HYPERTENSIVE CRISIS AND BRAIN NATRIURETIC PEPTIDE

Presented by Ben SherrillDoctor of Pharmacy CandidateUGA College of PharmacyClass of 2012

IntroductionPurpose:

◦Define Hypertensive Crisis and their guideline-based treatments

◦Explain the relationship of BNP and Hypertensive Crisis

◦Discuss recent studies relevant to the subject

Hypertensive CrisisEpidemiology

◦Affects ≈500,000 Americans annually◦1-2% of patients with essential hypertension

will experience hypertensive crisisAge/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

Hypertensive CrisisTwo 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.

Hypertensive CrisisPathophysiology

◦Can be caused by any disorder that causes hypertension Rate of change in BP will determine

likelihood that an acute hypertensive syndrome developsContributing factors

Genetic predisposition CatecholaminesSmoking Kininogen deficiencyOral contraceptives Kinin deficiencyHigh renin/angiotensin II Prostacyclin deficiencyAntidiuretic hormone Immunologic factors

Hypertensive CrisisPathophysiology 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

Hypertensive CrisisComplications

◦Myocardial infarction◦Hypertensive encephalopathy◦Left ventricular hypertrophy◦Retinopathy◦Cerebrovascular accident◦Chronic renal failure◦Aortic dissection

Hypertensive CrisisDiagnosis

◦Not made on basis of BP alone Rate of increase in BP is more important than

absolute BPPresentation

◦Varies depending on disease state◦Textbook symptom is “BP >180/120”◦Other symptoms:

Back pain Neurologic deficitsChest pain SeizuresDyspnea Altered mental status

Hypertensive CrisisDifferential DiagnosisBlunt head trauma Intracranial

hemorrhageThromboembolic stroke

Acute coronary syndrome

Subarachnoid hemorrhage

Aortic dissection

Bacterial meningitis Malignant hypertension

Alcohol withdrawal syndrome

Pulmonary edema Pre-eclampsia Acute renal failurePoisoning Drug ADR Chronic renal failureCerebral metastases

Primary malignant neoplasm of cerebrum

Viral encephalitis

Pheochromocytoma

Hypertensive CrisisPrognosis

◦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

Hypertensive Crisis: TreatmentHypertensive 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

Hypertensive Crisis: TreatmentHypertensive 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

Drug Dose TimeCaptopril 25mg to 50mg 1 to 2 hour

intervals

Clonidine 0.2mg initially, followed by 0.2mg hourly, to a max of 0.7mg

Given hourly until DBP is <110

Labetalol 200mg to 400mg Additional dose every 2 to 3 hours

Hypertensive Crisis: TreatmentHypertensive 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

Hypertensive Crisis: Treatment

Brain Natriuretic PeptideBNP is a hormone secreted by the heart

ventricles◦Secreted in response to stretching of

cardiomyocytesSystemically, 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

Brain Natriuretic PeptideSignificance

◦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

Brain Natriuretic PeptideStudies

◦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

STUDY 1: ELEVATED B-TYPE NATRIURETIC PEPTIDE BLOOD LEVELS DURING HYPERTENSIVE CRISIS

Di Somma, et al. High Blood Pressure & Cardiovascular Prevention. January 1 2008, Vol. 15. 1: 23-28

Study 1Observational studyObjectives

◦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

Study 1Rationale

◦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)

Study 1Methods

◦ 57 patients admitted to ED for acute elevated BP between March 2006 and July 2007

◦ All patients received: 12 lead EKG FunduscopyChest 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

Study 1

Study 1Methods

◦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

STUDY 1This chart is a breakdown of the statistical distribution of the target-organ lesions associated with hypertensive emergencies in the study population. ACS = Acute coronary syndromeHen = Hypertensive encephalopathyHS = Hemorrhagic strokeIS = Ischemic strokeTIA = Transient ischemic attack

Study 1Results

◦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

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)

Study 1

Study 1

Study 1Discussion

◦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

Study 1Limitations

◦Small study◦Circulating levels of BNP before the

hypertensive crisis are unknownConclusion

◦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

STUDY 2: D-DIMER AND BNP LEVELS IN ACUTE AORTIC DISSECTION

Sbarouni, et al. International Journal of Cardiology. January 17 2007, Vol. 122; 170-172

Study 2Letter to the editorProspective observational studyObjectives

◦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

Study 2Methods

◦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

Study 2Results

◦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)

Study 2

Study 2Discussion 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

Study 2Limitations

◦Very small◦BP was not measured◦Larger sample sizes needed with

more involvement from multiple study centers

Level of evidence◦IIIb

ConclusionBNP 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

Sources1. Pharmacotherapy: A pathophysiologic approach, 8th edition.

Joseph T. Dipiro, et al. 2011 McGraw Hill2. Hypertensive Crisis, Micromedex 2.o. Last update August 9,

20113. Clinical Features in the Management of Selected Hypertensive

Emergencies. William J. Elliot. Progress in Cardiovascular Diseases, March/April 2006. Vol. 48, 5; 316-325

4. Hypertensive Crisis: Hypertensive Emergencies and Urgencies. M. Aggarwal, I. Khan. Cardiology Clinics, 2006, Vol. 24; 135-146

5. 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

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