Compositions, apparatus and methods for facilitating surgical procedures

• US 6,060,454 A
• Filed: 08/07/1998
• Issued: 05/09/2000
• Est. Priority Date: 08/08/1997
• Status: Expired due to Term

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Duhaylongsod, Francis G.
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US09/131,075
• Time in Patent Office: 641 Days
• Field of Search: 607/4, 607/9, 607/11, 607/16, 607/17, 607/27, 607/28, 607/35, 600/16, 600/17, 604/246, 514/26, 514/46, 514/211, 514/231.5, 514/235.8, 514/236.8, 514/258, 514/245, 514/299, 514/304, 514/305, 514/306, 514/315, 514/331, 514/346, 514/350, 514/351, 514/356 , 514/357, 514/358, 514/397, 514/416, 514/468, 514/475, 514/506, 514/512, 514/513, 514/520, 514/534, 514/538, 514/540, 514/546, 514/549, 514/551, 514/601, 514/602 , 514/603, 514/608, 514/605, 514/617, 514/619, 514/620, 514/622, 514/627, 514/646, 514/649, 514/651, 514/652, 514/653, 514/671
• US Class Current: 514/26
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61M 2210/125 Heart
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

Methods are provided for conducting surgical procedures in a patient wherein, during the surgical procedure, autonomous ventricular electrical conductivity and escape beats are reversibly and transiently suppressed to facilitate the surgical procedure. Also provided are compositions which are capable of inducing ventricular asystole in a patient. The compositions may include an AV node blocker. In one embodiment, compositions including an atrioventricular (AV) node blocker and a β-blocker are provided, wherein the β-blocker is present in an amount sufficient to substantially reduce the amount of AV node blocker required to induce ventricular asystole in the patient. The compositions and methods may be used for inducing temporary ventricular asystole in a beating heart, and to facilitate the performance of a variety of surgical techniques, including minimally invasive microsurgical techniques. Methods for performing a surgical procedure on a human patient are provided wherein a composition capable of inducing transient reversible ventricular asystole is administered to the heart, for example by intracoronary injection. The heart then is electrically paced using an electrical pacing system, thereby to maintain the patient'"'"'s blood circulation. The electrical pacing then is selectively intermittently stopped to allow ventricular asystole to occur, and the steps of the surgical or therapeutic procedure, such as suturing, are conducted during the time that the electrical pacing is intermittently stopped. The methods and compositions advantageously may be used in a range of different surgical procedures including cardiac, vascular and neurosurgical procedures.

Claims

1. A method of inducing reversible ventricular asystole in a beating heart in a human patient, the method comprising administering a compound capable of inducing reversible ventricular asystole and a β

-blocker to the heart of the patient in an amount effective to induce ventricular asystole, while maintaining the ability of the heart to be electrically paced;

wherein the β

-blocker is administered in amount sufficient to substantially reduce the amount of compound required to induce ventricular asystole.

2. The method of claim 1 wherein the compound is an atrioventricular (AV) node blocker.

3. The method according to claim 2, wherein the β

-blocker is administered in an amount sufficient to reduce the amount of AV node blocker, which is required to induce ventricular asystole, to about 50% or less by weight of the amount of AV node blocker alone required to induce ventricular asystole.

4. The method according to claim 1, wherein the compound is a cholinergic receptor agonist.

5. The method according to claim 4, wherein the cholinergic receptor agonist is carbachol.

6. The method according to claim 4, wherein the cholinergic receptor agonist is selected from the group consisting of bethanechol, arecoline, norarecoline, and neostigmine.

7. The method according to claim 5, wherein the carbachol is administered in an amount of about 0.1 to 4.8 μ

g/kg body weight/min.

8. The method according to claim 1, wherein the β

-blocker is propranolol.

9. The method according to claim 8, wherein the propranolol is administered in an amount of about 0.01 to 0.07 mg/kg body weight.

10. The method according to claim 1, wherein the β

-blocker is selected from the group consisting of atenolol, acebutolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, celiprolol, betaxolol, bevantolol, bisoprolol, esmolol, alprenolol, carterolol, nadolol and teratolol.

11. The method according to claim 2, wherein the β

-blocker is propranolol and the AV node blocker is carbachol, and wherein the propranolol is administered prior to or during administration of the carbachol.

12. The method according to claim 11, wherein the propranolol and the carbachol are administered to the right or left coronary artery of the patient.

13. A method of inducing reversible ventricular asystole in a beating heart in a human patient, the method comprising administering a cholinergic receptor agonist and a β

-blocker to the heart of the patient in an amount effective to induce ventricular asystole, while maintaining the ability of the heart to be electrically paced;

wherein the amount administered of the cholinergic receptor agonist alone or the β

-blocker alone is not sufficient to induce ventricular asystole.

14. A method of conducting a procedure on a human patient comprising:

administering a β

-blocker and an AV node blocker to the heart of a human patient to induce reversible ventricular asystole while maintaining the ability of the heart to be electrically paced;

electrically pacing the heart;

selectively intermittently stopping the electrical pacing to allow ventricular asystole; and

conducting at least one step of the procedure during the time that the electrical pacing is intermittently stopped.

15. The method according to claim 14 wherein the β

-blocker is administered prior to the AV node blocker.

16. The method according to claim 14, wherein the AV node blocker is carbachol.

17. The method according to claim 14 wherein the the β

-blocker is administered in an amount sufficient to substantially reduce the amount of AV node blocker required to induce ventricular asystole.

18. The method according to claim 14 wherein the β

-blocker is administered in an amount which reduces the amount of the AV node blocker required to induce ventricular asystole, to about 50% or less by weight of the amount of the AV node blocker alone required to induce ventricular asystole.

19. The method according to claim 17, wherein the β

-blocker is administered prior to the AV node blocker.

20. The method according to claim 14, wherein the procedure is a cardiac surgical procedure.

21. The method according to claim 20, wherein the electrical pacing is selectively intermittently interrupted by a surgeon conducting the procedure by selectively manipulating a control that is operatively coupled to and remote from the electrical pacing system.

22. The method according to claim 14, wherein the AV node blocker is a cholinergic receptor agonist.

23. The method according to claim 22, wherein the cholinergic receptor agonist is selected from the group consisting of bethanechol, arecoline, norarecoline, and neostigmine.

24. The method according to claim 22 wherein the amount of the cholinergic receptor agonist administered alone or the β

-blocker administered alone is not sufficient to induce ventricular asystole.

25. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the left ventricle.

26. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the aorta.

27. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the right ventricle.

28. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the pulmonary artery.

29. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the pulmonary vein.

30. The method according to claim 22, wherein the cholinergic receptor agonist and the β

-blocker are administered to the coronary sinus.

31. The method according to claim 22, wherein the cholinergic receptor agonist is carbachol.

32. The method according to claim 31, wherein the carbachol is administered in an amount of about 0.1 to 4.8 μ

g/kg body weight/min.

33. The method according to claim 14, wherein the β

-blocker is propranolol.

34. The method according to claim 33, wherein the propranolol is administered orally.

35. The method according to claim 33, wherein the propranolol is administered in an amount of about 0.01 to 0.07 mg/kg body weight.

36. The method according to claim 14, wherein the β

-blocker is selected from the group consisting of atenolol, acebutolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, celiprolol, betaxolol, bevantolol, bisoprolol, esmolol, alprenolol, carterolol, nadolol and teratolol.

37. The method according to claim 14, wherein the β

-blocker is propranolol and the AV node blocker is carbachol, and wherein the propranolol is administered prior to or during administration of the carbachol.

38. The method according to claim 37, wherein the propranolol and the carbachol are administered to the aorta.

39. The method according to claim 37, wherein the propranolol and the carbachol are administered to the right or left coronary artery.

40. The method according to claim 39, wherein the propranolol and the carbachol are administered proximal to the AV node artery.

41. The method of claim 37, wherein the propranolol and the carbachol are administered to the AV node artery.

42. The method according to claim 37, wherein the propranolol and the carbachol are administered to the middle cardiac vein.

43. The method according to claim 37, wherein the propranolol and the carbachol are administered to the right atrium.

44. The method according to claim 37, wherein the propranolol and the carbachol are administered to the coronary sinus.

45. The method according to claim 39, wherein the propranolol is administered by a single bolus injection in the coronary artery, prior to the administration of carbachol, and wherein the carbachol is administered by a single bolus injection followed by continuous infusion into the coronary artery to maintain the ventricular asystole.

46. The method according to claim 14, wherein the electrical pacing is selectively stopped by the surgeon by selectively depressing a foot pedal.

47. The method according to claim 14, wherein the procedure comprises placement of a suture in the heart.

48. The method according to claim 14, wherein the procedure comprises a minimally invasive coronary bypass procedure.

49. The method according to claim 14, wherein the method further comprises control of significant hemorrhage during the procedure.

50. The method according to claim 14, wherein the procedure comprises the treatment of injuries to the liver, spleen, heart, lungs, or major blood vessels.

51. The method according to claim 14, wherein the procedure comprises an electrophysiologic procedure.

52. The method according to claim 14 wherein the procedure comprises cardiac surgery with cardiopulmonary bypass.

53. The method according to claim 14, wherein the procedure comprises a transmyocardial revascularization procedure.

54. A method of inducing reversible ventricular asystole in the heart of a human patient while maintaining the ability of the heart to be electrically paced comprising:

administering at least a first compound which is a cholinergic agent to the heart of the patient which is capable of inducing third-degree AV block of the heart; and

administering at least a second compound to the heart of the patient which alone or in combination with the cholinergic agent is capable of substantially suppressing ectopic ventricular beats in the heart while maintaining the ability of the heart to be electrically paced.

55. A method of inducing reversible ventricular asystole in the heart of a human patient, while maintaining the ability of the heart to be electrically paced comprising:

administering an AV-node blocker to the heart of the patient and administering a compound that reduces the amount of AV node blocker required to induce ventricular asystole, said AV node blocker and compound being administered in an amount effective to induce ventricular asystole, while maintaining the ability of the heart to be electrically paced.