This document discusses blood pressure control in neurocritical care. It provides background on hypertension prevalence and challenges with blood pressure control. It then summarizes the classification of blood pressure levels according to the JNC 7 report. The document discusses acute hypertensive crises and the importance of rapid blood pressure control. It reviews pathophysiology and examples of end-organ damage from hypertensive emergencies. Current intravenous antihypertensive agents and their mechanisms are also summarized.

1. Blood Pressure Control in Neuro Critical Care PJ Papadakos MD FCCM Director CCM Professor Anesthesiology, Surgery and Neurosurgery Rochester NY USA

4. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure JAMA . 2003;289:2560-2572. The JNC 7 Report BP Classification Systolic BP mm Hg Diastolic BP mm Hg Normal < 120 < 80 Prehypertension 120-139 80-89 Stage 1 140-159 90-99 Stage 2  160  100

5. STAT Registry Analysis Patient outcomes (%) † † *N=1,588 (all patients); † n=1,405 (patients alive at discharge and with 90-day follow-up). HTN=hypertension. Kleinschmidt K, et al. Society for Academic Emergency Medicine 2008 Annual Meeting. Poster #140.

6. Acute Hypertensive Crises Require Rapid BP Control Acute Hypertensive Crises Hypertensive Urgency 1 Severe BP elevation WITHOUT end-organ damage Hypertensive Emergency 1 Severe BP elevation WITH end-organ damage Perioperative Hypertension 2 Severe BP elevation occurring before, during, or after surgical procedures 1. Chobanian AV, et al. Hypertension . 2003;42:1206-1252; 2. Varon J, Marik PE. Vasc Health Risk Manag. 2008;4:615-627. BP=blood pressure.

7. Pathophysiology

8. Regulation of Blood Pressure Blood Pressure Adrenergic Tone Baroreceptor Reflexes Volume/Pressure Renin/Angiotensin Preload Cardiac Output Catecholamines Adrenal Gland CNS Veins Arteries Capacitance Resistance Heart Kidney Afterload

10. Examples of End-Organ Damage in Hypertensive Emergencies Brain Acute neurologic syndromes Hypertensive encephalopathy Cerebral infarction Subarachnoid or intracranial hemorrhage Retina Retinopathy Papilledema Cardiovascular System Myocardial ischemia and infarction Acute left ventricular dysfunction Acute pulmonary edema Aortic dissection Kidney Renal insufficiency Aggarwal M, Khan IA. Cardiol Clin . 2006;24:135-146.

11. Fibrinoid Necrosis

12. CT SCANS and X-rays

13. Reversible high T2 signal abnormalities in pre-eclampsia

14. Hypertensive Encephalopathy/Retinopathy

16. Current Drugs in the ICU

18. Traditionally Used IV Antihypertensive Agents The Merck Manual. http://www.merck.com/mmpe/sec07/ch071/ch071c.html#sec07-ch071-ch071c-464. Drug Class of Therapy Esmolol Beta-blocker Fenoldopam Dopamine agonist Hydralazine Vasodilator Labetalol Beta-blocker with alpha-blocking activity Nicardipine Dihydropyridine calcium channel blocker Nitroglycerin Nitrovasodilator Sodium nitroprusside Nitrovasodilator

19. Gold Standard ?

21. Metabolism of Sodium Nitroprusside Tinker JH, Michenfelder JD. Anesthesiology . 1976;45:340-354. Inactive Cytochromes CN - TOXICITY Thiocyanate (SCN - ) Thiosulfate Renal Excretion Cytochrome Oxidases Hepatic Rhodanase Nitroprusside Nitroprusside Radical Oxyhemoglobin Methemoglobin Non-enzymatic Cyanmethemoglobin

22. Nitrovasodilators Dilate Both Arterial and Venous Vessels NITROVASODILATORS - Hypotension - Reflex tachycardia - Exacerbated by volume depletion

23. Nitrovasodilators in Patients With Recent Stroke and Compromised Coronary Blood Flow Coronary Steal Syndrome

24. Nitrovasodilators in Patients With Decreased Cerebral Circulation and Compromised Coronary Blood Flow Decreased Cerebral Blood Flow

26. A Precipitous and Uncontrolled Fall in BP Can Have Lethal Consequences Infarct …. brain, heart, kidney Cerebral Blood Flow 60 mm Hg 120 mm Hg 180 mm Hg Mean Arterial Blood Pressure Acute Chronic

28. Calcium Receptor Modulation

29. Vascular Smooth Muscle Contraction Is Calcium Dependent Ca ++   Ca ++ plus calmodulin Myosin kinase Actin-myosin interaction  Contraction     Ca ++  Calcium influx into vascular smooth muscle may occur via opening of L-type calcium channels Release of intracellular stores may also be a source of Ca ++ Adapted with permission from Frishman WH, et al. Curr Probl Cardiol . 1987;12:285-346.

30. Ca2+ inf lux Voltag e- Operated Ca2+ specific Receptor- O perated Ca2+ / Cation Ligand-Operated Ca2+/Cation Plasma membrane channels Ca2+ Mitochondrial Ca Uptake Sarco-/Endo-plasmic reticulum Ca Uptake Ca/Mg pump Na-Ca exchg. Papadakos and Sayeed New Horizions Calcium Homeostasis 1997

31. Ca2 + I Ca Ca2+ Ca2+ Ca-pump CICR Sarcoplasmic reticulum L-type Channel Myofilament Voltage-operated Ca2+ Channel (VOCC) Electrical Impulse Papadakos and Sayeed New Horizons Calcium Homeostasis 1997

32. Vascular Smooth Muscle Contraction Is Calcium Dependent Calcium influx into vascular smooth muscle may occur via opening of L-type calcium channels

34. IV Calcium Channel Blockers The relative effects are ranked from no effect (0) to most prominent (+++++). Adapted from Goodman and Gilman, 9th ed. McGraw-Hill;1996 and Massie, Am J Cardiol . 1997;80:231-321. Compound Coronary Vasodilatation Suppression of Cardiac Contractility Suppression of SA Node Suppression of AV Node Verapamil ++++ ++++ +++++ +++++ Diltiazem +++ ++ +++++ ++++ Nicardipine +++++ 0 + 0

35. Dihydropyridine CCBs Drug Brand Name Oral preparations 1st Generation: 2nd Generation: nifedipine nicardipine amlodipine isradipine felodipine nimodipine nisoldipine Procardia ® , Adalat ® Cardene ® Norvasc ® DynaCirc ® Plendil ® Nimotop ® Sular ® Intravenous preparations 2nd Generation: nicardipine Cardene ® IV

36. Cleviprex™ (clevidipine butyrate) injectable emulsion

42. Effects on Central Hemodynamics: Clevidipine Pharmacodynamically Friendly vs. SNP Experiment in anesthetized dogs * p < 0.05 Norlander, M.B, etal. B J Aneasth 1996; * * * * Change from pre-drug (%) “ The blood pressure reduction caused by clevidipine is due to profound lowering of TPR with associated increased CO , while the effects of SNP results mainly from a reduction in CO , which is due to its venodilatory effect and leads to reduced ventricular filling”

44. Phase 1: Vasoselective Effects Clev/SNP : N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193

46. Clinical Studies

47. E fficacy S tudy of C levidipine A ssessing Its P reoperative Antihypertensive E ffect in Cardiac Surgery-1 (ESCAPE-1) E fficacy S tudy of C levidipine A ssessing Its P ostoperative Antihypertensive E ffect in Cardiac Surgery-2 (ESCAPE-2)

49. Tight Control

51. E V aluation of the E ffect of U L traSh O rt Acting C levidipine I n the T reatment of Severe H Y pertension

54. Titration Algorithm Maintain or further titrate after first 30 min to achieve desired long-term reduction in SBP; continue treatment for 18-96 h Initiate Cleviprex™ (clevidipine butyrate) infusion at initial rate of 2 mg/h (4 mL/h) Titrate every 3 min in doubling increments (2-4, 4-8, up to 32 mg/h maximum) to achieve prespecified ITR* 30 18-96 h 0 3 6 9 12 15 18 21 24 27 Determine ITR for each patient prior to infusion Time postinfusion (min) *Downward titration was also permitted. BP=blood pressure; HR=heart rate; ITR=initial target range (specific for each patient; 20-40 mmHg between upper and lower limits); SBP=systolic blood pressure. BP and HR measured with cuff every 3 min pre-ITR BP and HR measured with cuff every 15 min post-ITR for 2 h, then hourly until oral therapy I TR 60 90 75 45 2 h Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print].

55. Baseline Characteristics Safety population, N=126. HTN=hypertension. Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. Medical History Patients (%) End-organ injury 81 Myocardial infarction 5 Renal disease 25 Dialysis dependent 11 Coronary artery disease 28 HTN 97 Previous hospitalization for HTN 31 Congestive heart failure 18 Dyslipidemia 37 Smoker (current/former) 39/21 Diabetes 31 Stroke 11

56. Cleviprex™ (clevidipine butyrate) Rapidly Lowered BP to Target in ~90% of Patients *Patients whose SBP was above their prespecified ITR at the time of Cleviprex initiation. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 0 10 20 30 40 50 60 70 80 90 100 91% Minutes Probability of SBP ITR attainment in 30 minutes (%) Primary end point results: Kaplan-Meier curve demonstrating probability of attaining SBP ITR within 30 minutes (mITT population*, n=117) Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. BP=blood pressure; ITR=initial target range; mITT=modified intent-to-treat; SBP=systolic blood pressure.