Dr dr Haerani Rasyid, MKes, SpPD, KGH, SpGKDr dr Haerani Rasyid, MKes, SpPD, KGH, SpGKHasanuddin University HospitalHasanuddin University Hospital

MakassarMakassar

Hypertensive Hypertensive patientspatients

Severe Severe hypertensionhypertension

Hypertensive Hypertensive urgencyurgency

(70-75%)(70-75%)

HypertensivHypertensive emergencye emergency

(25-30%)(25-30%)

Hypertensive Hypertensive CrisisCrisis

Severe hypertensionSevere hypertension

- Blood pressure ≥ 180/110 mmHgBlood pressure ≥ 180/110 mmHg

- Absence of symptoms beyond mild or Absence of symptoms beyond mild or moderate headachemoderate headache

- Without evidence of acute target Without evidence of acute target organ damageorgan damage

Prim Care Clin Office Pract 2008; 35: 475–487

Hypertensive urgencyHypertensive urgency

- Blood pressure ≥180/110 mmHgBlood pressure ≥180/110 mmHg

- Presence of symptoms beyond mild or Presence of symptoms beyond mild or moderate headachemoderate headache

- Without evidence of acute target Without evidence of acute target organ damageorgan damage

Prim Care Clin Office Pract 2008; 35: 475–487

Hypertensive emergencyHypertensive emergency

- Very high blood pressure (often > Very high blood pressure (often > 220/140 mmHg)220/140 mmHg)

- Accompanied by evidence of life-Accompanied by evidence of life-threatening organ dysfunctionthreatening organ dysfunction

Prim Care Clin Office Pract 2008; 35: 475–487

Malignant hypertensionMalignant hypertension

Represents markedly elevated blood Represents markedly elevated blood pressure accompanied by papiledema pressure accompanied by papiledema (grade 4 retinopathy)(grade 4 retinopathy)

Accelerated hypertensionAccelerated hypertension

Present if markedly elevated blood Present if markedly elevated blood pressure is accompanied by grade 3 pressure is accompanied by grade 3 retinopathy, but no papilledemaretinopathy, but no papilledema

Prim Care Clin Office Pract 2008; 35: 475–487

Comparison of Hypertensive Emergencies and Urgencies

VariableVariable Hypertensive Hypertensive EmergencyEmergency

HypertensivHypertensive Urgencye Urgency

SymptomsAcute BP elevation

Acute organ damageHospitalizazionIntensive care

Route of therapyArterial line

Rate of BP loweringEvaluate for secondary

hypertension

YesYes YesYesYes

IntravenousYes

Minute to hoursYes

Non or minimalYesNoNoNo

OralNo

Hours to daysYes

EpidemiologyEpidemiology

Hypertensive crises are more prevalent Hypertensive crises are more prevalent in :in :

- ElderlyElderly- Afro-AmericanAfro-American- Men (affected 2 times more often than Men (affected 2 times more often than women)women)

- Noncompliant individualsNoncompliant individuals- Persons of lower socioeconomic statusPersons of lower socioeconomic status

Cardiol Rev 2010; 18: 102-107

Less than 1 % of hypertensive population

Precipitating factors in hypertensive crisis

1. Accelerated sudden rise in blood pressure in patient with preexisting essential hypertension

2. Renovascular hypertension

3. Glomerulonephritis-acute

4. Eclampsia5. Pheochromocytoma

6. Antihypertensive withdrawl syndromes

7. Head injuries

8. Renin secreting tumors

9. Ingestion of cathecolamine precursor in patients taking MAO inhibitors

HYPERTENSIVE URGENCY

- Accelerated malignant hypertension- Hypertension associated CAD- Perioperative hypertension- Severe hypertension in renal disease- Severe hypertension in the organ transplant- patient- Hypertension associated with burns- Severe, uncontrolled hypertension

Kaplan NM . Lancet 344:1335,1994

Venkata C, Silverstein RL , Curr Hypertens Rep 2009, 11:307-314

- Hypertensive encephalopathy- Intracerebral/Subarachnoid hemorrhage- Acute aortic dissection- Acute left ventricular failure- Acute myocardial infarction- Acute glomerulonephritis- Eclampsia- Hemorrhage : Post surgical, Severe epistaxis- MAO inhibitor + tyramine interaction- Head trauma- Catecholamine excess states : Beta blocker or clonidine withdrawal, Cocaine, phencyclidine hydrochloride use, Phaeochromocytoma Crisis

HYPERTENSIVE EMERGENCY

Kaplan NM . Lancet 344:1335,1994

Venkata C, Silverstein RL , Curr Hypertens Rep 2009, 11:307-314

Patophysiology of a hypertensive crisis is not

well known.

Normotensive : arteries dilate or constrict in respons to changes in blood pressure to maintain a constant flow to the tissue bed.

Chronic hypertension : functional and structural changes in the arterial tree that shift autoregulatory curve to the right, to maintain normal perfusion in important organs and avoid an increase in local blood flow at thehigher blood pressures.

Hypertensive emergency : blood pressure increased above the capacity of the autoregulatory mechanisms to compensate by vasoconstriction tissue damage, ischemia or loss of vascular integrity.

Known stimuli or Known stimuli or Unknown stimuliUnknown stimuli

The pressure The pressure hypothesishypothesis

The humoral The humoral hypothesishypothesis

Severe blood Severe blood pressure pressure elevationelevation

- - ↑ ↑ Vasoconstrictors : Endothelin, Vasoconstrictors : Endothelin, Norepinephne, Norepinephne, Angiotensin II, Angiotensin II, VasopressinVasopressin

- - ↓ ↓ Vasodilators : Nitric oxideVasodilators : Nitric oxide

Endothelial dysfunctionEndothelial dysfunctionMyointimal proliferationMyointimal proliferationFibrinoid necrosisFibrinoid necrosis

End organ End organ damagedamage Cardiol Rev 2010; 18: 102-107

The most widespread signs and symptoms at presentation for hypertensive urgency (Zampaglione et.al, Hypertension 1996;27:144-147)

-Headache (22%)-Epistaxis (17%)-Faintness (10%)-Psychomotor agitation (10%)-Chest pain (9%)-Dyspnea (9%)-Others : arrhytmias and paresthesias

The most widespread signs and symptoms at presentation for hypertensive emergency (Zampaglione et.al, Hypertension 1996;27:144-147) :

-Chest pain (27%)-Dyspnea (22%)-Neurologic deficits (21%)

-Associated end-organ damage includes cerebral infarction (24.5%), acute pulmonary edema (22.5%), hypertensive encephalopathy (16.3%), and congestive heart failure (12.0%)

PRA and aldosterone (if primary aldosteronism is suspected)PRA before and 1 hour after 25 mg Captopril (if renovascular hypertension is suspected).Spot urine for metanephrine (if pheochromocytoma is suspected)

Goal of Treatment

1.The goal of treatment in a hypertensive emergencies is to restore blood pressure to a range in which autoregulatory forcesmay be re-established.

2. The treatment target is often not a normal blood pressure, but instead one that is only moderately lower, just sufficient to allow autoregulation to be restored.

Management ofManagement ofHypertensive Emergency Hypertensive Emergency (general)(general)

Patients should be admitted to an Intensive Care Patients should be admitted to an Intensive Care Unit for continuous monitoring of BP and parenteral Unit for continuous monitoring of BP and parenteral administration of an appropriate agentadministration of an appropriate agent

The initial goal therapy is to reduce mean arterial BP The initial goal therapy is to reduce mean arterial BP by no more than 25% (within minutes to 1 hour).by no more than 25% (within minutes to 1 hour).

Then if stable, to 160/100 to 110 mmHg within the Then if stable, to 160/100 to 110 mmHg within the next 2 to 6 hours.next 2 to 6 hours.

Excessive falls in pressure that may precipitate Excessive falls in pressure that may precipitate renal, cerebral, or coronary ischemia should be renal, cerebral, or coronary ischemia should be avoided.avoided.

Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 2560-70

Management ofManagement ofHypertensive Emergency Hypertensive Emergency (general)(general)

If this level of BP is well tolerated and the If this level of BP is well tolerated and the patients is clinically stable , further gradual patients is clinically stable , further gradual reductions toward a normal BP can be reductions toward a normal BP can be implemented in the next 24 to 48 hours.implemented in the next 24 to 48 hours.

Exceptions :Exceptions :1.1. Patients with ischemic strokePatients with ischemic stroke2.2. Aortic dissection SBP should < 100 mmHgAortic dissection SBP should < 100 mmHg3.3. Patients whom BP is lowered to enable the Patients whom BP is lowered to enable the

use of thrombolytic agentsuse of thrombolytic agents

Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 2560-70

Parenteral Drugs for Treatment of Parenteral Drugs for Treatment of Hypertensive Emergencies based on JNC 7Hypertensive Emergencies based on JNC 7

DrugsDrugs DoseDose OnsetOnset Duration of Duration of ActionAction

Sodium Sodium nitroprussidenitroprusside

0.25-10 ugr/kg/min0.25-10 ugr/kg/min ImmediateImmediate 1-2 minutes after 1-2 minutes after infusion stopped infusion stopped

NitroglycerinNitroglycerin 5-500 ug/min5-500 ug/min 1-3 minutes1-3 minutes 5-10 minutes5-10 minutes

Labetolol HClLabetolol HCl 20-80 mg every 10-15 min 20-80 mg every 10-15 min or 0.5-2 mg/min or 0.5-2 mg/min

5-10 minutes5-10 minutes 3-6 minutes3-6 minutes

Fenoldopan HClFenoldopan HCl 0.1-0.3 ug/kg/min0.1-0.3 ug/kg/min <5 minutes<5 minutes 30-60 minutes30-60 minutes

Nicardipine HClNicardipine HCl 5-15 mg/h5-15 mg/h 5-10 minutes5-10 minutes 15-90 minutes15-90 minutes

Esmolol HClEsmolol HCl 250-500 ug/kg/min IV 250-500 ug/kg/min IV bolus, then 50-100 bolus, then 50-100 ug/kg/min by infusion; ug/kg/min by infusion; may repeat bolus after 5 may repeat bolus after 5 minutes or increase minutes or increase infusion to 300 ug/mininfusion to 300 ug/min

1-2 minutes1-2 minutes 10-30 minutes10-30 minutes

Chobanian AV et al, The JNC 7 report, JAMA 2003;389-2560-70

DrugDrug I.V. Bolus DoseI.V. Bolus Dose Continous Infus Continous Infus RateRate

LabetalolLabetalolNicardipineNicardipineEsmololEsmololEnalaprilEnalaprilHydralazineHydralazineNiprideNiprideNTGNTG

5 – 20 mg every 155 – 20 mg every 15’’NANA250 ug/kg IVP loading dose250 ug/kg IVP loading dose1,25-5 mg IVP every 6 h1,25-5 mg IVP every 6 h5 – 20 mg IVP every 305 – 20 mg IVP every 30’’NANANANA

2 mg/min (max 300mg/d)2 mg/min (max 300mg/d)5-15 mg/h5-15 mg/h25-300 ug/kg/m25-300 ug/kg/mNANA1,5-5 ug/kg/m1,5-5 ug/kg/m0,1-10 ug/kg/m0,1-10 ug/kg/m20-400 ug/m20-400 ug/m

AHA/ASA Guideline, 2007 update. Stroke. 2007;38: 2001-2023.

Parenteral Drugs for Treatment of Hypertensive Emergencies based on ASA Guideline

This parenteral drugs are approved for hypertensive emergency in acute ischemic stroke and intracerebral hemmorhage

Parenteral Drugs for Treatment of Parenteral Drugs for Treatment of Hypertensive Emergencies based on CHEST 2007Hypertensive Emergencies based on CHEST 2007

Acute Pulmonary edema / Acute Pulmonary edema / Systolic dysfunctionSystolic dysfunction

Nicardipine,Nicardipine, fenoldopam, or nitropruside combined with fenoldopam, or nitropruside combined with nitrogliceryn and loop diureticnitrogliceryn and loop diuretic

Acute Pulmonary edema/ Acute Pulmonary edema/ Diastolic dysfunctionDiastolic dysfunction

Esmolol, metoprolol, labetalol, verapamil, combined with Esmolol, metoprolol, labetalol, verapamil, combined with low dose of nitrogliceryn and loop diuretics low dose of nitrogliceryn and loop diuretics

Acute Ischemia CoronerAcute Ischemia Coroner Labetalol or esmolol combined with diureticsLabetalol or esmolol combined with diuretics

Hypertensive encephalopatyHypertensive encephalopaty NicardipineNicardipine, , labetalol, fenoldopamlabetalol, fenoldopam

Acute Aorta DissectionAcute Aorta Dissection Labetalol or combinedLabetalol or combined NicardipineNicardipine and esmolol or combine and esmolol or combine nitropruside with esmolol or IV metoprololnitropruside with esmolol or IV metoprolol

Preeclampsia, eclampsiaPreeclampsia, eclampsia Labetalol or Labetalol or nicardipinenicardipine

Acute Renal failure / Acute Renal failure / microangiopathic anemiamicroangiopathic anemia

NicardipineNicardipine or fenoldopamor fenoldopam

Sympathetic crises/ cocaine Sympathetic crises/ cocaine oveerdoseoveerdose

Verapamil, diltiazem, orVerapamil, diltiazem, or nicardipinenicardipine combined with combined with benzodiazepinbenzodiazepin

Acute postoperative Acute postoperative hypertensionhypertension

Esmolol,Esmolol, NicardipineNicardipine, , LabetalolLabetalol

Acute ischemic stroke/ Acute ischemic stroke/ intracerebral bleedingintracerebral bleeding

Nicardipine,Nicardipine, labetalol, fenoldopamlabetalol, fenoldopam

Marik Paul E, Varon Joseph, CHEST 2007;131:1949-62

• Nicardipine :

. Dihydropiridine class of CCB

• Reduce peripheral resistance --- blood pressure

• water soluble, light insensitive, -- can be parenteraly used (deference with nifedipine / sodium nitroprusid)

USE OF NICARDIPINE

• peripheral vasodilatation• preserve or enhanced cardiac pump activity

------ improve tissue perfusion• fall in systemic blood pressure, maintain at desired

level• in comparison with sodium nitropruside – equally

effective, but no cyanide toxic effect in long term use • not associated adverse effect on cardiovascular and

renal function

PRIMARY HEMODYNAMIC OF NICARDIPINE EFFECT

Comparison between Calcium AntagonistComparison between Calcium Antagonist

DrugDrug Coronary Coronary VasodilationVasodilation

SuppressionSuppressionof Cardiac of Cardiac

ContractilityContractilitySuppressionSuppressionof SA Nodeof SA Node

SuppressionSuppressionof AV Nodeof AV Node

VerapamilVerapamil(phenylalkylamine)(phenylalkylamine) ++++++++ ++++++++ ++++++++++ ++++++++++

DiltiazemDiltiazem(benzothiazepin)(benzothiazepin) ++++++ ++++ ++++++++++ ++++++++

Nicardipine(dihydropyridine ) ++++++++++ 00 ++ 00

Kerins DM. Goodman Gilman’s.10th ed.2001:843-70

Tissue selectivity betweenTissue selectivity betweenCalcium AntagonistCalcium Antagonist

Bristow et al. Br J Pharmacol1984; 309:82

Comparison Study with Comparison Study with Intravenous DiltiazemIntravenous Diltiazem

Subjects:Patients requiring a rapid reduction in BP (DBP 115 mmHg)

Design:Multicenter, randomized, single-blind comparative study

DosageNicardipine: Started at 0.5 g/kg/min

Increased up to 10 g/kg/min if necessaryDiltiazem: Started at 5 g/kg/min

Increased up to 15 g/kg/min if necessary

Duration of drug administration Dose titration: 1 hour Maintenance infusion: 24 hours

Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

Stability Effect

0

69

24.1

6.8

95.8

4.20

20

40

60

80

100

120

Stable Slightly unstable Undeterminable

%

PerdipineDiltiazem

Stability of antihypertensive Stability of antihypertensive effect effect better than Diltiazem Diltiazem

Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

Nicardipine vs NitrovasodilatorsNicardipine vs Nitrovasodilators

Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25.

DrugDrug NicardipineNicardipine(Perdipine(Perdipine®® IV) IV)

NitroprussideNitroprusside NitroglycerinNitroglycerin

Rapid Onset of Peak EffectRapid Onset of Peak Effect ++++++++ ++++++++ ++++++

Afterload ReductionAfterload Reduction ++++++++ ++++++++ ++

Preload ReductionPreload Reduction 00 ++++ ++++++++

Coronary Steal ReportedCoronary Steal Reported 00 ++ 00

Coronary Dilation: Large VesselCoronary Dilation: Large Vessel ++++++ ++ ++++++++

Coronary Dilation: Small VesselCoronary Dilation: Small Vessel ++++++ +/-+/- +/-+/-

TachycardiaTachycardia ++ ++++ ++++

Potential for Symptomatic Potential for Symptomatic HypotensionHypotension

++ ++++ ++++++

Ease of AdministrationEase of Administration ++++++++ ++++ ++++++

Cyanide ToxicityCyanide Toxicity 00 ++++++++ 00

Prevention

- Hypertensive crisis are largely preventable

- Risk factors of hypertensive crises : 1. Inadequate management of hypertension by the physician 2. Poor adherence to therapy by the patient 3. Insufficient access to care

Prim Care Clin Office Pract 2008; 35: 475–487

THANK YOU FOR YOUR ATTENTIONTHANK YOU FOR YOUR ATTENTION

TAKE CARE OF YOUR HEART, BRAIN, AND KIDNEY