Patent Application
20240075238
This invention pertains to apparatus used to assist breathing for patients requiring mechanical ventilation, and the administration of drugs with a nebulizer using mechanical ventilation breathing methods.
Positive pressure mechanical ventilation with an endotracheal tube, endotracheal tube, or positive airway pressure masks are an important therapeutic modality for patients who are unable to spontaneously breathe on their own, or unable to breathe efficiently, due to impaired lung function. Positive pressure mechanical ventilation conventionally uses a computer controlled breathing apparatus that regulates airflow to and from the patient. Patients requiring mechanical ventilation frequently require concomitant administration of drugs, and inhaled drugs in many cases are highly desirable. Inhaled drugs are normally delivered as an aerosol from a nebulizer. Thus, the administration of aerosolized drugs to patients on a mechanical ventilator is an important medical issue. The issues include maximizing efficient delivery of the drug to the lungs of the patient, which may be expensive and provision of properly humidified breathing gases. As used herein, the term “nebulized” is also referred to as “atomized” or “aerosolized,” and all three terms are interchangeable. The term “drug” as used herein is interchangeable with “pharmaceutical composition.”
Prior art approaches to administering aerosolized drug to patients typically involve nebulizers. Previous examples of nebulizers include the disclosures WO2016/019061 A1 and WO 2015/188179 A1. In some cases, special nebulizers have been designed to mate with specific ventilators. However, studies have shown the efficiency of prior art nebulizers can be excessively variable, resulting in inaccurate or unpredictable drug administration that can cause overdosing or underdosing of drug to the patient. Thus, accurate and predictable dosing is important.
Normally, patients on a mechanical ventilator require humidification of the inspired air or other gases. Ventilation circuits have previously been described in, e.g., US 2014/0238397 A1, published Aug. 28, 2014 and US 2015/0108670 A1, published Apr. 23, 2015. Methods for humidifying the respiratory tract have also been described in, e.g. U.S. Pat. No. 8,939,152B2, Jan. 27, 2015, as well as assemblies for ventilation circuits having nebulizers and humidifying devices, e.g. US 2006/0283447A1 published Dec. 21, 2006 and US 2014/0053830 A1 published Feb. 27, 2014.
The usual configuration requires that the nebulizer be positioned downstream from the ventilator, i.e., on the wet side of the humidifier (between the humidifier and the patient), or distal to a heat and moisture exchanger, separated from the circuit lumen by a T connector and located near the patient (see e.g., US 2006/0283447A1). Separation from the circuit lumen avoids drug contamination of the humidifier device and contamination of the nebulizer by patient secretions. The disadvantages of this configuration include losses during expiration which are greater when the nebulizer is closer to the patient. Locating the nebulizer near the ventilator outflow port may increase aerosol delivery because the inspiratory limb may act as a reservoir reducing aerosol lost during exhalation.
Another issue with the nebulizer downstream from the humidifier (i.e., on the wet side) is that condensation that can form in the nebulizer and nearby tubing from humidifier moisture and interrupt the operation of the nebulizer. If the nebulizer lumen in vibrating mesh nebulizers is in prolonged fluid communication with humidified ventilator gases, modern heated wire humidified circuits can result in condensation within the nebulizer and circuit occlusion may result. [1] This kind of prolonged contact with ventilator breathing gases may be used with the “Aerogen® Solo” vibrating mesh nebulizer which can be left in place in a breathing circuit for extended periods. The inventor found that humidified breathing gases can penetrate the vibrating membrane in the Aerogen device over 24-48 hours, causing occlusion.
Positive pressure ventilator circuits for assisted breathing are well known, see for example the disclosures in U.S. Pat. Nos. 3,739,776, 4,391,271, and 5,277,125. However, accurate delivery of atomized drug with a nebulizer to patients with concomitant humidification remains an ongoing challenge in these systems.
The present invention discloses a ventilation circuit for aerosol delivery of inhaled drugs during mechanical ventilation using a nebulizer, preferably utilizing a jet nebulizer, whereby the nebulizer is positioned on the dry side of the humidifier. By proper selection of the nebulizer producing sufficiently small aerosolized particles, there is minimal entrapment of drug in the humidifier. In an embodiment, the nebulizer remains in the circuit indefinitely free of condensation from humidified gases as well as respiratory secretions. In an embodiment, the jet nebulizer is powered by a high-pressure air supply that causes nebulization. In an embodiment, the nebulizer is interposed between the ventilator and a humidification device. This arrangement results in a particle distribution that minimizes significant contamination of the humidifier. All breathing gases flow through the nebulizer so there is no T-connector connecting the nebulizer to the inspiratory limb. The inventive system is also simpler than many prior art methods.
The present invention describes a novel ventilator circuit that minimizes the influences of duty cycle or the inhalation-exhalation (I/E) ratio, bias flow, and humidification by utilizing a design that results in aerosol generation primarily during inspiration and minimizes expiratory losses. Furthermore, the placement of the nebulizer near the ventilator in this embodiment ensures that the inspiratory limb acts as a reservoir. The circuit facilitates control of supplemental humidification and functions independently of the brand of the ventilator. In addition, breath actuated nebulization may be employed, using a pressure sensor in the inspiratory limb that detects the inhalation portion of the breathing cycle, and toggles high pressure air to the nebulizer and concomitant nebulization only when the patient is actually breathing.
The instant invention is designed to provide the benefits of nebulization with humidification. Additionally, the invention proposes a solution of the problem of liquid contamination in the ventilation circuit which requires frequent cleaning and maintenance.
In a first aspect, a breathing circuit apparatus is provided for the administration of nebulized drugs through an endotracheal tube, tracheostomy tube, to a patient on a mechanical ventilator that provides breathing gases for inhalation by the patient. The apparatus may include a mechanical ventilator with an inspiratory output port and expiratory input port, an inspiratory limb with a first end connected via a Y connector to an endotracheal tube intubated into a patient, and a second end connected to the inspiratory output port of the ventilator. An expiratory limb is part of the breathing circuit with a first end connected via the Y connector to the endotracheal tube, tracheostomy tube, or mask, and a second end connected to the expiratory input port of the ventilator. Also provided is a breath-enhanced jet nebulizer and humidifier forming part of the inspiratory limb, wherein the nebulizer has an input port and an output port. In an embodiment, the nebulizer input port is connected to the inspiratory output port of the ventilator, and the output port of the nebulizer is connected to the input port of a humidifier, and the output port of the humidifier is connected to the Y connector. In an embodiment, all inspiratory breathing gases pass through the nebulizer, regardless of whether the nebulizer is actually generating nebulized drug.
In an alternative embodiment, a breathing circuit apparatus is provided as above having a nebulizer forming part of the inspiratory limb, wherein the nebulizer has an input port and an output port, wherein the input port of the nebulizer is connected to the inspiratory output port of the ventilator, and wherein the output port of the nebulizer is connected to the Y connector, and wherein a heat and moisture exchanger (HME) is interposed between the Y-connector and the endotracheal tube, tracheostomy tube, or positive pressure inhalation mask (CPAP). All inspiratory breathing gases pass through the nebulizer.
In another aspect, a breathing circuit apparatus is provided for the administration of nebulized drugs through a non-invasive ventilation (NIV) method, such as a continuous positive airway pressure (CPAP) mask or biphasic positive airway pressure (BPAP) mask, to a patient on a mechanical ventilator that provides breathing gases for inhalation by the patient. The apparatus may include a mechanical ventilator with an inspiratory output port and an inspiratory limb with a first end connected to a non-invasive breathing mask or nasal cannula, and a second end connected to the inspiratory output port of the ventilator. Also provided is a breath-enhanced jet nebulizer and humidifier forming part of the inspiratory limb, wherein the nebulizer has an input port and an output port. In an embodiment, the nebulizer input port is connected to the inspiratory output port of the ventilator, and the output port of the nebulizer is connected to the input port of a humidifier, and the output port of the humidifier is connected to the Y connector. In an embodiment, all inspiratory breathing gases pass through the nebulizer, regardless of whether the nebulizer is actually generating nebulized drug.
In another aspect, a breathing circuit apparatus is provided for the administration of nebulized drugs with a jet nebulizer through an invasive or non-invasive breathing method, wherein an air pressure sensor is provided on an inspiratory limb. Such a pressure sensor will be in electronic communication with a solenoid valve that toggles compressed air to the nebulizer. The compressed air supply is required for a drug solution in the nebulizer to be nebulized for administration to the patient. The air pressure sensor detects when the patient is inhaling, such that nebulization is toggled on and is active only when the patient is in the inhalation portion of a breathing cycle.
In another aspect, the nebulizer is permanently affixed to an inspiratory limb of a breathing circuit assisting the breathing of a patient by an invasive or non-invasive method. By the phrase “permanently affixed” it is meant that the nebulizer is not removed at any time during the course of treatment for a particular patient, which can span hours to many days. This is possible with a nebulizer having a port for the addition of a drug solution to the nebulizer while it is in position in the breathing circuit. With such a nebulizer, there is no need to disassemble the nebulizer or interrupt the breathing circuit, even momentarily, to add a drug solution to the nebulizer.
Disclosed herein is a breathing apparatus for the administration of nebulized drugs to a patient breathing with the aid of a mechanical ventilator, an inspiratory limb, and a humidification device. In an embodiment, a breath enhanced nebulizer is integral with the inspiratory limb, such that all breathing gases from the mechanical ventilator pass through the nebulizer, regardless of whether the nebulizer is producing aerosolized drug. The nebulizer aerosolizes a drug solution for inhalation of the drug by a patient. In an embodiment, the nebulizer is a jet nebulizer that nebulizes drug solutions by shear forces from a compressed air supply to the nebulizer jet. In an embodiment, the nebulizer is another type of nebulizer, for example, a vibrating mesh nebulizer or an ultrasonic nebulizer.
In an embodiment, the nebulizer is permanently affixed to an inspiratory limb of a breathing circuit assisting the breathing of a patient by an invasive or non-invasive method. By the phrase “permanently affixed” it is meant that the nebulizer is not removed at any time during the course of treatment for a particular patient, which can span hours to many days. This is possible with a nebulizer having a port for the addition of a drug solution to the nebulizer while it is in position in the breathing circuit. With such a nebulizer, there is no need to disassemble the nebulizer or interrupt the breathing circuit, even momentarily, to add a drug solution to the nebulizer. This is a distinct advantage of the inventive method over prior art ventilation circuits.
In an embodiment as shown in
In an embodiment, the patient is a person in respiratory distress requiring mechanical assistance to breathe. The mechanical assistance may employ an invasive or a noninvasive breathing method. Exemplary invasive methods include an an endotracheal or tracheostomy tube, in which a flexible plastic tube is inserted through the mouth and into the trachea of the lungs. Other invasive techniques include cricothyrotomy and tracheotomy, which both involve incisions in the neck and the insertion of a tube into the lungs. Exemplary noninvasive methods include a positive airway pressure mask, such as a continuous positive airway pressure (CPAP) mask or biphasic positive airway pressure (BPAP) mask, also termed “BiPAP®”. Another non-invasive method is high flow nasal oxygen using a nasal cannula. All of these methods have the common feature of a mechanical device that forces air or other breathing gases into the lungs of a patient. All of these methods may employ humidification of the breathing gases. In addition, the need for the administration of drugs by inhalation is a common feature of all of these methods. In an embodiment, a nebulizer is used to produce aerosolized drug for inhalation. In an embodiment, the nebulizer is a breath enhanced nebulizer.
As used herein, the term “breathing gases” means either ordinary air or another breathing gas mixture indicated for use in mechanical ventilation, such as pure oxygen, oxygen enriched air, and may include anesthesia gases such as nitrous oxide.
An exemplary embodiment is shown schematically in
Exemplary mechanical ventilators include for example a “CareFusion Avea® ventilator system,” a “Dräger Evita® Infinity® V500 ventilator,” and a “Getinge® Servo-i® Ventilator.” These are devices in common use in respiratory therapy for patients in respiratory distress. These machines are computer controlled and have a broad array of controls and modes. Commonly, these machines fully take over breathing functions of the patient, forcing air (or other breathing gases) into the lungs during an inhalation, and withdrawing expiratory air during an exhalation. The inhalation and exhalation for the patient can be fully controlled by the ventilator.
Mechanical ventilators for a breathing circuit have an inspiratory output port (102) in which breathing gases are sent to the patient, and an expiratory input port (104) where exhaled air passes from the patient.
In embodiment, an inspiratory limb (120) is provided with a first end connected via a Y connector (124) to an endotracheal tube (110) intubated into a patient, and a second end connected to the inspiratory output port (102) of the ventilator. As shown in
In an embodiment (
In an embodiment, humidification may be used on the inspiratory limb. Thus, a humidifier (150) (
As shown in
In an embodiment, all inspiratory breathing gases from the ventilator pass through the nebulizer (140). There is no bypass pathway or branch connection with a nebulizer on a branch of the circuit. An example of a type of branched configuration, that the instant invention avoids, is in US 2014/0053830 A1 and
In an embodiment, the nebulizer may function in a breath actuated mode, meaning that the nebulizer can be activated only when needed, by toggling compressed air (176) on and off, for example under the control of a pressure sensor 172 that senses when a patient begins and ends the exhalation portion of a breathing cycle. With such a pressure sensor, the nebulizer only nebulizes drug when the patient is inhaling. This may limit wasted drug, i.e., drug nebulized when the patient is not inhaling, which can be important in some instances.
The permanent nature of the nebulizer on a breathing circuit is both a convenience and a safety feature. The safety emanates from not needing to break the circuit to service the nebulizer. For many situations, breaking the breathing circuit even momentarily is a problem where patients cannot breath properly on their own, and the circuit need not be broken with the instant invention. Moreover, by the use of a jet nebulizer such as described below, the nebulizer need not be disconnected to add drug, for example with a stopcock on a T-connection, or by unplugging and replugging pipe connections.
In an embodiment, the nebulizer used in this invention is a breath-enhanced jet nebulizer and generates aerosol by nebulization only when a compressed air flow at about 50 psig is provided at port 146 of the nebulizer. In a breath-enhanced jet nebulizer, such as that disclosed in co-pending patent publication WO2019/236896 A1, published 12 Dec. 2019, a Venturi effect within the nebulizer is created by a compressed air flow. Breath-enhanced nebulizers have an internal configuration that enhances, or amplifies, the rate of nebulization compared to prior art jet nebulizers. The Venturi effect is amplified (enhanced) from ventilator gases passing through the nebulizer supplementing the effects of the compressed air. The Venturi creates a low-pressure zone from an air jet adjacent to an orifice and liquid channel that draws a drug solution from a reservoir through the channel to the orifice where the solution is nebulized by shear forces from the adjacent air jet. Without the ventilator generated air flow, there is no enhanced Venturi effect, and the rate of nebulization is greatly reduced. Other nebulizer designs to date such as competing jet nebulizers, vibrating mesh nebulizers, and ultrasonic nebulizers do not have the enhanced nebulization capability. Moreover, other designs produce particle sizes that tend to contaminate the humidifier, resulting in drug loss and fouling of the humidifier.
Copending patent application PCT/US21/64554 filed Dec. 21, 2021 discloses embodiments of nebulizers useful in this invention having a port for the addition of a drug solution to the nebulizer while it is inline and ready for use, without having to disassemble the nebulizer or break the breathing circuit. A drug solution can be added to the nebulizer as a bolus, meaning an injection of up to 6 mL of drug solution (the capacity of the drug reservoir in the embodiment of PCT/US21/64554 is 6 mL), or the drug solution can be added continuously over an extended period as a steady drip added to the nebulizer, for example with a syringe pump. Both methods of adding a drug solution to the nebulizer can be used simultaneously with the nebulizer embodiments disclosed in PCT/US21/64554.
There have been suggestions in the literature that placing a nebulizer before a humidifier in the inspiratory limb of a breathing circuit can result in significant losses of aerosol during nebulization operations[2]. However, the inventors found that placing a nebulizer between the humidifier and the patient caused condensation that could not be avoided, so this configuration is not feasible.[1] Aerosols produced by the nebulizer according to WO2019/236896 have a mass median aerodynamic diameter of about 2 μm in size. This mean particle size results in minimal entrapment of drug in the humidifier and consistent dosing. By the term “about” here, it is meant±25% of any stated dimension. By comparison, other nebulizer technologies (including vibrating mesh designs) were found to cause significant humidifier contamination. The contamination caused by other nebulizers is likely due to particle size distributions produced by alternative nebulizer designs. Placing the nebulizer before the humidifier also means that relatively dry breathing gases flow through the nebulizer, resulting in more consistent particle distribution of the aerosol produced in the nebulizer.
A further benefit to the inventive inspiratory limb configuration is that the nebulizer resides permanently in the breathing circuit or inspiratory limb, and additional drug can be added to the nebulizer without breaking the circuit, interrupting the breathing gas flow, or disassembling the nebulizer. The maintains consistent ventilation to the patient. Additionally, this feature reduces the risk of infection since the integrity of the circuit remains intact at all times and neither the nebulizer or surfaces on the dry side of the humidifier get wet with condensation. Moreover, the nebulizer is insulated from contamination from patient secretions on the dry side of the humidifier.
Yet another benefit to the inventive design with the nebulizer near the ventilator is that the inspiratory limb and humidifier (if present) may act as an aerosol storage reservoir to reduce expiratory losses. A more conventional location of the nebulizer on a T connection close to the patient can result in substantial drug losses, with significant amounts of aerosol shunted to the expiratory limb. This also reduces the effect of the duty cycle on nebulizer losses during expiration.
In an embodiment, the nebulization in this invention is breath actuated. With a breath actuated nebulizer, compressed air is only provided to the nebulizer while the patient is inhaling, and no nebulization occurs in the absence of the compressed air flow, regardless of the breath enhanced configuration. The inhalation portion of a breathing cycle is also termed the “duty cycle,” the fraction of time of an overall inhalation/exhalation cycle when the patient is actually inhaling. The compressed air flow can be toggled on and off to the nebulizer such that compressed air flow to the nebulizer, and concomitant nebulization, only occurs during the inhalation portion of a breathing cycle.
In an embodiment, the compressed air flow in a breath actuated system is controlled with a pressure sensor that toggles the nebulizer air flow on when the patient is inhaling, and toggles the airflow off during all other portions of the breathing cycle (exhaling or neither inhaling or exhaling). In an embodiment, breath-actuation relies on a pressure sensor 172 that detects when a patient is inhaling, as opposed to exhaling or neither inhaling nor exhaling. The sensor is in electronic communication with a solenoid 170 that activates the flow of compressed air 176 to the nebulizer at 2-6 L/min and 50 psig. The compressed air is conveyed to the nebulizer compressed air inlet port 146 via compressed air tube 174.
In an embodiment, the pressure sensor is placed on a tube in fluid communication with the inspiratory outlet of the mechanical ventilator. As shown in
In a further embodiment, a drug solution can be added to the nebulizer at any time via a drug input port 148 as disclosed in WO2019/236896, without disassembling the nebulizer or interrupting the ventilation circuit even momentarily. Thus, the nebulizer is a permanent part of the inspiratory limb and is not removed during the course of treatment for a patient.
An alternative breathing circuit embodiment is shown in
The inventive systems in
A further embodiment of the inventive breathing circuit is shown in
In an embodiment illustrated in
In an embodiment illustrated in
The effectiveness of the inventive circuit is shown in
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/73117 | 12/27/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63145798 | Feb 2021 | US | |
| 63130439 | Dec 2020 | US |
