Patients at Risk:

New Insights Into Acute Blood Pressure Management

Edwin G. Avery IV, MD, CPI

Chief, Division of Cardiac Anesthesia

Associate Professor of Anesthesiology

Harrington-McLaughlin Heart and Vascular Institute

University Hospitals Case Medical Center

Case Western Reserve University School of Medicine

DISCLOSURES

The Medicines Company: funded research,

speaker’s bureau, advisory board

Cubist Pharmaceuticals: funded research,

advisory board

Covidien: funded research

Educational Initiative Learning Objectives

– Upon completion of this activity, participants should be able to:

• Identify the patients at risk for complications due to inadequate BP management

• Understand the evidence for BP management affecting outcomes

in the acute care setting

• Discuss the evolving treatment paradigm for BP management in the surgical and non-surgical patient

• Discuss how different patient conditions affect the treatment of acute BP.

ACKNOWLEDGEMENTS:

Sol Aronson, MD - Duke

Mac Dyke, MD - Houston

Jerrold Levy, MD - Emory

Alan Multz, MD - LIJ

Ed Avery - UHCMC

Al Cheung, MD - UPENN

Stan Shernan, MD - BWH

WHAT DO WE MEAN BY BP ?

• Ambulatory BP

• BP during Surgery

• BP during CPB

• BP during ICU

• Preoperative BP

• Systolic Blood Pressure (SBP)

• Diastolic Blood Pressure (DBP)

• Mean Arterial Pressure (MAP)dBP + 1/3 (sBP - dBP)

• Pulse Pressure (PP)Syst BP – Diast BP

https://www.nhlbi.nih.gov publication no. 02-5230 JNC7

JNC 7 ON PREVENTION, DETECTION,

EVALUATION & TREATMENT OF HIGH BP

Classification of Blood Pressure for Adults

Blood Pressure

Classification

SBP

mmHg

DBP

mmHg

Normal <120 and <80

Pre-hypertension 120-139 or 80-89

Stage 1 hypertension 140-159 or 90-99

Stage 2 hypertension ≥160 or ≥100

JNC - Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Chronic

Hypertension

Hypertension

Emergencies

HYPERTENSION: CLINICAL CONTEXT

Renovascular- e.g. renal artery stenosis

- renal parenchymal disease

Essential-Diastolic hypertension

-Systolic hypertension

Metabolic- e.g. pheochromocytoma

HYPERTENSIVE EMERGENCIES

• Acute cerebrovascular syndromes

– subarachnoid hemorrhage

– cerebral bleeding

– cerebral infarction

• Acute coronary syndromes

• Acute Decompensated Heart failure

• Aortic dissection

• Hypertensive encephalopathy

Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371.

Varon J, Marik PE. Chest. 2000;118:214-227.

Brain

Stroke

Hypertensive encephalopathy

Retina

Hemorrhages

Exudates

Papilledema

Cardiovascular System

Unstable angina

Acute heart failure

Acute MI

Dissecting aortic aneurysm

Kidney

Hematuria

Proteinuria

Decreasing renal function

End-Organ Damage in

Hypertension Emergencies:

Chronic

Hypertension

Hypertension

Emergencies

Acute

Hypertension

Syndrome

HYPERTENSION: CLINICAL CONTEXT

CARDIAC SURGERY PTS REQUIRED

ANTIHYPERTENSIVE TREATMENT

Vuylsteke A, et al. J Cardiothorac Vasc Anesth. 2000;14:269-273.

N=1,660 pts undergoing CABG, valve surgery, or both, as reported by 191 anesthesiologists who completed surveys

regarding antihypertensive therapy before, during, and after surgery. *P<.05. ICU=intensive care unit.

58

44

38

61

86

66

4946

68

90

0

20

40

60

80

100

Preoperative Intraoperative Postoperative ICU Overall

Pa

tie

nts

re

qu

irin

g

an

tih

yp

ert

en

siv

e t

he

rap

y (

%)

No previous hypertension (n=815)

Previous hypertension (n=845)

*

*

*

*

https://www.nhlbi.nih.gov publication no. 02-5230 JNC7

HYPERTENSIONTHE PROGRESSION OF DISEASE

1-Diastolic HTN, 2- Syst + Diast HTN, 3- Systolic HTN, 4- Pulse Pressure HTN, 5- Acute HTN

1

32

4

51

32

4

5

RISK OF STROKE AFTER CARDIAC SURGERY:

CORRELATED TO PULSE PRESSURE

Hypertension 2007;50:630-35

OR 1.35; CI 1.13-1.62 (P = 0.001) for each 10 mmHg ↑PP

N = 703

x = 348 days

Age

♀/♂

DM

CEREBRAL AUTOREGULATION

Zone of Autoregulation

Ce

reb

ral B

loo

d F

low

(CB

F;

50

ml/1

00

g/m

in)

Mean Arterial Pressure (MAP; mm Hg)

Pressure Passive

Collapse

Pressure Passive

Dilation

Adapted from Lang EW, et al. J Neurol Neurosurg Psychiatry. 2003;74:1053-1059.

Autoregulatory

Breakthrough Zone

Vasodilatory

Cascade Zone

60 150

OEF

Disruption

BBB

Neurocritical Care 2004; 3: 287-300

CEREBRAL VASCULAR

AUTOREGULATION

Traumatic Brain Injury

RISK OF ACUTE KIDNEY INJURY AFTER

CARDIAC SURGERY

Predictor Incidence(%) Risk Score OR (95% CI) P Value

Age > 75, yr 26/269 (9.7) 7 2.04 (1.23 – 3.37) 0.006

Pulse pressuremmHg ≤ 40 7/263 (2.7) 0 1.49 (1.17 – 1.89) 0.001

> 40 – 60 49/1158 (4.2) 4

> 60 – 80 36/752 (4.8) 8

> 80 – 100 17/184 (9.2) 12

> 100 3/24 (12.5) 16

CHF 71/833 (8.5) 9 2.38 (1.55 – 3.64) <0.001

MI 82/1498 (5.5) 6 1.75 (1.08 – 2.83) 0.023

RI 48/357 (13.5) 13 3.71 (2.41- 5.70) <0.001

Intraop Inotropes 63/544 (11.6) 10 2.75 (1.75 – 4.31) <0.001

IABP 18/63 (28.6) 15 4.41 (2.21 – 8.80) <0.001

CPB time ≥ 122 min 56/617 (9.1) 6 1.78 (1.15 – 2.74) 0.010

The Hosmer–Lemeshow goodness-of-fit chi-square test statistic was 4.1 (P = 0.844).

The C-index for the model was 0.839.

Circulation 115,733-42, 2007.

N Engl J Med 2007;357:797-805.

RENAL VASCULAR AUTOREGULATION

OR P value> 80 < 80

PP

RISK CARDIAC & CEREBRAL ADVERSE

OUTCOMES ( PP > 80)

Analg Anes 107,1122-9, 2008

N = 4,801

917 (19%) fatal & nonfatal complications

Urgent

SBP > 180 mmHg

DBP > 120 mmHg

No end organ damage

Emergency

SBP > 180 mmHg

DBP > 120 mmHg

End organ damage

Perioperative

HTN* occurring prior to,

during, or following

surgical procedures

Requires immediate BP

control

+/-End organ damage

ACUTE HYPERTENSION

JNC 7

www.nhlbi.nih.gov pub. No 02-5320

* Poorly Defined

Acute Hypertension

Small artery

Physiology:

exch

ange3

d.c

om

ACUTE HYPERTENSION

Pathophysiology: Endothelium

Smooth Muscle

= Nitric Oxide & Prostacyclin

= Norepinephrine

= Angiotension II

= Endothelin 1

= Aldosterone

= Vasopressin

= Thromboxane

Shear Stress

ACUTE HYPERTENSION

Collagen & von Willebrande factor

Disrupted

endothelium

Platelet adhesion

activates the coagulation

cascade

IV THERAPY FOR HYPERTENSION

• Beta Blockers / Adrenergic Antagonists– Esmolol

– Labetalol

– Phentolamine

• Dopamine Agonist– Fenoldopam

• ACE Inhibitors– Enalaprilat

• Hydralazine

• Calcium Channel Blockers– Clevidipine

– Nicardipine

• Nitrovasodilators– Nitroglycerin

– Nitroprusside

• Alpha-2 Agonist– Clonidine

Nitroglycerin Sodium Nitroprusside

Administration Continuous infusion Continuous infusion

Onset 2-5 min. 30 sec

Offset 5-10 min. 1-2 min.

Metabolism Generation of NO Release of CN, then NO

HR ++ ++

SVR Decreased Decreased

Cardiac output +/- +/-

Contraindications Hypovolemia Hypovolemia

NITROVASODILATORS

Bates JN: Biochem Pharmacol 1991; 42 Suppl: S157-65; Bates JN Basic Res Cardiol 1991; 86 Suppl 2: 17-26; Harrison DG,

Bates JN: Circulation 1993; 87: 1461-7; Kurz MA. Circ Res 1991; 68: 847-55

Tinker JH, Michenfelder JD. Anesthesiology 1976;45:340-354. Johanning RJ, et al. 1995;15:773-777. Robin ED, McCauley, R.

Chest 1992;102:1842-1845. Tung A, et al. Anesth Analg 1997;85:1045-1051.

Thiocyanate (SCN-)

Thiosulfate

Renal Excretion

Cytochrome Oxidases

Inactive Cytochromes

CN-

TOXICITY

Hepatic Rhodanase

Nitroprusside

Nitroprusside Radical

Oxyhemoglobin

Methemoglobin

Non-

enzymatic

Cyanmethemoglobin

METABOLISM OF SODIUM

NITROPRUSSIDE

Na+

CN

NO+

CN

Fe++

CN

CN

CN

Na+

NO – Nitric oxide, CN - cyanide

ACE INHIBITORS, DOPAMINE

AGONISTS, HYDRALAZINE

Enalaprilat Fenoldopam Hydralazine

Administration Intravenous Intravenous Intravenous

Onset 15-30 min < 5 min 5-20 min

Offset 6-12 hours 30 min 30-90 min

Metabolism Hepatic/Renal Hepatic Hepatic

HR Variable Increases Variable

SVR Decreased Decreased Decreased

Cardiac output Increased Increased Increased

Contraindications Angioedema Glaucoma ? Lupus

Harvey, Richard A., Pamela A. Harvey, and Mark J. Mycek. Lippincott's Illustrated Reviews: Pharmacology. 2nd ed. Philadelphia:

Lipincott, Williams & Wilkins, 2000. 19 Rang, Dale, Ritter and Flower. Pharmacology. 6th Ed, 2007.

-BLOCKERS, COMBINED

- AND -BLOCKER

Esmolol

-Blocker

Labetalol

- and -Blocker

Administration BolusContinuous infusion

BolusContinuous infusion

Onset Rapid (60 s)2 Intermediate (peak 5-15 min)2

Offset Rapid (10-20 min)2 Slow (2-4 h)2

Metabolism Blood and Tissue Esterase Liver

HR Decreased +/-

SVR 0 Decreased

Cardiac output Decreased +/-

Contraindications Sinus bradycardiaHeart block >1°

Overt heart failureCardiogenic shock

Severe bradycardiaHeart block >1°

Overt heart failureCardiogenic shock

1. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed.

New York, NY: McGrawHill; 1997:215-268. 2. Varon J, Malik PE. Chest. 2000;118:214-227

Nicardipine Clevidipine

Administration Continuous infusion Continuous infusion

Onset 5-10 min 2-4 min

Offset Hours

Dose Dependent

5-15 min

Non Dose Dependent

Metabolism Liver Blood & Tissue Esterase

HR + +

SVR Decreased Decreased

Cardiac output +++ +++

Contraindications Impaired liver function or portal hypertension; severe

aortic stenosis

Allergy to soy or eggs, defective lipid metabolism, severe aortic

stenosis

DIHYDROPYRIDINE CALCIUM CHANNEL

BLOCKERS

Kenyon KW: Ann Pharmacother 2009; 43: 1258-65; Aronson S: Expert Rev Cardiovasc Ther 2009; 7: 465-72;

Noviawaty IExpert Opin Pharmacother 2008; 9: 2519-29

SPRINT Results/CLV 250 recodec.avi

INTERDISCIPLINARY DIFFERENCES

Source: 2005 Solucient ACTracker Inpatient Hospital Database

Medicine &

Cardiology Neurology

Cardiac &

Vasc Surgery

Enalaprilat 15.7% 24.6% 8.0%

Esmolol 4.9% 6.2% 14.2%

Fenoldopam 0.2% 0.3% 1.8%

Hydralazine 15.3% 31.2% 20.4%

Labetalol 22.5% 59.8% 21.2%

Nicardipine 1.9% 13.4% 7.5%

Nitroglycerine 54.9% 9.5% 70.9%

Sodium nitroprusside 3.4% 13.8% 39.4%

Certain data used in this study were supplied by Solucient, a division

of The Medstat Group, Inc. Any analysis, interpretation, or conclusion

based on these data is solely that of the authors, and not Solucient.

COMPARATIVE STUDIES

Blood Pressure Control

and

Clinical Outcomes

Sweet Spot

Blo

od

Pre

ssu

re

Time

Overshoot

Undershoot

Inadequate Control

Rapid Control

Slow Control

Unreliable Control

ASSESSING BP CONTROL

Courtesy of Aronson

Blo

od

Pre

ssu

re

Time

ASSESSING BP CONTROL

Courtesy of Aronson

Magnitude of excursions

Duration of excursions

Number of excursions

Area Under the Curve (AUC) : mmHg*time

Mean Duration AUC

Nicardipine vs Nitroprusside for Hypertension

After Carotid Endarterectomy

Nicardipine

(n=29)

Nitroprusside

(n=31)

Time in Minutes

Dorman T, et al. J Clin Anesth. 2001;13:16-19.

83%*

t= 10 min

23%

t= 10 min

* (P < 0.01)

BP Area Under the Curve Analysis

Time (hours)

Lower limit

Upper limit

0 6 12 2418

SBP

(mmHg)

Upper limit

Lower limit

SBP

(mmHg)

Aronson S, et al. Anesth Analg. 2008;107:1111-1122.

BP=blood pressure; SBP=systolic blood pressure.

Nitroprusside use in

Cardiac Surgery

– similar effects seen in

carotid endarterectomy

EXCURSIONS OUTSIDE BP RANGE

PERIOPERATIVE CONTROL OF BP:

THE ECLIPSE STUDY

• Design: 3 parallel, prospective, randomized, open-label studies in pts

undergoing cardiac surgery at 61 medical centers

• Primary end point: Safety (30 day incidence death, MI, stroke, and renal dysfunction vs comparators)

• Secondary end points: BP control; other AEs

Clevidipinevs Nitroglycerin

Clevidipine vs Sodium

Nitroprusside

Clevidipine vs Nicardipine

Clevidipine

(n=268)

Nitroglycerin

(n=278)

Clevidipine

(n=296)

Sodium

nitroprusside

(n=283)

Clevidipine

(n=188)

Nicardipine

(n=193)

1:1 1:1 1:1

Aronson S, et al. Anesth Analg. 2008;107:1111-1122.

Perioperative Postoperative

AEs=adverse events; BP=blood pressure; MI=myocardial infarction.

2.82.3

1.1

7.9

3.8

2.41.7

7.9

0

2

4

6

8

10Clevidpine Comparators

COMPARATIVE OUTCOMES AT 30 DAYS POST

CARDIAC SURGERY

Death

30-D

ay e

vents

(%

)

(n=729) (n=700) (n=707) (n=700) (n=705) (n=712) (n=710)(n=719)

MI Stroke RenalDysfunction

Aronson S, et al. Anesth Analg. 2008;107:1111-1122.

MI=myocardial infarction.

Comparators = Nitroglycerine, Sodium Nitroprusside, Nicardipine

PRIMARY ENDPOINT BY

TREATMENT COMPARISON

5.9%

1.1%

1.1%

3.2%

NIC

8.3%

0.6%

2.3%

4.4%

Clevidipine

9.1%

1.5%

2.3%

4.7%*

SNP

8.5%

1.1%

1.4%

1.7%

Clevidipine

8.1%

2.3%

3.5%

3.4%

NTG

6.9%

1.6%

3.3%

2.8%

Clevidipine

Renal Dysfunction

Stroke

Death

MI

* p=0.045 Difference in mortality was driven by a reduced rate of CV

mortality with clevidipine

Perioperative Perioperative Postoperative

Only

Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.

Data of file, The Medicines Company.

16.30

24.33

28.02

22.37

44.48

39.51

35.84

40.40

0

5

10

15

20

25

30

35

40

45

50

4.14 4.37

1.763.79

8.8710.50

1.69

7.79

0

5

10

15

20

25

30

35

40

45

50

AUC BY TREATMENT GROUP

ECLIPSENTG

ECLIPSESNP

ECLIPSENIC

Clevidipinen=269

NTGn=278

Clevidipinen=295

SNPn=284

Clevidipinen=187

NICn=194

Clevidipinen=751

All Comparatorsn=756

ECLIPSENTG/SNP/NIC

Me

an

AU

C (

mm

Hg

x m

in/h

)

Me

dia

n v

alu

e in

Ita

lics

p = 0.0006 p = 0.0027 p = 0.0004p = NS

Aronson S, et al. Anesth Analg. 2008;107:1111-1122.

Data presented based on maintaining

SBP within a 70 mmHg range

Urinary Flow Rate Sodium Excretion Creatinine Clearance

Fenoldopam

Nitroprusside

Relative effects of fenoldopam or nitroprusside infusion on renal parameters

0

20

40

60

80

100

120

140

-10

Change f

rom

Baselin

e (

%)

Elliott WJ, et al. Circulation 1990;81:970-977

COMPARATIVE RENAL EFFECTS IN

SEVERE HYPERTENSION

*

*

*

* P<0.001

N = 28

CLINICAL OUTCOMES

Linking BP Control to Clinical Outcomes

COMPARATIVE OUTCOME after PRE-OP BP

TREATMENT IN CARDIAC SURG PATIENTS

BP treatment with SNP or NTG was assoc with increased 30 day mortality compared to CLV

Anesth Analg. 2008;106(SCA Suppl):56.

Independent predictors of ↑30 day mortalityN=282 (preincisional treatment)

30D mortality in these pts was 5.0% (CCB 3/137(2%) vs CMP 11/145(8%); p<0.03)

Variable P-value OR 95% CI

Treatment CLV v SNP/NTG 0.00155 7.5 1.5, 38.4

Additional Procedure 0.0085 5.8 1.6, 21.2

Preop Cr > 1.2 mg/dL 0.0168 4.9 1.3, 17.8

Any valve or redo CABG 0.0483 3.7 1.0, 13.4

Candidate variables;

Demographics

Baseline

characteristics

Medical history

Treatment group

Proc characteristics

AUC

p<0.05 required.

LOGISTIC REGRESSION RESULTS:

PREDICTORS OF MORTALITY

P-Value Odds Ratio95% CI

[Lower Limit, Upper Limit]

Surgery Duration (hour) <0.0001 1.517 [1.240, 1.856]

Age (year) 0.0003 1.070 [1.031, 1.110]

Pre-op Creatinine ≥ 1.2 mg/dL 0.0031 2.670 [1.392, 5.122]

AUC (area outside the range)* 0.0069 1.003 [1.001, 1.004]

Additional surgical procedures 0.0089 2.409 [1.246, 4.655]

Pre-op Hgb (g/dL) 0.0135 0.824 [0.707, 0.961]

Pre-op SBP >160 or DBP > 105 0.0228 2.386 [1.147, 4.963]

History of COPD 0.0228 2.326 [1.125, 4.812]

History of recent MI (<6 m prior) 0.0312 2.197 [1.073, 4.497]

*Every 1 mmHg per minute

American College of Cardiology; 2007; New Orleans, LA

1 mmHg x 60 min

2 mmHg x 60 min

3 mmHg x 60 min

4 mmHg x 60 min

0 1 2 3 4

5 mmHg x 60 min

PREDICTED 30 DAY MORTALITY BY MAGNITUDE OF AUC

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]

SBP outside of a

defined range

American College of Cardiology; 2007; New Orleans, LA

Composite Outcome: the worse the control, the poorer the outcome (Q4 vs Q1 P<0.05)

Anesthesiology. 2008;109:A1589.

CT Surgery PatientsHighest Risk 4th Quartile

Lowest Risk 1st Quartile

BP CONTROL PREDICTS 30-DAY DEATH,

CVA, MI & RENAL RISK

Q4

Q1

Q4 = Highest BP excursions, Q1= Lowest BP excursions

Perspective on the 4th Quartile

PREDICTORS OF 30-DAY RENAL

DYSFUNCTION

P value Odds Ratio

95% Confidence

Interval

Pre-op serum Cr ≥1.2 mg/dl <0.0001 5.466 3.506, 8.521

Pre-op hemoglobin (g/dL) <0.0001 0.785 0.699, 0.881

Body mass index 0.0074 1.049 1.013, 1.087

Surgery duration (hour) 0.0077 1.292 1.070, 1.559

Age (year) 0.0086 1.033 1.008, 1.059

BP (4th quartile of AUC*) 0.0126 1.785 1.132, 2.815

Race (African American) 0.0151 2.164 1.161, 4.035

Primary CABG + valve 0.0165 1.944 1.129, 3.348

Total AUC of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg intraoperatively;

AUC ≥75th percentile analyzed.

Multiple logistic regression analysis ECLIPSE trial

Candidate variables;

Demographics

Baseline

characteristics

Medical history

Treatment group

Proc characteristics

AUC

p<0.05 required.

Anesthesiology. 2007;107: A1253.

BP excursions

per 60 minO.R. 95% C I

1 mmHg/min 1.17 1.02-1.34

2 mmHg/min 1.38 1.05-1.81

3 mmHg/min 1.61 1.07-2.43

4 mmHg/min 1.89 1.10-3.27

5 mmHg/min 2.22 1.12-4.39

AUC calc for excursions outside sBP range of 85-145 mmHg pre, post-op, & 75-135 mmHg intra-op

Multiple Logistic Regression Analysis ECLIPSE trial:

AUC PREDICTS 30-DAY MI RISK

Anesth Analg. 2008;106(SCA Suppl):72.

Candidate variables;

Demographics

Baseline

characteristics

Medical history

Treatment group

Proc characteristics

AUC

p<0.05 required.

MEAN DURATION OF SBP EXCURSIONS

ASSOC WITH 30 MORTALITYMinutes SBP > 130 or < 105 mmHg per incident

P-Value < 0.0001, O.R.-1.07 (1.04-1.102)Anesthesiology 2010;113:305-12

OR = 1.03 per minute (95% CI 1.02-1.39); P<0.001

*Mean duration of SBP excursion

most predictive of 30D mortality

3.1M BP measured intraop (N=7,504 pts)

Deriviation 5,038; Validation 2,466

SUMMARY

Few data define perioperative BP control guidelines

or targets

Baseline (preop) hypertensive subclass

independently predicts (postop) risk

Intra-operative BP control predicts (postop) risk

Effectiveness of BP treatment depends on the

patient, situation, treatment and condition

Is that this

patient’s real

blood

pressure?

THANK YOU

Essential hypertension: Diastolic hypertension

Vascular Remodeling: Early Changes

J Hypertension 1995;14:1247

Eutrophic Remodeling*

Before After

Media to

Lumen

Ratio

*Resistance

Vessels

Histology:

Hypertrophic remodeling (conductance vessels)

ESSENTIAL HYPERTENSION: SYSTOLIC

HYPERTENSION

Before After

Media to

Lumen

Ratio