CA2229138C - Perfusion hyperthermia treatment system and method - Google Patents

Abstract

A perfusion hyper/hypothermia treatment system (100) comprising: a computer system (110); means for obtaining body fluid having a temperature; a plurality of temperature signals (201, 202, 203) coupled to the computer system (110), the temperature signals representative of temperatures at each of a plurality of patient (99) locations on or within a patient (99); means for generating at least one temperature value representative of at least one of the temperatures; a comparator coupled to the temperature value and to a set of stored parameters in the computer system (110) to generate a comparison value;
a signal generator which generates a control signal to control a change in the temperature of the body fluid based on the comparison value; and means for perfusing the body fluid into the patient (99).

Description

WO 97/06840 PCTrUS96/11476 PERFUSION HYPERTHERMIA TREATMENT
SYSTEM AND METHOD
Field of the Invention ~ The present invention relates to methods and d~ lldLUS for controlling medical hyperthermi~ or hypothermia tre~tment~ for ~ ; and other zlnims~
10 and more specifically for automatically controlling telllpl_ldLul~,s and rates of change of telll~c~dLulG in the subject of a perfusion hyperthermia or hypothermia tre~tmçnt using a programmed CO~ uL~,. system.
R~(~k~round of the Invention Fever is one mech~ni.cm by which a m~mm~l fights ~ c~e A number 15 of pathogens, including some bacteria, some c~nrlor~, and some viruses, such as the HIV retrovirus and other enveloped viruses, seem to be adversely affected byheat. In addition, certain processes which nnrm~lly fight ~ ç~e, such as tumor necrosis factor A, seem to be sfim~ ted with hyperthermi~ Fever can be thought of as a natural-response hyperth~rmi~ tre~tmtont of a m~mm~l to a 20 pathogen or disease condition which may have a more adverse effect on the pathogen or (1i~e~ed tissue than on the rest of the animal's body, thus allowingthe body to prevail against the disease condition.
In particular, artificially-in~l- ced whole-body hyperth~ mi~ as opposed to, for in~t~n~e, local application of heat to a tumor or extracorporeal 25 hyperthermi~ tre~tmente to blood, may be required to treat such ~ e~es as HIVinfection or a .n~ ?d cancer where the pathogen is universally distributed in the c;~,r,; . . .Pnt~l subject or clinical patient, since leaving any one part of the patient cooler (i.e., outside the boundary of the hyperthermia tre~tment) will provide a safe harbor for the pathogen, which will again spread into the rest of30 the body once the hyperth~mi~ tre~tment ends.
Hippocrates first described hy~.,.Lll~,.lllia tr~tm~nt~ around 480 BC, which used hot sand baths for patients with skin tumors. In 1927, a Nobel prize was awarded to a doctor, Warner Jauregg who used malaria-in-luçed fever to treat syphilis. However, by the mid-1930s the medical cOllllllul~iLy began to . CA 02229138 1998-02-10 2 - .. .
recognize the potential hazards of hyperthermic therapy, and a 1934 survey by the Council on Physical Therapy of the American Medical Association documented 29 deaths resulting from hyperthermia treatments. Among the adverse effects of hyperthermia are increases in cardiac output by as much as 200% of normal, increases in oxygen consumption, changes in serum enzymes, drops in phosphate, calcium, and magnesium levels, heart, liver and brain damage and failure, ~lissemin~te~l intravasular coagulation, hemolysis of red blood cells, spinal-cord necrosis, fluid loss from diuresis and p~l~,pildtisn, electrolyte shifts, and bleeding problems associated with systemic 1 0 heparinization.
Hyperthermia has been induced using hot baths, bacterial inoculation, hot wax, hot air systems, heated water blankets, etc.
Hyperthermia has been combined with radiation and/or chemotherapy to achieve synergistic results against cancers (i.e., when heat is combined with 15 those other therapies, destruction of neoplastic tissues occurs at smaller dosages of radiation or chemotherapy agents).
One shortcoming of prior-art systems and methods has been the lack of tight, fast, and automatic control over, and lack of visual feedback with respect to, the exact temperature achieved in particular parts of the body of the patient, the average temperatures of the body core or various body parts, the rates of temperature change, and temperature gradients between various body parts. In addition, known prior-art perfusion hyperthermia systems have not automated system checklists, patient-monitoring systems, alarms, treatment-procedure recording, nor the monitor indications and controls provided to the medical professionals who a-lminister the hyperthermia tre~tment United States Patent Nurnber 5,385,540 issued January 31, 1995 to Abbott et al. discloses a cardioplegia system employing a heart-lung machine with a conduit for diverting a portion of blood flow to a cardioplegia delivery line. A heat exchanger for controlling fluid temperature is provided in the 30 cardioplegia line. The cardioplegia line supplies the relatively small amount of blood as needed to the heart itself. The system includes patient monitoring of d~ E-tT

.

. . CA 02229138 1998-02-10 ': ~ . .; , ' 2a myocardial temperature and pressure, and sensing of temperature and pressure of the cardioplegia solution in the delivery line. Data input to a microprocessor may include desired temperature of solution in cardioplegia delivery line or desired patient temperature, and the microprocessor controls the circulation of 5 fluid in the heat exchanger circulation path either for obtaining a desired patient temperature or a desired output solution temperature.

Surnmary of the Invention What is needed, and what the present invention provides, is a system and 10 method that automatically monitors and controls a perfusion hyperthermia treatment using a system including one or more programmed computers, and mechanical and sensor subsystems. The system includes a fluid path between a patient and an external fluid-treatment subsystem, wherein control of the external fluid-treatment subsystem includes feedback from sensors coupled to the patient.15 The resulting integrated system provides an automated monitoring and control of the patient, the external J'S,~-D S~E~T

; .

fluid-treatment subsystem, and the treatment. In one embodiment, the fluid passing between the patient and the external fluid-tre~tment subsystem is blood.In one embodiment, an apparatus and method are provided for using a computerized system for a perfusion hyper/hypothermia treatment of a patient 5 which obtains a physiological fluid having a particular temperature. A plurality of temperature signals representative of temperatures at each of a plurality of patient locations on or within the patient are coupled to the computer system.
Measured temperatures are compared to a set of stored parameters in the computer system to generate a comparison value which controls a change in the 10 temperature of the physiological fluid which is made by the extracorporeal fluid-treatment system to control a rate of temperature change, m~int~in the '.
telll~el~L lre at a pre-determined value for a pre-determined time, then to change the temperature value at a second rate of change until it reaches another pre-determined value. The physiological fluid can then be perfused into the patient 15 to either warm, cool, or m~int:~in the current temperature ofthe patient. In one such embodiment, the physiological fluid is blood. In another such embodiment, the physiological fluid is saline.
In one embodiment, the supply voltage to the plurality of thermistors is provided by a circuit which provides a very short pulse, one at a time and 20 sequentially to each thermistor, in order to reduce heating of the thermistors and to reduce the electrical hazards, and via a multiplexor, couples the analog response signal to an A/D convertor.
In one embodiment, the mass of heat-exchange fluid in the heat-exchange fluid circuit is minimi7~d in order to improve the response time of the 25 temperature control feedback mech~ni~m In one embodiment, the volume of blood in the blood circuit is minimi7P~3 in order to reduce the amount of blood outside the patient and to improve the response time of the temperature control feerlb~- k mech~ni~m In one embodiment, a rate of change of temperature is measured and 30 controlled according to a stored parameter in the computer system.
In a further embodiment, checklist input is elicited and received from a AME~ T

user, and used to control operation of the computer system.
In another further embodiment, correct operation of the computer system is repeatedly verified with a self-test program.
In another further embodiment, correct coupling of the computer system 5 to external components is repeatedly verified with a self-test program.
One embodiment also provides a visualization of the monitored functions.
One embodiment also provides a recording over time of one or rnore of a set of measured parameters.
One embodiment provides for an integrated disposable physiological-fluid subsystem which mates with a reusable system interface.
Brief Dçscription of the Drawings In the following detailed description of the invention, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration only, specific exemplary embodiments in which the invention may be practiced. It is to be understood that other embodiments may be ~ltili7P-l, and structural changes may be made, without departing from the scope of the present invention.
Fig. 1 shows a high-level conceptual overview of perfusion hyperthermia/hypothermia treatment system (PHTS) 100.
Fig. 2A shows a more detailed conceptual drawing of PHTS 100.
Fig. 2B illustrates a schematic of disposable subsystem 301.
Fig. 2C illustrates a schematic of a system interface 390 which mates to disposable subsystem 301 of Fig. 2B.~5 Fig. 2D illustrates an exemplary perfusion system 400 used to effect intraperitoneal hyperthermia or hypoth~ of patient 99.
Fig. 2E illustrates an exemplary perfusion system 400 used to effect a single-organ perfusion hyperthermia or hypothermia of patient 99.
Fig. 2F shows a schematic of a circuit used to supply regulated voltage current to thermisters in the sensor probes in one embodiment of PHTS 100.
A'~ S~FT

WO 97/06840 PCT~US96/11476 Fig. 3 illustrates one embodiment of the monitoring and control connections between monitoring system 200, extracorporeal circuit (ECC) 300 and CO~ Jul~,. system 110.
Fig. 4 illustrates one embodiment of the control flow between some of the ~ S various software modules which monitor and control PHTS 100.
Fig. 5A illu~L dLes one embodiment of the time sequencing between some of the various software modules which monitor and control PHTS 100.
Fig. SB shows a graph of a typical te.l.~,.dlu.e vs. time for a patient 99 undergoing a perfusion hyperthermia tre~tm~nt for one embodiment of PHTS 100.
Fig. SC illu~llales a patient and system tepe.dL lre model used in one embodimentofPHTS 100.
Fig. 6 illu~lldles an exemplary display screen usable with a mouse-type point-and-click input device for one portion of the software-controlled user-int~r~t~tive start-up-procedure çhtoc~ t Fig. 7 illu~Lldles an exemplary display screen and bezel buttons of a second portion of the software-controlled user-int~rz~tive start-up-procedure checklist.
Fig. 8 illu:,l dLes an exemplary display screen usable with a mouse-type point-and-click input device for a third portion of the checklist.
Fig. 9 ill~.~l.,.l~s an exemplary display screen usable with a mouse-type point-and-click input device for a fourth portion of the ~h~ t Fig. 10 illu:iL dLes an exemplary display screen usable with a mouse-type point-and-click input device for a fifth portion of the che~ t 25 Fig. 11 illu~L aLes an exemplary display screen usable with a mouse-type point-and-click input device for a sixth portion of the ~hPc~ t Fig. 12 illu~LlaL~s an exemplary display screen usable with a mouse-type point-and-click input device for a seventh portion of the checklist.
Fig. 13 illustrates an exemplary display screen usable with a mouse-type point-and-click input device for a eighth portion of the checklist.
Fig. 14A is a simplified isometric view of one embodiment of blood pump 320.

W O 97/06840 PCT~US96/11476 Fig. 14B is a simplified plan view of the blood pump 320 shown in Fig. 14A.
Fig. 14C is a plan view of one embodiment of blood-pump int~rf~re 321.
Fig. 14D is a left elevation view ofthe blood-pump interface 321 shown in Fig.
14C.
5 Fig. 14E is a bottom elevation view of the blood-purnp intP,rf~re 321 shown in Fig. 14C.
Fig. 14F is a right elevation view of the blood-pump interface 321 shown in Fig. 14C.
Fig. 14G is a top elevation view of the blood-pump interface 321 shown in Fig.
14C.
Fig. 14H is a simplified plan view of the assembly operation of blood-pump intPrf~f~e 321 to the blood pump 320 shown in Fig. 14A.
Fig. 14I is a simplified plan view of blood-pump interface 321 assembled to the blood pu_p 320 shown in Fig. 14A.
Fig. 15A is a plan view of an ~ltern~tive embodiment of blood-pump intPrf~ e 321'.
Fig. 1 SB is a simplified plan view of blood-pump interface 321 ' assembled to a co~ ollding blood pump 320'.
Fig. 16A shows a front, open, view of a m~ r clam-shell heat PYrh;~y~"~
1600 according to the present invention which can be used as heat Pxehslnger 330 in PHTS 100.
Fig. 16B shows a simplified isometric view of a modular vertical-cylinder heat PY~h~nger 1600' according to the present invention which can be used for heat çYch~ngPr 330 in PHTS 100.
25 Fig. 16C shows a front view of a disposable blood-tube assembly 1700' accol.lh~g to the present invention which can be used in modular vertical-cylinder heat çx~h~nger 1600' of Fig. 16B .
Fig. 16D shows a simplified front view of a reusable vertical-cylinder assembly 1601' according to the present invention which can be used in modl-l~r vertical-cylinder heat Pxrh~nger 1600' of Fig. 16B.
Fig. 17A shows a front view of a disposable blood-tube assembly 1700 usable WO 97/06840 PCT~US96/11476 with modular clam-shell heat e~c:h~n~er 1600 of Fig. 16A according to the present invention.
Fig. 17B shows a cross-section view of the disposable blood-tube assembly 1700 of Fig. 17A.
5 Fig. 17C shows a front, open, view of a reusable clam-shell acsembly 1601 usable with modular clam-shell heat ~xch~n~er 1600 of Fig. 16A
according to the present invention.
Fig. 17D shows a side, closed, view of the reusable clam-shell assembly 1601 of Fig. 17C.
10 Fig. 17E shows a cutaway detail of one embodiment of the sealing ridges, grooves and gaskets of the edges of reusable clam-shell assembly 1601.
Fig. 17F shows a side, open, view ofthe reu_able clam-shell assembly 1601 of Fig. 17C.
15 Fig. 17G shows a front view of another embodiment of a disposable blood-tube assembly 1700" usable with modular clam-shell heat çxch~nger 1600 of Fig. 16A according to the present invention.
Fig. 18 shows a s~hPm~tic of some conn~ctif~nC of one embodiment of PHTS
100 having a simplified structure inc11l-1ing monilo~ g system 200, blood pump 320, heat exch~nger 330, and bubble detector 333.
Fig. 19 shows an isometric view of a cover ~ ;Lu~e for one embodiment of PHTS 100.
Fig. 20 shows an isometric view of one embodiment of PHTS 100.
Fig. 21 shows an isometric view of another embodiment of PHTS 100.
Fig. 22 shows an isometric view of yet another embodiment of PHTS 100.
D.ot~iled Vesc, ~Lior~ of the Preferred Fmbotliment In the following clet~iled description of the ~lere.l~;d embo-lim~nte, reference is made to the accolllpd.lyillg drawings which form a part hereof, andin which are shown, by way of illustration, specific embo~limPntc in which the 30 invention may be practiced. It is to be understood that other embo-limentc may be utilized and structural changes may be made without departing from the scope of the present invention.
The success of hyperthermia or hypothermia and whole-body hyperthermia or hypothermia treatment (as measured by efficacy of disease removal and by reduced patient complications and mortality) is related to the S multiple conkols over the absolute temperature achieved, temporal profiles of temperature, temperature distribution within the patient, and the rates of change of temperature. Each of these parameters is to some extent affected by numerous factors, such as heat shedding by the patient, the mass of the patient, cilculatory patterns or abnormalities (e.g., stroke) within the patient, and the flow through 10 the extracorporeal circuit (ECC). In turn, each of these temperature parameters affects the patient. For instance, a rapid temperature rise may lead to heat-shock protein generation or degradation, while a slow temperature rise may induce thermal tolerance in some cancers. Natural fevers have a temperature profile which changes over time, and may vary in distribution within the body, and such 15 speGifi~ ~i~e-var~ing ~rofiles may thus be effective in combatting certain pathogens. It is therefore desirable to have automatic, pre-determined temporal and spatial temperature profiles for a treatment.
In the following discussions, specific reference is made to the extracorporeal circulation and perfusion of blood as the fluid being treated by the 20 system and method of the present invention. Other embo-limen~ circulate and perfuse other physiological fluids, which are defined in this invention to include blood or other body fluids obtained from the patient and treated and returned byperfusion, as well as other fluids obtained from commercial sources, such as sterile saline (hereinafter collectively also called "body fluid(s)"), and for such 25 embodiments, the terms used in the descriptions for treating or transporting "blood" (such as "blood tubing" or "blood pump") or "body fluids" should be interpreted to treat or transport the relevant physiological fluid.
Figure 1 shows a conceptual drawing of one embodiment of a perfusion hyper/hypo~hermi~ treatment system (PHTS) 100 comprising co~ uLel system 30 110 for monitoring and controlling the system using input from a user, monitoring system 200 for measuring various parameters of the PHTS 100 and ~'~r~in'f~ ET

patient 99 (or other biological org~ni~m, organ, or p.~dlion being treated, hc.ch~drl~ . collectively called "patient 99") and for providing represçnt~tive signals to Co~ uLcl system 110, perfusion system 400 for withdrawing blood from patient 99 and later lcl~. Ili..g the blood after tre~tment and extracorporeal 5 circuit (ECC) 300 for treating the withdrawn blood. PHTS 100 can be used to effect either hyperthPrmi~ or hypothermia of patient 99, depending on the trç~tmPnt desired.
In one embodiment, the withdrawn blood is first circulated to observe or achieve an initiai stable "normal" tel~ cldlul-, (e.g., at a "normal" oral 10 t~ eldlule of, for example,98.6~F or 37~C) in patient 99 (i.e., in the c~e where the initial observed tclll~ldLulc is not stable or "normal," one embodiment controls the heat fee~b~c~ to achieve such a state). Heat is then added to the blood by ECC 300 at a rate which achieves a pre~letPrmin~l rate of Lt;lll~ ldlUlc increase as measured at one or more points measured in patient 9915 (and/or other L c~ p~.r~ll-.ed) until a stable hy~cll~ tre~tm~ont state isachieved. This hyperthermia is then . . .~; .~1;.; . ,~rl for a period of time, then heat is removed from the blood by ECC 300 at a rate which achieves a pre~ . ,..;"~1 rate of telll~ alulc decrease until the patient is returned to a "normal"
telllp~ldlulG and stabilized. In another embo~lim~nt~ the withdrawn blood is first 20 circulated to observe (or achieve) an initial stable "normal" tclllpeldLulc in patient 99, then heat is removed from the blood by ECC 300 at a rate which achieves a pre~let~rminlo~i rate of ~ ...I...c decrease as measured at one or more points measured in patient 99 (and/or other tre~tm~nt pe.rc,....ed) until astable }lypothermi~ tre~tmpnt state is achieved. This hypothermia is then 25 m~int~in~cl for a period of time, then heat is added to the blood by ECC 300 at a rate which achieves a pre<lçt-~rmin~~~l rate of tclll~ laLulc increase until the patient is returned to a "normal" tclllp~,.dLulc and stabilized. Such hypoth~ rmi~ can be used, for example, to reduce the metabolic rate of patient 99 for certain surgical procedures, or in certain me~lic~l management ;"~I;."~es (for example, in 30 children or infants with pulmonary insufficiency). In yet another embodiment, heat is added to, or removed, from the blood by ECC 300 at a rate which achieves a pre~et~rmin~d rate of tC;~ dlul~ increase or decrease as measured at one or more points measured in patient 99 (and/or other tre~tment performed) and until a stable tt:lllpcldlulc l.e~ state is achieved; in order, for example, f to bring a hypothermia victim back to normal telllpeldLule, or to remove excess 5 fever in a controlled fashion.
Figure 2A shows a more detailed conceptual drawing of one embodiment of PHTS 100 shown in Figure 1. Col.l~ul~. system 110 comprises co...~ul~,.
111, one or more interf~ee 120, one or more input device 130, and one or more output device 160. In one embodiment, monitoring system 200 comrri~es a plurality of patient-te.lll,~,.dlul~i probes 201 through 203. In one embodiment,ECC 300 comrri~çs blood tubing 302, blood pre-conditioner 310, blood pre-conditioner interf~ce 311, blood pump 320, blood-pump interface 321, heat exchzmger 330, heat-exch~nger interface device 331, blood post-conditioner 380, blood post-conditioner intPrf~f~e 381, water-conditioning ~ub:~y~lelll 340 (cl mrri~ing water reservoir 343, water reservoir level detector 342, "T"
c~ nnPctor 344, water heater 350, water cooler 360, and water pump 370, plus associated sensors for t~lllp~,ldlUl~ e:i:iul~, and/or water level). In another embodiment, ECC 300 omits blood pre-conditioner 310 and blood post-conditioner 380. Perfusion system 400 co,llp.lses canulae 410 and 420, and the pre-ECC and post-ECC colll~ollellt~, if any, in a particular embodiment.
In one embo-limPnt computer system 110 comprises an IBM-cn,~ ihle personal COlll~ul~L. In one embodiment, interf~re 120 is a signal-interf~e card or circuit board which resides within computer system 110, and provides signals to c~ ul~r 110 represellldli~/e of various lllcd~ d system par~metç~, such as 2~ ,lalulc, pl~ Ul~i, and flow rate. In one such emborlimPnt computer system 110 comrri~Ps colll~ul~l 111, which comprises a dedicated culll~ul~l board based on a high-l,clrollllance Intel microprocessor coupled to intPrf~ e circuit O
120, and which co"",ll,.,ic~tçc wit_ personal computer 170, which in turn provides input device 130 and output device 160 functions. In one embo-limPnt input device 130 comrri~ç~ a keyboard with an associated pointer input device, such as a track-ball or mouse, which is coupled to Colll~ult~l system 170. In another such embodiment, input device 130 comI-ri~es a touch-sensitive-screen input device such as is commonly known in the conl~ul~. art, wherein the user touches certain portions of the display screen which elicit input from the user under program conkol. In yet another such embodiment, input device 130 5 comprises a set of touch-sensitive bezel buttons physically located next to display screen 161. In one embo~liment, output device 160 compri~çs a display 161 having a video-graphics ~tt~chment (VGA) display screen, such ~ a cathode-ray-tube (CRT) or, preferably, a liquid crystal display VGA
(LCD-VGA) screen. In one such embo~1imP-nt output device 160 also compri~es 10 an audio output device 162, such as an eleckonically-driven buzzer or speaker, used to alert the user of various exigencies or other conditions. In one such embodiment, audio-output device 162 compri~çs a tone generator producing l sounds for alerting a user to various warnings or alarms. In another such embo-liment l~,colded or synthP~i7P<l voice signals are converted to sound 15 by audio-output device 162, for alerting a user to various warnings or alarms. In one such embo~limpnt output device 160 also compri~es a data-output device 163, such as a ~ e~ç drive, to write data from a Ll~l...e.~l operation onto a diskette, a m~gnPtic tape drive to write data from a tre~tmpnt operation onto m~gnPtic tape, and/or a network c~ ~-nP~ n (e.g., an FthPrnPt local-area 20 network) to write data from a tre-~tmpnt operation onto a dataset on a centrali_ed file server.
Monitoring system 200 measures various pdl~ll~Lt;l~ ofthe PHTS 100 and/or patient 99. In one embodiment, tt;lll~,.alulc probes 201 through 203 comprise solid-state thPrmi~tor devices which measure telllpeldlw~s at a 25 plurality of points on or within the subject patient 99. For in~t~n-~e~ in one embodiment, probe 203 measures the lt;m~c.dlul~ within the bladder, and probes 201 and 202 measure the Lylll~lic~n~"alwc in the right and left ears, respectively. In another such embc-liment, one or more ~dtlition~l or Altern~tive tellll~.,.dlulG probes also Illea,ulci rectal telll~,.dlulc (in one embodiment, two 30 such probes are used to measure te.ll~cldlul~, at two di~erent depths within the rectum), body- core tt;lll~ dlwc using deep subcutaneous pl~rPmPnt nasopharyngeal l~ .dLule, intracardiac and/or intrathoracic telllp~,ldLul~ usingthermodilution cardiac-output pl~rPment> intrapulmonary artery and/or vein lelllpeldlul~, esophagus telll~GldLule, limb skin t~ ,ldLwt;;, limb muscle telll~.,.aLule (by an embedded thermietor probe), and/or limb bone telllpeldLulcS (by an embedded thermistor probe). In other embo-limente, one or more additional or ~ltern~tive tt;~ alule probes also measure telllp~;ldLule at the çs~mll~tion site(s).
In one embc~limpnt the one or more t~ ldLwe probes 201-203 are thPrmietors calibrated to a suitable accuracy within the anticipated t~lllp~ldLulc 10 ranges ofthe tre~tm~nt In one such embo-liment, care is taken to,.,il,;,,,;~ the thermal mass and the thermal condu.iLivily path from embedded thermietPrs (e.g.,in muscle or bone) to the external el~vi~ u~-ent, in order that the thprmietor accurately measures core t~ .,ldLulci, without eipnifir~nt therrnal leakage to the r~rt~rn~l en-vi-~ llL. For inet~nre, a "trocar" (a hollow needle used to implant a 15 th~rmietor into a bone marrow site) left in place after implanting a thPrmi.etor can provide a significant thermal path from the th . " ,i!~lor site to the e~tPrn~l air, leading to errors in Lt;lll~,.dLul~, measurement, and therefore the trocar is partially or completely withdrawn after placing the 1hermietor in order to thPrm~lly isolate the thPrmietl~r. In another embo~lim~ont monitoring system 200 also includes 20 patient heart-signal ("ECG") probes, brain-signal ("EEG") probes, and blood-pLCi,~ probes to provide additional signals to be used for monitoring and display to computer 1 10.
Figure 2B illu~LldLes a srhpm~tic of disposable sub~y~L~lll 301. In one emborlimlont disposable subsystem 301 is m~mlf~ctured as a single illl~ cl 25 ~u~y~Lelll with all nrcee~;1,y tubing colll-e~,le~ and sealed, pretested for functionality and ~bsPnre of leaks, StPrili7P~l~ and packaged in a stPrjli7P~
delivery p~r~ge This disposable subsystem 301 provides an easy-to-use, sterile, reliable part which isolates all parts which come into contact with thepatient's fluids (e.g., blood), and can be quickly replaced for each new patient30 with a miniml-m of manual illL~ ellLion or adjnctmPnte In the embodiment shown in Figure 2B, a length of blood tubing 302 for receiving patient blood is coupled to blood-preconditioner interface unit 311, a further length of blood tubing 302 then couples the blood to blood-pump intPrf~re 321, a further length of blood tubing 302 then couples the blood to heat-çxrh~nger interface 321, a further length of blood tubing 302 then couples the blood to blood-~ 5 postconditioner interf~r,e 321, a further length of blood tubing 302 is then co-upled for rGil l ' l ling -u~e blood to ~ne paiieni. in one embodiment, disposabie sub~y~lGlll 301 includes disposable sensors, such as thermi~tçr.~ co..~ (e~l before and after the heat-çxch~nger interf~re 331 and plGS:iUlG sensors connçctç~ before and after blood-pump interf~re 321. In one embo-limçnt the heat exch~nger is 10 assembled such that the flow of heat exrh~nge fluid (e.g., water) is counter to the flow of patient fluid (e.g., blood), in order that the efficiency and amount of heat transfer is m~x;".i~cl (i.e., the end of heat exch~nger 330 having the warmest water is llalkir~ g heat energy to the coolest blood, and the end with the coolest water is L all~rG~ing to the warmest blood). Blood-preconditioner 15 ; ~ ~1 - . r~ce unit 311 comprises those parts of blood precon~iitil~n~r 310 which come into contact with the patient's blood, including any sensors which come into contact with the blood. In one embo-iiment, blood preconditioner 310 and blood-preconditioner intçrf~re unit 311 are used to add fluids, such as saline and/or various drugs, to the blood passing through disposable sub~y~lGnl 301.
20 Blood-postconditioner interf~re unit 381 comprises those parts of blood postçon-iitioner 380 which come into contact with the patient's blood, inrlu-lin~
any sensors which come into contact with the blood. In one emb~liment blood ~o~Lco-.diLioner 380 and blood-postconditioner interfAre unit 381 are used to add oxygen and/or remove carbon dioxide from the blood passing through disposable 25 sub:iy~lGnl 301. In one embo~iim~nt, disposable subsystem 301, which is otherwise as shown in Figure 2B, omits blood-preconditioner interface unit 311 and blood-postcorl~itioner interface unit 381.
Figure 2C illu:~ldLGs a sçhtom~tic of a system interf~re 390 to disposable ~ub~y~lGlll 301 of Figure 2B. In one embodiment, system intPrf~re 390 is 30 configured so that disposable subsystem 301 is easily assembled into system interface 390 to form ECC 300 by use of snap-in-place connectors, and plug-and-socket interfaces for both the mechanical and electrical subsystems thereof.In one such embodiment, disposable subsystem 301 is made so that correct assembly is easily p~,lrulllled and incorrect assembly is thereby prevented, as illustrated by the col~ ol-ding in1erf~c~es between disposable sub~y~l~lll 301 5 and system int~rf~e 390 in Figures 2B and 2C. In one embodiment, system f . r~ce 390 coml-riees blood pre-conditioner 310, blood pump 320, heat ~xc hAn~er 330, and blood post-conditioner 380. In another embodiment, system int~ e 390, which is otherwise as shown in Figure 2C, omits blood preconditioner 310 and blood postconditioner 380. In one such embodiment, 10 these colll~onents comprise only the pPrmAn~nt reusable positions, and electrical and merhAnical col~leclol~ of the respective devices, and do not comeinto contact with the patient's blood.
In one embodiment, disposable sub~y:jlelll 301 and system intPrf~e 390 are assembled together at the start of a perfusion hyper/hypothermia l1C;A I " ,~
15 (PHT) by a user such as a physician or perfusion technician. In one such embodiment, a sterile disposable subsystem 301 is delivered in a P1CA~ . . ,hledstate, and need only be removed from its p~Aging and AttAr hP(l to system intPrf,qce 390. In one such embodiment, disposable :~ub~y~L~.ll 301 is shipped empty of any fluid, and is "primed," in one case, by the user filling it with a 20 standard sterile saline solution. In another such embodiment, disposable subsystem 301 is shipped pre-filled with a standard sterile saline solution. Once disposable subsystem 301 is conn~cted to system intPrf~e 390 and has been filled with a priming fluid, the ECC 300 can be rhPcL Pd for fimCtionAlity~ which, in one embodiment, is done as part of a Alllol~lAIPd system-chPrl~liet procedure, 25 as is described more fully below. In one such embodiment, this functionality check includes pumping sterile saline solution from a supply bag through the blood circuit of ECC 300 to check the functionality (e.g., that the fluid is pumped and is heated and cooled and otherwise treated, when the a~ro~L;ate comm~n-le are sent be colll~ulel system 110), and then into an output bag for 30 later disposal.
Figure 2D illustrates an exemplary perfusion system 400 used to effect WO 97/06840 PCTrUS96/11476 hlL~d~cliloneal hyperthermia or hypothermia of patient 99; this perfusion system400 is connecte(1 to a CO111PUlG1 system 110 and ECC 300 which are :iub~ lly the same as shown in Figure 2A. In one such embodiment, perfusion system 400 compri~es canulas 410 and 420 used to effect h~ )Gl;loneal hyperthermia of 5 patient 99. In such an embo~limPnt, fluid (such as sterile saline) is provided into and treated by ECC 300, then pumped into canula 420 which is inserted into one point in the peritoneal cavity of patient 99; this fluid is then withdrawn through canula 410 (which was inserted into another point in the peritoneal cavity of patient 99). It is to be understood that in such an embodiment the description of 10 other parts of PHTS 100 apply, ~ub~ ..l;.,sJ the word "fluid" for the word "blood," when the context of the ECC 300 ll~ ...,..1 is of other than blood. In another such embo~limrnt the cerebrospinal fluid cavity is treated. Thus, circulation oftreated (e.g., by hG~uini;~lion, electrolyte adj~;l",- -,t chemotherapy, oxygenization, he~ting, cooling, filtPring, light, irr~ ti~m, 15 r~lin~rtivity, etc., by ECC 300) fluid into and from the peritoneal abdominalcavity or other body cavity of patient 99 (i.e., not within the circulatory system), as well as circulation through the blood system of patient 99, is specifically colltGlll~lated within the scope of the present invention. In one such embo~lim~nt, drugs (e.g., cancer chemotherapy drugs) are added to the fluid or 20 blood (e.g., to effect a combined heat/drug ll~ ~I"~r"l Wh~,.Gill the synergistic effect of the heat and drug therapies is desired to treat, for example, a stom~rh cancer which may have spread to the peritoneal cavity).
In another embo-lim~?nt individual organs (or portions of the body) are treated "in situ" in the body of patient 99. In one such embo~lim~nt the organ to 25 be treated is isolated from the circulatory system of patient 99 (via, e.g., laparoscopic andlor endoscopic surgical techniques via the peritoneal cavity), and perfused from and to PHTS 100 to treat isolated ~ eA~es (e.g., hepatic carcinoma). Figure 2E srhrm~tiç~lly illustrates an eY~nnpl~ry perfusion system - 400 used to effect such a single-organ perfusion hyperth~rmi~ of patient 99. In 30 one such embo-lim~?nt one or more clamps 95 (such as intra-abdominal vasculartourniquets) are placed on both an artery 97 (such as the hepatic artery) and a WO 97/06840 PCT~US96/11476 vein 96 (such as the portal vein) for an organ 98 (such as the liver) of patient 99, and canulae 410 and 420 are used to withdraw blood for trç~tment by ECC 300 and to perfuse the treated blood back into the organ 98, substantially as sehem~tically shown. One or more ld~ sco~ic incisions 90 and/or endoscopic 5 openings (such as the throat or rectum) are used in one embodiment to facilitate access for such a trc~tment Monitoring system 200 is used to monitor the organ 98 and/or the rest of patient 99 as shown in Figure 2A, and computer system 1 10is used to control the tre~tm~nt as described above for Figure 2A.
In yet another embodiment, an isolated (i.e., removed from the body of a 10 donor patient) organ (such as liver, kidney, pancreas or heart) is individually perfused and/or pretreated by PHTS 100 prior to implantation into a new patient 99. In one such embodiment, PHTS 100 is used, not to pe.ro~ hyperthermia trç~tmen1, but to m~int~in the removed organ in a state which rni1xi---;,~s viability of the organ for later impl~nt~ti~n; and in one such embo~1irnent PHTS15 100 is used to effect hypothermia and/or o~yge-ldLion of the isolated organ.
Figure 2F shows a sc1~ ;c of the thermietor electrical supply circuit 2300 used in one embodiment of PHTS 100 to supply regulated voltage pulses to thermietere in the t~ ldlu~e sensor probes 201-203. In order to reduce self-heating ofthe thermieters which would reduce the accuracy ofthe telll~.dlu 20 measu-~.--ents, and to reduce the electric~l hazard of possible leakage ~;Ull~
from th~rmietere which are threaded into a blood vessel or otherwise implanted or in contact with patient 99, one embodiment uses short-duty-cycle pulses to drive th~rmiet~re 201-203 as shown in ~Prnpl~ry circuit 2300. One embodiment uses a CMOS ripple counter 2304, such as CMOS part number 74HC4020, to 25 divide a DCLK signal which has a cycle time of ap~-o~ ely 139 nanoseconds to ge.l~.dle a Q12 signal with a cycle time of appro~im~tely 573 microseconds.
The Q12 signal is inverted by inverter 2306, such as CMOS part number 74HC04, to gen~.~Le the active-low signal ERR, which in~ t~s to colll~.
system 110 that the th~rrnietor pulse is too long (an error condition which 30 g~...,.l~s a safety alert). The falling edge ofthe ANALOG POWER signal (generated under software control by computer system 110) allows counter 2304 to start, and Q12 will remain low a~plo~illlately 573 microseconds afterwards.
Gate 2308, such as CMOS part number 74HCT32, will generate an active-low signal BLNK starting on the falling edge of the ANALOG POWER signal, and ending on the next rising edge of the ANALOG POWER signal or the rising 5 edge of Q12, whichever is first (thus Q12 stops the BLNK signal if the ANALOG POWER signal remains active too long). High-current driver 2302, such as Fujitsu part number UCN581 lA, provides a current pulse, sequentially, one at a time, to a plurality of precision voltage regulators 231 through 233 (asepdlaLe precision voltage regulator for each th~rrnietQr used in L~lllpel~Lul~,10 probes 201-203). By limitinp the RMS current, for example to a 1/2 milli.eecond or shorter pulse once per second or longer, the risk of serious injury or death to patient 99 can be reduced. The current pulse is sent as long as the BLNK signal is active to a selected one of the plurality of precision voltage regulators 231through 233, such as National Semiconductors Corp. part number LH0070. The 15 CLK input signal to driver 2302 is provided by collllJul~,~ system 110 to select the next sequential one of the plurality of precision voltage regulators 231 through 233 for the next pulse. (In one embodiment, a specified plurality of CLK pulses are sent to select a particular one of the precision voltage regulators in order to measure a particular Lcn~.dLu.~ probe, e.g., 201, 202, or 203.) For 20 example, a pulse generated on output O1 of driver 2302 is coupled to precision voltage regulator 231 which generates a precision voltage l~ r~ .~ .lce for a th~rmietor used in temperature probe 201, such as thlormietor model number 100-44033-1.5-RPS-NA/NA-12-ST made by Yellow Springs Instr lm~nte, Inc., of Yellow Springs, Ohio, phone number 1(800)765-4974. The reslllt~nt signal is 25 coupled by mux 121, such ~ part number CD4051, to A/D converter 122, such ~ Crystal part number CS5031 for conversion to a digital signal which is then coupled to culll~uLel system 110.
Figure 3 shows a srh~m~tic of a portion of electrical subsystem 700 int~hl.ling sensor and control cnn~tne and configuration for one embodiment 30 of ECC 300, monitoring system 200 and coll-puL~ l system 110. In one embo~lim~nt moniLolillg system 200 provides additional sensor probes for mP~nring various parameters of patient 99, which provide monitoring and control in addition to the probes of ECC 300 as shown in Figure 3. In one embotliment, each analog signal (each ,.,~.~se,.l;..g a se~dldL~ physical ~ t~
which is being llle~,ul._d such as p,~S~,Ulc;, flow rate, or telllpeldlul~,) is fed into S one or more multiplexor ("mux") 121, such as a CMOS CD4051 part, within int.orf~f~e circuit 120. The mux 121 sequentially couples one analog signal at atime to an analog-to-digital converter ("A/D") 122, such as a Crystal CS5031 part, also within interf~çe circuit 120. The A/D 122 converts each analog signalinto a digital value ~ st;llLdlive of the value of the physical parameter being 10 measured, and couples this digital value to co",~uL~. 1 1 1. Thus, analog signals are converted to digital values for procee~ing by digital colll~ 111 in a manner known in the art. Parameters which are measured directly by digital signals, such as the on-or-off states of circuits or the pulses which in~liç~te the speed of a motor, are buffered in buffer 123 on interf~-e circuit 120 (and in the 15 case of motor pulses, acc--nn~ ted into a pulse total over a short period of time) and coupled as digital values to co",~uL~, 111 in a known manner. Once the measured p~r~m~ters are processed by software 500 running in CU111~JUI~L 111, control signals are sent by computer 111 to d~-up.iate and known driver circuits124 on int~.rf~r.e circuit 120, which drive control signals back, for example, to 20 turn on-or-off blood pre-conditioner 310, control the speed of blood pump 320, control the heat gain-or-loss of heat ~xeh~nger 330, control the amount of ~yg~ldlion provided from blood post-conditioner 380, and/or control the heat gain-or-loss of water-c~ n-litic~ning sub 7y ,1,_.l1340.
The sensor probes of ECC 300 include probes 315 and 316 at the blood 25 input and output points"e;,l.e~;lively, to blood preconditioner 310, probes 325 and 326 at the blood input and output points, le~e~ilively, to blood pump 320, probes 335 and 336 at the blood input and output points, respectively, to heat ~-xrh~nger 330, probes 345 and 346 at the water input and output points, respectively, to water-conditioning subsystem 340, and probes 385 and 386 at 30 the blood input and output points"~ e~ilively, to blood postconditioner 380.
The sensor probes of ECC 300 include, for example, devices for mç~cllrinp the WO 97/06840 PCTrUS96/11476 ~les:iul~, in the blood circuit, the speed of and/or blood-flow rate through blood pump 320, the leml.~.dlulc gain of blood through heat exchanger 330, the fluid level of water reservoir 343, the tt;~ .dLule of the water exiting water heater 350, the speed of water pump 370, and whether there are bubbles in the blood S circuit.
In one such embo-lim~nt a first sensor measures a parameter of the blood at the ingress to a treating device, a second sensor measures that parameter of the blood at the egress from the treating device, and the two signals provide input to colll~ulel system 110 which is controlling the tr~tm~nt device, in order to 10 provide a closed-loop control system to tightly control the p~r~meter of interest.
For example, in one embo-liment probe 335 includes a first sensor mP~cllrinp blood l~ n~ at the blood input of heat ~ch~nger 33o~ and probe 336 inchl~les a second sensor measuring blood tc~ ,.dLul~ at the blood output of heat e~ch~nger 330; together, probes 335 and 336 provide co~ ul~,l system 110 15 with the output tt;lllp~,ld~ and the l~lllp~ldlule change across heat exch~ngt-,r 330, which in turn regulates water heater 350 or water cooler 360 to adjust the amount of heat flowing into or out of the blood, lc;s~e~;liv~ly~ and additionally monitors whether heat ~,cc1l5.. .gel 330 or any associdLed part thereof has failed.
In one embodiment, a zero-crossing ~letector and switch, such as a TRIAC, is 20 used to switch heater 350 on and offat the zero-crossing point of the 50/60 Hz power supply current in order to ~----~ electrical ~c~,Llulll noise which would otherwise result if the heater were ~wil~;hed on or off at a time other than at the ~ro crossing of a power cycle (in one embodiment, the TRIAC is turned on at s~lbst~nti~lly the "zero voltage cross" time and is turned offat subst~nti~lly 25 the "zero-current-cross" time). In one embodiment, a control interval of 1/6 second (i.e., ten AC cycles) is used for the software which controls the pl'UpOl Lion of "ON" versus "OFF" cycles of the current sent to heater 350.
According to the present invention, the software 500 running in colll~uL~,llll uses a nurnber of temperature parameters, including absolute t~ ~ . .p~ s in 30 various locations in the patient's body, tt;lll~ ldtU~c di~l~;lllials b~;Lwe~ll those various locations, rates of change of tc;lll~J~ldlules at those various locations, and/or the t~ dlul~ rise or fall across the heat exch~nger to control the heat added to or removed from the blood. In addition, various other parameters (such as oxygen col~ulll~lion, CO2 levels in the blood or exhaled breath, or other factors) can be analyzed by computer 111 in order to control the heat or other S L~ elll of the blood passing through ECC 300.
In another similar example, probe 385 includes a first sensor me~curing blood oxygen at the blood input of blood post-conditioner 380 in an embodiment which includes a blood oxygell~lor, and probe 386 in~ lec a second sensor , . ~e~c. l.; 1 Ig blood oxygen at the blood output of blood post-conditioner 380;
10 probes 385 and 386 provide Colllp~lltil system 110 with the output oxygen content of the blood and the oxygen-content change across blood post-conditioner 380, which in turn regulates blood post-conditioner 380 to adjust the amount of oxygen flowing into the blood, and additionally monitors whether blood post-conditioner 380 or any associated part thereof has failed. In other 15 embo~imlontc, the parameters measured and controlled by probes 385 and 386 and post-conditioner 380 include carbon dioxide, pH, and/or electrolytes.
In one embodiment, probe 386 includes a bubble ~let~ctor 333, such as an ultrasonic tr~nccl~lcer, which colllhlually monitors the blood path at a point near the egress from ECC 300, at a point just before the blood is returned to patient20 99, to detect any bubbles which may have entered the blood at any point before or within ECC 300. In one such embodiment, a bubble will cause a change in the echo signal of the ultrasonic tr~ncduc~r, thus indicating the presence of the bubble. In one such embodiment, blood post-conditioner 380 includes a bubble trap which removes any bubbles which may have entered the blood. In another 25 such embo-lim~ont, heat ~ h~n~er 330 inrluclec a bubble trap which removes any bubbles which may have entered the blood. In one such embodiment, such a bubble trap col"p, ;~es a subst~nti~lly vertical tube and/or çh~mber having a closed or closable end, and another end connected at subst~nti~lly right angles to a substantially hol;;~ll~l portion of the blood path such that as the blood passes 30 through the hcsliGulll~l path, any bubbles will rise into the vertical tube and thus be removed from the blood being returned to patient 99.

ECC 300 comprises blood tubing 302, optional blood pre-conditioner 310, blood pump 320, disposable blood-pump int~rf~e 321, heat çxch~nger 330, disposable heat-~o~cch~nger int~rf~-e 331, optional blood post-conditioner 380, and water-conditioning subsystem 340. Water-conditioning subsystem 340 S c~ mpriees a water circuit including water reservoir 343 (colJne~;lt;d via T-c~ ;lor 344), water heater 350, water cooler 360, and water pump 370. In one emboAimPnt water l~se.~/oil 343 is deeigneA to ...i.~ the amount of water (and thus the thermal mass) within the heating and cooling circuit, and thus ~tt~rhPs to water reservoir 343 via T-connector 344 in order to keep the thermalmass of the water in water reservoir 343 out of the heating and cooling circuit loop. In one embodiment, water reservoir 343 compri~es a water-high and water-low level sensor 342 of suitable conventional design which detects whether any fluid is added (for inet~nce due to a leak from the blood circuit into the water circuit) or removed (for inet~n~e, due to a leak of water out of the water circuit) from the water circuit. In one embodiment, water pump 370 is located within water-conAiti- nin~ circuit 340 so that it pumps water out of heat exch~nger 330, through water pump 370, and then through the rest of water-conditioning system 340, in order that the water ~ in heat PYchz~ng~r 330 is lowered (relative to other systems in which the outlet of the pump is c~ ed to the inlet of the heat ~xch~nger, thus increasing water pl~ in the heat x~h~nger). By having lower water ~Jle;,~ than blood ~ Ul~ within the heat ~x~ h A. ~g~ ~ 330, safety is hlcl~a3ed (in the possible event of a leak) since blood will leak into the water, rather than the water leaking into the blood and c~ ";"~l;"g the blood. In one such emboAim~nt the water circuit includes at least one clear section in order that any leak of blood into the water can be observed by the user of the system. In another such embodiment, a photoAetect~r is inclllded to automatically detect such discoloration and ~S/;;llt~ldlt~
a signal for collllJuh,. system 110 to report such a leak of blood into the water circuit.
One pl~r. .ll d embodiment uses water as a heat-exch~nge medium in a water-conditioning sub~y:ilelll 340. Another ~lc;Çt;lled embodiment instead uses air as the heat-e~ch~nge me~ m within conditioning system 340, with corresponding heat addition or removal operations and failure detection being performed, as with the water of a water-conditioning subsystem 340. It is to be understood that other heat-~ch~nge media are preferable in other embo~limentc, 5 and that while the description below is limited to a /li~cll~ n of water as t_e heat-e~rrh~nge medium, the invention is not limited to only water as a heat ~-xch~nge me~ m In one plere~ d embodiment, disposable circuit 301 compri~es all parts of ECC 300 which come into contact with the patient's blood, is disposable and 10 is ~le~ign~l to be highly reliable, easily sterili~d, easily assembled to the rest of ECC 300, to hold a relatively low volume of blood, and to be relatively low-cost.
In one embodiment, the volume of blood in the blood circuit is ,ni..;.,.;,e-1 inorder to ...;..;...;,.~ the amount of blood outside the patient. In one such embodiment, such minimi7~tion is provided by keeping the components in 15 disposable circuit 301 as close together as practic~l, and ~rr~nging the orientation of the components to . . ~ r! the length of col~e~;lhlg tubing. In one embo-liment the parts of disposable circuit 301 are made of clear, bio-compatible plastic which facilitates observation of the blood traveling through PHTS 100, and allows visual detectil n of faults. In the ~l~r~ d operation, 20 disposable circuit 301 is filled with sterile saline as part ofthe start-up process, and this saline is pulllped through the o~cldlillg ECC 300 to verify that all components of ECC 300 are functional, all immPrii~tely before the patient is ~tt~-~heA to perfusion hyperthermia L.~ -l system 100.
In one embodiment, perfusion system 400 comprises canulas 410 and 25 420 in order to effect extracorporeal circulation and tre~tm~nt of t_e blood of patient 99. In one such embctiiment~ as shown in Figure 2A, canula 410 is threaded into a femoral vein to a point relatively near the heart, and withdrawsblood for conditioning and tre~tment (e.g., by hep~rini7~tiQn, electrolyte adjnctment chemotherapy, oxygeni7ation, he~ting, cooling, filtering, light, 30 irradiation, and/or r~lio~ctivity, etc.) by ECC 300. The withdrawn blood is then returned to patient 99 through canula 420 into another femoral vein at a point WO 97/06840 PCT~US96/11476 relatively distal to the heart. The returned blood is then circulated throughoutpatient 99 by the patient's native circulatory system and heart. This warms the body tissues, and, in the end, will warm the lyll~hdlic fluid (which is not connPcte~l to the cardiovascular system, but runs in parallel), and other S non-circ~ tin~ fluids. The c~l~blo~ al fluid, otherwise known as central ~c;l ./~us system (CNS) fluid (the fluid that is in and around the brain and spinal column, particularly massed within the cerebral ventricles) also will be warmed.The control parameters are stored in co~ r system 1 10 and are used to target a specific and sellectable blood Iclll~cldLulc which targets a selectable body 10 tel,l~,~ lalu~e. The end point may be the body Ielllpcldlulc of 43.5 ~C, for example, which then warms the cerebral spinal fluid, and of course, the brain. In one embo~limtont fail-safe procedures and ",e~ ."c in software 500 provide and Ill~ nil~ a given, select~hle tennrer~tl-re di~ lel,Lial (typically less than 4~C, but in some cases as much as 8~C) between the water tClllp~.dlul-~ and the blood15 k~ ldlulc- in heat P~h~nger 330; and a IllnX;IIIIIIII telllpcldLulc ~ii~,.~,l~Lial (which may be preset at 8~C, for example, but which is also user-selectable/changeable) between the blood Iclll~,ldLul., and the body lclll~ laLul~.
Tympanic lcll~ Idluie3 are l--oniLol~d to control an absolute l~lllp~ldlulc no greater than that of the body-core 1~ l ll ." and also to control the ~li~elel.Lial 20 between the left lymp~fic or right lylll~culic, to make sure that those lelllp~ldlul~ s differ by less than 1.3 ~C.
One ~u,~ose for ~ g the treated blood at a location distant from the heart is to allow any heat added to fully mix with other venal blood and to partially r~ ir~te into the body core of patient 99 before the warmed blood 25 reaches the heart. This particular ~lcf~l~cd veno-venous perfusion arrangement is for illu:iLlalive pu,~,oses, and other arrang~lll~lll~ for withdrawing blood from either arteries or veins, and letl . . ~ g blood to either arteries or veins arecontemplated within the scope of the present invention.
Figure 4 shows a concc~ al flow of moniL-"",g and control between 30 some of the software modules within one embodiment of software 500. The software body profile/model 450 models how a particular patient will react to ; CA 02229138 1998-02-10 WO 97/06840 PCTrUS96/11476 tre~tmPnt (e.g., taking into account the patient's body weight, surface area, circulatory characteristics, heart rate, cardiac output, and other medical characteristics to provide a profile of how the patient's Le~ cldLulc will change as a result of a particular volume of blood at a particular tclll~,.dLIIlc being5 perfused into the patient), and the desired rates of telll~cldLulc change, absolute-t~ J. .dLulc targets, heart-rate limits, blood-l,lc~ule limits, and/or cardiac-output limits. Body parameters 451 from body profile/ model 450 then provide a colllllland input to the blood model 452 to help control how heat will be added or removed from the blood within the heat exchanger 330; blood model 452 uses 10 I,d d,~leters such as the known thermal coefficient of blood, the measured cardiac blood-flow rate, any blood-volume expansion, the known volume of blood in the ECC 300, and/or the measured flow rate of blood through the ECC 300. Blood par:~metrr~453 from blood model 452 then provide coll.,lland input, along with c~lvirol~llentp~r~metrr~4ss from the ~Ytrrn~l cllvhul~llcllL (such as the ambient 15 air l~. . .p~ . e~ if fan cooling of the water circuit is used), to the water model 454 to help control how heat will be added to or removed from the water within the water-con-litioning ~ub~y~Lclll34o. Other p~r~meterS used by the water model 454 include the volume of water in the water circuit (i.e., its thermal mass), the known . .~J. x i, . . -. . " power capacity of heater 3 50, and/or the known fan speed of cooler 360. Water p:~r~meter.~457 from water model 454 then provide colllllla~d input to the plant model 456 of how heat will be added to or removedfrom the blood, overall, by ECC 300. Plant model 456 in turn measures t~ .f ~ ~l I ll cs throughout PHTS 100 and provides f~ eclb~rl~ parameters 460 (for example, inrlir~tinp the various body tclllpclaLul~s)~461 (for example, in~lir~ting the blood telll~cl~lulcs and their rise or fall), and 462 (for example, indicating the water telllpC~ldLIll~. and its rise or fall through the heat exch~nger 330) into each of the other models, as shown in Figure 4.
In one embo~1im~?nt referring to both Figures 4 and 5A, continuous self-test module 506, water-lelll~,.d~ monitoring mûdule 507, blood-monitoring 30 module 510, and body-tclll~ . .dLulc-monitoring module 514, are parts of plant module 456; water-telll~. .dLulc-control module 508 is part of water model 454;

W O 97/06840 PCTrUS96/11476 blood-tc.l.~,.dLulc-control module 512 is part of blood model 452; and body-te --pe.dLu c-control module 516 is part of body profile/model 450.
Figure SA shows, for one embodiment, the major software components of software system S00 which run on computer system 110 and how they are ~ S invoked (or turned on and off) over time during a typical perfusion hyperthermia tre~tm~nt In one preferred embo~lim~?nt, each software component compri~es a task (or "job") which operates in a mllltit~c1~ing e..~dlolllllent in colll~ul~..lll.
In one such embo-lim~ont colll~ulcl system 110 comprises computer 111, which is a dedicated co;ll~ul~,. board based on a high-performance Intel or Motorola 10 microprocessor and coupled to interface circuit 120, and which Co~ .iC?teS
with an çxtt?rn~l personal CO111~UL~,1 170 providing input device 130 and outputdevice 160 functions, as shown in Figure 2A. In the embodiment shown in Figure SA, software system S00 comprises the following cc,lllpol-ents:
input/display module 560, power-on self-test module 502, operator start-15 procedure ch~c~ t module 504, continuous self-test module 506, water telllpcldLulc moniLolillg module 507, water-telllpl ~dLur~-control module 508, blood-monitoring module 510, blood-telllpcldlulc-control module 512, body-~enl~dL~ , monitoring module 514, body-tempe.dLul~-control module 516, tclll~,.dLu e-stabilization module 518, body-heating module 520, ...~
20 body-tclllpe.dLu e-at-target module 522, body-cooling module 524, body-temperature-stabilization module 526, operator blood-flow-rate adjllctmPnt module 528, and opcldLol end-procedure chPc~ t module 530.
The input/display module 560 has input/output functions including 1) acquir~ng user input, 2) gcll~.d~hlg continuous, real-time data display, and 3) 25 real-time data storage. This module is responsible for generating applupl;atedisplay information for the operator, acquiring and h~tc.~l. Ling o~,~.dLor input, and logging a~plu~liate information for further analysis. The stored data can betransferred to a removable lllediulll for postoperative analysis.
In one embodiment, input~display module 560 provides for control over 30 one or more of the following functions:
a) ch~ckli~t input - asking for, receiving, and processing user input W O 97/06840 PC~r~US96/11476 b) parameter-value selection - allowing the user to specify which parameters are measured and to specify limits for control of those p~r7lmet~rs c) display-data selection - allowing the user to specify which data are to be displayed and the display mode (graphical versus textual, differential versus absolute, and/or scaling, etc.) d) annotation selection - allowing the user to add annotations or expl~n~ti~ nc of events to the data being recorded e) audible-warning override - allowing the user to specify the sound associated with some or all warnings to be enabled/disabled and/or the volume or type of the sound to be adjusted. In one embo-1iment, alarm conditions should always cause an audible alarm regardless of the state of switch or parameter settingS; and the alarm tone should continue to sound until the condition is acknowledged by the ope.dlol.
f) flow-rate adjll~tment - allow the user to make adiu~tment~ to the blood-pump flow rate.
g) manual control - allowing the user to adjust and control various system col--pollents, with subject-(i.e., patient 99) and operator-safety aspects still being monitored by colllpul~,l system 1 10. In one embodiment, input/display module 560 disregards the manual-override setting if it could cause a condition hazardous to patient 99. In one embodiment, input/display module 560 continues to monitor absolute subject safety limits while operating in manual mode and limits the system outputs of PHTS 100 in a manner d~pr~ ~-;ate to any hazard ~letectecl In one embodiment, manual overrides are provided for the following:
1 ) Water pump (WP) automatic/of~on 2) Heater automatic/off/on 3) Fan automatic/off/on 4) Blood pump (BP) automatic/off/rate 5) Emergency shutoff(BP, WP, heater, fan). In one embo~liment, a CA 02229138 1998-02-lO

'pull to shut off emergency shut off switch is provided on the disposable face of the unit. This switch is capable of cimlllt~nloQusly stopping the blood pump, water heater, water-cooling fan, and water pump.
Power-on self-test module 502 checks for proper operation of components which comprise or are conn~ctrd to computer system 110, including ch~-r~ing the existence and functionality of the co~ Lt~ and its cc,lll~ollents, the interface electronics 120, and all ~tt~rh~d sen.cQnc Continuous self-test module 506 is then started, and continuously verifies proper function of 10 all sub ,~Lellls of PHTS 100. Operator start-procedure ch~?rl~lict module 504p~lrOlllls an i..~ Li~e operator checklist and eql-ipment check, intrr~Gtively and/or 2qlltom~tically verifying (a) that PHTS 100 is plopelly set-up, (b) that all sul~y~L~,~lls lc-luih;llg setup and checks for proper operation have been so pl~aled and ch~cl~cl (inrluf1in~ the input devices 130 and output devices 160 ofcomputer 170, mounting of disposable parts of ECC 300, confirmin~ tubing positions and flow directions, and water levels), and (c) that the patient is prc,~ lly ~l~pdl~ed ("prep'ed") for connection to PHTS 100. In one embodiment, this rhrr~lict is implemçntçd as a one-way chrrl~lict which lCi~lUil-,3 the operator or user to start a particular series of ch~rl~li ct procedures (or the entire checklist) from the beg;.~ (rather than being allowed to backup a little bit in the ch~rl~lict), in order to ensure that certain procedures which should be performed in a certain order m~int~in that order. Continuous self-test module 506 then continuously verifies cnntinlled proper function of all subsystems of PHTS 100, including ch~r~hle items which may have been co~ or started from the operator r.hçr~lict Water-L~ .dlulc-monitoring module 507 then starts, and measures water t~ dLUlC, ~ Ul~" and level. Water-l_lllpeldlulc-control module 508 then starts, and turns on the water pump, sets a target (preset) preheat t~ clalulc, and monitors and controls operation of the h~ting, cooling - and ~.Ulll~illg of water through water-conditioning sub:~y~L~.ll340~ Blood-moniLollllg module 510 then starts, and monitors some or all parameters of the blood (for inct~nre temperature at various points in the system of PHTS 100, WO 97/06840 PCT~US96/11476 pres~ulc~ flow, pH, oxygen level, level of any drugs that may have been added, and/or leakage, etc.). One output of blood- monitoring module 510 is to a display in output device 160 to inform the operator of the measured parameters.
Another function of blood-mol.ilol;llg module 510 is to confirm the ~ p~ld~UlC-S probe filnrtinn~lity. Blood-lt;---p~,.dLu-e-conkol module 512 controls the telll~,.dLulc of the blood as a function of the L~lllp~ldlul~s detected by blood-mo~ilo~hlg module 510. In one embodiment, before patient 99 is c-)nn~cted to PHTS 100, the functionality is checked by circul~ting sterile saline through ECC300 and verifying that heat can successfully be both added to and removed from 10 the saline. Body-tcl..peldLulc-monitoring module 514 is then started, and monitors the t~ ,ldLules, rates of change of l~ cldLulcs, and differential tc~llpeldLulc~ within patient 99. Body-telllpeldLulc-control module 516 providesadditional controls to blood-t~,...p~ldLu c-control module 512 in order to effect proper body-te...~,.,ldlure profiles, rates of change, and absolute Lt-ll~,ldlul~.
The perfusion hyperthermia tre~tment itself is then started, cornprieing modules 518-526. Tc;~-p~,ldLulc-stabilization module 518 measures and verifies proper initial stable body tt;lllp~,ldLulc of patient 99 as part of body-te~ dLulc control module 516, starting at time t. and ending at time tb (see Figure SB), this module assures that the patient is stable within c~tief~l tnry limits (e.g., at a 20 "normal" tcllllJcldLul~ of, for example, 37~C), assures that all initial parameters are within proper limits, d~l~ ....i..es which probes may have fallen out or failed and whether the tre~tment can be co~ , and provides a set of b~e~line and average tr~l.p~ cs (and other me~ellr~hle p~r~metl?re) for algorithm control.
Starting at time to (see Figure 5B), body-heating module 520 measures and 25 controls proper heating Lt;lll~cldLulc rates-of-change as patient 99's tclll~,ldLulc, is ramped up to the desired tre~trnent telllp~,ldlule. Starting at time tc (see Figure SB), m~ i,,g-body-teml~cldLu~c-at-target module 522 measures and controls proper tre~tment-stage body t~ . . . c (for example, stabilizing patient 99's te~ ;ldlulc at a tre~tment telll~cldLulc of 43.5 ~C for some amount of time, for30 example, for 20 min~tes between time tc and td (see Figure SB)) as part of body-t~lllp~,ldLu-c-control module 516. Starting at time td (see Figure SB), body-WO 97/06840 PCTrUS96/11476 cooling module 524 measures and controls proper cooling tenlp~,.dLIlre rates-of-change, cooling the patient back to a "normal" te;lllp~ldL~e at a controlled rate of tell,~.,.dLu,e change, as part of body-ttl"~.~,.dLule-control module 516. Starting at time te and ending at time tf (see Figure SB), body-telll~,.dLu,~-stabilization ~ S module 526 then measures and controls proper post-trÇRtm~nt le~
stabilization, ~,~.;ryillg that the patient has indeed stabilized at their normal tt;llllJe.dlUle, as part of body-t~ p~ldLI~re-control module 516. O~ldLor blood flow-rate-adjll~tment module 528 allows the operator to set blood-flow rates within parameter limits set by the software, and, if necÇ~ . y, to override those limits; this module also provides the operator with the capability to adjust allother thresholds and limits, such as rates of temperature change, water flow rates, etc. Operator end-procedure çh~r~ t module 530 elicits and receives operator input as to operations which must be performed and verified at the end of trçRtment such as R~llring that the data has been succcc~fully written to mRgnPtic media from data output device 163 (such as rlicl~ett~c)~ ~csllring proper disc.~..l;....i.li~ n of metlicRl treRtm~nt (such as l,~,~ru:jion of a volume of blood to colll~e.lsdL~ for blood left in the ECC 300), and logging total perfusion time, peak and average body and tympanic t~ .aLu.~,s.
Perfusion hyper/hypoth~rmiR tre~tm~nt system (PHTS) 100 is ~1eSigne~l to pe.ro",l whole-body hyperthermia ~lldco"-oreal circulation (WBHT-ECC), systemic perfusion hyperth~rmiR tre~tmPnt (SPHT), or i"ll~e,;Loneal perfusion hyperth~rmiR treRtm~nt (IPHT). In one embo~lim~ont PHTS 100 is to be incorporated into the o~.dLiilg room environment and will be part of the system for controlling and supporting the subject. One view of PHTS 100 co. ~ es sorLwdie subsystem 500, me~hRnicRl subsystem 600 which co~ e-;L~ to patient 99 and moves the blood (or other fluid) from patient 99 through ECC 300 and perfuses the blood (or other fluid) back into patient 99, and electrical subsy~L~,.
700 which pelr~lllls the moniLo~ g of pRrRmtoter~ and control of the trçRtment - In one embo~lim~nt the PHTS 100 provides an interface directly with a disposable subsystem 301. The meçhRnicRI subsystem 600 includes a chassis that provides the ~ttR~hment support for system interface 390 (into which is WO 97/06840 PCT~US96/11476 plugged the disposable subsystem 301) and encloses the majority of the electrical subsystem 700.
Figure 5C illu~Lldles a patient and system tClllp~ldLulc model used in one embodiment of PHTS 100. (Note that, unlike Figure SB, here Ta through Te S represent tclllp~.dlLlre differences rather than time reference points.) Tc-l-pc-dlulc~ Tl through T10 re~ ,sc..L various telllpcldlul~ measured throughout monitoring system 200 and ECC 300. In this model, Ta rc~l~,sclll~
the difference between T4, m~ ring the right LyllllJdllic tClll~ dLulc, and T5, me~cllring the left tympanic Icllll)cldLu,c. It is thought hllpolL~ to closely 10 control the absolute Lclllp.,ldLwc reached by T4 and T5 and to ~ e the difference Ta. In one embodiment, telll~cldLu~cs Tl, T2, T3, and T6 are averaged together to calculate an average body-core tCll~ dlUlC; T4 and T5 are averaged together to calculate an average brain tclll~claLulc; and Tb is calculated as the difference between these two averages. T7 is the blood l~ ldLulc at the 15 blood inlet to heat ç~eh~nger 330, and is generally equal to the average body-core lelll~,.dLulc. T8 is the blood tr.ll~ .c at the blood outlet from heat exchanger 330, and Tc is the difference between this and the average body-core tclll~ldLulc. Td is the lclllpcldLulc difference between T9 (the lclllpeldlul~, of water Pntçring the heat eY~hi1llge. 330) and T7 (the tclll~,ldLwc of blood entering 20 the heat çyeh~nger 330). Te is the tellll~.,ldLul., difference bcLwccll T10 (the Lclllp~.dLulc of water leaving the water heater/cooler 350/360) and T9 (the telllp~ Lu,., of water entçring the heat ç~ch~nger 330). In one embodiment, software 500 uses pre-içt.-rmined p~r~mPters as "~;ix;l"..." limits for Ta, Tb, Tc, Td, and Te, and controls heat addition/subtraction from the water in order to 25 keep these tc.ll~dLulc di~.-,nces within the specified pre~lçtermined limits. In one embodiment, the amount of heat added or subtracted is controlled at least inpart by the amount of tC~ CldLulc differential between the water (or other heat-h~nge me-lillnn) and the blood within heat exchanger 330 (i.e., a greater LclllpeldLulc di~,~,.lLial is used to transfer a greater amount of heat to or from 30 patient 99, a lesser temperature di~ ,.lLial is used to transfer a lesser amount of heat, and the t~llp~ldLulc differential is reversed to reverse the direction of heat W O 97/06840 PCTrUS96111476 transfer). In another embo~iment the blood-flow rate is varied in order to vary the amount of heat L~d l~r~ ll.,d. In yet another embodiment, both tt;llllJGldlul~
dirr~.~ .lLial and blood-flow rate are varied in order to vary the amount of heat transferred.
S Figure 6 illu~lldlGs an exemplary display screen usable with a mouse-type point-and-click input device 130 or a touch-screen input device 130 for one portion of the soft~,vare-controlled user-interactive start-up procedure cherl~lict Figures 6 through 13 1~nGSG11l screen displays for one embodiment; other embot1imentc include ~cl~litiQn~l fields, or remove certain fields from the displays shown. Option menu 606 l.,~ ,selll~ a typical "Windows"-type drop-down menu hll~.rdce which has been modified specifically for PHTS 100 to in~lir,~ts to an operator various submenus available. In one embodiment, one or more of the following submenus are available: a "file" submenu which has a plurality of fileco~ 1c such as "new", "open", "save", "save as", "print", and/or "exit" which operate in a manner f~milislr to windows users; a "create" submenu which has a plurality of create comm~n~lc such as "create new file" (which creates a new data file), "create new log" (which creates a log file for logging ~a""~rterc ~e~iflable by the o~ alur), and/or "create new record" (which creates a new patient record); an "edit" submenu which has a plurality of edit comm~n-lc such as "cut", "copy", and "paste" which are f~milizr to windows users, and/or "annotation" which allows the user to add an annotation (in one embodiment, a text annotation is provided, v~/llclc;n the user types in a textual annotation using a kGyl~o~ud, in another embo~liment a voice annotation is provided which allows the user to record a voice lGc(j..lillg of the annotation desired in a manner known 25 to the mllltime~ computer art) to a particular event (e.g., if an llmlell~l event occurs during the surgery l.c~ the doctor or perfusion technician can have a textual annotation typed in or voice annotation recorded and added to the datalog kept by computer 11 1, thus explaining the co~litic~ns present at the event which may not be evident from the measured and recorded par~mefl-re alone); a "view" submenu which has a plurality of view co.. ~ le such as "show graphical view" (which changes the display mode to a mode which ~lGsel.l~ data in a graphical manner), "show textual view" (which changes the display mode to a mode which PIGSG1It~ data in a textual or tabular form), "select parameters tograph and co.llpa G" (which allows the o~ldlol to choose which p~r~meters are displayed and/or compared), and/or "select parameters to compare" (which allows the operator to choose which parameters are culllpdl~,d); an "options"
submenu which has a plurality of options comm~nrlc such as "monitor only"
which directs PHTS 100 to only monitor parameters (such as tGl~ dLulG) without attempting dulollldlic control, "monitor and control" which directs PHTS100 to monitor ~n~l autom~tically control the measured parameters to a specifiedprofile, "cim~ tion" which directs c~ ,uL~" 111 to ~iml~ e aperfusion hyperthermia treatment session as if a patient with specified attributes were conntoctecl to PHTS 100 (used for developing software and user int~ cçs of PHTS 100), and/or "training" which also directs co---~uh,, 111 to ~imlll~te a perfusion hyperthermia tre~tm~nt session as if a patient with specified attributes were cl-nn~ct.od to PHTS 100 and also provides explanatory text to explain to the user what is hd~pGllillg and medical background lcga.-lillg certain parameters and how they change and what it means when they change in a certain way, and also measures operator .~ onses and timing to particular ~imnl~tçrl emergency events (used to train m~1ic~1 personnel as to the use of the m~hin~ and what to do in exigent situations -- such as if the patient might "go critical" in the middle of an operation); a "prGr~,Gllces" submenu )which allows the user to ~;U~lollli;~G
the plrS~ ;on of data and the user input/output interface); and a "return!"
submenu (which imm~ tely returns the user to the just-previous menu or display mode) Title field 608 displays an indication (viz, "WATER CIRCUIT
CHECKLIST PAGE 1 OF 8") of which checklist is being interactively filled in presently (or how it was previously filled in), and where the user cu~ llly is in the sequence of ch~ t~ Field 638 provides an operator input "button"
which is activated by the operator (for çY~mple, by moving a mouse pointer to the button icon on the screen, and pressing a switch on the mouse device of input device 130) to inrlir~te that the operator has verified that PHTS 100 power has been turned on and the power-supply cord has been secured to the wall-power outlet. Field 612 provides a check-box icon and an associated descriptor to indicate that the heat e~ch~nger 330 has been connPcted to the water supply.
Field 638 and field 612 show ~Itern~tive embo-1imentq of an interactive ~hPrkliqt S which ~l~s~ the operator with new action items as the operator completes the action ~iu~,.llly in~lic~tcd on the screen. Field 616 indicates the operator hasverified that the water reservoir has been filled ~ pelly. Field 640 is an example of an output-only field which indicates "LOW" until enough water has been provided, "OK" when ~ .ly filled within low and high limits, and 10 "HIGH" when too much water has been added (one embodiment uses the "WATER HIGH" indication during the tre~tnnent to indicate a possible leak of blood into the water system). Fields 612, 616, and 640 are grouped on the display under the title " WATER CIRCUIT." Field 620 indicates whether the o~ dlor has verified that the water telll~ dlulc~ probe at the "into" port of the 15 heat ex~ hA,~,l 330 has been connected and calibrated plu~,lly. Field 642 is an output-only field which indicates the digital t~lllp~,ldlull, value of the proberhPr~Pd at box 620. Similarly, field 624 in~liç~teq whether the operator has verified that the water-te...~,.dlu-~; probe at the "out of" port of the heat eYrh~nger 330 has been c~ nnt?cted and calibrated p~ ly. Field 644 is an 20 output-only field which indicates the digital Itilllp~ldlule value ofthe probe ch~rl~Pd at box 624. Field 620 indicates whether the opeldlor has verified that the water pump is ready to start. Field 646 (and the ALT-B key combination) inflir~te the operator desires to skip the cher~ t process (p~.lla~s due to an emergency which :~u~ edes the normal desirability of procee~lin~ through the 25 rhPr~ t process) and go immeAi~tely to the ~tom~tiC or manual control mode.
If field 646 is activated and control is moved to the automatic or manual control mode, the user can later go back and complete the çhPc ~ t~ after the e.ll~.~ ell-;y has been handled. In one embodiment, field 646 allowing bypassing of the - chPç~ t process is provided on every ch~ç~ t display screen.
Figures 6 and 7 illustrate exemplary display screens and input device options portions of the software-controlled user-interactive start-up procedure checklist. Figures 6 and 7 illustrate embodiment altern~tives for output display161 and input device 130: Figure 6 is directed towards an interactive interface in which the user provides input using a mouse-type point-and-click input device 130 or a touch-screen input device 130; wherein the user is presented a plurality 5 of windows-type screens and uses the mouse-type pointer (or a touch-screen) tointeract. Figure 7 is directed towards a bezel-button interface, wherein the text displayed next to a button-type switch indicates the function of that button, and this text changes from screen-to-screen, changing the function of the associatedbuttons as well. Some of the functions indicated on Figures 6 and 7 overlap 10 since they are from separate çher~liet embo-limente which address :iub~ 11y itl~nti~l functions.
On Figure 7, title field 708 displays an inr1ir~tion (viz., "STARTUP
PROCEDURE CHECKLIST PAGE 2 OF 8") of which ~h.o-1~liet is being hllela~;Li~rely filled in presently (or how it was previously filled in), and where 15 the user ~;ullc;nlly is in the sequence of ~h~cl~liete Field 712 provides a check-box icon and an associated descriptor to in-lic~te that the heat-PY~hz-nger intlorfa~e 331 has been mounted within heat PYrh~nger 330; bezel button 710, when pressed by a user, activates this function for this display screen. Field 716 provides a check-box icon and an associated desclipLor to intli~ ~t~ that the water 20 lines are connected to heat ~h~nger 330; bezel button 714, when pressed by a user, activates this function for this display screen. Field 720 provides a check-box icon and an aeeoci~ted des~;fi~,lor to indicate that the heat-~cch~nger 330 is ready to circulate water; bezel button 710, when pressed by a user, activates this function for this display screen; the circulation of water begins after buttons 718 25 and 722 have both been pressed. Field 724 provides a check-box icon and an associated descl;~or to indicate that the blood tubing 302 has been connected toheat-~xc~h~nger int~ e 331; bezel button 722, when pressed by a user, activates this function for this display screen. Field 730 (which, in this example, has nocheck-box icon) has a descriptor for increasing blood-flow rate through blood 30 pump 320; bezel button 732, when pressed by a user, activates this function for this display screen and increases blood-flow rate, which is indicated in output-W O 97/06840 PCT~US96/11476 only field 742, showing the flow rate in liters per minute. In one embo-liment for each activation of button 732 (i.e., for each press of the button by the operator), the blood rate is increased by a specified amount, for example, by 0.1 liter per minute. Field 734 has a desc.;~lol for de~,rea~ing blood-flow rate 5 through blood pump 320; bezel button 736, when pressed by a user, activates this function for this display screen and decreases blood-flow rate. In one embodiment, for each activation of button 736, the blood rate is decreased by a specified amount, for example, by 0.1 liter per minute. Field 738 has a descriptor for stopping blood pump 320; bezel button 740, when pressed by a 10 user, a~;liv~Lt;s this function for this display screen and stops blood pump 320.
Figure 8 illustrates an exemplary display screen usable with a mouse-type point-and-click input device 130 or a touchscreen input device 130 for a third portion of the rh~r~ t For Figure 8, no title field is provided; only an indication of where the user ~iu~ lly is in the se-lut;--ce of checklists ("PAGE 3 15 OF 8"). Field 812 provides a button icon and its associated des~ ,lol to intlir,~t~
that t_e button ("CONTINUE"), if pressed, will start the water pump and proceed to the next ch~c~ t screen (~ltcrn~tively, the user may press the alt-C
key combination to accomplish the same function). Field 810 provides a button icon and its associated descriptor to inrlic~tr that the button ("CANCEL"), if 20 pressed, will not start the water pump, but will proceed to the next chrr~ t screen (alternatively, the user may press the "Esc" key to accomplish the same escape function).
Figure 9 illustrates an exemplary display screen usable with a mouse-type point-and-click input device 130 or a touch-screen input device 130 for a fourth25 portion of a çhçr~ t On Figure 9, title field 908 displays an in-lir~tion (viz., "PERFUSION CIRCUIT CHECKLIST PAGE 4 OF 8") of which rhrr~ t is being il,le.a;lively filled in p-~:s~--lly (or how it was previously filled in), and where the user ~;u~ lly is in the sequence of çh--c~ t~ Field 910 provides a check-box icon and an associated descriptor to indicate that the blood tubing 302 30 (i.e., the blood-pump interface 321) has been mounted to the blood pump 320 so that blood flow travels in the proper direction (note that one embodiment of the WO 97/06840 PCTrUS96/11476 present invention provides a disposable circuit 301 and system interface 390 designed so that proper mounting and thus proper blood-flow direction is assured). Field 912 provides a check-box icon and an associated descriptor to indicate that proper occlusion of the blood tubing 302 is present at this point in 5 the procedure (i.e., that the blood-pump interface 321 has been adjusted to the blood pump 320 so that the tubing is ~lU~Clly pinched by the rollers; note that one embodiment of the present invention provides a blood-pump intP~ e 321 and blood pump 320 which are ~lecif~nPc~ to mate so that proper adju~;l...e..l and thus proper blood-flow occlusion are assured -- see the descriptions for Figures10 14A-14K below). Field 914 provides a check-box icon and an associated descriptor to indicate that the blood tubing 302 been plopclly connPctecl to heat P~ch~nger 330 (note for each of these similar checkboxes that one embodiment of the present invention provides a disposable circuit 301 and system infPrf~-~e390 fle~ignP~l so that proper mounting and thus proper blood connections are 15 assured). Field 916 provides a check-box icon and an associated descriptor toindicate that the perfusion circuit 400 is securely mounted to patient 99. Field918 provides a checkbox icon and an associated descriptor to indicate that the blood-pl~ w~ sensor in detector 335 is ~lvpclly connectc~l Field 920 provides a check-box icon and an associated des~ Lor to indicate that the blood-~l.,s:iwc20 sensor in detector 336 is prc".clly connected. The previous ~hPc~ t is grouped under the title "PERFUSION CIRCUIT."
The following ~hpc~ t is grouped under the title "BLOOD TEMP
PROBES CONNECTED AND FUNCTIONAL": Field 922 provides a check-box icon and an associated descriptor to indicate that the tCll~ dLwe probe in 25 detector 335 . . .~ l . .; . .g blood lr~ c at the blood ingress point of heat exch~nger 330 is connPctP~l and functional. Output-only field 940 in(1iç~tPs thetellll)cldlwc measured by detector 335. Field 924 provides a check-box icon and an associated descriptor to in-1ic~te that the l~ aLwc probe in detector 336 lll-,a jwhlg blood tellllJcldLwc at the blood egress point of heat P~cch~nger 330 is 30 co~ .;lr~l and functional. Output-only field 942 intlic~tPs the temperature measured by ~letPct- r 336.

WO 97/06840 PCTrUS96/11476 Fields 926 and 928 provide check-box icons and associated descriptors to indicate that the bubble detector 333 has been checked and that blood tubing 302has been connPctç~, respectively. Output-only field 944 indicates the bubble detector is clear of bubbles, or, if a bubble is detçcted by bubble detector 333, 5 shows a warning or alarm. Field 930 provides a check-box icon and an associated descriptor to indicate that the PHTS 100 is ready to prime the perfusion circuit with saline, blood, or other suitable fluid.
In a manner similar to that described for Figure 7, the blood-flow rate can be controlled, as shown at the bottom of the screen of Figure 9. Field 934 has an 10 icon for increasing blood-flow rate through blood pump 320, and when activated by a user, increases blood-flow rate. The blood-flow rate is in-lic~tPd in output-only field 932, showing the flow rate in liters per minute. Field 936 has an icon for declca~hlg blood-flow rate through blood pump 320, and when activated by a user, decreases blood-flow rate. Field 938 has a des~ ,lol for stopping blood 15 pump 320; when activated by a user, this function stops blood pump 320.
Figure 10 illu~L~dles an exemplary display screen usable with a mouse-type point-and-click input device for a fifth portion of a çh~c~ t, similar to Figure 8. For Figure 10, no title field is provided; only an indication of wherethe user ~;ull~lllly is in the sequence of ch~ckli~t~ ("PAGE 5 OF 8"). Field 1012 20 provides a button icon and its associated descriptor to indicate that the button ("CONTINUE"), if pressed, will start the blood pump and proceed to the next chPr~ t screen (~lt~rn~tively~ the user may press the alt-C key combination to accomplish the same function). Field 1010 provides a button icon and its associated des. li~tor to in-lic~te that the button ("CANCEL"), if pressed, will not 25 start the blood pump, but will proceed to the next rh~r~ t screen (~Itçrn~tively, the user may press the "Esc" key to accomplish the same escape function).
Figure 11 illU:jLldlCS an exemplary display screen usable with a mouse-type point-and-click input device for a sixth portion of the che~ t~ prim~rily for the priming of the perfusion circuit. Title field 1108 provides an indication 30 of where in the sequence of ch~ lict~ the user ~ullclllly is ("PAGE 6 OF 8").Output-only field 1114 indicates the bubble detector is clear of bubbles, or, if a bubble is dçtected by bubble det~ctor 333, shows a warning or alarrn. In one embodiment, fl~ehinp light spot 1124 flashes a warning or alarm color (such as yellow or red, .t;~e~lively) if a bubble is cletectecl in one such embodiment, an audio alarm is also sounded through speaker 162. In the embodiment shown, S output-only field 1116 shows the elapsed time since the last bubble was ~etect~
output-only field 1120 shows a target value for the parameter shown in field 1116 (in this example, it is desired that at least 2 minlltes pass after the last bubble is detectçd before the PHTS 100 is conn~?cted to a patient 99); and fl~ehing light spot 1126 flashes a warning color (such as yellow) if the time since 10 the last bubble is less than the target time, in one such embodiment, a soft audio alarm is also sounded through speaker 162. Output-only field 1118 shows the te~ Gldlul~; of the perfusion circuit (i.e., the te..-p~-dlu,e of the pelrL~dl~ within ECC 300), field 1122 shows the target value for this p~r~metto~r~ and fl~ehing light spot 1128 flashes a warning or alarm color (such as yellow or red, 15 ,~ e.ilively) if the t. ~ is slightly or grossly, l~,~e~lively, out ofthe target range. Field 1112 provides a button icon and its associated des~ lol to inAic~t~ that the button ("CONTrNUE"), if pressed, will proceed to t_e next ch.orl~liet screen (~lt~ ively, the user may press the alt-C key combination to accomplish the same function). Field 1110 provides a button icon and its 20 associated descriptor to indicate that the button ("CANCEL"), if pressed, will proceed to the previous rh~çl~liet screen (~ltrrn~tively, the user may press the"Esc" key to accomplish the same escape function).
Figure 12 illu~lldles an r~emrl~ry display screen usable with a mouse-type point-and-click input device for a seventh portion of the rhPrl liet ~rim~rily 25 for patient 99. Title field 1208 provides an indication of where the user ~;u~ .llly is in the sequence of çhrçl~liete ("SUBJECT PROCEDURE
CHECKLIST PAGE 7 OF 8"). An exemplary ~nl~sth~ei~ protocol is shown, with checkbox field 1210 completed by the user when the fluid ~Aminietration lines are primed, checkbox field 1212 completed by the user when the heparin 30 procedure is complete, and checkbox field 1214 completed by the user when thezmrsthPtic procedure is completed. Checkbox fields 1216-1225 are rherl~rd (completed) by the user after the eol.~~,~onding left tympanic, right tympanic, esophageal, indwelling, rectal/bladder and/or rectal t~ aLulc probes are connected and functionally tested; the output-only fields 1226-1235 show the telll~t;ldlu-es as measured by the co-.c;sponding probes indicated by fieldsl216-1225, respectively. Output-only fields 1236-1237 show the t~;lll~eldLulc;s as measured by two other temperature probes which are not cu-,l"-i~lecl to a control-type mea.,u.~ ent function. Output-only fields 1240-1241 show the flow rate and p-~ u-e of the blood inside ECC 300. Other fields have fi-n-~ti~n~ as previously described for other screen Figures.
Figure 13illu~ dleS an exemplary display screen usable with a mouse-type point-and-click input device for a eighth portion of the cherl~ t which in this case is a second portion of the "SUBJECT PROCEDURE CHECKLIST"
whieh is "PAGE 8 OF 8" of one exemplary l~h~ t Cheekbox 1310is ehecked-off to indieate that the user has turned off the blood pump (whieh was 15 "on" in order to prime and test the perfusion eircuit in ECC 300). Checkbox 1312is~hecLPrl-offto indicate that the user has conn~cted the blood lines to patient 99. Other fields have functions as previously described for other screenFigures.
Figure 14A is a simplified isometric view of one embodiment of blood 20 pump 320. Figure 1 4B is a simplified plan view of the blood pump 320 shown in Figure 14A. Base 329 provides a mounting structure and cover for other cunl~ollents such as the motor. Plate 328is eoupled to the motor, and rotates (in one embo~iiment~ elockwise), thus succe,~,ivc~ly eng~ging rollers 327 to s~lue~
tubing and thus move the blood co--ldi-.ed therein. Pin 325 and washer 326 25 attach roller 327 to plate 328. Pin 324iS provided to engage a co-,~;~olldinghook on one side of blood-pump interfAre 321. Spring-loaded retainer 323 holds the other side of blood-pump int~rf~re 321. In one embo~liment spring-loaded retainer 323 includes a screw-adJustable tension mounting which can be adjusted in order to provide (when a typical blood-pump interface 321is mounted to 30 blood pump 320) a proper amount of ocelusion (or squeezing) to the portion ofdeformable blood tubing 302 whieh is inside a typieal blood-pump int~rf~-~e 321, and this adjl-etment can then be left fixed, thus providing the proper arnount of occlusion for all subst~nti~lly similar blood-pump intPrfA~es 321 which are later mounted to that blood pump 320. In another embodiment, blood-pump interf~re 321, blood pump 320 and one or more spring-loaded retainers 323 are 5 m~nllf~ctured to sufficiently close toler~nces such that the proper amount of occlusion is achieved for all subst~nti~lly similar corresponding blood-pump interfaces 321 which are later mounted to that blood pump 320, even without manual adjlletmPnte Figure 14C is a plan (or front) view of one embodiment of blood-pump 10 intPrf~e 321 which mates with the blood purnp shown in Figures 14A and 14B.
Figure 14D is a left elevation view, Figure 14E is a bottom elevation view, Figure 14F is a right elevation view, and Figure 14G is a top elevation view of the blood-pump intPrf~-e 321 shown in Figure 14C. The positioning of pin 324 and spring-loaded retainer 323, the size (both inner and outer ~i~mPtPr) and l S m~teri~l of blood tubing 302, and the size and shape of blood-pump interface321 are ~lecignPd to ~--; -;---;~ or elimin~te the manual adj-lctmentc which aretypically required of conventional blood pumps. In one embodiment, this is accomplished by providing a screw adj~lctment to spring-loaded ~ e. 323 which, once set, will Ill~ ;ll proper adjlletmPnt for all similarly made blood-20 purnp intPrf~ee 321.
Figure 14H is a simplified plan view of the assembly operation of blood-pump interface 321 to the blood pump 320 shown in Figure 14A, wherein thé
hook portion of blood-pump ;. .~, r~ e 321 is first engaged to pin 324, and blood-pump intprf~ce 321 is then rotated into place and secured by spring-loaded 25 retainer 323. Figure 14I is a simplified plan view of blood-pump int~rfR~e 321 assembled to the blood pump 320 shown in Figure 14A.
Figure 1 SA is a plan view of an ~ltPrn~tive embodiment of blood-pump intPrf~se 321', wherein both sides of blood-pump intPrf~e 321' are provided with proL~ ions to engage with spring-loaded l~,tail~ 323. In an ~ ;v~
30 embodiment, the sides of blood-pump intPrf~ce 321 ' are made of a resilient material such as plastic, and provide the spring function, whereas the two W O 97/06840 PCTrUS96/11476 aincl~ 323 are rigidly fixed or adjustably fixed.
Figure 1 SB is a simplified plan view of blood-pump interface 321 ' - assembled (i.e., snapped into place) to a corresponding blood pump 320'. In one embc.liment, one or both spring-loaded let~ 323 include a screw-adjustable tension mounting which can be adjusted in order to provide (when a typical blood-pump intPrf~re 321' is mounted to blood pump 320') a proper amount of occlusion (or squeP7in~) to the portion of deformable blood tubing 302 which is inside a typical blood-pump inte-f~re 321', and this adjlletm~ont can then be left fixed, thus providing the proper amount of occlusion for all slilbst~nti~lly similar blood-pump int.orf~r~s 321' which are later mounted to that blood pump 320'. In another embodiment, blood-pump interf~ce 321', blood pump 320' and spring-loaded l~,tai~ 323 are m~mlf~rtured to sufficiently close tolc.a~lces such that the proper amount of occlusion is present for all ~ n~ y similar coll~onding blood-pump i~llr. r~r,es 321' which are later mounted to that blood pump 320', even without manual adjuetmPnte.
Figure 1 6A shows a front, open, view of one embodiment of a modular clam-shell heat exrh~nger 1600 according to the present invention which can be used for heat ç~rrh~nger 330 in PHTS 100. Modular clam-shell heat loxrhslngf r 1600 comrrieçs a disposable blood-tube assembly 1700 which is assembled within a reusable clam-shell assembly 1601 for use. Figure 1 6a shows blood-tube assembly 1700 in place within clam-shell half 1610 of clam-shell assembly 1601 before clam-shell half 1620 of clam-shell assembly 1601 has been closed and latched for use. In one embo-lim~nt a heat~ rh~nger door-interlock switch is provided to signal to CUIll~UI~,- system 110 whether or not clam-shell assembly 1601 is ~ c.ly closed onto blood-tube assembly 1700.
Figure 1 6B shows a eimplified isometric view of a modular vertical-cylinder heat ~xr.h~n~er 1600' according to the present invention which can be used for heat cxch~nger 330 in PHTS 100. In one embodiment, water-~ sltt~rhm~ nt no7 les 1616 are vertically related and pass through the cabinet of PHTS 100 to provide water inlet and outlet points as shown in Figure 19. In another embodiment, water-~tt~rhment no_zles 1616 are holi~ulllally related and WO 97/06840 PCT~US96/11476 connect to ext~rn~l tubing as shown in Figures 20 and 21. Figure 16C shows a front view of a disposable blood-tube assembly 1700' according to the present invention which can be used in modular vertical-cylinder heat exrh~nger 1600' of Figure 16B. In this embodiment, tubing 302 passes through the cap 1709, is S helically wound around one or more support posts which connect to bottom-end connector 1710', and tubing 302 then passes out through the cap 1709. In one embodiment, the helical-wound portion compri~ stainless steel tubing, which is coupled to blood tubing 302. Figure 16D shows a simplified front view of a reusable vertical-cylinder assembly 1601 ' which can be used in modular vertical-10 cylinder heat ~xrh~nger 1600' of Figure 16B.
Figure 17A shows a front view of a disposable blood-tube assembly 1700 usable with mnd~ r clam-shell heat çxch~nger 1600 of Figure 16A according to the present invention. One or more end connectors 1710 each provide a co~ eclion means to blood tubing 302, and are preferably formed of a rigid, 5 ~ ? bio-col~ Lible plastic. In the embodiment shown, a standard ribbed tubing connector is provided to connect blood tubing 302 to each end co~ or 1710. In another plcrellcd embo-1imrnt blood tubing 302 is glued or welded to end connectors 1710. Manifold 1720 provides a colllle-;lion means between heat-e~ch~nge tubes 1730 (only some of which are schematically shown in 20 Figure 17A) and end conn~ctors 1710, and is preferably formed of a rigid, transparent, bio-compatible plastic. A plurality of heat-çxch~nge tubes 1730 provide parallel paths having a large ag~ l~g~Le surface area between two end col~e-;lors 1710. Figure 17B shows a cross-section view of the disposable blood-tube assembly 1700 of Figure 17A across section line 17B. In one 25 embo-lim~nt one or more O-rings 1740 on each end col~le-;Lol 1710 help prevent water from leaking at those positions.
Figure 17C shows a front, open, view of a reusable clam-shell assembly 1601 usable with modular clam-shell heat çxrhs~nger 1600 of Figure 16A according to the present invention. Figure 17D shows a side, closed, view 30 ofthe reusable clam-shell assembly 1601 of Figure 17C. Figure 17E shows a cutaway detail of one embodiment of the sealing ridges, grooves? and gaskets of WO 97/06840 PCTrUS96/11476 the edges of reusable clam-shell assembly 1601. Figure 17F shows a side, open, view of the reusable clam-shell assembly 1601 of Figure 17C. Ridge 1611 mates ~ with groove 1618, in which is preferably a gasketing m~ten~l 1619; and ridge 1617 mates with groove 1612, in which is also preferably a gasketing m~t~riz~l 1619. On both ends of clam-shell assembly 1601, inner cylindrical grooves 1613 and outer cylindrical grooves 1614 formed into end openings 1615 each mate with co~ ol1ding O-rings 1740 (which are rubber O-rings or other g~Cl~eting material) of blood-tube assembly 1700 when clam shell 1601 and blood-tube assembly 1700 are assembled. Cavity 1650 provides a path for the heat-exçh~nge water to flow around and/or through blood-tube assembly 1700. Water nozzles 1616 provide water inlet and outlet points. One or more hinges 1630 and one or more latch assemblies 1640-1641 allow the clam shell to be opened or closed and secured. In one embodiment, an electrical signal is g~n~r~ted onlywhen the clam shell is pl~o~c~lly closed and secured to a blood-tube assembly 1700. One such embodiment uses a mi~ wilch, which is activated when the clam shell 1601 is fully closed, in series with a connector which passes the signal through both the clam shell 1601 and a particular COll~ olldirlg blood-tube assembly 1700 for that particular clam shell 1601. For example, various di~. .e.l~ clam shells 1601 would have electrical connections in dirr~lelll places for dirr~ col.c:,punding blood-tube assemblies 1700 in order to detect and prevent operation of PHTS 100 if the wrong blood-tube assembly 1700 (or a cou~le,r~il one) were inserted. Another such embodiment of PHTS 100 uses disposable and/or rep~ e~hle parts (such as blood-tube assembly 1700, disposable subsystem 301 as a whole, blood tubing 302, blood preconditioner int~rf~re unit 311, blood-pump; . .~. . rn. e 321, heat-exchanger int~rf~ce 321,and/or blood postconditioner interface 381) each of which includes an electricalcormector (or other signal coupling) to a read-only memory (ROM) which forms a part of the disposable unit and which stores data which is ch~c~l by software 500 in order to clrl~ the type and/or ~llth~nticity of the disposable and/or replaceable part (in order to prevent use of counterfeit parts and in order to de~ellllille and record the type and/or serial number of the disposable part used).

CA 02229138 1998-02-lO
W097/06840 PCTrUS96/11476 Further details of such an ~lthentication d~ lldLUS and method are described in U.S. Patent Number Re. 34,161 to Nakagawa.
Figure 1 7G shows a front view of another embodiment of a disposable blood-tube assembly 1700" usable with modular clam-shell heat exehzmger 1600 of Figure 16A accordi-lg to the present invention, in which blood tubing 302iS helicaIly wound to form a single unified heat-~xrh~nge tube 1730. In another such embo~liment a st~inles~-steel tube is helically wound to form a single heat-çxch~nge tube 1730, and is glued or other~vise sealed to blood tubing 302.
Figure 18 shows a sçhPm~tic of some connections of one embodiment of PHTS 100 having a ~implified structure incl~l-ling moniLu~ g system 200, blood pump 320, heat exch~nger 330, and bubble detector 333, blood-inlet-c ~letcctor 335,blood-outlet-telll~,.dLulG detector 336, and blood-iUIG detector 334.
Figure 19 shows an isometric view of a cover structure for one embodiment of PHTS 100.
Figure 20 shows an isometric view of one embodiment of PHTS 100 having a front-mounted beveled display for mounting display screen 161 using bezel buttons and knobbed ~wiLclles and dials for input device 130. Blood pump 20 320is mounted to the side of the cabinet, with blood tubing 302 connecting it to heat exch~nger 330, which has extern~lly connecte~l water tubing running water to and from the cabinet. A water drain is shown at the bottom of the front of the cabinet, a water-fill port on the top, and a gravity-fill path bGLv~ with water pump 370 at the lowest point of the water circuit.
Figure 21 shows an isometric view of another embodiment of PHTS
100, similar to Figure 20, except that the display screen and input devices 130 are mounted at an angle on the top of the cabinet.
Figure 22 shows an isometric view of yet another embodiment of PHTS 100, showing a personal-computer-type keyboard input device 130, some 30 manual control switches input device 130', an output device 160inchl-1ing a display screen 161, a disposable subsystem 301 (including blood tubing 302, blood preconditioner interface unit 3 l l, blood-pump 320', blood-pump interf~-~e 321 ', heat-e~' h~nger 330 and intçrf~ e 331, blood postconditioner interface 381, and a further length of blood tubing 302 for l~ . li . .g the blood to the patient) 5 coupled to system interface 390 located on the side of the cabinet of PHTS 100.
The useful fedlu,es of PHTS 100 include the integrated, self-contained construction of the mechanical (e.g., in one embodiment, the integrated p~ gjng of disposable subsystem 301 its int~rf~e to the integrated system int~ e 390) and electrical (e.g., col~l~ulel system l lO, lllolli~ g system 200,10 and the electrical sensor and control portions of ECC 300) systems, the disposable circuit 301, and the integrated çh~ t 504 and system fee-lb~cl~
controls, e.g., water tell~Gldlule control 508, blood tc;lllpeldlule control 512, and body l~ ;ldlul~ control 516 for water, blood, and body t~ ldLul~s, ~e~ ely. Many of the components of PHTS 100 can be based on exi~ting 15 heart-lung m~r~hine technology. In one embo~lim~nt PHTS 100 is 5~ ",nl;,.g current (AC) 110 volt line ~o~.ed, and includes an int~rn~tionally qualified power supply. PHTS 100 has a first mode of operation which is co"l~ul~ .-controlled with some amount of manual input from the user in order toverify certain conditions which cannot be electrically verified by the colll~ultil, 20 and a second mode of operation which is Co~ uL~ ~-monitored with manual overrides on the control nodes. In one embo~lim~nt, PHTS 100 includes start-up tests 502 which verify correct function of the major subjy~l~"ls before any operation of the device is allelll~Led, plus self-~ gnostics 506 which contin~ ly test for the co..~ g correct function of the ~ub~y~l~.lls and parts of PHTS 100 25 during operation. In one embo~1iment, PHTS 100 includes integrated p~ ul~-monitoring sensors for measuring pres~ulc; of blood in blood tubing 302 and of the water in the water-conditioning ~ulJ~y~l~;lll 340. In one embodiment,PHTS 100 also includes ~tom~ted data logging for therapy sessions, which ~ records all ch~ç~ t responses, all monitored pararneters during the operation, 30 and all control signals, along with 1;..,~ ,I~...l.s, onto a storage medium. In one embodiment, the storage medium is a paper ~lhlloul. In another embodiment, the storage meflil-m is a removable m~gn~tic ~ k~t~ç
In one embodiment, PHTS 100 comprises a blood pump 320 for controlled-rate p~rusdlt; pumping (one embodiment uses a DeBakey-type double-roller pump for pump 320); a heat exchanger 330 having water 5 connections 1616; sensors 345 and 346 for monitoring and controlling of the water telllpeldlule for the heat exchanger 330; sensors 335 and 336 for monitoring and controlling of the pclrusdte t~ .,.dLulc; up to ten or more sensors 201-203 for monitoring and controlling of the subject's 99 body-core telll~ldLule and controlling telllp~.dLules and tt:lllp~ldLulc dirr~ ,..Lials in various parts of the body of patient 99; sensors 333 (one embodiment uses ultrasonic sensors known to the art) for mnnitoring and acting on bubbles in the p r~
one or more input device 130 to provide an operator ability to set control points;
one or more input device 130 also used to provide an operator open loop control via manual switches; one or more display device 161 for L~ ,.dLule and ~ ule display; testing sensors and software for power up tests 502 arld continuous real time fault monitoring 506; an i~ n~;l;ve rh~r~liet 504 to elicitand receive operator responses to safety and setup ch~rkliete; visible warning and alarm indications (e.g., display fedLul.,s 640, 1114, 1124, etc.) on display161 and audible alarm inllir~tiorle on audio output 162; a controller 11 1 whichprovides a system safety fall-back to a passive state on a dçtçctçd component failure; system safety deeign~d into all aspects of the design and implçnnrnt~tiQn of the physical system, within accepted perfusion pr~cticçs; and removable storage means 162 for parameter data storage and transfer to removable media for post-procedure procçeeing and display.
Several factors, based upon human and animal investigations, have shown that the following seem to be critical factors in the survival of a subject treated with the hyperthermic processes:
A. ~; ..1~. .~. ,re of an adequate and stringently controlled water-to-blood l~.llp~,.dLuie gradient. The rate of heat transfer to the p.,.ru~dL~ and the effici~nciçe involved to effect heat input must be rigorously controlled.

B. Tracking of the various blood and body tG~ Gl~lulG levels and rates of change to assure uniform heating has been shown to affect the efficacy of the therapy.
C. Measuring the difr~ ial left and right Lylll~ic tGlllpel~lLulcs.
~ 5 Anecdotal evidence suggests that a large t~ l lpe~ l G di~,rGl.lial may be the cause of a neurological deficit (which resolved slowly over time) that occurred to a small subset of test subjects. It also appears to have contributed to strokes and sGiGw~ 3 that occurred to other test subjects.
D. Conkolled cooling is just as hllpoll~ as controlled h~ting Cooling too rapidly appears to be able to cause the same hlllpclcllulc diL[~.e,.lials, and potential problems, as heating too rapidly. There is also anecdotal evidence to suggest that there is a possibility that some subjects can reach certain elevated hlll~ ~dLul~ pl~t~lle Controlled extracol~u.Gal cooling is .e.lui-cd to trigger the body's own intrineic cooling . . ,~çh~ . . . into operation if one of these pl~tt~lle (hy~olllalamic change of set point) is reached.
In one embodiment, the disposable :~ub:~y~lG1ll301 int~ ces with one side of the chassis of mel~h~nir ~l subsystem 600 as shown in Figure 20. See 20 Figure 2C which illu~L~dles a 5~h~ ;c of such a system i--~- r~e to ~i~po~bleSUb~Y~lG1113O1 of Figure 2B. In one embo~imPnt disposable sub~y~ 301is pre-assembled and pre-sterili7~cl as an entire sub~y~h.ll or cartridge which is "plugged" (all electrical and/or mechanical connections made with few, if any, tools or manual ad~ trnpnt~) into the p~ nt reusable portion, i.e., system 25 int~rf~re 390 of ECC 300.
The following system co..lponents are under culll~LIh. control:
A. water pump 370 off/on B. water cooling 360 fan off/on C. water heater 350 off/on D. blood pump 320 off/rate-of-flow One embodiment of blood pump 320 utilizes a reusable roller portion of blood pump 320 to intçrfzlre with a disposable tubing/ tubing interface device 321 through which the blood moves (positive displ~rem~nt or p~ori~t~ltic style), and a means (i.e., sensors 325 and 326 along with software programmed feedb~cL
control from drivers 124 to the motor of blood pump 320 in order to adjust the 5 measured parameters to their desired levels) for controlling the flow rate, output ,U~ UlC, or throughput of the pump. The design of this pump 320is inherently such that the correct setup and assembly of the int~rf~re tubing provides a COllvcl ,ion factor between pump speed and calculate/çstim~ted blood-flow rate that closely reflects the actual blood flow.
The mrrh~nical sub.,y~ ,11 600 incllldes the h~ting/cooling water conditioning sub ,y 7L~ll. 340 which contains a water pump 370 and telll~cl~Lu.ccontrol assembly 350 and 360. In one embodiment, this assembly has the following major culllpollelll7 in the following water-flow order:
l. water pump 370 (one embodiment places water pump 370 at or near the lowest point in the water circuit in order to f~r.ilit~te priming the circuit with water, and pulling water out of the heat çYehs~nger330 in order to water p1e..~ul~ within the heat f~Yrh~nger330) 2. a water cooler 360 for cooling the water (one embodiment uses a radiator, such as an automobile ~ inn fluid cooler unit, and a fan to blow ambient room air across the radiator; one such embodiment also inrhlcles a float-type air purge valve such as are used in home water-heating systems in order to prime the system/fill it with water, another embodiment uses a Peltier-effect thermo-electric module to cool the water, yet another embodiment uses a refrigerator-type cooler to cool the water) 3. 'r-connector344 to 1~3e~vuir343, with the water passing sllhst~nti~lly ho-;~u--l~lly through the tangential section, and the 1cSc1vOiL cu~ ed above the subst~nti~lly vertical perpendicular section, as shown in Figure 2A, in order to "~;.,;,.~;,e heat ~,al.~r~. from the water circuit into the water in the heat eYrh~nger and to transfer air bubbles from the water circuit out into the reservoir 343, and to supply water to the water circuit) W O 97/06840 PCTrUS96/11476 4. water heater 350 for heating the water 5. tG~ dLulG probe 345 6. blood/water heat exch~nger 330 (the blood-contact portion 331is disposable) 7. IGlll~ dlUl~ probe 346, and back to water pump 370.
In another embodiment, air is used as the heat-exrh~nge me~ lm in conditioning :iubsy:ilG1ll340~ with the following major co---l)ollents:
1. air fan 3',70 2. air cooler 360 (one embodiment uses a Peltier-effect thermo-electric module to cool the water; another embodiment uses a refrigerator-type cooler) 4. air heater 350 5. ~ e.~ probe 345 6. blood/air heat exchanger 330 (the blood-contact portion 331is 1 5 disposable) 7. tGlllpC,ldlUle probe 346, and then vented out of the system.
The heating and cooling :~iUbSy~ilGlll 340comrrieçs an interf~re bclv~
disposable portion 331 and blood heat ~xch~nger 330 that effects the controlled change in the IGlll~,ldLUle of the blood passing through disposable portion 331.20 This in turn affects the LGlll~JGldlUl~ of various regions of the body of patient 99.
PHTS 100 thus incol~uldlGs a means to heat and cool the blood efficiently and in a closely and automatically controlled f~chion Research has shown that a water ~Yrh~nge system with a .. il~i.. of approxim~tely 500 Watts of heat, with a .. ;.. ;... water flow of approximsltely 25 10 liters per minute is sllfficient for adding the required calories to the blood at a minim~l blood-flow rate, while still causing the required change in the blood telllyGldlulG ll~ce~ y for overcu~ing native thermal losses. This llltim~tely results in the desired change in the body telll~JGldlulG of patient 99.
Computer system 110 comprises one or more colll~ul..lg elementc with sufficient proceeeing power, memory, and other resources to ~.rO---- the following control functions.

W 097/06840 PCT~US96/11476 1. Monitoring and Control a) One primary function of co~ ,uL~l system 1 10 is to acquire the l-~cç~ sensor data, interpolate and extrapolate this information, and execute the n~ cçcsstry control functions required to cause PHTS 100 to pGlrullll its specified therapy.
b) The tellll)eldlul~, controller is a programmed conl~ul~"
feedb~tr~ system which measures the telll~cldLulc of the various critical sites. The controller i..le~ and controls the rates of change in and between the various monitoring sites.
c) The pl~ iUlC monitoring provides a safety feature to detect a liminal occlusion.
d) Monitoring is performed on a contin~ous basis. Where a~plupliate~ monitored values have a warning threshold and an alarm threshold. The monitr~r may either issue a warning or issue an alarm and limit the device output as d~lupl;ate for the particular sensor.
2. Data Display and Removable Media Storage a) The inputldisplay module 560 has plilllaL~ fimrtion~
including 1) user input, 2) continllous, real time data display (in one embodiment, ~imnlt~n~ous gr~phic~tl displays are ~ dled to display screen 161 of a plurality of graphs of Lellll.cldLu.c versus time, co~ E predetermined desired lt;lllpc.dLulc profiles and measured actual telll~eldLul~i profiles; one such embodiment also inchldes gr~tphir~tl displays of cardiac, pulmonary, and/or blood-pfe~
signals), and 3) optional real time data storage. This module is responsible for ge~ dling a~lupliate display inform~tion for the op~dlol, acquiring and inl~ lelhlg operator input, and logging d~plu~liate information for further analysis. The stored data can be ~.,...~r~ d to a removable media for po~lopcldLive analysis.
All aspects of the design and implement must be l,~,rc lllled such that: No 30 single failure can prevent detection of a failure, or prevent PHTS 100 from rntering a fail safe state. See Table 1, Alarm and Warning Conditions for a list W O 97/06840 PCTrUS96/11476 of monitored parameters in one embodiment.
Because blood LGlllpGldlul~ changes can cause ~ 1g, a standard extracol~ lGal bubble detector is to be used in conju-1.;lion with a bubble trap. In one embodiment, the bubble trap is an integral part of the heat ç~ch~ngPr, and is 5 located dow.,sll~ al-- of the bubble trap within heat e~rh~np~er 330. This merh~ni~m provides a fail-safe way to stop the blood pump 320 in the event that a bubble is present in the ~~,-el-L ~ line of the blood path. Note: Bubbles are an expected part of any perfusion technique. However, the bubble trap and bubble detector 333 serve to reduce the risk of infusing a bubble into the subject (patient 10 99).
In one embodiment, the IG111~,.dLU1G monitor functions 507, SlO, and 514 limit the system outputs, and controls are activated if lt;lll~GldluL~ s and ICI11~G1alU1~ rates of change exceed pred~t~ Pd limits. These limits are set to prevent potential thermal injury to the blood, body, and brain of the patient.
In one embo-iimPnt the ples~u G monitor fi1nr-tif~n stops the blood pump 320 if the blood pump ~ PYcee~l~ a pre~i~L~ ; . .Pd level. This limit is setto prevent potential injury to patient 99.
The co~ ,uh 1 system l l O is to be progr~mmed to control the rate limits, process limits, rates of change, etc., for PHTS lO0. The co~ ul~1 system l lO
20 employs power up and continuous monitoring that PHTS l 00 is functioning.
Upon failure, the PHTS l 00 is driven to a fail-passive state.
In one embodiment, PHTS lO0 is d~PsignP-l and built to provide a specified system failure rate of less than l failed device for every 20,000 hours of field use. This co-.~jpollds to d~ ullldLely 5000 I-~ at a ....x; .~ ,.....
25 of 4 hours use per 1~
In one embodiment, PHTS lO0 is rl~Pcignpd to f~rilit~te field - ... ~;.. ~r~ e by trained PG1~O1111C1. In this embc!-limPnt a periodic preventative~ re (PM) regimen is established and major repairs are accomp1i~hPd under a depot system utili7inp field-replaceable-module concepts.
In one embodiment, display l 6 l is a text-based monochrome LCD-VGA
display screen. In one such embo-liment display 161 provides a visual digital W 097/06840 PCTrUS96/11476 indication of the value of each of the t~ cldLulG probes. In one such embodiment, display 161 is nr~ted at rate of at least once every two seconds (1/2 Hz.).
In one such embodiment, display 161 provides a digital display which 5 indicates the telll~c.dlule in tenths of a degree Celsius (~C) as three digits (tens, ones, ~leçim~l point, and tenths of a degree). In one such emborliment, display 161 is A~ign~d to be readable, by a person with 20/30 vision, at a rii~t~nre of 1.2 meters (4 ft) from display 161.
In one such embo-limPnt display 161 also provides a visual digital 10 indication of the value of each of the ~ S:iUl~ sensors, updated at a ...; ..i ........
rate of 1/2 Hz, and in-lir~t~s the pl~,S~ulc value in units of millimtoter.s of mercury (millimPt~or~ Hg) as three digits with leading zeros :iu~ s~ed. In one such embo~1im~ont the plci,~ule displayed on display 161 is de~ign~l to be readable, by a person with 20/30 vision, at a tii~t~n~e of 1.2 meters (4 ft) from display 161.
In one such embo-limPnt display 161 also provides a visual in-1ic~tinn of the state of the various safety sensors of PHTS 100. See Table 1, Alarm and Warning Conditions.
In one such embo-lim~ont, display 161 also provides an inrlir~tor that lights in the event that any system safety ~ ,t~l is exceeded. This indicator 20 should be visible at a ~ t~nre of 1.8 meters (6 feet) and should be red to inllic~te danger. In one such embo~lim~ont display 161 should update all displayed data atleast once every two secon-l~ In one such embodiment, display 161 also displays the version number of the software 500. In one such embo(1im~nt display 161 displays blood-flow rate based on the average rate of the 25 imm.~ t~ly ~1~ ce.l;..g 5 seconds. The accuracy of this indicated blood-flow rate is within 10% of the actual flow rate. In one such embodiment, display 161 also displays blood t~;lll~c.dLulc rate, which is recalculated based on the history of the immP~ t~ly prece-lin~: 60 seconds.

Table 1. ~larr~ and Warnin~ Conditions p~r~meter Alarm W~rnir~
Threshold Threshold 1. higherofthe two ly~ ic temps 43 ~C 42 ~C
2. delta lylll~ulictemp 1.0 ~C 0.8 ~C
3. body-core average le.~ dlulG 43 ~C 42 ~C
4. tGlllpGldlul~ofblood outofHE 46 ~C 45 ~C
5. P1~:jU1G of blood out of the blood pump 100 mm Hg 90 mm Hg 6. bubbles detected yes yes 7. water reservoir low yes yes 8. tympanic averagetemp rate 1.4 ~C/min 0.3~C/min 9. tympanic average temp, 4.0 ~C 3.0 ~C
core average temp .li~.Gnce 10. high core temp, low core temp dirrGl.,.lce 4.0 ~C 3.0 ~C

11. body-core average temp rate 0.4 ~C/min 0.3 ~C/min 12. blood-flow acceleration 0.25 l/min/ 0.231/min/
min mm 13. blood-flow rate 1.25 l/min 14. time body-core temp elevated above 3:00 nominal (or time subject blood ~ulll~ed) 15. time body-core temp above target temp 2:00 16. core th~rmi~tor failed yes yes 17. blood out of HE temp rate 4.0 ~C/min 18. dirr~-e.lce b~lWGeII blood out of HE temp, 4.0 ~C
body-core average temp dirr~ ce 19. di~.~llce bGlwGGn water into HE temp, 8.0 ~C
blood into HE temp In one emborlim~nt PHTS 100 has a water fill port that provides the capability to fill water-conditioning SUI~Y~lGI11 340 with water without spilling water.

: 54 In one embodiment, water-conditioning system 340 provides an indication to control computer 111 of nominal water-full range. In one embodiment, water-conditioning system 340 provides a m~nll~lly operated water-drain valve that is capable of ~lr~ining PHTS 100 of water. One purpose is to empty enough water such that freezing PHTS 100 does not cause damage due to ice expansion. In one embo~lim~ont~ water-con-litic ning system 340 provides a low-level sensor toin~lir~tç to control c~ LeL 111 that the water level is too low, which preferably triggers when the water is within 10% of exposing the heater çlennent 350.
When the low level sensor is triggered, it preferably causes PHTS 100 to stop the 10 water pump 370, water heater 350, and water cooling fan of water cooler 360, in order to prevent damage to the heating elem-~nt~
In one embodiment, water-con(1iti~ning system 340 provides a water flow detector sensor in detector 345 and/or 346 to allow early ~1~L~ . ., .i. ,~tion of system failure. This sensor is a seconrl~ry sensor since nltim~tç operational status of the device is primarily ~lçtçrmin~l by ~ ,.dlUlC~ changes throughout the system.
This sensor is prim~rily intrnrlPcl for use during the start-up safety check andself-test process. Failure to detect water flow at this time preferably ~ the initi~tinn of a therapy session. Failure to detect circulation during a session preferably g~illc-dlt;s a warning alarm.
In one embo-lim~nt, water-conditioning system 340 provides quick release ports for the water interf~rçs to the heat çyrh~nger: water from the chassis to the heat exch~nger and water from the heat çxrh~ng~r to the chassis.
In one emborliment~ PHTS 100 has chassis cooling air entry and exit vents and water cooling air entry and exit vents which are located and oriented such that air is not blown in the direction of the sterile field.
In one embo~limPnt, PHTS 100 inr,l~l~1es a blood pump 320 capable of providing up to not less than 1.25 liters/minute of blood flow. The blood pump 320:iU~Ull:i flexible tubing having 1/4" inside ~ mçter~
In one embc-limrnt, PHTS 100 includes a bubble detector 333 in the perfusion circuit near the exit point of the bubble trap incull~u.dl~d in heat exch~nger 330. This bubble detector 333is a secondary fault detector since a WO 97/06840 PCTAUS96/l1476 bubble trap is in-line u~Ll~dlll in the shunt circuit. This bubble detector 333 is capable of dçtectin~ any bubble larger than the inside diameter of the perfusioncircuit tubing at a flow rate of 1.25 liters/minute. This bubble detector 333 isdçci~nP~l such that false positive bubble indication occurs no more frequently ~ 5 than 1 false positive every 5,000 operational hours. In one embodiment, PHTS
100 is deeignPd such that the detection of a bubble preferably stops the blood pump immPrli~t~ly and sounds the audible alarm. The bubble detector 333 preferably accepts a 1/4" inside ~ mPtçr plastic tube.
In one embo~1imPnt, PHTS 100 incl~ P~s a heat çxçh~nger holder which 10 acco.lo-l~tçs the Electromedics model D1079E heat P~ch~nger. (This heat P~hz-nger is or will be a commercially available component. An d~ .;ate holder/clamp is used.) In one embo~limPnt PHTS 100 includes two plCS~ulc sensor inputs. One of these sensors is unco.. i 1 l ~d and the other is used to monitor the blood pump output. The ullco.. ;lled ple;,~ulc monitor is ~ç.;~ .lc to within ~10% for the entire range from 0 mm to 300 mm Hg. The unco~.. ;lled plC~UlC monitor is able to w;Lh~ the range from -50 mm to +450 mm Hg with no damage or loss of accuracy in its Ol)~.dlillg range. A failed sensor may cause the Ll~".l . ~ ~~- ~I to be ~re.ll~ ,ly tçrmin~tç~i The sensor failure rate should be less than 1 for every 10,000 hours of use.
In one embo~limPnt PHTS 100 uses a .. ;.. i... of six (6) 1~ .. c sensors for the purpose of monil~ lg subject body telllp~,ldluçcs during the course of a therapy session. Two of the sensors (e.g., 201 and 202) are placed such that they can measure the IC.11~.dlUI~ difr.,.~,..ce across the left and right 25 Lylll~dl ic mo..;l~.. ;..g sites. These probes are referred to as right tympanic and left Iylll~dllic. The ~~ ;..;..g body Iclll~cldlulci probes are placed at strategic locations throughout the body mass and are used to del~ ....;..P body-core ,.dlUIC. Two telll~cldlul~, sensors are required to monitor the blood t._.llpeldlulc. One (335) is located to provide the tc.ll~,.dlul~ at the heat 30 eYch~nger 330 inflow, while the other (336) is located at the heat exchanger 330 outflow. Two final t~ ,.dl-lre sensors (345 and 346) are located to monitor the water system temp~.aLu.~s. One sensor is located in the water path to the heat exch~nger 330 to monitor the water telllp.~.dlule of the heat source for the heat exch~nger. The other measures the water t~:lllp~;.dLLlre in the water path out of the heat exch~nger. In one embo-liment the water telllp~ldLul~ sensors are not 5 disposable (i.e., are not inten-led to be replaced by the operator). All othert~ pcldLules sensors are disposable and are int~nfled to be used for one therapysession only. It is highly desirable that the same technology be used for sensing all points.
In one embodiment, PHTS 100 provides twelve tt;lll~ .dLulc; probe 10 interf~ces Table 2 below shows a temperature probe list for one embodiment ofthe present invention. Given probes that are accurate to within +0.1 ~C, the system tt;lll~.,.dLulc me~ ring accuracy preferably is +0.3 ~C from 35 ~C through 65~C.
Table 2 Tf -npel al~.r~ Probe ~
T~ re Probe T oe~tion Di~osable OperatorAccessible 1. left tympanic 2. right Iylll~ ~c 3. esophageal, body 4. indwelling, body 5. rectal, body 6. rectal/bladder, body 7. unCu 8. UllC~
9. blood into the heat exch~nger 10. blood out of the heat exchanger 11. water into the heat exch~nger 12. water out of the heat ~xrh~nger In one embodiment, PHTS 100 does not provide electrocardiogram (ECG) interf~re or display capabilities. In another embodiment, ECG display is provided.

In one embodiment, PHTS 100 provides a me~hQni~m for logging to output device 163, such as magnetic diskette, the lGlllpGldlu,G and ~ S:iul~, - values acquired and Ol)GIdtul control selections during the course of a therapy sesslon.
1. Sampled data values will be logged at a sampling rate of 1 Hz.
2. All opeldlor control selections preferably are logged.
3. Upon operator selection, the log file preferably is copied to a floppy ~i~e~e 4. The logged data preferably is written to the floppy 5. Each data log file preferably includes the following:
a) The date and time that the file was opened.
b) The version of the application software.
c) Indication as to whether each chPclrli~t was completed or bypassed.
d) Thermal dose to the subject. Defined as the area under the subject te",~c,dlu,e versus time curve in units of~C-minlltes. See Figure SB showing thermal dose.
e) Total time at or above the target body-core average t~",~. dlUl ~ .
f) Total profusion time. Defined as the time that the blood pump was on while the system was co~ ;led to the subject.
g) ~x;~ ylllp~lic tGlllpe~alul~ during the procedure.
h) ~ 111 body-core average ~e~ d~ during the procedure.
6. Te.~p~ Id~ and pressure data values preferably are stored in binary forrnat.
7. Logged information that is not data values preferably are stored in ASCII format.
In one embodiment, PHTS 100 generates a tone or audible alarm on speaker 162 that sounds in the event that any system safety parameter is exc~ee~1e~1 This indicator preferably is clearly audible in an opeld~ g room Nlvhol)lllent from a distance of 8 meters (26 feet).
In one embodiment, PHTS 100 provides an output via an RS232 jack that provides tt;l~lpe.dLu~e, pl~,s:iule, and system state at the l l li lli 11111-11 rate of once 5 every 2 seconds. This information is provided for an optional ~xt~rn~l data display placed at a location remote from PHTS 100.
In one embo-lim~nt PHTS 100 is ~lç~i~n.od with a system power re4uh~.llc;lll int~n~ed to accommodate ill~ ;onal power standards with, at most, the use of an çxt~rn~l transformer.
1. The system preferably ~clrulllls its required capability or functionality with an input power of 100 to 130 VAC, 50 to 60 Hz.
2. Under power conditions that would result in the inability of the system to ~c.rullll its required functions, the system preferably is driven to a fail-passive state.
In one embodiment, PHTS 100 provides closed loop control of the water, blood, and body Lelllp~ldLu~,S. See Figure 5A showing the control block dlagram.
1. The blood pump rate preferably is increased at a rate not PYceerlinp the blood pump rate warning threshold. See Table 1, Alarm and Warning Conrlition~.
2. The blood pump rate preferably is set by operator input only. That is to say, the system will not change the blood pump rate autom~ti- ~lly. However, the system will ramp the blood pump rate to the rate selected by the GpGldLol at an acceleration that does not exceed the warning threshold.
3. The blood-flow rate preferably is adjustable from 0 to 1.2S
liters/minute in steps of 10 millilit~r~/minute with an accuracy of millilit~r~/minute.
4. PHTS 100 preferably autom~ti~ ~lly starts and stops the water pump -to ~,~,rO.. its functions.
5. PHTS 100 preferably automatically starts and stops the water heater 350 and water cooler 360 to perform its functions.
6. PHTS 100 preferably only uses the heater 350 while heating and ms.i . .l;.; . .i .~ the Lt;~ alulc of the subject (i.e. will not use the water cooling fan of water cooler 360).
7. PHTS 100 preferably only use the water cooling fan of water cooler 360 while cooling the subject (i.e. will not use the heater 350).
8. PHTS 100 preferably controls the water tGlll~ldLu.~ so that water-te;~,c~dlu~c-related warnings are not violated.
9. PHTS 100 preferably controls the blood IGlllp~,ldLulc so that blood-tGlllp~ldLul~i warnings are not violated.
10. PHTS 100 preferably controls the body telll~cldLul~s so that body and Lylllpal~ic tGlll~,ldlulc warnings are not violated.
11. PHTS 100 preferably uses the water telll~Gldlul~ to control the blood telll~Gld~ e, the blood telll~GldLul.~ to control the body lGlll~c.dLulc. Within the warning threshold limits, PHTS 100 preferably dUGllllJt~ to drive the subject body tGlll~ldLul~ to the target tGlll~eldlulG for the therapy duration selected.
Manual Control In one embo~lim~nt PHTS 100 provides the op~.dlor, via the manual control panel, the ability to m~ml~lly control the water pump, water heater, water cooling fan, and the blood pump rate. Even in manual mode, PHTS 100 mo~.ilc.. ;I~g will disable certain system control outputs upon warning and/or alarm activation.
25 1. PHTS 100 preferably reacts to op~.dlor selection on the manual front panel within 0.25 seconds.
2. Upon activation of a switch on the manual panel, PHTS 100 preferably stops automatic LG---~,G.dlul~ control of the water.
- 3. While the water pump is turned offm~ml~lly, PHTS 100 preferably turns the water heater and water cooling fan off.
4. Upon the OpG.dlol selecting manual control of the blood pump speed, PHTS 100 preferably sets the automatic speed to zero. This is to prevent the blood pump from starting automatically when the u~,.dloL selects automatic control after selecting manual control.
5. The manual control panel blood pump rate switch preferably is S capable of comm~n-ling a blood pump rate from 0 to 1.25 l/min.
Operator Input In one embodiment, PHTS 100 provides an op~.dlor an input capability via the display and bezel button switches listed in Table 3, Operator Input.
Table 3. Operator Input OperatorIn~ut Description B~ Tnt~rval 1. ch~ lict items yes/no 2. blood pump rate 0 to 1.25 I/min 0.10 l/min.
3. target body-core average t~ p~,.dlule 37 to 43 ~C 1.0 ~C
4. time at target telll~eldLu-~ 0:10 to 3:00 10 mimltes 5. log file annotations See Table 4 Table 4. ~ ;ct of I,o~ Fil~ ~nnotation~
T o~ File Ann~t~tion Text 1. Te~ .dlul~, probe change 2. Beta blocker ~-lminictered Monitoring In one embo-lim~nt PHTS 100 is dçci~nf d such that, upon the oc-;u~ nce of a warning condition, the display is r.hsmgp(1, if n~c~ , to provide information as to the precise nature of the warning.
In one embodiment, PHTS 100 is dccign~d such that upon the occurrence of an alarm condition, the display is changed delinP~ting the alarm.
In one embodiment, PHTS 100 is r1~ci~n~d such that the bezel button and screen interaction is impl~m~nted in order that an explicit alarm acknowledge isrequired before other information is displayed or u~ dLor selections allowed.
In one embodiment, PHTS 100 is dçcign~d such that to avoid nllic~n~e WO 97/06840 PCTrUS96/11476 alarm and warning display changes, transitioning in and out of an alarm or warning condition within a fixed time after that alarm or warning has been deline~tt-~1, does not cause a screen change.
In one embo-liment, PHTS 100 is designed such that PHTS 100 le~J,uilcs that at least 3 of the 4 body tt~ aLule probes be c~nnPcted, both Iylllpal~ic t~ dLule probes, both blood telll~ dLLIre probes, and both water t~;lllp~,~dluleprobes for operation.
In one embo-lim~nt, PHTS 100 is dc~i ned such that PHTS 100 monitors for and declares warning and alarm conditions as defined in Table 1, Alarm and 10 Warning Conditions.
In one embodiment, PHTS 100 is desi~n~d such that PHTS 100 provides the operator the capability to remove one of the four body Ltlllpcldlul~, probesfrom monitoring and use during calculations.
Operational Phases In one embodiment, PHTS 100 ~iU~J~JOlk; the following operational phases:
Power Up, Self Test phase, controlled by power-on self-test module 502, which:
1. In one embotlimPnt> upon power up, PHTS 100:
a) checks if the previous hyperth~ormi~ session had completed.
b) if the previous session had been completed, initi~tes power up self test.
c) if the previous session had not been completed and was started less than four hours ago, PHTS 100 by~a~ses the power up self test and enters the setup phase.
2. In one embo-lim~nt, PHTS 100 tests all inputs and outputs that do not require operator intervention.
- 3. In one embodiment, if the power up self test completes without any errors detecterl PHTS 100 enters the setup phase.

The setup phase, controlled by operator start-procedure checklist module 504, occurs when the operator is p~ g the device for connection to the subject. It provides part of the initial check-offrequired prior to commencementof a therapy session:
1. PHTS 100 preferably lists each step of the set up check list and display operator selections.
2. PHTS 100 preferably allow the operator to bypass any age of the checklist.
3 PHTS 100 preferably preheat the water to the water to blood warning limit.
4. The fluid that is used to prime the blood lines preferably is preheated to the blood to body warning limit.
5. PHTS 100 preferably allow and facilitate the priming of disposable subsystems as neces~ ~ for proper operation.
6. PHTS 100 preferably verifies water heating and cooling system functionality.
7. PHTS 100 preferably verifies blood pump functionality.
8. PHTS 100 preferably verifies the functionality of safety s~n~or~
9. PHTS 100 preferably verifies the blood pump tachometer calibration.
The subject-body-heating phase, controlled by body heating module 520, occurs when the operator completes the set up phase and initi~t~ a therapy session. Heat is applied to the water subsystem insuring that temperature 25 restrictions outlined above are enforced. The rate of rise for the body-core Ltl..p~,ldLu.e is one of the controlling parameters for this process. Once the body ~lll~J~,ldLul~; has been held at the target telllpeldLul~ for the al~plopliate period of time, the controlled cooling cycle is started. The physician will be the final arbiter as to whether or not a particular therapy session has been properly 30 completed:
I . Upon completion of the set up check list, PHTS 100 preferably enters the subject body heating phase.
2. PHTS 100 preferably drives the subject body-core average tCl~ dlUl~ to the target tclll~cldlul., while staying within the limits of Table 1, Alarm and Warning Conditions.
- 5 The subject-body-tclllpe.dLulc-m~ le~ ce phase, controlled by m~ g-body-tclll~Jcld~ule-at-target module 522, occurs when the proper target body-core telll~crdLule has been reached. PHTS 100 simply ..,i~ the target body-core tClllp~.dlUlC and monitors the LclllpcldLul~ dirr.,.~.lces between various probes to insure that no limits are exceeded:
1. Upon the average body-core tclllpeldLule rea~hing the target tcnl~cldlulc, PHTS 100 preferably enters the subject body Le~ cldLulc m~int~n~n~e phase.
2. PHTS 100 preferably m~int~in~ the subject body tem~,eldlule to within 0.5~C ofthe target l~ f~ , for the therapy duration while staying within the limits of Table 1, Alarm and Warning Conditions.
The subject-body-cooling phase, controlled by body cooling module 524, occurs when the required period of time for the therapy has been reached. In oneembodiment, ambient air is used to cool the water while in~ lrin~ that 20 tC~ dlUlC control restrictions are enforced. The rate of fall for the body-core telll~ dlulc is one of the controlling parameters for this process:
1. Upon the therapy duration el~p~ing, PHTS 100 preferably enters the subject body cooling phase.
2. PHTS 100 preferably drives the subject body-core average L~ dlul~ to 37~C while staying within the limits of Table 1, Alarm and Warning Conditions.
3. Upon the subject body-core average ~elll~,.dlul~, re~rhing 37~C, PHTS 100 preferably m~int~in~ the body-core - average Lcl.~e.dlule until the opcldtor stops the blood pump, while staying within the limits of Table 1, Alarm and Warning Conditions.

W O 97/06840 PCTnUS96/11476 The disposable subsystem 301 is an vital part of PHTS operation. The tc~ ldLul~ probe sensor technology chosen preferably is:
1. Accurate to within ~ 0.1 ~C for the entire t~,l,E,~ .dL lre range from 35 ~C through 65 ~C. It is not l-~ce~ that these sensors be linear in operation; however, their operation I"c r~.dbly is predictable enough such that the output can be interpolated or extrapolated by a processor to achieve the accuracy specified above.
2 Intrinsically non-hazardous (other than the bio-hazard resulting from use).
3. St~rili7~ble (or procured as a pre-sterilized unit), since some of these probes are implanted into the body mass or ecl in bodily fluids.
4. Small, in order to facilitate implantation. Target size for the probe is a 1.5 millimPt~r~ mpter cylinder which tapers imme~ tely to a ~ m~oter sufficient only to retain the electrical cabling interface. The geom~t y and electrical co~ e.;Lions to this probe must f~-~ilit~t~ pl~m~nt into various body cavities.
5. Bio-col"~dtible. The tc.ll~.dLulc: sensor must have a bio-cf mp~tihle coating that allows it to be placed in any body cavity without causing any deleterious effect on the subject.
6. Reliable. A failed sensor can cause the therapy session to be c~n~llerl, postponed, or inv~licl~tecl The sensor failure rate ~.ef. ~ably is less than 1 for every 10,000 hours of sensor use. Since each sensor is expected to be used for approximately 4 hours, this allows only 1 failure for each 2,500 sensors. Further, since 10 sensors are used in each therapy session, this means that 1 session in 250 may be hll~ u~L~d by a t~lllpc.dLule sensor failure of some type.

W O 97/06840 PCTrUS96/11476 7. Inexpensive, since they are disposable.
The ~re;,~ule sensor 326 is used to monitor the blood pump 330 output.
Either insufficient or excessive ~ iUlC iS a sign of possible serious malfunction.
This sensor interface preferably is:
1. Sterile. The actual pump int~rf~re coupling is required to be sterile and disposable.
2. Intrinsically non-hazardous. The disposable portion of the sensor interface preferably is non-hazardous (other than the biohazard rçsllltinp; from use).
3. In~ellsive. The actual pump interface coupling after sterilization and p~rk~ing preferably is less than $2.00 each in qll~ntitiçs In one emborlimPnt PHTS 100 is int~n-le(l for use in an op~.dLil~g-room c llvh~ lllllent, outside of the sterile field. This device preferably is capable of 15 storage and transport under the following conditions:
1. Ambient t~ alùl~ range, beLweell -55 to 70 ~C (-67 to 158 F) typically 18 ~C (65 F).
2. Moderate dust 3. Relative hllmiclity, ranging from 0-90%
4. Drop rçsi~t~nt, not ~xceefiing 150 millim~ter.s (6 inches) In one embo-lim~nt PHTS 100 is used to treat and control Acquired T...,.,--"r Deficiency Syndrome (AIDS).
In another embo-limPnt, PHTS 100 is used to treat and control cancer. It is thought that hyperth~rmi~ works in cancer due to a direct effect 25 upon the mitotic activity of cell growth. Cancer is a rapidly growing tissue with a non-dirr~ t~d cell structure. M~lign~nries that are formed exhibit circulatory collapse after hyperthermia with a stim~ tion of tumor-modlll~ting factors. Empirically, hyperthermia induces a localization factor that affects the - tumor, independent of normal tissue. Other factors which may relate to the 30 effect of WBHT on cancer may include water balance of the entire patient versus water balance within cancerous or virus-infected tissue.

WO 97/06840 PCTrUS96/11476 In one embodiment, blood-flow rates of belwt;ell 2 and 4.5 liters per minute though ECC 300 are provided for.
In one embodiment, whole-body hyperthermia is provided for. In another embodiment, perfusion to a single limb, or even local application of heat S to a tumor by perfusion are provided for.
It is to be understood that the above description is inten~le-1 to be illustrative, and not restrictive. Many other embodiment~ will be a~ L to those of skill in the art upon reviewing the above description. The scope of theinvention shouid, therefore, be ~l~l~....i.~e~l with reference to the appended 10 claims, along with the full scope of equivalents to which such claims are entitled.

Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A use of a computer system for hyper/hypothermia treatment of a physiological fluid having a temperature. comprising the steps of:
storing in said computer system a set of parameters representing:
a first rate of temperature change, a first predetermined temperature that is different than a normal physiological temperature of a human, a first predetermined length of time, a second rate of temperature change, and a second predetermined temperature;
maintaining an extracorporeal flow of the physiological fluid;
receiving into the computer system a plurality of temperature signals, the temperature signals representative of temperatures at each of a plurality of locations;
generating a series of temperature values and temperature-rate-of-change values representative of one of the temperatures;
comparing, in the computer system, the temperature values and temperature-rate-of-change values to values in the set of stored parameters in the computer system to generate a series of comparison values;
automatically controlling the temperature of the physiological fluid based on the series of comparison values to effect the first rate of temperature change of the one of the temperatures, to then maintain the temperature value at the first predetermined temperature for the first predetermined length of time, and to then change the temperature value at the second rate of temperature change until the temperature value reaches the second predetermined temperature.

2. The use according to claim 1, wherein the physiological fluid is blood.

3. The use according to claim 1, wherein the physiological fluid is saline.

4. The use according to claim 2 or claim 3, further including the step of:
measuring a time difference between a starting time and a current time;
and wherein the step of comparing further includes comparing the time difference to a stored parameter in the computer system in order to maintain the temperature value at the first predetermined temperature for the first length of time.

5. The use according to claim 2 or claim 3, further including the steps of:
interactively presenting a checklist to a user and eliciting and receiving checklist input from the user; and controlling operation of the computer system based on the checklist input from the user.

6. The use according to claim 2 or claim 3, further including the step of:
repeatedly verifying correct operation of the computer system with a self-test program.

7. The use according to claim 2 or claim 3, further including the step of:
repeatedly verifying correct coupling of the computer system to components external to the computer system with a self-test program.

8. The use according to claim 2 or claim 3, further including the steps of:
providing a short excitation pulse to a temperature transducer in order to reduce heating of the transducer and to reduce electrical hazards;
selecting an analog response signal from the transducer; and converting the analog response signal to a digital value.

9. A perfusion hyper/hypothermia treatment system (PHTS) including means for maintaining a flow of physiological fluid having a temperature, means for changing the temperature of the physiological fluid, and means for perfusing the physiological fluid into the patient, the system comprising:
a computer system, the computer system including storage that holds a set of stored parameters representing:
a first rate of temperature change, a first predetermined temperature that is different than a normal physiological temperature of a human, a second rate of temperature change, and a second predetermined temperature;
a receiver, coupled to the computer system, that receives a plurality of temperature signals, the temperature signals representative of temperatures at each of a plurality of locations;
means for generating a series of temperature values and temperature-rate-of-change values representative of one of the location's temperatures;
a comparator coupled to receive the series of temperature values and to receive the set of stored parameters in the computer system, and that generates a series of comparison values; and a signal generator which generates a control signal to control the temperature of the physiological fluid based on the series of comparison values to effect the first rate of temperature change of the one of the temperatures, to then maintain the temperature value at the first predetermined temperature for a first length of time, and to then change the temperature value at the second rate of temperature change until the temperature value reaches the second predetermined temperature.

10. The system according to claim 9, wherein the physiological fluid is saline.

11. The system according to claim 9, wherein the physiological fluid is blood.

12. The system according to claim 9, further comprising:
means for measuring a time difference between a start time and a current time; and wherein the comparator includes means for comparing the time difference to a stored parameter in the computer system in order to maintain the temperature value at the first predetermined temperature for a first length of time.

13. The system according to claim 9, further comprising:
means for verifying correct operation of the computer system with a self-test program.

14. The system according to claim 9, further comprising:
means for interactively eliciting and receiving checklist input from a user;
and means for controlling operation of the computer system based on the checklist input.

15. The system according to claim 9, wherein the means for changing the temperature of the physiological fluid further comprise:
a heat exchanger; and a heat-exchange-fluid conditioner coupled to the heat exchanger and coupled to the computer system, which, together with the heat exchanger, changes the temperature of the physiological fluid based on the control signal.

16. The system according to claim 15, wherein a pressure of a heat-exchange fluid in the heat exchanger is maintained at a lower pressure than a pressure of the physiological fluid in the heat exchanger, in order that any leaks cause the physiological fluid to leak out of its passage rather than having the heat-exchange fluid get into the passage.

17. The system according to claim 15, wherein at least a portion of a tubing holding a heat-exchange fluid in the heat exchanger is substantially clear in order to detect leaks of blood into the heat-exchange fluid.

18. The system according to claim 15, the system further comprising:
a main unit; and wherein the heat exchanger comprises:
a replaceable blood-flow heat-exchanger cartridge, the heat-exchanger cartridge having an end connector and a physiological-fluid path which provides an enclosed physiological-fluid passage within the heat-exchanger cartridge and extending through the end connector; and a heat-exchanger structure mounted to the main unit and configured to have the heat-exchanger cartridge inserted into the heat-exchanger structure and to have heat-exchange fluid introduced into the heat-exchanger structure and circulated around and/or through the blood-flow heat-exchanger cartridge.

19. The system according to claim 15, the system further comprising:
a main unit; and wherein the means for maintaining a flow of physiological fluid comprises:
a physiological-fluid-pump interface cartridge, the physiological-fluid-pump-interface cartridge comprising:
a substantially rigid connector; and a physiological-fluid path comprising a deformable plastic enclosure assembled to the connector; and a physiological-fluid pump structure mounted to the main unit and configured to have the physiological-fluid-pump interface cartridge attached thereto and to provide mechanical energy to the physiological-fluid-pump interface cartridge, wherein the pump structure and the connector cooperate to provide a predetermined occlusion to the deformable plastic enclosure when the physiological-fluid-pump interface cartridge is attached to the physiological-fluid-pump structure.

20. The system according to claim 15, the system further comprising:
a main unit;
a physiological-fluid-pump structure mounted to the main unit;
a heat-exchanger structure mounted to the main unit;
a replaceable perfusion system interface assembly, the perfusion system interface assembly comprising:
a replaceable physiological-fluid heat-exchanger cartridge, the heat-exchanger cartridge comprising:
at least one end connector; and a physiological-fluid path comprising an enclosed physiological-fluid passage within the heat-exchanger cartridge which extends through the end connector; and a replaceable physiological-fluid-pump-interface cartridge coupled to the heat-exchanger cartridge, the physiological-fluid-pump-interface cartridge comprising:
a substantially rigid connector; and a physiological-fluid path comprising a deformable plastic enclosure assembled to the connector, the connector providing a predetermined occlusion to the deformable plastic enclosure when attached to the physiological-fluid-pump structure.

21. The system according to claim 9, further comprising:
a plurality of temperature transducers that provide the temperature signals;
a circuit coupled to the transducers that provides a short excitation pulse, one at a time and sequentially to each transducer, in order to reduce heating of the thermistors and to reduce electrical hazards;
a multiplexor coupled to the thermistors that selects an analog response signal from one of the thermistors at a time; and an analog-to-digital (A/D) convertor coupled to an output of the multiplexor.

22. The system according to claim 9, wherein a mass of heat-exchange-fluid in the heat exchanger and the heat-exchange-fluid conditioner and a circuit there between is minimized in order to improve a response time of the system.

23. The system according to claim 11, wherein a volume of blood in the blood circuit is minimized in order to reduce the amount of blood outside the patient and to improve the response time of the system.

24. The system according to claim 9, further comprising a computer-display screen wherein a graphical visualization of monitored temperatures is presented.

25. The system according to claim 9, further comprising:
a data recorder that provides a recording over time of one or more of a set of measured parameters is provided.

26. The system according to claim 9, wherein the set of stored parameters includes parameters representing a maximum allowed temperature differential between two specified body temperatures, and wherein the control signal is adjusted to control the temperature of the physiological fluid based on a comparison value determined based on the maximum allowed temperature differential.