HOT TOPICS IN PERIOPERATIVE OUTCOMES AND PATIENT MANAGEMENT: PART 1
From the 61st Postgraduate Assembly in Anesthesiology, sponsored by the New York State Society of Anesthesiologists,
December 7-11, 2007, New York, NY
Educational Objectives
| The goal of this program is to improve the management of perioperative bleeding due to the use of antithrombotic
drugs and to apply the latest recommendations for glycemic control. After hearing and assimilating this program, the
clinician will be better able to:
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 | 1. Discuss the advantages and disadvantages of drug-eluting stents in the intra-arterial tree.
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| 2. Describe the risks for stent thrombosis in cardiovascular disease.
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| 3. Examine the relationship between increased bleeding and clopidogrel in cardiac surgery.
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| 4. Review treatment of perioperative bleeding due to the use of antithrombotic drugs.
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| 5. Improve control of hyperglycemia to minimize the risk for myocardial ischemia and infarction in patients undergoing
anesthesia and surgery.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning
committee reported nothing to disclose.
Acknowledgements
Drs. Shore-Lesserson and Kersten spoke in New York, NY, at the 61st Annual Postgraduate Assembly in Anesthesiology
, held December 7-11, 2007, and sponsored by the New York State Society of Anesthesiologists, Inc. The Audio-Digest
Foundation thanks the speakers and the NYSSA for their cooperation in the production of this program.
| MANAGING PERIOPERATIVE BLEEDING AND MEDICATIONS —Linda J. Shore-Lesserson, MD, Associate Professor
of Clinical Anesthesiology, Department of Anesthesiology, Albert Einstein College of Medicine of Yeshiva
University, and Director, Cardiothoracic Anesthesiology, Montefiore Medical Center, Bronx, NY
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| Introduction: primary care physician often prescribes antithrombotic agent for patient with cardiovascular disease but
who does not have intracoronary stent (only history of transient ischemic attack or angina); regional anesthesia relatively
contraindicated in patient taking clopidogrel (alone or in combination with aspirin); increased hemorrhagic complications
and morbid outcomes in cardiac surgery
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| Studies: adverse outcomes seen in patients undergoing surgery soon after placement of intracoronary stent; review from
Mayo Clinic looked at surgical start time after placement of intracoronary stent; found high incidence of death, myocardial
infarction (MI), thrombosis, or target vessel revascularization ≤5 wk after intracoronary intervention; another study
found high incidence of adverse events ≤2 wk after intracoronary intervention; unclear whether drugs should be stopped
and “when it might be safe to do so for surgery”
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| Drug-eluting stents: panacea at first; used by cardiologist interested in prolonging patency of intracoronary stent; bare-
metal stent placed in intra-arterial tree causes massive inflammatory response; intima growth may result in vessel occlusion
(known as restenosis); use of drug-eluting stents (coated with antiproliferative drugs [eg, sirolimus, paclitaxel] that
arrest intima growth) have eliminated this phenomenon; however, this averts healing process and becomes nidus for
thrombus formation
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| American College of Cardiology (ACC)/American Heart Association (AHA) guidelines: loading dose of
clopidogrel, ≥300 mg for every patient, regardless of intervention; administer before procedure (otherwise patient cannot
comply with order to take oral medication); in patients who have undergone percutaneous coronary intervention (PCI),
give clopidogrel daily for ≥1 mo after placement of bare-metal stent (unless patient at increased risk for bleeding, then
daily for 2 wk); daily clopidogrel given for 3 mo after placement of sirolimus stent, and for 6 mo after placement of paclitaxel
stent (ideally, for up to 12 mo if no risk for bleeding [those at risk for bleeding include patients with other bleeding
diatheses and surgical patients]); treat raw endothelial surface with antithrombotic drugs that are not long-term and irreversible
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| Preventing platelet activation: platelets activated by several agonists (eg, adenosine diphosphate [ADP] receptor-agonists,
thrombin-receptor agonists); glycoprotein IIb/IIIa receptor (responsible for mediating platelet aggregation) becomes
activated and participates in aggregation, then upregulated and bound to adjacent platelets by fibrinogen
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| Further studies: patient with 2 diseased coronary arteries; bare-metal stent placed in left anterior descending (LAD) artery,
and sirolimus drug-eluting stent placed in circumflex artery; patient underwent dual antiplatelet therapy for 1 yr; aspirin
and clopidogrel stopped before surgery; 2 wk after stopping aspirin, patient had anterior MI and underwent
angiography; LAD bare-metal stent patent, and sirolimus-eluting stent filled with thrombus; in similar patient, authors
placed bare-metal stent in obtuse marginal branch of circumflex artery and drug-eluting stent in LAD; drugs stopped for
surgery; major anterior MI; angiography revealed bare-metal stent patent in obtuse marginal branch of circumflex artery,
and LAD stent occluded
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| Risks for stent thrombosis: retrospective review found univariate and multivariate risk factors for late thrombosis;
univariate risk factors include discontinuation of antiplatelet therapy and premature discontinuation of therapy; multivariate
factors include premature discontinuation of any antithrombotic drug, stent placement in setting of acute MI, and long
stent length
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| Preventing thrombosis: laboratory monitor (clinically unavailable) is marker for platelet reactivity by specific receptor
antagonized by clopidogrel; vasodilator-stimulated phosphoprotein (VASP) molecule becomes phosphorylated when
ADP activated; phosphorylation does not occur with clopidogrel administration; platelet reactivity transposition of
amount of VASP phosphorylation
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| Clopidogrel resistance: genetics responsible for percentage of clopidogrel resistance; metabolized by liver (cytochrome
P 450 [CYP450 ] system); if genetic variant unable to metabolize drug (due to abnormal CYP450 3A4), “it’s not
going to work”
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| Cardiac surgery: increased bleeding seen in patients presenting for cardiac surgery who had been exposed to clopidogrel;
meta-analysis conducted to compare patients treated with clopidogrel within 7 days of surgery to those untreated
and undergoing cardiopulmonary bypass; qualitatively, more chest tube drainage, more transfusions, longer ventilator
times, increased length of stay, and higher incidence of reexploration for bleeding (1.5% incidence in general population
of cardiac surgery vs 7% to 10% with clopidogrel)
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| Preventing bleeding: monitor platelet function; antifibrinolytic drug aprotinin now under scrutiny by Food and Drug
Administration (FDA) and other regulatory agencies for use in cardiac surgery (randomized trial halted in Canada due to
evidence of increased mortality; data not yet formally analyzed); small prospective randomized studies show aprotinin
reduces bleeding in clopidogrel-treated patients; abnormal platelet function even more reason to use antifibrinolytic agent
to treat bleeding
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| Platelet tests: thromboelastography—modified to look for ADP antagonism; Platelet Works—Coulter counter; measures
platelet count in ADP tube (and platelet function as result of activation by ADP); all tests purportedly able to measure
clopidogrel activity; platelet function analyzer 100 (PFA-100)—provides in vitro bleeding time; blood perfused
across collagen- and ADP-coated membrane; touted to measure clopidogrel defect, but “it’s not one of the better ones”;
Verify Now—“mixing chamber for platelets and fibrinogen beads”
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| Investigations: speaker compared aggregometry (gold standard) with thromboelastography and Platelet Works devices
in healthy volunteers; found both instruments approximate same time course of platelet inactivation as aggregometry
(Verify Now test not approved by FDA at time of study); in other published studies, investigators performed angiography
in patients admitted to critical care unit (CCU) with acute coronary syndrome; patients given standard dose of aspirin,
clopidogrel, and heparin during procedure; light transmission aggregometry, PFA-100, Verify Now, and VASP tests analyzed
at 24 and 48 hr postoperatively; residual platelet reactivity defined as fourth quartile of platelet reactivity; residual
platelet reactivity occurred in 128 of 626 patients but not measured by PFA-100; similarly, 123 of 1000 patients had residual
platelet reactivity not detected by Verify Now; tests important for use in perioperative laboratory and preoperative
assessment area; patient who does not respond to clopidogrel, in addition to being at risk for thrombosis, may be candidate
for regional anesthesia or cardiopulmonary bypass; postoperative tests necessary for determining when to reinstitute
antithrombotic therapy
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| American Society of Regional Anesthesia (ASRA) guidelines: remain unchanged; recommend waiting 7 days
after clopidogrel exposure to perform surgery with regional anesthetic
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| Treatment after bleeding: in United States, activated factor VII indicated for hemophilia with inhibitors; initiates
thrombin burst by activating components that contribute to thrombin activity; tissue-factor-bearing cells hyperactivated
by activated factor VII; cascades occur with increased amplification; leads to increased platelet reactivity as result of
thrombin; usually treats bleeding at site of injury, not systemic thrombosis; study looking at use of activated factor VII in
cardiac surgical patients found increased morbidity (compared to patients not receiving factor VII); outcomes showed increased
length of stay and increased renal failure; cause may be drug, blood administration, or other factor
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| GLYCEMIC CONTROL —Judy R. Kersten, MD, Professor and Vice Chair of Anesthesiology, Medical College of Wisconsin,
Milwaukee
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| Hyperglycemia (studies): evidence indicates hyperglycemia alone independent predictor of increased cardiovascular
morbidity and mortality; occurs in patients with and without diabetes; study—looked at impact of fasting blood glucose
(BG) concentrations on 30-day mortality in patients being seen for acute MI; patients with normal fasting BG concentrations
had good survival (>30 days), but as fasting BG concentrations increased, mortality rates increased as well; 13-fold
increased risk for death after MI in patient who had hyperglycemia and not known to be diabetic, compared to 6-fold increased
risk in known diabetic; retrospective analysis—critically ill patients in intensive care unit (ICU); medical and
surgical problems, including variety of organ systems involved; as BG concentration increases, mortality rate also increases
(particularly at BG concentrations ≥150 mg/dL); animal study—found direct relationship between infarct size
and severity of hyperglycemia in diabetic animals and in acutely hyperglycemic animals; ischemic preconditioning and
anesthetic preconditioning ineffective in presence of hyperglycemia; results similar to observations in clinical population
during acute MI; another study—looked at relationship between outcomes and hyperglycemia in carotid endarterectomy;
significant increase in overall mortality, stroke, and MI; at BG concentration of 150 to 200 mg/dL, risk for adverse
outcome significantly increased; study of influence of intraoperative hyperglycemia on perioperative outcome in cardiac
surgery—used multivariate analysis to account for insulin use and postoperative BG; demonstrated independent relationship
between maximum and average intraoperative BG and adverse outcomes; found that increase of only 20 mg/dL
associated with 30% increase in adverse outcomes; risk increases when BG ≈150 mg/dL
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| Treatment of hyperglycemia: Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI)
study—patients randomized to receive either intensive insulin treatment or conventional treatment; BG concentrations
similar at randomization; however, better control of BG concentration seen in patients who were aggressively
treated (≈170 mg/dL after 24 hr) than in those conventionally treated (≈210 mg/dL); aggressively treated patients also
had lower mortality rates; Van den Berghe et al—prospective randomized trial of >1500 patients admitted to surgical
ICU (majority had undergone cardiac surgery); 20% to 25% previously diagnosed with diabetes; randomized to intensively
treated (continuous IV insulin for tight control of BG concentration at 80-110 mg/dL) and conventionally treated
(insulin only if BG concentration >215 mg/dL; aim to control BG at 180-200 mg/dL); better survival seen in intensively
treated group; another study—looked at influence of asymmetric dimethylarginine (ADMA; inhibits endothelial nitric
oxide synthase); found those who received aggressive treatment with insulin demonstrated stable concentrations of
ADMA, whereas concentrations increased in those conventionally treated; also found ADMA independent predictor of
mortality in ICU; Lazar et al—looked at benefits of insulin therapy during cardiac surgery; 140 patients with diabetes
started treatment with insulin 2 hr before induction of anesthesia, and continued for 12 hr postoperatively; aggressively
treated group received IV insulin to maintain BG at 120 to 200 mg/dL; conventional therapy group received subcutaneous
insulin to maintain BG <250 mg/dL; patients on cardiopulmonary bypass become more resistant to insulin; difficult
to tightly control BG concentrations during this period; significant decrease in number of hours on ventilation, use of inotropes,
incidence of atrial fibrillation, and length-of-stay in ICU and postoperatively seen in intensively treated group,
compared to conventional treatment group; more recent study—looked at role of intraoperative management of BG
concentration; 200 diabetic patients undergoing on-pump coronary artery bypass graft surgery; standardized revised Portland
protocol used to control BG concentration (aim, 150-200 mg/dL); patients classified as well-controlled or poorly
controlled (4 consecutive BG measurements >200 mg/dL); all patients had good control of BG in ICU; in poorly controlled
group, BG ≈220 mg/dL, compared to 140 to 150 mg/dL in tightly controlled group; total morbidity significantly
greater in poorly controlled group, and risk for morbidity increased ≈7-fold (vs tightly controlled); poor glucose control
also associated with increases in in-hospital mortality rates and increased length-of-stay; another investigator—showed
sternal wound infections in diabetic patients significantly decreased when BG concentrations aggressively controlled in
postoperative period; cardiac-related mortality significantly increases as average postoperative BG concentration increases
(≈150 mg/dL); variability in BG concentration also influences morbidity and mortality; both average BG and
variability independent predictors of ICU death
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| Recent AHA/ACC guidelines: class IIa recommendation—control BG concentration in patient with diabetes at risk
for MI and undergoing major noncardiac surgery with planned ICU admission; class IIb recommendation—uncertain if
strict control of BG concentration provides benefit to patient with diabetes undergoing intermediate-risk noncardiac surgery
with unplanned ICU admission
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| Sulfonylurea hypoglycemic agents: in 1970, University Group Diabetes Program study reported cardiovascular
mortality greater in diabetic patients receiving tolbutamide than in those treated with insulin or placebo; results of trial
initially criticized, partly because physiologic basis or pharmacologic mechanisms for findings not understood; target of
sulfonylurea drugs now known to be adenosine triphosphate-regulated potassium (KATP ) channel in pancreatic cells; sulfonylureas
block preconditioning by interfering with opening of KATP channel; patient with diabetes who undergoes angioplasty
also at greater risk if taking sulfonylurea; study conducted on how converting to insulin influences patients on
long-term treatment with glyburide before cardiac surgery; showed insulin had cardioprotective effect, regardless of
whether patient received isoflurane preconditioning, and glyburide blocked anesthetic preconditioning; study showed patients
treated with any insulin sensitizer agent had similar degrees of control of BG; however, over 10 yr, patients treated
with metformin had marked reduction in rates of cardiovascular death and MI; other studies have confirmed lower mortality
rates in patients with type 2 diabetes treated with metformin, compared to sulfonylurea or combination therapy; still
unknown whether metformin may eventually be beneficial in perioperative control of BG; thiazolidinediones agonists of
peroxisome proliferator-activated receptor γ (PPAR γ); produce variety of effects on lipids, blood pressure control, and
glycemic control; improve BG control and insulin sensitivity; however, these drugs (eg, rosiglitazone) may increase cardiovascular
mortality
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Suggested Reading
Coutinho M et al: The relationship between glucose and incident cardiovascular events. A metaregression analysis
of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 22:233, 1999; de la
Torre-Hernández JM et al: Drug-eluting stent thrombosis: results from the multicenter Spanish registry ESTROFA
(Estudio ESpañol sobre TROmbosis de stents FArmacoactivos). J Am Coll Cardiol 51:986, 2008; Di Mario
C et al: Biodegradable drug-eluting stents: promises and pitfalls. Lancet 371:873, 2008; Dundon BK et al: Very
late drug-eluting stent thrombosis. Heart Lung Circ 17:144, 2008; Flores-Ríos X et al: Late thrombosis of paclitaxel-eluting
stents: Long-term incidence, clinical consequences, and risk factors in a cohort of 604 patients. Am
Heart J 155:648, 2008; Hirose H: Clopidogrel (PLAVIX) increases risk of bleeding in a patient undergoing coronary
artery bypass grafting. Jpn J Thorac Cardiovasc Surg 54:420, 2006; Lazar HL et al: Tight glycemic control
in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic
events. Circulation 109:1497, 2004; Lindenauer PK et al: Lipid-lowering therapy and in-hospital mortality following
major noncardiac surgery. JAMA 291:2092, 2004; Malmberg K et al: Glycometabolic state at admission:
important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction:
long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI)
study. Circulation 99:2626, 1999; Ormiston JA et al: A bioabsorbable everolimus-eluting coronary stent system
for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 371:899,
2008; Ouattara A et al: Poor intraoperative blood glucose control is associated with a worsened hospital outcome
after cardiac surgery in diabetic patients. Anesthesiology 103:687, 2005; Pfisterer M et al: Drug-eluting or bare-
metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial:
study protocol and design. Am Heart J 155:609, 2008; Van den Berghe G et al: Intensive insulin therapy in the
critically ill patients. N Engl J Med 345:1359, 2001; Van den Berghe G et al: Outcome benefit of intensive insulin
therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med 31:359, 2003.
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