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HK1105174B - Aerosol delivery apparatus for pressure-assisted breathing systems - Google Patents

Aerosol delivery apparatus for pressure-assisted breathing systems Download PDF

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Publication number
HK1105174B
HK1105174B HK07110456.9A HK07110456A HK1105174B HK 1105174 B HK1105174 B HK 1105174B HK 07110456 A HK07110456 A HK 07110456A HK 1105174 B HK1105174 B HK 1105174B
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HK
Hong Kong
Prior art keywords
flow
patient
nebulizer
gas
aerosol
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HK07110456.9A
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Chinese (zh)
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HK1105174A1 (en
Inventor
J.芬克
Y．伊夫里
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亚罗擎公司
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Priority claimed from US10/828,765 external-priority patent/US7946291B2/en
Priority claimed from US10/883,115 external-priority patent/US7290541B2/en
Priority claimed from US10/957,321 external-priority patent/US7267121B2/en
Application filed by 亚罗擎公司 filed Critical 亚罗擎公司
Priority claimed from PCT/US2005/013488 external-priority patent/WO2005102431A2/en
Publication of HK1105174A1 publication Critical patent/HK1105174A1/en
Publication of HK1105174B publication Critical patent/HK1105174B/en

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Description

Aerosol delivery device for pressure-assisted breathing systems
Background
The present invention relates to devices, methods and formulations for delivering drugs to the respiratory system of a patient via a pressure assisted respiratory system. One aspect of the present invention is an apparatus and method for connecting an aerosol generator, preferably a nebulizer, to a Continuous Positive Airway Pressure (CPAP) system. Another aspect of the invention is an apparatus and method for improving the delivery of aerosolized medicament to a patient connected to a pressure assisted breathing system. Another aspect of the invention is methods and formulations for treating respiratory diseases, particularly those treated with pulmonary surfactant replacement therapy.
Pressure assisted breathing systems and therapies are the traditional form of ventilation therapy used to treat adult and child respiratory disorders. In particular, the existing reports show that: treatment with nasal CPAP ("nCPAP") to support respiration in combination with aerosolized medication, preferably a surfactant, has many advantages in the treatment of infant respiratory distress syndrome ("idrds") in early stage infants (newborns). For example, it has been found that early application of nCPAP to neonates with idrds and early application of nebulized surfactant can effectively reduce the need for mechanical ventilation, thereby reducing the corresponding risk of mechanical injury and infection, as well as other pathophysiological reactions. See, for example, "edit: aerosol treatment of surfactants for respiratory distress syndrome in spontaneously breathing premature infants "; pediatric lung science (pulmontology) 24: 22-224 (1997); "early use of surfactant and NCPAP improves the treatment of infant respiratory distress syndrome"; pediatrics 2004; 11; e560-e563 (as reported online by the Medscape Medical News group on 6/4/2004); and "nebulization of medication in nasal CPAP systems"; pediatric bulletin 88: 89-92(1999).
As used herein, the term "pressure-assisted breathing system" refers to any artificial ventilation system that applies continuous or intermittent pressure, typically positive pressure (i.e., above a reference pressure such as atmospheric pressure), to gas in or near the patient's airways during inhalation as a means of enhancing pulmonary ventilation. Any pressure assisted breathing system may be used in the present invention, which term is intended to include, for example, standard CPAP, nCPAP, and Bi-level CPAP (Bi-level CPAP) systems and mechanical ventilators that are used to perform a respiratory function on a patient and/or provide CPAP to assist the patient in breathing autonomously. The term is also intended to include both invasive and non-invasive systems. Systems employing endotracheal and tracheotomy catheters are examples of interventional pressure-assisted breathing systems. Systems employing nasal tubes and masks are examples of non-invasive pressure-assisted breathing systems.
Pressure assisted breathing systems use positive pressure during inspiration to increase and maintain lung volume and reduce the patient's work of breathing. The positive pressure is effective to inflate the airway and prevent it from collapsing. Delivery of positive airway pressure may be accomplished by a positive air flow source ("flow generator") that provides oxygen or an oxygen-containing gas through a flexible hose connected to a patient interface device such as a nasal cannula, nasopharyngeal or nasopharyngeal cannula, endotracheal tube, face mask, or the like. CPAP devices typically maintain and control continuous positive airway pressure with a gas outlet flow restricting device, such as a fixed orifice, threshold flow resistor, or pressure valve, which regulates the amount of gas exiting the airway to which the patient interface device is connected. The pressure regulating device may be disposed before or after the patient interface device and defines a primary pressure generating circuit.
These tubes, which are connected to commercially available pressure-assisted breathing systems, form a pneumatic circuit for the flow of gases by maintaining fluid communication between the various components of the circuit. These tubes may be made of a variety of materials including, without limitation, various plastics, metals, and composites, which may be rigid or flexible. These tubes may be connected to the various components of the air circuit in a removable or fixed connection by various connectors, adapters, connecting devices, and the like. These components are sometimes collectively referred to herein as a "connecting device".
As an example of such a connection device, a mechanical ventilation system may employ a ventilator circuit that includes an inspiratory tube (which is sometimes referred to as an "inspiratory cannula") that directs the flow of gas from the ventilator and an expiratory tube (or "cannula") that directs the flow of gas back to the ventilator or atmosphere. This circuit (sometimes referred to herein as the "ventilator circuit") communicates with a third tube ("breathing circuit") that directs the flow of gas to the patient interface device via a connecting device, typically a "Y" or "T" shaped tube. Such a connection device may include a first branch conduit connectable to an inspiratory conduit of the ventilator circuit, a second branch conduit connectable to an expiratory conduit of the ventilator circuit, and a third branch conduit connectable to the respiratory circuit. Other connection devices may be employed to connect, for example, a nebulizer or patient interface device to the appropriate airway of the ventilator system.
During conventional CPAP therapy, the patient may generally inhale only a portion of the total flow through the primary pressure generating circuit. For example, we estimate that CPAP flow of 8L/min may typically have about 2L/min of pharyngeal conduit flow. As a result, only 25% of the aerosolized drug introduced into the CPAP flow enters the pharynx. In addition, approximately two-thirds of the aerosolized drug may be lost during exhalation in 25% of this entry into the pharynx, assuming an inhalation/exhalation ratio of 1: 2. Thus, in conventional CPAP systems, only a very small amount, e.g., 10%, of the aerosolized drug may enter the patient interface device. This waste, particularly with extremely expensive surfactant drugs, can make the cost of administering aerosolized drugs via conventional CPAP systems unacceptable for routine clinical use. To reduce these costs, the prior art has addressed a need for improvements in methods of delivering aerosolized medicament, for example, the prior art has addressed a need for a method and apparatus that aerosolizes only upon inhalation.
A bi-level system delivers continuous positive airway pressure but is also capable of sensing when the patient is performing inspiration and expiration movements. The bi-level system responds to these inspiratory and expiratory actions by delivering a high level of inspiratory pressure (IPAP) while the patient inhales to keep the airway open to increase inspiratory capacity to reduce inspiratory effort, and a low level of expiratory pressure (EPAP) while the patient exhales to keep the airway and lungs open while exhaling. Thus, bi-level devices employ pressure sensors and variable pressure control devices to deliver at least two levels of air pressure that are set to coincide with the patient's inspiratory and expiratory actions. Bi-level has been found to be suitable for a wider range of respiratory disorders than CPAP alone, especially for infants and small children.
Aerosol generators in nebulizers have now come into use to deliver an aerosol of medicament through a ventilator into the respiratory system of a patient. For example, US6615824, published 9/2003, and also US 10/465023, filed 18/6/2003, and US 10/284068, filed 30/10/2002, each describe an apparatus and method for connecting a nebulizer to the airway of a ventilator to inject an aerosolized drug directly into the air stream delivered to the respiratory system of a patient.
It is necessary that the therapeutically effective dose of aerosolized drug reach the desired location in the patient's lungs to achieve satisfactory treatment, and it is also desirable that the delivery of the drug be as efficient as possible to minimize losses and waste. Although the effective amount of drug delivered to the patient's airway in nebulized form, such as by a nebulizer connected to a ventilator system, is significantly less than the amount required to deliver a therapeutically effective amount of drug systemically, current systems exhibit inefficiencies. For example, aerosolized particles carried in the airway of ventilator systems and other pressure-assisted breathing systems may become trapped on the inner walls of the tubes, deposit on irregular surfaces and obstructions in the tubes or other components of the airway, strike junctions between tubes of different diameters, or be diverted by sharp angular paths in the airway. In a particular example, aerosolized particles must "turn" as they travel at very high flow rates through the acute angle conduits of the "Y", "T" and "V" shaped connection devices currently used in the pneumatic circuits of conventional pressure-assisted breathing systems. As a result, the atomized particles may impinge on the walls of the connected equipment and a portion of the particles may be diverted from the primary atomized stream into various openings or branches in the gas path. In another example, aerosolized particles may be deposited at the connection of the patient interface device to the breathing tube connecting it to the ventilator circuit, and may be diverted or deposited within the patient interface device itself.
An important feature in all mammalian lungs is the presence of a surface active lining in the alveoli. These surface-active materials are lung surface-active substances composed of protein-lipid mixtures, such as surface-active proteins and phospholipids, which are naturally formed in the lung and are very important for the oxygen-absorbing function of the lung. They are able to continuously adjust the surface tension of the fluid normally present in the air sacs or alveoli lining the inside of the lungs to assist respiration. In the absence of lung surfactant or in the event that the function of lung surfactant is impaired, these balloons collapse and the lungs are unable to absorb sufficient oxygen.
Inadequate or dysfunctional surfactant in the lungs can lead to various respiratory ailments in infants and adults. For example, lung surfactant insufficiency may manifest as iRDS in premature infants, i.e. those born before 32 weeks of gestation, who have not fully developed sufficient amounts of native lung surfactant. Diseases involving lung surfactant dysfunction may include adult respiratory disorders such as Acute Respiratory Distress Syndrome (ARDS), asthma, pneumonia, Acute Lung Infection (ALI), etc., as well as infant diseases such as Meconium Aspiration Syndrome (MAS), in which term infants begin the first bowel movement in the uterus and aspirate meconium into their lungs. In these cases, the amount of lung surfactant may be normal, but the nature of the surfactant has been compromised by foreign matter, lesions, purulent blood and other infections, etc.
Diseases involving surfactant deficiency and dysfunction have historically been managed by administering surfactant material to the lungs, which is sometimes also referred to as surfactant (replacement) therapy. For example, surfactant therapy is now an established part of the clinical routine treatment of newborns with idrds. These surface-active materials are usually naturally occurring or synthetic lung surfactants, but they may also be non-phospholipid substances such as perfluorocarbons. As used herein, the terms "pulmonary surfactant" and "surfactant" include all surface active materials suitable for surfactant therapy. These lung surfactants can be administered in various ways, the simplest being by direct instillation of a liquid solution of the lung surfactant into the lungs. The initial dose usually required is 100mg/kg unit Body Weight (BW) to compensate for the lack of lung surfactant in these infants, and in many cases repeated treatments are required.
Another alternative is treatment with an aerosolized lung surfactant. Aerosol delivery of pulmonary surfactant into the lungs is generally less efficient than direct instillation, mainly because of the large losses of aerosol in the delivery system. In conventional delivery systems, the amount of aerosol reaching the lungs is much less if the particle size is too large, i.e., > 5 μm Mass Median Aerodynamic Diameter (MMAD), or if the aerosol delivery is not coordinated with slow inhalation and breath holding, or if the airway (especially an artificial airway) is too long and narrow. It is estimated that the amount of aerosolized surfactant delivered to the lungs is typically less than 1-10% of the liquid surfactant in the nebulizer, if the most conventional delivery systems are used.
However, testing of animals with the improved aerosol delivery system showed some improvement in efficiency. When using the aerosol method, it was seen that the improvement in gas exchange and mechanical properties was comparable to the instillation technique, but these improvements were only a fraction of the conventional instillation dose of 100mg/kg Body Weight (BW) (see MacIntyre, N.R., "aerosolized drugs for modifying pulmonary surfactant properties". respiratory care 2000; 45(3) -. In an improved aerosol delivery method of the prior art, the use of ultrasonic atomization rather than jet atomization has resulted in improved deposition of atomized surfactant in animal models. It has been reported that with spray atomization the deposition of lung surfactant is only 0.15-1.6 mg/kgBW/hour, but with ultrasonic atomization the deposition of lung surfactant reaches 10 mg/kgBW/hour (7-9 mg/kg BW at 50 min atomization). This is seen, for example, in "ultrasonic nebulization for effective delivery of surfactant in a model of severe lung injury-impact on gas exchange" am.j.respir.crit.careed, by Schermuly R et al; 1997156(2)445-453.
It has been reported that the use of an nCPAP system in conjunction with early lung surfactant instillation to support respiration has many advantages in treating infants with idrds. It has now been found that such treatment can effectively reduce the need for mechanical ventilation, thereby reducing the risk of mechanical injury and infection, as well as the pathophysiological response, but still requires intubation for the treatment with a surfactant. This is for example seen in the above "early use of surfactants and NCPAP improves the therapeutic effect of respiratory distress syndrome in infants".
Aerosol delivery of lung surfactant to infants weighing less than 5kg has been limited, primarily because the amount required is small and the flow rates of existing nebulizers and ventilation support devices are relatively high. It has been shown that premature infants, with and without ventilators, receive less than 1% of the nebulizer dose in their lungs. See "comparison of aerosol drug delivery efficiency from metered dose inhaler versus jet nebulizer in bronchopulmonary dysplastic infants". Pediatric lung, 5 months 1996; 21; (5): 301-9. There is little experimental data to suggest that nCPAP can be more effective because most animal and in vitro CPAP models demonstrate less than 3% deposition.
It has now been found that aerosol therapy (with a jet nebulizer) with simultaneous administration of surfactant in conjunction with a CPAP system is clinically feasible and results in better breathing parameters. See, for example, "edit by Jorch G et al: aerosol treatment of surfactants for respiratory distress syndrome in spontaneously breathing premature infants "; pediatric lung science (pulmontology) 24: 22-224(1997) and Smedsaas-Lofvenberg A, "nebulization of medication in nasal CPAP System"; pediatric bulletin 88: 89-92(1999). However, we have found that the loss of aerosolized lung surfactant and other aerosolized drugs used in CPAP systems is unacceptably high, primarily due to the continuing inefficiency of the delivery system. The authors suggested that as much as 10% of aerosolized surfactant could enter the pharyngeal conduit to which the patient's respiratory system was connected, but they did not test to quantify the assessment of such delivery (Jorch G et al, supra).
Several studies have been carried out in an attempt to combine nebulized surfactant with high frequency ventilation of infants with idrs and have been tried in the treatment of airway diseases such as cystic fibrosis and chronic bronchitis, which work has only been partially successful, again due to the inefficiency of the delivery systems used. (Mcintyre, supra).
It would therefore be desirable to find a way to improve the delivery of aerosolized particles in pressure-assisted breathing systems and reduce the loss of aerosolized particles in pressure-assisted breathing systems. The efficiency of the delivery of aerosolized drug is improved, resulting in a lower dose required for treatment, which is particularly useful for surfactant replacement therapy, where lung surfactant is very scarce and expensive.
Disclosure of Invention
In one embodiment, the invention provides a pressure assisted breathing system comprising: a pressure generating circuit for maintaining a positive pressure in the system; a patient interface device; and a breathing circuit for providing gas communication between the pressure generating circuit and the patient interface device, wherein a nebulizer is connected to the breathing circuit instead of the pressure generating circuit. The pressure generating circuit may include a tube connecting a flow generator to a pressure regulating device, wherein the flow generator generates a volume of gas flow through the tube, and wherein the pressure regulating device is configured to maintain CPAP. The breathing circuit may provide a small positive pressure flow of gas from the pressure generating circuit to the patient interface device for inhalation by the patient. The breathing circuit may include a tube connected at one end to the pressure generating circuit and at the other end to the patient interface device.
The nebulizer is connected to the breathing circuit and is adapted to inject a nebulized drug directly into a portion of the total air flow inhaled by the patient, preferably directly into the vicinity of the patient's nose, mouth or airway, thereby eliminating the dilution effect of introducing the nebulized drug into the bulk air flow of the pressure generating airway. Atomizers suitable for use in the present invention preferably comprise: a reservoir for containing a liquid medicament to be delivered to the respiratory system of a patient; a vibrating orifice type aerosol generator for atomizing the liquid medicine; and a connector for connecting the nebulizer to the breathing circuit. Particularly preferred atomizers of the invention are light and small. Such "miniature" nebulizers may have a very small reservoir to hold a unit dose of medicament and a light weight aerosol generator, such as an aerosol generator on the order of about 1gm in weight. Furthermore, the preferred nebulizer is very quiet in operation, e.g. it produces only less than 5 db of sound pressure, and can therefore be conveniently placed in close proximity to the patient's airway.
The present invention also provides a method of respiratory therapy comprising the steps of: providing a pressure assisted breathing system having a pressure generating circuit for providing positive airway pressure and a breathing circuit connected to the pressure generating circuit for providing a flow of gas to the patient's breathing system; and introducing an aerosolized medicament only into the flow of the breathing circuit. The present invention also provides a method of delivering a surfactant to the respiratory system of a patient.
In one embodiment of the present invention, the delivery efficiency of an aerosolized drug is greatly enhanced by eliminating the sharp corners or turns encountered by aerosol particles flowing in the airway of a pressure-assisted breathing system. In particular, the present invention provides devices and methods that provide a straight or slightly curved flow path for aerosol particles from an aerosol generator to introduce the aerosol particles into the flow of an air stream between the aerosol particles and the patient's respiratory system, thereby improving the efficiency of delivery of the aerosol medicament to the patient.
In a preferred embodiment, the present invention provides a pressure-assisted breathing system comprising a flow generator, a gas circuit connecting the flow generator to a patient's breathing system and an aerosol generator for emitting aerosol particles of a medicament into the gas circuit, wherein the gas circuit defines a flow path for said aerosol particles which has an angular variation of no more than 15 degrees, preferably no more than 12 degrees, more preferably no angular variation.
In another embodiment, the present invention provides a connection device for connecting various flexible hoses that comprise a pneumatic circuit of a pressure assisted breathing system. For example, the present invention provides a connector apparatus comprising (i) a tubular body member having a longitudinal cavity extending the full length thereof for directing a first gas stream carrying aerosol particles; and (ii) a tubular branch member in fluid communication with the longitudinal cavity for directing a second gas stream substantially free of said aerosol particles into or out of the longitudinal cavity. The connection device may further include: (iii) an opening is provided for connecting the aerosol generator to the body member, thereby introducing aerosol particles into the first air stream. A vibrating orifice type aerosol generator is preferably disposed in the opening such that the vibrating plate is flush with the inner surface ("wall") of the longitudinal cavity so that the emitted aerosol particles do not drag on the cavity walls. The invention also provides a ventilation system using the connecting device. Another embodiment of the present invention provides an improved nasal cannula for delivering aerosolized medicament to a patient.
In another embodiment, the present invention provides a ventilation system including a ventilation circuit and a patient interface device coupled to the ventilation circuit, wherein a nebulizer is disposed between the patient interface device and the ventilation circuit. In a further embodiment, a second atomizer is arranged in the venting circuit on the connection device of the invention.
In one embodiment, the present invention provides a method of delivering an aerosolized medicament to the respiratory system of a subject, comprising the steps of: coupling the subject to a pressure-assisted breathing system comprising an air flow generator, an airway coupling the air flow generator to the breathing system of the subject and an aerosol generator for projecting particles of the pharmaceutical aerosol into the airway, the airway defining a flow path for said aerosol particles that varies by an angle of no more than 15 degrees, preferably no more than 12 degrees, more preferably no angle; the pharmaceutical aerosol particles are then administered to the subject via the pressure assisted breathing system.
In other embodiments, the present invention provides a pressure assisted breathing system, such as a CPAC system, comprising: a pressure generating circuit for maintaining a positive pressure in the system; a patient interface device connected to a patient respiratory system; a breathing circuit for establishing gas communication between the pressure generating circuit and the patient interface device; means for introducing aerosol particles, such as an aerosolized drug, into the air stream of the breathing circuit; and means for interrupting the introduction of the aerosol particles into the breathing circuit upon expiration by the patient. The means for interrupting the introduction of aerosol particles may comprise a flow sensor disposed in an auxiliary circuit in fluid communication with the breathing circuit and electrically connected to the means for introducing aerosol particles into the flow of breathing circuit. A small part of airflow in the breathing gas circuit is diverted to flow through the flow sensor through the auxiliary gas circuit. Preferably, the flow rate in the auxiliary gas path should be adjusted to correspond to the middle of the flow rate measurement range of the flow rate sensor. Preferably, the flow sensor is adapted to detect small changes in the volumetric flow of gas in the auxiliary circuit and to send a corresponding electrical signal to the means for introducing aerosol particles into the breathing circuit.
In one embodiment of the invention, the means for introducing aerosol particles comprises an atomiser, more preferably the atomiser has: a reservoir for containing a liquid medicament to be delivered to the respiratory system of a patient; a vibrating orifice type aerosol generator for atomizing the liquid medicine; and a connector for connecting the nebulizer to the breathing circuit so as to entrain nebulized medicament from the aerosol generator into the gas flowing through the breathing circuit. As previously mentioned, the nebulizer is preferably electrically connected to the flow sensor through the circuitry of the CPAP system.
As with conventional CPAP operation, the CPAP system of the present invention maintains a constant flow of air in the breathing circuit (hereinafter "inspiratory flow") during inspiration by the patient. In the use of the invention, the air flow corresponding to the suction air flow but with a smaller flow rate is diverted into the auxiliary air passage. An adjustable valve, such as a damper valve, is preferably provided in the auxiliary air path to regulate the flow of air through the flow sensor. The valve may be used to reduce the flow of gas in the breathing circuit to a range that can be detected by the flow sensor, and preferably to the middle of that range. It is particularly preferred that the flow sensor has a flow rate in the range of 0 to 1 liter per minute ("L/min").
As the patient exhales, the flow of gas in the breathing circuit (and corresponding auxiliary circuit) increases due to the additional flow of gas generated by the patient's lungs (hereinafter referred to as "expiratory flow"). In a preferred embodiment, a flow sensor senses a change in flow rate of the auxiliary circuit corresponding to an expiratory flow in the breathing circuit and generates an electrical signal to turn off an aerosol generator of the nebulizer. When the expiratory airflow stops, the flow sensor detects a decrease in flow in the auxiliary air path and stops sending electrical signals to the nebulizer. As a result, the nebulizer turns on and continues to introduce aerosol particles into the breathing circuit. Thus, the system of the present invention is able to stop delivering aerosol particles during patient exhalation so that aerosol particles are only introduced into the breathing circuit during patient inhalation.
A disposable filter is preferably disposed in the auxiliary gas circuit upstream of the flow sensor. Bacteria, viruses or other contaminants from the patient's respiratory system may be present in the flow of the secondary air circuit as a result of a portion of the exhaled air flow being diverted into the secondary air circuit. The filter can remove these contaminants before the air stream passes through the flow sensor, preferably with a new filter for each new patient when using the device. This feature allows the flow sensor to be connected to the CPAP system circuitry at all times and remain in place without contamination from patient to patient when the device is used.
The present invention also provides a method of respiratory therapy in which a nebulized drug is introduced into a pressure-assisted breathing system only when the patient inhales. In another embodiment, the present invention provides a method of delivering an aerosol into a respiratory system of a patient, comprising the steps of: (a) providing a pressure assisted breathing system having a breathing circuit that provides a constant inspiratory flow to the patient during inspiration and generates an additional expiratory flow during expiration; (b) providing an auxiliary circuit to divert a portion of the total flow of air in the breathing circuit to a flow sensor; (c) measuring the flow in the auxiliary circuit with a flow sensor when the total flow in the breathing circuit includes only inspiratory flow, thereby generating a first electrical signal; (d) measuring the flow in the auxiliary circuit with a flow sensor when the total flow in the breathing circuit comprises an inspiratory flow and an expiratory flow, thereby generating a second electrical signal; (e) a nebulizer is provided that is electrically connected to the flow sensor and is capable of introducing the pharmaceutical aerosol particles into the breathing circuit upon detection of the first electrical signal and ceasing introduction of the pharmaceutical aerosol particles into the breathing circuit upon detection of the second electrical signal.
The present invention also provides an improved method for treating conditions involving a deficiency or dysfunction of surfactant in the lungs of a patient. In one embodiment, the method of the present invention comprises the steps of: providing a liquid lung surfactant preparation; nebulizing the lung surfactant preparation with a vibrating orifice aerosol generator to form a lung surfactant aerosol; and introducing the aerosol of pulmonary surfactant into an air flow in an airway of a pressure assisted breathing system, preferably a CPAP system, connected to the patient's respiratory system, thereby delivering a therapeutically effective amount of pulmonary surfactant to the patient's lungs. Preferred pulmonary surfactants include natural surfactants eluted from the lungs of animals as well as synthetic pulmonary surfactants.
In one embodiment, the vibrating orifice type aerosol generator of the present invention can use a liquid surfactant formulation, such as a lung surfactant formulation having a concentration of 20mg/ml to 120 mg/ml. The diluent may be any pharmaceutically acceptable diluent, such as water or physiological saline.
In another embodiment, 10-90%, preferably more than 30%, of the active lung surfactant provided to the aerosol generator is delivered to the airway of the patient and inhaled by the patient. Preferably, between 5 and 50% of the active lung surfactant is actually deposited in the lungs of the patient. In the practice of the present invention, a therapeutically effective amount (unit dose) of lung surfactant delivered to the lungs of a patient may be in the range of 2-400 mg. The flow rate of the vibrating orifice type aerosol generator of the present invention can be in the range of 0.1-0.5ml/min (milliliters/minute), which is much higher than the flow rate of comparable aerosol generators. Preferably, the delivery rate of the active surfactant to the airways of the patient is in the range of 2-800mg/hr (mg/hr). Preferably, the aerosol generator is tuned to produce a surface active substance having a particle diameter of less than 5 μm MMAD, most preferably 1-3 μm MMAD.
In one embodiment, the aerosol generator may be positioned to introduce the aerosol of surface active substance into a plenum chamber located outside the direct breathing circuit of the CPAP system, thereby enriching the concentration of the aerosol of surface active substance prior to discharge into the breathing circuit above that which would be produced by the aerosol generator alone.
Drawings
FIG. 1 is a schematic illustration of an embodiment of a CPAP system with a nebulizer;
FIG. 2 is a schematic illustration of another embodiment of a CPAP system of the present invention;
FIG. 3 is a perspective view of a CPAP apparatus of the present invention;
FIG. 4 is a perspective view of an atomizer device of the present invention;
FIG. 5 is a side sectional view of the atomizer device of FIG. 4;
FIG. 6 is a perspective view of a mask CPAP apparatus of the present invention;
FIG. 7 is a perspective view of an alternative CPAP construction in accordance with the present invention;
FIG. 8 is a schematic diagram of a pressure assisted breathing system with a "Y" shaped connection;
FIG. 9 is a cross-sectional view of the "Y" shaped connecting device of FIG. 8;
FIG. 10 is a schematic view of a pressure assisted breathing system with a connection device of the present invention;
FIG. 11 is a cross-sectional view of a connection device of the present invention;
FIG. 12 is a cross-sectional view of another attachment apparatus of the present invention;
FIG. 13 is a perspective view of a ventilator and breathing circuit of a pressure assisted breathing system of the present invention;
FIG. 14 is a cross-sectional view of the breathing circuit of FIG. 13;
FIG. 15 is a perspective view of a portion of an nCPAP system of the present invention;
FIG. 16 is a perspective view of the nasal cannula of FIG. 15;
figure 17 is a schematic illustration of an embodiment of a CPAP system in accordance with the present invention,
the CPAP system is provided with an auxiliary air passage containing a flow sensor;
FIG. 18 is a cross-sectional view of the CPAP system of FIG. 17;
FIG. 19 is a schematic illustration of a CPAP system of example 2;
FIG. 20 is a diagrammatic representation of an embodiment of the present invention when a gas collection chamber is employed;
FIGS. 21a and 21b are graphical representations of models used in determining aerosol delivery during nCPAP using a pattern that simulates infant breathing;
fig. 22 is a graphical representation of the inhalation mass range of the three types of nebulizers with nCPAP during simulation of infant ventilation using the model shown in fig. 21a and 21 b.
Detailed Description
Fig. 1 is a schematic diagram of a CPAP system 100 employing a nebulizer. The CPAP system 100 includes a primary pressure generating circuit P and a breathing circuit R. The gas circuit P comprises a flow generator 2 in fluid communication with a pressure regulating device 3. Breathing circuit R includes a patient interface device 4 in fluid communication with circuit P at connection point 5. The atomizer 6 is in fluid communication with the gas path P at a connection point 7 upstream of the connection point 5. In operation, a large volume of gas flow 8 is introduced into the gas path P from the flow generator 2 and flows to and through the pressure regulating device 3 to maintain a positive pressure in the system. The nebulizer 6 projects a nebulized drug 9 into the air flow 8 at the connection point 7, thereby forming a mixed air flow 10 containing the drug 9. The gas stream 10 flows through the connection point 5 and is fed to the pressure regulating device 3, which is finally fed to the atmosphere as part of the gas stream 12.
As the patient attempts to inhale through patient interface device 4, the momentary drop in pressure in breathing circuit R creates an inspiratory flow 13, which is inhaled from circuit P into circuit R and ultimately into the patient's respiratory system through patient interface device 4. As shown, the inhalation airflow 13 contains at least a portion of the medicament 9 entrained in the airflow 10. The exhalation motion of the patient through patient interface device 4 causes a momentary rise in pressure within breathing circuit R, thereby causing an expiratory flow of gas 14 from the patient interface device to flow through breathing circuit R to circuit P at connection point 5. The exhaled gas flow 14 merges with the gas flow 10 in the pressure-regulating gas circuit P at the connection point 5 to form a gas flow 11, which gas flow 11 in turn flows via the pressure-regulating device 3 as a gas flow 12 to the atmosphere.
A bi-level system is similar to system 100, but may employ a variable flow valve coupled to a pressure sensor to vary the pressure in breathing circuit R to coincide with the patient's breathing cycle. An interventional CPAP system is also similar to system 100, but employs, for example, an endotracheal tube as patient interface device 4.
In the embodiment of fig. 1, the aerosolized drug may be diluted by the large amount of air flowing through the pressure generating circuit and a portion of the drug may eventually be lost to the atmosphere and never reach the patient. The greater the amount of airflow in the pressure generating circuit, the smaller the percentage of aerosolized medicament in the flow of breathing air flowing through the patient interface device to the patient's respiratory system. For example, if an infant breathes from a total flow of 10 liters/minute through the pressure generating circuit of 0.2 to 0.6 liters/minute, the infant may inhale only a small percentage, e.g., 2-6%, of the aerosolized drug carried by the flow in the main pressure generating circuit.
In one aspect of the invention, delivery of aerosolized medicament to a pressure-assisted breathing system is achieved in an efficient manner without the aforementioned dilution or loss of medicament. One such configuration may relate to an improved CPAP or bi-level system that introduces a nebulized drug directly into the patient's inhaled air stream outside of the air stream in the primary pressure generating circuit during respiratory therapy. Such CPAP or bi-level systems may also be configured to use small amounts of liquid medication, e.g., 4ml or less of a unit dose, at each treatment. Also, the CPAP or bi-level system employs a nebulizer having a small, small volume reservoir, thereby providing a highly effective respiratory therapy method for smaller patients with CPAP or bi-level systems.
Referring now to fig. 2, one embodiment of a CPAP device incorporating the present invention will be described. Like parts in fig. 2 to those in fig. 1 have been given the same reference numerals.
The CPAP system 200 includes a primary pressure generating circuit P and a breathing circuit R. The term "gas path" as used herein refers to the path of a gas (or other fluid) between two points. The gas circuit P comprises a flow generator 2 in gaseous communication with a pressure regulating device 3. Respiratory circuit R includes a patient interface device 4 in gaseous communication with circuit P at connection point 5. Unlike the CPAP system 100 shown in fig. 1, the nebulizer 6 in the CPAP system 200 communicates with the breathing circuit R at a connection point 15 outside the pressure generating circuit P. During operation of the CPAP system 200, a volume of gas flow 8 is introduced into the airway P from the flow generator 2 and flows to and through the pressure regulating device 3 to maintain positive pressure in the system.
As the patient attempts to inhale through patient interface device 4, the pressure within breathing circuit R may momentarily drop causing inspiratory flow 18 to be drawn from circuit P into breathing circuit R and ultimately into the patient's respiratory system via patient interface device 4. Nebulizer 6 injects nebulized drug 9 into inspiratory air flow 18 at connection point 15, thereby forming air flow 19 with drug 9 entrained therein, which is carried through patient interface device 4 into the respiratory system of the patient. The medicament 9 is thus only injected into the airflow inhaled by the patient, thereby greatly improving the efficiency of delivery of the medicament 9 to the patient. The expiratory motion of the patient through patient interface 4 causes a momentary rise in pressure, thereby causing an expiratory flow of gas 14 from the patient interface to flow through respiratory pathway R to pathway P at connection point 5. The exhaled gas flow 14 merges with the gas flow 8 at the connection point 5 to form a gas flow 16, which gas flow 16 flows through the pressure regulating device 3 to the atmosphere as a gas flow 17. As shown in FIG. 2, the CPAP system 200 delivers a larger portion of the drug 9 directly to the patient in a smaller diluted amount and with a smaller amount lost to the atmosphere as compared to the CPAP system 100.
Fig. 3 illustrates an embodiment of the present invention that is particularly suited for use in CPAP treatment of neonates and infants. Referring now to fig. 3, the primary pressure generating circuit P may include a gas conduit, such as a flexible hose 32, that receives the bulk flow of gas generated by the flow generator 31. The flexible hose 32 directs the air flow through the connection means 33 to a flexible hose 35, which flexible hose 35 continues to carry the air flow to the pressure regulating device 34. The pressure regulating device 34 may be connected to a controller (not shown) that regulates the pressure in the system to the desired CPAP. Breathing circuit R may include a gas conduit, such as flexible hose 36, connected to a nebulizer 38, wherein nebulizer 38 is connected to patient interface device 39 either directly (not shown) or through a short length of flexible hose 36. As previously mentioned, nebulizer 38 is preferably disposed next to patient interface device 39.
Flexible hose 36 is preferably thinner, softer and of smaller diameter than flexible hoses 32 and 35. For example, the flexible hose 36 may be a commercially available silicone tube having an outer diameter of about 5 mm. The softer texture of flexible hose 36 allows the patient's head to move more freely without disconnecting patient interface device 39 from the patient's head.
Flow generator 31 may generally comprise any known source of pressurized gas suitable for use in a pressure assisted breathing system such as a CPAP or bi-level system. Generally, the flow generator is capable of providing a large gas flow at a pressure slightly greater than atmospheric pressure, which gas flow should include at least a portion of the oxygen. For example, the pressurized gas source may be a blower or a ventilator (as shown in fig. 3), or the pressurized gas may be generated by wall gas and/or oxygen supply means as seen by hospitals or medical institutions, or by a pressure tank or tanks. The pressurized gas may comprise various known mixtures of oxygen and air, nitrogen or other gases, which may be provided in a single stream as shown by element 8 in fig. 2 or may flow to the breathing circuit R.
The pressure regulating device 34 may comprise any known device capable of controlling and maintaining air pressure at a desired pressure level in a CPAP or bi-level system. Typically, the pressure regulating device 34 may include a gas outlet flow restricting device such as a pressure valve or threshold resistor (threshold) to regulate the flow of gas exiting the pressure regulating circuit P. The resistance to airflow may be varied to tailor the continuous positive airway pressure introduced by breathing circuit R to patient interface device 39 to the needs of the particular patient for which the apparatus is being used. Although the pressure regulating device 34 is usually arranged downstream of the connection means 33, it may also be arranged at the connection means 33 or upstream thereof.
The connection device 33 is where the breathing circuit R is in gaseous communication with the main pressure generating circuit P. The connection device 33 may comprise a "T" or "Y" shaped hollow device (sometimes referred to as a "WYE") to which the flexible hoses 32, 35 and 36 are connected. As shown in fig. 3, the connection device 33 may comprise an inlet arm 33a and an outlet arm 33b which together define a main gas duct through the body of the connection device 33. The breathing arm 33c defines a branch gas conduit that branches from and is in gaseous communication with the main gas conduit. A flexible hose 32 from the flow generator 31 is connected to the upstream opening of the inlet arm 33a, while a flexible hose 35 leading to the pressure regulating device 34 is connected to the downstream opening of the outlet arm 33b, thereby forming a pressure generating air passage P. Flexible hose 36 is connected to a downstream opening of breathing arm 33c and forms, together with patient interface device 39, breathing circuit R.
Patient interface device 39 is connected to nebulizer 38 either directly or through a short length of flexible hose of the same size and material as tube 36. Patient interface device 39 may comprise any known device capable of providing gas communication between a CPAP device and a patient's respiratory system. For example, the patient interface device may include a nasal cannula (as shown), a mouth/nose mask, a nasal mask, a nasopharyngeal cannula, an endotracheal tube, a tracheotomy tube, a nasopharyngeal tube, and the like.
A nebulizer 38 is disposed in breathing circuit R between primary pressure generating circuit P and patient interface device 39 so as to emit a nebulized drug into the flow of gas inhaled by the patient within breathing circuit R. Vibrating orifice atomizers are preferred atomizers for the present invention, see for example, U.S. patent documents US6615824, 5164740, 5586550, 5758637 and 6085740 and the unauthorized US patent application 10/465023 filed 6/18/2003 and 10/284068 filed 10/30/2002. The entire disclosures of said patents and applications are incorporated herein.
A particularly preferred nebulizer is a "micro" nebulizer 38 of the latest type of Pulmonary Drug Delivery System (PDDS) as shown in fig. 4 or marketed by Aerogen. As shown in FIG. 4, the atomizer 38 may include a cylinder 41 that is small in size, for example, about 15mm in outside diameter and about 20mm in length. The barrel 41 may have an upper port 42 at one end and may be connected to a generally L-shaped arm 43 at the other end. The distal end of arm 43 includes a generally "T" shaped connection 44 having an inlet mouth 45 and an outlet mouth 46. As shown in FIG. 3, connection of nebulizer 38 to breathing circuit R via connector 44 is accomplished by sliding the downstream end of tube 36 over inlet nozzle 45 and connecting patient interface 39 directly or through a short length of tube 36 to outlet nozzle 46. The cartridge 41 also includes a retaining clip 47 that includes a recessed channel 48, the retaining clip 47 being capable of gripping the flexible hose 36 to further secure and support the atomizer 38 on the tube 36. The atomizer 38 is preferably light, for example, 5gm or less, and most preferably 3gm or less, by net weight (without liquid). Particularly preferred atomizers of the invention have a dry weight of 1-2 gm.
Referring now to fig. 5, the cartridge 41 of the nebulizer 38 may include a reservoir 51 therein for holding a liquid medicament to be delivered to the respiratory system of a patient, and the nebulizer 38 may also include a vibrating orifice type aerosol generator 52 for nebulizing the liquid medicament. The upper port 42 may be used to deliver liquid medicament into the reservoir 51 and may be provided with a removable stopper (not shown) to seal the port 42. The reservoir 51 is sized to hold a small amount of medicament, for example a volume of 4ml or less, preferably 1-3 ml. The aerosol generator 52 may be arranged at the lower drug outlet 54 of the reservoir 51 to allow the liquid drug to flow by gravity from the reservoir 51 to the aerosol generator 52 (flow G).
The aerosol generator 52 may include a piezoelectric element and a vibrating member having a plurality of tapered holes extending between a first surface and a second surface thereof. Typical vibrating orifice type aerosol generators are described in detail in the previously cited U.S. patent documents US5164740, 5586550, 5758637, and 6085740, which are incorporated herein by reference in their entirety. Generally, the upwardly facing first surface of the vibrating member receives liquid medicament from the reservoir 51 and droplets of medicament are ejected from the orifices as the vibrating member vibrates, thereby forming aerosolized medicament at the second surface of the vibrating member. The aerosol generator of the present invention is preferably light and small, for example, about 1 gm.
The aerosol generator 52 is positioned to facilitate the flow of liquid medicament from the reservoir 51 to the aerosol generator 52 and to facilitate the flow of aerosolized medicament from the aerosol generator 52 into the arm 42. Arm 42 may include a supply tube 55 having one end in fluid communication with aerosol generator 52 and the other end in fluid communication with connection 93 so as to direct the stream of aerosolized drug (stream a) toward connection 93. The connection means 93 may comprise a gas duct 56 defined at one end by the inlet duct 57 in the inlet nozzle 45 and at the other end by the outlet duct 58 in the outlet nozzle 46. The gas conduit 56 of the connection device 93 may be small, for example less than 10cc in volume for use by infants, thereby reducing dead space in the breathing circuit.
The downstream end of flexible hose 36 (fig. 3) may be connected to inlet nozzle 45 of connection device 93 to direct flow B of the breathing gas circuit into inlet conduit 57 of gas conduit 56 of connection device 93. The stream a of aerosolized drug in the gas supply conduit 55 flows into the gas conduit 56 of the junction device 93 and the aerosolized drug is entrained in the stream B in the gas conduit 56. The entrained mixture of aerosolized drug and gas (flow AB) then exits gas line 56 through outlet line 58 in outlet nozzle 46 and continues to flow to the patient's respiratory system.
The atomizer 38 may be connected to a controller (not shown) for controlling the operation of the aerosol generator and for powering it. Preferably, the controller and other electronic components are connected by small, flexible wires, cables and connectors. Other components that may be associated with the nebulizer 38 may be, for example, a timer, a status indicating device, a liquid medication supply tube or syringe, etc., all of which are known to those skilled in the art and described in detail in the aforementioned patents and applications.
The miniature vibrating orifice atomizer of the present invention is so small and quiet that it can be placed in close proximity to the mouth, nose or artificial airway of a patient. Such placement further ensures that the aerosolized drug is introduced directly into the airflow (i.e., into the breathing circuit) inhaled by the CPAP patient and eliminates the dilution effect caused by the introduction of the drug into the large volume of airflow (i.e., the pressure generating circuit) generated by the flow generator. Figure 6 illustrates a typical adult CPAP/bi-level system comprising a flow generator 501 connected by a single flexible hose 502 to a nasal or full face mask 503. The pressure is maintained by the gas flow leaking through fixed holes in the rotary valve 504 between the tube 502 and the face mask 503. In an alternative embodiment, the fixation holes 505 may be disposed at the top of the mask 503 (over the bridge of the nose). In both embodiments, the entire breathing circuit R is contained within the patient interface device. The nebulizer 506 is connected to the face mask 503 so that the aerosolized drug exits the nebulizer directly into the breathing circuit around the patient's mouth and nose. In this way, the efficiency of the system is increased by reducing the stroke that the aerosolized drug must travel, i.e., reducing the length of the breathing circuit. In another embodiment, the aerosol generator operates only when the patient inhales, further increasing the efficiency of the system.
Figure 7 shows another embodiment of the present invention suitable for use in adults. The CPAP device 700 includes a flexible hose 701, the flexible hose 701 being used to direct an airflow F from a flow generator (not shown) through a "Y" connection 703 and a flexible hose 702 to a pressure regulating device (not shown) to form a pressure generating circuit P. Elbow connection 704 connects pressure generating circuit P to breathing circuit R at connection 703. Breathing circuit R includes a relatively small flexible hose 705 for conducting flow I from elbow 704 to a patient interface device (not shown). A nebulizer 706 is disposed on tube 705, as previously described, to entrain nebulized drug into the airflow I inhaled by the patient.
Figure 8 schematically illustrates an aeration system employing an atomizer. The ventilator system 800 includes a ventilator circuit V in fluid communication with a breathing circuit R. One component is "in fluid communication" with another component when it is connected to the other component by a passageway, opening, tube, or other conduit capable of allowing the passage of a gas, vapor, or the like.
The circuit V includes an airway device 802 in fluid communication with an inspiratory tube 803 and an expiratory tube 804, with the inspiratory tube 803 and expiratory tube 804 merging into a "Y" shaped junction 805. Breathing circuit R includes a patient interface device 806 in fluid communication with circuit V at connection 805. Atomizer 807 is in fluid communication with gas path V at a junction 808 upstream of junction 805. In operation, a pressurized gas stream 809 is introduced from the breather 802 into the suction duct 803 to and through the connection point 808. Nebulizer 807 injects a nebulized drug 810 into an air stream 809 at junction 808 to form a mixed air stream 811 containing the nebulized drug 810. The flow of gas 811 flows through the connection 805 and to the patient interface 806 and is ultimately delivered to the patient's respiratory system via the patient interface 806 when the patient inhales. The exhalation action of the patient through the patient interface 806 creates an exhalation flow 812 that flows from the patient interface 806 through the connection 805 to the exhalation tube 804 and back to the ventilator 802.
Referring now to fig. 9, connection 905 comprises branch inspiratory tube 921, which is connectable to inspiratory tube 903, branch expiratory tube 922, which is connectable to expiratory tube 904, and branch breathing tube 923, which is connectable to breathing circuit R. The airflow 911 (containing the medicament aerosol particles) flows from the inhalation tube 903 into the inhalation manifold 921 and then encounters an acute angle change in its flow path (denoted by Δ 1) at the junction 924. As the airflow 911 attempts to turn through the acute angle at the junction 924, a portion of the airflow 911 strikes the encountered tube wall and ridge at the junction 924. As a result, a portion 911a of the airflow 911 (and entrained aerosol particles of medicament) may pass to the expiratory limb 922 and be lost through the expiratory limb 904. The remaining portion of the gas flow 911 continues through the breathing manifold 923 and to the breathing gas circuit R. During exhalation, the exhaled gas flow 912 flows from breathing circuit R through branch breathing tube 923, branch exhalation tube 922, and exhalation tube 904 back to the ventilator (not shown).
Referring now to fig. 10, one embodiment of a mechanical breather system in accordance with the present invention will be described. The ventilator system 1000 includes a ventilator circuit V and a breathing circuit R. The ventilator circuit V includes a ventilator 1002 in fluid communication with an inspiratory tube 1003 and an expiratory tube 1004, wherein the inspiratory tube 1003 and the expiratory tube 1004 converge into a connection 1035 in accordance with the present invention. Respiratory circuit R includes a patient interface device 1006, which is in fluid communication with circuit V at connection 1035. The atomizer 1007 may be connected to and in fluid communication with a connection 1035. Alternatively, the atomizer 1007' may be connected to and in fluid communication with the aspirator 1003. During operation of the aerator system 1000, a pressurized gas stream 1009 is introduced from the aerator 1002 into the aspirator 1003 and flows to and through the connecting device 1035. The nebulizer 1007 (or 1007') ejects a nebulized drug 1010 into the air stream 1009 to form a mixed air stream 1011 containing aerosol particles of the drug 1010. Gas stream 1011 is delivered to patient interface device 1006 via connection 1035 and ultimately to the patient's respiratory system. The exhalation action of the patient through patient interface 1006 creates an exhalation gas flow 1012 from the patient interface device through connection 1035 to exhalation tube 1004 and back to ventilator 1002.
As shown in fig. 11, one embodiment of the coupling device 1135 may include a tubular body member 1141 having a generally longitudinal cavity 1142 with an opening at a first end 1143 connectable to the inspiratory line 1103 and an opening at a second end 1144 connectable to the respiratory circuit R. The coupling device 1135 may further include a manifold member 1145 having a cavity 1146, the cavity 1146 communicating with the cavity 1142 at a central opening 1147. An air stream 1111 (containing aerosol particles of medicament entrained in an air stream 1009 ejected into the inhalation tube 1003 by the nebulizer 1007' -see figure 10) flows from the inhalation tube 1103 into the cavity 1142 through an opening in the first end 1143. Unlike the "Y" shaped connector 905 of FIG. 9, the air flow 1111 (containing the aerosolized drug therein) provided by the connector 1135 flows along a straight unobstructed path to the breathing air circuit R, wherein no portion of the air flow passes to the branch 1145. In other words, the flow path of the air flow 1111 is substantially free of angular variation. As a result, all of the medicament aerosol particles contained in the air stream 1111 are efficiently delivered to the patient via the breathing circuit R. During exhalation by the patient, exhaled air 1112 flows from breathing air path R through cavity 1142 to cavity 1146 of manifold assembly 1145 and back to the ventilator (not shown) via exhalation tube 1104.
In another embodiment of the invention shown in fig. 12, the connection device 1250 includes a tubular body member 1251, a branch member 1254 (which is connectable to the exhalation tube 1104 of fig. 11), and an opening 1255 which is connectable to a nebulizer (not shown), wherein the tubular body member 1251 has a first end 1252 (which is connectable to the inhalation tube 1103 of fig. 11) and a second end 1253 (which is connectable to the breathing circuit R of fig. 11). A flow of gas 1209 from the breather 1002 (fig. 10) flows into the cavity 1258 through an opening in the first end 1252 of the body 1251. The nebulizer 1007 (fig. 10) introduces the aerosolized medicament 1210 into the airflow 1209 of the chamber 1258 through an opening 1255 adjacent the first end 1252 of the chamber 1258. It has been found that any protrusion into the chamber 1258 creates turbulence in the airflow 1209, which can result in aerosol particles being deposited on the walls of the chamber 1258. Thus, if a vibrating orifice-type atomizer is used, the atomizer's vibrating plate is preferably disposed entirely within the atomizer's opening 1255, which is most preferably flush with the inner surface (wall) of the chamber 1258. The aerosolized medicament 1210 is entrained in the gas flow 1209 to form a gas flow 1211 that contains the aerosolized medicament 1210. The flow 1211 travels along a straight path without obstruction through the chamber 1258 and exits the opening in the second end 1253 to the breathing circuit R. Upon expiration by the patient, an expiratory flow 1212 flows from the breathing gas path R through the chamber 1258 and the intermediate opening 1256 to the chamber 1257 of the branch 1254 and back to the ventilator via the expiration tube.
The breathing circuit of the present invention may include a patient interface, and optionally, the connectors and user tubing necessary to effect fluid communication between the ventilator circuit and the patient interface device. The patient interface device may comprise any of the previously described known devices for providing gaseous communication to a patient's respiratory system, such as nasal cannulas, mouth/nose masks, nasal masks, nasopharyngeal cannulas, endotracheal tubes, tracheostomy tubes, and nasopharyngeal tubes, among others.
In the embodiment of the invention shown in fig. 8-16, the nebulizer used in the invention may be any aerosol generator suitable for forming an aerosol such as droplets or dry powder particles (hereinafter referred to as "aerosol particles"), such as a spray bottle, a spray tube, a vibrating orifice type nebulizer, an ultrasonic nebulizer, a jet nebulizer, or the like. The atomizer may include: a reservoir for containing a liquid medicament to be delivered to the respiratory system of a patient; an aerosol generator for atomizing the liquid medicament. The nebulizer is positioned to introduce aerosol particles directly into an airway of the pressure-assisted breathing system. For example, the atomizer may be connected to an air path of a breather system via a separate connector, a connector integral with the atomizer body, or a connector integral with the connecting device. However, as mentioned above, a particularly preferred "vibrating orifice type" atomizer comprises a vibrating member and a dome-shaped orifice plate with a plurality of conical orifices. When the plate is vibrated at a frequency of 100000 times per second, micro-pumping will draw liquid through the conical orifice, thereby forming an aerosol with a low velocity and a droplet size within a well-defined range. Such atomizers are commercially available from Aerogen corporation of Mountain View, Calif.
As previously mentioned, the reservoir of the nebulizer may be sized to hold a smaller amount of drug as the efficiency of the invention is improved. For example, the volume of the nebulizer reservoir may be equal to one unit dose of medication, i.e., an amount sufficient for one treatment, while substantially all of the medication may be delivered to the patient without refilling the reservoir. This is particularly advantageous for respiratory therapy with phospholipid surfactants, since these drugs are very scarce, expensive and difficult to deliver due to their high viscosity. Furthermore, the present invention does not require pumping the drug from an external reservoir to the nebulizer, although this may be done in certain applications of the invention.
As described above in connection with fig. 3, the atomizer may be connected to a controller for controlling the operation of the aerosol generator and for powering the same, while the atomizer may be connected to other electronic components. In one embodiment, the controller may be integrated into the same housing as a CPAP system controller. At this point, the two systems may use the same power source and communicate electrically.
When used in a mechanical ventilator system, the nebulizer may be conveniently placed in the ventilator circuit or in the breathing circuit. In one example, the atomizer may be connected to the suction line of the breather circuit with a separate connector or a connector integrated with the body of the breather. Such a connector can provide a conduit for aerosol particles to travel from an aerosol generator of the atomizer into the air stream within the airway of the ventilator in order to entrain the aerosol particles into the air stream. In another example, the atomizer may be attached to an opening of an attachment device of the present invention as described above in connection with fig. 12.
For example, a connection device 1350 (which corresponds to connection device 1250 in fig. 12) is shown in fig. 13 connecting inspiratory tube 1363 and expiratory tube 1364 of ventilator circuit V to breathing tube 1369 of breathing circuit R. When an atomizer is required in the breather circuit, it may be attached to the opening 1355 of the connecting device 1350 as previously described in connection with fig. 12. Alternatively, the atomizer may be connected to the suction line 1363 using one of the connectors previously described.
In other embodiments, it may be advantageous to arrange the nebulizer in the breathing circuit. For example, placement of the nebulizer next to the patient's nose, mouth, or artificial airway, such as directly next to the inspiratory point of an endotracheal tube (ETT), or next to a nasal tube or mask, may further improve the efficiency and control of delivery of the aerosolized drug to the patient. Having the nebulizer as close as possible to the patient interface device enables the "dead space" between the aerosol generator and the patient interface device to be as small as possible, since aerosol particles may strike the edge of the connector when they attempt to enter the patient interface device, where significant deposition of aerosol particles may occur at the connection of the patient interface device. The reduction or elimination of such dead space can significantly reduce the loss of aerosol particles upon entry into the patient interface device.
Fig. 13 illustrates one example of how the nebulizer may be arranged in the breathing gas path R of the ventilator system. The nebulizer 1361 is disposed between the ETT tube 1367 and the ventilator circuit V, wherein the ETT tube and the ventilator circuit V are connected to each other by the connecting device 1365, the breathing tube 1369 and the connecting device 1350. In these embodiments, a first nebulizer is required in the breathing circuit R and a second nebulizer is required in the ventilator circuit V, which second nebulizer may alternatively be connected to the connecting device 1350 via the opening 1355 in the manner previously described. The connector 1365 is particularly well suited for this application because the manifold member 1368 of the connector 1365 defines an arcuate path for aerosol particles from a second nebulizer coupled to the coupling device 1350 via the breathing tube 1369. The arcuate path minimizes impingement of aerosol particles on the walls of the manifold member 1368 as they travel to the ETT tube 1367 and, as a result, minimizes loss of aerosol particles therein. The connector 1365 may also have an opening 1362 to administer fluid to the patient when desired.
Referring now to fig. 14, fig. 14 illustrates an enlarged cross-sectional view of the breathing circuit R of fig. 13, wherein the nebulizer 1461 may comprise a rectangular reservoir 1471, which is rounded at its corners and further carrying a connector mount 1473. The reservoir 1471 may be capable of holding a liquid drug for delivery to the respiratory system of a patient. The vibrating orifice type aerosol generator 1472 is in fluid communication with the reservoir 1471 and is capable of aerosolizing liquid medication that is supplied from the reservoir 1471 by gravity. Preferably, the reservoir 1471 is rotatably mounted to the connector base 1473 such that the reservoir 1471 may be moved, for example, about axis A. In this way, the location of the reservoir 1471 can be easily changed regardless of changes in the location of the patient and/or other components of the breathing circuit, such that liquid medicant can be optimally gravity fed to the aerosol generator 1472. For example, when the patient is lying down and the ETT tube 1467 is in a generally vertical position, the reservoir 1471 may be placed above the aerosol generator 1472 to deliver liquid medicant to the aerosol generator 1472 by gravity. If the patient is in a sitting position and the ETT tube 1467 is in a generally horizontal position, the reservoir 1471 may be rotated 90 degrees to maintain its optimal position above the aerosol generator 1472 so that the liquid medicant continues to be delivered to the aerosol generator 1472 by gravity.
Connector mount 1473 may further include a body member 1474, the body member 1474 having an inlet 1475 and an outlet 1476, wherein inlet 1475 may be interconnected to connector 1465 at one end of body member 1474, and wherein outlet 1476 may be interconnected to endotracheal tube 1467 at an opposite end of body member 1474. Longitudinal cavity 1477 extends from inlet 1475 through body member 1474 to outlet 1476, thereby forming a straight flow path for air flow from connector 1465 to endotracheal tube 1467. The vibrating plate of the aerosol generator 1472 is disposed in the opening 1478 of the connector base 1473 and is preferably flush with the inner wall of the cavity 1477 so that the medicament aerosol particles generated by the aerosol generator 1472 are ejected directly into the air flow within the cavity 1477 with a minimal amount of turbulence.
FIG. 15 illustrates an nCPAP system for a neonate or infant employing a nasal cannula of the present invention. The primary pressure generating circuit of the nCPAP system may include: flexible hoses 1581 and 1583, which are used to direct a large amount of airflow generated by a conventional airflow generator (not shown); a connection device 1582 for connecting the tubes 1581 and 1583 to the breathing circuit of the nCPAP system; and a pressure regulating device 1584. The pressure regulating device 1584 may be connected to a controller (not shown) that regulates the level of CPAP in the system. The nebulizer 1585 is coupled to the nasal tube 1586 via a breathing tube 1587, which is positioned to emit aerosol particles of medicament into the air flow from the coupling 1582 to the nasal tube 1586. Preferably, the breathing tube 1587 is thinner, softer and of smaller diameter than the flexible hoses 1581 and 1583. The breathing tube 1587 may be, for example, a commercially available silicone tube having an outer diameter of about 5 mm. The softer texture of the breathing tube 1587 allows the patient's head to move relatively freely without the nasal tube 1586 breaking away from the patient. The airflow 1588, containing the aerosol particles therein, flows through the breathing tube 1587 to the nasal tube 1586 and ultimately to the patient's nares and respiratory system.
Referring now to fig. 16, the nosepiece 1686 of the present invention can include a tubular inlet portion 1691 which is connected to a pair of nosepiece 1692 by a tubular bifurcated portion 1693. The cavity 1694 in the inlet portion 1691 is in fluid communication with the substantially parallel cavities 1695 and 1696 in each branch of the tubular diverging portion 1693, thereby forming a gradually diverging conduit extending from the inlet portion 1691 to the nose tube 1692. An air flow 1688 containing aerosol particles emitted by the nebulizer 1585 (fig. 15) is directed by a breathing tube 1687 through a cavity 1694 in the inlet portion 1691 and to a junction 1697 where the flow path of the aerosol particles is split to travel along the cavities 1695 and 1696 to the tube 1692. According to the present invention, the angle between cavity 1694 and cavities 1695 and 1696 at the flow path of the aerosol particles defined by junction 1697 varies relatively little, i.e. angles Δ 2 and Δ 3 are not greater than 15 degrees. As a result, substantially all of the medicament aerosol particles contained in the airflow 1688 reach the nasal cannula 1692, and ultimately the patient's nares. The efficiency of aerosol drug delivery is greatly enhanced because aerosol particles are minimized in the nasal cannula of the present invention.
The embodiment shown in fig. 15 and 16 is particularly suitable for treating idrds, which will be described in more detail later. This embodiment of the present invention provides an efficient way to integrate a vibrating orifice type aerosol generator with an nCPAP system that can deliver surfactant drugs while performing CPAP therapy. As a result, the administration of surface active drugs by extubation is not required, thereby reducing the risk of airway damage and secondary infection.
One embodiment of the present invention provides a method of delivering an aerosolized medicament to a subject, preferably a patient exhibiting one or more symptoms of an infection or other respiratory disease or disorder. The method generally comprises the steps of: coupling the subject to a pressure assisted breathing system comprising an air flow generator, an air circuit coupling the air flow generator to the breathing system of the subject, and an aerosol generator for ejecting particles of medicinal aerosol into said air circuit, wherein the air circuit defines a flow path for the ejected particles of aerosol having an angle of no more than 15 degrees. Larger angular variations of the flow path, such as 12-15 degrees, are best suited for pressure assisted breathing systems using nasal cannulae, particularly when used with surface active drugs. In other applications, it is preferred that the flow path have a small angular variation, i.e. no more than 12 degrees, and most preferably no variation in flow path angle (straight flow path).
The medicaments used in the practice of the invention may be any of those commonly used in aerosol form for the treatment of the above-mentioned diseases, such as various antibiotics or a mixture of antibiotics (which are preferably used in ventilation systems) and surface active drugs (which are preferably used in CPAP systems). Antibiotics include, for example: gram-positive agents such as macrolides, such as erythromycin, clarithromycin, and erythromycin; and glycopeptides such as vancomycin (vancomycin) and teicoplanin (teicoplanin); and other anti-gram-positive agents that can be dissolved or suspended and used as suitable aerosols, such as oxazolidinones (oxazolidinones), quinupristin/dalfopristin (quinupristin/dalfopristin), and the like. Antibiotics useful as anti-gram-negative agents may include: aminoglycoside antibiotics, such as gentamicin, tobramycin, amikacin, streptomycin sulfate, netilmicin; quinolones such as ciprofloxacin, ofloxacin, levofloxacin; tetracyclines such as oxytetracycline, minocycline, and sulfamethoxazole (cotrimoxazole); and other anti-gram-negative agents that can be dissolved or suspended and used as suitable aerosols. Surface active agents will be discussed in detail later.
The pressurized assisted breathing system of the present invention may also include any other components typically found in such systems, such as humidifiers, filters, gauges (gauge), devices for collecting sputum and other secretions, as well as controls for controlling the breathing cycle, nebulizers, and/or other components. The addition of a humidity regulator to the present system is particularly advantageous because the control of humidity can affect the efficiency of aerosol particle delivery. For example, significant hygroscopic expansion of the aerosol particles should be prevented because the particles, upon immersion in water, condense on the walls of the system. Respiratory cycle controllers are also well suited for use with the present invention because they can be used to cause aerosol administration only during the inspiratory phase of the respiratory cycle or when the humidifier is not active, thereby further improving the efficiency of the system.
Fig. 17 illustrates a preferred embodiment of the present invention, which includes a CPAP system 1700 having a primary pressure generating circuit P, a breathing circuit R, and a secondary circuit a, the system 1700 being provided. As previously mentioned, these tubes, which are connected to commercially available pressurized assisted breathing systems, create a "pneumatic circuit" for the flow of gas by maintaining fluid communication between various components on the pneumatic circuit. The tubes may be made of a variety of materials including, but not limited to, various plastics, metals, and composites, which may be rigid or flexible. These tubes may be connected to the various components of the airway in a removable or fixed manner using various connectors, adapters, connecting devices, and the like. The gas circuit P includes a flow generator 1702 in fluid communication with a pressure regulating device 1703 via a conduit 1701.
Breathing circuit R includes a patient interface device, namely a nasal tube 1704, which nasal tube 1704 communicates with circuit P via tube 1706 at a "T" connection 1705. The tube 1706 is preferably a flexible hose having a diameter less than the diameter of the pipeline 1701, for example, the tube 1706 having an outer diameter of 5-8mm or less. An atomizer 1707 (including an aerosol generator) is in fluid communication with the tube 1706 at a junction 1708. Nebulizer 1707 is capable of spraying the aerosolized drug directly into the airflow inhaled by the patient, i.e., the airflow in breathing circuit R, which is preferably disposed near the patient's nose, mouth, or artificial airway (e.g., endotracheal tube). The atomizer 1707 itself may include a built-in connector for connecting to the tube 1706 (as shown), which may also be connected by a separate tube or connector.
The auxiliary air path a includes a flexible hose 1711, preferably having the same outer diameter as the tube 1706. The flexible hose 1711 is used to connect the airflow sensor 1709 to the tube 1706 at a "T" connection 1710. The connection 1710 is preferably located close to the nose tube 1704, but upstream of the nebulizer 1707 so that aerosol particles emitted by the nebulizer 1707 are not diverted into the tube 1711. An adjustable damper valve 1712 may be disposed in the conduit 1711 between the junction 1710 and the flow sensor 1709 to adjust the flow of gas through the flow sensor 1709, preferably to a mid-range value of the optimal flow range for the sensor 1709. A disposable filter 1713 may also be disposed in the tube 1711 between the connection 1710 and the flow sensor 1709 to remove bacteria, viruses and/or other contaminants generated by the patient's diseased respiratory system that may be entrained by the exhaled gas flowing through the flow sensor 1709.
The operation of the CPAP system 1700 is illustrated in fig. 18, which is an enlarged cross-sectional view of the CPAP system 1700. A quantity of gas 1820 is introduced into gas path P from flow generator 1802 and flows through line 1801 to pressure regulating device 1803, which pressure regulating device 1803 maintains a continuous positive pressure throughout the system. An inspiratory flow 1821, which is typically about 10% of flow 1820, flows from the conduit 1801 of the pressure generating circuit P into the conduit 1806 of the breathing circuit R to provide a relatively constant flow of inspiratory air to the patient's respiratory system to assist in patient inspiratory effort in accordance with conventional CPAP system principles. At connection point 1810, a portion 1821a of the inhalation flow 1821 flows through tube 1806 to nose tube 1804, and a portion 1821b of the inhalation flow 1821 is diverted through tube 1811 to flow sensor 1809.
Airflow 1821a flows through connection 1808 where aerosolized drug particles 1822 generated by the aerosol generator of nebulizer 1807 are introduced into airflow 1821 a. The resulting airflow 1823 containing the entrained aerosol particles 1822 eventually flows through the nasal cannula 1804 to the patient's respiratory system, thereby delivering the aerosolized drug to the patient's respiratory system. Flow 1821b flows through tube 1811 and adjustable damper valve 1812, which is adjusted to reduce the flow of flow 1821b to reduced flow 1821c, e.g., flow 1821c may be approximately 20% of the flow of flow 1821 b. The reduced flow 1821c then flows through the disposable filter 1813 to the flow sensor 1809 and is ultimately released to the atmosphere. As the flow 1821c flows past the flow sensor 1809, the flow sensor 1809 senses a volumetric flow of the flow 1821c and generates a first electrical signal, such as an output voltage, in the circuitry 1825 of the CPAP system 1700 that is indicative of the flow 1821 c. Since the airflow 1821c is directly proportional to the inspiratory airflow 1821, the first electrical signal derived from the airflow 1821c can be used by the system to identify when the patient is inhaling and continuing to deliver the aerosolized drug.
When the patient exhales, the exhaled airflow 1824 flows through the nasal tube 1804 to the tube 1806, and then is diverted through the tube 1811 at the connection 1810. The exhaled flow 1824 mixes with the inhaled flow 1821b in the tube 1811 to form a flow equal to the sum of the flow rates of the flows 1824 and 1821 b. The combined flows of streams 1824 and 1821b flow through adjustable damper valve 1812, with the total flow reduced in the same manner as described above for individual stream 1821b (which is identified in FIG. 18 as the combined flows of streams 1821c and 1824 a). The disposable filter 1813 removes any bacteria, viruses, or other contaminants that may be present in the mixed gas stream, and as a result, the gas stream 1824a and the mixed gas stream then flow past the flow sensor 1809. When the combined flow of streams 1821c and 1824a flows past flow sensor 1809, flow sensor 1809 is able to detect a change (increase) in that flow relative to when only stream 1821c flows. As a result, flow sensor 1809 generates a second electrical signal in circuit 1825 that is different from the first electrical signal generated by airflow 1821c alone. This second electrical signal is sent by circuit 1825 to nebulizer 1807 and causes it to turn off its aerosol generator. The aerosol generator is deactivated such that the introduction of aerosol particles 1822 into airflow 1824a is also stopped. Since the second electrical signal is generated by the volumetric flow rate of the mixed flow of air streams 1821c and 1824a, it is indicative of the presence of the exhaled air stream 1824. Thus, the system may use the second electrical signal to identify when the patient is exhaling and stop the introduction of aerosolized drug. Thus, no aerosol is introduced into tube 1806 during patient exhalation, and therefore no aerosol is entrained in the exhaled air flow 1824 and eventually released to the atmosphere to be lost.
When the patient's exhalation activity ceases and inhalation begins again, the exhalation flow 1824 is interrupted and only the inhalation flow 1821 is present in the system. As a result, only flow 1821c flows through tube 1811. At this time, the flow sensor 1809 detects this change (decrease) in the flow rate and generates a first electrical signal, which is sent to the nebulizer 1807. The first electrical signal causes nebulizer 1807 to turn on the aerosol generator and resume the operation of introducing aerosol particles 1822 into airflow 1821 a. This activation and deactivation of the aerosol generator of the nebulizer 1807 in conjunction with the patient's breathing cycle enables the aerosolized drug to be introduced into the CPAP system of the present invention only when the patient inhales. The result is a greatly improved efficiency of drug delivery and a corresponding reduction in the loss of drug to the atmosphere.
As previously mentioned, the pressure regulating device 1803 may comprise any known device for controlling and maintaining the air pressure in a CPAP system at a desired constant level. The pressure regulating device 1803 may generally include a gas outlet restriction, such as a pressure valve or threshold flow resistor capable of regulating the flow of gas exiting the pressure regulating circuit P. In other applications, the regulation of the gas flow may be achieved by: the gas stream is released into a standard vessel containing a predetermined amount of water, wherein the pressure within the system is indicative of the elevated level of water in the vessel. Regardless of the pressure regulating device used, the flow resistance of the flow in the pressure generating circuit may be varied so that the continuous positive airway pressure directed by breathing circuit R to patient interface 1804 is tailored to the needs of the particular patient in which the device is used.
Although the attachment device 1805 may generally comprise a "T" or "Y" shaped hollow device (sometimes referred to as a "WYE"), it may take other shapes. As shown in fig. 18, a flexible hose 1806 is connected to the connection device 1805 and defines an air manifold that is separate from and in gaseous communication with the pressure generating air path P. Tube 1806 is ultimately connected to a patient interface device, such as nasal tube 1804, to form breathing circuit R. The flexible hose 1806 is preferably thinner, softer and of smaller diameter than the tube 1801 including the pressure generating gas path P. The flexible hose 1806 may be, for example, a commercially available silicone tube having an outer diameter of about 5-8 mm.
The nebulizer 1807 may be any known device capable of nebulizing (aerosolizing) medication for use with a CPAP system, but as noted above, is preferably a lightweight, small nebulizer with a vibrating orifice type aerosol generator.
The flow sensor 1809 of the present invention may be a known flow sensor that detects small changes in the volumetric flow of fluid flowing therethrough and generates an electrical signal, such as an output voltage, representative of the flow. A particularly preferred Flow Sensor for use in the present invention is available from Ohlong, Japan, under the Model number "MEMS Flow Sensor, Model D6F-01A 1-110". The flow sensor of the ohron is capable of detecting a flow of 0-1L/min (liter/min) (at 0 ℃ and a pressure of 101.3 kPa). The relationship between the flow measured by the ohm-dragon flow sensor and the output voltage generated thereby is summarized in table 1 below:
TABLE 1
Flow rate (L/min) 00.20.40.60.81.0
Output voltage (VDC + -0.12) 1.002.313.213.934.515.00
(Note: the measurement conditions in Table 1 are that the power supply voltage is 12VDC, the ambient temperature is 25 ℃ and the ambient humidity is 25-75% RH.)
The nebulizer 1807 may be connected to the flow sensor 1809 via the circuitry 1825 of the CPAP system. For example, the nebulizer 1807 may be connected to a controller (not shown) that turns the aerosol generator on and off in response to signals from the flow sensor 1809. Preferably, the controller and other electronics in the CPAP system are connected by small, flexible wires, cables, and connectors. Other components that may also be connected to the nebulizer 1807 may be, for example, a timer, a status indication device, a liquid drug supply tube or syringe, etc., all of which are known to those skilled in the art and described in detail in the aforementioned patents and applications.
The following examples will illustrate the invention with the above-described ohm-dragon flow sensor, but are not intended to limit the invention to the particular details thereof:
example 1
A CPAP system of the present invention as illustrated in fig. 18 may be used to provide respiratory therapy to an infant. The system may be pressurized to a pressure of 5cm of water and the flow generator 1802 may be provided into the pressure generating gas path P with a constant flow of gas at a rate of 10L/min. Approximately 1L/min (10%) of the air flow in the pressure generating circuit may flow into the flexible hose 1806 as an air flow 1821. During inhalation by the infant through nasal tube 1804, approximately 20% of the flow 1821 (identified as flow 1821b in fig. 18) may pass into tube 1811 at connection point 1810, by appropriate adjustment of damper valve 1812 to produce an approximately 0.2L/min (0.2X 1L/min) flow of flow 1821 c. The gas stream 1821c may also flow through a disposable filter 1813, but since the gas stream 1821c is only inhaled with very little, if any, contaminants, the filter does not filter anything noticeable from the gas stream 1821 c. The flow 1821c then flows through the ohm-dragon flow sensor at a rate of 0.2L/min, which generates an output voltage of approximately 2.31VDC according to Table 1 above. The circuitry of the CPAP system may be configured to turn on the aerosol generator of the nebulizer 1807 when the flow sensor sends this output voltage to the nebulizer 1807. The aerosol generator is turned on to introduce the aerosolized drug into the breathing circuit R of the CPAP system so that it can be inhaled by the infant.
During exhalation, the infant may exhale approximately 0.6L/min of airflow through the nasal cannula 1804, thereby forming an exhaled airflow 1824, which mixes with the airflow 1821b in the tube 1811. As described above with respect to only flow 1821b, damper valve 1812 is adjusted to reduce the flow of gas in tube 1806 to 20% of the original flow. Thus, flow 1821b may be reduced to flow 1821c at a rate of approximately 0.2L/min (0.2X 1L/min), and flow 1824 may be reduced to flow 1824a at a rate of approximately 0.12L/min (0.2 X0.6L/min). The flow rate of the mixed exhaled gas stream formed by the mixing of streams 1821c and 1824a is approximately equal to 0.32L/min. The combined exhaled gas stream then flows through a disposable filter 1813 to remove any contaminants that may be entrained in the exhaled gas stream 1824a, which then flows through an ohm-dragon flow sensor. Referring again to Table 1 above, it can be seen that the Oldham pressure sensor generates an output voltage of about 3.0VDC for a mixed expiratory flow of 0.32L/min. The circuitry of the CPAP system may be configured to turn off the aerosol generator of the nebulizer 1807 when the output voltage is delivered to the nebulizer 1807 by the circuitry 1825. Turning off the aerosol generator stops the introduction of aerosolized drug particles 1822 into the CPAP system breathing circuit R during the occurrence of the expiratory flow 1824. As a result, only a very small amount of aerosol is entrained in the exhaled airflow 1824 and eventually lost to the atmosphere. In some cases, circuit 1825 may include a phase shifting circuit that can advance or retard the deactivation of the aerosol generator when desired.
When the flow in the ohm-dragon flow sensor returns to 0.2L/min during inspiration, the output voltage of the ohm-dragon flow sensor also returns to 2.31 VDC. Since this voltage is indicative of the inspiratory phase of the patient's breathing cycle, the circuit 1825 may use this as a signal to re-activate the aerosol generator, whereby the introduction of the aerosolized drug into the CPAP system's breathing circuit may be resumed during inspiration. The cycle of opening and closing the nebulizer depends on the phase of the patient's breathing cycle, which is repeatable during respiratory therapy of the infant using the CPAP system, thereby greatly reducing the amount of medication required for such therapy.
Example 2
Referring to fig. 19, CPAP system 1900 is connected to a breath-mimicking piston pump 1930 (which is commercially available from Harvard Apparatus of Holliston MA 01746) to mimic the breathing cycle of an infant. The CPAP system 1900 includes an auxiliary airway a including a pressure valve 1938, a disposable filter 1939, and a flow sensor 1940, wherein the flow sensor 1940 is connected to a breathing airway 1942 by a tube 1943 according to the present invention. A removable filter 1931 is disposed at the inlet of the pump 1930. An adapter 1932 is attached to filter 1931 and has two openings 1933 that represent the nostrils of the infant (Argyle nasal cannula available from Sherwood Medical, St.l. Louis, MO 63013). Atomizer 1937 (available from Aerogen corporation of mountain View, CA)A proxy Nebulizer System) is disposed in respiratory circuit 1942 proximate to adapter 1932 to deliver an aerosolized medicament into the airflow passing through apertures 1933. During operation of pump 1930, gas containing entrained aerosolized drug flows back and forth through filter 1931, where filter 1931 collects the drug from the gas stream. The amount of drug collected by filter 1931 after each test is measured by High Pressure Liquid Chromatography (HPLC) and compared to the total amount nebulized, thereby providing a measure of the delivery efficiency of the aerosol to the system.
Pump 1930 sets the ventilation parameters for the infant with a tidal volume of 10ml and a breath rate of 40 breaths per minute. A constant flow of air 1934 of 10L/min is provided through the CPAP inlet 1935 and a resistance pressure regulator 1936 is set to generate a pressure of 5cm of water. The atomizer 1937 is filled with 3ml of salbutamol (albuterol) sulfate solution ("salbutamol"). To investigate the effect of simultaneous spraying (i.e. spraying only on inspiration) and continuous spraying, two sets of 4 tests were performed each. In a first set of tests, the nebulizer 1937 was run continuously during both the inhalation and exhalation cycles of the pump 1930. In a second set of tests, the input from the flow sensor 1940 is utilized to stop the nebulizer 1937 during the expiratory phase of the pump 1930 in accordance with the present invention. After each test, the amount of salbutamol collected by filter 1931 was measured by HPLC and compared to the amount of salbutamol nebulized to give an efficiency value in percent. The results are summarized in table 2 below:
TABLE 2
Continuous spraying:
test sequence numberEfficiency of
1 26％
2 24％
3 22％
4 27％
Average efficiency: 24.75 percent
Synchronous spraying:
test sequence numberEfficiency of
1 40％
2 44％
3 51％
4 43％
Average efficiency: 44.5 percent
The above results show that simultaneous spraying according to the present invention can deliver more orders of magnitude of salbutamol through the nasal cannula than continuous spraying during CPAP.
The high efficiency of the delivery of nebulized drug of the invention is particularly valuable for respiratory therapy with expensive or scarce drugs, such as the aforementioned nCPAP therapy with nebulized surfactant for idrds. Since most surface-active substances come from animals, the current supply is limited and, although artificial surface-active substances are also available, they are expensive and not elaborate to manufacture. Furthermore, surfactant drugs are often highly viscous and therefore difficult to deliver to the respiratory system of a patient. The increased efficiency of the pressure-assisted breathing system of the present invention, and the reduced amount of drug required for the treatment of the present invention, are advantageous when scarce and expensive drugs are used.
In a preferred embodiment, the nebulizer of the invention has a reservoir with a volume equal to a unit dose of the drug. For example, a dose of liquid phospholipid surfactant drug usually requires about 100mg of surfactant to be instilled into the lungs of an infant. However, the required aerosol dose appears to be much smaller. For example, animal researchers have found that inhalation of a dose of about 4.5mg/kg of surfactant is sufficient to significantly increase oxygenation in animal models. It has been shown indirectly that a sufficient unit dose of surfactant delivered as an aerosol to the lungs of a 1kg infant may be about 5-10 mg. Since liquid surfactant is typically distributed in the diluted solution at a concentration of 25mg/ml, about 2/5ml (10/25ml) of liquid surfactant is required to obtain 10mg of active surfactant. In accordance with the present invention, a neonatal CPAP system may be designed to deliver approximately 6-18% of the total aerosolized drug to the lungs of the infant in a normal breathing mode. For example, if the efficiency of the nebulizer is 10%, the amount of surfactant solution required in the nebulizer reservoir must be increased by a factor of 10, i.e. 10X2/5ml or 4ml, in order to deliver a unit dose of nebulized surfactant. Thus, according to the invention, a 4ml capacity of the nebulizer reservoir is sufficient to provide a unit dose of surfactant to a 1kg infant without refilling the reservoir.
The unit dose and corresponding reservoir size of the nebulizer herein may vary according to nebulizer efficiency, patient weight and amount of surfactant required, for example if the infant in the above example weighs 3kg, the unit dose (and corresponding reservoir size) is about 12ml of liquid surfactant (i.e. 3kgX4 ml/kg). Similarly, if the effective amount of surfactant required in the above example is 5mg, the unit dose is about 2ml of liquid surfactant (i.e. 5/25ml X10) and if the efficiency of the nebuliser is 15% in the above example, the unit dose is about 22/3ml (i.e. 2/5ml X100/15).
The nebulizer of the invention can be used to administer a unit dose from an aerosol in 20 minutes, and possibly as little as 5 minutes. The aerosol generation may be continuous or stepwise, or the delivery rate may be titrated quantitatively over time; for example, a maximum of 4ml of drug is aerosolized for 1 second out of every 10, 20 or 30 seconds.
In one embodiment, the invention provides a method of treating a disease involving surfactant deficiency (which is also referred to as "surfactant wasting") or surfactant dysfunction (which is also referred to as "surfactant dysfunction"). These diseases include, but are not limited to: infant Respiratory Distress Syndrome (iRDS), Acute Respiratory Distress Syndrome (ARDS), Meconium Aspiration Syndrome (MAS), asthma, pneumonia (various pneumonias including ventilator-associated pneumonia), neonatal Persistent Pulmonary Hypertension (PPHN), Congenital Diaphragmatic Hernia (CDH), sepsis, Acute Lung Infection (ALI), bronchitis, chronic obstructive pulmonary disease-chronic bronchitis, cystic fibrosis, lung transplantation disease, and Respiratory Syncytial Virus (RSV). Since the treatment of such diseases usually involves administering naturally occurring (animal derived) or synthetic (manufactured) lung surfactants to the lungs of a patient, the method is sometimes referred to in the art as "surfactant (replacement) therapy".
Generally, the method of the present invention comprises the steps of: providing a liquid lung surfactant preparation; nebulizing the lung surfactant preparation with an aerosol generator, preferably a vibrating orifice type aerosol generator, to form a nebulized lung surfactant (also referred to herein as a "surfactant aerosol"); and introducing the aerosol of pulmonary surfactant into an airflow in the airway of a pressure assisted breathing system, preferably a CPAP system, as described above, which is connected to the respiratory system of the patient, thereby delivering a therapeutically effective amount of the pulmonary surfactant to the lungs of the patient.
Pulmonary surfactant is a complex and highly surface active substance, which is usually composed of lipids and/or proteins. Their main properties are their ability to reduce surface tension in the lungs and protect the lungs from damage and infection by inhaled particles and microorganisms. The composition of naturally occurring lung surfactant may vary depending on various factors such as the species, age and health status of the subject. Thus, what a specific natural surfactant is and what should be included in a synthetic lung surfactant preparation depends on the specific conditions. The surfactant isolated from healthy mammalian lung lavage contains about 10% protein and 90% lipids, about 80% phospholipids and about 20% neutral lipids, including about 10% non-lipidated cholesterol.
Pulmonary surfactants are generally very viscous and difficult to administer. The lung surfactant may be mixed with a medical solvent such as water or physiological saline to provide a liquid surfactant preparation. In the practice of the present invention, it is preferred to use lung surfactant preparations in liquid form, e.g. in concentrations of 20-120mg/ml, preferably 20-80 mg/ml. Commercially available lung surfactants may be liquids that have been mixed well and are equally suitable for use in the present invention. Commercially available lung surfactants are for example: natural lung surfactant preparations under the trademarks curosurf (chiesi pharmaceuticals), alveofact (boehringer ingelheim) and survanta (abbott laboratories); and synthetic surfactant-like formulations sold under the trademarks EXOSRUF (Glaxo Wellcom) and SURFOAXIN (discovery laboratories).
Aerosol generators can form aerosols in a variety of ways, such as single-substance injection, centrifugal atomization, condensation, evaporation, scattering, ultrasound, jet atomization, and the like. As described above, the vibrating orifice type aerosol generator is a preferred embodiment of the present invention. The vibrating orifice type aerosol generator includes a unique dome-shaped orifice plate containing 1000 fine machined tapered orifices surrounded by a vibrating element. When energized, the orifice plate vibrates at a frequency of 100000 or more times per second. Such rapid vibration enables each well to act as a micro-pump that draws liquid in contact with the plate through the well to form droplets of uniform size. The result is a low velocity liquid aerosol particularly suited for maximum lung deposition. The preferred vibrating orifice type mist generator is highly efficient at atomizing liquids, leaves little residue, and operates without the use of a propellant or heat, thereby maintaining the integrity of the surfactant molecules. Typical vibrating orifice type aerosol generators are described in detail in the foregoing U.S. patent documents US5164740, 5586550, 5758637, and 6085740, which are incorporated herein by reference in their entirety.
The orifices in the orifice plate are shaped to increase the rate of droplet formation while also maintaining the droplets in a range of sizes, see for example, non-assigned U.S. patent application 09/822573 filed 3/30 2001, which is incorporated herein by reference. These pores may be particularly suitable for atomizing the viscous surfactant preparations of the present invention. A preferred vibrating orifice type aerosol generator is commercially available from Aerogen corporation of Mountain View, California.
Generally, the above-described apparatus includes a nebulizer having an aerosol generator therein positioned to introduce an aerosol of surfactant generated by the aerosol generator directly into an air flow in an airway of a pressure-assisted breathing system connected to a respiratory system of a patient.
As mentioned above, CPAP systems support spontaneous breathing by a patient, which generally includes: a pressure generating circuit for maintaining a positive pressure in the system; a patient interface device connected to the patient's respiratory system; and a breathing circuit for providing gas communication between the pressure generating circuit and the patient interface device. CPAP systems use a constant positive pressure during inhalation to increase and maintain lung volume while also reducing the workload of the patient during spontaneous breathing. This positive pressure effectively inflates the airway while preventing it from collapsing. The use of this CPAP system in combination with a vibratable orifice type aerosol generator can greatly enhance the delivery efficiency of an aerosol of surfactant to the lungs of a patient.
The vibrating orifice type aerosol generator has a number of aerosol delivery characteristics which make it particularly suitable for use with aerosolized medicaments in general, and with surface active substances according to the invention in particular for replacing aerosolized medicaments to be used in therapy. The vibrating orifice type aerosol generator is extremely efficient in generating aerosol particles, which can atomize almost 100% of the liquid surfactant directly contacting the orifice plate. This feature virtually eliminates a source of surfactant loss in the system.
In addition, the vibrating orifice type aerosol generator can deliver a low velocity aerosol with a precisely defined average particle size. The size distribution of the aerosol particles and the drug output can be modified by varying the size of the holes in the diaphragm to meet the needs of a particular patient or particular situation. The size of the aerosol particles should preferably be adjusted to less than 5 μm Mass Median Aerodynamic Diameter (MMAD), most preferably 1-3 μm MMAD, in order to maintain optimum efficiency. These smaller aerosol particles help to improve the delivery performance of the surfactant aerosol and the deposition around the lungs, thereby reducing the loss of aerosol from the system. In addition, the vibrating orifice type aerosol generator does not generate a large amount of heat and shear forces that would alter the characteristics and properties of the surfactant formulation.
The aerosol output (flow rate) of the vibrating hole type aerosol generator is obviously higher than that of other types of atomizers, and as a result, the treatment time of the method is greatly shorter than that of the conventional surface active substance treatment. For example, the therapeutic amount (unit dose) of aerosolized surfactant deposited in the lungs of a patient may be in the range of 2-400 mg. In the practice of the present invention, the liquid surfactant preparation may comprise a solution having a concentration of 20-120 mg/ml. The flow rate of the vibrating orifice type aerosol generator of the present invention is in the range of 0.1-0.5ml/min, which is significantly higher than the flow rate of comparable aerosol generators, e.g., the flow rate of a jet atomizer is typically less than 0.2 ml/min. For the treatment of surfactant deficiency, if a unit dose of aerosolized surfactant of 40mg (e.g., 40mg/ml liquid surfactant formulation of 1.0 ml) is required for a 1kg newborn, then the method of the present invention can produce 90% of the unit dose in less than 3 minutes using a vibrating orifice type aerosol generator with a flow rate of 0.4ml/min, whereas a comparable jet nebulizer requires 3ml of formulation to fill and takes more than 6 minutes to deliver the same unit dose. The method of the invention allows for less dosage requirements and shorter treatment times, which greatly increases the likelihood that a patient will receive benefits over direct instillation, or requires very little liquid surfactant to be placed in the nebulizer during a treatment regimen. In a preferred embodiment, the effective delivered amount of surfactant delivered to the patient's lungs is preferably in the range of 2-800mg/hr (mg/hr).
In a preferred embodiment, the small diameter and size of the reservoir for holding the liquid surfactant preparation in a nebulizer with a vibrating orifice type aerosol generator allows the nebulizer to be placed directly into the breathing circuit without the need for a large "rebreathed volume". For example, the preferred vibrating orifice type aerosol generator of the present invention may be charged with a rebreathing volume of no more than 5 ml. The term "rebreathing volume" as used herein refers to the volume of gas required in the system to produce a desired amount of aerosolized surfactant in a defined space. Pneumatic or jet nebulizers typically have a reservoir with a volume of 6-20ml, whereby if such a nebulizer is arranged in the breathing circuit between the primary air flow and the patient's airway in a CPAP system, the undesired rebreathing volume of the circuit is increased. This increase in rebreathed volume can produce a diluting effect on the aerosolized surfactant and reduce the efficiency of the delivery system.
In a preferred embodiment, which may be used for any aerosolized drug and is particularly suitable for surfactant therapy, an aerosol of surfactant from a vibrating orifice type aerosol generator may be formed in an air-collecting chamber with an internal volume of 5-400ml outside the direct breathing circuit (e.g., breathing circuit R in fig. 20). The gas collection chamber is capable of concentrating the surfactant aerosol to a higher concentration than would be produced by the aerosol generator alone prior to its discharge into the breathing circuit. It has now been found that the plenum chamber is capable of providing an inhalation volume of aerosol surfactant comparable to a breath-driven nebulizer, for example, less than 25% of the time the plenum chamber needs to provide an inhalation volume of 80% of the surfactant to the nebulizer for the same inhalation volume delivered by the breath-driven nebulizer.
As an example of an arrangement of the present invention employing a plenum, FIG. 20 illustrates a CPAP system 2000 in which a primary air flow 2071 travels in a pressure generating circuit P and a flow of breathing air 2072 travels in a breathing circuit R from the circuit P to a patient 2073. An aerosol generator 2074 of a vibrating orifice type is disposed above the gas collection chamber 2075 to enrich the aerosol 2076 of surfactant generated by the aerosol generator 2074 in the gas collection chamber 2075. The plenum 2075 is sized such that the plume (plume) of surfactant aerosol 2076 does not impinge on the sidewalls or bottom wall of the plenum 2075, thereby reducing any resulting impingement loss of surfactant aerosol. A controlled second airflow 2077 is introduced into the plenum 2075 via the inlet 2078 to drive an enriched aerosol flow of surfactant 2079 from the plenum 2075 through a conduit 2080 into the flow of breathing air 2072, the conduit 2080 of which intersects the breathing air path R at a point 2081 adjacent the airway of the patient 2073. The conduit 2080 may have a one-way valve or solenoid valve 2082 that controls the flow of the air 2079 into the breathing circuit R, thereby isolating the air space in the air collection chamber 2075 from the rebreathed volume, i.e., the air flow 2079 from the air collection chamber 2075 is only a small portion of the flow of breathing air 2072. The airflow 2079 may be continuous or intermittent, wherein the surfactant aerosol is introduced into the breathing circuit R during discrete portions of the breathing cycle.
The result of this unique combination of an aerosol generator, which is preferably a vibrating orifice type aerosol generator, and a pressure assisted breathing system, which is preferably a CPAP system having one or more of the efficiency enhancing features described above and in the aforementioned non-authorized patent applications, is that the patient is able to inhale 10-80% of the lung surfactant in the method of the present invention. In a particularly preferred embodiment, more than 30% of the lung surfactant is delivered to the lungs of the patient.
The following examples illustrate the efficiency improvements that result from the use of the present invention in practice, but the invention is not limited to the details mentioned herein. For example, the following examples are not limited to delivering a particular aerosolized drug.
Example 3
Fig. 21a and 21b are schematic diagrams of nCPAP systems 2100 and 2200 that can be used to determine aerosol delivery during nCPAP in a simulated infant breathing mode. The nCPAP systems 2100 and 2200 include breathing simulators 2101 and 2201 formed with an adapter with openings representing infant-sized nasal cannulas 2102 and 2202 (Argyle, n ═ 3) connected to true filters 2103 and 2203, the adapter connected to reciprocating pump-type animal ventilators 2104 and 2204, thereby forming an nCPAP system. The lung simulators 2100 and 2200 may be set to ventilation parameters (VT10ml, breathing rate 40/min) for the infant. A constant flow of 10L/min oxygen from ventilators 2104 and 2204 may be used to generate CPAP at 5cm of water, which may be regulated by threshold flow resistors 2105 and 2205.
In both systems, liquid medication (0.5ml of 0.5% salbutamol sulphate) may be nebulized with nebulizers 2106 and 2206 in one circuit of the nCPAP system. The drug may be collected on filters 2103 and 2203 distal to nasal cannulas 2102 and 2202, and the collected drug may be analyzed by High Pressure Liquid Chromatography (HPLC). Note that it must be ensured here that only aerosol reaches the filter and its condensate remains in the breathing circuit, the nebulizer or the adapter. This may be accomplished by tilting the system so that the atomizers 2106 and 2206 are below the respective filter components 2103 and 2203. The effectiveness of the nCPAP system can then be determined by expressing the amount of drug collected on the filter as a percentage of the drug dose placed in the nebulizer.
In test 1, the nebulizer 2106 may comprise a standard jet nebulizer arranged to discharge nebulized drug into the main gas flow of the pressure generating circuit of the nCPAP system 2100, see fig. 21 a. In test 2, the atomizer 2106 may comprise an atomizer with a vibrating orifice type aerosol generator (Aerogen corporation)Pro) arranged to discharge aerosolized medicament into the main air flow in the pressure generating circuit of the nCPAP system 2100 as well. In test 3, the nebulizer 2206 can comprise a lightweight, small nebulizer of one embodiment of the invention designed to be placed in close proximity to the infant's airway and using a vibrating orifice type aerosol generator (PDDS) nebulizer), as shown in fig. 21b (and fig. 12), the nebulizer 2206 being arranged to continuously discharge aerosolized drug into the reduced flow of the respiratory airway between the main flow and the simulated patient airway in the nCPAP System 2200 in accordance with another embodiment of the invention. In test 4, nebulized drug could be intermittently generated from PDDS nebulizer 2206 according to another embodiment of the present invention, wherein the aerosol generation operation was interrupted upon expiration.
As shown in fig. 22, when a vibration type orifice type aerosol generator of the present invention is used thereinA Pro nebulizer will generally be more efficient than a standard jet nebulizer when disposed in the pressure generating circuit of an nCPAP system. In addition, when a PDDS nebulizer with a vibrating orifice type aerosol generator of the present invention is disposed between the main airflow through the nCPAP system and the simulated patient airway, it is connected to the patient airwayOften delivering higher levels of medication through the nasal cannula to the filter. For example, PDDS nebulizer 2206 in the position shown in fig. 21b typically results in 26 ± 9% (mean + standard deviation) deposition of the drug dose in the nebulizer with continuous aerosol generation and 40 ± 9% deposition of the drug dose in the nebulizer with intermittent aerosol generation. During continuous aerosol generation, a significant amount of aerosol is typically delivered from the nebulizer into the expiratory limb of the nCPAP system pressure generating circuit. Discontinuing aerosol generation during exhalation according to one aspect of the invention eliminates this significant loss and increases the percentage of inhaled dose by nearly 50%. The lower deposition obtained in test 2 is the case even with higher efficiency vibratable orifice type aerosol generator nebulisers, which we believe is due in large part to the dilution of the aerosol output by the nebuliser by the large total airflow through the nebuliser when the nebuliser is arranged in the position shown in figure 21 a.
As demonstrated by the foregoing examples, the present invention utilizes a nebulizer that includes a vibrating orifice type aerosol generator that is generally more efficient than a standard jet nebulizer when used to deliver nebulized surfactant and other drugs to the airway of a patient via a typical CPAP system. In one embodiment of the invention, even further significant improvements in this efficiency can be achieved by placing a particularly preferred small nebulizer containing a vibrating orifice type aerosol generator in the low airflow breathing circuit of the CPAP system, more preferably in close proximity to the patient's airway. In another embodiment of the invention, higher efficiency may be achieved by generating the aerosol intermittently, for example only during inspiration and interrupted during expiration.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the description and drawings are intended to illustrate and not limit the scope of the invention, which is defined by the following claims and their equivalents.

Claims (23)

1. A pressure assisted breathing system, comprising:
a first gas conduit connecting a gas flow generator to a pressure regulating device to provide a first flow of a bulk gas to generate a continuous positive airway pressure;
a patient interface device connected to a patient respiratory system;
a second gas conduit for connecting said first gas conduit to said patient interface device to provide a second gas flow to said patient respiratory system, said second gas flow being less volumetrically intensive than said first gas flow; and
a nebulizer connected to the second gas conduit to inject a nebulized drug into the second gas flow.
2. The system of claim 1, wherein the first gas conduit comprises a conduit connecting a flow generator to a pressure regulating device.
3. The system of claim 1, wherein the first gas conduit comprises a first flexible hose and the second gas conduit comprises a second flexible hose, and wherein the second flexible hose has a smaller diameter than the first flexible hose.
4. The system of claim 1, wherein the nebulizer comprises: a reservoir for holding a liquid medicament to be delivered to the respiratory system of said patient; a vibrating orifice type aerosol generator for atomizing the liquid medicine; and a connector for connecting the nebulizer to the second gas conduit, thereby entraining the aerosolized drug from the aerosol generator into the gas flowing through the second gas conduit.
5. The system of claim 4, wherein the volume of the reservoir is equal to one unit dose of the drug.
6. The system of claim 5, wherein the reservoir has a capacity of 4ml or less.
7. The system of claim 4, wherein the dry weight of the atomizer is 5gm or less.
8. The system of claim 7, wherein the nebulizer generates an acoustic pressure of 5 decibels or less.
9. The system of claim 4, wherein the aerosol generator weighs about 1 gm.
10. The system of claim 1, wherein the nebulizer is located proximate to the patient's nose, mouth, or artificial airway.
11. The system of claim 10, wherein the second gas conduit comprises a gas conduit included in the patient interface device, and the nebulizer is integrated with the patient interface device.
12. The system of claim 1, wherein the patient interface device comprises a nasal cannula, a face mask, a nasopharyngeal cannula, a nasopharyngeal tube, a tracheostomy tube, or an endotracheal tube.
13. The system of claim 1, wherein the second gas conduit has a flow path angle that varies by no more than 12 degrees.
14. The system of claim 1, wherein the second gas conduit defines a straight flow path for the ejected aerosol particles.
15. The system of claim 4, wherein the reservoir is rotatable to maintain optimal gravity feed of liquid drug to the aerosol generator as the patient and/or other components of the system change position.
16. The system of claim 1, wherein the patient interface device comprises a tubular inlet portion connected to a pair of nasal prongs by a tubular bifurcated portion, wherein a cavity in the inlet portion is in fluid communication with a cavity in each leg of the tubular bifurcated portion to provide two substantially parallel flow paths for aerosol particles flowing therethrough, each flow path having an angle that varies by no more than 15 degrees.
17. The system of claim 1, further comprising a mechanism for interrupting aerosol particle introduction, the mechanism comprising: a flow sensor disposed in an auxiliary circuit in fluid communication with said second gas conduit and electrically connected to said nebulizer for introducing said aerosol particles into said second gas conduit gas flow, wherein said flow sensor is adapted to detect a change in the volumetric flow of gas in said auxiliary circuit during exhalation by said patient and to send a first electrical signal causing said nebulizer to close when such change is detected.
18. The system of claim 17, wherein the flow sensor is further adapted to detect a change in the volumetric flow of gas in the auxiliary airway when the patient stops exhaling, and to send a second electrical signal such that the nebulizer used to introduce aerosol particles is turned on when such a change is detected.
19. The system of claim 17, wherein the atomizer comprises: a reservoir for holding a liquid medicament to be delivered to the respiratory system of the patient; a vibrating orifice type aerosol generator for atomizing the liquid medicine; and a connector for connecting the nebulizer to the second gas conduit, thereby entraining the aerosolized drug from the aerosol generator into the second gas flow path.
20. The system of claim 19, wherein said flow sensor is capable of sending a second electrical signal to turn on said nebulizer upon detecting a decrease in said volumetric flow of gas in said auxiliary airway due to cessation of patient exhalation.
21. The system of claim 20, wherein each signal is a determined output voltage generated by the flow sensor.
22. The system of claim 1, said flow generator comprising a source of pressurized gas; wherein the patient interface device comprises a mask; wherein the second gas conduit comprises a flexible hose; and wherein the nebulizer is disposed proximate the patient's nose, mouth or artificial airway.
23. The system of claim 1, wherein the nebulizer nebulizes a surfactant of the liquid to discharge the nebulized drug into the second gaseous fluid.
HK07110456.9A 2004-04-20 2005-04-20 Aerosol delivery apparatus for pressure-assisted breathing systems HK1105174B (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US10/828,765 2004-04-20
US10/828,765 US7946291B2 (en) 2004-04-20 2004-04-20 Ventilation systems and methods employing aerosol generators
US10/883,115 US7290541B2 (en) 2004-04-20 2004-06-30 Aerosol delivery apparatus and method for pressure-assisted breathing systems
US10/883,115 2004-06-30
US10/957,321 2004-09-30
US10/957,321 US7267121B2 (en) 2004-04-20 2004-09-30 Aerosol delivery apparatus and method for pressure-assisted breathing systems
US11/080,279 US7201167B2 (en) 2004-04-20 2005-03-14 Method and composition for the treatment of lung surfactant deficiency or dysfunction
US11/080,279 2005-03-14
PCT/US2005/013488 WO2005102431A2 (en) 2004-04-20 2005-04-20 Aerosol delivery apparatus for pressure assisted breathing

Publications (2)

Publication Number Publication Date
HK1105174A1 HK1105174A1 (en) 2008-02-06
HK1105174B true HK1105174B (en) 2012-11-30

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