The section in quotations has been abstracted from JNCvi, the 6^th Report of the Joint National Committte on the Detection, Evaluation and Treatment of Hypertension (NIH/NHLBI 1997).

"Hypertensive Crises: Emergencies and Urgencies Hypertensive emergencies are those rare situations that require immediate
blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage. Examples include hypertensive encephalopathy, intracranial hemorrhage, unstable angina pectoris, acute myocardial infarction, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, or eclampsia. Hypertensive urgencies are those situations in which it is desirable to reduce blood pressure within a few hours. Examples include upper levels of stage 3 hypertension (> 180 / 110 mmHg), hypertension with optic disc edema, progressive target organ complications, and severe perioperative
hypertension. Elevated blood pressure alone, in the absence of symptoms or new or progressive target organ damage, rarely requires emergency therapy. Parenteral drugs for hypertensive emergencies are listed in the table. Most hypertensive emergencies are treated initially with parenteral administration of an appropriate agent. Hypertensive urgencies can be managed with oral doses of drugs with relatively fast onset of action. The choices include loop diuretics, beta-blockers, ACE inhibitors, alpha2-agonists, or calcium antagonists.

The initial goal of therapy in hypertensive emergencies is to reduce mean arterial blood pressure by no more than 25% (within minutes to 2 hours), then toward 160/100 mm Hg within 2 to 6 hours, avoiding excessive falls in pressure that may precipitate renal, cerebral, or coronary ischemia. Although sublingual administration of fast-acting nifedipine has been widely used for this purpose, several serious adverse effects have been reported with its use and the inability to control the rate or degree of fall in blood pressure makes this agent unacceptable. The routine use of sublingual nifedipine whenever blood pressure rises beyond a predetermined level in postoperative or nursing home patients is also not appropriate. Rather, the proximate causes of the elevated blood pressure, such as pain or a distended urinary bladder, should be addressed. Blood pressure should be monitored over 15- to 30-minute intervals; if it remains greater than 180/120 mm Hg, one of the previously mentioned oral agents may be given. If such high levels of blood pressure are frequent, adequate doses of long-acting agents should be provided.

Miscellaneous Causes for Increased Blood Pressure:

Cocaine. The majority of cocaine-dependent individuals are normotensive, and no evidence suggests that ongoing cocaine abuse causes chronic hypertension. However, cocaine abuse must now be considered in all patients presenting to an emergency department with hypertension-related problems. Clues include the presence of chest pain, tachycardia, dilated pupils, combativeness, altered mental status, and seizures. Cocaine may induce severe ischemia from coronary and cerebral vasoconstriction as well
as acute renal failure due to rhabdomyolysis. Nitroglycerin is indicated to reverse cocaine-related coronary vasoconstriction, but its antihypertensive efficacy may be inadequate and other parenteral agents may be needed . Nonselective beta-blockers such as propranolol should generally be avoided because of the risk of a paradoxical rise in blood pressure as well as coronary
vasoconstriction due to the exaggerated effect of catecholamines on unblocked alpha-receptors.

Amphetamines. Acute amphetamine toxicity is similar to that of cocaine but longer in duration, lasting up to several hours. Cerebral and systemic vasculitis and renal failure may occur. Treatment for amphetamine toxicity is similar to that for cocaine toxicity. "
 

Table 1: Drug Treatment of Hypertensive Urgencies and Emergencies according to co-morbidity or syndrome of acute end-organ dysfunction
 

Circumstance	Preferred Drugs	Drugs to Avoid (or Use With Caution)
Acute coronary syndromes (unstable angina, acute MI)	Nitroglycerin  Beta blocker  Fenoldopam	Nicardipine
Aortic dissection	Beta blocker  Sodium nitroprusside + beta blocker  Nitroglycerin + beta blocker	Avoid drugs likely to increase shear stress e.g. Hydralazine, Diazoxide, Nicardipine, Fenoldopam
Cocaine or Amphetamine Toxicity; other hyperadrenergic syndromes	Nitroglycerin (esp. for coronary vasoconstriction)  Sodium Nitroprusside  Fenoldopam  Phentolamine	There are no data from controlled studies. avoid Beta blockers - may cause paradoxical hypertension or coronary spasm from unopposed alpha-adrenergic activity; caution with Labetalol.
Encephalopathy, altered mental state, ischemic or hemorrhagic stroke, focal CNS signs, raised intracranial pressure	Nitroglycerin  Fenoldopam	Sodium Nitroprusside (can increase ICP)
Heart Failure	Loop diuretic  Nitroglycerin  Sodium Nitroprusside  Enalaprilat (avoid within 24 hours of acute MI)	Beta blockers  Labetalol  (Fenoldopam: may not reduce LVEDP; reduces afterload and increases cardiac output)
Liver Disease	Fenoldopam  Nitroglycerin	Sodium Nitroprusside (thiocyanate toxicity)
Postoperative	Beta blocker  Nitroglycerin  Fenoldopam  Nicardipine (avoid in CAD)	Sodium Nitroprusside (avoid in severely ill patients)
Pheochromocytoma	Sodium Nitroprusside  Labetalol (caution: paradoxical hypertension reported)	Paradoxical hypertension or coronary spasm from unopposed alpha-adrenergic activity: avoid Beta blockers. Caution with labetalol.
Pregnancy, eclampsia	Hydralazine  Labetalol	Sodium Nitroprusside.  Limited experience with all agents. Consider nifedipine.
Renal Insufficiency	Fenodopam  Nitroglycerin	Sodium Nitroprusside (thiocyanate toxicity)  Enalaprilat (undiagnosed renovascular disease; hyperkalemia)

 
 

Table 2 Management of Hypertensive Emergencies and Urgencies according to drug

Before ordering a medication, ask yourself the following questions:  Is this an acute or chronic increase in BP ? Is there evidence of acute target (end) - organ dysfunction, or a condition that is likely to improve with blood pressure reduction?  Does the patient need any treatment now? How quickly do I need to reduce the blood pressure? What is the target blood pressure in the short term?  Goals & Pearls:  · You should aim to preserve cerebral, coronary, renal & ocular perfusion -- NOT just to get BP numbers into a "normal" range.  · It is often more harmful to reduce BP than to leave it alone -- e.g, in acute ischemic CVA.  · It is frequently more harmful to reduce pressure quickly, than to control it gradually. Even oral agents for hypertensive ugencies have resulted in myocardial ischemia and cerebral ischemia.  · Patients with acutely raised BP may be relatively volume-constricted, and thus may have high BP that: a) is renin-angiotensin-dependent or b) falls very dramatically with even small doses of vasodilators.  · Hypertensive emergencies are those situations requiring immediate BP reduction (not necessarily to a normal range -- usually a 25-30% reduction in MAP over 1 hr) to prevent or limit target-organ disease -- e.g., hypertensive encephalopathy, intracranial hemorrhage, acute LVF with pulmonary edema, dissecting aortic aneurysm, eclampsia or severe hypertension associated with pregnancy, unstable angina, acute MI, microvascular hemolysis. Dental hemorrhage or nosebleed is rarely substantial enough to warrant uncontrolled blood pressure reduction. Accelerated hypertension is a funduscopic diagnosis -- bilateral hemorrhages or cotton wool spots or macular "stars," ±papilledema, which indirectly implies small vessel damage in other organs.  · Hypertensive urgencies are those situations which require BP reduction within 24 hours -- e.g., hypertension without severe symptoms or progressive target-organ complications, and severe perioperative hypertension..  · It is best to choose a drug and method of administration that enables a controlled reduction in BP over 30 minutes to several hours; catastrophic injury may result from overzealous therapy.  · Short-acting Nifedipine should not be used for therapy of any form of hypertension in adults. Nifedipine is not FDA-approved for any form of hypertension. PRN orders for nifedipine are inappropriate.  · Don't just substitute clonidine when you would otherwise have used nifedipine: stop and think first.

 

 

Drug	Dose	Onset	Cautions, Adverse Effects & Additional Comments (Because of limited space -- cannot be all-inclusive; consult other references for a particular drug.)
PARENTERAL VASODILATORS
Sodium Nitroprusside  (Nipride)	0.25-10mg/kg/min as IV infusion. Maximal dose rate must not be infused for > 10 minutes. If BP not controlled after 10 minutes at max rate -- terminate infusion.	Immediate  (0.5 - 1 minute)	BP must be monitored by arterial line: BP frequently drops too quickly for indirect (cuff) devices cycling at q. 5 min. Consider 1. Initial saline bolus 250 - 500 mL to 'prime' circulating volume; 2. Beta blocker (esp. if suspicion of myocardial ischemia or dissection).  Adverse effects: like other vasodilators, may cause ­ in intracranial pressure; nausea, vomiting, muscle twitching; prolonged use may cause thiocyanate intoxication, methemoglobinemia acidosis, cyanide poisoning. Toxicities greater with hepatic or renal disease, malnutrtion. V/Q mismatch, coronary steal reported.  Bags and infusion tubing must be protected from light.
Nitroglycerin	5-100 mg/min as IV infusion.  Initially, 5 mg/min; increase by 5 mg/min increments every 3-5 minutes. If no response at 20 mg/min, increase by 10-20 mg/min increments.	Immediate (2-5 minutes)	Continuously monitor BP, heart rate, PCWP etc., to achieve correct dose.  Adverse Effects: headache, tachycardia, vomiting, flushing, methemoglobinemia.  Requires special non-PVC tubing.
Fenoldopam (Corlopam®)	1.0 - 1.6 mcg / kg / minute	5 minutes	Glaucoma (increases intra-ocular pressure).  Acute left heart failure with high LVEDP (Corlopam does not improve LVEDP but does improve cardiac output).  Aortic dissection (may increase shear stress).  Beta blockers (experience with the combination is limited). Unpredictable hypotension or bradycardia may occur).  Hypokalemia (mild hypokalemia may occur).
Diazoxide  (Hyperstat®)	50-150 mg IV bolus, repeated, or 15-30 mg/min as IV infusion.	Immediate (1-2 minutes)	Virtually obsolete.  Avoid the 300mg dose which is less predictable, less controllable, and has been associated with angina and with myocardial and cerebral infarction. Avoid with aortic dissection.  Adverse effects: hypotension, tachycardia, aggravation of angina, nausea & vomiting. Transient hyperglycemia may result with repeated injections, but usually requires treatment only in diabetics.  Causes sodium retention; repeat injections may precipitate edema & CHF -- which (with adequate renal function) responds to diuretics.
Hydralazine  (Apresoline®)	5-20 mg IV bolus.  10-40 mg IM.	10 minutes  20-30 minutes	If no effect after 20mg (IV), try another agent; BP reduction  is unpredictable.  Adverse effects: tachycardia, headache, vomiting, aggravation of angina. If intracranial pressure is increased, lowering BP may cause cerebral ischemia.  Avoid in patients with aortic dissection.
Enalaprilat  (Vasotec IV®)  (Not Formulary)	0.625-1.25 mg IV over 5 minutes every 6 hours.	15-60 minutes	Adverse effect: renal failure in patients with bilateral renal artery stenosis, hypotension.  Also beneficial in CHF.  Patients at increased risk for hypotension include those with heart failure, hyponatremia, high-dose diuretic therapy, volume or salt depletion or patients on renal dialysis.
Nicardipine  (Cardene IV®)	Gradual reduction: 5mg/hr as constant infusion. (concentration 0.1mg/ml); increase by 2.5mg/hr every 15 minutes to MAX of 15mg/hr.  Rapid reduction: increase dose every 5 minutes. After goal is achieved, reduce rate to 3mg/hr and titrate to response.	Immediate (1-5 minutes)	Adverse effects: hypotension, tachycardia, aggravation of angina, headache, thrombophlebitis.  Contraindicated in patients with advanced aortic stenosis -- afterload reduction may worsen myocardial oxygen balance.  Use with caution in patients with CHF or significant LV dysfunction particularly if combined with beta-blocker.
PARENTERAL ADRENERGIC INHIBITORS
Labetalol  (Normodyne® Trandate®)	20-80 mg IV over 2 minutes every 10 minutes;  2 mg/min as IV infusion.	5 - 10 minutes	Monitor BP during and after completion of the infusion to avoid rapid or excessive fall in BP.  Adverse effects: bronchoconstriction, heart block, orthostatic hypotension.  May be useful with underlying CV disease, CAD, angina, MI, or after vascular surgical procedures. LV function may be compromised.  Try other agents first in asthmatics.  Be very careful in cocaine / amphetamine toxicity. Relatively weak alpha blocker; may precipitate myocardial ischemia from relatively unopposed alpha adrenergic activity. Recent NEJM review suggests avoiding in cocaine toxicity.
Phentolamine  (Regitine®)	5-15 mg IV bolus.	Immediate (1-2 minutes)	May also be used to treat hypertensive crises secondary to MAO inhibitors/sympathomimetic amine interactions, rebound hypertension on withdrawal of clonidine, propranolol or other antihypertensives.  Adverse effects: tachycardia, orthostatic hypotension. Marked hypotension may result in MI, or cerebrovascular spasm or occlusion.
Trimethaphan   (Arfonad®)	1-4 mg/min as IV infusion. (1mg/ml concentration)	Immediate (1-5 minutes)	Obsolete. Vigilant monitoring and adequate oxygenation must be assured throughout treatment period to assure coronary & cerebral circulation. Tachyphylaxis may develop.  Adverse effects: paresis of bowel & bladder, orthostatic hypotension, blurred vision, dry mouth, tachycardia, aggravation of angina.
Methyldopate  (Aldomet IV®)	250-500 mg IV infusion q6h.	30-60 minutes	Adverse effects: Drowsiness.
ORAL AGENTS
Captopril  (Capoten®)	25 mg PO, repeat PRN.	15-30 minutes	Adverse effects: renal failure in bilateral renal artery stenosis. Hypotension: UNPREDICTABLE. BE especially careful if hypovolemia, CHF, elderly or diuretic therpay.
Labetalol  (Normodyne® Trandate®)	200-400 mg PO, repeat q 2-3 hours.	30 min. - 2 hrs	Adverse effects: bronchoconstriction, heart block, orthostatic hypotension, nausea, vomiting, diarrhea.  No correlation between total IV dose & starting oral dose.
Clonidine  (Catapres®)	0.1 - 0.2 mg PO, repeat q hour PRN to a maximum dose of 0.3 mg.	30-60 minutes	Adverse effects: hypotension, drowsiness, dry mouth. Rebound is common when the drug is withdrawn after chronic therapy.  Avoid in patients, with bradycardia, sick sinus syndrome, or cardiac conduction defects.

 

Corlopam (Fenoldopam 1ml and 2 ml amps for IV infusion after dilution, Neurex Corp)

This drug is a selective Dopamine DA-1 type agonist, approved by the FDA for the in hospital, short-term (less than 48 hours) management of severe hypertension. It is more selective than dopamine itself for dopamine receptors. Fenoldopam is most useful for patients who need rapid, smooth, reduction in blood pressure (onset of reduction approximately 5 minutes, steady state 5-20 minutes), but not for patients who require immediate reduction (onset of reduction within seconds to minutes). The drug also shows promise as an alternative to low dose dopamine to provide renal protection in hypotensive states (such as cardiogenic shock), and may be less pro-arrhythmic in these patients, but is not FDA-approved for that use. The commonest side effects are headache, flushing, nausea and hypotension (each in about 5% of patients).

JNC vi suggests that Fenoldopam may be used in all forms of emergent hypertension.

The principal alternatives to Fenoldopam for the management of most hypertensive emergencies are Sodium Nitroprusside (Nipride) and Nicardipine (Cardene).

Although there are no comparative studies against Nicardipine, Fenoldopam may be preferred in patients with acute coronary syndromes, in asymptomatic patients with coronary artery disease and in post CABG patients by virtue of its reduced tendency to provoke reflex sympathetic activity. Nicardipine may reduce renal perfusion, in contrast to Fenoldopam, which is a renal vasodilator. Nicardipine is more difficult to titrate because of its longer half-life.

Sodium Nitroprusside is a difficult drug to use: an arterial line is necessary in most patients because of the very rapid onset and offset of effect. Because the drug photo-degrades, the bottle and infusion set must be shielded from light. Potentially fatal thiocyanate and cyanide toxicity may emerge unpredictably in patients treated with high doses for long periods, or sooner at lower doses in patients with malnutrition, renal or hepatic dysfunction. Nitroprusside is associated with worsening myocardial ischemia, coronary steal, increased alveolar-arterial oxygen gradient and intra-pulmonary shunting (the last two leading to arterial hypoxemia).

The wholesale price for Corlopam is $197.60 for 1ml (10mg) amp and $380.38 for 2 ml (20mg). We do not yet have contract pricing, which may be a little lower. The effective dose range is 0.1 - 1.6 mcg/kg/min. 1 ml is enough for 24 hours, at doses up to 0.3mcg/kg/min for 70kg patients. In comparison the costs of other injectable drugs are:

Nitroprusside is $1.22 per 50mg vial. In 1997 UHS bought 920 vials of Nitroprusside.
Nicardipine is $18.96 per 25mg vial. In 1997 UHS bought 240 vials.
Nitroglycerin < $1.00
Hydralazine < $5.00
Phentolamine $25.05
Esmolol 100 mg $26.00
Diazoxide $88.00
Trimethaphan no longer available

Use of Fenoldopam may be appropriate in the following circumstances:

1. Patients requiring a parenteral antihypertensive agent, and one of the following
2. Significant renal dysfunction (e.g. serum creatinine > 2.0 mg/dL)
3. Significant hepatic dysfunction or clinically apparent malnutrition, in patients who require Nitroprusside infusion rates exceeding 2 mcg/kg/min.
4. Patients requiring Nitroprusside in excess of 4 mcg/kg/min for more than 10 hours
5. Patients requiring more than 10mcg/kg/min Nitroprusside for any duration
6. Patients with evidence of thiocyanate or cyanide toxicity
7. Patients whose blood pressure remains labile on Nitroprusside
8. Post cardiac surgery
9. Post major non-cardiac surgery (in patients with renal dysfunction, significant postoperative wound site bleeding)
10. Patients in whom an arterial line is contraindicated or cannot be placed expeditiously
11. Dialysis patients
12. Baseline thrombocytopenia (Nitroprusside has been reported to cause thrombocytopenia)
13. Acute coronary syndrome and hypertension not adequately controlled by nitrates and beta-blockers (Nitroprusside is contraindicated)
14. Pregnancy (Fenoldopam is category B - i.e. no fetal toxicity in animal studies; no adequate studies in pregnant women. Nitroprusside is category C: fetal toxicity in animal studies)

1. Glaucoma
2. Acute left heart failure with high LV end diastolic pressure (Fenoldopam is an afterload-reducing agent, and does not improve LVEDP in these patients, although it does improve cardiac output)
3. Aortic dissection (Corlopam increases heart rate and may increase aortic shear stress. Co-administration of a beta-blocker should be done with caution)
4. Known sodium metabisulfite allergy (theoretic risk of anaphylaxis: not likely to be predictable)
5. Hypokalemia (Corlopam may cause mild hypokalemia).