valve can return to the first setting
It is also preferred to have

Under certain circumstances, it may be desirable to administer different fluids (gases) from the variable volume reservoir separately or mixed together. In this case, the conduit contains another (third)
3.) An inlet and another (fourth) valve should be provided and arranged to prevent or allow gas to flow from the third inlet through the conduit to the variable volume reservoir. Thus, the operation of the applicator for dispensing another fluid through the variable volume reservoir may be equivalent to the operation for dispensing the fluid from the first inlet, and the driver may include a fourth valve. Is preferably arranged so that it can also be controlled.

The operation of the driver of the applicator of the present invention is controlled in response to signals from the detector and operator-set inputs (eg, desired mass size and placement).
For example, it is preferably controlled by a computer.

Thus, in one embodiment, the present invention is an apparatus for accurately providing a gaseous substance carried in a gas to the lungs and respiratory system, comprising the following elements:

A first inlet (203) for introducing a first gaseous substance, in particular a gas containing polarized atoms (nuclei).

A metering device (230, 231) connected to the first inlet (203) for measuring the dose of the first gaseous substance.

A second inlet (30) for introducing a second gaseous substance, in particular air or an oxygen-containing gas.
1, 305).

A measuring device (304) for measuring the amount of the second gas substance introduced through the second inlet (301, 305).

Outlets (241, 243) for the first and second gaseous substances.

On the one hand, it is connected to the metering device (230, 231) and the second inlet (301, 305) and on the other hand to the outlet (241, 243), and in the first valve setting, the outlet (
241 and 243) to a second inlet (301, 305) and a switching valve for selectively connecting an outlet (241 and 243) to a metering device (230 and 231) in a second valve setting. (240).

Here, the weighing device (230, 231) comprises an extensible container (231) connected to the first inlet (203) and arranged in the housing (230). The housing (230) is provided with at least one vent (235, 236) to which another measuring device is connected. Thereby, it flows out of the housing (230) when the container (231) is extended, and / or
Alternatively, the gas flowing into the housing (230) when the container (231) contracts is measured.

A control unit (220) connected to the two measuring devices (304, 232, 244) and the switching valve (240). The control unit (200) measures the inflow of the first gaseous substance into the extensible container (231) of the metering device (230, 231), which is measured by another measuring device (232, 244). 230, 231) based on the amount of gas discharged from the housing (230), and based on the amount of the second gaseous substance measured by the first measuring device (304), or when a specific period of time After completion, the switching valve (240) is switched from the first valve setting to the second valve setting and the metering device (230,2,2) is measured by another measuring device (232,244).
The switching valve (240) is switched from the second valve setting to the first valve setting based on the amount of gas flowing into the housing (230) of 31).

The valves, conduits, etc. of the applicator are such that, after the second valve, a linear gas flow predominates, ie, to diffuse lumps and avoid turbulence mixing different gas types. Preferably it is constructed.

The applicator is desirably designed to allow for varying chunk volumes and to place the chunks in the desired portion of the overall respiratory intake. Further, the applicator is preferably designed to allow a single supply or a series of supplies that can vary, for example, the volume of the mass, the placement of the mass, the amount of respiration, and the like. In addition, it allows for the administration of a single gas or a mass of a gas mixture (eg, a mixture of a hyperpolarized gas such as ³ He and a gas that does not shorten the relaxation time of the hyperpolarized gas (eg, a gas such as nitrogen)). It is desirable to design the applicator to do so. In such cases, generally,
A non-relaxed gas (eg, N ₂ ) is first filled in the variable volume reservoir and immediately thereafter mixed with a selected amount of hyperpolarized ³ He. Then, a long mass of diluted ³ He can be administered, for example, to study gas flow.

[0036] Desirably, the applicator is operated, ie, a gas sequence is generated through the outlet, such that the subject's breathing is significantly interfered with or is appreciably obstructed. Not be.

In addition, the gas used (eg, ³ He) is expensive, so the applicator is preferably designed to recover it.

From a clinical point of view, the three types of respiration can be distinguished as follows:

(1) Free (unhindered) spontaneous breathing by individual effort.

(2) Spontaneous breathing with respiratory assistance.

(3) Respiratory controlled breathing.

The respirator may control respiration by pressure control or flow control. That is, in the breathing mode (3), the pressure or the flow of gas is controlled during inspiration. In spontaneous breathing, the amount of air inhaled varies with time, whereas in respiratory controlled volume breathing, the same respiratory gas volume is always introduced. The invention described herein is applicable to all these forms of respiration.

In the embodiment of the present invention for the introduction of hyperpolarized helium-3 gas ( ³ He), for example, ³ He MRI, some additional features are desired. These features will be described after briefly discussed the special feature of ³ the He MRI.

The nucleus of the ³ He atom carries the quantum number spin I = １ ／, associated with the magnetic moment μ. These moments orient themselves parallel or non-parallel to the lines of force in the presence of an external magnetic field. However, the number of atoms having a magnetic moment parallel to the magnetic field is imbalanced with the number of atoms having a magnetic moment non-parallel to the magnetic field. This is explained by the polarization equation above. Here, B ₀ is the magnetic field strength (more precisely, the magnetic flux density), k = 1.38 × 10 ⁻²³ J / K, the Boltzmann constant, and T is the Kelvin temperature. ^{In 3} He, the magnetic core dipole moment μ = 1. Since it is 075 × 10 ⁻²⁶ Am ² , the polarization P = 3.8 × 10 ⁻⁶ for a typical magnetic field in an MRI apparatus with B ₀ = 1.5 Tesla and T = 310 K. At gas density under normal conditions, ie, p = 2.33 × 10 ¹⁹ atoms / cm ³ (at 310 K and a gas pressure of 1.013 bar), this polarization is determined by MRI in the air space. Not enough to get an image of the gas distribution. The MR resonance signal is too weak.

However, the ³ He polarization is pulled up to a value close to 1 at ambient temperature and at low magnetic fields on the order of mT (ie, well above Boltzmann equilibrium polarization). This process is known as "optical pumping" and its technical realization and physical principles are described in Colegrove et al., Phys. Rev. 132 : 2561-2572 (1963), Wal
ters et al., Phys. Rev. Lett. 8 : 439-442 (1962); Schearer et al., Phys. Rev. Lett.
10: 108-110 (1963), Eckert et al., Nucl Instr & Meth A320:. .. 53-65 (1992),
Becker et al., Nucl. Instr. & Meth. A346 : 45-51 (1994), Heil et al., Phys. Lett. A 201 : 337-343 (1995), Becker et al., Journal of Neutron Research 5 : 1-10 (1996).
), And Surkau et al., Nucl. Instr. & Meth. A384 : 444-450 (1997). At B ₀ = 1.5 Tesla, a density p × P of polarized spins that is one to two orders of magnitude higher than the density of polarized protons in biological water or adipose tissue at Boltzmann equilibrium is obtained. (Typically, polarized protons act as a signal source in MRI, ie, in ¹ H-MRI).

In nuclear magnetic resonance, the magnetic moment is excited perpendicular to B ₀ , so that a magnetic resonance signal is induced in the appropriate receiving coil. This occurs at the expense of polarization. Polarization is partially or totally destroyed by how strongly the magnetic moment is deflected from the direction of the magnetic field during nuclear resonance excitation. ^The Boltzmann polarization used in ¹ H-MRI returns to its original state with a characteristic relaxation time T ₁ of 0.3 to 3 seconds, whereas the ³ He hyperpolarization has a characteristic relaxation of 10 to 30 seconds. At time T ₁ , it decays from a high initial value in the lungs to a much smaller Boltzmann equilibrium value.

A high magnetic field (B₀= 1.5 Tesla)^ThreeIn He MRI, RF excitation (nuclear resonance excitation) is repeated according to the matrix size required for the image. But the lungs
In the image,^ThreeHe gas filling is performed only once. Therefore, each^ThreeHe nuclear resonance excitation
The magnetic moment at each excitation is the cos (α) of the original polarization for the next RF excitation after each excitation.
) (Α = 2 °, cos (α) = 99.9%), for example, to save 2 °
B only for angle α₀Slightly deflected from the axis. (Ie, a spin echo sequence having a low flip angle, eg, a RARE sequence, or a FLASH sequence).
A gradient echo sequence such as an impedance is used. This was obtained externally ^Three It emphasizes that the hyperpolarization of He gas needs to be maintained during delivery.

In addition to nuclear spin excitation, there is a series of actions that can destroy the hyperpolarization of ³ He gas. The most important of these are relaxation by magnetic field gradients, relaxation on gas container walls, and mixing of oxygen (O ₂ ). Of about _{^{10 -7 / cm (dB z /}} dz)
The relative longitudinal gradient of the magnetic field of conventional commercial tomography at / B ₀ is very small. Since the lateral gradient (dB _r / dr) / B ₀ is of similar magnitude, for a gas pressure of 1 bar, the T ₁ value is

[0049]

(Equation 3)

Which is about 10 ⁻⁹ h ⁻¹ .

In other words, such a gradient can be measured by a measurable T₁Does not cause relaxation. (DB_r/ Dr) / B₀Is about 1.67 × 10^-Four/ Cm, acceptable for imaging
Only 1 / T at p = 1 bar, even at maximum gradient fields₁= 5 × 10^-Four/ H is only reached, which is negligible. However, the magnet opening of the MRI system
In the section, (dB_r/ Dr) / B₀= About 10^-1/ Cm, which is due to T ₁ = Corresponds to a relaxation time of about 21 seconds. Therefore, hyperpolarization^ThreeHe gas has residual polarization P (
P = P₀exp (−Δt / T₁), Where P₀Is the initial polarization), for example, keep it above 0.95 (95%) and keep it as high as possible
For example, it must be quickly conveyed through this area within a time Δt of less than one second.
Must.

Ferromagnetic materials distort a uniform magnetic field and obtain much stronger gradients. Therefore, ferromagnetic materials are preferably avoided as a material for constructing the applicator. For example, non-ferromagnetic materials such as plastic, titanium, or glass are basically suitable because they do not distort the magnetic field. However, non-ferromagnetic materials have different wall relaxation properties when used as gas container materials. In order to maintain ³ He polarization over a long period of time, a special glass container with a relaxation time T ₁ in the range of several hours to several days is preferred (see Heil et al., Supra). The valve in contact with the hyperpolarized gas is preferably formed of titanium (see Becker et al., (1994), supra). Plastics may be used, but are only appropriate to a limited extent. ³ He can penetrate the porous structure and become depolarized therein. A typical relaxation time is
Minute range. However, in nuclear spin tomography itself, all moving parts are usually made of plastic. This is because moving metal parts have been shown to interfere with nuclear resonance tomography.

In addition, paramagnetic impurities, including oxygen gas, are preferably removed from at least a portion of the applicator between the reservoir and the second valve. Oxygen provides a strong relaxation effect, at 299k,

[0054]

(Equation 4)

Is as follows. Here, [O ₂ ] is the oxygen density in amager units in ³ He gas (
Saam et al., Phys. Rev. A 52 : 862-865 (1995)). As a result, relatively thick walls, such as conduits, are desirable so that oxygen is removed, for example, by flowing nitrogen gas. When installing a new ³ He source to the applicator, a small amount (e.g., about 20 mL) washed away ³ He inlet at the ³ He (in FIG. 2 (203)), it is also desirable to remove the air.

When the applicator is used with a living subject, hygiene considerations must also be considered. Preferably, the portion that comes into contact with the patient's breathing gas under examination is disposable or sterilizable or sterilizable. Therefore, it is desirable that the materials used for such "contact" components be stable in shape at temperatures up to 120C.

Preferably, all of the components of the applicator are made of a non-magnetic material, especially a non-metallic material, more preferably a material that is not electrically conductive (eg, plastic). The movable part is preferably made of plastic.

The measuring device, which determines the amount of gas flowing into or out of the housing of the metering device during contraction and extension, respectively, consists of a flow meter connected to the housing vent and the interior of the housing and the outlet of the applicator. And a pressure gauge connected to the vent of the housing for measuring the pressure difference between The switching valve (second valve) can then be switched in response to the measurement.

By appropriate selection of the materials, the applicator of the invention can be placed in a nuclear spin tomograph. (The appropriate choice of material in this regard has already been described above).

For hyperpolarized gas dosing, it is desirable to minimize the dead space in the device, especially the space between the first inlet and the variable volume reservoir and between the reservoir and the outlet. This can help reduce unnecessary loss of polarization due to time delays or wall contact.

In addition to hyperpolarized ³ He, the applicator also contains other hyperpolarized gases, for example ¹²⁹ Xe and other hyperpolarized I = １ ／ nuclei (eg, ¹³ C, ¹⁵ N or ²⁹ Si). It may be used together with a compound.

According to another aspect, the invention relates to a fluid (preferably a gas, in particular a hyperpolarised gas) M
A magnetic resonance imaging method, wherein an R contrast agent is administered to a subject in a lump, and an MR image (preferably, an aprotic MR image) of at least a part of the subject in which the MR contrast agent is distributed is generated. Is administered using a device according to the invention, wherein said fluid is preferably administered to a subject's respiratory system.

Imaging according to the method of the present invention may be performed conventionally.

The administration of the bolus is 2-100% of the respiratory intake, more preferably 5-30%
And may be performed at any stage of respiratory intake. If the administered gas is hyperpolarised, it is preferably polarized to a P value of at least 5%, preferably at least 10%.

The documents referred to herein are incorporated by reference.

[0066] Embodiments of the present invention will now be further described with reference to the accompanying drawings.

FIG. 2 shows, by reference numeral (10), an overview of the device module used to supply the ³ He mass. The human (101) under examination is a nuclear spin tomograph (102).
A) lying in the magnetic field. Breathing air passes through the applicator (20) through the hose (301), which carries the air to the patient.
The exhaled air can be recovered through line (302).

When breathing is controlled, inspired air may be provided from the respirator (30) under controlled conditions. This also allows for special oxygen density adjustments in the breathing air. If the special gas is intended to be collected after breathing, the special gas may be collected, for example, in a bag (303).

The special gas mass is applied to an application placed in a nuclear spin tomograph near the patient's head.
Data (20) into the breathing air. As a result, avoid in the breathing hose
Except for the ineffective amount that cannot be changed, occurrence of an ineffective amount can be avoided. Hyperpolarization ^Three The He reservoirs (201-203) are considered herein as part of the applicator (20). The gas is externally hyperpolarized and placed in a container (201).
It is. Containers are filled under the supplier or manufacturer. Container (2
01) is, for example, a glass cell with a valve (202), and has a connection flange (2).
03) to the applicator (20).^ThreeThe He container (201) itself allows for very long relaxation times,^ThreeAll other surfaces in contact with He must be small. When a certain amount of gas passes, the corresponding body
Since the residence time in the product is shorter, the subsequent polarization loss is smaller. This is
This is why it is desirable to place the predicator in a nuclear spin tomograph. this
In contrast, a cleaning gas such as nitrogen is, for example, an externally located cylinder (21
0) through line (211). The applicator (20) itself
Via electrical, pneumatic and hydraulic instruments and control lines (221).
It is controlled by a computer (220) connected to the replicator (20).

FIG. 3 shows a schematic view of the applicator (20). Components within the area defined by the dashed line are located in the magnetic field of the tomograph. These materials and dimensions preferably fulfill the requirements described above. In particular, all the cross sections carrying the respiratory gas are preferably designed with a relatively large cross-sectional area, for example corresponding to the area of a circle with a diameter of 22 mm. This allows laminar flow up to 560 ml / sec.

Prior to providing the desired mass of gas, the patient is placed in line (301/305), valve (240)
, And exhale through line (241) and exhale through line (302). When administering the mass, when gas (2) (FIG. 1) is introduced into line (241), the normal gas flow from lines (301) and (305) is obstructed by valve (240). Instead, a certain amount of gas is delivered from the bellows (231) to the patient (see FIG. 4). Bellows (231) is located within housing (230). The bellows is connected to the line (305) using a switching valve in a switching position (the valve (240) shown in FIG. 3 has been replaced on the right). A housing (230) when the applicator (20) is connected to a respirator;
Is pre-pressurized with breathing air from the respirator. As a result, the bellows (2
31) is depressed and emptied, and the gas originally filling the bellows through line (206), valve (240) and line (241) is led to the patient. When the bellows (231) is empty (detected by an increase in pressure at the pressure difference sensor (244)), the valve (240) is reset and normal respiratory flow to the patient continues (see FIG. 3). ). The pressure difference sensor (244) is connected to a vent (235) in the housing (230) via a line (242).

If hyperpolarized gas is being administered, the exhaled air should preferably not return to the applicator. When the respirator is in use, the respirator monitors inspiration and expiration conditions and allows gas to pass freely through line (301), or a valve (not shown) at the end of line (302). ). In this mode of operation, lines (241) and (302) are connected directly to the mouth by a Y-piece and gas is supplied by a mouthpiece.

When the applicator (20) is used without a respirator, the patient will typically
Lines (301) and (305), valve (240), and line (241)
Inhale air through. A passively actuated valve (245) (FIG. 5) is used to prevent air from returning to the applicator (20). When exhaling, valve (245) closes line (241) and opens line (302). In this mode of operation, the patient inhales and empties the bellows (231) after the valve (240) is switched. Also in this case, the valve (240) is switched to the original state by the pressure difference in the pressure difference sensor (244).

FIG. 6 shows that the passively actuated valves (310) and (311) are
1) shows the applicator provided in the exhalation line (302). This can be accomplished by using a Y-piece in combination with these valves, thus avoiding the relaxation of hyperpolarized gas that can be caused by commercially available valves such as valve (245) in FIG. .

To monitor the patient's respiratory process, a flow meter (304) has been inserted into the inspiration branch (lines 301, 305). Bellows (231) is in the expiratory state, are filled from the through line (211) from an external gas cylinder, or ³ He tank (201) (the valve (202) is opened after being attached to the flange) You. The gas is filled into the bellows (231) previously emptied by pressing, respectively, by means of the computer-controlled valves (212) and (204).
The filling amount is determined according to the amount of the supplied mass. In this case, the gas flow is regulated by metering valves (213) and (205), respectively, such that the amount of gas carried is filled in bellows (231) within, for example, about 0.5 seconds. Measuring valve (
The setting of 205) is determined according to the pre-pressure (related to atmospheric pressure) in line (211) or tank (201). This preliminary pressure is applied to the tank (201)
Is usually 4 bar for nitrogen and 2 to 0 bar for ³ He, depending on how much gas remains in the reactor.

When filling the reservoir (231), air is removed from the housing (230),
It is discharged through a flow meter (232) connected to a vent (236), a valve (233), and a line (234) which is open in this state. The data measured by the flow meter is recorded when the bellows (231) is filled, and is temporarily accumulated. The amount of exhaust air determined in this way corresponds to the amount of gas charged into the bellows (231). Therefore, the latter amount is determined indirectly, and is advantageous in handling polarized gas, especially from the viewpoint of relaxation sensitivity when it comes into contact with a specific material. Based on this measured quantity, for a fill time of 0.5 seconds, the gas volume can be reproducibly filled with a relative error of less than 5%.

Since the switching time of the valve can be predetermined from the known gas flow, the temporary delay due to the valve switching time is compensated for and the valve can operate earlier by the known delay time. This means, in particular, that the dosing of the bolus takes place within an accuracy of less than 20 milliseconds, whereby assuming a respiratory flow of 500 ml / sec, the uncertain gas volume inhaled beforehand is Δq <500 ml / Limited to less than a second. In 20 milliseconds, ie less than 10 ml. Note that in all cases, gas from the dead volume in the line (241) between the valve (240) and the patient must be inhaled before the mass to be delivered reaches the patient. Accordingly, the applicator (20) is advantageously located right next to the patient's head. line(
The dead volume in 241) can be as much as 60 ml in the embodiments described herein.

As far as possible, the valves, metering valves and flow meters used may be any conventionally available components. The valves (204) and (233) in this embodiment operate hydraulically, are designed with the required dimensions, and can be manufactured from appropriately selected materials. The valve (240) is conveniently designed to operate hydraulically and in the switched state, all inlets and outlets are connected. Thus, the flow of gas to the patient is not obstructed when the valve is switched.

[0079] The polarization loss of ³ He as transferred through the applicator was tested and measured. The relaxation effect of the relevant components of the applicator was measured by the NMR method. Bellows formed with a He blocking membrane showed a relaxation time of 20 to 40 minutes after thorough flushing of all oxygen residues with pure nitrogen gas. Since only a single breath of gas is stored in the bellows for at most a few seconds before delivery, the polarization loss is less than 1%. Since the position-dependent relaxation time measured in the valve (240) varies between 10 and 20 seconds, more than 90% of the ³ He polarization is retained when flowing within 1 second. become. No significant polarization loss occurs when filling the bellows and flowing through other lines. Overall, more than 90% of the original polarization reaches the patient.

FIG. 7 shows how steeply and how the mass produced with the applicator can be arranged. Create three simulated breath intakes (a), (b) and (c) where the ³ He mass is located at different points in the breath intake, add carbon dioxide to the respiratory air, and use a conventional CO ₂ meter. It was indirectly measured ³ He content of the gas discharged from the outlet (mouthpiece) by measuring the CO ₂ content of the gas in the mouthpiece with. The ³ He content of the ^three simulated breaths is shown overlaid.

FIG. 8 shows how the chunk size (duration) changes. Four simulated respiratory intakes (d), (e), (f), and (f), in which the mass of ^{3 He} increases in order
g) Create and a ³ He content was determined in the same manner as in FIG. 7. As shown in FIG. 7, the results are shown in an overlapping manner.

[Brief description of the drawings]

FIG. 1 schematically shows a gas mass located between two other gas flows in a hose.

FIG. 2 is a schematic diagram of an applicator according to the present invention.

FIG. 3 is a schematic diagram of the applicator of FIG. 2 in an operative position in which air is being provided to a subject patient.

FIG. 4 is a schematic diagram of the applicator of FIG. 2 in an operating position where the patient of the subject is being supplied with a gas mass, eg, hyperpolarized ³ He

FIG. 5 is a schematic view of another applicator corresponding to the applicator of FIG. 3 with a passively actuated check valve to prevent air from returning to the outlet of the applicator.

FIG. 6 is a schematic diagram of another applicator in the same operating position as FIG. 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.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] December 14, 1999 (Dec. 14, 1999)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Name of invention

[Correction method] Change

[Correction contents]

[Title of the Invention] Applicator

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] Claim 1

[Correction method] Change

[Correction contents]

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] Claim 11

[Correction method] Change

[Correction contents]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Correction contents]

[0001] The present invention provides a fluid mass (eg, such as solid particles, liquid droplets, vesicles (eg, micelles, liposomes, microbubbles, microballoons, etc.), and the like, which is selectively arranged. The present invention relates to a device suitable for delivering a liquid or gaseous mass (hereinafter referred to as an "applicator"), in particular for the respiration of humans or air-breathing animals (e.g. mammals, reptiles or birds). US-A-4932401 (Perkins) is suitable for delivering a gas mass to a system and more particularly for delivering a hyperpolarized gas mass. the mixture discloses substituted measuring apparatus order to be administered to a patient with.

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0016

[Correction method] Change

[Correction contents]

According to one aspect, the invention includes a variable fluid reservoir, a fluid conduit leading from the reservoir to a fluid outlet, a first fluid inlet, a second fluid inlet, the conduit and the fluid conduit. A first detector arranged to detect fluid flow to and from a reservoir; and allowing or preventing fluid from flowing from the first inlet through the conduit to the reservoir. a first valve arranged to the second valve, and a arranged driver to control the operation of the first and second valve, the second valve is in the first set , while enabling the said second inlet fluid to flow to said outlet through said conduit, to prevent from the reservoir of fluid flows to the outlet through said conduit, second set of So yes from the reservoir fluid from Ru flows to the outlet through the conduit As well as the ability, through the conduit from the second inlet to prevent the fluid material from flowing into the outlet, so that the second detector detects the flow of fluid to the conduit from the second inlet A fluid administration device is provided, wherein the fluid administration device is disposed .

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW -Strasse 28 (72) Inventor Heil, Werner France, F 38760 Walce-Arière Elysées, La Girodiere (72) Inventor Kaukzer, Hans-Urich Germany, Day 65191 Wiesbaden, Kirchbachstrasse 24 (72) Inventor Lauer, Lars Germany, Day 55129 Mainz, Doctor. -Karl-Schram-Strasse 2 (72) Inventor Mark Staller, Claus Germany, Day 55218 Ingelheim, Hochstrasse 4 (72) Inventor Otten, Ernst Germany, Day 55127 Mainz, Karl-Orf-Strasse 47 (72) Invention Sukau, Rhinehard Germany, Day 55128 Mainz, Willi-Wolf-Strasse 22

Claims (14)

[Claims] 1. A variable volume fluid reservoir, a fluid conduit leading from the reservoir to a fluid outlet, a first fluid inlet, a second fluid inlet, and a fluid conduit between the conduit and the reservoir. A first detector arranged to detect flow, and a first valve arranged to allow or block fluid flow from the first inlet through the conduit to the reservoir. And, in a first setting, allowing fluid to flow from said second inlet through said conduit to said outlet and fluid flowing from said reservoir through said conduit to said outlet. And in a second setting, allowing fluid to flow from said reservoir through said conduit to said outlet and fluid flowing from said second inlet through said conduit to said outlet A second valve for preventing
A fluid comprising: a second detector arranged to detect a flow of fluid from the second inlet to the conduit; and a driver arranged to control the operation of the first and second valves. Dosing device. 2. The storage device according to claim 1, wherein the storage unit is a flexible container disposed in a rigid container having a vent, and the first detector is arranged to detect a flow of a fluid through the vent. The device according to claim 1. 3. Directing fluid flow from the outlet through the conduit to a second outlet or second reservoir, and acts to prevent the fluid flow from reaching the variable volume reservoir. Apparatus according to any one of claims 1 and 2, further comprising a valve. 4. The apparatus according to claim 1, further comprising a hyperpolarized gas source attached to the first inlet. 5. The apparatus of claim 1, further comprising a respirator attached to the second inlet.
The device according to any one of claims 1 to 4. 6. The apparatus further comprising a third inlet, and a third valve arranged to allow or block fluid flow from the third inlet to the variable volume reservoir, wherein the driver is Apparatus according to any of the preceding claims, further arranged to control the operation of the third valve. 7. The inner surface of the variable volume reservoir and all surfaces accessible to fluid entering the conduit through the first inlet and exiting the conduit through the outlet are non-magnetic materials. 7. The device according to claim 1, wherein the device is formed. 8. The apparatus of claim 7, wherein said non-magnetic material is selected from glass, titanium, and plastic. 9. The conduit of claim 1, wherein the conduit between the second valve and the outlet is configured such that fluid flow through the conduit is substantially laminar. The device according to item. 10. The device according to claim 1, wherein the device is made of a non-magnetic material. 11. A first gas substance, in particular a first inlet (203) for introducing a gas containing polarized primitives (nuclei), and said first gas substance connected to said first inlet (203). A metering device (230, 231) for measuring and administering an amount to be supplied, a second inlet (301, 305) for introducing a second gaseous substance, and the second inlet (301, 305). A measuring device (304) for measuring the amount of said second gaseous substance introduced therethrough; outlets (241, 243) for said first and second gaseous substances; (230, 231) and the second entrance (301, 305)
) And on the other hand connected to the outlets (241, 243), selectively connecting the outlets (241, 243) to the second inlets (301, 305) in a first valve setting, and in the second valve setting A switching valve (240) for selectively connecting the outlets (241, 243) to the metering devices (230, 231); and a housing connected to the first inlet (203) for extending the container (231). At least one other measuring device (232, 244) for measuring gas flowing out of (230) and / or into the housing (230) when the container (231) contracts. Vent holes (235, 23
The expandable container (23) located in the housing (230) with the
1) a weighing device (230, 231), the two measuring devices (304, 232, 244) and the switching valve (24)
0), wherein the flow rate of the first gaseous substance into the extensible container (231) of the metering device (230, 231) is measured by the other measuring device (232, 244). Controlling based on the amount of gas discharged from the housing (230) of the metering device (230, 231), based on the amount of the second gas substance measured by the first measuring device (304), or After a certain period of time, the switching valve (240) is switched from the first valve setting to the second valve setting, and the metering device (23) measured by the other measuring device (232, 244)
A control unit (220) for switching the switching valve (240) from the second valve setting to the first valve setting based on the amount of gas flowing into the housing (230) of the (230). Item 11. The apparatus according to any one of items 1 to 10. 12. The apparatus according to claim 1, further comprising computer control means. 13. The method according to claim 1, wherein the fluid MR contrast agent is administered in a lump to the subject, and an MR image of at least a part of the subject in which the contrast agent is distributed is generated. A magnetic resonance imaging method, wherein the magnetic resonance imaging method is administered using the device described in the section. 14. The method of claim 13, wherein said MR imaging is a ³ He-NMR imaging.