HYPERTENSIVE CRISIS AND BRAIN NATRIURETIC PEPTIDE

1. HYPERTENSIVE CRISIS AND BRAIN NATRIURETIC PEPTIDE Presented by Ben Sherrill Doctor of Pharmacy Candidate UGA College of Pharmacy Class of 2012

2. Introduction • Purpose: • Define Hypertensive Crisis and their guideline-based treatments • Explain the relationship of BNP and Hypertensive Crisis • Discuss recent studies relevant to the subject

3. Hypertensive Crisis • Epidemiology • Affects ≈500,000 Americans annually • 1-2% of patients with essential hypertension will experience hypertensive crisis • Age/gender • Peak incidence for urgencies and emergencies: • Male – 51 to 60 years / 61 to 70 years • Female – 61 to 70 years / 81 to 90 years • Rarely occurs in children, however… • Nearly 25% of children presenting with hypertension require emergency treatment compared to only 1% of adults

4. Hypertensive Crisis • Two types • Hypertensive urgency • BP >180/120 • Hypertensive emergency • BP >180/120 with acute or immediately progressing target organ damage • Examples of target organ damage: • encephalopathy, intracranial hemorrhage, unstable angina, dissecting aortic aneurysm, etc.

5. Hypertensive Crisis • Pathophysiology • Can be caused by any disorder that causes hypertension • Rate of change in BP will determine likelihood that an acute hypertensive syndrome develops

6. Hypertensive Crisis • Pathophysiology cont. • Arteriolar changes can occur in multiple organs • Necrotizing arteriolitis is most prominent in the kidneys, brain, heart, and eyes • Inflammation and necrosis of the arterioles • Worsened by platelet plugging, fibrin deposition, and hemolysis • Very prominent in the kidneys • Leads to renal failure and activation of the renin-angiotensin system

7. Hypertensive Crisis • Complications • Myocardial infarction • Hypertensive encephalopathy • Left ventricular hypertrophy • Retinopathy • Cerebrovascular accident • Chronic renal failure • Aortic dissection

8. Hypertensive Crisis • Diagnosis • Not made on basis of BP alone • Rate of increase in BP is more important than absolute BP • Presentation • Varies depending on disease state • Textbook symptom is “BP >180/120” • Other symptoms: Back pain Neurologic deficits Chest pain Seizures Dyspnea Altered mental status

9. Hypertensive Crisis

10. Hypertensive Crisis • Prognosis • Mortality • Related to the degree of renal dysfunction and severity of retinopathy • Lowest survival is associated with renal insufficiency and severe hypertensive retinopathy • Renal insufficiency is the strongest predictor of mortality

11. Hypertensive Crisis: Treatment • Hypertensive urgency • Ideally managed by adjusting maintenance therapy, adding a new antihypertensive, or increasing the dose of a current medication • Preferred approach because it allows for a gradual decrease in BP • Rapid decreases in BP are discouraged due to potential risks • CVA, MI, acute kidney failure • Requires reduction in BP with oral meds over the course of several hours to several days

12. Hypertensive Crisis: Treatment • Hypertensive urgency cont. • Possible to use acute administration on short-acting oral agents, such as captopril, clonidine, or labetalol. And carefully monitor the patient • Lacking data to support

13. Hypertensive Crisis: Treatment • Hypertensive emergency • Target organ damage • Require parenteral therapy • The goal is not to lower BP to less than 140/90 • Initial target is a reduction in Mean Arterial Pressure of up to 25% within minutes to hours • Once stable, BP can then be reduced to 160/100 – 160/110 within the next 2 to 6 hours • If taper is tolerated, more reduction can be made over the next 24 to 48 hours • Slow approach is due to the risk of end-organ ischemia or infarction • There is one exception to this approach • Patients presenting with acute ischemic stroke • Elevated BP is required for an extended period of time

14. Hypertensive Crisis: Treatment

15. Brain Natriuretic Peptide • BNP is a hormone secreted by the heart ventricles • Secreted in response to stretching of cardiomyocytes • Systemically, BNP decreases vascular resistance and central venous pressure • It also increases netriuresis • The net effect is a decrease in blood volume, which in turn lowers systemic blood pressure and afterload • This helps increase cardiac output (increased ejection fraction

16. Brain Natriuretic Peptide • Significance • Used for screening and diagnostic purposes • Acute decompensated heart failure • Higher levels have been associated with worse prognosis • Unfortunately, there is no clearly defined level which separates patients with or without heart failure • CHF patients – BNP is typically >100pg/mL • Diagnostic gray area in the 100-500pg/mL range • Many studies have been designed to test the significance of BNP in various disease states

17. Brain Natriuretic Peptide • Studies • BNP demonstrated to increase during acute decompensated heart failure and ACS • Result of direct myocyte injury from pressure or volume overload • Release of BNP results in improved myocardial relaxation • Also serves a regulatory role in response to acute increases in ventricular vol. • Opposes vasoconstriction, Na+ retention, and antidiuretic effect of the RAAS

18. Di Somma, et al. High Blood Pressure & Cardiovascular Prevention. January 1 2008, Vol. 15. 1: 23-28 STUDY 1: Elevated B-Type Natriuretic Peptide Blood Levels During Hypertensive Crisis

19. Study 1 • Observational study • Objectives • Assess the role of BNP in the course of hypertensive crisis • Evaluate the possible role of BNP in the differential diagnosis between HE or HU • Investigate the relationship between BNP concentration and BP acute burden with consequent myocardial ischemia or brain damage

20. Study 1 • Rationale • Recent studies found increased levels of BNP in hypertensive crisis compared with patients with normal BP • Studies had also demonstrated increased BNP associated with heart strain due to acute increased after load (as in HE)

21. Study 1 • Methods • 57 patients admitted to ED for acute elevated BP between March 2006 and July 2007 • All patients received: • 12 lead EKG Funduscopy Chest X-ray • CBC CMP Cardiac enzymes • If indicated, patients also received echocardiogram and brain CT • Inclusion criteria: • Hypertensive crisis and admitted to 1 of 2 ED’s • Exclusion criteria: • Pregnant, age <18 or >90, BMI >30, neoplasms, chronic kidney failure, atrial fibrillation, traumatic chest events, heart failure

22. Study 1

23. Study 1 • Methods • Patients were divided into 2 groups: 25 with HE (target organ damage) and 32 with HU • SBP and DBP were measured from both right and left arms • Average of 2 readings taken 30 s apart • MAP calculated as DBP + 1/3 Pulse Pressure • PP = SBP – DBP • Student t-test was used for comparison of characteristics between the two groups, and to find statistical differences in BNP between HE and HU

24. Study 1 This chart is a breakdown of the statistical distribution of the target-organ lesions associated with hypertensive emergencies in the study population. ACS = Acute coronary syndrome Hen = Hypertensive encephalopathy HS = Hemorrhagic stroke IS = Ischemic stroke TIA = Transient ischemic attack

25. Study 1 • Results • 44% incidence of HE, 56% incidence of HU • 2 subgroups were distinguished in HE • Cardiac involvement (40%) • 10 pts with ACS (8 w/ unstable angina, 2 w/ acute MI) • Neurological involvement (60%) • 15 pts total (7 w/ IS, 2 w/ TIA, 4 w/ HS, 2 w/ Hen) • No significant difference at the ED admission in SBP, DBP, MBP, PP, age, SCr, CrCl, BMI, or gender distribution • Avg hospital stays were 5 days for HE and 12 hours for HU

26. Study 1 • Results • Mean BNP for all pts was 62.85 +/- 74.24 pg/mL • In HE, mean BNP was 113.22 +/- 87 pg/mL (p<0.01) • In HU, mean BNP was 23.5 +/- 21.3 pg/mL (p<0.01) • Mean BNP for myocardial ischemia sub-group was 162.02 +/- 95.7 pg/mL (p<0.01) • Mean BNP for neurological sub-group was 80.7 +/- 65.2 (p<0.01) • No correlation between BNP and SBP, DBP, MAP, PP, and BMI • A statistical correlation between BNP and PP (r=0.37; p<0.05) was found for the HU group • A significant negative relationship was found between renal clearance in BNP (r=-0.36, p<0.01) • A positive correlation was found between age and BNP (r=0.4, p<0.05)

27. Study 1

28. Study 1

29. Study 1 • Discussion • BNP can help distinguish between HE (with heart or brain damage) and HU • Authors speculate that BNP is released into the blood during HE with heart involvement due to acute ischemic disease • Recent studies show possibility of BNP release during a sudden increase in BP as a result of heart involvement (such as in pre-eclampsia) due to increase of systemic vascular resistance • Also speculate that rise of BNP in HE should be attributed to the high increase of afterload due to sudden acute rise in systemic vascular resistance

30. Study 1 • Limitations • Small study • Circulating levels of BNP before the hypertensive crisis are unknown • Conclusion • BNP has a role as a diagnostic tool in the ED for the screening of HE due to myocardial involvement or brain injury • Level of evidence • IIIa

31. Sbarouni, et al. International Journal of Cardiology. January 17 2007, Vol. 122; 170-172 STUDY 2: D-dimer and BNP Levels in Acute Aortic Dissection

32. Study 2 • Letter to the editor • Prospective observational study • Objectives • To test if there is a simple and quick laboratory test to rule out AAD • They looked at D-dimer, C-reactive protein, BNP, and white blood cell count in patients with established AAD

33. Study 2 • Methods • Patients • 18 consecutive patients with diagnosed AAD admitted for surgery • 21 consecutive patients with chronic aortic aneurysm • 8 normal subjects • Diagnosis performed for all with computed tomography and echocardiogram • Dissection was classified according to Stanford classification • Serum levels of study substances were drawn as soon as the patient came to the hospital

34. Study 2 • Results • Significant difference between 3 study groups for all 4 parameters • WBC: p=0.0005 • D-dimer : p<0.0001 • CRP: p=0.0121 • BNP: p=0.0012 • For BNP: plasma levels were significantly higher in AAD and CAD groups compared to normal patient group (p=0.0005 and p=0.0016) • No significant difference between AAD and CAD group (p=0.32)

35. Study 2

36. Study 2 • Discussion and Conclusion related to BNP • Small sample size • To authors’ knowledge, first study comparing BNP with AAD and CAD • Elevated in both groups compared to control • AAD and CAD associated with longstanding HTN, which is often accompanied with diastolic abnormalities of the left ventricle and aortic regurgitation • Incompetence of the aortic valve presents with increased pulse pressure, which correlates positively with BNP levels in healthy adults • BNP is not a good diagnostic marker for AAD compared to D-dimer

37. Study 2 • Limitations • Very small • BP was not measured • Larger sample sizes needed with more involvement from multiple study centers • Level of evidence • IIIb

38. Conclusion • BNP has potential for use as a diagnostic marker in hypertensive emergency • Needs more evaluation with better designed studies • Circulating BNP levels pre-hypertensive event would provide a better idea of relationship • Impossible to predict • Many questions are left to be answered in the future

39. Sources • Pharmacotherapy: A pathophysiologic approach, 8th edition. Joseph T. Dipiro, et al. 2011 McGraw Hill • Hypertensive Crisis, Micromedex 2.o. Last update August 9, 2011 • Clinical Features in the Management of Selected Hypertensive Emergencies. William J. Elliot. Progress in Cardiovascular Diseases, March/April 2006. Vol. 48, 5; 316-325 • Hypertensive Crisis: Hypertensive Emergencies and Urgencies. M. Aggarwal, I. Khan. Cardiology Clinics, 2006, Vol. 24; 135-146 • Elevated B-Type Natriuretic Peptide Blood Levels During Hypertensive Crisis. S. Di Somma, et al. High Blood Pressure & Cardiovascular Prevention. January 1 2008, Vol. 15. 1: 23-28 • D-dimer and BNP Levels in Acute Aortic Dissection. Sbarouni, et al. International Journal of Cardiology. January 17 2007, Vol. 122; 170-172