DEFINITION :DEFINITION :

HYPERTENSIVE CRISIS A severe elevation in BP, generally a SBP > 220 mm Hg and / or DBP > 120 mm Hg. (JNC-VI, 1997)

HYPERTENSIVE EMERGENCIES Severe elevation in BP complicated by acute target organ

dysfunction, such as coronary ischemia, stroke, intracerebral

hemorrhage, pulmonary edema, or acute renal failure.

HYPERTENSIVE URGENCIES Severe elevations in BP without evidence of target organ

deterioration.

Colhum DA. Oparil S, New Engl. J. Med, 323 : 1177, 1990

PREVALENCE :PREVALENCE :

1. Hypertensive crisis reprensented 27 % of all medical emergencies encountered over a year interval (zampaglione et al, Turin, Italy, 1996)

2. In Patients with untreated primary hypertension before the availability of modern antihypertensive therapies, the incidency of accelerated hypertension with papiledema was 7% (Cahhoun DA, Oparil S, N. Engl. J. Med 332 : 1029, 1995)

3. Hypertensive emergencies occur most frequently in patients previously diagnosed with primary hypertension but who are non compliant.

4. At present + 1 % of patient with primary hypertension will progress to an accelerated-malignant form

PROGNOSIS :PROGNOSIS :1. In 1939, Keith et al found that patients with hypertension

and grade IV retinopathy had a mean survival of 10.5 months, with no survivors at 5 years.

2. In 1958, Dustan at al found that among 84 patients being treated for malignant hypertension, 70 % survived 1 year and 33 % survived 5 years.

3. In the 1960s, with use of more effective and better tolerated anti hypertensive agents, 5 year survival rates were 50 to 60 %.

4. 1970s, with increase use of dialysis 5 year survival rates + 75 %.

5. Current survival of patients with severe hypertension approaches that of patients with uncomplicated primary hypertension.

- Accelerated malignant hypertension- Hypertensive encephalopathy- Intracerebral/Subarachnoid hemorrhage- Acute aortic dissection- Acute left ventricular failure- Acute myocardial infarction- Acute glomerulonephritis- Eclampsia- Severe epistaxis- Perioperative hypertension, etc

HYPERTENSIVE CRISISDBP >120 mmHg

URGENCY BP within hours < 24 hours

EMERGENCY BP within minutes < 1 hours

(PARENTERAL / ORAL)(PARENTERAL / ORAL) (PARENTERAL)(PARENTERAL)

KAPLAN NM . Lancet 344:1335,1994

End-Organ Damage Associated Hypertensive EmergenciesEnd-Organ Damage Associated Hypertensive Emergencies

End-Organ Damage Type No of Cases (%)

Cerebral Infarction 26 (24.5)

Intracerebral or sub-arachnoid hemorrhage 5 (4.5)

Hypertensive encephalopathy 18 (16.3)

Acute pulmonary edema 24 (22.5)

Acute congestive heart failure 15 (14.3)

Acute myocardial infarction or unstable angina pectoris 13 (12.0)

Eclampsia 5 (4.5)

Aortic dissection 2 (2.0)

Zampaglione, et al. AHA ; 27 (1) : 144

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

M. Kaplan, Clinical Hypertension, 7th edition, Baltimore, 266 : 1998

Local Effects (Prostaglandins, Free Radical, etc.

Endothelial Damage

Platelet Deposition

Systemic Effects (Renin-angiotensin, Cathecol,

Vasopression

Critical Degree of Hypertension

Mitogenic and MigrationFactors

Myointimal Proliferation

Further Rise in Blood PressureAnd

Vascular Damage

Tissue Ischemia

Pressure Natriuresis

Hypovolemia

Further Increase inVasopressure

Lancet 2000; 356: 411–17

Putative Vascular Pathophysiology of Hypertensive Emergencies

Initial Evaluation of Patients with a Hypertensive Initial Evaluation of Patients with a Hypertensive EmergenciesEmergencies

M. Kaplan, Clinical Hypertension, 7th edition, Baltimore, 267 : 1998

HISTORY• Prior diagnosis and treatment of hypertension.• Intake of pressor agent : street drugs, sympathomimetics.• Symptom of cerebral, cardiac, and visual dysfunction.PHYSICAL EXAMINATION• Blood Pressure• Funduscopy• Neurologycal Status• Cardiopulmonary status• Body fluid volume assessment• Peripheral pulsesLABORATORY EVALUATION• Packed cell volume and blood smear• Urine analysis• Chemistry : creatinine, glucose, electrolytes• Electrocardiogram• 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)• Chest radiograph (if heart failure or aortic dissection is suspected)

Plasma Renin Activity in Hypertensive Plasma Renin Activity in Hypertensive CrisisCrisis

Laragh J.H., AJH 2001; 14 : 1154-1167

DISORDERS WITH HIGH RENIN• Malignant HypertensionOTHER MEDIUM TO HIGH RENIN STATES• Unilateral renovascular hypertension• Renal vasculitis (scleroderma, lupus, polyarteritis)• Renal trauma• Renin secreting tumors• Adrenergic crises ; pheochromocytoma, cocaine abuse, clonidine or methyl DOPA

withdrawal.PROBABLE MEDIUM to HIGH RENIN STATE : PRA 0.65 ng/mL/hour• Hypertensive encephalopathy• Hypertension with cerebral hemorrhage• Hypertension with (impending) stroke• Hypertension with pulmonary edema• Hypertension with acute myocardial infarction or with unstable angina.• Dissecting aortic aneurysm• Peri-operative hypertension.PROBABLE MEDIUM to HIGH RENIN STATE : PRA 0.65 ng/mL/hour• Acute tubular necrosis• Acute glomerulonephritis• Urinary tract obstruction• Primary aldosteronism• Low renin essential hypertension• Pre-eclampsia/eclampsia (PRA values falls from 6 to 10 range of normal pregnancy, to 1

ng/mL/hour.

Circumstances Requiring Rapid Treatment of Hypertension (DBP > 120 mmHg)

Accelerated-malignant hypertension with papilloedemaCerebrovascular• Hypertensive encephalopathy• Atherothrombotic brain infarction with severe hypertension.• Intracerebral hemorrhage, subarachnoid hemorrhage.

Cardiac• Acute aortic dissection• Acute left ventricular failure• Acute or impending myocardial infarction• After coronary bypass surgery

Renal• Acute glumerulonephritis• Renal crisis from collagen-vascular diseases.• Severe hypertension after kidney transplantation

Circumstances Requiring Rapid Treatment of Hypertension (cont…)

Excessive circulating – cathecolamines

• Pheochromocytoma crisis• Food and drug interactions with monoamine oxidase inhibitor• Sympathomimetic drug use (cocaine)• Rebound hypertension after suddent cessation of antihypertensive drugs.

Eclampsia, Surgical

• Severe hypertension in patients requiring immediated surgery.• Post-operative hypertension• Post-operative bleeding from vascular suturelines

Severe body burns, Severe epistaxis.

Kaplan NM : Management Hypertension Emergencies, LANCET, 344, 1994 : 1335

TreatmentTreatment

1. The goal of therapy is to reduce systemic vascular resistance.

2. The approach is to initially reduce mean arterial pressure by about 25 % with further reductions accomplished more gradually.

3. In general the initial reduction should be achieved over a period of 1 to 2 hours with less rapid reduction over the ensuring 6 hours to a DBP of + 100 mm Hg.

4. With the exception of patients with aortic dissection, the BP should not be reduce to normotensive and especially hypotensive levels, as target organ hypoperfusion may results.

Current Recommendation of the AHA :

• Hypertension in the setting of acute ischemic stroke should only be treated rarely and cautiously .

• Treat : DBP > 120-130 mmHg , objective reduction 20 % in the first 24 hours.

• Abandon oral nifedipine.• Short actingIV.

(labetalol,nicardipine,fenoldopam )• SNP increase ICP,cyanide poisoning

Intracerebral Hematoma• Hypertension serve to protect CBF

in the setting of high ICP.• Treat if : systolic blood pressure >

200 mmHg or DBP > 110 mmHg.• The rate of decline in blood

pressure was independently associated with increased mortality.

MANAGEMENT OF HYPERTENSIVE EMERGENCIESMANAGEMENT OF HYPERTENSIVE EMERGENCIES

• Reduce Mean Arterial BP no More than 25 % over 2 hours then Reduce to 160 / 100 mm Hg within 2-6 hours.

• Avoid excessive falls in Blood Pressure

• Titrate with Intravenous antihypertensives.

• Guideline of treatment based on concensus expert.

JNC-VI RECOMMENDATION

Profile of an ideal IV Profile of an ideal IV antihypertensiveantihypertensive• Preserves GFR and renal blood flow• Few or no drug reactions• Little or no potential for exacerbation of co-morbid

conditions• Rapid onset and offset of action• Minimal hypotension “overshoot”• Minimal need for continuous BP monitoring and frequent

dose titration• No acute tolerance• Ease of use and convenience• Safe and no toxic metabolites• Multiple formulations for short and long term use• Minimal symphathetic activation

End-Organ Complication of Hypertensive Emergencies

END-ORGAN

COMPLICATIONS THERAPEUTIC CONSIDERATIONS

Aortic Aortic dissection -BLOCKADE, labetolol (decrease dp/dt), SODIUM NITROPRUSSIDE with -BLOCKADE, avoid isolated use of pure vasodilators.

Brain Hypertensive encepha- lopathyCerebral infarction orHaemorrhage

Avoid centrally acting antihypertensive drugs such as CLONIDINE.Avoid centrally acting agents : avoid rapid decreases in blood pressure

Heart Myocardial ischaemiaMyocardial infarctionHeart failure

Intravenous GLYCERYL TRINITRATE, -BLOCKADE.

DIURETICs & ACE inhibitors useful, -BLOCKERS with caution.

Kidney Renal insufficiency DIURETICs with cautions, CALCIUM Antagonists useful.

Placenta Eclampsia HYDRALAZINE, LABETOLOL, CALCIUM Antagonists useful; avoid sodium nitroprusside.

dp/dt = change in pressure / change in time LANCET 2000; 356 : 411-417

Lancet 2000; 356: 411–17

Autoregulation of Cerebral Blood Flow

Auto regulation • Difficulty in balancing between

organ :• Brain , heart and kidney.• Different organ depending on the

preexisting lesion has a different threshold of perfusion pressure.

Intravenous Drugs for Hypertensive Emergency

Braunwald , 2001

DRUGS DOSAGE ONSET of ACTIONNitropruside 0.25 – 10 g/kg/min as IV Infusion Instantaneous

Nitroglycerin 5 – 100 g/min as IV Infusion 2 – 5 min

Nicardipine 5 – 15 mg/hours IV 5 – 10 min

Hydralazine 10 – 20 mg IV 10 – 20 min

10 – 50 mg IM 20 – 30 min

Enalapril 1.25 – 5 mg q 6 hours 15 min

Fenoldopam 0.1 – 0.3 g/kg/min < 5 min

Phentolamine 5 – 15 mg IV 1 – 2 min

Esmolol 500 g/kg/min for 4 min, then 150 – 300 g/kg/min IV 1 – 2 min

Labetolol20 – 80 mg IV bolus every 10 min

2 mg/min IV Infusion5 – 10 min

Lancet 2000; 356: 411–17

Commonly Used Parenteral Antihypertensive DrugsCommonly Used Parenteral Antihypertensive Drugs

Intravenous Drugs for Hypertensive Intravenous Drugs for Hypertensive Emergencies Available in IndonesiaEmergencies Available in Indonesia

VasodilatorsVasodilators

• Clonidine

• Nitroglicerin

• Sodium Nitropruside

Ca-AntagonistCa-Antagonist

• Diltiazem Hydrochloride

DILTIAZEM I.V. (HERBESSER)DILTIAZEM I.V. (HERBESSER) Useful for hypertensive emergency and urgency. Acts as calcium slow-channel blockers. Dose-dependent :

• Predictable onset of action

• Rapidly reduced BP.

• No rebound on withdrawn Adverse effect : bradycardia, hypotension, headache, flushing. Has antiischemic and antiarrhythmic effect (class-IV)

COMMONLY USED DRUG IN COMMONLY USED DRUG IN HYPERTENSIVE EMERGENCY HYPERTENSIVE EMERGENCY

CardioprotectiveHeart rateDilate: coroner

collateralAntiarrhytmicAntivasospasm

RenoprotectiveAfferentRBFEfferentCGP

Cerebroprotective

CBF Epstein M, 1991, Bakris GL, 1993, Mancia G, 1996, Messerly FH, 1996

Anti

-Is

chem

ic

Organ TargetOrgan Target HER CLON NTG NIFE

++++++++++

++++

--------

++++------

++----++

++

++

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++

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Dosage and AdministrationEach ampoule of DILTIAZEM-Injection should be dissolve in Each ampoule of DILTIAZEM-Injection should be dissolve in

at least 5 mL aquadest or NaCl or glucose solution before use.at least 5 mL aquadest or NaCl or glucose solution before use.

DILTIAZEM-Injection

BOLUS I.V. INJECTION

0.20 – 0.35 mg/kg BW Adult (50kg) : 1 Ampoule (1 – 3 minutes)

DRIP I.V. INFUSION (Flat)

5 – 15 mcg/kg BW/min Adult (50kg) : 15mg/hour – 45 mg/hour

DRIP I.V. INFUSION (maintenance)

1 – 5 mcg/kg BW/min Adult (50kg) : 5mg/hour – 15 mg/hour

Target MBPLevel

Bolus I.v.0.2 mg/kg

Drip infusion50 mg/hour

Drip infusion30 mg/hour

Drip infusion5-10 mg/hour

10% MBP reductionFrom Baseline

20% MBP reductionFrom Baseline

10’

20’

30’

Switch to Oral DILTIAZEM 180SR

Every 30-60 minutes observation

COMMONLY USED DRUG IN HYPERTENSIVE EMERGENCY

CLONIDINE I.V.CLONIDINE I.V.

• Reduce peripheral sympathetic tone by central stimulation of 2- receptor.

• Unpredictable onset of action.

• Adverse effect : sedation, dry mouth, constipation and a tendency to a overshoot or rebound hypertension on withdrawn.

W.H. Frishman, et al., Cardiovascular Pharmacotherapy, 1996

NITROGLISERIN I.V.NITROGLISERIN I.V.

• Strongth vasodilator (arterial- and veno-dilator).

• Direct interacting with nitrate receptors on vascular smooth muscle.

• A rapid onset and duration of action.

• Adverse effect : headache, tachycardia, nausea, vomiting.

COMMONLY USED DRUG IN COMMONLY USED DRUG IN HYPERTENSIVE EMERGENCY HYPERTENSIVE EMERGENCY

Conclusion :Conclusion :

1. Hypertensive emergencies require immediate BP reduction. This is most safely accomplished in the intensive care setting with use of an Intravenous agent.

2. With the advent of better tolerated, long-acting anti hypertensive agents, hypertensive crisis become less common, with an estimated prevalence rate of 1% among hypertensive patients.

3. Diltiazem IV is scalable and predictable effective to lower BP faster in avoiding complications of hypertensive emergency.

4. In hypertensive urgencies BP should be reduced more gradually with an fast-acting agents per os in an out patient setting.