U.S. patent application number 13/446706 was filed with the patent office on 2013-01-10 for organ care solution for ex-vivo machine perfusion of donor lungs.
Invention is credited to Anas ABDELAZIM, Ihab A. FATTAH, Waleed H. Hassanein, Robert HAVENER, Tamer I. KHAYAL, Paul LEZBERG.
Application Number | 20130011823 13/446706 |
Document ID | / |
Family ID | 47009719 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130011823 |
Kind Code |
A1 |
Hassanein; Waleed H. ; et
al. |
January 10, 2013 |
ORGAN CARE SOLUTION FOR EX-VIVO MACHINE PERFUSION OF DONOR
LUNGS
Abstract
An ex-vivo lung solution for machine perfusion of donor lungs on
OCS. The solution may be mixed with whole blood or packed red blood
cells to form the OCS lung perfusion solution.
Inventors: |
Hassanein; Waleed H.; (North
Andover, MA) ; FATTAH; Ihab A.; (North Andover,
MA) ; LEZBERG; Paul; (Westford, MA) ; KHAYAL;
Tamer I.; (North Andover, MA) ; HAVENER; Robert;
(Lynnfield, MA) ; ABDELAZIM; Anas; (Beachwood,
OH) |
Family ID: |
47009719 |
Appl. No.: |
13/446706 |
Filed: |
April 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61475524 |
Apr 14, 2011 |
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Current U.S.
Class: |
435/1.2 ;
435/284.1; 604/500 |
Current CPC
Class: |
A01N 1/0247 20130101;
A01N 1/0226 20130101 |
Class at
Publication: |
435/1.2 ;
435/284.1; 604/500 |
International
Class: |
A01N 1/02 20060101
A01N001/02; A61M 31/00 20060101 A61M031/00 |
Claims
1. An ex-vivo perfusion solution for machine perfusion of donor
lungs comprising: an energy-rich perfusion nutrient, a colloid, a
hormone, a steroid, a buffer, magnesium sulfate anhydrate, and at
least one of a phosphodiesterase inhibitor and a nitrate.
2. The solution of claim 1, wherein the phosphodiesterase inhibitor
is a phosphodiesterase 3 inhibitor.
3. The solution of claim 1, wherein the phosphodiesterase inhibitor
is milrinone.
4. The solution of claim 1, wherein the nitrate is
nitroglycerin.
5. The solution of claim 1, wherein the solution includes the
phosphodiesterase inhibitor and the nitrate, and the
phosphodiesterase inhibitor is milrinone and the nitrate is
nitroglycerin.
6. The solution of claim 5, wherein each liter of solution
comprises milrinone in amount of about 4000 mcg and nitroglycerine
in an amount of about 10 mg to 50 mg.
7. The solution of claim 1, additionally comprising whole
blood.
8. The solution of claim 1, additionally comprising red blood
cells.
9. The solution of claim 5, additionally comprising whole
blood.
10. The solution of claim 5, additionally comprising red blood
cells.
11. The solution of claim 5, wherein the nutrient includes glucose
monohydrate, sodium chloride, potassium chloride, and M.V.I.
Adult.RTM. multi-vitamin or equivalent; the colloid includes
dextran 40; the hormone includes insulin; the steroid includes
methylprednisolone; and the buffer includes disodium phosphate
anhydrate, monopotassium phosphate and sodium bicarbonate.
12. The solution of claim 6, wherein each liter of the solution
comprises dextran 40 in the amount of about 50 g; sodium chloride
in an amount of about 8 g; potassium chloride in an amount of about
0.4 g; magnesium sulfate anhydrate in an amount of about 0.098 g;
disodium phosphate anhydrate in an amount of about 0.046 g;
monopotassium phosphate in an amount of about 0.063 g; glucose
monohydrate in an amount of about 2 g; insulin in an amount of
about 20 IU; the multi-vitamin in an amount of about 1 unit vial;
sodium bicarbonate in an amount of about 15 mEq; methylprednisolone
in an amount of about 1 g.
13. The solution of claim 5, wherein the hormone comprises
insulin.
14. The solution of claim 5, wherein the hormone comprises about 20
IU insulin in each liter of solution.
15. The solution of claim 5, wherein nutrient comprises a
multi-vitamin and glucose monohydrate.
16. The solution of claim 15 wherein the multi-vitamin includes
fat-soluble and water-soluble vitamins.
17. The solution of claim 5, wherein nutrient comprises about 2 g
glucose monohydrate in each liter of solution.
18. The solution of claim 5 wherein the buffer comprises sodium
bicarbonate.
19. The solution of claim 5 wherein the buffer initially comprises
about 15 mEq sodium bicarbonate in each liter of solution.
20. The solution of claim 5 wherein the steroid comprises a
glucocorticoid steroid.
21. The solution of claim 20 wherein the glucocorticoid steroid
comprises methylprednisolone.
22. The solution of claim 5 wherein the steroid comprises 1 g
methylprednisolone in each liter of solution.
23. A method of perfusing a donor lung at or near physiologic
conditions comprising: flowing perfusion liquid through the lung,
the perfusion liquid being at a physiologic temperature, the
perfusion liquid comprising a nutrient, a colloid, a hormone, a
steroid, a buffer, magnesium sulfate anhydrate, an antimicrobial
agent and at least one of a phosphodiesterase inhibitor and a
nitrate.
24. The method of claim 23, wherein the nutrient includes glucose
monohydrate, sodium chloride, potassium chloride, and a
multi-vitamin; the colloid includes dextran 40; the hormone
includes insulin; the steroid includes methylprednisolone; the
buffer includes disodium phosphate anhydrate, monopotassium
phosphate and sodium bicarbonate; phosphodiesterase inhibitor
includes milrinone, and the nitrate includes nitroglycerin.
25. The method of claim 24, wherein each liter of liquid comprises
milrinone in an amount of about 4000 mcg; nitroglycerin in an
amount of about 10 mg to 50 mg; dextran 40 in the amount of about
50 g; sodium chloride in an amount of about 8 g; potassium chloride
in an amount of about 0.4 g; magnesium sulfate anhydrate in an
amount of about 0.098 g; disodium phosphate anhydrate in an amount
of about 0.046 g; monopotassium phosphate in an amount of about
0.063 g; glucose monohydrate in an amount of about 2 g; insulin in
an amount of about 20 IU; the multi-vitamin in an amount of about 1
unit vial; sodium bicarbonate in an amount of about 15 mEq;
methylprednisolone in an amount of about 1 g.
26. The method of claim 25 further comprising mixing the perfusion
liquid with whole blood.
27. The method of claim 25 further comprising mixing the perfusion
liquid with red blood cells.
28. The method of claim 25 further comprising mixing the perfusion
liquid with leukocyte-depleted whole blood.
29. A method of producing a solution for perfusing a lung at near
physiologic conditions comprising the steps of: adding pre-weighed
amounts of dextran 40, sodium chloride, potassium chloride (KCL),
magnesium sulfate anhydrate, disodium phosphate anydrate,
monopotassium phosphate, glucose monohydrate, milrinone,
nitroglycerin, antimicrobial agents and water to a container to
form a solution; mixing and heating the solution until fully
dissolved; monitoring the pH of the solution during mixing and
adjusting the pH with 1M hydrochloric acid; allowing the solution
to cool; filtering the solution; dispensing the solution into a
primary container; sterilizing the filled primary container with
heat using a sterilization cycle that has been validated to achieve
a Sterility Assurance Level of 10.sup.-6.
30. A method of producing a perfusion solution comprising combining
pre-weighed amounts of a nutrient, a colloid, a hormone, a steroid,
a buffer, magnesium sulfate anhydrate, and at least one of a
phosphodiesterase inhibitor and a nitrate to form a solution for
perfusing a lung at near physiologic conditions.
31. The method of claim 30 wherein the solution includes the
phosphodiesterase inhibitor and the nitrate, and the nutrient
includes glucose monohydrate, sodium chloride, potassium chloride,
and a multi-vitamin, wherein the multi-vitamin is selected from the
group consisting of M.V.I. Adult.RTM. or equivalent; the colloid
includes dextran 40; the hormone includes insulin; the steroid
includes methylprednisolone; buffer includes disodium phosphate
anhydrate, monopotassium phosphate and sodium bicarbonate; the
phosphodiesterase inhibitor includes milrinone, and the nitrate
includes nitroglycerin.
32. The method of claim 31, wherein each liter of solution includes
milrinone in an amount of about 4000 mcg; nitroglycerin in an
amount of about 10 mg to 50 mg; dextran 40 in the amount of about
50 g; sodium chloride in an amount of about 8 g; potassium chloride
in an amount of about 0.4 g; magnesium sulfate anhydrate in an
amount of about 0.098 g; disodium phosphate anhydrate in an amount
of about 0.046 g; monopotassium phosphate in an amount of about
0.063 g; glucose monohydrate in an amount of about 2 g; insulin in
an amount of about 20 IU; the multi-vitamin in an amount of about 1
unit vial; sodium bicarbonate in an amount of about 15 mEq;
methylprednisolone in an amount of about 1 g; the method further
comprising mixing and heating the solution until fully dissolved;
monitoring the pH of the solution during mixing and adjusting the
pH with 1M hydrochloric acid; allowing the solution to cool;
filtering the solution; dispensing the solution into a primary
container; sterilizing the filled primary container with heat using
a sterilization cycle that has been validated to achieve a
Sterility Assurance Level of 10.sup.-6.
33. The method of claim 32 further comprising mixing the perfusion
liquid with whole blood.
34. The method of claim 32 further comprising mixing the perfusion
liquid with red blood cells.
35. The method of claim 32 further comprising mixing the perfusion
liquid with leukocyte-depleted whole blood.
36. A system for perfusing a donor lung in a lung perfusion circuit
at or near physiologic conditions comprising: a single use
disposable lung care module including an interface adapted for
attachment to the single use module, and a lung chamber assembly
having a first interface for allowing a flow of a perfusion
solution into the lung and a second interface for allowing
ventilation of the lung with a ventilation gas; and a drain system
for draining a flow of perfusion solution from the lung chamber
assembly; and the perfusion solution including dextran 40; sodium
chloride; potassium chloride; magnesium sulfate anhydrate; disodium
phosphate anhydrate; monopotassium phosphate; glucose monohydrate;
milrinone; nitroglycerin; insulin; a multi-vitamin; sodium
bicarbonate; and methylprednisolone.
37. A method of flushing a lung prior to preservation on an OCS
comprising: flushing a donor lung prior to excising the lung from
the donor's body with a solution comprising a nutrient, a colloid,
a buffer, magnesium sulfate anhydrate, and a nitrate; excising the
donor lung from the donor's body; placing the lung on an organ care
system.
38. The method of claim 37 wherein the nutrient includes glucose
monohydrate, sodium chloride and potassium chloride; the colloid
includes dextran 40; the buffer includes disodium phosphate
anhydrate and monopotassium phosphate; and the nitrate includes
nitroglycerin.
39. The method of claim 38, wherein each liter of solution
comprises nitroglycerin in an amount of about 10 mg to 50 mg;
dextran 40 in the amount of about 50 g; sodium chloride in an
amount of about 8 g; potassium chloride in an amount of about 0.4
g; magnesium sulfate anhydrate in an amount of about 0.098 g;
disodium phosphate anhydrate in an amount of about 0.046 g;
monopotassium phosphate in an amount of about 0.063 g; glucose
monohydrate in an amount of about 2 g.
40. The solution of claim 1 further comprising an antimicrobial
agent.
41. The solution of claim 40, wherein the antimicrobial agent
comprises at least one of cefazolin, ciprofloxacin, and
voriconazole.
42. The solution of claim 40 wherein each liter of solution
comprises cefazolin in an amount of about 1 g, ciprofloxacin in an
amount of about 0.2 g, and voriconazole in an amount of about 0.2
g.
43. An ex-vivo perfusion solution for machine perfusion of donor
lungs comprising: an energy-rich perfusion nutrient, a colloid, a
hormone, a steroid, a buffer, magnesium sulfate anhydrate, at least
one of a phosphodiesterase inhibitor and a nitrate, and an
antimicrobial agent.
44. The solution of claim 6, wherein each liter of the solution
further comprises dextran 40 in the amount of about 50 g; sodium
chloride in an amount of about 8 g; potassium chloride in an amount
of about 0.4 g; magnesium sulfate anhydrate in an amount of about
0.098 g; disodium phosphate anhydrate in an amount of about 0.046
g; monopotassium phosphate in an amount of about 0.063 g; glucose
monohydrate in an amount of about 2 g; insulin in an amount of
about 20 IU; the multi-vitamin in an amount of about 1 unit vial;
sodium bicarbonate in an amount of about 15 mEq; methylprednisolone
in an amount of about 1 g; cefazolin in an amount of about 1 g;
ciprofloxacin in an amount of about 0.2 g; voriconazole in an
amount of about 0.2 g.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e), of provisional application U.S. Ser. No. 61/475,524,
filed on Apr. 14, 2011, entitled, "ORGAN CARE SOLUTION FOR EX-VIVO
MACHINE PERFUSION OF DONOR LUNGS", the entire subject matter of
which is incorporated herein by reference. This application also
incorporates by reference, the entirety of U.S. application Ser.
No. 12/099,715, filed on Apr. 8, 2008, entitled, "SYSTEMS AND
METHODS FOR EX VIVO LUNG CARE".
TECHNICAL FIELD
[0002] The disclosure generally relates a perfusion solution for
ex-vivo organ care. More particularly, the disclosure relates to a
solution for machine perfusion of donor lungs on an organ care
system ("OCS") at physiologic or near-physiologic conditions.
BACKGROUND
[0003] Current organ preservation techniques typically involve
hypothermic storage of the organ in a chemical perfusion solution.
In the case of the lung, it is typically flushed with a cold
preservation solution such as Perfadex.TM. and then immersed in
that same cold solution until it is transplanted. These techniques
utilize a variety of cold preservation solutions, none of which
sufficiently protect the lungs from tissue damage resulting from
ischemia. Such injuries are particularly undesirable when an organ,
such as a lung, is intended to be transplanted from a donor into a
recipient.
[0004] Using conventional approaches, tissue injuries increase as a
function of the length of time an organ is maintained ex-vivo. For
example, in the case of a lung, typically it may be preserved
ex-vivo for only about 6 to about 8 hours before it becomes
unusable for transplantation. As a result, the number of recipients
who can be reached from a given donor site is limited, thereby
restricting the recipient pool for a harvested lung. Compounding
the effects of cold ischemia, current cold preservation techniques
preclude the ability to evaluate and assess an organ ex-vivo.
Because of this, less-than-optimal organs may be transplanted,
resulting in post-transplant organ dysfunction or other injuries,
or resuscitatable organs may be turned down.
[0005] Prolonged and reliable ex-vivo organ care would also provide
benefits outside the context of organ transplantation. For example,
a patient's body, as a whole, can typically tolerate much lower
levels of chemo-, bio- and radiation therapy than many particular
organs. An ex-vivo organ care system would permit an organ to be
removed from the body and treated in isolation, reducing the risk
of damage to other parts of the body. Thus, there is a need to
develop techniques and perfusion solutions that do not require
hypothermic storage of the organ and extend the time during which
an organ can be preserved in a healthy state ex-vivo. Such
techniques would improve transplant outcomes and enlarge potential
donor and recipient pools.
SUMMARY
[0006] The disclosure provides improved methods, solutions, and
systems related to ex-vivo organ care. In general, in one aspect,
the disclosure features a lung OCS solution for machine perfusion
of donor lungs on OCS at near physiologic conditions. In another
aspect, the disclosure includes a system and method for perfusing
one or more lungs ex-vivo for an extended period of time in a
functional and viable state maintenance mode at near physiologic
conditions. In another aspect the disclosure includes a method of
producing a solution for ex-vivo perfusion of a donor lung at near
physiologic conditions.
[0007] The present disclosure describes an OCS lung perfusion
solution that can be used for machine perfusion of donor lungs on
OCS. The solution may include energy-rich perfusion nutrients, as
well as a supply of therapeutics, vasodilators, endothelial
stabilizers, and/or preservatives for reducing edema and providing
endothelial support to the lungs. In a preferred embodiment, the
solution comprises: dextran 40; sodium chloride; potassium
chloride; magnesium sulfate anhydrate; disodium phosphate
anhydrate; monopotassium phosphate; glucose monohydrate; milrinone;
nitroglycerin; insulin; a multi-vitamin (M.V.I. Adult.RTM. or
equivalent); sodium bicarbonate; methylprednisolone
(SoluMedrol.RTM. or equivalent); cefazolin; Ciprofloxacin;
voriconazole. The solution is mixed with whole blood or packed red
blood cells to form the OCS lung perfusion solution. The solution
provides the components for maintaining a functional (e.g., under
respiration) and viable lung ex-vivo at near physiologic
conditions.
[0008] According to certain embodiments, solutions with particular
solutes and concentrations are selected and proportioned to provide
for the organ to function at physiologic or near physiologic
conditions. For example, such conditions include maintaining organ
function at or near a physiological temperature and/or preserving
an organ in a state that permits normal cellular metabolism, such
as protein synthesis and increasing colloid pressure, minimize lung
edema and cell swelling.
[0009] In another embodiment, a method of perfusing a lung is
featured. The method includes: positioning the lung in an ex-vivo
perfusion circuit; circulating an OCS lung solution specifically
for machine perfusion of donor lungs on OCS through the lung, the
fluid entering the lung through a pulmonary artery interface and
leaving the lung through a left atrial interface; ventilating the
lung by flowing a ventilation gas through a tracheal interface;
deoxygenating the perfusion solution until a predetermined first
value of oxygen content in the perfusion solution is reached;
reoxygenating the perfusion solution by ventilating the lung with
an oxygenation gas until a predetermined second value of oxygen
content in the perfusion solution is reached; and determining a
condition of the lung based on a time taken for the lung to cause
the oxygen content level in the perfusion solution to change from
the first value of oxygen content to the second value of oxygen
content.
[0010] In another embodiment, a method of producing a solution for
perfusing a lung at near physiologic conditions is featured. This
method includes combining pre-weighed raw materials including
nutrients, colloids, hormones, steroids, buffers and vasodilators
with water for injection ("WFI") and mixed with heating until fully
dissolved, monitoring the pH level of the resulting solution,
allowing the solution to cool, filtering the cooled solution,
dispensing the solution into a primary container and sterilizing
the filled container.
[0011] In another aspect, a lung care system is featured. The lung
system includes: a single use disposable module including an
interface adapted to couple the single use disposable module with
the multiple use module for electro-mechanical interoperation with
the multiple use module; a lung chamber assembly optionally having
a first interface for allowing a flow of a lung OCS perfusion
solution into the lung, a second interface for allowing ventilation
of the lung with a ventilation gas, and a third interface for
allowing a flow of the perfusion solution away from the lung, the
lung chamber assembly including a dual drain system for carrying
the flow of the perfusion solution away from the lung, the dual
drain system comprising a measurement drain for directing a part of
the perfusion solution flow to a sensor of a perfusion solution gas
content and a main drain for receiving a remaining part of
perfusion solution flow; and an OCS lung perfusion solution
specifically for machine perfusion of donor lungs on OCS.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The following figures depict illustrative embodiments in
which like reference numerals refer to like elements. These
depicted embodiments may not be drawn to scale and are to be
understood as being illustrative and not as limiting.
[0013] FIG. 1 is a schematic diagram of the lung perfusion circuit
of the described embodiment.
[0014] FIG. 2 is an illustration of the organ care system drawn
from a 45-degree angle from the front view, according to the
described embodiment.
[0015] FIG. 3 is an illustration of the lung perfusion module,
according to the described embodiment.
[0016] FIG. 4 is an illustration of the pulmonary artery cannula,
according to the described embodiment.
[0017] FIG. 5 is an illustration of the tracheal cannula, according
to the described embodiment.
[0018] FIG. 6 is an exploded illustration of the lung chamber,
according to the described embodiment.
[0019] FIG. 7 is a schematic diagram of the described embodiment of
a portable organ care system including shows the gas-related
components of the lung perfusion module.
DETAILED DESCRIPTION
[0020] The following description and the drawings illustrate
embodiments sufficiently to enable those skilled in the art to
practice them. Other embodiments may incorporate structural,
logical, electrical, process, and other changes. Examples merely
typify possible variations. Individual components and functions are
optional unless explicitly required, and the sequence of operations
may vary. Portions and features of some embodiments may be included
in or substituted for those of others. The scope of embodiments
encompasses the full ambit of the claims and all available
equivalents of those claims.
[0021] Improved approaches to ex-vivo organ care are provided. More
particularly, various embodiments are directed to improved methods
and solutions relating to maintaining a lung at or near normal
physiologic conditions in an ex-vivo environment. As used herein,
"physiological temperature" is referred to as temperatures between
about 25 degrees C. and about 37 degrees C. A preferred embodiment
comprises a lung OCS perfusion solution that may be administered in
conjunction with an organ care system to maintain a lung in an
equilibrium state by circulating a perfusion solution through the
lung's vascular system, while causing the lung to rebreath a gas
having an oxygen content sufficient to met the lung's metabolic
needs.
[0022] The embodiments allow a lung to be maintained ex-vivo for
extended periods of time, such as, for example, 3-24 or more hours.
Such extended ex-vivo maintenance times expand the pool of
potential recipients for donor lungs, making geographic distance
between donors and recipients less important. Extended ex-vivo
maintenance times also provide the time needed for better genetic
and HLA matching between donor organs and organ recipients,
increasing the likelihood of a favorable outcome. The ability to
maintain the organ in a near physiologic functioning condition also
allows a clinician to evaluate the organ's function ex-vivo, and
identify organs that are damaged. This is especially valuable in
the case of the lung, since lungs are often compromised as a direct
or indirect result of the cause of the death of the donor. Thus
even a newly harvested lung may be damaged. The ability to make a
prompt assessment of a harvested organ allows a surgeon to
determine the quality of a lung and, if there is damage, to make a
determination of the nature of the problem. The surgeon can then
make a decision as to whether to discard the lung, or to apply
therapy to the lung. Therapies can include recruitment processes,
removing or stapling off damaged areas of lung, suctioning
secretions, cauterizing bleeding blood vessels, and giving
radiation treatment. The ability to assess and, if necessary
provide therapy to lungs at several stages from harvesting to
implantation greatly improves the overall likelihood of lung
transplant success and increases the number of organs available for
transplant. In some instances, the improved assessment capability
and extended maintenance time facilitates medical operators to
perform physical repairs on donor organs with minor defects.
Increased ex-vivo organ maintenance times can also provide for an
organ to be removed from a patient, treated in isolation ex-vivo,
and then put back into the body of a patient. Such treatment may
include, without limitation, pharmaceutical treatments, gas
therapies, surgical treatments, chemo-, bio-, gene and/or radiation
therapies.
Overview of OCS Perfusion Solution
[0023] According to certain embodiments, a lung OCS perfusion
solution with certain solutes provides for the lungs to function at
physiologic or near physiologic conditions and temperature by
supplying energy rich nutrients, oxygen delivery, optimal oncotic
pressure, pH and organ metabolism. The perfusion solution may also
include therapeutic components to help maintain the lungs and
protect them against ischemia, reperfusion injury and other ill
effects during perfusion. Therapeutics may also help mitigate
edema, provide general endothelial tissue support for the lungs,
and otherwise provide preventative or prophylactic treatment to the
lungs.
[0024] The amounts of solutes provided describes preferred amounts
relative to other components in the solution and may be scaled to
provide compositions of sufficient quantity.
[0025] In one embodiment, the solution may include a
phosphodiesterase inhibitor. To improve gas exchange and diminish
leukocytosis, an adenosine-3',5'-cyclic monophosphate (cAMP)
selective phosphodiesterase type III (PDE III) inhibitor such as
milrinone, aminone, anagrelide, bucladesine, cilostamide,
cilostazol, enoximone, KMUP-1, quazinone, RPL-554, siguazodan,
trequinsin, vesnarinone, zardaverine may be added. In a preferred
embodiment milrinone is added. Milrinone has the effects of
vasorelaxation secondary to improved calcium uptake into the
sarcoplasmic reticulum, inotropy (myocyte contraction) due to
cAMP-mediated trans-sarcolemmal calcium flux, and lusitropy
(myocyte relaxation) possibly due to improved actin-myosin complex
dissociation. In a preferred embodiment milrinone is present in
each 1 L of solution in an amount of about 3400 mcg to about 4600.
In a particularly preferred embodiment, milrinone is present in
each 1 L of solution in an amount of about 4000 mcg.
[0026] In certain embodiments the solution may include a nitrate
which is useful in the nitrogen cycle. Nitroglycerin is a nitrate
that may be added to the perfusion solution to promote
stabilization of pulmonary hemodynamics and improve arterial
oxygenation after transplantation. When a lung is removed from the
body, nitric oxide levels fall quickly because it is quenched by
superoxide generated during reperfusion, resulting in damage to the
lung tissue. Nitroglycerin can act to promote nitric oxide levels
in a lung ex-vivo by way of intracellular S-nitrosothiol
intermediates to directly stimulate guanylate cyclase or to release
nitric oxide locally in effector cells. To this end, Nitroglycerin
improves vascular homeostasis and improves organ function by
providing better arterial oxygenation after transplant. In a
preferred embodiment nitroglycerin is present in each 1 L of
solution in an amount of about 10 mg to about 50 mg.
[0027] In one other embodiment, magnesium sulfate anhydrate may be
added to the solution. Pulmonary artery blood pressure is lower
than blood pressure in the rest of the body and in the case of
pulmonary hypertension, magnesium sulfate promotes vasodilatation
in constricted muscles of the pulmonary arteries by modulating
calcium uptake, binding and distribution in smooth muscle cells,
thereby decreasing the frequency of depolarization of smooth muscle
and thus promoting vasodilatation. Magnesium sulfate anhydrate is
present in each 1 L of solution in an amount of about 0.083 g to
about 0.1127 g. In a particularly preferred embodiment magnesium
sulfate anhydrate is present in each 1 L of solution in an amount
of about 0.098 g.
[0028] In a preferred embodiment, the addition of colloids offers
numerous benefits including improving erythrocyte deformability,
preventing erythrocyte aggregation, inducing disbanding of already
aggregated cells and preserving endothelial-epithelial membrane.
Colloids also have anti-thrombotic effects by being able to coat
endothelial surfaces and platelets. In this embodiment dextran 40
is present in each 1 L of solution in an amount of about 42.5 g to
about 57.5 g. In a particularly preferred embodiment, dextran 40 is
present in each 1 L of solution in an amount of about 50 g.
[0029] The solution may also contain electrolytes, such as sodium,
potassium, chloride, sulfate, magnesium and other inorganic and
organic charged species, or combinations thereof. A suitable
component may be those where valence and stability permit, in an
ionic form, in a protonated or unprotonated form, in salt or free
base form, or as ionic or covalent substituents in combination with
other components that hydrolyze and make the component available in
aqueous solutions. In this embodiment, sodium chloride is present
in each 1 L of solution in an amount of about 6.8 g to about 9.2 g.
In a particularly preferred embodiment, sodium chloride is present
in each 1 L of solution in an amount of about 8 g.
[0030] In a preferred embodiment the solution may have a
low-potassium concentration. A low-level of potassium results in
improved lung function. A low potassium level may also protect the
lung during high flow reperfusion and lead to a lower PA pressure
and PVR, lower percent decrease in dynamic airway compliance, and
lower wet to dry ratio. In this embodiment potassium chloride is
present in each 1 L of solution in an amount of about 0.34 g to
about 0.46 g. In a particularly preferred embodiment potassium
chloride is present in each 1 L of solution in an amount of about
0.4 g.
[0031] The solutions may include one or more energy-rich components
to assist the organ in conducting its normal physiologic function.
These components may include energy rich materials that are
metabolizable, and/or components of such materials that an organ
can use to synthesize energy sources during perfusion. Exemplary
sources of energy-rich molecules include, for example, one or more
carbohydrates. Examples of carbohydrates include glucose
monohydrate, monosaccharides, disaccharides, oligosaccharides,
polysaccharides, or combinations thereof, or precursors or
metabolites thereof. While not meant to be limiting, examples of
monosaccharides suitable for the solutions include octoses;
heptoses; hexoses, such as fructose, allose, altrose, glucose,
mannose, gulose, idose, galactose, and talose; pentoses such as
ribose, arabinose, xylose, and lyxose; tetroses such as erythrose
and threose; and trioses such as glyceraldehyde. In a preferred
embodiment glucose monohydrate is present in each 1 L of solution
an amount of about 1.7 g to about 2.3 g. In a particularly
preferred embodiment glucose monohydrate is present in each 1 L of
solution an amount of about 2 g.
[0032] The solution may include other components to help maintain
the organ and protect it against ischemia, reperfusion injury and
other ill effects during perfusion. In certain exemplary
embodiments these components may include a hormone to promote and
regulate carbohydrate and fat metabolism. Insulin acts to improve
cell function by promoting optimum glucose and glycogen intake into
the cells. In this preferred embodiment each 1 L of the solution
may contain about 17 IU insulin to about 23 IU insulin. In a
particularly preferred embodiment each 1 L of the solution may
contain 20 IU insulin.
[0033] In addition, the solution may include a multi-vitamin that
provides anti-oxidants and co-enzymes and helps maintain the body's
normal resistance and repair processes. The multi-vitamin may
include certain fat soluble vitamins such as Vitamins A, D, E, and
K, and water soluble vitamins such as Vitamin C, Niacinamide,
Vitamins B.sub.2, B.sub.1, B.sub.6, and Dexpanthenol, as well as
stabilizers and preservatives. In a preferred embodiment, each 1 L
of the solution contains one unit vial of M.V.I. Adult.RTM.
multi-vitamin. M.V.I. Adult.RTM. includes fat soluble vitamins such
as Vitamins A, D, E, and K, and water soluble vitamins such as
Vitamin C, Niacinamide, Vitamins B.sub.2, B.sub.1, B.sub.6, and
Dexpanthenol, as well as stabilizers and preservatives in an
aqueous solution.
[0034] The solution may also include an anti-inflammatory agent
such as a glucocorticoid steroid. Glucocorticoid steroids act as
anti-inflamatory agents by activating to the cell's glucocorticoid
receptors which in turn up-regulate the expression of
anti-inflammatory proteins in the nucleus and reduce the expression
of pro-inflammatory proteins. Glucocorticoid steroids include
methylprednisolone, hydrocortisone, cortisone acetate, prednisone,
dexamethasone, betamethasone, triamcinolone, beclometasone,
fludrocortisone acetate and aldosterone. In this preferred
embodiment, each 1 L of the solution may contain about 0.85 g mg to
about 1.15 g methylprednisolone (SoluMedrol.RTM. or equivalent). In
a particularly preferred embodiment, each 1 L of the solution may
contain 1 g methylprednisolone (SoluMedrol.RTM. or equivalent)
[0035] In addition the solution may contain buffers to maintain the
solution at an optimal pH. These may include disodium phosphate
anhydrate, a physiologic balancing buffer or monopotassium
phosphate to maintain the average pH of the solution during lung
tissue perfusion. In this embodiment disodium phosphate anhydrate
is present in each 1 L of solution in an amount of about 0.039 g to
about 0.052 g, and/or monopotassium phosphate in an amount of about
0.053 g to about 0.072 g. In a particularly preferred embodiment,
disodium phosphate anhydrate is present in an amount of 0.046 g,
and/or monopotassium phosphate in an amount of 0.063 g. In some
embodiments, the solution contains sodium bicarbonate, potassium
phosphate, or TRIS buffer. In a preferred embodiment the sodium
bicarbonate is present in each 1 L of solution in an amount of
about 12.75 mEq to about 17.25 mEq. In a particularly preferred
embodiment each 1 L of the solution may initially contain about 15
mEq sodium bicarbonate (5 mEq to each 500 mL bottle and 2-3 bottles
are used), and additional amounts may be added throughout
preservation based on clinical judgment. For example, 20-40 mEq can
be added to the system as part of priming.
[0036] Other suitable buffers include 2-morpholinoethanesulfonic
acid monohydrate (MES), cacodylic acid, H.sub.2CO.sub.3/NaHCO.sub.3
(pK.sub.a1), citric acid (pK.sub.a3),
bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris),
N-carbamoylmethylimidino acetic acid (ADA),
3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris Propane)
(pK.sub.a1), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES),
N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), imidazole,
N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES),
3-(N-morpholino)propanesulphonic acid (MOPS),
NaH.sub.2PO.sub.4/Na.sub.2HPO.sub.4 (pK.sub.a2),
N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES),
N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid (HEPES),
N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)
(HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine
(Tricine), tris hydroxymethylaminoethane (Tris), glycineamide,
N,N-bis(2-hydroxyethyl)glycine (Bicine), glycylglycine (pK.sub.a2),
N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or
a combination thereof.
[0037] The solution may contain an antimicrobial or antifungal
agent to prevent infection. These may include bacteria and fungal
antimicrobial agents that provide protection against both gram
negative and gram positive bacteria. Suitable antimicrobial or
antifungal agents include cefazolin, ciprofloxacin, and
voriconazole or equivalent. In a preferred embodiment, cefazolin is
present in each 1 L of solution in an amount of about 0.85 g to
about 1.15 g, ciprofloxacin is present in each 1 L of solution in
an amount of about 0.17 g to about 2.3 g, and voriconazole is
present in each 1 L of solution in an amount of about 0.17 g to
about 2.3 g. In a particularly preferred embodiment, cefazolin is
present in each 1 L of solution in an amount of about 1 g,
ciprofloxacin is present in each 1 L of solution in an amount of
about 0.2 g, and voriconazole is present in each 1 L of solution in
an amount of about 0.2 g. Alternatively the solution may contain
any effective antimicrobial or antifungal agent.
[0038] The solutions are preferably provided at a physiological
temperature and maintained thereabout throughout perfusion and
recirculation.
[0039] In a preferred embodiment the OCS lung perfusion solution
comprises a nutrient, a colloid, a vasodilator, a hormone and a
steroid.
[0040] In another preferred embodiment the solution comprises a
nutrient including Glucose monohydrate, sodium chloride, potassium
chloride, a multi-vitamin including fat-soluble and water-soluble
vitamins; a colloid including dextran 40; a hormone including
insulin; a steroid including methylprednisolone; buffering agents
including disodium phosphate anhydrate, monopotassium phosphate and
sodium bicarbonate; vasodilators including milrinone, nitroglycerin
and magnesium sulfate anhydrate; antimicrobial or antifungal agents
including cefazolin, ciprofloxacin, and voriconazole.
[0041] In another preferred embodiment the solution comprises an
effective amount of dextran 40; sodium chloride; potassium
chloride; magnesium sulfate anhydrate; disodium phosphate
anhydrate; monopotassium phosphate; glucose monohydrate; milrinone;
nitroglycerin; insulin; a multi-vitamin (M.V.I. Adult.RTM. or
equivalent); sodium bicarbonate; methylprednisolone
(SoluMedrol.RTM. or equivalent); cefazolin; ciprofloxacin;
voriconazole.
[0042] In a preferred embodiment of the OCS lung perfusion
solution, each 1 L of solution includes, milrinone in an amount of
about 4000 mcg; nitroglycerin in an amount of about 10-50 mg;
dextran 40 in an amount of about 50 g; sodium chloride in an amount
of about 8 g; potassium chloride in an amount of about 0.4 g;
magnesium sulfate anhydrate in an amount of about 0.098 g; disodium
phosphate anhydrate in an amount of about 0.046 g; monopotassium
phosphate in an amount of about 0.063 g; glucose monohydrate in an
amount of about 2 g; insulin in an amount of about 20 IU; a
multi-vitamin (M.V.I. Adult.RTM. or equivalent) in the amount of
about 1 unit vial; sodium bicarbonate is initially present in an
amount of about 15 mEq; methylprednisolone in an amount of about 1
g.
[0043] In a particularly preferred embodiment of the OCS lung
perfusion solution, each 1 L of solution includes, milrinone in an
amount of about 4000 mcg; nitroglycerin in an amount of about 10-50
mg; dextran 40 in an amount of about 50 g; sodium chloride in an
amount of about 8 g; potassium chloride in an amount of about 0.4
g; magnesium sulfate anhydrate in an amount of about 0.098 g;
disodium phosphate anhydrate in an amount of about 0.046 g;
monopotassium phosphate in an amount of about 0.063 g; glucose
monohydrate in an amount of about 2 g; insulin in an amount of
about 20 IU; a multi-vitamin (M.V.I. Adult.RTM. or equivalent) in
the amount of about 1 unit vial; sodium bicarbonate is initially
present in an amount of about 15 mEq; methylprednisolone in an
amount of about 1 g; cefazolin in an amount of about 1 g;
ciprofloxacin in an amount of about 0.2 g; voriconazole in an
amount of about 0.2 g.
[0044] In certain embodiments, the perfusion solution is maintained
and provided to the lungs at a near physiologic temperature.
According to one embodiment, the perfusion solution employs a blood
product-based perfusion solution to more accurately mimic normal
physiologic conditions. The perfusion solution may be supplemented
with cellular media. The cellular media may include a blood
product, such as whole blood, or packed red blood cells; allogenic
packed red blood cells that are leukocyte depleted/reduced; donor's
whole blood that is leukocyte and platelet depleted/reduced; and/or
human plasma to achieve circulating hematocrit of 15-30%.
Overview of Method of Producing a Solution for Perfusing a Lung at
Near Physiologic Temperature
[0045] In another aspect, a method of producing a solution for
perfusing a lung at near physiologic temperature is provided. In a
preferred method, the pre-weighed raw materials and WFI are added
to a stainless steel mixing tank and mixed with heating until fully
dissolved. The pH of the resulting solution is monitored and
adjusted during the mixing process with 1M hydrochloric acid (HCl).
The solution is allowed to cool and then filtered through a 0.2
.mu.m filter and finally dispensed into a primary container. The
filled container is terminally sterilized with heat using a
sterilization cycle that has been validated to achieve a Sterility
Assurance Level of 10.sup.-6. The raw materials in a preferred
embodiment include a nutrient, a colloid, a vasodilator, a hormone
and a steroid for perfusing a lung at near physiologic
conditions.
[0046] In another preferred embodiment the raw materials include a
nutrient including glucose monohydrate, sodium chloride, potassium
chloride, a multi-vitamin including M.V.I. Adult.RTM. or
equivalent; a colloid including dextran 40; a hormone including
insulin; a steroid including methylprednisolone; buffering agents
including disodium phosphate anhydrate, monopotassium phosphate and
sodium bicarbonate; vasodilators including milrinone, nitroglycerin
and magnesium sulfate anhydrate; an antimicrobial or antifungal
agent.
[0047] In another preferred embodiment the raw materials include
dextran 40; sodium chloride; potassium chloride; magnesium sulfate
anhydrate; disodium phosphate anhydrate; monopotassium phosphate;
glucose monohydrate; milrinone; nitroglycerin; insulin; a
multi-vitamin (M.V.I. Adult.RTM. or equivalent); sodium
bicarbonate; methylprednisolone (SoluMedrol.RTM. or equivalent);
antimicrobial or antifungal agents including cefazolin,
ciprofloxacin, and voriconazole for perfusing a lung at near
physiologic conditions.
[0048] In a preferred embodiment, for each 1 L of solution, the raw
materials include milrinone in an amount of about 4000 mcg;
nitroglycerin in an amount of about 10-50 mg; dextran 40 in an
amount of about 50 g; sodium chloride in an amount of about 8 g;
potassium chloride in an amount of about 0.4 g; magnesium sulfate
anhydrate in an amount of about 0.098 g; disodium phosphate
anhydrate in an amount of about 0.046 g; monopotassium phosphate in
an amount of about 0.063 g; glucose monohydrate in an amount of
about 2 g; insulin in an amount of about 20 IU; a multi-vitamin
(M.V.I. Adult.RTM. or equivalent) in the amount of about 1 unit
vial; sodium bicarbonate is initially present in an amount of about
15 mEq; methylprednisolone in an amount of about 1 g; an
antimicrobial or antifungal agent.
[0049] In another particularly preferred embodiment, for each 1 L
of solution, the raw materials include milrinone in an amount of
about 4000 mcg; nitroglycerin in an amount of about 10-50 mg;
dextran 40 in an amount of about 50 g; sodium chloride in an amount
of about 8 g; potassium chloride in an amount of about 0.4 g;
magnesium sulfate anhydrate in an amount of about 0.098 g; disodium
phosphate anhydrate in an amount of about 0.046 g; monopotassium
phosphate in an amount of about 0.063 g; glucose monohydrate in an
amount of about 2 g; insulin in an amount of about 20 IU; a
multi-vitamin (M.V.I. Adult.RTM. or equivalent) in the amount of
about 1 unit vial; sodium bicarbonate is initially present in an
amount of about 15 mEq; methylprednisolone in an amount of about 1
g; cefazolin in an amount of about 1 g; ciprofloxacin in an amount
of about 0.2 g; voriconazole in an amount of about 0.2 g.
Overview of Method of Flushing an Organ with a Solution Between
Excise from the Donor and Instrumentation on OCS
[0050] In another aspect, there is provided a method of flushing an
organ with a solution between excise from the body and
instrumentation on OCS. In this embodiment, to prepare a donor lung
for surgical removal from the donor's chest and to remove all old
donor blood from the lung, the donor lung is flushed ante-grade
using the pulmonary artery with the solution until the temperature
of the donor lung is in the range of about 0 degrees C. to about 30
degrees C. Additionally, the solution may be used for retrograde
flush of the lung using the pulmonary veins to remove any blood
clots remaining in the donor lung prior to surgical removal of the
lung from the donor's chest, and to ensure adequate homogenous
distribution of flush solution to all lung segments. The lungs are
ventilated using a ventilator during both ante-grade and
retro-grade flushing to allow for homogenous distribution of the
solution and to increase the oxygen concentration in the donor lung
alveoli to minimize the impact of ischemia/reperfusion injury on
the donor lung. Once the ante-grade and retrograde flushing of the
donor lung is completed, the lung will be removed surgically while
inflated to minimize collapsing of the alveoli. Once the donor lung
is fully removed from the donor body, it is ready to the next phase
of OCS perfusion.
[0051] In one embodiment, the solution comprises an energy-rich
perfusion nutrient, a colloid, a hormone, a buffer, magnesium
sulfate anhydrate, and a nitrate. In another embodiment, the
solution comprises dextran 40; sodium chloride; potassium chloride;
magnesium sulfate anhydrate; disodium phosphate anhydrate;
monopotassium phosphate; glucose monohydrate; nitroglycerin.
[0052] In a particularly preferred embodiment each 1 L of solution
for ante-grade flush comprises dextran 40 in an amount of about 50
g; sodium chloride in an amount of about 8 g; potassium chloride in
an amount of about 0.4 g; magnesium sulfate anhydrate in an amount
of about 0.098 g; disodium phosphate anhydrate in an amount of
about 0.046 g; monopotassium phosphate in an amount of about 0.063
g; glucose monohydrate in an amount of about 2 g; nitroglycerin in
an amount of about 50 mg.
[0053] In another particularly preferred embodiment each 1 L of
solution for retrograde flush comprises dextran 40 in an amount of
about 50 g; sodium chloride in an amount of about 8 g; potassium
chloride in an amount of about 0.4 g; magnesium sulfate anhydrate
in an amount of about 0.098 g; disodium phosphate anhydrate in an
amount of about 0.046 g; monopotassium phosphate in an amount of
about 0.063 g; glucose monohydrate in an amount of about 2 g;
nitroglycerin in an amount of about 10 mg.
Overview of Method of Machine Perfusion Using Lung OCS Perfusion
Solution
[0054] In another aspect, a method for machine perfusion of a donor
lung is provided. The method includes perfusing the donor lung with
a OCS lung perfusion solution comprising: dextran 40; sodium
chloride; potassium chloride; magnesium sulfate anhydrate; disodium
phosphate anhydrate; monopotassium phosphate; glucose monohydrate;
milrinone; nitroglycerin; insulin; at least two vitamins; sodium
bicarbonate; methylprednisolone (SoluMedrol.RTM. or equivalent); a
microbial or antifungal agent.
[0055] In a further aspect, the method includes perfusing the donor
lung with a particularly preferred OCS lung perfusion solution
comprising for each 1 L of solution: milrinone in an amount of
about 4000 mcg; nitroglycerin in an amount of about 10-50 mg;
dextran 40 in an amount of about 50 g; sodium chloride in an amount
of about 8 g; potassium chloride in an amount of about 0.4 g;
magnesium sulfate anhydrate in an amount of about 0.098 g; disodium
phosphate anhydrate in an amount of about 0.046 g; monopotassium
phosphate in an amount of about 0.063 g; glucose monohydrate in an
amount of about 2 g; insulin in an amount of about 20 IU; a
multi-vitamin (M.V.I. Adult.RTM. or equivalent) in the amount of
about 1 unit vial; sodium bicarbonate is initially present in an
amount of about 15 mEq; methylprednisolone in an amount of about 1
g; cefazolin in an amount of about 1 g; ciprofloxacin in an amount
of about 0.2 g; voriconazole in an amount of about 0.2 g.
Overview of the Lung Perfusion Circuit
[0056] FIG. 1 illustrates an exemplary lung perfusion circuit which
can be used to circulate the perfusion solution noted above. The
circuit is housed entirely within a lung perfusion module, and all
its components may be disposable. The organ care system (OCS)
disclosure, U.S. application Ser. No. 12/099,715, includes an
exemplary embodiment of a lung perfusion circuit and is
incorporated in its entirety by reference. Lung OCS perfusion
solution 250 is placed in a reservoir and then circulates within
the perfusion circuit, passing through various components of lung
perfusion module before passing through the vascular system of
lungs 404. Pump 226 causes perfusion solution 250 to flow around
the lung perfusion circuit. It receives perfusion solution 250 from
reservoir 224, and pumps the solution through compliance chamber
228 to heater 230. Compliance chamber 228 is a flexible portion of
tubing that serves to refine the flow characteristics nature of
pump 226. Heater 230 replaces heat lost by perfusion solution 250
to the environment during circulation of the fluid. In the
described embodiment, the heater maintains perfusion solution 250
at or near the physiologic temperature of 30-37 degrees C., and
preferably at about 34 degrees C. After passing through heater 230,
perfusion solution 250 flows into gas exchanger 402. Gas exchanger
402 allows gases to be exchanged between gas and perfusion solution
250 via a gas-permeable, hollow fiber membrane. However, the gas
exchanger has an effective gas exchange surface area of about 1
square meter, which is only a fraction of the 50-100 square meter
effective exchange area of the lungs. Thus gas exchanger 402 has
only a limited gas exchange capability compared to the lungs. Blood
gas solenoid valve 204 regulates the supply of gas into gas
exchanger 402. Sampling/injection port 236 facilitates the removal
of a sample or the injection of a chemical just before perfusion
solution 250 reaches the lungs. Perfusion solution then enters
lungs 404 through cannulated pulmonary artery 232. Flow probe 114
measures the rate of flow of perfusion fluid 250 through the
system. In the described embodiment, flow probe 114 is placed on
the perfusate line as it leads towards the pulmonary artery.
Pressure sensor 115 measures pulmonary arterial pressure at the
point of entry of perfusion fluid 250 into the lungs. In the
described embodiment, perfusion solution 250 is the lung OCS
solution described previously.
[0057] FIG. 2 is an overall view of OCS console 100 showing the
single use, disposable lung perfusion module in a semi-installed
position. As broadly indicated in FIG. 2, single use disposable
lung perfusion module is sized and shaped to fit into OCS console
100, and to couple with it. Overall, the unit has a similar form to
the organ care system described in U.S. patent application Ser. No.
11/788,865. Removable lung perfusion module 400, is insertable into
OCS console 100 by means of a pivoting mechanism that allows module
400 to slide into the organ console module from the front, as shown
in FIG. 2, and then pivot towards the rear of the unit. Clasp
mechanism 2202 secures lung perfusion module 400 in place. In
alternative embodiments, other structures and interfaces of lung
perfusion module 400 are used to couple the module with OCS 100.
When secured in place, electrical and optical connections (not
shown) provide power and communication between OCS console 100 and
lung perfusion module 400. Details of the electrical and optical
connections are described in U.S. patent application Ser. No.
11/246,013, filed on Oct. 7, 2005, the specification of which is
incorporated by reference herein in its entirety. A key component
of lung perfusion module 400 is organ chamber 2204, which is
described in detail below. Battery compartments 2206 and
maintenance gas cylinder 220 (not shown) are located in the base of
the OCS console 100. OCS console 100 is protected by removable
panels, such as front panels 2208. Just below lung perfusion module
are perfusion solution sampling ports 234 and 236. Mounted on top
of OCS console 100 is OCS monitor 300.
[0058] FIG. 3 is a front view of lung perfusion module 400. Organ
chamber 2204 includes a removable lid 2820 and housing 2802.
Sampling ports, including LA sampling port 234 and PA sampling port
236 are visible below organ chamber 2802. Gas exchanger 402,
bellows 418, and bellows plate 2502 are also visible in the
figure.
[0059] The circulation path of the perfusion solution, which was
first described in connection with FIG. 2, in terms of the
components of lung perfusion module 400 is now addressed. Mounted
below organ chamber 2204 are perfusion solution reservoir 224,
which stores perfusion solution 250. The perfusion solution exits
through one-way inflow valve 2306, line 2702, and pump dome 2704 to
pump 226 (not shown). The perfusion solution is pumped through
perfusion solution line 2404 through compliance chamber 228, and
then to perfusion solution heater 230. After passing through heater
230, the perfusion solution passes through connecting line 2706 to
gas exchanger 402.
[0060] The pulmonary artery (PA) cannula connects the perfusion
circuit with the vascular system of lungs 404. An exemplary
embodiment of a pulmonary artery (PA) cannula is shown in FIG. 4.
Referring to FIG. 4, single PA cannula 802 has single insertion
tube 804 for insertion into a single PA, and is used to cannulate
the PA at a point before it branches to the two lungs. To connect
the cannula to the pulmonary artery, insertion tube 804 is inserted
into the PA, and the PA is secured onto the tube with sutures. The
tracheal cannula 700 is inserted into the trachea to provide a
means of connection between the lung perfusion module 400 gas
circuit and the lungs. FIG. 5 illustrate an exemplary tracheal
cannulae. Cannula 700 includes tracheal insertion portion 704 to
which the trachea is secured with a cable tie, or by other means.
The tracheal cannula may be clamped at flexible portion 706 prior
to instrumentation to seal off air flow in and out of the lungs
404. Also illustrated is an optional locking nut 708.
[0061] The perfusion solution exits gas exchanger 402 through
connecting line 2708 to the interface with the pulmonary artery.
After flowing through the lung and exiting via the pulmonary vein
and the left atrium, the perfusion solution drains through from the
base of organ chamber 2204, as described below. These drains feed
the perfusion solution to reservoir 224, where the cycle begins
again.
[0062] Having described OCS console 100 and lung perfusion module
400, we now describe organ chamber 2204. FIG. 6 shows an exploded
view of the components of organ chamber 2204. Base 2802 of chamber
2204 is shaped and positioned within lung perfusion module 400 to
facilitate the drainage of the perfusion solution. Organ chamber
2204 has two drains, measurement drain 2804, and main drain 2806,
which receives overflow from the measurement drain. Measurement
drain 2804 drains perfusion solution at a rate of about 0.5 l/min,
considerably less than perfusion solution 250 flow rate through
lungs 404 of between 1.5 l/min and 4 l/min. Measurement drain leads
to oxygen probe 118, which measures SaO.sub.2 values, and then
leads on to reservoir 224. Main drain 2806 leads directly to
reservoir 224 without oxygen measurement. Oxygen probe 118, which
is a pulse oxymeter in the described embodiment, cannot obtain an
accurate measurement of perfusion solution oxygen levels unless
perfusion solution 250 is substantially free of air bubbles. In
order to achieve a bubble-free column of perfusion solution, base
2802 is shaped to collect perfusion solution 250 draining from
lungs 404 into a pool that collects above drain 2804. The perfusion
solution pool allows air bubbles to dissipate before the perfusion
solution enters drain 2804. The formation of a pool above drain
2804 is promoted by wall 2808, which partially blocks the flow of
perfusion solution from measurement drain 2804 to main drain 2806
until the perfusion solution pool is large enough to ensure the
dissipation of bubbles from the flow. Main drain 2806 is lower than
measurement drain 2804, so once perfusion solution overflows the
depression surrounding drain 2804, it flows around wall 2808, to
drain from main drain 2806. In an alternate embodiment of the dual
drain system, other systems are used to collect perfusion solution
into a pool that feeds the measurement drain. In some embodiments,
the flow from the lungs is directed to a vessel, such as a small
cup, which feeds the measurement drain. The cup fills with
perfusion solution, and excess blood overflows the cup and is
directed to the main drain and thus to the reservoir pool. In this
embodiment, the cup performs a function similar to that of wall
2808 in the embodiment described above by forming a small pool of
perfusion solution from which bubbles can dissipate before the
perfusion solution flows into the measurement drain on its way to
the oxygen sensor.
[0063] Lungs 404 are supported by support surface 2810. The surface
is designed to support lungs 404 without applying undue pressure,
while angling lungs 404 slightly downwards towards the lower lobes
to promote easy drainage of the perfusion solution. Support surface
includes drainage channels 2812 to collect and channel perfusion
solution issuing from lungs 404, and to guide the perfusion
solution towards drain 2814, which feeds perfusion solution
directly to the blood pool for measurement drain 2804. To provide
additional support for the lungs, lungs 404 are wrapped with a
polyurethane wrap (not shown) when placed on support surface 2810.
The polyurethane wrap anchors lungs 404, helps keep the lungs in a
physiologic configuration, and prevents the bronchi from being
kinked and limiting the total volume of inflation. The wrap
provides a smooth surface for the exterior of the lung to interface
with organ chamber 2204, reducing the risk of the chamber applying
excessive pressure on any part of lungs 404, which might cause
undesirable hemorrhaging.
[0064] FIG. 7 is a schematic diagram of the described embodiment of
a portable organ care system including the gas-related components
of the lung perfusion module. Controller 202 manages the release of
maintenance and assessment gases by controlling the valves, gas
selector switch 216, and ventilator 214, thus implementing the
preservation of the lungs in maintenance mode, or the assessment of
the lungs in one of the assessment modes. Blood gas solenoid valve
204 controls the amount of gas flowing into blood gas exchanger
402. Airway pressure sensor 206 samples pressure in the airway of
lungs 404, as sensed through isolation membrane 408. Relief valve
actuator 207 is pneumatically controlled, and controls relief valve
412. The pneumatic control is carried out by inflating or deflating
orifice restrictors that block or unblock the air pathway being
controlled. This method of control allows complete isolation
between the control systems in lung console module 200 and the
ventilation gas loop in lung perfusion module 400. Pneumatic
control 208 controls relief valve 207 and bellows valve actuator
210. Ventilator 214 is a mechanical device with an actuator arm
that causes bellows 418 to contract and expand, which causes
inhalation and exhalation of gas into and out of lungs 404.
Use Models
[0065] An exemplary model for using the solution described above in
the organ care system is described below.
[0066] The process of preparing the OCS perfusion module 400 for
instrumentation begins by producing the solution by the method of
producing a solution for perfusing a lung at near physiologic
temperature as described previously. About 800 ml to about 2000 ml
of the OCS lung perfusion solution is then added into the Organ
Care System (OCS) sterile perfusion module 400. The solution is
then supplemented with about 500 ml to about 1000 ml of cellular
media. The cellular media may include one or combination of the
following to achieve total circulating hematocrit concentration
between 15-30%: typed allogenic packed red blood cells (pRBCs) that
is leukocytes depleted/reduce; donor's whole blood that is
leukocyte and platelet depleted/reduced; and/or human plasma to
achieve circulating hematocrit of 15-30%. The OCS device operates
to circulate and mix the solution and cellular media while warming
and oxygenating the solution using a built in fluid warmer and gas
exchanger 402. Once the solution is fully mixed, warmed and
oxygenated, the pH of the solution will be adjusted using sodium
bicarbonate or other available buffer solution as needed. Once the
solution's hematocrit, temperature and pH levels reach an
acceptable state, the donor lung will be instrumented on OCS.
[0067] Once the solution is fully mixed, pH is adjusted to
7.35-7.45 and hematocrit is adjusted to 15-30%, the donor lung will
be instrumented on OCS. To begin instrumentation, first set the
flow rate of the OCS Pump 226 to about 0.05 L/min. to ensure that
perfusion solution does not exit the PA line 233 prior to
connecting the trachea cannula 700. Place the lung in the OCS'
organ chamber 224 and connect the trachea cannula 700 to the OCS
trachea connector 710 and unclamp trachea cannula at section 706.
Then connect a PA pressure monitoring line with pressure sensor
115, to the PA cannula 802. Trim the OCS' PA cannula 802 and
prepare to connect to the OCS PA line connector 231. Next, increase
the OCS' pump 226 flow to about 0.3 to about 0.4 L/min. so that a
low-flow column of solution exits the PA line 233. Then remove any
air from the lung by connecting the lung PA cannula 802 to the OCS
PA line connector 231 and gradually filling the PA cannula 802 with
perfusion solution. Once an air-free column of solution is reached
inside the PA cannula 802, seal the connection between the PA
cannula 802 and the OCS PA line connector 231.
[0068] Next, gradually raise the OCS fluid warmer 230 temperature
to 37 degrees C., and bring the perfusion solution temperature from
about 32 degrees C. to about 37 degrees C. Then begin increasing
the pump flow gradually, ensuring that pulmonary arterial pressure
("PAP") remains below 20 mmHg, until pulmonary flow rate reaches a
target flow rate of at least 1.5 L/min. When the lung reaches a
temperature of about 30 degrees C. to about 32 degrees C., begin
OCS ventilation by turning the OCS ventilator 214 to "preservation"
mode. The ventilator settings for instrumentation and preservation
are specified in Table 1.
TABLE-US-00001 TABLE 1 Ventilator Settings (Instrumentation and
Preservation) Parameter Requirement Tidal Volume (TV) = or <6
ml/kg Respiratory Rate (RR) 10 breaths/min Positive End Expiratory
7-8 cm H.sub.2O Pressure (PEEP) Note: decrease to 5 cm H.sub.2O
after confirming adequate inflation of lungs (within 2 hours) I:E
Ratio 1:2-1:3 Peak Airway Pressure <25 cm H2O (PAWP)
[0069] Next, gradually increase the perfusion and ventilation rate
for up to about 30 minutes until reaching full ventilation and
perfusion and allow ventilation parameters to stabilize. Once
ventilation parameters of the donor lung on OCS have stabilized,
wrap the lung to avoid over inflation injury to the donor lung
ex-vivo. The lung may also be wrapped during "pause preservation"
before beginning ventilation. During preservation of lung on OCS,
ventilation settings are maintained as described in Table 1, the
mean PAP is maintained under about 20 mmHg, and the pump flow is
maintained at not less than about 1.5 L/min. Blood glucose,
electrolytes and pH levels are monitored and adjusted within normal
physiologic ranges by additional injections. Lung oxygenation
function may be assessed using the OCS lung system in addition to
lung compliance. In some instances it is desirable to provide
therapy to the lung as described previously. Fiberoptic
bronchoscopy may be performed for the donor lung ex-vivo on the OCS
device. Once preservation and assessment of the donor lung on the
OCS system is complete, the lung is cooled and removed from the OCS
system to be transplanted into the recipient.
[0070] Donor lung cooling may be achieved by first shutting off the
OCS pulsatile pump 226 and flush the donor lung with about 3 liters
of perfusion solution at a temperature of about 0 degrees C. to
about 15 degrees C. while continuing ventilation on the OCS system.
Once the flush is complete the trachea 700 and pulmonary artery 802
cannulae may be disconnected from the OCS and the lung will be
immersed in cold preservation solution until it is surgically
attached to the recipient (transplanted). Alternatively, the entire
system circulating OCS solution may be cooled down to 0 degrees C.
to about 15 degrees C. using a heat-exchanger and cooling device
while the lung is being ventilated on OCS. Once the target
temperature of about 0 degrees C. to about 15 is achieved, the
trachea 700 and pulmonary artery 802 cannulae will be disconnected
from the OCS and the lung will be immersed in cold preservation
solution until it is surgically attached to the recipient
(transplanted).
[0071] The described system may utilize any embodiment of the lung
OCS perfusion solution. In a preferred embodiment, the solution is
mixed with red blood cells and placed into a system reservoir for
use in the system.
[0072] It is to be understood that while the invention has been
described in conjunction with the various illustrative embodiments,
the forgoing description is intended to illustrate and not limit
the scope of the invention, which is defined by the scope of the
appended claims. For example, a variety of systems and/or methods
may be implemented based on the disclosure and still fall within
the scope of the invention. Other aspects, advantages, and
modifications are within the scope of the following claims. All
references cited herein are incorporated by reference in their
entirety and made part of this application.
* * * * *