1. β-blockers in Anesthesia Donald M. Voltz, M.D. Assistant Professor of Anesthesiology Case Western Reserve University/University Hospitals of Cleveland

2. Goals To provide everyone with enough information to begin comfortably using beta-blockers in the perioperative period.

3. Objectives Physiology of Adrenergic Receptors β -adrenergic antagonists Clinical Application of β-blockers Cardiac Protection Hemodynamic Control Decreasing Anesthetic Requirements Guidelines for Beta-blocker Usage in the OR

4. β -adrenergic Receptor Physiology

5. β-blocker Receptor Types β 1 Receptors Predominant receptor on cardiac myocytes β 2 Receptors Involved in contraction and relaxation of heart failure Peripheral vasodilitation and bronchial dilatation β 3 Receptors Negative inotropy via NO-dependant pathway May play a role in deterioration of cardiac function in heart failure

6. β – Receptor Biologic Responses Chronotropy Dromotropy Inotropy Cellular Growth Cellular Death (apoptosis)

7. β-Receptor Intracellular Signaling

8. β -Receptor Down-Regulation Phosphorylation (down regulation) Translocation (sequestration) Degredation

9. β -Receptor Down-Regulation Down-regulation begins within a few hours after an elevation of catecholamines Initial phase is the uncoupling of receptor and signal transduction Late phase results in degradation of receptors Down-regulation has been reported to persist for 1 week after laparotomy, thoracotomy, and cardiac bypass

10. β -Receptor Down-Regulation

11. Cell Death – Necrosis and Apoptosis Catecholamines are toxic to cardiac cells Tachycardia with Isoproterenol significantly increased apototic death than ventricular pacing Cardiac cell death is reduced in patients with subarachnoid bleeding when treated with atenolol

12. β -adrenergic Antagonist Medications

13. β -adrenergic Antagonists GenerationCharacteristicsMedications 1 st No ancillary Properties propranolol, timolol, nadolol 2 nd β 1 -selectivemetoprolol, atenolol, esmolol, bisoprolol 3 rd β 1 -selective, with ancillary properties carvedilol, bucindolol

14. β 1 / β 2 selectivity Medicationβ 1 / β 2 Selectivity Propranolol2.1 Metoprolol74 Atenolol75 Esmolol70 Bisoprolol119 Carvedilol7.2 Bucindolol1.4 Celiprolol300 Nebivolol293

15. Ancillary Properties of β-blockers Membrane-Stabilizing Activity Intrinsic Sympathomimetic Activity Lipid Solubility Antioxidant Activity Anti-adhesive Activity α 1 -Antagonistic Activity

16. Clinical Actions of β -blockers Lowering heart rate Decreasing blood pressure Decreasing atherosclerotic plaque stiffness Decreased platelet activation Anti-arrhythmic effects Cardiac protection – not HR dependant Decrease in anesthetic and analgesic requirements Improvement of immune response

17. Cardiac Effects of β-blockade

18. Clinical Evidence for β – blocker Use

19. Clinical Applications for β -blockade Cardiac Protection Hemodynamic Control Immune Modulation Modulation of Coagulation Decreased Anesthetic Requirements

20. Myocardial Protection Well studied in vascular patients who are at high risk for perioperative cardiac events Evolving evidence supports there use as a standard of care in at risk patients Likely to find increasing role in the future

21. Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery Dennis T. Mangano, Ph.D., M.D., Elizabeth L. Layug, M.D., Arthur Wallace, Ph.D., M.D., Ida Tateo, M.S., for The Multicenter Study of Perioperative Ischemia Research Group Next Next Volume 335:1713-1721December 5, 1996 Number 23

22. Mangano, et al. 1996 Randomized trial of atenolol vs. saline (n=99, n=101) Patient followed for 2 years Mortality decreased in atenolol group 0% vs 8% at 6 months 3% vs 14% at 1 year 10% vs 21% at 2 years

23. Wallace, et al. 1998 200 pts randomized to atenolol or saline EKG, Holter monitor, and CPK w/ MB were followed 24 hr prior and 7 days after surgery Atenolol 0,5, or 10 mg or placebo prior to induction and every 12 hours until po than qd for 1 week

24. Wallace, et al. 1998 Decreased perioperative myocardial ischemia 17/99 esmolol vs 34/101 placebo (days 0-2) 24/99 esmolol vs 39/101 placebo (days 0-7)

25. Polderman, et al. 1999 846 pts with one or more cardiac risk factors; 173 positive dobutamine stress tests Bisoprolol in 59; Placebo in 53 Nonfatal MI 0% bisoprolol 17% placebo group Cardiac Death 3.4% bisoprolol group 17% placebo group

26. What Patients are at Risk

27. B-blockers & At Risk Patients Presence of CAD History of Myocardial Infarction Typical Angina or Atypical Angina with + Stress Test At Risk for CAD (2 or more of the following) Age >65 years Hypertension Active Smoker Serum Cholesterol > 240 mg/dl Diabetes Mellitus

28. B-blockers and Cardioprotection How well are we doing with at risk patients? Not Very Well!

29. Prophylactic beta-blockade to prevent myocardial infarction perioperatively in high-risk patients who undergoing general surgical procedures. Taylor RC, Pagliarello G. Can J Surg. 2003 Jun;46(3):216-22 236 pts for laparotomy 143 pts at risk for CAD 60.8% did not receive B-blockers pre-op 33% pts had B-blockers discontinued

30. The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular Surgery Khether E. Raby, MD, FACC *, Sorin J. Brull, MD, Farris Timimi, MD, Shamsuddin Akhtar, MD, Stanley Rosenbaum, MD, Cameron Naimi, BS, and Anthony D. Whittemore, MD Anesth Analg. 1999 Mar;88(3):477-82

31. The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular Surgery Vascular Pts at High Risk for CAD underwent 24 hrs Holter Monitoring 26 of 150 pts had significant ischemia as measured by ST-depression – PreOp Randomized to Esmolol gtt (n=15) or Placebo (n=11) Titrated to HR 20% below ischemic threshold Holter Monitoring for 48 hrs PostOp

32. The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular Surgery Ischemia Present Post-Op 73% in Placebo Group (8 of 11) 33% in Esmolol Group (5 of 15) Number of Hours HR < Ischemic Threshold 9 of 15 pts in Esmolol group <20% and all without ischemia 4 of 11 pts in Placebo group <20%. 3 of 4 without ischemia

33. Anti-Arrhythmic Effects High risk pts with CAD under-going noncardiac surgery have PVCs or ventricular tachyarrythmias (50% incidence) Cardiac surgery pts are at high risk of developing atrial fibrillation Blunting sympathetic tone decreases incidence of both atrial and ventricular tachyarrythmias β-blockers counteract epinephrine-induced hypokalemia

34. Balanced Anesthesia and Beta-blockers

35. B-blockers and Anesthetic Reduction

36. Michael Zaugg, M.D.; Thomas Tagliente, M.D., Ph.D.; Eliana Lucchinetti, M.S.; Ellis Jacobs, Ph.D.; Marina Krol, Ph.D.; Carol Bodian, Dr.P.H.; David L. Reich, M.D.; Jeffrey H. Silverstein, M.D. ANESTHESIOLOGY 1999;91:1674-1686 Beneficial Effects from B-Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

37. N=63 patients for noncardiac surgery Monitored – Neuropeptide Y, epinephrine, norepinephrine, cortisol, and ACTH Randomly assigned Group 1: no atenolol Group 2: Pre- and Post-operative atenolol Group 3: Intraoperative Atenolol

38. Beneficial Effects from B-Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

39. Beneficial Effects from β -Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery Beta-blockade did not change neuroendocrine stress response Lower Narcotic Requirement Groups II and III – 27.7% less fentanyl Lower Anesthetic Requirements Group III – 37.5% less isoflurane (BIS same in all groups) Lower PACU Morphine requirements Shorter PACU times

40. Beta-blockers and Bariatric Surgery Randomized Study of Morbidly Obese Patients Undergoing Gastric Bypass Metoprolol vs. Placebo Evaluate Intraoperative Volatile Requirements PACU Pain Requirement PCA Usage

41. Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data Zaugg, et. al. Can J Anesth 2003; 50: 638-42

42. Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data Does atenolol result in light anesthesia with the reduction of volatile agents? Are our abilities to adequately judge anesthetic depth impaired with atenolol?

43. Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data 45 patients from the prior study we used (post hoc) Collected HR, MAP, SBP, and BIS output Subgroups were analyzed Group I n=12 Group II n=16 Group III n=17

44. Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data Group III received 39.5% less isoflurane than Group I Group II and III received 21% less fentanyl than Group I All Groups had similar intraoperative BIS levels (53-54) Atenolol reduces anesthetic requirements but not modify depth of anesthesia indicators

45. β-Blockers and Memory Lipophilic β-blockers can cross the blood- brain barrier Propranolol has been shown to blunt storage of emotionally charged events Some thoughts that perioperative β-blockade may be useful to blunt recall

46. Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia Jay W. Johansen Anesth Analg 2001; 93:1526-31

47. Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia N=20 patients Alfentanil Groups (50 or 150 ng/ml) Saline vs Esmolol infusion Monitored BIS output and Suppression Ratio

48. Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia BIS Output Esmolol – 40% reduction (3722) Saline – no change Suppression Ratio Esmolol – 13.4 fold increase (5 67) Saline – no change

49. Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia Smith, J. Van Hemelrijck, and P. White Anesth Analg 2003;97:1633-1638

50. Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia N=97 patients for arthroscopy Compared esmolol to alfentanil

51. Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia Esmolol decreased time to eye opening (7.2 vs 9.8 min) Esmolol reported more pain in PACU Esmolol required more opiods in PACU

52. Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration Jay W. Johansen, et al. Anesth Analg 1998; 87:671-6

53. Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration N=100; divided into 5 groups Isoflurane alone Isoflurane with large dose esmolol (250 mcg/kg/min) Isoflurane with Alfentanil Isoflurane, Alfentanil, small dose esmolol (50 mcg/kg/min) Isoflurane, Alfentanil, large dose esmolol (250 mcg/kg/min)

54. Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration MAC levels after steady state Isoflurane – 1.28% Iso + large dose Esmolol – 1.23% Iso + Alfentanil – 0.96%* Iso + Alfentanil + small dose Esmolol – 0.96% Iso + Alfentanil _ large dose Esmolol – 0.74%**

55. Perioperative Immune Modulation Stress response decreases immune function Natural killer cells have decreased cytotoxic activity in the perioperative period Nadolol has been shown to blunt a hypothermic decrease in natural killer cell cytotoxic activity

56. Contraindications of β -blockers

57. β-blocker Adverse Reactions Very well tolerated in the perioperative period May see hypotension in severely volume contracted patients Patients with severe heart failure may acutely have problems. Titrate slowly. Avoid in symptomatic bradycardia Caution in patients with advanced conduction impairments

58. β-blocker Adverse Reactions Bradycardia – is it symptomatic??? Bronchospasm in COPD/Asthma patients – no evidence to suggest problem in these patients with selective agents Heart Failure – use carefully in patients with low EF, however, has been shown to improve function with ACEI in end-stage CHF

59. Management of Complications Related to β- Blockade

60. Treatment of Symptomatic Bradycardia from β-blockers Use of Vagolytic Medications Glycopyrolate Atropine Glucagon 2.5 mcg/kg iv Pronounced chronotropic effect

61. Treatment of Hypotension from β-blockers β-agonists are not useful in treating cardiac decompensation Phosphodiesterase III inhibitors (milrinone) retain full hemodynamic effects without excessive tachycardia Combination of glucagon and milrinone restores cardiac output but often increases heart rate significantly Combination of β-blockers with PDE3Is may allow for perioperative β-blockade in severe heart failure

62. Guidelines for Using β -blockers in the OR

63. Summary for At Risk Patients Preemptive Bradycardia Think about heart rate as separate from blood pressure Be aggressive with heart rate control Incorporate into preoperative and postoperative care. Involve Primary Care Physician Involve Vascular Surgeon and Nursing

64. The End