2. BP Control and Stroke Pro Calcium Blockers “Melee Mayer” Con Calcium Blockers “Power-Punch Pancioli”

3. Stephan A. “Melee” Mayer, MD

4. Calcium Channel Blockers for Stroke: PRO Stephan A. Mayer, MD Associate Professor of Neurology & Neurosurgery Columbia University Director, Neuro-ICU New York Presbyterian Hospital New York, NY

6. Outcome after Acute Ischemic Stroke by Admission Blood Pressure 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – n = 18 < 120 n = 29 121 -140 n = 39 141 -160 n = 78 161 -180 n = 49 181 -200 n = 87 > 200 Post neurological outcome % Systolic BP on admission (mm Hg) C 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – n = 18 < 120 n = 29 121 -140 n = 39 141 -160 n = 78 161 -180 n = 49 181 -200 n = 87 > 200 Early neurological deterioration % Systolic BP on admission (mm Hg) A 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – Post neurological outcome % Diastolic BP on admission (mm Hg) D n = 38 < 70 n = 39 71 -80 n = 48 81 -90 n = 43 91 -100 n = 30 101 -110 n = 102 > 110 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – n = 38 < 70 n = 39 71 -80 n = 48 81 -90 n = 43 91 -100 n = 30 101 -110 n = 102 > 110 Early neurological deterioration % Diastolic BP on admission (mm Hg) B Castillo J, et al. Stroke. 2004;35:520–526.

7. Management of Hypertension in Acute Ischemic Stroke: Patients Not Eligible for tPA SBP <220 mm Hg or DBP <120 mm Hg –No antihypertensive therapy SBP >220 mm Hg or DBP >120 mm Hg –Labetalol 20, 40, 60, 80 mg IVP –Nicardipine 5–15 mg/h Adams HP, et al. Stroke. 2003;34:1056–1083. SBP, systolic blood pressure; DBP, diastolic blood pressure.

8. Management of Hypertension in Acute Ischemic Stroke: Patients Eligible for tPA (Pre and Post) Adams HP, et al. Stroke. 2003;34:1056–1083. SBP <180 mm Hg and DBP <105 mm Hg –No antihypertensive therapy SBP >180 mm Hg or DBP >105 mm Hg –Labetalol 20, 40, 60, 80 mg IVP –Nicardipine 5 – 15 mg/h

10. Treatment of Hypertension in Acute ICH (1999) Recommendations Maintain MAP <130 mm Hg and SBP <180 mm Hg if history of hypertension If ICP monitored, keep CPP (MAP – ICP) >70 mm Hg CPP, cerebral perfusion pressure; MAP, mean arterial pressure; ICP, intracranial pressure. Broderick JP, et al. Stroke. 1999;30:905–915.

11. High or Low Admission SBP in ICH Patients Correlates with Increased Mortality <120121-140141-160161-180181-200201-220>220 n = 7n = 24n = 34n = 50n = 39N = 24n = 13 0 10 20 30 40 50 60 70 80 90 100 † NC * N = 191. *P < 0.001 vs SBP 141–160 mm Hg on admission. †P < 0.05 vs SBP 141–160 mm Hg on admission. NC, confidence interval not calculated due to <8 cases. 1 month12 months Mortality Rate (%) SBP (mm Hg) Adapted from: Vemmos KN, et al. J Intern Med. 2004;255:257-265.

12. Cerebral Autoregulation Is Central to Treatment of Hypertensive Crises 100200 normotensive chronic hypertensive Increasing risk of hypertensive encephalopathy Increasing risk of ischemia 50150250 Patients with cerebral ischemia lose their ability to autoregulate vasoparalysis Cerebral Blood Flow Adapted with permission from Varon J, Marik PE. Chest. 2000;118:214–227. MAP (mm Hg)

13. Specific Agents

14. Antihypertensive Agents Used in Hypertensive Crisis Clonidine Diazoxide Enalaprilat Esmolol Fenoldopam Hydralazine Labetalol Nicardipine Nifedipine Nitroglycerin Nitroprusside Phentolamine Trimethaphan

15. Antihypertensive Agents Used in Hypertensive Crisis Clonidine Diazoxide Enalaprilat Esmolol Fenoldopam Hydralazine Labetalol Nicardipine Nifedipine Nitroglycerin Nitroprusside Phentolamine Trimethaphan

16. Antihypertensive “Escalation” for Emergency Treatment of Hypertension Nitroprusside –Cerebral vasodilation may produce or aggravate increased ICP Nicardipine Labetalol or esmolol –May worsen bronchospasm –Causes bradycardia –May worsen heart failure Nitropaste Increasing Severity of Hypertension

17. Nitroprusside: NOT the Greatest BP Agent for Patients with Stroke Unstable dose-response relationship Directly increases ICP via cerebral vasodilation Toxicity with longer infusions (>72 hours)

18. Nicardipine vs Nitroprusside: Postoperative Hypertension Titration of Study Medications Halpern NA, et al. Crit Care Med. 1992;20:1637–1643. Time to Response (min) Number of Dose Changes Adverse Events Nicardipine (n = 71) 14.1 ± 11.5 ± 0.27% Nitroprusside (n = 68) 30 ± 3.55.1 ± 1.418% P = 0.003P < 0.05 Mean ± SEM.

19. Nicardipine: Pharmacokinetics of IV Bolus Administration Adapted from Cheung AT, et al. Anesth Analg. 1999;89:1116. 0 50 100 150 00.51.01.52.02.53.03.5 Time after Drug Administration (h) Plasma Nicardipine Concentration (ng/mL) Group 1: 0.25 mg Group 2: 0.5 mg Group 3: 1.0 mg Group 4: 2.0 mg

20. Nicardipine vs Adrenergic Blockers Drug Nicardipine (Cardene ® IV) Esmolol (Brevibloc ® ) Labetalol AdministrationContinuous infusion* Bolus, continuous infusion Bolus, continuous infusion Onset + offsetRapid Slower Contractility0Decreased HRMinimal increaseDecreased SVRDecreased0 Cardiac outputIncreasedDecreased+/- Myocardial O 2 balance Positive ContraindicationsAdvanced aortic stenosis Bradycardia Heart block >1° CHF Bronchospasm COPD Bradycardia Heart block >1° CHF Bronchospasm COPD

21. Nicardipine Labetalol

22. The Evidence Base Randomized controlled trials comparing nicardipine and labetalol for BP control in ED-treated stroke patients HA HA HA!

23. Acute Intracerebral Hemorrhage Approximately 2 hours after onset of symptoms

24. “Soft Landing” in a Narrow Target Range 0 20 40 60 80 100 120 140 160 180 200 3:004:005:006:007:008:009:00 Time mm Hg 10 Nicardipine Infusion Dose (mg/h) 15 8 SBPMAPDBP Target SBP Target MAP Range

25. “Jagged” BP Profile with Intermittent IVP 0 20 40 60 80 100 120 140 160 180 200 3:004:005:006:007:008:009:00 Time mm Hg Labetalol 40 mg IVP SBPMAPDBP Target SBP Target MAP Range

30. Calcium Channel Blockers for Acute Stroke? Calcium channel blockers directly counteract the neurogenic pressor response Consider the IV infusion approach This is what we will do in the ICU EDs need to function as ICUs

31. Neurocritical Care Society www.neurocriticalcare.org

32. Arthur M. “Power-Punch” Pancioli, MD

33. Con: Blood Pressure Management in Stroke Calcium Channel Blockers Arthur M. Pancioli, MD, FACEP Associate Professor and Vice Chairman for Research Department of Emergency Medicine University of Cincinnati, College of Medicine Director of Emergency Cerebrovascular Research Greater Cincinnati/Northern Kentucky Stroke Team

34. Outline The Disease States Why Lower Blood Pressure? How to Do It?

35. The Disease States Acute ischemic stroke ICH Subarachnoid hemorrhage

36. Acute Ischemic Stroke

38. ICH

39. Early Hemorrhage Growth in Patients With ICH Growth at 1 hour on CT >33% Growth 33% Growth Change in NIH Stroke Scale 3.7 ± 5.2 0.4 ± 2.6 Rankin Scale (4–6 weeks) 4.5 ± 0.9 3.8 ± 1.6 30-Day mortality 44%34% Brott T, et al. Stroke. 1997;28:1–5.

40. Aneurysmal Subarachnoid Hemorrhage

41. Outcome If You “Rebleed” After Sentinel Subarachnoid Hemorrhage Rebleeding significantly increased the odds of death (OR, 2.6; 95% CI, 1.1 to 6.3; P = 0.048) Reduced the odds of survival with good outcome (OR, 0.34; 95% CI, 0.13 to 0.92; P = 0.041) Beck J, et al. Stroke. 2006;37:2733–2737.

42. The Dance CPP = MAP – (ICP or CVP) When is MAP high enough? When is MAP too high?

44. My Experience with Calcium Channel Blockers

45. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA, Volume 276, Number 16, October 23, 1996

46. Nimodipine: Subarachnoid Hemorrhage Nimotop ® (nimodipine) is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (ie, Hunt and Hess Grades I-V). DO NOT ADMINISTER NIMOTOP INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE- THREATENING ADVERSE EVENTS HAVE OCCURRED WHEN THE CONTENTS OF NIMOTOP CAPSULES HAVE BEEN INJECTED PARENTERALLY. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

47. Titratable Agents for Hypertensive Cerebrovascular Emergencies

48. What Do I Want? Predictability Speed Ease

49. Let’s Go Disease by Disease Acute Ischemic Stroke: SBP >220 mm Hg / DBP >120 mm Hg OR - when using tPA: SBP <185 mm Hg / DBP <110 mm Hg IF I MUST – Then I have a lot more experience with labetalol and it reliably does BOTH the things I want

50. Let’s Go Disease by Disease ICH: Keep MAP 70 mm Hg Subarachnoid Hemorrhage: Keep MAP 70 mm Hg General rule: keep SBP <160 mm Hg WHEN I CAN – I Like labetalol or esmolol; they do everything I want and I can choose how to do it

51. Pro Calcium Blockers “Melee Mayer”

52. Con Calcium Blockers “Power-Punch Pancioli”

53. My Memories of Your Therapy

54. By The Way If we haven’t said it yet: I am NOT a hydralazine fan –It has defined unpredictable in my world

56. By the Way, Nitroprusside and ICP Changes in Intracranial Pressure with Nitroprusside Therapy

57. Time for a CONFESSION