Sukh Brar MD FRCPC

Royal Columbian Hospital

October 26th, 2013

* Perioperative Hypertension

When Does it Matter?!

*Objectives

*1. Definitions

*2. Prevalence

*3. Pathophysiology

*4. Preoperative

*5. Intraoperative

*6. Postoperative

*7. Treatment

*8. Outcomes

*9. Summary

*Definition of Hypertension?

*Seventh Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure (JNC VII) [2003]

*British Hypertension Society Guidelines [1999]

*World Hypertension Society/International Society of Hypertension (WHO/ISH) guidelines

*Differ w.r.t inclusion of target organ damage and the limit for initiating treatment

Chronic Hypertension

Hypertension Emergencies

Acute Hypertension

Syndromes

Acute and Chronic Hypertension: Clinical Context

Classification of Severe Hypertension

JNC VI. Arch Intern Med 1997;157:2413-2448

*Uncomplicated Stage 3 HTN

*Hypertensive Crises

*Urgencies

*Emergencies

Hypertension with

Progressive target organ damage

Hypertensive Urgencies:Defined by Effects or Setting

Severe HTN with acute end organ damage:

Central nervous system Myocardial ischemia or heart

failure Renal damage Active hemorrhage Eclampsia Microangiopathic hemolytic

anemia Aortic dissection

Hypertensive Emergencies:Defined by Effects

Hypertensive Emergencies:

Hypertensive Emergencies:

*Acute Hypertension

Acute Hypertension

Hypertensive Urgency

Severe HTN WITHOUT acute end-organ damage

Requires BP control over severaldays-weeks

Hypertensive Emergency

Severe HTN (BP >180/120 mm Hg)

WITH end-organ damage

Requires immediate, aggressive BP control

Perioperative Hypertension

HTN* occurring prior to, during, or following surgical procedures

Requires immediate BP control

* Poorly defined

*Perioperative Hypertension*Hypertension occuring in the pre-operative,

intra-operative or post-operative period.

*Importance:*Increased risk of cardiovascular events

*Increased post-operative morbidity and mortality

*Association with end-organ damage

11.2

37.4

55.4

73.9

23.2

37.5

49.1

63.669.5

6.4

83.8

18.3

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

20-34 35-44 45-54 55-64 65-74 75+

Per

cent

of P

opul

atio

n

Men Women

Prevalence of HTN by Age

NHANES: 1999-2004. Source: NCHS and NHLBI.

HTN Risk > 115/75

*Pathophysiology

*Physiology Perioperative Hypertension

*Hyperadrenergic response to surgery

*Increase SVR, decrease preload

*Rapid intravascular volume shifts

*Renin angiotensin activation

*Adrenergic stimulation (cardiac & neural)

*Serotonergic overproduction

*Baroreceptor denervation

*Altered cardiac reflexes

*Inadequate anesthesia

*Cross clamp

SVR; Humoral vasoconstrictorsMechanical stressEndothelial injuryPermeabilityCoagulationFibrinoid necrosis

Marik P. Chest. 2007;131:1949-1962.

*Remodeling

Courtesy of Schiffrin EL.

Normal

Inward Eutrophic remodeling

Outward Hypertrophic remodeling

Small Arteries (eutrophic) in diastolic HTN

Large Arteries (hypertrophic) in PPH

Courtesy of Schiffrin EL.

Pathogenic Role of Mechanical Forces

Oscillatory Shear Stress* Occurs sites prone to lesion formation Carotid bulb Prox. Coronaries Distal aortaHigh Shear AtheroprotectiveLow Shear Atherogenic

*Wide PP Augments Oscillatory Shear

Elevated Stretch with Hypertension Pro-Inflammatory / Atherogenic

Pressure/Stretch

O

NO

PGI2

CatecholaminesAT-II

ADH (vasopressin)Aldosterone

TxA2

EndotheliumEndogenous vasoconstrictors

The Endothelium Modulates Vascular Tone

Courtesy of JJ Ferguson III, MD.

Endogenous vasodilators

O2-

X

Proposed Vascular Pathophysiology of Hypertensive Urgency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.Courtesy of JJ Ferguson III, MD.

Acute ↑ BP triggers ↑ cellular adhesion molecular expression

NO

PGI2

CatecholaminesAT-II

ADH (vasopressin)Aldosterone

TxA2

ET1( - ) ( + )

CAMs

Endogenous vasodilators

Endogenous vasoconstrictors

O2-

• Overwhelmed control of vascular tone leads to coagulation cascade activation• Loss of endothelial activity coupled with coagulation and platelets promotes DIC

Proposed Vascular Pathophysiology of Hypertensive Emergency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7. Courtesy of JJ Ferguson III, MD.

TxA2, PAI-1, TF

*Pathophysiology of Acute Hypertensive Syndromes

Mechanical stress on the vessel wall

↑BPRelease of Local humoral vasoconstrictors

Augments HTN

Endothelial damage

Activation of the clotting cascade

Further release of humoral vasoconstrictors

Fibrinoid necrosis of small blood vessels

Pressure natriuresis

Volume depletion

RAAS activation

Vasopressinendothelincatecholamines

Major physiologic derangements

Courtesy of JJ Ferguson III, MD.

Adrenergic ToneBarorecept

or Reflexes

Volume/Pressure

Renin/Angiotensin

Preload

Cardiac Output

Blood Pressure

Catecholamines

Adrenal Gland

CNS

Veins

ArteriesCapacitance

Resistance

Sympathetic Nervous System Regulation of Blood Pressure

Heart Kidney

Afterload

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure

Blood Pressure

KidneyVasoconstrict

ion

Angiotensin I

Renin Substrat

e

Angiotensin II

Renin

Sodium & Water

Reabsorption

Aldosterone

Adrenal Cortex

*Effects of Perioperative Hypertension

*CVS effects:*Increased BP→ ↑ afterload & myocardial oxygen demand → myocardial oxygen supply and demand imbalance.

*Chronic ↑ BP → myocardial hypertrophy → myocardial oxygen supply and demand imbalance

*Hypertrophied myocardium → decreased compliance → abnormal diastolic filling

*CNS effects:*Increased risk of stroke

*Impaired cerebral autoregulation

*Especially important in neurosurgical patients

*Effects on renal function*Effective control of BP prevents renal dysfunction

*Intraoperative urine output monitoring for assessment of perioperative renal function

*Effects of Perioperative Hypertension

*Preoperative Period

*Patients with well-controlled HTN preoperatively less likely to experience intraoperative BP lability & postop complications

*Recent UpToDate Meta-Analysis suggests that in patients with hypertension, elective surgery does not need to be delayed as long as the blood pressure is below 170/110 mmHg.

*Patients taking chronic antihypertensive meds should CONTINUE taking meds until time of Sx.

UpToDate June 27, 2013: Perioperative management of hypertension

*Preoperative Period

Comfere T et al. Anesth and Analg 2005; 100: 636-44

*Hemodynamic Response to Laryngoscopy

Kihara et al. Anesth Analg 2003; 96: 890-5

*Intraoperative Period

Prys-Roberts C et al. BJA 1971; 43: 122-137

*Intraoperative Period

*17,638 consecutive day surgery patients

*Hypertension and intraoperative adverse events

*Any event OR 2.2 (1.4-3.6)

*Cardiovascular events OR 2.5 (1.5-4.2)

*Hypertension 174 (76%)

*Arrhythmia 21 (9.2%)

*Hypotension 14 (6.1%)

*Bradycardia 13 (5.7%)

*Tachycardia 7 (3.1%)Cheung F et al. BJA 1999; 83: 262-70

*Intraoperative Period

*Acute BP elevations > 20% considered hypertensive emergency

*Chronic Htive patients more likely to be labile

*Result in increased risk of postop mortality & renal failure, especially during CV procedures

*Htive events more commonly during carotids > abdominal aorta > peripheral vascular > intraperitoneal > intrathoracic surgeries.

*If known LV dysfunction +/- CAD, increased risk of myocardial ischemia or CHF.

Perioperative hypertension: Diagnosis and Treatment. Varon 2011 NJCC

*Postoperative Period*More common in preop Htive patients & vascular Sx

*SBP > 190 mmHg and/or DBP > 100 mmHg on 2 consecutive readings post surgical intervention

*Occur in first 20 minutes of postop period

*Resolution can require up to 3 hours

*If left untreated, increases risk cv ischemia, AMI, CVA & bleeding

Perioperative hypertension: Diagnosis and Treatment. Varon 2011 NJCC

*Factors in the Development of

Acute HypertensionPACU

Pain

Anxiety

Distended Bladder

Hypervolemia

Vasoconstriction

ER/CC

Myocardial

Ischemia

Hypercarbia/Hypoxemia

Reduced organ perfusion

-Renal-Cerebral

OR

Vascular clamping (afterload)

Hyperdynamic Myocardium

MalignantHyperthermia

Diastolic Dysfunction

*Causes of Postoperative Hypertension

*Preoperative hypertension

*Withdrawal of antihypertensive medications

*Pain

*Emergence Delirium/Agitation

*Hypoxia

*Hypercarbia

*Hypothermia

*Hypervolemia

*Type of Surgery

*Hypertensive crises*Hypertensive encephalopathy

*Acute ICP elevation

*Acute Aortic Dissection

*Acute pulmonary edema with LVF

*Acute MI/Unstable Angina

*Eclampsia

*Acute Renal Failure

*Pheochromocytoma crisis

*Causes of Postoperative Hypertension

Hypertensive Emergencies Initiate treatment immediately

Hypertensive Urgencies Reduce BP within a few hours

Non-urgent Stage 3 Hypertension Reduce BP within one week

Treatment Guidelines*

*JNC VI. Arch Intern Med 1997;157:2413-2448

*Endpoints of Antihypertensive Therapy

Reduce MAP by 20-25%

or

Reduce MAP to 110-120 mmHg

(whichever is higher)

Achieve target BP within 2-4 hours

* Goals for an Ideal Antihypertensive Agent in Setting of Cardiac Surgery

*Rapid onset of action

*Predictable dose response

*Titratable to desired BP

*Highly vascular selective

*Maintain stroke volume and cardiac output

*Rapidly reversible

*Low risk of overshoot hypotension

*Low risk of adverse reactions

Levy JH. Anesthesiol Clin North Am. 1988;17:587-678.

Oparil S et al. Am J Hypertens. 1999;12:653-664.

Desirable Properties for Intravenous Agent

*Therapeutic Approaches to Arterial Vasodilation: Armamentarium

*ACE inhibition

*Alpha-1 adrenergic blockade

*Calcium channel blockade

*Dopamine-1 stimulation

*Ganglionic blockade

*Cyclic nucleotide stimulation

*PDE inhibition

*Potassium channel modulation

Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25.

Treatment Options

*Treatment Options

*Treatment Options

*Clevidipine

*3rd generation dihydropyridine CCB

*Approved for HTive crisis & when need tight BP control

*Ultra-short-acting, selective arteriolar vasodilator

*Half life of 1 minute!!!

*BP lowering effects seen within 2-3 minutes of infusion

H

*Clevidipine

*Rapidly metabolized by red blood cell esterases

*Metabolism not affected by renal or hepatic function

*Stroke volume and CO usually increase

*Increases coronary blood flow

*Protects against ischemia/reperfusion injury

*Nicardipine

*2nd generation dihydropyridine CCB

*High vascular and cerebral/coronary vasodilation

*Onset of action 5-15 min & duration 4-6 hours

*Reduces cardiac & cerebral ischemia

*Nicardipine

*Dosage independent of weight initial infusion of 5 mg/hr increase by 2.5 mg/hr q5min to max 15 mg/h

*Proven highly effective for postop HTN.

*BP control typically within 10-15 min & few changes

*Increases CO & CBF & improves CV02 supply vs demand

*Nitroglycerin

*Potent venodilator & only affects arterial tone and high doses

*In volume depleted patients, NTG may cause severe hypotension & reflex tachycardia

*Reduces BP by reducing preload and CO

*Increases severity of hyperadrenergic state found in APH.

*High doses may cause methemoglobinemia

*Low doses may support IV antihypertensive therapy in APH pts with ACS, RHF or pulmonary edema

*Nitroprusside

*Arterial and venous vasodilator, decreases both afterload and preload.

*Very potent agent, with an onset of action of seconds, duration 1-2 minutes and a T1/2 of 3-4 minutes.

*Concerns with cyanide toxicity! (44% cyanide by weight)

*In patients with CAD, a significant reduction in regional blood flow (coronary steal) can occur.

*Nitroprusside

*Can reduce renal blood flow and renal function

*Decreases cerebral blood flow & increases ICP

*Data suggests that SNP in excess of 4 mcg/kg/min for as little as 2-3 hours may lead to cyanide toxicity.

*ONLY use when other IV antihypertensive agents are unavailable, or in specific clinical circumstances with normal renal and hepatic function. (< 2 mcg/kg/min).

*Hydralazine

*Direct arteriolar vasodilator having little or no effect on venous circulation.

*Known to increase circulating catecholamines!

*Rapid onset (within 5-15 min)

*Decrease in BP can last up to 12 hours

*Can be difficult to titrate BP responses

*Recent meta-analysis in OB = increased complications!

*Fenoldopam

*Unique among IV BP agents in mediating vasodilation by acting on peripheral dopamine-1 receptors.

*10 times more potent than dopamine! Mediates renal arterial vasodilation & promotes natriuresis and diuresis.

*Onset of action is within 5 minutes & max response within 15 minutes.

*Duration of action is 30-60 minutes & no rebound HTN when stopped.

*Fenoldopam

*Quickly metabolized by conjugation in liver

*After starting at 0.1 mcg/kg/min, titrate q 15min

*Infusion range of 0.03 – 0.3 mcg/kg/min controls BP

*Particularly benificial in pts. With impaired renal function.

*HTive crisis + Renal Dysfunction = 1st or 2nd choice agent!

*Labetolol

*Combined selective alpha-1 and nonselective beta-adrenergic receptor blocker

*Alpha- to beta-blocking ratio of 1:7.

*Metabolized by the liver to inactive molecule

*BP lowering effect begins within 2-5 minutes after administration

*Peak at 5-15 minutes & lasts 2-4 hours.

*Labetolol

*Heart rate either maintained or slightly reduced

*Labetolol maintains CO & decreases SVR w/o reducing peripheral blood flow (maintains cerebral, renal and coronary blood flow)

*Loading dose of 20mg & repeated incremental doses of 20-80mg given at 10 minute intervals to reduce BP

*After initial loading dose, using infusion at 1-2 mg/min & titrating until hypotensive effect quite effective.

*Found to be safe and effective with response rate of 85 – 100%

*Esmolol

*Particularly useful in severe postop HTN with tachycardia

*Ultra-short-acting cardioselective, beta-adrenergic blocking agent.

*Onset of action within 60 seconds, duration of action 10-20 minutes.

*Metabolism of esmolol through rapid hydrolysis of ester linkages by red blood cell esterases

*Not dependent on renal or hepatic function.

*Esmolol

*Ideal beta-adrenergic blocker in postoperative patients who are at risk for CAD

*Available for both IV use as bolus & infusion

*Suitable agent in situations where CO, HR, BP increased

*Typically given as 0.5 – 1.0 mg/kg loading dose over 1 minute & infusion at 50 mcg/kg/min & increasing up to 300 mcg/kg/min as necessary.

*Enalaprilat

*RAAS hyperactive during/after major surgery & likely important mediator of microvascular ischemic injury

*Antagonism of RAAS with ACEI may afford protection against cerebrovascular and renal adverse outcomes

*1.25mg over 5 minutes every 6 hours titrated by increments of 1.25mg at 12-24 hours to a maximum of 5mg every 6 hours.

*Onset of action 15 minutes, peak effect in 1 hour and duration of action is 6 hours.

*Enalaprilat

*In context of hypertensive emergencies, IV long-acting ACEI such as enalaprilat NOT recommended due to unpredictable antihypertensive effects.

*Can use preemptively in patients undergoing craniotomy for control of HTN during emergence.

*Can combine with esmolol, labetolol or nicardipine to improve postoperative BP control.

► 1500 pts, 21 hospitals, 79% therapy in ED► Median age 58, Women 49%, AA 58%► Initial BP 201/110► 90% HTN, 33% kidney history , 17% drug

abuse

Granger et al. SCCM February 2008

Reason for Admission

Time to Initiation of IV Therapy

► 1500 pts, 21 hospitals, 79% therapy in ED► Median age 58, Women 49%, AA 58%► Initial BP 201/110► 90% HTN, 33% kidney history , 17% drug

abuse

Granger et al. SCCM February 2008

Reason for Admission

Time to Initiation of IV Therapy

Systolic BP Control Over 24 Hours by First IV Antihypertensive

n=982

*MedianGranger et al. SCCM February 2008

Regardless of 1st antihypertensive

50-75% of pts required > one agent

*Outcomes

“There are known knowns; there are things we know that we know.There are known unknowns; that is to say, there are things that we now know we don't know.But there are also unknown unknowns – there are things we do not know we don't know.”

Former United States Secretary of Defense, Donald Rumsfeld – February 2002

*MAP, SBP & PP Independently Predict Risk

*Each 10mmHg INCREASE PP

* 11% increase stroke

* 16% increase death

* 12% increase in recurrent MI

*Each 10mmHg RISE MAP = 20% increase stroke!

Hypertension,1999;34:375-80

*Systolic BP Control Over 24 Hours

Time (hours)

SBP

Lower

Upper

0 6 12 2418

135 – 145 mmHg

65 - 75 mmHg

I mm Hg x 60 min

2 mm Hg x 60 min

3 mm Hg x 60 min

4 mm Hg x 60 min

5 mm Hg x 60 min

Odds Ratio

95% CI [Lower Limit, Upper Limit]

1.20 [1.06, 1.27]

1.43 [1.13, 1.61]

1.71 [1.20, 2.05]

2.05 [1.27, 2.61]

2.46 [1.35, 3.31]

Excursions in Perioperative BP Control Related to Increased 30-day Mortality

Data on file, The Medicines Company.

0 1 2 3 4

Aronson S et al. SCCM 2008. Poster #557.

Perioperative BP Lability Predicts Mortality in Patients Undergoing Cardiac Surgery

► Analysis of DUKE Heart Center database in pts undergoing CT surgery

● N =5238● 3.1M BP

evaluations► AUC (95-

135mmHg) predictive of 30-day mortality

P=0.0139

OR =1.02 per 100 mm Hg x min

95% CI [1.004-1.037]

Mean Duration of Excursions

Minutes SBP > 135 or < 95mmHg per incident

P-Value < 0.0001, O.R.-1.068 (1.036-1.102)

Samples (n=7187)

DUKE patient population

Development & validationdatasets

Cardiac Surgery Patients – Inadequate BP Control

The worse the control, the poorer the outcomes.

SCA 2008

Increased risk of 30-day death, CVA, MI and renal dysfunction vs patients with tight BP control

*Summary

*1. Imperative to urgently treat BP >180/110 perioperatively when associated with end organ impairment or damage.

*2. Can proceed with elective surgery when BP < 170/110 and minimal comorbidities without increased postop morbidity/mortality. Continue talking majority of anti-HTN meds preop.

*3. Pathophysiology of HTN involves interactions with many organ systems including brain, heart, kidneys, adrenals and endothelium. Periop HTN leads to increased CVS, CNS, Renal and other end organ damage and increased morbidity

*4. Chronic HTN patients much more labile throughout periop period with potential for hypoperfusion if too aggressively treated.

*5. Postop HTN >190/100 occurs within 20 minutes & may require several hours to resolve. Many agents can be used with significant risks of excessive relative hypotension.

*Summary* 6. Quickly identify underlying mechanism of hypertension and treat.

* 7. Reduce MAP 20-25% or MAP <110-120 mmHg in HTive urgency/emergency w/i 2-4 hours.

* 8. Clevidipine, Esmolol are ideal short acting titratable agents. Labetolol is highly effective including as an infusion and fenoldopam is useful if coexisiting renal disease.

* 9. Majority of APH patients require 2-3 drugs and 2-4 hours to obtain adequate control. Potential for significant hypotension at 4-8 hour mark with many agents.

* 10. ECLIPSE trial suggests that more stringent targets of SBP 75 – 145 mmHg can reduce 30 day mortality. Time spent outside this range incrementally increases risks of death, CVA, MI and renal dysfunction.

* 11. Interdisciplinary rounds in the PACU facilitates improved quaility of care, reduces variation in care and may improve outcomes.

*Objectives

*1. Definitions

*2. Prevalence

*3. Pathophysiology

*4. Preoperative

*5. Intraoperative

*6. Postoperative

*7. Treatment

*8. Outcomes

*9. Summary

*References

* 1. Intraoperative Blood Pressure. Charlson et al., Ann Surgery 1990. Vol 212 (5): 567-580.

* 2. Risks of General Anesthesia and Elective Operation in the Hypertensive Patient. Goldman L and Caldera DL. Anesthesiology 50: 285-292, 1979.

* 3. The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery. Aronson S. Dept. of Anesthesiology DUHS.

* 4. Perioperative Hypertension: Diagnosis and Treatment. Soto-Ruiz KM et al. NJCC Vol 15 (3) June 2011.

* 5. Should Peri-Operative Hypertension Lead to Postponing Surgery. Howell, S. University of Leeds.

* 6. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC – 7). US Dept. of HHS May 2003.

* 7. Perioperative Management of Hypertension. Kaplan et al. UpToDate Jun 27, 2013.

* 8. Treatment of Specific Hypertensive Emergencies. Kaplan et al. UpToDate Feb 6, 2012.

* 9. The ECLIPSE Trials: Comparative Studies of Clevidipine to Nitroglycerin, Sodium Nitroprusside, and Nicardipine for Acute Hypertension Treatment in Cardiac Surgery Patients. IARS. Vol 107 (4), October 2008.

* 10. ACC/AHA 2007 Guidelines on Perioperative Cardiac Evaluation and Care for Noncardiac Surgery… Circulation 2007: 116: e418-e500.

* 11. Hypertension in the Inpatient Setting: Mechanisms and Pharmacologic Management. PPT.

* 12. Perioperative Management of Hypertension. Costas Tsioufis. Department of Cardiology, University of Athens. PPT

* 13. Perioperative Blood Pressure Variability in the Treated Hypertensive Patients. Kiyohara et al. Clinical and Experimental Hypertension, 2013: 35 (4): 291-294.

* 14. Esmolol Reduces Perioperative Ischemia in Noncardiac Surgery: A Meta-analysis of Randomized Controlled Studies. Landoni G et al. Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No. 2 (April 2010): 219-229.

*References

* 15. Hypertension Crisis. Papadopoulos et al. Blood Pressure. 2010; 19: 328-336.

* 16. Studying the Treatment of Acute hyperTension (STAT) Registry. Granger et al. Am Heart J 2009; 158: 599-606.

* 17. Improved Perioperative Blood Pressure Control Leads to Reduced Hospital Costs. Getsios et al. Expert Opin. Pharmacother. (2013) 14(10): 1285-1293.

* 18. Clevidipine: A New Intravenous Option for the Management of Acute Hypertension. Ndefo et al. Am J Health-Syst. Pharm. 2010; 65: 351-60.

* 19. Peri-operative hypertension and Acute hypertensive crises. Dr. Kunal Karamchandani. PPT

* 20. Hemodynamic Control and Clinical Outcomes in the Perioperative Setting. Aronson S and Varon J. Journal of Cardiothoracic and Vascular Anesthesia, Vol. 25, No 3 (June), 2011: pp. 509-525.

* 21. Interdisciplinary Rounds in the Postanesthetic Care Unit. Hoke N and Falk S. Anesthesiology Clin 30 (2012) 427-431.

* 22. Hemodynamic and Related Challenges: Monitoring and Regulation in the Postoperative Period. Plante A et al. Anesthesiology Clin 30 (2012) 527-554.

* 23. Perioperative Hypertensive Crises: Newer Concepts. Fontes ML & Varon J. International Anesthesiology Clinics 2012Volume 50, Number 2, 40-58.

* 24. Assessment and Nursing Management of Hypertension in the Perioperative Period. Nunnelee JD & Spaner SD. Journal of PeriAnesthetia Nursing Vol 15; No 3 (June); 2000: pp. 163-168.

* 25. Perioperative hypertension: A review of current and emerging therapeutic agents. Marik PE & Varon J. Journal of Clinical Anesthesia (2009) 21, 220-229.

* 26. Management of Perioperative Hypertensive Urgencies With Parenteral Medications. Ahuja K. Charap MH. Journal of Hospital Medicine 2010; 5: E11-E16.

* 27. Strategies for Managing Perioperative Hypertension. Desai RG et al.Current Hypertension Reports 2009; 11: 173-177.

* 28. Perioperative Hypertension: Defining At-Risk Patients and Their Management. Lien SF & Bisognano JD. Curr Hypertens Rep (2012) 14; 432-441.

Thank You!