1. Optimal Blood Pressure Control in Intracerebral and Subarachnoid Hemorrhage
Stephan A. Mayer, MD
Assistant Professor of Neurology (in Neurological Surgery), Columbia University College of Physicians and Surgeons; Director, Neurological Intensive Care Unit, Columbia-Presbyterian Campus of New York Presbyterian Hospital, Columbia University Medical Center, New York, New York
In the United States, an estimated 500,000 patients, many of whom have chronically elevated blood pressure (BP), will experience a hypertensive crisis during their lifetimes.1 Although this number is relatively small, the incidence of hypertensive crises is expected to rise with the increased use of high-risk surgical procedures and changing demographic factors.2 Furthermore, serious morbidity and mortality can result from inadequate treatment as well as overly aggressive treatment. The mortality rate within the first year following a hypertensive emergency (end-organ damage present) is 70% to 90%. Mortality approaches 100% at 5 years. With adequate reduction of BP, mortality drops to 25% and 50% at 1 year and 5 years, respectively.3
Despite the serious consequences of inappropriate treatment, the best approach for treating acute hypertension has never been addressed in large clinical trials. Recently, Cherney and Straus4 conducted a systematic review of literature describing the efficacy of various pharmacologic regimens in reaching predetermined target BP for patients with hypertensive urgencies and emergencies. From 1966 to 2001, only 4 hypertensive emergency trials and 15 hypertensive urgency trials were published. With no tested guidelines, management of these patients is often with off-label approaches to therapy.
The purpose of this educational program is to provide an overview of current pharmacologic options available to treat hypertensive crises in patients for whom intravenous (IV) treatment is necessary.
1. Calhoun D, Oparil S. N Engl J Med. 1990;323:
2. Oparil S, et al. Am J Hypertens. 1999;12:
3. Webster J, et al. Q J Med. 1993;86:
4. Cherney D, Straus S. J Gen Intern Med. 2002;17:

2. Disclosures Grant/Research Support: Medivance, Inc., Novo Nordisk
Speakers Bureau/Consultant: Astellas Pharma US, Inc., ESP Pharma, Novo Nordisk
Stock/Shareholder: Medivance, Inc., Radiant

3. Outline Physiology and pathophysiology Specific medications
Specific conditions: blood pressure targets

4. Acute Hypertension − Pathophysiology
Circulating and local factors acting on
endothelium and vascular smooth muscle
BP = SVR X CO
An excellent physiologic and clinical measure of perfusion is arterial pressure, which is determined by cardiac output (CO) and vascular resistance and can be defined by the equation in this slide. Because the mean arterial pressure (MAP) and CO can be measured directly, these 2 variables are used to describe tissue perfusion, although systemic vascular resistance (SVR) can be calculated as a ratio of MAP minus central venous pressure divided by CO.
Neural and hormonal reflexes and local factors act to regulate arterial pressure through modulation of CO, a product of heart rate (HR) and stroke volume (SV), or SVR, or both. Drugs used to reduce BP in hypertensive crises act by shifting the homeostatic balance toward lower SVR and decreased CO.
MAP can be approximated by the following equation:
MAP = BP + 1/3 Pulse Pressure (SBP – DBP)
Oates JA, Brown N J. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:
Abrupt  BP
(SV x HR)
Abrupt  SVR
SVR = systemic vascular resistance; CO = cardiac output; SV = stroke volume; HR = heart rate.
Oates JA, Brown NJ. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:

5. Common precipitants of post operative hypertension include fluid overload after cessation of positive-pressure ventilation, hypoxemia, anxiety, and pain. The principal therapeutic approaches should therefore concentrate on ensuring adequate oxygenation, pain control, and fluid control. In general, supplemental oxygen, morphine, and short acting anti-hypertensives are the mainstays of the treatment of postoperative hypertension.
Frequently, postoperative hypertension has a self-limited course of between 6 and 8 hours with no further need of medications after that period.

6. Cerebral Autoregulation is Central to Treatment of Hypertensive Crises
Cerebral Blood Flow
Patients with cerebral ischemia
lose their ability to autoregulate
Increasing risk of
hypertensive
encephalopathy
Autoregulatory failure
normotensive
chronic hypertensive
Increasing risk
of ischemia
Autoregulation refers to the inherent regulation of arterial diameter to allow maintenance of a relatively constant amount of blood flow in different vascular beds and is most frequently discussed in terms of cerebral tissue.1 Autoregulation is lost in ischemic tissue. In patients with chronic hypertension, the structure of the arterioles thickens and entire autoregulatory curve is shifted to the right. When BP is increased beyond the upper limits of autoregulation, “breakthrough” hyperperfusion occurs. In previously normotensive patients, whose vessels have not been altered by prior exposure to high pressures, breakthrough typically occurs at a MAP of about 120 mm Hg. In chronic hypertensive patients, the breakthrough may occur at 160 mm Hg.2
As such, a normotensive patient would be expected to develop end-organ damage at a lower BP than a chronic hypertensive. Lowering BP into the normal range in a poorly controlled, chronic hypertensive patient may actually accelerate end-organ damage.2
This difference in autoregulatory set points has important implications for the management of hypertensive urgency and emergency. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive BP reductions. Care should be exercised in patients with chronic hypertension, or patients whose previous BP status is unknown, that their MAP is not lowered to the point where they suffer from ischemia (“fall off the left side of the curve”).2
1. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Philadelphia, Pa: Mosby; 2001.
2. Strandgaard S. Circulation. 1976;53: 50
100
150
200
250
MAP (mm Hg)
Adapted with permission from Varon J, Marik PE. Chest. 2000;118:

7. Columbia Stepwise ICP Protocol
HYPOTHERMIA 7
PENTOBARBITAL 6
HYPERVENTILATION 5
OSMOTHERAPY 4
CPP OPTIMIZATION 3
SEDATION 2
SURGICAL DECOMPRESSION 1

8. ICP = intracranial pressure; CPP = cerebral perfusion pressure.
ICP/CPP Management 75
Passive
Maximum
Zone of Normal
Maximum
Collapse
Dilatation
Autoregulation
Constriction 50 50
Cerebral Blood Flow
(mL/100 g/min) 25
ICP (mm Hg) 25 25 50 75
100
125
150
Cerebral Perfusion Pressure (mm Hg)
ICP = intracranial pressure; CPP = cerebral perfusion pressure.

9. ICP = intracranial pressure; CPP = cerebral perfusion pressure.
ICP/CPP Management 75
Autoregulation Breakthrough Zone
Vasodilatory Cascade Zone
Passive
Zone of Normal
Collapse
Autoregulation 50 50
Cerebral Blood Flow
(mL/100 g/min) 25
ICP (mm Hg) 25 25 50 75
100
125
150
GOAL
Cerebral Perfusion Pressure (mm Hg)
ICP = intracranial pressure; CPP = cerebral perfusion pressure.

10. Antihypertensive Agents Used in Hypertensive Crisis
Clonidine
Diazoxide
Enalaprilat
Esmolol
Fenoldopam
Hydralazine
Labetalol
Nicardipine
Nifedipine
Nitroglycerin
Nitroprusside
Phentolamine
Trimethaphan

11. Antihypertensive Agents Used in Hypertensive Crisis
Clonidine
Diazoxide
Enalaprilat
Esmolol
Fenoldopam
Hydralazine
Labetalol
Nicardipine
Nifedipine
Nitroglycerin
Nitroprusside
Phentolamine
Trimethaphan

12. Nicardipine vs Adrenergic Blockers
Drug
Nicardipine
(Cardene IV)
Esmolol
(Brevibloc)
Labetalol
Administration
Continuous infusion*
Bolus,
Continuous
infusion
Continuous infusion
Onset + Offset
Rapid
Slower
Contractility
Decreased
HR1
Minimal increase
SVR
Cardiac output1
Increased
+/-
Myocardial O2 balance2
Positive
Contraindications
Advanced aortic stenosis
Bradycardia
Heart block >1°
CHF
Bronchospasm
COPD
In general, no detrimental effects on the cardiac conduction system have been seen with Cardene IV
Coronary dilatation induced by Cardene IV improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption.
Beta-blockers cause a positive myocardial oxygen balance by decreasing HR and contractility. Nicardipine causes a positive oxygen balance by increasing coronary blood flow.
Cardene IV package insert

14. Hypertension in Intracerebral Hemorrhage
Up to 80% of patients with intracerebral hemorrhage are hypertensive on presentation
Blood pressure spontaneously falls over next several days
Management is controversial
Britton M, et al. Stroke. 1986;17:
Carlberg B, et al. Stroke. 1993; 24:

15. 2.5 hrs post-symptom onset
Early Hematoma Growth
6.5 hrs post-symptom
2.5 hrs post-symptom onset
Occurs in ~35% of patients scanned <3 hours of onset, but not predicted by hypertension

16. Reasons to Treat Hypertension
Hypertension may predispose to hematoma enlargement
Hypertension may promote edema surrounding the hematoma
Hypertension is associated with poor outcome
Patients whose MAP can be controlled have a better outcome
End organ damage
Tuhrim S, et al. Ann Neurol. 1991;29:
Dandapani BK, et al. Stroke. 1995;26:21-24.

17. Reasons NOT to Treat Hypertension
Chronically hypertensive patients require higher perfusion pressure due to shift of autoregulatory curve
Lowering blood pressure may promote ischemia surrounding the hematoma
ICP may be elevated and lowering blood pressure reduces what could be marginal CPP
Blood pressure and CPP reduction may induce vasodilation and ICP plateau waves

18. Peri-clot Flow, Metabolism, and OEF
CBF
CMRO2
OEF

19. Treatment of Hypertension in Acute Intracerebral Hemorrhage (1999)
Recommendations
Maintain MAP <130 mm Hg if history of hypertension
IV labetalol
IV nicardipine
Immediately post-craniotomy, keep MAP <110 mm Hg
If monitored, keep CPP (MAP-ICP) >70 mm Hg
The 1999 guidelines recommend that BP levels be maintained below a MAP of 130 mm Hg in persons with a history of hypertension. In the immediate postoperative period, MAP <110 mm Hg should be avoided. If systolic arterial BP falls below 90 mm Hg, pressors should be given. In patients with elevated ICP who have an ICP monitor, CPP should be kept >70 mm Hg.
Broderick JP, et al. Stroke. 1999;30:
CPP = cerebral perfusion pressure; MAP = mean arterial pressure; ICP = intracranial pressure.
Broderick JP, et al. Stroke. 1999;30:

21. Global Cerebral Edema in Acute Subarachnoid Hemorrhage
The Columbia University
Subarachnoid
Hemorrhage
Outcomes
Project
Develops in 20% of SAH patients
Predicted by LOC at onset
Delayed edema associated with Triple-H Therapy!
Associated with increased mortality, disability, and cognitive impairment
SAH Day 0
SAH Day 18
Claassen J, et al. Stroke. 2002;33:
Kreiter KT, et al. Stroke. 2002;33:

22. Effect of Acute Physiologic Derangements on Outcome after Subarachnoid Hemorrhage
Score
Frequency
AA gradient >125 mm Hg 3
43%
HCO3 <20 mMol/L 2
21%
Glucose >180 mg/dL
31%
MAP <70 or >130 mm Hg 1
20%
Score range
SAH-PDS was independently associated with 3-month death or severe disability
Adjusted OR 1.3, 95% CI, 1.1−1.6
100 –
80 –
60 –
40 –
20 –
0 –
% severely disabled
% dead
SAH-PDS
N in each category
Claassen J, et al. Crit Care Med. 2004;32:

23. Effect of Acute Physiologic Derangements on Outcome after Subarachnoid Hemorrhage
Score
Frequency
AA gradient >125 mm Hg 3
43%
HCO3 <20 mMol/L 2
21%
Glucose >180 mg/dL
31%
MAP <70 or >130 mm Hg 1
20%
Score range −8
Claassen J, et al. Crit Care Med. 2004;32:

24. Rebleeding and Vasospasm after SAH
4 –
3 –
2 –
1 –
0 –
I I I I I I I I I I I I
Days after Subarachnoid Hemorrhage
Percent Probability
Symptomatic
Vasospasm
Re-bleeding
The daily percentage probability for the development of symptomatic vasospasm or re-bleeding after subarachnoid hemorrhage.
Day 0 denotes onset of subarachnoid hemorrhage.

25. Re-bleeding after Subarachnoid Hemorrhage
585 patients
6.7% re-bled
Risk factors
larger aneurysms
poor clinical grade
not BP
78% re-bled <72 hrs after index bleed
Associated with five-fold increased risk of death at 3 months V IV
III II I
Naidech AM, et al. Arch Neurol (in press).

26. Prevention of Re-bleeding in Subarachnoid Hemorrhage
Antihypertensive treatment to prevent re-bleeding is controversial
In the 1994 AHA Guidelines, antihypertensive therapy alone is not recommended, but may be combined with bed rest and/or anti-fibrinolytic agent
Many centers control SBP ≤160 mm Hg until aneurysm is secured
IV nicardipine
IV labetalol
Hypertension is a common risk factor for hemorrhagic stroke and increases the risk of serious complications if not effectively controlled during the early post-event phases. It is logical to conclude that elevated or rapidly changing blood pressure may increase the likelihood of rebleeding following subarachnoid hemorrhage. However, no clear benefit of antihypertensive therapy to reduce the incidence of rebleed in has been established. As a result, no specific antihypertensive recommendations were made in the 1994 Guidelines. Bed rest and antihypertensive therapy were suggested as part of a regimen including antifibrolytic therapy for patients at low risk for vasospasm or those for whom delayed surgery is preferred. In 2003, antifibrolytic therapy has been replaced by early clipping or coiling to prevent rebleeding.
Mayberg MR, et al. Circulation. 1994;90:
Mayer SA, Merritt’s Textbook of Neurology, 10th Ed, Page 256.
Mayberg MR, et al. Circulation. 1994;90:

27. Left MCA Vasospasm

28. Fluid Management Protocol for Symptomatic Vasospasm at Columbia University Medical Center
mL/hr
Place PAC
5% albumin 250 mL Q2H PRN PADP ≤14 mm Hg
SBP 180−220 mm Hg
Phenylephrine
Norepinephrine
Cardiac Index >4.0 L/min/m2
Dobutamine
Milrinone
Transfuse HCT >30%

29. Neurocritical Care Society www.neurocriticalcare.org

30. Management of Blood Pressure in Acute Ischemic Stroke
Mark J. Alberts, MD
Professor of Neurology, Northwestern University Medical School; Director, Stroke Program, Northwestern Memorial Hospital, Chicago, Illinois

31. Outline Natural history of HTN in AIS Physiology and pathophysiology
Clinical observational studies
Treatment studies
Guidelines
Medical therapies
Clinical implications

32. Elevated Blood Pressure with Acute Ischemic Stroke
Very common ─ seen in up to 85% of patients
Seen regardless of prior history of hypertension
Typically falls somewhat after first 24 hours
Some studies report spontaneous fall within 6–8 hours of stroke onset
May be a marker for pre-existing, but undiagnosed, hypertension in some patients

33. Pathogenesis of Hypertension with Ischemic Stroke
Several theories have been advanced
Sympathetic reaction
Hypoxic response
Exacerbation of underlying hypertension
Reaction to increased ICP ─ typically seen after 2–3 days

34. Cerebral Autoregulation and Cerebral Ischemia
Cerebral Blood Flow
Patients with cerebral ischemia
lose their ability to autoregulate
Increasing risk of
hypertensive
encephalopathy
ischemia
normotensive
chronic hypertensive
Autoregulation refers to the inherent regulation of arterial diameter to allow maintenance of a relatively constant amount of blood flow in different vascular beds and is most frequently discussed in terms of cerebral tissue.1 Autoregulation is lost in ischemic tissue. In patients with chronic hypertension, the structure of the arterioles thickens and entire autoregulatory curve is shifted to the right. When BP is increased beyond the upper limits of autoregulation, “breakthrough” hyperperfusion occurs. In previously normotensive patients, whose vessels have not been altered by prior exposure to high pressures, breakthrough typically occurs at a MAP of about 120 mm Hg. In chronic hypertensive patients, the breakthrough may occur at 160 mm Hg.2
As such, a normotensive patient would be expected to develop end-organ damage at a lower BP than a chronic hypertensive. Lowering BP into the normal range in a poorly controlled, chronic hypertensive patient may actually accelerate end-organ damage.2
This difference in autoregulatory set points has important implications for the management of hypertensive urgency and emergency. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive BP reductions. Care should be exercised in patients with chronic hypertension, or patients whose previous BP status is unknown, that their MAP is not lowered to the point where they suffer from ischemia (“fall off the left side of the curve”).2
1. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Philadelphia, Pa: Mosby; 2001.
2. Strandgaard S. Circulation. 1976;53:
Increasing risk
of ischemia 50
100
150
200
250
MAP (mm Hg)
Adapted with permission from Varon J, Marik PE. Chest. 2000;118:

35. Rationale for Not Treating Hypertension in Acute Ischemic Stroke
Defective autoregulation
Chronic hypertension shifts autoregulatory curve
Vulnerable ischemic penumbra
Unclear if patient taking their medications
Restarting in acute setting could cause significant decline in BP
Clinical experience--make stroke symptoms worse!

36. Enrolled 1,455 patients with acute ischemic stroke
Effect of Blood Pressure During the Acute Period of Ischemic Stroke Outcome (A Tertiary Analysis of the GAIN International Trial)
Enrolled 1,455 patients with acute ischemic stroke
Blood pressure treatment was at discretion of principal investigator
Evaluated outcomes
Aslanyan S, et al. Stroke. 2003;34:

37. Acute Blood Pressure Changes in GAIN
140 -
120 -
100 -
80 -
mm Hg
I I I I I I I I I
Hours
Aslanyan S, et al. Stroke. 2003;34:

38. Blood Pressure Changes and Outcomes
Statistically Significant Associations Between
Primary Outcomes and Blood Pressure Variables
30% Increase From Baseline MAP Weighted Average MAP
Outcome Time OR (95% Cl) P OR (95% Cl)* P
Mortality, HR 3 mo > ( ) >.01
Barthel Index (dead or 0-55 vs 7 d >.05 >.05
60-90 vs ≥95) 1mo 2.01 ( ) ( ) .01
3 mo 2.39 ( ) >.01 >.05
NIHSS score (dead or ≥2) 7 d >.05 >.05
1 mo 2.74 ( ) ( ) .03
3 mo 2.87 ( ) .01 >.05
Rankin Scale score (dead or ≥2) 1 mo 3.03 ( ) .01 >.05
3 mo >.05 >.05
*Per additional 10 mm Hg
Aslanyan S, et al. Stroke. 2003;34:

39. 304 patients with acute ischemic hemispheric stroke
Blood Pressure Decrease During the Acute Phase of Ischemic Stroke is Associated with Brain Injury and Poor Stroke Outcome
304 patients with acute ischemic hemispheric stroke
67 treated with blood pressure meds in ED (no guidelines)
31 treated with blood pressure meds in Stroke Unit (per guidelines)
Castillo J, et al. Stroke. 2004;35:

40. Outcome by Admission Blood Pressure
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
n = 18
< 120
n = 29
n = 39
n = 78
n = 49
n = 87
> 200
Early neurological deterioration %
Systolic BP on admission (mm Hg) A
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
n = 38
< 70
n = 39
71 -80
n = 48
81 -90
n = 43
n = 30
n = 102
> 110
Early neurological deterioration %
Diastolic BP on admission (mm Hg) B
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
n = 18
< 120
n = 29
n = 39
n = 78
n = 49
n = 87
> 200
Post neurological outcome %
Systolic BP on admission (mm Hg) C
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
Post neurological outcome %
Diastolic BP on admission (mm Hg) D
n = 38
< 70
n = 39
71 -80
n = 48
81 -90
n = 43
n = 30
n = 102
> 110
Castillo J, et al. Stroke. 2004;35:

41. Effect of BP Changes on Outcome
Every 10 mm drop in BP < 180 mm Hg was associated with a 25% increase in poor outcome
Every 10 mm increase in BP > 180 mm Hg was associated with a 40% increase in poor outcome
Mean infarct volumes increased at either extreme

42. Effects of Changing Blood Pressure
Adjusted Increase In Mean (95% Cl) Infarct Volume for SBP on Admission,
Use of Antihypertensive Drugs, and Differences in SBP During the First Day
SBP ≤180 mm Hg SBP >180 mm Hg (n = 161) R2 (n = 135) R2
Model 1 SBP, by 10 mm Hg 7.3 (4.0, 10.6) (1.6, 9.4) 0.87
Model 2 SBP, by 10 mm Hg … 1.4 (-3.8, 6.7) Hypotensive drugs … (28, 43.4)
Model 3 SBP, by 10 mm Hg 6.0 (2.5, 9.6) (-7.1, 3.7) Hypotensive drugs … (-9.9, 32.1) Difference in SBP: Decrease 0-20 mm Hg Decrease >20 mm Hg 61 (13.3, 109.6) (12.1, 52.3) Any increase in SBP 12.1 (-2.3, 26.6) …
Castillo J, et al. Stroke. 2004;35:

43. Evaluation of Acute Candesartan Cilexetil Therapy
The ACCESS Study
Evaluation of Acute Candesartan Cilexetil Therapy
in Stroke Survivors
342 patients with acute ischemic stroke
Randomized
Treated with candesartan 8–16 mg/day for hypertension
Trial stopped early due to efficacy results
Schrader J, et al. Stroke. 2003;34:

44. ACCESS Study Plan Study Design Cerebral Ischemia Hypertension Placebo
Hospitalized Outpatient
Day 1
1 Yr
Day 7
Cerebral Ischemia Hypertension
Placebo
Candesartan*
for Hypertension
No Antihyper Treatment
Normotension (n = 2)
* 4-16mg according to blood pressure levels, combination therapy if necessary.
Schrader J, et al. Stroke. 2003;34:

45. Blood Pressure in ACCESS
Blood Pressure Over Time (Days)
mmHg 250
200
150 50
100
Candesartan systolic
Placebo systolic X
Candesartan diastolic X
Placebo diastolic
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
3-Mon
6-Mon
12-Mon
Recruitment
Study start
Schrader J, et al. Stroke. 2003;34:

46. ACCESS Outcomes Candesartan 18.7 Placebo % Patients with Outcome 9.820
Candesartan 18
18.7
Placebo 16 14 12
% Patients with Outcome 10
9.8 8 6
7.2 4 2
2.9
Mortality
Vascular Events
Schrader J, et al. Stroke. 2003;34:

47. Days Under Observation
ACCESS Results .3 .2 .1
0.0
Cumulative
Event Rate
Cumulative Event Rate
Group
Placebo
Placebo-censored
Candesartan
Candesartan-censored
100
200
300
400
Days Under Observation
Log rank test P = .0261
Schrader J, et al. Stroke. 2003;34:

48. Guidelines for Treating Elevated Blood Pressure in Acute Ischemic Stroke
Treatment NOT recommended in most cases, unless blood pressure is ≥220/≥120
exceptions include hypertensive encephalopathy, aortic dissection, MI, etc.
Treatment to keep blood pressure <185/<110 in patients who receive thrombolytic therapy (up to 24 hrs after Rx also)
Use similar parameters for patients who require IV heparin therapy (limited data)

49. Current Guidelines
Moderately elevated blood pressure (SBP >220 mm Hg/DBP 121–140 mm Hg)
Labetalol mg IV; repeat up to 300 mg
Nicardipine 5 mg/hr IV
Severe hypertension (DBP >140 mm Hg)
Nitroprusside 0.5 mcg/kg/min IV
Thrombolytic patients
Labetalol or nitroglycerin paste PRETREATMENT
Labetalol, nicardipine, nitroprusside DURING/AFTER Rx
Labetalol drip 2-8 mg/min
Adams H, et al. Stroke. 2005;36:

50. HTN and Lytic Therapy
Important to keep BP under control with lytic therapy
24 hours post-lytic therapy is key time
Failure to control BP is associated with increased risk of hemorrhagic complications

51. Preferred Agents Mild reductions needed Labetalol Nitroglycerin paste
IV enalaprilat
Diuretic
More significant reductions needed
IV nicardipine
Sedation
Remember to treat ICP

52. No significant increase in ICP83
Theoretical Advantages of Dihydropyridine CCBs in Acute Ischemia or Hemorrhagic Stroke
May be neuroprotective in areas of sublethal brain ischemia (penumbra)1-4
Nicardipine IV allows rapid onset of effect and accurate titration6
No significant increase in ICP
Few if any cerebral, cardiac, pulmonary, allergic or renal side effects6
Cerebral ischemia results in an influx of calcium ions from the extracellular space, which disrupts basic cellular functioning activates membrane phospholipases and releases arachidonic acid. Thus, blockade of calcium entry may have a therapeutic effect following cerebral ischemia.1
In addition, vasospasm occurs in as many as 70% of patients with subarachnoid hemorrhage and is a leading cause of death and disability among these patients. Nicardipine has been shown to reduce the incidence of vasospasm. However, that reduction did not translate into reduced mortality at 3 months.1,2 Studies assessing the efficacy of nimodipine in reducing vasospasm have been equivocal.3
When treating hypertension in the setting of acute ischemic or hemorrhagic stroke, nicardipine allows for rapid and easily controlled regulation of BP with few cerebral, cardiac, pulmonary, allergic, or renal adverse effects.4
1. Flamm ES. Am Heart J. 1989;117:
2. Haley EC, et al. J Neurosurg. 1993;
3. Mayberg MR, et al. Circulation. 1994;90:
4. Cardene IV [package insert] Philadelphia, Pa: Wyeth Laboratories; 1996.
1. Flamm ES, et al. J Neurosurg. 1998;68:
2. Allen GS, et al. N Engl J Med. 1983;308:
3. Petruk KC, et al. J Neurosurg. 1988;68:
4. Sabbatini M, et al. Clin Exp Hypertens. 2002;24:
5. Flamm ES. Am Heart J. 1989;117:
6. Cardene IV [package insert].

53. Refractory HTN in Ischemic Stroke
Rule out other medical problems
Pain, infection, agitation, hypoxia
Evaluate for increased ICP
Brainstem/cerebellar strokes
Herniation syndrome

54. Our Approach Stop most blood pressure medications
Unclear if patients actually taking them
Half the doses of any ß-blockers and clonidine
Monitor blood pressure closely
Administer IV fluids
Patients often NPO and dehydrated on admission
May begin gentle blood pressure meds around discharge
No large vessel stenosis
Communicate with PCP on treatment plan

55. Conclusions Hypertension after acute ischemic stroke is common
Extremes of blood pressure are likely deleterious in many cases
Gradual blood pressure adjustments are generally recommended
Use antihypertensive agents that are well tolerated and easy to titrate

56. Considerations for Blood Pressure Control in Aortic Aneurysm Surgery
Louis M. Guzzi, MD, FCCM
Section Chief, Critical Care Medicine, Florida Hospital, Orlando, Florida; Associate Professor of Anesthesiology, Florida State University, Tallahassee, Florida

57. Disclosures Speaker/Honoraria ESP Pharma GlaxoSmithKline Pfizer Labs
Wyeth

58. Abdominal Aortic Aneurysm
13th leading cause of death in the U.S.
Most common in men >65 years
AAA causes 1.3% of all deaths among men aged 65−85 years in developed countries
Most abdominal aneurysms are asymptomatic until rupture
Kniemeyer HW, et al. Eur J Vasc Endovasc Surg. 2000;19: ; Gillum RF. J Clin Epidemiol. 1995;48: ; Sakalihasan N, et al. Lancet. 2005;365:

59. Abdominal Aortic Aneurysm − Epidemiology
Incidence has increased in the past two decades
Smoking
Aging population
Introduction of screening programs
Improved diagnostic tools
Prevalence in men > women
Men between 1.3%−8.9%
Women between 1.0%−2.2%
Lederle FA, et al. Arch Intern Med. 2000;160: ; Lindholt JS, et al. Euro J Vasc Endovasc Surg. 2000;20: ; Lederle FA, et al J Vasc Surg. 2001;34: ; Singh K, et al. Am J Epidemiol. 2001;154: ; Vardulaki KA, et al. Br J Surg. 2000;87: ; Sakalihasan N, et al. Lancet. 2005;365:

60. Abdominal Aortic Aneurysm − Diagnosis
Aneurysm = a permanent and irreversible localized dilatation of a vessel
Conventionally diagnosed if the aortic diameter is 30 mm or more
Dilatation affects the 3 layers of the vascular tunic
Otherwise the dilation is called pseudoaneurysm
Most are fusiform affecting the whole circumference of the artery
Aneurysms that only include part of the artery circumference are termed saccular
Sakalihasan N, et al. Lancet. 2005;365:

61. Abdominal Aortic Aneurysm − Diagnosis
Usually asymptomatic
Diagnosed incidentally during clinical exam
Ultrasonography is the simplest and cheapest diagnostic procedure
CT scans helpful to determine surgical treatment ─ endovascular or open surgery
MRI
Sakalihasan N, et al. Lancet. 2005;365:

62. Abdominal Aortic Aneurysm − Rupture
Most aneurysms discovered by screening are of small size and do not need immediate surgical repair
In general, the risk of rupture increases as the diameter of the aneurysm enlarges
Mortality rate for patients with ruptured AAA is 65%−85%
Approximately half of deaths attributed to rupture occur before the patient reaches the surgical room
Lederle FA, et al. N Engl J Med. 2002;346: ; N Engl J Med. 2002;346: ; Ashton HA, et al. Lancet. 2002;360: ; Sakalihasan N, et al. Lancet. 2005;365:

63. Proposed Management of an Asymptomatic Abdominal Aortic Aneurysm
<4.5 cm
4.5–5.0 cm
5.0–5.5 cm
>5.5 cm
Follow-up
Ultrasonography every 6 months
Follow-up
Ultrasonography every 3 months or 6 months
Surgery
Open or endovascular
Repair if:
Female patients
Familial cases
“Proved rapid growth
Positive PET scan
High serum markers (such as MMP-9)
Follow-up
Ultrasonography every 3 months or 6 months
Surgery
Open or endovascular
Adapted from: Sakalihasan N, et al. Lancet. 2005;365:

64. Surgical Treatment of Abdominal Aortic Aneurysm
Is endovascular repair preferable to open repair?
Open Surgical Treatment vs
Endovascular Repair
Advantages
Used for >50 yrs
Rate of failure 0.3%
Disadvantages
High rate of complications
Long recovery
Advantages
Reduced rates of operative morbidity and mortality
Shorter initial hospital stay
Shorter recovery time
Disadvantages
Rupture of AAA
Late complications?
Cost
Lederle FA. N Engl J Med. 2004;351: ; Sakalihasan N, et al. Lancet. 2005;365:

65. Major Outcomes in DREAM
Open Repair (%)
Endovascular Repair
(%)
Relative Risk
(95% CI)
Operative mortality
4.6
1.2
3.9
(0.9−32.9)
Operative mortality and severe complications
9.8
4.7
2.1
(0.9−5.4)
Operative mortality and moderate or severe complications
23.6
18.1
1.3
(0.9−2.0)
Prinssen M, et al. N Engl J Med. 2004;351:

66. Hypertension Management During Abdominal Aortic Aneurysm Surgery

67. Characteristics of Perioperative Hypertension
May last 2−12 hours
Requires rapid intervention
Systemic vasoconstriction often associated with intravascular hypovolemia
Mechanisms related to:
Vasoconstriction and tachycardia secondary to increased circulating catecholamines
Vasoconstriction secondary to activation of the RAAS
Perioperative hypertension may be self-limiting, lasting 2 to 12 hours.1 However, rapid intervention is required to avoid serious morbidity and mortality. Systemic vasoconstriction frequently accompanied by hypovolemia is characteristic of perioperative hypertension and can be precipitated by a number of factors. Pain, hypoxemia, hypercarbia, as well as some general anesthetic agents including desflurane and sevoflurane, may trigger an acute hypertensive episode by activating the sympathetic nervous system.
In addition to hypertensive crises, there is a risk of arterial vasospasm in patients undergoing cardiovascular surgery. Vascular endothelium in native arteries or the grafted artery may be damaged during mechanical manipulation, suturing, and sometimes during probing of the native arteries. The damaged endothelium may stop producing vasodilatory substances that would otherwise reduce the likelihood of coronary vasospasm or vasospasm of the grafted artery following cardiac surgery.2 Untreated, vasospasm can lead to serious ischemic complications. Because increased intracellular calcium is central to arterial vasospasm, CCBs are particularly useful in preventing and treating this complication.2
1. Mansoor GA, Frishman WH. Heart Dis. 2002;4:
2. Levy JH. Anesth Hypertens. 1999;17:
Mansoor GA, Frishman WH. Heart Dis. 2002;4:

68. Goal of Therapy for Perioperative Hypertension
Prevent postoperative hypertension (POH)
which is a significant risk factor for1,2
Myocardial ischemia and heart failure
↑ Left ventricular (LV) afterload leads to ↑ MVO2
Cerebrovascular events
Intracerebral hemorrhage
Postcraniotomy hypertension [SBP >160 mm Hg OR DBP >90 mm Hg] correlates with intracerebral bleeding3
Bleeding at suture sites
Failure to promptly treat perioperative HTN may result in acute cardiac and neurological complications, such as myocardial infarction (MI), heart failure, or intracerebral hemorrhage.1,2
Most notably, postcraniotomy HTN has been significantly correlated with intracerebral hemorrhage.3
Therefore, it is critically important to control BP in a rapid but precise manner in order to prevent poor, potentially fatal, outcomes.
1. Oparil S, et al. Am J Hypertens. 1999;12:
2. Neely C. In: Goldmann D, et al, eds. Perioperative Medicine. New York, NY: McGraw-Hill; 1994:
3. Basali A, et al. Anesthesiology. 2000; 93:48–54.
1. Oparil S, et al. Am J Hypertens. 1999;12:
2. Neely C. In: Goldmann D, et al, eds. Perioperative Medicine. New York, NY: McGraw-Hill; 1994:
3. Basali A, et al. Anesthesiology. 2000;93:48–54.

69. Properties of an Ideal Antihypertensive Agent
Treats underlying pathophysiology
Rapid onset of action
Predictable dose response
Titratable to desired BP
Minimal dosage adjustments
Minimal adverse effects
No increase in intracranial pressure (ICP)
Preserves glomerular filtration and renal blood flow
Acceptable cost to benefit ratio
No single agent is ideal for the treatment of hypertensive crises. However, agents that can be easily titrated with few dosage adjustments reduce the risk of precipitous drops in BP that lead to hypoperfusion and end-organ damage. Rapid onset and offset of action further contribute to controlled BP regulation.
Because most patients will have comorbidities and may be taking a variety of medications, risk of drug interactions and the likelihood of exacerbating comorbid conditions such as heart failure and chronic obstructive pulmonary disease are also important considerations.
In addition, convenience, cost for drugs and monitoring, association with toxic metabolites, and ease of conversion to oral agents must be assessed.
Oparil S, et al. Am J Hypertens. 1999;12:
Oparil S, et al. Am J Hypertens. 1999;12:
Levy JH. Anesthesiol Clin North Am. 1999;17:

70. Acute Antihypertensive Treatment During Anesthesia
Anesthesia may alter pharmacokinetics of antihypertensive agents1
Bolus dosing1,2
Shorter preparation time
Decreases time to effect
Shorter exposure to medications may reduce postoperative monitoring and critical care
It is not surprising that the pharmacokinetic/pharmacodynamic profile of antihypertensive agents may be altered by anesthesia. Drug effects that are apparent in the awake patient may be masked by the reduced sympathetic activity associated with anesthesia. For example, Cheung AT et al. (1999) found that bolus nicardipine in anesthetized patients decreased arterial pressure with minimal effect on LV preload, afterload and global systolic function. The blood pressure decreases in these patients were greater than those reported in response to equivalent doses administered to awake patients.2 In contrast to awake patients, nicardipine administered to anesthetized patients did not increase HR and CO.1
Another factor that may alter the behavior of an antihypertensive is the use of bolus administration. Bolus dosing has several advantages over continuous infusion. In addition to achieving a faster response to the medication, less time is required to prepare and administer the bolus dose. Since bolus therapy does not prolong exposure to medications to the extent occurring with continuous infusions, intensive care or constant arterial monitoring in post-procedural period may be avoided. For example, the decreases in SBP, DBP, and MAP after bolus nicardipine were greater in anesthetized patients than those reported in response to equivalent doses in awake patients. 1,2
1. Cheung AT, et al. Anesth Analg. 1999;89:
2. Cheung D, et al. Am Heart J. 1990;119:
1. Cheung AT, et al. Anesth Analg. 1999;89:
2. Cheung D, et al. Am Heart J. 1990:119:

71. Differential Diagnosis for POH
Blood pressure measurement error
Non-invasive
Cuff size
Cuff placement
Intra-arterial
Transducer at level of heart
Calibrate to accurate zero
Pain
Full bladder
Hypothermia
Vasoconstrictive response
Hyperthermia
Hypermetabolic state
Hypoxia
Hypercarbia
Bessman, ES. Invasive Monitoring, Pacing Techniques, and Automatic and Implantable Defibrillators. In: Tintinalli, J, Emergency Medicine: A Comprehensive Study Guide, 5th ed. McGraw-Hill, 2000;403.

72. Acute Hypertension: Treatment Options
Circulating and local factors acting on
endothelium and vascular smooth muscle
BP = SVR X CO
An excellent physiologic and clinical measure of perfusion is arterial pressure, which is determined by cardiac output (CO) and vascular resistance and can be defined by the equation in this slide. Because the mean arterial pressure (MAP) and CO can be measured directly, these 2 variables are used to describe tissue perfusion, although systemic vascular resistance (SVR) can be calculated as a ratio of MAP minus central venous pressure divided by CO.
Neural and hormonal reflexes and local factors act to regulate arterial pressure through modulation of CO, a product of heart rate (HR) and stroke volume (SV), or SVR, or both. Drugs used to reduce BP in hypertensive crises act by shifting the homeostatic balance toward lower SVR and decreased CO.
MAP can be approximated by the following equation:
MAP = BP + 1/3 Pulse Pressure (SBP – DBP)
Oates JA, Brown N J. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:
Abrupt  BP
Abrupt  SVR
(SV x HR)
ACE inhibitors
α-blockers
Calcium-channel blockers
Dopamine agonists
Nitrovasodilators
Treatment
Options
β-blockers

73. Treatment Options − Sodium Nitroprusside
Potent venous/arterial vasodilator
Immediate onset, 1- to 2-minute duration
May cause nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide poisoning
May  ICP
Requires special delivery system
Usually requires direct artery pressure monitoring
Causes significant venous pooling - watch in dehydrated patients
Abrupt cessation may cause coronary steal in patients with coronary artery disease
The JNC issued their sixth report in The stated goal of therapy in these guidelines is to reduce MAP by no more than 25% over the course of minutes to 2 hours. Initiation of lowering to 160/100 mm Hg is then recommended within 2 to 6 hours. Excessive drops in pressure should be avoided because they may lead to renal, coronary, or cerebral ischemia.1
The JNC recommends 10 parenteral drugs for the treatment of hypertensive emergencies.1 Hydralazine, diazoxide, and phentolamine are beyond the scope of this slide kit. The 2 nitrovasodilators recommended are nitroprusside and nitroglycerin. Both provide rapid onset of effect with short duration of action. Nitroprusside is recommended for most hypertensive emergencies. Nitroprusside is to be avoided in patients with potentially elevated ICP.1
Please note that in discussing hypertensive crises, the JNC VII refers to the JNC VI and does not add any new information. No discussion of parenteral agents is included in this new report.2
1. The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
2. Chobanian AV, et al. JAMA. 2003;289:
The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Arch Intern Med. 1997;157:

74. Treatment Options Nitroglycerin
Vasodilator
Onset, 2–5 minutes
Duration, 3–5 minutes
May cause headache, vomiting, methemoglobinemia
Tolerance with prolonged use
Special considerations
Acute left ventricular failure
Coronary ischemia
IV form requires special delivery system
May decrease CBF
Nitroglycerin has a rapid onset and short duration of action. However, more than 27% of patients develop headache with treatment.1 Tolerance may develop with prolonged use.1 Nitroglycerin is a venodilator that may cause venous pooling and decrease arteriolar resistance as well as lead to serious hypotension and intravascular hypovolemia.2 The JNC VI recommends nitroglycerin for patients with hypertensive crises who also have acute left ventricular failure.1
Please note that in discussing hypertensive crises, the JNC VII refers to the JNC VI and does not add any new information. No discussion of parenteral agents is included in this new report.3
1. The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
2. Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
3. Chobanian AV, et al. JAMA. 2003;289:
The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Arch Intern Med. 1997;157:

75. Nitrovasodilators Nitroprusside vs Nitroglycerin
Drug
Nitroprusside
Nitroglycerin
Rapid onset of peak effect
++++
+++
Afterload reduction +
Preload reduction ++
Coronary steal reported
Coronary dilation – large vessel
Coronary dilation – small vessel
+/-
Tachycardia
Potential for symptomatic hypotension
Ease of administration
Cyanide toxicity
Nitroprusside has a slightly faster onset of peak effect than nitroglycerin and has a greater effect on afterload reduction than preload. Nitroglycerin, on the other hand, reduces preload more than afterload at usual doses. At higher doses, additional afterload reduction occurs. Nitroglycerin dilates large coronary vessels to exert an antispasm effect.1
Nitroprusside treatment has been associated with coronary steal and cyanide toxicity.1
Both agents require special preparation for IV administration; nitroprusside must be protected from light and nitroglycerin must be used in glass containers.2
1. Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
2. The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
Pepine CJ. Clin Ther. 1988;10:

76. Treatment Options − - and -adrenergic Blockers
Drug
Onset of Action
Duration of Action
Adverse Events
Special Considerations
Labetalol
5–10 min
3–6 hours
Heart block Orthostatic hypotension
Most hypertensive emergencies except acute heart failure
Esmolol
1–2 min
10–20 min
Hypotension Nausea
Aortic dissection Perioperative
In the JNC VI guidelines, labetalol is recommended for most hypertensive emergencies except when heart failure is present.1 However, the pharmacologic effects of labetalol are complex because the drug is composed of 4 diastereoisomers, each with different relative activities.2 Labetalol blocks both 1- and 2-adrenergic receptors as well as selectively blocking 1-adrenergic receptors.
Esmolol is selective for 1-adrenergic receptors and has a shorter time to onset of action and a shorter half-life than labetalol.2 Esmolol is recommended for perioperative hypertension and aortic dissection.1 Patients with asthma or COPD may experience elevated BP due to treatment with corticosteroids and -agonists.1,3 Therefore, -adrenergic blockers and -adrenergic blockers should be avoided in these patients.1
Please note that in discussing hypertensive crises, the JNC VII refers to the JNC VI and does not add any new information. No discussion of parenteral agents is included in this new report.4
1. The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
2. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
3. Undem BJ, Lichtenstein. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
4. Chobanian AV, et al. JAMA. 2003;289:
The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Arch Intern Med. 1997;157:

77. -blocker Treatment Option − Esmolol
Advantages
Treats tachycardia and hypertension
Short duration of effect
Preserves myocardial O2 supply
Disadvantages
Bradycardia
Depresses myocardial contractility
Reactive airway disease
Continuous monitoring of BP/HR required
Esmolol is a cardioselective, -adrenergic blocker that has an extremely rapid onset (<60 seconds) and duration of action (10-20 minutes).1 This agent is rapidly metabolized by red blood cells and does not depend on hepatic or renal function for elimination.2 It is effective in patients who have both hypertension and tachycardia and is safe in patients with MI.3 The recommended initial dose is 0.5 mg/kg with a subsequent infusion of 25 g/kg/min to 300 µg/kg/min.1
1. Varon J, Malik PE. Chest. 2000;118:
2. Lowenthal DT, et al. Am J Cardiol. 1985;56:14F-18F.
3. Mooss AN, et al. Ann Pharmacother. 1994;28:
Oparil S, et al. Am J Hypertension. 1999;12:

78. Combined - and -blocker Treatment Option − Labetalol
Properties
No reduction in cerebral, renal, or coronary blood flow
Intermediate time to onset
Moderate effect/not easily titrated
May exacerbate reactive airway disease
Less potential for bradycardia
Can depress cardiac contractility
Ratio of α- to β- blockade, 1:7
Labetalol is a combined - and -adrenergic receptor blocker. The /-blocking ratio is 1:7 following IV administration.1 This agent has onset within 5 to 15 minutes with no reduction in cardiac output or cerebral, renal, or coronary blood flow.1,2
However, labetalol may be associated with arrhythmias and negative inotropic effects.1,2
1. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
2. Le Bret F, et al. J Cardiothorac Vasc Anesth. 1992;6:433.
Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological
Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill;1997:
Le Bret F, et al. J Cardiothorac Vasc Anesth. 1992;6:

79. -blocker vs Combined - and -blocker
Esmolol -blocker
Labetalol
- and -blocker
Administration
Bolus
Continuous infusion
Onset
Rapid (60 s)2
Intermediate (peak 5-15 min)2
Offset
Rapid (10-20 min)2
Slower (2-4 h)2 HR
Decreased
+/-
SVR
Cardiac output
Myocardial O2 balance
Positive
Contraindications
Sinus bradycardia
Heart block >1°
Overt heart failure
Cardiogenic shock
Severe bradycardia
The onset of action for esmolol is 60 seconds and the duration of action is 10 to 20 minutes. For labetalol, the onset of action begins within 2 to 5 minutes after a loading dose, but the peak effect requires up to 15 minutes. Several bolus doses of labetalol over a period of 1 hour may be required to achieve target BP. Once treatment is stopped, labetalol effects will last 2 to 4 hours.
Esmolol and labetalol differ in their effects on HR, SVR, and CO. In patients treated with esmolol, HR decreases, CO decreases with no change in SVR. Labetalol treatment may increase HR and CO slightly while decreasing SVR. Both agents result in positive effects on myocardial oxygen balance.
1. Varon J, Malik PE. Chest. 2000;118:
2. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:
Varon J, Malik PE. Chest. 2000;118:

80. Treatment Options − Calcium-channel Blockers (CCBs)
Drug
Onset of Action
Duration of Action
Adverse Events
Special Considerations
Nicardipine
~2.7 min
15–30 min; may exceed 4 hours
Tachycardia
Headache
Flushing
Local phlebitis
Most hypertensive emergencies
Nicardipine is a second-generation dihydropyridine calcium channel blocker (CCB) and is the only drug of this class to be available in IV form. Nicardipine differs from nifedipine in the modifications to the ester side chain from position 3 of the hydropyridine ring and the movement of the nitro group to the meta position of the phenyl ring. These structural differences make nicardipine 100 times more water soluble than nifedipine, allowing easily titratable IV administration. The onset of action of nicardipine is between 5 and 10 minutes during IV infusion, and the duration of action is 1 to 4 hours. Bolus dosing of nicardipine may cause quicker onset of action.1
Please note that in discussing hypertensive crises, the JNC VII refers to the JNC VI and does not add any new information. No discussion of parenteral agents is included in this new report.2
1. Cardene [package insert]. ESP Pharma, Inc; 2002.
2. Chobanian AV, et al. JAMA. 2003;289:
The 6th Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
Cardene IV prescribing information [package insert]. PDL BioPharma Inc. 2006

81. IV Dihydropyridine CCB − Nicardipine
Only IV dihydropyridine CCB available in U.S.
Arterial vasodilator1
Produces significant decreases in SVR2-5
More selective for vascular smooth muscle than cardiac muscle1
No AV nodal depression
Minimal myocardial depression
Cerebral and coronary vasodilator
No significant increase in ICP6
In patients treated for postoperative hypertension, the mean time to therapeutic response, defined as a >15% reduction in DBP or SBP, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg. Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (alpha half-life of 2.7 minutes), an intermediate phase (beta half-life of 44.8 minutes), and a slow terminal phase (gamma half-life of 14.4 hours) that can be seen only after long-term infusions. The apparent volume of distibution using a noncompartment model is 8.3 L/kg. The pharmacokinetics of nicardipine are linear over the dose range of 0.5 mg/h to 40.0 mg/h. Upon termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first 2 hours postinfusion. Nicardipine is highly protein bound (>95%).1
Nicardipine is rapidly and extensively metabolized by the liver. Approximately 49% was recovered in the urine and 43% in the feces. None of the dose was recovered as unchanged nicardipine. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. Caution is advised when titrating nicardipine in patients with congestive heart failure or impaired hepatic or renal function. Strong coronary artery dilation increases coronary blood flow. Weak cerebral artery dilation minimizes increased ICP.1
Cardene IV [package insert]. ESP Pharma, Inc; 2002.
Clarke B, et al. Br J Pharmacol. 1983;79:333P; 2. Lambert CR, et al. Am J Cardiol. 1987;60: ; 3. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S; 4. Lambert CR, et al. Am J Cardiol. 1985;55: ; 5. Visser CA, et al. Postgrad Med J. 1984;60:17-20; 6. Nishiyama T, et al. Can J Anaesth. 2000;47:

82. Nicardipine − Pharmacokinetics of IV Bolus Administration10
150
-10
Change in MAP (mm Hg)
-20
100
-30
-40
Plasma Nicardipine Concentration (ng/mL)
-50 20 40 60 80
100
120
140
Nicardipine concentration (ng/mL)
Plasma concentrations of nicardipine correlate linearly with the BP response. After IV bolus, pharmacokinetics fit a 2-compartment model, with an initial redistribution half-life of 2.7 minutes and an intermediate redistribution half-life of 44 minutes. The intermediate phase appears at higher doses of the drug (eg, >1-2 mg). The drug fits a 3-compartment pharmacokinetic model, with a terminal clearance half-life of 14.4 hours in patients receiving prolonged infusions.
Cardene IV [package insert]. ESP Pharma, Inc; 2002. 50
Group 1: 0.25 mg
Group 2: 0.5 mg
Group 3: 1.0 mg
Group 4: 2.0 mg
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Time after Drug Administration (hrs)
Adapted from Cheung AT, et al. Anesth Analg. 1999;89:

83. Calcium Channel Blockers
Nicardipine
(dihydropyridine)
Diltiazem
(benzothiazepine)
Verapamil
(phenylalkylamine)
Peripheral
Vasodilation1
+++++
+++
Coronary
Vasodilation2
++++
Suppression of SA Node2 +
Suppression of AV Node2
Suppression of Cardiac Contractility2 ++
CCBs inhibit the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. Such inhibition reduces HR (negative chronotropy); depresses contractility (negative inotropy); decreases conduction velocity (negative dromotropy); and dilates coronary, cerebral, and systemic arterioles. Verapamil, diltiazem, and nifedipine all produce such effects but to varying degrees and apparently by similar but different mechanisms. These mechanisms relate to the 3 different classes of calcium channel antagonists they represent: the phenylalkylamines, the benzothiazepines, and the dihydropyridines, respectively. Nifedipine is the most potent of the 3 as a smooth-muscle dilator, whereas verapamil and diltiazem have negative dromotropic and inotropic effects and vasodilating properties. Diltiazem has weak vasodilating properties compared with nifedipine and has less atrioventricular conduction effect than does verapamil. Thus, diltiazem can increase the PR interval and produce atrioventricular block. Coadministration of verapamil and a ß-blocker can lead to negative effects on HR, atrioventricular conduction, and/or cardiac contractility. Clearly, verapamil and diltiazem must be titrated very carefully when a patient is already taking a ß-adrenergic receptor–blocking drug or when adding ß-blocking drugs to verapamil or diltiazem. Although sublingual nifedipine has been used for the treatment hypertensive emergencies, serious adverse effects have brought this use into question. Because nifedipine cannot be administered parenterally, its utility in treating hypertensive emergencies is limited.1
Nicardipine is the first IV dihydropyridine available in the United States. Nicardipine is a parenteral dihydropyridine CCB that has become very popular in the treatment of postoperative hypertension. Nicardipine is titratable, is less negatively inotropic, and induces less tachycardia than nifedipine. Nicardipine acts predominantly as a vasodilator, but as with other CCBs, caution must be used when administered to patients with left ventricular failure.1
1. Marx J, et al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice. 5th ed. St. Louis, Mo: Mosby, Inc; 2002.
The relative effects are ranked from no effect (0) to most prominent (+++++).
Frishman WH, et al. Med Clin North Am. 1988;72:
Adapted from Goodman and Gilman’s: The Pharmacologic Basis of Therapeutics. 9th ed

84. Nicardipine vs Nitroprusside
Drug
Nicardipine
Nitroprusside
Rapid onset of peak effect
++++
Afterload reduction
Preload reduction ++
Coronary steal reported +
Coronary dilation – large vessel
+++
Coronary dilation – small vessel
+/-
Tachycardia
Potential for symptomatic hypotension
Ease of administration
Cyanide toxicity
A comparison of nicardipine and nitroprusside shows that both agents have a rapid onset of action and peak effect. Both agents reduce afterload, however, nicardipine has little or no effect on reducing preload. Nitroprusside is also may likely to cause coronary steal than nicardipine.
Nicardipine effectively dilates both large coronary vessels (antispasm effect) and small coronary vessels (resistance vessels) and less likely to induce tachycardia or symptomatic hypotension.

85. Nicardipine versus ß-adrenergic Blockers
Drug
Nicardipine
Esmolol
Labetalol
Administration
Continuous infusion
Bolus
Onset
Rapid
Intermediate
Offset
Slower
HR1
Minimal increase
Decreased
+/–
SVR
Cardiac output1
Increased
Myocardial O2 balance2
Positive
Contra-indications
Advanced aortic stenosis
Sinus bradycardia
Heart block >1°
Overt heart failure
Cardiogenic shock
Severe bradycardia
In general, no detrimental effects on the cardiac conduction system have been seen with nicardipine. Coronary dilatation induced by nicardipine IV improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. Beta-blockers cause a positive myocardial oxygen balance by decreasing HR and contractility. Nicardipine causes a positive oxygen balance by increasing coronary blood flow.

86. Summary
Optimal management of blood pressure must consider the disease process and the patient’s history
Predictability of response is essential
Patients best treated with titratable IV antihypertensive agents
The majority of complications are from overaggressive lowering of blood pressure