CA2085986A1 - Apparatus, catheter and method for chemical contact dissolution of gallstones - Google Patents

Abstract

A fully automatic organ pressure sensitive apparatus for dislodging and removing obstructions in body cavities or organs by both delivering (17) and removing (20) fluid thereto, operable by high rate continuous or intermittent infusion of fluid solvent over a set pressure range to effect rapid dissolution and removal of the obstruction without complications to the patient. By continuous feedback monitoring (22) of fluid pressure in the bodily organ or cavity (19) of interest, the apparatus can constantly vary infusion and aspiration rates to maintain the set pressure range. If the pressure persists above or below the set range, the apparatus activates a safety feature (32) leading to a period of maximal aspiration and cessation of infusion, followed by cessation of solvent transfer and triggering of an alarm (34) to alert the operator.

Description

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1"APPARA'rUS, CATHETER AND MæTHOD FOR CHEMICAL coNTA~r DISSO WTION OF GALLSTONES
~his application is a continuation-in-part of copending 5application Serial No. 07/180,099 filed April 11, 1988 which ` 6 was a continuation~in-part of application Serial No.
7 06/871,775, filed June 9, 1986.
8 BACKGROVND OF THE INV~NTION
g For most individuals who s~lffer from gallstones, the 1~ treatment of choice is to have a cholecystectomy, or surgical 11 removal of the gallbladder. Each year 500,000 such operations 12 are done in the United States alone. Recently, because of the 13 cost, prolonged recuperation time and possible side ef~ects 14 associated with this sùrqery, methods have been developed for chemicall~ removin~ gallstones ~L_~ib~ Generally, this proce-lure involves inserting a catheter into the gallbladder 17 followe~ by infusing a chemical solvent capable of dissolving 18i the gallstone. The procedtlre thus a~oids the need for and 19 attendant risk of surgery.
A variety of chemical solvents have been tried and found i 21 to exhibit varying efficiencies of gallstone dissolution, 22 depending on the chemical nature of the ~allstone. Gallstones ~! 23 are generally composed of cholesterol or calcium salts, 24 partic~larly calcium bilirubinate and calcium carbonate.
Lipi~ solvents are effective at dissolving cholesterol 26 gallstones, whereas these solvents have little or no .. i , 27 solubilizing e~fect on gallstones composed of calcium salts.
28 Thus, ~iethyl ether readily dissolves cholesterol gallstones, 29 àn~ ~ther solvents such as mono-octanoin, and octadiol 3~ (glyc~ry1-1-octyl ether) also have good solubili~ing 31 properties. Unfortunately, few if any solvents are 32 satisfactory for dissolving calcium gallstones~ The inven-tion 33 here.in will therefore find princ.ipal utility in cholesterol i .
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1 ~all~tone removal. It has been recognized that ether 2 compounds such as diethylether have excellent cholesterol 3 solubilizing properties, low viscosity and very good kine~ic 4 solubility but diethylether is hazardous since it boils below body temperature. Recently methyl tert-butyl ether (MTBE), 6 a solv~nt hithertofore used prlmarily a5 a gasoline additive 7 and a chromatographic 501vent ~nedia, has been used for 8 gallstone dissolution since it exhibits all the properties of g ethers. Moreover, MTBE boils above body temperature and the solvent rapidly dissolves the galls~ones without damaging the 11 mucosa of the gallbladder.
12 The ef fectiveness of such new solvents has led to 13 considerable activity focused on developing apparatus and 14 methods for delivering MTBE and similar solvents to patients suffering from gallstones in ways to most rapidly and 16 effectively solub~ lize gallstones wlthout the complications 17 arising from introducing such solvents into ~he body. (For 18 brevity herein, the description will be wit~ resp~ct to use 19 of the MTBE as a solvent. Xt will ~e recognized, however, that this invention will be applicable to a number of 21 different sol~ents).
22 Physicians currently tr~at cholestierol ~allstones by 23 infusing MTBE into the gallbl~dder throush a percutaneously 24 positioned catheter thro~gh which ~TBE ls manually passed using glass syring~s [Walker, L~ncet, ~ 874 (1891);
26 Shortsleeve, RadioloqY, 153, 547 (1984); and Teplick, 27 Radioloqy~ 379 ~1984)]. Additionally, phy~icians have 28 available fixed volume syringe pumps, such as described in 29 U.S. Patent No. 4,655,7~4 to ~histle et al. to infuse and aspirate MTBE. There are several complications associated ~1 with either the manual infusion or the fixed volumP pump-32 assisted i~fusion procedure.
33 When MTBE is delivered manually via glass syringes or .
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330 P~-r/U~;~ 1 /0 1 037 ~;~ 3 1 with the aid of a fixed volume-cycle pump, spontaneous 2 gallbladder contraction or over filliny of the gallbladder 3 cannot be detected or controlled. Consequently, MTBE
4 periodically empties into the duodenum, producing duodenal mucosal injury, which in turn produces nausea, vomiting, 6 duodenal erosions and ac ompanying pain of suf f icient 7 intensity to necessitate ~requen~ administration o~
8 analgesics. In addition, when ill ~he duodenum, MTBE can be 9 absorbed in~o the blood stream, which in turn may result ln somnolence or hemolysis and concomitantly the presence of the 11 intense and irritating MTBE odor in the patien~'s ~reath.
12 Other proble~s associated with the manual or pump 13 associated syringe method involve inefficient removal of 14 insoluble gallstone particles which constitute varying percentages of cholesterol gallstones. Such particle~ are 16 often left behind in the g~llbladder, after MTBE dissolves the 17 cholesterol portion, in procedures involving syringes or 18 syringe pumps. These particle~ often 6erve as the nidus for 19 new gallstone formation~ Addit~on~lly, both procedures are time consuming, laborious and require individual~ that are 21 highly skilled in their use. Consequently, the procedures are 22 expensive because of the attendant costs associated wit~
23 having a highly skilled staff of professional people to 24 perform the procedure for prolonged ti~s, often 12 hours or more. In addition, a fixed volume syringe pump can not , 26 prevent bile from entering the gallbladder during the course 27 of its secretion by the liver. Bile in the gallbladder 28 impedes the solvent's contact with stones and henca delays the 29 proceC~ sf dissolutisn It is obvious that delivering MTBE to a patient requires .
31 the utmost care to avoid releasing the solvent into the 32 patient's bodily fluids or outside the area o~ treatment.
- 33 Thus a key consideration in developiAy devices used in the ... .
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W~91/12X3~ ` PC~/US91/01037 l chemic~l therapy of gallstone dissolution ls ensuring the 2 contr~lled delivery and removal of the solvent used to 3 dissolve the gallstones. Considering that studies have shown 4 that solvents such as MT~E are injuriou~iif they pass into the intestine where they get absorbed, there is a critical need 6 for devices that ensure tihat ;such chemicals will not be 7 released during chemic~l therapy for gall~itone remov~l. At 8 the same time ~uch devices must be able to maintain high g solvent circulation rates into the gallbladder to create the necessar~ tur~ulence that will enhance dis~olution and aid in ll evacuating the insoluble residue.
12 Also, because of the need to ensure containment of 13 solvents, in addition to the sa~ety features described ~bove, 14 a sultable devloe should be "user friendly" ~nd not require the presence of highly skilled technicians to run the device.
16 Further, for the same reasons, it sho~ld be easily 17 maintainable.
18 With a little reflection, it becom2s apparent that ther~
19 are considerable hurdles to surmount if on~ is to develop a devioe that has the features descrlbed above~ ~or instance, 21 it must be 1'intelligent" and capable of sensing instantaneou~i 22 changes in gallbladder pressure brought about by ~allbladd~r 23 contractions or by infusing the solvent, and rapidly relay 24 this information to controlling feedback circuits. This is a crucial feature for suc~ a devic~. If a gallstone should 26 in some way prevent the necessary circulation of the solvent 27 throuqh the gallbladder, a crltical pressure will build up, 28 possihly rupturing the organ or causing leakage of the solvent 29 from the gallbladder through the cystic duct into the common duct and intestine. Thus the device must be "intelligent" in 31 the sense that i~ senses gall~ladder pressure changes over a 32 predefined range and reacts ~ast enough to keep the pressure 33 in that range, shutting down or reacting appropriately if ~he ~;

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WO 91/1~3n P(~ JS~)lt~)1037 ~ 5 ~ 9 ~ ~j 1 pressure persists outside the range. Moreover, it would be 2 desil-able to have a device that not only is capable ~f 3 shuttinc! down, but actually can flush out any debris causing 4 the ~lockage, and resume normal operation should the dehris be removedO Such device shoulcl prevent intra-gallbladder 6 pressure from rising above leak~ge llmit and from falling 7 below the pressure under which b.~le will be sucked in~co the 8 gallbladder from the biliary duct..

5-~MAR/ OF rHE INVENTION
11 The invention herein comprises an apparatus and a method 12 for its use wh~ch are for therapeutic treatment of obstruc-13 tions in bodily organs by high rate solvent circulation, 14 particularly for gallbladder or co~mon bile duck stones. The lS apparatus has the desirable feature of continuous high rate 16 infusion and aspiratlon while prevent-ing solvent leakage from 17 the bodily organ being tre~ted. The apparatus comprises a 18 forward or reverse acting solvent delivery means that is 19 linked via a pressure transducer to a feedback controller circuit.
21 The apparatus is preset to perfuse within a set pressure Z2 range. Continuous feed~ack of true intraluminal organ 23 pressure to a contrQller circult ~ia the t.ransducer controls 24 the rate and the net direction of solvent delivery by the apparatus ~nd is determinative of whether the apparatus acts 26 in the forward or reverse mode. Over this range the solven~
27 is constantly passed from a reservoir into the gallbladd~r, 28 and from the gallbladd r it is aspirate~ to a suitable 29 receptacle. D~livery and removal of khe solvent is at a rate sufficient to effect gallstone dissolution and fra~mentation, 31 agitation and aspiration of insoluble fraginents. Should there 32 : be an increase :in pressure, a feedback loop switches the 33 d~vice into a high pre~sure mode, thereby diverting the . ~..

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, , , ~VO 9 1 / 1 ~3() _ n ~.' PCr/~!S~) 1 /01 037 1 solvent away from the gallbladder. If after a predetermined 2 perio~ of time the pressure sensing transducer readings from 3 the gallbladder indicate a return to normal operating pressure 4 range, the device automatically reinitiates the normal infusion and aspiration (perfusion) mode.
6 An additional feature o the invention is a self purging 7 mechanism. After a preset interv2l1, if the pressure does not ~ decrease, the device enPers a reverse mode to purge the 9 aspiration port of the catheter, whereby 1uid is aspirated lo backward through the infusion port and infused through the 11 aspiration port to purge Por discrete short intervals, duriny 12 which time the pressure ~n the organ is continuously 13 monitored. Once the blockage is removed by this "self 14 purging" action, the pressure transducer again indicatss normal operating pressure, and the devlce resumes actlon 1n 16 the normal pressure ~ode. However, should the obstruction not 17 be removable after a predetermined number of purge cycles, an 18 alarm circuit is activated, so notifying the us~r. A further 19 feature of the invention is that it i8 able to distinguish clinically significant pressure changes occurring wi~hin the 21 gallbladder which leads to emptying o~ gallbladder contents 22 into the duodenum from those clinically in~ignificant chanqes 23 arising as a result of coughing, laughing or like behavior.
24 This feature prevents needless changes or operating modes.
A further aspect of the invention is a catheter for the 26 contact dissolu~ion of gallstones having a solven~ infusion 27 lumen and a solvent aspiration lumen in side-by-side 28 relationship~ The catheter is sized for introduction of its 29 distal. portion into the gallbladder from outside the body.
Each lumen has at least one opening in the distal portion ~or 31 c~mmunication between th~ gallbladder and a remotely located 3~ pump. A third lumen provides a means to continuously sense 33 intra-gallbladder fluid pressure and to transmit an indication ~ .

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1 thereef to the controller, for con~rol of infusion and aspiration of solvents via the lumens. An aspect of the 3 invention is that the cross-sectional area of the aspiration 4 lumen is larger than the cross-sectional area of the infusion lumen. Fluid moves into and out of each lumen by a series of 6 openings in the walls of the catheter. The cross-sectional 7 area of each opening is less than the cross-sectional area o 8 the lumen with which the opening is in communication. Thie 9 catheter further includes a retention means to prevent the catheter from being dislodged from the gallbladder. The 11 retention means is a curved formation of the distal portion 12 of the cat~eter. The pressure sensing means is located to lie 13 at the inner radius o~ the curved formation to prevent its 14 blockage by the mucosa of the gallbladder. Alternatively, the retention means may be an inflatable balloon located adjacent 16 to the distal portion.
17 A tension string for holding the distal portion of the 18 ca~heter in a curved configuration is included. The catheter 19 also has a string passagc lumen in which the string is located. Alternatively, the strin~ may bi~ located in eithex 21 the aspiration lumen, the infusion lumen or the pressure 22 sensing lumen.
23 The opening at the distal,end of the catheter is in 24 communication with the aspiration lumen. The catheter has ~t least one aspiration opening, in the wall of the catheter in 26 communication with the aspiration lumen, which is located 27 proximal to all infusion openings. The proximally-located 28 aspiration opening is located adjacent to the point of entry 29 of th~ catheter into the gallbladder when the catheter ls in position for operation.
31 The lumen and aspiration opening at the c~istal end of the 32 lumen are constructed and arranged to enable the catheter to 33 pass over a guide wixe. The catheter is made of material, for ., ~

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1 exam~l~ polyurethane, which is resistent to the solvent to be2 infu~e~ into said gallbladder.
The means for sensing the pressure of fluid within the 4 gallbladder includes a third fluid pressure transmitting lumen extending ~ide by side with the infusion and aspiration lumens 6 and having a distal opening in the di~tal portion of the 7 catheter. The lumen is constructed to communicate intra-8 gallbladder pressure to a remotely located pressuro transducer 9 via a hydrostatic 1uid column. The means for ~en~ing the pressure of fluid within the third lumen comprises ~ pres.sure 11 transducer located at the proximal portion of the catheter.
12 Alternati~aly, the pressure transduc~r may be located at ~he 13 distal end of the catheter and provide in situ. gallbladder 14 pressure measurements. Such transducers for in situ use can be piezoelectric, or ~iberoptic, and may be removably inserted 16 in a lumen of the catheter. The wlre~ or fiber of an in situ 17 transducer located at the distal end of the catheter can pass 18 through the pres~ure lumen, infusion lumen, or aspiraSlon 19 lumen or may be embedded into khe catheter's wall. The catheter has a structural formation at it~ proximal end that 21 permits it to be ~sed only with a solvent deltvery system 22 ha~ing a predetermined mating structural formation that 23 prevents inadvertent use with non-mating sys~ems.
24 Alternatlvely the catheter has an ele~trical or fi~eroptic connection at its proximal end th~t permits it to be used only 26 with 3 solvent delivery system having a predetermined 27 electrical or fiberoptic connection.
28 One aspect of the invent.ion is a microprocessor 29 programmed to execute an algorithm in response to an input pressure signal derived from the yallbladder through a 31 pressure deter~ining module; a pump control module, to control 32 the speed and direction of an infusion pump pumping solvent 33 through an infusion lumen into the gallbladd~r of the patient ., .
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WO ~1/12g3~ ~ -,, Pcr/us~ 37 I~ ~ 9 _ 1 and an aspiration pump pumping solvent through an aspiration lumen out of the gallbladder of the patienti and a response 3 determination module to control the functions of the pump 4 control module in response to the pressure determinations of the pressure determining module. The response determination ~ module generates an alann and initlates maximal cont~nuous 7 aspiration by both infusion and aspiration pumps in response 8 to a number o intra-gallbladder pressure conditions g including: no pressure variations of a predetermined ampl~tude detected for a predetermined period of time; abnormal pressure 11 detected for a predetermined period of time or after 12 predetermined volume has been used to purge said aspiration 13 lumen; more than a predetermined number of purge cycles 14 occurring within a predetermined period of time; detected 1~ pressure remaining less than a lower set limit for a 16 predetermined period of time or the system being unable to 17 maintain the pressure within normal range for a predetermined 18 period of time.
19 The response determination module also stops infusion and maintains aspiration in response to intra-gallhladder pressure 21 exceeding an upper set limit and aspirates through the 22 infusion lumen until the pressure falls to an acceptable 23 ran~e. The response determination module then reYerses flow 24 to purge the aspiration lumen~ The module also stops 2S aspiration in response to the condltion wherein the pressure 26 is less than the lower set limit.
27 Another aspect of the invention is a means Por 28 continuously measuring tha pressure within the gallbladder of 29 a patient and a means for controlling the in~usion and aspiration of a solvent into the gallbladder ill response So 31 those measurements to maintain said pre.ssure within the set 32 limits.
33 A further feature of the invention i5 a method for ,~

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.~, `' W~ 2~30 ~ - pcr/us9l/~1o37 - 1o ~j 1 dissolution of gallstones comprising the-steps of continuously 2 measuring the pressure within the gallbladder of a patient and 3 contrnlling the infusion and aspiration of a solvent into the 4 gallbladder in response to those measurements. The method further comprises the step of periodically measuring the 6 amount of cholesterol in the solvent ~nd replacing tha solvent 7 when the cholesterol concentration in the solvent reaches a 8 predetermined concentration limit.
g The method further comprlses, prior to introduct~on oP

10 solvent into the gallbladder, the ~easuring of a critical ,;;, ll leakage pressure at which fluid in the ~allbladder discharges 12 into an adjacent part of the body, and using the value oP that 13 pressure for controlling the in~usion and aspiration. T h e 14 st~p of measuring the critlcal leakage pressure ~omprises the injection into th~ gallbladder o~ a radiopaque dye at 16 increasing pressure until the disch~rge of th~ dye is observed 17 radiographically. The amount of pressure required to cause 18 the leakage of dye i5 recorded as the critical leakage 19 pressure and the amount of fluid required to rill the gallbladder is the available volume. The step of infusing the 21 solvent into the gallbladder occurs at a rate sufficient to 22 create solvent turbulence adjacent the gallstones.
23 An aspect of the invention furtb r includes a ~ystem, 24 including a sy~tem bus; a microprocessor in communic~tion with the system bus; a ~emory for holding algorithms, the memory 26 in communication with the system bus; an analog to digital 27 converter having an input terminal for receiving an analog 28 signal representative of the intra-gallbladder pressure and !
29 an output terminal ~or applying digital signals representing the pressure on said system bus; a pressure transducer having 31 a precsuxe sensor and an output terminal, the output terminal 32 af the pressure transducer in communication with the input 33 terminal of the analog to digital converter. The pressure WO ~1/12g~1) Pcr/us~/n~037 l tran~u~er generates a pressure signal related to the pressure 2 of the solvent within the gallbladder.
3 The system also includes ~ res~ervoir, for filling with 4 a gallstone dissolving solvent, an infusion pump connected by conduits to pu~p solvent from the reservoir into the 6 gallbladder, and an aspiration pump connected by conduits to 7 wi~hdraw solvent from the gallbladder and discharge the 8 solvent back into the reservolr. The system further includes 9 a pump controller having an input terminal in communication with the system bu~ and a plurality of output terminals, on~
~1 of said output terminals in communication with the aspiration 12 pump and one of said output terminals in communication with 13 tAe infusion pump, the microprocessor controlling said pump 14 con~roller, which in turn controls the aspiration and infusion pumps in respon~ie to signals received from said pressure ~6 transducer. The microprocessor terminates infusion and 17 initiates aspiration in response to signals indicating excess 18 pressure in the gallbladder.
19 hdditionally, the system also includes a catheter having 20 a plurality of lumens, a first one of the lumens connected at ~1 its proximal end to the infusion pump; a second one of the 22 lumens c~nnected at its pr~xlmal end to the aspiration pumpi 23 and a means to sens~ lntra gallbladder fluid pressure 24 as~ociated with the distal portion of the catheter for continuously providing an indication of the pressure of 26 fluid to the pressure transducer.
27 Yet another aspect of the invention is the ability to 28 safely dissolve gallstones when pressure measurements are 29 uncertain by infusing and aspirating intermittently a volume of solvent which is less than the available volume of the 31 gallbladder.

33 BRIElii' DESCRIPTION OF THE DRAWINGS

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1 Figure 1 is a sch~matic diagram of an apparatUs suitable 2 for delivering solvent to a gallbladder and for removing the 3 solv~nt containing dissolved or fragm~e~ted gallbladder stones.
4 Figure 2 is a schematic diagram of a controller circuit that regulates the pump units shown in Figure 1, as well as 6 other features of the apparatus.
7 Figures 3, 4 and 5 show features of a three-lumen 8 catheter, Figure 3 being a sectionaL YieW taken on 1 ine 3-3 9 of Figure 4.
Figure 6 is a schematic diagram of another embodiment of 11 the apparatus.

12 Figures 7 and 8 show features of another suitable three-13 lumen catheter, with Fi~ure 8 being ~ eectional view take~ on 14 line ~-8 of Pigure 7~
Figure 9 is a schematic diagram of an embcdlment of the 1~ catheter portion O~ the i~Vention in the ~or~ of a pigtail 17 catheter, Figure 9A ls a cross-sectional view o the catheter 18 of Figure 9 taken through lirle 9A-9A.
19 Figure lO i~ a block diagram of an embo~i~ent o~ the apparatus wherein a microprocessor controls the s::omponents of 21 the apparatus.
22 Figure 11 i5 a schematic diagram of the cathetsr of the 23 lnvention positioned within the gall bladder of a patient.
24 Figure 12 is a flow diagram of an embodiment of the 2 5 algorithm of the invention depicted in Figure lo. Figure 12A
26 is a flow diagram of the start pumps subroutine of the 27 algorithm of ~igure 12 . Figure 12B is a flow diagram o~ the 28 purge subroutine of figurP 12. Figure 12C is a 1OW diagram 29 ~ of th~ alarm subroutine of figure 12. Figure l~D is a flow 30 diagram of the check pressure limits subroutine o~ figure 12.
31 Figure 12E is a ~low diagram of the control pumps subroutine 32 of f igure 12 .

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2 The inventi~n described herein is suitably employed for 3 deli~ering fluids (solvents) to organs for removing 4 obstructions contained therein. It: will be appreciated at the outset that, while the subject invention described below 6 de~ails the inventton regarding the removal of gallstone~ rom 7 the gallbladder, the lnvention can be used to remove a variety 8 o~ obstructions from bodily cavitiles or organs other than the 9 gallbladder, and ~hus should not be construed as being narrowly limited to the treatment of gallstones. Indeed, it 11 will become readily apparent that the device is easily adapted 12 to removing obstructions from organ~ or bodily ca~ities in 13 general.
14 The invention described herein is an organ pressure sensitive apparatus having a ~olvent delive~y mean~ in 16 constant communica-ion with a controller circuit via one or 17 more pressure transducers th~t monitor the intra-organ ~8 pressure.
19 The pressure transducer may be positioned either within the gallbladder itself or external to the patient at the 21 proximal end of a fluid filled column whose distal end is 22 placed within the gallbladder. This can be accompli~h~d by 23 using the pressur~ sensing lumen either æs the fluid fllled 24 column or as the in situ location of the pressure sensing transducer itself. A variety of pressure transducers are 26 available for both _in_situ and fluid column use. In situ 27 transducers need be small and capable of ~ithstanding the 28 effects oP the solvent. Suitabl~ tran~ducers include but are 29 not limited to fiber optic pressure sensors, piezoelectric prPssure sensors and capacitative sensors. The wlres or 31 fibers of an in situ transducer pass through khe separate 32 pressure sensing lumen or through either of the solvent flow 33 lumens or may be embedded in the catheter wall. A suitable 9 1 / 1 ~3() PCI / U~i') l /0 1 037 ?--.

1 transducer for use on the proximal end of the fluid column is 2 a Statham Gould pressure transducer P23ID. When using an in 3 situ transducer, it is possible to have the transducer 4 remo~able from and insertable into the catheter once the catheter is in position within the gallbladder. I~ this way, 6 the transdu~er can be replaced during th~ proc~dure.
7 Additionally, such an insertable transducer would permit the 8 use of a smaller catheter for the same amount of fluid flow g since it could be placed in one of the flow lumens. The apparatus functions over a preset pressure range delivering 11 fluid to the gallbladder, causing the ~luid to contact and 12 dissolve the gallstones, and withdrawing fluid from the 13 gallbladder, thereby accompllshing the removal of dissolved 14 or fragmented gallstones. The rate of solvent delivery ~nd removal ca~ be adjusted to create the necessary turbulence to 16 dissolve or fragment gallstones. If the pressure exceeds that 17 of the normal operating range, the apparatus diverts solvent 18 from the organ, thereby preventing le~kage of the solvent fr~m 19 the sitP of treatment. Further, above the normal operating pressure range, the apparatus can be progr~mmed to be "self-Zl purging". This may be desirable in the instance when the 22 obstruction is only partially dissolvable, causing blockage 23 of the sol~ent removal or aspiration means. Rt pressures 24 below the normal operating pressure range, the rate of aspiration is decreased while infusion continues, thereby 26 reestablishing normal operating pressur~.
27 Dissolution time is minimized by operation at high 28 solvent flow rates. The maximum.flow is attained when the 29 instantaneous infusion flow matches the instantaneous aspir~tion flow. At such a null point, neither pump is slowed 31 down ~r shut off by the pressure deter,mining algorithm. A
32 feature of this in~ention is the calibration of the pump 33 . catheter sy~tem in both infusion and aspiration, hence ~V(> 91;1~83n rcr/l,~ss ..'.~.. - 15 - 2 ~ g c? ,~
1 gener~tinq a flow vs. control ~oltage relationship for both pump~. An input parameter is the desired flow r-ate. The 3 microFL-ocessor will not accept values which can not be 4 attain~d by both pumps and operate~ both pumps at the desired flow rates when the pressure is in the vicinity of the 6 pressure set point. As pressure rises above the set point the 7 aspiration pump speed is increased and as the pressure falls 8 below the set point the aspiration pump speed decreases thus 9 possessing an ability to dri~e the system to the set point~
During a procedure, the flow rate may be increased to a value 11 limited by either the aspiration, or infusion lumen, or the 12 size and compliance of the patient's gallbladder and/or the 13 attendant pressure excursions experienced.
14 A key consideration with regard to the organ pressure~
sensiti~e aspects of the syste~ is the realization that 16 leakage of solvent from the gallbladder occurs when the 17 intraluminal pressure exceeds that in the cystic duct, common 18 bile duct or ampulla (whichever is selected for the procedure 19 in a particular patient) and that neither the gallbladder ~0 volume per se nor the flow rate of solvent per se are 21 intimately involved. This in tUrn leads to recogni~ion ~hat 22 critical leakage pressure from the gallbladder differs from 23 patient to patient, and that leakage is a function not only 24 of solvent delivery but natural gallbladder contractions or external pressures to the gallbladder. The subject invention 26 take~ into account those pressure changes that are of 27 sufficient duration or strength to affect solvent leakage.
28 Because the critical leakage pressure from the 29 gallbladder differs from patient to patient, it is important to determine the critical leakage pressure for each individual 31 patient. To determine this pressure, a catheter is introduced 32 into the gallbladcler and, under fluoroscopy, a contrast 33 material is injected into the gallbladder with increasing ~ 3~) PCT/~S~1/01~37 1 pressure. The pressure at which the contrast medium enters 2 the intestine or leaks at the percutaneous entry point is the 3 critical lea~a~e pressure. As the gallbladder fills, its 4 pressure will increase until contrast medium is observed radiographically to flow through the cystic duct into the 6 common bile duct or leak at the percutaneous entry site. The 7 volume of dye present in the gallbladder at this pressure is 8 the a~ailable volume. This critical leakage pressure , or a 9 safety pressure below the critical leakage pressure I and, if desired, the available volume are entered as parameters in the 11 controller. From the critical leakage pressure value, the 12 high pressure or maximum operating point or upper set limit is 13 determined.
14 Typically, the maximum operating pressure is set at 75%
to 9~% of the measured critical leakage pressure, and the 16 maximum pressure alarm is typically 8S%-95% of the critical 17 leakage pressure.
18 To determine the mlnimum operating pressure or lower set 19 limit, the contrast medium is aspirated from the gallbladder.
As ~he pressure inside thei gallbladder falls, bile will 21 eventually begin being aspirated into the gallbladder from the 22 common bile duct. The pressure at which this occurs i the 23 bile aspiration pressure. The minimum operating pressure or 24 lower set limit is typically set 2 to 10 cm of water above the bile aspiration pressure to minimize solvent dilution with 26 bile. The minimum alarm pressure is set slightly belo~ the 27 bile aspiration pressure.
28 Accurate measurements of volumemetric flow, to and from 29 the gallbladder, will permit the calculation of net fluid retained in the patient. The signal of net volume of retained 31 fluid can be used as a backup safety check when pressure 32 measurements are controlling the pumps or as a primary control 33 msde when pressure measurements are not possible, e.g., an 7.
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1 aberr~nt c~stic duct, with no valves of Heister. To benefit from .olumetric flow measurements, pumping should be initiated 3 when the aallbladder is evacuated. When the net retained flow 4 approachec the predetermined gal:lbladder volume, an alarm should be established or net aspiration should be increased.
6 Figure 1 shows an exemplary app~ratus for removing 7 gallstones. Reservoir 10 contains a solvent that is a 8 chemical suitable for dissolving gallstones. Should the 9 gallstone be composed of choleste:rol, a variety of solvents would be efficacious. Particularly effective is methyl ter~-11 butyl ether (MTBE). The latter has been shown to r~adily 12 dissolve cholesterol stones rapidly both in vitro and in vivo.
13 At normal operating pressures, the solvent moves via a conduit 14 12 from the reservoir 10 by aid of a first pump 14. The fluid then moves through a valve 16 and from the ~alve through 16 infusion port 17 in a catheter 19 into t~e gallbladder.
17 Durinq this operation valve 2 6 is closed to prevent solvent 18 return to reservoir. The solvent is delivered at a 19 predet~rmined effective rate for gallstone dissolution thereby providing solvent turbulence and contact with the gallstones 21 for a period of time sufficient for effective gallstone 22 dissolution or fragmentation and fragment removal.
2~ Simultaneously with the delivery oP MTBE to the 24 gallbladder, a second pump 18 aspirates the fluid from the 25 gallbladder now containing dissolved gallstones and debris. .
26 This material passes out of the gallbladder via an aspiration 27 port ~0 in the catheter. The fluid is pumped from the 28 gallbladder by pump 18, passing through valve 23, and from 29 there it is deposited in a receiver reservoir. Either reservoir 10 used as the sourc~ of the solvent or a separate 31 reservoir is suitable for this purpose. Figure 1 shows the 32 same reservoir 10 being utilized as both the sourc~ of fluid 33 passed to the gallbladder and as the receiver of aspirated ~ x3n ^~' PC~/US91/0]037 l flui(l therefrom. It is worth noting that if the same reser-~oir is used, gallbladder stone fragments, bile, mucous 3 and th~ e removed from the gallbladder are heavier than the 4 solvent, MTBE, and therefore settle to the bottom of the reservoir and do not hinder continued withdrawal of 6 essentially pure fluid from the reservoir to effect further 7 stone dissolutlon.
8 ln the case where a single reservoir is used to supply 9 the solvent and receive the aspirat:ed fluid, the fluid should lo be periodically sampled and the cholesterol concentration in 11 the MTBE measured. Since the heavy debris falls to the bottom 12 of the reservoir, the sample of the ~luid should be taken of 13 the fluid from the upper portion of the reservoir. The sample 14 can then be tested to determine the cholesterol concentration level, for example by spectrophotom~tryO ~he fluid should be 16 removed and replaced when the rholesterol concentration 17 reaches a predetermined level ~e.g. about 30%). It should be 18 noted that higher or lower concentration levels of cholesterol 19 in the solvent only effect the efficiency of dissolutionO
Further, in a single reservoir system, since the 21 aspiration rate and the infusion r~te are in general not 22 equal, there is a provision to vent the reservoir. The 23 venting method should not allow the flammable fumes of ~he 24 solvent to escape. An alternative way o~ compensa'cing for rate differences is the use o a solvent resistant bladder for 26 the reservoir. Such a bladder expands or contracts as the 27 volume of fluid contained within it changes. This form of t.
28 closed reservoir prevents fumes rom escaping.
29 The pumps 14 and 18 are controlled by a controllPr circuit 22. The controller circuit 22 in turn receives 31 pressul-e readings from the transducer 24 causing the 32 controller circuit 22 to open or close flow valves 16 ,. 23 and 33 26 to inhibit infusion or aspiration as necessary to control , . . . .. ~ . , . ,, :

w~ 3n 1~CT/I'S91/01037 - 19 2~
l organ pressure depending on whether the transducer 24 2 indicate~ that the pressure in the gallbladder is within, 3 above, or below the normal operating pressure range. The 4 transducer in turn senses the gallbladder fluid pressure by c~mmunication through port 28 of the catheter 19.
6 At the normal operating pressur~, first pump l~ dellvers 7 fluid from reservoir lO through tube 12 and valve 16 to the 8 gallbladder. Simultaneously, and at a slightly slower rate, 9 second pump 18 aspirates the fluid from the gallbladder through catheter aspiration port 20. Fluid passes throuyh the ll valve 23 and thence through conduit 25 to the reservoir lO.
12 Conduit 12, catheter l9 and conduit 25 form a fluid 13 circuit connecting the source reservoir lO with the bodily 14 organ or cavity into which the catheter is inserted and then to the- receiving reservoir (which as noted may also be 16 reser~oir lO). The pumps 14 and 18 are in the circuit, in 17 conduits 12 and 25 respectively. (For the purpose of 18 description herein, the "forward" fluid flow direction will l9 be defined as flow in the direction of the arrows in Figures l and 6, and "reverse" flow will be flow in the direction 21 opposite the arrows.) 22 The controller 22 is progra~med to respond to pressures 23 that exceed or are below that of the normal operating pressure 24 range Above the normal operating pressure range ("hi~h pressure mode"), the controller 22 shuts ~own valve 16 and 26 simultaneously opens valve 26~ This provides a path for 27 diverting the incoming fluid away from the gallbladder. At 28 that time valve 23 is open to continue gallbladder emptying 23 to return the pressure to the normal operating range. If the press~1re in the gallbladder does not return to the normal 31 operating pressure setting within a preset time, for example 32 a few seconds, then the controller 22 can be programme~ to 33 instr~1ct the pumps to reverse the direction oP Pluid movement, ~'~91/1'~3~) ~, PCT/VS91/01037 - 20 ~
l and simultaneously valves 23 and 26 are closed. The 2 controller unit is programmed to close ~alve 23 after a slight 3 dela~ ~n that a small amount of fluid, approximately l ml, can 4 pass throuah the valve before it is shut. Valve 16 is opened to provide a path for fluid to be reverse aspirated from th~
6 gallbladder in this "self-purging" mode. This mode 7 essentially causes a small amount: of fluid to be pumped in 8 through the aspiration port 20 of the catheter l9 to clear it g of obstructions while aspir~tion is effected by pump 14 through valve 16. The fluid which is pumped into the 11 gallbladder passes from the reservoir lO through valve 23, 12 prior to valve Z3 closing in response to high pressure present 13 in the gallbladder. Generally this will consist of about l 14 ml of fluid passing through valve 23 b~fore it shuts. This mode of operation continues for a brief period oP time, and 16 then the controller unit 22 instructs the maçhine to resume 17 normal operation should the obstruc~ion be removed and the 18 pressure transducer 24 indicate reestablishment of the normal l9 operating pressure range. If the transducer continues to indicate pressures present in the gallbladder above the normal 21 operating pressure, the controller unit 22 again instructs the 22 pumping apparatus to purge the system. If, after several 23 "self purging" cycles, the obstruction is still not removed, 24 the controller unit 22 then shuts down the system and activates an alarm circuit 34 notifying the user of a 26 potentially dangerous condition.
27 Figure 2 illustrates a representatiYe controller unit 22.
28 The controller circuit 22 inst.ucts the pumps 14 and 18 to 29 deliver or aspirate fluid from the gallbladder. Thus, a circu.it will typically have a pressure transducer 30; such as 31 the ~tatham Gould pressure transducer P23ID, as mentioned 32 previously. The pressure transducer 30 relays information to 33 an amplification device 32 which amplifies the slgnal from the ~(>91~t7~3n PCr/US91/0103~
., .
- 21 ~
l trans~ucer 30 and transmits it to a high and low pressure alarm circuit 34, then either directly or through the 3 aver~?ing circuit 36 to a pressure-sensing circuit 38 that 4 read~ preset low and high pressure values and which is connected to the valves 16, 23 ancl 26. The latter valves are 6 typically solenoid flow valves or tube compression ~alves.
7 The averaging circuit 36 can be switched in if desired to 8 discriminate between pressure c'hanges in the gallbladder 9 arising from fluid ~uild~up due to obstructions or from hyperventilating, laughing or llke activ~ties. Thus the ll averaging circuit essentially screens out artificially high 12 or low pressure peaks which ln fact do not lead to gaillbladder l3 emptying.
14 The pressure sensing circuit 38 is connected to a cascade timer 40, which in turn is connected to a pump reverse relay 16 circuit 42. Thus, when gallbladder pressure exceeds that of 17 the normal operating pressure range and the obstruction is not 18 removed within a predetermined period, the cascade timer 40 l9 activates the pump reverse relay 42. T~e latter circuit is responsible for "self-purging1' t~ie system. Should high 21 pressure persist after se~eral brief ~self purging" cycles, 22 then the alarm circuit 34 is activated, causing an initial 23 period of aspiration in the reverse mode (with valves 16 and 24 23 open and val~e 26 closed), then stopping the pumping system by shutting off its power supply and the triggering of a 26 visual, audible or other alarm notifying the user. Note that 27 at any time during the pump reverse cycle, should the pressure 28 return to within the normal pressure range, the apparatus 29 resumeC normal operation.
It will be further noted as shown in Figure 2 that a pump 31 power relay circuit 44 and a pump speed control circuit 46 are 32 also interactive with the whole system. T~e pump speed 33 control circuit 46 derives power through the pump pow8r relay .. .. . . ,.. .... ; . ... ~.. , . - . - .. .- .. ., . ~ -~0 91/1~83() PCr/US~31/01037 rj ~ 7~ -- 2 2 ~
1 44, ~hich, in turn, is controlled by the alarm circuit 34.
The pump motor derives its power supply from the pump power 3 rela~ 4~. Any time an alarm condition exists, this relay 4 shutc off power to the pump, stopping it from pumping. The s pump speed control circuit 46 has a manual adjustment 6 capability through which the operator ca~ set the desired 7 perfusion rate for that specific situation. An a~alo~
8 pressure read-out 4~ is ~rovided for the operator to assess g effective operation and to refer to during calibration.
Alternatively, or in addition, the output can be fed to a 11 video display terminal 118 (of Fig. 10) driv~n by appropriate 12 software to provide the operator with an inter~ittent or 13 continuous display of system operating mode, pressure, etc., 14 and may be integrated with the indicators and alarm of alarm circuit 34.
lS Note that if desired, one or more appropria e 17 microprocessors can replace many of the components of the 18 system. Referring to Figure. 10, in a system controlled by 19 a microprocessor 100, the micropr~cessor 100 is connectQd to the pressure transducer 24 by an analog to digital converter 21 (A/D~ 116 connected to the system bus 122. The A/D converter 22 116 changes the pre~sure transducer's 24 analog signals to 23 digital signals for processing. Con~rol of the pumps is 24 accomplished by the microprocessor 100 through a digital/analog converter (~/A) 112, if the pump controller 26 tPC) 124 requires analog signals, or through a digital 27 parallel or serial interface (P/SI) 114 if the pump controller 28 124 is capable of responding to digital signals. The D~A 112 29 or the P/SI 114 can also be used to control the solenoid valvec 16 (only one shown for purposes of illustration).
31 The digital data is processed by the microprocessor 100 32 which ~ecutes algorithms located in memory 110 to perform the 33 functions otherwise performed by components of the pressure W~l/t'~3() PCr/VS~1/0l037 I - 23 ~ 2 ~ ~ 3c~ ~

1 sensinq circuit shown in Fig. 2. Specifically, the ~ micro~rocessor 100 by itself replaces the high and low 3 pressure detector 34, the signal averager 36, and the cascade 4 timer 40. The microprocessor 100 in ~onjunction with the A/D
converter 116 replaces the pressure sensing portion of the 6 pressure sensing and solenoid control interface 38, while the 7 microprocessor 100 in conjunction with the D/~ 112 or P/SI 114 8 replaces the solenoid portion of t~e pressure sensing and 9 solenoid control ~nterface 38. Further, dapending upon the form of the controller 124 actually controlling the pumps 14, 11 18, the microprocessor 100 and A/D 116 or P/SI 114 also may 12 replace the pump power relay 44, speed control circuit 46, and 13 pump reverse relay 42.
14 Figure 6 illustrates another alternative embodiment of the apparatus, which eliminates the valves by having separate 16 control of the two pumps 14 and 18. Each pump motor has its 17 own DC drive 47 and 45 respectively. Both drives are 18 controlled by controller 22', which has an appropriate 19 microprocessor to control the speed of each motor (and thus the flow rate of each pump) in response to the pressure 21 signals from transducer 24. Thus instead of opening and 22 closing valves to effect the proper infusion, aspiration or 23 purging, the controller 22~ regulates each pump's flow rate 24 and directivn of flow.
This embodiment has the advantage that all fluid conduits 26 (tubing, catheter, reservoir) can be made of easily 27 replaceable material. Thus each patient can be treated using 28 a system in which all wettable surfaces are limi~ed in use 29 solel~ to that one patient and one treating session. Again many of the components of this embodiment can also be replaced 31 with ~ microprocessor system.
32 There are several features of the apparatus that enhance 33 its performance. The pumps preferred in the subject invention , ~ 3~) PC~/U59l/01037 ~ , ~, . ~

1 are ~ristaltic pumps. This type of pump offers s~veral 2 advant~g~ such as the replaceable wettable surfaces mentioned 3 above, which in addition to their individual sterility will 4 be p~rticularly advantageous in those instances where the solvent being used to dissolve l:he obstructiorl is at all 6 corrosive- Moreover, peristaltic pumps are resistant to 7 clogging, in contrast to standard syringe type pumps.
8 However, it should be noted that ~yri~ge pumps are similarly 9 employable in the subject invention in those instances ~hPre the fluid used to dissolve and remove the obstruction is a 11 solvent, provided that the syringe pumps are constru~ted of 12 suitable material, preferably polytetrafluoroethylene (PTFE) 13 or glass. Syringe pumps made of plastic are not preferred in 14 instances where the solvents used are incompatible with the plastic compositio~ of the syringe. An addi~ional 16 disad~antage associated with the use of syringe pumps that is 17 not present in peristaltic pumps is that in those instances 18 where a solvent is being utilized, evaporation of the solvent 19 from between the plunger and the body can cause deposits in the body of the syringe, causing it to "freeze" and thus 21 interrupt deliv~ry of the ~luid to the orga~ being treated.
22 Lastly, peristaltic pumps are capable of much greater fluid 23 circulation rates than ar~ syringe pumps. This is 24 advantageous in certain instances where ~he obstruction ~o be removed, such as a gallstone, requires turbul~nt flow rates 26 across the surface of the gallstone to accelerate th~
27 dissolution process.
28 A predetermined normal operating pressure range is 29 programmed into the controller circuit ~2. Should the pressure in the gallbladder exceed normal operating pressure, 31 the action of the controller circuit 22 prevents leakage of 32 solvel~t from the gallbladder through the cystic duct in o the 33 commor~ ductj as well as into the intestine or around the entry ... , , .. .. .. ~

~vn ~ 3~ ^''~ ~ ^ PCT/U$91/010~7 ;~ - 25 -l site of the catheter. Also, because the controller circuit 2 "seeC'- true gallbladder pressure, it readily adjusts to 3 decre~se a~ well as increase pressure by adjusting the net 4 deli~er~ rate of the solvent to the gallbladder. For example, should the pressure fall below the normal operating pressure 6 range, the controller circuit 22 ceases or slows down the rate 7 of aspiration of solvent, and simultaneously con~inues 8 infusing solvent to reestablish normal operating pressure.
g The pressure sensitive ala~n circuit 34 is constantly comparing the system's set operating pressures and the ll gallbladder pressure. If gallbladder pressure cannot be 12 brought into ~he normal operating pressure range by the action 13 of the controller circuit 22 in a specified period of time, 14 it will revert to a period of maximal aspiration, then shut down the pumping system and sound an alarm drawing the 16 attention of the operator. The operator, after correcting the 17 problem, can resume normal operation by activating the reset 18 button 49.
l9 Referring to Fiqs. lO and 12, in the case of a microprocessor system, the microprocessor lO0 monitors the 21 pressure values produced by the transducer 24 and controls the 22 pumps 14, 18, and valves 16 in response to those pressure 23 values according to an algorithm stored in the system memory 24 llO. The algorithm can be generally partitioned into a module for periodically making pressure measurements, a module for 26 controlling pump speed and direction and a module for 27 determining the proper response to the various pressure 28 measurements.
29 The module for determining the proper response to the various pressure measurements checks several conditions. If 3l there are no variations of a predetermined amplitude in the 32 measur~d pressure for a predetermined amount of time, the 33 mvdule assumes that either the pressure lumen is blocked or ...
~., ~')~ 3~ ~ 26 - rc~/us9~ 7 1 that the pressure measurement subsystem has failed and sets 2 an al~lm condition. The setting of an alarm condition causes 3 the ~mp control module to set maximal continuous aspiration 4 by both pumps and to sound an alarm.
If the pressure measured is greater than th~ upper set 6 limit, the pressure measuring ~odule instructs t~e pump 7 control module to stop the infusion pump and cause the 8 aspiration pump to maintain aspiration. If the pressure g continues to remain above the upper set limit for more than a predetermined amount of time, the module a5sumes that th~.re 11 is a blockage in the aspiration openings or lumen. In 12 response to this condition, the pump control module instructs 13 the pump normally used for infuslon to aspirate. When the 14 pressure falls to the lower set limit, the pump control module 15 instru~ts the pump normally used for aspirat~on to switch to 16 infusion and the p~lmp normally used for infusion to swi~ch to 17 aspiration i~ an attempt to purge the side holes and lumien.

18 If the operating pressure does not return to normal within a 19 predetermined amount of time or after a predet~irmined volume has been used to purge the aspiration openings and lumen, an 21 alarm condition is set by the response determination module.
22 Further, if there are more than a predetermin~d number of ~3 purge cycles within a predetermined period of time, the 24 response determination module sets an alarm condition.
If the pressure measured ls less than the lower set Z6 limit, aspiration is stopped, and if the pressure remains less 27 than the lower set limit for a predetermined amount of ~ime, 28 an alarm condition is set. Finally, i~ the system is unable 29 to operate within its normal range for a predetermined amount of time, an alarm condition is also set.
3l Figure 12 is a flow diagram of the main program loop of 32 an embodiment of the algorithm used to determine the proper 33 response to various pressure measurements. Figures 12A-12E

~091/1~3n P(-r/~lS91/0~037 ~ 27 1 are flow diagrams of subroutines executed during the main 2 program loop. The main program calls the CHECK-PRESSURE-3 LIMIT~ subroutine 150 which in turn calls a series of other 4 subro~1tines to perform specific functions when the pressures and/or time delays are outside the desired ranges, and when 6 the pressure is above the upper pressure limit or below the 7 lower pressure limit. Within the desired pressure range, the 8 CONTROL PUMPS subroutine 152 operates the pumps in a 9 proportional fashion in an attempt to stay within th~ pressure limits. The main program begins by the operator entering the 11 operating parameters (operating pressures, alarm pressures, 12 etc.) into the system by the system keyboard and ~hen calling 13 the START-PUMPS subroutine 149.
14 When the main program is executed for the first time durin~ the procedure, or when the pumps have been stopped ~nd 16 must be restarted the subroutine START-PUMPS is called.
17 Referring to Figure 12A, the purpose of the START-PUMPS
18 subroutine is to determine from the present pressure 19 measurement which pump should be started. That is, if the pressure is high initially, only aspiration should oocur, 21 while if the pressure is low only infusion should occur.
22 Further, should the system be unable to come to the proper 23 pressure operating range within a fixed amount of time, an 24 alarm condition exists and the operator should be notified.
To accomplish this, the subroutine begins by determining if 26 the ~ressure in the gallbladder is greater than the lower 27 operating pressure limit 160 and if the pressure is not 28 greater, then the infusion pump is turned on and the 29 aspir~tion pump remains off 166. If the pressure is greater, the infusion pump r~mains off, the aspiration pump is turned 31 on 162, an aspiration timer is started, and the pressure is 32 compare~ to the lower operating pressure limit again 163. If 33 the p~essure is still above the lower operating limit 163, the ~01)1/12~3(1 ,`~` Pcr/ussl/olu l el~p~ time from the start of aspiration as indicated by the 2 aspir~tion timer is compared 164 to the maximum aspiration 3 time ~llowed parameter. If the elapsed time is less than the 4 maximum aspiration time allowed, the pressure is again compar~d with the lower operating pressure limit 163. If the 6 elapsed time is greater than the maximum allowed then 7 aspiration has failed to reduce the pressure and the alarm 8 subroutine is called in an alarm 0) condition l65.
9 I f the pressure is below the lower operating pressure limit 163, the infusion pump is turned on, the aspiration pump ll is turned off, the aspiration timer i5 cleared, an infusion 12 timer is started and the pressure compared to th~ upper 13 operating pressure limit 168. If the pressure is less than 14 the upper operating pressure the elapsed time of infusion is compared to th~ maximum infusion time parameter 17S. If the 16 elapsed time is greater than the allowed time 17~, indicating 17 a lea~age of solvent out of the gallbladder, the alarm 18 subroutine is called in an alarm (0) condition 178.
l9 If the pressure is qreater than the upper operating pressure limit, the infusion pump is turned off, the 21 aspiration pump is turned on, the infusion timer is cleared, 22 and the aspiration timer is again started. The pressure is 23 again compared to the lower operating limit l84 and if it is 24 less than the lower operating limit, the aspiration timer is cleared, the infusion pump i5 turned on and the aspiration 26 pump is turned off 187.
27 If the pressure exceeds the lower operating pressurP
28 limit 184, the aspiration timer is compared to the maximum 29 aspiration time parameter 186 and if the elapsed time exceeds the maximum time allowed, indicating that aspiration is unable 3l to reduce the pressure, the alarm subroutine is called in the 32 alarm (0) condition. If the elapsed time is less than the 33 maximum aspirati.on time, the pressure comparison cycle is : :

. - , - . , ~ .;. . . ., . . ,,, .. :: ., . ., , . , . . . : ..

~-091/1'830 . PCT/US~3/01037 - 29 - J ~ 8 ~
l repeato~ 1~4.
~ Once the infusion pump is on and the aspiration pump is 3 off 1~7. the pressure is compared to the operating set 4 pres~re l89 and if it is less, the pressure comparison loop is repeated. If the pressure exceeds the operating point the 6 subroutine simply returns to the ~ain routine.
7 When the it is determined that the aspiration pump is 8 unable to aspirate sufficiently t:o maintain pressure within 9 the requisite range below the upper pressure limit, the CHECX
PRESSURE subroutine causes both pumps to maximally aspirate, ll and if the lower pressure limit can be attained and the 12 allowed number of purges have not be n exceeded 314, 326, 328 13 322 and 330 of Fig. 12D, it is assumed that the aspiration 14 port is blocked and that a purge should be attempted. Th PUR~E subroutine is called to reverse flow through the 16 aspiration and i~fusion lumens in an attempt to clear the 17 aspiration lumen. Referring to Figure 12B, the PURGE
18 subroutine first starts a purge timer 196, and sets both the l9 infusion and aspiration pumps in reverse 192, 194 at the set flow rates in an attempt to clsar the aspiration lumen. The 21 elapsed time from the purge timer is compared 196 to the purge 22 cycle period, and the purge cycle is allowed to continue if 23 the elapsed time indicated by the purge timer is less than the 24 purge cycle period and the pressure of the fluid in ~he gallbladder is less than the upper opérating pressure limit 26 parameter 198. If the pressure is less than the upper 27 operating pressure limit, the purge continues and the elapsed 28 time compared 196 again. If the pressure exceeds the upper 29 pressure limit 198, the program will proceed through decision point 200, and the pressure check subroutine which will cause 31 maximum aspiration and ano~her purge cycle again if the number 32 of purge cycles has not been exceeded.
33 If the purge cycle time is exceeded without exceeding the - , .. , - ~., , . , , ., . . ~. . . . .

-'091/l2~3~) ~u~i P~r/us~ ~/01037 ~, ~, . ~, 1 ~ppeL- pressure limit, the pressure is compared to the operating set point 200. If the pressure is below the set 3 point, the aspiration pump is stopped 202, and the infusion 4 pump i~ operated at set point in the forward direction. If the pressure does not attain the operating set point 206 6 within the maximum infusion time, the system calls alar~
7 subro~tine 212 in an alarm (1~ state. If the operating set ~ point is attained within the time parameter 210, the system 9 returns to the operate cycle ~hrough 224 and 22~.
If, upon the completion of time 196, the pressure is 11 above the set point, the infusion and aspiration pumps are 12 turned on in the forward dir2ction 224, 226 and ~he program 13 returns to the operate cycle.
14 There are two alarm conditions depending upon whether an abnormal pressure condition is recoverable (alarm 16 (1) condition) or whether the condition is so hazardous that 17 normal operation should not be resumed (alarmi (0) condition).
18 In either case the first priority is to aspirate Prom bo~h 19 lumen to reduce the pressure. I~ the lower pressure limit can be attained within the alar~ aspiration ti~e, an alarm ~13 21 condition occurs and normal operations are resumed. I the 22 condition is an alarm (0), a warning is yiven and the operator 23 must intervene to stop aspiration, Referriny to Fig. 12C, the 24 ALARM subroutine, is entered in one of two states: alarm (0) 252, and alarm (1) 250. In elther state, the infusion pump 26 is set to maximum reverse 254, 256 while the aspiration pump 27 is set to maximum forward 258, 260 to generate maximum 23 aspiration. If the alarm (0~ state 252 was entered, a tone 29 is set 266, and aspiration is continued until the pumps are stopped by operator intervention 270. No further pumping 31 occur~ until the pumps are manually restar~ed ~74.
32 lf the alarm (1) state 250 was entered, a timer is 33 started and the pressure is compare to the lower operating ~9l/l'~30 PCT/US91/0iO37 ~. i'.~'LI 3l ~ pressl~re ~nd if it is less than the lower operating pressure, 2 the pumps are set to operate normally, infusing fluid 268 3 throuah the infusi~n lumen and aspirating fluid 272 from the 4 aspir~tion lumen. If the pressure is above the lower operating pressure, the elapsed time of maximum aspiration is S compared to a parameter which determines the maximum time 7 allowable at maximum aspiration and if that time has not be~Pn 8 reached the pressure is compared again 262. If the elapsed 9 time exceeds the maximum time allvwed, a tone is set 266, the pumps continue to aspirate at maximum rate untll they are 11 stopped 270 by manual intervention. No pumping commences 12 until the pumps are restarted manually 274.
13 The CHECK-PRESSURE-LIMITS subroutine is called by the 14 main routine to determine the proper response to the current lS pressure. Referring to figure l2D/ the CHECK-PRESSURE-LIMITS
16 subroutine begins by starting a timer to measure elapsed time 17 and calculating the pressure change in the last three seconds.
18 If the pressure change is less than l torr, it is assumed that l9 the ~ressure transducer is not operating correctly and the alarm subroutine is called in the alarm (0) state. If the 21 pressure change is greater than l torr, the pressur~ is 22 compared to the minimum alarm pressure 304 and if the pressure 23 is less than the minimum alarm pressure, the elapsed time 24 indicated by the timer is compared to the minimum alarm pressure trigger time parameter 306. If the time is greater 26 than the minimum alarm pressure trigger time, then, the 27 pressure has been below the minimum allowable pressure for too 28 long, and the alarm subroutine is called in the alarm (0) 29 s~ate. If the time is less than the minimum pressure alarm trigger time, the pressure is compared 310 to the maximum 31 alarm pressure and if it is less the maximum alarm pressure 32 is compared to the upper pressure limit 3i8.
33 In either case, the elapsed time is compared to the upper .

~VO9T/12830 PCT/US91/0l037 ~Q ;~ 32 -l press~re alarm trigger time 312 or upper pressure delay time 2 320 ~n~ if the upper pressure alarm trigger time is exceeded, 3 the number of purges is compared to the number allowed 314 and if to~ many purges have occurred, the alarm subroutine i~
called in the alarm ~0) state 316.
6 If the number of purges has not been ~xceeded, the 7 aspirate pump is set to maximu~ flow 326. The infusion pump B is reversed and ~et to maximum flow 328, and the counter of 9 the number of purges is incremented. The pressure is then compared to the lower pressure limit 322. If the pressure is ll below the lower limit within the alarm aspiration time 324 a 12 purge cycle is performed 330, if not the alarm subroutine is 13 called 332 in an alarm (0) state.
14 If the pressure is below the alarm pressure 310 and the lS upper pressure limit 318, the pressures are within the desired 16 lim~its and the system returns to the operate cycle.
17 When the pressure ~s below the upper limit and above the 18 lower limit, the CONTROL PUMPS subroutine con rols the pumps.
l9 Referring the Fig. 12E, the infusion pump will operate until the upper limit is a~tained 340, 342. The aspiration pump is 21 turned off upon the attainment of the lower limit 346, 352.
22 At pressures between the lower limit and 85% of the set point 23 pressure, the aspiration pump operat~s at 80% of set flow, 24 348, 354. At pressures between 115% of set pressure and the upper pressure limi~, the aspiration pump operates at 200% of 26 set flow, or maximum flow whichever is low~r 350, 356. When 27 the pressure is + 15% of the set pressure, both pumps operate 28 at set flow 358, 344.
29 The apparatus is completely automatic and is operable without any significant operator input beyond the critical 31 pressure and available volume. Mor~over, it is readily 32 converted to a completely closed circuit system in those 33 insta~ces where the therapeutic fluid is combustible. Thi~
~.
. : .

3n PCr/VS'Jl/~)1()37 ~ 33 - ~ ~8~f8~ ~
1 featu~ is required for particularly c~mbustible solvents.
2 An~ of a number of types of tubing is suitably used with 3 the ~umps of the subject apparatus. However, we have found 4 that tubing composed of "Tygon Special Formulation F~4040A"
(a ~ inyl material) or "Nalgene" (a polyurethane) is 6 particularly compatible with solvents such as methyl tert 7 butyl ether. Moreover, tubing with a large internal diameter 8 is favored for use with peristaltic pumps, enabling a high 9 volume per revolution ratio to be obtained, thereby permitting a low revolution per minute rate to be utilized, hence 11 minimizing torque build-up when a switch over to the high 12 pressure mode leads to pump motor reverse.
13 As discussed above, the subject apparatus can be utili~ed 14 for removing obstructions in a variety of organs. However, in the instance where it is used to remove gallstones from 16 gallbladders, perfusion rates of about 50 ml~min to 300 ml/min 17 are ~enerally more effective. This is readily accomplished 18 by manually adjusting the pump speed control circuit 46 of 19 Fig. 2. It is important that the flow rate is ~ufficlent to cause turbulent flow within the gallbladder. It has been 21 found that turbulence increases the ra~e of gallstone 22 dissolution and helps in remo~ing the non-dissolving 2 3 f ragments.
24 A variety of catheters usable to deliver and aspirate the fluid can be suitably employed. The catheter must be 26 insoluble in the solvent being infused. For example, a 27 polyurethane catheter is suitable ~or use with MTBE. Three-28 lumen catheters as shown in Figures 3 5 and 7-8 are favored 29 ~ince prPssure measurements as well as perfusion and aspiration of the fluid can all be carried out simultaneously.
31 A suitable three-lumen catheter should have an outside 32 diameter not larger than can be readily employed for the 33 surgi~al insertion of the catheter into the gallbladder, and W~91/~3n ; 1~. PCT/US91/01037 ? `~!J`' l shoul~ ha~e an aspiration lumen 50, a pressure sensing lumen 52 and an infusion lumen 54. The aspiration lumen preferably 3 shoul~:l be larger in cross-section than the other two lumen.
4 ~or the purpose of safety, while achieving effective flow in the system, the aspiration cross-sectional area should be 6 about 2.5 times the infusion cross-sectional area. In this 7 way, the volume removed by aspirat:ion can be greater than the 8 volume replaced by infusion under emergency conditions, while 9 allowing a substantial flow to be maintained through the 10 infusion lumen.
ll Each lumen communicates with the gallbladder through a 12 number of openings in the outside wall of the lumen. The sum 13 of the cross-sectional areas of openings to a lumen should be 14 greater than the cross-sectional area of that lumen in order to minimize flow impedance. The cross-sectional area of each 16 opening should b~ less than the cros -sectional area of its 17 lumen to prevent debris from obstructing the lumen. The 18 aspiration and infusion openings are distributed along the l9 length of the distal end of the cathPter. At least one aspiration opening is located proximal to all infusion 21 openings, preferably being loc:ated at the en~-ry point of the 22 catheter into the gallbladder when th catheter 's in posit on 2~ for operation. With this configuration, aspiration takPs 24 place nearest the insertion point of the catheter into the gallbladder. Any leakage of solvent from the gallbladder 26 throuqh the entry point of the catheter is therefore 27 immediately aspirated and does not damage surrounding tissues.
28 The aspiration lumen extends to the distal end of ~he 29 catheter and terminates in an opening at the distal end.
Referring to Fig. ll, this opening in the distal end of the 31 catheter also serves as a passageway thxough which a guidewire 32 can pass. Note that the number of openin~s is not invariant, 33 depending on the number of gallstones present in the ~() 91/1283() PCr/IJ~"1/01037 ~ _ 3 5 _ ~ ~ 8 3 9 8 ;5 l gall~ dder, as well as the desirable therap~utic need to ' effect rapid treatment.
3 The distal end of the catheter is preferably curved into 4 a pi~tail shape as shown in Figure 7 to aid in its being retained and positioned in the organ. Referring to Figs. 9 6 and 9A, such a pig-tailed catheter. can also include a string 7 74 which helps the catheter retain its pig~tailed shape since 8 fluid being pumped through the catheter and patient movement, g coughing or sneezing tends to cause the catheter to unwind.
A monofilament or wire can be used in place of a string. The ll retaining string can either pass through an opening 72 to its 12 own lumen 70 or can pass through the aspiration 50" or 13 infusion 54" lumen. Other means to retain the catheter within 14 the gallbladder are possible. For example, a balloon catheter for example may s~rve to retain the catheter.
16 Since the string 74 may pass through its own lumen 52, 17 and ~ince a balloon catheter generally alss requires its own 18 lumen, the system should not be construed as being limited ~o 19 a three-lumen catheter. A Yariety of catheters of different lumens will perform satisfactorily provided that the system 21 is modified to accommodate such catheters, such modifications 22 beinq well known to those skilled in the art.
23 When a pig-tailed catheter is used, openings to the 24 pressure lumen should be located on the inner radius of the curve. This location provides a clear opening for accllrate 2G pressure sensing and prevents the mucosa of the gallbladder 27 from interfering with the pressure measurements.
28 8ecause this procedure can be inherently dangerous, using 29 toxic and flammable solvents, it is desired that the catheter be use~ only with the proper pumping system. To assure this, 31 the catheter can have a structural, electrical or fiberoptic 32 connection at its proximal end which is connectable to a 33 similar structure in the remainder of the system. The system : . .. ;, ., . : ,~ ... ~ . .:, . . :.: - .. . .. .

~V~91/1 83(~ , ~, , PCl/~J~ 103 ~ 36 -1 may therefore be prevented from functioning with an ~ inappL-~priate catheter.
3 ~t will be appreciated by those skilled in the art ~hat 4 there are numerous modifications in the electrical circuitry, and the overall interconnecting features of the invention that ~ will achieve the efficacious removal o~ obstructions in 7 particular organs. For instance, while the automatic "self 8 purging" feature of the apparatus is desirable, a device 9 without this feature will perform adequately. Moreover, it should be further noted that, while the invention has been 11 described as applicable to the removal o~ gallstones from 12 gallbladders, its use should not be so narrowly construed.
13 Thus, it is the intent herein to present an invention tha~ is 14 generally applicable for the removal of obstructions from a variety of organs by dissolvin~ and dislodging the obstruction 16 using solvents.
17 What is claimed is:

'.,".

". '' ...

Claims (38)

1. A catheter for the contact dissolution of gallstones having, in generally side-by-side relationship, a solvent infusion lumen and a solvent aspiration lumen, the catheter sized for entry of its distal portion into the gallbladder from outside the body, each lumen having at least one opening in said distal portion for communication between the gallbladder and a remotely located pump means, the aspiration lumen having a greater flow cross-section than the infusion lumen; and means to sense intra gallbladder fluid pressure associated with said distal portion of the catheter for continuously sensing the pressure of fluid within said gall bladder, and transmitting an indication thereof proximally, for control of infusion and aspiration of solvents via said lumens.

2. The catheter of claim 1 wherein the cross-sectional area of said aspiration lumen is larger than the cross-sectional area of said infusion lumen.

3. The catheter of claim 2 wherein the ratio of the cross-sectional area of said aspiration lumen to the cross-sectional area of said infusion lumen is at least 1.5.

4. The catheter of claim 1 wherein the area of each opening is less than the cross sectional area of the lumen with which said opening is in communication.

5. The catheter of claim 1 wherein the catheter further includes a retention means to prevent said catheter from being removed from said gallbladder.

6 The catheter of claim 5 wherein said retention means is a curved formation of said distal portion of said catheter.

7. The catheter of claim 6 wherein said pressure sensing means is located to lie at the inner radius of said curved formation to prevent its blockage by mucosa of the gallbladder.

8. The catheter of claim 5 wherein said retention means is an inflatable balloon located adjacent to said distal portion.

9. The catheter of claim 1 wherein the catheter further comprises a tension string for holding said distal portion of said catheter in a pigtail configuration.

10. The catheter of claim 9 further comprising a string passage lumen in which said string is located.

11. The catheter of claim 9 wherein said string is located in one of said aspiration lumen or said infusion lumen.

12. The catheter of claim 1 further comprising an aspiration opening at the distal end of the catheter in communication with said aspiration lumen.

13. The catheter of claim 1 or 12 having at least one aspiration opening in the wall of the catheter in communication with said aspiration lumen located proximal to all infusion openings.

14. The catheter of claim 13 wherein said proximally-located aspiration opening is located adjacent to the point of entry of the catheter into the gall bladder when the catheter is in position for operation.

15. The catheter of claim 12 wherein said aspiration lumen and aspiration opening at said distal end of said lumen are constructed and arranged to enable the catheter to pass over a guide wire.

16. The catheter of claim 1 wherein the catheter comprises a material which is resistent to the solvent to be infused into said gallbladder.

17. The catheter of claim 16 wherein the material is polyurethane.

18. The catheter of claim 1 wherein said means for sensing the pressure of fluid within the gallbladder comprises a third fluid pressure transmitting lumen extending side by side with said infusion and aspiration lumens and having a distal opening in said distal portion of said catheter, said lumen constructed to communicate intra-gallbladder pressure to a remotely located pressure transducer.

19. The catheter of claim 1 wherein said means for sensing the pressure of fluid within the gallbladder comprises a pressure transducer located in said distal portion of said catheter.

20. The catheter of claim 19 wherein said transducer is piezoelectric.

21. The catheter of claim 19 wherein said transducer is fiberoptic.

22. The catheter of claim 19 wherein the transducer is removably inserted in a lumen of the catheter.

23. The catheter of claim 1 wherein the catheter has a structural formation at its proximal end that permits it to be used only with a solvent delivery system having a predetermined mating structural formation that prevents inadvertent use with non-mating systems.

24. The catheter of claim 1 wherein the catheter has an electrical formation at its proximal end that permits it to be used only with a solvent delivery system having a predetermined mating electrical formation that prevents inadvertent use with non-mating systems but use fiberoptic rather than electrical.

25. The catheter of claim 1 wherein the catheter has a structural formation at its proximal end that permits it to be used only with a solvent delivery system having a predetermined mating structural formation that prevents inadvertent use with non-mating systems.

26. An apparatus for use in the dissolution of gallstones comprising:
a microprocessor adapted to execute an algorithm comprising:
a gallbladder pressure determining module to determine the pressure within the gallbladder of a patient in response to an input pressure signal derived from the gall bladder;

a pump control module to control the speed and direction of an infusion pump pumping solvent through an infusion lumen into and an aspiration pump pumping solvent through an aspiration lumen out of the gallbladder of the patient; and a response determination module to control the functions of the pump control module in response to the pressure determinations of the pressure determining module.

27. The apparatus of claim 26 wherein said gallbladder pressure determining module, generates an alarm and initiates material continuous aspiration by both infusion and aspiration pumps in response to one of the set of conditions comprising:
no pressure variations of a predetermined amplitude for a predetermined amount of time;
pressure does not return to a normal range within a predetermined amount of time or after a predetermined volume has been used to purge said aspiration lumen;
more than a predetermined number of purge cycles occurring within a predetermined period of time;
pressure remains less than a lower set limit for a predetermined amount of time, system is unable to maintain the pressure within normal range for a predetermined amount of time;
stops infusion and maintains maximal aspiration in response to the condition of the pressure exceeding an upper set limit;
aspirates through infusion lumen until the pressure falls to the lower set limit and then infuses 1-2 ml. through aspiration lumen in response to the condition of pressure remaining above the upper set limit for more than a predetermined amount of time; and stops aspiration in response to the condition wherein the pressure is less than the lower set limit.

28. An apparatus for dissolution of gallstones comprising:
a means for continuously measuring the pressure within the gallbladder of a patient; and a means for controlling the infusion and aspiration of a solvent into the gallbladder in response to those measurements.

29. A method for dissolution of gallstones comprising the steps of:
continuously measuring the pressure within the gallbladder of a patient; and controlling the infusion and aspiration of a solvent into the gallbladder in response to those measurements.

30. The method of dissolution of gallstones of claim 29, further comprising the step of periodically measuring the amount of cholesterol in the solvent.

31. The method of claim 30 wherein the solvent is replaced when the cholesterol concentration in the solvent reaches a predetermined concentration limit.

32. The method of claim 31 wherein the limit is about 30%.

33. The method of claim 29 further comprising, prior to introduction of solvent into the gallbladder, the measuring of a critical pressure, at which fluid in the gallbladder discharges into an adjacent part of the body, and using the value of that pressure for controlling said infusion and aspiration.

34. The method of claim 33 wherein the step of measuring the critical pressure comprises the injection into the gallbladder of a radiopaque dye at increasing pressure until the discharge of said dye is observed radiographically.

35. The method of dissolution of gallstones of claim 29 wherein the step of infusing the solvent into the gallbladder occurs at a rate sufficient to create turbulence adjacent the gallstones.

36. An apparatus for the dissolution of gall stones comprising:
a system bus;
a microprocessor in communication with said system bus;
a memory for holding algorithms, said memory in communication with said system bus;
an analog to digital converter having an input terminal for receiving an analog signal representative of the intra-gallbladder pressure and an output terminal for applying digital signals representing said pressure on said system bus;
a pressure transducer having a pressure sensor and an output terminal, said output terminal of said pressure transducer in communication with the input terminal of said analog to digital converter, said pressure transducer generating a pressure signal related to the pressure of the solvent within the gall bladder;

a reservoir for filling with a gall stone dissolving solvent, an infusion pump connected by conduits to pump solvent from said reservoir into said gallbladder an aspiration pump connected by conduits to withdraw solvent from the gall bladder and discharge the solvent into said reservoir;
a pump controller having an input terminal in communication with said system bus and a plurality of output terminals, one of said output terminals in communication with said aspiration pump and one of said output terminals in communication with said infusion pump, said microprocessor controlling said controller, which in turn controls said aspiration and infusion pumps in response to signals received from said pressure transducer, said microprocessor terminating infusion and initiating aspiration in response to signals indicating excess pressure in the gallbladder; and a catheter having a plurality of lumens, a first one of said lumens connected at its proximal end to said infusion pump;
a second one of said lumens connected at its proximal end to said aspiration pump; and a means to sense intra-gallbladder fluid pressure associated with said distal portion of the catheter for continuously providing an indication of the pressure of fluid to said pressure transducer:
the distal end of said catheter for placement within the gall bladder of a patient.

37. The apparatus of claim 36 wherein said reservoir is a collapsible bladder.

38. A catheter for the contact dissolution of gallstones having, in generally side-by-side relationship, a solvent infusion lumen and a solvent aspiration lumen, the catheter sized for entry of its distal portion into the gallbladder from outside the body, each lumen having at least one opening in said distal portion for communication between the gallbladder and a remotely located pump means, the aspiration lumen having a greater flow cross-section than the infusion lumen; and means to sense intra gallbladder fluid pressure associated with said distal portion of the catheter for continuously sensing the pressure of fluid within said gall bladder, and transmitting an indication thereof proximally, for control of infusion and aspiration of solvents via said lumens.