Coated Circuit Research and
Inflammation: The Literature for
Developing a Guideline
Robert A. Baker PhD CCP(Aus), Flinders Medical
Centre, Flinders University
David C. Fitzgerald CCP, INOVA Fairfax Hospital
Guidelines
“Systematically developed statements to
assist practitioner and patient decisions
about appropriate health care for
specific clinical circumstances”
Institute of Medicine 1990
Guidelines not new!
• Medical organizations have been
developing for over 50 years
• “Appropriate care recommendations
date back to ancient times”
• Now emphasis on systematic,
evidence based guidelines
• Interest in process, effective use
and evaluation of guidelines
James Lind, M.D.
• 1600-1800: 1 million
sailors die of Scurvy
• 1747- Commissioned by
Royal Navy to investigate
Scurvy among sailors
• 1751 published clinical
findings
• 1800- widespread
adoption of citrus
Mosteller F. “Innovation and Evaluation.”
Science, 1981, 211, 881-886
Purposes or Value of guidelines
(1) Assisting clinical decision making by patients
and practitioners
(2) Reducing practice variation
(3) Educating individuals or groups.
(4) Assessing and assuring the quality of care.
(5) Guiding allocation of resources for health care.
IOM 1992 (modified)
IN GOD WE TRUST
Everyone else bring evidence?
Evidence-Based Medicine
• The conscientious, explicit and judicious use of
current best evidence in making decisions about
the care of individual patients. The practice of
evidence-based medicine means integrating
individual clinical expertise with the best available
clinical evidence from systematic research.
• Evidence-based medicine is not “cook-book”
medicine. External clinical evidence can inform,
but never replace individual clinical expertise.
(British Medical Journal 1996;312:71-2)
ICEBP Inflammatory Response Guidelines
Goals:
• To enhance the clinicians’ understanding of the
influence of CPB on inflammatory response.
• To produce meaningful and actionable evidencebased guidelines for the specific attenuation of the
inflammatory response generated during adult
cardio-pulmonary bypass.
Consensus Statement: Defining Minimal Criteria for
Reporting the Systemic Inflammatory Response
to Cardiopulmonary Bypass
R. Clive Landis, Joseph E. Arrowsmith, Robert A.
Baker, Filip de Somer, Wojciech B. Dobkowski,
Gregory Fisher, Richard A. Jonas, Donald S. Likosky,
John M. Murkin, Michael Poullis, David A. Stump,
Edward D. Verrier
Heart Surgery Forum 11(5), 2008. doi:10.1532/HSF98
Inflammatory Response and CPB
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Pharmacology
Emboli
Temperature
Cell Salvage
Coated Circuitry
Filtration
Pumps
Research Question
• Do coated circuits reduce the inflammatory
response during adult CPB as determined
by an influence of at least (1) major causal
marker?
Criteria for Consideration
• Peer reviewed
literature
– English language
(1970-2010)
• Adult procedures using
CPB
• At least (1) major
causal inflammatory
mediator measured
• Structured literature
searches
• ≥ 2 abstract reviewers
– 1 Yes included
• ≥ 2 paper reviewers
• All literature evaluated
through the Guideliner
web portal.
EBM - Guideliner
• Developed by the
Cardiac Surgery
Research and
Perfusion GroupFlinders Medical
Centre/Flinders
University
Problems with Circuit Coating RCT
evaluation
• Heterogeneity in circuit
“biocompatibility”
definition
• Controlling for
concomitant therapies
• Study design- e.g.,
sample size, blinding
• Differences in
measurements of
inflammatory mediators
Thrombosis Research (2006) 117,689-703
Heterogeneity in Metanalyses
Did not control for:
“Heparinization of the blood contact surface in
1.cardiopulmonary
Systemic
Heparinization
(280s vs 480s)
bypass has been promoted as an
2. Pump
vs cell salvage
important
stepsuction
in the development
of open-heart
surgery, 3.
as Open
it decreases
the inflammatory
vs closed
system response
resulting from the extracorporeal circulation”
European Journal of Cardio-thoracic Surgery 21 (2007) 1058-1069
Heterogeneity in Metanalyses
JECT. 1999(31);3:135-141
RCT Post-Hoc Analysis
• Identify common inflammatory
mediators from the literature
• Focus on “core” markers
• Analyze baseline and peak
measurements
• Establish consensus on
measuring intervals and
frequency
• Conduct a meta-analysis
48 Reported Inflammatory Mediators
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C3a: classical complement pathway
IL-6: immunoregulatory cytokine
IL-8: proinflammatory chemokine
TAT: thrombin formation, cross-over to inflammation
TNF-alpha: inflammatory cytokine
PMN elastase: neutrophil activation and destruction
MPO: neutrophil activation and destruction
IL-10: counterpoint to proinflammatory markers
J Card Surg 2008;23:288-293
“Sorry guys, this paper was long ago. I wouldn't
even know where to start”
Complement C3a assays
• Utilized in 25 of the RCT that met criteria
– Most widely used inflammatory marker
– Frequency of testing range
• Range (2-7)
• Median= 5
– Variances in observed peak intervals
• Start of CPB – 24 hours post-op
• Was there a peak observed?
Definition: Peak
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The most extreme possible amount or value
The highest level or degree attainable
The top or point of something
The highest point (of something)
Webster’s Online Dictionary
www.websters-online-dictionary.org
Ann Thorac Surg 1993;55:917-22
Size of the studies
• Stammers et al 1999
– 26 published studies
• 1515 patients (ave 58 per study)
• Mangoush et al 2007
– 41 published studies
• 1515 patients (ave 87 per study)
• Rannucci et al 2007
– 36 published studies
• 4360 patients (ave 121 per study)
Size of the studies
• Stammers et al 1999
– 26 published studies
• 1515 patients (ave 58 per study)
• End bypass C3a 80 patients
• End bypass TAT complex 155
• ICEBP in progress
– Data from 12 published studies
• C3a 10 studies, 577 patients
• TAT complex 3 studies, 346 patients
• Trial arm sizes run 7-101!
Guidelines
“Systematically developed statements to
assist practitioner and patient decisions
about appropriate health care for
specific clinical circumstances”
Institute of Medicine 1990
What we’ve learned
• Coated circuits appears beneficial in
reducing inflammatory response. Marker
data seems consistent in one direction.
• Data is very heterogeneous in nature, further
investigation is warranted.
• Need clearer consensus on study design
with respect to inflammatory markers.
What we’ve learned
• Identifying opportunities for improvement will
help improve future published research.
• Anecdotal decline in contemporary coated
circuit research
– Efficacy of uncoated tubing
• This is a marathon, not a sprint…..Enjoy the
ride!
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Rob Baker
Kenny Shann
Tim Dickinson
Donny Likosky
Randy Bullock
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Jane Ottens
Heinz Weitkemper
John St. Onge
Zack Beckman
Thank you