CA2238013A1 - Methods and apparatus for closed-circuit ventilation therapy - Google Patents

Abstract

Methods and apparatus are provided which allow for closed-circuit ventilation for the treatment or diagnosis of disorders. The closed-circuit ventilation apparatus of the present invention (200, 300, 400, 500, 600) provide a closed-circuit respirator that isolates the gas flow path from the ventilator apparatus. This allows the prolonged administration of expensive materials such as fluorochemicals without excessive loss due to evaporation. As such the provided methods and apparatus are particularly applicable to liquid ventilation including partial liquid ventilation and total liquid ventilation.

Description

r CA 02238013 1998-O~i-l~i METHODS AND APPARATUS FOR CLOSED-CIRCUIT \JENTILATION THERAPY
Fieid of the Invention The present invention relates to methods and 9~ ~ dll~o for ,~, ~ dlU~y ~....~;'_ and, more pa,i~
relates to closed-circuit ~.".lil~liùn the ll~all,l or diagnosis of various disorders.
Bc kl ~ -' of the Invention 1~ ~ ' di- . involves the : ' of fresh gases, especially oxygen, to the lung during , ,: and the removal of waste gases, particularly carbon dioxide, during expiration. In healthy 1i~ , ~ di- iS normally effected by s, t~ e~ ;'_ or breathing which results in the I,-': - of the - e y gases.
U fu.i : ~,anumberof"h~ ~ ' C 'and r-~ p~ mayc , I ~ -normal, ' y functionleading 10 to the inhibition of effective ,~, 1 or total ,., dt~ y failure. In such cases ,l ;~ , y therapy, often involving artificial ~.,..lildl to some degree, is indicated. For example"l, dlJry therapy is often indicated for patients ' ~ surgery or those suffering disorders and diseases of the r y air pr " - In particular, patients suffering from lung - n, diver's lung, post-traumatic ll, ~ y distress, post-surgical an l~ Ll~ ~, irritant in~uries, septic shock, multiple organ failure, '' ' ' -' 's disease, ol.OLl.,.,li.~ lung disease, ~ . y edema or 15 any other condition resulting in lung ;~ dCi ' d ri y or ~I, di y distress are strong - ' ' for ~,, y therapy. Typically, such IL ~ ~ ~' 7y therapy involves the use of ' ' .. i ' -s. ~ ' Oare simply clinical devices that effect ~ ' or, in other words, cause airflow into the lungs. More ~, ~c; ~1~, such devices typically force air into the lungs during the , ~ dliUII phase of the breathing cycle but allow a return to ambient pressure during s, : tAhdldl The forced influx of fresh air by ' ' ~
20 the, ' y mediated ,u.~ee ~ that comprise r., ~ . in ' One of these p .~ . removal of waste gases, is a primary ' by which carbon dioxide is excreted from the body. In normal gas mediated carbon dioxide ~emoval, fresh air is brought into contact with the alveoli (alveolar ,. ~ti~ n) thereby, ~ li..g gas exchange wherein carbon dioxide passes from the body and is exhaled. The other essential ' r ~ ~ OA~ . ;OCO
the abOu.r of oxygen into the blood from the lungs. It is primarily a function of the . ' whereby the partial 25 pressure of oxygen (P02) in, ' y capillary blood ~, ' ' dt~o with the partial pressure of oxygen in inflated alveoli.
The oxygen gradient between alveolus and capillary favors transfer of oxygen into blood because the repeated influx of fresh oxygen through .. ' ,, or assisted) maintains alveolar P02 at higher levels than capillary P02.
Modern ' ~ ' ~..lilalulo are designed to provide ~.: ' by ,. ~ ' ~ tidal volume (breath), flow rate, delivery profile and r~, ,_' y flow thereby cu.,~ , carbon dioxide excretion. Because they can also regulate airway 30 pressure and the ~ , - of inspired oxygen they offer control over GA~., ' as well.
At least twenty makes and models of ' -' .. ' O are used in North America today. Almost all the ~.i.,t '. O used in operating rooms, recovery rooms and intensive care units are volume-r I " ' ~~Lildlulo. With a device of this type the operator may set tidal volume"l, dloly rate, and ~ , i y rate allowing the ventilator to deliver a set volume of gas r.~ ." of the airway pressure. Such devices usually have a pressure cutoff to 35 prevent damage to the lungs. In contrast, pressure~ ,. ' ~ O are standard in neonatal intensive care, in chronic ~~-.lildlu, ~ and during patient transport. Pressure Gu"ll~ : ' I O typically allow the operator CA 02238013 1998-0~
WO. 97/19719 PCT/US96/18989

-2-to select the .., dlUIy rate, the;, dlury 3as flow and the peak airway pressure. The ~'u..'ilalul then delivers inspired gas, while i.." the tidal volume, until the desired pressure is reached. Each of these types of ti6i ~ dld a number of 5, ' ' ~' features which allow . . '~ control over the delivery of qases to the lung. For example, typical ' - ' . ..lilalu.~ offer a number of Gomplex delivery profiles designed 5 to optimize the il.l. ' : of gases into the lung taking into acGount the physiGal state of the patient, LIIGI~P~
~-, Olll_..lS and the ~ , pattern of the patient under different c~ " In order to meet the diverse needs of patients requiring ~"1'_: therapy, common ~ ;r a offer several ~ t !a: modes, each having a variety of ,u" " ~ pal~ ~, offering an almost unlimited ~_,.Jt "~y. Some common ~~ ilal;un modes include c..,.l-." d ' '~ ' n,assistcontrol, IOI ' i y~a,~: sy, ' . ~ IGIII~ L~ -' i y 10 ~C~.Lilai' 1, C ' positive airway pressure, pressure s 1.." ' ~ t;lai . pressure ~ '' ' inverse ratio ._..lilal;~m, pressure support as well as ' of modes. ul~r-.. tul~, in both types of ~ available iblul~ the expired gases, including any bioactive agents ;..I~. dl ' during , or exhaled pa ' j ' material, w. are typically released into the _...;.l during use.
In contrast to standard ' -~ ~ ,tjl ~I;--n~ liquid ., ' i is a technique which involves i..l, ' " an 15 OAY~, ' ' liquid medium into the r ~ y air passages for the purposes of waste gas exchange and OA~, E - 11~, there are two separate; ' , for r ru" E liquid ~. ' . total liquid ~ aliLln and partial liquid ~. ~a Total liquid ~1 ~;' or "TLV" is the, ' y ;..1,1 h of warmed, eAIIacG,r~ OA~
liquid .., alL.y promoter (typically r; ~ h ~ ~ at a volume greater than the rl ' residual capacity of the subject. The subject is then : ' to a liquid breathing system and tidal liquid volumes sre delivered at a 20 rr. ~y d, " ~ on le, ' di y I~ while exhaled liquid is pur~ed of C02 and tJA~ od o~ .IUI~ 9Y
between the breaths. CL Ø~ 1~, partial liquid ~. ' or "PLV" involves the use of e ~. -' ' ' ~,. ' i in r '' ~~i with r ' Y C ~ ~ ' of a ,.;~ ~l y promoter capable of OAYO l;UI1. As with TLV the .., al~..y promoter typiGally e ~ e.> ri . ~ -~ whiGh may be OA~ .d GAIII~UI~UUf~ prior to ~ ' In the instant 3~, '' " the term "liquid ~_.,~;' -" will be used in a generiG sense and shall be defined 25 as the hlll. ' : of any amount of ." aluly promoter into the lung, including the ' , of both partial liquid ..lilai and total liquid ~~...lilai' The concept of liquid ~ :!e t"i~, ~ more than thirty years ago when it was shown that animals ~ , -' in a h1~ ~.uA~, ' ~ , y promoter ~saline) could breath the liquid and . '~ resume gas b,Gai' g For practical purposes liquid ~G " " - became a viable teGhnique when it was di~",.ar~d that 30 L~.. ' -' Gould be used as the .., alO~y promoter. Liquid breathin~ using o~y~, elOd r . ~ has been d : ~I-,d on several occ- ;"~c For example, an animal ' ~, ' in an oxy~, lol r . ~ liquid may exchange oxygen and carbon dioxide normally when the lun~qs fill with the rl~,u.Jrl ' Although the work of breathing is increased in total: ' ~;JII experiments, the animal can derive adequate oxy,qen for survival by breathing the IIAY~, : ' rlUU,~ ' ~' liquid. In particular, it has been e '-' '-' that total liquid ~ ..lilaliùn may keep 35 mammals alh~e for extended periods prior to returning them to ~ ~. ' gas L~ ' "

r CA 02238013 1998-0~

3-Use of liquid ~IC.~t;' may provide v 'Ci I medical benefits which are not available through the use of : ~ ~ " ~~' ' ' ' ~c.,t;latu,~ , a breathable gas. For example, the weight of the 1~, ' dlUIy promoter opens alveoli with much lower ventilator pressure than is possible with gas. A'";' 11~, liquid .~.~t;lal' using li .-' ~ ' as the rl, ' al-..y promoter has been shown to be effective in rinsing out c~ng~ :' c materials 5 ~es~ d with r., ' ai y distress ;.~,ldl Moreover, liquid ~ i" ' has been shown to be a promising therapy for the 11,: : of 1. ,' dlUIy distress sy..d,. involving sulla..i ~ "~y or dy;,ll :1 Elevated alveolar surface tension plays a central role in the pai' , h~, ' ' 9J of the i"~, ' y Distress Syndrome ~RDS) in ~ a~
infants and is thought to s ~i' to the dy;,ll ' in children and adults. Liquid ~autildliua~ particularly using li ~ .~' ' is effective in - 1~ ' l-deficient disorders because it -' 1.,~ the airlfluid I ~ Icces in the lung 10 and thereby greatly reduces r-~ y surface tension. Moreover, liquid ~. " ' can be r r ~ , " ' ' without undue alveolar pressures or impairing cardiac output and provides excellent gas exchange even in ~ infants. Other beneficial aspects a~ss -~- d with liquid ~ ilai' include f_~"" " Of r ' y drug delivery and lung cancer h,~ i' luia.
Despite the . ' ' '' PIN i 15f ass ' ~ with liquid ~ lilai' n, the use of total liquid .~ ;'.. ' as a 15 therapypresents ',, " :: ," :'-~ TLVrequiresthattidalbreathsoftherl ,' ypromoterbe ' ' '1~
cycled into and out of the lungs. Ul "Ciid c.. ...:' ' I 3t' ' ' ~ I;hfIU~r such as those discussed above, will not work in total liquid ~ t;lai' p. ' c;..... Total liquid breathing in a hospital setting requires dedicated 1, :" ' equipment, currently not available r ..;ally, capable of handling liquids. Moreover, the 1l, ' di y promoter must be GAY~, d and purged of carbon dioxide t:AII r ~ , a difficult process requiring sr ' " ' e, ', and 20 large volumes of oxygen. Further, eAll-- r- lSdI scrubbing of the 1., ' aLI~Iy promoter, pal~iL ' 1~ -' - ' Is currently results in ': lid losses as part of the medium is vaporized during the, . ' ~. In addition, as the 1., y promoter is OAY~, ' and purged of carbon dioxide outside the body while being cyclically delivered to the lungs, a large and pul. " '1~ expensive priming volume of 1., ' allJIy promoter is required to fill the liquid breathing device. Acc~,.l" "'~, capital costs _ r lud with liquid breathing are '' _'' In order to obviate many of these , '' :' s, yet still retain the benefits inherent in liquid .. i'' ' the i ' ', of partial liquid .. ~;!a:' was ~ , ' Partial liquid ~. :" ' as described in Fuhrman, U.S. Patent No. 5,437,272 and published PCT A, '' ' No. WO 92119Z32, is a safe and ~ .~, ' clinical ,, " ' of liquid breathing using GAY~, ' I' ~ ' ' In PLV a liquid, vaporous or gaseous, , ' aluly promoter ~again typically a ~IUU(~b ' ~1' is ;,.l,. ' ' into the, ' y air passages at volumes ranging from just enough to interact with 30 a portion of the, ' y surface all the way up to the IL ~' residual capacity of the subject. ~ ,' a; y , ~ t~,~ are any: , ' that functions, sy ' '1~ or pulmonarily, to improve gas exchange and 1~
~rr y. R , ' d10ly gas exchange is :' t alt~,. ': ' ' for the duration of the, ~G ' ~ by Uilli positive ~ pressure ~~.llilai' using a .~.. ;' - ' open-circuit gas .~.,ti61~.. Like total liquid ~, :" i' . the, ' y i.ltl. ' ' of the 1l ,' di y promoter i" ' : ~ surface tension due to, ' - y airlfluid bll,,.ra..es as well as 35 improving, ' - - y function and gas exchange in ~..1 : : .' li~,;a,.~y and other disorders of the lung. As PLV does not require eAIIacGl,~,ult:al UAy1 :' and scrubbing or the cyclic i..ll.' :' - of the ,., ' "lury promoter to the lung, CA 02238013 1ss8-o~
WO 97/19719 PCTtUS96118989 ~4-the use of ~ q : is not required. Rather, well eOi '' ' ~d ~ ~_liondl off-the-shelf ..ti'~ O may be used to provide the ~ y l..~ tiùn and carbon dioxide purging in vivo. Moreover, as it is . . ' :Iy gas rather than liquid that moves in tidal fashion with each breath, the airway ~ O required for the, .,..edu.~ may be much lower than during TLV. Thus, the potential for ~d~OLI is ~ ' ~ reduced.
5 Finally, when the ~ d ~ is over the hl~ dl ' the liquid, gaseous or vaporous r~, dll~ly promoter is simply allowed to ~i. ale rather than being physically removed as in TLV.
AS, L.; ~ indicated, ~i ~ ' ' are the preferred ", alL.y promoter for both TLV and PLV. In general, r' o-' ' ~ , 1 ' ' with liquid ~ t;61ion will be clear, odorless, r " ' ' . and e - 'Iy insoluble in water. A~ , preferred 1; - . ' - ' are denser than water and soft tissue, haYe a low surfaGe tension 10 and, for the most part, a low viscosity. In particular, ' ~ ILd r; .~ are known to be safe, ~ ~ , :' ' ~ when ,, , ialLly used in medical 3~, ~' " It is i ' " '1~ known that oxygen, and gases in general, are highly soluble in some l; . ' ' For example, some " ~' ' liquids may dissolve over twenty times a much oxygen and over thirty times as much carbon dioxide as a ~ - '' amount of water. OAY'9 '' rlu.,r~ ' ~ ' act as a solvent for oxygen. They dissolve oxygen at higher tansions and release this oxygen as the 15 partial pressure de~.-dases. Carbon dioxide behaves in a similar manner. In addition to carrying gases and removing waste products, r~, ~ .: y ~.1 : O such as l; ~ ' ~ ' may be used as, ' y drug delivery vehicles, either in ~ with liquid .,,..;' or as ', ' : therapy. For example, aerosol delivery systems may rely on a mixture of a i' . pr ' '1~ active agent with one or more, , .: y p.~ : O to increase :", . efficacy and stability of the bioactive agent. Moreover, selected " ~l~l y ~., . : O, including, in particular, r ~ have 20 been shcwn to have, ~ y and systemic . 'I y effects. Acc...." ~'~, despite relatively high costs, it isdesirabletoemploy r h asthe.~, ~: ypromoterofGhoiceincurrentliquid~ ti6ti~ pr ~e' to and drug delivery.
While liquid ~ . - ' ~ is a ~ig '; : i ...~....~.,~ over - ~.at ' ~ ' . the escape of the 1l , dl~. y promoter, pali ' 1~ ~Iuu,.r' Is into the e...;.~ : in the form of vapors, c . the etr~.,li . of 25 both TLV and PLV therapy. During normal " I ll ' . ' p(~ ' to the ~ , and release of such vapor may be o;~dfi :. For example, in current PLV therapy ~ .. : ' r ' - ' .. ' t~o release the expired gas, including li ~-' ' vapors, into the e..,.;.~ or store them for future disposal. In adult PLV ~
--- e.~GIali~ ri . losses may ~ to 3~ 10-20% of r residual capacity per hour or 3~ u~dlllal~,h~ 400 to 800 grams of r; . per hour. 8:~ ' : f' -. ' ' losses also occur durinp 30 TLV ll~ai In this case, the greatest losses occur as the circulated liquid medium is subject to l:AIIaL~ dl o~.~. i and carbon dioxide purging. In particular, a yreat deal of gaseous oxygen must be ;..ll~d~ d into the r. , , t~ y promoter to ' and purge the e ' ' carbon dioxide prior to IL;..ll.dl t;un of the 1" , y promoter into the body. The majority of the oxy~qen passes through the 1l, al~.y promoter and is vented, carrying with it carbon dioxide and, ~ ,1' ' ' vapor. Of course, if the therapy is to be cu~lh~uLd additional 35 rl ;, y promoter must be added to maintain effective residual volumes. As Illlu. ' ' liquids and other ~-, all"y pllllllult~ suitable for liquid ~~..;' can be relatively expensive, such losses can -- b~: i 'Iy raise the .. .

, CA 022380l3 l998-o~
WO 97/19719 PCT/US96tl8989 cost of such Ihv., Moreover, in either type of Ilv, tl t, the loss of ll y promoter I , " Ies both dosing regimens and v the current volume of material in the lung.
Besides the loss of expensive material, the use of r , ~ ~ based ll, dluly p~ : v can damage C~ ...lilai' , ', I which ,Uuldl~ materials that are not - , '' For example, a number of 5 0 i v plastics used in current ~. ~;' l s tend to swell in the presence of r - ln other currently used Illalv.i ', exposure to r; .~ ~ will leach ,': v causing the material to become brittle and subject to failure under much less stress. Further, modern ~ . ' .v.ltildIv.v contain a number of delicate sensors for : v the levels and condition of both the , dIoly and ll, ~ y gases. As with the ~v..IilaIvrv i' ' vv, many of these sensors hlcl,.r alv materials that are not fully compatible with r 1-~ or other potential 10 ,l, ny p.~ Accordingly, the use of r -. ~ with r ~ ' systems may lead to a d~ r of sensory datâ and i..zcbu,dtv readings if the , dlvv iS not properly -- ud and I i d~ Such materials problems can be severe, if not fatal, ' " when trying to gain ~-v ': y approval of a Ihv.a~.vut;v method or ~ rdIiun of a specific device into a, . q" v.vd Il. Materials problems aside, each different ventilator used for liquid ~ ' n, including ~ available ' - will likely have to be ;.,u;.; h 'l~ cleared by the 15 Food and Drug Adm;..;vll prior to use in such I~ ~v. Obtaining such vleal -e, if possible, can be an .v and time consuming process that can limit the ~ .ad use of an ui' ~ ;vd proven and effective therapy.

U CU. ~ , no effective means of avd~ v these problems or providing ' ' ~ . ~. ' therapy currently exists. For instance, as indicated above c- 11~ available . ' ' ~. ' v vent, as a matter of 20 course, any beneficial gases or vapors present in the l ' y air passages along with the waste gases. On the other hand, I ' y -' vtiun devices . .' 1 v sealed delivery systems iack the ~ y ~ , and - r ~ delivery ability required for effective ~. ' therapy. For example, U.S. Pat. No. 4,928,683 describes a closed line - :' ,~, y ap~udlalvv using multiple fixed volume fluid driven c p, While delivering precise volumes, this complex fixed delivery system does not provide the s r~ profiles and ~ y neLessal y 25 for extended ~c..i k ~ therapy. Moreover, the disclosed 3~, al~v iS not modular and c - ' ' with off the shelf ., : Similarly, U.S. Pat. No. 5,119,810 provides a ~. ' system driven by a l ' ' powered piston.
Yet, this system does not allow for the use of existing ~ :' 7~, dlUv and does not isolate the '-~- from the l. _'I y gas. As such, neither of the disclosed devices solve the drv.~ ' problems.
Thus, there still remains a great need for a closed-circuit . ' Iiun system which allows for the isolation and retention 30 of ,~, dluly material.
Accul " v'~, it is an object of the present invention to provide methods and ., dlvv for closed-circuit ... ..
y ~ r, ~ lt is another object of the present invention to provide methods and _p, dlv-v for the efficient retention of a " ,l aIv.y promoter during partial liquid .v..i 1.
lt is yet another object of the present invention to provide methods and appdldIv-v for the retention of a l-, dIUly promoter during total liquid ~. ' -CA 02238013 1998-0~

SummarY of the Invention These and other eS;: _3 are achieved by the present invention which, in a broad aspect is directed to methods and Dppaldlu~ for closed circuit .~..lilaliun. More . '; 'I~, the present invention provides novel methods and devices for cs ' ~ ...lilai' using modular closed circuit ~, "' " systems that prevent the ' ' 5 loss of valuable t~.- Is including ~lùu., ' ' Is into the .,..~ As used herein the term N~_..li6liùn" will be held to mean airflow in the lungs. Ar~ , the term "-. "'; therapy" broadly means any ".. ' c, including the -~ ' ' aliun of any i' a~Jculi" or Fq, --:' agent, that r , i;~CS airflow in the lungs. As such, .. lilai' therapy may be used in ~ with both systemic and r ~ , localked ~
The methods and 3p~ dlU~ of the present invention may be used with any type of ._..li6liun including, but 10 not limited to, c~ nliùllal gas .. "' :' n, partial liquid ~ ti61iun and total liquid ~. '" :' Similariy, the methods and devices of the present invention may be used with any gas, vapor or liquid to effect ~ ilaliun therapy including, but not limited to, non . ' ' gases and vapors, bioactive agents including breathing gases, I , ' allJly pl~ : s including liquid breathing agents, ~IJdl" ~ and ,' . - li"al agents. In short the present invention may be practiced with any gas, liquid or vapor optionally : ' ~ a bioactive agent. Further, ~ ' ' liv....
15 of Illalcl' ' such as the use of ~ i ' agents in ~ :' with one or more .. ,' aluly p,. Ic.~ are , i" '~ with the present invention.
Another major 1~ O is that the closed-circuit ~ li61;_.. systems of the present invention may be operably ass"L;aled with c.,.... ' s, L;-~.U;l h ~ ' ~, t;i~ to provide sr, ' ~: : ' controls and sensors desirable in extended ~. ': therapy. Moreover, the closed-circuit devices of the present invention may be used 20 to isolate delicate and relatively expensive ' ~ -' ~_..li6 ~ from PJ~ damaging ch_.. ~ ' often employed in liquid ~.~..,i' ~ r i ' bS. The isolation of c , can greatly facilitate the . ~, ' y process inherent in obtaining approval for the use of new ~ , in existing 1.~ :' :- Il.c,~ - Further, as the devices of the ; present invention are modular, overall s 'ig - and a~ GL~;al~d r ., ~- ' devices, pali ' Iy ~c.llilaluls, ' ' s, sensors and the like may be easily ' :ilutcd or changed ', ' O on ' r~r~ " ~.".,.~t~ or 25 physician ".I:Fc" In addition, as the closed circuit ~ ; -a systems of the present invention may be r ~ il,aled from reliable, yet cost effective materials they may be designed to be 'i~, Q~ ' ' '3 ~ ~- ~1~ reducing operating costs in terms of F ~ ' and ~ ~r In a preferred . ' ' t, the invention provides a process for closed-circuit ~ -' therapy ~ the steps of:
a~ ~ ,,.' ~ g at least one r . - ': gas or vapor into I ' ~ air passages of a respiring 30 patient;
b) capturing ~ dt-ry gas from said patient in a closed circuit I , ' alur in r' I-c ' : O
c -i- with said F ' - y air p~sege~, said !, ~ dllJIy gas s~ carbon dioxide and at least a portion of said ~ t~ I gas or vapor;
c) .. ;.. ': ~ said i, ~ a~.y gas through a gas flow path defined by said closed-circuit ", alu 35 wherein at least a portion of said carbon dioxide is removed; and ~ CA 022380l3 l998-O~i-l~i d) Ih~,ba~ld, ~ ~ t.. ' " at least a portion of the G;IL h IUd I . ~ di y gas , ia;lly said i"l,~ ' gas or vapor into the r ~ Y air passages of the patient. P~r~.~.SI~ the ~ ~ gaâ or vapor is a bioactive agent other than oxygen or air. In other preferred bc ' : . the i..l~ ' gas or vapor is a ", _ y promoter and, in pa, ' l~ preferred bcd Ia iS the vapor of a ,~JIL~ .tll h -~' liquid breathing agent (for 5 example, a ~I~u.~ ' ~ 1, Gapable of 1~ " ~, oxy~en. In other - ' ~ ' Is at least a portion of the gas flow path may be I . s iL.,d to effect positive pressure ~.: '. ~ of the patient with this pressure p.~l "y provided by a I ' -' ventilator. In yet other bc~ of the process, the closed circuit n, alul may comprise a variable volume reservoir that may be ~ " 'I~ pressurized to provide positive pressure ~~..i ' ~- The variable volume reservoir may comprise an isolation chamber ' C~. balbd by a ~as , , ' ' compliant membrane, with the compliant 10 membrane ;._, a~a; IrJ the chamber into the variable volume reservoir in fluid-conducting . i with the , ' y air passages and a , ~aaiull reservoir in fluid - I with a c .anliullal open-circuit ventilator.
In such: bc' ls the open circuit ventilator may be isolated from the c;" ' ~ , ~ y promoter.
In another broad aspect of the present invention, a modular a" alua for closed-circuit ~...3aliun therapy is provided. In a preferred: ' ' t, the 3 ~ ~ k.~
a) a patient- - ~: capable of G ~; _~ : ": with r ' y air passages of a patient;
b) a variable volume reservoir;
c) a ~....lilai conduit sealingly affixed to said patient-G - and said variable volume reservoir wherein said patient-L e is placed in fluid-c ' ~ e ~ with said variahle volume reservoir to provide 20 a closed-circuit , defining a gas flow path; and d) a carbon dioxide separator in ~ ' :- g c i with said gas flow path.
Selected , ' ~ bc d of the present invention further include a variable volume reservoir an isolation chamber b;.u.bal..d by a yas pr I C~ ~ said compliant l"t~ L, , ai- O the chamber into a s , ~ reservoir and said variable volume reservoir, with the variable volume reservoir in fluid 25 r ' _ r with the pulmonary air p~s ~f S In such embodiments a cu.... ' c ' -- ' ventilator may be operably a ~r- with the r , 1~ reservoir of the isolation chamber whereby normal operation of the ~ ~-' i - will transmit a pressure wave to actuate the compliant I ' As with direct ~~ ..li61iuU systems ~where the ventilator is in fluid c~ , with the patient) the 1, ' pressure wave may be used to provide positive pressure ._ t' - Yet, in these b~' . unlike prior art systems, the gas li_ : " the 3~ wave from the ventilator is never in contact with the i ' y air r~ O
In another preferred embodiment, an: ,, atl... for bluscd L;ll ~ l;6liv~ iS provided c , i~;"g a) a patient-r :~r capable of c~i '' ' " fluid-c- ': ~, c ~ with ~ ' y air passages of a patient;
b) a .. :' ~ conduit sealingly affixed to said patient- -: to provide a closed-circuit ,. . alur 3b defining a yas flow path, said closed-circuit ,., alul operably a ~ lu~l with a ", ' ' .~ , and c) a carbon dioxide separator in fluid-~ s- : - with said gas flow path.

- CA 02238013 1998-o~

ln yet another bc~ I of the present invention, methods for providin~ closed-circuit partial liquid .,.1i61ion are provided. These methods generally comprise:
a) connecting an 9 ., closed-circuit r, dl~. defining a gas flow path to the, ' y air passages of a respiring patient;
bJ 1,, ' " a, , , y promoterinto said ~ air F: 3l~ .
c) capturing , y gas from said patient in said closed-circuit ,l, alul, said ~ dlO~y ~as " carbon dioxide and at least a portion of said illt~ I, d; y ~ ~ ~
d) sc~laldi C said at least a portion of carbon dioxide to provide a treated gas ~ ~, said I , ~ Y ~ IGI~ and e) ,~;.,l,. h ~ said treated gas into the I ' - y air passages of the patient.
rlGr~ h!~ the ., nlu,y promoter is a liquid breathin~q agent such as 8 li r~ ' l capable of 1, Li..g oxygen. Moreover, ~ of this method may further include the step of ~ a ., , d; y promoter to the r Y air passages of the patient prior to c.. ; ~ i 1 h: v between the present invention and the ! y air pr~ - _ It will further be q, r ~.;aluJ that the disclosed partial liquid 15 . ' liull methods may further comprise "" i ~ a portion of the gas flow path to effect positive pressure ~.,..i '~ of the patient, ~J.GrGI. "~ using pressure provided by a . ' ' ventilator. Other ' y of the process comprise a variable volume reservoir e ~d to the closed-circuit n dlOI. Any such reservoir may be t.~lu.l ~ G.~ Gd ~outside the closed-circuit, ) to provide positive pressure ~. ' The present invention also provides methods and devices for closed-circuit total liquid ~. 'a - In one bc " the method r , ;;IG~.
a) e ' ' ' ~, fluid-~ ': , & between r ~ Y air passages of a patient and a fluidflow path defined by a closed t;l~ 't 1', ' ~ said fluid flow path and said r ' y air passages - ' filled with a Cil~ liquid ,., aL~,.y ~., l, b) OAj~ the c;. ': " liquid ,., dlUIy promoter by Il. ' - " oxy~en into the closed circuit liquid Ib r dlUI to provide o,.~, liquid " , )~ y, ~ IGI~
C~ C;ll ~ JA~, ' ' liquid ~ : y promoter throu~h the fluid flow path and said F ' Y
air passages to provide - alù~y fluid - ~ ~ carbon dioxide;
d) . d;' ~, at least a portion of said carbon dioxide from the ~ : y fluid to provide i . : y fluid.
In preferred ~c the method will employ a second closed-circuit vapor sepr dlUI desiqned to remove carbon dioxide from a gaseous vapor before - ~ h ~ the treated vapor back into the l,bl,ulalilld liquid I , dl~.y promoter for l,,;..ll. r'~; to the patient. In other preferred ' - " ~. a liquid scrubbing means will be placed in the fluid flow path to remove carbon dioxide directly from the C;ICula;' " liquid r, dl~.y promoter prior to ll,;..;~,dul.; into the r Y air passages of the patient. Novel dppa.dll.s are also provided to perform the unique 35 total liquid ~I~...lilai p..r. ~ bS disclosed herein.

. . .

~ CA 022380l3 l998-0~

g In still another embodiment the present invention may comprise a method of operating a closed-circuit ~.,..~" " a~, d~ by ".. ~ v a closed-circuit respirator in fluid r ' v: with ~_' y air passayes of a patient to effect positive pressure ~ ~ ~t;~ In preferred e bc' - the 1- . i 9 step may be achieved by operating a ~ ' ventilator operably acso~ l with the ' ~c '- ~ ;, dlU~ while 5 isolated from the, ' y air p. ~~ v Yet other bc' of the present invention comprise treating fluid, gaseous or vaporous material from the lung of a patient by ~,;I. ' ~ the material through a .' '-c;.~ respirator while removing waste gases and h~ ' V oxygen. r~-c~-c~dbly the material is removed from the lung by effecting positive pressure ~.i..l;!~
For example, in a preferred: bc' : the invention r , iv~ a method of operating a system for partial 10 liquid ~~,..i '; or, . " llali.~, a method for treating a fluid, gaseous or vaporous ,~, aluly promoter obtained from the lung of a patient --, ~ the steps of:
a) establishing fluid conducting communication between the pulmonary air passages of a patient and a ", ~Lol defining a gas flow path;
b) i ~I v ~, à~u.y gas from said patient into said gas flow path, wherein said , al~ly gas 15 c , ises carbon dioxide and a fluid, gaseous or vaporous 1. di y promoter; and c) treating said . a y gas to separate at least a portion of said fluid, gaseous or vaporous ~ , dlary promoter from said y gas.
The ~., liun~d ' - ' : may further include the step of treating said !, ' dllay gas to separate at least a portion of said carbon dioxide from said c y gas. Sepala: of the rl, ai y promoter or waste gases 20 such a carbon dioxide may be achieved by means known to those skilled in the art such as filtration, chemical pc aliull, C~ ' ~d~ ~Ji or ~
Still another b~ " of the present invention involves a method of treating a ' eai~ ' ' gas in a closed-circuit ,c ,~ alul r , i,;..v the steps of:
a) i~ 1 v a breathing gas into a gas flow path defined by a closed-circuit " , alul, said gas flow path in fluid c ' 9 r with I ' y air passages of a patient; and b) : ' v a, ' ~ effective amount of a liquid, vaporous or gaseous ,. aluly promoter with said breathing gas in said gas flow path.
r-cru. ' '~ the breathing gas is oxygen or air and the ,~ ai Iry promoter is a r; . ~ In one bcd I the ,., alOly promoter may be combined with the breathing gas following ~. i or, ~ ~r Another bc " of the present invention is directed to a method of operating a partial liquid .~ ilaliull ~ system - . i-;.-v the step of applying pressure to a closed circuit ", alu. defining a gas flow path in fluid L - v - ' i' with, ' y air passages of a patient, said gas flow path having at least one " , alul y promoter disposed therein and said pressure beinv applied by a r ' ~ ventilator operably a-~s-: t~ d with said closed-circuit ", alul with the proviso that the ventilator is isolated from the gas flow path.

CA 02238013 1998-0~

F~lerdi ly, the 1,, aluly promoter will be ~;ll ' ted in ' ' liun with an !, ~ dloly gas. The method may further inGlude steps for isolating or , ' v the C;l~ y promoter such as a ~- ' or - vaporker.
Yet other b~ " are directed to methods for operating a closed-circuit total liquid ~a,.lila;' system 5 ~ . i v a~ e ''' b' Vfluid-~ 'l i g - ' :' between, ' ~ y airpassagesof a patientand afluid flow path defined by a closed circuit liquid respirator, said fluid flow path and said, ' y air passages filled with a liquid ll , ai )ry promoter;
b) removing at least a pottiûn of liquid ll, al.,.y promoter from the, ' y air passages to the 10 fluid flow path, said removed liquid ll, ' di y promoter r , ' ' ~ _ -': d carbon dioxide; and c) sL~ala v at least a portion of said ~C<O~' u, d carbon dioxide from the removed liquid IL, ' alL.y promoter without venting --': :' ' amounts of said liquid r~, ' all..y promoter to the su,l. ' L e.,.;.~ I in a vaporous state.
Other objects, features and ~ ; vr of the present invention will be apparent to those skilled in the art 15 from a ~ '' al' of the following detailed ' i, ;' ûf preferred ,' y ' ~ " thereof taken in con-junction with the figures which will first be described briefly.
Brief 1~4v~' ' of the Fi~ures - Fi~. 1 is a s ' t;.. n, I,v.,.. la;' of a ~ .. ' ' open-circuit ' ' ~ ' ' system;
Fig. 2 is a ~ n - i of an ! .' y closed-circuit ~ :' - v system formed in ac~.uldan~e 20 with the teachings of the present invention;
Fig. 3 is a ' rl,l,.l :' of an; , ' y closedcircuit passive ~ :" liun system ' ~ " v sn optional nebulizer;
Fig. 4 is a ' li.. I~,...senl~' of an .' y closedcircuit positive pressure .~.,t;lai' v system ~, , ;v;l.a a -'- ' ' ventilator formed in - d ~ E with the teachings herein;
Fig. 5 is a -' :' ", ~,.:' of a closed-circuit total liquid ~~.ltilai' system having a closed-circuit vapor separator p~ e v '~ with respect to the c1~,3.,d ~ , ' alul, Fig. 6 is a ' " " bv~ ai' of an - , ' y closed circuit total liquid ~ t;6liun system having a liquid scrubber in-line with the closed circuit respirator.
- ~etailed D~,v.,.i :' of the Preferred ' bc "
While the present invention may be embodied in many different forms, disclosed herein are specific "' '~ali.. , - bc'' thereof that exemplify the principles of the invention. It should be ' - ' ' that the present invention is not limited to the specific ~ "' t.àlbd.
C~ .. -' ''prior art ' ' ' ventilators, used for both partlal liquid ~..t;' ' and ll~d;t;ullal gas ~. " :' l are opencircuit .. " ~ meaning that waste gases, such as carbon dioxide are vented into the 35 ~ il 1. Total liquid ~v..lilali.,.. devices used today are also open-circuit devices in that the waste gases ~again primarily carbon dioxide) are vented into the L...;.l l foliowing thveir s, ai' - from the liquid ll , ' alory promoter . CA 02238013 1998-0~

used to improve gas exchange in the lung. In complete contrast to such prior art "open-circuit" designs, the present invention is directed to methods and devices which are used for "closed circuit" ~_..lildliun wherein gases are not generally vented into the ~u"- v ~ ;,. L but rather treated and returned to the patient. As used herein, the term ' '-L;~l " iS held to mean any ' I i 'l~ closed system that allows the retention of the majority of 5 ~ ~ ~.o, dtud materials c;r~ _5L'- ~ therein. Those skilled in the art will a~ Liale that this definition a i~e.S systems wherein selected waste gases may be vented to the d , ' 1~ following removal or isolation of valuable such as 1-, dlUly I, l~.,a.
More pal i ' I~, the exhaled gases or vapors (or liquid in the case of total liquid ~_ ' j from the patient are treated to remove waste products such as carbon dioxide and then returned to the patient. In ,o, . ~ , involving 10 liquid .. ' . this lll:ai l and IU.,;I. ' i of the exhaled gases, vapors or liquids ' ~ , reduces the amountofr,, dtl y promoterneededtoprovideeffective ~ ai inl~ ' 'gasv~ li' li,,n the[' ~r -1L;~I~L;t methods and devices of the present invention can reduce the loss of any ;..~u., dl~J gas or vapor or bioactive agent including those having phall ' efficacy such as tl,~l or diagnostic agents. Pursuant to this disclosure, Ib ~ ~ dlUI y gas exchange may be Id by positive pressure ~,c..ltilal using a CGIl~....i ' .~.nt;lci 15 By "~ :- positive pressure ~. ' ~ " is meant positive pressure I ~ ' ~' .. ~ ' ~i often with positive end-expiratory pressure, and may be a~- ' ' ~~ by any standard positive pressure ventilator. Either volume ,.~ ' d, time-cycled n, : s or pressure-limited time-cycled ,-, r~lu~a are suitable. Examples of .. , 11~ available ~.ililal~ that are - , _i ' ' with the present invention include, but are not limited to, Servo 900C ~Seimens Elema, S' ' u~, Ill.), Infant Star (Star Products, San Diego, CA), Bear 1,2,3 (Bear Medical, Browns, CA), Puriton Bennett 7200, (r-"i r ~l :l Corp., Carlsbad, CA) Baby Bird 2 IBird Corp., CA), and the ll~ "e Infant V~.,8!~ r. As ~u~u.iuu~5y alluded to, cu..~ t;ldl~,.a such as these may be used with the present invention in c ; ~ion with ' ~' gas ~e ': or with partial liquid ..
Fig. 1 provides a ' LLI, ~ of a L ~_ " ' "open-circuit" - ' ' ~..Lilaliùn system 10 ~Idlhl9 the principal features thereof. In the figure, I ' ' .~ ' system 10 is -L - lud to a patient 12 through a patient-- 14. Typically, patient-~ : 14 will comprise an . ' I, ~ ' tube or a mask that allows gas, vapors and liquids to be ' : ' to the lungs of the patient. In the al, dll~ shown, the distal end of patient-- 1 14 branches to form a Y-~ -: providing two separate distal c~ ~ ports. The distal c " ports are sealingly attached to the proximal ends of i, dtUIy .~,r,~;5~: ~, conduit 16 and , dll~
~,. ';' ~ conduit 18 ,,, t;.~,l), For the purposes of this ~,,' liu" the terms "conduit" or "~ t;ldlill~ conduit"
will be held to mean any hose, tube, bore, lumen, shaft or other void L ~ ~ ~ 9 structure capable of defining a fluid or gas flow path. Those skilled in the art will ~ r ~L;ale that ' y i , dlUIy llr k 1 ~ conduit 16 and ~ aluly ~~.~tildlilld conduit 18 are typically formed of '~ ~ , :'' flexible tubing having annular ,.' '~,., Is to prevent kinking or blockage. Moreover, such ~~.ILildthl9 conduits may be formed of materials s , l'' with specific ~l, alOIy, I a. ' , di y ~~...lilai ~, conduit 16 defines a gas flow path r , i~;"s a bore which is 35 capable of 1, , Drli..g gas to patient-cl lu, 14 where it is - ' ~ : ,:.1 to the I ' y air pas ag Similarly, CA 022380l3 l998-o~

~, al_.y ~,'t.... ~l " conduit 18 defines a gas flow path that may be used to transport;, aLOIy gas away from said patient upon e.~hdlai )r Arrows 58 illustrate the flow of gas through the system.
As with all ~ available ' -' .~..;' ~, ' -' 1,~ ' system 10 relies on ",.,..;,~"iL~;d gas source 40 for, ?lio power. In - ~.: ' ' -' ~.,.~tilalu~ d gas source 40 is provided by an external bulk gas delivery system ~i.e. "~ uliL~d tanks) or an internal: , ti~ul Inot shown) which i~G.~ air from the ~ u..~ I. In either case, p.~ i..,d air enters I ' -' ..i.,l' system 10 through inlet conduit 38 and pressure regulator 36. Although air from the, ~ d gas source is typically on - - the order of 50 Iblin2--i.e. 3.52 kglcm2, pressure regulator 36 reduces this to a working pressure of .
1.5 Iblin2 --i.e. 0.11 kglcm2 prior to ~ O it in ' ' ~ - system 10. Following the reduction of pressure the gas enters the distal or upstream end of , ~: y .. '; ~ conduit 16. \/~ tila; ~ conduits 16 and 18 are operably Acscr:~ed with r ~ ventilator 31 . allJ;. 20. By "operably a~ "' it is meant that gas flow and ~...t;!..: or d6Un5 using conduits 16 and 18 may be ~ d and effected by ventilator ~ ,c.,al-J~ 20. To this end ~, :' a" al~ 20 ~ .,s: , d10ly sensor assembly 28 and , ~a y sensor assembly 32 which monitor and control gas flow andlor gas r through - , ~: y ., ~ ~ " conduit line 16 and ài y ~ conduit line 18 n, 6~olt~ Among other data, sensor a~ '' - 28 and 32 provide real time " Illai regarding gas ~ . . i ., t:, pressure and flow rate. Ar- . "'~, gas entering , ' al~.y ~ conduit 18 is, od by , aluly sensor assembly 28. Based on the readings, gas injector 30 may be signaled or manually set to introduce oxygen or other gases to the gas flow path defined by , _ y ~. : !a- ~ conduit 18. Transfer lines 52, 54, 56 provide gas injector 30 with access to external sources of oxygen, nitrogen or other selected gases. Those skilled in the art will a~JulL~.;nlt: that qas inJector 30 may operate using b-..l" or may be E ~" ' by ventilator ar, ~lLJ;~ 20 based on f~ aliu.l from sensor r '' ~ 28 and 32 or using preset values.
Gas flow and pressure through conduits 16 and 18 is ph, 11~ r,u,.l,. " ' through , ~ alu.y flow valve 48 and optional ,, y flow valve 46 which are opened and closed based on, ., .O ' ~ iuns and :.lr- I : received from sensor ~ - "ier 28 and 32. Those skilled in the art will ~ , ~.,;ald that flow valves 46 and 48 may comprise any of a number of different types of valves including solenoid valves, digital solenoid valves and full-range p.e, i ' valves. As will be described below, flow valves 46 and 48 will be , ~ I.d to provide the desired wave form and pressure for ~. ' ~ Passing ' . ~ talll through . alOIy flow valve 48 the , ai y gas may be modified by ~ ' Cid~ 26 which : . ' vapor to the gas flow path. As with gas injector 30, ~ 26 may be E 11l" ~' by p,~u"O _ d ~ ~ - - manual settings or by ventilator a~paldl~ 20.
The , ~ alOly ~qas, now ~ adequate oxygen and water vapor is then ~ ,d along the gas flow path through one arm of patient-L ~or 14 and into patient 12. Optional ~ , ~ alory check valve 22 may be provided to ensure the ' O~.i- ' travel of the I, al y ~as.
Pl~ro~ bl~ the ~ .- alL.(y flow pattern is . ' ' to provide optional ~ aliull for the patient. That is, the wave form and pressure of the delivered gas may be optimized to minimize ,_~ y ..:: - and maximize -. CA 02238013 1998-o~
Wo 97/19719 PCT/US96/18989 r '- As l~lb~ ' d, ventilator a~, dlU~ 20 may be classified as either a pressure, volume, flow or time controller device. If the pressure ~ l does not change with changes in patient ~es;;,ld.,l.e and 5 ,~' , then the ventilator is e ' ~d a pressure controller. ~e .~ .,ly, if the delivered volume is measuted directly, then the ventilator is ~r ' ~d a volume controller. If the delivered volume is determined by a flow 5 1~ , then the ventilator is a flow controller. Finaily if both pressure and volume wave forms change with changes in patient Icv;~lallGe and , ' -e, then the ventilator is c ' .,d a time controller. Most ~
available e ' 1l ' . ' v are either pressure, volume or flow c...,lll" ~. It is primarily this ability to provide s~p' - II,d delivery patterns, and monitor and react to the changing ' ~. that ' '~cl~..Li~ll,c .. ' Il"~ from other gas delivery devices such as anesthesia machines.
Whatever delivery mode is used to introduce the , dl~.y gas to the r ~ y air passages ~not shown) of patient 12 under positive pressure, ~,~..1i61iv.. is effected upon ~ ' ~- ~ of the gas in the lungs to promote gas exchange and OAY~ . Those skilled in the art will .,, ~i~,ial~c that the fresh oxygen from the ~ t~uduLed inspiratory gas crosses the alveoli and enters the blood while waste gases ~carbon dioxide, etc.) are excreted from the body. As described in Fuhrman, U.S. Patent No. 5,437,272, published PCT A,,' No. W0 92119232, and co-pending U.S. Patent A~,' Ser. No. 081180,700 all illl,ul~Jùlal~d herein by lef.,.c ~n, a rl, _: y promoter (p.rc~c~ V a flu~ may be present in the pulmonary passages of patient 12 to facilitate the uptake of oxygen and excretion of waste gases. As oxygen passes into the ' ' ' ~., waste gases - ' ~ 1 collect in the lungs. When using cr . ' mechanical ~ ti61u.v, such as the one shown in Fig. 1, the h,ll~ ' : ), of i ~ dl.~.y gas will typically be pulsed or cycled. This ~ y period is known as the: ~ C~l..y phase of the 2~ breathing cycle. During the lull between the ~ ~ - of gases, the lungs return to ambient pressure and deflate due to tension on, ' y passages from vu., " " tissue. This rv - of the lun~s and ~ lU-r ~ v reduction in lung volume forces ~- ' ' gases and vapors, " 1~ known as; dlllly gas, from the lungs.
This form of i x, di- iS termed ' ' - In the case of l, ' ' ~as ~~..Lil~lio,) the c dLI~fy gas will comprise unused oxygen and waste gases including carbon dioxide. When a ",, - y promoter has been 25 lll' 31~ into the lung of the patient, such as when F ~- v PLV, the , y gas will comprise vaporized .~, dlL.y promoter in addition to u.,,l, _d oxygen and waste gases.
The i~ i 7~ L ~ _ of the lungs forces the - . ~y gas into patient c~ - ~ 14,, rc~
sealingly c- ~ed to patient 12. I' ', - ' i , ~ all/lY check valve 22 prevents the rCAIJkdIO(Y gas from i '1~ entering , dlDIy ~,..t' v conduit 16. Instead the ~ y gas is directed through, ' rCl~liul~d expiratory check valve 24 into !, ~ dtUry ~_.-li6i- v conduit 18. From here the y gas travels along the gas flow path defined by ", y ~c ~i - v conduit 18, through optional flow control valve 46, and into ventilator _ppr dlUv 20. Optionally, the , _: ~ gas may be passed through filter 50, p~ c along I ~lu~y ,c..lil~lli"g conduit 18, wherein p ' ~9 u~ - and other . ' '' material may be removed from the ,ry gas. After entering ventilator: , dll,~> 20 the gas flow path passes through sensor assembly 32 wherein 35 data may be gathered regarding the s~ - and flow of the I, ~ d; y gas as well as the breathing cycle. Those skilled in the art will o~ that the ' ~- ,., cv~,l.ldlion of the sensors in Fig. 1 is e ' y only and that CA 02238013 1998-0~

any sensors employed in ventilator 3p~ ' dtl.-.~ 20, including those - pr:'' with the present invention may collect the desired i 'c., lr using any effective means. Passing through ventilator 3~, ~ al~ 20 in the gas flow path defined by , ~ aluly ~_..i k " conduit 18 the -, ~: y yas proceeds through outlet conduit 42 and is vented into the: I ' ,9 e..~ I through exhaust aperture 44. It is this venting of the ! ll~alJd oases into the ;,.1,-l ' "
5 a; ;~ ' d that clsssifies such systems as "open."
Those skilled in the art will a~ ,_;alt: that selected ! ' ~ " l5 of the present invention may comprise a .~..liunal "open-circuit" ~_..I;Iai- system operably 855G~.;dll,d with a means for sepa. v selected ~
from the exhaled gas and rl l..~ ~ them at the a~ ial~ point of the gas flow path. For example, a:, al;..n means (not shown) placed along !, dluly ~ t;lalil~ conduit 18 of Fig. 1 may be used to -, vaporous or 10 gaseous ,l , ! ~y promoter from the I , ry gas. The , aL.. means may comprise, for example, a -' chemical a~' ' 1, filter or other ' ~ that can isolate at least a portion of the entrained ", dlory promoter.
This S_~.di Jr means may also be used to wean the patient from the ~." dlOIy promoter by gradually isolating it without ---' - u, 1 :, 'u ~;un. Following isolation of the ,l , y promoter, the depleted -x~ atùry gas may then be vented into the _...,;.
Of course it will also be ., I,_;all,d that the isolated ,e, dll~ly promoter may be safely disposed of or dULLd into the lung of the patient. For example, the ,~, at~ y promoter could be isolated in a flowing liquid state and 1, Ce.-.,d to a; ~ means (not shown) in fluid c- ' ~ contact with i , dlu~y ~ conduit 16. Most - '~, the ;..l,. 'l " means will comprise a nebulker or vaporker although the liquid ri ,~, y promoter could be trickled into ~ , ~ dlu.y ~_.llilal ~ conduit 16 or patient-c 14. In any case the, , ~ ~; ry 20 promoter, whether derived from, .,~ exhaled gas or freshly obtained, is :,. ' ' into the gas flow path where it is l,_ , ~ I.,d to lung. P~ 'y, the .., ~ .: y promoter is entrained in the i , : y breathing gas as a saturated vaporous , and carried to the pulmonary air passages during the normal r ;, dllJ.y cycle. This closed-circuit adaption of the open circuit ~. : ' system can ': - 'l~ reduce the loss of .l, , y promoter while ensuring promoter Sal~., of the, ' y e..~;,. - It will be ulld~l,: od that the features of the 25 foregoing b~ ' may be used in :- with the: ' - ' : described below.
The use of more elaborate '~ ~ L;I. systems is alsû c : . ' ' For example, in contrast to the "open-circuit" ~, ' system depicted in Fig.1, Fig. 2 -' 'l~ " la~ a "closedcircuit" positive pressure ~_..lilali~m system of the present invention. More pallil,ula;l~, Fig. 2 depicts a closed circuit ~_.llilaliun system that allows treated expiratory gas to be returned to the patient. As explained above, the term "closed circuit" is held to 30 mean any ': ~ closed system that allows the retention of selected materials .,;.l ' - ~, throuoh the system.
Thus, systems which vent treated , dluly gases, but allow for the retention of selected materials including , ~ dlury p.. t~.~, are c- ' .,d "closed-circuit systems" for the purpose of this d 'l 1: and are within the scope of the present invention.
-Unlike the ~ ~ ........... ' 3,, dll~ shown in Fig. 1, no external source of ~,n i~.:d air is required for the 35 closed-circuit system of the present invention. As discussed above, returning the treated gases (including vapors therein~ to the patient avoids the loss of valuable gases or vapors, including ~ , ' dlllly, ~ Idl:, such as bioactive . CA 02238013 1998-0~

agents or lluur~ ' -' to the e..~ I and minimizes the spread of pe ~v Ad~ 1y, this closed circuit system employs a ' ~ -' ventilator that is bc ~ the same as the one " ~dt~d in Fig.1. In actuality, the i..cv.~ aI1d ventilator 3~, alvv may be a suitably modified ~ .. ' ' ' ventilator or may be one s, '; ~ bailt to embody the closed-circuit design. In either case, control and operation of the novel closed-5 circuit system could be made similar enough to c,,..~..Iiunal cpr,..v;~ ~ t;'_ systems to promote operatorfamiliarity and More v~ vifi 11y, the gas flow path of Fig. 2 (shown by arrows 101) is defined by a closed circuit respirator - . i ~ g patient-c - - 64, .~ - v conduits 70, 86, 90, 94, 80 and carbon dioxide separator 72. As used herein, "closed-circuit ~., d~ " iS held to mean that portion of the closed-circuit ~ ;laliOi1 system defining the 10 primary flow path of whatever vapor, gas, or fluid is being used for the ~ t;laliuu ~""....du,t:. That is, the selected material or L , ' is ~ ' ~ ~I'r confined to this ' - '-v;, , ,' dlUI as it is n,~ ' lud in and out of the r y air pa ~ Q,~ , the closed-circuit ,,, _ r may comprise variable volume reservoir 88 and be in fluid- ' i v contact with gas injector 82 and nebulizer 98. The gas used for .. : ' . treated to remove carbon dioxide and p~ r ~ with oxygen, is ,rr 11~ circulated through this gas flow path during the 15 duration of the ", d~llly therapy. This is r- ,' ~ different from the open-circuit ~v~llilaF system of Fig. 1 where the ~_..i' v gas is used once and discarded without any ll~ai L .. . In the present invention, s , of the ~.,..lilai v gas other than carbon dioxide and oxygen rapidly reach an equilibrium lh~ t the closed-circuit ",, r and the, ' y air F~S v This eguilibria is very easy to maintain, requiring minimal addition of those elements lother than oxygen) which are being c;.. ': ' Even the addition of oxygen is reduced to 20 what the body has actually used rather than what is discarded in 1l_' ' systems. ALL.U.I' v~Y~ the closed circuit ..li6liull systems of the present invention are much cheaper and more efficient to operate, pali ' l~ when ., ~.G materials such as r; . ~ or, ' :- ' ayents are ~ ~ alLol in the Ih~ th, regimen.
As with the ._.lt;olldl ~ tLlivl) system of Fig. 1, Fig. 2 shows patient 6Z s ~ -: ' to closed-circuit v ' system 60 via patient-c 64. r,v~ , patient~- : 64 (typically an ' L, ': ' tube or 25 maskl sealingly provides fluid- v ~ ~ between closed-circuit .. l ' i system 60 and the r ~ Y
air passages (not shown) of patient 62. As discussed above, ~, alv.y gas is forced into the lungs of patient 62 using pulsed or cyclical positive pressure. Following ,., ~ .: . , alu.y gas is forced from the lung under pressure duringsr~ ~ eAl.dlal andpassesthroughbranchedpatient-c~ 64. Ll ' . ', alu,ycheckvalve 66 prevents the exhaled , aL-..y gas from entering the gas flow path defined by , aL~IIy ~. :' g conduit 80, 30 directing it instead through ~ iol.dl , a; y check valve 68 and into the gas flow path defined by , ~ dtL.y - ~. ' v conduit 70. While two separate .. ' v conduits are used in this bc' t, those skilled in the art will a~u~JILv;ale that many different c~ 'iv d' of conduit are acc~" '' being limited only by their ability to transport the ncce;.saly material. The ~, ~ alOIy gas may be may be moved along the gas flow path by the pressure of the ht.!~:- by negative pressure Isucking) provided by gas moving a~ pe all-v 92 or by a ~ ' ~ : - of both.
35 In any case, the expiratory gas travels through expiratory ~ t;laLi.-g conduit 70 and enters carbon dioxide separator 72 which is sealingly cu""- - u d in 1' ~ '-C- ' :- g r i with the defined gas flow path.

CA 02238013 1998-0~
WO 97/19719 PCT~US96/18989 Pl~r-,.ably, the materials used in the closed-circuit, ,, r are ~ . :'' with any ,., dlUIy promoter.
F~ preferred fàLli _ materials are generally L , "' ' with ~lu~ ' ' In particular, such materials include, but are not limited to cellulose acetate +, r-l~L ~r1; , pCl~u~lhd-lC, p~yc:lhllu.,e, HDPE, p~
difluoride, stainless steel, Teflon FEP, Teflon PTFE, Teflon, Viton, Yiton A, acrylic, brass, chrome-plated Illàl~l' ', 5 Cycolac ABS, polyvinyl chloride, pr'y~ ,"' - difluoride +, rubber, ~ 'y~alb~ . polyester, and high density p~ h,' Carbon dioxide s.!pa.di 72 iS used to remove at least a portion of the carbon dioxide from the ~, y gas. E 'Iy it is a device which ' 'l~ or physically binds carbon dioxide and removes it from the gas flow path. In preferred e b~ . carbon dioxide separator 72 ~ c;- one or more canisters o ~ g a material 10 such as soda lime, sodium h~l~. - ' or lithium hydroxide in a solid form. As the -, dl~y gas, l~ , iSv _ ~ . ~d oxygen, carbon dioxide and any ~ , dl~ly promoter passes through the canisters, the carbon dioxide reacts with the base to form a cafb~ndle on the exposed surface and water. This reaction removes the carbon dioxide from the gaseous phase. Those skilled in the art will a~ ;al~ that such carbon dioxide S3~ dlU., generally reusable, are 'l~ available in a variety of forms. As such, various ~ cjg di- , models and types of carbon dioxide , are - , :'' with the present invention and may be used in ~ ~c ,' with the i ' ~ herein.
In Fig. 2 the treated , alo~y gas ~with lower carbon dioxide levels) exits carbon dioxide pz alv, 72 and passes through -,, y ~ conduit 70 to optional vapor analyzer 74. It must be ,' -' that the '~" I shown is ,' y only and that carbon dioxide separator 72 and vapor analyzer 74 may be placed along the gas flow path defined by the closed-circuit, , d;~. Wherever it is placed, optional vapor analyzer 74 may be used to ,, ' : the sensors provided in ventilator 3~, alu;l 84. In particular, vapor analyzer 74 may comprise means for 'I ~ the amount and r , - of any vaporked ." dlUI~ promoter present in the gas flow path during partial liquid ~I.,..lilai Of course vapor analyzer 74 may be used to provide h.r., regarding other vapors in the gas, i.e. water vapor, as well as general pal. ~ of the gas. Aor d Ig~, it may be used to --, " : other sensors or in lieu of other sensors. In preferred ' - " data from vapor analyzer 74 may be fed to ~~.. ;' 3~, dlu.- 84 or to optional nebulizer 98 to regulate the amount of Li-l ' ' ~ vaporized 1. ,~ di y promoter in the gas flow path. r,~. hE~, the c;.l ' v vaporized ,l, di y promoter is kept at :~al di' )r levels for the desired i , ~. In the illustrated ' ~' t, the treated and analyzed:, y gas continues through expiratory ~ ilalillu conduit 70, through any ~, dlo.y sensor assembly 76 in \I .,t;lalol a~ ardl 84 and passes into outlet ~~.lt;la~ ~ conduit 86. As described PIL~ , optional , dl~..y flow control valve 100 30 may be used to control the flow and pressure of the gas.
In direct contrast to c~ . ' open-circuit ' ' ~~..lila~ " the gas is not vented into the ;~U~I v ~ following passage through outlet conduit 86 but rather, is directed into variable volume reservoir 88. Variable volume reservoir 88 acts as a pulse damping ... ~ I~ L ~- and gas reservoir to ensure the smûoth flow of gas Ih. ~ ' : the gas flow path defined by the closed-circuit ,l, al~,l. In preferred bc~ L~ variable 35 volume reservoir may comprise a b~ device or bellows. In other e b.~ L:i, the reservoir may be a , " : gas , ' ' ' ~.',a which expands and contracts with ~alialiuns in the pressure of the gas in the . CA 022380l3 l998-0~

defined flow path. The treated . y gas is suGked from variable volume reservoir 88 and through transfer ,g conduit 90 by gas moving ., dl~. 92 which ;s in " ' r ' ~ing contact with the gas flow path.
r~Gi~..Jhl~ gas moving 1" ~ll,., 92 is a low pressure (on the order of 1.5 Iblin2 or less--i.e. 0.11 kg~cm2) pump or blower capable of c;,~, v the gas through the gas flow pipe. The effect of the ~ .dled negative pressure on 5 - dlL.y ~ I;!L g conduit 70 may be regulated by expiratory flow control valve 100. While high pressure (on the order of 60 Iblin2 or more--i.e. 4.23 kglcm2 or more~ pumps may be used as gas moving s,l~ dl~ 92, the increase in pressure may condense vaporized ~G, ' dtl,.y promoter present in the gas flow path. I~cr~ " _~, low pressure pumps or blowers which maintain the phase equilibria of the ventilating gas are desirable.
Gas moving 3~ pr dll-~ 92 propels the treated y gas through inlet conduit 94 and into ventilator a~Jrz.dlu;. 84. In the bo' : shown, ~.. 61dlul a~Jpdlalus84 is n, bS~.. ldli.. , of a ~ available open circuit I ' ' ventilator which has been modified in -~ c ~ d e with the present invention. Accordingly, pressure regulator 96, ;- y on open-circuit ~ 'ig dliu..~ ,' ,; 9 a high pressure external gas source is bypassed in the embodiment shown. Other ~ ,' y ~"~;I.al of such systems could include the illcGIpr~ of ii ' -' ~ , : ' ' materials along the gas flow path. While Fig. 2 is ","., li.~ of a modified t~, 15' ' ~ t;61ul, it should be: , ' ' that a ventilator ~" ~LIl, ' " to that shown may be 3"eLifi ~1~
desi~qned for closed circuit ..,..t;!a~ therapy. In such a device the high pressure regulator would be omitted entirely.

Upon i ~r~ 'h.~ to ventilator 3~ ~ dll-~ 84, the gas enters i at y ~. - ' v conduit 80. As discussed above, gas injector 82 is in r; - ~ with the gas flow path defined by , dll~ry .,. - ' ~, 20conduit 80 and may introduce oxygen, nitrogen or other gases supplied by lines 104, 106, 108 to the gas flow path.
SinGe I , I,d oxygen is present in the c;.~ as, the ' 3r' ~ c .~ of the present invention allow effective I , dluly therapy with much less input of oxygen and other , ' I ' gases. Essentially, it is only the ~ases which are actually used by the body that must be replace in the . .Itila; gas. This is in sharp contrast to open circuit .. : ' tl.. systems where the external air must ~ be ~ Gas flow continues through 25, dlDIy . ~3.~: ~ conduit 80 past ,, y sensor assembly 78 where gas flow, pressure and ~ , - are ~~ ud as discussed above. Data from , dlU.y sensor assembly 78 is, G~Gr~ ' IY used to control gas injector 82 and , ~y flow control valve 102 allowing gas flow to be modified. r,. I,d by gas moving .9, r dllJ;~ 92, the aluly gas ll .~ ,s the gas flow path defined by , àlG, y ~ , conduit 80, passes optional nebulizer 98, and enters the r ' y air passages of patient 12 through " "~; -' , ai y check valve 66 and patient-~ 14 to effect positive pressure .. ~ udu~.~,d with the: , dll.~y ~as is at least a portion of any rl, _: y promoterr ~..L~LSI~ present in the r ~ ~ y air possages That is, the le, dlUly agent or liquid medium has been IG~;II ' ~.( ' Optional nebulizer 98 is in i' ~-r ' ~ r with the gas flow path defined by i, : y .~,..lilaOI,u conduit 80. As used herein "I ~ n will mean any type of nebulizer, ' "'k.. or vaporizer which may 35 be used to deliver pdl lil~UldlG or vaporized material to the gas flow path. While p- 3rl along ;~ dlUI y ventilating conduit 80 in Fig. 2, nebulizer 98 may be placed ,~: G along the closed-circuit defining the gas flow path. Those CA 02238013 1998-0~
WO 97/197~9 PCT/US96/~8989 skilled in the art will app~ .;al~ that nebulizer 98 may be used to introduce aerosols, mists, sprays, vapors, powders or . ' - thereof into the gas flow path thus i g - ' equilibria of the ~ tilalillg gas or addin~
,~, y agents. Normally nebulizer 98 is activated only during the i , aloly phase without affecting the delivered tidal volume or inspired oxygen. In particular, nebulizer 98 may be used to deliver liquid medium, r er~
5 r' ' '! to the gas flow path for partial liquid ~.,..lildlia.l. In especially preferred al ~e " . nebulizer 98 is used to provide r ~- . heated above body i , alul~, to the ~.,..lilai _ gas in the form of a vapor. This may be as~( . ' ' ~d by spraying or ! ' ' " a wetted surface or wick with the gas to form droplets. In this form, the rluulL-' ' liquid medium is pal ' l~ well dispersed in the lungs. As the ri . -' ' vapor cools in the body it is deposited on the F-' - y surfaces to assist in gas exchange and UA~, liu~. In addition to nebulizer 98, 10 the gas flow path may further contain heating means such as a wick or electric elements in the ._..li6li..~ conduit to prevent r~r ' liu,. of the .. " di y promoter and water.
Those skilled in the art will , l,.,;ald that a ~, _ means (not shown) may be operably assoL.;al~d with the gas flow path and used to regulate the level of ll alury promoter in the l,huillai _ gas. As discussed above, suitable - p~ dlillg means may comprise c~ ' ~, chemical adsu.L treated surfaces or any other 15 that provides for the , dliul, of the ,l, di y promoter from the gas phase. In selected bc " such ' - may be used to gradually wean the patient off the ,e, dlUly promoter by removing it from the c;. ' ~, gas without ~ " ' : That is, as the ,., d~ y promoter naturally ~i~a, dll,.~ from the lungs it may be removed from the gas flow path and stored, p.er~. ' 'I in a liquid state. This allows for the gentle transfer of the - patient from partial liquid ~.,.llila ' to r r .~ - l;.m without the loss of valuable or .;. ~ sensitive 20 material.
It should be , ' ' that the present invention is pdl i' ' Iy useful when used in L ; with liquid tilaliull and 11~ partial liquid ~...1i6i Partial li~quid ~ ti6; has a number of benefits over ..
gas ~.c..~;'_: The lungs are bathed in a L -'' fluid. Lung trauma is minimized and this permits lung ...alL.d and repair. Partial liquid ~ ' is more amenable to use than total liquid breathing since air or gas 25 can still be inhaled and exhaled. Partial liquid ~. -' can be used in s : with s, - . passive or ' ~, ~;'_: in er .' e with the present invention and, because it is more natural, precludes the necessity of deep sedation andlor paralysis of ,., ~ nloly muscles. In addition,, ' , ~ r ' : can be added to the rlua. ' -' to further promote ,. ' of, ' y and systemic disorders.
P~.ru. _ PLV in e . with the present invention may comprise the ~ ,dliun of very low doses 30 (on the order of .01 mlJkg or less) of the desired rl~ ' or s ' i of fi ~ ' ' Ls;.~..,~i 'I~, a -'l~ effective amount s i;~bS enough to form a thin coating on a portion of the lung. CL ~ .Jy, the level of ri ~ ' ln- ' in the lung may actually exceed the r, : residual capacity of the patient. That is, the amount of r .S used for partial liquid ~.,..i' may 9~, ~ : the volume of air remaining in a healthy lung of similar size following ' '; . or ~' llali.~, that volume plus the volume of the ' lla~htdl tube. The 35 actual volumes will depend on the ~ a~ ..l protocol, the weight and size of a patient, as well as the lung capacity.
While not limiting the scope of the present invention to any one e '- ~ . it is believed that the ,. hnLI~ low CA 02238013 1998-0~

surface tension of biocompatible r; r- ' ' alters the I e ' ' behavior of the rl , ~lo,y system during partial liquid ~c..i': Observed changes in ~ , ~ dl-..y ' su~qgests that, following the, ' y i . 'l of low doses of a r; rc-' l a thin film of FC with a low surface tension is formed due to ~ and covers the interior of the lung. This ~'l ~ ' ' film reduces surface tension at the alveolar air-liquid interface thereby 5 I- : v lung ---r ~ and ~ ~ ~, oxygen a~ y.
Thus, during partial liquid ~ in e ~' with the present i..~.., the lungs retain sufficient air capacity ~above and beyond the volume of l; r~ ~' ' in the lung) to permit inhalation such that normal breathing can proceed. The amount of air entering the lungs on inhalation is sufficient to GA~9r ~ the li - ' ~ ' liquid.
Further, the fluorochemical liquid may be UA~ prior to use to provide oxygen to the alveolar surfaces of the 10 lung ~ 'yupon initial contact with the f; . ' ~ -' In a particularly preferred a Sc' of the present invention the desired amount of IL,.,.L~hc ' is ' ~ ~ cd to the lung and the closed-circuit .~ ildi- ~1 ~ppr dll... is attached. R, dlU~y therapy is begun.
. -cfc. ' ly with positive pressure \,.,..t with the tl , ' e in the lung and the closed circuit ." dLul defining the gas flow path quickly becoming saturated with ~I,.a,. ' ~ ' Oxygen and small amounts of ll~ur. ' ~ ' are 15 added to maintain the desired I .:.l : while the rc.,;~ ud ~ gas is treated to remove carbon dioxide.
Pt-cll~ hl~, the process is ~ cd by sensors in the r., ~ .~ p~ dlUs and a vapor analyzer is used to control the amount of ri . ' ' added to the c' - ~-c;" system. Following c . ' of the therapy the system is removed and the ~luu.~ ' ' is allowed to bC~_~ alc.
In another preferred G bc'- 1, the dl . ' process is carried out without the ~."' y 20 ~ ' ~ ~ Idli"n of rluu" ' ' to the lung. Rather the liquid medium is added to the closed circuit system, j c~.,.a~1 in a nebulized or vaporized form. Again the c~..i,~ l quickly reaches - ' lial , "' i for the c pc of the e~ li,.~ gas other than carbon dioxide and oxygen. These levels are then easily -' by small additions of material from the nebulizer and gas injector. This method is pal; ~ I~ preferred for PLV involving the p- ' y : h.' ~i of " ,~ J,y promoter at volumes less than r..,.~P - residual capacity of the patient.
As ;' ' above, PLV may be ' i ' using any liquid medium which provides the desired ,c ' y Ihc" : ~b, For example, in some; " i hlr UA~, ' ' saline may be used in ae .' -e with the present ;... c - P~ ,:lel "~, however, PLV will be r ~ using a r; . ~ ~ Particularly preferred bL ' employ fi ~ ' ' that are liquid at body i , -c.
By ''lluu.~-' -"' is meant any r illatt,d carbon -- ,)r_ ' with 3~, 1, iall: physical p", li~s of 30 ' pr i ' ' ~y. These, ~ , are generally met by ri .- having low viscosity, low surface tension, low vapor pressure, and high solubility for oxygen and carbon dioxide making them able to readily promote gas exchange while in the lungs. For example, it is preferred that the r r- ' ' have at least 3 or 4 carbon atoms andlor that its vapor pressure at 37~C is less than 760 Torr. The ~' rL ' ~ ' may be made up of atoms of carbon and fluorine, or may be a r~ having atoms other than just carbon and fluorine, e.g., bromine or other nu..l' b~-c 35 ' :s. Those skilled in the art will ., cL.;dle that the range of L , "' ri .. is: b~ F ~1~
brl,ad~ .d by the present invention.

CA 022380l3 l998-o~
Wo 97/19719PCT/US96118989 More ;, '; ~ , one of the major P '-_ i " - of the present invention is that closed-circuit ~c.,lilai' aliows the extended Ihel: use of r; r~ ' ' that were ~ too volatile to use efrl,.,~ c F~ , some - volatile lluo~ '' were used for short term drug therapy where ' - y retention time was not critical. With the present ..,.. n, high vapor pressure r; ~ may be used erru 0. 'y as they are not lost to the outside 5 L - ,' G. That is, the closed-circuit systems of the present invention promote s b~ lial '' i for most . ': " gas rl pc- including volatile " ~ ' ' Ar- ~ steady r~ y levels of these rll . ' ' are rapidly reached and easily - ' using the novel ~' I C;,I,.J;t systems described herein.
P~Gr~ the selected r; ~ ~ ~ will be able to cover a - ': ' amount of F-' y tissue with relatively little volume. The ability of a given s ' s e to cover a measured surface area can be described by its~0 spreading cc rri..;.,..L. The spreading c ~liL;_.~ts for ri . ' ' can b e c l;.,sed hy the following equation:
S (o on w~- ~wla-[9wlo + 9ola) Where S (o on w) ~ ts the spreading ~o ~ri l; 9 ~ IGI ral,;dl tension; wla ~ v ~IGII~ , WIO ~ GI ~ , and ~ Olâ ~ oillair.
Fluù, -' ' exhibitiny a positive spreading cc_rri~ , will tend to spread over the . , dlO.y 15 ;, i '~. r. ~- ~ - having spreading c '~i-,;_..ls of at least one are ~ preferred. If the spreading . - 'ri.,;_..~ is negative, the - ' will tend to remain as a lens on the ' ~ surface. Adequate coverage of the lung surface is desirable for restoring oxygen and carbon dioxide transfer and for ' ' ~ ~ the lung surfaces to minimize further F ' y trauma.
n~G~ ldli.- r~ useful in the present invention include bis(F-alkyl~ ethanes such as 20C4F9CH CHC4Fg ~d "F 44E"), i-C3FgCH~CHC6F13 ("F-i36E"), and C6F~3CH-CHC6F13 (nF-66E");cyclic rll I ' ' such as C~oF18 (nF-decalin", "p i" - ~ ' ' " or "FDCn), Fer' ? (nFA"l F-.~_th1' ' i ("FMA"), F-1,3:" 0~' ' ("FDMA"), Fdi-or FlH"~rlh~ y~,lu~3,3,1]nonane ("nonane");
P~.r' iudll,d amines, such as F-lH~ r~ "'FTPA") and F-tri LLt'1; - ("FTBA"), F 4111GIIIY' h~,.h-, " -(nFMOQ"), F-n-methyld~- h~dn , ' ("FMIQ"), F-n, h~;' h~d~ -line ~"FHQ"), Fnc~ ' ' yl,~u.,l' ' ("FCHPn) and F-21 ~ylltllnh1d~ur all ("FC-75"or "RM101"). Bl : ' rluu.. hl ~ ~ include 1-bromo ', I..d~i..ari u-octane (C8F17Br, s : ' ~, : d F r~l r- ~l bromide or "PFUBn), 1-bI , Id-ducdr; oh_~i (C7F15Br), and 1 l 1 ~ " n' (C6F13Br, known as p~.P I ' yl bromide or "PFHB"). Other L, : ~ ri I ' ' are disclosed in US Patent No. 3,975,512 to Long.
Also e~ t~ ' ~ are ~'l . ' -' having ~ . such as pelr; ~ .D~:yl chloride, pGI r' ~ l hydride, and similar . , ~ having different numbers of carbon atoms.
A~ ' B . ' ' ,' d in acc.,.. la.. Le with this invention include F r~ -'k~,ldted ethers or po')GLh.s, such as (CF3)2CFO(CF2CF2)20CF(CF3)2, (CF3)2CFO-(CF2CF2)30CF(CF3), (CF3)CFO(CF2CF2)F, (CF3)2CF0(CF2CF2)2F, (C6F13)20. Further, C' ~ ' ' h,.'r~- l , ' . such as, for example, r , -havingthe generalformulacnF2n+1 Cn~F2n~+1~ CnF2n+1ocn~F2n~+1~orcnF2n+1cF CHCn,F2n,+1, wheren andn~ are 35 the same or different and are from about 1 to about 10 (so long as the ~ ,ac ' is a liquid at room l~.llr .dlulG).
Such - pr ' for example, include C8F17C2H5 and C6F13 CH~CHC6H13. It will be apu,~c;aled that esters, . CA 02238013 1998-0~

and other variously modified mixed r;~. h,dr~- b -- , --~lc are also ~ within the broad definition of r; rc~' ~ -"' liquids suitable for use in the present invention. Mixtures of R ~ -' ' are also ~ , ' lbd and are ~ ,d to fall within the meaning of "llu~.--' ' liquids" as used herein. A~' ' --' ri ~l I ~ ~ I 1l bC~ d are those having, ., li~s that would lend i' s~' . to r ~ y gas exchange including FC-75, FC-77, RM-101, Hostinert 130, APF 145, APF-140, APF-125, perfll ~ ' ' . r R - .~ :ylb,~
p~.r; ISC~yl-lbl, h~ urvb.~.,, rJ~.r; ~ ll h~d~m~all, dimethylc' e~ yl!~ y 'l nonane, and mixtures thereof. In pa,tiL ' , preferred r; .-~ .aicals are cha~ablb~iLvd by having: ~a) an average ' - ' weight range from about 350 to 570; (b) viscosity less than about 5 Cvb~ti~ ' at 25~C; (c) boiling point greater than about 55~C; (d) vapor pressure in the range from about 5 to about 75 Torr, and more p.er-b._"~ from about 5 to about 50 Torr, at 25~C; (e) density in the range of about 1.6 to about 2 gmlcm3; and (f) surface tensions (with air) of about 12 to about 20 dynbqlcm.
As 1..~ indicated, the volume of ~' ~ ' ' liquid illll. ' e-' into the r ~ ~ y air passages should r bFd(_'~y be _b~ ' to 0.01% to 100% of the normal, ' y r, : - residual capacity IFRC) of the host. By "p ' y functional residual capacity" is meant the volume of space in the pulmonary air passages 15 at the end of expiration. For different .,'i~ s, different amounts of ri b are preferred. In one : ~ 1 t, the volume of r; , liquid is at least 1%, 2%, 3% or 5% of the r ~ _ y FRC of the host.
F~r~. ' 'y, the volume of r; or' ' liquid is at least 10% of the host's, ' y FRC. In another ' - ~- t, the volume of r . liquid is at least 20% of the F ~ y FRC of the host. In other preferred . ~ -~ t .
the volume of R' ' ' liquid is not more than 30%, 50% or 75% of the host's r ~ ~ y FRC. Al~ lai '~, 20 the volume of r; ri ~' -' liquid is not more than 20% of the r ~ y FRC of the host. The normal, ' y FRC of the host is o ' ' Ibd by methods well known in the art. It will be 3~ r b~.;.Jtbd by those skilled in the art that preferred volumes of filling the lungs wlth r; . may be within certain ranges instead of discrete p~. . v s Thus, preferred . ' - ' of the invention include c ' , of r; . ~ of 0.01 1%, 0.01-10%, 1 10%, 1-20%, 5-50%, 10-70%, 50-75%, 50-100% and 75-100% of the host's r ~ y FRC, - ' ': ' using standard Z5 methods known in the art. Delivery of r . to a single lobe, ' dl) or local portion ~lobar, v 1, is also c An ' ~lali._ ~ bc ' of the ' ' ~, ~ ' ;- systems of the present invention is ~ ' : 'l~
illustrated in Fig. 3. In the ' - ' : shown, the patient is ' ~. v passive ~I~ - ' meaning that no external pressure, other than that g alvd by the s~ " di- of the patient, is being put on the closed-circuit 30 ,. , ~ . Accu,. ,.'~, this - bL ' : is IJ~b~ used on patients requiring r., y therapy but whose natural y function is strong enough for life support purposes. That is, for patients which do not require positive pressure ~.,..lildliun. This ' ' may be used for both ll_ ' ' gas "c ' I - v the administration of a rl, ~ dlOIy agent and for partial liquid ~. ';
For example, this ' ' : may be used in v ~ s~ tinnc or in the home where p~ - 3r~
35 - ' ' ,, I is , ablibdk Another favored use for the depicted bc " would be for ~ y drug therapy, with or without an adjunct liquid medium, such as for the ~ aLioa of _ ' ~ Libv in ~lb~.. ' ~ cases.

CA 022380l3 l998-0~
WO 97/19719 PCT/US96/~8989 The use of such a closed-circuit system would greatly reduce the chance of infection in care givers and fellow patients.
Moreover, the closed circuit ~~,..lil.. - 1~, a~ depicted in Fig. 3 could be made, at least in part, from reliable yet .~. materials making it !'-, ' ', Spe~.;f' ~1~, the closed-circuit ,~ " dl-~( defining the gas flow path could be made of cost effective material allowing one readily dispose of it after " - v the more t:--r ~ and 5 reusable ~ used for monitoring r ~q e C~r.~ , the entire system could be made reusable.
Turning now in detail to the figure, closed-circuit ~i..i' system 110 is sealingly 15~fiC ~I d with patient 112 via patient-c~~ : 114 ~ ; ' C- v s between the r y air passayes (not shown) and the closed-circuit l~ ,~, . In this bc" t/ patient-~ u~ 114 t , i;._s a proximal mask covering the mouth and nose of patient 112 and a distal Y-c- ~. 116. Distal Y-~ - : 116 of patient-co 114 is sealingly affixed to , y .~.. i' ., conduit 118 and:, alù~y ~~.. i" '' v conduit 120. As discussed above, patient 112 is _ ' ~ ~ ~., ai' c , ~ ' " an , . phase and an , phase. However, unlike the: ' " of the present invention, L~ --d, this ,-, di' is ,. ' and does not require positive pressure ~, ': for i Rather, the natural ,, of the, ' y cavity will provide the nEcessd,y pressure to force the gas through the gas flow path defined by the closed-circuit ,~, alul.
Under ;, - tAhdlai pressure the - dl~.. y gas is forced through patient-c : and into expiratory ~...l;lai' ~ conduit 120. Once again the y gas ~t, iV_j carbon dioxide, ~ d oxygen and, optionally, liquid medium or a .,, di y agent. Ambient gas already in , ~: y ~ , conduit 118, and confined therein by . " ~.,i ' , y check valve 126, will prevent . ' tidl entry of the - aluly gas.
Arrows 152 indicate the direction of gas flow through the :' ~-c;~,,uil r,, al~JI. Following entry into the proximal end of ~ Y ~ : v conduit 120, the , Vt y gas passes through carbon dioxide separator 122 in fluid-c ' : v c - - with the gas flow path defined by di y ~. " ' V conduit 120. Upon I a~,liuU with carbon dioxide separator 122, at least a portion of the carbon dioxide in the , dlo;y gas is removed as F
Following removal of the carbon dioxide, the treated dl y gas is forced through: " L~,liUll ,' dtoly check valve 124 and annular c 148 and exits the distal end of dlu~ ;Ia~ conduit 120 into variable volume reservoir 154.
In the " : alLd ' " : variable volume reservoir 154 is defined by compliant ' 128 and rigid member 130. Annular v 148 and 150 sealingly couple, .., : . '~, , , y .. ~ conduit 120 and - , dloly ~. :' v conduit 118 to rigid member 130. V~...lilai' _ conduits 120 and 118 are attached to rigid member 130 adjacent to their distal ends. The distal ends of ventilating conduits 120 and 118 extend into variable 30 volume reservoir 154 thereby establishing fluid-c~ ' :- v : between each individual ~ tila~illg conduit 118, 120 and variable volume reservoir 154. Of course, those skilled in the art will 1" ~...iale that the " '.dlLd c : s are .' y only and that any sealing i : ~ or c 'iL which e ' ' the desired fluid-c ' ~;.,9 liu,l between the ~ lilai' v conduits and the variable volume reservoir is , :' ' with the present invention. I~.r- d- vl~ the r~ ~-C;lLuit I ,' dllJI illustrated in Fig. 3 c . iSL3 patient-c- : 114, ~ dlh~9 conduits 118, 120 and variable volume reservoir 154.

CA 022380l3 l998-0~
WO 97/19719 PC~rAUS96/18989 ln the instant ~ ,' y: bc " I, variable volume reservoir 1b4 is defined by rigid member 130 which is sealingly attached to compliant . ' ~ ~ 128. As the treated ai y gas is forced into variable volume reservoir 154 ;~ a~ the pressure therein, . ' ' ~ 128 expands to increase the volume defined by rigid member 130 and r .~' I r ' ~ 128. That is, the volume of variable volume reservoir 154 iS increased to equalize the 5 interior pressure and the exterior pressure. The interior pressure of variable volume reservoir may be regulated by biasing , alO~y check valve 126 in a ciosed position. The amount of bias will :' ~ the allowed pressure "'I~,L.,t;dl between the pressure in the gas flow path defined by ~ , di y ~ lilat v conduit 118 and the pressure in variable volume reservoir 154. This bias may be regulated by simple ' ' I~ L built into i, aluly check valve 126 or may be adjusted based on data received from sensor means. In any case, when the pressure 10 "'I~ idl exceeds the biasing force, such as when negative pressure is exerted on the gas flow path defined by , alury ~.,ti6i ~, conduit 118, check valve 126 will open and ~ v gas will pass from variable volume reservoir 154, ~ reducing its volume, into .. ' i " conduit 118.
Those skilled in the art will app,ec;al~ that the illustrated L CL~l...a1u.. of variable volume reservoir is r, .~ y only and that numerous designs exhibiting the desired l,ha~aL.I~H~ s of , or cGr,llal,liu.. may be 15 employed in the present invention. For example, the variable volume reservoir may be in the form of a balloon like structure, a bellows or a floating piston. Whatever form is selected, it is clearly within the scope of the present invention to manually or ' ~ 'l~ manipulate the variable volume reservoir so as to effect positive pressure ~..lilalion. This i ' . is ' ~s to "bagging the patient" with r ~..i ' open-circuit ~ devices and may be especially useful in ~ y, . c ' . ~. When used in this manner the closed-circuit system " :l al~.d in 20 Fig. 3 may be employed without any sensors or electro ' ' ~ .. For example, oxygen may be slowly metered into the gas flow path defined by the closed-circuit r., ai while rl, ai is effected spr ~ ~ or by , ' :- v the variable volume reservoir. Such methods may be used to stabilize the patient and keep them alive until more ~ h',lP ~l~'d ;..;.ll_ ' i ~ iS available. Of course the same i ' , may be used in non-~".~.v y s:~c:
For more c :l " ~ ;,ituai i, such as in-home care, sensors and gas . ' devices are p,~r~ used in L~ni " with the closed-circuit ~ : system. In Fig. 3, . al-..y gas controller 132 may be used to introduce oxygen and other gases to the ~ . y gas. Sensor assembly 134 l ' re. Jbly ~ ., r;ses an oxygen sensor and may ~ I Gr-~Ju~ald pressure, . v~ ~, flow, vapor and gas sensors. As the ~~,..lil~.: gas passes through i . al~.,y ~I~.ltila; v conduit 118 data is obtained from sensor assembly 134 and fed into; ~ y gas controller 132 and, optionally, nebulizer 144. ' . y gas controller 132 is -- : ' to external gas sources, including oxygen, through gas transfer lines 136, 138 and 140 and will introduce them into the gas flow path based on data from sensor assembly 134 in c ' - with, ., ~ u~.liu.,,. r~ hl~ these gases are . ' -d into variable volume reservoir through gas i"l,. ' line 142 to minimize pressure l' : and ensure mixing. However they may be i ~. '.,...id at any point in the gas flow path. Similarly, nebulizer 144 may be used 35 to introduce liquid medium or ll .- . y agents to the gas flow path as described above. Optional nebulizer check flow valve 146 reduces the chances of undesired backflow during the; . - phase. Finally, the i" . alOIy gas, CA 02238013 1998-O~i-l~i inciuding any c;, ulal~id ~ y agent or liquid medium passes through patient-r r : 114 and is i,.ll . d ~d into the ! ' v- y air passages where the cycle starts a new.
Fig. 4 is a c ' li,, ,~,,,.. ~ r of an P ' - ' : of the present invention similar to that shown in Fio.
3 but capable of ~ . ' positive pressure ~ t ti More pal ' Iy, the closed-circuit ..,..lil~ .n system 5 depicted in Fig. 4 --n7, ia~;5 a closed-circuit ,l alol defining a gas flow path that is operably r~~~~- ' with an "' ' open-circuit ' - ' ventilator. By "operably as ~r' ~ '" it is meant that gas flow and other ve.~t;la ' o, , ' - may be cc: ." d, - ' ~d and effected by the ~ ted ventilator n,~ dlU~. As with the previous bc'' : of the present invention, the closed circuit ,l, al_. allows the ~_..lilai g gas, treated to remove carbon dioxide, to be c;. ' ' in and out of the patient along with any ' I a~.d vapor, gas or ~l , ' allJI y promoter. This 10 closedcircuit ~ ilaliull provides all the p,..~ discussed ~ such as retention of ---r ~ Is improved ' of ~.~..lilai vgas- - ~andc i lofpa'~O ' agents. Yet,the- bc" Ishown in Fiog. 4 provides the - ' "-' - ' 9~1~ ; _ of allowing closed-circuit positive pressure ~ ' . and pal ' ' l~ partial liquid V~ ;lai' . using off the shelf open-circuit ' ' ' ~ with all their ;~o~.~h'~ al~ d ll . ' al~;y controls.
At the same time, isolation of the gas flow path from the ventilator , alu;l allows modular - ' '"'ty, reduces 15 materials compatibility ~ ' . reduces l _ ' y c " i' and -" ' Ib.~ 5 ' ' ;- problems from the ~ repeated use of hard to sterili7e ~. ~ ~a ~. Moreover, as "' ~,dll,d in Fig. 4, the present invention uniquely solves all of these problems in a simple, direct and cost efficient manner.
As ' ' d, closed-circuit ~..lilai- system 160 depicted in Fig. 4 ~ c.~ many of the same elements as the I ' - ' : shown in Fig. 3. As with the ' ~' I of Fig. 3, the closed-circuit ,., alur defining the gas flowpath(ll, I ~I'byarrows198~ O;~patient-~ : 164,~,. ' 5conduits168and170andvariable volume reservoir 180 wherein variable volume reservoir 180 is b~ ' to variable volume reservoir 154 of Fio. 3 with the exception that the compliant ' - 218 divides the chamber 178 into two ,~ . ~ s that are not in fluid-~ Patient-c- 164, in this case an - ' l~ ' ' tube, is o ~ ~ to establish fluid-c~ ' v com: Ik.,- between the, ' y air passages and . , ry ~, ' - v conduit 170.
During the s, - ~ .' aOu~l phase, , al~.y gas passes through the gas flow path defined by ~ y ~. :" i' O conduit 170 and throuOgh carbon dioxide separator 172 where it is treated as, L.' 1~ des.., ' -' iJpon sxiting carbon dioxide ., di 172, the treated gas advances through '' . :' ' check valve 174 and annular t~ 176 where it exits the distal end of - ' . y .. :" " _ conduit 170 into variable volume reservoir 180 of isolation chamber 216.
As will be d;.~.uas~l in detail below, the ~. " O gas ~L , ~ ~ lg treated - ~ y gas ~.u.
illll~ ' ' 11, ~ d; r~, agents or ~ may be forced through annular c~ ~tu. 194 and . " ~"liuna: check valve 192 into ' ,' ~ y .. ' ~' _ conduit 168. Prior to ;..l., ' l into ~, dlo~y l..,..lila; _ conduit 168, the ~.,..lilai' _ gas may be . . r~ lo., with oxygen and other gases ~ ' ~ into variable volume reservoir 180 by ' , ai y gas controller 200 from gas transfer lines 186, 188, 190 as r 1~ dl ~ b~. ~ The ., ' : d gas, u.l:r~,,' ly under positive pressure, then travels through ' , ~, y ~ ~ _ conduit 168, past sensor assembly 196 and into patient-c )~ 164. Like the '-" I of Fig. 3, sensor assembly 196, ~ b!~ transfers data to both CA 02238013 1998-0~

~ , ~ al~. y gas controller 200 and nebulizer 2D2. Nebulizer Z02 may then interject vaporized 1., dlUI y agent or liquid medium to ,, ' : the r u~ ' ' material present in the , ~ dl-.l'y gas. The; dlUIy gas c ~ ~ the ~ 1; d ~e~ agent or liquid medium is then forced into the ~ ' y air passages of patient 162 to effect positive pressure ~. ' Unlike the c Sc' l depicted in Fig. 3, closed circuit ~~.. i ' system 160 of Fig. 4 - ~alll ,, '~
..dlGs an d-'i~d open circuit eL' ~ ' ventilator 214 in a modular cm riuu~di' More ;,uE.,;r 'I~, -' ventilator 214 is operably e~Yrr l~d with the closedcircuit r, dlu. defining the gas flow path.
'' ' 11 ventilator 214 may be any r ~ ' available ~ and CG,Il, n ' 8~ to the , c;,~ ~
t;6; r system depicted in Fig. 1 wherein ~,..lilai " ~qaS is supplied from an external source and i, : y gas 10 is vented into the s...,. ' " C..v;ll l. In the ~ , GS~ i of Fig. 4 the internal workings of the ~. '-' 9~, d~ have been omitted for simplicity. Pressure conduit 210 and exhaust conduit 208 define a gas flow path (rG~IlG~el~t~d by arrows 212) which transmits pressurized gas from the ' ~ ~' ventilator 214 and vents exhaust gas. Those skilled in the art will a~ .L~;ale that ' -' ventilator 214 e i all the S-r~ ~ ~;Lall~d control and delivery functions normally found on r~r... - ' ' ~ -' .~,..lilalul~, thereby allowing a wide range 15 of gas ~ ' ~, modes to be selected. In the preferred ' -' of the present invention shown in Fig. 4, ' ' ventitator Z14 may be used to effect positive pressure ~~..t;!~t ~n on patient 162 by Ll pressure waves through isolation chamber 216 and into the closed circuit " dlOI as defined above. As depicted, isolation chamber 216 , i.Gs chamber 178 which is birl.,l,~t.,d by compliant ' 218 to define variable volume reservoir 180 and c , G.>S;UII reservoir 182. The small arrows in chamber 178 are indicative of gas pressure on the various surfaces. Variable volume reservoir 180 and c~ G ~ reservoir 182 are in direct pressure r h r ~ liun through compliant ' 218 but not in fluid c~ ct ~ i - r~G~G,~ ' ~y chamber 178 is c~ ~., d of a rigid or semi rigid material. ' , dlL.y ~ conduit 168 and , ~ al~,.y ~ ai ~ conduit 170 are sealingly affixed to chamber 178 thereby ~- ~ ' ' ' ~ v fluid r ' v ~ ~ :- between the dt~ y gas flow path and variable volume reservoir 180 as well as the ~ dlOIy gas flow path and variable volume reservoir 180. Fi~q. 4 also shows that pressure conduit 210 and exhaust conduit 208 are sealingly attached to chamber 178 by annular c ~,. 206 thereby e: ' ' ' ~ r; p~ ~ ~ c ~ ~- between - ' ~ ' ~. ': 214 and r ., reservoir 182. Those skilled in the art will a~ ., ~: that the 'i, I depicted is e ' y only and that other e ~ may work equally well. For example, chamber 178 may be spherical or variable volume reservoir 180 and L~ ~ reservoir 182 may be oriented l''rL.~--ll~.
In any case, isolation chamber 216 may be used to p.e~auliLGr in a cu"l, " ' manner, the gas flow path defined by the closed-circuit ,l, ~ dlul. As d- d above, the treated i, dlUIy gas is forced through the gas flow path defined by I, dlOry ~ conduit 170 and into variable volume reservoir 180 by pr ~ h.A!a:-U ' ~ y check valve 174 prevents ~ '' backflow. ': ,~ of the treated , dl y gas increases pressure in variable volume reservoir 180. C ' ' ~ 218 adjusts to this pressure ri - by moving to increase the volume of variable volume reservoir and normalize pressure between variable volume reservoir 180 and r , 'I 1~.- reservoir 182.

CA 022380l3 l998-o~
Wo 97/19719 PCT/US96/18989 At the same time, l ' -' ventilator 214 is delivering gas under positive pressure through pressure conduit 210 to c . reservoir 182. It will be ~" I.v;al~d that the gas may be delivered ' r _ any one of the ~ ,as ~ tud delivery profiles available with modern ~.lilai ~. r,ti~ the delivery profile will be c dh~aleJ with the ,~, .,i efforts of patient 162. As the gas is ;.~ du..~d under pressure to cv~,u~ ;un reservoir 182, : , ' ~ - ' 218 reacts to increase the volume of - - , . reservoir 182 while reducing the volume of variable volume reservoir 180 and ~...s ~ the 9âS flow path defined by the closed-circuit ", . This increased pressure forces .. ' v gas through , dlory ~.;..lildli..g conduit 168 to effect positive pressure ~. '; of patient 162. In other words, the pressure rlu~,luai - j dll:d by ~.?~ ';!i, 214 are ll . tl:l I ..d to the gas flow path through isolation chamber 216. Ad~,_ lugeo~.ily, the delivery profile produced by I ' ' ~ tilal~l 214 is . .~d as it is ll ' though isolation chamber 216. Acr ~" _1~, delivery profiles may be selected which maximize c , ' and minimize ,, As indicated above, the unique modular c ~, of the ~ -L;..,..i~ .~ ' l; systems of the present invention allows different .. ' i I:j to be - ': lud or ;lltl~ ' d, " " on the specific needs of the rh~ ~ ' For example, in the ' - " depicted in Fig. 4 any c . 11~ available ' ' ~c..t;!~
15 may be operably --- ' with the selected c'( ~n,;. . . , ~ rapidly and easily. Similarly, optional e, ~i~
such as sensors and ~ , mây be quickly changed to modify the I cj~ aliun of the .. ~;' system based on ' a~J~.Jth. mueds. This ' ' ily allows the closid .,;.. systems of the present invention to be rapidly changed F " 'I~, for example to avoid bacterial ~rowth, without unduly ~ v the II,e~ pl~.~.edL.I:. In this case the c~ v 1u,;.~ ", dlOI could be rapidly :" ' from the patient and any s ' ventilator and replaced 20 with a fresh sterile one which had been r~'. ~~' _ ' Further, in G ~' ~~ with the i ' herein, the used closcd c;-- r , ' I could be sterilized and reused or d ' The modular r ~ ,i of the present invention also i -" Its ' I and system cleaning.
As, ~ ly indicated the present invention provides for the ', ' : delivery of ~II,a,l..aL~;~.li.,al agents or their use in: : with other vapors or gases such as I , di y, I :>. Moreover, the devices and 25 methods of the present invention may be used for the i' ' ~: of ~'- ",~ ' agents in ~ ~ with any type of ~.at;!~: In particular, c ' ~ i. ' dosing regimens with liquid ~. : ' therapy has a number of r 1~ over other forms of drug delivery. The i' -' 1- ' ~ delivery can be used for " : thatwould ' ~ ;_~be i ~r~li. or d~: uradby delivery a~ tl ' ~1~. For example, proteins usually cannot be -' : L d orally because they are ' :r~"~d in the ' taly tract. Some proteins may invoke 30 severe allergic reactions and shock in the host if _' ~d sy~ such as ;.,l, ' l~ or ;,.I,u~
For example, :' li.,:, and antivirals may be provided in c ' i with a r- ,1 ~1 ' liquid during either partial liquid ~. ' t;u" or total liquid ~ n One particular F- ' _ agent, .,~l ' .;,u, can induce life-ll" i: ~ cases of ~ in immunocompromised patients. These " ' ' often require ~ ' i therapy.
F' .- bcn 1d : ~: in ~ ' i with the ~ ' ir analog, 9 (1,3 d S~ d~UAy'2' 35 plUpOA~ lh11)9 ', Ui' ~ known as ~ ' .;. or DHPG, may provide an effective therapy that could q '~ inhibit viral ,~. ' snd facilitate oxygen transport in the c , . ~ lung.

~ CA 02238013 1998-o~
Wo 97/19719 PCT/US96/18989 The precise amount of, ' , - Li.. al agent ' ~d in ~ : : with the methods and devices of the present invention is d, ' upon the agent of choice, the required dose, and the form of the drug actually ~ l, d ' Those skilled in the art will 1" ~..;ale that such d~ may be made by using well-known te ' , in r ' :- with the teachinys of the present invention.
Preferredp~- - :- 'agentscomprise~, dlu.yagents, ' t;~.s,. t;.;.. ' l ,'iali.. ~ ,' ~s, anti- " i)~ " r l' ~ ,': . -~i:h t;.s, o,':' ' agents, Cald ~a ' agents, active , i ~i,' s, nucleic acids, genetic material, i - t;~ agents, imaging agents, ~ - , ~s;~ agents, 9a;,lll - -' agents and ' - ~ thereof. Further e , ' y bc ' of the present invention comprise y agents such as the 1' ~c l;LGSI~II - (i.e. ,c i- ~ e, I th 10 L i ' - n . ~,1 ' ' ~ di~ ., i - . T~ ' - ac~,; ' rl ~. xanthines fi.e. t' e, h~" .
caffeine), ~ , - (i.e. cy ' p~~, ' ~ ' . Iomustine, :' I~AdL~, cisplatin, taxane ~1 i.ali.~.3), ~ ' ~ Li-.s such as the B;,! él9_ (i.e. adrenaline,; , . ' . - ' ~1, albuterol, - ": I, II,.L ' . I. I"ul~ and ~.r ~ Still other exemplary embodiments include alB ~ lr~ u blockers (i.e. ~ , Tl ' I~:G), 15 ~ " I c~ ..,.i " enzyme inhibitors (i.e. Vasotec'!3), . Iidlll.t' s, beta blockers, calcium channel blockers, inotropic agents, v_ '' I ~, ~es, . - - ~, ~ - ' (i.e. I I ' ) and a, ' :' ' agents fi.e. F. '~. ~Aill B, rs~ ~C;~l~ c~
In addition to enhanced drug delivery, liquid mediums such as ~i ~ ' ' can be used to remove ' g or foreign material from the interior nf the lungs during closed circuit ~. ' - therapy. FI\J~
20 liquid can be ' l : ~ for ~ .. ' ph~ ' saline solutions used in lavage and may be i..l,.' ' as described herein. Because r' . ' ~ ' are OA~l, ~ '' . they provide oxygen to the person during the ll~dtu.~
allowing for longer and less :' " ~ lavaqe ,u,.~ ' ~. In addition, because some ~luu.~ ' -' have lung su~racl I, Lr li~i., removal of the natural lung ~ is, ~ ~ ~' The density of ~i . ' ~ ' liquids is generally twice that of water and body tissue which permits the r~ ~rl -I ' to sink below and displace the material 25 to be removed. Then when the li . ~'- ' is removed by ' ' means well known in the practice of lavage, the displaced material will float and be .- ' -- '~ removed. These, I",~ are p~.lh,ularl~ ~, lalll when lavage is combined with liquid ~ drug delivery as a complete 1~. ~ of, for example, a patient with cystic fibrosis whose lungs ~ ' excess mucinous s.,~,..:
As ~ d above, effective r" ~ aluly therapy and, ' y delivery of phal - : ' agents may also be achieved using total liquid ~.. lilai In TLV both the lungs and the .~, li' -~i a system are b~ :- 'Iy filled with UA~ I-al '' liquid .., ~ y promoter which is then c;.. ' ~' in and out of the ~ ' y air passages to effect r" _: As a liquid ,~ ala~y promoter is employed rather than a gas or vapor saturated gaseous medium, C .. i- ' ' ~ ~' ~,.,.llilala.5 may not be used in the ~ C? ' ~. Further, when "~i.t~, ~ " TLV using dedicated liquid ~,~,..lihi ~r e, . t,: ' - ' amounts of the liquid ,., dll~.y promoter are lost into the ~u.,. " "
35 ~,...;.l due to the tc ' , - used to remove the carbon dioxide exhaled by the patient. U~ .lalel~, the loss CA 02238013 1998-0~
WO g7/19719 PCT/US96/18989 of the pO~L..'' 'l~ expensive liquid ,l, ' alOIy promoter renders a relatively promising lh~.~ . ,...~q ' ~ much less all. ~;.., in today's fiscal P .;.~ t~
The methods and a~ aldl.J of the present invention, as shown by the b~ " in Figs. 5 and 6, largely obviate this problem and - ' ~L, " ~Iy increase the cost ~r~ sv of the therapy while, at the same time, enhance its efficacy. Fig. 5 is a ~r ' " 1~. rt_~,.. ldi' 7 of closed-circuit TLV system 300 attached to patient 302. As may be seen by: ' :' of the figure, ' r ~ c;.. TLV system 300 actually achieves the -b; I;.~,~, of the present invention by ~l ' ' ' v two '~ -c;~ l all.~ .u~ to provide total liquid -.,.~t;lai' with the efficient retention of the c;~ ' ' v liquid I , ~ di -y promoter. ~1e 'f; ~'I~, the illustrated: ' ~ ' : of the present invention combines a closed-circuit liquid I . alul, operably IGd with a liquid ~ ' , with a closed-circuit gaseous 10 carbon dioxide removal system to provide 8 unique ., dlUS for TLV therapy. By operably ~ - tod it is meant that fluid flow and .. ~;' 'Jr p.~ ' bv are ~ r :,l " ' and - ~ d by the liquid ventilator. In short, the carbon dioxide from the lungs is d' assr ' ~ from the c;ll '~ i v liquid rG ., y promoter through the illl,~ ' - of gaseous oxygen, r.GlG,.Jbl~ in a gas exchange unit. The d -- ' carbon dioxide, now in a gaseous form, is then , al~,d from closed-circuit TLV system 300 as it circulates through the second closed circuit system --, i.;"g a vapor 15 , àlOr before the treated gas is returned to the 1,;.l ' i' v liquid ,., ' di y promoter.
More pal;' ' I~, in Fig. 5 closed-circuit TLV system 300 is in fluid-r h " v r ~ :- via patient-~ r 304 which in this; ' -' : is an ~ ' ' tube. During the , ~ ~: phase of the ,., aliull cycle, oxygen rich liquid ,l ;l a~y promoter is illll ~ -d into the, ' y air passages under positive pressure. During ~ ' I a portion of this liquid ,l, ' all..y promoter r . i ' v, ' y waste products including carbon dioxide 20 is forced from the lungs either by -r ' ~ ~ ' ~ ' or under negative pressure supplied by the c' d-c;, l ' liquid ~ . ' dlUI. The carbon dioxide aceo: ' ' with the liquid ., , ' ~: y promoter may be, but is not . ~ r 2~, dissolved.
In any case this ! .' dll..y Iiquid passes through patient- 304, past Y-~L - 306 and, as with the 'y described ' - " . into the fiuid flow path defined by . ' dllJI y .ant" " conduit 314. In dCCuld with the other ' '' : I a y ' ~ l -' check valve 308 and i , ', y . ' ~..,i ' check valve 310 ensure that the . dlory fluid only enters . ~ di y ~ ~ '- v conduit 314. Arrows 316 depict the fluid flow path definedbythe~ 'I ' liquid, .', -oftheinstant ' '' :. The . di y fluidpassesthrough . di y :' v conduit 314 and enters liquid ~ " v 3~ r dll~ 318 driven by optional . ' all~ly fluid pump 322 in fluid-c h ' ~ ' ' with the fluid flow path. Those skilled in the art will r Gl~ialG that liquid ~G.Ii'l; ' . 318 ~ performs many of the same functions regarding " i v and control of the r ~r-' G as do the ' ' ' ~ ' devices ~ described. In particular liquid ventilator 318 c . i.Gs a number of sensors ~not shown) that provide real time data on system pal :, such as medium ~ , dl G~ C~. pr ~'- . flow rate, pressure, oxygen levels, carbon dioxide levels, etc. Further, based on the i.,l~ - received and ,~ r' ;llvlll - r~
liquid ~~.~Il;lalur 318 controls the flow rate,, ' - y delivery profile and pressure of the chL.rJIai v liquid ,., ' d; y promoter through fluid pumps 318 and 322 and a series of flow control valves (not shown). With such controls, liquid 35 ~~t" ~ 3t8 may provide delivery profiles and specific medium .- ': as complex as those produced by 1- gas ~.. hildlu~

. CA 022380l3 l998-0~
WO 97/19719 PCTrUS96118989 Optional c ~q ~ dl~.(y fluid pump 322 propels the ~, dl~.y fluid c iaboJ carbon dioxide into gas e 326 from the distal end of - dll~ly ~ , conduit 314. Those skilled in the art will a~ ;al~ that gas 326 is not limited to any one car'i~ ~ or method of operation but rather may be any 9" d~ that allows the " ~ :- r of carbon dioxide from the ., dlD.y fluid. In the . bul ~ shown, gas ' 326 5 ~ , iaeS fluid reservoir 340 wherein oxygen and other ~ases are bubbled through collected liquid 1l , ~ dlUIy promoter CO..IIJ-- ~ O a .r - Ie~l carbon dioxide. Here, as will be discussed in detail later, gaseous oxygen is i _d ~d into gas 326 from vapor inlet conduit 342 which is in ~ ' 5 communication with fluid reservoir 340. As is known in the art, the il.l~ of oxygen into liquid ~., : y promoter cc, i v assû";alcd carbon dioxide will force the ' :L ~ - of carbon dioxide from the medium and drive it into the gas phase. As the same time 10 the oxygen -- ,nc : with the liquid r , ~ di y promoter, r ~r~ in a dissolved state. Of course, as with other d~ so~ ,d gases, the carbon dioxide will bubble to the surface of the Lbl ' ' _ liquid " di y promoter. For the purposes of the present invention enough gaseous oxygen is introduGed to fluid reservoir 340 to ' - ~: r ~ ' at least a portion of the carbon dioxide contained in the liquid I pi. d~ y promoter. Bubbles 336 represent the gaseous oxygen and resulting 1 Il,d carbon dioxide passing through the liquid " , alOI y promoter to fluid surface 338.
15 Suitable sensors (not shown~ will be normally be provided to monitor the gas G~, ~ 'i~ of the liquid 1,, a; y promoter and provide real time data for control of the system.
Following diu - : of the carbon dioxide, the G~ liquid 1l , dll..y promoter passes through the fluid flow path defined by inlet ~- alildl v conduit 344 and is propelled into i , dlU~y . :' ~, conduit 312, , e~ by , ~ ~l".y fluid pump 320. In the ~ bl. ' ~ shown, inlet ~ conduit is : ' in fluid-c- ' i ,, ~ i with fluid reservoir 340 below fluid surface 338 in order to prevent the _ ~ . ' : of free gas into the fluid flow path. ' y fluid pump 320 forces the G..~" ~ t~d liquid u, ~ _: y promoter, -- i ~ material which had ~ àly been i.lt,. ~u d into the lungs, through the fluid flow path defined by , dllJ,y .. ,.. 61alill9 conduit 312, Y- : 3n6 and patient-- : 304, passing, ' . - -' , y check valve 306 prior to entry into the r ~ y air p~es?ge~ That is, liquid r~ . dll~.y promoter is ci,. ' through the gas flow path defined by patient- ~ 304, i . - dlUIy .. ~;!a~i " conduit 314, ~as ~ ~ v 336, inlet ~~ ~i'a l, conduit 344 and i , d~l~ly ~ conduit 316 to be ,. ~. dl ' into the ~ ' y air passages thereby effecting total liquid .. ': The liquid r , di y promoter may be .,,.,;,- ' ' in and out of the lung ' ~; - 1~ in this manner.
As p.~ cu5~ oxygen is bubbled through fluid reservoir 340, ~ under pressure, to 30 ~ G- l~ carbon dioxide from the liquid medium L c~ used for ,1, di- Following the 1 r-- of the carbon dioxide from the ..;.. ' ~ liquid r~ r- - ' Y promoter and its passage through fluid surface 338. Typically, not all of the ;"l-. ~ d oxygen is A~ d with the treated liquid ,., al~.y promoter leaving some to travel through gas ~ 326 and pass through fluid surface 338. Moreover, a ' - ' amount of the liquid ,- dllJ.y promoter is forced into a vaporous state above fluid surface 338 due to system ' . -dy - In 35 G~ .. ' ~, I,bl"~;l TLV systems, this vaporous mixture ~ , ~ oxygen, carbon dioxide and vaporized liquid medium would be vented into the . .~ " ~ medium and lost. Conversely, in the - bu " : of the present invention CA 02238013 1998-0~
WO 97/19719 PCT~S96/18989 ~3Q~
dl~d in Fig. 5 this vaporous mixture enters closed-circuit vapor separator 350 defining a vapor flow path. Vapor .. I through the vapor flow path is 1,, G ' ' by arrows 355. Passing through this vapor flow path, the carbon dioxide is ' ~ 'Iy bound and removed from a gaseous state while the treated vapor ~t . i;d~ liquid ~ ~ dlllly promoter and oxygen is 1.;.~ ': ' and ,~ ~d d to fluid reservoir 340 thereby _ the loss of 5 liquid r , ai y promoter during ~, ' therapy.
More pdl i- ' 1~ the vapor is forced into the vapor flow path defined by vapor inlet conduit 348 via positive pressure from gas ' ~ v 326. From here the vapor passes through optional gas pressure controller 346 and into vapor transfer conduit 328. Gas pressure controller may be used to regulate the pressure and flow of the vapor thereby i ~ ~ _ Ih~ . , '' i and a constant fluid level in fluid reservoir 340 and this may vent 10 excess gas pressure from the system as required to maintain near ambient pressure. The vapor passes along the vapor fiow path propelled by vapor moving ,, al~ 330 Wh;Gh jS in ri '-r ' ~il,d with vapor transfer conduit 328. Those skilled in the art will , ~=.,;al~ that vapor moving 1, r dl~ 330 may be pr along the vapor flow path and may comprise a blower or a pump. The vapor then passes into carbon dioxide separator 332~ in fluid-~ ' ~ 9 ~ with the vapor flow path, where at least a portion of the carbon dioxide is 15 removed from the gas phase and deposited on the surface of a solid as, .~ ' ' From here the treated vapor passes through the vapor flow path defined by vapor transfer conduit 328 and vapor inlet conduit 342 before being ll ~.. ' d into liquid reservoir 340. Optional controller 324 may be used to introduce oxygen or other gases to the vapor flow path or directly to gas ' _ . r~ r~l !y controller 324 jS receiving data from liquid ventilator 318 or from -'~, ' sensors regarding flow rate, vapor I . . OA~, '- Ievels, etc. Of course those 20 skilled in the art will a~ Lial~ that oxygen and other geses may be i.,ll~ ~ ~ at any point alona the fluid flow path or the vapor flow path.
Another ' -' of the present invention that may be used for closed-circuit TLV therapy is s ' ~ 'l~
depicted in Fig. 6. As with the previous Sc " :, the instant figure " ~.dles a closed circuit TLV system ~ ~ . i g a ~ -L;.~U;L l~, ' di operably . ~ ~ ' with a liquid ventilator. However, unlike the Sc' I
25 detailed in Fig. 5, Fig. 6 shows a r,lused ci.~ TLV system ~ , i a liquid scrubber rather than a closed-circuit vapor sepal . This liquid scrubber is in r; '-~ ' g r- ~ with the closed-circuit n ,~ G- - and !, dlt~ carbon dioxide directly from the .,;.~ ' - _ .l , ~ a; y promoter rather than from a gaseous vapor. Following removal of at least a portion of the carbon dioxide, the liquid ~l , . y promoter is r A~ ' and L;l ~ ,d through the ll h of the system to be IL;..III ' I to the lungs of the patient.
SF-- ' - ~1~, closed-circuit TLV system 400 is Cl - ' to patient 402 via patient-.,.,.. ,~ " 404 e: ' ' ' fluid-. ' : ~ ~ ~- between the, ' y air passages and the fluid flow path ~ - dlLd by arrows 416 defined by the closed-circuit ~t, ~ di . Patient 402 ;S ~ - _ total liquid ~ tinn as, L~ IY described. Upon dliun, the , dluly fluid from the r y air passages is forced through patient-~ - 404, past .liolldl ~ , ai Jr~ check valve 408 and into , al.,.y . -.,tilai- _ conduit 414. Optional fluid pump 422 propels the ~AIJhdi y fluid into liquid ventilator 418 and into liquid scrubber 424 which is in fluid-~ S 81~ ~
with the fluid flow path defined by the clusbd c;.. - Iiquid, , di . As described above, r ~r~laLI~ the closed circuit ~ CA 02238013 1998-0~

liquid ,l, d; iS operably _ -e~ lud with liquid ventilator 418 which monitors and controls the parameters of the i' , procedure.
Liquid scrubber 424 iS, ~,F~ a modular unit ~ a liquid ~, ' ' shell c y a material capable of binding carbon dioxide and -1pZ di' 9 it from the c;-~ ' li.." -l ,'.dlUIy promoter. As with the carbon 5 dioxide:, alu~:~ alluded to earlier, liquid scrubber 424 may comprise a base material which reacts with the carbon dioxide in the Li(e_l~.'' ,. Iiquid ,. pi~l ~y promoter to form a cnlL that is r'l~lL " ~' on the surface of the material and water. r- , ' y materials that are suitable for use as liquid ~L.r~ in the present invention comprise, but are not limited to, lithium hydride and soda lime. r,~ bl~, the modular units will be easy to change or recharge without s -'-s 'l~ .i C with ongoing therapy. Moreover, in preferred bc' : the fluid flow exiting from liquid scrubber 424 will be ~d using sensors e ~ ' with liquid ventilator 418 to provide real time data as to the amount of carbon dioxide being . ~t.,L
Following s, _ of at least a portion of the carbon dioxide as~o~:-lr~l with the c . di y fluid, the treated liquid n, ~ di y promoter is propelled through the ,. '~l of , ai y ~ :' S conduit 414 and into gas i ' ~1y 440. In the illustrated .; bc " t, gas . ' " 440 ~ e5 fluid reservoir 442 which is filled with liquid ~~ dlO.y promoter havin~q a fluid surface 338. Gaseous bubbles 432, y dl~.i by yas injector 426 and d from gas inlet line 448, are rising throuyh the liquid .~, dtu.y promoter which is, ~I~. "y being agitated or stirred. Plbr~ , gas release rates and - . are regulated by gas controller 428 which is receiving data regardiny physical pal~....~.t~ with gas . ' j 440 and from liquid ventilator 430. Among other gases, oxygen may be i ~ ~ ed to gas ' 1~ 440 to UA~,, ' the liquid l . dloly promoter therein. Those skilled 20 in the art will ~ ..;ale that oxygen may be i.ll.. ~ ~d ,. ' ~ along the fluid flow path to provide UA~ . ' ' liquid .., ~ dl~.y promoter and that the s~ fi~ ~ and inclusion of gas ' y 440 iS ~ y only.
Unlike the . ~ - ' ~ depicted in Fiy. 5 where b ' amounts of oxyyen was i ~ d to di- c~O ~
carbon dioxide from the liquid .. . ai)~y promoter, the oxygen :..t,.~ -d in the instant . bc' L is merely to replace the oxygen used by patient 402 during r~, ~ di- ~ , relatively small amounts of oxygen need be 25 ;.~tll ' ~' into the c;,~ ~ ~ liquid ,l pi.all~y promoter to provide the desired oxygen content. Moreover, the gas r may be done very gently allowing most of the lll ' i oxygen to dissolve in the liquid and leaving very little to actually bubble through fluid surface 438. The gentle ;..lr~)~ : and low amounts of oxygen ;..I- ' -' mean that very little liquid .l, allJly promoter is vapori~ed above fluid surface 438. Further, due to the slow of oxygen and its " ' - in the C;.l ': liquid ,., ~t y promoter, pressure buildup in gas ~, 440 iS relatively low. However, optional gas outlet conduit 444, in fluid s~ Id : " - lion with fluid reservoir 442, may be provided for the venting of gases to maintain a stable ~, '' iu.,, in gas; ' ~ " 440.
Small amounts of gaseous oxygen c , i ~ low levels of ,l al y promoter may be released through vent 446 in this manner. The amount of released promoter is much lower than the b~ Iial amounts of 1, . dluly promoter released during llt:ai ' usiny . ~..i ' TLV systems. Pressure " ~ ' Ll,.~ or valves (not shown) on optional gas 35 outlet conduit 444 may be used to further reduce the amount of liquid ,~ . ,: y promoter lost.

:
CA 02238013 1998-0~
WO 97/19719 PC~r~US96/18989 Those skilled in the art will a,u~,.ec;dl-G that all the TLV systems disclosed herein provide for the effective of patients without losing a b~ : ' amount of ,., a~ y promoter as with prior art systems. For the purposes of the instant cl ~t G/ the term "s b : ' amounts" would c, , d to the loss of over 50% vlv of the employed promoter over the course of In t. In the present invention, the amount of iI, t y promoter lost to the SU,~ during the course of l.ea I will be less than 40% VIV of the total volume employed and more PIG~ Y less than 30% vlv, 20% vlv, 10% vlv, 5% vlv or even 1% vlv.
Following OA~, '', the o,-~, ' liquid n ,'a~u~y promoter is ~ .l to patient 402 and 1. , ~ --' into the r ~ y air passages ~-S i 'l~ as described above. In particular, the liquid IG ,' dI~J~Y
promoter is forced into , àl~"y ~ ilai' " conduit 412, ll_ , ILd through optional , alùly reservoir 434 and 10 passes through , al~;y fluid pump 420. From here the o,.~" d ~b, ' di J~y promoter passes along the fluid flow path defined by , y 1, :': ~, conduit 412, past . " . ' , alll,y check valve 410 and Yc- I
406, through patient-L : 404 and into the I ' y air passages whereby total liquid .. ' - is effected.

Those skilled in the art will further ., ~_ialG that the present invention may be embodied in other specific 15 forms without departing from the spirit or central all~ ' - thereof. In that the foregoing d i~, of the present invention discloses only c , ' y . SL " l~ thereof, it is to be I ' ~l d that other ~la~' " are C( I . ': ' as being within the scope of the present invention. Accc.P ~'~, the present invention is not limited to the particular S~ which have been described in detail herein. 2ather, reference should be made to the appended claims as indicative of the scope and content of the invention.

Claims (34)

WHAT IS CLAIMED IS:

1. A modular apparatus for closed-circuit ventilation therapy comprising:
a patient-connector (64) capable of establishing fluid-conducting communication with pulmonary air passage of a patient;
a variable volume reservoir (88);
a ventilating conduit sealingly affixed to said patient-connector and said variable volume reservoir wherein said patient-connector is placed in fluid-conducting communication with said variable volume reservoir to provide a closed-circuit respirator (60) defining a gas flow path (101);
and a carbon dioxide separator (72) in fluid-conducting communication with said gas flow path.

2. The apparatus of claim 1 wherein said ventilating conduit comprises an expiratory ventilating conduit (70) defining an expiratory gas flow path and an inspiratory ventilating conduit (80) defining an inspiratory gas flow path, said inspiratory and expiratory ventilating conduits having a proximal end and a distal end.

3. The apparatus of claim 2 wherein the proximal ends of said inspiratory ventilating conduit said and expiratory ventilating conduit are sealingly attached to said patient-connector and the distal ends of said inspiratory and expiratory ventilating conduits are sealingly attached to said variable volume reservoir.

4. The apparatus of claim 1 further comprising a respiratory promoter contained in said gas flow path.

5. The apparatus of claim 4 wherein said respiratory promoter is selected from the group consisting of gases, liquids and vapors.

6. The apparatus of claim 4 wherein said respiratory promoter is a liquid breathing agent.

The apparatus of claim 1 wherein said variable volume reservoir comprises a chamber (178) bifurcated by a gas impermeable compliant membrane (218), said compliant membrane separating said chamber into a compression reservoir (182) and said variable volume reservoir isolated from one another, said variable reservoir in fluid-conducting communication with said ventilating conduit.

The apparatus of claim 7 further comprising a mechanical ventilator (214) capable of providing positive pressure ventilation, said mechanical ventilator operably associated with said compression reservoir of said chamber whereby operation of the ventilator will transmit a pressure wave through said compliant membrane into said variable volume reservoir.

The apparatus of claim 1 further comprising a nebulizer (98) in fluid-conducting communication with said gas flow path.

The apparatus of claim 1 further comprising a gas injector (82) in fluid-conducting communication with said gas flow path.

A modular apparatus for closed-circuit ventilation therapy comprising:
a patient-connector (64) capable of establishing fluid-conducting communication with pulmonary air passages of a patient;
a ventilating conduit sealingly affixed to said patient-connector to provide a closed-circuit respirator (60) defining a gas flow path (101), said closed-circuit respirator operably associated with a mechanical ventilator (84); and a carbon dioxide separator (72) in fluid-conducting communication with said gas flow path.

The apparatus of claim 11 wherein said ventilating conduit comprises an expiratory ventilating conduit (70) defining an expiratory gas flow path, an inspiratory ventilating conduit (80) defining an inspiratory gas flow path and a recovery ventilating conduit having a first end and a second end defining a recovery gas flow path, said inspiratory and expiratory ventilating conduits having a proximal end and a distal end.

The apparatus of claim 12 wherein the proximal ends of said inspiratory ventilating conduit and said expiratory ventilating conduit are sealingly attached to said patient-connector and the distal ends of said inspiratory and expiratory ventilating conduits are sealingly attached to said first and second ends of said recovery ventilating conduit respectively, wherein fluid-conclucting communication is established between said distal end of said inspiratory ventilating conduit and said distal end of expiratory ventilating conduit.

The apparatus of claim 13 further comprising a variable volume reservoir in fluid-conducting communication with said closed-circuit respirator.

The apparatus of claim 11 further comprising a gas moving apparatus in fluid-conducting communication with said closed-circuit respirator.

The apparatus of claim 11 further comprising a respiratory promoter contained in said gas flow path.

The apparatus of claim 16 wherein said respiratory promoter is selected from the group consisting of gases, liquids and vapors.

The apparatus of claim 16 wherein said respiratory promoter is a liquid breathing agent.

The apparatus of claim 11 further comprising a nebulizer in fluid-conducting communication with said gas flow path.

The apparatus of claim 11 further comprising a gas injector in fluid-conducting communication with said gas flow path.

A method for closed-circuit partial liquid ventilation comprising:
connecting an exogenous closed-circuit respirator (160) defining a gas flow path (198) to the pulmonary air passages of a respiring patient;
introducing a respiratory promoter into said pulmonary air passages ;
capturing expiratory gas from said patient in said closed-circuit respirator, said expiratory gas comprising carbon dioxide and at least a portion of said introduced respiratory promoter;
separating at least a portion of said carbon dioxide to provide a treated gas comprising said respiratory promoter; and reintroducing said treated gas into the pulmonary air passages of the patient.

The method of claim 21 further comprising the step of administering a respiratory promoter to said pulmonary air passages of said respiring patient prior to said connecting step.

The method of claim 21 wherein said respiratory promoter is a liquid breathing agent.

The method of claim 21 wherein said, respiratory promoter is a fluorochemical.

The method of claim 24 wherein said fluorochemical is a liquid at body temperature.

The method of claim 21 further comprising the step of pressurizing at least a portion of said gas flow path to effect positive pressure ventilation of said patient.

The method of claim 26 further comprising the step of effecting positive pressure ventilation of the patient by applying pressure to said gas flow path from a mechanical ventilator (214) operably associated with said closed-circuit respirator.

The method of claim 21 further comprising the step of:
providing said closed-circuit respiratory by affixing a ventilating conduit to a patient-connector (164) capable of establishing fluid-conducting communication with pulmonary air passages of a patient and a variable volume reservoir (180), wherein said patient-connector is placed in fluid-conducting communication with said variable volume reservoir.

29. The method of claim 28 further comprising the step of pressurizing said variable volume reservoir to effect positive pressure ventilation of said patient.

30. The method of claim 29 further comprising the step of effecting positive pressure ventilation of the patient by applying pressure to said variable volume reservoir using a mechanical ventilator operably associated with said closed-circuit respirator.

31. The method of claim 28 wherein said variable volume reservoir comprises a chamber bifurcated by a gas impermeable compliant membrane (218) wherein said chamber is separated into said variable volume reservoir and a compression reservoir (182) isolated from each other.

32. The method of claim 31 further comprising establishing fluid-conducting communication between said pulmonary air passages and said variable volume reservoir; and operably associating a mechanical ventilator (214) with said closed-circuit respirator by establishing fluid-conducting communication between said mechanical ventilator and said compression reservoir.

33. The method of claim 32 further comprising the step of effecting positive pressure ventilation of the patient by using said mechanical ventilator to generate pressure waves to actuate said gas impermeable membrane wherein pressure is exerted on said gas flow path.

34. A method for treating an expiratory gas comprising a fluid, gaseous or vaporous respiratory promoter obtained from the lung of a patient comprising the steps of:
a) establishing fluid conducting communication between the pulmonary air passages of a patient and a respirator defining a gas flow path;
b) introducing expiratory gas from said patient into said gas flow path, wherein said expiratory gas comprises carbon dioxide and a fluid, gaseous or vaporous respiratory promoter; and c) treating said expiratory gas to separate at least a portion of said carbon dioxide from said expiratory gas.

A method of treating a breathable gas in a closed-circuit respirator comprising the steps of:
a) introducing a breathing gas into a gas flow path defined by a closed-circuit respirator, said gas flow path in fluid conducting communication with pulmonary air passages of a patient; and b) combining a pharmaceutically effective amount of a liquid, vaporous or gaseous respiratory promoter with said breathing gas in said gas flow path.