Perioperative Management of the Cardiac Surgical Patient at Risk for Stroke

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Stroke in Cardiac Surgical Patients Management
Etiology

• Robert J. Frumento, MD
• Department of Anesthesiology
• Divisions of Cardiothoracic Anesthesia and
  Surgical Critical Care
• Columbia University College of Physicians
  Surgeons
• New York, NY USA

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Fear and Anxiety(General Population)
Public Speaking 27 Stroke 22 Cancer 19 D
eath 18 Other 14
PK Smith-WP
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Fear and Anxiety(Cardiac Surgical Population)
Awareness 32 Stroke 30 Pain 14 Death
12 Other 2
n200, CUMC data
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Perioperative Stroke in Cardiac Surgery
n16,184

Mohr, Ann Thor Sur, 2003
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Perioperative Stroke in Cardiac Surgery
Retrospective - Mohr, Ann Thor Sur, 2003
(n16,184) Prospective Mckhann, Stroke, 2006
(n5,326)
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Perioperative Stroke When Does it Occur?

Early Deficit present after emergence Late
Deficit present after first awakening
Hogue,Circulation,1999
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Timing of Perioperative Stroke (n563 Cardiac
Surgical Patients)

Postoperative Day
McKhann et al. Stroke 2006
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Outcomes of Stroke in Cardiac Surgery

Roach, NEJM,1996
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Risk Factors for Early or Delayed Stroke after
Cardiac Surgery

• Early Stroke Delayed Stroke
• Prior neurological event - Prior neurological
  event
• Aortic atherosclerosis - Aortic atherosclerosis
• CPB duration - Diabetes
• Female sex - Female sex
• - Low cardiac output
• - Atrial fibrillation

Hogue, Circulation, 1999
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Non Pharmacologic Neuroprotection Techniques
Studied in Cardiac Surgery

• OPCAB
• Temperature
• Heparin bonded circuits

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Early Perioperative Stroke- Diagnosis
Suspicion on Emergence from GA
Neurology Evaluation (NIHSS etc.)
Stable Patient Obtain Brain Image
DWI-MRI if possible
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Diffusion-Weighted Imaging (DWI) - MRI
Bendszus, M. et al. Arch Neurol 2002591090-1095.
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Sensitivity of DW-MRI Following CABG
Bendszus, M. et al. Arch Neurol 2002591090-1095.
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T2-weighted (upper left) and orthogonal axis
diffusion-weighted images at the same level of a
71-year-old man before (A) and 1 day after (B)
coronary artery bypass grafting 2 small new
ischemic lesions (arrows) appear in the left
frontal lobe postoperatively, which are already
visible on the T2-weighted image
Bendszus, M. et al. Arch Neurol 2002591090-1095.
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Perioperative Stroke- Treatment

• Majority of early (24 hours) events are treated
  conservatively
• Blood pressure maintenance
• Moderate hypothermia
• Majority of late (gt48 hours) events are treated
  conservatively
• - Case reports of early IA thrombolytic therapy
  ????
• - TX usually case and patient specific

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Optimal Treatment for Perioperative Stroke
?PREVENTION
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OPCAB

• Potential Advantages
• - Reduced transfusion rate
• Reduced incidence postoperative atrial
  fibrillation
• Reduced hospital and ICU LOS
• Potential Disadvantages
• Reduced graft patency rate
• Increased rate of recurrent angina

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OPCAB
Neuroprotective ?
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A Word on Cognitive Deficit

• Elderly patients frequently experience a
  deterioration in cognitive function after surgery
  and anesthesia. The two most common cognitive
  disorders are delirium and PostOperative
  Cognitive Dysfunction (POCD).
• POCD is much more subtle than delirium and
  therefore neuropsychological testing is necessary
  for the detection
• Whereas delirium has been associated with
  increased hospital stay and mortality POCD has
  not.
• Age and pre-existing brain disease are the most
  important risk factors for both disorders

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OPCAB

• Van Dijk, Circulation, 2001
• RCT (n281) 2.4 grafts
• Equivalent outcomes
• CVA
• OPCAB 0.7
• CPB 0.7
• No differences in neurocognitive function at 1
  year

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OPCABPuskas JAMA,2004
RCT (n200) Single surgeon, single center -
Baseline characteristics were similar except
for - History CVA OPACB 1 CPB 9.1
p0.02 - Similar Outcomes and graft patency -
CVA OPCAB 1 CPB 2 p0.7
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Risk Factors for Early or Delayed Stroke after
Cardiac Surgery

• Early Stroke Delayed Stroke
• Prior neurological event - Prior neurological
  event
• Aortic atherosclerosis - Aortic atherosclerosis
• CPB duration - Diabetes
• Female sex - Female sex
• - Low cardiac output
• - Atrial fibrillation

Hogue, Circulation, 1999
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Ascending Aorta Atherosclerosis is a Independent
Predictor of Stroke and Mortality in Cardiac
surgical Patients

Davila,JACC,1999
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Propensity Score Analysis

• The conditional probability of being treated
  given the covariates of all subjects
• Significantly reduces the biased estimates of
  treatment effects

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Propensity Matched Analysis OPCAB vs. CPB in
Patients w/ Aortic Atherosclerosis

• AA definition Katz grade 4 (protruding atheroma
  gt 5 mm) and grade 5 (mobile atheroma) of
  ascending aorta or aortic arch
• 985 patients with AA
• 281 (28.5) OPCAB
• 245 propensity score matched CPB

Sharony, JTCVS, 2004
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New Stroke in Patients w/ Aortic Atherosclerosis

p0.03
Sharony, JTCVS, 2004
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Non Pharmacologic Neuroprotection Techniques
Studied in Cardiac Surgery

• OPCAB
• Temperature
• Heparin bonded circuits

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Temperature

• Normothermic versus hypothermic cardiopulmonary
  bypass
• Several well controlled randomized trials
• Mixed results regarding PostOperative Cognitive
  Dysfunction
• No study showed decrease incidence of stroke

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Non Pharmacologic Neuroprotection Techniques
Studied in Cardiac Surgery

• OPCAB
• Temperature
• Heparin bonded circuits

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Heparin Bonded Circuits

• Have been shown to reduce the inflammatory
  response after CPB
• Several small RCTs
• ? complement activation
• ? leukocyte activation
• ? cytokine release
• Clinical outcomes have been mixed including
  POCD

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Heparin Bonded Circuits

• Wildevuur et al randomized 805 CABG patients
• No differences in morbidity or mortality
• Stroke rates were equivalent between groups HB
  (1.6) Control (1.6)
• Limitation Low risk 1 CABG

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Heparin Bonded Circuits

• McCarthy et al randomized 350 CABG and CABG/valve
  repeat sternotomy patients
• No differences in morbidity or mortality
• Equivalent stroke rates between the groups HB
  (1.2) Control (2.4)

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Pharmacologic Neuroprotection Agents Studied in
Cardiac Surgery

• Thiopental
• Propofol
• Adenosine regulators
• Aprotinin
• Nimodipine
• Lidocaine
• Beta blockers
• Pexelizumab
• Statins

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Perioperative Beta BlockadeIncidence of CVA/Coma

p0.01
n2,575

Any Beta Blocker Use
Amory, JCTVA, 2005
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Perioperative Beta BlockadeIncidence of
CVA/Coma/TIA/Confusion

p0.003
53 ?

n2,575
Any Beta Blocker Use
Amory, JCTVA, 2005
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Pharmacologic Neuroprotection Agents Studied in
Cardiac Surgery

• Thiopental
• Propofol
• Adenosine regulators
• Aprotinin
• Nimodipine
• Lidocaine
• Beta blockers
• Pexelizumab
• Statins

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Preoperative Statin Therapy(Ali et al. Int. Jour
Card, 2005)

• Retrospective database analysis
• 5,469 consecutive cardiac surgical patients
  (excluding VAD,HTx)
• Report unadjusted outcomes
• Report adjusted propensity matched outcomes

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Preoperative Statin Therapy- Unadjusted
Outcomes(Ali et al. Int. Jour Card, 2005)
Outcome No-Statin Statin Pvalue In-hospital
mortality 5.0 2.6 0.0001 IABP 2.2
1.7 0.13 Stroke 3.3 1.9 0.001 PeriOp
MI 1.1 1.5 0.23 ETT gt 24 hours
16.6 10.2 0.0001 LOS 7 (5-10) 6
(5-8) 0.0001 Composite 19.5 12.7 0.001
n3555
n1914
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Preoperative Statin Therapy- Adjusted
Outcomes(Ali et al. Int. Jour Card, 2005)
Outcome No-Statin Statin Pvalue In-hospital
mortality 4.6 4.0 0.41 IABP 2.3
2.0 0.61 Stroke 3.3 3.0 0.59 PeriOp
MI 1.1 1.5 0.41 ETT gt 24 hours
15.7 15.8 0.96 LOS 7 (5-10) 6
(5-9) 0.01 Composite 18.8 19.9 0.85
n1443
n1443
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Pharmacologic Neuroprotection Agents Studied in
Cardiac Surgery

• Thiopental
• Propofol
• Adenosine regulators
• Aprotinin
• Nimodipine
• Lidocaine
• Beta blockers
• Pexelizumab
• Statins

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Acadesine(Mangano et al , Anesthesiology 1995)

• Multi center RCT
• 633 CABG patients randomized
• Low dose (0.05 mg/kg/min, n214)
• High dose (0.1 mg/kg/min, n207)
• Placebo (n212)
• Primary Outcome incidence of perioperative MI

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Acadesine(Mangano et al , Anesthesiology 1995)

• No differences in primary outcome
• Both Low dose and High dose significantly reduced
  the incidence of perioperative stroke

plt0.02


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Pharmacologic Neuroprotection Agents Studied in
Cardiac Surgery

• Thiopental
• Propofol
• Adenosine regulators
• Aprotinin
• Nimodipine
• Lidocaine
• Beta blockers
• Pexelizumab
• Statins

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Aprotinin

• A Serine Protease Inhibitor
• Binds with the human serine proteases
• Trypsin
• Plasmin
• Plasma kallikrein
• Tissue kallikrein
• Elastase
• Urokinase

Fritz H Wunderer G, Drug Research,
198333(1)479-494
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Aprotinin Adverse Events
EVENT
Patients Treated With Aprotinin () n 2002
Patients Treated With Placebo () n 1084
Thrombosis 1.0 0.6 Shock 0.7 0.4 Cerebrovascular
accident 0.7 2.1 Thrombophlebitis 0.2 0.5 Lung
edema 1.3 1.5 Pulmonary embolus 0.3 0.6 Kidney
failure 1.0 0.6 Acute kidney failure 0.5 0.6 Kidne
y tubular necrosis 0.8 0.4
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Aprotinin Meta-Analysis
35 Studies / gt 3800 Patients / 6 Specific
Outcomes
Sedrakyan A et al. JTCVS 2004128442
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The Risk Associated with Aprotinin in Cardiac
Surgery Dennis T. Mangano, Ph.D., M.D., Iulia C.
Tudor, Ph.D., Cynthia Dietzel, M.D., for the
Multicenter Study of Perioperative Ischemia
Research Group and the Ischemia Research and
Education Foundation
Volume 354353-365      January 26, 2006      Number 4
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The Risk Associated with Aprotinin in Cardiac
Surgery
Mangano, NEJM 2006
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The application of FDA data-quality practices in
Phase 4 studies would preclude criticisms of the
data analysis, such as the lack of source
documentation and the lack of on-site review of
the accuracy of data and accuracy of data entry
in the study by Mangano et al.
Gus J. Vlahakes, M.D. NEJM, 2006
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Accuracy?
CNS complication neurologic death, new CVA,
encephalopathy, coma or stupor and TIA
Mangano et al The Risk Associated with Aprotinin
in Cardiac Surgery NEJM-2006
Identical EPI II Database
Mangano et al Aspirin and Mortality From
Coronary Bypass Surgery- NEJM,2002
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Accuracy?

• NEJM 2006 predefined cerebrovascular events n
  180/4374, 4.1
• NEJM 2002 - predefined cerebrovascular events n
  152/5022, 3.0
• Nussmeier Tex Heart Inst. J- 2005 predefined
  cerebrovascular events n139/4782, 2.9

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Stroke Analysis High Risk Patients Undergoing
CABG

• Retrospective Review of High Risk Patients
• Presence of aortic atheroma on TEE
• History of hypertension
• History of diabetes mellitus
• Age gt 70 years
• History of stroke or TIA
• Control, Half- and Full-dose aprotinin
• Matched for all factors/procedures

Frumento RJ et al. Ann Thorac Surg 200375479
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Preoperative Stroke Risk Index
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Stroke Analysis High Risk Patients Undergoing
CABG - Results

• Control Aprotinin Aprotinin
  Half Dose Full Dose
• Stroke 16 22 0
• (9/56) (15/67) (0/26)
• p lt 0.05

Frumento RJ et al. Ann Thorac Surg 200375479
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Prospective Observational Study

• Incidence of adverse neurological outcome (Type I
  Type II)
• VADS, Heart Transplants, Emergencies Excluded
• 6 Month period
• FDA vs. HDA

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Prospective Observational StudyResults

• 77 patients received aprotinin
• 70/77 (91) underwent repeat sternotomy
• 38 patient received FDA 38 HDA
• Similar SRI - 126
• No differences in baseline characteristics

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CNS Outcome Categories

• Type I Death due to stroke or hypoxic
  encephalopathy, new non fatal stroke or TIA
• Type II New ? intellectual function, confusion,
  agitation, memory deficit, disorientation, non
  metabolic seizure without focal injury

Wolman, Circulation, 1999
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Prospective Aprotinin Stroke Analysis in CABG

• Half-Dose Full-Dose
• Aprotinin Aprotinin
• Type I 12 (5/39) 0 (0/38) p lt 0.05
• (stroke, TIA)
• Type II 18 (7/39) 18 (7/38) p ns
• (seizure, confusion)

Frumento RJ et al. ASA Meeting. October 2003
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Mechanisms?
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Incidence of Stroke and Common Surgical
Practices Retrospective of 5 CABG Studies
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Control
Cell Saver Reinfusion
Thoracic Suction Blood Reinfusion
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Platelet Infusion
Stroke Incidence ()
4
2
0
All CABG
Redo CABG
(N 171 162 171)
(N 861 835 861)
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Stroke Correlation withPlatelet Transfusion
Spiess BD et al. Transfusion 2004441143
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Platelet Administration and Outcomes
(Multivariate Logistic Regression Analysis)
Spiess BD et al. Transfusion 2004441143
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The Protease Activated Receptor
PAR-1, a recently discovered G-protein coupled
platelet receptor, is activated by thrombin
binding, but proteolytic cleavage of the receptor
between amino acids 41 and 42 is also required to
generate the intracellular signal (and platelet
activation).
Coughlin Proc Natl Acad Sci 199996, 11023-7
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The Protease Activated Receptor
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Aprotinin Inhibits Platelet Aggregation through
PAR-1
Poullis et al, J Thorac Cardiovasc Surg 2000120,
370-378
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Genetic Polymorphisms and the Risk of Stroke
After Cardiac Surgery

• Do genetic variants have an impact on the
  incidence of stroke in cardiac surgical patients?

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Grocott et al, Stroke 2005

• Analyzed 26 different single-nucleotide
  ploymorphisms
• Coagulation Inflammation Lipid
• prothrombin ? CRP ? APOE
• Tissue factor ? IL-6
  
• Factor V ? TNF
• Fibrinogen
• Glycoprotein

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Grocott et al, Stroke 2005

• 1,635 patients analyzed
• Combination of 2 minor alleles of
• CRP (3UTR 1846C/T)
• IL-6 (-17G/C)
• Occurred in 36 of patients (583)
• Significantly associated with stroke (OR-3.3
  CI-1.4-8.1, p0.002)
• Remained significantly associated with stroke
  after controlling for covariates including age
• Indicates a pivotal role for inflammation

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Conclusion

• Stroke is a devastating complication of cardiac
  surgery
• Incidence will increase as the complexity of
  cases increase
• Mechanism of stroke in this setting is
  multi-factorial
• No one therapy or technique is a true panacea in
  prevention

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Conclusion

• The use of FDA may be beneficial in patients at
  moderate to high risk
• OPCAB in selected patients may be beneficial
• Low incidence Large expensive RCTs
• High costs to patients and society