(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2002/0013537 A1
`
`Rock
`(43) Pub. Date:
`Jan. 31, 2002
`
`US 20020013537A1
`
`(54)
`
`IMPEDANCE SPECTROSCOPY SYSTEM
`AND CATHETER FOR ISCHEMIC
`MUCOSAL DAMAGE MONITORING IN
`HOLLOW VISCOUS ORGANS
`
`(76)
`
`Inventor: Emilio Sacristan Rock, Santa Ursula
`Xitla (MX)
`
`Correspondence Address:
`Commonwealth of Massachusetts
`
`171 Dwight Road
`Longmeadow, MA 01106-1700 (US)
`
`(21) Appl. No.:
`
`09/907,781
`
`(22)
`
`Filed:
`
`Jul. 18, 2001
`
`Related US. Application Data
`
`(63) Non-provisional of provisional
`60/219,281, filed on Jul. 19, 2000.
`
`application No.
`
`Publication Classification
`
`(51)
`
`Int. Cl.7 ................................ A61B 5/05; A61B 5/04
`
`(52) us. Cl.
`
`............................................ 600/547; 600/372
`
`(57)
`
`ABSTRACT
`
`An impedance spectroscopy system for monitoring ischemic
`mucosal damage in hollow viscous organs comprises a
`sensor catheter and an impedance spectrometer for electri-
`cally driving the catheter to obtain a complex tissue imped-
`ance spectrum. Once the catheter is in place in one of a
`patient’s hollow viscous organs, the impedance spectrom-
`eter obtains the complex impedance spectrum by causing
`two electrodes in the tip of the catheter to inject a current
`into the mucosal tissue at different frequencies, while two
`other electrodes measure the resulting voltages. A pattern
`recognition system is then used to analyze the complex
`impedance spectrum and to quantify the severity of the
`mucosal injury. Alternatively, the complex impedance spec-
`trum can be appropriately plotted against the spectrum of
`normal tissue, allowing for a visual comparison by trained
`personnel.
`
`
`
`Nevro Corp.
`Ex. 1017
`
`US. Patent No. 8,650,747
`
`Nevro Corp.
`Ex. 1017
`U.S. Patent No. 8,650,747
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 1 0f 13
`
`US 2002/0013537 A1
`
`20
`
`22
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`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 2 0f 13
`
`US 2002/0013537 A1
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`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 3 0f 13
`
`US 2002/0013537 A1
`
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`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 4 0f 13
`
`US 2002/0013537 A1
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`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 5 0f 13
`
`US 2002/0013537 A1
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`Patent Application Publication
`
`Jan. 31, 2002 Sheet 6 0f 13
`
`US 2002/0013537 A1
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`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 7 0f 13
`
`US 2002/0013537 A1
`
`A
`
`LEVEL OF
`MUCOSAL
`
`DAMAGE
`
`NORMAL
`.t.
`
`CAPILLARY
`PERM EABI LITY
`
`I
`
`MUCOSAL
`PERMEABILITY
`
`I
`
`VILLOUS LAYER
`T
`CRIPT LAYER
`I
`MUSCLE
`LAYER
`I
`/———8—-——~ TIME (HOURS)
`
`9
`
`FIG. 6
`
`VOLTAGE
`
`15d
`16c
`I6b
`COMPLEX
`
`MEASUREMENT
`
` 160 i
`
`IBo—IBd
`
`FIG. 7
`
`CURRENT
`
`DISTRIBUTION
`
`EQUIPOTENTIAL
`LINES
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 8 0f 13
`
`US 2002/0013537 A1
`
`2(0)
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`7
`
`_.._
`'
`
`Normal
`lschemic
`
`/
`
`/
`
`
`
`1.0 —
`
`0 5 A‘
`
`0.0M
`1e+1
`1e+2
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`Frequency (Hz)
`
`FIG. 8A
`
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`
`40
`
`20
`
`0
`
`-20
`
`-4O
`
`-60
`
`-80
`
`-100
`
`-120
`
`
`
`/
`
`Normal
`—’- lschemic
`_._
`
`r—-———r-———-1-———T———‘_"‘—
`1e+1
`1e+2
`1e+3
`16”
`19*5
`Frequency (Hz)
`
`FIG. SB
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 9 0f 13
`
`US 2002/0013537 A1
`
`_..—
`_._
`
`Normal
`lschenflc
`
`
`
`FIG. 8C
`
`3.5
`
`Normal
`lschemic
`
`-°-'
`_.._.
`
`2(0)
`
`1e+1
`
`1e+3
`1e+2
`Frequency (Hz)
`
`1e+4
`
`”+5
`
`FIG. 9A
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 10 0f 13
`
`US 2002/0013537 A1
`
`¢ (°)
`
`40
`
`20
`
`.2:
`
`-40
`.60
`80
`'
`.100
`
`I 11W
`
`X
`
`L
`
`I
`
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`
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`
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`
`Normal
`lschemic
`
`420W
`1e+1
`1a+7
`1p+3
`1o+d
`1e+5
`
`Frequency (Hz)
`
`FIG. 9B
`
`
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 11 0f 13
`
`US 2002/0013537 A1
`
`3.5
`
`Normal+
`--I
`Ischemic
`
`
`
`1e+1
`
`1e+3
`1e+2
`Frequency (Hz)
`
`1e+4
`
`1e+5
`
`FIG. 10A
`
`2(0)
`
`4? (°)
`
`4
`
`0
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`~80
`
`400
`
`-120
`
`Normal
`+ Ischemic
`-i—
`
`T
`
`
`
`p/
`
`FIG. 1013
`
`L
`
`\ I
`
`
`1e+1
`1e+2
`1e+3
`1e+4
`1e+5
`Frequency (Hz)
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 12 0f 13
`
`US 2002/0013537 A1
`
`_.._ Normal
`——o—— lschemic
`
`2
`
`26mm
`
`Real 2
`
`
`
`FIG.
`
`10C
`
`Z(Q)
`
`1e+1
`
`1e+2
`
`1e+3
`
`“3+4
`
`“3+5
`
`FIG. 11A
`
`

`

`Patent Application Publication
`
`Jan. 31, 2002 Sheet 13 0f 13
`
`US 2002/0013537 A1
`
`40
`
`480
`
`-100
`
`—0—- Normal
`——I——|schenflc+repedused
`
`-120
`
`r——‘—’I—‘——F"‘““‘-—"‘T——-"‘I—___
`1e+1
`1e+2
`1e+3
`1e+4
`1e+5
`
`f (Hz)
`
`FIG.
`
`1 18
`
`X
`
`2
`
`-—~— Normal
`
`+ Ischemic+reperfused
`
`
`
`FIG.
`
`11C
`
`

`

`US 2002/0013537 A1
`
`Jan. 31, 2002
`
`IMPEDANCE SPECTROSCOPY SYSTEM AND
`CATHETER FOR ISCHEMIC MUCOSAL DAMAGE
`MONITORING IN HOLLOW VISCOUS ORGANS
`
`[0001] This application claims the benefit of a Provisional
`Application, Serial No. 60/219,281 filed Jul. 19, 2000.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to systems and inter-
`nal sensors for monitoring and quantifying ischemic damage
`in tissues.
`
`BACKGROUND OF THE INVENTION
`
`[0003] The gastrointestinal mucosa is at great risk of
`ischemia in the critically ill, and its disruption has been
`shown to be the motor of multiple organ failure, a leading
`cause of death. Knowledge of the level of damage can help
`guide therapy, reversing moderate damage and/or preventing
`further complications. For example, as indicated by path A
`in FIG. 6, the status of a healthy person’s mucosa changes
`little, if at all, over time. Path C shows how the damage level
`of an ill person’s ischemic mucosa greatly increases over the
`course of several hours if unchecked. However, as shown by
`path B, further damage can be arrested if the ischemic
`damage is detected and an appropriate course of treatment is
`undertaken. Unfortunately, there exists no clinically suitable
`method to directly monitor ischemic mucosal damage in the
`gastrointestinal tract of the critically ill patient.
`
`Impedance spectroscopy has been used to detect
`[0004]
`ischemia (a condition of inadequate blood flow and oxygen
`delivery to a given tissue) in biological tissues using differ-
`ent instrumental methods. Impedance spectroscopy differs
`from other impedance measurements (which have long been
`used for a variety of biomedical applications such as cardiac
`output estimation, body fat measurement, and plethismog-
`raphy) in that it involves multiple measurements over a
`range of frequencies that as a whole contain significantly
`more information of the structural and electrical properties
`of the sample. For example, US. Pat. No. 5,454,377 to
`Dzwoczyk et al. teaches the assessment of ischemia in the
`myocardium, US. Pat. No. 5,807,272 to Kun et al. teaches
`the assessment of ischemia in directly accessible tissues
`(surface or subjacent tissue), and US. Pat. No. 6,055,452 to
`Pearlman shows the general characterization of the status
`and properties of tissues. However, none of these references
`show or describe a clinically acceptable method for imped-
`ance spectroscopy measurements of the inner wall of hollow
`viscous organs such as the gastrointestinal mucosa, in vivo
`or in situ.
`
`[0005] On the other hand, several other methods have
`been devised to detect and/or monitor gastrointestinal
`ischemia using different measurement technologies. These
`include tonometry (as shown in US. Pat. Nos. 5,788,631
`and 6,010,453 to Fiddian-Green), direct in situ measurement
`using an electrochemical sensor (as shown in US. Pat. No.
`5,158,083 to Sacristan), and direct
`in situ measurement
`using an optochemical sensor (as shown in US. Pat. No.
`5,423,320 to Salzman et al.) Additionally, US. Pat. No.
`5,771,894 to Richards et al. shows external, non-invasive
`measurement using a magnetometer.
`
`[0006] Numerous gastrointestinal catheter combinations,
`using electrodes or other sensors, have been used over the
`
`years for various measurements and medical applications.
`For example, US. Pat. No. 5,657,759 to Essen-Moller
`discloses a gastrointestinal output catheter, US. Pat. Nos.
`5,848,965 and 5,438,985, both to Essen-Moller, show a
`gastric pH sensor/catheter combination, and US. Pat. No.
`5,477,854 to Essen-Moller discloses a helicobaterpylori
`gastric infection sensor. Furthermore, US. Pat. No. 5,833,
`625 to Essen-Moller shows a gastric reflux monitor, US.
`Pat. No. 6,010,453 to Fiddian-Green shows a pressure
`nasogastric sump and tonometer combination, US. Pat. No.
`5,158,083 to Sacristan et al. discloses a miniature pCO2
`probe and catheter, and US. Pat. No. 5,423,320 to Salzman
`et al. shows an air tonometry sensor and catheter.
`
`[0007] Several therapies have been proposed to limit or
`reverse the gastrointestinal mucosal damage and/or the
`associated complications in critical patients, including, for
`example, aggressive hemodynamic resuscitation (as shown
`in Gutierrez et al.), NO synthase modulators (as shown in
`US. Pat. No. 5,585,402 to Moncada et al.), rBPI protein (as
`shown in US. Pat. No. 6,017,881 to Ammons et al.), oral
`glutamine (as shown in US. Pat. No. 5,981,590 to Panigrahi
`et al.), and DHEA (as shown in US. Pat. No. 5,922,701 to
`Araneo). All of these can be optimally effective if they are
`administered within ideal treatment time windows depend-
`ing on the status of the mucosa.
`
`[0008] Accordingly, it is a primary object of the present
`invention to provide an impedance spectroscopy system, not
`only for detecting ischemia, but also for monitoring and
`quantifying ischemic mucosal damage,
`that
`is of great
`clinical value as a therapeutic guide for patients with intes-
`tinal ischemia and/or shock.
`
`[0009] Another primary object of the present invention is
`to provide a catheter, for use with an impedance spectros-
`copy system, that is optimized for impedance spectroscopy
`in hollow viscous organs.
`
`[0010] Yet another primary object of the present invention
`is to provide an impedance spectroscopy system and catheter
`for the continuous monitoring of the level of damage of the
`gastric mucosa in critically ill patients.
`
`SUMMARY OF THE INVENTION
`
`[0011] An impedance spectroscopy system for monitoring
`ischemic mucosal damage in hollow viscous organs com-
`prises a sensor catheter and an impedance spectrometer for
`electrically driving the catheter to obtain a complex imped-
`ance spectrum of tissue proximate the catheter. According to
`the present invention, the complex impedance spectrum is
`used to determine the extent to which the tissue is damaged,
`as opposed to determining if the tissue is ischemic. More
`specifically, as mentioned above, ischemia is a condition of
`inadequate blood flow and oxygen delivery to a given tissue,
`which may or may not result in tissue damage (i.e., ischemic
`tissue can be undamaged, and vice versa). Thus, detecting
`tissue ischemia does not result in a measurement of tissue
`
`damage, and a different process, as implemented in the
`present invention, must be utilized to do so.
`
`[0012] The catheter, which is configured to be inserted
`into any hollow viscous organ, comprises four Ag/AgCl
`electrodes positioned on an end tip of the catheter. The
`electrodes are functionally ring-shaped, and are coaxially
`spaced apart a short distance from one another. The outer
`
`

`

`US 2002/0013537 A1
`
`Jan. 31, 2002
`
`two ring electrodes inject current into the tissue, and the
`inner two electrodes measure the resulting voltage. Leads,
`electrically connected to the electrodes, extend along the
`wall of the catheter tubing or in a lumen portion of the
`tubing, and terminate at an interface plug suitable for
`connection to the impedance spectrometer. Once the catheter
`is in place in one of a patient’s hollow viscous organs, the
`impedance spectrometer causes the electrodes in the tip of
`the catheter to inject a current into the mucosal tissue at
`different frequencies, allowing for the measurement of the
`tissue’s complex impedance spectrum. The spectrum con-
`tains information of the structural and metabolic status of the
`
`tissue, and can be used to quantify the level of damage. More
`specifically, the spectrum can be appropriately graphically
`plotted against the spectrum of normal tissue, allowing for
`a direct visual comparison by trained personnel, and, there-
`fore, an indication or measurement of damage. Alternatively,
`a standard pattern recognition system or the like may be used
`to automatically analyze the complex impedance spectrum
`and quantify the severity of the mucosal injury.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0013] These and other features, aspects, and advantages
`of the present invention will become better understood with
`respect to the following description, appended claims, and
`accompanying drawings, in which:
`
`[0014] FIG. 1 is a schematic view of an impedance
`spectroscopy system for monitoring ischemic mucosal dam-
`age in hollow viscous organs;
`
`[0015] FIG. 2A is a cross-sectional elevation view of a
`catheter for use with the impedance spectroscopy system;
`
`[0016] FIG. 2B is a perspective view of an electrode
`portion of the catheter;
`
`[0017] FIG. 2C is a cross-sectional plan view of an
`alternative upper portion of the catheter;
`
`[0018] FIG. 3 is a cross-sectional elevation view of a
`second embodiment of the catheter;
`
`[0019] FIG. 4A is an exploded view of a third embodi-
`ment of the catheter;
`
`[0020] FIG. 4B is an elevation view, partly in cross-
`section, of a portion of the catheter shown in FIG. 4A, once
`assembled;
`
`[0021] FIG. 4C is a detail view of a portion of FIG. 4A;
`
`[0022] FIGS. 5A-5C are perspective views of a fourth
`embodiment of the catheter;
`
`[0023] FIG. 6 is a diagrammatic graph showing mucosal
`structure (e.g., as lining an intestinal wall) and different
`courses of mucosal ischemic pathogenesis;
`
`[0024] FIG. 7 is a schematic illustration of the operation
`of the catheter; and
`
`[0025] FIGS. 8A-11C are various graphs or plots illustrat-
`ing how ischemic mucosal damage in hollow viscous organs
`is detected and/or quantified according to the present inven-
`tion.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0026] Turning now to FIGS. 1-11C, preferred embodi-
`ments of an impedance spectroscopy system 10 and cath-
`
`eters 12a-12d for ischemic mucosal damage monitoring in
`hollow viscous organs, according to the present invention,
`will now be given. The catheters 12a-12d are generally
`similar, in that each one has two or four electrodes with
`annular side surfaces positioned at a distal end of the
`catheter. For example, the catheter 12a comprises a flexible
`tube 14 and two or four generally cylindrical electrodes
`16a-16d disposed at one end thereof. The electrodes 16a-
`16d are electrically connected, via leads 18a-18d extending
`up through the tube 14, to an impedance spectrometer 20
`portion of the system 10. The spectrometer 20 is used in
`conjunction with a signal processing device 22, such as an
`appropriately-programmed general purpose computer, for
`processing the complex impedance spectrum to detect tissue
`damage. To monitor mucosal damage, the catheter is placed
`in one of a patient’s hollow viscous organs 24, and current
`is injected by two of the electrodes 16a, 16d at a range of
`frequencies. The other two electrodes 16b, 16c measure the
`resulting voltage spectrum, which is subsequently processed
`and analyzed by the spectrometer 20 and signal processing
`device 22.
`
`[0027] FIGS. 2A-2C show a first embodiment of the
`catheter 12a. The catheter 12a comprises the flexible plastic
`tube 14 that can be inserted in any hollow viscous organ
`(e.g., 14-16 french). At the distal end or tip of the tube 14 are
`located the two or four electrodes 16a-16d (i.e., the catheter
`can be provided with either two electrodes or four elec-
`trodes) that function as ionic-current-to-electronic-current
`transducers, such as Ag/AgCl electrodes. The electrodes are
`substantially identical. As shown in FIG. 2B, each has a
`cylindrical central portion 24 having a first diameter and an
`annular side surface, and two cylindrical extensions 26
`attached to the ends of the central portion and coaxial
`therewith. The extensions 26 have a second, reduced diam-
`eter, and each electrode 16a-16d has an axial through-bore.
`
`[0028] The electrodes 16a-16d are spaced equally apart
`from one another along the distal tip of the catheter 12a, and
`are separated by spacers (short lengths of tubing) 27a-27d.
`As best seen in FIG. 2A, the annular side walls of the central
`portions 24 of the electrodes 16a-16d are the only portions
`thereof that are exposed to the outside of the catheter 12a.
`Thus, each electrode 16a-16d is ring-like in functionality,
`and the distal end of the catheter (with the electrodes) is
`generally radially symmetric. The catheter, therefore, will
`provide the same measurements regardless of its radial
`orientation in an organ.
`
`[0029] The diameters of the central electrode portions 24
`are about the same as the outer diameter of the tube 14. This
`
`ensures that the outer surface of the catheter 12a is relatively
`smooth, e.g., that is has no more than minor surface rough-
`ness or undulations. The electrodes 16a-16d are respectively
`electrically connected to the leads 18a-18d (via soldering,
`welding, or the like) in the electrodes’ axial through-bores.
`The leads from the distal three electrodes 16b-16d extend
`
`through the axial through-bores of the other electrodes, as
`applicable. The electrodes 16a-16d,
`leads 18a-18d, and
`short portions of tubing are kept in place and stabilized via
`an epoxy or plastic fill 28.
`
`[0030] The catheter 12a may be a stand alone sensor
`catheter, or it may be provided as part of a feeding/sump
`tube or some other type of life support tube or catheter. For
`example, as shown in FIG. 2A, the catheter 12a doubles as
`
`

`

`US 2002/0013537 A1
`
`Jan. 31, 2002
`
`a feeding tube. More specifically, the end of the catheter 12a
`is provided with the electrodes 16a-16d, while the remainder
`of the tube 14 is left hollow to act as a feeding line 29.
`Additionally,
`the catheter tube 14 may include a second
`lumen for sampling and feeding, like a Levin type gastric
`catheter, and/or a third lumen for a vented feeding/sump
`tube, as in a Salem type gastric catheter. For example, as
`shown in FIG. 2C, the electrical leads 18a-18d extend down
`through a side wall portion of the tube 14 having a vent
`lumen 30 and a feeding/sump lumen 32.
`
`[0031] To manufacture the catheter 12a, the leads 18a-18d
`are fed through the tube 14, if needed (since the leads may
`be provided as part of the tube 14 during the tube’s manu-
`facturing process), and through the electrode through-bores,
`as applicable. The leads are subsequently electrically con-
`nected to the respective electrodes. Then,
`the proximate
`electrode 16a is inserted in the end of the tube 14, one of the
`short lengths of tubing is affixed to the proximate electrode
`16a, and so on. Adhesive may be used to hold the compo-
`nents together in this manner. Finally, the plastic or epoxy
`fill 28 is injected into the space between the tubing portions,
`electrodes, and partially into the tube 14, and is allowed to
`set. The end of the fill 28 is rounded, as shown in FIG. 2A,
`to ease insertion of the catheter into a patient. As will be
`appreciated by those of skill in the manufacturing arts, the
`catheter 12a can be manufactured according to a number of
`different methods and/or steps. For example, the catheter
`could be extruded from a machine.
`
`If the catheter 12a is provided with four electrodes,
`[0032]
`the two outer ring electrodes 16a, 16d inject a current into
`the tissue, and the two inner electrodes 16b, 16c measure the
`resulting voltage, as shown schematically in FIG. 7. In the
`two electrode configuration (not shown), the electrodes are
`used for both current source and voltage measurement. As
`mentioned above, the electrodes 16a-16d are respectively
`connected to the leads 18a-18d that provide an electrical
`connection to the other end of the catheter along the wall of
`the tubing or in the lumen. At the other, proximal end of the
`catheter, the leads 18a-18d end in an electrical multi-channel
`connector 34 that can be plugged into the impedance spec-
`trometer 20.
`
`[0033] FIG. 3 shows a second, alternative embodiment of
`the catheter 12b. Here, the catheter 12b has four tubular or
`ring-like electrodes 36a-36d simply placed over
`(and
`adhered to) the exterior surface of the tubing 14, with the
`leads extending from the electrodes down through the tube
`wall. In this case, the electrodes would have to be as thin as
`possible to minimize surface roughness.
`
`[0034] FIGS. 4A-4C show a third embodiment of the
`catheter 12c. The catheter 12c is generally similar to the
`catheter 12a, but has spacers 42, provided with annular
`internal lips,
`into which flanged electrodes 44 lock into
`place. More specifically, each flanged electrode 44 has a
`cylindrical central portion 46 having a first diameter and an
`annular side surface, two extensions 48 attached to the ends
`of the central portion and coaxial therewith, and an axial
`through-bore. The extensions 48 each have a second,
`reduced diameter, but instead of being purely cylindrical, the
`extensions 48 have annular lips 50 that face towards the
`central portion 46. Additionally, the spacers 42, which are
`made of flexible plastic tubing or the like, each have two
`annular,
`inwardly-facing shoulders 52 spaced back a bit
`
`from the open ends of the spacers 42. As shown in FIG. 4B,
`the electrode extensions 48 are dimensioned to fit within the
`
`spacers 42, such that the lips 50 abut the shoulders 52,
`locking the flanged electrodes 44 to the spacers 42.
`
`[0035] The catheter 126 is assembled similarly to the
`catheter 12a, as described above. More specifically, the leads
`18a-18d are electrically connected to the electrodes 44 and
`are threaded through the spacers and electrodes, and the
`electrodes 44 are locked into successive spacers 42 to form
`an assembly of two or four electrodes 44. As should be
`appreciated, since the electrodes 44 simply snap into the
`spacers 42, assembly is much quicker. Finally, the assembly
`is filled with the epoxy or plastic fill 28 to further hold the
`assembly together and to provide a rounded tip, e.g., as
`shown in FIG. 2A. Also, the ends of the leads 18a-18d are
`connected to the multi-channel connector 34.
`
`To give the catheter 12c a smooth, low-friction
`[0036]
`outer surface, the diameter of the central portions 46 of the
`electrodes 44 may be initially slightly greater than the outer
`diameter of the spacers 42, as shown in FIG. 4C. Then, once
`the catheter 12c is assembled,
`the outer surface of the
`catheter is sanded, removing the portions 54 of the elec-
`trodes 44 that extend past the spacers 42.
`
`[0037] FIGS. 5A-5C show a fourth embodiment of the
`catheter 12d. The catheter 12d comprises: an injection-
`molded, plastic tip 60; two or four electrodes 62a-62a'; one
`or three spacers 64a-64c (i.e., in the case of two electrodes,
`one spacer is needed, while three spacers are needed for a
`four electrode catheter); dual-lumen tubing 66 or the like;
`and the cables or leads 18a-18d. As best shown in FIG. 5B,
`the plastic tip 60 comprises a rounded fore portion 68 and a
`rounded, trough-like projection 70 that extends back from
`the fore portion 68. As indicated, the tip 60 can be injection
`molded, or it can be made via another suitable manufactur-
`ing process. The electrodes 62a-62d and spacers 64a-64c are
`generally similar in shape. Each has a small, cylindrical
`passageway 72 for the cables 18a-18d, as well as a rounded
`through-bore 74 through which the trough-like projection 70
`of the tip 60 is dimensioned to fit (i.e., the rounded through-
`bores 74 and projection 70 are complementary in shape).
`Additionally,
`the outer diameters of the electrodes and
`spacers are the same as the outer diameter of the tip 60,
`which has the same outer diameter as the tubing 66. To
`assemble the catheter 12d, the cables 18a-18d are respec-
`tively electrically connected to the electrodes 62a-62d, and
`alternating electrodes 62a-62d and spacers 64a-64c are slid
`over the projection 70. Simultaneously, the cables 18a-18d
`are inserted through the passageways 72, as applicable.
`Then,
`the portion of the projection 70 not covered by
`electrodes and spacers is slid into the tubing 66, as shown in
`FIG. 5A. Appropriate fastening means, such as a solvent or
`an adhesive, are used to hold the components of the catheter
`12d together.
`
`the rounded through-
`[0038] As should be appreciated,
`bores 74 and projection 70 can be provided in any of a
`number of complementary shapes. For example, the projec-
`tion and through-bores can be V—shaped, square, or circular.
`However, having a V— or trough-shaped projection, or a
`projection with another shape where the electrodes and
`spacers have to be oriented in a particular manner to be
`positioned over the projection, facilitates assembly and
`enhances structural stability.
`
`

`

`US 2002/0013537 A1
`
`Jan. 31, 2002
`
`[0039] Referring back to FIG. 1, the system 10 generally
`consists of three elements: any of the catheters 12a-12d; the
`impedance spectrometer 20; and the signal processing
`device 22. The impedance spectrometer 20 is an electronic
`instrument that includes electrical patient isolation and can
`measure the impedance spectrum of the mucosa in the range
`of 10 Hz (or thereabouts) to 10 MHZ (or thereabouts). The
`spectrum may be obtained by a frequency sweep from a
`synthesizer or by a pulse, and processed by such methods as
`synchronous demodulation or Fast Fourier Transform, or
`any other similar method. The output of the spectrometer 20
`is the complex impedance spectrum measured in digital
`form. Spectrometers and processing methods suitable for
`adaptation for use in the present invention are well known to
`those of skill in the art, for example, as shown in US. Pat.
`No. 5,807,272 to Kun et al., US. Pat. No. 5,633,801 to
`Bottman, and US. Pat. No. 5,454,377 to Dzwonczyk et al.
`The entireties of these patents are hereby incorporated by
`reference.
`
`[0040] Once the complex impedance spectrum is obtained,
`the results are processed by the signal processing device 22.
`The signal processing device 22 may be an appropriately-
`programmed general purpose computer, or a dedicated ana-
`log and/or digital device, both of which are well known to
`those of ordinary skill in the art. For processing the complex
`impedance spectrum obtained by the spectrometer 20, the
`signal processing device 22 may graph or plot the spectrum
`for visual analysis, as discussed in further detail below.
`Alternatively, the signal processing device 22 may utilize a
`pattern recognition algorithm or system (e.g., running as
`software) or the like for analyzing the complex impedance
`spectrum itself. The pattern recognition system uses a pre-
`viously trained or calibrated algorithm to classify the imped-
`ance spectrum measured and provided by the spectrometer
`20. The output of this system is a numerical score (or other
`reference point) in an ischemic damage index scale 80
`validated experimentally via MRI’s, chemical analysis,
`biopsy samples, or the like. In other words,
`the signal
`processing device 22, implementing the pattern recognition
`system, analyzes the impedance spectrum to determine to
`what extent the impedance spectrum of the analyzed tissue
`deviates from that of normal tissue. The degree and char-
`acter of deviation provides an actual measure of tissue
`damage, which translates into the ischemic damage index
`scale 80, as validated experimentally (e. g., heavily damaged
`tissue, as determined experimentally, will have a certain
`pattern, and slightly damaged tissue, as also determined
`experimentally, will have a different pattern).
`
`[0041] More specifically, as discussed above, the imped-
`ance spectrum of the analyzed tissue is obtained by making
`multiple complex impedance measurements at different fre-
`quencies over the range of interest. At each frequency, an
`amplitude, Z, and a phase,
`, of the tissue response are
`obtained. These values are then plotted as a function of
`frequency, or combined and plotted in the complex plane
`(resistance vs. reactance) in a Nyquist or a Cole-Cole plot
`(this latter term applies specifically to tissue impedance
`spectra plots), where resistance (R) and reactance (X) are
`defined as:
`
`R=Z cos
`X=Z sin
`
`Eq. 1.
`Eq. 2.
`
`[0042] Analysis of these plots shows that normal tissue
`spectra have a characteristic shape or pattern. According to
`
`the Cole-Cole electric model of biological tissues, this shape
`is the arc of a circle when plotted in the complex plane.
`However, if tissue is damaged after an extended period of
`ischemia,
`the spectra of the damaged tissue loses this
`characteristic shape. In fact, when plotted in the complex
`plane, the spectra of the damaged tissue become sigmoid- or
`S-shaped, deviating significantly from the normal
`tissue
`spectra.
`
`[0043] FIGS. 8A-11C show averaged experimental data
`obtained in the small intestine of a group of test subjects
`subjected to a period of intestinal ischemia followed by a
`period of reperfusion (restored blood flow), in comparison to
`a group of test subjects in which normal perfusion and
`oxygenation was maintained. The data is presented in both
`the frequency plots and in the complex plane. For the
`Nyquist plots (complex plane), the data has been normalized
`so that the shapes of the curves can be more easily com-
`pared, e.g., the point at the highest measurement frequency
`(300 KHz) has an adimensional impedance of 1 and a phase
`angle of 0.
`
`[0044] FIGS. 8A-8C show the impedance spectra of intes-
`tine with less than ten minutes of reduced blood flow,
`wherein the intestine is already ischemic, with associated
`rising acidity. In particular, FIGS. 8A and 8B show the
`average amplitude and phase impedance spectra, respec-
`tively, of both normal intestine and the intestine subjected to
`reduced blood flow, while FIG. 8C shows the normalized
`Nyquist plot of the normal and ischemic intestinal tissue. As
`can be seen, although the intestine with reduced blood flow
`is ischemic, the tissue is not yet damaged, and the spectra are
`not easily distinguishable from the spectra of the normally
`perfused intestines. Note that the spectra contain some noise,
`but resemble the circular arc predicted by the Cole-Cole
`model.
`
`[0045] FIGS. 9A and 9B show the average amplitude and
`phase impedance spectra, respectively, of both normal intes-
`tine and intestine after 1.5 hours of severe ischemia, while
`FIG. 9C shows the normalized Nyquist plot of the normal
`and ischemic intestinal tissue. Here, the ischemic tissue has
`suffered moderate damage, and the spectra have become
`clearly distinguishable B the ischemic tissue spectra have
`lost their circular shape and have taken on a sigmoidal shape
`with several inflection points.
`
`[0046] FIGS. 10A-10C show similar plots for normal
`intestines and intestines after two hours of severe ischemia.
`
`By now, the damage is even more severe, and the spectra
`have become even more distorted.
`
`[0047] FIGS. 11A-11C show the spectra of normal intes-
`tines and intestines after an hour of ischemia followed by 1.5
`hours of reperfusion. After an hour of ischemia, the tissue
`has suffered some damage. However, after being reperfused,
`most of this damage has been reversed, and the spectra of the
`damaged tissue have largely regained their characteristic
`shape, although they are still somewhat abnormal and are
`still moderately distinguishable from the spectra of the
`normal tissue.
`
`[0048] As should be appreciated, a plot or graph of the
`complex impedance spectrum of potentially damaged tissue
`versus the spectrum of normal tissue, e.g., as shown in FIGS.
`8A-11C, can be used by appropriately-trained personnel to
`determine the level of damage due to ischemia, by way of a
`
`

`

`US 2002/0013537 A1
`
`Jan. 31, 2002
`
`the signal processing
`visual comparison. Accordingly,
`device 22 may be configured to graph or plot the spectrum
`for visual analysis, accordingly the general guidelines given
`above, on a screen or monitor, or by way of a print-out.
`
`[0049] Alternatively, the signal processing device 22 can
`be configured to automatically determine tissue damage, by
`way of the pattern recognition system or other standard
`signal processing techniques, such as filtering, or smoothing
`and extracting inflection points by analysis of derivatives.
`Another alternative is the use of principal component
`decomposition or any other method of extracting a charac-
`teristic vector describing the shape of the spectrum. Such a
`characteristic vector can then be analyzed by a classifying or
`pattern recognition algorithm to provide a score in a prede-
`termined tissue damage scale. Such an algorithm can use one
`of many standard techniques for classification and/or pattern
`recognition, such as Bayesian statistics, neural networks,
`fuzzy logic, statistical classifiers, expert systems, or any