β-blocker’s in Anesthesia

Donald M. Voltz, M.D.Assistant Professor of Anesthesiology

Case Western Reserve University/University Hospitals of Cleveland

Goals

To provide everyone with enough information to begin comfortably using beta-blockers in the perioperative period.

Objectives

Physiology of Adrenergic Receptors β -adrenergic antagonists Clinical Application of β-blockers

Cardiac Protection Hemodynamic Control Decreasing Anesthetic Requirements

Guidelines for Beta-blocker Usage in the OR

β -adrenergic Receptor Physiology

β-blocker Receptor Types

β 1 Receptors Predominant receptor on cardiac myocytes

β 2 Receptors Involved in contraction and relaxation of heart failure Peripheral vasodilitation and bronchial dilatation

β 3 Receptors Negative inotropy via NO-dependant pathway May play a role in deterioration of cardiac function in

heart failure

β – Receptor Biologic Responses

Chronotropy Dromotropy Inotropy Cellular Growth Cellular Death (apoptosis)

β-Receptor Intracellular Signaling

β -Receptor Down-Regulation

Phosphorylation (down regulation)

Translocation (sequestration)

Degredation

β -Receptor Down-Regulation

Down-regulation begins within a few hours after an elevation of catecholamines

Initial phase is the uncoupling of receptor and signal transduction

Late phase results in degradation of receptors

Down-regulation has been reported to persist for 1 week after laparotomy, thoracotomy, and cardiac bypass

β -Receptor Down-Regulation

Cell Death – Necrosis and Apoptosis

Catecholamines are toxic to cardiac cells Tachycardia with Isoproterenol significantly

increased apototic death than ventricular pacing

Cardiac cell death is reduced in patients with subarachnoid bleeding when treated with atenolol

β -adrenergic Antagonist Medications

β -adrenergic Antagonists

Generation Characteristics Medications

1st No ancillary Properties

propranolol,

timolol, nadolol

2nd β1-selective metoprolol, atenolol, esmolol, bisoprolol

3rd β1-selective, with ancillary properties

carvedilol, bucindolol

β 1/ β 2 selectivity

Medication β 1/ β 2 Selectivity

Propranolol 2.1

Metoprolol 74

Atenolol 75

Esmolol 70

Bisoprolol 119

Carvedilol 7.2

Bucindolol 1.4

Celiprolol 300

Nebivolol 293

Ancillary Properties of β-blockers

Membrane-Stabilizing Activity Intrinsic Sympathomimetic Activity Lipid Solubility Antioxidant Activity Anti-adhesive Activity α1-Antagonistic Activity

Clinical Actions of β -blockers

Lowering heart rate Decreasing blood pressure Decreasing atherosclerotic plaque stiffness Decreased platelet activation Anti-arrhythmic effects Cardiac protection – not HR dependant Decrease in anesthetic and analgesic

requirements Improvement of immune response

Cardiac Effects of β-blockade

Clinical Evidence for β –blocker Use

Clinical Applications for β -blockade

Cardiac Protection Hemodynamic Control Immune Modulation Modulation of Coagulation Decreased Anesthetic Requirements

Myocardial Protection

Well studied in vascular patient’s who are at high risk for perioperative cardiac events

Evolving evidence supports there use as a standard of care in at risk patients

Likely to find increasing role in the future

Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery

Dennis T. Mangano, Ph.D., M.D., Elizabeth L. Layug, M.D., Arthur Wallace, Ph.D., M.D., Ida Tateo, M.S., for The Multicenter Study of Perioperative Ischemia Research Group

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Volume 335:1713-1721 December 5, 1996     

Number 23

Mangano, et al. 1996

Randomized trial of atenolol vs. saline (n=99, n=101)

Patient followed for 2 years Mortality decreased in atenolol group

0% vs 8% at 6 months 3% vs 14% at 1 year 10% vs 21% at 2 years

Wallace, et al. 1998

200 pts randomized to atenolol or saline EKG, Holter monitor, and CPK w/ MB were

followed 24 hr prior and 7 days after surgery Atenolol 0,5, or 10 mg or placebo prior to

induction and every 12 hours until po than qd for 1 week

Wallace, et al. 1998

Decreased perioperative myocardial ischemia 17/99 esmolol vs 34/101 placebo (days 0-2) 24/99 esmolol vs 39/101 placebo (days 0-7)

Polderman, et al. 1999

846 pts with one or more cardiac risk factors; 173 positive dobutamine stress tests

Bisoprolol in 59; Placebo in 53 Nonfatal MI

0% bisoprolol 17% placebo group

Cardiac Death 3.4% bisoprolol group 17% placebo group

What Patients are at Risk

B-blockers & At Risk Patients

Presence of CAD History of Myocardial Infarction Typical Angina or Atypical Angina with + Stress Test

At Risk for CAD (2 or more of the following) Age >65 years Hypertension Active Smoker Serum Cholesterol > 240 mg/dl Diabetes Mellitus

B-blockers and Cardioprotection

How well are we doing with at risk patients? Not Very Well!

Prophylactic beta-blockade to prevent myocardial infarction perioperatively in high-risk patients who undergoing general surgical procedures.

Taylor RC, Pagliarello G.

Can J Surg. 2003 Jun;46(3):216-22

236 pts for laparotomy 143 pts at risk for CAD 60.8% did not receive B-blockers pre-op 33% pts had B-blockers discontinued

The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular

Surgery

Khether E. Raby, MD, FACC*, Sorin J. Brull, MD  , Farris Timimi, MD, Shamsuddin Akhtar, MD, Stanley Rosenbaum, MD, Cameron Naimi, BS, and Anthony D. Whittemore, MD  

Anesth Analg. 1999 Mar;88(3):477-82

The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular Surgery

Vascular Pts at High Risk for CAD underwent 24 hrs Holter Monitoring

26 of 150 pts had significant ischemia as measured by ST-depression – PreOp

Randomized to Esmolol gtt (n=15) or Placebo (n=11) Titrated to HR 20% below ischemic threshold

Holter Monitoring for 48 hrs PostOp

The Effect of Heart Rate Control on Myocardial Ischemia Among High-Risk Patients After Vascular Surgery Ischemia Present Post-Op

73% in Placebo Group (8 of 11) 33% in Esmolol Group (5 of 15)

Number of Hours HR < Ischemic Threshold 9 of 15 pts in Esmolol group <20% and all

without ischemia 4 of 11 pts in Placebo group <20%. 3 of 4

without ischemia

Anti-Arrhythmic Effects

High risk pts with CAD under-going noncardiac surgery have PVC’s or ventricular tachyarrythmias (50% incidence)

Cardiac surgery pts are at high risk of developing atrial fibrillation

Blunting sympathetic tone decreases incidence of both atrial and ventricular tachyarrythmias

β-blockers counteract epinephrine-induced hypokalemia

Balanced Anesthesia andBeta-blockers

AmnesiaAnalgesia

Unconsciousness Paralysis

Hemodynamic Control

Components of Balanced Anesthesia3/15/2003 - v2

B-blockers and Anesthetic Reduction

Michael Zaugg, M.D.; Thomas Tagliente, M.D., Ph.D.; Eliana Lucchinetti, M.S.; Ellis Jacobs, Ph.D.; Marina Krol, Ph.D.; Carol Bodian, Dr.P.H.; David L. Reich, M.D.; Jeffrey

H. Silverstein, M.D.ANESTHESIOLOGY 1999;91:1674-1686

Beneficial Effects from B-Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

Beneficial Effects from B-Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

N=63 patients for noncardiac surgery Monitored – Neuropeptide Y, epinephrine,

norepinephrine, cortisol, and ACTH Randomly assigned

Group 1: no atenolol Group 2: Pre- and Post-operative atenolol Group 3: Intraoperative Atenolol

Beneficial Effects from B-Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

Beneficial Effects from β -Adrenergic Blockade in Elderly Patients Undergoing Noncardiac Surgery

Beta-blockade did not change neuroendocrine stress response

Lower Narcotic Requirement Groups II and III – 27.7% less fentanyl

Lower Anesthetic Requirements Group III – 37.5% less isoflurane (BIS same in

all groups) Lower PACU Morphine requirements Shorter PACU times

Beta-blockers and Bariatric Surgery

Randomized Study of Morbidly Obese Patients Undergoing Gastric Bypass

Metoprolol vs. Placebo Evaluate

Intraoperative Volatile Requirements PACU Pain Requirement PCA Usage

Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data

Zaugg, et. al.

Can J Anesth 2003; 50: 638-42

Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data

Does atenolol result in light anesthesia with the reduction of volatile agents?

Are our abilities to adequately judge anesthetic depth impaired with atenolol?

Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data

45 patients from the prior study we used (post hoc)

Collected HR, MAP, SBP, and BIS output Subgroups were analyzed

Group I n=12 Group II n=16 Group III n=17

Atenolol May Not Modify Anesthetic Depth Indicators in Elderly Patients – A Second Look at the Data

Group III received 39.5% less isoflurane than Group I

Group II and III received 21% less fentanyl than Group I

All Groups had similar intraoperative BIS levels (53-54)

Atenolol reduces anesthetic requirements but not modify depth of anesthesia indicators

β-Blockers and Memory

Lipophilic β-blockers can cross the blood-brain barrier

Propranolol has been shown to blunt storage of emotionally charged events

Some thoughts that perioperative β-blockade may be useful to blunt recall

Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia

Jay W. Johansen

Anesth Analg 2001; 93:1526-31

Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia

N=20 patients Alfentanil Groups (50 or 150 ng/ml) Saline vs Esmolol infusion Monitored BIS output and Suppression Ratio

Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia

BIS Output Esmolol – 40% reduction (37→22) Saline – no change

Suppression Ratio Esmolol – 13.4 fold increase (5 → 67) Saline – no change

Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia

Smith, J. Van Hemelrijck, and P. White

Anesth Analg 2003;97:1633-1638

Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia

N=97 patients for arthroscopy Compared esmolol to alfentanil

Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia

Esmolol decreased time to eye opening (7.2 vs 9.8 min)

Esmolol reported more pain in PACU Esmolol required more opiods in PACU

Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration

Jay W. Johansen, et al.

Anesth Analg 1998; 87:671-6

Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration

N=100; divided into 5 groups Isoflurane alone Isoflurane with large dose esmolol (250

mcg/kg/min) Isoflurane with Alfentanil Isoflurane, Alfentanil, small dose esmolol (50

mcg/kg/min) Isoflurane, Alfentanil, large dose esmolol (250

mcg/kg/min)

Esmolol Potentiates Reduction in Minimal Alveolar Isoflurane Concentration

MAC levels after steady state Isoflurane – 1.28% Iso + large dose Esmolol – 1.23% Iso + Alfentanil – 0.96%* Iso + Alfentanil + small dose Esmolol – 0.96% Iso + Alfentanil _ large dose Esmolol –

0.74%**

Perioperative Immune Modulation

Stress response decreases immune function Natural killer cells have decreased cytotoxic

activity in the perioperative period Nadolol has been shown to blunt a

hypothermic decrease in natural killer cell cytotoxic activity

Contraindications ofβ -blockers

β-blocker Adverse Reactions

Very well tolerated in the perioperative period May see hypotension in severely volume

contracted patients Patients with severe heart failure may acutely

have problems. Titrate slowly. Avoid in symptomatic bradycardia Caution in patients with advanced conduction

impairments

β-blocker Adverse Reactions

Bradycardia – is it symptomatic??? Bronchospasm in COPD/Asthma patients –

no evidence to suggest problem in these patients with selective agents

Heart Failure – use carefully in patients with low EF, however, has been shown to improve function with ACEI in end-stage CHF

Management of Complications Related to β-Blockade

Treatment of Symptomatic Bradycardia from β-blockers Use of Vagolytic Medications

Glycopyrolate Atropine

Glucagon 2.5 mcg/kg iv Pronounced chronotropic effect

Treatment of Hypotension fromβ-blockers β-agonists are not useful in treating cardiac

decompensation Phosphodiesterase III inhibitors (milrinone) retain full

hemodynamic effects without excessive tachycardia Combination of glucagon and milrinone restores

cardiac output but often increases heart rate significantly

Combination of β-blockers with PDE3I’s may allow for perioperative β-blockade in severe heart failure

Guidelines for Using β -blockers in the OR

Summary for At Risk Patients

Preemptive Bradycardia Think about heart rate as separate from blood

pressure Be aggressive with heart rate control Incorporate into preoperative and

postoperative care. Involve Primary Care Physician Involve Vascular Surgeon and Nursing

The End