Perfluorocarbon associated gas exchange.

Description: TECHNICAL FIELD [Detailed description of the invention]

Technical field The present invention provides breathing methods and devices including means for inhaling breathing gas under positive pressure in an attempt to maintain respiratory gas exchange in a perfluorocarbon-filled pulmonary airway. Conventional technology The present invention primarily relates to well-known mechanical and liquid ventilation techniques. A mechanical switch is a clinical device that creates an air flow to the lungs. Generally, a metered positive pressure ventilator or a metered positive pressure ventilator is used for respiratory assistance during intensive care. This type of device forces air into the lungs during inspiration but returns to atmospheric pressure during spontaneous exhalation. In a metered ventilator, a preset tidal volume is inhaled to the patient regardless of the pressure required to inhale the deep inhalation volume. In pressure-controlled ventilators, the maximum inspiratory pressure is limited because it is measured by the console. Also, in general, breath O₂Various controls are made to select the mixture, inspiratory and exhalation time, and ventilation cycle. There are several companies that manufacture and sell such conventional respiratory organs. Liquid ventilation is a radically different technique involved in the method of temporarily filling the pulmonary airways with an oxygenated fluid medium. This was first demonstrated in 1962 when mammals submerged in hyperoxygenated saline successfully inhaled fluid and resumed gas respiration (1; see attached citation). However, a sufficient amount of O₂Is practically difficult to dissolve in saline (even at high pressures), and saline flushes away much of the surfactant on the surface of the alveoli, leading to liquid ventilation (LV). The road has been virtually closed (2). This problem was resolved in 1966 by biochemist Leland Clark, the first person to assist the respiration of mice, cats and puppies using a perfluorocarbon solution (currently oxygenated at atmospheric pressure). (3). Perfluorocarbon (PFC) solutions can be derived from ordinary organic compounds by substituting fluorine atoms for all (ie, substantially all) carbon-bonded hydrogen atoms to achieve the objects herein. This liquid is colorless and transparent, odorless, nonflammable and basically insoluble in water. PFC fluid is denser than water and soft cells, has lower surface tension, and is usually less viscous. Perfluorocarbon liquid is unique in that it has a high affinity for gas, and it has more than 20 times more O than water.₂And more than triple CO₂Dissolve. Like other highly inert fluorocarbons, perfluorocarbon solutions are completely non-toxic and biocompatible. See (4) for an overview. Looking back, it was clearly demonstrated that mammals can breathe oxygenated perfluorocarbons (&gt; 3 hours) for extended periods of time (&gt; 3 hours) and return to gas breathing for extended periods of time without adverse effects (5, 6). Another study also found that there were no morphological, biochemical, or histological side effects after perfluorocarbon respiration (7, 8). Studies of lung lavage (cleansing) using perfluorocarbon solution have also been conducted (9) and have been shown to be effective in irrigation of congestive substances involved in adult respiratory distress syndrome (RSD) in humans (10). .. Although it cannot be said that the side effects of total respiratory support in both lungs by the perfluorocarbon solution are not eliminated, such effects are generally insignificant transient (slow acidosis, low blood pO).₂, Increased pulmonary vascular resistance, decreased pulmonary compliance) (11-14). Some biomedical uses of perfluorocarbon solution respiration have important findings (15, 16). High fever of lung cancer due to conversion with ultrasound and / or perfluorocarbon solution has also been reported (17). In particular, perfluorocarbon fluid respiration appears to be useful in the treatment of respiratory distress syndrome, including surfactant deficiency and dysfunction. Increased alveolar surface tension plays an important role in the pathophysiology of immature respiratory distress syndrome (RDS) (18, 19) and may contribute to pulmonary dysfunction in adult respiratory distress syndrome (20). Perfluorocarbon solution respiration is effective in surfactant-deficient immature animals because it eliminates the air / fluid interface of the lung and significantly reduces the surface tension of the lung (11). Liquid ventilation can be achieved with safe alveolar pressure without adversely affecting cardiac output (21), and even extremely immature animals can perform exceptional gas exchange (23). It has also been reported that a human clinical trial of perfluorocarbon solution breathing was successful in extremely immature infants suffering from RDS (24). There is also literature on potential clinical uses of liquid ventilation and obstacles to applying liquid ventilation to clinical trials (25). In liquid ventilation, perfluorocarbon solution is oxygenated outside the body to remove carbon dioxide, and in test respiration of this liquid, inhalation into the lungs and exhalation from the lungs are mechanically repeated using a research device. I want you to remember. Unfortunately, such extracorporeal liquid ventilators are not commercially available. In addition, it is currently discouraging because there is no safe fallback assist system to protect patients in the unlikely event that liquid ventilation should be stopped suddenly. In addition, since perfluorocarbons are periodically inhaled into the lungs after oxygenation and carbon dioxide removal outside the body, a large and expensive starting amount of perfluorocarbons is required to fill the liquid ventilator. These operational shortcomings and safety issues severely constrain the widespread use of liquid ventilation techniques that would otherwise be promising. Disclosure of invention The present invention solves the above-mentioned drawbacks by providing a perfluorocarbon-mediated gas exchange method that is mechanically different from continuous positive pressure breathing and liquid ventilation. The central method involves the introduction of a perfluorocarbon solution into the pulmonary airways of a mammalian host in an amount substantially equivalent to the functional residual capacity of the host's lungs. The respiratory gas exchange in the pulmonary airways filled with perfluorocarbon solution is then maintained (eg, for 1 hour or longer) by continuous positive pressure breathing using a well-known gas exchanger (ventilator). After this procedure, the perfluorocarbon solution is vaporized from the pulmonary airways. The data shown below show that perfluorocarbon-mediated gas exchange is a method of respiration and gas exchange that is substantially as effective as continuous positive pressure respiration in healthy piglets. In addition, perfluorocarbon-mediated gas exchange is an appropriate gas exchange at an airway pressure comparable to that of volume-adjusted continuous positive pressure respiration. Like liquid ventilation, perfluorocarbon-mediated gas exchange offers great benefits in the treatment of surfactant deficiency or dysfunction, but in perfluorocarbon-mediated gas exchange, extracorporeal oxygen addition is also perfluorocarbon "liquid inhalation" lungs. Also does not require periodic inhalation into. Therefore, it is not necessary to improve the research instrument in advance in order to perform perfluorocarbon liquid therapy for various disorders and diseases including detergent deficiency in the lungs. In addition, the airway pressure required to achieve perfluorocarbon-mediated gas exchange is greater than the airway pressure required to perform liquid breathing, as it is primarily the gas, not the liquid, that moves cyclically with each breath. Quite low. Therefore, the possibility of pressure damage to the pulmonary airways is reduced. The results also show that the lung time constant (the product of airway resistance to fluid flow time compliance) is much smaller when perfluorocarbon-mediated gas exchange is performed than when liquid breathing is performed. Therefore, the patient can be ventilated more quickly when the perfluorocarbon-mediated gas exchange is performed than when the liquid breathing is performed, and the ventilation time can be significantly extended. Finally, backup gas exchangers suitable for perfluorocarbon-mediated gas exchange are readily available in the general clinical environment, reducing safety issues associated with mechanical device failures and the like. A brief description of the drawing Figure 1 is a videotape of the respiratory cycle during perfluorocarbon-mediated gas exchange, with both lungs virtually aspirated at the end of exhalation (Figure 1A) but at the end of inspiration (Figure 1B). ) Indicates that the air bubble oxygen is substantially added. FIG. 2 is a diagram showing an example of a system for implementing the present perfluorocarbon-mediated gas exchange method. FIG. 3 is a diagram showing an example of a PAGE adapter for adjusting the fluid flow rate by switching between perfluorocarbon-mediated gas exchange and continuous positive pressure respiration. Figures 4A and 4B show other examples of adapters for repeated perfluorocarbon-mediated gas exchange and continuous positive pressure breathing. FIG. 5 is a diagram showing an example of a PAGE device for maintaining a functional residual liquid amount during PAGE treatment. FIG. 6 is a pressure / volume characteristic diagram of an air-filled lung (white circle) and a perfluorocarbon-filled lung (black circle). FIG. 7 is a diagram comparing an example of the flow rate / volume relationship during continuous positive pressure respiration (white circle) and perfluorocarbon-mediated gas exchange (black circle). FIG. 8 is a diagram comparing the exhalation time and exhalation volume during continuous positive pressure respiration (white circles) and perfluorocarbon-mediated gas exchange (black circles). 9A and 9B are diagrams showing two possible bubble growth patterns within a perfluorocarbon fluid-filled alveoli. Best mode for carrying out the invention In the past, it was almost unthinkable that the gas could be forcibly inhaled into the lungs filled with liquid, and that the gas could be exhaled almost completely from the lungs before the liquid was also exhaled. However, this specification describes such a respiratory assist method and its effective use in healthy piglets, referred to as perfluorocarbon-mediated gas exchange (PAGE). A large amount of perfluorocarbon solution, which corresponds to the amount of functional residual air in the lungs under normal conditions, was injected into the trachea and "foamed oxygen was added" in vivo for several hours in the lungs, which are directly involved in gas exchange. Surprisingly, this could be done using a well-known gas exchanger. Simply put, this respiratory gas exchange maintenance method is a step of introducing (or less) an amount of perfluorocarbon solution into the lung airways of a mammalian host, which is substantially equivalent to (or less) the amount of functional residual air in the lungs of the host's normal lungs. And; with the step of maintaining respiratory gas exchange in the pulmonary airways filled with perfluorocarbon fluid by continuous positive pressure breathing during the treatment time (eg, within 1 hour or more); vaporizing the perfluorocarbon fluid from the pulmonary airways. Includes steps and; This perfluorocarbon-mediated gas exchange method offers the advantages of both liquid ventilation and continuous positive pressure breathing. Liquid ventilation with oxygenated perfluorocarbon eliminates surface tension at the pulmonary air / fluid interface and improves lung function and gas exchange during deficiency of surfactants. In liquid ventilation, perfluorocarbons are oxygenated to remove carbon dioxide, and research equipment is used to repeatedly inhale and recall the fluid into the lungs. On the other hand, perfluorocarbon-mediated gas exchange uses well-known gas exchangers such as those used in continuous positive pressure breathing. As will be explained in detail later, a large amount of perfluorocarbon corresponding to the normal functional residual air volume (30 ml / kg) is injected into the left trachea of 13 healthy piglets and metered gas respiration (FIO).₂= 1.0) was applied. Over 1 hour, perfluorocarbons were continuously bubble oxygenated in the lungs, which is directly involved in gas exchange. From the results obtained, arterial PaO₂And PaCO₂Was found to average 401 ± 51 and 40 ± 4 torr (53.6 ± 6.8 and 5.3 ± 0.5 kPa). Maximum airway pressure when perfluorocarbon-mediated gas exchange (22 ± 2 cm H in 1 hour)₂O) and during continuous positive pressure breathing (23 ± 4 cm H)₂O) was almost equal. Intravenous oxygen saturation and pH were normal (73 ± 8% and 7.43 ± 0.05 at 1 hour). Perfluorocarbon-mediated gas exchange was uniformly well within the permissible range, resulting in near continuous positive pressure breathing. These results show that the application of perfluorocarbon breathing techniques to lung disease is no longer constrained by existing machinery and problems associated with periodic fluid flow. In the present specification, "method of maintaining respiratory gas exchange" refers to arterial pO.₂And pCO₂Means a means to bring the value as close to the normal value as possible. This is O in cells throughout the body₂And CO₂Means a proper exchange of. The primary purpose of perfluorocarbon-mediated gas exchange is to ensure such proper gas exchange. If gas exchange can be carried out reliably, it is possible to determine the patients suffering from the disease by excluding unnecessary morbidity and mortality. Arterial pO when assisting gas exchange₂It is preferable to maintain at about 80 torr or more, and the arterial pCO₂Is preferably maintained at about 60 torr or less. Obviously, the value achieved is the normal value (pO)₂= 100, pCO₂The closer you are to = 40), the more satisfying your clinical condition will be. PO in newborns₂Excessively high oxygen causes post-lens growth and blindness, so it is advisable to reduce the oxygen fraction during perfluorocarbon-mediated gas exchange to prevent excessive oxygen tension, as in the well-known continuous positive pressure respiration. "Respiratory airway" means the respiratory passage, space, and volume of a normally air-filled trachea, left and right bronchioles, bronchioles, and alveoli. "Mammalian host" includes humans and means mammals such as immature lambs, piglets, rabbits, cats and dogs for research and veterinary purposes. The perfluorocarbon solution aids in (a) bubble oxygen addition during the inhalation phase of the PAGE cycle (see below) and (b) minimal foam formation during the expiratory phase of the PAGE cycle and the resulting liquid loss. It shall include all fluorocarbon compounds having suitable physical properties. Such requirements are mainly met by low viscosity, low surface tension, low vapor pressure perfluorocarbons. Of course, O₂It is also necessary to have high solubility in. The "perfluorocarbon liquid" may be composed of only carbon and fluorine atoms, or may be a fluorine compound containing atoms such as bromine in addition to carbon and fluorine. Typical perfluorocarbon solutions that can be used for perfluorocarbon-mediated gas exchange are FC-75, FC-77, RM-101, Hostelert 130, APF-145, APF-140, APF-125, perfluorodecanoic acid, perfluorooctanoic acid, Perfluorobutyl tetrahydrofuran, perfluoropropyltetrahydropyran, perfluorodimethyladamantan, perfluorotrimethylbincrononan, mixtures thereof and the like. Preferred perfluorocarbons are (a) average molecular weight of about 350 to about 570; (b) viscosity at 25 ° C less than about 5 centipoise (cp); (c) boiling point of about 55 ° C or higher; (d) at 25 ° C. Steam pressure of about 5 to about 75 torr, more preferably about 5 to about 50 torr; (e) Density of about 1.6 to about 2.0 gm / cm³(F) It is characterized by a surface tension of about 12 to 20 dyne / cm (when air is included). The perfluorocarbon solution is introduced primarily into the pulmonary airways at least 10-15 minutes after pure oxygen respiration. Perfluorocarbon may be introduced via endotracheal intubation by simply injecting a liquid into the endotracheal intubation between breaths, as is well known, or by inhaling this liquid under pressure as is done during liquid breathing. May be good. The volume of perfluorocarbon fluid introduced into the pulmonary airways is preferably substantially equal to the host's normal pulmonary functional residual capacity (FRC). "Functional residual air volume of the lungs" means the space capacity in the pulmonary airways at the end of exhalation. This FRC capacity changes with lung dilation during perfluorocarbon-mediated gas exchange. Filling the functional residual volume with perfluorocarbon (a) maintains the functional residual volume during exhalation and prevents surface tension-induced alveolar closure; (b) removes carbon dioxide during exhalation. Clarifies the need for alveolar air involvement in gas exchange by "bubble oxygenating" the alveolar perfluorocarbon storage; (c) for bubble formation and bubble expansion from the beginning to the end of exhalation. Provides a medium with low surface tension; (d) The surface tension can be reduced along most of the surface of the alveoli coated with perfluorocarbon in the inner layer of the alveoli. Prevent the barometric pressure disturbance associated with the liquid breathing technique described above without exceeding the patient's FRC, and ensure proper gas exchange by adding bubble oxygen. PAGE treatments based on inhalation of less than 1 FRC (eg, 3/4 FRC or 1/2 FRC) of perfluorocarbon solution are also considered herein. It is also possible to perform unilateral (unilateral) or topical (leaf, segmental) PAGE treatments, such as PAGE drug-added drug injections into specific parts of the patient's lung airways. According to the description herein, respiratory gas exchange in such a perfluorocarbon-filled pulmonary airway is maintained, preferably by continuous positive pressure breathing using a well-known respiratory system. "Continuous positive pressure breathing" means positive pressure mechanical breathing that can be performed with a standard positive pressure respirator, usually using positive end-expiratory positive pressure breathing. A metered-rate periodic respirator or a pressure-restricted periodic respirator is suitable. This type of respirator is commercially available. Servo 900C (Siemens Flema, Shammburg, IL); Infant Star (Star Products, San diago, CA); Bear 1,2,3 (Bear Medical, Bowings, CA) Baby Bird 2 (Bird Corp., CA); Healthdyne Infant Ventilator; Airshields and more. As will be described later, the combination of bubble oxygen addition, gas impulse separation from perfluorocarbon to alveolar blood vessels, and respiration / perfusion matching during perfluorocarbon-mediated gas exchange is greater than gas exchange during continuous positive pressure respiration. It is not close. "Bubble oxygenation" means well exposing the bubbles to equilibrium between the bubbles and the liquid. In this state, the liquid is oxygenated and carbon dioxide is removed from the liquid. When inhaling, a large amount of inhalation is forcibly inhaled into the lungs, and a tremendously large branch of the airway (10)²³) To form small bubbles in the millions of terminal alveoli so that bubbles are formed substantially uniformly throughout the lung. Referring to FIG. 1, a black-and-white photograph (created from color videotape) of the respiratory cycle during perfluorocarbon-mediated gas exchange shows the addition of bubble oxygen. The dark tones (ie colors) of the perfluorocarbon fluid-filled lungs at the end of exhalation (Fig. 1A) can be clearly contrasted with the light tones (ie colors) of the air-filled liquid-filled lungs during inspiration (Figure 1B). Following the perfluorocarbon-mediated gas exchange procedure, the perfluorocarbon solution is removed from the pulmonary airways. A suitable method for this particular purpose is simply to vaporize perfluorocarbons from the pulmonary airways. Continued gas breathing without additional perfluorocarbon injection (to maintain functional residual capacity) completely vaporizes from the lungs to virtually low within a few hours (determined by the vapor pressure of perfluorocarbon). To do. For certain purposes (discussed below), liquid breathing of perfluorocarbons is periodically repeated, inhaled into and expelled from the pulmonary airways during the treatment period. More specifically, this perfluorocarbon-mediated gas exchange (PAGE) method can be used effectively with a simpler respiratory assist system by eliminating continuous periodic fluid flow and extracorporeal gas exchange. Can be done. With reference to FIG. 2, an exemplary system 10 suitable for this purpose is the movement of fluid between a well-known gas exchanger 12, a PAGE device 14 for processing perfluorocarbon fluid, and the patient's lung airways 18. Equipped with a PAGE adapter 16 that enables The PAGE device 14 is basically for injecting a predetermined amount of perfluorocarbon into the patient's lung airway 18 via the PAGE adapter 16. The gas exchanger 12 is for ventilating the perfluorocarbon-filled pulmonary airways 18. The PAGE adapter 16 is a means of repeating the liquid mobile phase and the gas ventilation phase of treatment. The PAGE device 14 repeats (a) inhalation of perfluorocarbon into the lungs (and excretion from the lungs as needed); (b) functions during perfluorocarbon-mediated gas exchange treatment, eg, at the end of each liquid-circulating breath. Reconstruct the appropriate amount of residual fluid; (c) Control the process of connecting liquid breathing under the control of a PAGE device and breathing by a gas exchanger; (d) Inject fluid into the pulmonary airway 18. Oxide perfluorocarbons to remove carbon dioxide; (e) perform the process of inhaling perfluorocarbons into the lung airway 18 first if necessary; (f) recirculate the fluid into the lung airway 18 Purify the previously decomposed perfluorocarbons; (g) Adjust the temperature of the perfluorocarbons; (h) Measure the pressure and flow rate in the perfluorocarbon conduits of the PAGE device 14 and / or PAGE adapter 16; (i) Various Obtain various physiological measurements; (j) Function to properly process the input from the console and the output from the computer. The PAGE adapter 16 mechanically performs (a) the process of linking liquid circulation (PAGE device) and gas exchanger (perfluorocarbon-mediated gas exchange) respiration under the control of PAGE device 14; (b) PAGE device 14 Allows mechanical recovery of proper functional residual fluid volume in the pulmonary airway 18; (c) Physically interlocking two liquid transfer devices (gas exchanger 12 and PAGE liquid transfer device 14) And function to apply this perfluorocarbon-mediated gas exchange method most effectively. The use of such a system 10 (PAGE device 14, PAGE adapter 16 and gas exchanger 12) can be exemplified by the following treatment protocols. In suitable patients, perfluorocarbons are injected into the pulmonary airways 18 as described in the examples below or by using the PAGE device 14 and the PAGE adapter 16. Perfluorocarbon-mediated gas exchange is generally an important method for assisting respiratory gas exchange during the treatment period. The gas exchanger 12 inhales a single volume of gas into the perfluorocarbon-filled lung 18 as determined by the console of the gas exchanger 12. This gas oxygenates perfluorocarbons and removes carbon dioxide with each breath in its original position, the in vivo lung airways 18. Repeat this process. Referring to FIG. 3, the valves 20 in the PAGE adapter 16 provided at intervals on the operation table of the PAGE device 14 move left and right to exchange gas from the extracorporeal tube 22 leading to the patient's lung airway 18. The vessel 12 is disconnected or the gas exchanger port 24 is opened to the atmosphere. At the same time, the valve 20 allows the fluid to communicate between the PAGE device 14 and the patient's lung airways 18. Perform one or more PAGE device controlled liquid breaths to achieve one or more of the above mentioned objectives of the PAGE device 14. Subsequently, the valve 20 of the PAGE adapter 16 is moved (by the signal supplied from the PAGE device 14), the PAGE device 16 is disconnected, and the PAGE device 16 is recommunicated with the gas exchanger 12 to continuously assist the gas exchange. This cycle (communication between the lung airway 18 and the gas exchanger 12 and then to the PAGE device 14 and the gas exchanger 12 in that order) is repeated sequentially by the computer of the PAGE device 14 in response to the instruction from the console. You may. The illustrated PAGE adapter 16 is a Y-conduit for perfluorocarbon, air, respiratory gas, and exhaled gas. Adapter 16 rotates two upper wings (PAGE device conduit 26 and gas exchanger conduit 28), a low dead space common chamber 30, a hinged valve 20 with a twisted stem 32, and a twisted stem. It is equipped with a switch mechanism (not shown) that moves to reciprocate the valve 20. The gas exchanger conduit 28 is essentially short (to minimize dead space) and allows the movement of gas between the respirator 12 and the common chamber 30. This gas conduit 28 is reversibly sealed on the reciprocating end of the hinged valve 20 by, for example, a pad 34, when the valve 20 and the gas exchanger 12 are engaged, with the valve 20 and the PAGE device 14. May include an opening or port 24 that is open when the gas is engaged. The common chamber 30 basically has a lower dead space and is locked to the distal hub 36 of the patient's extracorporeal tube 22. The common chamber 30 has two other outlets, 36 of which lead to the gas exchanger conduit 28 and 38 to the PAGE device conduit 26. The common chamber 30 can reversibly communicate with either the gas outlet 36 or the liquid outlet 38 by the valve 20. The valve 20 is in the form of a hinged valve 20 mounted with a twisted stem 32 as shown. When the stem 32 is rotated, the valve 20 rotates and engages the orifices 36, 38 of the conduit 28 or 26. Each PAGE device conduit 26 contains three channels leading from the orifice 38 of chamber 30 to the port of PAGE device 14. These channels (a) air from PAGE device 14 to common chamber 30 via channel 40; (b) perfluorocarbon influx (to the patient) from PAGE device 14 to common chamber 30 via channel 42. (C) The perfluorocarbon effluent is to be supplied directly from the common chamber 30 to the PAGE device 14 via the channel 44. The PAGE device 16 described above is merely an example, and for example, the fluid control valve means 20 can be in the form of a well-known rotatable channel valve 20'as shown in FIG. 4A, as shown in FIG. 4B. Sliding piston channel valve 20 may be used. Referring to FIG. 5, the exemplary PAGE device 14 has three ports into which the distal ends of channels 40, 42, 44 from the PAGE adapter conduit 26 have been inserted, and fluid through channels 40, 42, 44. A storage room with a pump and valve to regulate the flow, a computer with a clock, a device and a connector for processing perfluorocarbon, an oxygen (or air-fuel mixture) source port, a console, and a PAGE adapter. It includes a control cable for operating the valve 20, an input channel and an output channel, and an auxiliary electronic device for collecting data used by the computer and driving each component of the system 10. Port 46 couples the inflow channel 42, which transfers perfluorocarbon from the PAGE device 14 to the common chamber 30 of the PAGE adapter 16, with the PAGE device 14. This port 46 is connected to the perfluorocarbon storage chamber 50 by a pump 48. The pump 48 is controlled by the computer 54 via the output link 52 according to the instructions of the console 56. The inflow pump 48 sends a predetermined amount of perfluorocarbon to the port 46 at a predetermined time. The pressure at this port is measured by the input link 58 to the computer and is continuously monitored. The second port 60 connects the outflow conduit 44 from the common chamber 30 with the perfluorocarbon storage chamber 50 of the PAGE device 14 by a pump 62. Perfluorocarbons return to the storage chamber through this port 60. The interlocking pump 62 is controlled by the computer 54 via the output link 52 according to the instructions of the console 56, and returns a predetermined amount of perfluorocarbon to the port 60 in a predetermined time. The pressure at this port 60 is measured by the input link 58 to the computer and is continuously monitored. The third port 64 couples the PAGE device 14 and the air channel 40 to and from the common chamber 30. The port 64 allows air to flow into the common chamber 30 during a predetermined time segment of the PAGE device cycle. The computer 54 sets the maximum pressure at which air can pass through channel 40 through the one-way air valve 66 and port 64. By connecting the three ports 46, 60, 64 with the pumps 48, 62 and valve 66 connected to them, the PAGE device 14 can restore functional residual fluid volume at the end of liquid circular breathing. .. When the air valve 66 is closed, the outflow pump 62 removes the perfluorocarbon fluid from the pulmonary airways 18 by negative pressure (preset by the console 56 and computer 54). When air is free to flow into the common chamber 30 of the PAGE adapter 16 through port 64, the PAGE device 14 removes perfluorocarbons expelled from the common chamber 30 by passive recoil of the lungs and thorax. Only do. For example<img file="JP2606994B2_D0001.tif" />In this representative example, the pump 48 connected to the inflow port 46 inhales 60 ml of perfluorocarbon into the pulmonary airways 18. A pump 62 connected to the outflow port 60 removes 40 ml of perfluorocarbon from the pulmonary airway 18 in 6-10 seconds. Lung recoil sends the difference between functional residual capacity (at atmospheric pressure) and lung volume at a clock time of 10 seconds to common chamber 30 in the next 6 seconds. Since it is not possible to create a "vacuum" in which the pump 62 sucks the liquid faster, the speed is the same as the speed at which the liquid can be transferred by reaction, that is, the air valve 66 is opened and the difference is made at the 10 ml / sec set for the pump 62. The volume is removed by the outflow pump 62. The difference between the set pump flow rate and the rate at which perfluorocarbons can be sent to the common chamber 30 by lung recoil is caused by the influx of air at the set (atmospheric) pressure. A respiratory tachometer (not shown) may be placed at air port 64 to ensure that functional residual capacity has been reached. With the air valve 66 open and no lung recoil, the velocity set for the pump 62 is equal to the inflow velocity to the air port 64. In this way, the PAGE device 14 can easily monitor and recover the functional residual quantity (FRC). On the other hand, this is a complicated problem in liquid breathing because a large amount of liquid must be injected into the lungs and removed from the lungs every minute. The amount of fluid handled by the PAGE device 14 is extremely small, the volume to be purified is small, the amount of liquid to be heated is small, and there is no need to continuously load the patient to monitor the FRC. The computer 54 of the PAGE device 14 collects the following inputs. That is, (a) the setting values for the timing and flow velocity of the three ports set on the operation table for the pump and valve; (b) the circulation timing of the PAGE adapter valve 20 set on the operation table; (c) the three ports. Inputs from pressure and flow sensors related to; (d) Physiological measurements signals such as esophageal pressure; (e) Inputs from sensors related to storage chamber operation. The output of the computer is (a) timed and operated the pump and air valve in the PAGE device 14; (b) timed and operated valve 20 of the PAGE adapter 16; (c) all measurements. And the calculated value are notified to the meter of the operation console, and an auxiliary output data port (not shown) is used to notify an external computer or a hard copy recording device located away from the device 14. The storage chamber 50 stores perfluorocarbon, adds bubble oxygen to obtain a preselected oxygen fraction, adjusts the temperature to a physiologically or therapeutically necessary range, and purifies and purifies the decomposed perfluorocarbon. , Serves the function of tracking the loss of liquid volume from the system. The console 56 allows the operator to set the parameters for operating the PAGE device 14 and the PAGE adapter 16; (b) interprets the significant output from the computer and displays it for human response. (C) It functions to emit a warning sound when the measured parameter exceeds the limit set for the operation of the PAGE device 14. In order to achieve perfluorocarbon-mediated gas exchange using a well-known gas exchange 12, PAGE adapter 16, and PAGE device 14, the operating range of the following parameters is a typical example. The gas exchanger 12 interacts with the patient for up to 95% of the time and at least 75% of the time. The gas exchanger 12 operates at a minimum of 5 breaths per minute and a maximum of 40 breaths per minute. Maximum pressure is 15 cmH₂O to 60 cmH₂In the range of O, probably 25 cmH₂O degree would be ideal. The oxygen fraction of the PAGE device 14 or switch 12 is at least 21% and at most 100%. The tidal volume delivered to the extracorporeal tube 22 of the well-known exchanger breathing is a minimum of 6 ml / breath and a maximum of 18 ml / breath. Positive end-expiratory breathing (PEEP) may or may not be required with the well-known exchanger 12. Ideally PEEP 5cmH₂It should be O or less, but PEEP is up to 20 cmH when performing perfluorocarbon-mediated gas exchange treatment.₂Up to O is possible. The PAGE device 14 interacts with the patient sequentially during one liquid breath or several (eg, 3 or 4) liquid breaths. Atmospheric pressure or plus or minus 10 to 20 cmH from atmospheric pressure₂It is also possible to open the air valve 66 of the PAGE device 14 with a pressure of about O. The system 10 described herein may be provided with condensing means (not shown) to collect and recirculate perfluorocarbon vapors. Perfluorocarbon solutions are biologically inert and non-toxic, especially in their pure form, suitable for direct infusion into the pulmonary airways, but are dangerous in the presence of perfluorocarbon vapors in the surrounding environment. Although this fact has been ignored in most liquid ventilation research history, the amount of vaporization loss of perfluorocarbons is extremely high (10-20% of the functional residual capacity per hour is about 400 in adult PAGE treatment. (Equivalent to the amount of vaporization loss to the environment at ~ 800 gm / hour), so it is closely related to the implementation of PAGE therapy. The reasons why perfluorocarbon vapor is dangerous are, for example, high temperature light sources, lit cigarettes, bare flames, ovens, incandescent electrical elements, electric arcs (such as those used in common motors), When it comes into contact with a general heat source such as an electric surgical device or a surgical laser, it decomposes and becomes a dangerous by-product. The most typical degradation products are perfluoroisobutene (PFIB) and hydrogen fluoride (HF). The properties of highly corrosive and toxic HF are well known. Since PFIB boils at 7 ° C, it exists as a gas mixed with the atmosphere in the clinical environment. Inhalation of extremely low concentrations of PFIB, about 0.5 parts / million, can be fatal in some cases, even for a few hours. Even with proper room temperature recirculation and ventilation to significantly reduce the toxic concentration before and after the PAGE process, the production of potential toxic emissions in the neighborhood is itself a worthy cause. In addition, perfluorocarbon solutions are extremely expensive, so when PAGE treatment is performed on a patient for a long time (for example, a few hours or more), the vaporized perfluorocarbon solution is recovered and reused in the same patient during treatment. There is a good reason to do it. Thus, condensing and recovering vaporized perfluorocarbon losses from both the lungs and the PAGE device while ventilating with a single flow rate of gas is a safe and economical motivation. This condensing function can be performed in the effluent vapor condensing module, similar to the function of reintroducing condensed perfluorocarbon vapor into the PAGE device. This device ventilates both the outflow gas / vapor mixture flowing out of the PAGE device and the exhaled gas / vapor flow from the patient by a gas exchanger (before the mixture is ventilated into the atmosphere). Incorporate while. The exhaled mixture is either (a) the outlet of the connector near the proximal end when using passive exhalation or (b) the exhaled flow of the gas exchanger (if the exhaled gas is actually expelled through the gas exchanger itself). Pumped to the module from one of the outlets of. The condensing module may be integrated with the PAGE device 14 or used as an accessory to be attached to the gas exchanger 12. Perhaps the flow from the proximal point of the exhalation flow near atmospheric pressure or slightly positive pressure would have to be incorporated into a condensing module connected to the patient's exhalation tube (during passive exhalation). Patients should not be "loaded" in the sense that pumping the gas / vapor mixture creates significant airway resistance during exhalation. This alone also allows the module to "drain" the mixture through a check valve from a ventilated high pressure close to atmospheric pressure (collecting the breath mixture just outside the patient). Such discharge, that is, suction of fluid may be performed by using a vacuum pump or the like. In order to meet the requirements for patient reuse of perfluorocarbons during extended treatment periods, the condensing module (a) periodically at regular intervals and (b) detection of the module's perfluorocarbon storage chamber. Based on the minimum accumulated amount, the perfluorocarbon solution stream is pumped into the PAGE device storage chamber 50 by either (c) continuous pumping. The return pumping of such perfluorocarbons is controlled by the PAGE computer 54. The PAGE method simplifies the oxygen addition mechanism and the carbon dioxide purification mechanism to provide a preferred gas exchange method suitable for respiratory application of perfluorocarbon technology. This PAGE method can reduce the problem of "ventilation" for one of the air movements. This is a problem that has not come to mind with conventional liquid breathing techniques that require a relatively large amount of fluid to be injected into or drained from the lungs. Conventional liquid breathing requires the movement of such a large amount of fluid per minute because the fluid must be infused and expelled from the lungs almost continuously at relatively high airway pressure. Therefore, the safety limits of conventional liquid breathing are narrow and their flexibility is also limited. Even if the distal airways and alveoli are in a very low pressure state, the proximal airways are in a high inspiratory pressure state. The PAGE method described here reduces the risks associated with such proximal airway pressure problems, greatly increases the flexibility of liquid breathing techniques, and simplifies the problem of adjusting the functional residual air volume of the lungs. To do. PAGE can be applied more extensively and flexibly than the examples described above, as the use of PAGE may simplify the respiratory mechanism and reduce respiratory movements in the affected lung. This includes intermittent command breathing (IMV), intermittent demand breathing (IDV), high cycle jet breathing (HFJV), high cycle oscillating breathing (HFOV), pressure support breathing (PSV), and airway pressure release during PAGE. Inhale gas into the fluid-filled lung or gas from the lung by mechanical breathing modules such as breathing (APRV), continuous positive pressure breathing (CPAP), and various variants and modifications of other clinically beneficial forms of mechanical breathing assistance. It is useful for achieving mechanical movements such as calling. In addition, it is understandable that by reducing the instantaneous breathing movements of patients suffering from lung disease, it is possible to achieve PAGE safely and effectively by allowing patients to breathe momentarily after infusion of fluid. Yeah. This embodiment according to the present invention is particularly preferable in terms of minimizing the incidence and severity of secondary lung disorders (barometric pressure disorders in the lungs). By simplifying the gas exchange problem when applying perfluorocarbon breathing techniques, the PAGE method makes the process of recirculating perfluorocarbons, removing decomposition products from perfluorocarbons and adjusting the temperature even more effective. It can be done easily with a simple device. The PAGE process can be performed using the PAGE adapter 16 and PAGE device 14, but this process also partially changes the priority of selecting the most suitable liquid for liquid breathing techniques. The PAGE device itself is suitable for respiratory applications of liquids other than perfluorocarbons. Therefore, the fluid can be selected with the surface tension and the viscosity at the time of sending bubbles as the main criteria, and the solubility of oxygen and carbon dioxide as secondary. Chemicals that are not well known for liquid breathing may be effective vehicles on the PAGE. For example, low water content (eg a few percent to about 25% H)₂Perfluorocarbon emulsions (up to about O) are unsuitable for gas exchange by well-known liquid breathing, but are highly preferred as vehicles for PAGE that clean the degradation products and carry the drug. When using such weak water or saline emulsions, the critical factor appears to be the presence of perfluorocarbons outside the aqueous phase, which is acceptable at exhalation if not outside the aqueous phase. External foam and liquid loss are likely to occur. This perfluorocarbon-mediated gas exchange method is effective in treating various disorders and diseases of the pulmonary airways. In particular, by limiting the maximum surface tension that must be eliminated when ventilating the lungs to the maximum surface tension of perfluorocarbon itself, perfluorocarbon-mediated gas exchange can be used for respiratory distress syndrome associated with surfactant deficiency and dysfunction. Functionally less severe throughout the duration of the procedure. The other clinical uses of the perfluorocarbon-mediated gas exchange method will be described below. PAGE includes lungs with surface active substance deficiency (premature infant respiratory distress syndrome), surface active substance dysfunction and capillary leakage syndrome (eg adult respiratory distress syndrome (ARDS), meconium aspiration syndrome, and various other acute lung diseases. ) Is a particularly beneficial method for lung ventilation. The use of PAGE for prophylactic purposes may prevent lung dysfunction due to, for example, ARDS, immune-mediated lung injury, lung irritation disorders, psychiokin-mediated disorders, endotoxin-mediated disorders, and other causes of lung disorders. .. By simplifying gas exchange during liquid breathing, PAGE uses perfluorocarbon products as a cleaning medium, such as meconium aspiration syndrome, alveolar proteinosis, life-threatening asthma, pancreatic cyst fibrosis, etc. Intrapulmonary debris associated with swallowing syndrome can be washed and removed. PAGE allows the lungs to be filled with a low surface tension perfluorocarbon solution for extended periods of time, allowing the use of perfluorocarbons to reduce the severity of lung disease and dysfunction in patients prone to APDS. Capillary leakage is a function of surface tension in the alveolar lining and can be significantly reduced in patients with the constant presence of perfluorocarbons. The surface tension of perfluorocarbon itself may be 10 to 20 dynes / cm, but the surface tension of the alveolar inner layer / perfluorocarbon interface should be as close as possible to 1 dyne / cm, and the surface tension of the alveolar inner layer in the absence of surface active substances should be as close as possible. It may be smaller than the normal surface tension. PAGE has many advantages over well-known gas breathing when resuscitating from cardiopulmonary arrest. Since liquid perfluorocarbons are not compressible, they can increase the rate of precordial pressure transfer to the stopped heart during CRP. PAGE has many advantages over standard resuscitation after falling into a variety of conditions characterized by hypothermia and cardiac arrest, including cold drowning. Perfluorocarbons can be used to warm the septum and central blood flow during PAGE using the PAGE device 14, so extracorporeal oxygenation (ECMO) and cardiac bypass are required in such cases. Can be prevented. Continuous treatment of perfluorocarbons, septal and cardiac temperatures can be achieved using the PAGE device 14. The PAGE method and system 10 can also be used for cooling and / or rewarming in the event of surgical hypothermia. This is of particular application in cardiac surgery. The PAGE method and system 10 may be used for cooling and / or rewarming during the treatment of head injuries and brain injuries. PAGE can be applied to the treatment or prevention of "decompression pain" as it provides an effective means of removing nitrogen bubbles from the blood after acute decompression from the depths. PAGE provides a safe alternative to well-known liquid breathing and can ensure the safety of this technology (against the potential for liquid breathing equipment failure). By using the PAGE adapter 16, even if a device failure should occur during the well-known liquid breathing, the safety of the well-known liquid breathing can be enhanced by surely performing the rapid infusion of PAGE. Since PAGE preferentially contains gas rather than single-flow liquid, it is effective in diseases characterized by a combination of airway obstruction and increased alveolar surface tension. ARDS is an example of such a disease. The PAGE Adapter 16 allows easy and intermittent use of well-known liquid breathing techniques by allowing the transition between well-known liquid breathing and PAGE-based gas breathing to be performed safely and conveniently. The PAGE device 14 and the PAGE device 16 work together to facilitate the maintenance of optimal lung functional residual capacity at the same value at all times. This enhances the safety of the breathing application of perfluorocarbon breathing and greatly simplifies the safe execution of the well-known liquid breathing process. PAGE facilitates mechanical respiration in the presence of cardiac pulmonary edema. This method can also slow down the rate of lung water accumulation during the presence of cardiac pulmonary edema. PAGE is preferably performed in System 10 described above and provides a means of "enhancing the heart" by reducing postcardiac load in patients suffering from congestive heart disease. Transferring the weight of perfluorocarbons to the epigastric during PAGE reduces postventricular afterload. PAGE is beneficial for re-dilation of the atelectasis area. This is especially valuable when re-inflating the collapsed lung area during extracorporeal oxygenation (ECMO). In fact, if the lungs are supported for an extended period of time when ECMO is present, PAGE is superior to well-known gas respiration because it suppresses the progression of barometric damage during lung healing and maintains alveolar and airway patency. ing. Prolonged presence of perfluorocarbon in the airways and alveoli during PAGE also alters the healing process of lungs with some disease or infected lungs and may prevent the progression of airway obstruction. is there. Prolonged presence of perfluorocarbon in the airways and alveoli can ameliorate immunological lung injury and irritable lung disease by suppressing the inflammatory process by the PAGE method and system 10. PAGE can be an effective adjuvant physiotherapy for infants suffering from neonatal persistent pulmonary hypertension by improving the stimulation of pulmonary vasoconstriction. PAGE provides a reservoir for relatively static perfluorocarbon fluids to provide a variety of pharmaceutical and pharmaceutical reagents and therapeutics, including surfactants, mucolytics and agents that alter the normal state of bronchial motility. Etc. can be effectively dispersed or left in their original positions. Drugs that can be used for this purpose include vasoactive substances such as epinephrine and norepinephrine, proteolytic enzymes used to break inhibition in pancreatic cystic adenomyosis, bronchodilators such as terbutaline and albuterol, steroids and others. Includes anti-inflammatory agents, cromarines, chemotherapeutic antibodies and therapeutic antibody reagents. PAGE also promotes gas dispersion in the lungs during inspiration and reduces the expansion pressure required to ventilate the lungs with inherently high surface tension, thereby reducing the incidence of pulmonary barometric damage during mechanical breathing. Can be reduced. Hereinafter, the present invention will be described in more detail by way of examples. Example Method and material The following studies were approved by the Animal Care and Use Committee of the Children's Hospital of Pittsuburgh in Pittsburgh. Animal care and handling followed NIH guidelines. From 3 to 21 days after birth, 13 piglets weighing 2.9 ± 0.6 kg were anesthetized with α-chlorarose (50 mg / kg) and paralyzed with metocrine iodide (0.3 mg / kg). The airway was secured by intubation following tracheal intubation, and the trachea was firmly fixed to the tracheal opening tube. Commercial switch (Servo 900C; Siemens Elema, Shaumburg, We performed metered continuous positive pressure breathing using IL). A femoral vein was incised and an arterial and central venous catheter was inserted for vascular pressure measurement and blood sampling. These measurements were interfaced to a fiber optic recorder (PPG Biomedical, Pleasantville, NY). The animals were tested in the supine position with the chest closed. Upon stabilization, 5 ml / kg of dextran (5% Gentran) was administered to achieve a right atrial pressure of 5-8 mmHg. Finely adjust the ventilation volume and PaCO at a breathing rate of 18 to 25 breaths / minute₂Was set to 30 to 45 torr (4 to 6 kPa). Inhalation is limited to 25% of the respiratory cycle, 2-5 cmH₂O End-respiratory positive pressure was applied. Oxygen in the lungs (FIO)₂ Ventilated with 1.0). Lung pressure / volume relationships were investigated for total tidal volume-related lung volumes in 5 piglets prior to perfluorocarbon-mediated gas exchange. Proximal airway pressure was continuously measured using a dry transducer. Sustained positive pressure breathing was stopped. The chest was allowed to secure a passive functional residual air volume at atmospheric pressure. Subsequently, 10 ml of air was used to inflate the lungs to 15 to 25 ml / kg, which is more than the functional residual air volume. 10 ml was recovered until the airway pressure dropped below atmospheric pressure, and degassing of the pressure / volume curve was measured in the same manner. In these same piglets, a respiratory tacometer (Hans Rudolph, Kansas City, MO) was placed between the respiratory tract and the tracheal opening tube to examine the expiratory flow / volume relationship during continuous positive pressure breathing and respiratory integration. Vessel (Hewlett Packard, Waltham, Interfaced to MA). Later, flow and volume were recorded simultaneously during continuous positive pressure breathing to construct a flow-capacity curve and an immediate (real-time) volume curve. All tests had a density of 1.75 g / ml, a viscosity of 0.66 cm stroke, a surface tension of 14 dynes / cm, a vapor pressure of 75 torr (10 kPa), oxygen and carbon dioxide solubility at 1 atm 56 and 198 ml gas / 100 ml perfluorocarbon (37 °). It was performed using FC77 (3M, St Paul, MN) which is C). FC77 is very similar to other perfluorocarbons that are immiscible with water and have a lung absorption rate that can be ignored. After achieving a stable state with continuous positive pressure respiration, arterial blood and venous blood were sampled, respiratory measurements were taken, and vascular pressure was recorded to obtain the data shown in the table below. FIO FC77 with a capacity of 30 ml / kg selected to be close to the normal functional residual air volume₂ Preoxygenated at 1.0, warmed to 37 ° C, and infused into the trachea over 30-60 seconds. Gas respiration of perfluorocarbon-filled lungs was performed (perfluorocarbon-mediated gas exchange) with the same respiratory settings used for continuous positive pressure respiration. Perfluorocarbon-mediated gas exchange was continued for 1 hour without changing respiratory settings. At the end of this time, 10-20 ml of FC77 needed to replace the vaporization loss and compensate for the change in functional residual air volume was added to the lungs and the perfluorocarbon at the standing outlet of the clear tracheal opening tube. The exhaled meniscus was maintained at atmospheric pressure. There was no time to excrete perfluorocarbons from the lungs. No other medicines or fluids were added. Blood measurements, breath measurements, and hemodynamic measurements were repeated 5, 15, 30, and 60 minutes after perfluorocarbon-mediated gas exchange. 60 minutes after the perfluorocarbon-mediated gas exchange, the pressure / volume and flow / volume were repeatedly examined (as described above) in the same piglet tested before the perfluorocarbon-mediated gas exchange, and gas-induced lung swelling. And the effect of perfluorocarbon injection on degassing was confirmed. Perfluorocarbons were not emitted until these measurements were made. Ventilation was interrupted to investigate static pressure / volume relationships after perfluorocarbon-mediated gas exchange. The perfluorocarbon-filled lungs were prepared to secure their residual air pressure at atmospheric pressure. No attempt was made to measure this functional residual volume or to compare the functional residual volume of perfluorocarbon-filled lungs with the functional residual volume during continuous positive pressure breathing. The perfluorocarbon meniscus was uniformly present on the clear standing axis of the airway opening tube. Proximal airway pressure was measured again continuously using a dry transducer. Subsequently, 10 ml of air was used to inflate the lungs to 15 to 25 ml / kg, which is more than the functional residual air volume. 10 ml was recovered until the airway pressure dropped below atmospheric pressure, and degassing of the pressure / volume curve was measured in the same manner. With the flow rate of air during the perfluorocarbon gas exchange (as described above) to later construct the flow rate-capacity curve and the immediate capacity curve to study the flow rate-capacity relationship during the perfluorocarbon-mediated gas exchange. The capacity was recorded at the same time. Subsequently, potassium chloride was administered with a large pill to kill the animal. After death, several piglets were selected and the sternum was incised and the right chest wall was resected. Postmortem ventilation was performed and the lung ventilation pattern during perfluorocarbon-mediated gas exchange was observed. The measurement results obtained repeatedly over 1 hour during perfluorocarbon-mediated gas exchange and the values measured during continuous positive pressure respiration were compared using analysis of variance. After this, the test results were Neuman-Keuls corrected for multiple comparisons. result Infusion of FC77 was extremely tolerant in all animals, with no extremely poor respiratory or hemodynamic results. Also, perfluorocarbon-mediated gas exchange was initiated without side effects. No side effects were seen during perfluorocarbon-mediated gas exchange in any of the animals. Gas exchange: PO at the start of perfluorocarbon-mediated gas exchange₂There was a significant decrease in the mean PaCO of each animal throughout the study period.₂Was stable (401 ± 51 torr (53.6 ± 6.8 kPa) and arterial blood was sufficiently saturated. The results are shown below.<img file="JP2606994B2_D0002.tif" /> Gas exchange during PAGE was substantially as effective as during CPPB. HCO₃^-The unit of is meq / 1. All values are mean ± SD (standard deviation), * p &lt;0.05 and ** p &lt;0.01 are for values at CPPB, which is ANOVA with Newman-Keuls correction for multiple comparisons. It is due to. PaCO during perfluorocarbon gas exchange (PAGE)₂PaCO measured during continuous positive pressure breathing (CPPB)₂It wasn't so different. The alveolar arterial oxygen partial pressure difference during perfluorocarbon-mediated gas exchange (after correction of perfluorocarbon vapor pressure) and during continuous positive pressure respiration was similar. Perfluorocarbon-mediated gas exchange did not cause metabolic acidosis. Respiratory parameters: Using metered breathing, we were able to compare high tidal volumes during perfluorocarbon-mediated gas exchange and continuous positive pressure breathing. The maximum pressure generated by constant volume respiration during continuous positive pressure respiration and perfluorocarbon-mediated gas exchange was comparable. Static inspiratory terminal pressures before and during perfluorocarbon-mediated gas exchange (PAGE) are also comparable, and these calculated inspiratory resistance and thoracic compliance are comparable to those measured during sustained positive pressure respiration (CPPB). there were. The results are shown below.<img file="JP2606994B2_D0003.tif" /> The lung mechanisms at PAGE and CPPB were substantially equal. Pmax = maximum airway pressure, Pei = static inspiratory terminal positive pressure breathing, Paw = average airway pressure, all in cmH₂It is O. ETV = effective tidal volume (ml) sent to the animal. Total thoracic compliance calculated as Ct = ETV / (Pei-PEEP), in units of ml / cmH₂It is O. Raw = (Pmax-Pei) / Inspiratory terminal airway resistance calculated as flow rate, in cmH₂O / 1 / sec. All values are mean ± SD. * p &lt;0.05 and ** p &lt;0.01 are for values at CPPB and by ANOVA with Newman-Keuls correction for multiple comparisons. Pressure-volume relationship: Within the tidal volume range, FC77 was present in the lungs to consistently change the pressure-volume relationship. Regardless of the anterior-posterior diameter of the entire thorax, which averages 9.3 ± 0.8 cm, the pressure generated by the perfluorocarbon-filled lungs is air-filled lungs due to the amount of gas added above the functional residual capacity (Fig. 6). ) Only 4 cmH₂It was only about O. With reference to Figure 6 in more detail, the gas capacity above FRC (ml) is plotted on the y-axis and the static airway pressure (cmH).₂O) is plotted on the x-axis. Air-filled lungs are indicated by white circles, and PFC-filled lungs are indicated by black circles. The static airway pressure required to gas the lungs to a capacity above the functional residual air volume (FRC) was higher in the perfluorocarbon (PFC) -filled lungs within the tidal volume range. Since air-filled lungs and PFC-filled lungs probably have different volumes at FRC, the origins of the two curves indicate zero volumes above FRC and not the same lung volumes. The pressure-volume relationship of perfluorocarbon-filled normal lungs exhibits hysteresis as in the case of air-filled lungs. Pressure-capacity curves for air-filled lungs and perfluorocarbon-filled lungs are approximately 4 cmH₂There is a difference of about O (p &lt;0.01 in ANOVA for each lung swelling level). The data are mean ± sem. Expiratory flow rate: The expiratory flow rate-volume relationship was changed by the infusion of perfluorocarbon. From this, it was found that there was a gradual increase in expiratory resistance (Fig. 7). The maximum expiratory flow decreased, but the time to reach the maximum did not change. In addition, the lung time constant increased only slightly (from 0.19 seconds to 0.23 seconds). Exhalation was virtually complete in the first 0.5 seconds of exhalation (Figure 8). With reference to FIG. 7 in more detail, the flow rate-volume relationship is shown with the expiratory flow rate (ml / sec) on the y-axis and the expiratory volume (ml) on the x-axis. White circles are CPPB data, and black circles are PAGE data. The expiratory flow-capacity relationship between perfluorocarbon-mediated gas exchange (PAGE) and sustained positive pressure respiration (CPPB) differs in that the maximum flow rate is reduced by the gradual increase in airway resistance that occurs during perfluorocarbon-mediated gas exchange. There is. The data are mean ± sem. With reference to FIG. 8, the expiratory volume (ml) is taken on the y-axis and compared with the expiratory time (seconds) taken on the x-axis. White circles are CPPB and black circles are PAGE. 2 ~ 5cmH₂Momentary exhalation for positive end-expiratory breathing of O was minimized by the presence of perfluorocarbons during perfluorocarbon-mediated gas exchange. Lung time constant (Tc) increased from 0.19 seconds to 0.23 seconds during perfluorocarbon-mediated gas exchange. ETV = effective tidal volume sent to animals. The data are mean ± sem. The range is not statistically significant. Direct observation of lung swelling: Direct observation of the lungs during perfluorocarbon-mediated gas exchange during thoracotomy of postmortem animals revealed a tendency for alveolar air to swell sequentially. The upper lung area was inflated by gas before the other dependent areas. Exhalation seemed to be more uniform. The lungs were virtually aspirated (Fig. 1) almost throughout the exhalation, and the cut surface of the lung at the end of the exhalation was moistened with perfluorocarbon, but there were no bubbles. Compressing the cut surface of the exhaled lung expelled fluid, but no air. With reference to FIG. 1 in more detail, the expiratory end (A) and inspiratory end (B) photographs of the respiratory cycle taken on videotape during perfluorocarbon-mediated gas exchange are shown. The right battlement was resected to reveal the color feature changes (shown in dark here) and lung tissue structure that occur when air flows into the alveoli during perfluorocarbon-mediated gas exchange. The lungs were virtually aspirated at the time of exhalation for 1.5-2 seconds of the 3-second respiratory cycle. Hematological variables: Perfluorocarbon-mediated gas exchange did not cause significant changes in heart rate, systemic arterial pressure, or right atrial pressure. Oxygen delivery to tissues during perfluorocarbon-mediated gas exchange was sufficient to prevent metabolic acidosis, but venous oxygen saturation was slightly lower than during continuous positive pressure respiration. The results are shown below.<img file="JP2606994B2_D0004.tif" /> It can be seen from the blood flow measurement values that the cardiac output is moderately reduced. Pao = mean aortic pressure, Pra = mean pressure in the right atrium, both in mmHg. Sat V = right atrium oxygen saturation. All values are mean ± SD. ** p &lt;0.01 is for the value at CPPB and is due to Newman Keuls corrected ANOVA for multiple comparisons. Briefly, this description details the efficacy of perfluorocarbon-mediated gas exchange in healthy piglets, and ventilation and oxygenation in healthy animals used sustained positive pressure respiration by perfluorocarbon-mediated gas exchange. It shows that it can be assisted as effectively as in the case. Below, the principle of perfluorocarbon-mediated gas exchange that aids oxygenation and ventilation in healthy animals, the intervention of perfluorocarbons in the lungs with surfactant deficiency and dysfunction as a result of increased surface tension in the lungs. A typical application example of gas exchange will be described. Gas exchange during perfluorocarbon-mediated gas exchange: In this study, the tidal volume of gas sent to piglets significantly exceeded the estimated (2 ml / kg) dead space of the airways. Naturally, most of the 15 ml / kg respiratory air will be dispersed in the terminal airways and alveoli. It can be seen that the dispersion of inspiration in the high-generation respiratory tract and alveoli caused the gas and perfluorocarbon to come into mutual contact, creating an environment suitable for "foam oxygen addition" in Invivo. Otherwise, the explanation that the oxygen dissolved by perfluorocarbon at 15 ml / kg or less could be infused at the time when the perfluorocarbon-mediated gas exchange was started, so that the excellent oxygenation state was maintained throughout the test process. There is no way to put it on. Air-induced alveolar swelling during perfluorocarbon-mediated gas exchange is asynchronous, which may probably reflect the airway pressure dependence of gas-induced perfluorocarbon displacement at different standing heights of the lungs. It was revealed in a direct test of open breast animals. In addition, the entire lung was aspirated almost throughout the exhalation. Respiratory tachometer measurements revealed that exhalation was 86% complete 0.32 seconds after the start of exhalation. Therefore, the lungs were virtually aspirated for the last 1.5-2 seconds of the 3-second respiratory cycle. In such an aspirated state, perfluorocarbons were the only obvious alveolar oxygen reservoir. From the observation that oxygen addition during perfluorocarbon-mediated gas exchange was extremely good despite the prolonged aerobic state, it is clear that perfluorocarbon is directly involved in lung gas exchange. If not, most of the pulmonary blood flow should indicate an intrapulmonary shunt. However, residual air appears to remain in the lungs of closed-chest piglets at the end of exhalation, and this gas residual air volume is the only one that has led to the very good oxygenation observed in this study to assist in exhalation exchange. It seems to be the cause of. Figure 9 shows two possible relationships between one large bubble and the alveolar surface during perfluorocarbon-mediated gas exchange. Bubble growth in fluid (Fig. 9A) is observed at the two interfaces: gas / perfluorocarbon (X) and alveolar inner layer / perfluorocarbon (Y). Bubble growth on the alveoli lining (Fig. 9B) is observed at another interface, the alveoli / gas (Z). Inspiration (Insp) appears to inflate the surface to minimize the total increase in interfacial force generated at any of these possible interfaces. Red blood cells (RBC) are found in the capillaries within the alveoli. The ability of red blood cells to take up oxygen from perfluorocarbons is PaO during perfluorocarbon-mediated gas exchange.₂Will be an important determinant of. At the time of maximum inspiration, 30 ml / kg of perfluorocarbon is accumulated in the alveoli in addition to tidal volume gas and residual air. If perfluorocarbons cannot assist in gas exchange, blood flow in the capillaries that perfuse the alveolar surface region adjacent to perfluorocarbons indicates a right-to-left shunt in the lung, even during inspiration. PaO during perfluorocarbon-mediated gas exchange₂And an intrapulmonary shunt greater than 15% cannot be obtained at the same time. In addition, the PO seen when perfluorocarbon-mediated gas exchange was initiated by infusion of perfluorocarbon (after correction of perfluorocarbon vapor pressure).₂The decrease in shunts in the lungs did not show an increase of more than 3% to 4%. This increase indicates a maximum intrapulmonary shunt due to the presence of fluid in the alveoli that was not involved in gas exchange. FIO₂PaO during perfluorocarbon-mediated gas exchange than during sustained positive pressure breathing at 1.0₂Was low. By performing ideal gas exchange, arterial PaO₂Is PAO₂= FIO₂× (pB-pH₂O-pPFC)-pCO₂/ RQ (where p is pressure, B is barometric pressure, PFC is perfluorocarbon, RQ is respiratory quotient), the theoretical alveolar value (PaO)₂). The average measured atmospheric pressure was 748 ± 5 torr (78.1 kPa). Therefore, the mean alveolar oxygen-arterial oxygen partial pressure difference (185 ± 50 torr (24.7 ± 6.7 kPa)) during perfluorocarbon-mediated gas exchange was measured during continuous positive pressure respiration (159 ± 61 torr (21.2 ± 8.2 kPa)). )) Was not substantially different. In addition, PaCO during perfluorocarbon-mediated gas exchange₂Is PaCO during continuous positive pressure breathing₂Equivalent to (40 ± 4 vs. 38 ± 6 torr (ie 5.3 ± 0.5 vs.) It was 5.1 ± 0.8 kPa)). Thus, the combination of bubble oxygen addition during perfluorocarbon-mediated gas exchange, gas outflow from perfluorocarbon to the alveolar blood vessels, and ventilation / perfusion matching is greater than gas exchange during continuous positive pressure respiration. It was not inferior. Mechanical properties of perfluorocarbon-filled lungs: Perfluorocarbon-mediated gas exchange was initiated using a well-known metered rhythmic respirator. No changes were made to instantaneous ventilation, respiratory rate, inspiratory duration, or positive end-expiratory pressure breathing to achieve perfluorocarbon-mediated gas exchange. Clinical measurements of mechanical lung function did not differ significantly between perfluorocarbon-mediated gas exchange and sustained positive pressure breathing. No increase in maximum airway pressure was observed after the infusion of FC77. During the perfluorocarbon-mediated gas exchange, static inspiratory terminal respiration also did not increase at all. The presence of perfluorocarbons did not have a significant adverse effect on the mechanical functioning of the lungs. At the beginning of exhalation, the maximum flow rate was lower with perfluorocarbon-mediated gas exchange than with continuous positive pressure breathing. Inspiratory resistance for perfluorocarbon-mediated gas exchange and sustained positive pressure breathing is 68 and 57 cmH, respectively.₂It was O / 1 / sec. Airway resistance was clearly higher during perfluorocarbon-mediated gas exchange, but was reported in newborn sheep weighing 1.66 kg during liquid breathing (3600 cmH).₂O / 1 / sec) (26) was not approached. From this, it can be seen that there is a slight bulk movement of perfluorocarbon along the airway during perfluorocarbon-mediated gas exchange. Most of the bulk flow that occurs during perfluorocarbon-mediated gas exchange must exhibit gas rhythmic motion, and resistance to gas flow is slightly different between perfluorocarbon-mediated gas exchange and sustained positive pressure respiration. ing. The pressure-capacity curve of air-filled lungs and perfluorocarbon-filled lungs is only 4 cmH at each gas expansion increment.₂Only O was different. This is an unexpected result, with an average lung height of about 6 cm (taking into account chest and back thickness of 3 cm) and a density of perfluorocarbons alone at the end of exhalation in the most addictive lung area. 10.5cmH₂O pressure was generated. In fact, simply moving perfluorocarbon from the vertical part of the extracorporeal tube out of the airway is 3-4 cmH.₂O airway pressure was needed. Therefore, the pressure required to move perfluorocarbons out of the lung area during bubble formation may be less than the pressure indicated by the height of the expiratory fluid column in the lung. This surprising finding probably reflects two factors: the irregular shape of the lungs and the obstruction of the airway fluid column by gas during lung expansion. In gas-free perfluorocarbon-filled lungs, pressure (P) (ie P = FC77 density x fluid column height) was generated in the dependent alveoli by higher fluids. This suggests that perfluorocarbons in the airways are moved by air, resulting in loss of fluid continuity between standing-related lung areas as the lungs swell with gas. To estimate the alveolar pressure that is always in the area and keep the lungs above this alveolar pressure, approximate the weight of the lungs with the perfluorocarbons above the area and divide this weight by the standing high cross-sectional area of the lungs. .. The shape of the lungs is irregular, with a larger cross-sectional area on the dorsal side (lower side) than on the ventral side (upper side). Therefore, its capacity is less than the product of the standing height and the cross-sectional area of the lung floor. Naturally, when the airways are filled with gas and fluid continuity is lost, the effect of perfluorocarbon weight on alveolar pressure is less than suggested by the height of the lungs. In addition, there are at least two other possible causes for the pressure-volume relationship of perfluorocarbon-filled lungs to shift to the right during gas expansion. First, perfluorocarbon is added to the lungs when the meniscus in the tracheal opening tube drops during perfluorocarbon-mediated gas exchange. Some of the decrease in tracheal opening fluid concentration is due to a gradual increase in the amount of functional residual air during perfluorocarbon-mediated gas exchange. Functional residual air volume increased during the study due to the weight of perfluorocarbon and its effect on lung reaction pressure at the end of exhalation, and the function of obtaining a pressure-capacity curve before and after perfluorocarbon-mediated gas exchange. The amount of residual air may be somewhat different. Second, in addition to 30 ml / kg of perfluorocarbon infused into the lungs when initiating perfluorocarbon-mediated gas exchange, functional residual air during perfluorocarbon-mediated gas exchange to maintain visible meniscus in the tracheal opening tube. It is also considered that the maximum amount of perfluorocarbon added to the amount left residual air in the lungs of closed-chested piglets at atmospheric pressure at the end of exhalation. This may have increased the functional residual capacity, and the pressure-capacity curve may have been determined based on the increased functional residual capacity after the perfluorocarbon-mediated gas exchange. If any one of these phenomena is actually involved in the movement of the pressure-capacity curve to the right after the perfluorocarbon-mediated gas exchange, it is clear about the pressure-capacity relationship of the buoyancy of the gas in the perfluorocarbon. Significance can be even smaller. During continuous positive pressure breathing, thoracic compliance can be defined as the effective tidal volume of expansion divided by the pressure range for each breath from positive end-expiratory breathing to static end-expiratory inspiratory breathing. By this provision, thoracic compliance is 3.0 ml / cmH at the start of perfluorocarbon-mediated gas exchange.₂3.1 ml / cmH from O₂Increased to O, then 3.3 ml / cmH₂Increased to O. However, during perfluorocarbon-mediated gas exchange, the pressure-volume relationship contains forces that are completely uncorresponding during sustained positive pressure respiration. The static pressure-volume relationship between perfluorocarbon-mediated gas exchanges cannot be well explained by a single quantitative compliance calculation. Nor does the calculated compliance reflect solely the "stiffness" during perfluorocarbon-mediated gas exchange . When the lungs swell, the fluid in the airways is moved by the gas and bubbles are "blown" into the perfluorocarbon-filled alveoli. Since these bubbles move the fluid, some airway pressures measured during perfluorocarbon-mediated gas exchange offset the buoyancy of the gas in the liquid perfluorocarbon. In addition, airway pressure is relative to the surface tension of bubbles, the clinical opening pressure of bubbles, the surface tension at the interface with perfluorocarbon or gas in the inner layer of the alveoli, the elasticity between alveoli, and the elastic properties of the thorax. The relative contributions of these forces cannot be clarified in this study, but the following comments are justified. First, in healthy piglets, gas respiration during perfluorocarbon-mediated gas exchange is characterized by pressure-volume hysteresis, similar to air respiration and liquid ventilation (27). However, it is unclear whether hysteresis is required for proper gas exchange during perfluorocarbon-mediated gas exchange. During perfluorocarbon-mediated gas exchange, it is not necessary to inflate the alveoli with gas during exhalation for proper gas exchange. There is a reservoir of dissolved oxygen in perfluorocarbons. Second, Avery et al. (28) showed that the gas opening pressure could be reduced by injecting saline into the alveoli in advance. When the lungs are partially inflated with saline, the gas opening pressure of the excited dog's lungs is 5 cmH higher than the gas-free collapsed lung opening pressure.₂O became low. Perhaps the presence of fluid increases the radius of curvature of the alveoli, which works well before lung swelling. A similar effect is clearly seen when exchanging perfluorocarbon-mediated gas. This is because at the end of exhalation, the alveoli swell with perfluorocarbons, as in the case of liquid swelling. In addition, if the lungs are virtually aspirated (as seen) at the end of exhalation during perfluorocarbon-mediated gas exchange, the open pressure that contradicts gas expansion should be the open pressure for bubble formation. Should be. Bubble formation should begin in the perfluorocarbon-filled distal airway with the presence of a perfluorocarbon / gas interface in the early stages. Surface tension along the inner alveoli should have little involvement in the open forces involved in bubble formation in perfluorocarbon-filled alveoli. Moderate airway pressure measured in this study will be sufficient to offset the open force inherent in this interface, regardless of the surface tension of the alveoli. Third, because the alveolar surface tension is so low in the normal lung, bubbles are likely to grow during inspiration (after initial formation) against the surface tension of the alveolar inner layer outside of perfluorocarbon. (Fig. 9B). This is an exception if there is a detergent deficiency or dysfunction. Bubble growth in surfactant-deficient lungs occurs within perfluorocarbons by another mechanism (Fig. 9A). Therefore, healthy lung compliance during perfluorocarbon-mediated gas exchange exceeds surfactant-deficient lung compliance, and low airway pressures as measured in this study provide adequate ventilation in surfactant-deficient lungs. I don't think it will happen. During perfluorocarbon-mediated gas exchange, surface forces acting along the alveolar lining must be used to prevent inspiratory alveolar dilation during both continuous positive pressure breathing and instantaneous breathing. These forces should be kept low even in the absence of detergents at the alveolar lining / perfluorocarbon interface. This may explain the improvement in pulmonary compliance during liquid breathing in surfactant-deficient animals. However, assuming that perfluorocarbon-mediated gas exchange was performed on the surfactant-deficient lung, and if the perfluorocarbon did not separate the air bubbles from the alveolar inner layer when the lung swelled, a greater force would be exerted along the alveolar inner layer / gas interface. Occurs (see Z in Figure 9). From this, it can be inferred that the bubbles expand in the perfluorocarbon-filled alveoli at least to the extent that they can withstand the surface force. If the surface force at the alveolar inner layer / gas interface exceeds the surface force at the gas / perfluorocarbon interface (see X in Figure 9), the bubbles are likely to expand toward the perfluorocarbon, which has a lower surface tension. The surface tension of the gas / perfluorocarbon interface (14 dynes / cm) is substantially smaller than the surface tension confirmed at the air / water interface in the absence of any surface active action (70 dynes cm). Also, this value is significantly smaller than the range of surface tension measured in the lungs of infants who died of respiratory distress syndrome during premature age. The surface tension of fluids derived from the lungs of such infants is generally 20-30 dynes / cm in the minimum membrane region and 50-60 dynes / cm in the maximum membrane region (29). Yet other effects on the pressure-capacity relationship justify the argument. During perfluorocarbon-mediated gas exchange, bubble growth occurs adjacent to the inner layer of the alveoli regardless of the surface tension of the alveoli due to the large radius of curvature of the alveoli. If this is correct, even in lungs lacking surface active substance, the alveolar inner layer / perfluorocarbon interface (Y in Fig. 9) with large surface tension and low surface tension expands together with the alveolar inner layer / gas interface due to bubble growth in the alveolar inner layer. .. If this is correct, proper gas exchange will occur at low expansion pressures as measured in this study, even in the absence of surfactant. Unexpected properties of perfluorocarbon-mediated gas exchange: So far, host diseased properties have contributed to the efficacy of perfluorocarbon-mediated gas exchange in healthy piglets. The validity of gas exchange during perfluorocarbon-mediated gas exchange is basically consistent with the "uniform" bubble oxygenation of perfluorocarbons and the "non-uniform" in the process. It depends on the "unevenness" of perfusion. For example, if the upper area of the lung was more favorable for alveolar formation, perfusion would have to be incomparably poorly distributed, or blood flow to the dependent lung would act as an interalveolar right-to-left shunt. And severe arterial hypoxia may occur. The severe non-uniformity of air bubbles, even if fully reflected by redistributing perfusion, severely constrains the cross-sectional area of pulmonary vessels that can be involved in pulmonary blood flow and adversely affects pulmonary circulatory action. To exert. It was not clear from the above-mentioned limited blood flow data that perfluorocarbon-mediated gas exchange significantly impedes pulmonary blood flow. Therefore, the effect of ventilation / perfusion matching and the efficiency of gas exchange during perfluorocarbon-mediated gas exchange are rather surprising. Liquid breathing, perfluorocarbon-mediated gas exchange, surface tension disorders: After liquid breathing, air breathing can be easily continued. Generally, at the end of liquid breathing, the animal excretes perfluorocarbons and restores the functional residual capacity of the gas before continuing continuous positive pressure breathing. However, the process of expelling perfluorocarbons after liquid breathing is incomplete. Calderwood et al. (30) reported that 200-400 ml of perfluorocarbon remained in the lungs of 10-19 kg dogs despite attempts to completely eliminate them. Shaffer et al. (31) reported a retention of 5 ml / kg in immature lambs after infusion of an amount corresponding to the measured functional residual capacity. This condition is different from the environment in which 30 ml / kg of perfluorocarbon is infused into the trachea and the original position on the left side during gas exchange with perfluorocarbon, but continuous positive pressure breathing is performed after liquid breathing (described later). Data gained from continued experience indicate that perfluorocarbon-mediated gas exchange has specific clinical uses in the event of surface active substance deficiency or dysfunction. Normal lung function is not enhanced by exposure to perfluorocarbons by liquid breathing, but post-excretion lung function is virtually normal despite complete radiographic opacity of the lung area (32). However, in immature animals, possession of perfluorocarbon enhances lung function. Small pigs (95 days gestation) showed a 2-3-fold increase in lung compliance when returning to air breathing 20 minutes after liquid breathing (9). Shaffer et al. (34) studied liquid breathing in lamb at 135-138 days of gestation in clinical RDS, with maximal cases of continuous positive pressure breathing before and after liquid breathing. Intertracheal pressure is low (36 ± 6 vs. 24 ± 8 cmH)₂O) I observed that. In lambs with similar gestation, Shaffer et al. (12) found that returning to sustained positive pressure breathing after liquid breathing significantly improved lung compliance and maximum tracheal pressure, with no change in airway resistance. I found it. Continued positive pressure breathing after liquid breathing is more PaO than before or during liquid breathing₂Is big, PaCO₂Was low. Gestations are similar, and in immature lambs (35), which were complicated at birth due to meconium aspiration, continued positive pressure breathing after liquid breathing with values before or during liquid breathing. Arterial PaO in comparison₂And PaCO₂Has been improved. From such favorable effects of perfluorocarbon on gas exchange and mechanical lung function in immature animals, it can be seen that perfluorocarbon-mediated gas exchange can effectively improve surfactant deficiency and dysfunction. Obstacles to clinical application of liquid breathing: One of the key obstacles to clinical application of liquid breathing technology is the complexity and experimentation of the machinery required for extracorporeal gas treatment and the rhythm of perfluorocarbons in and out of the lungs. There is a characteristic. In view of these points, perfluorocarbon-mediated gas exchange is a less complex and less dramatic innovation than liquid breathing. This method uses a well-known exchanger for the treatment of perfluorocarbons in the lungs. Citations (1) Klystra, JA et al., Of mice and fish, Transactions of the American Society for Artificial Internal Organs 8: 378-383, 1962. (2) Reufer, R., Surfactant and alveolar surface forces after breathing of an inert fluoridated liquid, Federation Proceedings 29 (5): 1813-1815, 1970. (3) Clark, LC, and F. Gollan, Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure, Science 152: 1755-1756, 1966. (4) Biro, PB, and P.Blais, Perfluorocarbon blood substitutes, CRC Critical Reviews in Oncology / Hematology 6 (4): 311-374, 1987. (5) Modell, JH, et al., Long-term survival of dogs after breathing oxygenated perfluorocarbon liquid, Federation Proceedings 29 (5): 1731-1739, 1970. (6) Modell, JH, et al., Liquid ventilation of primates, Chest 69: 79-81, 1976. (7) Calderwood, HW, et al., Residual levels and biochemical changes after ventilation with perfluorinated liquid, Journal of Applied Physiology 139: 603-607, 1975. (8) Forman, D., et al., A fine structure study of the liquid-ventilated new rabbit, Federation Proceedings 43: 647, 1984. (9) Rufer, R., and L. Sbitzer, Liquid ventilation in the respiratory distress syndrome, Chest 66 (Suppl): 29-30, 1974. (10) Puchetti, B., et al., Liquid ventilation in man: first clinical experiences on pulmonary unilateral washing fluorocarbon liquid, Fourth World Congress for Bronchology (Abstracts), p.115,1984. (11) Shaffer, TH, A brief review: liquid ventilation, Undersea Biomedical Research 14 (2): 169-179, 1987. (12) Shaffer, TH, et al., The effects of liquid ventilation on cardiopulmonary function in preterm lambs, Pediatric Research 17: 303-306, 1983. (13) Shaffer, TH, et al., Physiological effects of ventilation with liquid fluorocarbon at controlled temperatures, Undersea Biomedical Research 11 (3): 287-298,1984. (14) Lowe, CA, and THShaffer, Increased pulmonary vascular resistance during liquid ventilation, Undersea Biomedical Research 8 (4): 229-238, 1981. (15) Gollan, F., and LCClark, Prevention of bends by breathing an organic liquid, Transactions of the Association American Physicians 29: 102-109, 1967. (16) Sass, DJ et al., Liquid breathing: prevention of pulmonary arterio-venus shunting during acceleration, Journal of Applied Physiology 32: 451-455, 1972. (17) Sekins.K., et al., International Publication No.W091 / 03267. (18) Avery.ME, and J.Mead, Surface properties in relatin to atelectasis and hyalino membrane disease, Am J Dis Child 97: 517, 1959. (19) Pattle, RE, et al., Inability to form a lung-lining film as a cause of the respiratory-distress syndrome in the newborn, Lancet ii: 469, 1962. (20) Holm, BA, and S. Matalon, Role of pulmonary surfactant in the development and treatment of adult respiratory distress syndrome, Anesth Analg 69 (6): 805,1989. (21) Curtis, SE, et al., Airway and alveolar pressures during perfluorocarbon breathing in infant lambs, J Appl Physiol 68 (6): 2322, 1990. (22) Curtis, SE, et al., Cardiac output during liquid (perfuluorocarbon) breathing in newborn piglets, Cirt Care Med 19 (2): 225-230, 1991. (23) Wolfson, MR, et al., A new experimental approach for the study of cardiopulmonary physiology during early development, J Appl Physiol 65 (3): 1436,1988. (24) Greenspan, JS, et al., Liquid ventilation of human preterm neonates, J Pediatr 117 (1 part I): 106, 1990. (25) Fuhrman, BP, Perfluorocarbon liquid breathing: the first human trial, J Pediatr 117 (1 part I): 73, 1990. (26) Shaffer, TH, et al., Cardiopulmonary function in very preterm lambs during liquid ventilation, Pediatr Res 17: 680, 1983. (27) Barrow, RE, Volume-pressure cycles from air and liquid filled intact rabbit lungs, Respiration Physiology 63: 19,1986. (28) Avery, ME, et al., The inflationary force produced by pulmonary vascular distension of excised lungs: the possible relation of this force to that needed to inflate the lungs at birth, J Clin Invest 38: 456, 1959. (29) Avery ME, and BD Fletcher, The Lung and Its Disorders in the Newborn Infant, Third Edition, Philadelphia, WB Saunders, p.216, 1974. (30) Calderwood, HW, et al., Pulmonary lavage with liquid fluorocarbon in a model of pulmonary edema, Anesthesiology 38 (2): 141A, 1973. (31) Shaffer, TH, et al., Fulmonary lavage in preterm lambs, Pediatr Res 12: 695, 1978. (32) Shaffer, TH, and GDMoskowitz, Demand-controlled liquid ventilation of the lungs, J Appl Physiol 36: 208, 1974. (33) Gollan, F., et al., Compliance and diffusion during respiration with fluorocarbon fluid, Federation Proceedings 29 (5): 1725, 1970. (34) Shaffer, TH, et al., Gaseous exchange and acid-base balance in premature lambs during liquid ventilation since birth, Pediat Res 10: 227, 1976. (35) Shaffer, TH, et al., Liquid ventilation: effects on pulmonary function in distressed meconium-stained lambs, Pediat Res 18 (1): 47,1984. Although preferred embodiments of the present invention have been described above, those skilled in the art can effectively change the subject matter described herein by simply reading the above specification, and make various modifications such as constructing an equivalent one. Let's be able to. Therefore, the protection provided by this letter of patent shall be limited only by the scope of the appended claims and the content contained in the equivalent.