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Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
Blood Pressure Control in Neuro ICU
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Blood Pressure Control in Neuro ICU

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    • 1. Blood Pressure Control in Neuro Critical Care PJ Papadakos MD FCCM Director CCM Professor Anesthesiology, Surgery and Neurosurgery Rochester NY USA
    • 2. Disclaimer <ul><li>Speakers Bureau Medicines Company </li></ul><ul><li>NIH, Erasmus University </li></ul>
    • 3. Hypertension <ul><li>Common clinical problem </li></ul><ul><ul><li>1 billion people worldwide </li></ul></ul><ul><ul><li>60 million Americans </li></ul></ul><ul><li>At least 15% of African-Americans </li></ul><ul><li>Increases with age </li></ul><ul><li>Male +/- higher than females? </li></ul><ul><li>30% undiagnosed </li></ul><ul><li>15%-30% adequate BP control </li></ul>
    • 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
    • 9. Understanding the Pathophysiology of Acute Hypertension Is Key to Effective Treatment Marik P, Varon J. Chest. 2007;131:1949-1962. <ul><li>Hypertensive crisis is thought to be initiated by an abrupt increase in systemic vascular resistance likely related to humoral vasoconstrictors </li></ul><ul><ul><li>Mechanical stress </li></ul></ul><ul><ul><li>Endothelial injury </li></ul></ul><ul><ul><ul><li>Permeability </li></ul></ul></ul><ul><ul><ul><li>Coagulation </li></ul></ul></ul><ul><ul><ul><li>Fibrinoid necrosis </li></ul></ul></ul>
    • 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
    • 15.  
    • 16. Current Drugs in the ICU
    • 17.  
    • 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 ?
    • 20. Sodium Nitroprusside <ul><li>4 of the 5 CN – ions are promptly released </li></ul><ul><li>44% of fractional weight is cyanide </li></ul>2 Na + NO + CN - CN - Fe ++ CN - CN - CN -
    • 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
    • 25.  
    • 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
    • 27.  
    • 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
    • 33. Nicardipine <ul><li>2nd generation dihydropyridine Ca++ blocker with high vascular selectivity </li></ul><ul><li>100 times more water soluble than nifedipine; easily titratable IV formulation </li></ul><ul><li>Onset within 5-10 min; duration of action 4-6 h </li></ul><ul><li>Decreases cardiac and cerebral ischemia in hypertensive emergencies </li></ul><ul><li>No significant rebound once infusion is stopped </li></ul><ul><li>5 mg/h up to 30 mg/h </li></ul>
    • 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
    • 37. Cleviprex™ (clevidipine butyrate): Metabolism <ul><li>Cleviprex is rapidly metabolized by hydrolysis of the ester linkage primarily by esterases in the blood and extravascular tissues </li></ul><ul><ul><li>Elimination is unlikely to be affected by hepatic or renal dysfunction </li></ul></ul><ul><ul><li>The potential of Cleviprex to interact with other drugs is low </li></ul></ul><ul><ul><li>No dosage adjustment is required in patients with underlying hepatic or renal impairment </li></ul></ul>Cleviprex + + Esterases Figure adapted from Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564. Cl O O O O N H Cl O O O O N H Cl O O Cl H Primary metabolite O H O H H O
    • 38. Rapid pharmacokinetics of clevidipine 0.1 1 10 100 0 20 40 60 80 Time (min) Blood [clevidipine] (nmol/L) 20 minute infusion (12 nmol/kg/min) arterial venous *Redrawn from Ericsson et al . Anesthesiology, 2000 <ul><li>Approximate half-life: 1 min </li></ul><ul><ul><li>T 1/2 (triphasic): alpha, 48 sec; beta, 2.3 min; terminal, 21.7 min </li></ul></ul><ul><ul><li>85%–90% eliminated in first T ½ </li></ul></ul><ul><ul><li>After 72 hrs cont. infusion </li></ul></ul><ul><ul><ul><li>No tachyphylaxis </li></ul></ul></ul><ul><ul><ul><li>No rebound </li></ul></ul></ul><ul><ul><ul><li>No drug accumulation </li></ul></ul></ul><ul><ul><ul><li>Rapid offset maintained </li></ul></ul></ul>
    • 39. Clevidipine: Linear Pharmacokinetics <ul><li>At steady state, there is a linear relationship between dosage and arterial blood concentrations </li></ul><ul><li>Linear relationship maintained for dosages as high as 21.9 mcg/kg/min </li></ul>*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion. Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001. Ericsson H, et al. Anesthesiology . 2000;92:993-1001. Ericsson H, et al. Br J Clin Pharmacol. 1999;47:531-538. 120 100 80 60 40 20 0 0 5 10 15 20 35 Clevidipine Concentration at Css (nmol/L)* Dose Rate (nmol/kg/min) 25 30
    • 40. Clevidipine: Rapid Onset <ul><li>BP-lowering effects seen within ~1 minute of clevidipine infusion </li></ul>SBP changes for patients receiving clevidipine during a 30-minute treatment period. Levy JH, et al. Anesthesiology. 2005;103:A354. 10 5 0 – 5 – 10 – 15 – 20 – 25 – 30 0 5 10 15 20 25 30 % Change From Baseline Time (min) SBP SBP Changes
    • 41. Clevidipine: Rapid Offset <ul><li>After discontinuation of clevidipine infusion, there was a rapid clearance </li></ul><ul><li>BP returned to baseline in <10 minutes in healthy volunteers </li></ul>Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001. 100 90 80 70 60 50 40 – 5 0 5 10 15 20 35 MAP (mm Hg) and HR (beats/min) Time (min) 25 30 Clevidipine Infusion MAP`
    • 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”
    • 43. Coronary and Systemic Hemodynamic Effects of Clevidipine After CABG surgery <ul><li>Objective: Compare the hemodynamic effects of Clevidipine in a cross-over design vs Sodium Nitroprusside (SNP) </li></ul><ul><li>Methods: The effects of clevidipine on central hemodynamics, myocardial blood flow and metabolism were studied at two different phases after CABG. </li></ul><ul><li>Phase 1 (n=13), the hypertensive phase, the effects of clevidipine were compared to those of SNP when used to control postoperative hypertension in a crossover fashion </li></ul><ul><li>Phase 2 (n=9), the normotensive phase, clevidipine dose-response relationship was established. </li></ul>N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193
    • 44. Phase 1: Vasoselective Effects Clev/SNP : N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193
    • 45. Phase 2: DOSE RESPONSE: Clevidipine Rapid onset, linear relationship N = 9. N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193 <ul><li>C1 </li></ul><ul><li>0.375 </li></ul><ul><li>0.75 </li></ul><ul><li>1.5 </li></ul><ul><li>3 </li></ul><ul><li> </li></ul><ul><li>g/kg/min </li></ul><ul><li>C1 </li></ul><ul><li>0.375 </li></ul><ul><li>0.75 </li></ul><ul><li>1.5 </li></ul><ul><li>3 </li></ul><ul><li>0 </li></ul><ul><li> </li></ul><ul><li>g/kg/min </li></ul><ul><li>units </li></ul><ul><li>1200 </li></ul><ul><li>1400 </li></ul><ul><li>1000 </li></ul><ul><li>bmp </li></ul><ul><li>mm Hg </li></ul><ul><li>Heart Rate </li></ul><ul><li>80 </li></ul><ul><li>90 </li></ul><ul><li>70 </li></ul><ul><li>Mean Arterial Pressure </li></ul><ul><li>80 </li></ul><ul><li>* </li></ul><ul><li>90 </li></ul><ul><li>70 </li></ul><ul><li>0 </li></ul><ul><li>0.375 </li></ul><ul><li>0.75 </li></ul><ul><li>Systemic Vascular Resistance </li></ul><ul><li>1.5 </li></ul><ul><li>3 </li></ul><ul><li>ml/min </li></ul><ul><li>Stroke Volume </li></ul><ul><li>0 </li></ul><ul><li>70 </li></ul><ul><li>75 </li></ul><ul><li>65 </li></ul><ul><li>units </li></ul><ul><li>1200 </li></ul><ul><li>1400 </li></ul><ul><li>1000 </li></ul><ul><li>bmp </li></ul><ul><li>mm Hg </li></ul><ul><li>Heart Rate </li></ul><ul><li>80 </li></ul><ul><li>90 </li></ul><ul><li>70 </li></ul><ul><li>Mean Arterial Pressure </li></ul><ul><li>80 </li></ul><ul><li>* </li></ul><ul><li>90 </li></ul><ul><li>70 </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>0 </li></ul><ul><li>0.375 </li></ul><ul><li>0.75 </li></ul><ul><li>Systemic Vascular Resistance </li></ul><ul><li>1.5 </li></ul><ul><li>3 </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>ml/min </li></ul><ul><li>Stroke Volume </li></ul><ul><li>0 </li></ul><ul><li>70 </li></ul><ul><li>75 </li></ul><ul><li>65 </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>µ g/kg/min </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul>
    • 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)
    • 48. ESCAPE Results: Onset and Time-to-Target Effect <ul><li>Onset of BP-lowering effect: within 1–2 minutes of infusion </li></ul><ul><li>Time to target BP (15% reduction): ESCAPE-1 = 6.0 min*; ESCAPE-2 = 5.3 min † </li></ul>Levy JH et al. Anesth Analg . 2007;105:918-925. Data on file, The Medicines Company. *Reproduced from Levy JH, et al. Anesthesiology. 2005;103:A354. † Reproduced from Singla N, et al. Anesthesiology. 2005;103:A292. 10 5 0 – 5 – 10 – 15 – 20 – 25 – 30 0 5 10 15 20 25 30 % Change From Baseline Time (min) SBP 5 0 – 5 – 10 – 15 – 20 – 25 – 30 0 5 10 15 20 25 30 % Change From Baseline Time (min) SBP ESCAPE-1 ESCAPE-2 SBP Changes SBP Changes
    • 49. Tight Control
    • 50. Excursions Outside Target BP Range Define Control <ul><li>BP control was assessed as a prespecified secondary end point by measuring the magnitude and duration of SBP excursions outside the predefined pre- and postoperative target range (75-145 mmHg) and intraoperative SBP target range (65-135 mmHg) </li></ul>Illustration of a single patient’s excursions used to assess BP control Upper limit Lower limit SBP (mmHg) Aronson S, et al. Anesth Analg . 2008;107:1111-1122. BP=blood pressure; SBP=systolic blood pressure.
    • 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
    • 52. Overview and Enrollment Criteria <ul><li>Multicenter, phase 3, open-label, single-arm study to confirm the safety and efficacy of Cleviprex™ (clevidipine butyrate) using a predefined, non–weight-based dosing algorithm in patients presenting in the ED or ICU with severe HTN </li></ul><ul><li>Inclusion criteria </li></ul><ul><ul><li>Age ≥18 years </li></ul></ul><ul><ul><li>SBP >180 mmHg and/or DBP >115 mmHg assessed on 2 successive occasions, 15 minutes apart </li></ul></ul><ul><li>Exclusion criteria </li></ul><ul><ul><li>SBP ≤180 mmHg and DBP ≤115 mmHg </li></ul></ul><ul><ul><li>Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hours </li></ul></ul><ul><ul><li>Known or suspected aortic dissection </li></ul></ul>Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. DBP=diastolic blood pressure; ED=emergency department; HTN=hypertension; ICU=intensive care unit; IV=intravenous; SBP=systolic blood pressure.
    • 53. Objectives <ul><li>Primary end points </li></ul><ul><ul><li>Patients (%) in whom SBP fell to within the SBP ITR within 30 minutes of initiating infusion </li></ul></ul><ul><ul><li>Patients (%) in whom SBP fell below the lower limit of the SBP ITR within 3 minutes of initiating infusion </li></ul></ul><ul><li>Secondary end points </li></ul><ul><ul><li>Time to achieve SBP ITR within the initial 30 minutes </li></ul></ul><ul><ul><li>Proportion of patients successfully transitioned to oral antihypertensive therapy </li></ul></ul><ul><ul><li>Safety of prolonged (≥18 hours) Cleviprex™ (clevidipine butyrate) infusion </li></ul></ul>Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. Please see Important Safety Information and accompanying full Prescribing Information. ITR=initial target range; SBP=systolic blood pressure.
    • 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.
    • 57. Cleviprex™ (clevidipine butyrate) Minimized Overshoot <ul><li>2 patients (1.6%) fell below the lower ITR limit within the first 3 minutes </li></ul><ul><ul><li>In 1 patient, the ITR was narrower than specified by protocol (205-195 mmHg), with SBP 15 mmHg below the lower limit </li></ul></ul><ul><ul><li>In 1 patient, the lower limit was 160 mmHg and the SBP fell 4 mmHg below this </li></ul></ul><ul><ul><li>Both patients continued Cleviprex infusion beyond 18 hours without AEs </li></ul></ul>Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. AEs=adverse events; ITR=initial target range; SBP=systolic blood pressure.
    • 58. Rapid, Sustained BP Control 0 30-minute titration to ITR Time after start of infusion (h) 0 3 6 9 12 15 18 – 5 – 10 – 15 – 20 – 25 – 30 Additional titration BP adjustment and maintenance <ul><li>Per protocol, patients were infused for a minimum of 18 h </li></ul><ul><li>Dose adjustments 2 </li></ul><ul><ul><li>On average, 2 dose adjustments were needed to attain ITR </li></ul></ul><ul><ul><li>Mean number of adjustments needed after attainment of ITR through 18 h = 0.33/h </li></ul></ul>1. Pollack CV, et al. Ann Emerg Med . 2008; Jun 6. [Epub ahead of print]. 2. Data on file. The Medicines Company. Mean SBP reduction from baseline (%) 1 BP=blood pressure; ITR=initial target range; SBP=systolic blood pressure.
    • 59. Cleviprex™ (clevidipine butyrate) in Patients With Renal Impairment <ul><li>Cleviprex reduced systolic blood pressure (SBP) in a post hoc analysis of patients with renal dysfunction (dialysis dependent and nondialysis dependent) </li></ul>Peacock WF, et al. Society of Critical Care Medicine 37th Critical Care Congress; 2008. Poster #310. Time (min) Mean SBP change from baseline (%) With renal dysfunction (n=22) Without renal dysfunction (n=95) 3 6 9 12 15 18 21 24 27 30 5 0 – 5 – 10 – 15 – 20 – 25 – 30 – 35
    • 60. Cleviprex™ (clevidipine butyrate) in Patients With Acute Heart Failure <ul><li>Cleviprex decreased systolic blood pressure (SBP) in a post hoc analysis of patients with acute heart failure and severe hypertension, without causing hypotension </li></ul>Peacock WF, et al. Society of Critical Care Medicine 37th Critical Care Congress; 2008. Poster #302. Time (min) With acute heart failure (n=17) Without acute heart failure (n=100) 3 6 9 12 15 18 21 24 27 30 5 0 – 5 – 10 – 15 – 20 – 25 – 30 – 35 Mean SBP change from baseline (%)
    • 61. clevidipine butyrate <ul><li>May be the esmolol of calcium blockers </li></ul>
    • 62.  

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