1. Hypertensive Emergencies Herb Russell D.O. September 28, 2006

2. Why this is a difficult topic Hypertension is common (up to 25%,  50 million) but emergencies are rare Failing to treat an emergency AND treating a non-emergency can have serious consequences for the patient Blood pressure alone is a poor indicator of an emergency

3. Why this is a difficult topic The physical exam is often not helpful Different emergencies have vastly different goals in BP reduction The first line agent for one emergency may be contraindicated for another emergency Lack of consensus regarding definitions, therapeutic goals, and 1 st line medications

4. JNC - 7 New classification scheme: PreHTNSBP 120-139DBP 80-89 Stage ISBP 140-159DBP 90-99 Stage IISBP  160DBP  100

5. Definitions Hypertensive Emergency: A relatively high blood pressure with evidence of target organ damage (CNS, CV, renal). Urgent lowering in minutes to hours. Hypertensive Urgency: Severely elevated BP without target organ damage. Lower in days to weeks.

6. Definitions Acute Hypertensive Episode: SBP >180 or DBP >110 and no target organ damage Transient Hypertension: Hypertension that occurs in association with Pain Withdrawal syndromes Some toxic substances Anxiety Cessation of medications

7. ED Evaluation History History of HTN Blood pressure trends Prescribed medications OTC medications Review of systems directed at: CNS (HA, hemiparesis) Cardiac (CP, dyspnea) Compliance Past medical history Family history Illicit drug use Renal (hematuria)

8. ED Evaluation Physical Exam Appropriate sized cuff Measure both arms and legs Brachial difference <20mm Hg Focus on areas of potential target-organ damage -CNS-Heart-Retina -Pulmonary-Pulses-Renal

9. Cotton wool spot (soft exudates)

10. Hard exudates

11. Disk Edema

12. Diagnostic Studies CBC-hemolytic anemia BUN/Cr-azotemia, ARF Urine-proteinuria, RBC cast CXR-Pulmonary edema, aortic dissection ECG-ischemia, infarction pattern Head CT-hemorrhage, infarction

13. Schistocytes

14. What precipitates an emergency? 1. Non-compliance with medications in a chronic hypertensive patient 2. Those with secondary hypertension (e.g. pheochromocytoma, reno-vascular hypertension, Cushing’s Reflex) 3. Hypertension during pregnancy is a major risk factor for women

15. Our Job ED physician must: 1. Appropriately evaluate patients with elevated BP. 2. Correctly classify the HTN. 3. Determine aggressiveness and timing of the therapeutic interventions. 4. Make the correct disposition.

16. General Management Goals Reduce BP so autoregulation can be re- established Typically, this is a ~25% reduction in MAP Or, reduce MAP to 110-115 Avoid Lowering the BP too much or too fast. Treating non-emergent hypertension

17. General Management Goals Exceptions: aortic dissection and eclampsia In aortic dissection and eclampsia, BP should be lowered to normal levels Search for secondary causes

18. Pharmacology-Nitroprusside Dose: 0.3-10 mcg/kg/min Actions: Equally rapid decrease of both preload and afterload (arterialor and venous smooth muscle). Indications: All hypertensive emergencies including post-partum eclamplsia Half-life: 3-4 minutes Metabolism: Liver

19. Pharmacology-Nitroprusside Excretion: Kidney Adverse Effects: Cyanide toxicity with prolonged use (rare) Prolonged use and >10  g/min Inhibits hypoxia induced pulmonary vasoconstriction Coronary steal syndrome Increased ICP Contraindications: Other cyclic GMP inhibitors (i.e. sildenafil, etc.)

20. Pharmacology-Labetalol Dose: Bolus of 20mg IV, double bolus up to 80 mg, or infusion of 2mg/min to maximum total of 300mg Peds: 0.4-1 mg/kg/hr Actions: Selective α 1 and nonselective β– blocker 4-8 times that of α-blockade. Indications: Hypertensive emergencies, including those from catecholamine stimulation and PIH. Does not decrease cerebral or coronary blood flow.

21. Pharmacology-Labetalol Onset: 5-10 min Half-life: 5.5 hrs Metabolism: Hepatic Adverse Effects: May exacerbate CHF and induce bronchospasm In low doses, may have a paradoxical increase in BP when used in catecholamine excess

22. Pharmacology-Esmolol Dose: Loading dose of 500mcg/kg over 1 min, then infusion of 50- 300mcg/kg/min Actions: Ultra-short acting β 1 - selective adrenergic blocker Indications: Used in conjunction with nitroprusside or phentolamine for hypertensive emergencies

23. Pharmacology-Esmolol Onset: Less than 5 mins Half-life: 9mins Metabolism: Erythrocytes Adverse Effects: May induce bronchospasm (rare) Bradycardia and heart block Avoid as sole agent in catecholamine excess

24. Pharmacology-Nitroglycerin Dose: Infusion rate 5-10mcg/min, titrate up 10mcg every 5 mins Actions: Greater preload reduction than afterload, until high rates, then equal Indications: Agent of choice for moderate hypertension complicating unstable angina, MI or pulmonary edema

25. Pharmacology-Nitroglycerin Onset: Immediate Half-life: 4 mins Metabolism: Hepatic Adverse Effects: HA, tachycardia, hypotension Contraindications: Other cyclic GMP inhibitors (i.e. sildenafil, etc.)

26. Pharmacology-Hydralazine Dose: 10-20 mg, repeated in 30 mins Peds: 0.1 mg/kg Actions: Direct arteriolar dilator Indications: PIH, pre-eclampsia Onset: 10 mins Half-life: 2-4 hrs Metabolism: Liver acetylation Excreted: Urine

27. Pharmacology-Hydralazine Adverse Effects: Decrease dose in renal insufficiency High incidence of hypotension in “slow acetylators” Reflex tachycardia Should not be used in aortic dissection and Coronary artery disease Lethargy Drug-induced Lupus

28. Pharmacology-Enalaprilat Dose: 0.625-1.25mg IV bolus Actions: Afterload reduction with lowered MAP, PCWP and increased coronary vasodilatation Indications: Hypertensive emergencies Onset: Within minutes Metabolism: None

29. Pharmacology-Enalaprilat Excreted: Urine Adverse Effects: Angioedema Cough Worsening renal function Hyperkalemia

30. Pharmacology-Others Trimethaphan-ganglionic blocking agent Fenoldopam-dopaminergic receptor agonist Nicardipine-dihydropyridine calcium channel blocker Urapidil-peripheral a 1 -receptor blocker and a central 5-HT 1A -receptor agonist

31. Categories of Hypertensive Emergencies Hypertensive encephalopathy Stroke syndromes Embolic Hemorrhagic Subarachnoid hemorrhage

32. Categories of Hypertensive Emergencies Cardiovascular Acute LV failure (“Flash” pulmonary edema) Acute coronary syndrome Aortic dissection Pregnancy related hypertension Pre-eclampsia Eclampsia HELLP syndrome

33. Categories Catecholamine excess Pheochromocytoma MAOI + tyramine Cocaine/amphetamines/OTCs Clonidine withdrawal Other Renal failure Epistaxis Childhood hypertension

34. Hypertensive Encephalopathy Symptoms: Mental status change – somnolence, confusion, lethargy, stupor, coma, seizure Focal neurologic deficit Headache – alone not sufficient to diagnose a hypertensive encephalopathy Nausea and vomiting Signs: Papilledema, cotton wool exudates

35. Diagnostics Hypertensive encephalopathy is a diagnosis of exclusion – thus, exclude the other possibilities! Only definitive criteria is a favorable response to BP reduction. However clinical improvement may lag behind BP improvement by hours to days

36. Pathophysiology A loss of cerebral autoregulation causing edema and microhemorrhages. Autoregulation is best studied in the brain but present in heart and kidneys as well Represents the body’s attempt to maintain constant FLOW of blood to perfuse the cells despite change in BP.

37. Autoregulation In the uninjured, normotensive brain, autoregulation is effective over MAP ranging from about 50 – 150 In the chronic hypertensive, this range is increased (e.g. 80 – 180)

38. Autoregulation

39. Pathophysiology Loss of autoregulation leads to: Cerebral hyper-perfusion Vascular permeability Cerebral edema Vasospasm Ischemia Punctuate hemorrhages

40. Therapy Untreated, hypertensive encephalopathy leads to coma and death Goal is to reduce MAP by 20-25% in the first hour This will get MAP back into range where autoregulation is re-instituted

41. Therapy Nitroprusside 1 st line, 0.3 – 10 mcg/kg/minute Labetalol Enalaprilat Fenoldopam

42. Stroke Syndromes

43. Thrombo-Embolic CVA Represent 85% of all strokes BP elevations are generally mild- moderate and represent a physiologic response to maintain cerebral perfusion pressure to the penumbra, which has lost its ability to autoregulate

44. Embolic CVA - Dilemma Inappropriate lowering of the BP may convert the potentially salvageable ischemic penumbra to true infarction. However, persistent BP >185/110 is a contraindication to thrombolytic therapy (it significantly increases risk of intra-cranial bleeding)

45. Embolic CVA – When to treat HTN For thrombolytic candidates, 1-2 doses of labetalol (5mg) or nitroglycerin paste may be used in attempt to get BP <185/110 If thrombolytics are given, then the BP MUST be aggressively kept below 185/110!

46. Embolic CVA – When to treat HTN According to National Institutes of Neurologic Disorders and Stroke: SBP <220, no treatment DBP <120, no treatment Tintinalli suggests not treating DBP <140 Others use MAP <130

47. Embolic CVA – When to treat If complicated by: Aortic dissection Hypertensive encephalopathy AMI Renal failure

48. Embolic CVA – How to treat HTN Goal is to reduce MAP 10-20% in uncomplicated embolic CVA with markedly elevated pressures Labetalol: 5mg doses Nitroglycerin IV or nitroprusside

49. Why not treat everybody? Danger of being too aggressive in acute CVA is well documented. Many studies show a worsening of neurologic outcome when the above guidelines are not followed.

50. Hemorrhagic CVA Unlike embolic CVA, BP elevations in hemorrhagic CVA are profound However, this again represents a physiologic response to increased intracranial pressure (and free blood irritating the autonomic nervous system) Typically is transient

51. Hemorrhagic CVA – When to Rx Evidence to support anti-hypertensive therapy in acute intracranial hemorrhage is lacking. There is no evidence to suggest that HTN provokes further bleeding in ICH. However, modest reductions of ~20% MAP have not been show to adversely affect outcome.

52. Hemorrhagic CVA - Rx Labetalol is agent of choice ACE inhibitor can be used but not as well studied. Vasodilators such as nitroprusside and nitroglycerin are contraindicated because they may raise the ICP

53. Subarachnoid Hemorrhage A special subset of hemorrhagic CVA. Evidence suggests that there may be less vasospasm and less re-bleeding if SBP <160 or MAP <110 Agents: Oral nimodipine 60mg q 4hr x 21 days IV nicardipine 2mg bolus, then 4-15mg/hr

54. Acute Left Ventricle Failure

55. Pathophysiology Abrupt, severe increase in afterload leads to systolic and diastolic dysfunction. Vicious cycle ensues : Heart failure causes poor coronary perfusion, LV ischemia and worsening failure CHF leads to hypoxia and worsens LV ischemia Renal hypoperfusion leads to renin release and this increases afterload

56. Signs and Symptoms Abrupt and severe dyspnea, tachypnea, and diaphoresis Rales, wheezes, distant breath sounds, frothy sputum, and gallop rhythm

57. Goals of therapy 1. Reduce preload and afterload! 2. Minimize coronary ischemia by increasing supply (blood to coronary arteries) and decrease demand (wall tension, tachycardia) 3. Oxygenate, ventilate, clear pulmonary edema.

58. Therapy Nitroglycerin First Line in combination with ACE-I Arterial (especially coronaries) and veno-dilator, reducing preload and afterload ACE inhibitor Interrupts the renin-angiotensin-aldosterone axis Lasix Initially a vasodilator, then diuretic Morphine Vasodilator and sympatholytic

59. Acute Coronary Syndrome Elevated BP significantly increases LV wall tension Wall tension is one of main determinants of myocardial oxygen demand.

60. ACS therapy goals Goal is to decrease wall tension by decreasing preload and afterload. Typical agents do this well: Nitroglycerin, beta-blockers, morphine Avoid hydralazine and minoxidil, as they increase myocardial oxygen demand.

61. Aortic Dissection

62. Classification Stanford A Involves ASCENDING aorta More common More often fatal REQUIRES surgery for survival Stanford B Involves DESCENDING aorta May be managed medically DeBakey (old) 1 – Ascending and Descending 2 – Ascending Only 3 – Descending Only A – above diaphragm B – below diaphragm

63. Risk Factors Male HTN Pregnancy Chest Trauma Cocaine CV Surgery Marfan’s Ehrler-Danlos MDMA (ecstasy)  -1 antitrypsin def. Age >60

64. Pathophysiology Degeneration of the media Normal aging Pregnancy Marfan’s and Erhlers-Danlos syndromes Hypertension Bicuspid aortic valve Flexion of aorta with each heartbeat Atherosclerosis – minor factor

65. Pathophysiology Hydrodynamic force of blood column tears the intima and dissects into the media, creating a false lumen. Can extend proximal or distal, re-enter the aorta through the intima (rare), or dissect through the adventitia (fatal)

66. Pathophysiology Worsening of the dissection dependent on: 1. Level of elevated BP 2. Slope of the pulse wave – dP/dt. This increases the “shear force” on the dissection. Increased shear force leads to propagation of the dissection

67. Complications Retrograde Dissection Into AV – acute regurgitation and CHF Into pericardium – tamponade Into coronary arteries - AMI Anterograde Dissection Into carotid artery – CVA Into subclavian artery – Ischemic limb Into renal arteries – ARF Into anterior spinal artery - paraplegia

68. Signs and Symptoms Severe tearing chest pain, maximal at onset, radiates to back, may migrate as the dissection propagates Diaphoresis N/V Feeling of impending doom (angor animi) and anxiety

69. Diagnostics CXR may be normal in up to 12% !! Wide mediastinum Calcium sign Deviation of trachea or NG tube to right Left pleural effusion Apical cap Left Mainstem Bronchus shift

70. Diagnostics - CXR

71. Therapy Goal is to reduce both the BP and the slope of the pulse wave! BP goal is SBP of 100-120 If patient presents with normal BP, still need to decrease the shear forces!!

72. Therapy Beta-blocker for decreasing the slope of the pulse wave (e.g. esmolol) Nitroprusside for BP reduction (started after or with the beta-blocker to avoid reflex tachycardia) Labetalol as monotherapy Trimethaphan if beta-blocker contraindicated

73. Doses Esmolol: 500mcg/kg bolus, then 50-300 mcg/kg/min Nitroprusside: 0.3 – 10 mcg/kg/min Labetalol: 20mg IV q5-10 minutes, increasing by 20mg up to 80mg per dose, total not to exceed 300mg. Trimethaphan: 1 – 2mg/minute

74. Pregnancy and Hypertension Complicates 5% of pregnancies Risk factors: Nulliparity Age >40 African American Chronic renal failure Diabetes mellitus Multiple gestations

75. Pregnancy and Hypertension Accounts for 18% of maternal deaths Most common risk factor for placental abruption Defined as: Greater than 140/90 SBP increased >20 from baseline DBP increased >10 from baseline

76. Pregnancy and Hypertension Pre-eclampsia Hypertension Proteinuria >300mg per 24 hr. Peripheral edema or weight gain >5 lbs in 1 week Presents >20 weeks except in gestational trophoblastic disease Eclampsia Pre-eclampsia + seizures – This is an emergency !!!! HELLP syndrome Variant of pre- eclampsia Blood pressure lower Predilection for multigravids

77. Pathophysiology Pre-eclampsia and eclampsia may occur up to 6 weeks post partum Not well understood, but thought to be loss of normal vasodilatation: Increased thromboxane Increased endothelin Increased sympathetic nerve activity Decreased nitric oxide formation Oxidative stress

78. Signs and symptoms Restlessness and hyper-reflexia early Headache Visual disturbance Peripheral edema Abdominal pain

79. Therapy Any pregnant patient with BP >140/90 and any symptoms should be hospitalized Eclampsia and patients with pre- eclampsia + severe symptoms (HA, abdominal pain) but no seizures should be treated very aggressively!

80. Therapy Definitive therapy is delivery of the fetus and placenta Magnesium: 4-6gm over 15 minutes, drip 1-2gm per hour Hydralazine: 5-10mg IV, drip 5-10mg per hour Labetalol: 20mg IV, repeat prn q 10 minutes, drip 1-2mg per minute

81. Catecholamine excess Pheochromocytoma Monoamine oxidase inhibitor + tyramine Cocaine/amphetamines/OTC herbals (PPA, ephedra, trytophan) Clonidine withdrawal

82. Pheochromocytoma Is a tumor of adrenergic cells Most common site is adrenal medulla Increased risk in patients with von Recklinhausen’s disease (aka neurofibromatosis)

83. Neurofibromas and café au lait spots

84. Signs and symptoms Chronically elevated BP with paroxysms of palpitations, diaphoresis, tachycardia, malaise, apprehension, HA, abdominal pain, and angina Episodes precipitated by physical or emotion stress, eating, position, or micturation

85. Diagnosis Commonly mislabeled as panic attacks or anxiety disorder Diagnosed by detecting elevated levels of catecholamines and their by-products in the urine

86. Clonidine withdrawal Occurs in patients on clonidine who abruptly discontinue therapy Symptoms very similar to pheochromocytoma Occur 16-48 hours after last dose Treatment is to re-start clonidine

87. MAOI + tyramine Tyramine is found in many foods, is a sympathomimetic like amphetamine, and causes a transient release of norepinephrine (NE) in all people when ingested Patients on MAOIs (Nardil, Parnate, Marplan) experience an exaggerated response to tyramine, resulting in prolonged and severe hypertension

88. Foods containing tyramine Beer Wine Aged cheeses Chocolate Coffee Cream Chicken liver Pickled herring Broad beans (dopamine) Yeast Citrus fruits Snails

89. MAOIs and medications Some pharmaceuticals can also cause severe hypertension when taken with MAOIs Meperidine Ephedrine TCAs Reserpine Dopamine Methyldopa Guanethidine

90. Ingestions Cocaine blocks re-uptake of NE, dopamine, and serotonin Amphetamines Stimulate release of and block re-uptake of catecholamines Also may directly stimulate catecholamine receptors

91. Ingestions Over-the counter medications Ephedra – weight loss supplements PPA – (Phenylpropanolamine ) decongestants and weight loss supplements Tryptophan – supplement for depression, insomnia, migraines

92. Treatment goals Typically the goal is to reduce MAP by ~25% over several hours

93. Treatment for catecholamine excess Phentolamine Alpha blocker; the mainstay of therapy Dose: 1-5mg IV bolus or drip 5-10mcg/kg per minute Beta-blocker May be added to control tachycardia Benzodiazepines May be helpful in cocaine/amphetamine

94. Treatment for catecholamine excess Labetalol Its use as monotherapy is controversial Recall that its alpha : beta is 1:3 to 1:8 Some texts recommend it; others note the potential for worsening BP with it as monotherapy for the catecholamine excess conditions Probably best to use phentolamine 1 st

95. Treatment of Hypertensive Urgencies Goal: Gradual reduction of blood pressure over 24 hours Treatment: Restart prescribed anti-hypertensive medications for the non-compliant patient Clonidine Captopril Losartan Follow up within 24 hours Sublingual nitroglycerine Nifedipine (don’t use)

96. Treatment of Hypertensive Episode Treat cause of hypertensive episode (i.e. pain, anxiety) Refer to a primary care physician and start anti-hypertensive medications only upon advice of referring physician

97. Why not treat all elevated BP in the ED? Association of overly aggressive BP reduction in setting of stroke with worse neurologic outcome widely shown What about the person incidentally found to have elevated BP?

98. From Journal of Emergency Medicine, 2000, pp 339-45. “Stroke Precipitated by Moderate Blood Pressure Reduction” 6 cases total; All presented to an ED. 2 with completely resolved TIAs and 4 with no neurological complaints at all. All suffered CVAs and had permanent dysfunction or death.

99. Case 1 60 year male with “malaise” Initial BP 170/100, remainder of exam normal Treated with 10mg nifedipine sublingual Returned 3 hours later with BP 120/88 and left hemiparesis. MRI showed infarct.

100. Case 2 30 year female with “abdominal pain” Known hypertensive, off meds for 2 weeks BP 280/120 initially All HTN meds restarted in ED: captopril, triamterene/HCTZ, nifedipine, and hydralazine

101. Case 2 2 hours later in the ED, complained of severe vision loss BP 160/85 Ophthalmology consult confirmed retinal ischemia Only partial recovery of vision

102. Starting anti-HTN therapy in the ED May mislead the patient to believe that they are cured May interfere with office assessment of the true nature of the HTN Best treatment in the ED is education regarding the chronic nature of hypertension and need for follow up!

103. Summary – Neurologic emergencies Hypertensive encephalopathy Embolic CVA Hemorrhagic CVA SAH Nitroprusside, goal ~25 reduction Only if >220/120 or>185/110 for t-PA Labetalol for ~10- 20% reduction Nimodipine 60 mg Q4hrs x 21 days

104. Summary – Cardiovascular emergency Aortic dissection Acute LV failure Acute coronary syndrome Nitroprusside + Esmolol or Labetalol – SBP ~100 NTG, ACEI, Lasix for symptoms and ~10-15% reduction NTG, MS04, beta- blocker for symptom improvement

105. Summary – Other emergencies Eclampsia and HELLP Catecholamine excess Goal DBP ~90; magnesium, hydralazine, labetalol, delivery! Phentolamine +/- beta blocker for ~25% reduction over several hours

106. Summary – Hypertensive Urgency Unnecessary to lower BP in the ED May be harmful-First do no harm No history of renal dysfunction? Normal UA obviates need for lab tests History of renal dysfunction? UA and BMP Symptoms of cardiac dysfunction or chest pain CXR and ECG Disposition If above negative, refer for outpatient evaluation within 7 days

107. Questions and Comments