METHODS OF ADMINISTERING NITRIC OXIDE TO ARTERIAL OR ARTERIALIZED BLOOD

Abstract

The present invention provides methods of administering nitric oxide (NO) to a patient, the method comprising delivering nitric oxide-containing gas directly into arterial or arterialized blood. The methods of the present invention may be used in the treatment or prevention of a variety of diseases and disorders responsive to nitric oxide, including those resulting from ischemia or hypoxia.

Claims

1. A method of treating a disease, disorder or condition responsive to nitric oxide in a patient in need thereof, comprising: oxygenating withdrawn blood through an oxygen permeable membrane of an oxygen transfer unit within an oxygenation compartment of an extracorporeal membrane oxygenation system (ECMO) to produce arterialized blood; administering a therapeutically effective amount of nitric oxide (NO)-containing gas directly into the oxygenated blood of the patient through an NO permeable membrane of an NO transfer unit of a gas transfer unit downstream of the oxygen transfer unit; and infusing the blood produced in step b) into the patient.

2. The method of claim 1, wherein the blood is infused into the patient via an arterial cannula.

3. The method of claim 1, wherein any remaining oxygen is removed from the oxygen transfer unit though an oxygen venting device and any remaining NO is removed from the NO transfer unit through an NO venting device.

4. The method of claim 1, wherein the administration is a bolus administration of the nitric oxide-containing gas.

5. The method of claim 1, wherein a delivery concentration of nitric oxide-containing gas is in a range of 0.1-500 ppm.

6. The method of claim 1, wherein the administration is a continuous administration.

7. The method of claim 1, wherein the treated disease, disorder or condition is ischemia or hypoxia.

8. The method of claim 1 wherein the nitric oxide-containing gas is administered before onset of the disease, disorder or condition.

9. The method of claim 1 wherein the nitric oxide-containing gas is administered after onset of the disease, disorder or condition.

10. The method of claim 1, wherein the NO transfer unit is inside the oxygenation compartment.

11. The method of claim 1, wherein the NO transfer unit is outside the oxygenation compartment.

12. The method of claim 1 further comprising: introducing the oxygen into the oxygen transfer unit from an oxygen source in fluid communication with the oxygen transfer unit through an inlet in the oxygen transfer unit; and introducing the NO into the NO transfer unit from a NO delivery device in fluid communication with the NO transfer unit through an inlet in the NO transfer unit.

13. The method of claim 12 further comprising generating and/or storing NO in a NO generator/reservoir connected to the NO delivery device.

14. An extracorporeal membrane oxygenation (ECMO) system comprising: a chamber, wherein blood enters an oxygenation compartment though an inlet in the chamber; an oxygen transfer unit having an oxygen permeable membrane, wherein the oxygen transfer unit is within the oxygenation compartment; and a nitric oxide (NO) transfer unit having an NO permeable membrane, wherein the oxygen transfer unit is separated from an upstream portion of the chamber by the oxygen permeable membrane which exchanges oxygen for carbon dioxide in the blood to produce arterialized blood, and the NO transfer unit is separated from a downstream portion of the chamber by the NO permeable membrane which exchanges NO for oxygen in the arterialized blood.

15. The ECMO system of claim 14 further comprising an oxygen venting device in fluid communication with the oxygen transfer unit through an outlet of the oxygen transfer unit operable to receive any remaining oxygen and an NO venting device in fluid communication with the NO transfer unit through the outlet of the NO transfer unit operable to receive any remaining NO.

16. The ECMO system of claim 14, wherein the NO transfer unit is inside the oxygenation compartment.

17. The ECMO system of claim 14, wherein the NO transfer unit is outside the oxygenation compartment.

18. The ECMO system of claim 14 further comprising: an oxygen source in fluid communication with the oxygen transfer unit through an inlet in the oxygen transfer unit; and an NO delivery device in fluid communication with the NO transfer unit through an inlet in the NO transfer unit.

19. The ECMO system of claim 18 further comprising a NO generator/reservoir connected to the NO delivery device for generating and/or holding the NO.

20. The ECMO system of claim 18, wherein the NO delivery device is a metering device, an injector or a pump.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0024] FIG. 1 illustrates a nitric oxide delivery system that can be used in accordance with one or more embodiments of the invention.

[0025] FIG. 2 illustrates a first embodiment of the oxygenation compartment of an ECMO device.

[0026] FIG. 3 illustrates an alternative embodiment of the oxygenation compartment of an ECMO device.

[0027] FIG. 4 illustrates a further alternative embodiment of the oxygenation compartment and NO delivery system of an ECMO device.

DETAILED DESCRIPTION OF THE INVENTION

[0028] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0029] The term arterialized blood refers to venous blood which has been converted to arterial blood by absorption of oxygen and excretion of CO.sub.2 Such conversion may be accomplished in vivo (e.g., by absorption of oxygen in the lungs) or ex vivo (e.g., by extracorporeal oxygenation).

[0030] The term arterial blood refers to oxygenated blood in the arterial circulation of the body.

[0031] The term biological material refers to any living biological material, including cells, tissues, organs, and/or organisms. It is contemplated that the methods of the present invention may be practiced on a part of an organism (such as in cells, in tissue, and/or in one or more organs), or on the whole organism. The term in vivo biological material refers to biological material that is in vivo, i.e., still within or attached to an organism.

[0032] Therapeutically effective amount refers to that amount of NO gas that, when administered via arterial or arterialized blood to a subject, preferably a human, is sufficient to effect treatment as defined herein. The amount of a compound of the invention which constitutes a therapeutically effective amount will vary depending on the compound, the condition and its severity, and the manner of administration, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0033] Treating or treatment as used herein covers the treatment of the disease or condition of interest in a subject, preferably a human, having the disease or condition of interest, and includes: (i) preventing the disease or condition from occurring in the subject, (ii) inhibiting the disease or condition, i.e., arresting its progression; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition. As used herein, the terms disease, disorder, and condition may be used interchangeably.

[0034] Delivery concentration refers to the concentration of NO gas in a composition of NO-containing gas for medical use which is delivered to arterial or arterialized blood. In addition to NO gas, such compositions for medical use may further comprise an inert diluent gas. It is to be understood that the delivery concentration will be diluted upon contact with blood, where it is mixed and distributed to the target biological material.

[0035] Prior to the present invention, NO was thought to react with oxyhemoglobin to form methemoglobin and nitrate or heme iron nitrosyl Hb, and thereby lose all vasodilating properties. However, it has been found that a stable derivate that retains vasodilatory properties is formed by a reaction resulting in nitrosylation of a conserved cysteine residue of the 13 subunit of Hb: S-nitrosylated-Hb (SNO-Hb). This reaction is favored in the presence of oxyhemoglobin whereas the prior reaction is favored in the deoxygenated state. Thus the present invention provides methods that maximize the formation of SNOHb, thereby maximizing the systemic effects of NO.

[0036] One aspect of the current invention relates to a method of delivering nitric oxide (NO) to a patient comprising administering NO-containing gas directly into arterial or arterialized blood, the administered gas having a delivery concentration of 0.01 to 10 ppm NO. In certain embodiments, the delivery concentration is in the range of 10 to 40 ppm. According to one or more embodiments, the delivery concentration is in the range of 40 to 100 ppm. In other embodiments, the delivery concentration is greater than 100 ppm.

[0037] In one embodiment, the NO-containing gas is administered continuously, for example by continuous infusion.

[0038] In another embodiment, the NO-containing gas is delivered as a bolus rather than via a continuous administration method. A bolus refers to a single administration delivered over a short period of time, for example by injection from a syringe. Multiple bolus administrations may be given to the subject, each separated by a period of time.

[0039] In another embodiment, the NO-containing gas is delivered in a pulse as opposed to continuous administration. A pulse refers to multiple short administrations within a time period.

[0040] In an additional embodiment, a device can monitor the arterial or arterialized blood and administer the NO-containing gas at any delivery rate or concentration as necessary to provide sufficient results. Administration can automatically or manually adjust or otherwise change the flow, concentration or amount of NO during the course of delivery.

[0041] The present invention includes improved methods of systemically treating diseases and disorders with nitric oxide, which comprise administering nitric oxide gas directly into arterial or arterialized blood. Further, the present invention provides improved methods of enhancing cell survival, inducing stasis, or protecting cells or tissue from injury due to hypoxia or ischemia, which comprise administering NO-containing gas directly to arterial or arterialized blood. The invention further includes methods and devices for the preparation and administration of NO-containing gas to a subject via arterial or arterialized blood. Without wishing to be bound by any particular theory, it may be that administration of NO gas directly to oxygenated blood (e.g., after blood passes through an extracorporeal oxygenation system) or directly through an arterial catheter or intra-arterial injection will maximize the formation of SNO-Hb and thus maximize the systemic effects.

[0042] In certain embodiments, methods, compositions, and devices of the present invention are used to systemically treat or prevent any of a variety of diseases and disorders that benefit from treatment with nitric oxide. In particular embodiments, the methods of the present invention may be used to modulate biological pathways regulated or affected by nitric oxide.

[0043] Nitric oxide mediates blood pressure (causing vasodilation), learning and memory, immune responses and inflammatory responses. Accordingly, diseases, disorders or conditions potentially treatable by systemic administration of NO gas directly into arterial or arterialized blood according to the invention include respiratory, cardiovascular, pulmonary, and blood diseases, disorders or conditions, as well as hypoxemia, tumors, infections, inflammation, shock, sepsis and stroke. In specific examples, respiratory distress syndrome, asthma, bronchospastic disease, myocardial infarction, hemorrhage, sickle cell disease, platelet aggregation and major surgery may be treatable according to the methods of the invention. Further specific examples include pulmonary hypertension and hypoxemia following cardiopulmonary bypass, mitral valve replacement, heart or lung transplantation, and pulmonary embolism.

[0044] Systemic administration of nitric oxide gas into arterial or arterialized blood may be useful in suppressing, killing, and inhibiting pathogenic cells, such as tumor cells, cancer cells, or microorganisms, including but not limited to pathogenic bacteria, pathogenic mycobacteria, pathogenic parasites, and pathogenic fungi. Examples of microorganisms include those associated with a respiratory infection within the respiratory tract.

[0045] Systemic administration of nitric oxide gas into arterial or arterialized blood may enhance the survivability of biological materials, including, e.g., organs and tissues, that are subjected to ischemic or hypoxic conditions. In related embodiments, the present invention provides methods of preventing or reducing damage to biological materials, including, e.g., including cell, organ or tissue injuries resulting from ischemia or hypoxia. It is understood that a whole biological material or only a portion thereof, e.g., a particular organ, may be subjected to ischemic or hypoxic conditions.

[0046] The ischemic or hypoxic conditions may be the result of an injury or disease suffered by an organism. Examples of specific diseases that can induce ischemia or hypoxia include, but are not limited to, traumatic injury or surgery, respiratory or cardiac arrest, tumors, heart diseases, and neurological diseases. Examples of specific injuries that can result in ischemic or hypoxic conditions include, but are not limited to, external insults, such as burns, cutting wounds, amputations, gunshot wounds, or surgical trauma. In addition, injuries can also include internal insults, such as stroke or heart attack, which result in the acute reduction in circulation. Other injuries include reductions in circulation due to non-invasive stress, such as exposure to cold or radiation, or a planned reduction in circulation, e.g., during heart surgery.

[0047] In certain embodiments, methods of the present invention include systemically administering NO-containing gas directly into arterial or arterialized blood prior to development of a disease, disorder or condition treatable with NO gas, e.g., prior to an ischemic or hypoxic injury or disease insult. Examples of such situations include, but are not limited to, major surgery where blood loss may occur spontaneously or as a result of a procedure, cardiopulmonary bypass in which oxygenation of the blood may be compromised or in which vascular delivery of blood may be reduced (as in the setting of coronary artery bypass graft (CABG) surgery), or in the treatment of organ donors prior to removal of donor organs for transport and transplantation into a recipient. Other examples include, but are not limited to, medical conditions in which a risk of injury or disease progression is inherent (e.g., in the context of unstable angina, following angioplasty, bleeding aneurysms, hemorrhagic strokes, following major trauma or blood loss).

[0048] In certain embodiments, methods of the present invention include systemically administering NO-containing gas directly into arterial or arterialized blood after development or onset of a disease, disorder or condition treatable with NO, e.g., after an ischemic or hypoxic injury or disease insult, or after onset any of the diseases, disorders or conditions discussed above. In a particular aspect of such embodiments, NO-containing gas may be administered to a patient suffering from the disease, disorder or condition upon recognition or diagnosis of the disease, disorder or condition.

[0049] In certain embodiments, inflammatory-related diseases or disorders may be treated by administration of NO-containing gas directly into arterial or arterialized blood. Inflammatory-related diseases or disorders which may be treatable by the methods of the present invention include, e.g., multiple sclerosis, arthritis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, diabetes, psoriasis, progressive systemic sclerosis, scleroderma, acute coronary syndrome, Crohn's Disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, and inflammatory autoimmune myositis.

[0050] In a specific embodiment, the methods of the invention comprise administration of NO-containing gas directly into arterialized blood in an extracorporeal oxygenation system. The extracorporeal oxygenation system may be, for example, an extracorporeal membrane oxygenation system or a CPB circuit. In such methods the NO-containing gas is administered into the blood at any point in the system which is after oxygenation of the withdrawn blood. An example of CPB system 20 according to the invention is illustrated in FIG. 1.

[0051] Venous blood is withdrawn from the patient through venous cannula 20, which may be inserted in the right atrium, vena cava or femoral vein. Withdrawn venous blood is collected in reservoir 11 and circulated into oxygenator 13 by pump 12, where it is oxygenated and typically cooled by heat exchanger 14 to slow the body's basal metabolism during bypass surgery. The oxygenated blood is generally filtered through filter 15 prior to return to the body via arterial cannula 16, which may be inserted in the ascending aorta or the femoral artery. NO-containing gas may be introduced into the CBP circuit via NO delivery device 18 which is and in fluid communication with NO generating device/NO reservoir 17 and with CBP system 20 downstream of oxygenator 13. NO-containing gas may be introduced into the CBP circuit at any point after oxygenator 13 for return to the arterial circulation. In the CBP circuit illustrated in FIG. 1, this includes introduction between oxygenator 13 and filter 15 (as shown) or between filter 15 and arterial cannula 16 (not shown). Alternatively, NO-containing gas may be introduced into the CBP circuit in oxygenator 13, provided blood is oxygenated prior to contact with the NO-containing gas within oxygenator 13.

[0052] In a further aspect, the invention provides extracorporeal oxygenation systems which comprise a component for introduction of NO-containing gas into oxygenated (arterialized) blood prior to infusion into the body of a patient. Such structure of such apparati are generally as described above, with the addition of a device for introduction of NO-containing gas into the portion of the circuit which contains arterialized blood. The device for introduction of NO-containing gas into oxygenated blood prior to infusion may comprise a container, gas cylinder or receptacle for holding or locally generating the NO-containing gas, referred to as an NO generator/receptacle. The device for introduction of the NO-containing gas into the arterialized blood will typically include a pump, injector or metering device to facilitate delivery of the NO-containing gas into the oxygenated blood of the extracorporeal circuit for return to the patient, referred to as an NO delivery device.

[0053] Extracorporeal oxygenation systems are simplified CBP circuits which provide cardiac and respiratory support oxygen to patients. In these systems venous blood is withdrawn from the patient, oxygenated outside of the body, and returned either via the arterial system or the venous system. A typical extracorporeal oxygenation system uses a membrane oxygenator and is referred to as an extracorporeal membrane oxygenation (ECMO) system. The system comprises a venous cannula typically placed in the right common femoral vein for extraction and an arterial cannula placed either into the right femoral artery (veno-arterial ECMO) or the right internal jugular vein (veno-venous ECMO) for infusion. In the methods of the invention, to obtain direct administration of NO-containing gas into arterialized blood, the NO-containing gas is introduced into the withdrawn blood at any point between the oxygenator and the venous or arterial infusion cannula. Alternatively, NO-containing gas may be introduced into the withdrawn blood in the oxygenator, provided blood is oxygenated prior to contact with the NO-containing gas within the oxygenator.

[0054] In a particular embodiment, the NO-containing gas is administered via a device, for example an ECMO device. The NO-containing gas may be administered within the oxygenation compartment of the device, wherein the oxygenation compartment contains two components. The first component is a first gas exchange membrane (also referred to as a membrane oxygenator) which exchanges oxygen for CO.sub.2 in blood to produce arterialized blood. The second component is a second gas exchange membrane which exchanges NO for O.sub.2 in the arterialized blood. The first and second components can be either structurally separate components in fluid communication or combined as one structure containing separate reaction areas within the oxygenation compartment. In either case, the second component is down-stream of the first component, as defined by the direction of blood flow in the device. Thus, NO-containing gas is administered either into the oxygenation compartment after O.sub.2 has been administered into the oxygenation compartment and after CO.sub.2 has been released, or NO is administered downstream of the oxygenation compartment (after blood has left the oxygenator but before it is delivered back into the patient) or both.

[0055] FIG. 2 illustrates oxygenation compartment 113 of an ECMO device, wherein oxygenation of blood and delivery of NO both occur within gas transfer unit 121. In this embodiment, blood enters oxygenation compartment 113 through inlet 127, flows into chamber 123, and exits oxygenation compartment 113 through outlet 126. Chamber 123 is in contact with gas permeable membrane 124 of gas transfer unit 121. Oxygen source 125 is also in fluid communication with gas transfer unit 121 through inlet 131. As blood enters the upstream portion of chamber 123, oxygen introduced into gas transfer unit 121 from oxygen source 125 diffuses through gas permeable membrane 124 into the blood, exchanging oxygen for CO.sub.2. The portion of gas transfer unit 121 downstream of inlet 131 is in fluid communication with NO delivery device 118, through inlet 132. NO delivery device 118 is in fluid communication with NO generator/reservoir 117 to deliver NO to gas transfer unit 121. As the oxygenated blood in chamber 123 comes into contact with gas permeable membrane 124 downstream of inlet 131, NO introduced into gas transfer unit 121 through inlet 132 diffuses through gas permeable membrane 124 into the oxygenated blood, exchanging NO for oxygen. After delivery of oxygen and NO to the blood, remaining oxygen and NO may be removed from gas transfer unit 121 to venting device 122 via outlet 133 in fluid communication with gas transfer unit 121.

[0056] FIG. 3 illustrates oxygenation compartment 113 of an ECMO device, wherein oxygenation of blood and delivery of NO occur within structurally separate components 221 and 229 of oxygenation compartment 213. In this embodiment, blood enters oxygenation compartment 213 through inlet 227, flows into chamber 223, and exits oxygenation compartment 213 through outlet 226. Chamber 223 is in contact with oxygen permeable membrane 224 of oxygen transfer unit 221. Oxygen source 225 is also in fluid communication with oxygen transfer unit 221 through inlet 231. As blood enters the upstream portion of chamber 223, oxygen introduced into oxygen transfer unit 221 from oxygen source 225 diffuses through oxygen permeable membrane 224 into the blood, exchanging oxygen for CO.sub.2. Downstream of inlet 231, remaining oxygen may be removed from oxygen transfer unit 221 to oxygen venting device 222 via outlet 233 in fluid communication with oxygen transfer unit 221. The downstream portion of chamber 223 is in contact with NO permeable membrane 230 of NO transfer unit 229. NO delivery device 218 is also influid communication with NO transfer unit 229 through inlet 232. NO delivery device 218 is in fluid communication with NO generator/reservoir 217 to deliver NO to NO chamber 229. As oxygenated blood flows to the downstream portion of chamber 223, it comes into contact with NO permeable membrane 230 of NO transfer unit 229, and NO introduced into NO transfer unit 229 through inlet 232 diffuses into the oxygenated blood, exchanging NO for oxygen. After delivery of NO to the blood, remaining NO may be removed from NO transfer unit 229 to NO venting device 228 via outlet 234 in fluid communication with NO transfer unit 229.

[0057] FIG. 4 illustrates oxygenation compartment 313 of an ECMO device, wherein oxygenation of blood occurs within oxygenation compartment 313 and delivery of NO to the blood occurs downstream of and outside oxygenation compartment 313. In this embodiment, blood enters oxygenation compartment 313 through inlet 327, flows into chamber 323, and exits oxygenation compartment 313 through outlet 326. Chamber 323 is in contact with oxygen permeable membrane 324 of oxygen transfer unit 321 within oxygenation compartment 313. Oxygen source 325 is also in fluid communication with oxygen transfer unit 321 through inlet 331. As blood enters the upstream portion of chamber 323, oxygen introduced into oxygen transfer unit 321 from oxygen source 325 diffuses through oxygen permeable membrane 324 into the blood, exchanging oxygen for CO.sub.2. Downstream of inlet 331, remaining oxygen may be removed from oxygen transfer unit 321 to oxygen venting device 322 via outlet 333 in fluid communication with oxygen transfer unit 321. The downstream portion of chamber 323 is in contact with NO permeable membrane 330 of NO transfer unit 329, which is outside oxygenation compartment 313. NO delivery device 318 is also influid communication with NO transfer unit 329 through inlet 332. NO delivery device 318 is in fluid communication with NO generator/reservoir 317 to deliver NO to NO chamber 329. As oxygenated blood exits oxygenation compartment 313 and flows to the downstream portion of chamber 323, it comes into contact with NO permeable membrane 330 of NO transfer unit 329, and NO introduced into chamber 329 through inlet 332 diffuses into the oxygenated blood, exchanging NO for oxygen. After delivery of NO to the blood, remaining NO may be removed from NO transfer unit 329 to NO venting device 328 via outlet 334 in fluid communication with NO transfer unit 329.

[0058] The NO-containing gas may be administered in the oxygenator after the blood has been partially oxygenated or fully oxygenated and may be administered separately from the addition of the oxygen. The NO-containing gas is typically administered after O.sub.2 administration and CO.sub.2 release.

[0059] In various embodiments, methods of the present invention include delivery of NO-containing gas directly into arterial blood by injection, catheterization, infusion, or continuous infusion into an artery, for example, a central or peripheral artery (e.g., the aorta, femoral, brachial, radial, ulnar, dorsalis pedis, etc.).

[0060] Reference throughout this specification to one embodiment, certain embodiments, one or more embodiments or an embodiment means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases such as in one or more embodiments, in certain embodiments, in one embodiment or in an embodiment in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0061] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention include modifications and variations that are within the scope of the appended claims and their equivalents.