HK1238582B - Improved method and system for the administration of a pulmonary surfactant by atomization - Google Patents

Description

Improved methods and systems for administering pulmonary surfactant by aerosolization

Technical Field

The present invention relates to the field of retropharyngeal instillation of drugs, and in particular, to a method and system for administering pulmonary surfactant by aerosolization.

Background Art

The problem that the use of drugs in the lungs usually faces is to find a good balance between efficacy and treatment invasiveness. This is especially difficult for infants (hereinafter, the term neonate is used as a synonym for infant). Premature neonates may be affected by nRDS (neonatal respiratory distress syndrome), a lung disease caused by the general immaturity of a lack of pulmonary surfactant. For many years, exogenous pulmonary surfactant has been administered as a pill to premature neonates who are intubated under mechanical ventilation by tracheal instillation to treat nRDS. Although this treatment is very effective (proven by a reduction in mortality), it may have some defects that are inherent to mechanical ventilation (volume/barotrauma) and to the intubation procedure, which is always invasive anyway.

In view of the potential complications associated with intubation and mechanical ventilation, attention has focused on different methods of administering exogenous pulmonary surfactant.

Specifically, the use of non-invasive ventilation procedures, such as early nasal continuous positive airway pressure (nCPAP), which delivers air to the lungs through a specially designed device (e.g., a mask), has been introduced in neonatal intensive care as a possible respiratory support.

Following this orientation, in the last fifteen years, more attention has also been focused on finding alternative ways of administering pulmonary surfactants. Most of the studies conducted have focused on administering aerosolized surfactants (i.e. particles with a mass diameter of <10 μm) by means of commercial nebulizers connected to a ventilation circuit, based on the assumption that a gentler and more gradual administration should prevent the high cerebral blood flow that can occur with bolus administration (see, for example, Mazela J, Merrit TA, Finner NN "Aerosolized surfactants" Curr Opin Pediatr. 2007; 19(2): 155; or Mazela J, Polin RA "Aerosol delivery to ventilated newborn infants: Historical challenges and new directions" Eur J Pediatr. 2011: 1-12; or Shah S "Exogenus surfactant: Intubated present, nebulized future?" World Journal of Pediatrics. 2011; 7(1): 11-5). Although surfactants produce a more uniform distribution, the differences in lung function improvements achieved across studies are quite large, and they do not demonstrate the effectiveness of the nebulization method. In other studies, surfactant nebulization systems were connected to a non-invasive ventilator setup (i.e., CPAP via nasal prongs); under these conditions, the amount of nebulized surfactant that reaches the lungs appears to be negligible (less than 20%). Furthermore, nebulized surfactant administered during CPAP does not have a conclusive beneficial effect on lung function, as shown in pilot studies in preterm neonates (see, for example, Berggren E, Liljedhal M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al. "Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome" Acta Paediatrica 2000;89(4):460-4; or Finner NN, Merritt TA, Bernstein G, Job L, Mazela J, Segal R, "An open label, pilot study of Aerosurf combined with nCPAP to prevent RDS in preterm neonates" Journal of aerosol medicine and pulmonary drug delivery. 2010;23(5):303-9; or Jorch G, Hartl H, Roth B, Kribs A, Gortner L, Schaible T, et al. "Surfactant aerosol treatment for premature neonates" Journal of aerosol medicine and pulmonary drug delivery. 2010;23(5):303-9; or Jorch G, Hartl H, Roth B, Kribs A, Gortner L, Schaible T, et al. "Surfactant aerosol treatment for premature neonates" of respiratory distress syndrome inspontaneously breathing premature infants” Pediatr Pulmonol. 1997; 24(3): 222-4). These studies are very heterogeneous, and the authors applied different conditions with reference to several parameters, such as: 1) placement and type of aerosol generator, 2) ventilation mode, 3) humidity, 4) air flow, 5) particle size, 6) nRDS model, 7) surfactant dilution, etc.

Therefore, it is difficult to make a correct comparison between them.However, known systems generally prove to be not very efficient.

Furthermore, when aerosolized surfactant is administered with a nebulizer via a face mask and is not synchronized with the neonate's breathing, some portion may be exhaled during expiration, deposited into the upper airway or tube/connection, or exhaled through the expiratory flap. Furthermore, the delivery of aerosolized surfactant increases the dead space in the breathing circuit, which may promote _CO2 retention, which may become dangerous if the end state of hypercapnia is reached, given that premature neonates may have a tidal volume of 1 ml or even less.

Wagner et al. have proposed an interesting approach that could partially mitigate the above risks (Wagner MH, Amthauer H, Sonntag J, Drenk F, HW, Obladen M "Endotracheal surfactant atomization: an alternative to bolus instillation?" Crit Care Med. 2000; 28(7): 2540), showing encouraging results. It is based on a modified endotracheal tube in which a nebulizer is inserted at the end of the tube. Only during inspiration (identified by the operator) does the nebulizer generate particles with a SMD (Sauter mean diameter) of >100 μm. The option of placing the nebulizer directly into the tube presents technical difficulties.

The favorable results of the Wagner method may be due to the relatively large particle size, which allows the pulmonary surfactant to be distributed and absorbed by similar mechanisms involved in similar bolus administration. Specifically, it can be hypothesized that large particles will be deposited in the more central airways, able to reach the unexpanded alveoli through diffusion gradients, the Marangoni effect, and capillary action, while small aerosolized particles are able to pass through the upper airways and can be exhaled during expiration or deposited in the already opened alveoli that generate air flow during breathing, without reaching the atelectatic regions of the lung and without contributing to the even more uneven distribution of the lung time constant. Another advantage of the Wagner method is that the pulmonary surfactant is only administered during inspiration, which allows for better control of the amount of drug effectively delivered, resulting in improvements in cost savings and clinical effectiveness.

The drawback of Wagner is that the catheter must reach the trachea (where the nebulizer is placed) in order to be able to deliver particles of a relatively large size that will be filtered out by the upper airways, a process that is invasive and can cause problems, especially for newborns. On the other hand, all known prior art systems that implement non-invasive (i.e., without entering the tracheal tube) delivery methods are only able to administer small-sized particles that can overcome external barriers but are not able to effectively reach all areas of the lung that need to be treated.

Furthermore, according to Wagner's experiments, the "synchronization" of drug delivery and inspiratory rhythm was achieved manually, which is not ideal for obvious reasons (including product waste). On the other hand, all attempts known in the art to implement such synchronization, such as disclosed in EP692273, depend on the presence of a device such as a mechanical ventilator. However, this solution requires connection to the neonate's airway, increasing the dead space and mechanical load on the patient's breathing.

For all of these reasons, there is a great need for improved non-invasive methods and systems for administering exogenous surfactants that can combine the advantages of Wagner et al., in part with appropriate automated delivery synchronization.

Summary of the Invention

It is an object of the present invention to overcome at least some of the problems associated with the prior art.

The present invention provides methods and systems as described in the accompanying claims.

According to one aspect of the present invention, there is provided a system for delivering a medication including a pulmonary surfactant to a spontaneously breathing patient, comprising: i) a catheter adapted to reach a posterior pharyngeal region of the patient, the catheter comprising at least a first channel adapted to convey a flow of liquid medication in the pharyngeal region of the patient, and at least a second channel adapted to convey a flow of pressurized gas in the pharyngeal region of the patient, ii) a first pump member connected to a first end of the at least first channel and adapted to generate a pressure that pushes a column of liquid medication toward a second end of the at least first channel;

-iii) a second pump member connected to the first end of the at least second channel, adapted to generate the pressurized gas flow, so that when the liquid drug column and the pressurized gas meet in the pharyngeal cavity, the liquid drug column is broken up into a plurality of particles, so that the aerosolized drug is delivered to the patient's lungs; -iv) a pressure detection member separated from the first channel and the second channel, for measuring a value representing the pressure in the patient's pharyngeal cavity, which is used to determine whether the patient is in the inhalation phase or the exhalation phase, and wherein the first pump member is selectively activated only during the inhalation phase.

In a preferred embodiment, respiratory activity is assessed by measuring pressure changes in the posterior pharyngeal cavity; in a more preferred embodiment, the pressure detection component includes: a third channel adapted to convey a flow of aqueous solution in the pharyngeal region of the patient; a third pump component for generating a constant flow of aqueous solution; and a pressure sensor connected to the third channel for measuring a value representing the pressure of the aqueous solution flow.

The use of a liquid-filled lumen (either embedded in the catheter assembly or completely separate from the catheter assembly) for estimating pressure changes in the pharyngeal cavity has specific advantages over other methods: 1) it provides a very fast response of the catheter-pressure transducer system (liquid is incompressible and increases the minimum coherence of the measurement system, resulting in a very fast time constant) to allow rapid detection of the respiratory state of the neonate (small premature neonates may have a respiratory rate greater than 60 breaths per minute, orders of magnitude greater than that of adults); and 2) the presence of liquid in the lumen prevents the tip of the catheter from becoming occupied by fluid that is always present in the pharynx (such as saliva or moisture due to a water vapor saturated environment), which is an important advantage over air-filled lumens for pressure sensing.

Preferably, the catheter is made of a flexible plastic material. Alternatively, the catheter may include a partially rigid support. Preferably, the at least second channel comprises a plurality of channels arranged around the first channel. In a preferred embodiment, the third channel is embedded in the catheter assembly. In a specific embodiment, the third channel is one of the channels arranged around the first channel.

Preferably, the aerosol medicament comprises an exogenous lung surfactant, for example selected from the group consisting of modified natural lung surfactant (eg porcine alfa), artificial surfactant and reconstituted surfactant.

Additionally, in preferred embodiments, the pressurized gas comprises air or oxygen.

According to another embodiment, a spacing member is disposed on an outer surface of the catheter such that when the catheter is in place for aerosol therapy, at least the second end of the first channel and at least the second channel remain spaced apart from the wall of the pharyngeal cavity.

In a second aspect of the present invention, a method for preventing and/or treating respiratory distress syndrome in a spontaneously breathing patient is provided, the method comprising the steps of delivering aerosolized medication to the posterior pharyngeal region of the patient by means of a multi-channel flexible catheter, wherein a low-pressure column of liquid medication passes through at least a first channel of the multi-channel catheter and a pressurized gas stream passes through at least a second channel of the multi-channel catheter; wherein when the column of liquid medication and the pressurized gas meet in the posterior pharyngeal cavity, the column of liquid medication is broken up into a plurality of particles; detecting the patient's inspiratory activity by means of a pressure sensor, for example connected to at least a third channel, the third channel being adapted to convey a stream of aqueous solution in the posterior pharyngeal region; wherein the providing step is performed only during inspiratory activity. In a preferred embodiment, the aqueous solution is a physiological saline (0.9% w/v sodium chloride) aqueous solution, optionally buffered at a physiological pH.

More preferably, the method of the present invention comprises administering a non-invasive ventilation procedure, such as nasal continuous positive airway pressure (nCPAP), to the patient.

In a third aspect of the invention, a kit is provided comprising: a) a pharmaceutical composition comprising a pulmonary surfactant suspended in a pharmaceutically acceptable aqueous medium; b) a system of the invention; c) a member for positioning and/or facilitating the introduction of a catheter into the posterior pharyngeal region; and d) a container member for containing the pharmaceutical composition, the system and the positioning member. In a certain embodiment of the invention, the member for positioning comprises a laryngeal mask. In a fourth aspect of the invention, a method for preventing and/or treating respiratory distress syndrome in spontaneously breathing premature newborns is provided, the method comprising the steps of delivering pulmonary surfactant to the posterior pharyngeal cavity of the newborn only during the inspiratory phase detected by means of a pressure sensor. Another aspect of the invention provides a computer program for controlling the above method.

The method and system according to the preferred embodiment of the present invention can optimize the distribution of surfactant and can effectively deliver aerosolized particles to the lungs without the need for invasive procedures for placing catheters. The method and system of the present invention provide several advantages, including: a gentler aerosolization process due to the air-blast aerosolization catheter, with less mechanical impact on the surfactant; the ability to monitor and synchronize the patient's breathing pattern without the need to introduce sensors, airway openings or connections at the second lumen; the flexibility of the device, which can be applied during spontaneous breathing or used when providing non-invasive ventilation, such as during nCPAP or other non-invasive ventilation procedures, such as during nasal intermittent positive pressure ventilation (NIPPV); the components used are already familiar to hospital staff, such as catheters and disposable pressure sensors (similar to components used for invasive blood pressure monitoring); all components that come into contact with the lung surfactant and the patient are low-cost and disposable, providing more hygienic and safer handling than the existing technology, which is particularly important when the patient is a premature newborn.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference will now be made by way of example to the accompanying drawings, in which:

FIG1 is a schematic diagram of a system for implementing a preferred embodiment of the present invention;

FIG2 shows two examples of catheter assemblies according to embodiments of the present invention, including a third channel for measuring posterior pharyngeal pressure and a multi-lumen catheter.

FIG3 shows an example of a specific shape of a channel in a multi-lumen catheter according to an embodiment of the present invention;

4a and 4b respectively show a pressure sensor and a circuit for controlling the pressure sensor according to an embodiment of the present invention;

FIG5 shows an exemplary retropharyngeal pressure signal acquired in a premature neonate.

FIG6 shows the steps of a method according to a preferred embodiment of the present invention;

FIG7 is a diagram illustrating a tidal volume associated with a fetus treated using methods and systems according to embodiments of the present invention;

Figure 8 shows the effect of aerosolized surfactant on the alveolar-arterial oxygen concentration ratio (aA ratio). Open circles: aerosolized lambs; closed diamonds: CPAP control group. Oxygenation was measured 105 minutes after birth.

Because baseline values of aA ratio were extremely variable, data are reported as changes from baseline. The nebulized group demonstrated significantly better changes in aA ratio at 90 and 105 minutes from birth compared to the CPAP group (p < 0.05 and p < 0.001, respectively, two-way ANOVA with Sidak's effect test).

DETAILED DESCRIPTION

definition

By the term "pulmonary surfactant" is meant exogenous pulmonary surfactant administered to the lungs and may belong to one of the following categories:

i) "Modified natural" lung surfactants, which are lipid extracts of minced mammalian lung or lung lavage. These preparations have variable amounts of SP-B and SP-C protein and, depending on the extraction method, may contain non-lung surfactant lipids, proteins, or other components. Certain modified natural lung surfactants available on the market, such as Survanta ^™ , are adulterated with synthetic ingredients such as palmitin, dipalmitoylphosphatidylcholine, and palmitic acid.

ii) "Artificial" lung surfactants, which are simple mixtures of synthetic compounds, primarily phospholipids and other lipids, formulated to mimic the lipid composition and properties of natural lung surfactant. They lack lung surfactant proteins;

iii) "reconstituted" lung surfactant, which is a synthetic lung surfactant to which has been added lung surfactant proteins/peptides isolated from animals or produced by recombinant technology, such as disclosed in WO 95/32992, or synthetic lung surfactant protein analogs, such as disclosed in WO 89/06657, WO 92/22315 and WO 00/47623.

The term "non-invasive" ventilation (NIV) procedure defines a form of ventilation that supports breathing without the need for intubation.

Reference is made to Figure 1, which illustrates an implementation of a method and system according to a preferred embodiment of the present invention. In the examples discussed herein, the problem of delivering the correct amount of aerosolized medication to a patient is addressed: specifically, administering a lung surfactant (e.g., porcine alfa, commercially available from Chiesi Farmaceutici SpA) to, for example, premature neonates.

However, any pulmonary surfactant currently used or later proposed for use in respiratory distress systems and other pulmonary conditions may be suitable for use in the present invention. These include modified natural, artificial, and reconstituted pulmonary surfactants (PS).

Current modified natural lung surfactants include, but are not limited to, bovine lipid lung surfactant (BLES ^™ , BLES Biochemicals, Inc., London, Ontario), calfactant (Infasurf ^™ , Forest Pharmaceuticals, St. Louis, MO), bovactant (Alveofact ^™ , Thome, Germany), bovine lung surfactant (Lung Surfactant TA ^™ , Tanabe, Tokyo, Japan), porcine alfa phospholipid (Chiesi Farmaceutici SpA, Parma, Italy), and beractant (Survanta ^™ , Abbott Laboratories, Inc., Abbott Technology Park III).

Examples of artificial surfactants include, but are not limited to, pumactant (Alec ^™ , Britannia Pharmaceuticals, UK), and Exosurf ^™ , GlaxoSmithKline plc, Middlesex.

Examples of reconstituted surfactants include, but are not limited to, lucinactant (Surfaxin ^™ , Discovery Laboratories Ltd., Warrington PA) and products having the ingredients disclosed in Table 2 of Example 2 of WO 2010/139442, the teachings of which are incorporated herein by reference.

Preferably, the lung surfactant is a modified natural surfactant or a reconstituted surfactant. More preferably, the lung surfactant is porcine alfa. In another preferred embodiment, the reconstituted surfactant has the composition disclosed in WO2010/139442 (see Table 2 of Example 2).

The dose of pulmonary surfactant to be administered varies with the size and age of the patient and the severity of the patient's condition. One skilled in the art will readily determine these factors and adjust the dose accordingly.

According to the present invention, other active ingredients can be advantageously included in the medicament, including small chemical entities, macromolecules, such as proteins, peptides, oligopeptides, polypeptides, polyamino acid nucleic acids, polynucleotides, oligonucleotides and high molecular weight polysaccharides, and mesenchymal stem cells derived from any tissue (especially neonatal tissue). In a specific embodiment, the small chemical entities include those currently used to prevent and/or treat neonatal respiratory diseases, such as inhaled corticosteroids, such as beclomethasone dipropionate and budesonide.

The catheter 101 delivers aerosolized medication (e.g., surfactant) directly to the posterior pharyngeal region, thereby increasing the efficiency of drug administration without invasive procedures. This is particularly important for very young patients, such as premature newborns with neonatal respiratory distress syndrome (nRDS). According to a preferred embodiment of the present invention, the catheter is made of a biocompatible, flexible material (e.g., a plastic material). The catheter can be coupled to a rigid support (e.g., metal) to increase the rigidity of the device and improve ease of positioning. In a preferred embodiment of the present invention, delivery of the aerosolized medication is achieved using air-blast technology. The use of air to assist aerosolization is a well-known technique that can provide complete atomization even when low pressure and low flow conditions are required (see, for example, Arthur Lefebvre, "Atomization and Spray," Taylor and Francis, 1989). Such techniques are based on a small amount of gas (e.g., air, but could be other compressed gases, such as oxygen, nitrogen, or helium) flowing in one or more channels separate from the medication being delivered in liquid form; the air flow accelerates and breaks up the liquid column, causing aerosolization of the medication. Therefore, the multi-lumen catheter 101 includes multiple channels (at least two, one for drug and one for air) for simultaneously delivering drug and air streams. When the two streams (air and liquid drug) exit the catheter channels and meet in the posterior pharyngeal region, the turbulence caused by the air flowing near or around them breaks up the liquid drug column into droplets. The median diameter of the atomized droplets is at least 20 microns, preferably equal to or greater than 40 microns, and more preferably equal to or greater than 60 microns. It is believed that this effect is caused by the air flow, which accelerates the instability of the lamellar flow. The air also helps to disperse the droplets, preventing collisions between droplets and facilitating drug diffusion in the lungs by reducing the likelihood of contact between particles and the walls of the posterior pharyngeal cavity. In a preferred embodiment, the cross-section of the air duct decreases near the outlet, as shown in Figure 3. According to Poiseuille's law, flow resistance increases linearly with the length of the catheter and is inversely proportional to the fourth power of the lumen radius. Therefore, by using a catheter with a larger lumen for most of the total length, the total resistance of the air path is significantly reduced, reducing the pressure applied to the catheter inlet required to aerosolize the drug.

In one embodiment of the present invention, the air duct can be shaped to change not only the speed of the gas flow, but also the direction of the gas flow. For example, it can have a wing-shaped duct that can simulate a spray angle.

In a preferred embodiment of the present invention, a medication (e.g., a surfactant) is delivered via a pump 103 connected to one end of a catheter. The pump forces the liquid medication out of the opposite end of the catheter, where it meets a stream of air (delivered through a different channel of the catheter) and is atomized by the pressurized air, i.e., broken into a plurality of small particles (droplets). Pump 103 can be implemented as a device capable of generating flow, such as an infusion pump. In a preferred embodiment of the present invention, pump 103 is comprised of a mechanical frame, including a structure for holding a syringe containing the liquid medication, and a stepper motor, which pushes the syringe piston. In embodiments of the present invention, pump 103 can be controlled by a control unit 109; such a control unit can be implemented as a computer, a microprocessor, or more generally, any device capable of performing data processing activities. Pump device 105 (which may include a pressurized source, a pressure regulator, and a filter) is connected to one or more channels for delivering the air flow. Those skilled in the art will understand that the term pump encompasses any device capable of applying pressure to a liquid or gas flow. Pump 105 can be controlled by a control unit, as described for pump 103. The flow rate of pump 103 should be in the range of 9-18 ml/H, while the flow rate of pump 105 should be less than 1 L/min, in a preferred embodiment, less than 0.75 L/min, so as not to interfere with any spontaneous or assisted breathing activity.

In a preferred embodiment of the present invention, the conduit 101 includes multiple channels, wherein a main (e.g., central) channel carries the surfactant, surrounded by multiple additional channels (e.g., lateral) that carry pressurized airflow. The advantage provided by the air blast technology described herein is that the surfactant is more gently broken. Current nebulizers for drug delivery are typically based on orifices, while the method according to the present invention employs an atomizing conduit that utilizes an air blast method. The geometric configuration of a straight orifice typically narrows at the distal end of the conduit (nozzle), which accelerates the liquid to produce high instability under high pressure drops (greater than 1 Atm), thereby accelerating the breakup of the liquid into particles. In contrast, the air blast conduit according to a preferred embodiment of the present invention is a multi-lumen conduit: the surfactant flows into the main lumen, while the pressurized air flows into the lateral lumens. The turbulence generated by the small airflow breaks up the surfactant in a very gentle manner. Furthermore, the use of a straight orifice requires a very high pressure differential on both sides of the nozzle to induce atomization, while an air blast conduit does not require applying a high driving pressure to the surfactant because the atomization process is driven by the turbulent air flow surrounding the surfactant.

The pulmonary surfactant is preferably administered as a suspension in a sterile pharmaceutically acceptable aqueous medium, preferably a buffered physiological saline (0.9% w/v sodium chloride) aqueous solution.

The concentration should be appropriately adjusted by those skilled in the art.

Advantageously, the concentration of the surfactant may be between 2 and 160 mg/ml, preferably between 10 and 100 mg/ml, more preferably between 40 and 80 mg/ml.

The volume applied should generally not exceed 5.0 ml, preferably not exceed 3.0 ml. In some embodiments, it may be 1.5 ml or 3 ml.

Pulmonary surfactant administration is synchronized with the patient's respiratory phase. To implement this feature, a sensing component for any variable related to respiratory activity must be used for indirect but accurate measurement of the inspiratory phase. Possible embodiments of such a pressure sensing component include a micropressure sensor at the distal end of a catheter, an expiratory induction pneumograph, or a fiber optic pressure sensor. According to a preferred embodiment of the present invention, the pressure sensing component includes a dedicated channel 111 (a third channel, e.g., a catheter, distinct from the at least one first channel for delivering the surfactant medication and the at least one second channel for delivering air for a plenum effect) that delivers a flow of an aqueous solution, such as a saline solution (0.9% w/v sodium chloride), optionally buffered at a physiological pH according to conditions well known to those skilled in the art. As shown in FIG1 , pressure sensor 107 monitors respiratory rhythm by sensing the pressure on the saline solution column in the posterior pharyngeal region/pharyngeal area. Not shown in FIG1 , the system according to a preferred embodiment of the present invention also includes a (third) pump component (possibly including a pressurization source, a pressure regulator, and a filter) connected to the third channel for delivering the aqueous solution. Those skilled in the art will understand that the term pump encompasses any device capable of providing a constant flow of liquid. This third pump may be controlled by the control unit as described for pumps 103 and 105. Preferably, the flow rate of the third pump should be in the range of 0.1-10 ml/hour to avoid adding too much fluid in the pharynx during delivery of the surfactant.

Two possible implementations of a catheter assembly 200 are shown in FIG2 : specifically, FIG2 a shows two views (a cross-sectional view and a longitudinal view) of a catheter assembly according to an embodiment of the present invention, wherein a third channel 205 is completely separated from a multi-lumen catheter comprising a drug lumen 201 and a plurality of air lumens 203; and FIG2 b shows a similar view of an embodiment in which the third channel is attached to a multi-lumen catheter. In a preferred embodiment, the cross-section of the central drug lumen is 0.25 to 0.5 mm, while the cross-section of the air lumen should be between 0.05 and 0.15 mm, wherein the ratio of the surfactant to the air lumen area should be between 0.2 and 2, taking into account the cumulative cross-sectional area of the corresponding lumens at the catheter tip.

A pressure sensor is coupled to the third channel and inserted along the aqueous solution catheter. This measurement is possible due to the lower pressure in the channel that transmits the aqueous solution, allowing an uninterrupted column of aqueous solution to be administered to measure the posterior pharyngeal pressure, with the goal of synchronizing atomization with the patient's breathing pattern and helping the attending medical staff place the catheter in the correct position and monitor the maintenance of the correct position during treatment so that incorrect positioning of the catheter tip (e.g., positioning in the esophagus) can be identified. As described above, the pump (third pump member) ensures that a constant liquid flow is maintained to avoid blockage at the opening of the third channel.

As described above, Fig. 2 shows a specific embodiment of a multi-channel catheter according to a preferred embodiment of the present invention. The air blast nebulizer of this embodiment is realized by means of a multi-lumen catheter, and this multi-lumen catheter has a central lumen 201, and this central lumen is surrounded by several smaller lumens 203. The surfactant is driven by an infusion pump and flows into the main central lumen, while gas (such as air, oxygen-enriched air or pure oxygen) flows through the lateral lumen. The pressure drop of the central catheter depends on its length and inner diameter. In a preferred embodiment of the present invention, the length of the catheter can be 7-15cm, and the inner diameter can be 0.6-0.8mm. According to a preferred embodiment, the diameter of the surfactant lumen is 0.75mm, and the lateral lumen for gas can be a single lumen for the entire catheter length except the 5 mm tip at the end, at which end, its shape can be changed into multiple lumens coaxial with the surfactant lumen. This solution can reduce the total resistance of the gas lumen, reduce the gas pressure required for atomization, and in addition, the speed of the gas increases to facilitate the atomization process. In this case, considering a surfactant flow rate of 3 mL/20 min, the pressure drop is in the range of 3.5-8 cmH ₂ O. In this way, no nozzle is required, and the particle size is mainly determined by the air flow into the lateral channel. To generate the gas flow into the lateral lumen, a compressor or a pressurized gas source (such as a cylinder or medical gas wall plug) can be used: the pressure is regulated by a pressure regulator and a mechanical filter to avoid dust flow through the system.

Such pressurized gas flow is not able to significantly change the pressure of the pharynx since the pressurized gas flow is quite restricted and the anatomy is open to the atmosphere: in a preferred embodiment, the pressurized gas flow is equal to or less than 1 L/min.

Figure 3a shows a possible embodiment of a conduit, wherein the third channel (carrying an aqueous solution) 301 is one of the channels surrounding the first (central) channel 201; both channel 301 and channel 203 are placed around the central channel, wherein channel 203 carries pressurized air and channel 301 carries the aqueous solution.

FIG3 b shows an optional feature of the catheter assembly of the present invention, wherein the air lumen 203 has a cross-section that decreases toward the outlet. FIG3 b shows a longitudinal cross-sectional view. In a preferred embodiment, this reduction in the cross-section of the air lumen is due to a corresponding expansion of the central drug delivery lumen 201. The embodiment shown in FIG3 b is only one of the possible options for implementing such a feature: as a possible alternative, the outer wall of the multi-lumen catheter can become thicker toward the end, so that the air lumen is restricted; another possible embodiment can be to reduce the total cross-section of the multi-lumen catheter, keeping the size of the central channel (lumen) unchanged.

The particle size distribution obtained using a preferred embodiment of the present invention was characterized using a commercial laser diffraction particle size analyzer (Malvern, Particle Sizer RT). Measurements were performed using exemplary conditions of 0.75 bar pressurized air; under the conditions used, the surfactant flow rate (ranging from 9 mL/h to 1.2 mL/min) did not affect particle size. Consequently, the majority of particles were between 20 and 100 microns in size.

As a possible additional feature, the catheter used in the method and system of the present invention may be provided with some spacers on the outer surface, which help to position the catheter and maintain a minimum distance between the catheter itself and the wall of the posterior pharyngeal cavity. This spacing ensures that the aerosolized surfactant is delivered to the lungs by the inspiratory air flow without being projected onto the wall of the pharyngeal cavity. An example is shown in Figure 2b, in which some ribs extend along the outer surface of the catheter; these ribs may also have a rigidity function to add a certain amount of rigidity to the catheter (as an alternative to the above-mentioned metal support). The ribs may have other shapes, for example they may be in the shape of one or more rings around the catheter, these rings being spaced apart from each other by a predetermined distance: it will be understood by those skilled in the art that several equivalent alternatives may be implemented.

A laryngoscope is another tool known to those skilled in the art that can be adapted for use in positioning a catheter in the posterior pharyngeal cavity.

In addition, Magill forceps, oro-pharyngeal cannula (such as Mayo, Guedel, Safar and Bierman cannula) and laryngeal mask can facilitate the introduction of the catheter. In a certain embodiment, during the entire delivery period of the surfactant, the Mayo cannula is used to facilitate the introduction of the high end and position the catheter tip in the correct position, that is, away from the pharyngeal wall and pointing to the entrance of the trachea. In another embodiment, a laryngeal mask can be used.

As mentioned above, the third channel must be kept separate from at least the first channel for conveying the surfactant drug, and kept separate from at least the second channel for conveying the air flow, because measuring the pressure too close to the blast area may result in inaccurate measurements, however, several possible solutions are available, including keeping the third channel completely separated, or connecting the third channel to the other two channels in some way. The catheter assembly can be designed to include the third channel to form a gap between the outlet of the third channel and the outlet of the drug and air channels. Another possible embodiment is to embed the aqueous solution delivery channel (the third channel) into a positioning tool, such as a Mayo cannula.

Figure 4a illustrates a possible implementation of the aforementioned pressure sensor 107, which is used in an embodiment of the present invention to detect the pressure of air originating from or flowing into the pharyngeal cavity. The pressure thus measured serves as an indicator of the patient's breathing rhythm, and the system synchronizes medication administration accordingly. This synchronization offers significant advantages in terms of therapeutic efficacy and reduced medication waste. This efficacy is due to the delivery of the aerosolized medication via the inspiratory flow; the savings are due to the fact that medication is delivered only when needed, avoiding wastage during the patient's exhalation. In an embodiment of the present invention, a pressure sensor is inserted along the aqueous solution line (third channel) and transduces the pressure from the catheter tip (i.e., the pressure in the neonatal pharynx) to a sensing element acting as a variable resistor. When the motor is activated, a syringe gently pushes surfactant into the aerosolization catheter, allowing an average flow rate between 0.5 and 3 ml/h, preferably 2.4 ml/h (this parameter can be adjusted depending on the treatment program). The aqueous solution flow in the third channel can be reduced as needed to prevent mucus adhesion, for example to 1 ml/h. As shown in Figure 4b, the sensor uses the piezoresistive phenomenon to convert mechanical pressure into a voltage drop; it has an internal Wheatstone bridge connection, which means it can internally compensate for ambient temperature fluctuations.

The sensor may be, for example, a disposable pressure sensor, similar to sensors used for invasive blood pressure measurements.

The fact that surfactant is administered only during inspiration is a significant advantage offered by the present invention: this results in better control of the effective amount reaching the alveoli and avoids waste of the supplied surfactant. This requires measuring signals related to breathing pattern under ventilated conditions of premature newborns (breathing spontaneously and maintained under nCPAP or other non-invasive ventilation procedures, such as NIPPV) to detect end-inspiration and end-expiration and to predict the infant's "future" breathing pattern. According to an embodiment of the present invention, surfactant administration is started before the start of inspiration and stopped before the start of expiration in order to:

1) Consider mechanical delays in atomization;

2) Preventing surfactant loss since surfactant delivered at the end of inspiration will remain in the pharyngeal cavity and thus be expelled during initial exhalation.

In Figure 5, posterior pharyngeal pressure traces obtained from a representative premature infant of 28 weeks' gestational age and 1650 g are reported. Panel a shows the entire trace, which is characterized by very high fluctuations, with several peaks and baseline fluctuations; an amplification of the same signal is reported in panel b. The data have been statistically analyzed and a prediction algorithm has been designed. Its main steps can be referred to the flowchart of Figure 6, with the relevant functions. In particular, after removing dynamic and high-frequency noise, the signal is integrated to obtain a new signal proportional to the lung volume, and by querying the maximum and minimum values, the end-inspiration and end-expiration points can be detected. The statistical analysis also includes the measurement of the pressure involved, which is approximately 1 _cmH2O under all different conditions.

Using this method, exemplary simulations were obtained, administering 97±0.8% surfactant for 60±21 minutes to 7 premature neonates with a gestational age of 29.5±3 weeks and a body weight of 1614 g (±424 g).

All operations of the system described herein are controlled by a microprocessor (eg, a microcontroller of the PIC18F series or more advanced versions from Microchip Technology Ltd.) running software suitable for implementing the method according to the preferred embodiment of the present invention.

It will be appreciated that modifications and variations may be made to the above-described embodiments without departing from the scope of the present invention. Naturally, those skilled in the art may make numerous modifications and variations to the above-described schemes in order to meet specific local requirements. Specifically, although the present invention has been described in depth with reference to preferred embodiments, it will be appreciated that eventual omissions, substitutions, and changes in form and detail, as well as in other embodiments, may be made; furthermore, it is expressly contemplated that specific elements and/or method steps described in connection with any disclosed embodiment of the present invention may be incorporated in any other embodiment as a general matter of design choice.

For example, similar considerations apply if a component (such as a microprocessor or computer) has a different structure or comprises equivalent units; in any case, the computer can be replaced by any code execution entity (such as a PDA, mobile phone and the like).

Similar considerations apply if the program (which can be used to implement certain embodiments of the present invention) is constructed in a different manner, or if additional modules or functionality are provided; similarly, the memory structure can be of other types, or can be replaced by equivalent entities (not necessarily consisting of physical storage media). In addition, the solutions of the present invention themselves can be implemented in equivalent methods (with similar or additional steps, even in a different order). In any case, the program can take any form suitable for application by or in conjunction with any data processing system, such as external or built-in software, firmware, or microcode (in object code or source code). In addition, the program can be provided on any computer-usable medium; the medium can be any element suitable for containing, storing, communicating, disseminating, or transmitting the program. Examples of such media are hard disks (on which the program can be pre-loaded), removable disks, tapes, cards, wires, fibers, wireless connections, networks, broadcasts, and the like; for example, the medium can be electronic, magnetic, optical, electromagnetic, infrared, or semiconductor types.

In any case, the solution according to the present invention itself is implemented using a hardware structure (for example, integrated in a semiconductor material chip), or using a combination of software and hardware. The system of the present invention is particularly suitable for preventing and/or treating respiratory distress syndrome (RDS) in newborns (nRDS). However, it can be advantageously used to prevent and/or treat adult/acute RDS (ARDS) associated with surfactant deficiency or dysfunction and the following conditions, in which respiratory distress may be caused by, for example, meconium aspiration syndrome, lung infection (such as pneumonia), direct lung injury and bronchopulmonary dysplasia.

Advantageously, the system of the present invention is applied to spontaneously breathing premature neonates, and preferably to extremely low birth weight (ELBW), very low birth weight (VLBW) and low birth weight (LBW) neonates of gestational age of 24-35 weeks, showing early signs of respiratory distress syndrome as indicated by clinical signs and/or supplemental oxygen requirement (fraction of inspired oxygen ( _FiO2 ) > 30%).

More advantageously, nasal continuous positive airway pressure (nCPAP) is applied to said neonate according to a procedure known to those skilled in the art.

Preferably, a nasal mask or nasal prongs is used. Any commercially available nasal mask, such as those provided by CPAP Store LLC and CPAP Corporation, can be used.

Nasal CPAP is typically applied at a pressure of between 1 and 12 cm of water, preferably between 2 and 8 cm of water, but this pressure may vary depending on the age and lung condition of the newborn.

Alternatively, other non-invasive ventilation procedures, such as nasal intermittent positive pressure ventilation (NIPPV), high-flow nasal cannula (HFNC), and bilevel positive airway pressure (BiPAP), may be used in neonates.

Possible alternative embodiments include:

A computer-implemented method for delivering aerosolized medication to a spontaneously breathing patient, comprising:

- selectively activating a first pump member for providing, in the posterior pharyngeal cavity, by means of the multichannel flexible conduit, a column of low-pressure liquid medicine through at least a first channel of the multichannel conduit;

- selectively activating a second pump member for providing a flow of pressurized gas through at least a second channel of the multi-channel conduit;

- providing a continuous flow of pressurized aqueous solution through at least a third channel;

- detecting the patient's inspiratory activity by means of a pressure sensor connected to at least the third channel;

wherein, when the liquid drug column and the pressurized gas flow meet in the posterior pharyngeal cavity, the liquid drug column is broken up into a plurality of particles such that aerosolized drug is delivered into the patient's lungs; and wherein the step of providing the liquid drug column through at least a first channel of the multi-channel catheter is performed only during an inspiratory event.

A computer program for implementing the steps of the above-mentioned computer-implemented method when the program is executed on a computer.

A method for preventing and/or treating respiratory distress syndrome in a spontaneously breathing patient, the method comprising the following steps: delivering aerosolized lung surfactant drug to the patient's posterior pharyngeal region by means of a multi-channel flexible catheter, wherein a low-pressure liquid drug column passes through at least a first channel of the multi-channel catheter and a pressurized gas flow passes through at least a second channel of the multi-channel catheter; wherein when the liquid drug column and the pressurized gas meet in the pharyngeal cavity, the liquid drug column is broken up into a plurality of particles, further comprising the following steps: detecting the patient's inspiratory activity by means of a pressure sensor, the pressure sensor being connected to at least a third channel, the third channel being suitable for conveying an aqueous solution flow in the posterior pharyngeal region; wherein the providing step is performed only during the inspiratory activity.

The above-mentioned prevention method, wherein nasal continuous positive airway pressure (nCPAP) is applied to the patient using a nasal device, such as a mask or prongs.

The invention will now be described with the aid of the following non-limiting examples:

Examples

Example 1 - In vivo efficacy

The in vivo efficacy of aerosolized surfactant (in this case, porcine alfa, as described above) was evaluated in premature neonatal rabbits at gestational age day 27 (term = 31 ± 1 days). The chosen model closely resembles premature infants affected by RDS, in that the lungs of these animals are not yet able to produce surfactant on their own, but gas exchange is maintained, allowing them to expand in response to exogenous surfactant administration.

Treatment was delivered via the trachea at a volume of 2 ml/kg (corresponding to a 160 mg/kg dose). The fetus, anesthetized with pencuronium (0.02 mg ip), was then placed in a plethysmographic system at 37°C and ventilated with pure oxygen at a constant pressure (rate of 40/min, inspiratory/expiratory ratio of 60/40). No positive end-expiratory pressure (PEEP) was applied. An "open" pressure of ₃₅ cmH2O was first applied for 1 minute to overcome the initial resistance caused by capillary action in the finer conducting airways. This was followed by 15 minutes at ₂₅ cmH2O, 5 minutes at ₂₀ cmH2O, 5 minutes at _{15 cmH2O} , and a final 5 minutes at ₂₅ cmH2O.

Respiratory flow was measured every 5 minutes via a Fleish tube connected to each chamber of the plethysmographic system. Ventilatory volume (Vt) was automatically obtained by integration of the flow curve.

Two sets of experiments were performed.

In the first group, five samples (1 ml each) were received. The lung surfactant applied to each sample was: non-aerosolized porcine alfa-phospholipid, aerosolized porcine alfa-phospholipid at air pressures of 0.0, 0.2, 0.5, and 0.8 bar. The lung surfactant was aerosolized using a preferred embodiment of the present invention.

In this group of trials, a control group was included that did not receive any treatment.

All nebulized samples, including those without any applied pressure, were as effective as non-nebulized porcine alfa (P < 0.05, one-way ANOVA followed by Tukey's test; plotted on Medical Prism). No statistically significant differences were found between the different nebulization conditions.

In the second group, three samples (1 ml each) were received. The lung surfactant applied to each sample was: non-nebulized porcine alfa, and porcine alfa nebulized at air pressures of 0.2, 0.5, and 0.8 bar.

In this set of trials, two additional groups were included, a control group that received no treatment and a group that was treated with a batch of porcine alfa that had been released on the market.

The same results were observed in a second set of experiments.

When the results from the two groups were consistent, the data were pooled (Figure 7). Statistical analysis of these data confirmed the previous results.

In conclusion, the efficacy of porcine alfa was not affected by the nebulizer in premature fetal rabbits using the preferred embodiment of the present invention. Specifically, nebulization at pressures between 0.2 and 0.8 bar did not significantly affect the efficacy of porcine alfa, with the use of 0.5 bar appearing to be the most suitable, but no significant differences were observed between the different nebulization conditions.

Example 2 – Sedimentation Study

1. Group

Use old pigs, weighing between 0.8 and 2.0 kg.

1.1 Ensure group (control)

Under sedation with levometocillin and ketamine and after local anesthesia of the pharynx with lidocaine spray, the piglets were orally intubated. Anesthesia was supplemented by small doses of propofol IV as needed. Tube position was confirmed by bilateral auscultation of the lungs and careful assessment of the depth of the endotracheal tube. The piglets lay on the side determined by the randomization scheme. Thoroughly mixed with 300 MBq of Tc-labeled nanocolloid, the animals received 200 mg/kg (80 mg/mL) slowly instilled through a catheter that was advanced through the tube and terminated precisely 5 mm beyond the end of the tube. Following the slow instillation, the lungs were ventilated with PS (pressure-support, 4-8 cmH ₂ O, for PEEP) and PEEP of 10 cmH ₂ O for one minute, followed by PS med 4 cmH ₂ O PEEP via the endotracheal tube for at least 30 minutes, at which point the animals were moved to a gamma camera to assess lung deposition of Tc-labeled surfactant.

1.2 Nasal-CPAP, combination with a catheter according to the invention

The operation is performed as follows: the piglet inhales 10 mg of lidocaine and lidocaine gel is applied to the oropharynx just before inserting the Mayo oropharyngeal aerosol cannula. The piglet then lies on one side according to the randomization scheme and the correct positioning of the oropharyngeal cannula just above the pharyngeal entrance is assessed by fiberoptic bronchoscopy. Completely mixed with 300 MBq of Tc-labeled nanocolloid, the animal receives a total of 200 mg/kg (80 mg/mL) through an aerosol catheter placed in the oropharyngeal airway. The surfactant aerosolization process is divided into 4 stages (doses): each stage delivers a quarter of the total surfactant dose when the piglet breathes spontaneously on nasal-CPAP (via a specific nasal mask, see details in the method), followed by 5 minutes of PS-ventilation with PEEP (via a nasal mask) to avoid atelectasis and promote surfactant delivery to the lower airways. When all the surfactant has been delivered, the oropharyngeal cannula is removed and the piglet receives PS-ventilation for 15 minutes. _FiO2 is adjusted to keep saturation above 85%. To secure the airway to the gamma camera and scintigraphy in case of delivery, the animal's trachea was cannulated and manual ventilation was performed using a Laerdal Silicone Resuscitator.

2. Methods

The piglets were premedicated with intramuscular injections of ketamine, midazolam, and atropine. The marginal ear vein was cannulated and the animals were sedated with continuous iv infusion of levomethoxazole and ketamine. Sedation was supplemented by small intermittent iv boluses of propofol as needed. Under local anesthesia, an arterial catheter was placed in the femoral artery. Invasive blood pressure, pulse oximetry, cerebral oxygen saturation (INVOS), and diaphragm electrical activity (NAVA catheter) were monitored in all animals.

Blood gases were obtained after preparation, before the start of surfactant administration, 15 minutes after the start of surfactant administration, and 2 minutes after the end of surfactant administration.

Group assignment was random and arranged so that pigs from the same litter were evenly distributed between the groups where possible. Piglets were randomly placed on the right or left side during surfactant administration.

The study included the following groups of piglets receiving 2.5 mL/kg (80 mg/mL):

1 - Nasal-CPAP, nebulized with a catheter according to the invention: Nasal-CPAP+ delivery via a custom-made product placed in the oropharynx just above the laryngeal entrance and epiglottis.

2-"Ensure Protocol": PS-ventilation is performed via the endotracheal tube for at least 30 minutes in spontaneously breathing animals.

2.1 Ventilation

In the nasal-CPAP group, a special "nasal mask" with "glove fingers" and an endotracheal tube connector was formed in the laboratory to seal the piglet's nostrils. This "nasal mask" helped reduce leaks in the CPAP system and seemed to make the animals more comfortable, thus requiring less anesthesia. The mask was connected to the Y-shaped part of the ventilator tube, and CPAP was generated by a SERVO-i ventilator (McKV, Sweden). Depending on the piglet's breathing pattern and the degree of airway obstruction, the ventilator was adjusted to maintain a continuous positive airway pressure (CPAP) of 4-8 _cmH2O with an inspired oxygen fraction ( _FiO2 ) of 40%, which was adjusted during treatment to maintain oxygen saturation above 85%. The mouth was kept closed as much as possible. At the end of the operation, the piglet underwent PS-ventilation for 15 minutes before intubation and transport to the gamma camera.

In the assurance group, a SERVO-i ventilator was used for PS ventilation, wherein a PEEP of 10 cmH ₂ O was applied for one minute after instillation, followed by PS with a PEEP of 4 cmH ₂ O. _{The FiO 2} was 40%.

2.2 Measurement of surfactant distribution

The volume delivered to each piglet by aerosolization was 2.5 mL/kg (80 mg/mL), but the infusion of the delivery catheter and syringe required an average of 2.5 mL of extra surfactant/pig; Therefore, in this study, the Tc-labeled nanocolloid dose was increased to 300 MBq (compared to the 200 MBq in the aforementioned study utilizing Chiesi). The activity of the Tc-labeled nanocolloid was measured in a radiation counter. For each piglet, just before "catheter infusion," 300 MBq of technetium-labeled nanocolloid particles were thoroughly mixed with the colloid.

The distribution of aerosolized or slowly instilled surfactant was studied using gamma scintigraphy. Images were acquired before and after the intravenous injection of Tc-labeled macro-polymeric human serum albumin (MAA), a substance trapped in lung capillaries, to delineate the lung region. In addition, MAA injections were used to calibrate the images. This allowed the determination of the amount of Tc-labeled nanocolloids deposited in the lungs and, by inference, the amount of surfactant deposited.

Prior to transport to the gamma camera, the animal is intubated to secure the airway and prevent the development of atelectasis and hypoventilation.

3. Results

The primary outcome of the test is the percentage of radioactivity deposited in the lungs, which can be deduced from the radioactivity described by scintigraphy according to methods known to those skilled in the art.

3.1 Deposition results

If not stated otherwise, the results in this paragraph are presented as median (range).

By manually segmenting the images, it was possible to separate the regions where surfactant was deposited into four compartments: posterior pharynx, trachea, lungs and stomach. The mean and associated standard deviation (std) for each compartment are reported in Table 1 .

Table 1

By looking up the table, it can be seen that more than 48% of the surfactant is deposited in the lungs, and in addition, less than 10% of the surfactant reaches the stomach.

A further analysis can be performed to introduce a second partitioning, which is explained in more detail herein. Surfactant that enters the trachea will flow into the lungs, while surfactant that is deposited in the posterior pharynx is expected to expand and be deposited in the stomach; thus, it is possible to define: 1) the respiratory compartment provided by the sum of the trachea and lungs; and 2) the remaining compartment, which is provided by the sum of surfactant that enters the stomach and that found in the pharynx.

By this method it was possible to calculate the percentage of surfactant that reached the respiratory compartment out of the total amount entering the piglet.

The results reported in Table 2 are as follows

Table 2

The total amount of surfactant reaching the respiratory compartment had a mean value of 69.4% with a standard deviation of 8.2%, with individual values ranging from 62.4% to 84.4%, which means that approximately 70% of the surfactant was deposited into the respiratory compartment.

In conclusion, the results of the trial showed that a significant amount of surfactant was deposited into the lung compartment, exceeding 61%. This result can be attributed to the high performance of the delivery method, which delivers aerosolized surfactant into the pharynx, and the high performance of the device, which allows the administration of surfactant only during inspiration (95%).

Example 3 - In vivo study in premature lambs

The aim of this study was to compare the effects of exogenous surfactant aerosolization during spontaneous breathing on CPAP with CPAP alone in a premature lamb model of neonatal respiratory disease.

animal

Date-matched Border-Leicester ewes of gestational age 130-134 days were studied. The ewes were pretreated with ketamine (250 mg) and xylazine (3 mg), anesthetized with nitrous oxide, isoflurane, and propofol, and cannulated with arterial and venous catheters. Light anesthesia was maintained with nitrous oxide, propofol infusion, and the lowest possible concentration (<2%) of isoflurane. The animals were ventilated with SIMV+ pressure support at a set rate of 12-15 bpm, a tidal volume of 10 mL/kg, and _an initial _FIO2 of 0.4-0.5. Arterial blood gas samples were obtained, and ventilation rate, tidal volume, and _{FIO2 were} adjusted accordingly. The animals were placed in a supine position and prepared for Caesarean delivery.

2. Preparation of Lung Surfactant

The surfactant was labeled with samarium oxide (SmO ₃ ) at a concentration of 0.33 mg SmO ₃ per 3 mL (1× vial) using an ultrasonic mixer.

3. Fetal Instruments

After delivery of the fetal head and neck via laparotomy, five FG catheters were placed in the neck vessels using an undercut technique. The neck wound was sutured and infiltrated with bupivacaine. An arterial flow probe (Transonic) was implanted around the carotid artery for measurement of cerebral blood flow (CBF). From this point, the ewe was maintained anesthetized with the lowest possible propofol concentration, with isoflurane reduced to 0% as much as possible.

The fetal head is then dried and 10% lignocaine spray (lignocaine pump spray, Astra Zeneca, North Ryde, Australia) is introduced into both nostrils and applied to the vocal cords under direct laryngoscopy. An endotracheal tube with a size 4.0 cuff is then inserted into the fetus via the mouth, 5 cm below the vocal cords. An esophageal balloon catheter (Foley catheter with a size of 10 FG, Covidien, Mansfield, USA) is then inserted through the nostrils, over a 0.025 inch (0.64 mm) J-welded guidewire and positioned in the esophagus. When the balloon is inflated with 3 mL of saline, the position is checked to see if it is in the middle of the cervix and 6 cm below the cricoid cartilage.

A 4.0 endotracheal tube (ETT) was then inserted into each other nostril using a stylet/guidewire to a depth of 7 cm and a custom CPAP adapter was attached, enabling the system to be connected to a standard T-piece F&P circuit.

With the placenta still supported, the fetal chest was delivered and the lungs drained, with an expected recovery of at least 10 mL/kg. The ETT was then removed and the nasal cavity was tightly wrapped with an elastic bandage (Coban, 3M, St. Paul, MN) to seal the mouth.

For lambs randomized to the nebulization group (vide ultra), the nebulization delivery system was placed in the oropharynx with the tip 1.0 cm above the tongue above the epiglottis. With this device, the nebulization catheter can be advanced later so that it does not contact the oropharyngeal wall and upper airway structures (epiglottis) and esophagus during nebulization delivery. Placement was performed using a fiber optic microscope under direct visual guidance and at the insertion length marked on the device (which was subsequently removed).

Finally, a respiratory induction pneumograph (RIP) belt was placed around the chest and abdominal cavity. Prior to delivery, the oropharynx was suctioned to remove any accumulated fetal fluid. EIT electrodes were also placed in some lambs using previously published methods (Tingay et al. Ped Res 2013 Nov).

4. Group

4.1 CPAP without surfactant: This involves maintaining the lamb on CPAP PEEP of 6-10 cm _H2O (as needed) for a minimum of 90 minutes (after establishment of CPAP) and a maximum of

2.5–2.75 hours of total study time.

4.2 Nebulization: Once established on CPAP, the nebulization catheter according to the present invention was reinserted into the oropharynx using pre-defined procedures and secured with a Coban after vigorous suction to clear secretions. The nebulization catheter was inserted, and the system was prepared and checked. Initially, the _FI O ₂ was increased by 0.1, and the PEEP was increased to 10 cm H ₂ O.

With arterial blood gas readings obtained 15 minutes after system insertion, nebulization of 200 mg/kg of nebulized steroids was initiated. Following the nebulization period (typically 45-75 minutes), the nebulization system was removed, and the lamb was maintained on CPAP alone. The study continued until 2.5–2.75 hours of age and a minimum of 90 minutes of data were obtained after the start of nebulization.

4.3 Assurance: A group of lambs were assigned to receive the Assurance method (see Example 2). For Neopuff with a PIP of 40 cm _H2O and a Rate of 30-40 bpm, the three animals studied were cannulated immediately after stabilization on CPAP for at least 15 minutes and 200 mg/kg of Curosurf ^™ was administered via a closed delivery system during PPV. The animals were then removed from the cannula immediately following CPAP and managed as in the CPAP-only group.

5. Post-delivery measurements

Peripheral oxygen saturation ( _SpO2 ), heart rate, arterial blood pressure, and rectal temperature were applied at birth and displayed continuously thereafter (HP48S, Hewlett Packard, Andover, MA). Ventilatory volume (VT) and respiratory pattern were measured using a DC-coupled RIP (Respitrace200 ^™ , NIMS Inc., North Bay Village, FL), sampled at 200 Hz using the method described in Tingay DG et al. Crit Care Med. 2013;41(1);237-44.

Arterial blood gas analysis was performed periodically at 15-30 minute intervals.CBF was measured by a flow probe (Transonic, AD Instruments, Sydney) placed around the carotid artery, using ultrasound gel to maintain signal quality as needed.

6. Post-game analysis

The lungs and trachea were removed intact from the chest and inflated via an ETT (no leak) and Neopuff at 30 cm H 2 O for 15 s, followed by 15-30 s at 15 cm H 2 O. Upon inflation, the lungs were wrapped in aluminum foil and flash-frozen in liquid nitrogen and stored at -20°C for analysis of SmO ₃ concentration in the lungs.

7. Data Collection and Analysis

Data were manually recorded for each arterial blood gas. _SpO2 , heart rate, arterial blood pressure, delivered airway pressure, RIP, chest and abdominal waveforms, tidal volume and flow (during intubation only), temperature, and cerebral blood flow waveforms were digitized (PowerLab ^™ system) and recorded at 1000 Hz in LabChart ^™ V7 (AD Instruments, Sydney, Australia) for subsequent analysis. EIT recordings in the form of tidal ventilations in the chest were also performed. All data were stored in a Neonatal Research (MCRI) computer. Blood gas and manually recorded data were directly entered into an Excel spreadsheet for integration with LabChart Data.

At each analysis point, 30 seconds of stable respiratory data representing the animal's respiratory pattern and condition at that time were extracted, and the following parameters were calculated:

1. Oxidation: SpO ₂ , _FI O ₂ , aA ratio (lower values indicate more severe lung disease), and AaDO ₂ .

2. PaCO2

3. Applied PEEP (and PIP, if applicable)

4. Heart rate, arterial blood pressure (average, systolic and diastolic), cerebral blood flow waveform. CBF pulsation amplitude and minimum CBF were extracted using LabChart Peak Analysis software.

5. The RIP (and, chest and abdominal) waveforms for the entire 30 s period. Respiratory rate is determined from this. The amplitude of the sum of the RIP data is used to determine the associated ventilatory volume (VT) for each spontaneous breath, expressed dimensionlessly (see Tingay DG et al. Crit Care Med. 2013 Jan;41(1), 237-44), and referenced to the RIP VT at t0 to determine the associated VT over time.

6. Use FOT and PV curves to perform static lung mechanical function analysis.

7. EIT data were reconstructed over the same 30-second time period using a custom EIT analysis program that takes into account the unique shape of the lamb chest. The images were then analyzed in MatLab and AUSPEX to generate functional EIT scans of the ventilation distribution over a 30-second time period for each of 32 gravity-dependent (anterior to posterior) left and right hemithorax slices using the SD method described in Frerichs I et al. Am J Respir Crit Care Med. 2006; 174(7); 772-9.

From these data, the fractional ventilation patterns within lung regions (compared to global VT) were determined at t0, t60 (immediately after surfactant in the nebulized group), and t90 (30 minutes after surfactant administration) and compared.

All statistical analyses were performed by MCRI in PRISM (GraphPad Software, CA, USA).

Data were tested for normality and analyzed using parametric or nonparametric tests as appropriate. Longitudinal comparisons between groups were analyzed using two-way ANOVA with time and surfactant strategy as variables and Sidak post-test.

Qualitative data including lamb comfort scores, interventions required, respiratory patterns, complications, and staff observations are also reported.

8. Results

In the majority of lambs, the nebulization system of the present invention was tolerable and showed promising respiratory patterns. Specifically, as can be seen in Figure 8, the aA _O2 ratio appeared to be improved compared to CPAP alone.

Claims (15)

1. A system for delivering a drug comprising a pulmonary surfactant to a patient who is breathing spontaneously, comprising: -i) A catheter adapted to reach the posterior pharyngeal region of a patient, the catheter comprising at least a first channel and at least a second channel, the first channel being adapted to deliver a flow of liquid medication in the pharyngeal region of the patient, and the second channel being adapted to deliver a flow of pressurized gas in the pharyngeal region of the patient. -ii) A first pump component connected to a first end of the at least first channel, adapted to generate pressure that pushes a column of liquid drug toward a second end of the at least first channel; -iii) A second pump component connected to the first end of the at least second channel, adapted to generate the pressurized gas flow; Thus, when the liquid drug column and pressurized gas meet in the pharynx, the liquid drug column is broken into multiple particles, allowing the nebulized drug to be delivered into the patient's lungs; -iv) A pressure sensing component, separated from the first and second channels, for measuring a value representing the pressure in the patient's pharynx, used to determine whether the patient is in the inspiratory or expiratory phase, wherein the first pump component is selectively activated only during the inspiratory phase, and wherein the pressure sensing component includes: - A third channel, which is adapted to deliver a flow of aqueous solution in the patient's pharyngeal region; - A third pump component, which is connected to the first end of the third channel and is adapted to generate the aqueous solution flow; - A pressure sensor, connected to the third channel, is used to measure a value representing the pressure of the aqueous solution flow. 2. The system of claim 1, wherein the at least second channel comprises a plurality of channels arranged around the first channel. 3. The system of claim 2, wherein the cross-section of the plurality of channels decreases toward the second end of the channel. 4. The system according to any one of claims 1-3, wherein the conduit is made of a flexible plastic material. 5. The system according to any one of claims 1-3, wherein the catheter comprises a partially rigid stent. 6. The system according to any one of claims 1-3, wherein the third channel is embedded in the catheter assembly and spaced apart from the at least first channel and the at least second channel. 7. The system of claim 1, wherein the at least second channel comprises a plurality of channels arranged around the first channel, and the third channel is embedded in the catheter assembly and spaced apart from the at least first channel and the at least second channel, the third channel being one of the channels arranged around the first channel. 8. The system according to claim 6, wherein the outer cross-section of the third channel is equal to or less than 2.5 mm. 9. The system according to claim 7, wherein the outer cross-section of the third channel is equal to or less than 2.5 mm. 10. The system according to any one of claims 1-3, wherein the pulmonary surfactant is selected from the group consisting of modified natural pulmonary surfactants, artificial surfactants and reconstituted surfactants. 11. The system according to any one of claims 1-3, wherein the pressurized gas comprises air. 12. The system according to any one of claims 1-3, wherein the aqueous solution comprises an aqueous solution of physiological saline (0.9% w/v sodium chloride), selectively buffered at physiological pH. 13. The system according to any one of claims 1-3, wherein the patient is a premature newborn who breathes spontaneously. 14. A kit comprising: a) a pharmaceutical composition comprising a lung surfactant suspended in a pharmaceutically acceptable aqueous medium; b) a system for delivering a medicament comprising a lung surfactant to a patient who is breathing spontaneously according to any one of claims 1-13; c) a component for positioning and/or facilitating the introduction of a catheter into a posterior pharyngeal region; and d) a container component for containing the pharmaceutical composition, the system, and the positioning component. 15. The kit of claim 14, wherein the component for positioning and/or facilitating catheter introduction includes a laryngeal mask.