U.S. patent application number 10/508610 was filed with the patent office on 2005-07-28 for method and system for treating tissue swelling.
Invention is credited to Odland, Rick Mathew.
Application Number | 20050165342 10/508610 |
Document ID | / |
Family ID | 28040504 |
Filed Date | 2005-07-28 |
United States Patent
Application |
20050165342 |
Kind Code |
A1 |
Odland, Rick Mathew |
July 28, 2005 |
Method and system for treating tissue swelling
Abstract
A system and related methods and components for treating a
tissue site exhibiting interstitial hypertension, including tissue
swelling, and particularly swelling associated with cerebral edema,
compartment syndrome, and congestive heart failure, by the use of
water removal therapy, in order to remove only water from
biological fluids. Included also is a system for such use that
incorporates one or more monitors, optionally in addition to the
use of water removal therapy. By removing only water, all other
biologic agents, including essentially all solutes and formed blood
elements (such as cells) are increased in concentration in the
remaining bodily fluid(s). WRT can be applied to several clinical
conditions in which there is an excess of water, and is ideally
used in an extracorporeal fashion, in combination with other
functions and related components as well, including
ultrafiltration.
Inventors: |
Odland, Rick Mathew;
(Roseville, MN) |
Correspondence
Address: |
INTELLECTUAL PROPERTY GROUP
FREDRIKSON & BYRON, P.A.
200 SOUTH SIXTH STREET
SUITE 4000
MINNEAPOLIS
MN
55402
US
|
Family ID: |
28040504 |
Appl. No.: |
10/508610 |
Filed: |
September 22, 2004 |
PCT Filed: |
March 21, 2003 |
PCT NO: |
PCT/US03/08921 |
Current U.S.
Class: |
604/5.01 ;
210/650 |
Current CPC
Class: |
A61M 25/00 20130101;
A61M 27/008 20130101; A61M 27/00 20130101; A61B 5/031 20130101;
A61M 1/0023 20130101 |
Class at
Publication: |
604/005.01 ;
210/650 |
International
Class: |
A61M 037/00; C02F
001/44 |
Claims
What is claimed is:
1. A method of treating tissue swelling, the method comprising the
step of employing one or more semipermeable membranes in
combination with a hydratable medium in order to remove
substantially only water through the semipermeable membrane(s) and
from a biological fluid associated with the tissue swelling.
2. A method according to claim 1, wherein the biological fluid is
associated with either localized tissue swelling or systemic tissue
swelling.
3. A method according to claim 2 wherein the localized tissue
swelling is selected from cerebral edema, pulmonary edema,
lymphedema, compartment syndrome, acute renal failure, ischemic
heart disease, and solid tumors, and the systemic tissue swelling
is selected from congestive heart failure, and acute renal
failure.
4. A method according to claim 3 wherein the method is used to
perform targeted treatment within a tissue site exhibiting
localized tissue swelling.
5. A method according to claim 1, further comprising the use of one
or more semipermeable membranes in order to perform ultrafiltration
on the same or different biological fluid, in order to remove both
water and permeable solutes from the biological fluid, and either
in series or parallel with the water removal step.
6. A method according to claim 5 wherein the method is used to
treat swelling associated with congestive heart failure, and
provides a desired combination of ultrafiltration to remove water
and permeable solutes, together with water removal therapy to
remove substantially only water.
7. A method according to claim 6 wherein both ultrafiltration and
water removal therapy are performed in an extracorporeal fashion
comprising respective extracorporeal cartridges in which both
ultrafiltration and water removal are performed in parallel on
different aliquots of blood.
8. A method according to claim 6 comprising respective
extracorporeal cartridges in which both ultrafiltration and water
removal are performed in series, with water removal therapy
performed following ultrafiltration, and on at least a portion of
the ultrafiltrate.
9. A method according to claim 1 wherein the method comprises an
arteriovenous method based on a pressure differential between
arterial and venous blood to drive blood through a water therapy
removal cartridge.
10. A method according to claim 1 wherein the method comprises a
venovenous method based upon the pumping action of vaporization
itself.
11. A method according to claim 1 wherein the cartridges each
comprise a plurality of hollow fibers together with extraluminal
and intraluminal flow paths, the hydratable medium comprises a
desiccated gas delivered to the intraluminal flow path, and the
biological fluid comprises blood or ultrafiltrate delivered to the
extraluminal flow path.
12. A method according to claim 1 wherein the cartridges each
comprise a plurality of hollow fibers together with extraluminal
and intraluminal flow paths, the hydratable medium comprises a
desiccated gas delivered to the extraluminal flow path, and the
biological fluid comprises blood or ultrafiltrate delivered to the
intraluminal flow path.
13. An apparatus for treating a tissue site exhibiting interstitial
hypertension, comprising one or more semipermeable membranes
adapted to be used in combination with a hydratable medium in order
to remove substantially only water through the semipermeable
membrane(s) and from a biological fluid associated with the
hypertension.
14. An apparatus according to claim 13, wherein the apparatus
comprises a cartridge containing one or more semipermeable
membranes and positioned in an extracorporeal circuit.
15. An apparatus according to claim 14 wherein the one or more
semipermeable membranes are in the form of hollow fibers.
16. An apparatus according to claim 1 wherein the hydratable medium
comprises a gas.
17. An apparatus according to claim 13 wherein the fibers are
formed of materials selected from the group consisting of
polyacrylonitrile, polyethersulfone, cellulose and polysulfone.
18. An apparatus according to claim 13, further comprising one or
more monitoring components physically and/or functionally
integrated with the placement and/or operation of the semipermeable
membrane component.
19. An apparatus according to claim 18 wherein the monitoring
components are associated with the system of this invention, in
that that one or more components of the monitoring components are
physically and/or functionally integrated with the placement and/or
operation of the semipermeable membrane component.
20. An apparatus for treating tissue swelling, comprising one or
more semipermeable membranes adapted to be used in combination with
a hydratable medium in order to remove substantially only water
from a biological fluid associated with the swelling, wherein the
apparatus comprises a plurality of hollow fibers positioned within
a cartridge in order to provide corresponding intraluminal and
extraluminal flow paths within the cartridge, the flow paths being
adapted to position both a biological fluid and a hydratable
medium, respectively, on opposite surfaces of the fibers, under
conditions suitable to remove substantially only water from the
biological fluid.
21. A method according to claim 1, wherein the method is adapted to
improve the delivery of systemically or remotely delivered
bioactive agents to a confined tissue site within the body.
22. A method according to claim 21, wherein the confined tissue
site is a solid or semisolid tumor site exhibiting interstitial
hypertension, and the method comprises the steps of: a) providing
one or more semipermeable water removal catheters, b) positioning
the catheter(s) within a confined tissue site within a body, c)
delivering the bioactive agent to a body fluid in fluid
communication with the confined tissue site, and d) employing the
positioned catheter(s) to remove water, and optionally other
permeable solutes, from the confined tissue site in a manner
sufficient to lower interstitial pressure within the confined
tissue site, and in turn, improve the transfer of the bioactive
agent, by perfusion, from the fluid to the tissue site.
23. An apparatus according to claim 13, wherein the apparatus is
adapted to improve the delivery of systemically or remotely
delivered bioactive agents to a confined tissue site within the
body.
24. An apparatus according to claim 23, wherein the confined tissue
site is a solid or semisolid tumor site, and the apparatus
comprises one or more semipermeable water removal catheters.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods and apparatuses for
addressing situations in which interstitial hypertension (elevated
tissue pressure) occurs within the body, including in situations of
tissue swelling and the hypertension associated with formation of
solid and semisolid tumors. In another aspect, the invention
relates to diagnostic and therapeutic methods and apparatuses that
include the placement of semipermeable catheters and membranes
within the body, for use in removing water and/or fluid components
from the tissue site and/or for delivering agents such as bioactive
agents to sites exhibiting interstitial hypertension. In yet
another aspect, the invention relates to diagnostic and therapeutic
methods and apparatuses adapted to monitor various physiologic
parameters in the course of tissue swelling, as well as methods and
apparatuses adapted to deliver media, including gases and liquids,
to catheters positioned within a tissue, including to treat
biological (e.g., bodily) fluids external to the body. In a final
aspect, the invention relates to systems, and components thereof,
for recovering fluids from sites of tissue swelling.
BACKGROUND OF THE INVENTION
[0002] A number of clinical conditions involve (e.g., are caused by
and/or themselves cause) impaired circulation, and particularly
circulation within interstitial spaces and within discrete,
localized tissues. Among the more vexing examples of such
circulatory afflictions are those that involve localized tissue
swelling, including compartment syndrome and edema (and in
particular, cerebral edema), as well as solid and semisolid tumors
forming confined sites within the body.
[0003] Acute compartment syndrome generally involves impaired
circulation within an enclosed fascial space (e.g., the anterior
compartment of the lower leg), leading to increased tissue pressure
and necrosis of muscle and nerves. The soft tissue of the lower leg
is contained within four compartments, each bounded by heavy
fascia--the anterior, lateral, superficial posterior, and deep
posterior compartments. Once diagnosed, the injury requires
immediate decompression through surgical release of the skin and
fascia covering the area. Other proposed treatment strategies
include the use of a sympathetic blockade, hyperbaric oxygen
therapy, and treatment with mannitol and/or alloperinol.
[0004] Cerebral edema (also known as brain swelling), includes
vasogenic cerebral edema (the most common form of edema) which
manifests itself in the form of increased permeability of small
vessels (breakdown of blood-brain barrier) and the escape of
proteins and fluids into extracellular space, especially of white
matter. Cerebral edema can be caused by ischemia, loss of oxygen,
or focal disruption or loss of blood supply such as stroke. The
diagnosis of cerebral edema is based on changes in mental status,
imaging, and measurement of intracranial pressure. There remain few
conventional treatment options, and they tend to be of limited
efficacy.
[0005] Monitoring of intracranial pressure (ICP) is considered
appropriate for all patients with severe traumatic brain injury
(TBI). While the placement of an ICP monitor is invasive, the
benefits of ICP monitoring are felt to offset this factor, carry a
relatively small risk of complications (e.g., infection,
hemorrhage, malfunction, obstruction or malposition), and rarely
result in increased patient morbidity. Percutaneous devices (e.g.,
ventriculostomy catheters) for use in monitoring ICP are
commercially available in a variety of styles and from a number of
sources. Such devices are commonly placed within the cerebral
ventricles, where they enable accurate and reliable monitoring of
ventricular pressure and can be used for the therapeutic convective
drainage of cerebrospinal fluid ("CSF").CSF drainage has been
described as a potentially effective method of lowering ICP,
particularly when ventricular size has not been compromised. CSF
drainage typically requires penetration of the brain parenchyma
with a ventricular catheter. A variety of ventricular catheters are
available for such purposes, e.g., the "MoniTorr" product available
from Integra Lifesciences, Inc. As fluid is removed, however, brain
swelling often progresses to the point where the ventricular system
is compressed and the ability to drain CSF can be compromised. This
may be exacerbated by overdrainage, leading to the ventricular
walls or the choroid plexus actually collapsing in a manner that
occludes the orifices of the catheter. The therapeutic efficacy of
convective CSF drainage by conventional ventriculostomy catheters,
therefore, has been limited to date.
[0006] On a separate subject, gases have long been used for various
medical procedures. For instance, oxygen is generally used to
enriched the atmosphere for patient therapy and procedures, though
oxygen is considered a drug and is dispensed by prescription.
High-pressure oxygen is used for hyperbaric treatment, while in
other situations, medical air is inhaled by patients, often through
secondary pneumatic equipment. Nitrous oxide provides the first and
second stages of anesthesia, while nitrogen itself powers pneumatic
surgical tools. Carbon dioxide gas is becoming more common in piped
systems as it gains more use in advanced respiratory treatment and
operating room procedures. Also helium, and mixtures of helium with
oxygen, have been described for the treatment of patients having
certain respiratory conditions.
[0007] An assortment of references also describe either the
delivery or recovery of media, such as gases or hyperosmolar
liquids, for various purposes and into various locations within the
body. Such references include, for instance, situations in which
oxygen is delivered to the body by means of catheters positioned
within the blood, as well as those in which gases are themselves
measured within bodily fluids. See, e.g., U.S. Pat. No. 4,274,417
(Instruments for use in the measurement of gases in body fluids);
U.S. Pat. No. 4,726,381 (Dialysis system and method); U.S. Pat. No.
4,340,615 (Apparatus for analysis of absorbed gases); U.S. Pat. No.
5,865,789 (Percutaneous oxygenator for inducing a retrograde
perfusion of oxygenated blood); U.S. Pat. No. 5,336,164
(Intravascular membrane lung apparatus); and U.S. Pat. No.
5,501,663 (Inflatable percutaneous oxygenator with transverse
hollow fibers).
[0008] See also Levin, et al. U.S. Pat. No. 6,287,608, which
describes a method and apparatus for the treatment of congestive
heart failure by improving perfusion of the kidney by infusion of a
vasodilator.
[0009] On yet another subject, medical-surgical vacuum and drainage
systems exist in the art as well. For instance, the American
Society for Testing and Materials provides standard specifications
(F960-86(2000)) for medical and surgical suction and drainage
systems that include applications such as oral, nasal and tracheal
suction, gastrointestinal drainage, pleural space and mediastinal
drainage, and closed wound drainage. Other examples, though not
included within this specification, can include drainage by the use
of catheters and similar instruments inserted into tissue sites,
syringes, breast pumps, dentistry suction, and waste gas
scavenging. See, for instance, the Mini VAC (Vacuum Assisted
Closure) device, available from KCl (San Antonio, Tex.). The VAC
device provides negative pressure therapy for the treatment of
chronic and acute wound, and allows for the measurement and
monitoring of therapy at the wound site through micro-processor
control and multi-lumen tubing. In use, the negative pressure is
applied to a special dressing positioned in a wound cavity or over
a flap or graft. The pressure distributing wound dressing, in turn,
is said to help remove fluids from the wound.
[0010] In a more recent approach, a "mechanical leech" has been
developed, with the intent of attaching to a wound site in order to
remove blood and promote wound heeling. See, for instance, the
University of Wisconsin press release dated Dec. 12, 2001, "Novel
Device Takes Over Where Medicinal Leeches Leave Off".
[0011] See also U.S. Pat. No. 5,484,399, which describes a method
and apparatus for reducing interstitial fluid pressure in tissues,
particularly in tumors, by applying suction to the interior of the
tissue. The method comprises inserting into the tissue one or more
needle-like, elongated tubes, each having at least one hole at or
near the end that is inserted into the tissue and each having means
to apply suction to the protruding end. Components may be provided
to measure the pressure within the tissue and to use this
measurement to control the suction applied to the tissue through
the tubes.
[0012] A variety of references describe the placement and use of
semipermeable membranes within the body. See, for instance, Mishra
(U.S. Pat. No. 5,441,481) which describes a microdialysis probe
arranged to have a primary (e.g., electrical) probe secured to it
to enable both the microdialysis and primary probe to be extended
as a unit for selective sampling and/or administration of compounds
to the body. The microdialysis probes are quite large, said to be
on the order of 3-4 mm in diameter. Although the reference makes
passing reference of the possible "therapeutic application" of
their probe, e.g., at column 9, lines 6-20, the suggested delivery
of a viscous dextran solution would seem to require the application
of tremendous pressures. Moreover, the passage of water through the
semipermeable membrane is taught as occurring via chemical
(osmotic) means, as compared to water passage brought about by
mechanical means, as the result of hydrostatic forces.
[0013] Applicant has also previously described methods and related
systems for use in site specific therapy of a tissue site. See
issued U.S. Pat. No. 6,030,358 and published PCT application No.
PCT/US98/16416, the disclosures of which are incorporated herein by
reference. In one embodiment, the PCT application provides a system
that comprises one or more catheters adapted to be positioned
within the tissue site and a delivery/recovery mechanism for
employing the catheter(s) to control the movement of bulk fluids
and/or active fluid components within or between tissue portions or
adjacent tissues in a manner that achieves a therapeutic effect.
The catheter(s), in turn, can comprise one or more semipermeable
microcatheters, adapted to effect the movement of fluid or fluid
components within the tissue site by microdialysis within the
tissue site. In its various embodiments, the system previously
described by Applicant can be used for the treatment of a variety
of disorders, including cerebral edema and compartment
syndrome.
[0014] In yet another embodiment, Applicant's PCT application
describes an apparatus for performing site specific therapy in the
event of cerebral edema, the apparatus comprising one or more
catheters, each comprising one or more semipermeable membranes,
adapted to be positioned in the parenchymal portion of the brain,
and adapted to be flowably connected to a source of negative
pressure sufficient to remove fluid from the brain in order to
alleviate intracranial pressure.
[0015] While the embodiments of Applicant's U.S. patent and PCT
application remain viable, and valuable, options for various
applications, it has become clear that continued efforts, and
alternative approaches, are in order with respect to the treatment
of tissue swelling, and particularly cerebral edema, as well as
compartment syndrome.
[0016] Congestive heart failure (CHF) provides yet another example
of tissue swelling, and particularly nonlocalized tissue swelling.
CHF involves the diminished capacity of the heart to circulate
blood as a result of injury. The low blood pressure triggers
mechanisms to retain body water causing fluid overload or tissue
swelling. If CHF is severe, blood flow to the kidneys is restricted
such that renal function is impaired without treatment. Over 5
million US patients have CHF with 500,000 newly diagnosed patients
each year. Diuretic drugs are currently the primary treatment for
CHF patients, but many patients become resistant to further
diuretic drug therapy. This resistance leads to fluid overload and
a diminished quality of life. Severe fluid overload often leads to
hospitalization and more intensive medical therapy. There are about
1 million CHF related hospitalizations each year, typically lasting
4 days, costing an average of $15,000 per hospitalization for a
total annual cost of $15 billion.
[0017] In addition to the tissue swelling that occurs during CHF,
the failing heart is not able to maintain perfusion to vital
organs. The body senses low perfusion as a loss of blood volume,
and initiates mechanisms designed to retain body water. Sodium is
retained as one method to prevent renal excretion of water.
Overall, more water than sodium is retained, and hence, serum
sodium concentrations are typically low. This, in turn, stimulates
additional measures to retain sodium. With increasing water and
sodium retention, the venous system becomes overfilled, resulting
in an increase in interstitial fluid, and the resulting clinical
symptoms of CHF. Excess interstitial fluid results in pulmonary
edema, pitting edema of the lower limbs, sacral edema, and ascites.
Failure to respond to medicines completes the clinical picture of
refractory CHF. These patients must be admitted to the hospital for
treatment.
[0018] CHF patients often present with low sodium, low potassium,
and low magnesium levels. Patients who are hospitalized with
chronic CHF have a 32-40% incidence of serum sodium less than 135
mmol/l. Low sodium levels are a problem for several reasons,
including:
[0019] 1) Poor response to drug treatment. Loop diuretics require
sodium to be effective. Patients with low sodium become refractory
to medical treatment and require hospitalization.
[0020] 2) Longer length of stay.
[0021] 3) Increased risk of inpatient death.
[0022] 4) Increased risk of mortality after discharge.
[0023] Several new therapies have emerged to manage late stage CHF,
particularly in patients that have become refractory to diuretic
drug therapy. These new therapies include hemofiltration,
ventricular assist devices, and sophisticated combination drug
therapies. These therapies, including hemofiltration, have not only
been shown to treat fluid overload, but have also demonstrated the
potential reversibility of CHF. None of the emerging therapies
address the problem of hyponatremia (low sodium) however, and some
can actually tend to aggravate the problem.
[0024] Efforts to employ ultrafiltration technology in CHF, to
date, have focused on using hemofiltration-like systems to treat
CHF fluid overload. Such systems, like conventional hemofiltration
used to treat renal failure (kidney dialysis therapy), can remove
up to 4 liters in an 8-hour period. The ultrafiltrate is removed
from the blood, which results in decreased blood volume and
subsequent refilling of plasma fluid from the interstitial space.
With ultrafiltration, only molecules less than the molecular weight
cutoff of the membrane (generally about 50,000 Daltons) are removed
with the water component of the blood. Since most proteins are not
removed, ultrafiltration tends to cause a slight increase in
colloid osmotic pressure, which can aid refilling of the
intravascular space.
[0025] Ultrafiltration does not, however, improve serum sodium
levels. To the contrary, small molecules such as salts will be
quite easily removed with the ultrafiltrate. Furthermore,
ultrafiltration alone does not increase renal excretion of sodium,
and studies have shown a reduction in urinary sodium levels after
ultrafiltration. Ultrafiltration reduces intravascular volume,
which can stimulate the renin-angiotensin system. Renin-angiotensin
results in retention of sodium and water and is counterproductive
to the intention of ultrafiltration.
[0026] One author stressed the importance of a negative sodium
balance in treatment .sub.of CHF (Haller 2000) While total body
sodium is elevated in CHF, the neurohumeral axis responds to serum
levels. Increasing serum levels will result in normalization of
sodium excretion mechanisms, and, ultimately, urinary excretion of
sodium. Others have actually given small boluses of hypertonic
saline with diuretics and have found increased responsiveness to
CHF treatment. (Forssell et al. 1980, Patema et al. 2000). Yet
another group has found that administration of an osmotic agent
improved salt excretion. In a single case report of treatment of
refractory CHF, urea was given. This resulted in increased salt
excretion, increased diuresis, reduced body weight, and corrected
sodium deficit (120 mmol/l to 136 mmol/l). (Cauchie et al. 1987)
Thus osmotic gradients that favor mobilization of body sodium into
the vascular space and thereby elevating serum sodium may be
important for normalization of the neurohumeral axis.
[0027] Based on published results to date, it would appear that
ultrafiltration must be used to treat CHF in combination with other
means, typically drugs, to achieve the intended benefit. For
instance, only those patients using ACE-inhibitors (which block the
renin-angiotensin system) saw urinary excretion of sodium and
continued reduction of body water. Guazzi et al. (1994) saw an
increase in sodium urinary excretion after ultrafiltration, but one
third of their patients had been on ACE-inhibitors, and all were on
diuretics. Guazzi et al. concluded that ultrafiltration "may
interrupt a positive feedback loop between salt and water retention
and activation of the neurohumeral axis." Agostoni et al. (2000),
noting weight loss four days after ultrafiltration (5.8 kg) was
greater than the weight of fluid removed during ultrafiltration
(3.9 kg), agree that restoring diuresis and response to diuretics
is a key factor in treatment of CHF with ultrafiltration (most (22
of 28) of their patients were also on ACE-inhibitors). Even with
pharmacological treatment, however, it appears that hyponatremia
persists.
[0028] A company known as CHF Solutions is a leading advocate of
the hemofiltration approach, and focuses on using hemofiltration to
treat CHF fluid overload, removing 2 to 4 liters in a 4 to 8 hour
period. Their system is very much like conventional hemofiltration
used to treat renal failure (kidney dialysis therapy), though it is
designed to avoid the use of anti-coagulants. The reusable
equipment portion of the system costs about $10,000 per patient
station and the disposables sell for $1,000 per patient. See, for
example, published International Patent Applications Nos. WO
02/36068, WO 02/47609 and WO 02/053098, assigned to CHF Solutions,
Inc., the disclosures of which are incorporated herein by
reference. While the CHF Solutions technology may provide desirable
attributes, it appears to be neither intended nor designed to
address corresponding hyponatremia.
[0029] Finally, it can be seen that refractory CHF patients have
the following features: 1) low serum sodium concentrations, 2)
excess total body water, 3) excess total body sodium, 4) low blood
pressure, and 5) non-responsive to medical treatment.
[0030] It would therefore be highly desirable to have a treatment
regimen that could result in: 1) normalization of serum sodium
concentrations to turn off signals to retain sodium, 2) increased
urinary excretion of sodium after normalization of inappropriate
neurohumeral signals to retain sodium, 3) a net loss of body water,
primarily from the interstitial space, and 4) avoidance of
excessive intravascular volume loss that can aggravate low blood
pressure.
[0031] On another topic, bioactive agents such as drugs have long
been delivered to the body in a vast array of ways, including by
ingestion, inhalation, injection, transdermally, and others. As
with any remote or systemic delivery, the ability of the delivered
drug to access its intended site of action is often dependent on a
number of parameters, including: a) the flow kinetics of fluids
containing such drugs, such as blood, into or through the desired
site, b) the concentration and form of such drugs within those
fluids, and c) the extent to which the drug is able to be
transferred to, or concentrated within, the desired site from the
fluid. As compared to systemic delivery, site specific approaches
for delivering drugs have been developed as well, and include the
use of indwelling catheters, and implantable drug delivery
devices.
[0032] The delivery of drugs to tumors, however, poses additional
challenges beyond those associated with both systemic and site
specific delivery techniques. Reduced perfusion to tumors is known
to limit the ability to effectively deliver chemotherapeutic agents
to the tumor. One of the most pervasive and compelling theories
regarding causation is the Baxter-Jain hypothesis, which states
that elevated tissue pressure within the tumor limits tumor
perfusion. The theory and modeling suggest that absence of
lymphatics plays a key role in pathogenesis of the interstitial
hypertension.
[0033] A variety of approaches have been considered to improve the
delivery of drugs to tumors. For instance, infusion of fluid
directly into tissues bypasses the microcirculatory system, and has
been attempted with mixed results. Investigators have showed, for
instance, that fluid injected too rapidly into tumors caused a
shearing action that results in an inhomogeneous distribution.
[0034] More recently, improved perfusion by the removal of excess
interstitial fluid has been proposed as well. See the papers and
patents or applications of DiResta et al., including Ann. Biomed.
Eng. 28: 543-555 (2000) and Ann. Biomed Eng. 28:556 564 (2000), as
well as U.S. Pat. No. 5,484,399 ("Process and Device to Reduce
Interstitial Fluid Pressure in Tissue"), and U.S. Patent Pub. NO.
U.S.2001/0047152 ("Apparatus and Method for Reducing Interstitial
Fluid Pressure and Enhancing Delivery of a Therapeutic Agent").
[0035] DiResta et al. suggest a therapeutic effect can be derived
by the alleviation of interstitial hypertension and have developed
an "artificial lymphatic system" or "ALS". These various references
establish that removal of fluid from tumors increased blood flow,
oxygenation, and delivery of a dye to the hypoperfused center. In
these studies, an "aspiration probe", in the form of a stainless
steel needle, was used to remove tissue fluid. DiResta et al. also
demonstrated that fluid removal will result in shrinkage of the
tumor compared to controls when chemotherapeutic drug is given
systemically. The device consists of a needle that is inserted into
the center of the tumor through which suction is applied. Treatment
with ALS has reduced interstitial hypertension, increased tumor
blood flow, and enhanced dye penetration into the tumor. When used
with intravenous chemotherapy, ALS has resulted in a significant
reduction in tumor growth.
[0036] U.S. Patent Publication No. 2001/0047152 (DiResta, et al.)
further describes the manner in which cancer therapy may be
categorized into three major approaches: surgical excision,
radiotherapy, and chemotherapy. Chemotherapy is defined as the
treatment of cancer by a systemic administration of drugs.
Unfortunately, most drugs which showed promising effects in vitro
have failed to be as effective in vivo, particularly in solid
tumors. It has been proposed that one of the major reasons for this
failure is the impediment of drug transport into tumors. In
particular, a physiological barrier created by raised interstitial
fluid pressure appears to be responsible. The interstitial fluid
pressure is raised in tumors primarily because of the lack of
lymphatics in tumors and growth of tumor cells in confined spaces.
The raised interstitial fluid pressure in tumors is a principal
transport-retarding factor for the delivery of drugs such as
macromolecules, i.e., large molecular weight molecules such as
monoclonal antibodies (MoAb), tumor necrosis factor, and other
chemotherapeutic agents.
[0037] The above-cited DiResta et al. application goes on to
describe an interstitial fluid pressure reducing apparatus that
includes an aspiration probe having a body with an open proximal
end and a closed distal end, an interior chamber defined by the
body and proximal and distal ends, and at least one slit along the
body providing fluid communication between the chamber of the
aspiration probe and tissue upon insertion of at least a portion of
the aspiration probe in tissue. The proximal end is configured and
dimensioned for coupling to a suction source for generating suction
in the chamber of the aspiration probe upon connection with the
aspiration probe to thereby reduce interstitial fluid pressure of
the tissue.
[0038] Despite these promising findings, the above-cited DiResta et
al. articles each describe various "limitations" to their use of
ALS, including apparent limitations regarding the extent of vacuum
that can be safely applied to the aspiration probe, and the concern
that drugs may be removed along with the fluid itself. The authors
describe the range of about -50 to -80 mm Hg as being an optimal
vacuum range under their experimental conditions. In addition, the
small holes in the ALS may tend to become blocked with time. As a
result, long term use of the ALS could potentially be problematic.
Long term use of the ALS may further be complicated by the lack of
a mechanism to secure the drains of the ALS to the tissue so that
the drains remain spatially fixed. Finally, the ALS had no features
that facilitate use with adjunct therapies that enhance drug
delivery. Use of various other therapies to enhance efficacy of the
ALS would be desirable. However, until now, no other adjunct
therapy has been used in conjunction with the ALS.
[0039] What is clearly needed are systems, including methods and
apparatuses, for addressing situations of interstitial hypertension
with the body, including that associated with tissue swelling and
that associated with the formation of tumors.
BRIEF DESCRIPTION OF THE DRAWING
[0040] In the Drawing:
[0041] FIG. 1 shows components of a system of the current
invention, including a pressure monitor associated with a
semipermeable membrane catheter, for use in treating compartment
syndrome.
[0042] FIG. 2 shows a cross section taken along A-A of the catheter
of FIG. 1.
[0043] FIG. 3 shows an enlarged detailed view of the distal end of
the catheter of FIG. 1.
[0044] FIG. 4 shows a set of introducer components for use in the
system of FIG. 1.
[0045] FIG. 5 shows components of an alternative preferred system
of the invention adapted to provide a hydratable medium, for use in
treating cerebral edema.
[0046] FIG. 6 shows a cross section taken along A-A of the catheter
of FIG. 5.
[0047] FIG. 7 shows a cross section taken along B-B of the catheter
of FIG. 5.
[0048] FIG. 8 shows an enlarged detailed view of the distal end of
the catheter of FIG. 5.
[0049] FIG. 9 shows an enlarged detailed view of the soft distal
tip of the catheter of FIG. 5.
[0050] FIG. 10 shows component parts for use in accessing the brain
tissue, in order to place the catheter of FIG. 5.
[0051] FIG. 11 is a diagram with the catheter shown in position
within the brain of a patient.
[0052] FIGS. 12-21 provide various views and steps arising in the
use of a system such as that shown in FIGS. 1-4.
[0053] FIGS. 22 and 23 show optional design characteristics as
described herein.
[0054] FIGS. 24-26 show alternative schematic diagrams of the use
of ultrafiltration in combination with water removal therapy.
[0055] FIG. 27 shows a diagram of a cartridge of the type prepared
and used in Example 1 below.
[0056] FIG. 28 is a cross-sectional view of a catheter assembly 300
in accordance with an exemplary embodiment of the present
invention.
[0057] FIG. 29 is a cut-away perspective view of a catheter
assembly 400 similar to the catheter assembly shown in FIG. 28.
[0058] FIG. 30 is a cross-sectional view of catheter assembly 500
in accordance with an additional exemplary embodiment of the
present invention.
[0059] FIG. 31 is a cut-away isometric view of catheter assembly
600 in accordance with an additional exemplary embodiment of the
present invention.
[0060] FIG. 32 is a cross-sectional view of catheter assembly in
accordance with a still another exemplary embodiment of the present
invention.
[0061] FIG. 33 is a cut-away perspective view of a catheter
assembly similar to the catheter assembly shown in FIG. 32.
[0062] FIG. 34 is a cross-sectional view of a catheter assembly in
accordance with a yet another exemplary embodiment of the present
invention.
[0063] FIG. 35 is a graphical comparison of WRT with UF,
reinfusion, and combinations of UF and reinfusion.
[0064] FIG. 36 shows the manner in which blood plasma can be
removed (and replaced with normal saline) to concentrate
sodium.
SUMMARY OF THE INVENTION
[0065] A system of the present invention provides an integrated
combination of features and functions for use in therapy involving
tissue swelling due to excess water, including localized tissue
swelling, in conditions such as cerebral edema, pulmonary edema,
lymphedema, compartment syndrome, acute renal failure, ischemic
heart disease, and the interstitial hypertension associated with
solid tumors, as well as systemic tissue swelling, in conditions
such as congestive heart failure, and acute renal failure. In turn,
the system provides various embodiments of a method and apparatus
for addressing, including treating, situations in which
interstitial hypertension occurs within the body, including in
situations of the swelling of normal tissues and the interstitial
hypertension associated with solid tumors.
[0066] One preferred system comprises one or more recovery
catheters comprising semipermeable membranes, in combination with
recovery components for recovering bulk fluid or fluid components
through the semipermeable membranes, and a hydratable medium,
preferably in the form of a hydratable gas, adapted to be delivered
to a lumen provided by the membranes under conditions suitable to
remove water from the environment surrounding the membranes. In yet
another preferred system, the semipermeable membrane and hydratable
gas are used in an extracorporeal fashion, e.g., with the gas
provided either within or surrounding hollow fibers, in order to
withdraw water vapor from fluid (e.g., blood, ultrafiltrate, etc.)
that is contacted with the opposite fiber surface.
[0067] The membranes can be positioned in any suitable position
with respect to a tissue site (including a tumor) exhibiting
swelling, including directly within the tissue itself, within a
remote tissue (e.g., circulating blood) having an indirect
physiologic effect on the tissue exhibiting swelling, or externally
to the body itself, as in the form of a remote (e.g.,
extracorporeal) unit functionally connected to the body, as by a
fluid (e.g., hemofiltration) flow circuit, and in turn to the
swollen tissue site. Optionally, the system also includes one or
more introducing components, as described further herein.
[0068] In a further preferred embodiment, the present invention
provides a method and system for delivering and/or improving the
delivery of bioactive agents to tissue sites within the body. In
such an embodiment, the method and system are adapted to improve
the delivery of systemically or remotely delivered bioactive agents
to confined tissue sites, such as tumors, and particularly solid
tumors, within the body.
DETAILED DESCRIPTION
[0069] In a particularly preferred embodiment, where the catheters
are positioned directly or indirectly within a tissue site
exhibiting swelling the system comprises:
[0070] a) one or more recovery catheters comprising semipermeable
membranes, each of such semipermeable membranes being preferably in
the form of a hollow fiber,
[0071] b) recovery components for recovering bulk fluid or fluid
components (e.g., water) through the semipermeable membranes and
from the tissue site, in order to achieve a therapeutic result,
preferably in the form of a reduction in swelling or improved
perfusion, and either
[0072] c) a hydratable medium, e.g., filtered or dehydrated gas,
adapted to be delivered to the tissue site and within the
semipermeable membrane(s) under conditions suitable to remove water
from the tissue site in the form of hydrated medium, or
[0073] d) one or more components of a monitoring system associated
in an integral fashion with the recovery catheter(s).
[0074] In a particularly preferred embodiment, the system provides
one or more introducing components adapted to position the recovery
catheter(s) within a tissue site, and preferably directly within a
confined tissue site exhibiting swelling and/or interstitial
hypertension. In a further preferred embodiment, the system
includes the hydratable medium of feature (c) above, and even more
preferably it includes both features (c) and (d) in
combination.
[0075] Various embodiments of this invention, and particularly
those that employ the hydratable medium described herein, permit
one to perform "water removal therapy" (or for short, "WRT") in
order to remove substantially only water from biological fluids and
particularly from fluids associated with sites exhibiting tissue
swelling. Such fluids can include, for instance, those within the
tissue itself, including interstitial fluids, and/or fluids such as
blood and lymphatic fluids that are in fluid communication with the
tissue exhibiting swelling.
[0076] By removing only water, all other biologic agents, including
essentially all solutes and formed blood elements (such as cells)
are increased in concentration in the remaining bodily fluid(s).
WRT can be applied to several clinical conditions in which there is
an actual excess of water, and therefore used therapeutically, or a
potential accumulation of water (as in compartment syndrome), and
therefore used in a prophylactic fashion. Water removal of this
type cannot typically be accomplished by any other clinical
method.
[0077] In a particularly preferred embodiment, the present
invention therefore includes a functional, and ideally physical,
combination of ultrafiltration and water removal, and more
preferably where both are performed using semipermeable hollow
fibers positioned within corresponding extracorporeal circuits.
Both UF and WRT can be performed in any suitable manner, e.g., in
series or parallel, and with one or both being performed in an
extracorporeal circuit, as compared to intravascular manner.
[0078] In yet another embodiment, an intravascular access catheter
is composed of hollow fiber membranes. Thus, ultrafiltration occurs
within the blood vessels. Ultrafiltrate is removed and passed
through an extracorporeal WRT cartridge. The embodiment provides
the advantages of reduced viscosity of the fluid entering the WRT
cartridge, and no intravascular loss of formed blood elements
(essentially no blood priming volume). Concentrated plasma
ultrafiltrate can be returned to the intravascular space. See, for
example, International Journal of Artificial Organs, Volume 22,
number 5, 1999, pp 342-346, Extracorporeal therapies: C. Ronco.
[0079] In other preferred embodiments, blood is removed from the
vessels and passed through one or more extracorporeal cartridges
containing semipermeable membranes (typically in the form of hollow
fibers). Extracorporeal circuits of a type used for hemofiltration
in the course of congestive heart failure can be adapted and used
in a system of the present invention. Applicant has found that
extracorporeal WRT allows the use of a large cartridge, that can
accommodate correspondingly higher rates of water removal if
indicated. A system of this invention can also be adapted, for
instance, for arteriovenous and/or venovenous use.
[0080] Some or all components of a system of this invention can be
adapted for intravascular use as well. Intravascular WRT is
possible, for instance, at low water removal rates, while
intravascular UF, follow serially by extracorporeal WRT, offers
several advantages.
[0081] As described herein, WRT can be used in combination with one
or more other treatment processes as well, including
ultrafiltration, hemodialysis and reinfusion, in order to achieve
desired results.
[0082] WRT followed by ultrafiltration or hemodialysis, for
instance, can allow greater separation of toxic agents.
Hemodialysis can be of a form commonly used for chronic renal
failure in which blood flows through a hollow fiber while another
liquid (dialysate) flows outside the hollow fiber. Exchange occurs
between blood and dialysate by diffusion from high concentrations
to low concentrations. Agents that are to be removed from the blood
are absent in the dialysate; likewise agents to be delivered to the
blood have high concentrations in the dialysate. Clearance of some
agents may be enhanced by first concentrating the solution using
WRT and then performing dialysis, particularly since a greater mass
transfer can be achieved with concentrated rather than dilute
elements. Since WRT will tend to concentrate all elements in the
remaining fluid, it will allow greater removal of those elements
with subsequent treatment. Clinical examples of this application
include the removal of toxins, poisons, endotoxins, or other
noxious agents.
[0083] The method and system of the present invention can also be
used in the treatment of lymphedema, a condition in which the
lymphatic system does not function properly, due to injury or
disease. The lymphatic system normally functions to remove excess
interstitial fluid, as capillary cannot remove all the fluid that
enters the interstitial space from the arteriolar side of the
capillaries. The lymphatic system will occasionally dysfunction
after infections, trauma, radiation therapy, vascular disease and
surgery. A common cause of lymphedema in the arm, for instance, is
radical mastectomy, especially with node dissection. The result can
be chronic interstitial edema of the extremity. The use of hollow
fibers in the manner presently described can be of potential
benefit in such conditions, e.g., by the use of large pore hollow
fibers to remove accumulated interstitial proteins.
[0084] In a further preferred embodiment, a system of this
invention that includes the hydratable medium of feature (c), is
used in cooperation and combination with an intravascular or
extracorporeal hemofiltration process and system. The resulting
combination can provide an optimal combination of the both tissue
water removal, by vaporization, as well as ultrafiltration of bulk
fluid, including fluid components below a desired size and/or
molecular weight cutoff. This combination of both ultrafiltration
(of water and small solutes) and vaporization (of substantially
water only) can be performed either sequentially and/or
simultaneously, and on either the same or different aliquots of
bodily fluid, with either or both processes being performed either
in situ within the body or in an extracorporeal fashion.
[0085] When WRT is used in combination with ultrafiltration, a
desired and controllable combination of water and mass removal can
be achieved. Specific combinations of water and mass cannot be
accomplished by any other conventional methods without extensive
plasma water turnover. WRT can be applied to congestive heart
failure, acute and chronic renal failure, hyponatremia, water
excess syndromes (including Syndrome of Inappropriate Antidiurectic
Hormone "SIADH" and water intoxication), and other systemic
conditions. By specific placement of access catheters, WRT can also
be applied to organ-specific conditions of edema such as Acute
Respiratory Distress Syndrome or Acute Renal Failure by placement
of vascular access catheters in the vena cava or aorta,
respectively. In turn, WRT can result in increased serum sodium
levels while removing total body water while maintaining low plasma
turnover. WRT in combination with ultrafiltration can produce
removal of body water and direct removal of sodium while increasing
serum sodium concentrations to normal levels. WRT results in
retention of desired (and optionally all) solutes in the blood.
Thus, not only is there a slight increase in colloid osmotic
pressure (as seen in ultrafiltration) but also a slight increase in
crystalloid osmotic pressure. The result is more even refilling of
the intravascular volume, with a net therapeutic effect.
[0086] In tissues exhibiting swelling, removing fluids from the
intravascular space causes excess interstitial fluid to flow into
the vascular space, in a process referred to as "interstitial
refilling". If the rate of fluid removal from the body or blood
exceeds interstitial refilling rates, intravascular blood volume
will fall, and patients will experience hypotension. In turn,
agents that are found primarily in the blood vessels (albumin,
protein, and hemoglobin) will increase in concentration. If
vascular refilling from the interstitial space equals the rate of
water removal, however, the concentration of intravascular agents
will not change. Thus, large agents that are not found in the
interstitial space and that are not removed by treatment can be
used to monitor fluid status. Since neither WRT or UF are typically
designed to remove these large agents, both will result in
increased concentration of hemoglobin if fluid removal rates are
excessive.
[0087] As compared to UF, only WRT is designed to remove
substantially only water, though both WRT and UF cause interstitial
refilling. Because salts are not removed from the vascular space,
but are brought into the vascular space from the interstitial
space, WRT will result in an increase in salt concentration even at
low levels of treatment. UF will bring salt into the vascular space
with refilling, but there remove salt at the same concentration
level in the blood.
[0088] Using a combination of UF and WRT, therefore, both
mobilization of interstitial fluid and salt, and elimination of
salt will occur. During treatment, serum sodium can be monitored.
Treatment will be stopped when sodium levels normalize, and thus
potassium and magnesium levels will also be normalized. Improved
sodium levels in the blood stream will signal natural mechanisms to
increase sodium excretion via the renin-angiotensin systems. Thus,
normalization of the neurohumeral axis may be the primary benefit
of ultrafiltration, and increased serum levels of sodium as
provided by WRT may be more effective in accomplishing that
goal.
[0089] In a further preferred embodiment, the present invention
provides a method and system for delivering and/or improving the
delivery of bioactive agents to tissue sites within the body. In
such an embodiment, the method and system are adapted to improve
the delivery of systemically or remotely delivered bioactive agents
to confined tissue sites, such as tumors, and particularly solid
tumors, within the body. As used herein, the word "confined" will
generally refer to those sites having reduced or ineffective
perfusion by bodily fluids, such as blood or other interstitial
fluids, as compared to other tissues. Typically the confined tissue
site will be characterized by having high interstitial pressure,
characteristic of tissue swelling, and in turn, a decreased ability
to be perfused by fluids.
[0090] In one embodiment, the method comprises the steps of:
[0091] a) providing one or more semipermeable water removal
catheters,
[0092] b) positioning the catheter(s) within a confined tissue site
within a body,
[0093] c) delivering the bioactive agent to a body fluid in fluid
communication with the confined tissue site, and
[0094] d) employing the positioned catheter(s) to remove water, and
optionally other permeable solutes, from the confined tissue site
in a manner sufficient to lower interstitial pressure within the
confined tissue site, and in turn, improve the transfer of the
bioactive agent, by perfusion, from the fluid to the tissue
site.
[0095] The use of semipermeable water removal catheters provides a
variety of benefits over the above-described needles of DiResta et
al., including for instance, improved spatial distribution of water
removal within the tumor, the ability to achieve greater vacuum
pressures, including the use of intermittent vacuum, the ability to
provide catheters having improved flexibility and tissue
compatability for long term use, and the ability to limit or avoid
entirely the removal of therapeutic agent itself.
[0096] DiResta ea al. describe the use of alpha ("a"), as a
dimensionless lumped parameter representative of a tumor's physical
transport characteristics, and suggest that a should increase as
extravasated fluids are aspirated from an elastic tumor
interstitium. The method and system of the present invention permit
alpha to be maintained in the desirable range of about 0.1 to about
0.5
[0097] Bioactive agents suitable for use in the method and system
of this invention include a variety of synthetic and naturally
occurring compounds. Preferred bioactive agents include therapeutic
agents, and more preferred are chemotherapeutic agents having
antitumor (also known as antineoplastic) activity.
[0098] Examples of useful chemotherapeutic agents include, but are
not limited to: antimetabolites, plant alkaloids, alkylating
agents, antitumor antibiotics, heavy metal compounds, immune
therapies, gene therapies, and other therapeutics such as
trans-retinoic acid, L-asparaginase, estramustine, and
hydroxyurea.
[0099] Suitable antimetabolites include, for instance,
capecitabine, cladribine, cytarabine, fludarabine, fluorouracil,
gemcitabine, 6-mercapturine, pentostatin, and 6-thioguanine.
Suitable plant alkaloids include, for instance, docetaxel,
etoposide, irinotecan, paclitaxel, teniposide, topotecan,
vincristine, vinblastine, and vinorelbine. Suitable alkylating
agents include, for instance, busulfan, carmustine, chlorambucil,
cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine,
melphalan, procarbazine, and thiotepa. Suitable antitumor
antibiotics include bleomycin, dactinomycin, daunorubicin,
doxorubicin, idarubicin, mitomycin C, and mitoxantrone. Suitable
heavy metal compounds include carboplatin and cisplatin. Suitabie
immune therapies include aidesleukin, interferon, and
rituximab.
[0100] Gene therapy generally involves the transfer of nucleic
acids (DNA or RNA) into target cells to correct or disrupt a
pathologic process. Such therapy is currently provided by either of
two approaches--in vitro therapy, where genes are transferred into
cells cultured outside the body, and in vivo therapy, which
involves the direct administration of a gene to a target cell
within the body. These approaches, in turn, can be used to achieve
either replacement (or knock out) gene therapy, suicide gene
therapy, or immunomodulatory gene therapy. Replacement gene therapy
is often used to replace a mutated or missing gene, such as a tumor
suppression gene. Knock out gene therapy primarily targets the
products of oncogenes in an effort to inactivate them. Suicide gene
therapy, also known as chemosensitizing genes, involves the
transduction of a gene that transforms a nontoxic form of a drug
(pro-drug) into a toxic substance.
[0101] The present invention further provides a method of preparing
such a system by the fabrication and/or combination and functional
assembly of its various components, and a method of using such a
system to achieve a therapeutic result, as well as various
components and subcombinations thereof, several of which are
considered to be novel in their own right. The system and method
can be used to directly or indirectly treat a tissue site
exhibiting swelling. When used to directly treat a site of
swelling, for instance, the semipermeable membrane(s) will
typically be positioned within a region that itself exhibits
swelling.
[0102] When used to indirectly treat a site of tissue swelling, the
semipermeable membrane(s) can instead (or in addition) be
positioned and used in a site remote from (including externally
to), but physiologically associated with, the swollen tissue. For
instance, the system can be used to dehydrate tissue fluids, such
as blood (e.g., intravascularly) or CSF (e.g., intraventricularly),
that are physiologically associated with swollen tissue, leading to
dehydration of those tissues as well, and ultimately, to a
reduction in swelling. The system can be used for the removal of
excess fluid in a variety of situations, including pulmonary edema,
congestive heart failure, acute renal failure, ischemic heart
disease, as well as in cerebral edema and compartment syndrome.
[0103] A recovery catheter of this invention comprises at least
one, and preferably a plurality, of semipermeable membranes. As
used herein, the term "semipermeable membrane" will generally refer
to a membrane forming some or all of the wall of a microcatheter
(e.g., "hollow fiber"), preferably with a substantially open lumen
having at least one open end accessible to liquid or fluid flow
within the lumen. The membrane portion itself is adapted to permit
the passage of bulk tissue fluid or fluid components (e.g., water),
while substantially precluding the passage of cells or non-fluid
tissue. Such passage can be accomplished using any suitable means,
e.g., through pores provided by the membrane itself, as well as by
the preparation of membranes having suitable chemico-physical
properties (e.g., hydrophilicity or hydrophobicity) to effectively
control passage of fluid and its components in a predictable and
desired fashion.
[0104] The introducing components, in turn, can include any
introducing component, or set of components, that is suitable and
adapted to position the recovery catheter(s) within a tissue site,
and preferably within a site that itself exhibits swelling. Such
components can be provided, for instance, in the form of a totally
or partially circumferential covering (e.g., stationary or
removable delivery sheath), and/or by the inclusion of one or more
components (e.g., stylets) positioned internally, adjacent to,
and/or along the length of the semipermeable membrane(s) and
designed to impart sufficient properties (e.g., stiffness,
lubricity) to the overall catheter assembly or portions
thereof.
[0105] Finally, a system of the current invention includes recovery
components for moving and/or recovering bulk fluid or fluid
components (e.g., water) through the semipermeable membranes and/or
from the tissue site, in order to achieve a therapeutic result at a
site of tissue swelling (including a site, such as a tumor,
exhibiting interstitial hypertension). The movement of fluid or
fluid components can be considered to occur in up to at least three
modes, including 1) the movement of interstitial fluid within the
tissue itself (e.g., by convective flow of interstitial fluid
toward a semipermeable membrane positioned therein), 2) the
movement of fluid from the tissue and through a semipermeable
membrane(s) positioned therein, e.g., by diffusion or convection
through the membrane wall and into its lumen), and 3) the movement
of fluid from or within the semipermeable catheter(s) (e.g., to a
remote site, typically outside the body).
[0106] A recovery component of this invention can be provided in
any suitable form or combination of forms, including by the use of
hydrostatic pressure, diffusion, and combinations thereof, and can
be designed to affect any or all of these modes of fluid transport.
Hydrostatic pressure, for instance, can be provided as either
negative hydrostatic pressure (vacuum or suction) and/or in the
form of positive hydrostatic pressure. Diffusion, in turn, can be
accomplished using the physical-chemical forces that result from
the proximity of two different media, or forces that occur within a
suitable membrane positioned at a liquid/gas interface. Such forces
result, for instance, in the diffusion of water through the
membrane and into the gas, on the basis of either vapor pressure of
the liquid itself and/or of liquid components, e.g., volatile
compounds such as ketones, as in diabetic coma, or ammonia
(including in its various forms, including ammonium hydroxide), as
in the course of liver failure.
[0107] Hydratable Medium
[0108] The system further includes components for providing a
hydratable medium or a physiological monitor, or preferably, both.
In one preferred embodiment, a system of this invention permits
fluid to be effectively withdrawn from the tissue site by the
delivery of a medium adapted to be hydrated by, and upon contact
with, moisture within the tissue site. In turn, the removal of
moisture from the tissue site, upon the removal of hydrated medium,
preferably achieves, or contributes to, a therapeutic effect
brought about by a reduction in swelling. The word "hydratable", as
used in connection with an embodiment of this invention, will refer
to a medium capable of being converted from a state of lower
moisture content (e.g., lower relative humidity for a gas) to a
level of detectably greater moisture content ("hydrated"), by the
accumulation of water (e.g., in the form of vapor or liquid) from
within the tissue.
[0109] The present invention provides a method and system for the
delivery of a medium to a tissue site, under conditions suitable to
permit the medium to be hydrated by moisture, e.g., within the
tissue site, in order to achieve a therapeutic effect upon the
withdrawal of hydrated medium from the site. In a particularly
preferred embodiment, the medium comprises a gas that can be
delivered in a relatively less hydrated (e.g., desiccated or
tending toward desiccated) form, and recovered in a more hydrated
(e.g. saturated or tending toward saturated) form.
[0110] In both such embodiments, the medium is preferably delivered
within one or more semipermeable interface materials, preferably in
the form of membranes or catheters (e.g., hollow capillary fibers),
each having a lumen formed, in whole or in part, by wall portions
adapted to permit the accumulation of moisture (and optionally,
small solutes), between the tissue and the lumen, while
substantially preventing the unrestricted flow of bulk fluids
therebetween. One or more catheters are used to form an insertable
catheter assembly that can include associated protective and/or
placement catheter portions, and conduits providing lumen for the
delivery and/or recovery of hydratable gas, as well as negative
pressure. In another embodiment, a plurality of hollow fibers can
be used to prepare a cartridge for extracorporeal use, in which
case the tissue (blood) is contacted with the fibers outside the
body, to be treated there and subsequently returned to the
body.
[0111] The system of this invention, and corresponding catheter
assemblies, can be designed to permit the hydration of the medium
(as by vaporization of the water component of blood) to occur
either as the dehydrated medium is traveling toward and/or away
from the distal catheter tip, and to a distal air plenum. In each
case, typically a single impermeable lumen will serve to transfer
the gas in the opposite direction, e.g., to return hydrated gas
from the plenum or deliver dehydrated gas to the plenum,
respectively.
[0112] The catheter(s) can be provided in any suitable form and
configuration, e.g., as one or more closed and/or open ended
individual fibers, as a plurality of closed and/or open ended
parallel fibers, and/or as circuitous loops of fibers. In such
configurations, the lumen of each catheter will typically include
an entry orifice for the delivery of hydratable gas and a recovery
orifice for the recovery of hydrated medium from the lumen.
[0113] The fibers can be delivered to the tissue site using any
suitable introducing components, e.g., they can be positioned
within a surrounding placement catheter (e.g., conventional
ventricular catheter or customized introducer) that can itself be
removed or permitted to remain in place in the course of using the
delivery/recovery catheter. Optionally, or in addition, the
delivery/recovery catheters can be accompanied by one or more
delivery guidewires, stylets, or trocars, and combinations thereof,
e.g., adapted to position the semipermeable membrane(s) within the
tissue site.
[0114] An apparatus and system of this embodiment finds particular
use in the treatment of cerebral edema. While not intending to be
bound by theory, it appears that an increase in brain tissue water
content occurs after brain injury. Osmotic pressure exerted by
intracellular osmolarity, estimated to range between 317 and 587 mm
Hg in ischemic tissues (Kobari et al., 1985), creates a gradient
for the movement of fluid into cells after ischemic injury, leaving
large, osmotically active behind in the extracellular spaces
(Odland, Sutton, 1999). Such osmotic fluid shifts after ischemic or
traumatic injuries may underlie the frequent failure of
contemporary therapy to attenuate cerebral edema.
[0115] Clearance of edema fluid from tissue to CSF is considered to
be a primary mechanism for the resolution of vasogenic brain edema.
Hydrostatic pressure gradients are important for fluid movement in
the extracellular space, though these hydrostatic pressure
gradients become less effective if there is cellular swelling. To
date, very few authors have suggested that the manipulation of CSF
osmolarity can influence cerebral edema formation after brain
injury. See, e.g., Onal et al. 1997, in which the administration of
a bolus infusion of albumin into the cerebral ventricles resulted
in a significant reduction of tissue water content at 6 hours post
injury. Although the effect was transient, and could not be
repeated at 24 hours post injury, these results nevertheless
support Applicant's suggestion that increasing the osmolarity of
CSF after brain injury, by even a small amount, can increase
movement of water into the CSF and thus reduce edema.
[0116] In one preferred embodiment, therefore, the system of the
present invention can be used to counteract the gradient that is
thought to result from water movement into tissue, and following
injury. Water can be directly and effectively removed from within
the cerebral ventricles, and indirectly from the tissue, to
decrease tissue edema. With the removal of water from the
ventricles, by vaporization into a hydratable gas, fluid can be
pulled from the edematous brain tissue. If water vaporization rates
do not exceed tissue edema reduction rates, the osmolarity and
colloid osmotic pressure of the CSF will remain constant. With such
a method, both crystalloid and colloid osmotic pressure can
increase, in a manner sufficient to maximize the relative effects
of both types of pressure in the reduction of edema.
[0117] The system of the present invention also preferably provides
a hydratable medium, suitable for use in removing water or volatile
compounds (e.g., ketones or ammonia in its various forms) from the
lumen of hollow fibers. Any medium that passes through the lumen of
the hollow fibers can sweep the vapor clear. The rate of flow of
the transport media can affect removal, as can water capacity of
the media. Gaseous media have much greater flow rates for similar
pressure gradients, and are typically more preferred for many
embodiments of the present system.
[0118] Several gases can be used to sweep away vapors from within
the lumen of hollow fibers of the present invention. The selection
of a suitable gas can include consideration of both the effect of
the gas on the tissues, and the physical properties of the gas
itself. With respect to tissue effect, a suitable gas for use in
this invention preferably has no deleterious effect on tissue,
under the conditions of use. Rather, the gas is either inert with
respect to tissue, or can have a favorable effect, such as the
effect of oxygen in improving oxygenation of the tissues. Carbon
dioxide is typically less preferred, particularly under conditions
where it might increase acidosis, but it may also have some
vasodilatory effects that may be beneficial.
[0119] A gas suitable for use in the system of this invention
preferably also provides an optimal combination of physical
properties, including chemical inertness and stability, water
content, and the ability to be provided in sterilized form. Air is
readily available, and can be dehydrated and filtered for
sterility. Nitrogen is inert, commonly available, and as a
compressed gas would be of low humidity. Helium is an inert gas
with very low density, and thus low resistance to flow. High flow
rates can be achieved while maintaining low Reynolds numbers. Those
skilled in the art will also appreciate the manner in which
temperature will effect the humidity of all gases, and a resistor
to drop pressure may also be used in order to reduce gas
humidity.
[0120] In addition to water, other volatile compounds may be
removed from, or delivered to the tissue, in order to achieve a
therapeutic effect using a system of this invention. Examples
include removal of ketones in diabetic coma, removal of ammonia in
hepatic coma and liver failure, and removal of urea in renal
failure. Similarly, mixtures of hydratable gases can be used in
order to effectively deliver beneficial agents, such as nitric
oxide or oxygen, to the tissue site.
[0121] In a further preferred embodiment, the system of this
invention, including a hydratable medium, is used in an
extracorporeal process and system to remove substantially only
water. WRT can be combined with hemofiltration, for instance, in
order to provide an optimal combination of bulk fluid recovery, as
provided by hemofiltration, with the vaporization and removal of
water by WRT, to the controlled exclusion of electrolytes and
larger constituents. This combination of both ultrafiltration and
vaporization can be performed either sequentially and/or
simultaneously, and on either the same or different aliquots of
bodily fluid. In such an embodiment, the present system and method
can be used to perform treatment in a manner that removes only
water, or in a manner that removes both water soluble components,
in a controllable manner and to the extent desired to achieve a
therapeutic effect.
[0122] In a preferred embodiment, the method can be used to remove
water by circulating dry air through hollow membrane fibers that
vaporizes water in the blood.
[0123] The water vapor is then swept out of the membrane fiber with
the constant flow of dry air. The benefit of there being
substantially no salt removal will be particularly beneficial to
those CHF patients having low salt concentrations in their blood.
About one third of hospitalized patients have sodium levels below
normal, and low sodium levels are a risk factor for death due to
CHF. Other cation concentrations are frequently low in CHF patients
as well, particularly potassium and magnesium, and retention of
these cations will be similarly improved.
[0124] Increasing ions in the blood will tend to increase
crystalloid osmotic pressure, which in turn will have the effect of
increasing the rate of vascular refilling. Although ion
concentration is increased in the blood, bulk flow of interstitial
fluid into the capillaries will prevent diffusion of ions into the
interstitial space. WRT can also be accomplished with a
microcatheter placed directly into the vascular space.
Alternatively, an ultrafiltration catheter can be used to remove
plasma directly from the vascular space, with WRT being performed
on the ultrafiltrate and/or on separate aliquots of whole
blood.
[0125] By contrast to conventional hemofiltration, which typically
does not improve low salt concentrations, a system of the present
invention will remove body fluid while retaining salt in the
vascular system. Increased urine output will occur by 1) increased
responsiveness to loop diuretics (which require sodium), 2)
correction of inappropriate signals to retain water and salt, and
3) increased blood pressure.
[0126] In one preferred embodiment, therefore, the present
invention provides a functional combination of water recovery
therapy, ultrafiltration and optionally, reinfusion. These
processes can be performed simultaneously (e.g., in parallel)
and/or in any suitable order (e.g., in series), and on either the
same or different tissue samples or sites. WRT and diffusional
hemodialysis, ultrafiltration, and reinfusion (replacement fluids)
can be used in varying combinations in order to provide increased
exchange by the creation of concentration gradients. See, for
instance, Table II showing various advantages associated with
varying combinations of these processes, including varying
combinations and/or sequences, of WRT with other processes, as well
as various embodiments of WRT per se. These options include, for
instance, those in which a hydratable medium is delivered within
the intraluminal space, as compared to extraluminal space, of a
collection of hollow fibers within a cartridge. In the first column
of Table II, the particular processes are identified, generally in
the order in which they will be applied to blood or other bodily
tissue. The following two columns describe the relative positions
of blood, desiccated gas, ultrafiltrate, etc. with respect to the
fibers within corresponding cartridges, and the final column
provides related comments, including potential advantages,
associated with each.
[0127] Extracorporeal circulation can be used to reduce generalized
body fluid overload, and also can target specific organs, depending
on placement of the withdrawal and infusion catheters. For example,
catheters placed in the vena cava will have more specific effect on
pulmonary edema and myocardial edema. Catheters placed in the aorta
proximal to the renal artery distribution will have a specific
effect on renal edema.
[0128] Several features of WRT make it amenable for outpatient, or
even home use. Arteriovenous hemodialysis relies on the pressure
differential between arterial and venous blood to drive blood
through the cartridge. The same method can be used with WRT. Given
wide spacing of hollow fibers, low pressure airflow can remove
water at sufficient rates to allow daily or weekly preventive
treatment. The low flow of this system may require an internal
heater to maintain blood at normal temperatures. WRT of
ultrafiltrate can be appropriate for this application, particularly
to reduce viscosity, and possible sludging.
[0129] Venovenous treatment can be performed with pumping action of
vaporization itself. Normally, venovenous ultrafiltration requires
the use of a mechanical pump to move blood out of the vein, through
the cartridge, and back to the vein. Vaporization itself can
provide pumping action by using a proximal switch valve and distal
check valve. During vaporization with the proximal valve closed and
subsequent loss of water volume within the hollow fibers,
hydrostatic pressure will fall inside the hollow fibers. Periodic
opening of the proximal switch will refill the cartridge. Emptying
the cartridge and return of blood to the vein is accomplished by
gravitational flow and reduced venous pressure. Thermal effects
will also contribute to blood flow within the system. Cooling of
blood occurs with WRT. Thus, the effluent will be cooler and more
dense than afferent blood. The cool blood will be sink at a higher
rate. Compliance of the hollow fibers will avert the need for
venting. Because blood flow through the cartridge will be at low
flow rates, an internal heater or other suitable means can be used
to maintain blood temperature and therefore water vapor
pressure.
[0130] Transdermal WRT is an option as well. WRT can be performed
without the need for intravascular access, although typically at
lower rates. Methods to increase skin conductivity could allow
transdermal treatment. Transmucosal water loss is also possible.
Subdermal interstitial fluid can be accessed by micropuncture and
other suitable means.
[0131] Various aspects concerning WRT can be assessed using the
following mass transfer formula. This formula has particular
applicability to the preferred embodiment in which blood or other
fluid is passed external to the lumen of one or more hollow fibers,
and hydratable medium (e.g., desiccated gas) is passed within the
lumen of such fibers.
Water removal rate/fiber=flow (concentration out-concentration
in)
[0132] More particularly, the following formula for water mass
transfer in pertains to gas flow within the hollow fibers:
[0133] Water removed per
fiber=Q((1-e.sup.-2k/rv*Cw.sub.saturated)-Cw.sub.- intake)
[0134] where Q is the rate of airflow through the fiber (in
m.sup.3/sec),
[0135] Cw.sub.saturated is the equilibrium vapor concentration (in
mmoles water/m.sup.3) based on water vapor
[0136] pressure of tissue at 37 degrees C.,
[0137] Cw.sub.intake is the concentration of water vapor (in mmoles
water/m.sup.3) in air entering the system,
[0138] l is the length of the hollow fiber (in meters),
[0139] r is radius (in meters), and
[0140] v is the flow velocity (in m/sec), and
[0141] k is the mass transfer coefficient determined for the
particular fibers and conditions of use.
[0142] A corresponding formula can be used in the alternate
embodiment, in which desiccated gas will flow outside the hollow
fibers, with blood or other liquid flowing within.
Water removed per
fiber=Q((1-e.sup.2k1r/(r2-r2)v*Cw.sub.saturated)-Cw.sub.-
intake))
[0143] Water removal with blood or ultrafiltrate in the hollow
fiber and gas outside the hollow fiber can be modeled as above. The
surface area and mass transfer coefficient are unchanged. The
variable to consider is cross-sectional area outside the fiber
available for airflow. In this model of coaxial cylinders,
increasing the cross sectional area reduces velocity, so there is
no change in water removal for a given airflow. Increased
cross-sectional area will reduce resistance to flow, so airflow
will improve with larger spaces between the fibers.
[0144] Based on this formula, it can be seen that increasing
airflow can often be the simplest and most efficient means of
increasing water removal. Even though the air coming out of the
system will be less than completely saturated, that inefficiency
can be more than compensated by the increased volume of gas
recovered.
[0145] Given this formula, it can be seen that a number of
variables can be considered and adjusted as necessary, in order to
achieve water removal at any desired rate and and/or total amount.
For instance, in order to achieve water removal at a rate within
the currently preferred range of about 100 ml/hr to about 500
ml/hr, and employing a corresponding number of fibers.
[0146] For instance, given this rate of water removal, Q can be
provided in the range of from about 10.sup.-8 to about 10.sup.-5
and more preferably from about 10.sup.-7 to about 10.sup.-6.
Cw.sub.saturated is between about 0.1 to about 50 mmoles water/m3,
and more preferably between about 5 to about 20 based on water
vapor pressure of tissue at 37 degrees C.
[0147] Cw.sub.intake, though expressed in mmoles water/m.sup.3, can
be determined from corresponding dewpoint values (where dewpoint is
the temperature at which air must be cooled for condensation to
occur). With increasing amounts of water in the air, it can require
only a slight reduction in temperature to cause condensation. If
the air is fairly dry, it requires colder temperatures to produce
condensation. Dewpoint, in turn, can be converted to g/m.sup.3 or
mmoles/m.sup.3. The experimental results below show that even
relatively moist gas can be used effectively, so long as its
velocity is sufficiently high. Hence where the hydratable medium is
air or similar gas, its dewpoint is preferably less than about 10,
and more preferably less than about 1.
1 Dewpoint, .degree. C. g/m.sup.3 mmoles/m.sup.3 Very dry air -73
0.003 0.17 (desiccated) Relatively dry air 0.39 5 278 50% relative
humidity 11.3 10.2 567 at room temperature
[0148] The length (l) of the fibers can be on the order of about 1
cm to about 100 cm and preferably is between about 5 cm and about
20 cm. The radius (r) is typically derived using fibers having an
inner diameter (ID) of between about 50 microns to 5000 microns,
and more preferably about 100 microns to about 1000 microns,
[0149] The flow velocity v of gas within the fibers can be between
about 1 l/min to about 100 l/min, and preferably between about 2
l/min and about 25 l/min, all per 1000 cm.sup.2 of fiber surface
area, and k can be on the order of about 0.1 to about 50, and more
preferably is between about 2 and about 20. Given a particular
water removal rate, per fiber, the total water removal then becomes
largely a function of the number of fibers employed. An
extracorporeal cartridge for use in the present invention will
typically include between about 1 and about 10,000 such fibers more
preferably between about 1,000 and about 5,000 fibers.
[0150] Suitable monitors include, but are not limited to, those
adapted to qualitatively and/or quantitatively assess various
parameters, preferably in a substantially "real time" fashion
during and in the course of using a system of this invention. Such
parameters can physiologic parameters associated with the tissue
itself, as well as performance parameters associated with the
function of the system or its components. Examples of suitable
physiologic parameters include, but are not limited to, tissue
pressure (total and partial pressures), blood flow, hydration
(water content), temperature, pH, sodium, and biochemical
parameters (e.g., myoglobin levels).
[0151] Such parameters can be determined using any suitable means,
for instance, pressure can be determined using conventional fluid
column techniques (e.g., diaphragm or manometer), or fiberoptic
techniques, while fluid (including blood) flow can be determined
using near IR spectroscopy and laser Doppler techniques, and tissue
hydration can be determined by a variety of means, including the
placement of a suitable probe or electrode to determine electrical
impedance.
[0152] In a particularly preferred embodiment, the monitoring
components are "associated" with the system of this invention, in
the sense that one or more portions of the monitoring components
are physically and/or functionally integrated with the placement
and/or operation of the semipermeable membrane component. As shown
in the preferred embodiments of FIGS. 1-4, for instance, the
overall catheter assembly is configured to provide a fluid column
component for the determination of tissue pressure. Typically, the
associated components of such monitoring components will in turn be
used with other, conventional, components, such as conduits,
connectors and monitors. For example, the Figures depict the manner
in which components of a conventional pressure monitoring system
(available from Stryker) can be readily adapted for use with a
system of this invention.
[0153] When used for the treatment of cerebral edema, a system of
the present invention can include monitoring components for a
variety of parameters. In a preferred embodiment, the parameter is
that of intracranial pressure or ICP. In adults, the average ICP
ranges from 0-10 mm Hg. 20 mm Hg is considered to be the maximal
upper limit of tolerable ICP and pressures exceeding 40 mm Hg are
considered extremely elevated. The type of monitor used is
dependent on a number of clinical factors, not the least of which
is the neurologic disease causing the pressure increase.
[0154] Suitable materials for use as semipermeable membranes of the
present invention provide an optimal combination of such properties
as mass transfer properties, biocompatibility, surface-to-volume
ratio, processability, hydrophobicity and hydrophilicity, strength,
transport rate, and porosity. Examples of suitable hollow fibers
are described, for instance, 1. Cabasso, "Hollow-Fiber Membranes",
pp 598-599 in Kirk Othmer Concise Encyclopedia of Chemical
Technology. In a preferred embodiment, such membranes are provided
in the form of "hollow fibers" or "microcatheters", having walls
(or portions thereof) formed of such membrane material. In
alternative embodiments, the membranes can be provided in any
suitable form or configuration, e.g., in the form of pleated or
corrugated membrane sheets, and the like, preferably positioned
within and/or by a recovery catheter. In situations where the
semipermeable membrane(s) are provided in other than
circumferential (e.g., fiber) form, the hydratable medium can be
delivered to a major surface of the membrane, opposite the surface
in contact with, or accessible by, the tissue fluid itself.
[0155] The dimensions of a hollow fiber will depend largely on the
intended use of the apparatus. In a number of preferred
embodiments, a hollow fiber will be provided in the form of a
capillary having an outer diameter of between about 0.1 mm and
about 10 mm, preferably between about 0.2 mm and about 3 mm, and
more preferably between about 0.3 mm and about 1 mm. Such capillary
fibers preferably also provide a substantially open lumen, defined
by an inner fiber diameter that is typically on the order of 50% or
more, and preferably 70% or more the corresponding outer
diameter.
[0156] Such membranes preferably also provide permeability cutoffs
suitable for use in the intended application. The permeability of
hollow fiber membranes for use as microdialysis fibers is generally
phrased in terms of kiloDaltons (and can range between about 10 kD
to about 1000 kd). By comparison, the permeability of fibers used
for ultrafiltration is typically considerably greater, and hence
phrased in terms of microns, with typical ranges from about 0.1
micron (corresponding roughly to the 1000 kD cutoff at the higher
range above) to about 1 micron. Fibers suitable for use in the
system of the present invention, therefore, typically provide
permeability in the range of from about 1 kD to about 200 microns,
preferably from about 10 kD to about 10 microns, and more
preferably between about 50 kD and about one micron.
[0157] Permeability can be determined using suitable techniques,
such as conventional wet sieving techniques. See, for instance,
Spectrum Laboratories, Inc. product information which describes the
manner in which both the membrane molecular weight cut-off (MWCO)
and pore size are related and can be determined.
[0158] Hollow fiber performance can be characterized by the
molecular weight at which 90% of the solute will be retained
(prevented from permeating) by the membrane. This value is called
the Molecular Weight Cut-Off (MWCO), which in turn is described as
the molecular weight of the largest globular protein that can pass
through the pores of the membrane. In general, proteins that weigh
more than the MWCO will be retained by the membrane. In addition to
the molecular weight, the permeability of a particular solute is
dependent on the shape of the molecule, its degree of hydration,
and its charge. Each of these may be influenced by the nature of
the solvent, its pH, and its ionic strength.
[0159] The MWCO is controlled, in turn, by the size of the pores in
the membrane. Separation efficiency is influenced by the pore size
distribution and the presence of a substantial number of pores much
larger than the average will allow leakage of high molecular weight
solutes. Thus, a narrow pore size distribution is highly
desirable.
[0160] The cross-sectional structure of such membranes is either
symmetric or asymmetric depending on the type and use. Symmetric
membranes, such as dialysis tubing, have pores of the same diameter
throughout their thickness while asymmetric membranes, such as
unsupported flat sheets, have smaller pores that control the MWCO
in a very thin layer or skin at one surface and larger pores in the
remainder. The pore size distribution is equally important in the
two types.
[0161] Sample flow perpendicular to the membranes, renders the
membrane susceptible to blockage. The phenomenon can be reduced by
sample mixing during filtration. Mixing can be achieved by either
stirring or by passing the sample parallel to the membrane.
Semipermeable hollow fibers suitable for use in the system of the
present invention can be prepared using conventional methods, and
are available commercially. Hollow fibers are typically provided in
the form of minute tubules, the entire walls of which are
constructed of a semipermeable material. The material, in turn,
will typically determine what can or cannot pass through the wall
of the tubules. The selection of hollow fiber material is based
primarily on the size of molecules to be removed or retained, as
well as other physical properties. By comparison, reverse osmosis
(RO) membranes have even smaller pores than either microdialysis or
ultrafiltration. Reverse osmosis is typically performed with
excessive pressures, and is therefore not widely used for clinical
treatment. RO membranes are used for removing salt from water, and
purifying water. The pores are small enough that only water can
pass through (a hydrated water molecule being approximately 0.04
microns diameter). With the small pore size, water flux through the
membrane is also limited. For purposes of the present invention, RO
membranes are generally less preferred, however, if only in view of
their limited availability and high hydrostatic pressure
requirements.
[0162] Water vapor and other gases will pass through very thin
silicone or other materials. These membranes have no open pores,
yet allows water vapor to pass through the very thin, permeable
membranes. The rate of water removal is reduced, but the possible
advantage is that no bulk flow can occur, even after a period of
wetting or exposure to transmembrane hydrostatic pressures. Yet
other membranes used for water vapor removal do have pores, but the
pores do not allow liquid water to pass. Pores in hydrophobic
materials do not wet, for instance, but instead allow vaporization
at the liquid water-vapor interface within the pores.
[0163] Such hydrophobic materials can be provided, for instance, in
the form of microporous hydrophobic membranes (MHMs), of the type
described in Goldberg et al., "Design Solutions Using Microporous
Hydrophobic Membranes", Medical Devices and Biomaterials Magazine
1997 (http://devicelink.com/mpb/archive/97/03/002.html). Numerous
polymers can be employed to form MHMs. Today, the predominant
polymers used are PTFE (polytetrafluoroethylene), polypropylene,
PVDF (polyvinylidene difluoride), and acrylic copolymers. All of
these polymers can be treated in order to obtain specific surface
characteristics that can be both hydrophobic and oleophobic
(repelling liquids with low surface tensions).
[0164] The Goldberg et al. article describes the manner in which
MHMs block liquids, while allowing air or gases to flow through the
membrane. The low surface tensions of MHMs cause them to repel
fluids from the surface, leaving the pores of the membrane filled
with air. The porosity of the membrane allows air to flow freely
through the material. Because of their diverse surface tensions and
microstructures, membranes made from various polymers have
significantly different properties, including chemical inertness,
water-entry pressures, airflows, and surface release
characteristics. The hydrophobic nature of an MHM prevents fluid
from passing while allowing air to flow freely across the membrane,
facilitating accurate pressure measurements. Those skilled in the
appropriate art will understand the manner in which the choice of a
particular MHM will depend on a number of design considerations,
and will include such considerations as fluid containment, fluid
surface tension and fluid pressure. Other considerations, of
particular relevance to the present invention, will include airflow
rates, surface area, temperature, sterilization method (e.g., MHMs
can be sterilized by autoclaving, ethylene oxide, or gamma
irradiation), life expectancy, biocompatibility and chemical
compatibility, as well as membrane quality and consistency.
[0165] There are many parameters used to characterize the
functional attributes of specific MHMs. Listed below are some of
the key terms and their definitions: Water-Entry Pressure (WEP).
Also known as water breakthrough, WEP is the pressure required to
force water through a hydrophobic structure. This property is
typically expressed in pounds or bars per square inch. Gurley
Value. This variable provides a reliable measure of the airflow
through an MHM. Usually expressed in seconds, the Gurley value will
describe the length of time a specific volume of air under a
specific pressure takes to pass through a specific area of an MHM.
Bubble Point. Used to characterize the MHM's reference pore size,
the bubble point is the lowest pressure that is required to
displace a low-surface-tension fluid from the pore structure of an
MHM, and is typically expressed in pounds or bars per square
inch.
[0166] MHMs can be sealed to plastic devices using several
different methods. Depending on the device material and the polymer
makeup of the MHM, alternatives can include ultrasonic welding,
radio-frequency (RF) sealing, heat sealing, insert molding, or
adhesive bonding.
[0167] Ion-exchange polymers are another class of useful membrane
materials that are typically used in electrodialysis. They have
cation and anion groups within the matrix that can assist in water
vaporization and removal processes. These materials are described
in "Electrodialysis", T. A. Davis and D. A. Glassner, Handbook of
Downstream Processes, Blackie Academic & Professional, London,
Elliot Goldberg editor, pages 140 to 166.
[0168] In a preferred embodiment, the system of the present
invention accomplishes the removal of water, by tissue
ultrafiltration, as a therapeutic treatment. Removal of
substantially only water can be accomplished by use of RO membranes
or water vaporization. Water, salts, and some proteins can be
removed by membranes having permeability in the range of
conventional microdialysis fibers. All molecules, including large
proteins can pass through fibers having the characteristics of
conventional ultrafiltration probes.
[0169] The removal of substantially only water will increase the
crystalloid and colloid osmolarity of the fluid left behind, while
the removal of water and salts will increase the colloid osmotic
pressure of fluid left behind. Tissue osmolarity will be maintained
by the water that is transmitted through the corresponding tissue.
Increasing the osmolarity of extracellular fluid, or preventing a
decrease in osmolarity, will have the effect of improving
convection and diffusion in a tissue. These effects will improve
edema removal, and can also be used to advantage for drug delivery.
Suitable drugs for delivery in this manner include, for instance,
neuroprotectant agents, antimicrobial agents (e.g., antibacterials
and antivirals), vasodilators (e.g., nitric oxide), anticoagulants,
genetic vectors, and anti-inflammatory agents (e.g., steroids for
the treatment of compartment syndrome).
[0170] Hollow fibers suitable for use in the present invention
provide an optimal combination of other properties as well, such as
inner diameter, outer diameter, wall thickness, tensile strength,
compressive strength, and transmembrane conductance. Collectively
these properties are suitable to provide the fiber with the ability
to withstand positive or negative pressure. Transmembrane
conductance is a measure of the ability to transmit water and other
substances. High transmembrane conductance is seen in large pore
fibers.
[0171] These fibers can be used singly or can be grouped into
bundles, e.g. containing anywhere from a plurality to several
hundred or even several thousand such fibers. In most cases, a
hollow fiber will be used as a cylindrical membrane in a manner
that permits selective exchange of materials across its walls.
Optionally, such fibers can be used in varying combinations, such
as coaxial fibers having differing permeabilities to oxygen, cells,
and fluid or its components. Such combinations can be designed and
used to provide a sequential selectivity with respect to fluid
flowing sequentially through the fibers or fiber portions.
Preferred embodiment as compared to in-situ methods.
[0172] Semipermeable membranes can be prepared in any suitable
manner, e.g., by microperforating an otherwise intact capillary or
by spinning hollow fiber membranes from natural or synthetic
polymers. Such fibers can be formed having any desired
characteristics, e.g., isotropic (dense or porous) and anisotropic
(asymmetric). Examples of suitable materials for use as
microcatheters of this invention include, but are not limited to,
microinfusion tubing such as polyethylene tubing available from
Clay Adams under the designations PE-10 (0.28 mm/0.61 mm, inner and
outer diameters), PE-20 (0.38 mm/1.09 mm), PE-50 (0.58 mm/0.965 mm)
and PE-90 (0.86 mm/1.27 mm). Such tubing can be microperforated by
any suitable means, such as lasers and the like.
[0173] Optionally, and preferably, microcatheters used in this
invention can have regions of varying characteristics, including
varying porosity, rigidity, and the like, for instance those that
vary between sequential and adjacent, or suitably spaced,
longitudinal sections, or in or any other suitable pattern. Such
variations can be used, for instance, in a size exclusion fashion
to improve or provide the ability to retain or permit the passage
of solutes of varying sizes in a predetermined manner. Such
variations can also be used to provide regions of greater rigidity
or varying structure (e.g., fluted), in order facilitate their
placement in tissue. Such variations can also include the
incorporation of means (e.g., radioopaque materials) to facilitate
the visualization of implanted catheters. Such variations can also
be used to place regions of semipermeable membranes in desired
locations within the tissue, e.g., in order to effect a gradient
between two or more regions, or to avoid the placement of
semipermeable regions in particular tissues or areas thereof.
[0174] When blood or body fluids are treated with extracorporeal
circuits, hollow fibers can be used in a sequential manner to
improve separation. WRT can be performed first, which will improve
separation, when trying to remove certain agents by ultrafiltration
or other means. Also, serial flow through hollow fibers or
cartridges of various cutoffs can exclude or retain specific ranges
of molecules of given molecular weight.
[0175] Suitable membranes are available commercially, including
from Applied Membrane Technologies, as their line of "AMT" type
membranes, and from Minntech, Inc. Examples of suitable membranes,
including the materials and available pore sizes and dimensions,
are provided in TABLE I below.
2TABLE 1 Pore Size (expressed in kiloDaltons (KD) ID OD Source
Material or microns) (mm) (mm) A/G Polysulfone 10 KD 0.25, 0.5, 1,
Technology 0.5, 1 1.8 Corp. Needham, MA Polysulfone 30 KD 0.5, 1,
1, 1.8, 2, 3 3, 4 Polysulfone 50 KD 0.5, 1 1, 1.8 Polysulfone 0.1
.mu.m 0.75, 1, 2 1.5, 1.8, 3 Polysulfone 0.2 .mu.m 1 1.8
Polysulfone 0.45 .mu.m 1 1.8 Akzo Nobel Cellulose 10 KD 0.2 0.216
Asahi Polyacrylonitrile 50 KD 0.25 0.32 (PAN) Corsep PAN 50 KD 0.2
0.31 Polyethersulfone 0.1 .mu.m 0.6 1.0 Polyethersulfone 0.2 .mu.m
0.6 1.0 Polyethersulfone 0.5 .mu.m 0.6 1.0 Minntech
Polyethersulfone 10 KD 0.2 0.28 (Minneapolis, MN) Polyethersulfone
30 KD 0.28 0.36 70 KD 0.2 0.28 Polyethersulfone 0.05 .mu.m 0.28
0.36 Polyethersulfone 0.2 .mu.m 0.28 0.36 Polyethersulfone 0.45
.mu.m 0.28 0.36 Spectrum Polyethersulfone 0.2 .mu.m 0.5, 1.0 0.9,
1.4 Laboratories (Rancho Dominquez, CA) Cellulose 0.1 .mu.m 0.64
0.86 Cellulose 0.2 .mu.m 0.64, 1 0.86, 1.2
[0176] One or more introducing components are preferably included
in a catheter system of this invention and can be provided in any
suitable form, e.g., using suitable introducers (typically in the
form of one or more sheaths used to facilitate the placement of a
catheter through the skin, typically into a vein or artery),
guidewires (e.g., typically coiled wires adapted to fit inside a
catheter assembly for the purpose of directing the catheter into or
through a tissue site), stylets or trocars (e.g., sharp pointed
instrument used with a cannula for piercing a vessel or chamber to
facilitate insertion of the cannula), and combinations thereof. In
turn, the introducing components, including various components, can
provide an assembly that is steerable or nonsteerable, useful with
open incision or using minimally invasive means, and/or adapted to
be dilated, expanded, or compressed, thermally regulated.
Optionally, an introducing component can comprise or be provided in
the form of a shaped memory alloy, such as Nitinol (NiTi).
[0177] The invention will be further described with reference to
the Figures, wherein FIG. 1-4 show a preferred system of the
invention for use in treating compartment syndrome, and FIG. 5-10
show a preferred system of the invention for use in treating
cerebral edema.
[0178] FIG. 1 shows a catheter assembly 10 that includes an
implantable catheter body 12 providing a conduit leading through
Y-adaptor 25 to a pressure line and associated connector 14 for
attachment to a pressure monitor (not shown), as well as a conduit
and associated connector 16 for attachment to a vacuum source (not
shown). Within the vacuum conduit, and attached by Y-connectors 24
and 26, are a filtrate collection assembly 18 and filter/cap
assembly 28/29, respectively. The collection assembly can take any
suitable form, and is here shown as including a syringe collection
chamber 21, above which is positioned the proximal end of the
incoming portion of collection tube. Also associated with the
vacuum conduit is filter/cap assembly 29. With the cap 29 removed,
fluid is vented via Y-connector 26 and collected via drip tube 20
and syringe 21.
[0179] FIG. 2 shows a cross-section taken across A-A of the
catheter assembly 12, showing the outer impermeable tube wall 30 of
catheter assembly 12, within which are positioned a central fluid
filled tube 32 for pressure measurement, and seven
circumferentially placed semipermeable membranes 34.
[0180] FIG. 3, in turn, shows an enlarged detailed view of the
distal end of catheter assembly 12 as shown in FIG. 1, including
the distal portions of semipermeable catheters 34, which are shown
terminating within a circumferential collar portion 40 that itself
terminates distally in a split end, to prevent constriction by
surrounding tissue. In this particular embodiment, the catheters
are also closed on their distal ends, within a region of suitable
adhesive 44. In the region proximal to collar portion 40, however,
the walls of the membranes are accessible for direct contact with
surrounding tissue. Also shown is the fluid filled pressure lumen
32, extending distally beyond collar 40 and into the split end 42,
in order to provide unimpeded contact with tissue fluid. Adhesive
41 is shown providing a seal between collar 40 and split end
42.
[0181] FIG. 4 shows components of introducing components suitable
for use with the catheter assembly of FIG. 1, including a trocar
needle 50 and split sheath 52. In use, the trocar can be positioned
within the sheath, and the combination positioned within the tissue
site. Once positioned, the trocar can be removed from the sheath,
leaving the sheath in position within the body, whereupon the
catheter portion 12 of assembly 10 can be inserted into the sheath.
With the catheter positioned, the sheath can be finally removed,
leaving the catheter effectively in place within the body.
Following use, the catheter assembly can itself be removed from the
tissue site, or permitted to remain in place for subsequent
use.
[0182] In the course of using the system shown in FIGS. 1-4, the
vacuum source is operated in order to draw a vacuum through the
associated conduit, and ultimately, on the proximal ends of closed
membranes 34. In turn, water and permeable solutes are drawn
through the membrane walls and into the lumen for removal from the
tissue. Simultaneously, the fluid filled, open-ended, central tube
can be operated to measure tissue pressure within the split end
42.
[0183] Turning briefly to FIGS. 5-10 there is shown a preferred
embodiment of a system of the present invention having particular
use in the treatment of cerebral edema. FIG. 5 shows a catheter
assembly 60 that includes an implantable catheter body 62 that is
adapted to be controllably and operably connected (via Y-adaptor
82) with a conduit and associated connector 64 for attachment to a
pressure monitor (not shown). The catheter body 62 is also adapted
to be controllably and operably connected (via Y-adaptors 82, 74
and 70, sequentially) with a conduit and associated connector 66
for attachment to a vacuum source (not shown). The pressure monitor
line provided by conduit 64 further includes a coupling portion 85
near Y-adaptor 82, which is shown in its uncoupled form, to permit
the placement of an introducer (e.g., positioning stylet) through
the corresponding access aperture 83 and longitudinally down the
body of catheter 62.
[0184] Attached within the vacuum conduit, via Y-connectors 82 and
74, respectively, are an assembly of components (including stopcock
78, desiccant dryer 80 and an air filter 81) for providing
filtered, desiccated air or other suitable gas from a remote source
(not shown) to catheter 62. Also attached within the vacuum
conduit, via connectors 82, 74 and 70, respectively, are a drip
tube 71 and associated syringe collection chamber 72. With stopcock
78 in the open position, air or other suitable gas can be delivered
to the catheter distal end positioned within the body.
[0185] FIG. 6 shows a cross section taken across A-A of catheter
assembly 62, including the outer impermeable tube portion 84
enclosing a central inner tube 86, fluid filled for pressure
measurement, and six semipermeable membrane catheters 88, as well
as an impermeable tube 90 for the supply of desiccated gas. FIG. 7,
by contrast, shows a cross section taken across B-B of the catheter
assembly of FIG. 5, and shows the outer wall 92 of the Y-connector
82, enclosing the central inner tube 86 adjacent the desiccated gas
supply tube 90. The semipermeable membranes, which are located
distally from this point, are open-ended on both ends, in order to
permit desiccated gas to be delivered via supply tube 90 to their
distal ends, and to then traverse the membranes in a proximal
direction toward Y-connector 82, becoming hydrated through the
walls of the membranes by surrounding tissue.
[0186] The operation of the various parts is depicted in FIG. 8, in
which the distal end of catheter portion 62 is shown in enlarged
detail, as having a collar portion 96 attaching, distally, a soft
distal tip 98 (e.g., in an adhered or press fit connection) and
attaching proximally the assembled catheters (including membranes
88, air supply tube 90, inner fluid filled lumen 86). The collar
provides an open space 100 (plenum) between the distal tip and
catheter assembly, for use as an air return chamber. The distal tip
is provided with open pores 102 in order to permit free access of
surrounding tissue fluids to the catheter tips. The inner fluid
filled lumen extends sufficiently into the distal tip to permit
pressure determination to be made there.
[0187] In use, desiccated air (or other suitable gas) is supplied
through air supply tube 90 and into the air return chamber, where
it circulates in order to enter the open lumen of the semipermeable
catheters, and traverse the lumen of those catheters in a proximal
direction. With the walls of the membranes in contact with
surrounding tissue, the desiccated air can be drawn by the vacuum
applied from a proximal direction on the open ended membranes.
Simultaneously, the fluid filled inner lumen can be used to
determine tissue pressure, by its proximal functional attachment to
a suitable pressure measurement device (not shown). As compared to
the embodiment of FIGS. 1-4, the membranes of FIGS. 5-10 are
open-ended on both ends, to permit the flow of desiccated gas
therein. FIG. 9 shows an isolated view of distal tip 98, showing a
typical arrangement of access pores 102, while FIG. 10 shows a
stylet 104 adapted to be used for assistance in placing the
catheter portion 62 of FIG. 5. Optionally, this embodiment can be
operated with the stopcock 78 closed to get suction only. As a
further optional feature, some (e.g., alternating) fibers can be
closed at distal end such that these fibers operate only as suction
devices while other fibers have circulating dry air.
[0188] FIG. 10 shows an assortment of components adapted for use in
preparing the skull and/or positioning a catheter according to FIG.
5. In particular, there is shown a positioning stylet 54 (FIG.
10a), self tapping bolt 55 (Fi. 10b), burr hole drill 56 (FIG. 10c)
and tunneling trocar 57 (FIG. 10d). In use, the burr hole drill can
be used to provide access through the skull and to the parenchymal
tissue beneath. The catheter assembly of this invention can be
positioned with the stylet and in the desired location directly, by
first securing the bolt into the skull, and positioning the
catheter assembly therethrough. Optionally, the catheter assembly
can be positioned to a site remote from the access hole, by
employing the tunneling trocar 10d beneath the skull as sufficient
distance under the scalp, then inserting the catheter assembly
therein.
[0189] Finally, FIG. 11 shows a schematic diagram showing the
placement and use of a catheter assembly such as that shown in FIG.
5. The catheter is shown positioned within the brain tissue site
exhibiting swelling, in a manner that permits the controllable flow
of desiccated air from desiccant 80 and through stopcock 78 and
into air supply tubes 90 within the catheter body. As the
desiccated air travels through air supply tube 90 exiting into the
air return chamber at the distal end of the catheter body, where it
is drawn into the plurality of open-ended semipermeable membranes.
As the desiccated air travels back, proximally, through the
membranes, it draws moisture through the exposed portions of those
membranes in a manner sufficient to remove water or vapor from the
surrounding tissue. Once removed from the body, fluid is drawn
toward the collection chamber by vacuum source 66, showing also
optional exit desiccant 75, with drip tube 72 providing a suitable
trap to permit fluid to be withdrawn from the vacuum line.
[0190] As shown in FIGS. 5-11, the preferred system also provides
an associated pressure monitor 64 and associated conduits and
connectors, which is adapted to be used simultaneously with the
delivery and recovery of desiccated gas.
[0191] A system such as that shown in FIGS. 1-4 can be used with
the following protocol and instructions in order to treat sites at
risk for compartment syndrome. Patients considered candidates for
prophylactic use of compartment syndrome therapy must meet all of
the following criteria: 1) be at risk for compartment syndrome, 2)
have a single fracture, 3) have closed or Gustilo grade I open
tibial shaft fracture that requires surgical stabilization, 4) are
skeletally mature (generally over age 16), 5) have no other
traumatic injury, and 6) be mentally alert and able to sign patient
consent form.
[0192] Patients not considered candidates for compartment syndrome
therapy include the following: 1) have fracture currently or
previously treated by closed methods (casting, bracing, or
splinting), 2) have grade II or grade III open fractures, 3) have
evidence of CS at the time of admission, 4) are greater than 80
years of age, 5) have medical condition(s) which preclude use of
indwelling catheters for up to 48 hours, and 6) have co-morbidities
that may increase the incidence of compartment syndrome (shock,
major abdominal or thoracic trauma, massive soft tissue
trauma).
[0193] Certain cautions will typically be followed with regard to
the use of such a system, including:
[0194] 1. Care should be taken when inserting the introducer to
avoid any nerves or large blood vessels in vicinity of treatment
site.
[0195] 2. Slit tubing tip and hollow fiber bundle are fragile. Care
should be taken when inserting catheter into sheath. Damage to the
tip may lead to false pressure readings.
[0196] 3. If the catheter is not located in desired location,
remove the catheter and reinsert the introducer to reposition the
catheter at new location.
[0197] 4. To ensure accurate pressure reading, the pressure
monitor's transducer diaphragm must be positioned at same height as
the tip of the catheter.
[0198] The system is designed to remove interstitial fluid from
body muscle compartments while simultaneously monitoring
compartment pressure. The goal is to reduce the severity of
compartment syndrome by reducing fluid volume while monitoring
tissue pressure within the affected muscle compartment. A preferred
system and related components is shown in FIGS. 12 and 13, showing
the functional arrangement of a CST catheter 100 inserted into a
compartment, and including a pressure monitor 102, fluid collection
reservoir 104 and vent 106, as well as a line 108 to an
intermittent vacuum pump 110. Various components making up a
preferred system of this type are shown in FIG. 13 as including the
CST catheter set 112 and tubing extension set 114, as well as a 3
cc syringe with cap 116 and introducer 118.
[0199] To place the catheter, an introducer, consisting of a
Teflon.TM. sheath over a stainless steel trocar, is initially
inserted into the muscle compartment at the site of therapy. After
the introducer is positioned, the stainless steel trocar is used as
a radio-opaque marker to fluoroscopically verify sheath position.
After position is verified, the trocar is removed and the catheter
is then inserted through the open sheath lumen. The sheath is then
longitudinally split and separated for removal, allowing the
catheter to be in intimate contact with the surrounding tissue. The
catheter is designed to be in-dwelling for up to 24 hours.
[0200] The catheter, in combination with a suitable pressure
monitor (e.g., shown here as a Stryker Intra-Compartment Pressure
Monitor), can measure the intra-muscular pressure during therapy.
Optionally, the system can include continuous injection, provided
by a syringe pump, in combination with disposable pressure sensors
(as currently used for arterial blood pressure measurement) that
are adapted to be plugged into standard hospital pressure monitors.
To measure this pressure, the catheter's distal tip employs a slit
tube to ensure fluid communication with the surrounding tissue.
Applicant has discovered the manner in which conventional pressure
monitoring systems can be modified so as to permit the infusion of
on the order of one to fifty microliters per hour of saline into
the fluid column to maintain patency and accuracy.
[0201] The catheter has a bundle of seven (7) filtration fibers
located near its distal tip. A vacuum pressure of negative 50 mm Hg
is applied intermittently to remove interstitial fluid in the
vicinity of the catheter. The vacuum pressure "On" and "Off" time
is set at (3) three minutes on and (3) three minutes off. After
removal, the fluid is collected in a graduated 3 cc syringe with a
female luer distal end. Optionally, both the vacuum applied and the
timing of vacuum can be adjusted as desired. For instance, such
vacuum pressure can be used at between about -1 to about -760 mm
Hg, and more preferably between about -50 to about -500 mm Hg. The
vacuum pressure can be cycled so as to provide "On" and "Off"
cycles at periodic time intervals (e.g., from a few seconds to on
the order of 30 minutes "on", followed independently by a few
seconds to on the order of 30 minutes off. After removal, the fluid
is collected in a graduated 3 cc syringe with a male luer on the
distal end.
[0202] The system can be provided in the form of one or more
individually packaged sterile sets, including an introducer and
catheter set, that can be used in combination with one or more
other components commercially available in order to provide a
compartment syndrome therapy ("CST") system of this invention
(e.g., a pressure monitor with associated disposable components, a
vacuum pump (e.g., Medela brand), a syringe with cap, and an
extension tubing set.
[0203] The introducer provides access into the muscle compartment
for placement of the CST catheter. As shown, the set consists of a
5 French tear-away sheath placed over a mating stainless steel
trocar. After placement and optional x-ray verification, the trocar
is removed, the catheter is inserted, and then the sheath's hub and
shaft are split longitudinally and removed from the in-dwelling CST
catheter. The CST introducer 118 is illustrated in FIG. 14.
[0204] The tear-away sheath 120 is composed of a thin-walled
plastic tube sized to allow introduction of the 5 French CST
catheter. Both the hub 122 and sheath 124 are designed to be
longitudinally split for easy removal around the in-dwelling CST
catheter. The mating trocar 126 is composed of 304 stainless steel.
Its three-(3) facet tip is electro-polished to a sharp point.
[0205] The CST catheter set is designed to remove excess
interstitial fluid buildup and simultaneously monitor compartment
pressure. One or more catheter sets can be used, of the same or
different types and in varying positions during the course of
treatment. The catheter portion of the set is 5 French in diameter
and contains a bundle of seven (7) porous hollow fibers near its
distal tip. The fibers remove the surrounding interstitial fluid
through both passive drainage and active vacuum. The fluid is
collected in a fluid trap located in-line with the vacuum source.
The fluid collection port is connected to a 3 cc syringe. A
filtered vent is connected to the vacuum line to relieve vacuum
when desired.
[0206] With the vacuum source turned on or off, the catheter
supports compartment pressure monitoring by providing a fluid
column from the tissue through the slit lumen at the catheter's tip
to the external Stryker pressure transducer. FIG. 15 is a drawing
of the CST catheter set 112 with its major components identified
and a detail drawing of the catheter's tip section.
[0207] The catheter body 128 can be composed, for instance, of two
coaxial polyimide tubes affixed independently to each of the two Y
connector ports, or more preferably, a polyimide outer tube and a
stainless steel inner lumen tube to give the catheter more
stiffness. The outer tubing is connected to the fibers and is used
for fluid drainage. It is fiber reinforced to minimize kinking. The
inner tubing is the pressure monitoring lumen. At its distal tip,
the inner tubing extends beyond the outer tubing to support the
slit tip and ensure fluid communication with the tissue.
[0208] Near the distal end of the catheter is a bundle of seven (7)
hollow fibers 130. The fibers are porous hollow filters that pass
water and interstitial fluid. The active vacuum is applied to the
inside lumen of the filters. The fluid is drawn from the
surrounding tissue, through the fibers, out the vacuum lumen and
into the fluid collection syringe.
[0209] The pressure monitoring line 132 is connected to the inner
tubing. The female luer at its proximal end is connected to a
Stryker Pressure Monitoring device. The line is fluid filled to
maintain communication with the Stryker device. The Stryker
Intra-Compartmental Pressure Monitor System is indicated for use on
compartment syndrome. Stryker Instruments (Kalamazoo, Mich.),
Pressure Monitor (part # 295-1), quick pressure monitor set (part #
295-2), normal saline syringe (3 cc NaCl Fill/Syringe, part #
295-5), and quick pressure monitor pack (part # 295-2, including
side ported needle, 18 ga..times.2.5 inch and diaphragm
chamber.)
[0210] The vacuum line 134 is connected to the catheter's outer
tubing. The female luer at its proximal end is connected to the
vacuum pump. A vent 136 with a 0.2-micron filter is attached to the
vacuum line. The vent is normally closed and can be opened to
relieve vacuum pressure by removing the attached cap. The fluid
collection line is connected to the vacuum line. The female luer at
its proximal end along with the protruding drip tube 138 are
inserted into a 3 cc syringe acting as a sample collection
reservoir. Sterile 3 cc syringe with cap (Becton Dickinson,
Franklin Lakes, N.J.), part # B-D, 3 ml Luer-Lok.TM. syringe.
[0211] The Stryker Intra-Compartment Pressure Monitor is a
hand-held, portable pressure monitor specifically designed to
measure intra-muscular pressures. A complete description of the
device and its associated disposables, the diaphragm chamber and
saline filled syringe, are described in its instruction for use
provided by Stryker. See the monitor 102 in FIG. 16, in the form of
a Stryker Pressure Monitor, Model 295-I with disposable diaphragm
chamber and syringe.
[0212] The vacuum pump is used to control the vacuum pressure, the
"suction" interval, and the "pause" interval. The pump is connected
to the catheter set's vacuum line. A suitable pump is manufactured
by Medela, Inc. (McHenry, Ill.) as model 046. The Medela Pump meets
Class IIa medical product basic requirements in accordance with
Appendix 1 of the Council Directive 93/42/EEC Governing medical
products.
3 Pump Setting Ranges: Vacuum Pressure 0-55 mm Hg Suction Time 0-99
minutes in 1 minute steps Pause Time 0-99 minutes in 1 minute
steps
[0213] A standard sterile 3 cc syringe with a female luer fitting
is used as the fluid reservoir. It can be easily attached to the
catheter set's fluid collection port. A standard sterile extension
tubing set is used to connect the vacuum line to the vacuum source,
e.g., as available from Medex (Dublin, Ohio), as part # # 536040
(60 in/152 cm Mini Vol. Ext. APV 0.3 ml). Specific length is
dependent on the pump location. The tubing set is supplied sterile
in a pouch. It comes with one male and one female luer connector
with protective caps.
[0214] Prepare catheter for placement following standard wound care
practice. Connect the syringe to the catheter's fluid collection
port. Set the syringe plunger to approximately the 2 cc graduation,
and connect the sterile 3 cc syringe to the fluid collection port.
Connect the catheter to the transducer, following instructions
provided by the manufacturer. Connect the pressure monitoring line
to the pressure monitoring device. Prime the pressure monitoring
line, leaving the CST catheter's protective cover in place until
the catheter is ready for implantation.
[0215] When connected, hold the catheter above the monitor pointing
the catheter's distal tip up from horizontal at a 45-degree angle.
Slowly flush fluid from the Stryker syringe until a steady stream
of fluid is observed flowing from the catheter. FIG. 17 provides a
diagram for the connection of the syringe and pressure line priming
using the assembly 112 and pressure monitor 102.
[0216] Set vacuum pump PRESSURE, SUCTION Interval, and PAUSE
Interval (reference vacuum pump instruction for use provided by the
manufacturer.)
[0217] 1. Set vacuum pump pressure. Adjust the pump's pressure
control knob to -50 mm Hg +/-5 mm Hg.
[0218] 2. Set SUCTION Interval. Adjust the pump's "Suction Time" to
03 minutes.
[0219] 0.3. Set PAUSE Interval. Adjust the pump's "Pause Time" to
03 minutes. (See FIG. 18 for pump settings 140).
[0220] 4. Monitor pump parameters. Throughout treatment, monitor
the pump settings to ensure pump is working and that unauthorized
or accidental changes in pump parameters have not occurred.
[0221] Insert the introducer into the muscle compartment. Prepare
the skin surface at point of insertion using standard antiseptic
methods. Remove the introducer's protective cover and insert the
introducer into the site of therapy. Avoid excessive bending or
manipulation of the introducer during insertion to minimize
distortion of sheath when the trocar is removed. (See FIG. 19).
Care should be taken when inserting introducer to avoid any nerves
or large blood vessels in vicinity of treatment site. If considered
necessary, verify the introducer position using fluoroscopy or
other suitable means. Remove the trocar by slowly twisting the
trocar hub to disengage from the sheath hub and then gently
removing the trocar 126 and disposing of according to normal
procedures. (See FIG. 20).
[0222] Insert the catheter by removing and disposing of the
protective cover from the catheter. Carefully insert the catheter's
tip into the sheath hub. Care should be taken during insertion to
ensure that the slit tubing at the catheter's tip is not damaged or
distorted. Continue inserting the catheter into the sheath until
the silicone tubing on the catheter touches the sheath hub. This
will place the distal tip of the catheter approximately 2 to 3 mm
from the distal end of the sheath. Since the slit tubing tip and
hollow fiber bundle are fragile, care should be taken when
inserting the catheter into the sheath.
[0223] Remove the tear-away sheath. With the catheter in desired
position, gently break the sheath hub and begin pulling the sheath
out. As the sheath is removed, continue to tear apart the sheath
while holding the catheter in place. Two people may be necessary to
ensure a steady catheter position during sheath removal. Dispose of
the separated sheath using standard practice. (See FIG. 21). If the
catheter is not located in desired location, remove the catheter
and reinsert the introducer to reposition the catheter at new
location.
[0224] Maintain the indwelling catheter, using typical standard of
care for indwelling catheters at the catheter entrance site.
Stabilize the catheter shaft to prevent excessive bending which
could kink catheter. After visually confirming that the catheter
has been properly placed, position the silicone tubing to prevent
kicking.
[0225] Position the pressure monitor and syringe reservoir.
Position the pressure monitor according to instructions included
with monitor. Position the syringe with plunger handle pointing
down and near the insertion site, and affix to the body using tape.
To ensure accurate pressure reading, the pressure monitor's
transducer diaphragm must be positioned at same height as the tip
of the catheter.
[0226] Connect the vacuum line by connecting the vacuum extension
line to the male luer connector on the catheter vacuum line. Next
connect the vacuum extension line to the vacuum pump connector.
Prime the connecting line with saline. Pressure can be monitored at
any time. To ensure patency, inject less than {fraction (3/10)} cc
of saline into the compartment. Refer to the Stryker Instructions
for Use. Record the pressure reading, waiting for the display to
reach equilibrium. At the doctor's discretion record the pressure
reading at timed intervals.
[0227] Remove interstitial fluid by turning on the pump and
verifying that the vent cap is attached. Continue therapy for a
desired period of time (e.g., up to 72 hrs). Continue therapy until
muscle compartment pressure is stabilized at acceptable level.
During the course of therapy, monitor the fluid drip rate into the
syringe reservoir. Remove and replace the syringe whenever 1 to 2
ml of fluid is collected.
[0228] Remove and replace the syringe by opening the vent and
removing the cap from the vent portion to release vacuum. Aspirate
the vacuum line by pulling back the syringe plunger to remove fluid
lying in tubing between the vent and syringe.
[0229] Remove and cap the syringe for analysis of its contents.
Immediately attach a new sterile 3 cc syringe and replace the vent
cap to continue fluid removal.
[0230] Remove the catheter by gently pulling straight back. Set
aside and allow vacuum to continue draining. If any resistance is
met when retracting the catheter, inject up to 1/2 ml of saline and
attempt removal again. If resistance is still met, leave the device
in place for 30 minutes without vacuum, and attempt removal again.
Clean the puncture site and apply dressing according to standard
procedures, continue standard puncture wound therapy at the therapy
site. Dispose of the catheter set using standard practice.
[0231] A system such as that shown in FIGS. 5-11 can be used with
the following protocol and instructions in order to treat sites at
risk for cerebral edema. Prepare the catheter and system by opening
the associated packaging while maintaining sterility. The catheter
can be placed intracranially by several options at the discretion
of the clinician using components found in FIG. 10. Determine the
desired site of therapy. The catheter can be placed directly into
brain parenchyma with the pressure-monitoring tip placed within the
cerebral ventricles.
[0232] Position the pressure line and monitor according to
instructions. Caution: To ensure accurate pressure reading, ensure
that the pressure monitor's transducer diaphragm is positioned at
same height as the tip of the catheter. Connect the vacuum line by
attaching the vacuum extension line to the catheter vacuum line.
Connect the vacuum extension line to the vacuum pump connector. An
optional fluid trap including syringe collection chamber and
desiccant cartridge may be included in the vacuum line to measure
fluid removal. In conditions of high humidity, an optional air
desiccator can be used. Remove the air filter from the air intake
line and attached the desiccant cartridge using sterile technique.
Replace the air filter on the intake of the desiccant
cartridge.
[0233] A. Monitor Intracranial Pressure
[0234] 1) Pressure can be monitored at any time.
[0235] 2) Record Pressure Reading. Wait for the display to reach
equilibrium.
[0236] Record the pressure reading at the appropriate
intervals.
[0237] B. Remove Edema Fluid
[0238] 1) Turn on pump or other vacuum source. Confirm flow of air
through the air intake.
[0239] 2) Monitor fluid collection. During the course of therapy,
fluid may accumulate in the syringe and desiccant. Remove the fluid
in syringe or replace desiccant when necessary.
[0240] 3) Replace optional air intake desiccant cartridge as
necessary.
[0241] C. Termination of Treatment
[0242] Clinicians will determine the appropriate time for
termination of treatment based on severity of injury and response
to treatment. Remove the catheter assembly by gently removing the
catheter by pulling straight back. Set aside and allow vacuum to
continue draining.
[0243] FIGS. 24-26 show various alternative embodiments of systems
that employ WRT and ultrafiltration in the manner presently
described and claimed.
4 UF WRT Series Blood/Gas Gas/Blood UF WRT Parallel Blood/Gas
Gas/Blood UF WRT Stepped Air Ultrafiltrate alternative UF WRT
Stepped Ultrafiltrate Air FIG. 26 as shown UF WRT counterflow Air
Ultrafiltrate
[0244] Ultrafiltration cartridge 206 is shown as a hollow fiber
cartridge that allows blood flow through the lumen of the hollow
fibers. Ultrafiltrate flows across the hollow fiber walls and out
the cartridge sideport under negative pressure. Ultrafiltration
pressure sensor 208 measures the flow pressure of the ultrafiltrate
draining from the ultrafiltration cartridge, while ultrafiltration
waste collection bag 210 collects the ultrafiltrate draining out of
the ultrafiltration cartridge.
[0245] WRT cartridge 212 is also provided in the form of a hollow
fiber cartridge that allows blood flow through the lumen of the
fibers, while the WRT dry air technology removes water
transluminally from the blood. Water vapor is removed from the
cartridge through a side port. A dry air source will be attached to
one side port while the vacuum is pulled through the condenser
which is in turn attached to the other side port. Both the UF
cartridge and WRT cartridge can be provided in the form of an
elongate housing defining a central axis; the housing containing a
plurality of elongate hollow fibers each positioned within the
housing substantially parallel to the central axis and defining an
extrafilamentary space within the housing, each of the hollow
fibers being formed of a material which allows molecular transport
therethrough.
[0246] Generally, vacuum is used to pull gas through the WRT
cartridge. Vacuum is limited in pressure magnitude, but eliminates
the possibility of air entering the fluid space. Positive pressure
gas can further increase airflow, and if used with hollow fibers
without pores-increase flow, especially with no-pore fibers.
[0247] The cartridge generally further provides one or more fiber
inlet ports and one or more fiber outlet ports, the ports
communicating through the hollow fibers to define corresponding
intraluminal fiber flow paths. The cartridge generally also
provides one or more housing inlet and outlet ports, the housing
ports communicating through the extraluminal space to define an
extraluminal flow path, the extraluminal flow path being isolated
from the intraluminal flow path such that a material in one path
may enter the other path only by molecular transport through the
material comprising the hollow fibers.
[0248] Those skilled in the art, given the present description,
will appreciate the manner in which water vaporization can depend
on several factors, including airflow velocity and temperature
dependence. Water vapor pressure is directly dependant upon
temperature. The key to removal of water with this method is to
sweep the water vapor from the lumen of the semipermeable membrane
by high velocity airflow.
[0249] Water vapor pressure at room temperature is 17 mmHg, while
at body temperature it is 47 mmHg. Higher vapor pressure increases
mass transport of water. The selection of hollow fiber material can
depend upon the molecular species to be removed and/or to be
retained. Typically selection is made of a suitable pore size
corresponding to the size of the molecules, and particularly
biomolecules, keeping in mind the manner in which molecular charge,
shape, and other factors can play a role as well, under the
particular conditions of use. Generally, water, salts, and/or
proteins are targets for removal using a system of this invention,
while cells and tissue segments are retained.
[0250] Those skilled in the art, given the present description,
will appreciate the manner in which a variety of other system
components and operating conditions can affect WRT system
performance and operation.
[0251] With regard to water vaporization efficiency, for instance,
it is desirable to obtain the maximum water transport across a per
unit area of membrane to minimize cost, minimize blood prime volume
and to minimize the amount of air flow, which together will tend to
reduce the size of the air handling components as well as the
operating costs. Those skilled in the art, given the present
description, will appreciate the manner in which various elements
can play a role in obtaining the highest water vaporization
efficiency, including uniform fluid flow.
[0252] One means of improving water vaporization efficiency is to
provide uniform air and blood fluid flow within the cartridge
housing the membrane elements. Instances of a poor distribution
create dead spots where water is not transported through the
membrane and lowers the vaporization efficiency. Mass transfer
using packed hollow fibers is very efficient, and optimal
efficiency is achieved with uniform flow from across the length and
cross sectional area of the cartridge. Fluid can be passed through
the lumen and gas flowing externally, alternately, gas can be
passed through the lumen of the hollow fibers and the fluid can be
passed outside the hollow fiber but within the shell of the
cartridge.
[0253] Improved water vaporization efficiency can also be achieved
with low humidity air entering the cartridge, since this allows
more water to become vapor up until air saturation is achieved.
Means of lowering humidity include passing air through an
evaporative condenser, desiccant, hollow fiber air dryer or through
a mechanical resistor, or using a compressed gas source.
[0254] Further, both vapor pressure and the heat of vaporization
can impact performance. It is desirable to have a high vapor
pressure for the fluid entering the membrane cartridge in order to
obtain maximum water flux efficiency. Vapor pressure is the
pressure exerted by a gas (in this case, water vapor) that is in
contact with its fluid state. The higher the water vapor pressure,
the greater the amount of water vapor present that can be removed.
Vapor pressure can be increased by increasing the temperature of
the fluids entering the cartridge.
[0255] Water vaporization is accompanied by drops in temperature
due to the latent heat required for vaporization. Levels of
vaporization can be regulated by adjusting cartridge airflow and/or
fluid temperatures. Blood flow rates can range from about 10 mL/min
to about 500 ml/min, with a preferred range of from about 20 ml/min
to about 200 ml/min. Other means to counter the temperature drop
due to vaporization can be provided by including impervious tubes
in the membrane cartridge that contain a circulating warm fluid
such as air or water. Yet other means include the placement of
wires in the cartridge that can be heated resistively by
electricity.
[0256] In the course of performing WRT, it is desirable that the
blood gases remain within normal limits. Depending on the
composition of the circulating air, the oxygen and carbon dioxide
levels can be altered by the water vaporization system. Standard
means of controlling blood gases within physiologic limits as used
in blood oxygenation for heart lung machines can be applied to WRT
systems. These means include oxygenation of blood prior to
reintroducing into subject using standard blood gas
oxygenators.
[0257] Controls systems can impact performance as well, e.g., in
order to avoid removing fluid from blood so quickly as to result in
hypotension. There are number of means to avoid this including the
measurement of hematocrit over time as provided in equipment
marketed by HemaMetrics (Crit-Line), Gish (StatSat), Medtronic
(BioTrend) and Terumo (CDI 100). Electrolytes measurements can be
used to stop, start and control the system operation, as can
various other physiologic limits. In line sensors and analytic
instruments can be used to measure electrolyte concentrations, with
automated controls and fail safe mechanisms employed as desired.
Electrical conductivity can also be monitored, in order to
determine concentrations in effluent or various other points within
a flow path.
[0258] A desirable system control parameter will be water removal
rates. Utilizing air humidity at the inlet very close to 0%, the
fluid collected as the air exits the cartridge will encompass the
fluid removed from blood. Like the components used to lower
humidity of the air entering the cartridge, these same devices can
be used to remove water removed by WRT. The water removed by WRT
can be measured by mass or volumetrically. Temperature differences
of the blood entering and exiting the cartridge correlates with
magnitude of water vaporization and can be used to indicate rates
of water loss. Preliminary studies have shown greater hemodynamic
stability is obtained with fluid removal rates of about 100 ml per
hour.
[0259] As also shown in FIG. 24-26, dry air source 214 will
generally be provided in any suitable form as a source of dry air
which is pulled through the housing of the cartridge (via one side
port) to create vaporization of fluid within the counter current
(or optionally, concurrent) flow of blood, e.g. hospital supplied
air, desiccant dried air, or a commercial air drier. Condenser 216,
in turn, is an apparatus which will be used to condense the water
vapor removed from the blood. Vacuum pump 218 will be used to pull
a vacuum through the condenser and in turn the WRT cartridge from
the other side port of the cartridge housing. This will pull dry
air through the housing and across the surface of the hollow
fibers, removing water from the blood.
[0260] As also shown, infusion pressure sensor 220 is attached to
tubing (in-line) that will measure the blood flow pressure at the
end of the system before it returns to the patient.
[0261] Infusion Catheter 224 is positioned at a distal end of the
system in order to return blood to the patient through a vein. At
another terminal point, water vapor collection bag 222 will collect
the condensed water vapor pulled from the blood by the WRT
cartridge.
[0262] In the schematic of FIG. 24, blood is withdrawn from the
body through withdrawal catheter 200 (an IV catheter inserted in
the vein to withdraw blood out of the patient and into the system)
using blood pump 204. Blood pump 204 can be provided in the form of
a roller pump that pumps blood out of the patient while minimizing
damage to red blood cells. The blood can be monitored by withdrawal
pressure sensor 202 that allows for the measurement of blood flow
out of the patient before reaching the blood pump. Discrete
portions of the withdrawn blood are delivered via control valve 205
to the respective inlet ports of both ultrafiltration cartridge 206
and WRT cartridge 212, for ultrafiltration and water removal
therapy, respectively. The amounts sent to each cartridge, in terms
of both total amounts and in relative proportions of the whole, can
be varied using the valve, depending on desired outcome.
Additionally, some or all of the ultrafiltrate can be directed to
the inlet port of the WRT cartridge 212 for further processing, in
the manner described below.
[0263] The advantages of the approach shown in this schematic
include: 1) it permits considerable flexibility in determining the
proportions of blood that will be treated by UF as compared to WRT,
2) it permits highly efficacious treatment via the respective
routes, 3) it permits blood to be delivered in a significantly
higher flow rate to the WRT cartridge, and 4) it permits blood to
be delivered at its normal viscosity to the WRT cartridge. By
contrast, however, this approach typically requires increased blood
priming volume.
[0264] In use, the withdrawal IV catheter 200 is placed in the
vein. Once placed, the catheter is attached to the system's tubing
set (to the end closest to the blood pump). The infusion IV
catheter 224 can be placed at the same time into a separate vein in
the patient and attached to the tubing at the opposite end of the
system. Pressure sensors can be included in the circuit as desired,
e.g., to monitor blood pressures flowing away from the patient and
returned to the patient. Blood pump tubing is placed within the
blood pump and connected to the first valve 205. The withdrawal
blood pump 204 is turned on, to begin pumping the blood out of the
patient and through the entire system. In FIG. 24, the valve 205
prior to the ultrafiltration and WRT cartridges can also be
adjusted to allow the appropriate amount of blood flow to the
lumens of both cartridges.
[0265] On the ultrafiltrate cartridge 206, tubing is connected to
the side port 207, which is in fluid communication with the
extraluminal space, and attached to the ultrafiltrate pump 209. The
ultrafiltrate pump contains controls for the rate of ultrafiltrate
removal from the cartridge. In turn, the tubing is connected to a
valve 211 that allows control over the rate at which ultrafiltrate
is delivered either as waste drainage into the ultrafiltrate
collection bag 210, or permitted to continue on to the WRT
cartridge 212. Ultrafiltrate that flows to the WRT cartridge can
therefore be concentrated further, with water vapor removed and
solutes returned to the blood stream. A pressure sensor 208 allows
pressure monitoring of ultrafiltrate removal from the ultrafiltrate
cartridge.
[0266] Another valve 221 is positioned just in front of (upstream
from) the WRT cartridge 212 in order to permit control over the
relative amounts of blood and ultrafiltrate that enter the hollow
fibers 213 contained within the WRT. To create the WRT effect, one
side port 217 of the WRT cartridge is connected with tubing to a
dry air source 214 (for example, a hospital wall supply, a
desiccant cartridge, or an air drier). Another side port 219 of the
WRT cartridge is connected with tubing to a condenser 216 which, in
turn, is connected to a vacuum source 218. The vacuum source pulls
dry air through the cartridge housing, removing water vapor from
blood via transmembrane conductance. The humidified air is
delivered to a condenser 216, which in turn, delivers liquid water
to the water vapor collection bag 222.
[0267] The condenser operates by circulating cool water through an
internal coil that condenses the external water vapor into liquid
water. The condenser delivers liquid water to the water vapor
collection bag. From the backside of both cartridges, tubing is
connected, optionally via a valve 203, in order to permit
recombining of the filtered blood before it re-enters the patient.
A sensor is optionally and preferably placed here to allow the user
to know the pressure at which the blood is flowing back to the
patient. The tubing after the valve is connected to the IV infusion
catheter that returns the blood to the patient.
[0268] In the schematic of FIG. 25, a UF cartridge is used in
series (here prior to) the use of a WRT cartridge. The blood
components that are not removed from the ultrafiltration cartridge
206, therefore, are directed to the WRT cartridge 212 for water
removal therapy. Water vapor is sent to the water vapor collection
bag 222 while blood is delivered back to patient. In essence, the
blood is subjected to ultrafiltration, with water removal therapy
being performed on post-ultrafiltrate blood. This approach gives
the highest combination of solute removal and solute concentration.
On the other hand, blood will be of higher viscosity after passing
through the ultrafiltration cartridge. Priming volume with two
sequential cartridges will be increased.
[0269] The system of FIG. 25 is set up and operated in a manner
analogous to that described with respect to FIG. 24. For instance,
blood pump 204 can be used to adjust the appropriate amount of
blood flow to the lumen of the fibers within the UF cartridge.
Ultrafiltrate from the UF cartridge, in turn, is delivered using
ultrafiltrate pump 209 that contains controls for the rate of
ultrafiltrate removal. Ultrafiltrate waste would flow directly into
a waste collection bag 210. There is no further concentration of
the ultrafiltrate in this schematic, post-ultrafiltrate blood would
then flow directly to the WRT cartridge. The system is also
operated in a similar fashion as described with respect to FIG. 24,
in terms of the manner in which WRT is performed.
[0270] Finally, in the schematic of FIG. 26, ultrafiltrate from the
ultrafiltration cartridge 206 is delivered to the water removal
therapy cartridge 212. Treated ultrafiltrate from the WRT cartridge
212 is delivered back to the patient along with blood from the
ultrafiltration cartridge 206, again in a manner that permits both
total and proportional amounts of each to be controlled. In
essence, UF is performed on blood, with water removal therapy being
performed on ultrafiltrate only. The advantages of this approach
include: 1) reduced viscosity of ultrafiltrate compared to whole
blood, and 2) reduced effect on hemoglobin levels of carbon dioxide
and oxygen. On the other hand, this approach provides: 1) minimal
effect on reduction of carbon dioxide and increased levels of
oxygen if that effect is desired and 2) reduced flow rate of the
ultrafiltrate through the WRT cartridge. Also, relatively high flow
rates can often be required to prevent a drop in temperature, while
low flow rates may require internal WRT cartridge heating.
[0271] With the withdrawal IV catheter 200 positioned, the blood
pump 204 is used to adjust the appropriate amount of blood flow to
the lumen of the ultrafiltration cartridge. On the ultrafiltrate
cartridge 206, tubing is connected to the side port and attached to
the ultrafiltration pump 209. The ultrafiltration pump contains
controls for the rate of ultrafiltrate removal. The tubing is
connected to a valve 211 that allows control over the rate of
drainage into the ultrafiltrate collection bag 210 as waste or onto
the WRT cartridge. Ultrafiltrate that flows to the WRT cartridge is
concentrated further, (water vapor only pulled out, solutes
returned to the blood stream).
[0272] To create the WRT effect one side port of the WRT cartridge
is connected with tubing to a dry air source 214 (for example, a
hospital wall supply, a desiccant cartridge, or an air drier). The
other side port of the WRT cartridge is connected with tubing to a
condenser 216 which, in turn, is connected to a vacuum source 218.
The vacuum source pulls dry air through the cartridge housing,
removing water vapor from blood via transmembrane conductance The
humidified air is delivered to the condenser.
[0273] The condenser operates by circulating cool water through an
internal coil that condenses external water vapor into liquid
water. The condenser delivers liquid water to the water vapor
collection bag 222. From the back side of the WRT cartridge, tubing
is connected to a suitable connection (optionally including a
valve) that permits recombining of the filtrate(from the WRT
cartridge) and filtered blood (from the ultrafiltration cartridge)
before it re-enters the patient. A sensor 223 is placed after the
WRT cartridge to allow the measurement of the pressure at which the
filtrate is flowing out of the WRT cartridge. Another sensor 220 is
placed after the final valve to measure the pressure at which the
blood is flowing back to the patient. The tubing after the valve is
connected to the IV infusion catheter that returns the blood to the
patient.
[0274] Recirculation of Post WRT Fluid to Maintain High Flow and
Temperature.
[0275] A limitation of performing WRT on ultrafiltrate is the flow
of ultrafiltrate though the WRT cartridge is decreased compared to
blood flow. One embodiment that will overcome this limitation is to
recirculate a portion of the post-WRT fluid back into the WRT
inlet. Optionally, the recirculated fluid can be heated prior to
return to the WRT inlet.
[0276] One embodiment that can provide improved efficacy is shown
as FIG. 22, based on the premise that shorter fibers will typically
be more efficient than long hollow fibers. Multiple short hollow
fibers will produce the same surface area but at greater efficacy
compared to fewer long fibers. Short, larger ID fibers also tend to
reduce pressure drop along the length of the fiber, and therefore
create a more uniform transmembrane pressure. Low magnitude,
uniform transmembrane pressure may allow use of hydrophilic fibers
without bulk flow of fluid into the lumen, or optionally, with
increasing transmembrane pressure, ultrafiltration can be performed
with the same cartridge.
[0277] FIG. 23, by contrast, shows a diagram of the flow
encountered using both WRT and UF fibers in the same cartridge,
with WRT being performed on the ultrafiltrate within the
cartridge.
[0278] FIG. 28 is a cross-sectional view of a catheter assembly 300
in accordance with an exemplary embodiment of the present
invention. Catheter assembly 300 comprises a shaft 302 having an
outer wall 304 and an inner wall 306. In FIG. 28, it may be
appreciated that outer wall 304 and inner wall 306 define a first
lumen 320 and a second lumen 322 of shaft 302. Catheter assembly
300 also comprises a plurality of hollow fibers 324. In a preferred
embodiment, hollow fibers 324 comprise a membrane material. Each
hollow fiber 324 defines a fiber lumen 326. In the embodiment of
FIG. 28, a first group 328 of hollow fibers 324 can be seen
extending into first lumen 320 of shaft 302. Likewise, a second
group 330 of fibers can be seen extending into second lumen 322
defined by shaft 302. In the embodiment of FIG. 28, hollow fibers
324 are fixed to shaft 302 at a joint 332. In the embodiment of
FIG. 28, joint 332 comprises a bead of adhesive 334. In FIG. 28, a
distal portion of each hollow fiber 324 is disposed inside of a
catheter tip 336.
[0279] A gas flow 338 through catheter assembly 300 is illustrated
using a number of arrows in FIG. 28. In this exemplary embodiment,
gas flow 338 exits first lumen 320 and enters the hollow fibers 324
of first group 328. Gas flow 338 exits hollow fibers 324 of first
group 328 and enters a plenum 340 defined by catheter tip 336. Gas
flow 338 then passes through the second group 330 of hollow fibers
324 and enters second lumen 322 of catheter shaft 302.
[0280] FIG. 29 is a cut-away perspective view of a catheter
assembly 400 similar to the catheter assembly shown in FIG. 28.
Catheter assembly 400 comprises a shaft 402 having an outer wall
404 and an inner wall 406. In FIG. 29 it may be appreciated that
shaft 402 defines a first lumen 420 and a second lumen 422. A first
group 428 of hollow fibers 424 are partially disposed within first
lumen 420 and a second group 430 of hollow fibers 424 are partially
disposed within second lumen 422. With reference to FIG. 29, it
will be appreciated that hollow fibers 424 define an imaginary
cylinder 442. Accordingly, it will be appreciated that hollow
fibers 424 occupy a generally cylindrical area. When catheter
assembly 400 is immersed in a fluid, the outer surface of each
hollow fiber 424 may be wetted by that fluid.
[0281] FIG. 30 is a cross-sectional view of catheter assembly 500
in accordance with an additional exemplary embodiment of the
present invention. Catheter assembly 500 comprises a shaft 502
including a tube wall 544. Tube wall 544 defines a tube lumen 546.
In FIG. 30, an inner tube 548 is shown disposed within tube lumen
546. Catheter assembly 500 also includes a plurality of hollow
fibers 524 that are disposed about inner tube 548. In FIG. 30, a
proximal portion of each hollow fiber 524 can be seen extending
into tube lumen 546. Hollow fibers 524 are fixed to tube wall 544
at a joint 532. Hollow fibers 524 are fixed to a catheter tip 536
of catheter assembly 500 by a second joint 532. In the embodiment
of FIG. 30, each joint comprises a bead of adhesive 534.
[0282] In FIG. 30 it may be appreciated that catheter tip 536
defines plenum 540. In the embodiment of FIG. 30, a gas flow 538 is
shown entering plenum 540 via inner tube 548. In FIG. 30 gas flow
538 is illustrated using a number of arrows. In this exemplary
embodiment, gas flow 538 flows through an inner lumen 552 of inner
tube 548 and enters plenum 540. Gas flow 538 then passes through
hollow fibers 524 and enters tube lumen 546 of catheter shaft
502.
[0283] FIG. 31 is a cut-away isometric view of catheter assembly
600 in accordance with an additional exemplary embodiment of the
present invention. Catheter assembly 600 is similar to the catheter
assembly shown in FIG. 30. Catheter assembly 600 comprises an inner
tube 648 and a plurality of hollow fibers 624 disposed about inner
tube 648. In FIG. 30, inner tube 648 and hollow fibers 624 are
shown extending into a tube lumen 646 defined by a tube wall 644.
An imaginary cylinder 642 defined by hollow fibers 624 is
illustrated with dashed lines in FIG. 31. With reference to
imaginary cylinder 642, it can be appreciated that hollow fibers
624 occupy a generally cylindrical volume. In a preferred
embodiment, each hollow fiber 624 comprises a membrane material. In
some advantageous embodiments of the present invention, the
membrane material of each hollow fiber 624 contacts a fluid when
catheter assembly 600 is immersed in that fluid.
[0284] FIG. 32 is a cross-sectional view of catheter assembly 700
in accordance with yet another exemplary embodiment of the present
invention. Catheter assembly 700 comprises a shaft 702 including a
tube wall 744. An inner tube 748 is disposed within shaft 702 in
the embodiment of FIG. 32. Inner tube 748 and tube wall 744 define
a first lumen 720 and a second lumen 722 of shaft 702. Catheter
assembly 700 also comprises a plurality of hollow fibers 724. In a
preferred embodiment, hollow fibers 724 comprise a membrane
material. Each hollow fiber 724 defines a fiber lumen 726. In the
embodiment of FIG. 32, a first group 728 of hollow fibers 724 can
be seen extending into first lumen 720 of shaft 702. Likewise, a
second group 730 of fibers can be seen extending into second lumen
722 defined by shaft 702. In FIG. 32, a distal portion of each
hollow fiber 724 is disposed inside of a catheter tip 736.
[0285] A gas flow 738 through catheter assembly 700 is illustrated
using a number of arrows in FIG. 32. In this exemplary embodiment,
gas flow 738 exits first lumen 720 and enters the hollow fibers 724
of first group 728. Gas flow 738 exits hollow fibers 724 of first
group 728 and enters a plenum 740 defined by catheter tip 736. Gas
flow 738 then passes through the second group 730 of hollow fibers
724 and enters second lumen 722 of catheter shaft 702. A bulk fluid
flow 762 is also illustrated with arrows in FIG. 32. Bulk fluid
flow 762 enters a distal orifice of catheter assembly 700 and
travels through an inner lumen 752 defined by inner tube 748.
[0286] FIG. 33 is a cut-away perspective view of a catheter
assembly 800 similar to the catheter assembly shown in FIG. 32.
Catheter assembly 800 comprises a shaft 802 and an inner tube 848.
In FIG. 33 it may be appreciated that shaft 802 and inner tube 848
define a first lumen 820 and a second lumen 822. A first group of
hollow fibers 824 are partially disposed within first lumen 820 and
a second group of hollow fibers 824 are partially disposed within
second lumen 822.
[0287] FIG. 34 is a cross-sectional view of catheter assembly 900
in accordance with still another exemplary embodiment of the
present invention. Catheter assembly 900 comprises a shaft 902
including a tube wall 944. An inner tube 948 is disposed within
shaft 902 in the embodiment of FIG. 34. Inner tube 948 and tube
wall 944 define a first lumen 920 and a second lumen 922 of shaft
902. Catheter assembly 900 also comprises a plurality of hollow
fibers 924. In a preferred embodiment, hollow fibers 924 comprise a
membrane material. Each hollow fiber 924 defines a fiber lumen 926.
In the embodiment of FIG. 34, a first group 928 of hollow fibers
924 can be seen extending into first lumen 920 of shaft 902.
Likewise, a second group 930 of fibers can be seen extending into
second lumen 922 defined by shaft 902. In FIG. 34, a distal portion
of each hollow fiber 924 is disposed inside of a catheter tip
936.
[0288] A gas flow 938 through catheter assembly 900 is illustrated
using a number of arrows in FIG. 34. In this exemplary embodiment,
gas flow 938 exits first lumen 920 and enters the hollow fibers 924
of first group 928. Gas flow 938 exits hollow fibers 924 of first
group 928 and enters a plenum 940 defined by catheter tip 936. Gas
flow 938 then passes through the second group 930 of hollow fibers
924 and enters second lumen 922 of catheter shaft 902. A bulk fluid
flow 962 is also illustrated with arrows in FIG. 34. Fluid may pass
between hollow fibers 924 and enter a central space 964 defined by
hollow fibers 924. Bulk fluid flow 962 is shown traveling through
an inner lumen 952 defined by inner tube 948 in FIG. 34.
EXAMPLE 1
[0289] Initial studies were performed to demonstrate that WRT
removes water in the vapor phase and not in the liquid (bulk)
phase.
[0290] WRT cartridges were made by potting hollow fibers in plastic
tubing, in the configuration shown in FIG. 27. The tube material
was typically polycarbonate with nominal dimensions of 60 mm in
length and 8 mm I.D. After potting, exposed length of fibers was
4.5-5 mm. Various numbers of fibers in any particular cartridge
were examined. Side ports were attached to the tubing in order to
allow either air or fluid flow along the outside of the fibers.
[0291] A fluid loop was attached to the side ports while desiccated
air was passed through the hollow fiber lumens. Initial tests
examined various fiber types/manufacturers and the ability to
remove water vapor from an electrolyte solution in a flowing loop.
After removing water vapor, the solution was examined for
concentrated electrolytes (sodium, potassium and chloride). The
electrolyte levels in the concentrated solution matched the values
expected (for example, remove 10% of the water from the solution,
the electrolytes were concentrated 10%). Various temperatures and
flow rates of fluid and desiccated air were examined.
[0292] Two cartridges each containing 24 hollow polypropylene
fibers (0.026 cm O.D. with exposed length of 4.5 cm) were examined.
Desiccated room temperature air was passed through the hollow fiber
bundle at 500 ml/min. Room temperature blood (sheep) was circulated
through tube at 1 ml/min. After 80 minutes, 11% of the blood volume
was removed. Electrolytes of the concentrated blood matched
expected values.
[0293] In order to determine if hollow fibers may pass electrolytes
(via bulk water) in addition to water vapor, a commercially
available cartridge containing polypropylene fibers was used.
Desiccated 37.degree. C. air was passed through the hollow fiber
bundle at 61 liters per minute. 37.degree. C. blood (sheep) was
circulated external to the fibers at 60 ml/min. Water vapor was
collected and analyzed. Sodium, potassium and chloride were present
at levels less than the detection limit of the instrumentation used
(0.1, 0.02 and 0.15 meq, respectively).
[0294] Based on the results obtained above, it can be seen that
removal of water vapor concentrates fluids, including blood,
without loss of electrolytes from the fluid. Bulk water removal can
be eliminated as a cause since there were no electrolytes observed
in the collected fluid.
EXAMPLE 2
[0295] WRT and other methods can be used singly or in various
combinations. Each combination will have specific effects on three
independent parameters; 1) rate of solute flux, 2) effluent
concentrations solutes, and 3) rate of water flux. These
relationships can be quantified by mass balance formulas.
[0296] Two methods are currently used to treat fluid overload:
ultrafiltration, and combination ultrafiltration and reinfusion of
replacement fluid. Both result in a net removal of water. The
combination treatment can accomplish net removal of water by
removing more plasma (ultrafiltration) than is replaced with
reinfused saline.
[0297] A comparison of WRT with UF, reinfusion, and combinations of
UF and reinfusion are shown in FIG. 35. Each data point on the line
represents an increase in fluid transfer rate. Reinfusion alone
results in an increase of sodium and plasma volume. A one to one
combination of reinfusion and UF results also results in an
increase in sodium, but no change in plasma volume. Neither of
these conditions would have any benefit for treatment of CHF.
Ultrafiltration alone will result in net sodium removal while
removing up to 480 ml/hr of fluid. A 3:1 combination of UF and
reinfusion will result in up to 480 ml/hr fluid loss and a
reduction of total body sodium, but there is little improvement in
serum sodium concentrations. WRT alone will remove 480 ml/hr of
water, and increase sodium concentrations. Increased sodium
concentrations will normalize the neurohumeral axis. Given these
limitations of low plasma turnover, WRT is unique in its ability to
concentrate sodium.
[0298] A combination of UF and reinfusion can result in net removal
of fluid and normalization of the serum sodium concentrations, but
at the cost of high plasma turnover. FIG. 36 shows how much blood
plasma must be removed (and replaced with normal saline) to
concentrate sodium. The calculations are for starting serum levels
of 130 meq/l. As the fluid removal rate is increased, the
concentration of effluent increases, but 62% versus 9.6% blood
volume has to be removed per hour for ultrafiltration and
reinfusion versus WRT alone. Over 8 hours, that is 5.times. versus
0.8.times., respectively. For UF-Reinfusion, that is 25 liters out
and 21 liters reinfused (versus target 4 liters for WRT alone). In
addition to serum sodium, all the other electrolytes and other
materials would also have to be replaced.)
[0299] It can be seen that there is less difference between the two
methods if less net fluid removal is required and if hypertonic
saline is infused. Given complications of high plasma turnover,
costs of replacement of species other than sodium, and ability to
only remove water, WRT (alone or in combination with UF) offers
advantages over UF and replacement.
[0300] Thus, WRT offers a unique advantage in removal of water and
concentration of solute. In combination with UF, removal of solute
can also be performed to advantage.
EXAMPLE 3
[0301] Efficacy of WRT can be confirmed with in vivo studies. These
studies are designed to test water removal by extracoporeal WRT in
normal, non-injured animals. Replacement fluids are provided to
maintain fluid homeostasis.
[0302] Design Outline for short-term study:
[0303] 1. Induce general anesthesia.
[0304] 2. Femoral artery and vein is cannulated.
[0305] 3. Bladder is cannulated with suprapubic catheter.
[0306] 4. Serum and urinary samples are taken.
[0307] 5. Begin circulation.
[0308] 6. After six hours, serum and urine samples are taken.
[0309] 7. The animal is euthanized.
[0310] Design Outline for long-term study:
[0311] 1. Induce general anesthesia.
[0312] 2. Femoral artery and vein is cannulated.
[0313] 3. Bladder is cannulated with suprapubic catheter.
[0314] 4. Serum and urinary samples is taken.
[0315] 5. Begin extracorporeal circulation.
[0316] 6. After six hours, serum and urine samples are taken and
the animal is allowed to recover.
[0317] 7. At twenty four hours the animal is anesthetized again,
serum and urine samples taken again, and the animal then
euthanized.
[0318] The study is performed with male Yorkshire/Hampshire pigs
weighing 40 lbs (.+-.5 lbs). Restrict the animals from food for
twelve hours prior to surgery with water ad libitum. The pigs are
pre-anesthetized with a mix of ketamine (100 mg/ml)/xylazine (100
mg/ml) at 10 cc/1.5 cc respectively at 0.15 cc per pound IM. In a
surgical prep room the animals are shaved at the ear and neck. Once
transferred to the surgery room, the animal is placed on a heating
pad to maintain 100.0-102.0 F.degree. core temperature, and
connected to a Nellcor pulse-oximetry unit to monitor pulse and
oxygen saturation. The carotid artery is cannulated for blood
pressure measurement and blood sampling. The carotid line will be
maintained post-anesthesia for blood sampling (Wilcox et al. 2000).
The auricular vein is cannulated with a 22 gauge IV (Jelco, J&
J Medical, Arlington, Tex.) catheter and connected to an
intravenous minidrip set and bag of Lactated Ringers with 5%
Dextrose solution (Baxter Health Corp, Deerfield, Ill.), at a rate
of 2.7 drops per second (5-10 ml/kg/hour).
[0319] The animal is intubated with a 5 mm endotracheal tube, and
given oxygen at 2 L/min, Isoflurane (3.0-2.0%) and Nitrous Oxide
(1/2 rate of Oxygen) until a deep plane of anesthesia is reached.
Vitals are recorded every 60 minutes including systemic pressure,
oxygen saturation, temperature, pulse, and respirations. A baseline
blood samples are taken through the arterial line.
[0320] Extracorporeal Circulation. The method of Kim et al. (2002)
is utilized for extracorporeal circulation. After induction of
general anesthesia and neck exposure, a two-lumen hemodialysis
catheter (Arrowgard Blue catheter, 12 Fr, 20 cm, Arrow
International, Reading Pa.) is placed into the jugular vein. The
neck wound is stapled closed. Heparinized the animal with a bolus
intravenous injection of 5000 Units.
[0321] Primed the system tubing and pump with heparinized saline.
The system is connected to the hemodialysis catheter. The blood
pump is run at 100 ml/min. One-quarter normal saline is given to
replace water loss. The goal is to maintain homeostasis. Water loss
will be determined by on-site measurement of serum sodium. Water
replacement will be adjusted accordingly. At the endpoint of 6
hours, the animal is in a deep plane of anesthesia (Isoflurane),
and final blood and urine sample taken. For the six hour treatment
animals, the pigs are euthanized immediately. For the twenty-four
hour animals, then animals are allowed to recover and returned to
the cage. Immediately before awakening, a one-time injection of
Banamine (flunixin meglumide 2.2 mg/k) is given IM for pain relief.
Food and water are given ad libitum. At twenty-four hours, the pig
is re-anesthetized with the same ketamine/xylazine mix. Once the
drug has taken effect, serum and urine samples are drawn, and then
the pig is euthanized with 40 mEql of potassium chloride.
[0322] This study can demonstrate the ability of WRT to remove
water from plasma. Possible compensatory mechanisms and regulation
of respiratory gases can be studied in vivo.
[0323] Safety of WRT was demonstrated in a porcine model. These
studies were designed to test water removal by extracorporeal WRT
in normal, non-injured animals. Replacement fluids were provided to
maintain fluid homeostasis. The objective was not to show
concentration of ions or hemoglobin, but to show that the WRT
system can safely remove water in an animal model. The safety
outcomes were stability of vital signs, electrolytes, and
hematocrit.
[0324] Two Male Yorkshire/Hampshire pigs weighing 31 lbs were
obtained from Midwest Research Swine. Each animal was food
restricted for twelve hours prior to surgery with water ad libitum.
The pig was pre-anesthetized with a mix of ketamine (100
mg/ml)/xylazine (100 mg/ml) at 10 cc/1.5 cc respectively at 0.15 cc
per pound IM. In a surgical prep room the animal was shaved at the
ear and neck. Once transferred to the surgery room, the animal was
placed on a heating pad to maintain 100.0-102.0 .mu.l core
temperature, and connected to a Nellcor pulse-oximetry unit to
monitor pulse and oxygen saturation.
[0325] The animal was intubated with a 5-mm endotracheal tube, and
given oxygen at 2 LJmin, Isoflurane (0.3-2.0%) and Nitrous Oxide (1
L/min) until a deep plane of anesthesia was reached. The carotid
artery was cannulated with a 16 gauge IV catheter for blood
pressure measurement and blood sampling. The ear vein was
cannulated with a 22 gauge IV catheter(Jelco, J& J Medical,
Arlington, Tex.) and connected to an intravenous minidrip set with
Lactated Ringers with 5% Dextrose(Baxter Health Corp, Deerfield,
Ill.) fluid replacement. Vitals were recorded every 30 minutes
including systemic pressure, oxygen saturation, temperature, pulse,
and respirations. Electrocardiography was performed using dermal
leads during the entire procedure. A baseline blood sample was
taken through the arterial line. Pre treatment and post treatment
urine samples were taken by a suprapubic catheter. Urine output was
monitored over time.
[0326] Extracorporeal Circulation
[0327] The swine hemofiltration method of Kim et al. (2002) was
utilized for extracorporeal circulation and WRT. After induction of
general anesthesia and neck exposure, a 16 gauge.times.2" standard
IV catheter was placed in each external jugular vein. The animal
was heparinized with a bolus intravenous injection of 5000
Units.
[0328] Operation of the WRT system is described above. The jugular
vein catheters were connected to the blood loop tubing. The system
was primed with heparinized saline (2000 units/l), and then
connected to the venous catheters. A roller type blood pump was
then turned on and ran at 100-200 ml/min. The blood was drawn out
of one jugular vein via the pump, and passed into the WRT
cartridge. In contrast to bench studies where blood is heated prior
to the cartridge, the jugular vein blood will be warm. To prevent
hypothermia, a heat exchange system was used after the WRT
cartridge to warm blood prior to return to the animal. Operation of
airflow was identical to the bench system.
[0329] In order to maintain homeostasis, Lactated Ringers with 5%
Dextrose (5 to 10 ml/kg/hr) was given to replace water loss. Water
loss was estimated by measuring the condensate (based on 56%
recovery of water vapor for this system in bench studies). On-site
hourly measurements of electrolytes, hematocrit, and blood gases
were done using a Heska i-stat hand held blood chemistry analyzer.
Blood samples were taken hourly from the carotid artery. Proximal
and distal pressure measurements across the cartridge were recorded
every ten minutes. At the end of the study, the animal was in a
deep plane of anesthesia (Isoflurane), and final blood and urine
samples were taken. After turning off the blood pump, the animal
was euthanized immediately using 40 meq of potassium chloride
IV.
[0330] In the first animal study, WRT removed 80-100 ml/hr of water
over a three-hour treatment period. Electrolytes, hematocrit, and
vital signs were stable demonstrating WRT safety potential.
[0331] For the second animal, sweep gas was changed to 5% CO.sub.2
in air, a new heat exchanger was used, and the addition of
maintenance heparin boluses (18 units/kg/hr) were employed. Water
removal rates again were 80-100 ml/hr. Plasma carbon dioxide levels
remained stable, and alkalosis did not develop. Blood chemistries
and vital signs were stable.
EXAMPLE 4
Tumor Perfusion
[0332] Various models can be used to assess the method and system
of this invention for use in improving the delivery of particular
bioactive agents to various types of solid and semisolid
tumors.
[0333] Gelatin Model
[0334] A gelatin model can be used to evaluate the properties of
the system in an ideal environment of uniform "interstitial" space
in a well-hydrated matrix using a small acrylic chamber. Hydration
of the gelatin is maintained by slow infusion by peripheral
ultrafiltration fibers. This model allows testing of hollow fiber
techniques without venous or lymphatic adsorption, protein binding
of dye, or inhomogeneity of tissues that could affect the function
of the catheters.
[0335] The commercial availability of many suitable gelatin test
materials assures both the supply and homogeneity of the test
material. The effects of hyperosmosis cannot be tested, and there
are no lymph flow pathways, but gelatin is an alternative to ex
vivo tissue if tumor tissue is not available. Slow fluid infusion
into the gelatin to maintain hydration may be adequate for the use
of gelatin for catheter design testing.
[0336] Tumor Model
[0337] Preparations of ex vivo tumors can be obtained from animal
research laboratories and used to evaluate such factors as
treatment efficacy and fluid removal rates. Infusion of saline into
the ex vivo tumor allows modeling of transcapillary
ultrafiltration. A variety of tumor types can be tested, each of
which may have unique hollow fiber interactions or transport
parameters.
[0338] If reduction of tissue pressure within a tumor results in
improved circulation to the tumor, hollow fiber treatment should
result in increased delivery of a marker to the center of the
tumor. A tumor model can be used to examine fluid transit within
the tumor, using a marker as a test of perfusion, rather than a
chemotherapeutic agent. This approach will allow understanding
perfusion of the tumors, without the variable of chemotherapeutic
response.
[0339] Animal Model
[0340] Male Sprague-Dawley rats weighing 250-300 gms are used. Dual
Walker 256 mammary carcinoma tumors are propagated, by harvesting
tumor tissue from a tumor-bearing rat. The tumor is divided into
small chips with a volume of about 5-10 mm.sup.3. After removing
hair from the rat's back with a medical depilatory, the area is
cleaned with surgical betadine solution. Over the flank muscles on
both sides of the animal a small pouch underneath the skin is
created, and a single chip of the previously divided tumor is
placed into the pouch. The incision is then closed with a surgical
stapler (3M), and the area again cleaned with betadine. The animal
is returned to it's cage and allowed normal activity.
Post-operative antibiotic is provided by oral penicillin (15,000
IU/20 ml water) immediately after surgery.
[0341] Tumor growth characteristics are determined by weekly
measurements of the tumor volume using calipers. It takes
approximately 50 to 55 days to grow tumors to 2 cm diameter size.
For dual tumor studies, animals are only used if both tumor volumes
are within 10% of each other. About half the rats will achieve dual
tumors that are within 10% volume symmetry. When appropriate size
and symmetry requirements are met, the animals are anesthetized and
catheters will be placed in the tumors. Rats are re-anesthetized
with intraperitoneal sodium pentobarbital (50 mg/kg). Rectal
temperature will be monitored (Physitemp, Clifton N.J.), and body
temperature is maintained with a heating pad. Mean arterial
pressure is maintained at 115.+-.5 mm Hg by venous infusion of 0.9%
saline, as needed, through a butterfly placed in the tail vein. The
rat is ventilated by passing a 2% Isoflurane-98% oxygen mixture
through a fitted nose cone.
[0342] One or more treatment catheters of the present invention are
inserted centrally within the tumor. Blood flow probe (laser
Doppler, Vasamedics) is placed at the tumor surface 90.degree.
relative to the midpoint of the catheter. Pressure sensor (Codman)
is inserted (using standard IV catheter) 90.degree. relative to the
midpoint of the catheter and advanced to a distance of
r/R.sub..infin., where R.sub..infin.=tumor radius and r=depth of
insertion.
[0343] Treatment is begun and blood flow monitored throughout the
course of the evaluation. Once pressure stabilization is observed,
pressure measurements throughout the tumor is performed by
retreating the sensor incrementally. When the study is complete, a
blood sample is taken, the animal euthanized and the tumor
harvested.
[0344] With one or more treatment catheters inserted centrally
within the tumor, two hundred microliters of 30% Evan's blue dye
(molecular weight =960.8, Sigma Chemical Co., St. Louis, Mo.) in
saline is given intravenously via a tail vein. The dye binds to
albumin, so distribution is similar to what one would expect for a
macromolecule. Treatment then commences for a total of four hours.
The rats are awakened and returned to their cage. The next day, the
rats are anesthetized for blood flow and tissue pressure
measurements. The rats are then euthanized and the tumors harvested
and examined for dye penetration.
[0345] Tumor blood flow and pressure measurements will be recorded
every ten minutes. When pressure stabilizes during treatment, the
sensor will be withdrawn at increments of r/R.sub..infin.=0.1 to
examine pressure differences throughout the tumor. The volume of
fluid removed will be measured.
[0346] Evan's blue dye (EBD) will stain the tissue dark blue, so it
is an excellent visual marker of perfusion. The tumors are cut in
half, photographed, and the proportion of EBD uptake is digitized.
EBD is quantified in serum and ultrafiltrate. The concentration of
Evan's blue dye is proportional to its spectrophotometric
absorption using a standard bench spectrophotometer. EBD is assayed
in the ultrafiltrate (when TUF is used), and final serum levels
will be determined. The volume of fluid removed will be measured.
For monitoring and dye uptake studies, whole blood electrolytes
(Na+, K, CO.sub.2, O.sub.2, Hct, and creatinine) can be assayed for
immediate physiology using a Heska i-stat hand held unit. Serum and
ultrafiltrate samples will be assayed in duplicate (10 uL samples)
for osmolality using a Wescor Vapor Pressure Osmometer (Model #5520
with AC-066 Head). The readings obtained (mmol/kg of osmolality)
will be recorded and averaged for each sample.
[0347] Data can be analyzed in the method of Diresta et al. Fluid
removal rates are compared and dye penetration photographed and
digitized. Percentage of dye penetration is compared in treated and
control tumors by paired t-test. A p value of 0.05 or less is
considered significant, and a power of 0.8 is satisfactory.
EXAMPLE 5
Clinical Application for Cancer Therapy
[0348] The method and system of the present invention can be used
in conjunction with intravenous chemotherapy to enhance tumor
response rate by increasing penetration of drug into the tumor. A
suitable hollow fiber catheter is placed into the tumor prior to
initiation of chemotherapy or radiation therapy.
[0349] With regard to initial patient selection, patients with
solid tumors are possible candidates. Large tumors that are easily
palpable and accessible would be ideal targets. Tumor types that
are known to have poor response to treatment are particular
candidates, as well as tumors that must be treated with toxic
agents are included. As risk benefit ratio is established, all
solid tumors can be treated with the method of the present
invention, to maximize the therapeutic effect while minimizing
systemic side effects.
[0350] In a preferred embodiment, the catheter is placed into the
tumor. For palpable tumors, placement is performed clinically, with
confirmation of the catheter position done by x-ray or ultrasound.
For deeper tumors, or tumors adjacent to important structures,
catheter placement can be done under ultrasound or CT guidance.
[0351] Hollow fiber treatment is initiated after catheter
placement. Vacuum or dry air circulation is performed for
ultrafiltration or WRT treatment, respectively. Timing of treatment
and administration of the intravenous dose of chemotherapy or
radiation sensitizer will vary depending on tumor type. Tumors that
have high hydraulic conductance will have the most rapid response
to treatment. Effectiveness of treatment can be monitored with
tissue pressure recordings and rate of fluid removal. Monitoring
the ultrafiltrate (TUF treatments) for drug levels or tracer dyes
(e.g., methylene blue) can be done. When maximal treatment effect
is approached, the intravenous dose can be given. Dosing for oral
medications should account for the time to reach peak serum levels.
The medication(s) can be delivered in any suitable manner, e.g.,
orally, locally, or by the use of catheters of the type described
herein.
[0352] Duration of treatment will depend on half-life elimination
of the agents. Slow elimination, or agents that are given with slow
infusion, will require that the catheter treatment be continued for
several hours. Repeated dosing on daily or weekly basis will
require repeated treatment with catheters of this invention.
Catheters could be left in position and sealed with not in use.
Alternatively, catheters could be removed and repositioned when
needed again. An aperture system that maintains a tract through the
skin and subcutaneous tissue can be used for repeated, frequent
placement of catheters.
[0353] As currently used in clinical studies of compartment
syndrome, the catheter may have ancillary assay capability to
assist in treatment. The hollow fiber catheter may also measure
pressure, measure tissue blood flow or oxygenation, assays levels
of drug delivered to the tumor, or a combination of these features.
Such catheters can also be used to give direct infusion into the
tumor.
5TABLE II Process(es) Inside Outside Advantages WRT Gas Blood
Maximal concentration of all species. Higher gas velocity possible,
depending on design WRT Blood Gas Maximal concentration of all
species. WRT Blood For removal of ketones, ammonia, other vapors
using soluble media, including gas or liquids WRT UF Blood/Gas
Gas/Blood Combination of salt removal and concentration WRT UF HD
Blood/Gas Gas/Blood Combination with maximal options. WRT UF HD RI
Blood/Gas Gas/Blood Combination with maximal options. WRT UF RI
Blood/Gas Gas/Blood Combination with maximal options. WRT UF RI HD
Blood/Gas Gas/Blood Combination with maximal options. WRT HD
Blood/Gas Gas/Blood Will improve dialysis exchange by increasing
concentration WRT HD RI Blood/Gas Gas/Blood Improved exchange, with
maximal options. WRT HD RI UF Blood/Gas Gas/Blood Improved
exchange, with maximal options. WRT HD UF Blood/Gas Gas/Blood
Improved exchange, with maximal options. WRT HD UF RI Blood/Gas
Gas/Blood Improved exchange, with maximal options. WRT RI Blood/Gas
Gas/Blood Further options for specific concentrations. WRT RI UF
Blood/Gas Gas/Blood Further options for specific concentrations.
WRT RI UF HD Blood/Gas Gas/Blood Further options for specific
concentrations. WRT RI HD Blood/Gas Gas/Blood Further options for
specific concentrations. WRT RI HD UF Blood/Gas Gas/Blood Further
options for specific concentrations. UF Blood Ultrafiltrate Retains
molecules greater than MWCO. No concentration UF HD UF HD RI UF HD
RI WRT UF HD WRT UF HD WRT RI UF RI UF RI WRT UF RI WRT HD UF RI HD
UF RI HD WRT UF WRT series UF WRT parallel UF WRT stepped UF WRT
stepped UF WRT counterflow UF WRT HD UF WRT HD RI UF WRT RI UF WRT
RI HD HD Diffusional exchange only, by concentration gradient HD RI
HD RI WRT Improved viscosity for WRT HD RI WRT UF Improved
viscosity for WRT HD RI UF HD RI UF WRT Improved viscosity for WRT
HD WRT Further options HD WRT UF Further options HD WRT UF RI
Further options HD WRT RI Further options HD WRT RI UF Further
options HD UF HD UF RI HD UF RI WRT HD UF WRT HD UF WRT RI RI No
hollow fibers involved. Simply giving intravenous fluid RI HD RI HD
UF RI HD UF WRT Improved viscosity for eventual WRT RI HD WRT
Improved viscosity for eventual WRT RI HD WRT UF Improved viscosity
for eventual WRT RI UF RI UF WRT Improved viscosity for eventual
WRT RI UF WRT HD Improved viscosity for eventual WRT RI UF HD RI UF
HD WRT Improved viscosity for eventual WRT RI WRT Improved
viscosity for eventual WRT RI WRT HD Improved viscosity, with
potential for high exchange rates without net fluid removal. RI WRT
HD UF Improved viscosity, with potential for high exchange rates
without net fluid removal. RI WRT UF Improved viscosity, with
potential for high exchange rates without net fluid removal. RI WRT
UF HD Improved viscosity, with potential for high exchange rates
without net fluid removal.
* * * * *
References