Sukh Brar MD FRCPC Royal Columbian Hospital October 26 th, 2013

* 1. Definitions * 2. Prevalence * 3. Pathophysiology * 4. Preoperative * 5. Intraoperative * 6. Postoperative * 7. Treatment * 8. Outcomes * 9. Summary

* 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

ChronicHypertension HypertensionEmergencies AcuteHypertensionSyndromes Acute and Chronic Hypertension: Clinical Context

Classification of Severe Hypertension JNC VI. Arch Intern Med 1997;157: * 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:

Acute Hypertension Hypertensive Urgency Severe HTN WITHOUT acute end-organ damage Requires BP control over several days-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

* 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

Prevalence of HTN by Age NHANES: Source: NCHS and NHLBI. HTN Risk > 115/75

* 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 vasoconstrictors Mechanical stress Endothelial injury PermeabilityCoagulation Fibrinoid necrosis Marik P. Chest. 2007;131:

Courtesy of Schiffrin EL. NormalNormal InwardEutrophicremodeling OutwardHypertrophicremodeling 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 Carotid bulb Prox. Coronaries Prox. Coronaries Distal aorta Distal aorta High Shear  Atheroprotective Low Shear  Atherogenic Occurs sites prone to lesion formation Carotid bulb Carotid bulb Prox. Coronaries Prox. Coronaries Distal aorta Distal aorta High Shear  Atheroprotective Low Shear  Atherogenic * Wide PP  Augments Oscillatory Shear Elevated Stretch with Hypertension Pro-Inflammatory / Atherogenic Elevated Stretch with Hypertension Pro-Inflammatory / Atherogenic Pressure/StretchPressure/Stretch

O NO PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 Endothelium Endogenous vasoconstrictors The Endothelium Modulates Vascular Tone Courtesy of JJ Ferguson III, MD. Endogenous vasodilators O2-O2- X

Proposed Vascular Pathophysiology of Hypertensive Urgency Vaughan CJ, Delanty N. Lancet. 2000;356: Courtesy of JJ Ferguson III, MD. Acute ↑ BP triggers ↑ cellular adhesion molecular expression NO PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 ET 1 ( - )( + ) CAMs Endogenous vasodilators Endogenous vasoconstrictors O2-O2-

Overwhelmed control of vascular tone leads to coagulation cascade activation Overwhelmed control of vascular tone leads to coagulation cascade activation Loss of endothelial activity coupled with coagulation and platelets promotes DIC Loss of endothelial activity coupled with coagulation and platelets promotes DIC Proposed Vascular Pathophysiology of Hypertensive Emergency Vaughan CJ, Delanty N. Lancet. 2000;356: Courtesy of JJ Ferguson III, MD. TxA 2, PAI-1, TF

Mechanical stress on the vessel wall ↑ BP ↑ BP Release 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 Tone Baroreceptor Reflexes Volume/Pressure Renin/Angiotensin Preload Cardiac Output Blood Pressure Catecholamines Adrenal Gland CNS VeinsArteries CapacitanceResistance Sympathetic Nervous System Regulation of Blood Pressure HeartKidney Afterload

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure Blood Pressure Kidney Vasoconstriction Angiotensin I Renin Substrate Angiotensin II Renin Sodium & Water Reabsorption Aldosterone Adrenal Cortex

* 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

* Effects of Perioperative Hypertension

* 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

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

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

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

* 17,638 consecutive day surgery patients * Hypertension and intraoperative adverse events * Any event OR 2.2 ( ) * Cardiovascular events OR 2.5 ( ) * 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:

* 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

* 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

PACU Pain Anxiety Distended Bladder Hypervolemia Vasoconstriction ER/CC Myocardial Ischemia Hypercarbia/ Hypoxemia Reduced organ perfusion -Renal -Cerebral OR Vascular clamping (afterload) Hyperdynamic Myocardium Malignant Hyperthermia Diastolic Dysfunction

* 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

 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:

Reduce MAP by 20-25% or Reduce MAP to mmHg (whichever is higher) Achieve target BP within 2-4 hours Reduce MAP by 20-25% or Reduce MAP to mmHg (whichever is higher) Achieve target BP within 2-4 hours

* 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: Oparil S et al. Am J Hypertens. 1999;12: Desirable Properties for Intravenous Agent

* 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): Treatment Options Treatment Options

* 3 rd 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

* 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

* 2 nd generation dihydropyridine CCB * High vascular and cerebral/coronary vasodilation * Onset of action 5-15 min & duration 4-6 hours * Reduces cardiac & cerebral ischemia

* 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 min & few changes * Increases CO & CBF & improves CV0 2 supply vs demand

* 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

* 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 T 1/2 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.

* 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).

* 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!

* 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 minutes & no rebound HTN when stopped.

* 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 = 1 st or 2 nd choice agent!

* 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.

* 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%

* 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 minutes. * Metabolism of esmolol through rapid hydrolysis of ester linkages by red blood cell esterases * Not dependent on renal or hepatic function.

* 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.

* 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 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.

* 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 ► 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 ► 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*Median Granger et al. SCCM February 2008 Regardless of 1st antihypertensive 50-75% of pts required > one agent

“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

* 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

Time (hours) SBP Lower Upper – 145 mmHg 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

Aronson S et al. SCCM 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 ( mmHg) predictive of 30- day mortality P= OR =1.02 per 100 mm Hg x min 95% CI [ ]

Mean Duration of Excursions Minutes SBP > 135 or 135 or < 95mmHg per incident P-Value < , O.R ( ) Samples (n=7187) DUKE patient population Development & validation datasets

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

* 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.

* 6. Quickly identify underlying mechanism of hypertension and treat. * 7. Reduce MAP 20-25% or MAP < 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.

* 1. Definitions * 2. Prevalence * 3. Pathophysiology * 4. Preoperative * 5. Intraoperative * 6. Postoperative * 7. Treatment * 8. Outcomes * 9. Summary

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