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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
Next
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