Methods for treating patients who are candidates for inhaled nitric oxide treatment

• US 8,795,741 B2
• Filed: 11/21/2012
• Issued: 08/05/2014
• Est. Priority Date: 06/30/2009
• Status: Active Grant

• Current Assignee: Mallinckrodt Critical Care Finance Inc (Mallinckrodt plc), Mallinckrodt Pharma Ip Trading DAC (Mallinckrodt plc), Therakos, Inc (Mallinckrodt plc)
• Original Assignee: INO Therapeutics LLC (Mallinckrodt plc)
• Inventors: Baldassarre, James S.
• Primary Examiner(s): ARNOLD, ERNST V
• Application Number:
  US13/683,417
• Publication Number:
  US 20130078321A1
• Time in Patent Office: 622 Days
• Field of Search: None
• US Class Current: 424/718
• CPC Class Codes: A61B 5/02007 Evaluating blood vessel condition, e.g. elasticity, compliance
• CPC Class Codes: A61B 5/0205 Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
• CPC Class Codes: A61B 5/08 Detecting, measuring or recording devices for evaluating the respiratory organs A61B5/0205 takes precedence
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61B 5/7275 Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
• CPC Class Codes: A61B 5/7278 Artificial waveform generation or derivation, e.g. synthesising signals from measured signals A61B5/327 takes precedence
• CPC Class Codes: A61B 8/0883 for diagnosis of the heart
• CPC Class Codes: A61B 8/48 Diagnostic techniques A61B8/13 takes precedence
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61M 16/0057 Pumps therefor
• CPC Class Codes: A61M 16/104 specially adapted for anaesthetics A61M16/18 takes precedence
• CPC Class Codes: A61M 16/12 by mixing different gases
• CPC Class Codes: A61M 60/139 inside the aorta, e.g. intra-aortic balloon pumps
• CPC Class Codes: A61M 60/295 Balloon pumps for circulatory assistance
• CPC Class Codes: A61M 60/497 for balloon pumps for circulatory assistance
• CPC Class Codes: A61M 60/841 of balloon pumps for circulatory assistance
• CPC Class Codes: A61M 60/857 : Implantable blood tubes
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: F17C 2201/058 : portable (<30 l)
• CPC Class Codes: F17C 2203/0646 : Aluminium
• CPC Class Codes: F17C 2221/014 : Nitrogen
• CPC Class Codes: F17C 2221/03 : Mixtures
• CPC Class Codes: F17C 2223/0123 : gaseous, e.g. CNG, GNC
• CPC Class Codes: F17C 2223/036 : Very high pressure (>80 bar)
• CPC Class Codes: F17C 2270/025 : Breathing
• CPC Class Codes: G06Q 99/00 : Subject matter not provided for in other groups of this subclass
• CPC Class Codes: G16H 20/10 : relating to drugs or medications, e.g. for ensuring correct administration to patients

Abstract

Disclosed are methods of reducing the risk that a medical treatment comprising inhalation of nitric oxide gas will induce an increase in pulmonary capillary wedge pressure in the patient, leading to pulmonary edema.

Claims

1. A method of treating patients who are candidates for inhaled nitric oxide treatment, which method reduces the risk that inhalation of nitric oxide gas will induce an increase in pulmonary capillary wedge pressure (PCWP) leading to pulmonary edema in neonatal patients with hypoxic respiratory failure, the method comprising:

(a) identifying a plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment;

(b) determining that a first patient of the plurality does not have left ventricular dysfunction;

(c) determining that a second patient of the plurality has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide;

(d) administering 20 ppm inhaled nitric oxide treatment to the first patient; and

(e) excluding the second patient from treatment with inhaled nitric oxide, based on the determination that the second patient has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide.

2. The method of claim 1, wherein the first patient has congenital heart disease.

3. The method of claim 1, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

4. The method of claim 1, wherein the second patient is determined to be at particular risk not only of increased PCWP leading to pulmonary edema, but also of other serious adverse events, upon treatment with inhaled nitric oxide, and the second patient is excluded from inhaled nitric oxide treatment based on the determination that the second patient has left ventricular dysfunction and so is at particular risk not only of increased PCWP leading to pulmonary edema, but also other serious adverse events, upon treatment with inhaled nitric oxide.

5. The method of claim 4, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

6. The method of claim 1, wherein determining that the first patient does not have pre-existing left ventricular dysfunction and the second patient does have pre-existing left ventricular dysfunction comprises performing at least one diagnostic process on each of the first and second patients.

7. The method of claim 1, wherein determining that the first patient does not have pre-existing left ventricular dysfunction and the second patient does have pre-existing left ventricular dysfunction comprises performing echocardiography on the first and second patients.

8. The method of claim 1, wherein the second patient has a PCWP that is greater than or equal to 20 mm Hg.

31. The method of claim 1, wherein identifying the plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment comprises performing at least one diagnostic process.

9. A method of treating patients who are candidates for inhaled nitric oxide treatment, which method reduces the risk that inhalation of the nitric oxide gas will induce an increase in PCWP leading to pulmonary edema in neonatal patients with hypoxic respiratory failure, said method comprising:

(a) identifying a plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment;

(b) determining that a first patient of the plurality does not have left ventricular dysfunction;

(c) determining that a second patient of the plurality has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide;

(d) administering 20 ppm inhaled nitric oxide treatment to the first patient; and

(e) excluding the second patient from treatment with inhaled nitric oxide based on the determination in (c), or, despite the second patient'"'"'s ongoing need for inhaled nitric oxide treatment for hypoxic respiratory failure, discontinuing the second patient'"'"'s treatment with inhaled nitric oxide after it was begun, the discontinuation being in view of the determination in (c).

10. The method of claim 9, wherein the discontinuation is in view of both the determination in (c) and the second patient'"'"'s experiencing an adverse event upon treatment with inhaled nitric oxide.

11. The method of claim 10, wherein the adverse event comprises pulmonary edema.

12. The method of claim 10, wherein the adverse event comprises at least one of increased PCWP, systemic hypotension, bradycardia, or cardiac arrest.

13. The method of claim 9, wherein (c) comprises determining that the second patient has a pulmonary capillary wedge pressure that is greater than or equal to 20 mm Hg.

14. The method of claim 9, wherein the first patient has congenital heart disease.

15. The method of claim 9, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

16. The method of claim 14, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

17. The method of claim 9, wherein

the second patient is determined to be at particular risk not only of increased PCWP leading to pulmonary edema, but also of other serious adverse events, upon treatment with inhaled nitric oxide;

and

either (i) the second patient is excluded from inhaled nitric oxide treatment based on both the determination in (c) and the determination that the second patient is also at risk of other serious adverse events upon treatment with inhaled nitric oxide;

or (ii) despite the second patient'"'"'s ongoing need for inhaled nitric oxide treatment for hypoxic respiratory failure, the second patient'"'"'s treatment with inhaled nitric oxide is discontinued after it was begun, the discontinuation being in view of both the determination in (c) and the determination that the second patient is also at risk of other serious adverse events upon treatment with inhaled nitric oxide.

18. The method of claim 17, wherein the other serious adverse events comprise one or more of increased PCWP, systemic hypotension, bradycardia, or cardiac arrest.

19. The method of claim 17, wherein the discontinuation is in view of:

the determination in (c), the determination that the second patient is also at risk of other serious adverse events, and the second patient'"'"'s experiencing an adverse event upon treatment with inhaled nitric oxide.

20. The method of claim 19, wherein the adverse event experienced by the second patient comprises pulmonary edema.

21. The method of claim 19, wherein the adverse event experienced by the second patient comprises at least one of increased PCWP, systemic hypotension, bradycardia, or cardiac arrest.

22. The method of claim 9, wherein determining that the first patient does not have pre-existing left ventricular dysfunction and the second patient does have pre-existing left ventricular dysfunction comprises performing at least one diagnostic process on each of the first and second patients.

23. The method of claim 9, wherein determining that the first patient does not have pre-existing left ventricular dysfunction and the second patient does have pre-existing left ventricular dysfunction comprises performing echocardiography on each of the first and second patients.

32. The method of claim 9, wherein identifying the plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment comprises performing at least one diagnostic process.

24. A method of treating patients who are candidates for inhaled nitric oxide treatment, which method reduces the risk of inducing an increase in PCWP leading to pulmonary edema in neonatal patients with hypoxic respiratory failure, the method comprising:

(a) identifying a plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment;

(b) determining that a first patient of the plurality does not have pre-existing left ventricular dysfunction;

(c) administering a first treatment regimen to the first patient, wherein the first treatment regimen comprises administration of 20 ppm inhaled nitric oxide for 14 days or until the first patient'"'"'s hypoxia has resolved;

(d) determining that a second patient of the plurality has pre-existing left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide; and

(e) administering a second treatment regimen to the second patient, wherein the second treatment regimen does not comprise either (i) administration of inhaled nitric oxide for 14 days or (ii) administration of inhaled nitric oxide until the second patient'"'"'s hypoxia has resolved.

25. The method of claim 24, wherein the second treatment regimen does not comprise administration of inhaled nitric oxide.

26. The method of claim 24, wherein the second treatment regimen comprises beginning administration of inhaled nitric oxide but discontinuing the administration upon determination that inhaling nitric oxide has increased the second patient'"'"'s PCWP and/or induced pulmonary edema in the second patient.

27. The method of claim 24, wherein the first patient has congenital heart disease.

28. The method of claim 24, wherein the pre-existing left ventricular dysfunction of the second patient is attributable to congenital heart disease.

29. The method of claim 24, wherein the diagnostic process comprises echocardiography.

30. The method of claim 24, wherein the second patient has a pulmonary capillary wedge pressure that is greater than or equal to 20 mm Hg.

33. The method of claim 24, wherein identifying the plurality of term or near-term neonatal patients who have hypoxic respiratory failure and are candidates for 20 ppm inhaled nitric oxide treatment comprises performing at least one diagnostic process.

34. A method of treating patients who are candidates for inhaled nitric oxide treatment, which method reduces the risk that inhalation of nitric oxide gas will induce an increase in pulmonary capillary wedge pressure (PCWP) leading to pulmonary edema, the method comprising:

(a) identifying a plurality of patients who are children with a condition that makes them candidates for 20 ppm inhaled nitric oxide treatment;

(b) determining that a first patient of the plurality does not have left ventricular dysfunction;

(c) determining that a second patient of the plurality has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide;

(d) administering 20 ppm inhaled nitric oxide treatment to the first patient; and

(e) excluding the second patient from treatment with inhaled nitric oxide, based on the determination that the second patient has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide.

35. The method of claim 34, wherein the second patient is determined to be at particular risk not only of increased PCWP leading to pulmonary edema, but also of other serious adverse events, upon treatment with inhaled nitric oxide, and the second patient is excluded from inhaled nitric oxide treatment based on the determination that the second patient has left ventricular dysfunction and so is at particular risk not only of increased PCWP leading to pulmonary edema, but also other serious adverse events, upon treatment with inhaled nitric oxide.

36. The method of claim 34, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

37. A method of treating patients who are candidates for inhaled nitric oxide treatment, which method reduces the risk that inhalation of the nitric oxide gas will induce an increase in PCWP leading to pulmonary edema in neonatal patients with hypoxic respiratory failure, said method comprising:

(a) identifying a plurality of patients who are children with a condition that makes them candidates for 20 ppm inhaled nitric oxide treatment;

(b) determining that a first patient of the plurality does not have left ventricular dysfunction;

(c) determining that a second patient of the plurality has left ventricular dysfunction, so is at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide;

(d) administering 20 ppm inhaled nitric oxide treatment to the first patient; and

(e) excluding the second patient from treatment with inhaled nitric oxide based on the determination in (c), or, despite the second patient'"'"'s ongoing need for inhaled nitric oxide treatment for hypoxic respiratory failure, discontinuing the second patient'"'"'s treatment with inhaled nitric oxide after it was begun, the discontinuation being in view of the determination in (c).

38. The method of claim 37, wherein the discontinuation is in view of both the determination in (c) and the second patient'"'"'s experiencing an adverse event upon treatment with inhaled nitric oxide.

39. The method of claim 38, wherein the adverse event comprises pulmonary edema.

40. The method of claim 38, wherein the adverse event comprises at least one of increased PCWP, systemic hypotension, bradycardia, or cardiac arrest.

41. The method of claim 37, wherein the left ventricular dysfunction of the second patient is attributable to congenital heart disease.

42. The method of claim 37, wherein

the second patient is determined to be at particular risk not only of increased PCWP leading to pulmonary edema, but also of other serious adverse events, upon treatment with inhaled nitric oxide;

and

either (i) the second patient is excluded from inhaled nitric oxide treatment based on both the determination in (c) and the determination that the second patient is also at risk of other serious adverse events upon treatment with inhaled nitric oxide;

or (ii) despite the second patient'"'"'s ongoing need for inhaled nitric oxide treatment for hypoxic respiratory failure, the second patient'"'"'s treatment with inhaled nitric oxide is discontinued after it was begun, the discontinuation being in view of both the determination in (c) and the determination that the second patient is also at risk of other serious adverse events upon treatment with inhaled nitric oxide.

43. The method of claim 42, wherein the other serious adverse events comprise one or more of increased PCWP, systemic hypotension, bradycardia, or cardiac arrest.

44. The method of claim 42, wherein the discontinuation is in view of:

the determination in (c), the determination that the second patient is also at risk of other serious adverse events, and the second patient'"'"'s experiencing an adverse event upon treatment with inhaled nitric oxide.