WO1999016492A1 - Detection of oxygen carriers in exhaled gases - Google Patents

Abstract

Methods and apparatus for the monitoring and quantifying of a respiratory promoter following its pulmonary introduction are disclosed. In preferred embodiments, the present invention provides methods and apparatus for calculating the evaporative loss of respiratory promoters, and particularly fluorochemicals, during medical procedures such as liquid ventilation.

Description

DETECΗON OF OXYGEN CARRIERS IN EXHALED GASES

Field of the Invention:

In a broad aspect the present invention relates to methods and apparatus for the detection of respiratory promoters or blood substitutes following their introduction into a patient. More particularly, the present invention is directed to monitoring and quantifying the evaporative loss or excretion rate of respiratory promoters or intravenous oxygen carriers during or after medical procedures. Background of the Invention:

Respiration involves the introduction of fresh gases, especially oxygen, to the lung during inspiration and the removal of waste gases, particularly carbon dioxide, during expiration. In healthy individuals respiration is normally effected by spontaneous ventilation or breathing which results in the introduction of necessary gases. Unfortunately, a number of physiological and pathological processes may compromise normal pulmonary function leading to the inhibition of effective respiration or total respiratory failure. In such cases respiratory therapy, often involving artificial ventilation to some degree, is indicated. For example, respiratory therapy is often indicated for patients undergoing surgery or those suffering disorders and diseases of the pulmonary air passages. In particular, patients suffering from lung contusion, diver's lung, post-traumatic respiratory distress, post-surgical atelectasis, irritant injuries, septic shock, multiple organ failure, Mendelssohn's disease, obstructive lung disease, pneumonia, pulmonary edema or any other condition resulting in lung surfactant deficiency or respiratory distress are strong candidates for respiratory therapy. Typically, such respiratory therapy involves the use of mechanical ventilators. Mechanical ventilators are clinical devices that effect ventilation or, in other words, cause air (or gas) flow in the lungs. More specifically, such devices typically force air into the lungs during the inspiration phase of the breathing cycle but allow a return to ambient pressure during spontaneous exhalation. The forced influx of fresh air by mechanical ventilation facilitates the pulmonary mediated processes that comprise respiration in mammals. One of these processes, removal of waste gases, is a primary mechanism by which carbon dioxide is excreted from the body. In normal gas mediated carbon dioxide removal, fresh air is brought into contact with the alveoli (alveolar ventilation) thereby promoting gas exchange wherein carbon dioxide passes from the body and is exhaled during the expiration phase of the breathing cycle. The other essential bioprocess, oxygenation, comprises the absorption of oxygen into the blood from the lungs. It is primarily a function of a mechanism whereby the partial pressure of oxygen (P0₂) in pulmonary capillary blood equilibrates with the partial pressure of oxygen in inflated alveoli. The oxygen gradient between alveolus and capillary favors transfer of oxygen into blood because the repeated influx of fresh oxygen through ventilation (spontaneous or assisted) maintains alveolar P0₂ at higher levels than capillary P0₂. Modern mechanical ventilators are designed to provide ventilation by regulating tidal volume (breath), flow rate, delivery profile and respiratory flow thereby controlling carbon dioxide excretion. Because they can also regulate airway pressure and the concentration of inspired oxygen they offer control over oxygenation as well. Recently alternative techniques, particularly liquid ventilation, have been developed to obviate at least some of the complications associated with mechanical gas ventilation, in contrast to standard mechanical ventilation, liquid ventilation involves introducing an oxygenatable liquid medium into the pulmonary air passages for the purposes of gas exchange and oxygenation. Essentially, there are two separate techniques for performing liquid ventilation, total liquid ventilation and partial liquid ventilation. Total liquid ventilation or "TLV" is the pulmonary introduction of warmed, extracorporeally oxygenated liquid respiratory promoter (typically fluorochemicals) at a volume greater than the functional residual capacity of the subject. The subject is then connected to a liquid breathing system and tidal liquid volumes are delivered at a frequency depending on respiratory requirements while exhaled liquid is purged of C0₂ and oxygenated extracorporeally between the breaths. This often involves the use of specialized fluid handling equipment. Conversely, partial liquid ventilation or "PLV" involves the use of conventional mechanical ventilation in combination with pulmonary administration of a respiratory promoter capable of oxygenation. As with TLV, the respiratory promoter typically comprises fluorochemicals which may be oxygenated prior to introduction. In the instant application the term "liquid ventilation" will be used in a generic sense and shall be defined as the introduction of any amount of respiratory promoter into the lung, including the techniques of both partial liquid ventilation and total liquid ventilation. Avoiding some of the complications associated with TLV, partial liquid ventilation, as described in Fuhrman, U.S.

Patent No. 5,437,272 and Faithfull et al. U.S. Patent No. 5,490,498, is a safe and convenient clinical application of liquid breathing using fluorochemicals which are oxygenated in vivo. In PLV a liquid, vaporous or gaseous respiratory promoter (i.e. a fluorochemical) is introduced into the pulmonary air passages at volumes ranging from just enough to interact with a portion of the pulmonary surface all the way up to the functional residual capacity (FRC) of the subject. Respiratory promoters are any compound that functions, systemically or pulmonarily, to improve gas exchange and respiration efficiency. Respiratory gas exchange is thereafter maintained for the duration of the procedure by spontaneous breathing or assisted ventilation. Typically, breathing gases are introduced and waste gases removed by continuous positive pressure ventilation using a conventional open-circuit gas ventilator. Like total liquid ventilation, the pulmonary introduction of the respiratory promoter eliminates surface tension due to pulmonary air/fluid interfaces while improving pulmonary function and gas exchange in surfactant deficiency and other disorders of the lung. Finally, when the procedure is over the introduced the liquid, gaseous or vaporous respiratory promoter may be allowed to evaporate from the lung rather than being physically removed as in TLV.

As previously indicated, fluorochemicals are the preferred respiratory promoter for both TLV and PLV. Generally, fluorochemicals compatible with liquid ventilation will be clear, odorless, nonflammable, and essentially insoluble in water. Preferred fluorochemicals are denser than water and soft tissue, have a low surface tension and, for the most part, a low viscosity. In particular, many brominated fluorochemicals are known to be safe, biocompatible substances when appropriately used in medical applications. It is additionally known that oxygen, and gases in general, are highly soluble in some fluorochemicals. For example, some fluorochemical liquids may dissolve over twenty times a much oxygen and over thirty times as much carbon dioxide as a comparable amount of water. One particularly preferred respiratory promoter is LiquiVent® (sterile perfluorooctyl bromide; Alliance Pharmaceutical Corp., San Diego, CA). Perfluorooctyl bromide (PFOB or Perflubron) is a clear, radioopaque, odorless, inert perfluorochemical fluid which is being successfully used in clinical trials. While it has a density approximately twice that of water, a relatively low vapor pressure allows it to evaporate from the lungs following completion of the liquid ventilation procedure.

In addition to carrying gases and removing waste products, respiratory promoters such as fluorochemicals may be used for lavage or as pulmonary drug delivery vehicles, either in conjunction with liquid ventilation or as independent therapy. For example, aerosol delivery systems may rely on a mixture of therapeutically active agents with one or more respiratory promoters to increase dispersion, efficacy and stability of the bioactive agent. Fluorochemicals are also used in an emulsified form as blood substitutes to provide oxygen during surgery and reduce the use of transfused blood. Moreover, fluorochemicals have been shown to have pulmonary and systemic anti-inflammatory effects when introduced in a neat or emulsified form. Accordingly, despite relatively high costs, it is desirable to employ fluorochemicals as an oxygen carrier or vehicle in current liquid ventilation procedures, pulmonary drug delivery and blood substitutes.

While liquid ventilation is, in many ways, a significant improvement over conventional ventilation, the escape of fluorochemicals into the environment in the form of vapors gases or aerosols, may complicate PLV therapy. That is, many of the most desirable fluorochemicals are volatile to some extent and naturally evaporate over the course of the treatment. During normal liquid fluorochemical ventilation procedures, the generation and release of such vapor may be significant. For example, there is continuous evaporation of PFOB from the lungs during PLV at a rate such that the 1.0 FRC volume of Ligυ/Vent® would be completely expired from a patient after 1-2 days. Since PLV treatment with the lungs kept liquid- filled is typically done for 1-5 days, there is need to redose Liqu/Vent®. Moreover, to maintain a stable resident dose in the lungs, frequent redosing every few hours may be required. Current methods to determine evaporative loss are largely qualitative, and include radiographic assessment and visual inspection of liquid level in the patient endotracheal tube. The quantitation of PFOB evaporative loss would facilitate LiquiVenl® dose maintenance.

In a similar fashion, although at a lower rate, emulsified fluorochemicals introduced intravenously for use as an oxygen carrier also evaporate from the lungs. More specifically, as fluorochemical particulates such as PFOB pass through the pulmonary vasculature they cross the pulmonary membrane and are excreted as a vapor entrained in the exhaled breath of the patient. This mechanism appears to be the primary mode of fluorocarbon excretion for patients receiving emulsified blood substitutes although there is some indication that minor amounts of fluorocarbon actually pass through the skin and into the surrounding environment. As with liquid ventilation procedures it would be beneficial to monitor the rate of fluorocarbon excretion from patients that have received emulsified blood substitutes for the purposes of determining how much drug remains in circulation. Accordingly, it is an object of the present invention to provide simple and cost effective methods of monitoring the evaporative rate of a respiratory promoter from the pulmonary air passages of a patient.

It is another object of the present invention to provide methods for performing liquid ventilation comprising monitoring the evaporative rate of the introduced respiratory promoter.

It is yet another object of the present invention to provide a system for monitoring the loss of a respiratory promoter during liquid ventilation. It is still another object of the present invention to provide method of quantifying the amount of respiratory promoter present in the lung of a patient.

It is a further object of the present invention to provide methods for monitoring the excretion rate of a fluorochemical blood substitute from a patient. Summary of the Invention:

These and other objectives are achieved by the present invention which, in a broad aspect, is directed to methods and apparatus for the detection of exhaled vapors from a patient. In preferred embodiments, the present invention provides methods and devices for use in liquid ventilation procedures to monitor and quantify the evaporative loss of material, including fluorochemical respiratory promoters, from the lungs of a patient. In other preferred embodiments the disclosed methods and apparatus may be used to monitor and quantify the excretion rate of intravenous oxygen carriers which pass from the lungs of a patient in the form of a vapor. Preferably, the vapor to be monitored in each of the embodiments is a fluorochemical vapor. Among other advantages, the apparatus and methods disclosed herein reduce the cost of such therapy by allowing for more accurate dosing, decreasing the interruptions in ventilatory care and reducing the requirement for operator intervention. More specifically, the present invention advantageously uses a detector capable of monitoring the concentration of an oxygen carrying compound in the expiratory gas of a mammal. As used herein the term "oxygen carrying compound" shall be held to mean any compound that is capable of transporting therapeuticallγ beneficial amounts of oxygen for the facilitation of respiration. Accordingly oxygen carrying compounds, including fluorochemicals, may be used as respiratory promoters or blood substitutes. For the purposes of the instant applciation the three terms will be used interchangeably unless the context of the passage dictates otherwise.

The present invention is generally predicated that the concentration of a vaporized oxygen carrying compound in expiratory gases corresponds to the volume of that compound in the lung or in circulation. With regard to the lung, an introduced respiratory promoter can only evaporate from those lung surfaces that are wetted with the respiratory promoter. Accordingly, the concentration of respiratory promoter in the expired air has suprisingly been found to be proportional to the surface area of the lung wetted with the promoter. In this respect, it would be expected that the expired air from a fully wetted pulmonary surface area would be equivalent to the concentration of vapor found in saturated gas at body temperature. That is, the percent of respiratory promoter saturation measured in the expired gas has been found to be proportional to the percent of active pulmonary surface that is wetted by the respiratory promoter. Knowing the amount of wetted surface it is possible to calculate the amount of dosing necessary to maintain a desired fluid level in the pulmonary air passages.

Thus, in preferred embodiments the present invention provides processes for determining the concentration of a vaporized oxygen carrying compound in exhaled gas from pulmonary air passages of a mammal comprising the steps of: interrogating said exhaled gas with a dectector capable of perceiving said oxygen carrying compound whereby said detector provides an output signal representative of the concentration of oxygen carrying compound entrained in said exhaled gas; and determining the concentration of the oxygen carrying compound in the exhaled gas based on the output value. .

As contemplated herein, any type of detector capable of observing or perceiving the exhaled vapor of the oxygen carrying compound of interest is within the scope of the present invention. For example, detectors comprising ion capture and gas chromatograph detection could be used in accordance with the teachings herein. More preferably, spectroscopic detectors that monitor selected portions of the electromagnetic spectrum (i.e. ultraviolet or visual wavelengths) will be used to observe levels of oxygen carrying compound. In this regard use of an ultraviolet spectrophotometer it clearly contemplated as being within the scope of the invention. However, in particularly preferred embodiments the detector will comprise an infrared analyzer such as a single or multi-wavelength infrared photometer. Those skilled in the art will appreciate that such detectors have been used for various purposes for some time and are conceptually relatively simple. Typically they comprise a light source, a means of varying the wavelength, a sample cell, a signal detector and a signal processor. In this respect the detector will preferably provide an output signal (i.e. in either analog or digital form) representative of the concentration of oxygen carrying compound entrained in said exhaled gas. The processing and manipulation of such signals to provide desired data displays or calculated values is well known to those skilled in the art and may easily be achieved without undue experimentation. As to the detector itself, a single wavelength infrared instrument may be particularly compatible with the present invention as the optimal analytical wavelength may be selected with high accuracy with reproducibility ensured by an interference filter.

Regardless of what type of detector is selected, it may be used to monitor and quantify the evaporative loss or excretion of oxygen carrying compounds from a patient. Accordingly, in one embodiment of the invention the detector is used to monitor the evaporative loss of respiratory promoter from the lung of a mammal undergoing liquid ventilation. In other preferred embodiments, the concentration of the detected vapors may be measured and used to quantify the amount of respiratory promoter remaining in the lung. The disclosed invention further includes methods of performing liquid ventilation, and associated systems, that comprise monitoring vaporized respiratory promoter entrained in the expiratory gases of a mammal.

Accordingly, it will be appreciated that the present invention may be used with respiratory promoters, including breathing liquids (i.e. fluorochemicals), bioactive agents and pharmaceutical agents to effect ventilation therapy including, but not limited to, partial liquid ventilation. As used herein the term "ventilation" will be held to mean airflow in the lungs. Thus, the term "ventilation therapy" broadly means any procedure, including partial liquid ventilation or the pulmonary administration of any therapeutic or diagnostic agent, that comprises airflow in the lungs. As such, ventilation therapy may be used in connection with the present invention to treat both systemic and localized pulmonary conditions. Another major advantage of the present invention is that the disclosed methods and apparatus may optionally be used with conventional mechanical ventilators desirable in extended ventilation therapy. In particularly preferred embodiments, the methods of the present invention are used in conjunction with partial liquid ventilation techniques employing the pulmonary introduction of a breathing liquid or respiratory promoter in conjunction with a mechanical ventilator. These partial liquid ventilation techniques may be practiced using any detector capable of monitoring vapor of the instilled respiratory promoter. Of course it will be appreciated that the methods and apparatus of the present invention are also compatible with patients undergoing spontaneous respiration following the pulmonary introduction of a respiratory promoter. In either case, optimization of the dosing regimen will enhance the efficiency of the treatment.

In accordance with the teachings herein, it will be appreciated that the present invention may be used to treat patients suffering from almost any pulmonary disorder. Particular disorders that are compatible with the disclosed methods and apparatus include, but are not limited to respiratory distress syndrome, lung contusion, chronic lung injury, acute lung injury, diver's lung, post-traumatic respiratory distress, post-surgical atelectasis, irritant injuries, septic shock, multiple organ failure, Mendelssohn's disease, obstructive lung disease, pneumonia and pulmonary edema. Moreover, the invention may be used in conjunction with the pulmonary administration of a bioactive agent associated with a respiratory promoter, particularly a breathing liquid. It will be further appreciated that a respiratory promoter may be introduced into the pulmonary passages of the patient at any time during the disclosed methods. That is, selected embodiments of the invention comprise introducing the respiratory promoter prior to connecting the detector while in others the promoter may be introduced after the patient is intubated and undergoing ventilation. In particularly preferred embodiments the patient is initially dosed with an effective amount of respiratory promoter, preferably a fluorochemical liquid or vapor, prior to the initiation of mechanical ventilation. Additional respiratory promoter is then added intermittently, based on the monitored levels of exhaled vapor, to maintain the desired pulmonary volume over the treatment period.

In addition to those methods associated with liquid ventilation, the methods and apparatus may be used in conjunction with hemodilution or other procedures comprising the intravenous administration of an oxygen carrying compound. As alluded to above, the disclosed invention may be used to monitor and quantitate excretion of the compound from the lungs of a patient. Systems compatible with this aspect of the invention are substantially similar to those systems which may be used to monitor patients undergoing liquid ventilation procedures.

Other objects, features and advantages of the present invention will be apparent to those skilled in the art from a consideration of the following detailed description of preferred exemplary embodiments thereof taken in conjunction with the Figures which will first be described briefly. Brief Description of the Figures:

Fig. 1 is a schematic representation of a mechanical ventilation system comprising a vapor detector in accordance with the present invention;

Fig. 2 is a graphical representation illustrating the dose-dependent increase in the concentration of fluorochemical vapor in expiratory gases with respect to increasing fluorochemical dosing; Fig. 3 is a graphical representation showing a decrease in the concentration of fluorochemical vapor in the expiratory gases of animals as the amount of fluorochemical in the lung goes down over time;

Fig. 4 is a graphical representation illustrating the fact that there is a gradual linear decrease in fluorochemical vapor concentration in the expiratory gases of an animal at low dosing levels of approximately 0.1 FRC to approximately 0.33 FRC. Detailed Description of the Invention:

While the present invention may be embodied in many different forms, disclosed herein are specific illustrative embodiments thereof that exemplify the principles of the invention. It should be emphasized that the present invention is not limited to the specific embodiments illustrated. As those skilled in the pertinent arts will appreciate, the current invention is related to the use of detectors to monitor and/or quantify the evaporative mediated removal of an oxygen carrying compound from the lung of a mammal. In selected embodiments the methods and systems of the present invention may be used in conjunction with liquid ventilation procedures including partial liquid ventilation. The instant disclosure also teaches novel methods and systems that may be used to observe oxygen carrying compounds which are excreted following hemodilution or other procedures involving the administration of blood substitutes. In preferred embodiments the oxygen carrying compound or respiratory promoter is a fluorochemical that is, at least in part, volatile at body temperature. Accordingly, the methods and apparatus of the present invention may be used to improve the efficiency of pulmonary therapies and blood substitute administration while driving down associated costs. Moreover, the invention reduces the discomfort of the patient by decreasing the number of interruptions in ventilatory therapy while, at the same time, lowering the burden on the care giver. Those skilled in the art will further appreciate that the disclosed methods and apparatus may advantageously be used any time a respiratory promoter is introduced into the lungs. As previously discussed, the respiratory promoter may be any liquid, gaseous liquid or vapor that improves the pulmonary exchange of physiological gases. Preferably, the respiratory promoter is administered in the form of a free flowing liquid, vapor, suspension, mist or aerosol. In particularly preferred embodiments the respiratory promoter is a breathing liquid and, in especially preferred embodiments, a fluorochemical. It should also be emphasized that the present invention may be used in conjunction with any type of mechanical ventilation (including patient initiated assisted ventilation) or when the subject is breathing spontaneously. In either case, the disclosed methods and apparatus can substantially improve the maintenance of respiratory promoter levels over the course of the treatment.

In particularly preferred embodiments the respiratory promoter will be a liquid introduced for the purpose of performing partial liquid ventilation, facilitate the pulmonary administration of a bioactive agent or perform bronchoalveolar lavage. Partial liquid ventilation, or PLV, as described in U.S. Pat. Nos. 5,540,225, 5,655,521, 5,437,272 and 5,562,608, each of which is incorporated herein by reference, has a number of benefits over conventional gas ventilation. The lungs are bathed in a biocompatible breathing fluid thereby minimizing lung trauma and permitting lung maturation or repair. Moreover, partial liquid ventilation is extremely amenable with conventional therapies since air or gas is still inhaled and exhaled. The amount of air entering the lungs on inhalation is sufficient to oxygenate, at least in part, the breathing liquid contained therein. Further, in preferred embodiments, the breathing liquid may be oxygenated prior to use to provide oxygen to the alveolar surfaces upon initial contact. As previously discussed, partial liquid ventilation can be used in conjunction with either spontaneous breathing or mechanical ventilation systems. In addition, pharmacologic substances can be added to the respiratory promoter to further enhance resolution of pulmonary and systemic disorders. In the following discussion common medical terms for the orientation of a ventilatory system will be used. Accordingly, the "distal" end of a system component, conduit or other element will be the farthest away from the attached patient while the "proximal" end or section is the closest to the patient. Moreover, as used herein, the term "patient" applies to any respiring mammalian subject including livestock, pets and other animals as well as humans. Referring now to the drawing Figures, Fig. 1 provides a schematic representation of mechanical ventilation system 10 illustrating the selected features of the present invention. With respect to the instant invention, Fig. 1 represents a ventilation system that may be used in conjunction with a respiratory promoter and, in particular, with partial liquid ventilation. In the Figure, mechanical ventilation system 10 is connected to a patient 12 through a patient-connector 14. Typically, patient-connector 14 will comprise an endotracheal tube or a mask that allows gas, vapors and liquids to be administered to the lungs of the patient. In the illustrated apparatus, the distal end of patient-connector 14 branches to form a Y-connector providing two separate distal connecting ports. The distal connecting ports are sealingly attached to the proximal ends of inspiratory ventilating conduit 16 and expiratory ventilating conduit 18 respectively. For the purposes of this application the terms "conduit" or "ventilating conduit" will be held to mean any hose, tube, bore, lumen, shaft or other void containing structure capable of defining a fluid or gas flow path. Those skilled in the art will appreciate that exemplary inspiratory ventilating conduit 16 and expiratory ventilating conduit 18 are typically formed of biocompatible flexible tubing having annular reinforcements to prevent kinking or blockage. Moreover, such ventilating conduits may be formed of materials compatible with specific respiratory promoters. Inspiratory ventilating conduit 16 defines a gas flow path comprising a lumen or bore which is capable of transporting gas to patient-connector 14 where it is introduced into the pulmonary air passages. Similarly, expiratory ventilating conduit 18 defines a gas flow path that may be used to transport exhaled or expiratory gas away from patient 12. Taken together ventilating conduits 16 and 18 comprise a ventilating circuit which, when connected with patient- connector 14 define a respiratory gas flow path. Arrows 58 illustrate the flow of gas through the system.

As with the majority of commercially available mechanical ventilators, mechanical ventilation system 10 relies on pressurized gas source 40 for pneumatic power. In conventional mechanical ventilators pressurized gas source 40 is provided by an external bulk gas delivery system (i.e. pressurized tanks) or an internal compressor (not shown) which pressurizes air from the surrounding environment. In either case, pressurized air enters mechanical ventilation system 10 through inlet conduit 38 and pressure regulator 36. Although air from the pressurized gas source is typically on the order of 50 lb/in², pressure regulator 36 reduces this to a working pressure of approximately 1.5 lb/in² prior to employing it in mechanical ventilation system 10. Following the reduction of pressure the gas enters the distal or upstream end of inspiratory ventilating conduit 16.

Ventilating conduits 16 and 18 are operably associated with conventional mechanical ventilator apparatus 20. By "operably associated" it is meant that gas flow and ventilation operations using conduits 16 and 18 may be controlled, monitored and effected by ventilator apparatus 20. To this end ventilator apparatus 20 comprises inspiratory sensor assembly 28 and expiratory sensor assembly 32 which monitor and control gas flow and/or gas composition through inspiratory ventilating conduit line 16 and expiratory ventilating conduit line 18 respectively. Among other data, sensor assemblies 28 and 32 provide real time information regarding gas composition, temperature, pressure and flow rate. Accordingly, gas entering inspiratory ventilating conduit 18 is monitored by inspiratory sensor assembly 28. Based on the readings, gas injector 30 may be signaled or manually set to introduce oxygen or other gases to the gas flow path defined by inspiratory ventilating conduit 18. Transfer lines 52, 54, 56 provide gas injector 30 with access to external sources of oxygen, nitrogen or other selected gases. Those skilled in the art will appreciate that gas injector 30 may operate using preprogrammed instructions or may be controlled by ventilator apparatus 20 based on information from sensor assemblies 28 and 32 or using preset values.

Gas flow and pressure through conduits 16 and 18 is physically controlled through inspiratory flow valve 48 and optional expiratory flow valve 46 which are opened and closed based on preprogrammed instructions and information received from sensor assemblies 28 and 32. Those skilled in the art will appreciate that flow valves 46 and 48 may comprise any of a number of different types of valves including solenoid valves, digital solenoid valves and full-range proportional valves. As will be described below, flow valves 46 and 48 will be manipulated to provide the desired wave form and pressure for ventilation. Passing downstream through inspiratory flow valve 48 the inspiratory gas may be modified by humidifier 26 which introduces vapor to the gas flow path. As with gas injector 30, humidifier 26 may be controlled by preprogrammed instructions manual settings or by ventilator apparatus 20. The inspiratory gas, now containing adequate oxygen and water vapor is then transported along the gas flow path through one arm of patient- connector 14 and into patient 12. Optional inspiratory check valve 22 may be provided to ensure the directional travel of the inspiratory gas.

Following introduction of the inspiratory gas into the pulmonary air passages (not shown) of patient 12 under positive pressure, ventilation is effected upon distribution of the gas in the lungs to promote gas exchange and oxygenation. Those skilled in the art will appreciate that the fresh oxygen from the inhaled inspiratory gas crosses the alveoli and enters the blood while waste gases (carbon dioxide, etc.) are excreted from the body. As previously alluded to, a respiratory promoter (preferably comprising a fluorochemical) may be present in the pulmonary passages of patient 12 to facilitate the uptake of oxygen and excretion of waste gases. While oxygen passes into the bloodstream, waste gases simultaneously collect in the lungs. As previously discussed this introductory period is known as the inspiratory phase of the breathing cycle. During the lull between the introduction of gases, the lungs are typically allowed to return to ambient pressure and deflate due to tension on pulmonary passages from surrounding tissue. This contraction of the lungs and corresponding reduction in lung volume forces accumulated gases and vapors, collectively known as expiratory gas or gases, from the lungs. In the case of traditional gas ventilation the exhaled expiratory gas will comprise unused oxygen and waste gases including carbon dioxide. When a respiratory promoter has been introduced into the lung of the patient, such as when performing PLV, the exhaled gas will typically comprise vaporized respiratory promoter in addition to unrespired oxygen and waste gases.

The spontaneous contraction of the lungs forces the exhaled gas into patient-connector 14, preferably sealingly connected to patient 12. Unidirectional inspiratory check valve 22 prevents the expiratory gas from substantially entering inspiratory ventilating conduit 16. Instead the expiratory gas is directed through unidirectional expiratory check valve 24 into expiratory ventilating conduit 18. As will be described more fully below, the expiratory gases may be sampled, or pass through, detector 60 which is associated with expiratory ventilating conduit 18.

From here the expiratory gas travels along the gas flow path defined by expiratory ventilating conduit 18, through optional flow control valve 46, and into ventilator apparatus 20. Optionally, the expiratory gas may be passed through conventional filter 50, positioned anywhere along expiratory ventilating conduit 16, wherein pathogenic organisms and other undesirable material may be removed from the expiratory gas. After entering ventilator apparatus 20 the gas flow path passes through sensor assembly 32 wherein data may be gathered regarding the composition and flow of the expiratory gas as well as the breathing cycle. Those skilled in the art will appreciate that the schematic representation of the sensors and detector apparatus in Fig. 1 are exemplary only and that any sensors employed in ventilator apparatus 20, including those compatible with the present invention may collect the desired information using any effective means. Passing through ventilator apparatus 20 in the gas flow path defined by expiratory ventilating conduit 18 the expiratory gas proceeds through outlet conduit 42 and is vented into the surrounding environment through exhaust aperture 44. Unfortunately, any respiratory promoter exhaled by the patient is also vented necessitating replacement to effectively continue the therapeutic regimen. Preferably, detector 60 is associated with expiratory ventilating conduit 18. By associated with, it is meant that detector 60 is in observational communication with expiratory gases passing through expiratory ventilating conduit 18. The observational communication may or may not comprise physical contact with the expiratory gases. In the illustrated schematic embodiment, detector 60 is connected to processor 66 by cables 62 and 64. Those skilled in the art will appreciate that cables 62 and 64 are exemplarly only and merely provide for communication between detector 60 and processor 66 and, for example, may comprise wires, fiber optics, coaxial cable, etc. Preferably cables 62 and 64 will carry the output signal from the detector to the processor and instructions from the processor to the detector. The processor may be any computer or microprocessor in an integrated, stand alone or network configuration with the detector and having the appropriate data storage capacity and input capabilities. In a preferred embodiment the processor will be a personal computer having an Intel 80486 microprocessor or will be integrated into the detector. Regardless of the form, the processor preferably calculates the desired values based on the output signal from the detector and transmits them to the desired display or output.

As indicated above, preferred embodiments of the invention comprise a spectroscopic detector that analyzes at least a portion of the electromagnetic spectrum to determine the presence of a compound. Particular preferred embodiments comprise an infrared spectrophotometer which analyzes a single predetermined wavelength. One such instrument compatible with the invention is the Specific Air Monitor (SAM-I, General Analysis Corporation, South Norwalk, Conn.) infrared analyzer which has a wavelength range of from 1 to 20 μm. Typically, the IR detector will have a continuum source of radiation with an interference filter that only allows transmission of a selected wavelength. Thus, in accordance with the present invention the SAM-I may be equipped with narrow bandpass interference filters for a wavelength which is strongly absorbed by the compound of interest. For example, the detector may be configured to only transmit at a wavelength corresponding to the C-F stretch wavelength of approximately 1250 cm^'1 (8 μm). This radiation will be strongly absorbed by fluorochemical compounds that typically have a number of these bonds. Similarly, the path length of the optical cell may be configured and sized to provide the optimal signal for the concentration range being tested. With regard to the present invention, one would expect the concentration range to be on the order of milligrams/liter for liquid ventilation applications and on the order of micrograms/liter for measuring the excretion of an intravenously injected oxygen carrier. In the preferred embodiment of the invention used for the Examples below, the cell path length was 1 cm. It will be appreciated that optimization of the detection wavelength and path length will provide a relatively sensitive detector that can provide extremely accurate measurements of the amount of vaporized compound in a gaseous sample. During operation, radiation at the selected wavelength is preferably transmitted through an optical cell. When the sample cell is empty of compounds which absorb at the radiated wavelength, the full radiant power of the source is registered by the detector and converted to an output signal for further processing. As the concentration of absorbing sample increases in the sample or optical cell, there is a corresponding decrease in the amount of radiant energy registered by the detector which, in turn, provides a different output signal than that of the empty detector. More particularly, the logarithm of the ratio of the two registered signals is proportional to the absorbing sample concentration. Of course these output signals may be processed using means well known in the art to provide a single concentration value. In this regard the SAM-I provides two electronic functions for linearization and calibration which are set by the user to obtain readings that are linear with respect to sample concentration in whatever units are desired. Common techniques for calibrating the instrument and providing linearization data are completely compatible with the instant invention and may be derived without undue experimentation.

As will be discussed in more detail in Example 3 below, knowledge of the vaporized respiratory promoter concentration in the exhaled gas allows for the calculation of the volume of respiratory promoter left in the lung. Specifically, the measured concentration of respiratory promoter (in mg/ml) may be multiplied by the rate of ventilation (in L/min) and the time (min) over which the concentration measurement was taken to provide the evaporative loss rate. The obtained value can then converted to units of ml from units of mg by dividing by the density of the respiratory promoter.

It will be appreciated that the dose of respiratory promoter remaining in the lungs after a known initial fill and a period of PLV may be computed by subtracting the cumulative evaporative loss from the initial dosing volume. For these calculations the cumulative loss over time may be tallied by keeping a log of respiratory evaporative losses during predetermined time intervals. Based on these calculations the data may be presented in any form or units desired such as % saturation of expiratory gases, mole fraction, ml of liquid respiratory promoter lost per liter, % FRC volume remaining, etc.

In preferred embodiments of the invention both the inlet and outlet lines to the detector will be heated above body temperature to ensure that condensation does not take place and produce erroneous readings. It must be emphasized that the detector does not have to placed in line with the expiratory ventilating conduit but may sample the exhaled gas periodically. For example, the detector may be connected in series to the expiratory conduit using sample conduits. The gaseous sample is then pumped from the expiratory conduit into the cell where the reading is obtained. The cell may then be voided by pumping the gas back into the conduit and recalibrated if desired. For other embodiments the cell may continuously be filled with the expired air. In either case the sampling pump may be run at approximately 1-2 L/min. Alternatively, the sample cell may be placed in line and monitored continuously. As illustrated by a preferred embodiment of the invention shown in Fig. 1, the disclosed methods and apparatus may be used in conjunction with conventional ventilation systems to markedly improve ventilation procedures incorporating the pulmonary administration of a respiratory promoter. That is, while not required to practice the invention, respiratory gas exchange may be maintained by continuous positive pressure ventilation using a conventional ventilator. By "continuous positive pressure ventilation" is meant positive pressure mechanical ventilation, often with positive end- expiratory pressure, that may be accomplished by any standard positive pressure ventilator. Either volume regulated, time- cycled respirators or pressure-limited time-cycled respirators are compatible with the instantly disclosed processes and apparatus. Examples of commercially available ventilators that are compatible with the present invention include, but are not limited to. Servo 900C (Seimens Elema, Shaumburg, III.), Infant Star (Star Products, San Diego, CA), Bear 1,2,3 (Bear Medical, Browns, CA), Puritan-Bennett 7200, (Puritan-Bennett Corp., Carlsbad, CA) Baby Bird 2 (Bird Corp., CA), and the Healthdyne Infant Ventilator. Of course, the disclosed methods and apparatus are entirely compatible with procedures involving the pulmonary administration of a respiratory promoter in the absence of a ventilator.

Performing PLV in accordance with the present invention may comprise the administration of very low doses (on the order of .005 ml/kg or less) of respiratory promoter preferably incorporating the desired fluorochemical or combination of fluorochemicals. Essentially, a therapeutically effective amount comprises enough to form a thin coating on a portion of the lung. Preferably the volume should be substantially equivalent to about 0.01 % to about 100% of the normal pulmonary functional residual capacity (FRC) of the host. By "pulmonary functional residual capacity" is meant the volume of space in the pulmonary air passages at the end of expiration. That is, the amount of breathing liquid used for partial liquid ventilation may approximate the volume of air remaining in a healthy lung of similar size following exhalation, or alternatively, that volume plus the volume of the endotracheal tube. It will further be appreciated by those skilled in the art that preferred volumes may be within certain ranges. Thus, selected embodiments of the invention include administration of fluorochemical of 0.01-1 %, 0.01-10%, 1 % -10%, 1-20%, 5-50%, 10-70%, 50-75%, 50-100% and 75-100% of the host's pulmonary FRC, calculated using standard methods known in the art. Of course the recited ranges are approximations only and the amount of introduced breathing liquid may fluctuate beyond the recited ranges during therapy. In practice the actual volumes will depend on the treatment protocol, the weight and size of a patient, as well as the lung capacity. Delivery of fluorochemical to a single lobe (unilateral) or local portion (lobar, segmental) is also contemplated.

In a particularly preferred embodiment of the present invention the desired amount of fluorochemical is administered to the lung prior to the ventilation system comprising a detector, or vapor detector, is attached. Respiratory therapy is begun, preferably with positive pressure ventilation, with the atmosphere in the lung quickly becoming saturated with vaporized breathing liquid. Preferably, the process is monitored by sensors in the ventilation system and the detector is used to control the amount of respiratory promoter added to the pulmonary passages to maintain the desired volume. Following completion of the therapy the system is removed and the respiratory promoter is typically allowed to evaporate. In another preferred embodiment, the aforementioned process is carried out without the preliminary administration of fluorochemical to the lung. Rather the respiratory promoter is added to the ventilation system, preferably in a nebulized or vaporized form, following connection with the patient. Preferably the respiratory promoter will be added upstream of the detector, i.e. into patient-connector 114. Again the pulmonary environment reaches substantial equilibrium that may be easily maintained by small additions of material from a nebulizer or gas injector. This method is particularly preferred for PLV involving the pulmonary introduction of respiratory promoter at volumes less than functional residual capacity of the patient. As discussed above, PLV may be undertaken using any respiratory promoter which provides the desired pulmonary therapeutic response. Preferably, the respiratory promoter is a breathable liquid in the form of a fluid, aerosol, vapor or mist. More preferably however, PLV will be performed using a breathing liquid comprising a fluorochemical. Particularly preferred embodiments employ fluorochemicals that are liquid body temperature although possessing a vapor pressure that allows them to evaporate from the lung over time. By "fluorochemical" is meant any fluorinated carbon compound with appropriate physical properties of biocompatibility. These properties are generally met by fluorochemicals having low viscosity, low surface tension, high solubility for oxygen and carbon dioxide making them able to readily promote gas exchange while in the lungs. For example, it is preferred that the fluorochemical have at least 3 or 4 carbon atoms and/or that its vapor pressure at 25°C is less than 760 Torr. That is, it is preferable that the fluorochemical is a liquid under ambient conditions. The fluorochemical may be made up of atoms of carbon and fluorine, or may be a fluorochemical having atoms other than just carbon and fluorine, e.g., bromine or other nonfluorine substituents or sulfur hexafluoride. Those skilled in the art will appreciate that the range of compatible fluorochemicals is substantially broadened by the present invention which allows pulmonary levels to be accurately monitored.

More particularly, one of the major advantages of the present invention is that the incorporation of a detector allows the extended therapeutic use of fluorochemicals that were previously too volatile to use effectively. With the present invention, relatively high vapor pressure fluorochemicals may be used effectively as their rate of loss by evaporation is effectively monitored. That is, the incorporation of detectors capable of monitoring the rate of evaporation in ventilation systems allows for the efficient dosing of oxygen carrying compounds including relatively volatile fluorochemicals. Accordingly, steady pulmonary levels of these fluorochemicals are rapidly reached and easily maintained using the ventilation systems described herein.

Representative fluorochemicals useful in the present invention include bis(F-alkγl) ethanes such as C₄F₉CH = CH₄CFg (sometimes designated "F-44E"), i-C₃F₉CH = CHC₆F₁₃ ("F-i36E"), and C₆F₁₃CH = CHC₆F₁₃ ("F-66E"); cyclic fluorochemicals, such as C10F18 ("F-decalin", "perfluorodecalin" or "FDC"), F-adamantine ("FA"), F- methyladamantane ("FMA"), F-1,3-dimethyladamantane ("FDMA"), F-di-or F-trimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated amines, such as F-tripropylamine("FTPA") and F-tri-butylamine ("FTBA"), F-4-methyloctahydroquinolizine ("FMOQ"), F-n-methyl-decahydroisoquinoline ("FMIQ"), F-n-methyldecahydroquinoline ("FHQ"), F-n-cyclohexylpurrolidine ("FCHP"), perfluorooctyl hydride and F-2-butyltetrahydrofuran ("FC-75" or "RM101 "). Brominated fluorochemicals compatible with the teachings herein include 1-bromo-heptadecafluoro-octane (C₈F₁₇Br, sometimes designated perfluorooctylbromide or "PFOB"), 1-bromopenta-decafluoroheptane (C₇F₁₅Br), and 1-bromotridecafluorohexane (C₆F₁₃Br, sometimes known as perfluorohexylbromide or "PFHB"). Other brominated fluorochemicals are disclosed in US Patent No. 3,975,512 to Long. Specific fluorochemicals having chloride substituents, such as perfluorooctyl chloride (n-C₈F,₇CI), 1,8-dichloro-F-octane (n-CIC₈F,₆CI), 1,6-dichloro-F-hexane (n-CIC₆F,₂CI), and 1, 4-dichloro-F-butane (n-CIC₄F₈CI) are also preferred.

Also contemplated are fluorochemicals such as perfluorooctyl chloride, dichlorofluorooctane, , and similar compounds having different numbers of carbon atoms.

Additional fluorochemicals contemplated in accordance with this invention include perfluoroalkylated ethers or polyethers, such as (CF₃)₂CF0(CF₂CF₂)₂0CF(CF₃)₂, (CF₃)₂CF0-(CF₂CF₂)₃0CF(CF₃), (CF₃)CF0(CF₂CF₂)F, (CF₃)₂CFO(CF₂CF₂)₂F, (C₆F₁₃)₂0. Further, fluorochemical-hydrocarbon compounds, such as, for example, compounds having the general formula C„F₂„₊rC„.F_2n.₊₁, C„F_2n+ιOC_nF_2n.₊,, or C„F_2n+lCF=CHC_n.F_2n.₊₁, where n and n' are the same or different and are from about 1 to about 10 (so long as the compound is a liquid at room temperature). Such compounds, for example, include C₈F,₇C₂H₅ and C₆F₁₃CH=CHC₆H,₃.

It will be appreciated that esters, thioethers, and other variously modified mixed fluorochemical-hydrocarbon compounds are also encompassed within the broad definition of "fluorochemical" liquids suitable for use in the present invention. Mixtures of fluorochemicals are also contemplated and are considered to fall within the meaning of "fluorochemicals" as used herein. Additional fluorochemicals contemplated are those having properties that would lend themselves to pulmonary gas exchange including FC-77, Hostinert 130, APF-145, APF-140, APF-125, perfluorodecalin, perfluorobutyl-tetrahydrofuran, perfluoropropyl-tetrahydropyran, dimethyl-adamantine, trimethyl-bicyclo-nonane, and mixtures thereof.

Still other fluorochemicals compatible with the present invention include cyclic fluorochemicals such as perfluoroperhydrophenanthrene, perfluorotetramethylcyclohexane (AP-144) and perfluoro n-butyldecalin. Still other useful fluorinated compounds include perfluorophenanthrene, perfluoromethyldecalin, perfluorodimethylethylcyclohexane, perfluorodimethyldecalin, perfluorodiethyldecalin, perfluoromethyladamantane and perfluorodimethyladamantane.

Those skilled in the art will appreciate that the detectors described herein may be positioned anywhere in fluid conducting communication with the gas flow path. That is they do not have to be placed immediately proximate of the Y- connector. Specifically, selected embodiments (not shown) of the present invention may use a plurality of vapor detectors, operating in concert to effect particularly accurate readings. When used in concert, the detectors preferably monitor different aspects of the exhaled respiratory promoter such as absorption at different wavelengths. it must be emphasized that the embodiments of the invention employing a ventilation system comprising a mechanical ventilator are exemplary only and do not, in any way, limit the scope of the subject matter disclosed herein. More specifically, those skilled in the art will appreciate that the disclosed methods and apparatus are entirely compatible with ventilation techniques that do not use a mechanical ventilator. For example, a spontaneously breathing patient may be fitted with a mask or other patient-connector comprising a detector in accordance with the present invention. Yet, in this case the detector assembly would not be a component of a mechanical ventilation system but rather would introduce and discharge inspiratory and expiratory gases directly into the surrounding environment. In particular, at least one respiratory promoter would be introduced into the lungs of a naturally respiring patient.

A mask or other patient-connector comprising a detector would be fitted so as to establish fluid conducting communication with the pulmonary air passages. Upon exhalation expiratory gas comprising vaporized respiratory promoter would be forced from the lungs and pass through the patient-connector to a space associated with a detector. As the warm expiratory gas passes through the vapor detector at least a portion of the expiratory gases comprising vaporized respiratory promoter is sampled by the detector. The exhaled gas then passes from the detector or detector sampling apparatus into the surrounding atmosphere to conclude the expiratory phase of the breathing cycle. At the start of the inspiratory phase the lungs expand to draw in breathing gas from the environment. Note that, in this embodiment, no ventilator is required to force air into the lungs of the patient. Of course it will be appreciated that additional respiratory promoter may be added periodically, or more preferably based on or as a result of, the readings obtained from the detector to maintain the desired pulmonary levels. Such methods are particularly useful for treatments conducted outside a hospital critical care setting such as in emergency situations or in the home.

The present invention is not limited to methods of performing liquid ventilation. In particular, the disclosed methods and apparatus provide for the independent delivery of pharmaceutical agents or their use in conjunction with other vapors or liquids such as respiratory promoters. Moreover, the devices and methods of the present invention may be used for the therapeutic administration of pharmaceutical agents in conjunction with spontaneous breathing or mechanical ventilation. In particular, combining pharmaceutical dosing regimens with liquid ventilation therapy has a number of advantages over other forms of drug delivery. The fiuorochemical-enhanced delivery can be used for medicaments that would otherwise be ineffective or destroyed by systemic delivery. For example, those skilled in the art will appreciate that proteins usually cannot be administered orally because they are destroyed in the alimentary tract. Some proteins may invoke severe allergic reactions and shock in the host if administered through systemic routes such as intramuscularly or intravenously.

In particularly preferred embodiments antibiotics, antivirals and chemotherapeutic agents may be provided in combination with a fluorochemical liquid during partial liquid ventilation. As an example of such treatments it is well known that the pathogenic cytomegalovirus can induce life-threatening cases of pneumonia in immunocompromised patients. These individuals often require ventilation therapy to stay alive. The administration of a respiratory promoter, particularly a fluorochemical, in combination with the guanosine nucleoside analog, 9-(1,3-dihydroxy-2- propoxymethyDguanine, otherwise known as Ganciclovir or DHPG, may provide an effective therapy that could simultaneously inhibit viral replication and facilitate oxygen transport in the compromised lung. Preferred pharmaceutical agents for use in the present invention comprise respiratory agents, antibiotics, antivirals, mydriatics, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, cardiovascular agents, active principles, nucleic acids, genetic material, immunoactive agents, imaging agents, immunosuppressive agents, etc. and combinations thereof.

The precise amount of pharmaceutical agent administered in conjunction with the methods and devices of the present invention is dependent upon the agent of choice, the required dose, and the form of the drug actually introduced. For the purposes of the present invention, the drug will preferably be administered to the lungs in the form of a reverse emulsion having a fluorocarbon continuous phase or in the form of a particulate dispersion comprising a fluorocarbon suspension medium. Those skilled in the art will appreciate that such determinations may be made by using well-known techniques in combination with the teachings of the present invention.

In addition to enhanced drug delivery, liquid mediums such as fluorochemicals can be used to remove endogenous or foreign material from the interior of the lungs in accordance with the present invention. Because fluorochemicals are oxygenatable, they provide oxygen to the person during the treatment allowing for longer and less dangerous lavage procedure. The density of fluorochemical liquids is generally twice that of water and body tissue which permits the fluorochemical to sink below and displace the material to be removed. Thus, when the fluorochemical is removed by mechanical means well known in the practice of lavage, the displaced material will float and be removed simultaneously. These properties are particularly important when lavage is combined with liquid ventilation-enhanced drug delivery as a complete treatment of, for example, a patient with cystic fibrosis whose lungs accumulate excess mucinous secretions. In this embodiment the methods and systems of the present invention may be used to monitor residual fluorochemical evaporation from the lung.

The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of preferred methods of practicing the present invention and are not limiting of the scope of the invention or the claims appended hereto.

Example 1 Partial Liquid Ventilation of Swine Swine (20-50 kg) were anesthetized, intubated, placed on a positive pressure gas ventilator (tidal volume = 13 mL/kg, respiratory rate = 12-14/min, positive end expiratory pressure [PEEP] = 5 cm H₂0, Fi0₂ = 1.0), and instrumented for measurement of hemodynamics and lung mechanics. Following stabilization and paralysis, animals were filled intratracheally with LiquiVenl® (Alliance Pharmaceutical Corp., San Diego, CA) through a sideport adapter on the endotracheal tube. The dosing regimen and body positioning during PLV depended on the specific experimental protocol (described below). Example 2

Measurement of the Concentration of Perfluorooctyl Bromide Vapor in Expiratory Gases of Swine Undergoing Dosing for PLV An infrared-based Specific Air Monitor (SAM-I, General Analysis Corporation, South Norwalk, Conn.) was customized to measure perflubron vapor in air up to and above 270 mg/L, which is the concentration of gas saturated with PFOB vapor at 37°C. The device was calibrated using the ideal gas law to be linear and to read out directly in mg of PFOB per L of air. Expiratory gas (waste gases plus water vapor and PFOB vapor) was sampled from the expired limb of the ventilatory circuit via tubing which connected in series to the device and was heated to prevent condensation. The sample cell was also heated to approximately 60°F to prevent condensation with the sample pump running at about 2 L/min. During the instillation of the respiratory promoter for PLV, the concentration of PFOB vapor in the exhaled gas was measured continuously and recorded at periodic intervals.

Two sets of measurements were made and recorded as follows:

• n - 2 pigs with incremental dosing of 25, 50, 75, and 100% of FRC

• n = 2 pigs with incremental dosing of 10, 20, 30, ... 100% of FRC The results of the measurements are shown in Figure 2. In general there was a dose-dependent linear increase in

PFOB concentration with incremental dosing up to ^" 0.6 FRC dose. Complete lung filling was achieved within an hour so there was no appreciable evaporative loss during the experiment. The shaded box highlights the range of PFOB doses corresponding to the dosing levels used to generate the evaporation curves discussed in Example 4 (Fig.4).

Example 3 Determination of Pulmonary Respiratory Promoter Volume Based on

Measured Concentrations of Fluorochemical Vapor in Expiratory Gases of Swine A single pig was dosed with perfluorooctyl bromide as described in Example 1 to an initial FRC of 0.33%. The concentration of fluorochemical vapor in the exhaled gases were then measured over time using the infrared spectrophotometer described in Example 2. From these measurements the volume of PFOB evaporating from the lungs during PLV was calculated from the equation:

PFOB evaporative loss = C_PF0B • V_E • Δt Eqn. [1]

where V_E is the rate of ventilation (in L/min) and Δt is the time (in min) over which the concentration measurement (C_PFOB) was taken. The value was converted to units of mL from units of mg by dividing by the density of PFOB (1.92 g/mL - 1920 mg/mL).

The dose of respiratory promoter remaining in the lungs after a known initial fill and a period of PLV was computed from the equation:

Computed residual PFOB dose =

Initial PFOB Dose - Cumulative PFOB evaporative loss Eqn. [2]

with the cumulative loss over time tallied by keeping a log of PFOB evaporative losses during 5-30 min time intervals. The results of these calculations and the measurements are shown in Figure 3. More particularly, Figure 3 shows the C_PF0B response over time after an initial PFOB dose of 0.33 FRC (10 mL/kg for a pig). Using Eqn. [1], the evaporative loss during consecutive measurement points was calculated. The residual PFOB dose in the lungs during evaporation as computed from Eqn. [2] is shown in terms of mL/kg at the top of the graph (for reference, 0.10 FRC = 3 mL/kg). Example 4

Determination of Residual Pulmonary Respiratory Promoter Volume Based on Measured Fluorochemical Vapor in Expiratory Gases Seven swine were dosed with perfluorooctyl bromide as described in Example 1 to an initial FRC of 0.33%. The concentration of fluorochemical vapor in the exhaled gases were then measured over time using the infrared spectrophotometer described in Example 2. More particularly the pigs were dosed as follows:

• n = 2 pigs, dosing and PLV in supine position

• n = 5 pigs, dosed with half of volume on each side, supine position for PLV

X-rays were taken post dosing to qualitatively assess PFOB distribution in the lungs. The respiratory rate was increased to 20/min and the PEEP increased to 10 cm H₂0 (in all but one animal) to enhance PFOB evaporation. PLV was performed for a period of 6-10 hours to achieve significant reduction in residual PFOB dose in the lungs. Residual respiratory promoter volume was calculated as described in Example 3. The results are illustrated in Figure 4 where open symbols represent results from 20 kg pigs and the closed symbols represent results from 40-50 kg pigs.

As seen in the Figure, there is a gradual linear decrease in C_PF0B as a function of residual PFOB dose. The overall slope of the evaporative curves is shallower than the dosing curves over the 0.2 to 0.3 FRC range of PFOB doses and the Cp_f0B is significantly greater (compare to highlighted box in Figure 2). There is a trend for the curves to become steeper at PFOB doses between 0.10-0.15 FRC. This suggests there is a rapid loss of PFOB surface area, possibly due to previously PFOB-filled lung sections becoming "dry". The cross and triangle closed symbols are animals that were dosed supine and the open circle symbol is the animal who did not have PEEP increased. The rate of PFOB evaporative loss for the large pigs with normal lungs (no injury) was approximately 1.1 mL/kg/h. Example 5

Effects of Body Position and Dosing Volume on the Concentration of Respiratory Promoter in Expiratory Gases Several pigs were dosed with perfluorooctyl bromide as described in Example 1 to various initial volumes. Dosing was undertaken with the animals in either a supine position or with the respiratory promoter administered to both the right and left sides of the lungs. The concentration of fluorochemical vapor in the exhaled gases were then measured over time using the infrared spectrophotometer described in Example 2. The results of these measurements are shown in Table 1 immediately below. Table 1

As shown in the table, the C_PF0B values are greater with larger lung doses of respiratory promoter and there is no apparent change over 5 h for the 0.5-1.0 initial FRC dose. In the low dose animals (0.33 FRC) after 1 h PLV, C_PF0B is greater if dosing was done on each side possibly due to improved distribution in the lung. X-rays confirmed more PFOB in non-dependent lung regions as compared to these regions in animals dosed supine. The rate of PFOB evaporative loss is proportional to C_PF0B.

Those skilled in the art will further appreciate that the present invention may be embodied in other specific forms without departing from the spirit or central attributes thereof. In that the foregoing description of the present invention discloses only exemplary embodiments thereof, it is to be understood that other variations are contemplated as being within the scope of the present invention. Accordingly, the present invention is not limited to the particular embodiments which have been described in detail herein. Rather, reference should be made to the appended claims as indicative of the scope and content of the invention

Claims

WHAT IS CLAIMED IS:

1. A process for determining the concentration of a vaporized oxygen carrying compound in exhaled gas from pulmonary air passages of a mammal comprising the steps of: interrogating said exhaled gas with a dectector capable of perceiving said oxygen carrying compound whereby said detector provides an output value representative of the concentration of oxygen carrying compound entrained in said exhaled gas; and determining the concentration of the oxygen carrying compound in the exhaled gas based on the output value.

2. The process of claim 1 further comprising the step of collecting said exhaled gas in a ventilating conduit prior to interrogation.

3. The process of claim 1 wherein said oxygen containing compound is a respiratory promoter.

4. The process of claim 1 wherein said oxygen containing compound is a fluorochemical.

5. The process of claim 1 wherein said oxygen containing compound in said exhaled gas is derived from an emulsion administered intravenously to the mammal prior to the interrogating step.

6. The process of any of claims 1 to 5 wherein said oxygen carrying compound is perfluorooctyl bromide.

7. The process of claim 1 further comprising the step of calculating the evaporative loss of said oxygen contining compound from the pulmonary air passages based on the concentration of said oxygen containg compound in said exhaled gas.

8. The process of claim 1 further comprising the step of providing said exhaled gas by effecting positive pressure ventilation of said mammal.

9. The process of claim 7 further comprising the step of effecting positive pressure ventilation using a mechanical ventilator.

10. The process of claim 1 further comprising the step of providing said exhaled gas by spontaneous respiration of said mammal.

11. The process of claim 1 wherein said detector is a spectroscopic detector

12. The process of claim 11 wherein said spectroscopic detector is an infrared absorption detector.

13. A process for performing partial liquid ventilation, comprising: introducing a respiratory promoter into the pulmonary air passages of a respiring patient, whereby vaporized respiratory promoter becomes entrained in gas exhaled by said patient; associating an exogenous detector with said pulmonary air passages so that exhaled gas from the patient is perceptible to said detector; interrogating at least a portion of said exhaled gas with said detector whereby the concentration of said vaporized respiratory promoter is determined; calculating the evaporative loss of respiratory promoter based on said determined concentration; computing the volume of said respiratory promoter remaining in said pulmonary air passages; and administering additional respiratory promoter to the pulmonary air passages of said patient based on said computed volume.

14. The process of claim 13 wherein said respiratory promoter is a fluorochemical.

15. The process of claim 14 wherein said fluorochemical is a liquid at body temperature.

16. The process of claim 13 further comprising the step of effecting positive pressure ventilation of said patient.

17. The process of claim 16 further comprising the step of effecting positive pressure ventilation using a mechanical ventilator.

18. The process of claim 13 wherein said patient is undergoing spontaneous respiration.

19. The process of claim 13 wherein said patient suffers from a disorder selected from the group consisting of respiratory distress syndrome, lung contusion, chronic lung injury, acute lung injury, diver's lung, post- traumatic respiratory distress, post-surgical atelectasis, irritant injuries, septic shock, multiple organ failure, Mendelssohn's disease, obstructive lung disease, pneumonia, pulmonary edema and combinations thereof.

20. The process of claim 13 wherein said detector is a spectroscopic detector

21. The process of claim 20 wherein said spectroscopic detector is an infrared absorption detector.

22. A system for performing partial liquid ventilation comprising: a patient-connector capable of establishing fluid conducting communication with pulmonary air passages of a patient; a ventilating circuit sealingly affixed to said patient connector and defining a gas flow path capable of transporting an inspiratory gas into the pulmonary air passages and removing subsequently generated expiratory gases; a vaporized respiratory promoter dispersed in said gas flow path; and a detector associated with said gas flow path whereby said detector is capable of determining the concentration of said vaporized respiratory promoter.

23. The system of claim 22 further comprising a mechanical ventilator operably associated with said ventilating circuit.

24. The system of claim 22 wherein the dispersed respiratory promoter is in a form selected from the group consisting of vapors, mists, suspensions, aerosols and combinations thereof.

25. The system of claim 22 wherein said respiratory promoter is a fluorochemical.

26. The system of claim 22 wherein said detector is a spectroscopic detector

27. The system of claim 26 wherein said spectroscopic detector is an infrared absorption detector.

28. The system of claim 22 further comprising a processor associated with said detector.

29. A process for determining the concentration of a vaporized respiratory promoter in gas from pulmonary air passages of a mammal comprising the steps of: introducing a respiratory promoter into pulmonary air passages of a respiring patient whereby vaporized respiratory promoter becomes entrained in gas exhaled by said mammal;; associating an exogenous detector with said pulmonary air passages so that exhaled gas from the patient is perceptible to said detector; and interrogating at least a portion of said exhaled gas with said detector whereby the concentration of said vaporized respiratory promoter is determined.