HK1117732A - Methods and systems for operating an aerosol generator - Google Patents
Methods and systems for operating an aerosol generator Download PDFInfo
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- HK1117732A HK1117732A HK08107753.4A HK08107753A HK1117732A HK 1117732 A HK1117732 A HK 1117732A HK 08107753 A HK08107753 A HK 08107753A HK 1117732 A HK1117732 A HK 1117732A
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Description
Technical Field
The present invention relates generally to systems and methods for delivering aerosolized medicaments. More particularly, embodiments of the present invention relate to the connection of an aerosol generator to a ventilator circuit, allowing aerosolized medicament to be inhaled directly by a patient.
Background
Aerosolized medicaments are used to treat patients suffering from various respiratory diseases. The medicament can be delivered directly to the lungs by having the patient inhale the aerosol through a tube and/or mask connected to an aerosol generator. By inhaling the aerosolized medicament, the patient can quickly receive a dose of the medicament that is concentrated at the treatment site (e.g., the patient's small bronchial passages and lungs). Generally, this is a more effective and efficient method of treating respiratory diseases than the first administration (e.g., intravenous injection) through the circulatory system of the patient. However, delivery of aerosolized medicaments still presents a number of problems.
A patient who is unable to breathe properly without the aid of a ventilator may only be able to receive aerosolized medicament through the ventilator circuit. The aerosol generator should therefore be suitable for delivering aerosol through a respirator. Unfortunately, the drug delivery efficiency of nebulizer-ventilator system combinations is rather low, often dropping below 20%. The ventilator circuit typically forces the aerosol to move through a series of valves, conduits, and filters before reaching the mouth and nose of the patient, and all surfaces and obstructions provide many opportunities for the aerosol particles to condense back into the liquid phase.
One problem is that conventional aerosolization techniques are not well suited for incorporation into a ventilator circuit. Conventional nozzles and ultrasonic nebulizers typically require 50 to 100 milliseconds to direct the aerosolized medicament into the circuit. These devices also tend to produce aerosols with large average droplet sizes and poor aerodynamic characteristics, which make the droplets more likely to form condensation on the walls and surfaces of the circuit.
The delivery efficiency is also affected when delivering aerosol when the patient exhales into the ventilator, a common nebulizer delivers a constant flow of aerosol into the ventilator circuit, and aerosol may be delayed or even escape from the circuit when the patient is not inhaling. The delayed aerosol is more likely to condense within the system and eventually be forced out of the circuit without any benefit to the patient.
The inability of a significant amount of aerosolized medicament to reach the patient is problematic for several reasons. First, the dose of medicament actually inhaled by the patient may be quite inaccurate, as the amount of medicament actually received by the patient into the patient's respiratory system may vary with fluctuations in the patient's breathing pattern. Second, a large amount of aerosolized medicament may eventually be wasted, and some medicaments are quite expensive, thus increasing the cost of healthcare.
Some unused agents may also escape into the ambient atmosphere. This can ultimately allow passive administration to people in the vicinity of the patient, exposing them to the risk of adverse health effects. In a hospital setting, these people may be healthcare providers who may have prolonged exposure to such air pollution, or other patients who may be debilitating or susceptible to exposure to non-prescribed or overdosed medications.
For these reasons, it is desirable to increase the delivery efficiency of nebulizer-ventilator systems. Embodiments of the present invention address these and other problems associated with conventional systems and methods for treating a patient with an aerosolized medicament.
Disclosure of Invention
The present invention provides devices and methods for increasing the level of safety to a patient and for improving the efficiency of aerosol delivery to a patient.
Embodiments of the invention include methods of treating a patient with a pulmonary disease. The method includes intermittently delivering a dose of aerosolized medicament to a ventilator circuit coupled to a respiratory system of a patient.
Embodiments of the present invention also include methods of treating a patient with a pulmonary disease by administering to the patient a nebulized aerosol comprising from 100 μ g to about 500mg of a medicament through a ventilator circuit. The efficiency of the method is such that at least 40% of the aerosolized aerosol is delivered to the patient.
Embodiments of the present invention also include methods of disconnecting a patient from a ventilator and administering a nebulized aerosol comprising from about 100 μ g to about 500mg of a medicament to the patient to treat a patient with a pulmonary disease.
Embodiments of the invention additionally include methods of administering to a patient a medicament comprising an antibiotic dissolved in an aqueous sodium chloride solution adjusted to a pH between 5.5 and 6.3 to treat a patient with a pulmonary disease. The medicament is administered by nebulization using a vibratable member with an aperture, the vibratable member being configured to produce 70% or more aerosol particles with a mass mean aerodynamic diameter from about 1 μm to about 7 μm.
Embodiments of the invention additionally include a method of treating a patient having a pulmonary disease by administering to the patient an aerosolized medicament and intravenously administering to the patient a second medicament that is also used to treat the pulmonary disease.
Embodiments of the invention additionally include aerosolized medicaments for treating pulmonary diseases. The medicament comprises amikacin mixed with an aqueous solution adjusted to a pH of from about 5.5 to about 6.3. The pH was adjusted by adding hydrochloric acid and sodium hydroxide to the aqueous solution.
Embodiments of the invention also include methods of atomizing liquids. The method includes taking one or more breaths and measuring a breath characteristic. Another breath is taken and an aerosol generator is operated according to the measured characteristics of the breath or breaths.
Another embodiment of the invention includes a method of providing a nebulizer system comprising a housing, an aerosol generator, a controller connected to the aerosol generator, and a reservoir in communication with the aerosol generator.
In other embodiments of the present invention, a nebulizer system is provided that includes a housing defining a channel adapted to deliver aerosolized liquid to a user. The aerosol generator is positioned to provide an aerosolized liquid entry path. A controller having a memory and a set of aerosol generator operating programs that control operation of the aerosol generator is connected to the aerosol generator.
In other embodiments of the present invention, an aerosolization component is provided that is positioned to provide aerosolized fluid into a ventilator circuit to provide the aerosolized fluid to a patient receiving air from a ventilator. It should be understood that the aerosolization component is also referred to herein as an aerosolization component, and the ventilator (ventilator) is also referred to herein as a ventilator (respirator).
Embodiments of the present invention also provide an operational sequence in which the aerosol is provided at a predetermined point within the respiratory cycle provided by the ventilator. In one aspect, the present invention provides an operating sequence in which aerosol generation begins at a predetermined point during an inhalation phase, which may also be referred to herein as an inhalation phase, and stops at a second predetermined point during the same inhalation phase. In another aspect, the present invention provides an operating sequence, which may also be referred to herein as an operating program, in which aerosol generation begins at a predetermined point during the inhalation phase and stops at a point after the inhalation phase has ended, i.e., at a point during the exhalation phase. It will be appreciated that the exhalation phase may also be referred to as the exhalation phase and may include the entire period during which the inhalation phase is not being performed, in other words, the exhalation phase may include not only the actual exhalation of the patient, but also any pauses that may occur before or after exhalation. In another aspect, the invention provides an operating sequence in which aerosolization begins at a predetermined point during an exhalation phase and stops during the exhalation phase, or alternatively, begins at a predetermined point during an exhalation phase and stops at a predetermined point during a subsequent inhalation phase.
Embodiments of the present invention also provide for the selection of a particular order of operations from within a set of available orders of operations. Similarly, the present invention provides modes of operation, which may include one or more sequences of operations.
The present invention also provides algorithms to set up an operational sequence, selection of an operational sequence, or selection of an operational mode.
The present invention also provides for the consideration in executing the algorithm of identification, selection of an operational mode, or selection or running of an operational sequence of a medicament to be administered.
Embodiments of the invention also provide nebulization of specific groups or various agents, for example, antibodies, such as IgG, or antibiotics, such as aminoglycosides, such as amikacin.
Embodiments of the present invention also provide an aerosolized droplet ejection apparatus for use with a ventilator, wherein the apparatus generates droplets by vibrating an apertured member during selected intervals of a breathing cycle.
Embodiments of the present invention also provide apparatus and methods for altering the particle size distribution of an atomized cloud by altering the orifice discharge diameter of an apertured vibrating atomizing member.
Additional embodiments and features are set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The features and advantages of the invention may be realized and obtained by means of the instruments, combinations, and methods described in the specification.
Drawings
FIG. 1A shows components of a pulmonary medicament delivery system according to an embodiment of the invention;
FIG. 1B illustrates an embodiment of a connector device that can be used in a pulmonary drug delivery system according to an embodiment of the present invention;
FIG. 2 illustrates a respirator-attached configuration of a pulmonary medicament delivery system according to an embodiment of the present invention;
figure 3 shows a schematic perspective view of a nebulizer incorporated into a breathing circuit of a respirator according to the invention;
FIGS. 4A-D illustrate a pulmonary medicament delivery system according to an embodiment of the present invention in a disconnected configuration from a ventilator;
FIG. 5 shows a nebulizer connected to a T-adapter for a ventilator circuit, according to an embodiment of the invention;
FIG. 6 shows an exploded view of a nebulizer according to an embodiment of the invention;
figure 7 shows a cross-sectional view of an aerosol generator according to the present invention;
figure 8 illustrates a cut-away cross-sectional view of the aerosol generator of figure 6A;
FIG. 9 shows an exploded view of the atomizer connected to a filter according to an embodiment of the present invention;
10A-B illustrate the flow of gas and medicament through a nebulizer-filter according to an embodiment of the invention;
11A-B illustrate the flow of gas through a chamber and filter in accordance with embodiments of the present invention;
12A-C show graphs of various aerosolization patterns across a respiratory circulation path;
FIG. 13 illustrates a simplified method of the present invention;
FIG. 14 shows a schematic diagram of an algorithm of an operational sequence according to the present invention;
FIG. 15 shows a schematic diagram of an alternative to the algorithm of the sequence of operations of FIG. 14;
FIG. 16 illustrates another schematic diagram of the sequence of operations algorithm illustrated in FIG. 15 in accordance with the present invention; and
fig. 17 shows a schematic diagram of an algorithm with which an operation sequence can be selected based on a combination of sets of independent information.
Detailed Description
SUMMARY
As noted above, conventional nebulizer-ventilator systems have low medicament delivery efficiencies (e.g., less than 20%). Embodiments of the invention include methods for increasing the efficiency of delivery by at least 40%, and in many cases to about 70% or more. The increased efficiency for delivering an aerosol medicament may be due in part to one or more features implemented within embodiments of the present invention. These features include synchronizing aerosol generation with the inhalation phase of the ventilator cycle (e.g., staged delivery). These features may also include supplying air (e.g., "air flow") following aerosol generation, which cleans the endotracheal tube and reduces the amount of medicament exhaled by the patient. These features may also include a hub (hub) that connects the aerosol generating unit directly to an endotracheal tube connected to the patient. Other features also include producing aerosolized medicament having a relatively small particle size (e.g., about 1 to 5 μm average diameter). Other features may include storing the medicament in a conical reservoir to reduce the volume of residual medicament.
Embodiments of the present system may be configured such that administration of an aerosolized medicament to a patient may turn both the ventilator on and off. A method of ventilator-on therapy includes administering a nebulized aerosol to a patient through a ventilator circuit. Aerosol doses containing from about 1mg to about 500mg of medicament may be delivered in a phased or non-phased manner through the ventilator circuit. The off-ventilator treatment method may include disconnecting the patient from the ventilator prior to administering the nebulized aerosol. Once the treatment period is over, the patient may again be connected to the ventilator, or may breathe on his or her own without assistance.
Embodiments of the present invention provide for the treatment of a variety of conditions using a variety of aerosolized medicaments. These conditions may include pulmonary diseases such as ventilator-associated pneumonia, nosocomial pneumonia, cystic fibrosis, mycobacterial infections, bronchitis, staphylococcal infections, fungal infections, viral infections, protozoal infections, and acute exacerbations of chronic obstructive pulmonary disease, among others. Aerosolizable agents for use in treating these conditions can include antibiotics, antioxidants, bronchodilators, corticosteroids, leukotrienes, protease inhibitors, and surfactants, among other agents.
Exemplary pulmonary drug delivery System
Fig. 1A shows an embodiment of a pulmonary drug delivery system ("PDDS") 100 according to the present invention.
The PDDS100 may include a nebulizer 102 (also referred to as an aerosolizer) that aerosolizes a liquid medicament stored in a reservoir 104. Aerosol exiting nebulizer 102 may first enter T-adapter 106, which connects nebulizer 102 to a ventilator circuit. The T-adapter 106 is also connected to a circuit wye 108 having branched ventilator limbs 110 and 112.
Connected to one of the ventilator limbs 110 or 112 may be an air pressure feedback unit 114 that balances the pressure within the limb using a pressure feedback tube 116 connected to a control module 118. In the illustrated embodiment, the feedback unit 114 has a female connection end (e.g., an ISO 22mm female fitting) operable to receive the ventilator limb 112, and an oppositely facing male connection end (e.g., an ISO 22mm male fitting) operable to be inserted into the ventilator. The feedback unit is also operable to receive a filter 115 that is capable of capturing particles and bacteria that are intended to pass between the ventilator circuit and the tube 116.
The control module 118 may monitor the pressure within the ventilator limb via the tube 116 and use the information to control the nebulizer 102 via the system cable 120. In other embodiments (not shown), the control module 118 may control aerosol generation by a wireless control module that transmits wireless signals to the nebulizer 102.
During the inhalation phase of the patient's respiratory cycle, aerosolized medicament entering the T-joint 106 may mix with the breathing gas flowing from the inspiratory ventilator limb 112 to the patient's nose and/or lungs. In the illustrated embodiment, the aerosol and breathing gas flow through the nasal cannula 122 and into the nasal passages of the patient's breathing pathway.
Other embodiments of the loop wye 108 shown in fig. 1A are also contemplated within embodiments of the present invention. For example, an alternative embodiment of the Y-tube 108 is shown in FIG. 1B, which shows an engagement means 135 that may be configured downstream of the atomizer 102. The gas stream 150 containing aerosolized medicament in the downstream shape enters the junction device 135 at the first end 143 and exits at the second end 144 of the breathing circuit. The engagement means 135 comprises a tubular body member 141 having a straight longitudinal cavity 142, the straight longitudinal cavity 142 connecting an opening at a first end 143 connectable to the breathing tube 112 and an opening at a second end 144, the second end 144 connectable to a patient interface, such as to the nasal cannula 122. The junction device 135 may also include a tube branch member 145 having a lumen 146, the lumen 146 communicating with the lumen 142 at a medial opening 147. The gas flow 150 contains aerosolized particles of the medicament discharged by the nebulizer 102 that enter the lumen 142 from the breathing tube 112 through the opening in the first end 143.
In contrast to the "Y" shaped junction device, the junction device 135 provides that the flow of gas 150 (containing aerosolized medicament) follows a straight unobstructed path through the breathing circuit without any portion being delivered into the branch member 145. In other words, the path angle of the gas flow 150 is not actually changed. As a result thereof, the full amount of aerosol particles of medicament contained in the gas flow 150 is efficiently delivered to the patient through the breathing circuit. Under the exhalation action of the patient, the exhaled gas flow 152 follows a path through the interior 142 to the interior 146 of the branch member 145 and back to the ventilator (not shown) through the exhalation tube 110.
Fig. 2 shows another embodiment of the PDDS200, in which the nasal cannula 122 is replaced with an ET tube 222. In this embodiment, the aerosolized medicament generated by the nebulizer 202 during inhalation is carried by the flow of breathing gas through the ET tube 222 and into the patient's bronchial passages and lungs.
Referring to fig. 3, there is shown a nebulizer 85 that may have a top portion 93 through which liquid may be supplied, the nebulizer 85 may be incorporated into a ventilator breathing circuit of a ventilator-worn patient. The breathing circuit may include a "Y" connector 88, which may have, in order, an inlet portion 89, an endotracheal tube portion 90, and an outlet portion 91. The inlet portion 89 carries air provided to the patient from the ventilator 92. The endotracheal tube portion 90 of the Y-connector 88 carries the incoming air to the patient's respiratory pathway; this direction is indicated by arrow "a". The endotracheal tube portion 90 also carries the patient's expired air to the outlet portion 91 of the Y connector 88, and the outlet portion may cause an exhaust, represented by arrow "b", to purge the patient's expired air from the system. The aerosolizing means of the nebulizer 85 of the invention produces an aerosol cloud 94, which aerosol cloud 94 is substantially retained within the inlet portion 89 of the Y-connector 88 when no inhalation air flows through the inlet portion, by means of which aerosolizing means, as described above, a low velocity cloud is produced. In this way, aerosol generated when inhalation air is not provided will not be carried out through the outlet portion 91 of the Y-connector and lost to the surrounding environment. Thus, a dose of aerosolized medicament may be pre-loaded, i.e., substantially generated and placed within inlet portion 89 before the inhalation phase is delivered by ventilator 92. In this way, the medicament may be flushed into the respiratory system of the patient at the beginning of the inhalation cycle. This may be particularly advantageous in the case of neonatal patients and other situations where insufflation gas will reach a target part of the respiratory system only at the beginning of the inhalation phase. In an alternative embodiment, the ventilator may generate a continuous bias flow of gas through the ventilator circuit. This bias flow may push some of the aerosolized medicament through the outlet portion 91, but there is also an overall benefit from having the aerosolized medicament pre-loaded through the ventilation circuit.
A PDDS system similar to that shown in fig. 1-3 may include apparatus for staged delivery of aerosolized medicament. Such a device may include a respiratory characteristic sensor capable of monitoring the respiratory characteristics of a patient using the PDDS. The sensor can send breathing characteristic information to the PDDS controller to allow the controller to select the appropriate aerosol delivery cycle to the patient. Typically, the breathing characteristic sensor can be used to measure the breathing pattern, peak flow, breathing rate, exhalation parameters, breathing regularity, etc. of the patient. Such measurement characteristic data may be delivered to the controller via analog or digital signals and operated on by software algorithms to determine the appropriate delivery sequence of the measured respiratory cycle relative to the patient.
For example, one exemplary breathing characteristic that may be detected by a sensor is the circulation of a ventilator that provides air to a patient; for example, the beginning of an inhalation cycle generated by a respirator. The sensor may also detect other parameters, for example, the sensor may be an acoustic sensor that is energized by advancing the patient's respiratory airflow through an acoustic chamber to produce an acoustic tone that is proportional to the respiratory airflow rate. The frequency of the audible tone is indicative of the rate of inspiratory flow in any instance of the respiratory cycle. The audio signal can be detected by the controller so that the integration of airflow rate with time produces a tidal volume. Both the airflow rate and tidal volume can then be used by the controller to determine when and at what mass flow rate the aerosol generator produces droplets so that maximum deposition of droplets can be achieved. Further, the audio tones may be recorded to produce a record of the patient's breathing pattern, which may be stored in the microprocessor. This information can later be used to synchronize the ejection of droplets to the same patient. This information can also be used later for other diagnostic purposes. A more complete description of such a sensor is set forth in commonly owned U.S. patent 5,758,637, which is incorporated herein by reference.
In certain embodiments, the sensor can be used to monitor the patient's breathing characteristics throughout the entire delivery period, thereby ensuring that aerosol is effectively delivered throughout the aerosolization procedure. In such an embodiment, the controller is capable of adjusting the delivery of the aerosol in response to any measured changes in the patient's breathing pattern during aerosolization. With such monitoring and adjustment, the predetermined time for starting and ending the aerosolization can be reset according to the patient's actual breathing. However, in other embodiments, the respiration sensor can be used to determine the respiration cycle of tidal breathing and select the appropriate preprogrammed delivery cycle stored in the memory of the controller. In other embodiments, the controller may be configured to provide the aerosol on a time basis. For example, the controller may be configured to start aerosol generation at the beginning of the inhalation phase of the breathing cycle and stop at a predetermined percentage of the inhalation completion point. Alternatively, the controller may be configured to start aerosolization at a first point where a first predetermined percentage of inhalation is complete and stop aerosolization at a second point where a second predetermined percentage of inhalation is complete. Alternatively, the aerosol may begin during the inhalation phase and end during the subsequent exhalation phase. Alternatively, the controller may be configured to start aerosol generation at some point during exhalation and stop during that exhalation or during a subsequent inhalation. Accordingly, embodiments of the PDDS may include a nebulizer having an aerosol generator and a controller configured to begin aerosolization during an exhalation and to stop during that exhalation or a subsequent inhalation. In other embodiments, the controller may be configured to begin generating aerosol at the beginning of a respiratory cycle and continue generating aerosol for a period of time, regardless of changes in the patient's respiratory cycle. At the end of this period of time, aerosol production is stopped until the next starting point in the breathing cycle. In another embodiment, the controller may be configured to start and stop generating aerosol for a pre-programmed period of time independent of the patient's breathing cycle.
The controller may be operable to allow selection of a mode of operation, for example, a mode in which aerosolization is initiated once a certain respiratory characteristic is detected, such as a sufficient inhalation level, and is stopped when there is no longer a sufficient level; another mode, in which aerosolization begins once a certain respiratory characteristic is detected, such as a sufficient level of inhalation, and ends at a predetermined time within the inhalation cycle, such as before the inhalation level drops below the level required for operation of the aerosolization component, or alternatively at any other point within the inhalation cycle, such as after the inhalation phase of the cycle before exhalation begins, or after exhalation has begun.
The inhalation level may be detected by a pressure sensor. Such sensors may monitor a decrease or increase in air pressure within a chamber in fluid communication with the ventilator circuit. In this manner, the pressure drop may be detected as the patient's inhalation through the circuit, for example, in a situation where the ventilator provides supplemental ventilation caused by the beginning of the patient's inhalation. Similarly, a pressure rise may be detected in a situation where the ventilator pushes inhaled air to the patient without the patient starting to breathe. Another mode in which the controller may operate is one in which the on/off operation of the aerosol generator is triggered by time determined by an internal clock means, such as a clock built into the microprocessor, or by an external source. Another mode in which the controller may operate is one in which the on/off of aerosol operation is triggered by the controller receiving an external signal, such as a signal from the ventilator corresponding to a point in the ventilator cycle at which the ventilator begins to push inhaled air into the ventilator circuit. The controller may operate between modes including a mode in which aerosolization begins at a predetermined time within the respiratory cycle and ends at a predetermined time within the respiratory cycle. The first and second predetermined times within the third mode may be during inhalation. Alternatively, the first and second predetermined times may be during exhalation, or the first predetermined time may be during exhalation and the second predetermined time may be during a subsequent inhalation. These times may correspond to a percentage of the inhalation phase that is occurring or any other point of reference within the respiratory cycle.
Alternatively, the first predetermined time and the second predetermined time may be designed as any point within a single breathing cycle, or alternatively, the first predetermined point may be at any point within a breathing cycle and the second predetermined point may be at any point within a subsequent breathing cycle. The controller may make a determination when to start and operate to start aerosolization and make a determination when to stop aerosolization to stop and cause aerosolization to stop. The controller may make such decisions and such actions based on algorithms that access the storage. The controller may receive a signal from the ventilator that establishes a reference point, although the controller, which makes decisions and takes action based on stored algorithms and/or obtained information regarding identifying the medicament to be administered, may cause aerosol generation to begin and/or end independent of the instantaneous position of the ventilator relative to the ventilator cycle.
Embodiments also include a controller operable to allow a single mode of operation, which may be any mode including, but not limited to, the modes described above. For example, a mode in which aerosolization begins as soon as a sufficient level of a certain respiratory feature, such as inhalation, is detected, and ends when there is no more sufficient level. Similarly, the controller may operate in a mode in which aerosolization begins once a certain respiratory characteristic, such as a sufficient level of inhalation, is detected, and ends at a predetermined time within the inhalation period before there is no more sufficient level or aerosolization element.
Alternatively, the mode may be one in which aerosolization is initiated in response to a signal from the ventilator indicating that a certain point within the ventilation output cycle or the patient's inhalation cycle is reached (the ventilation output cycle of the ventilator may coincide with the patient's inhalation cycle such that the ventilation output period of the ventilator output cycle occurs substantially simultaneously with the inhalation period of the patient's breathing cycle). Such a point may be during the output phase of the output cycle of the ventilator, or during the inhalation phase of the inhalation cycle of the patient. The predetermined point may be selected to correspond to a certain output level from the ventilator, or a certain point in time within the output cycle of the ventilator. Such a predetermined point may be a particular point within the output period of the ventilator cycle, or a particular point within the non-output period of the ventilator, for example, timed according to a previous or subsequent output period of the ventilator. In another aspect, the invention provides a respirator and aerosol generator and controller. In one aspect of the invention, the predetermined time may be based on the timing of the supply of air to the user's respirator. In this way, the controller may be set to de-time the ventilator in one mode and the patient's respiratory effort in another mode, or a mode that allows a combination of the patient's respiratory effort and the timing of the ventilator, for example, where the ventilator is set to assist the patient by supplying air when the patient is trying, or in the event that the patient has not been able to make sufficient effort within a predetermined period of time.
Exemplary disconnected respirator shape
Referring now to fig. 4A-D, an embodiment of the disconnected shape of the PDDS from the respirator is shown. In fig. 4A, the PDDS400 disconnected from the ventilator includes an end piece 402 connected to a nebulizer 404 and a Y-tube 406. The nebulizer 404 may include a reservoir 408 that supplies aerosolized liquid medicament into a connector 410. The connector 410 can provide a circuit for aerosolized medicament and gas to travel from the Y-tube 406 to the end piece 402 and then into the patient's mouth and/or nose. The first Y-shaped tube limb 412 may be connected to a pump or pressurized source of breathing gas (not shown) that flows through the Y-shaped tube limb 412 to the end piece 402. A one-way valve 413 may also be placed in the limb 412 to prevent the flow of breathed gas back to the gas pump or source. The limb 412 may also include a pressure feedback port 414 that may be connected to a gas pressure feedback unit (not shown). In the illustrated embodiment, a feedback filter 416 may be connected between the pressure feedback port 414 and the feedback unit.
The PDDS400 disconnected from the ventilator may also include a second Y-tube limb 420 that includes a filter 422 and a one-way valve 424 through which gas may pass during the exhalation cycle. The filter 422 may filter out aerosolized medicament and infectious agents exhaled by the patient to prevent these substances from escaping into the ambient atmosphere. The check valve 424 can prevent ambient air from flowing back into the PDDS 400.
Fig. 4B shows another embodiment of the PDDS450 disconnected from the respirator, where the end piece is replaced with a mouthpiece (mouthpiece)452 operable to sealingly engage the patient's lips. Mouthpiece 452 represents a bracket where a connector 454 connected to a tee 456 removably connects to a PDDS450 disconnected from the respirator. The connector 454 may be made of a resilient material (e.g., rubber, silicone rubber, etc.) that is capable of resiliently engaging the mouthpiece 452 to the tee 456. In the illustrated embodiment, the PDDS450 also includes a gas inlet 458 capable of being sealingly connected to an additional gas source (not shown), such as oxygen, on a breathing limb 460 of the Y-tube 462.
Fig. 4C shows another embodiment of the PDDS470 disconnected from the ventilation box, wherein the end pieces are replaced by a mask 472 operable to sealingly enclose the patient's nose and mouth. The visor 472 may have a connection end capable of resiliently connecting the visor to the PDDS470 bracket. The connecting end may be continuous with the mask 472 carrier to form a single piece.
Fig. 4D shows another embodiment of the PDDS490 disconnected from the respirator, wherein the end piece, T-piece and Y-piece form a single continuous piece 492. A gas inlet may be continuously formed in the continuous member 492 to connect to a source of gas, such as a source of oxygen. An atomizer inlet may also be formed in the continuous piece 492 to removably receive an atomizer. Additionally, a filter 496 and a one-way valve 498 may be coupled to the branching end of the continuum 492. The other branch end of the continuity member 492 may also be connected to a one-way valve 499 operable to prevent gas from flowing back to a gas pump or other source of pressurized gas (not shown) connected to the branch end.
The shape of the PDDS with ventilator on and off allows for continuity of treatment when the patient switches between on ventilation and off ventilation treatment shapes. If continuity of treatment is provided when the patient transitions from ventilator therapy on to ventilator therapy off, the patient can receive the same aerosolized medicament at the same dosage level within both shapes. This is particularly useful for extended treatment regimens when the patient receives aerosolized medicament for days or weeks.
Example atomizer
With respect to nebulizers (i.e. aerosol generators), they may be of the type in which a vibratable member is vibrated at ultrasonic frequencies, for example, to produce droplets. Some specific, non-limiting examples of techniques for generating fine droplets are by supplying liquid to a perforated plate having a series of tapered holes, and vibrating the perforated plate to eject droplets through the holes. This technology is generally described in the following U.S. patents: nos.5,164, 740; 5,938,117, respectively; 5,586,550, respectively; 5,758,637, respectively; 6,014,970, and 6,085,740, the complete disclosures of which are incorporated herein by reference. It should be understood, however, that the present invention should not be limited to use with only such devices.
Referring now to fig. 5, an atomizer 502 coupled to a tee 504 is shown. The atomizer 502 may include a reservoir 506 oriented non-perpendicular to the tee 504. For example, the reservoir 506 may be shaped at an angle of between about 10 and about 75 relative to an axis collinear with the bottom tube of the tee 504. The reservoir 506 may have a cap 508 capable of sealingly engaging an opening of the reservoir 506 to contain a liquid medicament 509 within a reservoir housing 510. The top of cap 508 and tank 506 may have conjugate threads or grooves that can be sealingly engaged to close the tank. Alternatively, the cap 508 may be made of a resilient material that can resiliently seal or snap into place around the opening of the tank 506. The reservoir 506 may be refilled by removing the cap 508, adding liquid medicament to the reservoir housing 510, and resealing the cap 508 over the reservoir 506. In the illustrated embodiment, about 4ml (milliliters) of medicament may be stored within the reservoir housing 510. In other embodiments, the stored medicament may range from about 1ml to about 10ml, and larger reservoirs may hold 10ml or more of medicament.
The nebulizer 502 may also include a power inlet 512 that may receive a plug 514 that supplies power to the nebulizer. Alternatively, the power inlet 512 may be replaced or supplemented by a cord with a plug end that may be plugged into a power source (not shown). The power inlet 512 may also receive electronic control signals that control the timing and frequency at which the nebulizer aerosolizes medicament controlled from the reservoir 506.
Fig. 6 shows an exploded view of atomizer 600 disengaged from a tee (not shown) in accordance with an embodiment of the present invention. An opening 602 in the atomizer 600 that is connected to a tee or some other inlet in the PDDS may include an aerosolizing member 604 secured within the opening 602 by a retaining member 606. In operation, medicament from the reservoir 608 advances through the outlet 610 and is aerosolized by the aerosolizing member 604. The aerosolized medicament may then drift or flow through the retaining member 606 and into the PDDS. An alternative embodiment, not shown, may have the aerosolizing member 604 permanently affixed or integral with the opening 602, and possibly without the retaining member 606.
The aerosolization component 604 can have a vibrating component that moves relative to the perforated plate to aerosolize the liquid medicament. Aerosol generation can be controlled to a precision level of microseconds or milliseconds, thus providing accurate dosing, by using an aerosol generator that generates aerosol by the energization of a vibratable component that causes a perforated plate to eject liquid through its apertures at one face thereof as a cloud from the other face thereof, substantially as described above (and substantially as described in the following U.S. patent nos.5,164,740; 5,938,117; 5,586,550; 5,758,637; 6,085,740; and 6,235,177, all of which are hereby disclosed and incorporated herein by reference). The timing of aerosol generation can be made solely according to the following criteria: a predetermined timing within a breathing cycle; timing in conjunction with the length of the previous breath or a portion thereof; other respiratory characteristics; the specific agent administered; or any combination of these criteria.
The aerosolizing member may be constructed from a variety of materials, including metals, which may be electroformed to create apertures upon formation, such as described in U.S. patent No.6,235,177 to the present assignee, which is hereby incorporated by reference in its entirety. Palladium is believed to be particularly suitable for making an electroformed porous aerosolization member and operating the member to aerosolize a liquid. Other metals that can be used are palladium alloys, such as PdNi alloys of 80% palladium and 20% nickel. Other metals and materials may also be used without departing from the invention.
Referring now to fig. 7 and 8, aerosolizing member 70 may be configured to have a curvature like an arch, which may be spherical, parabolic, or any other curved shape. The aerosolizing member 70 may be configured to have an arcuate portion 73 over a majority thereof, and the arcuate portion may be concentric with a center of the aerosolizing member, thus leaving a portion of the aerosolizing member as a substantially planar peripheral ring portion 75. The aerosolizing member has a first face 71 and a second face 72. As shown in fig. 8, the aerosolizing member may also have a series of through-holes 74. The first face 71 may comprise a concave side of the arched portion 72 of the aerosolizing member 70, and the second face 72 may comprise a convex side of the arched portion 72 of the aerosolizing member 70. The holes may be tapered to have a narrow portion 76 at the first face 71 of the aerosolizing member 70 and a wide portion 78 at the second face 72 of the aerosolizing member 70. Typically, the liquid will be placed on the first face of the aerosolizing member where it can be drawn into the narrow portion 76 of the aperture 74 and ejected from the wide portion 78 of the aperture 74 of the second face 72 of the aerosolizing member 70 as an aerosolized mist or cloud 79.
The aerosolizing member may be mounted on an aerosol actuator 80 defining a through-hole 81. The mounting may be performed in such a way that the arched portion of the aerosolizing member protrudes through the through-hole 81 of the aerosol actuator 80, and the substantially planar peripheral ring portion 75 on the second face 72 of the aerosolizing member 70 abuts against the first face 82 of the aerosol actuator 80. A vibration member 84 may be provided and may be mounted on the first face 82 of the aerosol actuator 80 or, alternatively, may be mounted on the opposing second face 83 of the aerosol actuator 80. The aerosolizing member may be vibrated in such a manner to draw the liquid through the apertures 74 of the aerosolizing member 70 from the first face to the second face, where the liquid is ejected from the apertures as an aerosolized cloud. The aerosolizing member may be vibrated by a vibrating member 84, which may be a piezoelectric member. The vibration member may be mounted to the aerosol actuator such that vibration of the vibration member may be mechanically transmitted to the aerosolization member by the aerosolization actuator. The vibrating member may be annular and may surround the aperture of the aerosol actuator, e.g. in a coaxial arrangement.
Embodiments of the present invention include aerosolization components or aerosol generators comprising aerosolization components 70, aerosol actuator 80, and vibration components 86, which may be replaced with corresponding components having different sized apertures, such as different discharge diameters, to generate a cloud having a different aerosol particle size. The circuit 86 may provide power from a power source. The circuit includes a switch operable to cause the vibrating member, and thus the aerosolization member, to vibrate, and aerosolization in this manner may be achieved within milliseconds of operation of the switch. The circuit may include a controller 87, such as a microprocessor, that is capable of providing power to the vibration member 84 to generate aerosol from the aerosolizing member within milliseconds or fractions of milliseconds of the signal. For example, aerosol generation may begin within about 0.02 to about 50 milliseconds of such a signal, and may stop within about 0.02 to about 50 milliseconds from the cessation of the first or second signal, either of which may serve as a trigger for switching aerosolization. Similarly, aerosol generation may begin and end within about 0.02 milliseconds to about 20 milliseconds of such a corresponding signal. Similarly, aerosol generation may begin and end within about 0.02 milliseconds to about 2 milliseconds of such a corresponding signal. Furthermore, this manner of aerosolization provides complete aerosolization with a substantially uniform particle size of the low-velocity cloud 79, which is effectively instantaneously generated by the operation of the switch.
The switch described above may be operated by means of a pressure sensor that can be positioned within the mouthpiece of the atomiser. The pressure sensor may be in electrical communication with the circuit, and a microprocessor may also be in electrical communication with the circuit, and the microprocessor may interrupt the electrical signal from the pressure sensor, and may also operate a switch to initiate aerosolization. In this way, aerosolization can begin substantially immediately at the same time as the user inhales with the mouthpiece. An example of such a sensor switch is found in commonly assigned and commonly assigned U.S. patent application 09/705,063, assigned to the present assignee and incorporated herein by reference in its entirety.
Another sensor may be used to detect the presence of liquid in the reservoir, for example by detecting a difference between the vibrational characteristics of the aerosolizing member, for example, a difference in frequency or amplitude between wet and substantially dry vibrations. In this way, when substantially no more liquid is aerosolized, i.e., when the end of a dose is reached, the circuit may stop the vibration, e.g., with the aid of a microprocessor, thus minimizing the operation of the aerosolizing member in the dry state. Similarly, the switch may prevent vibration prior to delivering a subsequent dose into the reservoir. An example of such a switch is shown in commonly assigned and commonly applied U.S. patent application 09/805,498, the entire contents of which are incorporated herein by reference. Exemplary atomizer-filter configuration
Fig. 9 shows an exploded view of a nebulizer 902 attached to a filter 904, according to an embodiment of the invention. This configuration of nebulizer 902 and filter 904 may be part of a device disconnected from the ventilator for delivering aerosolized medicament to a patient. The filter 904 may be sandwiched between a first retaining component 906 and a second retaining component 910, the first retaining component 906 having a nebulizer mouth 908 to receive the nebulizer 902, the second retaining component 910 having an opening 912 to receive a mouthpiece, mask, nasal cannula, or the like. The first retaining member 906 may have one or more openings that allow filtered gas to advance through the filter 904 to escape to the surrounding environment. The first component 906 may also have a gas inlet 914 that can be sealingly engaged with a source of pressurized breathing gas (e.g., oxygen, air, etc.) or a gas pump (not shown). The second retaining member 910 may have a pressure port 916 that is sealingly engageable with a pressure sensor (not shown) that measures the pressure of gas within the device.
Fig. 10A-B illustrate the nebulizer-filter configuration described above in operation during the inhalation phase (fig. 10A) and exhalation phase (fig. 10B) of the patient's respiratory cycle. During inhalation, the pressurized gas advances through the gas inlet 914 and the filter 904 into the region where the gas mixes with the aerosolized medicament generated by the nebulizer 902. The mixture of aerosol and gas then flows through the openings 912 and into the patient's lungs. During the exhalation phase, gases breathed by the patient enter the device through opening 912 and are filtered by filter 904 and expelled through openings in retaining member 906.
The pressure within the device may be monitored throughout the breathing cycle using a pressure sensor connected to the pressure port 916. A pressure sensor (not shown) may generate an analog or digital electronic signal containing information about the pressure level within the device. This signal may be used to control the amount of aerosolized medicament and/or gas entering the device during the course of a patient's respiratory cycle. For example, when the pressure within the device decreases upon inhalation by the patient, the pressure signal may cause nebulizer 902 to increase aerosolizing the medicament to the device, and/or cause the gas source or gas pump to increase the gas through inlet 914. Subsequently, when the pressure within the device increases as the patient exhales, the pressure signal may cause the nebulizer 902 to stop adding medicament to the device, and/or cause the gas source or pump to stop adding gas through the inlet 914. The control of the aerosol and/or gas flow, i.e. the staged delivery of gas and aerosol, in accordance with the respiratory cycle of the patient will be described in additional detail below.
Exemplary Aerosol Chamber
Embodiments of the invention may include a chamber 1102 capable of holding a mixture of gas and aerosol for delivery to the lungs of a patient. The chamber may be used in both on and off configurations with the ventilator. The expanded volume within the chamber reduces the surface area to volume ratio of the patient interface end of the system, which can increase aerosol delivery efficiency. Figures 11A-B illustrate an embodiment of such a chamber with flow paths for gases and aerosols being inhaled and exhaled by a patient. The chamber 1102 may include a series of openings including a gas inlet 1104 capable of receiving gas from a respirator, a gas pump, and/or a source of compressed gas (e.g., a compressed air bottle, an oxygen bottle, etc.). The chamber 1102 may also include a second opening 1106 configured to receive a nebulizer (not shown) and a third opening 1108 configured to receive an end piece (e.g., mouthpiece, mask, etc.).
Opening 1108 may include a valve 1110 configured to alter the fluid flow path through opening 1108 according to the phase of the patient's breathing cycle. For example, during inhalation (fig. 11A) the valve 1110 may be pushed away from the chamber 1102, directing the flow of gases and aerosols around the valve end, into an end piece (not shown), and ultimately into the patient's lungs. Subsequently, during the exhalation phase (fig. 11B), the valve 1110 is pushed by the patient's breathing gases to close the opening 1108, forcing the gases through the opening 1112 and the filter 1116 before exiting the filter housing 1117 into the surrounding atmosphere. The filter housing 1117 may include perforations to allow exhaled gas to escape, and/or be made of a gas permeable material that enables exhaled gas to diffuse therethrough.
Exemplary medicaments
Embodiments of the present invention contemplate various medicaments that can be aerosolized and delivered to the lungs of a patient. These agents may include antibiotics such as aminoglycosides, beta-lactamases, and quinolines, among others. Aminoglycosides can include amikacin, gentamicin, kanamycin, streptomycin, neomycin hydrochloride, netilmicin, and tobramycin, among others. Other agents may also be used, including antioxidants, Branch vessel dilators, glucocorticoids, leukotrienes, prostacyclin, protease inhibitors and surfactants, among others. Table 1 lists the classes of agents and indications that may be treated with their aerosolized state.
TABLE 1 classes of aerosolizable agents
| Classes of agents | Indications of | Dosage form | Time of treatment |
| Antioxidant agent | RDS prevents BPD, ALI, ARDS | 1-4 days | Time of ventilation |
| Bronchodilators | Asthma, COPD, ARDS, RDS | 1-4 days | According to the requirements |
| Glucocorticoids | Asthma, COPD, BPD | 1-2 days | Time of ventilation |
| Leukotrienes or related adrenoreceptor agonists | Immunodeficiency, COPD, treatment/prevention of pneumonia or RSV infection | 1-4 days | 5-14 days |
| Prostacyclin or related analogs | PPHN, secondary pulmonary hypertension, ARDS after cardiac surgery | In succession | To be determined |
| Protease inhibitors | AECOPD，ARDS，RDS，BPD | 1-2/day | 5-14 days |
| Surface active agent | RDS, BPD, ARDS prevention | 1-2/day | To be determined |
The table is abbreviated:
AECOPD: acute exacerbation of COPD
ALI: acute lung injury
ARDS: acute respiratory distress syndrome
BPD (BPD): bronchopulmonary dysplasia
COPD: chronic obstructive pulmonary disease
PPHN: persistent pulmonary hypertension
RDS: respiratory distress syndrome (also known as infectious respiratory distress syndrome)
RSV: respiratory syncytial virus
Exemplary staging method
Fig. 12A-C show graphs of various aerosolization patterns during the course of a respiratory cycle. Figure 12A shows a continuous aerosolization mode in which aerosolized medicament is generated at a constant rate throughout the respiratory cycle. Continuous (i.e., non-staged) production patterns typically have aerosol delivery efficiencies of about 10% to 15%. Figure 12B illustrates a staged delivery pattern wherein the aerosolized medicament is administered during substantially all of the inhalation phase of the respiratory cycle. This mode typically has an efficiency of about 15% to about 25%. Figure 12C illustrates another staged delivery pattern in which the aerosolized medicament is administered during a predetermined portion of the inhalation phase, e.g., beginning at the beginning of the inhalation. It has been found that these modes typically have a delivery efficiency of between about 60% to about 80% by weight of the total amount of aerosolized medicament.
Embodiments of the present invention take advantage of this discovery by controlling delivery to a predetermined percentage of the respiratory cycle, such as a predetermined percentage portion of the inspiratory phase of the respiratory cycle, to provide greater delivery efficiency than either continuous delivery or delivery throughout the inspiratory phase. Embodiments of the present invention also take advantage of the surprising discovery that the percentage increase in efficiency of delivery over the entire inhalation phase in such predetermined portions of the inhalation phase is itself greater than the increase in efficiency of delivery over non-phased administration of an aerosol at the time of inhalation phase.
The staged delivery method may include measuring a characteristic of the patient's inhaled breathing, typically tidal breathing, and using the measurement to control the operation of the aerosol generator. Figure 13 provides a simplified flow chart illustrating steps of the staged delivery of an aerosolized medicament in accordance with embodiments of the present invention. The staged delivery method may include the steps of: making one or more breaths 1320 to the patient; and measuring characteristics 1322 of the breath. Respiratory characteristics that can be measured include, but are not limited to, breathing pattern, peak inspiratory flow rate, respiratory rate, exhalation parameters, regularity of breathing, tidal volume, and the like, and from this information, the user's respiratory capacity can be evaluated.
The user can make another tidal breath (tidal breath) and the aerosol generator can operate 1324 according to the measured characteristics of the tidal breath. However, it should be understood that instead of tidal breathing, the patient may take other types of breathing.
Alternatively, the controller may be timed to the operation of the aerosol generator so that aerosol is generated for a particular period of the breathing cycle. For example, the controller may operate the aerosol generator during the first 50% of the inhalation phase. Alternatively, the controller may operate the aerosol generator to generate aerosol after a portion of the inhalation occurs and to cease aerosol generation after another portion of the inhalation occurs. For example, the controller may cause aerosol to be generated to start after 20% of inhalation has occurred and cause aerosol generation to stop after 70% of inhalation has occurred. The controller may start aerosol generation after, for example, 90% of exhalation occurs, and stop aerosol generation after, for example, 30% of subsequent inhalations occur. By controlling the specific timing of the supply of aerosolized medicament into the breathing circuit within the breathing cycle, greater dosing efficiency can be achieved.
Since some drugs to be aerosolized may be more efficiently delivered near the beginning of a patient's respiratory cycle and other drugs may be more efficiently delivered near the end of a patient's respiratory cycle, the timing of aerosol generation should be dependent on the type of medicament being delivered. If it is known what type of medicament is being delivered, the controller can select the optimal time to deliver the aerosol within the patient's breathing cycle according to a predetermined pattern for that medicament stored in memory. As an additional benefit, for example, by measuring respiratory volume and respiratory rate, an assessment of the patient's age and/or illness can be made. Such measurements may affect the dose efficiency requirements of each breath. These and other variables can be used to establish various means for aerosol delivery, particularly for delivery into the breathing circuit of a respirator. These means may be stored in memory and subsequently accessed by the controller to suit a given patient condition.
For example, for a bronchodilator, the optimal delivery time may be halfway through the inspiratory phase of the breath, where the shock will be reduced due to the reduced inspiratory flow. For steroids, delivery is best near the end of the inspiratory phase of respiration. For antibiotics it is preferred that it is slightly preloaded, for example, by delivering the aerosol during the exhalation phase, or just at the beginning of the breath. For example, the antibiotic may be delivered at the beginning of inhalation provided by the ventilator, and the aerosol delivery may be stopped after a predetermined inhalation percentage is provided. One class of antibiotics that can be administered in accordance with the present invention are the antibiotics known as aminoglycosides. Antibiotics of this type are typically administered intravenously, however, such delivery can sometimes have undesirable side effects that affect the body. Embodiments of the invention provide for the administration of these antibiotics, such as aminoglycosides including amikacin, by delivering them in aerosolized form into the respiratory circuit of a patient wearing a ventilator. In this manner, amikacin can be used to treat pulmonary infections typically occurring when a patient is mechanically ventilated, and amikacin or other aminoglycosides or other antibiotics can be delivered directly to the target of treatment, i.e., the pulmonary route, avoiding side effects otherwise caused by intravenous administration. Moreover, since these agents are very expensive, much higher efficiencies are achieved through the pulmonary delivery. As described above, with reference to fig. 12C, delivering an aerosol during the beginning percentage portion of the inhalation phase of the respiratory cycle can achieve an efficiency of between about 60% and about 80%, significantly higher than continuous aerosolization or aerosolization during the entire inhalation phase of the inhalation cycle.
Embodiments of the present invention provide for performing various aerosolization regimes depending on the state. For example, in fig. 14, a selection between the first, second, and third modes is shown. The mode may be selected manually or automatically, for example by selecting the application of the algorithm of the operating program based on input or stored information. For manual selection, a user may operate a mechanical switch to select a mode, or may enter such a selection into an electronic input device, such as a keyboard. Alternatively, the controller may automatically select a mode, as described above, by matching the medicament code on the medicament nebulizer with a library of medicament-mode combinations. (it should be noted that in FIGS. 14-17, there is shown a schematic flow chart of the operating program algorithm. although the items therein are referred to as steps for ease of discussion, they may refer more broadly to operating states or modes that the system may exist or cycle through.
In step 1400, a selection is made to follow a particular pattern. In this case, mode I is a method in which aerosol generation continues (step 1402). Regime II provides aerosol generation only during the inhalation phase (step 1404). In this case, in step 1406, aerosol generation is set to start at the beginning of the inhalation phase, and in step 1408, aerosol generation is set to stop when the inhalation phase stops. In step 1410, aerosol generation begins at the beginning of the inhalation phase. In step 1412, aerosol generation is stopped when the inhalation phase ends (step 1414).
Regime III provides inhalation during a predetermined percentage of the inhalation period (step 1416). The predetermined percentage of inhalation (or exhalation) may be based on a measured time from a discontinuity in the ventilator cycle, such as the instantaneous onset of inhaled air generation by the ventilator. Alternatively, such predetermined percentage may be based on a time interval between successive discontinuities within the respirator, such as successive onsets of successive air inhalations by the respirator. Alternatively, such percentage may be based on air pressure within the ventilator circuit or any other parameter. With regard to regime III, in this case, in step 1418, a first predetermined point is set to correspond to the completion of a first predetermined percentage of the inhalation. In step 1420, the second predetermined point is set to a completion corresponding to a second predetermined percentage of the inhalation percentage. For example, as described above, the first predetermined point may correspond to a completed 20% inhalation phase and the second predetermined point may correspond to a completed 70% of the same inhalation phase. In step 1422, aerosol generation begins at a first predetermined point during the inhalation phase. In step 1424, when the second predetermined point is reached, the controller proceeds to step 1414 and stops aerosol generation.
Similarly, as described above, other approaches may be followed, for example, where the aerosol generation begins during the inhalation phase and ends during the exhalation phase, or begins during the exhalation phase and ends during the exhalation phase, or begins during exhalation and ends during a subsequent respiratory cycle, e.g., at a predetermined point during a subsequent inhalation phase. Turning then to FIG. 15, at step 1430 a selection can be made between mode II (step 1432) and mode III (step 1434) as described above, as well as an alternative to mode IV (step 1436-.
In regime IV, aerosol generation may begin at a first predetermined point (step 1436), and the first predetermined point may be after a predetermined percentage of the inhalation phase is complete, or a predetermined point after the inhalation phase is complete. This point may be, for example, a predetermined point after a predetermined percentage of the exhalation phase is complete, or a predetermined point before the beginning of the subsequent inhalation phase. Aerosol generation may stop during exhalation (regime iva, step 1438) at the completion of exhalation (regime IVb, step 1440), or aerosol generation may continue into the next respiratory cycle (regime IVc, step 1442), e.g., after a predetermined point of a subsequent inhalation phase.
In this example, the controller is provided with a choice between operating sequences corresponding to modes II, III and IV, a schematic of which is shown in fig. 16. In step 1450, one mode is selected. In step 1452, the aerosol generator controller selects an operating sequence based on the selected mode. In step 1454, the controller receives a signal indicating that the ventilator has begun to deliver an inhalation phase. The signal, as described above, may be a signal provided directly by the ventilator. Alternatively, the signal may be a signal provided by a sensor, and the sensor may detect the start of an inhalation phase provided by means of the ventilator by detecting a pressure change in the breathing circuit, as described above. In step 1456, the controller performs a selected operation sequence. In the case of mode II (step 1548), the controller engages the ventilation mist generator at the beginning of the inhalation phase provided by the ventilator. The controller continues to operate the aerosol generator until a point at which the inhalation phase is complete (step 1460). In step 1462, the controller turns off the aerosol generator.
In the case of regime III, the controller takes no action to begin aerosol generation until a predetermined point within the inhalation phase corresponding to a percentage of the inhalation phase is complete (step 1464). At a predetermined point during the inhalation phase, the controller receives the aerosol generator in step 1466. In step 1468, aerosol generation continues until a second predetermined point of the inhalation phase corresponding to the completion of a second percentage point of the inhalation phase. At this point, the controller proceeds to step 1462 and turns off the aerosol generator. With respect to regime IV, aerosol generation begins after a predetermined point of the inhalation phase has been completed (step 1464), and this point may be predetermined to occur after the inhalation phase has been completed and the exhalation phase has begun (step 1470). In step 1472, control turns on the aerosol generator to begin aerosolization. Some changes may be made, such as the point at which the aerosol is broken. If aerosol generation is desired to be completed before the expiration period is complete (manner VIa), aerosol generation may continue until a predetermined point prior to a subsequent inhalation (step 1476). Alternatively, it may be desirable to continue aerosolization until the end of exhalation, which corresponds to the beginning of a subsequent inhalation, as in regime IVb (step 1478). Alternatively, it may be desirable to follow a regime, such as regime IVc, in which aerosol generation continues through a subsequent respiratory cycle (step 1480), for example, until a predetermined percentage of a subsequent inhalation phase has been completed (step 1482). In these modes, aerosolization will continue until these conditions are met (step 1476 for mode IVa, step 1478 for mode IVb, or step 1482 for mode IVc), at which point the controller proceeds to step 1462 and stops the aerosol generator. This process may continue with the next signal, step 1454, indicating that the ventilator has begun to provide an inhalation phase.
Further, the selection of which sequence of operations to follow may depend at least in part on the identity of the medicament to be administered, information of which can be taken into account by the controller, as described above. Further, it should be understood that changes may be made to these examples without departing from the invention. For example, a system may be configured or a mode may be implemented that can choose to follow more than three starting modes. For example, modes I, II, III and IV described above may be selected simultaneously. Also, various steps may be modified, e.g., some steps may not be intermittent steps. Thus, step 1456 may not be a discrete step, but rather a following of the operating procedure in a selected manner. Similarly, the order of the steps may also be changed, such as the controller may select an operational sequence (step 1452) after receiving a signal indicating that the ventilator has begun to provide an inhalation period (step 1454). Steps may also be combined, for example, in regime IV, steps 1464 and 1470 may be combined as a single step, as these two steps represent successive criteria for determining that a single first predetermined point has been met. Similarly, step 1474 may be combined with steps 1476, 1478, or 1480, as step 1474 is the decision to test for the conditions specified in each of the other successive testing steps 1476, 1478, or 1480. The algorithm examples may also be changed to form other sequences of operations. For example, one operating program may require the controller to initiate aerosol generation at the beginning of an inhalation cycle provided by the nebulizer, as in regime II, at step 1458, and turn off the aerosol generator at a predetermined point when a predetermined percentage of the inhalation phase has been completed, as in regime III, step 1468 (and step 1462). In a similar manner, other criteria may be used to trigger the turning on or off of the aerosol generator. For example, as described above, the start of aerosolization can be triggered by detecting a particular pressure or pressure change within the ventilator circuit, and can be ended by a disconnect sequence following mode III (steps 1468 and 1462) or mode IV (steps 1474, 1476, 1478 or 1480 and 1482, followed by step 1462, as described above).
Fig. 17 is a schematic diagram of an algorithm by which a sequence of operations for providing an aerosolized medicament to a patient receiving air from a ventilator may be selected based on a combination of a series of independent sets of information, in this case, the medicament identity and a signal from the ventilator. In step 1700, a library of drug regimens based on the various drugs that may be administered is provided. In step 1702, a particular medication is provided to the system, and this, as described above, may be provided by a label on the medication-containing nebulizer that is readable by the system. In step 1704, the controller looks up the modes from the stored mode library to select one mode based on the particular medicament to be administered. In step 1706, the controller receives a signal from the ventilator. In step 1708, the controller then selects an operational sequence based in part on the identity of the medicament and the medicament regime, and in part on the independent information provided by the signal from the ventilator. In step 1710, the controller executes an operational sequence that may be to generate aerosol at predetermined intervals of the ventilation cycle according to the medicament and the regime provided for the medicament in relation to the inhalation cycle factor of the ventilator. These illustrations are exemplary, and thus the order of the steps may be varied, and other variations, additions and modifications may be made to the invention as described above.
The staging method described above may also be implemented with additional systems, such as a continuous active airway pressure (CPAP) system, such as those described in the following U.S. patent applications: 10/828,765 filed on 20 th month of 2004, 10/883,115 filed on 30 th month of 2004, 10/957,321 filed on 9 th month of 2004 and 10/______ filed on __ th month of 2004, the entire contents of all of which are incorporated herein by reference for all purposes.
Experiment of
The delivery efficiency test was performed using PDDS aerosolized amikacin sulfuric acid in water, connected to a ventilator. The PDDS ventilator circuit shape is similar to that shown and described above with respect to fig. 2. A400 mg dose of amikacin was delivered through the PDDS. The PDDS is configured to deliver aerosolized medicament by a phased delivery method similar to that shown in fig. 12C. The dose of medicament is delivered over a period of about 50 to about 60 minutes.
Table 2 lists delivery efficiency data for delivering an aerosolized medicament to a system according to an embodiment of the present invention. Within the experimental setup, aerosolized droplets deposited on an inhalation filter placed on a patient-end interface were weighed and compared to the total dose weight of the aerosolized medicament. The percentage of the dose deposited on the inhalation filter represents the proportion of the total aerosolized dose that should be inhaled by the patient, and the efficiency of the system is thus evaluated.
Table 2 percentage of dose deposited on the inhalation filter
| Transport sequence number | Percentage deposited on the filter | Mean value of | Standard deviation of | The percent standard deviation (% RSD) was determined repeatedly |
| 1 | 69％ | |||
| 2 | 75％ | |||
| 3 | 75％ | |||
| 4 | 77％ | 71％ | 0.04 | 6％ |
| 5 | 69％ | |||
| 6 | 66％ | |||
| 7 | 68％ |
Table 2 shows that the efficiency for seven deliveries of a system according to one embodiment of the invention has an average efficiency of 71% ± 6%. This level of efficiency is much higher than conventional systems for delivering aerosolized medicaments, which typically have an efficiency level of 10% or less.
Having described several embodiments, it will be recognized by those of skill in the art that alternative structures or equivalents may be used without departing from the spirit of the invention. In addition, a number of well known processes and components have not been described in detail herein in order to avoid unnecessarily obscuring the present invention. Therefore, the above description should not be taken as limiting the scope of the invention.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range is also specifically disclosed. Also included are intervening values between any recited value or range of recited values and any other recited or intervening value in that stated range. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range, whether or not both limits are included in the smaller ranges, is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.
As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a process" includes a series of such processes, and reference to "the electrode" includes reference to one or more electrodes and equivalents thereof known to those skilled in the art, and so forth.
Also, the words "comprise," "comprising," "include," and "including," when used in this specification and the appended claims, are intended to specify the presence of stated features, elements, components, or steps, but do not preclude the presence or addition of one or more other features, elements, components, steps, acts, or groups thereof.
Claims (43)
1. A method of treating a patient with a pulmonary disease, the method comprising:
a dose of aerosolized medicament is intermittently delivered to a ventilator circuit connected to a respiratory system of a patient.
2. The method of claim 1, wherein the intermittent delivery of the aerosolized medicament includes starting and stopping delivery during each inhalation phase of the patient's respiratory cycle.
3. The method of claim 1, wherein the intermittent delivery of the aerosolized medicament includes beginning delivery during each inhalation phase of a respiratory cycle of the patient and stopping delivery during each exhalation phase of the respiratory cycle.
4. The method of claim 1, wherein the intermittent delivery of the aerosolized medicament includes initiating delivery during each exhalation phase of the patient's respiratory cycle.
5. The method of claim 1, wherein the ventilator circuit is in a disconnected configuration from the ventilator.
6. The method according to claim 1, characterized in that the pulmonary disease is selected from the group consisting of: ventilator-associated pneumonia, nosocomial pneumonia, cystic fibrosis, mycobacterial infection, bronchitis, staphylococcal infection, fungal infection, viral infection, protozoal infection, and acute exacerbations of chronic obstructive pulmonary disease.
7. The method of claim 1, wherein the agent comprises an antibiotic.
8. The method of claim 1, wherein the agent is selected from the group consisting of: antioxidants, bronchodilators, glucocorticoids, leukotrienes, protein ester inhibitors, and surfactants.
9. Method according to claim 8, characterized in that the antibiotic is selected from the group consisting of: aminoglycosides, β -lactam esters and quinolines.
10. The method of claim 9, wherein the aminoglycoside comprises amikacin.
11. A method of treating a patient with a pulmonary disease, the method comprising administering to the patient a nebulized aerosol comprising from about 100 μ g to about 500mg of a medicament via a ventilator circuit, wherein at least 40% of the nebulized aerosol is delivered to the patient.
12. The method of claim 11, wherein at least 70% of the aerosolized aerosol is delivered to the patient.
13. The method according to claim 11, characterized in that the administration of the agent is once or twice daily for at least three days.
14. A method of treating a patient with a pulmonary disease, the method comprising:
disconnecting the patient from the ventilator; and
administering to the patient an aerosolized aerosol comprising from about 100 μ g to about 500mg of the medicament.
15. A method according to claim 14, wherein at least 70% of the nebulised aerosol is inhaled by the patient.
16. A method of treating a pulmonary disease, the method comprising administering to a patient a medicament comprising an antibiotic dissolved in an aqueous solution containing sodium chloride, the aqueous solution being adjusted to a pH between 5.5 and 6.3, the administration being by nebulization using a vibratable member with a bore, the vibratable member being configured to produce 70% or more aerosol particles with a mass mean aerodynamic diameter from about 1 μ ι η to about 7 μ ι η.
17. The method of claim 16, wherein the agent is administered for about 1 hour.
18. The method according to claim 16, wherein the agent is administered to the patient once or twice daily.
19. The method according to claim 18, wherein the treatment lasts three days or more.
20. The method according to claim 16, wherein the agent is administered at a dose of about 400mg amikacin.
21. A method of treating a patient with a pulmonary disease, the method comprising:
administering an aerosolized medicament to the patient; and
a second agent that is also useful for treating a pulmonary disease is administered intravenously to the patient.
22. The method of claim 21, wherein the aerosolized medicament and the second medicament share an active ingredient.
23. The method according to claim 22, wherein the active ingredient is an antibiotic.
24. The method of claim 23, wherein the antibiotic comprises amikacin.
25. An aerosolized medicament for treating a pulmonary disease, the medicament comprising amikacin mixed with an aqueous solution having a pH adjusted to from about 5.5 to about 6.3, wherein the pH adjustment is achieved by adding hydrochloric acid and sodium hydroxide to the aqueous solution.
26. The medicament according to claim 25, wherein the amikacin comprises amikacin sulfate.
27. The medicament according to claim 25, wherein the concentration of the medicament is about 125 mg/ml.
28. The medicament of claim 25 further comprising a surfactant.
29. A nebulizer-filter device for delivering an aerosolized medicament to a respiratory system of a patient, the device comprising:
a filter replaceably held in place by connecting together facing first and second holding members;
a first port formed in the first retaining member and a second port formed in the second retaining member;
a nebulizer that generates an aerosolized medicament, the nebulizer being detachably connected to the first port; and
a patient breathing interface removably connected to a second port;
wherein during an inhalation phase of the patient, aerosolized medicament is moved from the nebulizer to the respiratory system of the patient, and during an exhalation phase of the patient, remaining aerosolized medicament passes through the filter.
30. The apparatus of claim 29 wherein a ventilator port is formed in the first retaining member and is removably connected to a conduit that delivers air from the ventilator to the patient respiratory interface.
31. The apparatus of claim 30, wherein air from the ventilator passes through a filter before reaching the patient's respiratory interface.
32. An apparatus according to claim 29, wherein the patient's respiratory interface comprises a mouthpiece, mask or nasal cannula operable to connect to the patient's respiratory system.
33. The apparatus of claim 29, wherein the filter is shaped as a circular disc with an opening in the center of the disc.
34. The device of claim 33, wherein the aerosolized medicament is delivered from the nebulizer to a respiratory interface of the patient through an opening in the disc.
35. A system for aerosolizing a medicament, the system comprising:
an aerosolization chamber for mixing an inhalation gas and an aerosolized medicament;
a first inlet formed within the chamber and connected to the nebulizer, wherein the nebulizer provides aerosolized medicament to the aerosolization chamber through the first inlet;
a second inlet also formed in the chamber and connected to a source of inspiratory gas, wherein the source of inspiratory gas provides inspiratory gas to the aerosolization chamber through the second inlet;
an outlet formed in the aerosol chamber to provide a mixture of the inhalation gas and the aerosolized medicament to a respiratory system of the patient; and
a filter housing connected to the outlet, wherein the filter housing includes a filter that reduces an amount of aerosolized medicament escaping from the system during an exhalation cycle of the patient.
36. The system of claim 35, wherein the outlet comprises a one-way valve that prevents exhaled fluid from the patient from entering the aerosolization chamber.
37. The system of claim 36, wherein the filter housing includes a plurality of openings to allow exhaled fluid to exit the system.
38. The system of claim 37, wherein the exhaled fluid passes through a filter before being expelled through the opening.
39. The system of claim 35, wherein the source of inspiratory gas comprises a ventilator, an air pump, or a source of compressed gas.
40. The system of claim 35, wherein the outlet is connected to a patient respiratory interface.
41. The system of claim 40, wherein the patient's respiratory interface comprises a mouthpiece, a mask, or a nasal cannula operable to connect to the patient's respiratory system.
42. A system for aerosolizing a medicament, the system comprising:
an aerosolization chamber for mixing an inhalation gas and an aerosolized medicament;
a first inlet formed within the chamber and connected to a nebulizer, wherein the nebulizer provides an aerosolized medicament to the aerosolization chamber through the first opening;
a second inlet also formed in the chamber and connected to a source of inspiratory gas, wherein the gas source provides inspiratory gas to the aerosolization chamber through the second inlet; and
an outlet formed within the aerosolization chamber to provide a mixture of an inhalation gas and an aerosolized medicament to a respiratory system of a patient, wherein the outlet comprises a one-way valve that prevents exhaled fluid from the patient from entering the aerosolization chamber.
43. The system of claim 43, wherein a filter housing is connected to the outlet, the filter housing containing a filter that reduces the amount of aerosolized medicament escaping from the system during an exhalation cycle of the patient.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/090,328 | 2005-03-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1117732A true HK1117732A (en) | 2009-01-23 |
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