Surgery – Miscellaneous – Methods
Utility Patent
1997-11-21
2001-01-02
Nguyen, Dinh X. (Department: 3738)
Surgery
Miscellaneous
Methods
C128S200240
Utility Patent
active
06167887
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of biological gas exchange in mammals using C-10 perfluorinated hydrocarbons (perfluorocarbons) as a medium of the exchange. More particularly, the present invention is directed to use of those C-10 perfluorinated hydrocarbons in biological gas exchange, primarily in liquid ventilation, which due to their chemical structure can be readily obtained or purified in a state free of isomeric contaminants.
2. Brief Description of the Prior Art
It has been known for a long time that perfluorocarbons are chemically and biologically inert substances and have the unique capability of dissolving very large volumes of gases, including oxygen and carbon dioxide. Taking advantage of these properties of the perfluorocarbons, it was demonstrated as early as 1966 that the lives of experimental animals, such as mice, can be sustained while the animals are submerged in an oxygenated perflurocarbon liquid medium.
The above-noted pioneering discovery spurred extensive further research in this field by the present inventor, his coworkers and by other scientists as well. As a result, perfluorocarbons emerged as leading candidates for gas-transporting components of artificial blood, and as mediums of gas exchange in liquid ventilation.
Specifically, liquid ventilation is a term used for describing gas exchange, i.e. breathing of a mammal, where a certain volume of gas transporting liquid is added to fill the entire or partial volume capacity of the lungs, and where the presence of the liquid facilitates the breathing process. The term “tidal liquid ventilation” or “total liquid ventilation” is used to describe liquid ventilation where the lungs of the mammal are completely filled with the liquid which is oxygenated by bubbling or by passing it through a membrane oxygenator. It is now generally accepted in the art that although the feasibility of using perfluorinated hydrocarbons to sustain the lives of experimental animals was initially demonstrated by this method (the animal was submerged in the liquid medium) “total liquid ventilation” is unlikely to become a medically accepted procedure to be used with humans who need respiratory assistance.
Another form of liquid ventilation where only the functional residual volume of the lung is filled with the perfluorocarbon and where gas exchange is assisted with the use of a mechanical ventilator, is termed “partial liquid ventilation”. In partial liquid ventilation approximately 30 milliliters (ml) of the perfluorocarbon (or mixture of perfluorocarbons) is used per kilogram (kg) body weight of the mammal.
Still another form, which has been suggested relatively recently by one of the present inventors is “low volume” or “alveolar” ventilation where the perfluorocarbon (or mixture of perfluorocarbons) is added in sufficient quantity only to fill the alveoli (air sacs) of the lung and the mammal is allowed to breath normally, or with the assistance of a mechanical ventilator. In this “low volume” method only approximately 0.1 to approximately 10 ml of the perfluorocarbon (or mixture of perfluorocarbons) is used per kg body weight of the mammal.
The research prompted by the 1966 discovery of the possibility of “liquid breathing” in a perfluorocarbon medium, resulted in voluminous scientific and patent literature on the medical aspects of the subject. It also led to the development of voluminous literature pertaining to the manufacturing and selecting suitable perfluocarbons for “liquid breathing” and “artificial blood” purposes. A substantial list of scientific papers, publications and patents is provided in an Information Disclosure Statement, which is filed in connection with this application for patent. An article titled “Liquid Ventilation A State of the Art Review” by Shaffer et al. in Pediatric Pulmonology 14:102-109 (1992) reviews the properties of perfluorocarbons which are pertinent to liquid breathing and provides a long list of references pertinent to the subject.
A publication titled “Response of the rabbit lung as a criterion of safety for flurocarbon breathing and blood substitutes” by Clark Jr. et al. in Biomat., Art. Cells & Immob. Biotech 20(2-4) 1085-1099 (1992) describes hyperinflated non-collapsible lung syndrome (HNCL) which has emerged as a serious problem associated with the use of certain perfluorocarbons in liquid breathing and in artificial blood as well. Briefly, it was found in experimental rabbits, and later in other mammals as well, that when perfluorinated decalin (F-decalin) and certain other perfluorocarbons are administered to rabbits either as an emulsion (artificial blood) or by intratracheal infusion, the animals tend to develop hyperinflated non-collapsible lungs, which can eventually prove to be fatal. The hyperinflated non-collapsible lungs are fatal to the animal because, the lobes completely fill the thorax and are not compliant.
The above-noted article in Biomat., Art. Cells J. Immob. Biotech and a poster presented by Clark Jr. et al. at a symposium Hot Topics '95 in Neonatology, Dec. 3-5, 1995, Washington D.C., titled “Fluorovent™: A New Perfluorocarbon for Liquid Ventilation”, describe the scientific quest for perfluorocarbons which would be ideally suited for use in liquid ventilation and artificial blood as well. The criteria mentioned for ideal, or at least better suitability is avoidance of hyperinflated lung syndrome and an acceptably low “body dwell time” after administration of the perfluorocarbon liquid to the mammal. Out of an abundance of caution it is considered desirable for the fluorocarbons to be completely removed from the body after treatment. Alternatively, if complete removal after treatment is impossible, it is in any case desired for the perfluorocarbon to have as short a residual dwell time as possible. In this regard it is noted that the primary mechanism by which the mammalian body eliminates fluorocarbons is through exhalation by the lungs. Although the precise mechanism of this removal by exhalation is not presently known the rate of removal has been recognized to be related to the volatility (vapor pressure at body temperature) of the perfluorocarbon liquid. While, as mentioned above, excessive persistence of the perfluorocarbon in the mammalian body after treatment is undesirable, excessive or too rapid loss by exhalation/evaporation is also undesirable since it requires replenishment of the perfluorocarbon liquid during treatment. As it is readily understood by those skilled in the art, the rate of loss due to exhalation/evaporation is also related to the volatility (vapor pressure at body temperature) of the perfluorocarbon substance.
Finally, as manifested in the above-mentioned article by Clark Jr. et al. in Biomat., Art. Cells & Immob. Biotech 20(2-4) 1085-1099 (1992) and in the Abstract of the poster presentation by Clark Jr. et al. at a symposium Hot Topics '95 in Neonatology, the prior art recognized that causation of hyperinflated non-collapsible lung syndrome (HNCL) is also related to the volatility of the perfluorocarbon liquid, whether it is used in artificial blood or in liquid ventilation. For example, perfluorinated decalin (F-decalin) having a boiling point of 141-142.5° C. is known to cause hyperinflated lung syndrome, while perfluorinated methyldecalin (F-methyldecalin) having a boiling point of 161° C. does not. F-methyldecalin, however, persists somewhat longer in the body than what is considered desirable. Thus, the article in Biomat., Art. Cells & Immob. Biotech 20(2-4) 1085-1099 (1992) refers to a search for flurocarbons “having boiling points between 140° C. and 165° C. “in order to find a perfluorinate with the highest transpiration rate, and hence vapor pressure, compatible with an acceptable body dwell time.”. The abstract of the presentation at the above-mentioned symposium refers to an evaluation of the properties of many perfluorocarbons (PFCs) . . . “to find the optimum PFC for liquid ventilation”. The abstract mentions “two properties—boiling point related
Clark Leland C.
Hoffmann Richard E.
Klein & Szekeres LLP
Nguyen Dinh X.
Synthetic Blood International, Inc.
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