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Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
Prevention and Awareness of Asthma
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Prevention and Awareness of Asthma

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    • 1. Severe Hypertension: Disease State Awareness
    • 2. Hypertensive Crisis: JNC-7 definitions Chobanian AV et al. Hypertension. 2003;42:1206-1252. Hypertensive Crisis Operating room post-anesthesia care Emergency department Intensive care unit Hypertensive emergency Severe elevation in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction Hypertensive urgency Severe elevation in BP without progressive target organ dysfunction Hypertensive urgency Hypertensive emergency Perioperative hypertension
    • 3. Severe Hypertension: Epidemiology <ul><li>Hypertensive emergency 1 </li></ul><ul><ul><li>Hypertension affects approximately 50 million people in the USA and approximately 1 billion people worldwide. </li></ul></ul><ul><ul><li>Estimates are that approximately 1% of these patients will develop hypertensive crisis at some point in their lives </li></ul></ul><ul><ul><li>Hospital admissions for hypertensive emergency tripled from 1983 to 1990 (from 23,000/yr to 73,000/yr) in the USA. </li></ul></ul><ul><li>Perioperative hypertension </li></ul><ul><ul><li>Frequently occurs with cardiovascular surgery (30%–80%) 2,3 </li></ul></ul><ul><ul><ul><li>80% incidence following carotid endarterectomy </li></ul></ul></ul><ul><ul><li>Preoperative incidence: 2,4 </li></ul></ul><ul><ul><ul><li>50% of cardiac surgery patients </li></ul></ul></ul><ul><ul><ul><li>25% of non-cardiac surgery patients </li></ul></ul></ul><ul><ul><li>Intraoperative incidence: 2 </li></ul></ul><ul><ul><ul><li>50% of patients undergoing cardiac surgery </li></ul></ul></ul>1. Varon J, Marik PE. Crit icalCare . 2003 7:374-384 2. Cheung AT. J Card Surg. 2006;21:S8-S14 3. Oparil S et al. Am J Hypertens. 1999;12:653-664. 4. Goldman L et al. N Engl J Med. 1977;297:845-850
    • 4. Severe Hypertension: Clinical Outcomes Aortic Dissection Stroke, Encepha- lopathy Myocardial Infarction Renal Dysfunction CHF and Pulmonary Edema Severe HTN
    • 5. Severe Hypertension: End-Organ Damage <ul><li>End-Organ Damage Type No. of Cases (%) </li></ul><ul><li>Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy 18 (16.3) </li></ul><ul><li>Acute Pulmonary Edema 24 (22.5) Acute CHF 15 (14.3) Acute MI 13 (12) </li></ul><ul><li>Aortic Dissection 2 (2) </li></ul><ul><li>Eclampsia 5 (4.5) </li></ul>Zampaglione, B. Hypertension 1996;27:144-147. 108 Hypertensive Emergencies* *All Caucasians
    • 6. Severe Hypertension: Short-Term (Up to 6 months) Outcomes Acute Condition Death Rehospitalization ACS 1,2,3 5-7% 30% CHF 4 8.5% 26% Severe Hypertension 5 7-9% 37% <ul><li>OASIS-5 NEJM 2006. </li></ul><ul><li>GUSTO IIb NEJM 1996. </li></ul><ul><li>GRACE JAMA 2007. </li></ul><ul><li>IMPACT-HF J Cardiac Failure 2004. </li></ul><ul><li>Kleinschmidt, SAEM, STAT registry, 2008 </li></ul>
    • 7. Severe Hypertension: May Occur Throughout the Hospital <ul><li>ED </li></ul><ul><li>MICU </li></ul><ul><li>SICU </li></ul><ul><li>OR </li></ul><ul><li>PACU </li></ul>Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.
    • 8. Severe Hypertension: Etiologies <ul><li>Medical </li></ul><ul><ul><li>Uncontrolled HTN </li></ul></ul><ul><ul><ul><li>Noncompliance </li></ul></ul></ul><ul><ul><li>Drug-induced HTN </li></ul></ul><ul><ul><ul><li>Cocaine, amphetamines </li></ul></ul></ul><ul><ul><ul><li>Drug withdrawal </li></ul></ul></ul><ul><ul><ul><li>Drug-drug interactions </li></ul></ul></ul><ul><ul><li>Endocrine disorders </li></ul></ul><ul><li>Surgical </li></ul><ul><ul><li>Cardiac surgery </li></ul></ul><ul><ul><li>Major vascular surgery </li></ul></ul><ul><ul><ul><li>Carotid endarterectomy </li></ul></ul></ul><ul><ul><ul><li>Aortic surgery </li></ul></ul></ul><ul><ul><li>Neurosurgery </li></ul></ul><ul><ul><li>Head and neck surgery </li></ul></ul><ul><ul><li>Renal transplantation </li></ul></ul><ul><ul><li>Major trauma – burns or head injury </li></ul></ul>Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.
    • 9. Treatment Goals for Hypertensive Emergency <ul><li>Reduce MAP by ≤ 25% during the first minute to 1 hour </li></ul><ul><li>If stable, reduce BP to 160/100-110 mmHg in next 2-6 hours </li></ul><ul><li>Gradual reductions toward normal BP over next 24-48 hours </li></ul><ul><li>Excessive falls in BP may cause renal, cerebral, or coronary ischemia </li></ul><ul><li>Conditions requiring special management </li></ul><ul><ul><li>Ischemic stroke </li></ul></ul><ul><ul><li>Stroke eligible for thrombolytic agents </li></ul></ul><ul><ul><li>Aortic dissection </li></ul></ul>Chobanian AV et al. Hypertension. 2003;42:1206-1252.
    • 10. Use of Intravenous (IV) Antihypertensive Therapy <ul><li>Hypertensive emergency </li></ul><ul><li>Hypertensive urgency when oral therapy is not feasible </li></ul><ul><li>Perioperative hypertension </li></ul><ul><li>Special patient populations </li></ul><ul><ul><li>Hemorrhagic stroke </li></ul></ul><ul><ul><li>Ischemic stroke prior to thrombolytics </li></ul></ul><ul><ul><li>Aortic dissection </li></ul></ul><ul><ul><li>NPO patient </li></ul></ul>Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Varon J, Marik PE. CHEST. 2000;118:214-227. Varon J, Marik PE. Crit Care. 2003;7:374-384.
    • 11. Severe Hypertension: Treatment Options
    • 12. Goals of an Ideal Agent for Treatment of Severe Hypertension <ul><ul><li>Rapid onset of action </li></ul></ul><ul><ul><li>Short acting </li></ul></ul><ul><ul><li>Easily titratable </li></ul></ul><ul><ul><li>Require minimal dosage adjustments </li></ul></ul><ul><ul><li>Minimal risk of hypotension (“overshoot”) </li></ul></ul><ul><ul><li>Lack significant side effects </li></ul></ul><ul><ul><li>Mild reduction in myocardial contractility </li></ul></ul><ul><ul><li>Vascular effects confined to arteriolar bed </li></ul></ul><ul><ul><li>Easy conversion to oral agents </li></ul></ul><ul><ul><li>Low cost, including drug and monitoring costs </li></ul></ul>Feneck R. Drugs. 2007;67:2023-2044. Oparil S et al. Am J Hypertens. 1999;12:653-664. Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 13. IV Antihypertensive Utilization Trends All Patients Treated with Drug Thomson Patient Level Data. 2006
    • 14. IV Antihypertensive Agents Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Rynn KO et al. J Pharm Pract . 2005;18:363-376. Agent Onset/ Duration Elimination Half-Life Adverse Events Cautions/Concerns Enalaprilat <15 min/ 12–24 h 11 h Precipitous fall in BP in high-renin states, headache, cough, renal failure, hyperkalemia, angioedema Avoid in acute MI, long duration of action Esmolol 1–2 min/ 10–30 min 2–9 min Heart block, hypotension, nausea, bronchospasm, overt heart failure, cardiogenic shock Reduces cardiac output, which may impair organ perfusion Fenoldopam mesylate 5–15 min/ 30 min–4 h 5 min Tachycardia, headache, nausea, dizziness, flushing, hypotension, increased intraocular pressure Caution with glaucoma Hydralazine 10–20 min/ 1–4 h 1 h Marked hypotension, tachycardia, flushing Avoid in aortic dissection, MI, severe renal disease; prolonged and unpredictable effects; difficult to titrate Labetalol <5 min/ 3–6 h 5.5 h Bradycardia (heart block), overt heart failure, cardiogenic shock, edema, nausea, vomiting Avoid in acute heart failure; severe bradycardia; heart block, asthma   Nicardipine 5–15 min/ 15 min–6 h 44.8 min Tachycardia, headache, nausea, flushing, thrombophlebitis, hypotension, vomiting Avoid in acute heart failure; caution with coronary ischemia; long duration of action Nitroglycerin 2–5 min/ 5–10 min 1–4 min Flushing, headache, vomiting, hypotension, methemoglobinemia, decreased arterial resistance, reflex tachycardia Reduction in preload and cardiac output undesirable in patients with compromised renal and cerebral perfusion Sodium nitroprusside Immediate/ 2–3 min 2–3 min Nausea, muscle twitching, sweating, thiocyanate and cyanide intoxication, hypotension Increases intracranial pressure; may reduce coronary perfusion pressure (coronary “steal”); cyanide toxicity
    • 15. Enalaprilat <ul><li>ACE Inhibitor </li></ul><ul><ul><li>Reduces vasoconstriction and circulating catecholamine levels </li></ul></ul><ul><ul><li>Balanced reduction in afterload and pre-load </li></ul></ul><ul><ul><li>Reduces CVP, PCWP, SVR, with minimal effect on CO, HR </li></ul></ul><ul><li>Pharmacokinetics </li></ul><ul><ul><li>Moderate to slow onset of action </li></ul></ul><ul><ul><li>Longer duration of action </li></ul></ul><ul><ul><li>Full effect may not be seen for 24 hours </li></ul></ul><ul><li>May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash </li></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 16. Esmolol <ul><li>B 1 selective adrenergic blocker </li></ul><ul><ul><li>Reduction in heart rate (HR) and cardiac output (CO) </li></ul></ul><ul><ul><li>May see increase in PCWP, CVP, and SVR </li></ul></ul><ul><li>Rapid onset and short duration of action </li></ul><ul><li>Elimination via plasma esterases </li></ul><ul><li>May cause bradycardia, bronchospasm, seizures, and pulmonary edema </li></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 17. Labetalol <ul><li>Non-selective adrenergic blocker </li></ul><ul><ul><li>Alpha-1, Beta-1, Beta-2 </li></ul></ul><ul><ul><li>1:7 ratio of alpha:beta effects </li></ul></ul><ul><ul><li>Reduces SVR with little effects on HR, CO </li></ul></ul><ul><ul><li>Little to no effect on cerebral blood flow </li></ul></ul><ul><li>Moderate onset, long duration of action </li></ul><ul><li>Commonly used in HTN emergency and in ICH </li></ul><ul><li>Generally given by IV bolus in ED, OR; IV infusion used in ICU </li></ul><ul><li>May cause bronchospasm, bradycardia, heart block, delayed hypotension </li></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 18.  -Blocker vs Combined  - and  -Blocker <ul><li>Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:215-268. </li></ul><ul><li>Varon J, Malik PE. Chest. 2000;118:214-227. </li></ul>Parameters Esmolol  -Blocker Labetalol  - and  -Blocker Administration Bolus Continuous infusion Bolus Continuous infusion Onset Rapid (60 s) 2 Intermediate (peak 5-15 min) 2 Offset (Duration of action) Rapid (10-20 min) 2 Slower (2-4 h) 2 HR Decreased +/- SVR 0 Decreased Cardiac output Decreased +/- Myocardial O 2 balance Positive Positive Contraindications Sinus bradycardia Heart block >1° Overt heart failure Cardiogenic shock Severe bradycardia Heart block >1° Overt heart failure Cardiogenic shock
    • 19. Nitroglycerin <ul><li>At lower doses, works primarily by ↓ preload </li></ul><ul><ul><li>Reduces CVP, PCWP </li></ul></ul><ul><li>At higher doses, works primarily by ↓ afterload </li></ul><ul><ul><li>Some reduction in SVR, further reduction PCWP </li></ul></ul><ul><ul><li>Increase HR </li></ul></ul><ul><li>Administered as continuous infusion; onset of action 2-5 min; duration of action 5-10 min </li></ul><ul><li>Useful in managing BP </li></ul><ul><ul><li>Angina patients: improved coronary blood flow </li></ul></ul><ul><ul><li>Pulmonary edema/heart failure: decreasing preload </li></ul></ul><ul><li>Limitations: tachyphylaxis, headache, significant hypotensive effects in patients who are hypovolemic, caution in RCA IHD </li></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 20. Hydralazine <ul><li>Directly relaxes arteriolar smooth muscle – reduction in afterload </li></ul><ul><ul><li>Reduces SVR </li></ul></ul><ul><ul><li>Increases HR </li></ul></ul><ul><li>Used primarily in management of preeclampsia and eclampsia although some use in the OR, in combination with pure beta-blockers in patients who are difficult to control </li></ul><ul><li>Moderate onset; long duration of action </li></ul><ul><li>Limitations: </li></ul><ul><ul><li>reflex tachycardia often dose limiting </li></ul></ul><ul><ul><li>use associated with lupus-like syndrome </li></ul></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 21. Sodium Nitroprusside <ul><li>Arterial and venous vasodilator </li></ul><ul><ul><li>↓ Preload and afterload </li></ul></ul><ul><ul><li>Reduces SVR, CVP </li></ul></ul><ul><ul><li>Increases HR </li></ul></ul><ul><li>Onset: Immediate </li></ul><ul><li>Duration of action: 1-2 min </li></ul><ul><li>Adverse effects </li></ul><ul><ul><li>Tachycardia, nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication, coronary steal, maldistribution of blood flow </li></ul></ul><ul><li>Light sensitive: requires special delivery system </li></ul>Rynn KO et al. J Pharm Pract. 2005;18:363-376.
    • 22. Nicardipine <ul><li>Dihydropyridine calcium channel blocker </li></ul><ul><ul><li>Coronary and cerebral arterial vasodilation </li></ul></ul><ul><ul><li>No negative inotropic or dromotropic effects </li></ul></ul><ul><ul><li>Reduces SVR, little to no effect on HR/CO </li></ul></ul><ul><li>Onset: 5-15 min </li></ul><ul><li>Duration of action: 15 min-6 hours </li></ul><ul><li>Adverse effects: </li></ul><ul><ul><li>Tachycardia (+/-), headache, flushing, local phlebitis </li></ul></ul><ul><ul><li>Fluid load may be an issue for some patients </li></ul></ul>Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Rynn KO et al. J Pharm Pract . 2005;18:363-376.
    • 23. Cleviprex (clevidipine butyrate) Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Please see full prescribing information.
    • 24. Clevidipine: Overview <ul><li>Dihydropyridine calcium channel blocker (CCB) </li></ul><ul><li>T ½ ≈ 1 min </li></ul><ul><li>Selective arteriolar dilation </li></ul><ul><ul><ul><li>↓ Systemic vascular resistance </li></ul></ul></ul><ul><ul><ul><li>↓ Afterload </li></ul></ul></ul><ul><ul><ul><li>↑ Stroke volume </li></ul></ul></ul><ul><ul><ul><li>↑ Cardiac output </li></ul></ul></ul><ul><li>No venous dilation </li></ul><ul><ul><li>No effect on cardiac filling pressure </li></ul></ul><ul><li>No effect on HR </li></ul><ul><li>Clevidipine is selective for vascular as opposed to myocardial smooth muscle </li></ul>Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.
    • 25. Clevidipine: Metabolized by Plasma and Tissue Esterases <ul><li>Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite and formaldehyde </li></ul>+ Clevidipine + Reproduced from: Ericsson H, et al. Eur J Clin Pharmacol . 1999;55:61-67. Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37. O H O H H O Cl O O O O N H Cl O O Esterases O O N H Cl O O Cl H Primary metabolite
    • 26. Clevidipine: Pharmacokinetics <ul><li>Clevidipine butyrate is >99.5% bound to proteins in plasma at 37°C </li></ul><ul><li>Carboxylic acid metabolite is inactive as an antihypertensive </li></ul><ul><li>In vitro studies show that clevidipine butyrate and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme </li></ul><ul><li>83% of the drug is excreted in the urine or feces, with the major fraction (63-74%) excreted in urine </li></ul>Clevidipine Product Information August 2008; The Medicines Company
    • 27. Vascular and Myocardial Inhibitory Potency of Various Calcium Antagonists* Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50. In vitro studies comparing effects of calcium antagonists on isolated rat portal vein (vascular) vs. left ventricular rat papillary muscle (myocardial ) *Clinical significance of selectivity is unknown pIC 50 IC 50 Compounds Vascular Myocardial Selectivity Ratio Verapamil 6.6 6.46 1.4 Diltiazem 6.36 5.5 7 Nifedipine 7.62 6.47 14 Felodipine 7.47 5.40 118 Clevidipine 6.37 4.69 48
    • 28. Clevidipine Clinical Development Tolerability, Safety, PK Dose Response ESCAPE: Efficacy Clevidipine vs Placebo VELOCITY: Severe Hypertension PK, Metabolism, Rates and Routes of Excretion PK/BP ESCAPE: Efficacy Clevidipine vs Placebo PK PK/PD: Clevidipine vs Placebo ECLIPSE: Safety vs NTG QTc Study ECLIPSE: Safety vs SNP ECLIPSE: Safety vs NIC Dose Response: Clevidipine vs Placebo Hemodynamics: Clevidipine vs SNP BP, HR: Clevidipine vs SNP BP, Dose/PK BP: Clevidipine vs Placebo Phase I N=89 Phase II N=300 Healthy Volunteers Patients: Mild to Moderate Hypertension N=86 Phase III N=1821 Perioperative Hypertension N=1721 Severe Hypertension N=100 Patients: Perioperative N=214 Data on file. The Medicines Company.
    • 29. Clevidipine: Linear Pharmacokinetics <ul><li>At steady state, there is a linear relationship between dosage and arterial blood concentrations </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. N=12 normal volunteers 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
    • 30. Clevidipine: Linear Dose Response Bailey JM et al. Anesthesiology. 2002;96:1086-1094. Phase II dose-ranging study in cardiac surgery patients with hypertension *Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration. n=19 Infusion Rate (mcg/kg/min) 0 10 20 30 40 50 60 70 80 90 100 0 0.05 0.18 0.32 1.37 3.19 Responders* (%) n=0 n=1 n=4 n=6 n=9
    • 31. Clevidipine: Ultrashort Half-Life <ul><li>Approximate initial phase half-life: 1 min* </li></ul>Reproduced from Ericsson H et al. Anesthesiology . 2000;92:993-1001. *Accounts for 85-90% of clevidipine butyrate elimination. Clevidipine Product Information August 2008; The Medicines Company Triphasic Elimination arterial measurements venous measurements Representative subject – normal volunteer Graph developed from mean concentrations following 7 nmol/kg/min dose given over a 20 minute period;.
    • 32. Clevidipine: Rapid Onset <ul><li>BP-lowering effects seen within 1-2 min of clevidipine infusion </li></ul>Levy JH et al. Anesth Analg. 2007;1-5:918-925 10 5 0 – 5 – 10 – 15 – 20 – 25 – 30 0 5 10 15 20 25 30 Mean % Change From Baseline Time (min) Systolic Blood Pressure N=105
    • 33. Clevidipine: Rapid Offset Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001. N=12 normal volunteers 100 90 80 70 60 50 40 – 5 0 5 10 15 20 35 MAP (mm Hg) Time (min) 25 30 Clevidipine Infusion MAP
    • 34. Clevidipine: Hemodynamics * P <0.05, † P <0.001, ‡ P <0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg / min –1 and post-drug control. Values are mean ± SEM. Adapted from: Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193. 12 mm Hg 8 4 0 C1 0.375 0.75 1.5 3 C2 10 6 2 mcg/kg/min Central Venous Pressure C2 Systemic Vascular Resistance 1400 Units 1200 1000 0 C1 0.375 0.75 1.5 3 ‡ † † † mcg/kg/min C2 Mean Arterial Pressure Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients C1 is baseline/control before CLV administered C2 is post-CLV control after CLV discontinued † 90 80 70 * † † C1 0.375 0.75 1.5 3 mcg/kg/min mm Hg
    • 35. Clevidipine: Hemodynamics * P <0.05. † P <0.001. SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193. Stroke Volume Cardiac Output * Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients C1 is baseline/control before CLV administered C2 is post-CLV control after CLV discontinued L • min –1 0 1 2 3 4 5 6 C1 0.375 0.75 1.5 3 C2 Infusion Rate (µg • kg –1 • min –1 ) C2 75 mL/beat 70 65 0 C1 0.375 0.75 1.5 3 † * Infusion Rate (µg • kg –1 • min –1 )
    • 36. Clevidipine: Effect on Heart Rate Preoperative HR Changes in Non-Anesthetized Patients N=53 Postoperative HR Changes in Anesthetized Patients N=61 Levy JH et al. Anesth Analg . 2007;105:918-925. Singla N et al. Anesthesiology. 2005;103:A292. 10 5 0 – 5 0 5 10 15 20 25 30 % Change From Baseline Time (min) HR 5 0 – 5 0 5 10 15 20 25 30 % Change From Baseline Time (min) HR HR change for patients during the 30-minute treatment period HR change for patients during the 30-minute treatment period
    • 37. Clevidipine: Pharmacodynamics <ul><li>Clevidipine is titrated to the desired reduction in blood pressure. The infusion rate for which half the maximal effect is observed is approximately 10 mg/hr. </li></ul><ul><li>Onset: In the perioperative patient population, clevidipine produces a 4-5% reduction in SBP within 2-4 min of starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr). </li></ul><ul><li>Offset: In most patients, full recovery of blood pressure is achieved within 5-15 minutes after the infusion is stopped. </li></ul><ul><li>Duration of effect: In studies up to 72 hours, there was no evidence of tolerance; in these studies, if patients were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following discontinuation of clevidipine therapy. </li></ul>Clevidipine Product Information August 2008; The Medicines Company
    • 38. Clevidipine: Pharmacodynamics <ul><li>Hemodynamics: Clevidipine causes a dose-dependant decrease in systemic vascular resistance </li></ul><ul><li>Heart rate: An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate can be pronounced. If this occurs, decrease the dose of clevidipine. </li></ul><ul><li>Electrophysiologic effects: In healthy volunteers, clevidipine butyrate or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady state), did not prolong cardiac repolarization. </li></ul>Clevidipine Product Information August 2008; The Medicines Company
    • 39. IMPORTANT SAFETY INFORMATION <ul><li>Cleviprex is intended for intravenous use. Titrate drug depending on the response of the individual patient to achieve the desired blood pressure reduction. Monitor blood pressure and heart rate continually during infusion, and then until vital signs are stable. Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. </li></ul><ul><li>Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products; defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia; and in patients with severe aortic stenosis. </li></ul><ul><li>Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. </li></ul>Clevidipine Product Information August 2008; The Medicines Company Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Please see full prescribing information.
    • 40. IMPORTANT SAFETY INFORMATION: continued <ul><li>Most common adverse reactions (> 2%) are headache, nausea, and vomiting. </li></ul><ul><li>Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. </li></ul><ul><li>Maintain aseptic technique while handling Cleviprex. Cleviprex contains phospholipids and can support microbial growth. Do not use if contamination is suspected. Once the stopper is punctured, use and discard within 4 hours. </li></ul>Clevidipine Product Information August 2008; The Medicines Company Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Please see full prescribing information.

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