Department of OUTCOMES RESEARCH
Causes of Death
Bartels, et al., 2013, Anesthesiology
Wound Infection
Cancer Recurrence
Red Cell Transfusion
Glycemic Control
Myocardial Infarction
Anesthetic Toxicity
Persistent Pain
Delirium & POCD
Mortality
Long-term Outcomes of Anesthesia
www.OR.org
Interventions to improve outcomes weeks,
months, and years after surgery
Blood loss and transfusion
•Red cell storage duration
Regional analgesia and cancer
Perioperative myocardial injury
Transfusion can save lives
• Appropriate triggers unknown
Associated with complications
• Viral infection not major risk
• Most commonly transmitted
infection is babesiosis
Potential risk mechanisms
• Highly immunogenic
• Nitric oxide depletion
Blood Transfusion
Randomized Trials: Infection
0
2
4
6
8
10
12
14
16
18
Restrictive (Hb 7-8
g/dL)
Liberal (Hb 9=10 g/dL)
% with Infection
Hospital-acquired Infection by
Transfusion Strategy
Rohde, et al, JAMA, 2014
RR = 0.82
Randomized Trials: Cancer Recurrence
Amato et al, Cochrane 2006
RR=1.36, P=0.03
Transfusion and Mortality
Carson, JAMA 2013
RR=0.85, P = 0.1
Stored Blood Degrades Over Time
Older blood
Younger blood
Berezina, J Surg Res, 2002
Younger blood
Older blood
Free hemoglobin in stored blood scavenges NO,
provoking systemic and pulmonary vasoconstriction
Storage Duration and Survival
Koch, NEJM, 2008
Older blood
Younger blood
Older blood
Younger blood
Storage Duration, Non-cardiac
Observational Mortality, n=380,000
Edgren, Transfusion 2011
ABLE Trial (n=2,430)
Lacroix et al. N Engl J Med 2015
Critical care patients
Blood aged 6 vs. 22 days
Recess Trial (n=1,098)
Steiner et al. N Engl J Med 2015
Cardiac surgery patients
Blood aged 7 vs. 28 days
CCF Cardiac Surgery Trial
Randomized trial of younger versus older blood
Cardiac surgical patients
Target n=2,838 transfused patients
• n≈1,200 so far
• Next interim analysis at n=1,814
Primary outcome
• STS Composite of serious complications
Koch, et al.
INFORM Trial
Randomized trial of younger versus older blood
Virtually all patients at five centers
• Not restricted to surgical patients
Target n=31,500 transfused patients
• >24,000 so far
Primary outcome: in-hospital mortality
Eikelboom, et al.
Causes of Long-term Mortality
Cause of Death %
Cancer 52%
Cardiovascular 17%
Renal/Liver Failure 5%
Respiratory Failure 4%
Pulmonary Emboli 2%
Sepsis/Infection 2%
Monk, A&A 2005
≈10% one-year
mortality in
patients ≥65 yrs
Cancer Surgery
Cancer recurrence is usually lethal
Surgery remains primary treatment
• Releases tumor cells into blood stream
• There is always minimal residual disease
Natural killer (NK) cells are major defense
• Spontaneously recognize and kill tumor cells
Surgery and anesthesia impair NK Cell function
• Neuroendocrine stress response to surgery
• Volatile anesthetics
• Opioids
Regional Analgesia Protective?
Regional anesthesia & analgesia
• Reduces stress response to surgery
• Reduces or eliminates general anesthetics
• Obviates need for postoperative opioids
All three help preserve NK cell function
Hypothesis:
• Regional anesthesia & analgesia reduces risk of
cancer recurrence
Rats: Bar-Yusof, Anesthesiology 2001
Paravertebrals & Breast Cancer
Retrospective analysis of 129 mastectomies for CA
• 50 had combined general & paravertebral analgesia
• 79 had general and morphine analgesia
Exadaktylos,
Anesthesiology 2006
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0 12 24 36
0
70
80
90
100
Time (mo)
% Recurrence-free
Paravertebral
General
P = 0.012
Epidurals & Prostate Cancer
Scavonetto, BJA 2014
Epidural & GA
GA Alone
Negative Retrospective Results
Ismail et al: BJA 2010
• Brachytherapy for cervical cancer
– 63 neuraxial vs. 69 general anesthesia
Gottschalk et al: Anesthesiology 2010
• Colectomy for colon cancer
– 256 epidural vs. 253 general anesthesia
Tsui et al: CJA 2010
• Epidural analgesia for prostate cancer
– 49 epidural vs. 50 general anesthesia
Forget et al: EJA 2011
• Epidural analgesia for prostate cancer
– 578 epidural vs. 533 general anesthesia
Day et al: BJA 2012
• Laparoscopic colectomy
• 107 epidural; 144 spinal; and 173 general alone
And others…
MASTER Trial Follow-up
Epidural (n=230)
General (n=215)
Myles, BMJ, 2011
Also negative:
Tsui 2010
Christopherson 2008
Binczak, et al 2013 (n=132)
Randomized to epidural
vs. GA
Recurrence-free survival
P=0.1, favoring epidural
Trials of
breast and
lung
cancer in
progress
Major abdominal surgery
Perioperative Mortality
Intraoperative mortality rare
Thirty-day postoperative mortality
• 1% nationwide in United States
• 80% of one-month deaths during initial hospitalization
• Mostly cardiovascular or consequent
Postoperative MI poorly understood
• Etiology?
• Prediction?
•
Prevention? (today’s focus)
• Treatment?
Postoperative MIs are Common
≈230 million non-cardiac operations / year
MI incidence 8% among inpatients >45 years
• ≈10 million postoperative infarctions per year
Nearly all non-ST segment elevation
• Plaque rupture?
• Supply-demand mismatch?
• Thrombus?
VISION: JAMA 2012 and Anesthesiology 2014
Silent and Deadly
80% of MIs only detected by troponin
• Most do not have chest pain, SOB, ECG changes
Mortality identical after apparent & silent MIs
• It’s not just “troponitis”
Mortality is 10% at 30 days
• Twice as high as non-operative infarctions
–Different?
–Unrecognized?
–Untreated?
VISION: JAMA 2012 and Anesthesiology 2014
Troponin Predicts Mortality
“Prognosis define diagnosis”
Even slight troponin elevations predict death
Peak Troponin
(ng/ml)
30-day Mortality
(%)
Time to death
(days)
<0.01 1
—
0.02 4
13
0.03-0.29 9
9
≥0.3 17
6
ENIGMA-2
Background
• N
2
O increases plasma homocysteine
• N
2
O impairs endothelial function
Hypothesis
• N
2
O increases 30-day death or major CV events
• MI required troponin elevation & clinical event
Randomized trial in 7,000 high-risk patients
• 70% nitrous oxide
• 70% nitrogen
Myles, Lancet, 2014
POISE-2 Background
Surgery
• Inflammatory response activates platelets
• Promotes tachycardia
Aspirin
• Impairs platelet aggregation
• Prevents non-operative primary & secondary MI
Clonidine
• Moderates central sympathetic activation
• Heart rate control
• Less hypotension than beta blockers
• Analgesic and anti-inflammatory
POISE-2 Design
10,000 inpatients >45 yrs at cardiovascular risk
Blinded 2 X 2 factorial trial
• Aspirin 100 mg/day vs. placebo for 7 or 30 days
• Clonidine 75 µg/day vs. placebo for 72 hours
Primary outcome
• Death or MI within 30 days
• MI required troponin elevation and clinical events
POISE-2 Results, Aspirin
Devereaux, NEJM 2014
Outcome
Aspirin
(4998)
Placebo
(5012)
HR
(95% CI)
P
1
O
outcome:
death or
nonfatal
MI
351 (7.0)
355 (7.1)
0.99 (0.86-
1.15)
0.92
Major bleed
229 (4.6)
187 (3.7)
1.23 (1.01-
1.49)
0.04
Stroke
16 (0.3)
19 (0.4) 0.84 (0.43-
1.64)
0.62
No interaction with clonidine
Aspirin, Death & MI
Clonidine, Death & MI
%
POISE-2, Clonidine Results
Outcome
Clonidine
(5009)
Placebo
(5001)
HR
(95% CI)
P
Clinically
important
hypotension
2385 (48)
1.32 (1.24-
1.40)
<0.001
Clinically
important
bradycardia
600 (12) 403 (8)
1.49 (1.32-
1.69)
<0.001
Stroke
18 (0.4) 17 (0.3)
1.06 (0.54-
2.05)
0.87
Devereaux, NEJM 2014
No interaction with aspirin
POISE-2 Conclusions
Aspirin
• Does not prevent death or MI
• Increases life-threatening bleeding
• Should not be used for MI prophylaxis
Clonidine
• Does not prevent death or MI
• Causes clinically important hypotension
• Should not be used for MI prophylaxis
A safe and effective way to prevent perioperative
myocardial infarctions remains unknown
Association with MAP
Mascha, Anesthesiology, in press
30% mortality
increase per
5 mmHg!
Summary of Long-Term Outcomes
Prolonged storage of transfused red cells
• Association with complications in some studies
• Randomized trials in progress
Regional analgesia and cancer recurrence
• Immunologic & animal data suggest reduced risk
• Current human data poor and conflicts
• Randomized trials in progress
Perioperative heart attacks
• Common, silent, and deadly
• Predication, etiology, prevention, and treatment remain unknown
Department of OUTCOMES RESEARCH