AU4013099A - Perfluorocarbon associated gas exchange and partial liquid breathing of fluorocarbons - Google Patents

Description

S F Ref: 254287D2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Sa Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: University of Pittsburgh of the Commonwealth System of Higher Education 911 William Pitt Union Pittsburgh Pennsylvania 15260 UNITED STATES OF AMERICA Nicholas Simon Faithfull and Jeffry Greg Weers.

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Perfluorocarbon Associated Gas Exchange and Partial Liquid Breathing of Fluorocarbons The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 PERFLUOROCARBON ASSOCIATED GAS EXCHANGE AND PARTIAL LIQUID BREATHING OF FLUOROCARBONS Technical Field The present invention provides respiratory methods and devices, involving means for supplying respiratory gas under positive pressure, to maintain respiratory gas exchange in perfluorocarbon liquid-filled pulmonary air passages. In addition, the present invention relates to the use of biocompatible liquid fluorocarbons and lung surfactant supplements in the treatment of various pulmonary conditions.

Background of the Invention Mechanical ventilators are clinical devices that cause airflow into the lungs. For ventilatory support in the "setting of intensive care, volume-controlled or pressureregulated positive pressure ventilators are generally used.

Such devices force air into the lungs during inspiration but oooo allow a return to ambient pressure during spontaneous exhalation. In volume-controlled ventilation, a preset tidal volume is delivered to the patient regardless of the pressure required to deliver the inspiratory volume. In pressureregulated ventilation, peak inspiratory pressure is limited, as determined by the operating console. Controls are o typically also provided to select the inspired 02 mixture, inspiration and expiration time, and ventilatory frequency.

25 Such conventional ventilators are available from several manufacturers.

Liquid ventilation (LV) is a radically different technique that involves temporarily filling pulmonary air passages with an oxygenated liquid medium. It was first demonstrated that mammals submerged in hyperoxygenated saline could breathe liquid and successfully resume gas breathing by Klystra et al. (Trans. Am. Soc. Art. Int. Org, 8:378-383, 1962) However, this approach to LV was eventually abandoned, due to the practical difficulties of dissolving sufficient quantities of 02 in saline (even at hyperbaric pressures), and because saline rinses away much of the surfactant lining the lung alveoli (Reufer et al., Fed. Proc., 29:1813-1815, 1970).

-2- These problems were overcome by Clark et al., who were the first to use perfluorocarbon liquids (now oxygenated at atmospheric pressure) to support the respiration of mice, cats, and puppies (Science, 152:1755-1756, 1966).

Perfluorocarbon (PFC) liquids are derived from common organic compounds by the replacement of all (or, for the purposes of the present disclosure, substantially all) carbonbound hydrogen atoms with fluorine atoms. These liquids are clear, colorless, odorless, nonflammable, and essentially insoluble in water. PFC liquids are denser than water and soft tissue, and have low surface tension and, for the most part, low viscosity. PFC liquids are unique in their high affinity for gases, dissolving more than twenty times as much 02 and over three times as much CO 2 as water. Like other 15 highly inert carbonfluorine materials, PFC liquids are extremely nontoxic and biocompatible. For a review, see Biro et al., CRC Crit. Rev. Oncol./Hematol., 6:311-374, 1987.

Fluorocarbons have been used in medical applications as imaging agents and as blood substitutes. U.S. Patent No.

20 3,975,512 to Long uses fluorocarbons, including brominated PFCs, as a contrast enhancement medium in radiological imaging. Brominated fluorocarbons and other fluorocarbons are known to be safe, biocompatible substances when appropriately used in medical applications.

For a general discussion of the objectives of "fluorocarbons as blood substitutes and a review of the efforts and problems in achieving these objectives see "Reassessment of Criteria for the Selection of Perfluorochemicals for Second-Generation Blood Substitutes: Analysis of Structure/Property Relationship" by Jean G. Riess, Artificial Organs 8:34-56, 1984.

Fluorocarbon emulsions act as a solvent for oxygen. They dissolve oxygen at higher tensions and release this oxygen as the partial pressure decreases. Carbon dioxide is handled in a similar manner. Oxygenation of the fluorocarbon when used intravascularly occurs naturally through the lungs. For other applications, such as percutaneous transluminal coronary

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angioplasty, stroke therapy and organ preservation, the fluorocarbon can be oxygenated prior to use.

To date it has been clearly established that mammals can breathe (total ventilation support) oxygenated PFC liquids for long periods hours) and return to gas breathing without untoward long-term effects (Modell et al., Fed. Proc., 29:1731-1739, 1970; Modell et al., Chest, 69:79-81, 1976).

Additional studies have shown that no adverse morphological, biochemical, or histological effects are seen after PFC ventilation (Calderwood et al., J. Appl. Physiol., 139:603- 607, 1975; Forman et al., Fed. Proc., 43:647, 1984). PFC liquids have also been investigated for lung lavage (washing) (Rufer et al., Chest, 66(Suppl):29-30, 1974), and have been found to be effective in rinsing out congestive materials 15 associated with Respiratory Distress Syndrome (RDS) in adult humans (Puchetti et al., Fourth World Congress for Bronchology(Abstracts) p. 115, 1984). While total respiratory support of both lungs via PFC liquids is not without side effects, these effects are generally minor and transient (mild acidosis, lower blood pO,, increased pulmonary vascular resistance, and decreased lung compliance) (Shaffer, "Undersea Biomed. Res., 14:169-179, 1987; Shaffer et al., Ped.

Res., 17:303-306, 1983; Shaffer et al., Undersea Biomed. Res., 11:287-298, 1984; Lowe et al., ibid., 8:229-238, 1981). Other biomedical applications of PFC liquid ventilation have received serious research efforts (Gollan et al., Trans.

Assoc. Am. Phys., 29:102-109, 1967; Sass et al., J. Appl.

Physiol., 32:451-455, 1972). Lung cancer hyperthermia via ultrasound and/or convection with PFC liquids has also been reported (PCT W091/03267).

In particular, PFC liquid ventilation is a promising treatment of respiratory distress syndromes involving surfactant deficiency or dysfunction. Lung surfactant is composed of a complex mixture of phospholipid, neutral lipid and protein. Surfactant is roughly 90% lipid and 10% protein with a lipid composition of 55% diphosphatidylcholine

(DPPC),

phosphatidylcholine 12% phosphatidylglycerol

(PG),

-4r Phosphatidlyethanolamine sphingomyelin and phosphatidylinositol (PI).

Lung surfactant functions to reduce surface tension within the alveoli. It mediates transfer of oxygen and carbon dioxide, promotes alveolar expansion and covers the lung surfaces. Reduced surface tension permits the alveoli to be held open under less pressure. In addition, lung surfactant maintains alveolar expansion by varying surface tension with alveolar size (The Pathologic Basis of Disease, Robbins and Cotran eds. W.B. Saunders Co. New York, 1979). There are a number of medical therapies or regimes that would benefit from the use of surfactant supplements. For example, surfactant supplementation is beneficial for individuals with lung surfactant deficiencies. In addition, there are a variety of medical procedures requiring that fluids be added to the lung, for example, as a wash to remove endogenous or exogenous matter. The use of a biocompatible liquid for these applications would be advantageous. Routinely, balanced salt solutions or balanced salt solutions in combination with a given therapeutic agent are provided as an aspirate or as a lavage for patients with asthma, cystic fibrosis or bronchiectasis. While balanced saline is biocompatible, lavage procedures can remove endogenous lung surfactant.

Further, lavage with such aqueous liquids may not permit 25 adequate delivery of oxygen to the body. Therefore, it is contemplated that the use of substances having at least some of the functional properties of lung surfactant could decrease lung trauma and provide an improved wash fluid.

At present, surfactant supplements are used therapeutically when the amount of lung surfactant present is not sufficient to permit proper respiratory function.

Surfactant supplementation is most commonly used in Respiratory Distress Syndrome (RDS), also known as hyaline membrane disease, when surfactant deficiencies compromise pulmonary function. While RDS is primarily a disease of newborn infants, an adult form of the disease, Adult Respiratory Distress Syndrome (ARDS), has many of the same characteristics as RDS, thus lending itself to similar therapies.

ARDS occurs as a complication of shock-inducing trauma, infection, burn or direct lung damage. The pathology is observed histologically as diffuse damage to the alveolar wall, with hyaline membrane formation and capillary damage.

Hyaline membrane formation, whether in ARDS or RDS, creates a barrier to gas exchange. Decreased oxygen produces a loss of lung epithelium yielding decreased surfactant production and foci of collapsed alveoli. This initiates a vicious cycle of hypoxia and lung damage.

RDS accounts for up to 5,000 infant deaths per year and .affects up to 40,000 infants each year in the United States alone. While RDS can have a number of origins, the primary 15 etiology is attributed to insufficient amounts of pulmonary surfactant. Those at greatest risk are infants born before the 36th week of gestation having premature lung development.

Neonates born at less than 28 weeks of gestation have a 60-80% chance of developing RDS. The maturity of the fetal lung is assessed by the lecithin/sphingomyelin ratio in the amniotic fluid. Clinical experience indicates that when the ratio approximates 2:1, the threat of RDS is small. In those e neonates born from mothers with low L/S ratios, RDS becomes a life-threatening condition.

25 At birth, high inspiratory pressures are required to S"expand the lungs. With normal amounts of lung surfactant, the lungs retain up to 40% of the residual air volume after the first breath. With subsequent breaths, lower inspiratory pressures adequately aerate the lungs since the lungs now remain partially inflated. With low levels of surfactant, whether in infants or adults, the lungs are virtually devoid of air after each breath. The lungs collapse with each breath and the neonate must continue to work as hard for each successive breath as it did for its first. Thus, exogenous therapy is required to facilitate breathing and minimize lung damage.

Type II granular pneumocytes synthesize surfactant using one of two pathways dependent on the gestational age of the fetus. The pathway used until about the 35th week of pregnancy produces a surfactant that is more susceptible to hypoxia and acidosis than the mature pathway. A premature infant lacks sufficient mature surfactant necessary to breathe independently. Since the lungs mature rapidly at birth, therapy is often only required for three or four days. After this critical period the lung has matured sufficiently to give the neonate an excellent chance of recovery.

In adults, lung trauma can compromise surfactant production and interfere with oxygen exchange. Hemorrhage, infection, immune hypersensitivity reactions or the inhalation of irritants can injure the lung epithelium and endothelium.

15 The loss of surfactant leads to foci of atelectasis. Tumors, mucous plugs or aneurysms can all induce atelectasis, and these patients could therefore all benefit from surfactant therapy.

The critical threat to life in respiratory distress is 20 inadequate pulmonary exchange of oxygen and carbon dioxide resulting in metabolic acidosis. In infants this, together with the increased effort required to bring air into the ".lungs, produces a lethal combination resulting in overall mortality rates of 20-30%.

25 Optimally, surfactant supplements should be biologically compatible with the human lung. They should decrease the surface tension sufficiently within the alveoli, cover the lung surface easily and promote oxygen and carbon dioxide exchange.

Elevated alveolar surface tension plays a central role in the pathophysiology of the RDS of prematurity (Avery et al., Am. J. Dis. Child, 97:517, 1959; Avery et al., The Lung and its Disorders in the Newborn Infant, Third Edition, WB Saunders, Philadelphia, p.216, 1974) and is thought to contribute to lung dysfunction in ARDS (Holm et al., Anesth.

Analg., 69:805, 1989). PFC liquid ventilation is effective in surfactant-deficient premature animals because it eliminates

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air/fluid interfaces in the lung and thereby greatly reduces pulmonary surface tension (Shaffer et al., Undersea Biomed.

Res., 14:169-179, 1987). Liquid ventilation can be accomplished at acceptable alveolar pressures (Curtis et al., J. Appl. Physiol., 68:2322, 1990) without impairing cardiac output (Curtis et al., Crit. Care Med., 19:225-230, 1991) and provides excellent gas exchange even in very premature animals (Wolfson et al., J. Appl. Physiol., 65:1436, 1988). A successful human trial of PFC liquid ventilation in very premature infants with RDS has recently been reported (Greenspan et al., J. Pediatr., 117(1 part 1) :106, 1990).

Other potential clinical applications of liquid ventilation, and the hurdles to implementation of clinical liquid ventilation trials, have been described (Fuhrman, J.

15 Pediatr., 117(1 part 1) :73, 1990). Recall that, in liquid ventilation, perfluorocarbon liquid is extracorporeally oxygenated and purged of carbon dioxide, and tidal breaths of the liquid are mechanically cycled into and out of the lungs using an investigational device. Unfortunately, such 20 extracorporeal liquid ventilators are not commercially available. Moreover, enthusiasm has also been dampened by the apparent lack of a safe fall-back support system to protect the patient should it be necessary to suddenly discontinue the liquid breathing treatment. Furthermore, because the PFC is 25 oxygenated and purged of carbon dioxide outside the body, and cyclically delivered to the lungs, a large and expensive priming volume of PFC is required to fill, the liquid breathing device. Such operational disadvantages and safety concerns have greatly hindered more widespread use of the otherwise promising liquid ventilation techniques.

Ventilation assistance is commonly used to provide sufficient oxygen to surfactant deficient patients. These ventilation regimes include continuous positive airway pressure, or continuous distending pressure procedures.

Recently, surfactant replacement therapy has been used either alone or in combination with ventilation therapy.

Initial work with surfactant replacements used preparations of human lung surfactant obtained from lung lavage. The lavaged fluid is collected and the surfactant layer naturally separates from the saline wash. This layer is harvested and purified by gradient centrifugation. These preparations worked well as surfactant replacements for RDS and thus provided some of the original data to suggest that surfactant replacement was a necessary therapy. Supplies of human surfactant are limited and expensive, and therefore alternate sources were explored for use in replacement therapies.

The second generation of surfactant substitutes are purified preparations of bovine and porcine lung surfactant.

Preparations of bovine lung surfactant have been administered to many surfactant deficient patients. Like human surfactant, bovine lung surfactant is difficult to prepare, sources are 15 few and availability is limited. Further, while the use of bovine lung surfactant in neonates does not present a problem immunologically, in adults it could immunologically sensitize olo patients to other bovine products.

To minimize the immunologic problems associated with the 20 use of bovine lung surfactant, the harvested surfactant is further extracted with chloroform/methanol to purify its lipid component. This work led to the discovery that there are [three major proteins (SP-A, SP-B and SP-C) associated with lung surfactant. SP-A is hydrophobic and has some documented o"t 25 antibacterial activity. SP-B is most closely associated with traditional surfactant function. These proteins can be purified or cloned, expressed and added back to purified lipid preparations. However, these procedures are also time consuming. In addition, the use of purified animal-derived surfactant protein creates the same immunological problems noted above.

Some of the functional domains within each of the surfactant proteins are now mapped and the individual lipid components of lung surfactant are being tested to determine if a semi-synthetic or synthetic product can be used effectively to replace purified endogenous surfactant. To this end,

I

synthetic peptides of SP-B have been added to mixtures of DPPC and PG to create an artificial surfactant product.

An artificial surfactant would readily cover the lung surfaces and facilitate oxygen exchange. The surfactant would be sterilizable, amenable to large scale production and be relatively storage stable.

Summary of the Invention The present invention overcomes the above-stated disadvantages by providing a perfluorocarbon associated gas exchange (PAGE) method that differs mechanistically from either continuous positive pressure breathing (CPPB) or liquid ventilation The subject method involves introducing into the pulmonary air passages of a mammalian host a volume of perfluorocarbon liquid between about 0.1% and less than about 100% of the functional residual capacity (FRC) of the host. Respiratory gas exchange is thereafter maintained in the perfluorocarbon liquid-laden pulmonary air passages by CPPB, using a conventional gas ventilator. Following this treatment, the perfluorocarbon liquid is allowed to evaporate 20 from the pulmonary air passages.

The data presented below indicates that PAGE is virtually as efficient a means of ventilation and gas exchange as CPPB in normal piglets. Furthermore, PAGE provided adequate gas exchange at airway pressures comparable to those of volumeregulated CPPB.

Like liquid ventilation, PAGE confers special advantages in the treatment of surfactant deficiency or dysfunction, yet PAGE does not require either extracorporeal oxygenation or cyclic delivery of perfluorocarbon "liquid breaths" to the lungs. As a result, further refinement of investigational instrumentation is no longer a prerequisite to the application of perfluorocarbon liquid treatments to surfactant deficiency and other disorders and diseases in the lung. Moreover, because it is predominantly gas, rather than liquid, that moves in tidal fashion with each breath, the airway pressures required to accomplish PAGE are far lower than those required to accomplish liquid breathing. Thus, the potential for barotrauma to the pulmonary air passages is alleviated.

Another result is that the pulmonary time constant (product of the airways' resistance to fluid flow times compliance) is far lower during PAGE than during liquid breathing. This makes it possible to ventilate the patient more rapidly, and to achieve far greater minute ventilation, during PAGE than during liquid breathing. Finally, safety concerns associated with potential equipment breakdowns are allayed because backup gas ventilators suitable for implementing PAGE are readily available in general clinical settings.

One embodiment of the present invention is a method for maintaining respiratory gas exchange, comprising the steps of: first introducing into the pulmonary air passages of a mammalian host an effective therapeutic amount of a S: 15 fluorocarbon liquid, the amount being between about 0.1% and not more than about 100% of the pulmonary FRC of the host; and thereafter moving a breathing gas into and out of the pulmonary air passages so that upon inhalation the breathing gas 20 forms bubbles in and oxygenates the introduced amount of fluorocarbon liquid in the pulmonary air passages.

According to one aspect of this embodiment, the host is in need of treatment for pulmonary surfactant deficiency e*e.

or dysfunction and the fluorocarbon liquid has favourable lung surfactant replacement characteristics. CPPB may be provided into the perfluorocarbon liquid containing air passages by external ventilation equipment.

Advantageously, the external ventilation equipment is either a volume-regulated, time-cycled respirator or a pressure-limited, time-cycled gas respirator.

Preferably, the volume of fluorocarbon liquid is maintained substantially equivalent to the pulmonary FRC of the host. Alternatively, the volume of perfluorocarbon liquid introduced into said pulmonary air passages may be at least about 1/2 or 3/4 of the pulmonary FRC of the host. Preferably, the fluorocarbon is a brominated fluorocarbon. Advantageously, the -11brominated fluorocarbon is perfluorooctylbromide. In another aspect of this embodiment, the equilibrium coefficient of spreading of the fluorocarbon is at least The amount of fluorocarbon liquid introduced into the mammalian host may be at least about 0.1% and less than 50% ot the FRC of the host. Alternatively, this introduced amount may be between at least 0.1 ml/kg of the host's body weight and not more than about 50 ml/kg of the host's body weight. The host may also be in need of removal of material from inside the pulmonary air passages, further comprising the step of removing the fluorocarbon liquid, together with the material, from the air passages. Further, the method may further comprise the steps of: 15 permitting the material to float on the fluorocarbon; and removing the floating material from the air passages.

Advantageously, the fluorocarbon liquid contains a 20 pharmacologic or diagnostic agent in particulate form, whereby the agent is suspended in the fluorocarbon liquid and the agent is delivered to the air passages of the host.

Preferably, the particulate is a solid particulate; most preferably, the pharmacologic agent is a hydrophilic lung surfactant in powdered form. Avantageously, the breathing gas is oxygen. The methods described above may be performed on a host in need of resuscitation, cardiopulmonary resuscitation, or on a host having a respiratory distress syndrome.

Another embodiment of the invention is a medicament for the treatment of a respiratory disease by introducing an amount of the medicament into the lung of a patient such that the introduced amount does not exceed the FRC of the lung of the patient upon exhalation, taking into consideration any positive or negative end expiratory pressure applied to said patient's lung, and then moving a breathing gas into and out of the patient's lung such that the breathing gas oxygenates the introduced amount of medicament within the lung, so that -12the patient is breathing a gas while the introduced amount of medicament is in the lung, wherein the medicament has a positive coefficient of spreading and comprises fluorocarbon liquid.

Still another embodiment of the invention is a medicament for the treatment of a respiratory disease, wherein a volume of the medicament is introduced into the lung of a patient, and the introduced amount is between 0.1% and not more than about 100% of the patient's FRC, wherein upon moving a breathing gas into and out of the patient's lung the breathing gas oxygenates the introduced amount of medicament within the lung, so that the patient is breathing a gas while the introduced amount of medicament is in the lung, the medicament .comprising a fluorocarbon liquid.

15 The invention also provides a method for facilitating oxygen delivery through the lungs, comprising the steps of: first introducing into the lung of the patient an effective oxygen delivery-facilitating amount of a liquid fluorocarbon in the form of an aerosol; and then moving a breathing gas into and out of the patient's lung so that the fluorocarbon oxygenates the introduced amount of fluorocarbon aerosol within the lung.

Preferably, the effective amount is at least about 0.1% and less than about 100% of the FRC of the lung of the patient upon exhalation, taking into account any positive or negative end expiratory pressure applied to the patient's lung.

Additionally, the fluorocarbon further comprises a dispersed pharmacological agent which may be in particulate form.

Still another embodiment is a device for regulating fluid flow during PAGE, comprising; first and second conduits having distal and proximal ends; an endotracheal tube; a chamber adapted for establishing fluid communication between the endotracheal tube and the

I

-13conduits, the chamber interposed between the conduits and the endotracheal tube; at least one valve connected to the conduits to reversible establish fluid communication between the chamber and either the proximal end of the first but not the second conduit, or the proximal end of the second but not the first conduit; means associated with the first conduit to introduce and remove a fluorocarbon liquid to and from the chamber and into the lung; and means associated with said second conduit to introduce and remove breathing gas to and from the chamber to permit a patient into whom the endotracheal S"tube is introduced to breathe a breathing gas into and S 15 out of the perfluorocarbon-containing pulmonary passages into which the perfluorocarbon liquid has been introduced by said device.

Preferably, the first conduit comprises first, second, and third channels having proximal ends that collectively establish fluid communication with the chamber as regulated by the valve means and the second conduit comprises a single channel having an aperture to the ambient environment.

Advantageously, the valve means opens the aperture to the ambient environment when fluid communication is established between the chamber and the first, but not the second conduit, and closes the aperture when fluid communication is established between the chamber and the second but not the first conduit.

The present invention also includes a system for implementing PAGE, comprising: a device for first introducing perfluorocarbon liquid into a patient's pulmonary air passages, a gas ventilator for maintaining respiratory gas exchange in the patient's perfluorocarbon liquidcontaining pulmonary air passages by secondly introducing and removing multiple breaths of breathing gas into the passages during a treatment period so that the breathing -14gas physically admixes with the perfluorocarbon liquid in the pulmonary air passages, so that the passages simultaneously contain both the breathing gas and the perfluorocarbon liquid, and a device operably associated with both the introducing device and the gas ventilator for regulating the aforesaid introduction of liquid and introduction and removal of gas during the treatment period.

Brief Description of the Drawings FIGURE 1 shows an exemplary system for carrying out the subject PAGE method; FIGURE 2 shows an exemplary PAGE adapter for regulating fluid flow by switching between PAGE and CPPB; FIGURES 3A and 3B show other exemplary adapters for S 15 cycling between PAGE and CPPB; FIGURE 4 shows an exemplary PAGE device for maintaining e the liquid FRC during the PAGE treatment regimen; FIGURE 5 presents pressure/volume curves of air-filled (open circles) and perfluorocarbon-filled (solid circles) 20 lungs; FIGURE 6 compares the expiratory flow/volume relationship during CPPB (open circles) and PAGE (solid circles); FIGURE 7 compares time in expiration and exhaled volume during CPPB (open circles) and CPPB (solid circles); and S. 25 FIGURES 8A and 8B depict two possible patterns of bubble growth within a perfluorocarbon fluid-filled alveolus.

FIGURE 9 is a graphic representation of the effect of intratracheal PFOB instillation of the blood oxygen levels in rabbits following lung lavage to remove endogenous surfactant as compared with intratracheal saline instillation.

FIGURE 10 is a graphic representation of the effect of intratracheal PFOB instillation on blood carbon dioxide levels in rabbits following lung lavage to remove endogenous surfactant.

Figure 11 is a graphic representation of the effect of intratracheal PFOB instillation on mean and peak lung airway

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pressures in rabbits following lung lavage to remove endogenous surfactant.

Detailed Description of the Preferred Embodiments It was, a priori, almost unimaginable that gas can be forced into a liquid-filled lung, and that the gas will then almost completely leave the lung before the liquid is also exhaled. Nevertheless, this disclosure describes such a method of respiratory support, termed perfluorocarbon associated gas exchange (PAGE) and its successful use in normal piglets. A volume of perfluorocarbon liquid equivalent to the normal pulmonary FRC was instilled into the trachea and "bubble-oxygenated" for up to several hours in vivo, within the lungs, where it directly participated in gas exchange.

This was surprisingly accomplished using a conventional gas ventilator.

Briefly stated, the PAGE method of maintaining respiratory gas exchange includes the steps of: introducing into the pulmonary air passages of a mammalian host a volume of perfluorocarbon liquid substantially equivalent to (or less than) the normal pulmonary FRC of the host; maintaining respiratory gas exchange in the perfluorocarbon liquid-laden pulmonary air passages by CPPB for a treatment period of time up to an hour or more); and thereafter allowing evaporation of the perfluorocarbon liquid from the pulmonary air passages.

This method provides advantages of both liquid ventilation and of CPPB. Liquid ventilation with oxygenated perfluorocarbon eliminates surface tension due to pulmonary air/fluid interfaces, and improves pulmonary function and gas exchange in surfactant deficiency. In liquid ventilation, perfluorocarbon is oxygenated, purged of carbon dioxide, and the fluid is cycled into and out of the lungs using an investigational device. In contrast, PAGE uses a conventional gas ventilator as in CPPB.

As described in detail below, in thirteen normal piglets a volume of perfluorocarbon equivalent to the normal FRC ml/kg) was instilled into the trachea, left in situ, and *~ee -16volume-regulated gas ventilation (FIO 2 1.0) was resumed.

For one hour, perfluorocarbon was continuously bubbleoxygenated within the lungs, where it directly participated in gas exchange. The results showed that arterial PaO 2 and PaCO 2 averaged 401 51 and 40 4 torr (53.6 6.8 and 5.3 kPa). Peak airway pressure during PAGE (22 2 cm H 2 0 at 1 hour) and during CPPB (23 4 cm H 2 0) were nearly identical.

Venous oxygen saturation and pH were normal (73 8% and 7.43 0.05 at 1 hour) PAGE was uniformly well tolerated, and its efficiency approached that of CPPB. These results indicate that applications of perfluorocarbon breathing technology to lung disease are no longer limited by the state of existing instrumentation or the constraints associated with tidal liquid flow.

15 In this disclosure, by "method of maintaining respiratory gas exchange" is meant the means by which arterial pO,, pH, and pCO 2 are maintained as close to normal as possible. This signifies adequate 02 and CO, exchange in tissues throughout the body. The first objective of PAGE is the assurance of 20 such adequate gas exchange. The patient's underlying illness 9 may then resolve without needless morbidity or mortality. In supporting gas exchange, arterial p0 2 is preferably maintained above 80 torr, and arterial pCO 2 is preferably maintained below 60 torr. Clearly, the closer the achieved values are to 25 normal (pO 2 100, pCO 2 =40) the more satisfactory the clinical situation. In neonates, excessively high pO 2 may cause retrolental fibroplasia and blindness, and so during PAGE, as during conventional CPPB, the oxygen fraction may be reduced to prevent excessive oxygen tensions.

By "pulmonary air passages" is meant the pulmonary channels, spaces or volumes in the trachea, left and right bronchi, bronchiolus, and alveoli of the lungs that are normally occupied by air.

By "mammalian host" is meant to include humans, and, for research and veterinary purposes, premature lamb, piglet, rabbit, cat, dog, and other mammals.

-17- By "perfluorocarbon liquid" is meant to include any fluorinated carbon compound with appropriate physical properties for supporting bubble-oxygenation (see below) during the inspiration phase of the PAGE cycle, and (b) minimal foaming and resultant liquid loss during the expiration phase of the PAGE cycle. These requirements are generally met by PFCs having low viscosity, low surface tension, and low vapor pressure. A high solubility for 02 is, of course, also required. The "PFC liquid" may be made up only of atoms of carbon and fluorine, or may be a fluorochemical having atoms, bromine, other than carbon and fluorine. Representative PFC liquids for use in PAGE include FC-75, FC-77, RM-101, Hostinert 130, APF-145, APF-140, APF-125, perfluorodecalin, perfluorooctylbromide (PFOB), 15 perfluorobutyl-tetrahydrofuran, perfluoropropyltetrahydropyran, dimethyladamantane, trimethyl-bicyclo-nonane, and mixtures thereof. Preferred PFCs are characterized by having: an average molecular weight in range of from about 350 to about 570; viscosity less than about 20 centipoise (cp) at 25 0 C; boiling point greater than about 0 C; vapor pressure in the range from about 5 to about torr, and more preferably from about 5 to about 50 torr, at 15 0 C; density in the range of about 1.6 to about gm/cm 3 and, surface tensions (with air) of about 12 to 25 about 20 dyne/cm.

The PFC liquid is typically introduced into the pulmonary air passages after a period of at least ten to fifteen minutes of pure oxygen breathing. The PFC may be conventionally introduced by simply injecting the liquid into and through an endotracheal tube between breaths, or by delivering the liquid under pressure, as is done during liquid breathing.

The volume of PFC liquid introduced into the pulmonary air passages should preferably be substantially equivalent to the normal pulmonary FRC of the host. By "pulmonary FRC" is meant the volume of space in the pulmonary air passages at the end of expiration. This FRC volume may change as the lung expands during the course of PAGE. Filling the FRC with PFC -18maintains FRC and prevents surface tension-induced alveolar closure during expiration; obviates the need for alveolar air participation in gas exchange during expiration by purging of carbon dioxide and "bubble-oxygenating" an alveolar PFC reservoir; provides a low surface tension medium for bubble formation and bubble expansion throughout inspiration; and, reduces surface tension along much of the alveolar surface, where PFC lies against the alveolar lining. By not exceeding the patient's FRC, the barotrauma associated with prior liquid breathing techniques is avoided, and adequate gas exchange via bubble-oxygenation is assured.

PAGE treatments based on delivering volumes of PFC liquid less than one FRC 3/4 FRC or 1/2 FRC) are also contemplated oooo by this disclosure. Unilateral (one lung) or local (lobar, 15 segmental) PAGE treatments may also be employed, for **PAGE-mediated drug delivery to specific parts of the patient's ••co pulmonary air passages.

Pursuant to this disclosure, respiratory gas exchange is maintained in such PFC liquid-laden pulmonary air passages by 20 preferably CPPB using a conventional ventilator. By "continuous positive pressure breathing" is meant positive pressure mechanical ventilation, often with positive endexpiratory pressure, and may be accomplished by any standard positive pressure ventilator. Either volume-regulated, time- 25 cycled respirators or pressure-limited, time-cycled respirators are suitable. Such ventilators are commercially available. Representative models and manufacturers include: Servo 900C (Siemens Elema, Schaumburg, IL); Infant Star (Star Products, San Diego, CA); Bear i, 2, 3 (Bear Medical, Bowins, CA); Baby Bird 2 (Bird Corp., CA); Healthyne Infant Ventilator; Airshields; etc. As discussed below, the combination of bubble-oxygenation, gas diffusion from PFC to alveolar vessels, and ventilation/perfusion matching during PAGE was not appreciably less efficient than was gas exchange during CPPB. By "bubble-oxygenation" is meant intimate exposure of liquid to bubbles of gas such that bubbles and liquid equilibrate. This condition oxygenates the liquid and

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-19purges it of carbon dioxide. In inspiration, a volume of air is forced into the lungs and divided into small aliquots by the tremendous branching (1023) of the airway passages, so that bubbles form substantially uniformly throughout the lungs in the millions of terminal alveoli.

Following the PAGE regimen, the PFC liquid is removed from the pulmonary air passages. The preferred technique for this particular purpose is to simply permit the PFC to evaporate from the pulmonary air passages. Continuation of gas ventilation without instillation of additional PFC (to maintain the FRC) results in substantially complete evaporation from the lungs in a time period (determined by the vapor pressure of the PFC) on the order of hours.

For certain purposes (discussed below), liquid breaths of 15 the PFC may be periodically cycled into and out of the pulmonary air passages during the treatment period.

Considered in more detail, the subject PAGE method, by obviating the needs for continuous tidal liquid flow and extracorporeal gas exchange, can be advantageously implemented 20 using a much simplified respiratory support system.

Referring to FIGURE 1, an exemplary system 10 for this purpose includes a conventional gas ventilator 12, a PAGE device 14 for handling and processing the PFC liquid, and a PAGE adapter 16 that provides fluid communication with the 25 patient's pulmonary air passages 18. The PAGE device 14 basically instills the predetermined volume of PFC though the PAGE adapter 16 into the patient's pulmonary air passages 18; the gas ventilator 12 provides ventilation of the PFC-laden pulmonary air passages 18; and the PAGE adapter 16 provides a means of cycling between these liquid movement and gas ventilation phases of the treatment.

The PAGE device 14 functions to: cycle PFC into (and, if desired, out of) the lungs; reestablish the proper volume of liquid FRC, at the end of each liquid cycled breath, during the PAGE treatment; control the process of coordinating PAGE device-controlled liquid breaths and gas-ventilator breaths; oxygenate the PFC and purge it of carbon dioxide before instilling the liquid into the pulmonary air passages 18; perform the process of initially loading the pulmonary air passages 18 with PFC if so desired; periodically cleanse the PFC of debris prior to recycling the liquid into the pulmonary air passages 18; (g) regulate PFC temperature; measure pressures and flows within the PFC conduits of the PAGE device 14 and/or PAGE adapter 16; receive and process various physiologic measurements; and, manage input from its operating console and output of its computer.

The PAGE adapter 16 functions to: mechanically, under control of the PAGE device 14, perform the process of coordinating liquid-cycled (PAGE device) and gas-ventilator o breaths; mechanically permit the PAGE device 14 to 15 restore appropriate liquid FRC within the pulmonary air passages 18; and, physically link the two types of fluid delivery devices (the gas ventilator 12 and the PAGE liquiddelivery device 14) for optimal application of the subject PAGE method.

20 The use of such a system 10 (PAGE device 14, PAGE adapter 16, and gas ventilator 12) is exemplified by the following treatment protocol: In appropriate patients, PFC is instilled into the pulmonary air passages 18, either as described in the following Examples, or by use of a PAGE device 14 and PAGE 25 adapter 16. PAGE is generally the primary method of supporting respiratory gas exchange during the treatment period. The gas ventilator 12 delivers tidal volumes of gas to the PFC-laden lungs 18 as determined by the operating console of the gas ventilator 12. The gas oxygenates the PFC and purges the liquid of carbon dioxide in situ, in vivo, within the pulmonary air passages 18, with every breath. This process is performed repeatedly.

Referring to FIGURE 2, at intervals set on the operating console of the PAGE device 14, a valve 20 in the PAGE adapter 16 is flipped to disengage the gas ventilator 12 from an endotracheal tube 22 leading to the patient's pulmonary air passages 18, and to open a gas ventilator port 24 to the I

I

-21ambient atmosphere. This valve 20 simultaneously establishes fluid communication between the PAGE device 14 and the patient's air passages 18. One or more PAGE device-controlled liquid breath(s) are then instilled and withdrawn to accomplish one or more of the above-stated purposes of the PAGE device 14. The valve 20 of the PAGE adapter 16 is then flipped (by a signal from the PAGE device 14) to disengage the PAGE adapter 16 and to reengage the gas ventilator 12 for continued support of gas exchange. This cycle (of engaging the pulmonary air passages 18 to the gas ventilator 12, then the PAGE device 14, then the gas ventilator 12) may be repeated as sequenced by a computer in the PAGE device 14, in response to instructions from its operating console.

The illustrated PAGE adapter 16 is a Y-shaped conduit for S 15 PFC, air, ventilator gas, and expired gas. The adapter 16 has S"two upper limbs (a PAGE device conduit 26 and a gas ventilator conduit 28), a low dead-space common chamber 30, a flap valve with twist stem 32, and a switch mechanism (not shown) that rotates the twist stem 32 to reciprocally operate the valve e 20 The gas ventilator conduit 28 is typically short (to minimize dead space) and establishes gaseous communication **between the ventilator 12 and the common chamber 30. This gas conduit 28 may contain an aperture or port 24 that is 25 reversibly sealed, by a pad 34 on the reciprocal end of flap valve 20, when the valve 20 engages the gas ventilator 12, but open when the valve 20 engages the PAGE device 14.

The common chamber 30 typically has low dead space and fits the distal hub 36 of the patient's endotracheal tube 22.

The common chamber 30 has two outer outlets, one 36 to the gas ventilator conduit 28, and the other 38 to the PAGE device conduit 26. The common chamber 30 reversibly communicates with either this gas outlet 36 or this liquid outlet 38 by means of valve 20. This valve 20 can take the form, as shown here, of a flap valve 20 mounted on an axle or twist stem 32.

Turning the stem 32 rotates the valve 20 to engage the orifice 36, 38 of one conduit 28 or the other 26.

I I -22- The PAGE device conduit 26 contains three channels, each of which courses from the orifice 38 of the chamber 30 to a port on the PAGE device 14. These channels direct flow of: air via channel 40 from the PAGE device 14 to the common chamber 30; PFC inflow (to the patient) via channel 42 from the PAGE device 14 to the common chamber 30; and, PFC outflow via channel 44 from the common chamber 30 to the PAGE device 14.

It should be understood that the above-described PAGE adapter 16 is merely illustrative. The fluid-control valve means 20, for example, can alternatively take the form of a conventional rotatable channel valve 20' as shown in FIGURE 3A; or a sliding piston channel valve 20" as shown in •co FIGURE 3B may be employed.

15 Referring to FIGURE 4, an exemplary PAGE device 14 has "three ports to receive the distal ends of the channels 40, 42, 44 from the PAGE-adapter conduit 26, pumps and valves to 999* control fluid flow through the channels 40, 42, 44, a computer with clock, a reservoir with connectors and apparatus for processing PFC an oxygen (or blender) source port, an operating console, a control cable to operate the PAGE-adapter valve 20, input and output channels, and support electronics to gather data for the computer's use and to drive components of the system 25 One port 46 couples the PAGE device 14 to the inflow channel 42 that carries PFC from the PAGE device 14 to the 9 common chamber 30 of the PAGE adapter 16. This port 46 is linked by a pump 48 to the PFC reservoir 50. The pump 48 is controlled via an output link 52 by the computer 54 as directed by the operating console 56. This inflow pump 48 delivers a predetermined volume of PFC to the port 46 over a predetermined period of time. Pressure at this port is measured and continuously monitored by an input link 58 to the computer.

A second port 60 couples the outflow conduit 44 from the common chamber 30 to the PFC reservoir 50 in the PAGE device 14, again by way of a pump 62. PFC returns to the reservoir -23through this port 60. The associated pump 62 is controlled via an output link 52 by the computer 54, as directed by the operating console 56, in order to return a predetermined volume of PFC to the port 60 over a predetermined period of time. Pressure at this port 60 is measured and continuously monitored by an input link 58 to the computer.

The third port 64 couples the air channel 40 between the common chamber 30 to the PAGE device 14. This 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 pressure below which air is allowed to pass through a oneway air valve 66 through the port 64 and into the channel Coordination of the three ports 46, 60, 64 and their associated pumps 48, 62 and valve 66 permits the PAGE device S 15 14 to restore liquid FRC at the end of the liquid cycled e "breath. When the air valve 66 is closed, the outflow pump 62 e e removes PFC liquid from the pulmonary air passages 18 by e e negative pressure (as preset by the console 56 and computer 54). When air is free to pass through port 64 into the common 20 chamber 30 of the PAGE adapter 16, the PAGE device 14 will only remove any PFC that wells up into the common chamber by passive recoil of the lung and thorax. For example: SClock Time On Clock Time Off (air valve open) (air valve closed) Setting Inflow pump 48 0 sec 6 sec 10 mI/sec Outflow pump 62 6 sec 16 sec 10 ml/sec Air valve 66 10 sec 16 sec atmospheric pressure In this representative example, pump 48 associated with inflow port 46 delivers 60 ml of PFC to the pulmonary air passages 18. Pump 62 associated with outflow port 60 removes 40 ml of PFC from the pulmonary passages 18 between 6 and 10 seconds.

Recoil of the lung delivers the difference between FRC (at atmospheric pressure) and lung volume at clock time 10 seconds 11M111111 -24to the common chamber 30 over the next 6 seconds. That volume is removed by the outflow pump 62 at the rate at which the liquid is delivered by recoil, because pump 62 cannot create a "vacuum" to withdraw the liquid faster, at the 10 ml/sec rate set for the pump 62, with the air valve 66 open. The difference between set pump flow rate and the rate at which PFC is delivered to the common chamber 30 by recoil of the lung is made up by air inflow at set (atmospheric) pressure.

A pneumotachometer (not shown) may be placed in the air port 64 to ascertain when FRC has been reached. With the air valve 66 open, when there is no further lung recoil, the rate set for pump 62 would equal the flow into the air port 64. In this manner, the PAGE device 14 can readily monitor and ee restore FRC, whereas this is a complex problem in liquid 6 breathing because of the large volumes of liquid delivered to *oft* "and removed form the lungs every minute. The PAGE device 14 oo•• notably has less flow to deal with, less volume to purify, less liquid to heat, and does not require continuous weighing of the patient to monitor FRC.

20 The computer 54 of the PAGE device 14 collects the

S.

following input: settings for timing and flow rates for the pumps and valves of the three ports as set on the .ee operation console; cycle timing for the PAGE-adapter valve 4909 as set on the operating console; input from pressure 25 and flow sensors related to the three ports; physiologic .measurement signals such as esophageal pressure; and, (e) input from sensors related to reservoir activities.

Computer output functions to: time and operate the pumps and air valve within the PAGE device 14; time and operate the valve 20 of the PAGE adapter 16; and, report all measurements and computations to meters on the operating console and, by auxiliary and output data ports (not shown), to hard copy recorders or external computers remote from the device 14.

The reservoir 50 functions to: store PFC, bubble oxygenate it to preselected oxygen fraction, regulate itstemperature over the physiologic or therapeutic range desired, purify and cleanse it of debris, and track loss of liquid volume from the system.

The operating console 56 functions to: allow the operator to set parameters for operation of the PAGE device 14 and PAGE adapter 16; display significant output from the computer for interpretation and human response; and, sound alarms when measured parameters exceed the limits set for operation of the PAGE device 14.

To accomplish PAGE using a conventional gas ventilator 12, a PAGE adapter 16, and a PAGE device 14, the following operational range of parameters are considered to be representative. The gas ventilator 12 is engaged to the patient as much as 95% of the time, or as little as 75% of the eooe time. The gas ventilator 12 operates at as few as 5 breaths 15 per minute, or as many as 40 breaths per minute. Peak o pressure ranges from as low as 15 cm H 2 0 to as high as 60 cm

H

2 0; 25 cm H 2 0 would probably be ideal. Oxygen fraction of the 999* PAGE device 14 or ventilator 12 may be as low as 21%, or as high as 100%. Tidal volumes of conventional ventilator 20 breaths delivered to the endotracheal tube 22 may be as small as 6 ml/breath, or as large as 18 ml/breath. Positive endexpiratory pressure (PEEP) may or may not be required on the .9 conventional ventilator 12. Ideally, no more than 5 cm H 2 0 PEEP is required, but PEEP may be as high as 20 cm H 2 0 at 25 times during PAGE treatment. The PAGE device 14 may be engaged to the patient for single liquid breaths, or for multiple 3 or 4) liquid breaths in sequence. The air valve 66 of the PAGE device 14 may open at ambient pressure, or at 10-20 cm H 2 0 above or below ambient.

The disclosed system 10 may also be provided with condensation means (not shown) to capture and recirculate PFC vapors. While PFC liquids are indeed biologically inert and nontoxic in the pure form that would be appropriate for direct infusion into the pulmonary air passages, the existence of PFC vapors in the surrounding environment is, paradoxically, hazardous. This fact, while ignored through most of the research history of liquid ventilation, is profoundly relevant -26to the practice of PAGE therapy, since evaporative PFC losses may be quite high (10-20% of FRC per hour could translate into environmental vapor losses of about 400-800 gm/hour for adult PAGE treatments).

The reason for PFC vapor hazard is that the vapors can decompose into hazardous byproducts upon contact with common sources of heat, hot light sources, burning cigarettes, open flames, ovens, glowing electrical elements, electrical arcs in common motors), electrosurgical devices, surgical lasers, and so on. The most typical decomposition products are perfluoroisobutylene (PFIB) and hydrogen fluoride The highly corrosive and toxic nature of HF is well known. Since PFIB boils at 7 0 C, it will exist as a gas mixed eo with the ambient air in the clinical environment. Inhaling S 15 PFIB in concentrations as low as about 0.5 parts-per-million ooooo for even a few hours can be fatal.

00.0Even where adequate room air recirculation and 900. ventilation exist to keep toxic concentrations around the PAGE process fairly low, the very creation of potentially toxic 20 emissions in the local environment is cause for concern.

Additionally, based on the extremely high expense of PFC liquids, extensive patient PAGE treatments greater than a few hours) will warrant the recapture of the evaporated PFC 000.

liquid and recycled use in the same patient during the 25 treatment. Thus, there are safety and economic motivations for the condensation recovery of evaporated PFC loss both from the PAGE device and from the lungs while being ventilated with gas tidal flows. This condensation function, as well as the additional function of reintroducing the condensed PFC vapors back into the PAGE device, can be carried out by an effluent vapor condensation module. This device takes in both effluent gas/vapor mixture form the PAGE device and expiratory gas/vapor flow from the patient while being ventilated by the gas ventilator (at the point before this mixture vents to the ambient atmosphere). The expiratory mixture is pumped into the module from either the outlet of a connector near the proximal end of the endotracheal tube in passive expiration -27use, or the outlet of expiratory flow from the gas ventilator (in cases where expiratory gas is actually drawn through the gas ventilator itself). The condensation module may be integrated into the PAGE device 14 or may be employed as an attachment to the gas ventilator 12.

The condensation module connected to a patient's expiration tube (for passive expiration) will likely be required to take flow from a proximal point in the expiratory flow which is near atmospheric pressure or at slightly positive pressure. The patient should not be "loaded" in the sense that the pumping of the gas/vapor mixture creates a significant series airway resistance on expiration. As such, the module can be required to "draw" mixture from a vented plenum (which receives the expiratory mixture just outside the S 15 patient) near atmospheric pressure through a check valve. The drawing or suction of this flow may be provided by a vacuum pump.

To meet the requirements for patient PFC reuse for extended treatments, the condensation module pumps PFC liquid 20 flow to the PAGE-device reservoir 54 either periodically at fixed time intervals, on the basis of sensed minimum accumulated volumes in the module's PFC storage reservoir, or by continuously pumping. Such PFC return pumping is controlled by the PAGE-device reservoir 54.

S 25 The subject PAGE method, by simplifying the mechanisms of oxygenation and carbon dioxide clearance, provides a preferred means of gas exchange for respiratory applications of PFC technology. The PAGE method reduces the matter of "ventilation" to one of air movement, whereas prior liquid breathing techniques have been hampered by the need to move relatively large volumes of liquid into and out of the lungs.

Traditional liquid breathing requires the movement of such large volumes of fluid per minute that it becomes necessary to force fluid into or out of the lung, at relatively high airway pressure, almost continuously, this reduces the margin of safety of conventional liquid breathing, and limits its flexibility. It exposes the proximal airway to high -28inspiratory pressures, even though distal airways and alveoli are exposed to far lower pressure. The PAGE method may reduce the risk of these high proximal airway pressures, greatly increase the flexibility of liquid breathing technology, and simplify the problem of regulating pulmonary FRC.

PAGE may prove to be more widely and flexibly applicable than the representative embodiments disclosed above because of its potential to facilitate the mechanics of breathing and reduce work of breathing in the diseased lung. It may be beneficial to accomplish the mechanical movement of gas into and out of the liquid filled lungs, during PAGE, by other modes of mechanical ventilation such as: Intermittent Mandatory Ventilation (IMV), Intermittent Demand Ventilation (IDV), High Frequency Jet Ventilation (HFJV), High Frequency *e S 15 Oscillatory Ventilation (HFOV), Pressure Support Ventilation o o (PSV), Airway Pressure Release Ventilation (APRV), Continuous Positive Airway Pressure (CPAP), and other variations and e modifications of clinically useful forms of mechanical respiratory support. It is also understood that, by reducing 20 the work of spontaneous breathing in the patient with lung disease, PAGE may be safely and effectively accomplished by permitting the patient to breathe spontaneously after instillation of the liquid. This embodiment of the invention is especially desirable to minimize the incidence and severity of secondary lung injury (pulmonary barotrauma) By simplifying the problem of gas exchange during respiratory applications of PFC breathing technology, the PAGE method readily permits more efficient, less complex apparatus for the processes of recycling PFC cleansing it of debris, and regulating its temperature.

The process of PAGE, permissibly practiced with a PAGE adapter 16 and a PAGE device 14, also modifies the priorities that determine selection of the best liquids for liquid breathing techniques. The PAGE process lends itself to respiratory applications of classes of liquids other than PFCs. Fluids can now be selected more on the basis of surface tension and viscosity for transmission of gas bubbles, and -29less on the basis of solubilities for oxygen and carbon dioxide. Chemicals poorly suited to conventional liquid breathing may prove effective vehicles for PAGE. For example, low water content from several percent up to about

H

2 0) PFC emulsions may be highly desirable for PAGE as vehicles for lavage of debris and delivery of drugs, though they might be unsuitable for gas exchange by conventional liquid breathing. The critical factor, when such weak water or saline emulsions are employed, is to assure that the PFC is on the outside of the aqueous phase; otherwise, unacceptable foaming and liquid loss during expiration will likely result.

The subject PAGE method is useful for treating various disorders and diseases of the pulmonary air passages. In .particular, respiratory distress syndromes associated with S 15 surfactant deficiency or dysfunction are functionally made less severe throughout the duration of PAGE, by limiting the maximum surface tension that must be overcome in ventilating the lung to that of the PFC itself. Other clinica applications of the PAGE method are discussed below.

20 Thus, PAGE is a particularly useful way to ventilate the lung with surfactant deficiency (RDS of prematurity), and the lung with surfactant dysfunction and capillary leak syndrome ARDS), meconium aspiration syndrome, and various forms of acute lung injury) Prophylactic use of PAGE is also contemplated for preventing or minimizing lung dysfunction associated with, S• ARDS, immune-mediated lung injury, irritant injuries to the lung, cytokine-mediated or endotoxin-mediated injuries, and other sources of lung injury.

PAGE, by simplifying gas exchange during liquid breathing, should facilitate the use of PFC products as lavage media to cleanse the lung of debris associated with, e.g., meconium aspiration syndrome, alveolar proteinosis, lifethreatening asthma, cystic fibrosis, and other aspiration syndromes.

PAGE should make it possible to keep the lung full of low surface tension PFC liquid for a prolonged period of time and thereby permit the use of PFCs to prevent or reduce the severity of lung injury and lung dysfunction in patients prone to ARDS. Capillary leak is a function of surface tension at the alveolar lining, and could be significantly reduced in by the constant presence of PFC. Though the surface tension of the PFC itself may be between 10 and 20 dynes/cm, that of the alveolar lining/PFC interface is much closer to 1 dyne/cm, and may be lower than the normal surface tension of the alveolar lining even in the absence of surfactant.

PAGE should provide advantages over conventional gas ventilation in cardiopulmonary resuscitation. The noncompressible nature of liquid PFC may enhance the transmission of precordial pressure to the arrested heart during CPR.

15 PAGE should provide advantages over standard therapy for *o.resuscitation after cold-water drowning and other states characterized by hypothermia as well as cardiac arrest. The o PFC can be warmed, using the PAGE device 14, and, during PAGE, used to rewarm the mediastinum and central blood volume, thereby obviating the need for Extracorporeal Membrane Oxygenation (ECMO) or cardiac bypass in such cases.

Continuous manipulation of PFC, mediastinum, and heart Se.

e temperature may be accomplished using the PAGE device 14.

The PAGE method and system 10 may also find applications for cooling and/or rewarming in conjunction with operative hypothermia. This may find special applications in cardiac surgery.

The PAGE method and system 10 may find applications for cooling and/or rewarming in conjunction with the management of head trauma or brain injury.

PAGE should also provide an effective means for removal of nitrogen bubbles from blood after acute decompression from depth, and so will find applications in treatment or prevention of the "bends." PAGE should provide a safe alternative to conventional liquid breathing, thereby assuring the safety of that technique (against the possibility of liquid breathing -31equipment failure). Use of the PAGE adapter 16 will enhance the safety of conventional liquid breathing by assuring rapid institution of PAGE should equipment failure occur during conventional liquid breathing.

PAGE, because it predominantly involves tidal flow of gas rather than liquid, should provide effective in diseases characterized by combined airway obstruction and elevated alveolar surface tension, i.e. ARDS.

The PAGE adapter 16 will facilitate intermittent use of conventional liquid breathing techniques, by making it possible to safely and conveniently convert from conventional liquid breathing to PAGE.

The PAGE device 14 and PAGE adapter 16, together, serve to facilitate the consistent maintenance of an optimal pulmonary FRC. This enhances the safety of respiratory applications of PFC breathing technology, and greatly simplifies the safe execution of conventional liquid breathing.

PAGE should facilitate mechanical ventilation in the 20 presence of cardiogenic pulmonary edema and may also reduce the rate of accumulation of lung water during cardiogenic pulmonary edema.

PAGE, preferably practiced with the disclosed system may provide a means of "cardiac augmentation" by reduction of cardiac afterload in patients with congestive cardiac failure.

Transmission of the weight of PFC to the cardiac fossa may, during PAGE, reduce left ventricular afterload.

PAGE may prove useful in the reexpansion of atelectatic lung segments. It may have special value in the reinflation of lung segments that collapse during ECMO. PAGE may, in fact, prove superior to conventional gas ventilation in the long-term support of the lungs during ECMO, as it may reduce the tendency to further barotrauma and maintain alveolar and airway patency during lung healing.

The long-term presence of PFCs within the airways and alveoli during PAGE may alter the healing process of the -32injured or infected lung, and prevent progression to airway obliteration.

The long-term presence of PFCs within the airways and alveoli made possible by the PAGE method and system 10 may depress the inflammatory process, and thereby ameliorate the lung injury associated with immunologic and hypersensitivity lung disease.

PAGE may, by ameliorating stimuli to pulmonary vasoconstriction, prove to be an effective support modality for infants with persistent pulmonary hypertension of the neonate.

PAGE may, by providing a relatively static pool of pulmonary liquid, effectively distribute and leave in situ various drugs and pharmacologic or diagnostic agents, S 15 including surfactant, mucolytics, and agents that alter bronchomotor tone. Representative agents for this purpose include vasoactive substances such as epinephrine and norepinephrine, proteolytic enzymes such as those used to break up blockages in cystic fibrosis, bronchodilators such as 20 terbutaline and albuterol, steroids and other antiinflammatory agents, chromalyn, chemotherapeutic or diagnostic antibody reagents, and so on.

~PAGE may also, by promoting the even distribution of gas in the lung during inspiration, and by reducing the distending 25 pressure required to ventilate lungs with high intrinsic surface tension, reduce the incidence of pulmonary barotrauma during mechanical ventilation.

FLUOROCARBONS IN PARTIAL LIQUID BREATHING AND AS SURFACTANT

REPLACEMENTS

Fluorocarbons useful as surfactant replacements are generally able to promote gas exchange, and most of these fluorocarbons readily dissolve oxygen and carbon dioxide.

There are a number of fluorocarbons which are contemplated for medical use. These fluorocarbons include bis(F-alkyl) ethanes such as C 4

FCH=CH

4

CF

9 (sometimes designated "F-44E") i-

C

3

FCH=CHC

6

F

1 3 ("F-i36E") and C 6 Fi 3

CH=CHC

6

F

1 3 ;cyclic fluorocarbons, such as C10F18 ("F-decalin", "perfluorodecalin" -33or F-adamantane F-methyladamantane F- 1,3-dimethyladamantane F-di-or Ftrimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated amines, such as F-tripropylamine("FTPA") and F-tri-butylamine ("FTBA") F-4-methyloctahydroquinolizine F-n-methyldecahydroisoquinoline F-n-methyldecahydroquinoline F-n-cyclohexylpurrolidine ("FCHP") and F-2butyltetrahydrofuran ("FC-75"or "RM101") Other fluorocarbons include brominated perfluorocarbons, such as 1-bromoheptadecafluoro-octane (CsF 1 ,Br, sometimes designated perfluorooctylbromide or "PFOB"), 1-bromopentadecafluoroheptane (C 7 ,FiBr) and 1-bromotridecafluorohexane (CFl 3 Br, sometimes known as perfluorohexylbromide or "PFHB") Other brominated fluorocarbons are disclosed in US S 15 Patent No. 3,975,212 to Long. Also contemplated are fluorocarbons having nonfluorine substituents, such as e.

e perfluorooctyl chloride, perfluorooctyl hydride, and similar compounds having different numbers of carbon atoms. In addition, the fluorocarbon may be neat or may be combined with 20 other materials, such as surfactants (including fluorinated surfactants) and dispersed materials.

Additional fluorocarbons contemplated in accordance with this invention include perfluoroalkylated ethers or polyethers, such as (CF 3 2 CFO (CF 2

CF

2 2 OCF (CF 3 2, (CF 3 2

CFO-

25 (CF 2

CF

2 3 0CF (CF 3

(CF

3 CFO (CF 2

CF

2 F, (CF 3 2CFO (CF 2

CF

2

F,

(C

6

F

1 3 2 0. Further, fluorocarbon-hydrocarbon compounds, such as, for example compounds having the general formula CnF 2 n+, Cn,F2n',+, Cn 2n+1OCn, F2n', or CnF2nICF=CHCn,F2n,,, 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 C 8

F,,C

2 Hs and C 6 Fl 3

CH=CHCH

3 It will be appreciated that esters, thioethers, and other variously modified mixed fluorocarbon-hydrocarbon compounds are also encompassed within the broad definition of "fluorocarbon" materials suitable for use in the present invention. Mixtures of fluorocarbons are also contemplated.

Additional "fluorocarbons" not listed here, but having those -34properties described in this disclosure that would lend themselves to pulmonary therapies are additionally contemplated.

Some fluorocarbons have relatively high vapor pressures which render them less suitable for use as a surfactant replacement and for partial liquid breathing. These include PFHB and FC-75. Lower vapor pressures are additionally important from an economic standpoint since significant percentages of fluorocarbon having high vapor pressure would be lost due to vaporization during the therapies described herein. In a preferred embodiment, fluorocarbons having lower surface tension values are chosen as surfactant supplements.

The fluorocarbon of choice should have functional oo characteristics that would permit its use temporarily as a lung surfactant, for oxygen delivery, in removal of material "from the interior of the lung, or for inflation of collapsed portions of the lung. Fluorocarbons are biocompatible and most are amenable to sterilization techniques. For example, they can be heat-sterilized (such as by autoclaving) or .o 20 sterilized by radiation. In addition, sterilization by ultrafiltration is also contemplated.

One group of preferred fluorocarbons have the ability to reduce the surface tension in the lung. As noted above, surfactants function to decrease the tension between the 25 surface molecules of the alveolar fluid. The lung surfactant is solubilized in a water-continuous fluid lining the alveolus. Typically, the surface tension in the absence of lung surfactant is ca. 60 dynes/cm decreasing to 5-30 dynes/cm in the presence of lung surfactant. Fluorocarbons have low surface tension values (typically in the range of 20 dynes/cm) and have the added benefit of dissolving extremely large quantities of gases such as oxygen and carbon dioxide.

Perfluorocarbons are particularly suited for this use, and brominated fluorocarbons are particularly preferred.

Although reduction in surface tension is an important parameter in judging fluorocarbons and perfluorocarbons as potential lung surfactant supplements or for use in partial liquid breathing, a novel and non-obvious characteristic of some fluorocarbons is their apparent ability to spread over the entire respiratory membrane. The ability of some fluorocarbons to spread evenly and effectively over lung surfaces may be of even greater importance than the ability of fluorocarbons to reduce surface tension.

The total surface area of the respiratory membrane is extremely large (ca. 160 square meters for an adult). Thus, an effective fluorocarbon for partial liquid breathing should be able to cover the lung surfaces with relatively little volume.

The ability of a given substance to cover a measured surface area can be described by its spreading coefficient.

The spreading coefficients for fluorocarbons can be expressed S 15 by the following equation: "S (o on Yw/a-(Tw/o Yo/a) il Where S (o on w) represents the spreading coefficient; y= interfacial tension; w/a water/air; w/o water/oil; and o/a oil/air.

S 20 If the fluorocarbon exhibits a positive spreading Scoefficient, then it will spread over the entire surface of the respiratory membrane spontaneously. Fluorocarbons having spreading coefficients of at least one are particularly preferred. If the spreading coefficient is negative, the S. 25 compound will tend to remain as a lens on the membrane surface. Adequate coverage of the lung surface is important for restoring oxygen and carbon dioxide transfer and for lubricating the lung surfaces to minimize further pulmonary trauma.

The spreading coefficients for a number of perfluorocarbons are reported in Table I. Each perfluorocarbon tested is provided together with its molecular weight and the specific variables that are used to calculate the spreading coefficient S (o on The perfluorocarbons reported are PFOB, perfluorotributylamine (FC-17), perfluorodecalin (APF-140), dimethyl perfluorodecalin (APF- 175), trimethyl decalin (APF-200), perfluoropherhydro- -36phenanthrene (APF-215), pentamethyl decalin (APF-240), and octamethyl decalin (APF-260).

These perfluorocarbons are representative of groups of perfluorocarbons having the same molecular weight that would produce similar spreading coefficients under similar experimental conditions. For example, it is expected that ethyl perfluorodecalin will have a spreading coefficient similar to that of dimethylperfluorodecalin. Propyl or other 3 carbon-substituted decalin would have a spreading coefficient similar to that reported for trimethyl decalin, pentamethyldecalin is representative of other decalins substituted with 5 substituent carbons, and octamethyldecalin is also representative of other combination substituted decalins of identical molecular weight.

S 0..

-37- TABLE I ofpfluorocarbon onsalne (T=25 C) Spreading coefficients Perfiucrocarbon MW (g/mol) PFOB 499 (perfiucrooctyibromide) FC-47 671 (perfluorotributylamine) APF-140 468 (perfluorodecalin) APF-175 570 (dimethyl decalin) to.APF-200 620 :*-(trimethyl decalin) APF-215 630 (perfiucroperhydrophenanthrene) APF-240 770 (pentamethyl decalin) .APF-260 870 (octamethyl decalin) (mN/rn) 18.0 17. 9 18.2 20.7 21.4 21.6 22.6 22.4 y~(mN/rn) 51.3 55.1 55.3 55.9 55.9 56.0 56.3 56.1 S (O on w) +2 .7 -4.6 -5.3 -5.6 -6.9 -38- It can be seen from this limited sampling of fluorocarbons that PFOB provides a positive spreading coefficient. In addition, PFOB has a low vapor pressure (14 torr 37 0 further illustrating that PFOB is a particularly preferred choice for use as a lung surfactant replacement. Because of the reduced vapor pressure, PFOB will have a decreased tendency to vaporize during use.

Perfluorodecalin (APF-140) and perfluoroamine (FC-47) have also been tested in potential blood substitute formulations.

These compounds exhibit negative spreading coefficients on saline. However, other perfluorocarbons, similar to APF-140 and FC-47, but having decreasing molecular weights, exhibited decreasing surface tensions and increasing 9 spreading coefficients. This suggests that lower molecular weight perfluorocarbons might also have useful spreading coefficients. However, decreasing molecular weight will increase vapor tension and make the compounds less suitable for this use.

*9e 20 Both fetal and adult rabbits have been used to study 99* RDS. Much of the work with surfactant replacements was initiated in these animals. For studies on RDS therapies, the method of fetal animal ventilation used should closely mimic the ventilation methods used for the neonate. Other fetal and adult animals studied include lamb, dog or baboon.

In vivo studies in animals are necessary to correlate the in vitro characteristics of a given fluorocarbon with its in vivo benefits.

An analysis of the therapeutic benefit or the usefulness of a given fluorocarbon or a lung additive containing fluorocarbon necessarily includes an analysis of a number of experimental parameters. These parameters include measurements of dynamic lung compliance, blood gas quantitations, alveolar/arterial oxygen tension ratios, lung water estimates, vascular protein leakage into the lung, inflammatory cell infiltrates, chest radiographs, ventilatory support indices over time and the like. Lung histologies -39from experimental subjects are used to demonstrate the resolution of atelectasis, evidence of necrosis, desquamation and inflammation. Individuals skilled in the art will be familiar with the test parameters listed above, therefore no further information needs be provided to facilitate these tests. Fluorocarbons providing beneficial test results in experimental animals are candidates for human use.

It is contemplated that there are a variety of uses for fluorocarbons in partial liquid breathing applications. Lung lavage can be used as both a diagnostic and therapeutic procedure. Diagnostic washings are often obtained by bronchoscopy. Diagnostic lavage requires the introduction of a small amount of fluid into the lungs in order to sample lung cells, exudate, or to obtain a sample for 15 microbiological analysis.

Therefore, in accordance with one aspect of this invention, it is contemplated that PFOB or another fluorocarbon meeting the positive criteria disclosed herein could be used for such a procedure.

20 Large volume lung lavage is sometimes used as an S"emergency procedure to remove irritants, poisons or mucous plugs from the lungs. The procedure is also used in neonates to remove aspirated meconium. A pulmonary catheter is to.

inserted into the bronchial airway and a solution is flushed into the lung. The use of saline in the lung for large .*volume lavage creates several problems. The procedure must be performed quickly because oxygen transfer at the membrane/air interface cannot occur efficiently in the presence of saline, and large volumes of saline flushed into the lungs effectively dilute and remove any functional lung surfactant present.

It is also contemplated that fluorocarbons could be used to inflate collapsed portions of lungs or collapsed lungs in general. The use of fluorocarbon to inflate portions of the lung is less damaging than the current methods employing increased air pressure. As noted previously, increased air pressures in lungs, particularly lungs that are compromised by disease or trauma, can produce barotrauma and induce additional lung damage.

If the lungs have been compromised by an irritant then surfactant replacement may be necessary. Oxygenatable fluorocarbons with positive spreading coefficients and low vapor pressures could provide an improved lavage fluid.

The fluorocarbon could also be provided as a liquid or aerosol in combination with an expectorant. The biocompatible fluorocarbon is easily taken into the lung and the expectorant additive facilitates the removal of the secretions of the bronchopulmonary mucous membrane. Examples of contemplated expectorants include but are not limited to ammonium carbonate, bromhexine hydrochloride and terpin g" hydrate.

15 In accordance with another aspect of this invention, it goo*: 0 0 is further contemplated that PFOB or another suitable fluorocarbon could be used as a surfactant supplement. PFOB is able to spread easily over the surfaces of the lung and can facilitate oxygen transport. Any condition characterized 20 by a lung surfactant deficiency would be amenable to this therapy. In addition to RDS in neonates, ARDS in adults caused by severe hypovolemic shock, lung contusion, diver's lung, post-traumatic respiratory distress, post-surgical oleo atelectasis, septic shock, multiple organ failure, Mendelssohn's disease, obstructive lung disease, pneumonia, Spulmonary edema or any other condition resulting in lung surfactant deficiency or respiratory distress are all candidates for fluorocarbon supplementation.

The amount of surfactant supplement given should be sufficient to cover the lung surface and should be at least 0.1% of the infant or adult's total lung capacity. In RDS, it is particularly important to stabilize the infant while minimizing and preventing additional lung damage for roughly four or five days. Those infants with RDS that survive this critical time frame have an 80% survival rate. The fluorocarbon is provided by direct instillation through an endotracheal tube. If the fluorocarbon is provided together -41with a surfactant powder, the powder can either be mixed into the fluorocarbon or provided to the infant or adult as an aerosol prior to fluorocarbon administration. The addition of lung surfactant powder to fluorocarbon provides a surfactant particulate dispersed throughout the fluorocarbon liquid.

During administration, the infant is placed in the right and left lateral decubitus positions while being mechanically or manually ventilated. Chest radiographs reveal that unlike other surfactant replacements in use that lack positive spreading coefficients, fluorocarbon is unilaterally distributed in the chest cavity. Since neonates are often difficult to intubate, only those individuals experienced in neonatal intubation should attempt this procedure.

15 Mechanical ventilator usage and initial settings of breaths/minute, positive inspiratory pressures, positive-end expiratory pressure and inspiratory durations should be set initially as determined by the known standards for given infant weight and gestational ages, but should be monitored 20 closely and altered accordingly as pulmonary function improves.

The use of partial liquid breathing is not restricted to cases where lung surfactant supplementation is necessary.

Any condition requiring facilitated oxygen delivery, for 25 example, is amenable to use of partial liquid breathing.

Because the volume of fluorocarbon in the lung is such that liquid fluorocarbon is not exhaled by the patient, conventional ventilation equipment can be used. This overcomes a major obstacle to liquid breathing as contemplated in the prior art.

In addition to oxygen delivery, fluorocarbons can be used to remove endogenous or foreign material from the interior of the lungs. Lavage can be practiced using fluorocarbons as a substitute for conventional saline solutions. In this procedure, oxygen is provided to the patient by the fluorocarbon liquid itself, permitting a more lengthy and less dangerous lavage procedure. Moreover, -42removal of lung surfactant through the lavage is not a major problem because of the lung surfactant properties of selected fluorocarbons. The lavage procedure is further facilitated by the density of the fluorocarbon. The density of these liquids is generally 2, that is, twice that of water; they therefore tend to displace the material to be removed. This material can then be removed by removing the fluorocarbon, or can be removed from the surface of the fluorocarbon on which it will generally float.

In addition to the lung surfactant properties, the density of the fluorocarbon can facilitate inflation of collapsed alveoli and other portions of the lung. Under the influence of gravity, the fluorocarbon will apply positive 15 pressure above and beyond breathing pressure to inflate such 15 collapsed portions of the lung.

The use of fluorocarbons for partial liquid breathing requires a volume as little as 0.1% of the total lung capacity upon full natural inflation. However, it is preferred that the amount used be at least and more 20 preferably at least 0.3% or 0.5% of the total lung capacity.

Minimum amounts of or 5% of total lung capacity are preferred. It is additionally contemplated that fluorocarbon could be added in amounts up to about 50% of the total lung capacity.

25 Thus a method for partial liquid breathing is provided as another aspect of this invention.

Partial liquid breathing has a number of benefits over the total liquid breathing methods contemplated primarily for use in neonates. It appears that the difficult transition from total liquid breathing to total air breathing can be reduced by partial liquid breathing. The lungs are bathed in a biocompatible fluid. Lung trauma is minimized and this permits lung maturation and repair. Partial liquid breathing is more amenable to use in adults than total liquid breathing since air or gas can still be inhaled and exhaled. Partial liquid breathing can be used in conjunction with spontaneous, passive or mechanical ventilation. In addition, -43pharmacologic substances can be added to the fluorocarbon to further promote resolution of lung injury.

The amount of fluorocarbon introduced into the patient's lung is, at a minimum, necessarily sufficient to cover the surfaces of the lung. The actual volumes will depend on the treatment protocol, the weight and size of a patient as well as the lung capacity. It is contemplated that the useful range of fluorocarbon should be at least 0.1 ml of fluorocarbon liquid per kilogram patient body weight and not more than about 50 ml/kg.

It is further preferred that the maximum amount of fluorocarbon used for partial liquid breathing will approximate the volume of air remaining in a healthy lung of '"similar size following exhalation. The amount of air 15 remaining in the lung at the end of exhalation can be measured in a number of ways that are known by those with skill in the art. Physiology-related equations relate the size, age, or weight of an individual to his exhaled lung volume.

20 Thus, during partial liquid breathing in accordance with the present invention, the lungs retain sufficient air *..capacity (above and beyond the volume of fluorocarbon in the lung) to permit inhalation such that normal breathing can proceed. The amount of air entering the lungs on inhalation 25 is sufficient to oxygenate the fluorocarbon liquid. Further, the fluorocarbon liquid may be oxygenated prior to use to provide oxygen to the alveolar surfaces of the lung instantaneously upon initial contact with the fluorocarbon.

If ventilation therapy is required, unlike total liquid breathing, standard ventilation equipment can be used.

Partial liquid breathing can be used to reverse ventilary failure, as a prophylactic to prevent respiratory failure or as a therapeutic. As a therapeutic, fluorocarbon solution can be administered alone to minimize further lung trauma, or in combination with a given therapeutic agent. Fluorocarbon liquid can be provided together with a particulate therapeutic agent such as lung surfactant. These powder -44surfactants may be synthetic mixtures of phospholipids. For example, a mixture of diphosphatidylcholine and phosphoglycerol in a ratio of 7:3 could be mixed with a volume of fluorocarbon. Additionally, the surfactant powder may be in the form of dried extracts prepared from human or animal lung lavage. It was noted earlier that there are three major proteins (SP-A, SP-B and SP-C) associated with endogenous lung surfactant. Therefore, it is additionally contemplated that these proteins may be added as full length or as truncated fragments to the fluorocarbon mixture.

Partial liquid breathing according to the present invention is useful for a variety of medical applications.

As a lavage, the technique is useful for meconium aspiration, gastric acid aspiration, asthma, cystic fibrosis, and 15 pneumonia to remove adventitious agents. A fluorocarbon lavage may also be provided to patients with pulmonary alveolar proteinosis, bronchiectasis, atelectasis and immotile cilia syndrome. In addition, fluorocarbon may be used in emergency lavage procedures to remove food aspirates 20 and other foreign materials.

Loss of lung resiliency can occur in both ARDS and RDS.

The use of fluorocarbons in both of these syndromes is discussed above. In addition, lungs can become stiff from hydrocarbon aspiration, smoke inhalation, and lung 25 contusions. Fluorocarbon therapy can be provided either as a surfactant supplement or for partial liquid breathing to supply oxygen to a patient or to facilitate a therapeutic regime. Treatment of pulmonary fibrosis, emphysema, and chronic bronchitis can all benefit from fluorocarbon therapy.

It has been noted above that a fluorocarbon liquid may be supplied to a patient in combination with a powdered surfactant or as a route for pulmonary drug delivery.

Antibiotics and antivirals may be provided in combination with a fluorocarbon liquid. For example, cytomegalovirus can induce life-threatening cases of pneumonia in immunocompromised patients. These individuals often require ventilation therapy. Fluorocarbon administration in combination with the guanosine nucleoside analog, 9-(1,3dihydroxy-2-propoxymethyl)guanine 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.

In addition, anti-inflammatory agents could be added alone or in combination to the antimicrobial agents contemplated above. These anti-inflammatory agents include but are not limited to steroid and steroid derivatives or analgesics. The fluorocarbon could be administered together with a bronchodilator including but not limited to Albuterol, Isoetharines, perbuteral or an anti-allergenic agent.

The various pharmaceuticals that can be combined with fluorocarbons to provide therapy via administration to the 15 lungs are too numerous to list. Except in some particularly preferred embodiments listed herein, the choice of pharmaceutical is not critical. Any non-damaging pharmaceutical that can be adsorbed across the lung membranes, or that can treat lung tissue, can be used. The 20 amounts and frequency of administration for all the various possible pharmaceuticals have been established. It is not contemplated that these will be significantly different for administration through use of fluorocarbon vehicles in partial liquid breathing. Thus, those of ordinary skill in the art can determine the proper amount of pharmaceutical and the timing of the dosages in accordance with already-existing information and without undue experimentation.

The fluorocarbon liquid may also be administered in combination with an antimitotic agent for cancer therapy.

Fluorocarbon liquid can also be used to facilitate oxygenation under anesthesia for patient's suffering from lung diseases such as emphysema, chronic bronchitis, and pulmonary fibrosis. Furthermore, fluorocarbons can be used for partial liquid breathing for any of the above mentioned maladies or any additional medical condition that would lend itself to this therapy.

The fluorocarbon liquid may advantageously be supplied to the physician in a sterile prepackaged form. Aliquots of the fluorocarbon are removed for administration under sterile conditions. Individual dosage volumes can be supplied for administration to newborns since newborn lung capacities are within a fairly narrow range. For those applications requiring a mixture of fluorocarbon and saline or powdered surfactant, each component can be provided separately and prepared for individual use. For lavage purposes, neat fluorocarbon or prepared emulsions of fluorocarbon and saline are provided prepackaged. It will be readily appreciated that there are a large number of potential additives that, in .combination with fluorocarbon liquid, have important medical applications in the lung.

15 Those with skill in the art will readily appreciate the 999 varied applications for fluorocarbon administration.

The invention is described in additional detail by the following representative examples.

PAGE EXAMPLES 20 Methods and Materials The following studies were approved by the Animal Care and Use Committee of the Children's Hospital of Pittsburgh.

Care and handling of animals conformed to NIH guidelines.

Thirteen piglets, ages 3 to 21 days, and weighing 2.9 25 0.6 kg, were anesthetized with alpha-chloralose (50 mg/kg) and paralyzed using metocurine iodide (0.3 mg/kg). Airways were secured by intubation followed by tracheostomy, and the trachea was tightly secured to the tracheostomy tube.

Volume-controlled CPPB was instituted using a commercially available ventilator (Servo 900C, Siemens Elema, Schaumburg, IL). Arterial and central venous catheters were placed by femoral cutdown for vascular pressure measurement and blood sampling. These measurements were interfaced to a fiberoptic recorder (PPG Biomedical, Pleasantville, NY). Animals were studied supine and with chest closed.

During stabilization, dextran (Gentran, was administered in 5-ml/kg aliquots to achieve a right atrial I I -47pressure between 5 and 8 mm Hg. Minute ventilation was adjusted to obtain PaCO, between 30 and 45 torr (4 and 6 kPa) at respiratory rates of 18 to 25 breaths/minute. Inspiration was restricted to 25% of the respiratory cycle, and 2 to 5 cm

H

2 0 positive end-expiratory pressure was applied. Lungs were ventilated with oxygen (FIO 2 In five piglets, the pulmonary pressure/volume relationship was studied, before institution of PAGE, over the range of lung volume associated with tidal breathing.

Proximal airway pressure was measured continuously with a dry transducer. CPPB was discontinued. The thorax was allowed to assume passive FRC at ambient pressure. The lungs were then inflated with air in 10-ml aliquots to 15 to 25 ml/kg above FRC. The deflation limb of the pressure/volume curve 15 was similarly determined by withdrawing 10-ml aliquots until airway pressure decreased below the ambient pressure.

In these same piglets, the expiratory flow/volume relationship was studied during CPPB by interposing between the ventilator and the tracheostomy tube a pneumotachometer 20 (Hans Rudolph, Kansas City, MO) interfaced to a respiratory integrator (Hewlett Packard, Waltham, MA). Flow and volume were recorded simultaneously during CPPB for later construction of flow-volume and real-time volume curves.

All studies were performed using the perfluorocarbon 25 FC77 (3M, St. Paul, MN), known to have a density of 1.75 g/ml, viscosity of 0.66 centistokes, surface tension of 14 dynes/cm, vapor pressure of 75 torr (10 kPa), and solubilities for oxygen and carbon dioxide of 56 and 198 ml gas/100 ml perfluorocarbon at 1 atmosphere pressure, respectively (all at 37 0 FC77 is immiscible in water and is closely related to other perfluorocarbons known to have negligible pulmonary absorption.

Once steady state was achieved during CPPB, arterial and venous blood were sampled, ventilatory measurements were performed, and vascular pressures were recorded to obtain data tabulated below.

I

I

-48- A volume of 30 ml/kg FC77, chosen to approximate the normal FRC, was preoxygenated at FIO 2 1.0 and warmed to 370c, and was then instilled into the trachea over 30 to seconds. Gas ventilation of the perfluorocarbon-filled lung was then resumed (PAGE) using the same ventilator settings as those used during CPPB.

PAGE was continued for 1 hour without changing ventilator settings. Over this period, 10 to 20 ml of FC77 was added to the lungs as needed to replace evaporative losses and compensate for changes in FRC, in order to maintain an expiratory meniscus of perfluorocarbon in the vertical outlet of the transparent tracheostomy tube at ambient pressure. At no time was perfluorocarbon drained from the lungs. No other drugs or fluids were administered.

15 After 5, 15, 30, and 60 minutes of PAGE, blood, respiratory, and hemodynamic measurements were repeated.

After 60 minutes of PAGE, pressure/volume and flow/volume studies were repeated (as described above) in the same piglets studied before PAGE to ascertain the effects of 20 perfluorocarbon instillation on inflation and deflation of the lungs with gas. Perfluorocarbon was not drained prior to these measurements.

To study static pressure/volume relations after PAGE, ventilation was interrupted. The perfluorocarbon-filled lung 25 was allowed to assume its FRC at ambient pressure. No attempt was made to measure this FRC nor was an effort made to assure that FRC of the perfluorocarbon-filled lung was comparable to FRC during CPPB. A meniscus of perfluorocarbon was uniformly present in the transparent vertical shaft of the tracheostomy tube. Proximal airway pressure was again measured continuously with a dry transducer. The lungs were then inflated with air in 10-ml aliquots to a 15 to level above FRC. The deflation limb of the pressure/volume curve was similarly determined by withdrawing 10-ml aliquots of air until airway pressure fell below ambient.

To study the flow/volume relationship during PAGE, air flow and volume were simultaneously recorded as described -49above for later construction of flow-volume and real-time volume curves.

Animals were then killed by bolus injection of potassium chloride. After death, selected piglets underwent sternotomy and resection of the right chest wall. Ventilation was resumed postmortem to observe the pattern of lung aeration during PAGE.

Measurements repeated throughout the hour of PAGE were compared to values measured during CPPB using analysis of variance. Post hoc tests were subjected to a Newman-Keuls' correlation for multiple comparisons.

Results Instillation of FC77 was well tolerated in all animals eooe with no apparent adverse respiratory or hemodynamic 15 consequences, and PAGE was instituted without adverse effects. No animal had an adverse event during PAGE.

Gas exchange: Although there was a significant decline in PO 2 on institution of PAGE, mean PaCO 2 remained stable (401 51 torr (53.6 6.8 kPa)) and arterial blood was fully 20 saturated in every animal throughout the study period.

Results are shown in Table II.

Table II Gas exchange during CPPB and PAGE CPPB Duration of PAGE (min) S 25 pH 7.42+.05 paCO 2 ,torr 38+6 paCO 2 ,kPa 5.1 +0.8 paO2,torr 503 64 paO,,kPa 67.2+8.6 HCO,- 24+2 AadO 2 ,torr 159+61 AaDO 2 ,kPa 21.3+8.2 5 15 30 7.41 +.04 7.432+.05 7.42+.05 7.43+.05 40+5 40+4 40+4 39+4 5.3+0.7 5.3+0.5 5.3+0.5 5.2±0.5 429+55** 384+38** 392±40** 394+62** 57.4+7.4** 51.3±5.1** 52.4+5.3 52.7+8.3** 25+3 26±2 25+2 25+2 157+54 201+37* 194+40 192+61 21.0+7.2 26.9+4.9 25.9+5.3 25.7+8.2 Gas exchange during PAGE was virtually as efficient as during CPPB. HC03- is expressed in meq/1. All values are means SD. p<.05 and p<.01 vs. values during CPPB, by ANOVA with Newman Keuls' correction for multiple comparisons.

PaCO 2 was not significantly different during PAGE from PaCO 2 measured during CPPB. Alveolar-arterial oxygen difference during PAGE (after correction for perfluorocarbon vapor pressure) and during CPPB were comparable. PAGE did not cause metabolic acidosis.

Ventilatory parameters: The use of volume-regulated ventilation assured that gross tidal volume during PAGE and during CPPB would be comparable. Peak pressure generated by breaths of fixed volume was comparable during CPPB and during PAGE. Static end-inspiratory pressure was also comparable 15 before and during PAGE. During PAGE, both calculated endinspiratory airways resistance and thoracic compliance were comparable to values determined during CPPB. Results are shown below.

Lung mechanics during CPPB and PAGE 20 CPPB Duration of PAGE (min) 15 30 Pmax 22.8+4.2 22.5±2.9 21.8+2.9 22.7+3.2 21.8±2.2 Pei 19.6+3.4 18.8+2.0 18.2+1.9* 18.7+2.2 17.6±1.6** Paw 7.3+1.0 7.9+1.1 7.6+1.0 7.7+0.9 7.4+0.8 25 ETV 43.6+8.7 43.7+8.8 44.0+8.7 43.6+8.7 44.0+8.9 Ct 3.0+1.1 3.1±0.8 3.2±.07 3.1 0.8 3.3+0.8 Raw 57+21 66+14 63 13 72+27 74+26 Lung mechanics were virtually identical during PAGE and CPPB.

Pmax peak airway pressure, Pei static end-inspiratory pressure, Paw mean airway pressure, all in cm H 2 0. ETV effective tidal volume delivered to the animal Ct total thoracic compliance, calculated as ETV/(Pei-PEEP), expressed in ml/cm H 2 0. Raw end-inspiratory airway resistance, calculated as (Pmax-Pei)/flow, is expressed in cm

I

-51- H0O/l/sec. All values are means SD. *p<.05 and **p<.ol vs. values during CPPB, by ANOVA with Newman Keuls' correlation for multiple comparisons.

Pressure/volume relationship: Within the range of tidal breathing, the pressure/volume relationship was consistently altered by the presence of FC77 within the lung. Despite a total thoracic anteroposterior diameter that averaged 9.3 0.8 cm, the perfluorocarbon-filled lung generated only about 4 cm H 2 0 more pressure for any volume of gas added above FRC than did the air filled lung (FIGURE Referring to FIGURE 5 in more detail, volume of gas above FRC (ml) is plotted on the y-axis, and static airway pressure (cm H 2 0) on the x-axis. Data for air-filled and PFC-filled lungs are shown as open circles and solid circles, S 15 respectively. The static airway pressure required to inflate the lungs with gas to volumes above FRC, within the range of tidal breathing, was greater for the perfluorocarbon

(PFC)

laden lung. Air-filled and PFC-filled lungs probably have different volumes at FRC, so the origins of the two curves 20 represent 0 volume above FRC, but do not represent identical lung volumes. The pressure/volume relationship of the perfluorocarbon-laden normal lung displays hysteresis, as does that of the air-filled lung. The pressure/volume curves of air-filled and perfluorocarbon-filled lungs differ by 25 about 4 cm H 2 0 (p<0.01 by ANOVA at every level of lung inflation). Data is mean sem.

Expiratory flow: The expiratory flow/volume relationship was altered by instillation of perfluorocarbon, suggesting a modest increase in expiratory airway resistance (FIGURE Peak expiratory flow was decreased, but time to peak flow was unchanged, and pulmonary time constant was only slightly increased (from 0.19 to 0.23 sec). Exhalation was virtually complete in the first half-second of expiration (FIGURE 7).

Referring to FIGURE 7 in more detail, the flow/volume relationships are expressed in terms of expiratory flow (ml/sec) on the y-axis versus exhaled volume (ml) on the x- -52axis. Open circles are CPPB data; solid circles are for PAGE. Expiratory flow/volume relationships for PAGE and CPPB differ in that peak flow is attenuated by the modest elevation of airway resistance that occurs during PAGE. Data is mean sem.

Referring to FIGURE 7, exhaled volume (ml) on the y-axis is compared with expiration time (sec) on the x-axis. Open circles are CPPB; solid circles are PAGE. Spontaneous exhalation against 2 to 5 cm H 2 0 positive end-expiratory pressure is minimally delayed by the presence of perfluorocarbon during PAGE. The pulmonary time constant (Tc) is prolonged from 0.18 to 0.23 seconds during PAGE. ETV effective tidal volume delivered to the animal. Data is mean sem. Differences are not statistically significant.

S 15 Direct observations of lung inflation: Direct inspection of lungs during PAGE in open-chest postmortem eo animals revealed a tendency toward sequential inflation of alveoli with air. Superior lung segments inflated with gas before dependent portions. Exhalation appeared to be more 20 even.

Hemodynamic variables: PAGE did not cause significant changes in heart rate, systemic arterial pressure, or right atrial pressure. Oxygen delivery to tissues was sufficient to prevent metabolic acidosis during PAGE, although venous 25 oxygen saturation was slightly lower than that during CPPB.

Results are shown in Table III.

Table III Gas exchange during CPPB and PAGE CPPB Duration of PAGE (min) 15 30 HR 180+37 182±30 189+32 189+35 189+38 Pao 96+11 94±11 94±11 95±10 96+8 Pra 6+1 5+1 5+1 6+2 5+1 Sat V 79+9 73+8** 71+8** 73+6** 73+8** -53- Hemodynamic measurements suggest a modest decline in cardiac output. Pao aortic mean pressure, Pra right atrial mean pressure, both in mm Hg. Sat V right atrial oxygen saturation. All values are means SD. vs. values during CPPB, by ANOVA with Newman Keuls' correction for multiple comparisons.

In summary, this disclosure details the efficacy of PAGE in normal piglets, and indicates that, in normal animals, ventilation and oxygenation can be supported almost as effectively by PAGE as by CPPB. Below are discussed the principles by which PAGE supports oxygenation and ventilation in normal animals, the implications of elevated pulmonary surface tension, and representative applications of PAGE to lungs with surfactant deficiency or dysfunction.

S 15 Gas exchange during PAGE: The total volume of gas eeo delivered to piglets in the present study greatly exceeded the estimated (2 ml/kg) dead space of airways. It follows that most of each 15-ml/kg breath was dispersed among 20 terminal airways and alveoli. It appears that dispersion of 20 inspired gas among higher generation airways and alveoli allowed intimate contact between gas and perfluorocarbon, and provided a suitable environment for in vivo "bubbleoxygenation." Otherwise, it is nearly impossible to explain the persistence of excellent oxygenation over the course of 25 these studies, for no more than 15 ml/kg dissolved oxygen could have been instilled with the perfluorocarbon at the onset of PAGE.

It was apparent on direct inspection of open-chest animals that inflation of alveoli with air during PAGE was asynchronous, perhaps reflecting the airway pressure dependence of perfluorocarbon displacement by gas at differing vertical heights in the lung. Moreover, the entire lung appeared airless throughout much of expiration.

Pneumotachometer measurements revealed that exhalation was 86% complete by 0.32 seconds after the onset of expiration.

Thus, the lungs were virtually airless throughout the last to 2 seconds of the 3-second respiratory cycle. In this -54airless state, perfluorocarbon was the sole apparent alveolar oxygen reservoir. The observation that oxygenation was excellent during PAGE, despite this prolonged airless state, strongly suggests direct participation of perfluorocarbon in pulmonary gas exchange. Were this not so, much of the pulmonary blood flow would represent an intrapulmonary shunt.

It might, however, be presumed that residual air is trapped in the lung of the closed-chest piglet at endexpiration and that this gaseous residual volume supports expiratory gas exchange and is solely responsible for the excellent oxygenation observed in this study. FIGURE 8 illustrates two possible relations of large, single bubbles to alveolar surfaces during PAGE. Bubble growth within the fluid (FIGURE 8A) would present two interfacial surfaces: S 15 gas/perfluorocarbon and alveolar lining/perfluorocarbon *oo*: Bubble growth against the alveolar lining (FIGURE 8B) would present an additional interface: alveolar lining/gas Inspiration (Insp) might be expected to distend surfaces in such a way as to minimize the total rise in 20 surface forces that occurs along all of these possible interfaces. Erythrocytes (RBC) are shown in capillaries within the alveolar septum. Their capacity to take up oxygen from perfluorocarbon would be an important determinant of PaO, during PAGE.

25 At peak inspiration, alveoli accommodate 30 ml/kg perfluorocarbon, in addition to tidal and residual gas.

Blood flow through capillaries that perfuse regions of the alveolar surface adjacent to perfluorocarbon would represent an intrapulmonary right-to-left shunt, even in inspiration, if the perfluorocarbon were unable to support gas exchange.

Values for PaO, during PAGE are incompatible with more than intrapulmonary shunt. Furthermore, the decline in P 2 O on instillation of perfluorocarbon and start of PAGE (after correction for perfluorocarbon vapor pressure) could not represent more than a 3% to 4% increment in the intrapulmonary shunt. This increment represents the maximum intrapulmonary shunt that could be attributed to the presence within alveoli of fluid that did not participate in gas exchange.

PaO 2 was lower during PAGE than during CPPB at FIO, of Ideal gas exchange would allow arterial PaO 2 to approach a theoretical alveolar value (PAO 2 of: PAO 2

FIO,

x (pB pH20 pPFC) pCO 2 /RQ (wherein p is pressure, B is barometric, PFC is perfluorocarbon, and RQ is respiratory quotient). Measured barometric pressure averaged 748 torr (100 0.7 kPa). If we assume an RQ of 1, theoretical PaO 2 would be 586 torr (78.1 kPa). Thus, the mean alveolararterial oxygen difference during PAGE (185 50 torr (24.7 6.7 kPa)) did not differ substantially from that measured during CPPB (159 61 torr (21.2 8.2 kPa)) Moreover, PaCO 2 during PAGE was comparable to PaCO 2 during PAGE (40 15 4 vs. 38 6 torr (or 5.3 0.5 vs. 5.1 0.8 kPa)). Thus, the combination of bubble-oxygenation, gas diffusion from perfluorocarbon to alveolar vessels, and ventilation/perfusion matching during PAGE was not appreciably less efficient than was gas exchange during CPPB.

20 Mechanical properties of the perfluorocarbon-laden lung: PAGE was instituted using a conventional volume-regulated, time-cycled ventilator. Minute ventilation, respiratory rate, inspiratory time, and PEEP were not altered to accomplish PAGE. Clinical measures of mechanical lung 25 function were not substantially different during PAGE than during CPPB. Peak airway pressure was not elevated after the instillation of FC77. Nor was static end-inspiratory pressure elevated during PAGE. The presence of perfluorocarbon did not have important adverse effects on mechanical function of the lung.

Early in expiration, peak flow was lower during PAGE than during CPPB. End-inspiratory airways resistances were 68 and 57 cm H 2 0/l/sec during PAGE and during CPPB, respectively. Although airways resistance was clearly higher during PAGE, it did not approach values reported for 1.66 kg infant lambs during liquid ventilation (3600 cm H 2 0/l/sec) This suggest that there is little bulk movement of

I

-56perfluorocarbon along airways during PAGE. Most of the bulk flow that takes place during PAGE must represent tidal movement of gas, and resistance to gas flow is little different during PAGE than during CPPB.

The pressure/volume curves of air-filled and perfluorocarbon-laden lung differed at every increment of gaseous inflation by only 4 cm HO0. This was unexpected, for the average lung height (allowing 3 cm for chest and back thickness) was approximately 6 cm, and the density of the perfluorocarbon alone would create a pressure of 10.5 cm H 2 0 at end-expiration in the most dependent segments of the lung.

In fact, an airway pressure of 3 to 4 cm H 2 0 was required to merely displace perfluorocarbon from the vertical portion of the endotracheal tube outside the airway. Therefore, the pressure required to displace perfluorocarbon from lung segments during bubble formation may be less than that suggested by the height of the end-expiratory fluid column within the lungs. This surprising finding probably reflects two factors: irregular shape of the lung, and interruption 20 of the airway fluid column by gas during lung inflation.

In the gas-free perfluorocarbon-filled lung, pressure generated in a dependent alveolus by the fluid above it is: P FC77 density x fluid column height. It is reasonable to suppose that, as the lung inflates with gas, 25 liquid continuity between vertically related lung segments is I lost, for the perfluorocarbon within airways is displaced by air. To estimate the alveolar pressure that must exist within a segment to support the lung above it, one would approximate the weight of lung and perfluorocarbon above the segment and divide that weight by the cross-sectional area of the lung at that vertical height. The lung is irregular in shape, and has greater cross-sectional area dorsally (below) than ventrally (above). Therefore, its volume is less than the product of vertical height and cross-sectional area of the base. It follows that, once airways have filled with gas and fluid continuity has been lost, the contribution of -57perfluorocarbon weight to alveolar pressure will be less than might be suggested by vertical height of the lung.

Moreover, there are at least two other possible explanations for the rightward shift of the pressure/volume relation of the perfluorocarbon-filled lungs during inflation with gas. First, perfluorocarbon was added to the lungs as the meniscus in the tracheostomy tube fell during the hour of PAGE. Some of this decrease in tracheostomy fluid level may have reflected a gradual increase in FRC during PAGE. It is possible that the weight of the perfluorocarbon and its effects on end-expiratory pulmonary recoil pressure caused FRC to climb over the course of the study, and that pressure/volume curves before and after PAGE were performed at somewhat different FRC. Second, it is also possible that, S 15 in addition to the 30 ml/kg perfluorocarbon instilled into "6 the lungs at the onset of PAGE and on top of any volume of perfluorocarbon added to FRC during PAGE to maintain a visible meniscus in the tracheostomy tube, some residual gas remained in the lungs of closed-chest piglets at end-

C.

20 expiration at ambient pressure. This could, again, have caused an elevation of the FRC from which pressure/volume curves were determined after PAGE. If either of these phenomena actually contributed to the rightward shift of the pressure/volume curve after PAGE, that would further reduce 25 the apparent significance of buoyancy of gas in perfluorocarbon to the pressure/volume relationship.

During CPPB, thoracic compliance may be defined as the effective tidal volume of inflation divided by the pressure excursion with each breath from PEEP to static endinspiratory pressure. By this definition, thoracic compliance increased from 3.0 to 3.1 ml/cm H 2 0 on institution of PAGE, and to 3.3 ml/cm H 2 0 over the ensuing hour. But, during PAGE, the pressure/volume relationship involves forces that have no counterparts during CPPB. The static pressure/volume relationship during PAGE cannot be adequately described by a single quantitative compliance calculation.

Nor does calculated compliance reflect "stiffness" alone -58during PAGE. As the lung inflates, gas displaces fluid in airways, and bubbles of gas are "blown" in perfluorocarbonfilled alveoli. These bubbles displace fluid, so some of the airway pressure measured during PAGE offsets the buoyancy of gas in liquid perfluorocarbon. Airway pressure also opposes the surface tension of the bubbles, their critical opening pressures, the surface tension of the alveolar lining at its perfluorocarbon or gas interface, the elasticity of the alveolar septae, and elastic properties of the thorax. The relative contributions of these forces cannot be deduced from this study, but the following comments are warranted.

First, in normal piglets, gas breathing during PAGE is characterized by pressure/volume hysteresis, just as it is during air breathing and during liquid ventilation (Barrow, 15 Respir. Physiol., 63:19, 1986). Yet it is not clear that hysteresis is required for adequate gas exchange to occur during PAGE. During PAGE, alveoli need not be distended with gas in expiration for adequate gas exchange to occur. There is a reservoir of dissolved oxygen in the perfluorocarbon.

20 Second, Avery et al. Clin. Invest., 38:456, 1959) have shown that gaseous opening pressure can be lowered by prior instillation of saline into alveoli. When lungs were partially distended by saline, the gaseous opening pressure of excised dog lungs was lowered by 5 cm H 2 0 relative to the 25 opening pressure of gas-free, collapsed lungs. Presumably, *the presence of fluid increases the alveolar radius of curvature that prevails prior to lung inflation. A similar effect apparently occurs during PAGE because alveoli are distended with perfluorocarbon at end-expiration, just as they are during liquid ventilation.

Moreover, during PAGE, if the lung is (as it appears to be) virtually airless at end-expiration, the opening pressure that opposes gas inflation should be that of bubble formation. Bubble formation should be initiated in perfluorocarbon-filled distal airways and therefore involve primarily the perfluorocarbon/gas interface. Surface tension along the alveolar lining should, in the perfluorocarbon- -59filled alveolus, contribute little to the opening forces associated with bubble formation. It appears that the modest airway pressures measured in this study may suffice to offset the opening forces intrinsic to that interface, regardless of alveolar surface-tension.

Third, in normal lungs, alveolar surface tension is so low that bubbles might be expected to grow during inspiration (after initial formation) against the surface tension of the alveolar lining, rather than within the perfluorocarbon (FIGURE 8B). This may not be the case in surfactant deficiency or dysfunction. Bubble growth could, in the surfactant deficient lung, occur by a different mechanism, *within the perfluorocarbon (FIGURE 8A). Therefore, the compliance of a normal lung may exceed that of a surfactant- 15 deficient lung during PAGE and it cannot be assumed that adequate ventilation will occur in surfactant deficient lungs at airway pressures as low as those measured in this study.

During PAGE, inspiratory alveolar distension must be opposed by surface forces acting along the alveolar lining, 20 the same as during CPPB and during spontaneous breathing. At the alveolar lining/perfluorocarbon interface, these forces should be minor, even in surfactant deficiency. This is a possible explanation for the improvement in lung compliance deserved during liquid ventilation in surfactant-deficient S: 25 animals.

However, if surfactant-deficient lungs were subjected to PAGE, and if bubbles were not separated from the alveolar lining by perfluorocarbon as the lung inflated, greater forces could develop along alveolar lining/gas interfaces (see in FIGURE It is reasonable to speculate that bubbles will expand within perfluorocarbon-filled alveoli in such a way that they are least opposed by surface forces. If surface forces at an alveolar lining/gas interface did exceed those at the gas/perfluorocarbon interface in FIGURE 8), one might expect bubbles to expand within the lower surface tension perfluorocarbon. The surface tension of the gas/perfluorocarbon interface (14 dynes/cm) is substantially lower than would be experienced at an air/water interface in the complete absence of any surfactant effect (70 dynes/cm) It is also well below the range of surface tensions measured in lungs of infants who died of the Respiratory Distress Syndrome of prematurity. Fluid derived from lungs of such infants generally have surface tensions between 20 and dynes/cm at minimal film area and between 50 and 60 dynes/cm at maximal film area (Avery et al., The Lung and its disorders in the Newborn Infant, Third Edition, W. B.

Saunders, Philadelphia, p.216, 1974).

One further influence on the pressure/volume relationship warrants discussion. During PAGE, bubble growth might take place adjacent to the alveolar lining, regardless of alveolar surface tension, because of its large radius of 15 curvature. If this were true, bubble growth at the alveolar lining would distend the large, low surface tension alveolar lining/perfluorocarbon interface in FIGURE as well as the alveolar lining/gas interface, even in surfactantdeficient lungs. Were this the case, adequate gas exchange 20 might occur at distending pressures as low as those measured in this study, even in surfactant deficiency.

Fortuitous properties of PAGE: A host of as yet illo*oo defined properties contribute to the efficacy of PAGE in the normal piglet. Adequacy of gas exchange during PAGE is 25 fundamentally dependent on "even" bubble-oxygenation of perfluorocarbon, and matching of any "unevenness" in this process to concomitant "unevenness" of pulmonary perfusion.

For instance, if bubble formation was greatly favored in superior lung segments, perfusion would have to be comparably maldistributed, or blood flow to the dependent lung would act as an intrapulmonary right-to-left shunt and create severe arterial hypoxemia. A severe nonuniformity of bubbling, even were it perfectly mirrored by redistribution of perfusion, would greatly restrict the cross-sectional area of lung vasculature able to participate in pulmonary blood flow and, thus, adversely affect pulmonary circulation. The limited hemodynamic data presented above does not suggest that PAGE -61severely impedes pulmonary blood flow. Therefore, the efficiency of ventilation/perfusion matching and gas exchange during PAGE is rather surprising.

Liquid ventilation, PAGE and disorders of surface tension: Resumption of air breathing is readily accomplished after liquid ventilation. Typically, at the termination of liquid ventilation, animals have been drained of perfluorocarbon to restore gaseous FRC before resumption of CPPB. However, the process of draining perfluorocarbon after liquid ventilation is incomplete. Calderwood et al.

(Anesthesiology, 38:141A, 1973) noted that 200 to 400 ml of perfluorocarbon was retained in the lungs of 10- to 19-kg dogs, despite attempted complete drainage. Shaffer et al.

(31) reported retention of 5 ml/kg in premature lambs after 15 instillation of volumes equivalent to measured FRC. While this situation differs from circumstances during PAGE, in which 30 ml/kg perfluorocarbon in instilled into the trachea and left in situ, data from experience in the resumption of CPPB after liquid ventilation (see below) indicates there may be special clinical applications for CPPB in surfactant deficiency or dysfunction.

Function of normal lungs does not appear to be enhanced by perfluorocarbon exposure during liquid ventilation, yet pulmonary function after drainage is virtually normal 25 (Shaffer et al., J. Appl. Physiol., 36:208, 1974), despite complete radiographic opacity of the lung fields (Gollan et al., Fed. Proc., 29:1725, 1970). In premature animals, however, retention of perfluorocarbon does improve lung function. Studies of minipigs (95 day gestation) showed a 2to 3-fold increase in lung compliance on return to air breathing after 20 minutes of liquid ventilation; these measurements approach those of the mature lung Shaffer et al. (Pediat. Res., 10:227, 1976) studied liquid ventilation in lambs of 135 to 138 days gestation with clinical RDS, and observed that peak intratracheal pressures were lower when CPPB was resumed after liquid ventilation than before (25 8 vs. 36 6 cm H 2 0) In lambs of similar -62gestation, Shaffer et al. (12) found that lung compliance and peak tracheal pressure were significantly improved on reinstitution of CPPB after liquid ventilation, and that airway resistance was unchanged. PaO 2 was greater and PaCO 2 was lower when CPPB was reinstituted after liquid ventilation than either before or during liquid ventilation. In premature lambs of similar gestation whose births were complicated by meconium aspiration (Shaffer et al., Pediat.

Res., 18:47, 1984), arterial PaO, and PaCO 2 improved on resumption of CPPB after liquid ventilation, when compared to values either before or during liquid ventilation.

These favorable effects of perfluorocarbon retention on gas exchange and mechanical lung function in immature animals indicate that PAGE may prove effective in surfactant 15 deficiency and dysfunction.

Impediments to clinical applications of liquid ventilation: One of the important impediments to clinical introduction of liquid ventilation techniques has been the complexity and experimental nature of the instrumentation required for extracorporeal gas processing and cycling of perfluorocarbon into and out of the lungs. In these respects, PAGE is less complex and less dramatic an innovation than liquid ventilation, because the subject method uses a conventional ventilator to process perfluorocarbon within the lung.

The following examples provide information relating to the effect of PFOB treatment on respiratory insufficiency in an experimental rabbit model. The general protocol for partial liquid ventilation of the rabbits is described below.

Animal Preparation New Zealand rabbits weighing between 2.8 and 3. 0 kg were anesthetized with 50 mg/kg of phenobarbital sodium iv and a cannula was inserted through a tracheotomy midway along the trachea with its tip proximal to the carina. Ventilation with a Servo ventilator 900C (Siemens-Elema, Sweden) was initiated using pure oxygen and zero end-expiratory pressure with a constant tidal volume of 12 ml/kg, frequency of and inspiratory time of 35%. Anesthesia was maintained with additional doses of pentobarbital, as required, and pancuronium bromide was administered as an intravenous bolus (0.1mg/kg) and followed by a continuous infusion (0.lmg/kg/hr) for muscle paralyzation. A solution of dextrose and 0.45% NaCi was administered continuously at a rate of l0ml/kg/hr as a maintenance fluid. A heating pad maintained core temperature at 37±+1C, monitored by an esophageal thermistor (Elektroalboratoriet, Copenhagen).

Left femoral artery and vein were each cannulated with polyvinyl catheters for arterial and central venous pressure recording and blood sampling. A special indwelling catheter (Mikro-pO 2 -Messkatheter, Licox) was inserted into the right femoral artery for continuous oxygen pressure monitoring S 15 (Licox, GMS, Germany). Arterial blood gas and Hb (hemoglobin) measurements were made by Osm-2 Hemoximeter and ABL-330 (Radiometer Copenhagen). Lung mechanics and endtidal CO 2 were measured by means of Lung Mechanics Calculator -940 (Siemens-Elema, Sweden) and CO 2 Analyzer 930 (Siemens- 20 Elema, Sweden), respectively. Intravascular pressure monitoring was made by using a Statham P23XL transducer (Spectramed, USA) and all tracings including ECG were recorded by a Sirecust 1280 recorder (Siemens).

Model of Respiratory Insufficiency S 25 After the control observations were made, lung lavage with 30ml/kg of warm saline (37 0 C) was performed to induce respiratory insufficiency. After the first lavage, positive end expiratory pressure (PEEP) was increased to 6 cmH 2 O and lung lavages were repeated to get an arterial pO 2 below 100 mmHg with the initial ventilatory settings (between 4-6 lavages). The same ventilation mode was used throughout the experiment (volume control ventilation; FiO 2 I, tidal volume: 12ml/kg, PEEP: 6 cm H 2 0, frequency: 30/min, inspiratory time: Partial Liquid Ventilation Procedure: After respiratory insufficiency was induced, PFOB liquid was administered through the tracheal cannula into the -64animal's lungs with incremental doses of 3 ml/kg up to a total volume of 15 ml/kg. Animals were ventilated for minutes after each dose of PFOB instillation with the same ventilatory settings as mentioned above and thereafter arterial blood gases, cardiocirculatory parameters and pulmonary mechanics were measured. After the last dose PFOB measurements, animals were sacrificed by administration of h i g h d o s e p e n t o b a r b i t a l Mean arterial oxygen tensions following PFOB administration Figure 9 is a graphic representation of the results of the experimental protocol described above. The mean arterial oxygen tension in the six rabbits tested was 504.2 mmHg.

Following lung lavage to remove surfactant the arterial oxygen tension dropped to a mean value of 75.1 mmHg. The 15 administration of increasing volumes of PFOB resulted in increasing arterial oxygen tensions. Doses of 15ml/kg of PFOB increased oxygen pressures to 83% of their original value. These results are compared to the use of saline for partial liquid ventilation. Increasing volumes of saline in 20 place of PFOB yielded an additional drop in arterial oxygen pressure. This data indicates that the administration of the perfluorocarbon PFOB significantly improved the arterial 0000.0 oxygen tension in the experimental animals as compared to saline treated controls.

25 Mean arterial carbon dioxide tensions following PFOB administration Mean arterial carbon dioxide tensions were calculated following lung lavage using the experimental protocol described above. Figure 10 is a graphic representation of these results. Before lavage the average arterial carbon dioxide tensions in the lungs was 37 mmHg. Following the lavage procedure the carbon dioxide levels increased to 48.7 mmHg. This level decreased after administration of PFOB, indicating that CO 2 transport was also facilitated by PFOB administration.

Mean airway pressures following PFOB administration Mean airway pressures were determined following

PFOB

supplementation of surfactant deficient animals. Figure 11 shows mean airway pressures measured in cmH20 as a function of increasing volumes of PFOB added. Following lung lavage the airway pressures increased due to surfactant depletion.

PFOB supplementation decreased mean airway pressure.

The data for the above three Examples are provided in Table IV.

*e *a *a *a

S.

S. a a. a a.

a. S S S S S *SS S S S S a a a.

a *5a .a Table IV INTRATRACHEAL PFOB mi/kg

BEFORE

LAVAGE

504.2 a ,2 x mmHg

ARDS

75. 1 3 159.6 6 9 12 296.7 365.7 398.2 419.9 1- 1 I 39.7 15. 0

I

a 'C 2 x mmHg

SD

Peak Airway X Pressure cmHO

SD

37.0 2.6 12.4 1.4 48.7 6.0 25.5 1.0 38.1 42.8 4.7 21.3 54.4 4.8 20.6 33.4 45.0 35.7 44.8 4.6 4.8 20.6 20. 6 1.6 1.5 27.3 45.5 4.4 21.1 1.4 1.4 1.2

Claims (32)

1. 2. The method of Claim 1, wherein the host is in need 15 of treatment for pulmonary surfactant deficiency or dysfunction and said fluorocarbon liquid has favourable lung surfactant replacement characteristics.
2. 3. The method of Claim 1, wherein continuous positive pressure gas breathing is provided into the perfluorocarbon 20 liquid containing air passages by external ventilation equipment.
3. 4. The method of Claim 3, wherein said external ventilation equipment a volume-regulated, time-cycled respirator or a pressure-limited, time-cycled gas respirator. 25
4. 5. The method of Claims 1 to 4, wherein the volume of fluorocarbon liquid is maintained substantially equivalent to the pulmonary functional residual capacity of the host.
5. 6. The method of any one of Claims 1 to 5, wherein the volume of perfluorocarbon liquid introduced into said pulmonary air passages is at least about 1/2 of the pulmonary functional residual capacity of the host.
6. 7. The method of any one of Claims 1 to 5, wherein the volume of perfluorocarbon liquid introduced into said pulmonary air passage is at least about 3/4 of the pulmonary functional residual capacity of the host.
7. 8. The method of Claims 1 to 7, wherein the fluorocarbon is a brominated fluorocarbon. I -68-
8. 9. The method of Claim 8, wherein the brominated fluorocarbon is perfluorooctylbromide. The method of any one of Claims 1 to 9, wherein the equilibrium coefficient of spreading of said fluorocarbon is at least
9. 11. The method of any one of Claims 1 to 10, wherein the amount of fluorocarbon liquid introduced into the mammalian host is at least about 0.1% and less than 50% of the functional residual capacity of the host. 1 0
10. 12. The method of any one of Claims 1 to 11, wherein the amount of fluorocarbon liquid introduced into the host is at least 0.1 ml/kg of the host's body weight and not more than about 50 ml/kg of the host's body weight.
11. 13. The method of any one of Claims 1 to 12, wherein 15 the host is in need of removal of material from inside the pulmonary air passages, further comprising the step of removing said fluorocarbon liquid, together with said material, from the air passages.
12. 14. The method of Claim 13, further comprising the 20 steps of: permitting said material to float on said fluorocarbon; and removing said floating material from the air passages. 25
13. 15. The method of any one of Claims 1 to 14, wherein said fluorocarbon liquid contains a pharmacologic or diagnostic agent in particulate form, whereby said agent is suspended in the fluorocarbon liquid and said agent is delivered to the air passages of the host.
14. 16. The method of Claim 15, wherein said particulate is a solid particulate.
15. 17. The method of Claim 15 or Claim 16, wherein said pharmacologic agent is a hydrophilic lung surfactant in powdered form.
16. 18. The method of any one of Claims 1 to 17, wherein said breathing gas is oxygen. I -69-
17. 19. The method of any one of claims 1 to 18, wherein said method is performed on a host in need of resuscitation. The method of any one of claims 1 to 18, wherein said host is in need of cardiopulmonary resuscitation.
18. 21. The method of any one of claims 1 to 18, wherein said host has a respiratory distress syndrome and said method is effective to alleviate said respiratory distress syndrome.
19. 22. A method for maintaining respiratory gas exchange, substantially as hereinbefore described with reference to any one of the examples.
20. 23. A medicament for the treatment of a respiratory disease by introducing an amount of the medicament into the lung of a patient such that the introduced amount does not exceed the functional residual capacity of the lung of the 15 patient upon exhalation, taking into consideration any oe positive or negative end expiratory pressure applied to said ooe patient's lung, and then moving a breathing gas into and out of the patient's lung such that said breathing gas oxygenates said introduced amount of medicament within the lung, whereby 20 the patient is breathing a gas while the introduced amount of medicament is in the lung, wherein the medicament has a positive coefficient of spreading and comprises fluorocarbon *o. Sliquid.
21. 24. A medicament for the treatment of respiratory disease, wherein a volume of said medicament is introduced into the lung of a patient, and said introduced amount is o between 0.1% and not more than about 100% of the patient's functional residual capacity, wherein upon moving a breathing gas into and out of the patient's lung said breathing gas oxygenates said introduced amount of medicament within the lung, whereby the patient is breathing a gas while the introduced amount of medicament is in the lung, said medicament comprising a fluorocarbon liquid. A medicament for the treatment of respiratory disease substantially as hereinbefore described with reference to any one of the Examples.
22. 26. A method for facilitating lung function, comprising the steps of: first introducing into the lung of the patient an effective amount of a liquid fluorocarbon in the form of an aerosol; and then moving a breathing gas into and out of the patient's lung.
23. 27. The method of Claim 26, wherein said effective amount is at least about 0.1% of the functional residual capacity of the lung of the patient upon exhalation, taking into account any positive or negative end expiratory pressure applied to said patient's lung. ~28. The method of Claim 26, wherein said fluorocarbon further comprises a dispersed pharmacological agent. 15 29. The method of Claim 28, wherein said pharmacological agent is in particulate form. emeo
24. 30. A device for regulating fluid flow during perfluorocarbon associated gas exchange, comprising; first and second conduits having distal and 20 proximal ends; an endotracheal tube; a chamber adapted for establishing fluid communication between said endotracheal tube and said conduits, said chamber interposed between said conduits 25 and said endotracheal tube; at least one valve connected to said conduits to reversible establish fluid communication between said chamber and either the proximal end of the first but not the second conduit, or the proximal end of the second but not the first conduit; means associated with said first conduit to introduce and remove a fluorocarbon liquid to and from said chamber and into the lung; and means associated with said second conduit to introduce and remove breathing gas to and from said chamber to permit a patient into whom the endotracheal tube is introduced to breathe a breathing gas into and -71- out of the perfluorocarbon-containing pulmonary passages into which said perfluorocarbon liquid has been introduced by said device.
25. 31. The device of Claim 30, wherein the first conduit comprises first, second, and third channels having proximal ends that collectively establish fluid communication with the chamber as regulated by the valve means.
26. 32. The device of Claim 30 or 31, wherein the second conduit comprises a single channel having an aperture to the ambient environment.
27. 33. The device of any one of Claims 30 to 32, wherein the valve means opens the aperture to the ambient environment when fluid communication is established between the chamber and the first, but not the second conduit, and closes the 15 aperture when fluid communication is established between the chamber and the second but not the first conduit.
28. 34. A device for regulating fluid flow during perfluorocarbon associated gas exchange, substantially as hereinbefore described with reference to the accompanying 20 drawings. A system for implementing perfluorocarbon associated gas exchange, comprising: ~a device for first introducing perfluorocarbon liquid into a patient's pulmonary air passages, S 25 a gas ventilator for maintaining respiratory gas exchange in said patient's perfluorocarbon liquid- containing pulmonary air passages by secondly introducing and removing multiple breaths of breathing gas into said passages during a treatment period so that said breathing gas physically admixes with said perfluorocarbon liquid in said pulmonary air passages, so that said passages simultaneously contain both said breathing gas and said perfluorocarbon liquid, and a device operably associated with both said introducing device and said gas ventilator for regulating the aforesaid introduction of liquid and introduction and removal of gas during the treatment period.
29. 36. A system for implementing perfluorocarbon associated gas exchange, substantially as hereinbefore described with reference to the accompanying drawings.
30. 37. Use of a fluorocarbon liquid for the preparation of a medicament for maintaining respiratory gas exchange in a mammalian host requiring said maintenance, said maintenance comprising the steps of: first introducing into the pulmonary air passages of a mammalian host an effective therapeutic amount of a fluorocarbon liquid, said amount being between about 0.1% and not more than about 100% by volume of the pulmonary functional residual capacity of the host; and thereafter 1o moving a breathing gas into and out of the pulmonary air passages so that upon inhalation said breathing gas forms bubbles in and oxygenates said introduced amount of fluorocarbon liquid in the pulmonary air passages.
31. 38. A fluorocarbon liquid when used for maintaining respiratory gas exchange in a S.o. mammalian host requiring said maintenance, said maintenance comprising the steps of: 15 first introducing into the pulmonary air passages of a mammalian host an effective therapeutic amount of a fluorocarbon liquid, said amount being between about 0.1% and not more oooo than about 100% by volume of the pulmonary functional residual capacity of the host; and thereafter moving a breathing gas into and out of the pulmonary air passages so that upon inhalation said breathing gas forms bubbles in and oxygenates said introduced amount of 20 fluorocarbon liquid in the pulmonary air passages.
32. 39. A method for maintaining respiratory gas exchange, comprising the steps of: introducing into pulmonary air passages of a mammalian host an effective therapeutic amount of a fluorocarbon liquid, said amount being between about 0.1% and not more than about 100% by volume of the pulmonary functional residual capacity of the host; and moving a breathing gas into and out of the pulmonary air passages. Dated 15 July, 1999 University of Pittsburgh of the Commonwealth System of Higher Education Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:\LIBZZ00 IO:MMS