WO2011041838A1

WO2011041838A1 - Method, system and apparatus for ventilation

Info

Publication number: WO2011041838A1
Application number: PCT/AU2010/001316
Authority: WO
Inventors: Andreas Fouras; Marcus John Kitchen; Stuart Brian Hooper; Robert Arnold Lewis
Original assignee: Monash University
Priority date: 2009-10-08
Filing date: 2010-10-08
Publication date: 2011-04-14

Abstract

The invention relates to a ventilator for delivering fluid pressure to the lungs of a subject, the ventilator having; a pump in operative connection with a first pressure vessel for control of the peak inspiratory pressure (PIP) of the subject, wherein the volume of the first pressure vessel is substantially greater than the volume of the lungs of the subject.

Description

METHOD, SYSTEM AND APPARATUS FOR VENTILATION

FIELD OF INVENTION

. The present invention relates to the field of ventilation for physiological, clinical or research application.

In one form, the invention relates to pressure-controlled ventilation for infants or small animals.

In one particular aspect the present invention is suitable for use in ventilation of a humidicrib or similar device.

In another particular aspect the present invention is suitable for ventilation of a subject being subjected to imaging for research or diagnosis.

It will be convenient to hereinafter describe the invention in relation to ventilation of subjects during imaging such as phase contrast x-ray imaging, however it should be appreciated that the present invention is not so limited and can be used for a wide range of applications including resuscitation. Furthermore while the invention will be further described with reference to ventilation of small animals, it should be appreciated that the present invention is not so limited and can be applied to any small human or animal subject.

BACKGROUND ART

It is to be appreciated that any discussion of documents, devices, acts or knowledge in this specification is included to explain the context of the present invention. Further, the discussion throughout this specification comes about due to the realisation of the inventor and/or the identification of certain related art problems by the inventor. Moreover, any discussion of material such as documents, devices, acts or knowledge in this specification is included to explain the context of the. invention in terms of the inventor's knowledge and experience and, accordingly, any such discussion should not be taken as an admission that any of the material forms part of the prior art base or the common general knowledge in the relevant art in Australia, or elsewhere, on or before the priority date of the disclosure and claims herein.

Premature Infants

Medical ventilators are widely used to mechanically move breathable gas into and out of the lungs of a subject, thus providing the mechanism of breathing. Typically ventilators are used for subjects who are physically Unable to breathe, or . breathing insufficiently. For example, respiratory disease is a major cause of morbidity and mortality in humans of all ages and positive pressure ventilation is commonly used clinically to provide respiratory support in patients suffering respiratory failure. Currently there is much diversity in the types of positive pressure ventilation strategies available for use in patients and the choice of strategy usually depends on the type and degree of lung disease. Furthermore the ventilation strategy used may need to vary as the lung disease progresses or mitigates following treatment.

Newborn infants are another group of patients that often require respiratory support. The most appropriate methods for ventilating newborn infants at birth are still under investigation, particularly for infants born prematurely. Currently there is a poor understanding of how the lungs aerate at birth and the factors that regulate this process.

Before birth, the foetal lungs are liquid-filled and at birth the airways must be cleared of liquid to allow the entry of air before pulmonary gas exchange can begin. However infants born prematurely usually fail to establish effective gas exchange and require respiratory support. As trans-pulmonary pressures generated during inspiration are important for airway liquid clearance at birth, respiratory support that maintains a pressure gradient across the airway wall. is essential.

However, as lung compliance markedly increases during lung aeration, the pressures and airflows required to ventilate the lung are dynamic, requiring accurate and variable control. Thus assisted ventilation of newborn infants immediately after birth is greatly complicated by the presence of airway liquid and changes in ^"the spatial distribution of this liquid can markedly alter ventilation dynamics. Before the lung is fully aerated it is considered important to have (i) long inspiratory times which overcome the long time constant of the water-filled airways and (ii) the application of an end-expiratory pressure.

Mechanical ventilation is also known to cause or exacerbate lung injury, especially for those with compromised respiratory systems, Neonates in particular have stiff lungs due to surfactant deficiency, and are thus prone to collapse. Repeated collapse and re-opening of airways causes injury, which may lead to bronchopulmonary dysplasia, a leading cause of infant mortality and morbidity - 30 % of very iow weight neonates develop bronchopulmonary _s dysplasia due to ventilator induced injury

Efforts have been made to investigate the mechanisms of lung injury and develop new ventilation strategies that minimise the risk of injury. Efforts have also been made to research and identify the specific components of mechanical ventilation that facilitate lung aeration and protect the immature lung immediately after birth. Recent advances in image acquisition techniques have given researchers the ability to investigate lung injury' and disease pathogenesis in-vivo using small animal models, improving understanding of safer mechanical ventilation strategies. Magnetic Resonance Imaging (MRI) and ultrasound have been .used in the past to image soft tissue in 3D, but are highly limited by spatial resolution when capturing images of small airways in the lungs. Phase contrast X- ray imaging (PCXI) is capable of dynamically imaging the lung by utilising the principle of refraction between the air and tissue boundary with in the airways to capture breathing motion at high spatial and temporal resolution. For example, PCXI has been used to explore the factors regulating lung aeration at birth and to examine the ability of different ventilation strategies to effectively and uniformly ventilate the neonatal lung. Furthermore, PCXI imaging is conducted in a lead- lined enclosure that must be vacated whilst the x-ray beam is operational so direct access to the ventilator is not possible. However, one of the problems limiting these investigations is the absence of a ventilator that can be operated remotely to vary different aspects of inspiration and expiration in a consistent and stable manner.

Small Animals

Most commercially available ventilators for small animals either utilise a piston to deliver airflow or an air pump that delivers airflow at a predetermined rate until a set positive inspiratory pressure (PIP) is reached. Piston driven ventilators regulate inspiratory gas flow rates by regulating the speed of the piston and limit the PIP using either a pressure release valve or feedback control of the piston speed. However, it is difficult to regulate the Inspiratory pressure wave form and lengthy end-inspiratory pauses at a constant pressure are problematic. Pauses during the respiratory cycle can be important for high resolution imaging, particularly at end-inspiration, to avoid motion blur. Dynamic changes in lung compliance alter the pressure/volume relationship and the need to move the piston to generate flow makes it difficult to maintain a stable airway pressure, particularly in a partially aerated lung in which the compliance is rapidly changing.

Ventilators that use an air pump to generate airflow usually limit the PIP by opening the expiratory valve once the PIP is reached or have a pressure-release valve. Thus the inspiratory time can be truncated if the flow is high and the PIP is reached before the preset inspiratory time. If the flow is lowered to maintain a constant inspiratory time the PIP achieved is not constant and rarely reaches the set PIP. Furthermore a post-inspiratory pause at constant pressure is not possible. On the other hand, pressure release valves, particularly if they are spring activated, can lead to airway pressure spikes that are potentially injurious to the lung. Furthermore, most ventilators generate a positive end-expiratory pressure (PEEP) by placing the end of the expiratory line at a set depth below the surface of a water-filled container. However, the resulting bubble formation can initiate pressure waves that are transmitted to the lung which can add to motion blurring during high resolution image acquisition.

SUMMARY OF INVENTION

An object of the present invention is to provide a ventilator apparatus, system or method that permits remote operation to vary different aspects of inspiration and expiration in a consistent and stable manner.

A further object of the present invention is to alleviate at least one disadvantage associated with ventifation apparatus, systems or method of the related art such as truncation of the inspiratory time in situations of high air flow, generation of airway pressure spikes that are potentially injurious to the lung, or the inability to provide a post-inspiratory pause at constant pressure.

It is an object of the embodiments described herein to overcome or alleviate at least one of the above noted drawbacks of related art systems or to at feast provide a useful alternative to related art systems.

In a first aspect of embodiments described herein there is provided a ventilator for delivering fluid pressure to the lungs of a subject, the ventilator having;

a pump in operative connection with a first pressure vessel for control of the peak inspiratory pressure (PIP) of the subject, wherein the volume of the first pressure vessel is substantially greater than the volume of the lungs of the subject.

The pressure in the ventilator may be controlled by any convenient means. For example, in one embodiment the pressure may be controlled through a sequence of measurements (via sensors) and adjustment of valves controlled through the Nl USB device and software. In another more preferred embodiment, the ventilator pressure may be controlled through a feedback sequence which in turn is controlled locally by a microprocessor within the ventilator. The latter embodiment provides a much faster and more stable system.

In a particularly preferred embodiment, the ventilator of the present invention includes a microprocessor controlled pneumatic bleed system to quickly and accurately control PIP and PEEP.

In a second aspect of embodiments described herein there is provided a ventilator for delivering fluid pressure to the lungs of a subject, the ventilator having;

a pump in operative connection with a first pressure vessel for control of the peak inspiratory pressure (PIP) of the subject,

a housing for enclosure of the subject, the housing being in operative connection with the first pressure vessel.

In one embodiment, the ventilator vents to the atmosphere, in another embodiment the ventilator includes a second pressure vessel for control of the positive end expiratory pressure (PEEP),

In a third aspect of embodiments described herein there is provided a ventilator for delivering fluid pressure to a subject, the ventilator having;

a second pressure vessel for control of the positive end expiratory pressure (PEEP) of the subject,

a housing for enclosure of the subject, the housing being in operative connection with the first pressure vessel and the second pressure vessel,

wherein the volumes of the first pressure vessel and the second pressure vessel are substantially greater than the volume of the lungs of the subject. During ventilation of a subject, air flows from the first pressure vessel into the housing as the subject's lungs are inflated (inspiration); air flows from the housing into the second pressure vessel (expiration) and the subject's lungs are deflated.

In a preferred embodiment of the ventilator of the present invention the pressure in the vessel is controlled by having both a pump and a bleed to atmosphere controlled by a microprocessor. Using this embodiment, if a pressure increase is required, the connection to the pump can be opened and conversely, the bleed line allowed for a pressure decrease. This allows the reservoir to quickly and easily attain any pressure range within the range from pump pressure to bleed pressure (zero relative pressure or atmospheric pressure).

In a further preferred embodiment of the ventilator of the present invention the pressure vessel is connected to two pumps, one providing a source of air and one providing a sink, or suction. This permits faster response times when reducing pressure in the vessel, in particular if zero pressure is requested. This also allows for negative (or more correctly 'sub-atmospheric') pressure.

In a fourth aspect of embodiments described herein there is provided a method of delivering stable pressure to the lungs of a subject, the method comprising the steps of;

(1 ) enclosing the subject within a housing, the housing being in operative connection with a first pressure vessel held at a first (PIP) pressure and a second pressure vessel held at a second (PEEP) pressure, respectively,

(2) admitting air from the first pressure vessel into the housing, then (3) admitting air from the housing into the second pressure vessel, and

(4) repeating steps (2) and (3) multiple times.

If the inspiration time is sufficiently long, or the flow rate is sufficiently fast, the air may be admitted until the housing reaches a desired first pressure (in step 2) or a second pressure (In step 3).

Preferably the first and second pressure vessels each have a capacity significantly greater than the volume inspired or expired. Typically the pressure vessels are each at least 10x the inspired or. expired volume, more preferably at least 100x the inspired or expired volume. Preferably the housing is in operative connection with the first pressure vessel via a first solenoid valve and with the second pressure vessel via a second solenoid vatve, At the start of inspiration the first solenoid valve is opened whilst the second solenoid valve remains closed for the entire set inspiratory time until the PIP is reached. Upon expiration, the states of the solenoid valves are simultaneously flipped, ailowing the subject's lungs to deflate to the PEEP level for a preset period.

A variable restrictor valve may be associated with the first solenoid valve to allow almost infinite variation of the rate of gas flow into the lungs from the first pressure vessel. A variable restrictor valve may also be associated with the second solenoid valve to regulate airflow from the housing into the second pressure vessel. The variable restrictor valves and solenoids may be controlled remotely via a virtual interface during ventilation.

In a fifth aspect of embodiments described herein there is provided a system for delivery of stable pressure during ventilation of the lungs of a subject, the system comprising;

a pump in operative connection with a first pressure vessel at a peak inspiratory pressure,

a second pressure vessel held at a positive end expiratory pressure, and a housing for enclosure of the subject in operative connection with the first pressure vessel and second pressure vessel respectively,

wherein the volume of each of the first and second pressure vessels is at least 100x greater than the volume of the lungs of the subject, such that opening and closing the operative connection between the housing and the first pressure vessel and the second pressure vessel does not change the pressure within, the ^• vessels by more than ± 10%.

Preferably the pressure within the vessels does not change by more than ± 5%, more preferably ± 1 %.

The ventilator of the present invention may also be used to provide standard ventilation, or high frequency ventilation, such as often used for critically ill patients in clinical medicine. High frequency ventilation is often referred to as 'jet ventilation' because a very high frequency input of gas is created. The inclusion of fast acting valves and microprocessor control makes the ventilator of 1316

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the present invention particularly well adapted to provide the rapid response times necessary for high frequency ventilation.

In recent times High Frequency Oscillatory Ventilation {HFOV) has become more popular. HFOV requires high pressure and a matched low pressure, or put more simply, a jet (push) followed by a suction/negative jet (pull). HPOV can readily be provided by the ventilator of the -present invention, particularly when the pressure vessel is connected to two pumps, one providing a source of air and one providing suction as previously described. Using this arrangement it is possible to very quickly switch between conventional ventilation and HFOV.

In some situations it is advantageous to simultaneously use HFOV and conventional standard ventilation. In one embodiment, the ventilator of the present invention includes one or more additional vessels and pressure control as described here in to simultaneously provide standard and HFOV ventilation.

Preferably the ventilator of the present invention is used in conjunction with static imaging techniques such as CT or MRI. For example a timing control system is included for synchronisation with imaging equipment and control of other devices such as data acquisition or medical equipment.

In a sixth aspect of embodiments described herein there is provided a method of imaging a subject, the method comprising the steps of:

providing stable respiration pressures to a subject enclosed within the housing of a ventilator of the present invention, and

acquiring multiple images of the lungs of the subject.

In a seventh aspect of embodiments described herein there is provided a method for computer tomography of a subject, the method comprising the steps of:

providing stable respiration pressures to the lungs of a subject enclosed within the housing of a ventilator of the present invention; and

acquiring respiratory gated projection radiographs of the subject.

Other aspects and preferred forms are disclosed in the specification and/or defined in the appended claims, forming a part of the description of the invention.

In essence, embodiments of the present invention stem from the realization that stable pressure can be delivered to the lungs of a subject by using a ventilator having an independent pressure vessels for control of the PIP. Having a further independent vessel for control of the PEEP can further reduce pressure fluctuations during the ventilation process.

Advantages provided by the present invention comprise the following:

• a high degree of stability of applied PIP and PEEP pressures during ventilation;

• produces stable breath over long inspirations times;

• a high degree of control of the ventilation process and flexibility of ventilation parameters by;

• almost infinite control of the variability of the rate of gas flow into the subject's lung from the pressure vessel,

• the ability to vary the inspiratory pressure wave form,

• the ability to set the length of an inspiratory pressure plateau (as a proportion of inspiration time) by regulating the inspiratory airflow independently of the PIP,

• the ability to regulate airflow from the lung into the PEEP vessel during expiration,

• the ability to update both the inspiratory and expiratory times in software while the ventilator is operating,

• the ability to change any parameter at any point within the respiratory cycle.

• elimination of the risk of exposing the subject's lung to pressure spikes by use of a PIP vessel;

• remote control of ventilation parameters;

• permits synchronisation between ventilation and image acquisition to facilitate better understanding of the lung ventilation process;

« suitability for static imaging techniques such as RI and CT;

• suitability for commercial production.

Further scope of applicability of embodiments of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure herein will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS ,

Further disclosure, objects, advantages and aspects of preferred and other embodiments of the present application may be better understood by those skilled in the relevant art by reference to the following description of embodiments taken in conjunction with the accompanying drawings, which are given by way of illustration only, and thus are not limitative of the disclosure herein, and in which:

Figure 1 is a schematic representation of the electrical wiring between components of one embodiment of the ventilator and data acquisition system according to the present invention, wherein black lines represent outputs and grey lines represent inputs from the data acquisition system;

Figure 2 is a schematic representation of air flow through the ventilator of Figure 1 , with arrows indicating the direction of flow which is generated by a gas pump;

Figure 3 depicts the control panel of the ventilator of Figure ;

Figure 4 is a schematic representation of the geometry for propagation based PCXI which shows the water plethysmograph used to measure lung air volume;

Figure 5 is a graph of airway pressure recorded during PCXI experiments;

Figure 6 is an enlarged view of part of the graph of Figure 5 highlighting the stable pressure provided during long inspiration followed by a slight instability upon commencing standard ventilation;

Figure 7 is a graph of data recorded from the plethysmograph in response to the pressure signal shown in Figure 5;

Figure 8 is an enlarged view of part of Figure 7 showing artifacts (oscillations) due to motion of the subject (a pup) within the plethysmograph chamber;

Figure 9 is a graph of airway pressure recorded during image acquisition for a sequence during which the PIP was adjusted several times;

Figure 0 is a graph of data recorded fro the plethysmograph in response to the pressure signal shown in Figure 9; Figure 11 is a phase contrast image of a rabbit pup showing (a) a fluid- filled lung, (b) the major airways, and (c) peak inflation, corresponding to the image acquisition times labelled in Figure 5. (Image size: 20,97 x 16.87 mm². Exposure time: 250 ms. Energy: 24keV)

Figure 12 is a CT lung image of a rabbit pup. (Image size: 22.51 x 21.95 mm². Energy: 24 keV. Exposure time per projection: 250 ms. Total scan time: 15 mins.)

Figure 13 is a comparison between automated PEEP control on a ventilator according to the present invention and manual PEEP control,

Figure 14 is a schematic diagram of the pneumatic systems for (a) a ventilator according to the present invention, (b) a flexiVent ventilator and (c) a

SAR-830/AP ventilator.

Figure 5 is a flow chart depicting the experimental set up for comparison of the three ventilators referred to in Figure 14.

Figure 6 comprises graphs of airway pressure as a function of time for (a) a ventilator according to the present invention, (b) a flexiVent ventilator and (c) a

SAR-830/AP ventilator.

Figure 17 comprises graphs of airway pressure as a function of time for continuous respiration using short inspiration and expiration times for (a) a ventilator according to the present invention, (b) a flexiVent ventilator and (c) a

SAR-830/AP ventilator.

Figure 18 comprises graphs of variation in PIP as a function of time for (a) a ventilator according to the present invention, (b) a flexiVent ventilator and (c) a

SAR-830/AP ventilator.

Figure 19 is a graph of variation in PIP as a function of time for a ventilator according to the present invention.

DETAILED DESCRIPTION

A time-cycled pressure-limited ventilator was developed, the ventilator operating using LabVIEW's Virtual Instrument (VI) controls to synchronise image acquisition with mechanical ventilation of small animals. A personal computer

(PC) along with a data acquisition module (Nl USB-6259) and National

Instruments Lab VIEW software were used to control the ventilator, as illustrated in Figure 1. tn Figure 1 , the following identifiers are used: U2010/001316

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1 - Personal computer

2 - Data acquisition box Nl USB-6259

3 - Peak Inspiratory Pressure (PIP) differential pressure transducer

4 - PIP valve

5 - PIP vessel

6 - Peak End-Expiratory Pressure (PEEP) vessel

7 - PEEP differential pressure transducer

9 - PEEP valve

10 - Expiration solenoid valve

11 - Inspiration solenoid valve

12 , - Expiration valve

13 - Airway pressure differential pressure transducer

14 - solenoid valves

Table 1 provides a detailed description of the ventilator components, The data acquisition system connects to the PC with a Universal Serial Bus (USB) cable and can handle up to 4 analog outputs, 80 analog inputs and 48 digital input/output channels at 1.25 MS/s, LabVIEW can simultaneously control multiple devices and readily interface with external hardware since many hardware drivers are included in the programming library, The main advantage of the virtual interface is that all parameters (eg air pressure and flow rate) can be controlled remotely with real-time display.

TABLE 1 :

Component Function Specification

Data acquisition system (Nl To synchronise the PC with 4 analog outputs, 80 analog USB-6259) the ventilator components inputs (16-bit), 48 digital

I/O, 1.25 MS/s

LabVIEW software To record outputs from and Version 8.5

send inputs to the data

acquisition system

Pump To provide a continuous

flow of air

Muffler To dampen the pulsatile 250 cm^a

flow from the pump Component Function ·.^'.·/ ^' _· ^'.^'' Specification : .

Pressure vessels {PIP and To supply air of a fixed Volume = approx. 10Ox PEEP) pressure to the lung during larger than total volume of inspiration and expiration lung and tubing

Solenoid valve (Cole- To open and close during Response time: 15 ms Parmer, EW-01367-50) inspiration and expiration Max flow rate: 16 LPM

Stepping motor valves, To maintain the pressure Speed: 0-5 V DC Maximum Aalborg, SMV40-S inside the PIP and PEEP flow rates: 1000 sL/min vessels and air flow to the Direction : TTL logic lung · LED indicators

Differential pressure To measure pressure within LED range indication transducer (DPT), Ashcroft PIP and PEEP vessels and Differential pressure DXLdp the lung ranges: 3-127 cm(H₂0)

Figure 2 depicts the manner in which air was cycled around the ventilator and delivered to the lung. In Figure 2, the following identifiers are used:

21 - Pump

22 - Muffler

23 - PIP vessel

24 - PEEP vessel

25 - PIP differential pressure transducer

26 - PIP valve

27 - direction of venting to atmosphere

28 - PEEP differentia! pressure transducer

29 - PEEP valve

30 - Inspiration solenoid valve

31 - Expiration solenoid valve

32 - Inspiration valve

33 - Expiration valve

34 - Lung

35 - Airway pressure transducer

Two pressure vessels, set at different pressures were used to control the PIP and PEEP. At the start of inspiration the inspiratory solenoid valve opened whilst the expiratory solenoid remained closed (Figures 1 and 2) for the entire set inspiratory time. Air from the PIP vessel flowed to the lung through the inspiratory solenoid via a variable restrictor valve; this allowed the air to flow into the lungs until the airway pressure reached the pressure of the PIP vessel. As the PIP and PEEP vessels were of sufficiently large volume (~1 L/box), the volume change associated with opening and closing of the respiratory solenoids did not significantly influence the pressure within the vessels. This provided a high degree of stability with the applied PIP and PEEP pressures. A variable restrictor valve allowed almost infinite variability of the rate of gas flow into the lung from the pressure vessel, which in turn was controlled remotely via the virtual interface. As a result the inspiratory pressure wave form could be varied and the length of an inspiratory pressure plateau (as a proportion of inspiration time) could be set by regulating the inspiratory airflow independently of this PIP. Upon expiration the states of the respiratory solenoids are simultaneously flipped, allowing the lungs to deflate to the lower PEEP level for a preset period. During expiration, airflow from the lung into the PEEP box could also be regulated via a restrictor valve, as shown in Figure 2. Both the inspiratory and expiratory times can be updated in software while the ventilator is operating. As a safety precaution the solenoids simultaneously closed when the ventilation sequence was terminated to prevent over-distension of the airways.

In studies focused on imaging and ventilation, it is important that the lung inflates uniformly to a constant pressure to provide consistency in lung inflation from breath to breath. As the inflation pressure is simply provided by opening the inspiratory solenoid and exposing the lung to the pressure within the P!P vessel, the inspiratory pressure cannot exceed the pressure in the PIP vessel thereby eliminating the danger of exposing the lung to large pressure spikes. Furthermore as the PIP and PEEP vessels had a capacity of approximately 100 times the inspired volume, pressures in the PIP and PEEP vessels remained stable throughout ventilation, allowing end-inspiratory pressure to be maintained at a very constant pressure for 5 mins or more; this is usually performed in dead animals during computer tomography (CT) imaging. Although these large pressure vessels make the system somewhat cumbersome, the stability in airway pressure they provide far exceeds and concerns relating to ventilator size. The ventilator (Figure 2) used a pump to supply air flow into the PIP and PEEP pressure vessels and a muffler was connected in line to dampen the generated pressure waves. Air pressure and flow to the PIP and PEEP vessels and to the lung were controlled by stepping motor restrictor valves. The speed of the stepper motors was controlled using Lab VIEW via a logarithmic function of motor speed (in Volts) against the difference between the set and measured pressures. Thus the bigger the pressure difference between set and measured pressures, the faster the stepper motor moved and vice versa. The asymptotic logarithmic function ensures the motor speed is limited to prevent over-shoot of the required pressure to protect the lungs against sudden pressure rises. Motor speeds were updated every 00 ms after sampling the pressure in the PI P and PEEP vessels. Sampling faster than this occasionally led to communication errors between the. Lab VIEW and the data acquisition system.

Pressure in the PIP and PEEP vessels was measured via differential pressure transducers (DPTs) connected to the data acquisition system (Figure ). Before each experiment the pressure transducers were calibrated in the Lab VIEW software using a. digital manometer and a two-point calibration; these transducers were very stable and their calibration varied little between experiments. The pressure transducers were chosen so that the pressure ranges to be measured fell within the linear region of their response curves. The software displayed the calibrated pressure readings and regulated pressures within the vessels by activating the relevant stepper motor control flow valves that vented the vessels to the atmosphere. If the pressure was too high, then the relevant valve opened to a greater degree to allow more air to flow to atmosphere; conversely if the pressure is too low the valve restricts flow to atmosphere. The virtual interface enabled the desired PIP and PEEP settings to be adjusted while the ventilator was operational.

Tubing dimensions throughout the ventilator were optimised to stabilise the air flow and pressure to each component. For example, large diameter tubing (exhibiting low resistance to flow) was connected to the input of the higher pressure (PIP) vessel with higher resistant tubing connected to the lower pressure (PEEP) vessel. The airway pressure at mouth opening was recorded using a DPT . Figure 3 depicts the control panel of the ventilator of Figure 1 and includes buttons or other actuators for the following tasks set out in Table 2:

Table 2

Examples

The present invention will be further described with reference to the following non-limiting examples using a ventilator according to the present invention.

Example 1

In this example mechanical ventilation according to the present invention was successfully performed on newborn rabbit pups. A ventilator according to the present invention was included in a PCXI experiment which was configured according to the geometry shown in Figure 4. In Figure 4, the following identifiers are used:

40 - Bending magnet X-ray source

41 - Monochromator

42 - Fast shutter

43 - Plethysmograph

44 -Sample holder

45 - Water column T/AU2010/001316

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46 - Pressure transducer

47 - CCD camera

48 - direction of inspiration

49 - airway pressure

50 - direction of expiration

The ventilator provided stable pressure that enabled reliable respiratory gated acquisition of projection radiographs and enabled a stable prolonged (15 minute) breath-hold for high-resolution computed tomography of the deceased rabbit pups.

Procedure

Changes in lung air volume were measured directly using a water-filled piethysmograph (Figure 4). Plethysmography follows the Archimedean principle of volume measurement via fluid displacement; in this instance the volume of fluid displaced by the increase in lung gas volume as the rabbit pups inhale. This volume was equal to the amount of water that flowed from the main chamber into a water column during each breath. A PowerLab data acquisition unit was used in conjunction with LabChart software (LabChart, ADI Sydney Australia) to display, record and analyse the airway pressure, lung air volume and inspiratory/expiratory waveforms. The airway volume was calibrated using a pressure transducer by measuring the pressure increase for a known addition of 1mL of water.

Imaging Method

Rabbit pups were mechanically ventilated and simultaneously imaged in vivo on beamline 20B2 in the Biomedical Imaging Centre at the Sprtng-8 synchrotron radiation research facility, Japan.

For live imaging experiments, pups were delivered by caesarean section, intubated via tracheotomy, and connected to the ventilator. The pups were then immediately placed in a pre-warmed water-filled Perspex imaging chamber (head out) inside the experimental hutch.

A digital output from the ventilator data acquisition system was used to gate triggers sent to the fast x-ray shutter and CCD (Charge Coupled Device) camera during the ventilation cycle (Figure 4). The x-ray shutter was employed to avoid delivering unnecessary radiation dose to the pups between exposures. A custom-designed pulse generator provided a train of 7 triggers to the fast shutter during each ventilation cycle. A Uniblitz V M-T1 delay generator (Vincent Associates, NY, USA) sent the same pulse train, delayed by 50 ms, to the CCD camera to ensure the x-ray shutter was fully open during the exposure. The opening period of the shutter was also recorded by Powerlab to enable synchronisation of imaging data with the chart recordings.

• High resolution CT scans . were also performed for quantitative in situ measurements of the lung's alveolar dimensions as a function of airway pressure. For CT sequences, the pups had been humanely killed shortly after completing the live imaging experiments. Minimising motion blur was critical for a quantitative reconstruction of the minor airways. Initial experiments employed respiratory gating, whereby each rotated projection image was recorded at end expiration. However, reconstructed images revealed an unacceptable amount of motion throughout the scan. Subsequent experiments were performed using a constant pressure, Due to the dynamic compliance of the lung it was essential to reduce the acquisition time to minimise detectable changes in airway morphology. A scan time of just 15 minutes was enabled by continuously rotating the pups throughout the scan. The ventilator was thus required to maintain a highly stable pressure for 15 mins. Flat field images were recorded at the beginning and end of the CT for normalisation of the 1200 projections used for reconstruction. CT slices were reconstructed using a fi!tered-back projection algorithm using a Hanning filter.

For all imaging experiments, an X-ray energy of 24 keV was chosen to achieve good phase and absorption contrast. A Gadox (GD2O2S) scintillator and tandem-lens coupled to a CCD camera (Hamamatsu C4742-95HR) with an effective pixel size of 22,47 pm was used to image the rabbit pups, which provided sufficient spatial resolution to observe the terminal airways (-120-150 pm}.

Results

For several rabbit pups a sequence of images was acquired during mechanical ventilation. Some experiments employed a long (20 s) inspiration period at the start of ventilation to facilitate airway liquid clearance and enhance aeration of the distal gas exchange regions of the lungs. This iong inspiration 6

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period required a highly stable pressure and demonstrates both the flexibility and stability of the ventilator. Figure 5 iliustrates that the PIP remained constant throughout the experiments, with Figure 6 showing a magnified view of the initial ventilation curve of Figure 5. In Figure 2, the following identifiers are used to indicate the following:

60 - Valve opening

61 - Long inspiration period

62 - Inspiration period

63 - Expiration period

These figures show an initial long inspiration period of 20 s, followed by a ventilation cycle with the inspiration and expiration times set at 1 s. During the long inspiration the lung is pressurised to the same pressure n the PIP vessel. Figure 6 clearly illustrates that the ventilator is able to maintain an extremely stable pressure for a prolonged period. This demonstrates the benefit of utilising vessels containing air at fixed pressures over the piston base system whereby a piston must be constantly driven to create a pressure. At the beginning of the ventilation process (Figures 5 and 6) there is a slight instability in the PIP within ± 3 cm(H₂0) of the set value, which stabilises to within ± 0.5 cm (H₂0) by the 8^th cycle. It was found that the system stabilises more rapidly for lower pressures and that the stability can be tuned for higher pressure by varying the gas flow rate delivered by the pump.

Figure 7 shows the volume of air delivered to the lungs of the pup ventilated by the pressure waveform shown in Figure 5, as measured using the plethysmograph. This figure demonstrates the ability of the ventilator to deliver a steady volume of gas to the lungs. The artifacts in the volume signal that are evident at inspiration onset and during early expiration (Figure 8), are not caused by the ventilator. The result from pressure waves and the inertial of water as it moves from the main chamber into the water column and back. Figure 8 shows a magnified view of Figure 7, with oscillations indicated (70)..

Figure 9 further demonstrates the stability in the ventilation process upon altering the PIP several times during imaging. The PIP was initially set to 35 cm(H₂0) for an initial sustained inflation (20 s) and after 6 standard respiratory cycles, the PIP was reduced to achieve an appropriate tidal volume. The final T/AU2010/001316

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PIP setting was 25 cm (H2O). The lung air volume measured via the plethysmograph varied in response to the pressure changes (Figure 10). Pressure fluctuations were again within¹ ± 3 cm (H2O) immediately once the pressure was changed, with the uncertainty reducing to + 0.5 cm (H₂0) within a few breaths. These pressure fluctuations can be easily reduced by slowing the time taken to reach the set pressure in the software control.

Figure 11 shows a few images acquired during the ventilation cycle displayed in Figure 5. At the beginning of imaging, the lungs are fluid-filled and so were not visible with PCXI (Figure 11 (a)). Once ventilation commenced the air moved rapidly into the smallest and most distal airways as is evident in the appearance of the Trachea, major Bronchi and some of the smaller airways. In Figure 11(b) the partially inflated lung and some of the airways are also visible. Figure 1 1(c) shows the lung at peak inflation.

Figure 12 shows an axial slice of the reconstructed computer tomography (CT) image of a deceased rabbit pup chest, which show the fully aerated lung. Dark grey areas represent airways, moderate grey areas represent soft tissues and the lightest grey regions represent high density boy structures, The CT reconstruction shows only minimal motion blurring despite the long acquisition time of 15 minutes. The small artifacts are likely due to slight movement of the pup as it rotates, although small changes in lung volume can occur, due to changes in lung compliance, despite the fixed pressure. The excellent image quality reflects the remarkable stability in the air pressure maintained by the ventilator hardware.

In the embodiment' described, the pressure in the ventilator is controlled through a sequence of measurements (via sensors) and adjustment of valves controlled through the Nl USB device and software.

In another embodiment, the ventilator pressure may be controlled through a similar feedback sequence which in turn is controlled locally by a microprocessor within the ventilator. This is a much faster and more stable system.

Example 2

This example illustrates advantages of the present invention when incorporating a novel microprocessor controlled pneumatic bleed system to quickly and accurately control PEEP and PIP. This is particularly advantageous when used^■ in conjunction with, for example, a timing control system for synchronisation with imaging equipment and control of other devices, such as data acquisition or medical equipment.

A device according to the present invention has been assessed against two commercially available small animal ventilators, the flexiVent and SAR- 830/AP in response to changes in ventilation parameters such as inspiration time as well as PIP and PEEP. The results show the new ventilator delivers a more stable and accurate pressure for all strategies in comparison to the other devices.

As mentioned previously, PEEP is an important strategy to minimise lung injury and as such accurate control of PEEP pressure is important. Current commercially available small animal ventilators provide PEEP in a number of ways. The Harvard Inspira ASVP (Harvard Apparatus, Holliston, Massachusetts, USA) closes the expiratory valve to trap the air at the required pressure in the animal, while the flexiVent (SCIREQ Scientific Respiratory Equipment Inc ^' _. Montreal, Quebec, Canada) and TOPO Small Animal Ventilator (Kent Scientific Corporation, Torrington, Connecticut, USA) both use a PEEP trap. The flexiVent has a PEEP trap in which the expiration tube is submerged in a container of water to produce the required back pressure, that is, submerging the tube 2cm generates a pressure of 2 cm H2O. This process is manually controlled by the user, via a knob which controls the depth of submersion of the tubing into the water and is reliant on the user visually gauging the depth. The TOPO Small Animal Ventilator uses a similar principle but requires the PEEP trap to be filled with water to the required depth with the expiratory tube connected to an inlet that allows air to bubble from the bottom of the PEEP trap, thus producing the pressure.

Several adverse issues arise when using the submersion method because an accurate PEEP is difficult to achieve using this procedure. Figure 13 compares airway pressure from submerging the expiratory line and the pressure obtained from the pressure control system in a ventilator according to the present invention. Specifically a balloon was ventilated at PIP 20 cm H₂0, PEEP 3 cm H₂0. Manual PEEP was achieved by submerging the expiratory line into a vessel 2010/001316

22

of water. At expiration an error of 1 .5 cm H₂0 for the submersion method of PEEP control can be seen. In Figure 13, the following identifiers are used:

81 - Manual PEEP control

82 - Automatic PEEP control

83 - Error line

The required PEEP of 3 cm H₂0 was maintained by the pressure control system in the new ventilator, however as indicated by the error line, on average the submersion method overshoots by 1 .5 cm H2O. This is due to surface tension, which causes water to draw up the tube, thus increasing PEEP. While this may be corrected for by gauging water line inside the tube, accuracy is still compromised due to inaccurate visual gauging of the water level. Furthermore, spontaneous inspiratory efforts by the animal during the ventilator expiratory cycle, will cause water to draw further up the tube and potentially overshoot PEEP pressures during subsequent expiration.

The expired air may contain impurities such as mucus or other substances, which can^ contaminate the water within the PEEP trap. As such, the water should be replaced for every experiment. However, differences in water level will arise between experiments as the water is replaced, thus compromising the accuracy and also the ability to compare between different experiments and animals. Experiments conducted show that PEEP is highly dependent on a variety of factors such as the tubing length, inner diameter and material used. The table below shows the effect of the variation in expiratory airway pressure when these parameters are changed using the submersion method.

Inner Material Length Required Average Difference diameter (cm) PEEP (cm Actual PEEP in PEE (inches) H₂O) (cm H₂6) (cm H₂0)

1 /8" Silicone 25 2.0 3.0 1.0

1 /8" Silicone 25 3.0 3.5 0.5

1 /8" Silicone 25 4.0 4.0 0.0

1/16" Silicone 25 2.0 2.7 0.7

1/16" Silicone 25 3.0 3.9 0.9 Inner / Material Length Required Average Difference diameter (cm) PEEP (cm Actual PEE in PEEP (inches) H₂0) (cm H₂0) (cm H₂0)

1/16" Silicone 25 4.0 4.7 0.7

1/ 6" Silicone 25 3.0 4.1 1.1

1/8" Silicone 50 3.0 7.7 4.7

1/16" Silicone 50 3.0 4.4 1.4

The data strongly suggest that it is not possible to have a single length of tubing that can produce a variety of PEEP pressures accurately. It is these results which have led to the development of the separate PIP and PEEP vessels.

The second generation ventilator, shown in Figure 3a, incorporates the design of the separate pressure vessels, and improves on the first generation design by implementing a pneumatic bleed system to deliver rapid changes in pressure without compromising stability. It dynamically monitors the PIP and PEEP pressure and is capable of quickly changing the required pressure value. The ability to implement PEEP ventilation strategies is important due to the reasons discussed herein

The bleed system utilised in the ventilator of the present invention has a number of advantages over the PEEP trap method. System accuracy is dependent on the rate at which the system operates, that is, 1 kHz, thus oscillations produced in the pressure output will be minimal, which are shown in the performance study (following). These fast changes in PEEP are also stable. The ventilator of the present invention does not require a water vessel to generate PEEP, eliminating the risk of spillage and contamination. Finally, as the PEEP vessel is located within the ventilator, minimal space is used. This offers the possibility of significant reduction in weight of the ventilator as compared with ventilators of the prior art.

As previously mentioned, the ventilator of the present invention can also be programmed to trigger an Imaging system and has been seamlessly incorporated into the software that manages respiration, giving a high level of experimental control by centralising operations. A user may specify the exposure time, delay between frames and number of frames. A TTL signal train output to the imaging system ensures that images are acquired at the same point in the breathing cycle and has been a key feature in achieving successful imaging experiments. This synchronised timing has also allowed the high speed imaging technique of X-ray velocimetry to be utilised to capture movement of the lungs.

The triggering system can also be utilised to control other devices, such as data acquisition modules or medical equipment.

The device may be remotely controlled via a computer (such as a small laptop to increase portability) running a custom coded executable program on a Windows operating system. Both the respiration and timing controls would typically be present in the GUI and all parameters adjustable by the user.

Comparison Ventilators

The ventilator of the present invention was compared with two commercially available ventilators. In particular, various ventilation characteristics such as pressure and timing were compared. .The flexiVerit and the SAR-830/AP

(CWE Inc, Ardmore, Pennsylvania, USA) were the two commercial ventilators employed in the comparison. The flexiVent was developed in 1995 and has been used in research since becoming commercially available. The SAR-830/AP was also chosen for this comparison of the pneumatic system of the present invention with a controlled flow-rate ventilator.

SAR-830/AP. Indicators used in the diagram are as follows:

90,110 - Pump

91 ,92 - Proportional valves

93,94, 101 ,102,114 - Pressure transducers

95,98 - Bleed valves

96,112 - Inspiration valve

97,105,113 - Expiration valve

100 - Linear actuator

103 - Three-way valve

104 - Air flow

06 - Peep trap 111 - Manual flow restrictor valve

A. fiexiVent Small Animal Ventilator

The fiexiVent (as depicted in Figure 14(b)), is a volume controlled small animal ventilator with limited pressure control. The device comes with its own software that controls ventilation, piston calibration and synchronisation triggers. To perform complex ventilation strategies the user is required to write scripts which are then executed by the fiexiVent software. The fiexiVent also has the ability to determine respiratory parameters such as lung compliance and control other devices.

The fiexiVent is a piston driven device with interchangeable cylinder modules and respiration valves for different sized animals that require markedly different tidal volumes. Piston movement is regulated by a linear actuator, which is connected to an electronic processor that also controls the three-way solenoid valve upstream of the piston and inspiration and expiration valves. During expiration, the three-way valve closes the line to the animal, while simultaneously ^' opening the outlets to atmosphere and the piston cylinder module. This allows atmospheric air to fill the piston chamber as the piston head is pulled back to the starting position b the linear actuator. At the same time the expiration valve is open to allow the e air to flow out of the anirria through the PEEP trap or directly to atmosphere if PEEP is not required. At the end of the expiration cycle, the three way valve closes and isolates the piston chamber from the atmosphere, fixing the volume of air with in the piston chamber. At- the onset of inspiration, the three-way valve opens the inspiratory line between the piston and the animal, and the actuator drives the piston, forcing air into the animal until a set tidal volume is achieved, as determined by the position of the piston head. When in pressure control mode, a sensor continuously measures airway pressure PAW (at the mouth opening) which provides feedback to the fiexiVent software and regulates PAW by altering the piston head. At the completion of inspiration, which is usually determined by a preset inspiratory time, the three-way valve again opens the animal to the expiratory iimb of the circuit, which allows the piston head to reset and the chamber to refill. B. SAR-830/AP Small Animal Ventilator

The SAR-830 /AP (depicted in Figure 14(c)) is primarily a pressure controlled ventilator but can also run in volume mode by utilising the flow-time principle. In this mode, airflow into the animal can be set at a known value, which is assumed to be constant, allowing tidal volume to be simply regulated by altering the inspiration time.

An internal pump continuously supplies air to the ventilator and the airflow rate is manually controlled by a valve and displayed by a flow meter. The respiratory rate (in breaths per minute), peak inspiratory pressure and inspiration time are set by the user,^' whereas the expiratory time is inferred from this information. The inspiration valve opens and expiration valve closes at the onset of inspiration and the pressure in the ventilation circuit rises, the rate of which depends on the rate of air flow through the circuit. Inspiration continues for ht preset inspiration time, irrespective of whether the preset peak inspiratory pressure is reached, or is truncated if the preset peak inspiratory pressure is reached before the inspiration time finishes. During expiration, the inspiration valve closes and expiration valve opens and expired air is released to atmosphere, as this ventilator ahs no automated PEEP capabilities.

Procedure for comparison

The three ventilators were assessed by varying the ventilation parameters of PIP, PEEP, inspiration time and expiration time as listed in the Table below.

These four ventilation strategies were chosen because the parameters of pressure and time are commonly adjusted in experiments involving ventilation studies. A SI has been shown to increase FRC and facilitate tidal volume recruitment immediately after birth, and are often utilised during Ri and CT to reduce imaging blurring. Inspiration and expiration times vary for different types of animals depending on their size and the type of imaging required. For example, common inspiration and expiration times for mice are 0.1s and 0.2s respectively, whereas newborn rabbit pups are typically ventilated with much longer inspiration and expiration times (0.3s to 1 s, and 0.6s to 1.5s respectively). Pressure values are routinely altered during an experiment to regulate tidal volume, depending upon the resistance and compliance of the lung. PEEP is also used to facilitate FRC.

In this experiment expiration times of 1s and 1.5s were used for all strategies except the short expiration method.

Figure 15 illustrates the general experimental setup, In Figure 15, the following identifiers are used:

Ventilator

Inspiration line

Mouse

Expiration line

Pressure transducer

Data acquisition module

Personal computer

A computer controlled the ventilator through software, except in the case of the SAR-830/AP where the user was required to manually control the ventilator. Airway pressure was monitored by a pressure transducer out putting to the MotionPro Data Acquisition module (IDT Inc., Tallahassee, Florida USA). Data was recorded onto the computer through the use of the Data acquisition module. All three ventilators were fitted with the same 1/16" (1.59mm) inner diameter inspiration and expiration tubing, PAW transducer and animal. PAW data was used as the basis of this comparison and was recorded on the MotionPro data acquisition module on a portable computer.

The pressure transducer used to measure PAW (ASDX series Honeywell International Inc, Morristown, New Jersey USA) was calibrated prior to the experiment and was capable of monitoring pressures to ±1 psi (+70 cm H₂0). A 1 mm inner diameter Y piece fitting was used to connect the PAW sensor to the expiration line, which was located 15 mm from the Y piece that connected the inspiration and expiration lines.

The experiments were performed on a 12 week old female mouse weighing 19 gm. The animal was anaesthetised with passively humidified 2% isoflurane in oxygen, before being euthanized with 200 microlitres of 64.8 mg/ml Somnopentil immediately prior to study. The mouse was intubated to ensure no air leakage to obtain the most accurate pressure readings.

Results

Figure 16 comprises graphs of airway pressure as a function of time for (a) a ventilator according to the present invention, (b) a flexiVent ventilator and (c) a SAR-830/AP, for sustained inflation of 10 seconds applied over one breath. For subsequent breaths, inspiration and expiration times were 1 second and 1.5 seconds respectively. Figure 16(a) shows a stable plateau produced by the new ventilator once 20 cm H₂0 pressure had been reached during the breath hold. After the SI, the ventilator reverted to the respiration times of 1 s inspiration and 1.5s expiration. Both PIP and PEEP were stable during both the sustained and standard inflations and the computer controlled interface allowed easy manipulation of these parameters. The_^small amount of noise visible on the trace is due to the bleed valves maintaining the pressure as air continually enters and bleeds from the- pressure vessels.

To execute the SI and PIP variation strategies using the flexiVent, the user was required to write a macro or script. The scripts are relatively labour intensive to write. In order to execute the script, the user must stop ventilation before executing the required strategy. This pause in ventilation may be detrimental to anesthetised animals if performed repeatedly, as it results in apnea. The PAW pressure trade in Figure 16(b) shows that the flexiVent maintained a pressure breath hold at 20 cm H₂0 over the 10 s SI. However, the user was required to manually re-start ventilation to execute the standard respiration following the SI, resulting in the shortened expiration time.

In terms of pressure control, while the PIP was accurate, the delivered PEEP was shown to be 3 cm H₂0, instead of the required 2 cm H₂0, despite visual gauging of PEEP trap. The results highlight the inaccuracy of the 0 001316

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submersion method. The error was not identified until after most of the experiments had been performed and was only rectified for the short respiration strategy.

Figure 17 comprises graphs of airway pressure as a function of time for continuous respiration using short inspiration and expiration times for (a) a ventilator according to the present invention, (b) a flexiVeht ventilator and (c) a SAR-830/AP ventilator. In addition, a noticeable drop in pressure is shown at the start of Si which is also apparent in the short respiration experiment (Figure 7). One possible cause of this pressure spike may be the late closing or early opening of the three-way valve, causing asynchronous timing with the piston head movement and can have serious implications, as the pressure drop may cause the lungs to collapse, PEEP is implemented to avoid this, however as seen in Figure 16(b) the pressure drop to 1 cm H₂0 could -not be prevented by the PEEP trap submersion method employed.

The SAR-8307 AP was unable to sustain a PIP pressure throughout the 0 s SI because inspiration is truncated when PIP is reached. As a result, the airflow and inspiration time have to be carefully adjusted to that PIP is reached only after 10 s has elapsed; this produces a very different pressure profile to both other ventiiators. A longer inspiration time (by 0.6s) resulted form the complexity of the timing adjustment, requiring the user to manually adjust timing and flow rate. The SAR-830 / AP was not as easy to use as the other two ventilators because inspiration time was inferred from the airflow rate and PIP. This required the user to manually pre-determine the dial settings to implement the ventilation strategy. In this case, as stopwatch was used to adjust timing, introducing human error.

The pressure responses at faster ventilation rate are shown in Figure 17.

The pressure curve of the ventilator of the present invention was very consistent across the three cycles, with a PIP undershoot of 2% (0.4 cm H2O). Furthermore, as the inspiratory plateau was not fiat during the short inspiration times, there was insufficient airflow into the animal to reach the required PIP due to the resistance of the ventilation circuit. However, this has been remedied by controlling the required PIP during ventilation using the pressure transducer measuring pressure at the mouth opening rather than in the PIP vessel. This was not changed for this experiment due to time restrictions. Small fluctuations in end-expiratory pressure, oscillating between 1.9 cm H2O and 2.4 cm H₂0, occurring at ~5Hz, is likely to be biological in origin, possibly the animal's heart beat. Inspiration times were consistently 0.30 s, although the expiration times differed from the required time by 0.03 s. A delay had been added into the software to ensure the inspiration and expiration valves remained synchronised but this issue .has now been addressed to ensure the ventilator produces the required timing,

Figure 17(b) shows the PAW output of the flexiVent during the fast ventilation component of the experiment. This ventilator was unable to maintain fixed inspiration and expiration times^' with expiration time varying from 0.5s to 0.7s. The same discrepancy was present in all data collected for this strategy using the flexiVent and the cause of this is unclear.

During inspiration, the flexiVent consistently produced an overshoot in PIP, reaching 21 cm H₂0 before decreasing down to 19 cm H2O at the end of inspiration as indicated by the hollow arrows in Figure 17(b). There may be several possible reasons for this. For example it may be due to the feedback control system not being sensitive enough to adequately slow and control piston movement ass the maximum PiP pressure is reached.

The airway pressure decreases rapidly during expiration, slowing to form a shoulder in the pressure curve before it briefly drops below the preset PEEP value (indicated by solid arrows). This reduction was also present during the SI (Figure 16(b)). The fast ventilation strategy appeared to magnify the bubbling effect on the PEEP level which varied between a maximum of 5 cm H₂0 and minimum of 0.7 cm H₂0. Although it is not clear why this should occur, it is ^' possible that during inspiration, when the expiratory airflow is zero, water moves up the expiratory tube. Then following the onset of expiration, the pressure in the expiratory line increases until it overcomes the resistance to force water out of the expiratory tube so that air can exit; this phenomenon is probably responsible for the shoulder in the expiratory pressure curve. The sudden release of the first bubble from the end of the expiratory tube likely accounts for the decrease in PEEP below the set value.

The SAR-830/ AP overshoots PIP by 0.5 cm H₂0 (Figure 17(c)) and as the inspiration is truncated when the preset PIP is reached, it is difficult to preset the inspiration and expiration times. Zero PEEP was recorded so expiratory performance could not be evaluated against those of the flexiVent and the ventilator of the present invention.

Comparing the rate of pressure rise across all there ventilators, the ventilator of the present invention produces the steepest rise. This occurred over 0.04s, before the rate markedly decreases as the required PIP pressure is approached. The pressure^" curve in Figure 17(a) is similar to one produced by a commercially available human infant volume controlled ventilator, the Babylog VN500 (Drager Medical, Lbeck Germany) in pressure-support mode.

Figure 18 comprises graphs of variation in PIP as a function of time for (a) a ventilator according-to the present invention, (b) a flexiVent ventilator and (c) a SAR-830/AP ventilator. The graphs show variation in PIP starting from 15 cm H₂0 and increasing in increments of cm H₂0 to 25 cm H₂0 before a drop to 5 cm H₂0. Dotted lines indicate pressures at 17 cm H2O and 23 cm H₂0. Changes in PIP are commonly used to regulate the tidal volume administered to the lung. Figure 18(a) shows the speed at which changes in PIP pressure can be implemented by the new ventilator during a 20 s period of inspiration. On average, the 2 cm H₂0 increase in PIP occurred within 0.2s, while the decrease in pressure from 25 to 15 cm H₂0 took 0.49s. A similar demonstration of the rapidity with which PIP pressures can be changed during a single inflation was not possible using the flexiVent. Through use of a script, the flexiVent executed the PIP variation strategy by changing these parameters in subsequent breaths (Figure 18(b)). The ventilator was programmed to change the PIP pressure every two breaths, following the strategy outlined above. The flexiVent was able to perform this strategy, however it requires the user to write and execute as script which greatly restricts the ability to quickly alter ventilation parameters when required; for instance in response to changing variables. It is also pertinent to note that at a PIP of 19 cm H₂0 and again at 25 cm H₂0 three breaths were delivered even though the script specified only two breaths were to be executed. Despite efforts to change this, the error could not be rectified.

As with the flexiVent, a stable pressure breath hold could not be executed with the SAR830/ AP, and accordingly, a multi-breath strategy similar to the flexiVent was employed (Figure 18(b)). It was possible to vary PIP using this 10 001316

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ventilator; however it required more effort to control as it is manually operated. As the flow rate was predetermined to obtain the correct PIP, increasing the set PIP, ^■ without increasing the flow rate, necessarily increased inspiration time. By the end of the strategy, the inspiration time had increased from 1.03s to 1.42se, resulting in a 27.5% change, while expiration decreased from 1.71s to 1.07s, a 37% reduction. While changing the PIP clearly had an effect on the inspiration •and expiration time, the overall resper4ation cycle time of 2.5s was maintained. Thus, using this ventilator it is difficult to maintain inspiration times constant when varying the PIP.

Figure 19 id a graph showing variation in PEEP during expiration for the ventilator of the present invention starting form 0 cm H₂0 and increasing in increments of 2 cm H₂0 to 10 cm H₂0 before a drop back to 0 cm H₂0 . Dotted lines indicate pressures at 4 cm H₂0 and 8 cm H₂0 . The flexi ent and SAR- 830/AP were not capable of performing this ventilation strategy. The ventilator of the present invention was the only device to contain automated PEEP. In the trace shown in Figure 19 it took an average of 0.27s to increase PEEP by 2 cm H₂0. The relatively slow and gentle 10 cm H₂0 pressure drop occurred within 1.2s. The PEEP pressure changes were slower than the PIP changes despite having the same pneumatic bleed principle. The difference is due to the input air flow rate from the pump. As the PIP requires relatively higher pressures, air is pumped into the vessel at a higher rate. PEEP is usually set at 5 cm H₂0 and while the ventilator can increase this to 5 cm H₂0, the airflow is reduced to effectively control the pressure at low pressures. This results in a slightly longer time for pressure changes to occur.

Of the three ventilators tested, the ventilator of the present invention was the only one that could implement all ventilation strategies tested. Neither the flexiVent nor SAR-830/AP had automated PEEP. Both the flexiVent and SAR- 830/AP ventilators exhibited linear rates of inspiration, most clearly shown by Figures 17(b) and 17(c).. This is to be expected as both ventilators rely on constant airflow rate to calculate the tidal volume delivered and a linear distribution is the simplest method of achieving this. However as shown in Figure 17(c), the SAR-380/AP has a slight curve in the output, indicating that the ventilator may have delivered a higher tidal volume than required. As this ventilator is used to ventilate small animals with tidal volumes of less than 1 ml, an increase in volume may have an amplified effect on the lungs, potentially leading to volutrauma.

Although the flexiVent has the capability to perform sustained inflation and PIP strategies the need to execute programs to achieve relatively simple changes in ventilation, coupled with the long time taken to write the scripts to implement the strategy, restricts the usability of this ventilator. On the other hand, the ventilator of the present invention allows the user to change any parameter at any point within the respiratory cycle via the GUI, eliminating the need for scripts and allowing adjustments to be made when required.

The ability of the ventilator of the present invention to produce a more stable breath over longer inspiration time, makes it suitable for static imaging techniques such as MRI and CT. Neither PIP nor PEEP is compromised over the short respiration strategies and pressure variations are executed quickly. These results, coupled with the ability to control the image timing sequence, make the ventilator particularly well suited for commercial production.

The ventilation apparatus, system and method of the present invention may be partially or fully automated. This may for example include the use of a server. It should be noted that where the term "server" or similar terms are used herein, a communication device is described that may be used in a communication system, unless the context otherwise requires, and should not be construed to limit the present invention, to any particular communication device type. Thus, a communication device may include, without limitation, a bridge, router, bridge-router (router), switch, node, or other communication device, which may or may not be secure.

It should also be noted that where a flowchart is used herein to demonstrate various aspects of the invention, it should not be construed to limit the present invention to any particular logic flow or logic implementation. The described logic may be partitioned into different logic blocks (e.g., programs, modules, functions, or subroutines) without changing the overall results or otherwise departing from the true scope of the invention. Often, logic elements may be added, modified, omitted, performed in a different order, or implemented using different logic constructs (e.g., logic gates, looping primitives, conditional logic, and other logic constructs) without changing the overall results or otherwise departing from the true scope of the invention.

Various embodiments of the invention may be embodied in many different forms, including computer program logic for use with a processor (e.g., a microprocessor, microcontroller, digital signal processor, or general purpose computer), programmable logic for use with a programmable logic device (e.g., a Field Programmable Gate Array or other PLD), discrete components, integrated circuitry (e.g., an Application Specific Integrated Circuit), or any other means including any combination thereof. In an exemplary embodiment of the present invention, predominantly all of the communication between users and the server is implemented as a set of computer program instructions that is converted into a computer executable form, stored as such in a computer readable medium, and executed by a microprocessor under the control of an operating system.

Computer program logic implementing all or part of the functionality where described herein may be embodied in various forms, including a source code form, a computer executable form, and various intermediate forms (e.g., forms generated by an assembler, compiler, linker, or locator). Source code may include a series of computer program instructions implemented in any of various programming languages (e.g., an object code, an assembly language, or a high- level language such as Fortran, C, C++, JAVA, or HTML) for use with various operating systems or operating environments. The source code may define and use various data structures and communication messages. The source code may be in a computer executable form (e.g., via an interpreter), or the source code may be converted (e.g., via a translator, assembler, or compiler) into a computer executable form.

The computer program may be fixed in any form (e.g., source code form, computer executable form, or an intermediate form) either permanently or transitorily in a tangible storage medium, such as a semiconductor memory device (e.g, a RAM, ROM, PROM, EEPROM, or Flash-Programmable RAM), a magnetic memory device (e.g., a diskette or fixed disk), an optical memory device (e.g., a CD-ROM or DVD-ROM), a PC card (e.g., PCMCIA card), or other memory device. The computer program may be fixed in any form in a signal that is transmittable to a computer using any of various communication technologies, including, but in no way limited to, analog technologies, digital technologies, optical technologies, wireless technologies (e.g., Bluetooth), networking technologies, and inter-networking technologies. The computer program may be distributed in any form as a removable storage medium with accompanying printed or electronic documentation (e.g., shrink wrapped software), preloaded with a computer system (e.g., on system ROM or fixed disk), or distributed from a server or electronic bulletin board over the communication system (e.g., the Internet or World Wide Web).

Hardware logic (including programmable logic for use with a programmable logic device) implementing all or part of the functionality where described herein may be designed using traditional manual methods, or may be designed, captured, simulated, or documented electronically using various tools, such as Computer Aided Design (CAD), a hardware description language (e.g., VHDL or AHDL), or a PLD programming language (e.g., PALASM, ABEL, or CUPL).

· Programmable logic may be fixed either permanently or transitorily in a tangible storage medium, such as a semiconductor memory device (e.g., a RAM, ROM, PROM, EEPROM, or Flash-Programmable RAM), a magnetic memory device (e.g., a diskette or fixed disk), an optical memory device (e.g., a CD-ROM or DVD-ROM), or other memory device. The programmable logic may be fixed in a signal that is transmittable to a computer using any of various communication technologies, including, but in no way limited to, analog technologies, digital technologies, optical technologies, wireless technologies (e.g., Bluetooth), networking technologies, and internetworking technologies, The programmable logic may be distributed as a removable storage medium with accompanying printed or electronic documentation (e.g., shrink wrapped software), preloaded with a computer system (e.g., on system ROM or fixed disk), or distributed from a server or electronic bulletin board over the communication system (e.g., the Internet or World Wide Web).

While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modification(s). This application is intended to cover any variations uses or adaptations of the invention following in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.

As the present invention may be embodied in several forms without departing from the spirit of the essential characteristics of the invention, it should be understood that the above described embodiments are not to limit the present invention unless otherwise specified, but rather should be construed broadly within the spirit and scope of the invention as de ined in the appended claims. The described embodiments are to be considered in all respects as illustrative only and not restrictive.

Various modifications and equivalent arrangements are intended to be included within the spirit and scope of the invention and appended claims. Therefore, the specific embodiments are to be understood to be illustrative of the many ways in which the principles of the present invention may be practiced. In the following claims, means-plus-function clauses are intended to cover structures as performing the defined, function and not only structural equivalents, but also equivalent structures.

"Comprises/comprising" and "includes/including" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. Thus, unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', 'includes', 'including' and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including,_, but not limited to":

Claims

1. A ventilator for delivering fluid pressure to the lungs of a subject, the ventilator having;

wherein the volume of the first pressure vessel is substantially greater than the volume of the lungs of the subject.

2. A ventilator according to claim 1 which further comprises a bleed to atmosphere, the pump and bleed being controlled by a microprocessor.

3. A ventilator for delivering fluid pressure to the lungs of a subject, the ventilator having;

4. A ventilator for delivering fluid pressure to a subject, the ventilator having; a pump in operative connection with a first pressure vessel for control of the peak inspiratory pressure (PIP) of the subject,

wherein the volumes of the first pressure vessel and the second pressure vessel are substantially greater than the volume of the lungs of the subject.

5. A ventilator according to claim 4 which includes a microprocessor controlled pneumatic bleed system for control of PIP and PEEP.

6. A ventilator according to claim 4 or claim 5 which comprises two pumps, a first pump providing a source of gas and a second pump providing suction.

7. A ventilator according to any one of claims 1 to 6 when used for providing ventilation chosen from the group comprising standard ventilation, high frequency ventilation, high frequency oscillatory ventilation or combinations thereof.

8. A method of delivering stable pressure to the lungs of a subject, the method comprising the steps of;

(1) enclosing the subject within a housing, the housing being in operative connection with a first pressure vessel held at a first (PIP) pressure and a second pressure vessel held at a second (PEEP) pressure, respectively,

(2) admitting air from the first pressure vessel into the housing, then

(3) admitting air from the housing into the second pressure vessel, and

(4) repeating steps (2) and (3) multiple times.

9. A method according to claim 8 when used to provide standard ventilation, high frequency ventilation, high frequency oscillatory ventilation or simultaneous combinations thereof.

10. A system for delivery of stable pressure during ventilation of the lungs of a subject, the system comprising;

a first pump in operative connection with a first pressure vessel at a peak inspiratory pressure,

wherein the volume of each of the first and second pressure vessels is at least 100x greater than the volume of the lungs of the subject, such that opening and closing the operative connection between the housing and the first pressure vessel and the second pressure vessel does not change the pressure within the vessels by more than ± 10%.

11. A system according to claim 10 which further comprises;

a second pump for providing suction, the first pump providing a source of gas,

and wherein the system can switch between conventional ventilation and high frequency oscillatory ventilation.

12. A method of imaging a subject, the method comprising the steps of:

providing stable respiration pressures to a subject enclosed within the housing of a ventilator according to any one of claims 3 to 7, and using a timing control system for synchronisation of the ventilator with imaging equipment to acquire multiple images of the lungs of the subject.

13. A method for computer tomography of a subject, the method comprising the steps of:

providing stable respiration pressures to the lungs of. a subject enclosed within the housing of a ventilator of the present invention; and

acquiring respiratory gated projection radiographs of the subject.

14. Apparatus adapted to perform mechanical ventilation of a subject, said apparatus including processor means adapted to operate in accordance with a predetermined instruction set, said apparatus, in conjunction with said instruction set, being adapted to perform the method as claimed in any one of claims 8 to 13