perioperative myocardial infarction myocardial... · at reducing perioperative acute myocardial...
TRANSCRIPT
Gregory M.T. Hare, MD, PhD, FRCPC Professor
Depts. of Anesthesia and Physiology
ScientistThe Keenan Research Centre
Li Ka Shing Knowledge Institute
St. Michael’s HospitalUniversity of Toronto
Perioperative Myocardial InfarctionWhich β- Blocker is More Protective?
CAS 2014St. John’s
Disclosures
1) Forest Laboratories Inc. Operating grant to study the impactof Nebivolol on Cerebral Perfusion During Anemia
2) Johnson & Johnson Medical Companies:Academic Salary SupportCo-Director of Center of Excellence for Patient BloodManagement at St. Michael’s Hospital
Talk Outline
1) Mechanism of Perioperative MI2) Is there a belter β-blocker?3) Anemia as a Diagnostic Interoperative Stress Test
Incidence of Perioperative MI
Postoperative Days
Why is Perioperative Myocardial Ischemia Feared?
High Mortality ~ 30 to 50%
Nagele P. Anesthesiology, 2011Ghaferi A.A. NEJM, 2009
Unknown or Unpredictable Mechanism
Demand Ischemia~55%Thrombotic ~26%
Non-obstructive ~19%
Duvall W.L. Catheter Cardiovasc. Interv. 2012
Clinical Question
A 73 yo Woman Present in the PAF for THA tomorrow!Very limited exercise tolerance (< 4 METS)EKG-nonspecific ST changes; Hb 110 g/L
The Optimal Approach Includes:
A) Proceed to surgery tomorrow.B) Prescribe metoprolol 25 BID; proceed to surgery tomorrow.C) Prescribe metoprolol 25 BID and delay surgery for 1 week.D) Prescribe bisoprolol 2.5 OD and delay surgery for 1 week.E) Delay surgery, get a dobutamine echo, consider
appropriate β-blockade; diagnose and treat anemia.
Clinical Question
The 73 yo Woman has chest pain in the PACU after THATroponin-T > 0.03, HR 105; lateral ST depression; Hb 78 g/L
The optimal Treatment Includes:
A) Admission to the CCU/ICU for monitoringB) Consider anti-platelet therapy (ASA)C) Transfusion of 1 U PRBCsD) Consider acute beta-blockadeE) All of the above
Which β-Blocker Should We Use? Drug Solubility Rec.
Spec.1/2-Life
Metab. Indication Dose (Start/Max)
Metoprolol β1>β2+
3-7 hrs.
BP,HF CAD, Post-MI,
12.5-25 BID(400 BID)
Atenolol β1>β2++
6-14 hrs.
BP, Angina, Post-MI
12.5-25 OD(200 OD)
Bisoprolol β1>β2+++
10-12 hrs.
BP 1.25-2.5 OD20 OD
Carvedilol β1/β2α
6-8 hrs.
Heart Failure 3.125 BID(50 BID)
Labetalol β1/β2α
6-8 hrs.
BP, AnginaPreclampsia
100 OD (600 BID)
Nebivolol β1>β2+++++
12-19hrs.
BP 2.5 OD(40 OD)
-Liver-Kidney-Water Soluble-Lipid Soluble
Clinical Question
After transfusion to Hb 100 g/L, a dobutamine stress echo demonstrated a lateral wall motion abnormality. You have decided to start a β-blocker for HR control and to minimize risk of ongoing ischemia.
Which drug would you choose?
A) Atenolol 12.5 mg/kg ODB) Metoprolol 25 mg BIDC) Carvedilol 6.5 mg ODD) Bisoprolol 2.5 mg ODE) Nebivolol 2.5 mg OD
de Lemos JAMA 2013
The Cardiac Myocyte is the Source of Troponin
Universal Definition of a Myocardial Infarction
Circulation, JACC; 2012
A rise in Troponin:
And one of-i) Symptoms of myocardial ischemiaii) New ST-T wave changes or LBBBiii) New pathological Q waveiv) Imaging showing new loss of myocardial functionv) Intracoronary thrombus on angiogram
Universal Definition of a Myocardial Infarction
JACC Vol 60 2012
A rise in Troponin:
And one of-i) Symptoms of myocardial ischemia
Landesberg G Circulation 2013
Perioperative MI Caused by:1) Plaque Rupture and 2) Demand Ischemia
Landesberg G Circulation 2013
Perioperative MI Caused by:1) Plaque Rupture and 2) Demand Ischemia
Revascularization
Landesberg G Circulation 2013
Perioperative MI Caused by:1) Plaque Rupture and 2) Demand Ischemia
Treat the Underlying Cause
Perioperative MI Caused by:1) Plaque Rupture and 2) Demand Ischemia
Focal MI (Type I)Plaque Rupture
Global Ischemia (Type II)Troponin Leak?
TROPONIN TROPONIN
Perioperative MI Defined by Increased Troponin? Demand Ischemia (Type II)
Troponin Leak
êOxygen Supply
éOxygen Demand
Perioperative Ischemia leads to MI and Death??
Oxygen Supply/Demand Imbalance (Ischemia)
ST Depression
Troponin Leak
Myocardial Infarction
Sympathetic Nervous System Activation
Surgery and Blood Loss
Death
The Vascular Events in Noncardiac SurgeryPatients Cohort Evaluation (VISION)
Devereaux PJ JAMA 2012
Peak TnT level was associated with 30 Day Mortality
Anesthesiology 2014
Re-evaluation of the Definition of Myocardial InjuryAfter Noncardiac Surgery (MINS)
Utilized the VISION data to determine if:Myocardial injury caused by ischemia (+/- necrosis)Has a prognostic relevance within 30 Days of surgery
Definition of MINS-TnT >0.03 due to myocardial ischemia
30 Day Mortality with MINS ~9.8% vs. 1.1% MINS predicted: nonfatal Cardiac arrest (OR 14.6 [CI 5-37])CHF (OR 10.3 [CI 8-13]), Stroke (OR 4.6 [CI 2-7])
Non-vascular Death 46%; Vascular death 54%
POISE 1, 2- Goal of Perioperative Treatment: To Reduce Risk of Perioperative MI and Death
Pre-Cellular Injury CellularInjury Post-Cellular injury
Treat Risk:(POISE-1:β-Blockade)(POISE-2: Clonide)
Supportive Interventions to Optimize Perfusion and Reduce the Risk of Organ Injury & Mortality
Optimal Pointof Intervention
Devereaux PJ NEJM 2014
POISE-2
POISE 2-Clonidine in Patients UndergoingNon-cardiac Surgery
Devereaux PJ NEJM 2014
Assumptions-
Activation of the sympathetic nervous systemDuring surgery leads to O2 supply demand imbalance and MI.
Clonidine can prevent the increased sympathetic outflow.
Hypothesis-Perioperative clonidine can prevent 30 day MI and death
Is it a Good Idea to Impair the Brains Sympathetic Signaling to the Body???
Heart
Brain
Liver
Kidney
Troponin
S100
Hepcidin
KIM
Rationale for POISE-2
Anesthesiology 2004
POISE 2-Clonidine Did Not Reduce MI + Death
Devereaux PJ NEJM 2014
POISE 2-Clonidine Outcomes
Hypotension and Major Bleeding Increase the Risk of MI
β Blockers in General Medicine: the GOODβ-blockers are GOOD at reducing mortality after an acute myocardial infarction
MIAMI Trial (Metoprolol)Eur Heart J 1985
MIAMI- Metoprolol in acute myocardial infarction
POISE 1-Metoprolol in Patients UndergoingNon-cardiac Surgery
Are β-blockers GOOD at reducing perioperativeacute myocardial infarction?
Non-Fatal MIComposite Outcome
Beta Blocker
Beta Blocker
PlaceboPlacebo
Time, days
0 10 20 30 0 10 20 30
Ris
k, %
Devereaux PJ Yang H, POISE 2008
β Blockers in Perioperative Medicine: the GOOD
β-blockers are GOOD at reducing perioperativeacute myocardial infarction
Perioperative MI Defined by Increased Troponin:Beta-Blockers Prevent Perioperative MIMyocardial IschemiaTroponin Leak?
Beta-BlockadePrevents MI
β Blockers Protect Against Perioperative MI
Favors β-Blockade Favors ControlBangalore Lancet 2008
β-Blockers ↓ Non-Fatal MI
Lindenauer, NEJM 2005;353:349
Perioperative β-Blocker Therapy and MortalityAfter Major Noncardiac Surgery
Patients atHigh risk for MI
Benefit fromβ-Blockade.
London MJ et al. JAMA 2013
Current β Blocker Recommendations + GuidelinesClass I (Benefit>>>Risk)
Do Not Discontinueβ-Blocker Therapy
ACCF/AHAContinue in patients using
β blockers for otherAHA Class I Guidelines
(Level C)
ESCKnown IHD or myocardialIschemia on stress testing
(Level B)
Class II (Benefit>Risk)
β Blocker TherapyIndicated for Patients
with ↑Cardiac Risk
ACCF/AHAVascular or Intermediate
risk surgery with apositive stress test or more than 1 risk factor
(Level C to B)
ESCIntermediate risk surgery
(Level B)
Class III (Risk>>Benefit)
Do Not Routinely Treat Low Risk Patients with High Dose β Blockers
ACCF/AHAHigh dose β blockers
without titration(Level B)
ESCHigh dose β blockers
without titration(Level A)
Fleishmann KE, Circulation 2009;120:2123-51, London M, Can J Anesth 2010
Level of Evidence A (Gold); B (Silver); C (Bronze)
Stroke Death
Time, days
Beta Blocker
Beta Blocker
Placebo
Placebo
Devereaux PJ Yang H, POISE 2008
β Blockers in Perioperative Medicine: the BADβ-blockers are BAD because they may impair cardiovascular responses (cardiac output) required for organ perfusion
Ris
k, %
BMJ 2005
β Blockers Increase Bradycardia, Hypotension, Perioperative Stroke?
β Blockers Increase Perioperative Stroke?
Bangalore Lancet 2008
β-Blockers ↓ Non-fatal MI
β-Blockers ↑ Non-fatal Stroke
Favors β-Blockade Favors Control
β Blockers Increase Perioperative Stroke?
Beattie WS 2014
Heart
Brain
The Job of The Heart is to Perfuse the Brain
Heart
Brain
β-Blockade
Risk vs. Benefit with β Blockade: Summary of Clinical Trial Outcomes
Yang and Beattie CJA 2008
Trial Intervention Benefit Cost
CIBIS-II Bisoprolol vs. Placebo-CHF
Reduced Mortality (11.8 vs. 17.3%)
Increased Stroke Rate (31 vs. 16)
ASCOT-BPLA
Amlodipine + Periindopril vs.
Atenolol + Thiazide-HT
Reduce MAPIncreased Stroke
Rate (327 vs. 423)
NOR-DIL Beta Blocker vs. Diltiazem Reduce MAP Increased Stroke
Rate (159 vs. 196)
COMMIT Metoprolol vs. Placebo-Early MI
Reduced Re-Infarction, VT
Increased Cardiogenic Shock
(1141 vs. 885)
COMET Carvedilol vs. Metoprolol-CHF
Increased Survival with Carvedilol
Increased Mortality with Metoprolol(512 vs. 600)
Lancet 2003
Is there a Problem with Metoprolol?
Is there a Problem with Metoprolol?
Wallace A, Anesthesiology , 2011
Anemia Associated with Increased Mortalityin Non-Cardiac Surgical Patients
Beattie WS, Anesthesiology 2009
Pre-operative Hemoglobin Concentration
Prob
abilit
y of
Mor
talit
y
Beattie WS, Anesthesiology 2009
β Blockers Increase Risk Associated with Perioperative Anemia
β-Blockade + Anemia Increases Incidence of MI
β-Blocked Group
Relative Risk of Major Adverse Cardiac Event with β-blockade: 2.38 (1.43-3.96) p=0.0009
Anesthesiology 2010
Hemoglobin < 100 g/L
Acute β-Blocker Withdrawal Increases MI Risk
Van Kei WA, Anesthesiology 2009
β Blocker withdrawal Increased MI incidence
β Blocker treatmentincreased MI incidencein low risk patients
Increased Stroke Risk In Perioperative Patients
Beatiie WS TGH
Clinical Question
After transfusion to Hb 100 g/L, a dobutamine stress echo demonstrated a lateral wall motion abnormality. You have decided to start a β-blocker for HR control and to minimize risk of ongoing ischemia.
Which drug would you choose?
A) Atenolol 12.5 mg/kg ODB) Metoprolol 25 mg BIDC) Carvedilol 6.5 mg ODD) Bisoprolol 2.5 mg ODE) Nebivolol 2.5 mg OD
Which β-Blocker Should We Use? Drug Solubility Rec.
Spec.1/2-Life
Metab. Indication Dose (Start/Max)
Metoprolol β1>β2+
3-7 hrs.
BP,HF CAD, Post-MI,
12.5-25 BID(400 BID)
Atenolol β1>β2++
6-14 hrs.
BP, Angina, Post-MI
12.5-25 OD(200 OD)
Bisoprolol β1>β2+++
10-12 hrs.
BP 1.25-2.5 OD20 OD
Carvedilol β1/β2α
6-8 hrs.
Heart Failure 3.125 BID(50 BID)
Labetalol β1/β2α
6-8 hrs.
BP, AnginaPreclampsia
100 OD (600 BID)
Nebivolol β1>β2+++++
12-19hrs.
BP 2.5 OD(40 OD)
-Liver-Kidney-Water Soluble-Lipid Soluble
Metoprolol Has Lowest β1-Adrenergic Receptor Specificity of Commonly Used β1-Blockers
β1 antagonist fold selectivity β1/β2
CGP 20712A 501.2ICI 89406 69.2Practolol 14.1Xamoterol 14.1Bisoprolol 13.5Betaxolol 6.8AtenololICI 215001 3.2Acebutolol 2.4Metoprolol 2.3
Baker, Br J Pharmacol, 2005
Cross-reactivity with β2-ARs may inhibit adrenergic mediated vasodilation.
4.1
-0.5
0
0.5
0 5 10 15
LOG
OD
DS
RAT
IO F
OR
PO
ST O
PER
ATIV
E ST
RO
KE
RATIO BETA 1 TO BETA 2 ACTIVITY
BISOPROLOL
ATENOLOL
METOPROLOL
OTHERS
β Blockers Increase Perioperative Stroke?
Beattie et al TGH
Sufgery(Adrenergic
Stress)
Anemia(Blood Loss)
β-Blockade
What is the Interaction Between SurgeryAnemia and β-Blockade?
Systemic Effect of Surgery Acute Blood Loss
Medical Intervention
How Does Anemia (Acute Blood loss) ImpactPerioperative MI and Stroke?
POISE-2 –Acute Blood loss ↑ the Risk of MI
POISE-1 –Acute Blood loss ↑ the Risk of Stroke
Lancet 2008
Anemiaê Blood Oxygen Contenté Cardiac Output
é Coronary Blood Flow(çè Oxygen Extraction)
BloodO2
Content
CardiacOutput
AndMyocardialO2 Demand
Anemia-The Ultimate Cardiac and Brain Stress Test!!!!
O2 Supply-Demand Un-Balanced
Troponin Leak?
JAMA 1998
Anemia-The Ultimate Cardiac and Brain Stress Test!!!!
Hemoglobin Concentration
Met
abol
ic C
onsu
mpt
ion
of O
2
HighLow
Total BodyBrain
Myocardium
Gut, Kidney andOther Tissue
Anemia-The Ultimate Cardiac Stress Test!!!!
Hare GM, Tsui AKY et al., Best Pract Res Clin Anesth 2013
Haemoglobin Concentration (g/L)
MAP CBF
CO Brain PO2
Cardiovascular Responses to Acute Anemia in Mice
Fan F-C et al, Am J Physiol 1980
Increased Cardiac Output is Preferentially Diverted to the Brain and Heart During Anemia
Heart
Brain
Anemia-Brain Oxygen Delivery Bioassay
Heart
BrainHypoxia
Anemia +/-β-Blockade
The Impact of β-BlockadeOn Cerebral O2 Delivery
CAS Richard Knill Award 2005Hare et al Brit J Anaesth 2006
Anemia ≈ MortalityéWith MetoprololBeattie et al. Anesthesiol 2009
Anemia + Metoprolol ≈ éCerebral Hypoxia
Ragoonana et al. Anesthesiol 2009
Anemia + β-Blockade ≈ éMACE
Beattie et al. Anesthesiol 2011
β2-Blockade ≈ êCerebral Vasodilation
El Beheiry et al. J Appl. Physiol 2011
Low Dose β1-Blockade Maintained Cerebral O2
Hu et al. Anesth & Analg 2013
β-Blockade + Anemia ≈ éStroke (not nebivolol)
Beattie et al. Anesthesiol 2013
Potential Mechanisms by which Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ1 Receptor
Β2 Receptor
Β1,2 ReceptorBeta Blocker
Central Nervous System
Interrupted Oxygen Delivery to Tissue
~30 torr ~20-30 torr
~10-20 torr?
O2
O2
O2
Capillary Tissue Brain Cell
Mitochondriaβ-Blockade
Inhibit CO Response to Anemia
Cardiac Output
Mouse Brain Perfusion is Limited by MetoprololHeart Rate MAP
Cerebral Blood Flow Brain PO2
Baseline Saline vs. Drug Baseline Saline vs. Drug
Baseline Saline vs. DrugEl Beheiry J Appl Physiol 2011
Adrenergic Stress Anemia
β-blockade
Why are Patients at High Risk ofPoor Outcomes Following Surgery?
Systemic Effect of Surgery Acute Blood Loss
Associated Medical Therapy
POISEAnemia ↑ Stroke
Risk by 2X
Potential Mechanisms by which Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ1 Receptor
Β2 Receptor
Β1,2 ReceptorMetoprolol
Central Nervous System
Metoprolol Impairs the Cardiac Response to Anemia
Ragoonanan T et al, Anesthesiology 2009
Cardiac Output Carotid Blood Flow
-Anemia
-Anemia + β-Blockade
Ragoonanan T, Anesthesiology 2009
Metoprolol Dramatically Reduces Brain Tissue PO2During Acute Hemodilution
0 20 40 60 80 100
Hip
poca
mpa
l Tis
sue
Oxy
gen
Tens
ion,
mm
Hg
10
20
30
40
* #
Hemodilutionβ1 Blocker or Saline
DMicrovascular PO2 Tissue PO2
-Anemia
-Anemia + β-Blockade
Potential Mechanisms by which Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ1 Receptor
Β2 Receptor
Β1,2 ReceptorICI 118,551
Autonomic Nervous System
β2 Mediated Cerebral Vasodilation
Cerebral Vasodilation and Increased CBF
Vascular Smooth Muscle
NO
NO
nNOS
NO
Nitric Oxide Synthase (NOS)
NitrogenergicNeuron
β2 Adrenergic Receptor
NE
GTP cGMPGC
Lee et al Am J Physiol 2000;279: H808-16
NoradrenergicPerivascular
Neurons
β2
Inhibition of the β2-AdrenoreceptorAccentuated Cerebral Perfusion In Anemic Rats
Hare GMT. Brit J Anaesth 2006
CAS Richard Knill Research Award 2005
β2-Adrenoreceptor Antagonist – ICI 118, 551
Cerebral Blood Flow Cerebral Cortical PO2
β1
β2 VasodilationVASOCONSTRICTION Organ
Ischemia
Metoprolol Impairs Cardiovascular Functionβ-blockers may be UGLY because they could impair global perfusion and microvascular vascular function
metoprolol
β1
β2
↑Cardiac Output
Assessment of Resistance Artery Functionby Pressure Myography
Metoprolol Impairs Resistance Artery Dilation to β-Adrenergic Agonists
-9 -8 -7 -6 -5 -40
20
40
60
80Control, n=750µM Metoprolol, n=7
log [isoproterenol (mol/L)]
% d
ilatio
n
-7 -6 -5 -4 -30
20
40
60
80 Control50µM Metoprolol
*#
##
##
#
log [isoproterenol (mol/L)]
% d
ilatio
n
Mesenteric Artery Posterior Cerebral Artery
El Beheiry et al J Appl Physiol 2010β1
β2
β1
β2Metoprolol
Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ Receptor
β Receptor
β ReceptorMetoprolol
Autonomic Nervous System
0
10
20
30
0 1 2 3 4 5 6 7
POSTOPERATIVE DAY
NU
MBE
R O
F ST
ROKE
S
Temporally similar to POISE
Ashes et al Anesthesiology 2013
β Blockers Increase Perioperative Stroke?
Date of download: mm/dd/yyyy
Copyright © 2012 American Medical Association. All rights reserved.
0.0%
0.5%
1.0%
80 100 120 140 160
Lowest recorded Haemoglobin
Prob
abili
ty o
f Pos
tope
rati
ve s
trok
e
METOPROLOL
BISOPROLOL
Ashes C, Anesthesiology 2013
Relationship Between β-blockade, Anemia, Stroke
Metoprolol was associated with a 4.2 ↑ in stroke incidence.
Mashour GA et al Anesthesiol 2013
Metoprolol Associated with Perioperative Stroke
Potential Mechanisms by which Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ1 Receptor
Β2 Receptor
Β1,2 ReceptorBeta Blocker
Central Nervous System
Clinical Question
After transfusion to Hb 100 g/L, a dobutamine stress echo demonstrated a lateral wall motion abnormality. You have decided to start a β-blocker for HR control and to minimize risk of ongoing ischemia.
Which drug would you choose?
A) Atenolol 12.5 mg/kg ODB) Metoprolol 25 mg BIDC) Carvedilol 6.5 mg ODD) Bisoprolol 2.5 mg ODE) Nebivolol 2.5 mg OD
Nebivolol has the Highest β1-Adrenergic Receptor Specificity of Available β1-Blockers
β1 antagonist fold selectivity β1/β2
CGP 20712A 501.2ICI 89406 69.2Practolol 14.1Xamoterol 14.1Bisoprolol 13.5Betaxolol 6.8AtenololICI 215001 3.2Acebutolol 2.4Metoprolol 2.3
Baker, Br J Pharmacol, 2005Bristow et al. 2005
Cross-reactivity with β2-ARs may inhibit adrenergic mediated vasodilation.
4.1
Nebivolol ~40
Metoprolol has Relatively Poor β1 SelectivityWhile Nebivolol is much more β1 Selective
Compound β1/β2Selectivit
y
Propranolol 1.0
Metoprolol 74
Bisoprolol 103
Nebivolol 321
Bristow et al. (2005)
Hypothesis:
A highly β1 specific antagonist (nebivolol) will
NOT attenuate the increase in cerebral blood flow needed to maintain cerebral oxygen delivery
during anemia.
Can Treatment with Nebivolol Preserve Cerebral Perfusion During Anemia?
β1: ~0.7 nMβ2: ~225 nM
Results nebivolol drug levels areproportional to dose
# p<0.05 vs. baselinep<0.05 vs. 1.25 Nebivolol
Vehicle Control 1.25 Nebivolol2.5 Nebivolol
Time (minutes)10 60 120
Neb
ivol
ol C
once
ntra
tion
(nM
)
0
50
100
150
200
250
Vehicle orNebivolol
No detecteddrug levels
Hemodilution#
#
#
#β2 Affinity Threshold
Affinity (Ki) for β1 and β2
Levels
Hu et al A&A 2013
Time (minutes)10 40 90 120
Car
diac
Out
put (
mL/
min
ute)
50
100
150
200
250
300
Vehicle orNebivolol
Administration
Hemodilution#
#
# ###
Cardiac Output Effect
n = 5 per group
# p<0.05 vs. baseline
Vehicle Control 1.25 Nebivolol2.5 Nebivolol
Hu et al A&A 2013
Time (minutes)0 20 40 60 80 100
Mic
rova
scul
ar C
ereb
ral C
ortic
al
Oxy
gen
Tens
ion
(mm
Hg)
0
20
40
60
80
100
120 Vehicle orNebivolol
Administration
Hemodilutionp=0.01 for 1.25 Nebivolol
vs. 2.5 Nebivolol (2-way repeated measures ANOVA)
n = 5 – 11 per group
Vehicle Control 1.25 Nebivolol2.5 Nebivolol
Cerebral Oxygen Tension Effect
Hu et al A&A 2013
Only High Dose Nebivolol Increases HIF-1αLevels
GSNORHIF-2αHIF-1α
α-tubulin (55 kDa)
Nebivolol(2.5 mg/kg)
Nebivolol (1.25 mg/kg)
VehicleControl
Hemodilution
HIF-1α(120 kDa)
HIF-2α(120 kDa)
GSNOR(40 kDa)
α-tubulin (55 kDa)
α-tubulin (55 kDa)
Nebivolol(2.5 mg/kg)
Nebivolol (1.25 mg/kg)
VehicleControl
Hemodilution
Nebivolol(2.5 mg/kg)
Nebivolol (1.25 mg/kg)
VehicleControl
Hemodilution
Treatment GroupVehicle Control 1.25 Nebivolol 2.5 Nebivolol
Cer
ebra
l Cor
tical
GS
NO
R P
rote
inLe
vel N
orm
aliz
ed to
Alp
ha-T
ubul
in
0.0
0.2
0.4
0.6
0.8
1.0
1.25 1.25
Treatment Group Vehicle Control 1.25 Nebivolol 2.5 NebivololC
ereb
ral C
ortic
al H
IF-1
alp
ha P
rote
in
Leve
l Nor
mal
ized
to A
lpha
-Tub
ulin
0.0
0.2
0.4
0.6
0.8#
1.25
Treatment GroupVehicle Control 1.25 Nebivolol 2.5 NebivololC
ereb
ral C
ortic
al H
IF-2
alp
ha P
rote
inLe
vel N
orm
aliz
ed to
Alp
ha-T
ubul
in
0.0
0.2
0.4
0.6
0.8
#
#
* p<0.05 vs. baseline# p<0.05 vs. control group
Vehicle Control 1.25 mg/kg Nebivolol 2.5 mg/kg Nebivolol
Hu et al A&A 2013
Control Nebivolol Bisoprolol Atenolol
Control Nebivolol Bisoprolol Atenolol
β-2
Med
iate
d Po
tass
ium
Shi
ft β-
2 M
edia
ted
Glu
cose
Res
pons
e
Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ 1-Receptor
β Receptor
β ReceptorNebivolol
Autonomic Nervous System
Clinical Question
After transfusion to Hb 100 g/L, a dobutamine stress echo demonstrated a lateral wall motion abnormality. You have decided to start a β-blocker for HR control and to minimize risk of ongoing ischemia.
Which drug would you choose?
A) Atenolol 12.5 mg/kg ODB) Metoprolol 25 mg BIDC) Carvedilol 6.5 mg ODD) Bisoprolol 2.5 mg ODE) Nebivolol 2.5 mg OD
What about Other Vasodilating β-Blockers?
DeNicolantonioAm J Col Cardiol 2013
Dea
thN
on-F
atal
MI
What is the Next Step for β-Blocker Therapy?
Patients on Chronic β-Blocker Therapy (metoprolol)
Randomization
ContinueMetoprolol
Convert toBisoprolol
Assess Composite Clinical Outcome(Stroke-Hypotension-MI-Death)
Protected Heart
Brain
Hypoxic Brain
+Peri-Operative β Blockade
Non-Stressed β-Blockade β-Blockade + Anemia
Brain
+
Brain
VeryHypoxic Brain
+
Protected Heart
Acknowledgements:
Acknowledgements:
Dept. of AnesthesiaSt. Michael’s HospitalUniversity of Toronto
SMH Anesthesiologists
Dr. A. BakerDr. R. ByrickDr. P. HoustonDr. J. LaffeyDr. P. LeungDr. C.D. Mazer
Research Collaboration
Dr. W.S. BeattieDr. S.S. BolzDr. K. ConnellyDr. P. DorianDr. S. HeximerDr. B. KavanaghD. H Leong-PoiDr. P.A. MarsdenDr. D. Wilson
Canadian Anesthesiologists SocietyPhysicians Services Incorporated FoundationSociety of Cardiovascular Anesthesiologists
Research Associates & Students
Neil DattaniMostafa El Beheiry (MSc)Tina Hu (MSc)Elaine Liu (MD)Tim MakAnya McLaren (MSc)Tenille Ragoonanan (MSc)Albert Tsui (PhD)Julie Yu
Trinity College, University of Toronto
Acknowledged Funding Support:
Potential Mechanisms by which Perfusion Limited by β-Blockade During Anemia
Cardiac Output
Pump Regulated Blood Flow
Resistance Aertry
InadequateTissue PO2
BrainHeart
Kidneyβ1 Receptor
Β2 Receptor
Β1,2 ReceptorBeta Blocker
Central Nervous System