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INDUSTRY SESSION: Basic Scientists, Industry and Clinicians – Are Three a Crowd?
Coated Circuits: Identifying the right target, Building the Prototype, and Implementing
and Measuring Outcomes
Clive Landis
Edmund Cohen Laboratory for Vascular Research University of the West Indies, Barbados
Disclosures
Barbados Diabetes Foundation Bayer Healthcare British Heart Foundation Cave Shepherd Ltd. Cellplex Destiny Group of Companies Edmund Cohen Foundation Medicor International Point Care Technologies
“Using biocompatible surfaces without other measures to contain blood activation results in a limited clinical benefit”
36 studies on heparin coating since 1992
Scientists Industry
Clinicians Government
ideas research tools
1. coagulation 2. flow cytometry 3. army 4. aviation 5. rheumatology ...
cross cutting disciplines …
1. coagulation 2. flow cytometry 3. army 4. aviation 5. rheumatology ...
celebrate achievements
more rational targeting of coagulation ?
XII XIIa
XI XIa
X VIIa VII
Prothrombin Thrombin
Contact pathway
prekallikrein Kallikrein prekall. HMWK
IX
X Xa
TF
Foreign surface
Fibrinogen Fibrin Thrombus
(+)
HMWK
Bradykinin
extrinsic pathway
more rational targeting of coagulation ?
XII XIIa
XI XIa
X VIIa VII
Prothrombin Thrombin
Contact pathway
prekallikrein Kallikrein prekall. HMWK
IX
X Xa
TF
Foreign surface
Fibrinogen Fibrin Thrombus
(+)
HMWK
Bradykinin
extrinsic pathway
McNeely,T.B. and Griffith,M.J. (1985). The anticoagulant mechanism
of action of heparin in contact-activated plasma: inhibition of factor
X activation. Blood 65, 1226-1231
more rational targeting of coagulation ?
XII XIIa
XI XIa
X VIIa VII
Prothrombin Thrombin
Contact pathway
prekallikrein Kallikrein prekall. HMWK
IX
X Xa
TF
Foreign surface
Fibrinogen Fibrin Thrombus
(+)
HMWK
Bradykinin
extrinsic pathway
Spanier TB, Oz MC, Minanov OP, Simantov R, Kisiel W, Stern DM, Rose EA, and Schmidt AM 1998 Heparinless cardiopulmonary bypass with active-site blocked factor IXa: a preliminary study on the dog. J Thorac Cardiovasc Surg 115, 1179-88
more rational targeting of coagulation ?
XII XIIa
XI XIa
X VIIa VII
Prothrombin Thrombin
Contact pathway
prekallikrein Kallikrein prekall. HMWK
IX
X Xa
TF
Foreign surface
Fibrinogen Fibrin Thrombus
(+)
HMWK
Bradykinin
extrinsic pathway
Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman
RW, Edmunds LH Jr. 1993 Aprotinin inhibits the contact, neutrophil, and platelet activation systems during
simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 106:1-9
Contact of blood with the foreign surface of the bypass circuit activates:
The holistic view of blood activation
Coagulation System Cytokines and white cells Fibrinolytic System Platelets Complement System Hemolysis
Platelet activation
Endothelial activation
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
systemic
local
Thrombin
organ injury
Adhesion to plastic has been described as “frustrated phagocytosis” and engages inflammatory and ROS signaling pathways
Snerbulent splench-sucker that captures prey by sticking to their faces and suffocating them - its suckers are impossible to prize off. Unfortunately, it can’t catch anything as it can’t move from the rock it was born on.
— “Flanimals” by Ricky Gervase
Underblenge
CD18 as possible target
1. mediates adhesion to plastic 2. mediates diapedesis 3. mediates phagocytosis 4. mediates oxidative burst
The systemic host response to CPB:
• Cytokines & white cells • Coagulation • Fibrinolysis • Complement • Hemolysis
The systemic host response to CPB:
• Cytokines & white cells • Coagulation • Fibrinolysis • Complement • Hemolysis
a multi-pronged host response requires a multi-
targeted intervention
Problem
• Combinatorial interventions will cause mushrooming sample sizes + cost
• Precludes use of rare clinical end-points (e.g. stroke)
• Need to agree on practical clinical endpoints + standardized data collection
Heart Surgery Forum (2008);5:316-322.
1. Mandatory reporting of CPB and perfusion criteria that can affect outcomes
Recommendations of consensus statement
2. Reporting of causal biochemical markers linked to adverse outcomes
3. Reporting of practical clinical end-points of organ injury
1. PERFSORT (www.perfsort.net)
Future solutions …
3. Standardised data collection forms ?
2. ICEBP International Perfusion Registry
Basic Scientists, Industry and Clinicians ...
Three is not a crowd: it’s a quorum
Imperial College London Betsy Evans Ken Taylor
Edmund Cohen Laboratory Andre Greenidge
Kim Quimby
ICEBP pharma writing group Rob Baker
Jeremiah Brown John Murkin
Donny Likosky
Consensus Statement writing group
Dartmouth Eric Toler
Bob Kramer
Joe Arrowsmith Filip de Somer
Wojciech Dobkowski Gregory Fisher Richard Jonas Michael Poullis David Stump Ed Verrier
systemic factors organ injury local trigger + =
Intervention: pharmacologic/ circuit modification approaches
Intervention: clinical management changes
Landis, C. J Extracorpor Technol 2007;39:281 Landis RC. Core Topics in Cardiac Anaesthesia, 2nd Ed. 2009 …
long term strategy
immediate
Platelet activation
Endothelial activation
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
systemic
local Inflammation, cytodestruction
Thrombin
Ritter LS et al. Stroke 2000;31:1153
Rat Model
Midline cerebral artery
Ischemia/Reperfusion
Pre-occlusion
ischemic reperfused
local trigger
Cognitive impairment is associated with perioperative ischemia and is more severe with greater ischemic load
Preventing local triggers:
How adequate is tissue perfusion in your patient?
Marco Ranucci, Barbara De Toffol, Giuseppe Isgrò, Federica Romitti, Daniela Conti and Maira Vicentini. Crit Care Med 2006;10:R167
“Every attempt should be applied to avoid hyperlactatemia during CPB, and the critical Do2 value of 260 to 270 ml/minute per m2 should be
considered whenever setting the pump flow and the maximum acceptable hemodilution degree”
Marco Ranucci, Barbara De Toffol, Giuseppe Isgrò, Federica Romitti, Daniela Conti and Maira Vicentini. Crit Care Med 2006;10:R167
cerebral oxymetry
cerebral oxymetry
“Monitoring cerebral rSO2 in coronary artery bypass patients avoids profound cerebral oxygen
desaturation and is associated with significantly fewer incidences of organ dysfunction”
ABNORMAL BLOOD FLOW HYPERCOAGULABILITY
ENDOTHELIAL INJURY
Virchow RR. Cellular Pathology. London, Churchill, 1860
vessel trauma/injury local trigger
Intact internal elastic lamina
Graft intima
Internal elastic lamina
disrupted
Elastin stain 200X 200X
Prior to pressure distention After pressure distention
Hand injection with standard syringe
CD31 immunohistochemistry
Intact endothelium
CD31 immunohistochemistry
Disrupted endothelium
Slide courtesy of: Rob Poston
Intraoperative Conduit Imaging
Slide courtesy of: Rob Poston
LA = 4.25
1 mm
Before
harvest
LA = 1.74 LA = 2.04 LA = 1.01
LA = 4.17 LA = 3.04
LA = 4.39 LA = 3.94 LA = 4.88
Before harvest
1 mm
LA = 4.58 LA = 3.92 LA = 4.22
Harmonic Scalpel
Electrocautery
Proximal Middle Distal
Slide courtesy of: Rob Poston
HAMMON JH, et al. CABG WITH SINGLE CLAMP IMPROVES NEUROPSYCHOLOGICAL OUTCOMES Ann Thorac Surg 2007;84:1174.
clamp
local trigger
aortic x-clamp: - multiple - excessive force
Immediate interventions to attenuate the systemic inflammatory approach:
Preventing local triggers
Whole team approach gentle handling & clamping of vessels minimize tissue ischemia cell saver/leukofiltration temperature/emboli/rSO2 monitoring
Immediate interventions to attenuate the systemic inflammatory approach:
Preventing local triggers
Whole team approach gentle handling & clamping of vessels minimize tissue ischemia cell saver/leukofiltration temperature/emboli/rSO2 monitoring
TITLE: An evidence-based review of pharmaceutical interventions to limit the systemic inflammatory response in cardiac surgery AUTHORS: Landis RC, *Brown JR, †Murkin JH, *Likosky DS, §Baker RA for the International Consortium for Evidence Based Perfusion AFFILIATION: Edmund Cohen Laboratory for Vascular Research, University of the West Indies, Barbados; *The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH, USA; †London Health Sciences Center, London, Ontario, Canada; §Flinders Medical Center, Adelaide, Australia. INTRODUCTION: We report here the first evidence-based review of pharmaceutical strategies to limit the systemic inflammatory response in adult coronary artery bypass grafting surgery.
Pharmaceutical suppression of
the evidence base
systemic factors
Landis, RC, Brown JR, Murkin JM, Likosky DS, Baker RA. Heart Surg Forum (2008);5:E308. Brown JR, Toler AWJ, Toler RE, Landis RC. J Extracorpor Technol (2009) - in press
Mesh search terms
Search 1: ((("thoracic surgery"[TIAB] NOT Medline[SB]) OR "thoracic surgery"[MeSH Terms] OR cardiac surgery[Text Word]) OR ((("cardiopulmonary bypass"[TIAB] NOT Medline[SB]) OR "cardiopulmonary bypass"[MeSH Terms] OR
("coronary artery bypass"[TIAB] NOT Medline[SB]) OR "coronary artery bypass"[MeSH Terms] OR"Heart-lung machine"[MeSH Terms]) OR ((("heart valves"[TIAB] NOT Medline[SB]) OR "heart valves"[MeSH Terms] OR valve[Text
Word]) OR valves[All Fields] OR valvular[All Fields]) AND ("surgery"[Subheading] OR "operative surgical procedures"[Text Word] OR "surgical procedures, operative"[MeSH Terms] OR "surgery"[MeSH Terms] OR surgery
[Text Word]))) AND (#19) Limits: Humans, Randomized Controlled Trial, English Search 2: (aprotinin OR dexamethasone OR steroids OR cortisol OR aspirin OR tranexamic acid OR aminocaproic
acid) AND ((Inflammation OR cytokines OR interleukin OR tnf OR (tumor necrosis factor) OR (leukocyte count) OR granulocytes OR immunoelectrophoresis OR monocytes OR (cell adhesion molecules) OR leukocyte OR aprotinin OR dexamethasone OR steroids OR cortisol OR aspirin OR tranexamic acid OR aminocaproic acid) AND (cardiac surgery OR ((("cardiopulmonary bypass"[TIAB] NOT Medline[SB]) OR "cardiopulmonary bypass"[MeSH Terms] OR ("coronary artery bypass"[TIAB] NOT Medline[SB]) OR "coronary artery bypass"[MeSH Terms]) OR (valve OR valves OR valvular)
AND and surgery))) AND ((Humans[Mesh]) AND (English[lang]) AND (Randomized Controlled Trial[ptyp])) Search 3: (("thoracic surgery"[TIAB] NOT Medline[SB]) OR "thoracic surgery"[MeSH Terms] OR cardiac surgery[Text
Word]) OR ((("cardiopulmonary bypass"[TIAB] NOT Medline[SB]) OR "cardiopulmonary bypass"[MeSH Terms] OR ("coronary artery bypass"[TIAB] NOT Medline[SB]) OR "coronary artery bypass"[MeSH Terms] OR"Heart-lung
machine"[MeSH Terms]) OR ((("heart valves"[TIAB] NOT Medline[SB]) OR "heart valves"[MeSH Terms] OR valve[Text Word]) OR valves[All Fields] OR valvular[All Fields]) AND ("surgery"[Subheading] OR "operative surgical
procedures"[Text Word] OR "surgical procedures, operative"[MeSH Terms] OR "surgery"[MeSH Terms] OR surgery[Text Word]))
Search 4: (("complement activation"[MeSH Terms] OR complement activation[Text Word]) OR ("complement system proteins"[MeSH Terms] OR complement system proteins[Text Word]) OR complement[Text Word]) OR
("kallikreins"[MeSH Terms] OR kallikrein[Text Word]) or (inflammatory[All Fields])
Systematic search of the literature … 1970 - 2008 randomised drug trials inflammatory response 439 papers
Exclusion criteria … pediatric off-pump, valve, other CT procedures
Inclusion criteria … adult CABG measure at least one inflammatory marker
64 papers
16 papers
Measure organ function to heart, lung, brain, kidney, gut
Systematic search of the literature … 1970 - 2008 randomised drug trials inflammatory response 439 papers
Exclusion criteria … pediatric off-pump, valve, other CT procedures
Inclusion criteria … adult CABG measure at least one inflammatory marker
64 papers No meta-analyses met inclusion criteria
16 papers
Measure organ function to heart, lung, brain, kidney, gut
Conclusions
The evidence base is poor
Most studies do not measure a single inflammatory marker
No meta-analyses
Only Methylprednisolone merited a Class IIa clinical recommendation based on multiple randomised trials
Conclusions
The evidence base is poor
Most studies do not measure a single inflammatory marker
No meta-analyses
Only Methylprednisolone merited a Class IIa clinical recommendation based on multiple randomised trials Reveals need to define criteria for carrying out
such studies in future
Pharmaceutical interventions are not a short term option
Any plausible pharmaceutical strategies in the long term?
long term pharmaceutical strategies
1. combinatorial approach
Platelet activation
Endothelial activation
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
systemic
local
Thrombin
organ injury
1. combinatorial strategy
2. thrombin receptor antagonists
long term pharmaceutical strategies
Fibrin
Fibrinogen
Hemostasis
Controlled thrombin generation
Hemostasis
Controlled thrombin generation
PAR1
Fibrin
Fibrinogen
Thrombin burst
new drug target ?
pl rich occlusive thrombus
Platelets – aggregation Endothelial cells – inflammation Neural cells - apoptosis
? ? ?
No increase in TIMI bleeding
(46% reduction in MACE)
TRA-PCI: Phase II
Becker RC, et al. Lancet 2009; 373:872.
1. combinatorial strategy
2. thrombin receptor antagonists
3. leukocyte adhesion antagonists
4. improved circuit coating
long term pharmaceutical strategies
systemic factors organ injury local trigger + =
Intervention: pharmacologic/ circuit modification approaches
Intervention: clinical management changes
Landis, C. J Extracorpor Technol 2007;39:281 Landis RC. Core Topics in Cardiac Anaesthesia, 2nd Ed. 2009 …
long term strategy
immediate
Imperial College London Betsy Evans Ken Taylor
Edmund Cohen Laboratory Andre Greenidge
Kim Quimby
ICEBP pharma writing group Rob Baker
Jeremiah Brown John Murkin
Donny Likosky
Consensus Statement writing group
Dartmouth Eric Toler
Bob Kramer
Joe Arrowsmith Filip de Somer
Wojciech Dobkowski Gregory Fisher Richard Jonas Michael Poullis David Stump Ed Verrier
Adhesion to plastic has been described as “frustrated phagocytosis” and engages inflammatory and ROS signaling pathways
Snerbulent splench-sucker that captures prey by sticking to their faces and suffocating them - its suckers are impossible to prize off. Unfortunately, it can’t catch anything as it can’t move from the rock it was born on.
— “Flanimals” by Ricky Gervase
Underblenge
Platelet activation
Endothelial activation
Thrombin
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
Platelet activation
Endothelial activation
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
systemic
local
Thrombin
organ injury
Platelet activation
Endothelial activation
Bradykinin
Leukocyteactivation
XII
intrinsic coagulation
Kallikrein
fibrinolysis
tPA
Plasmin C3
C5
IgM/IgG
classical complement
white cell adhesion
Oxidative stress
hemolysis/ RBC transf
systemic
local
Thrombin
organ injury
systemic factors
systemic factors organ injury local trigger + =
Intervention: pharmacologic/ circuit modification approaches
Intervention: clinical management changes
Imperial College London Betsy Evans Ken Taylor
Edmund Cohen Laboratory Andre Greenidge
Kim Quimby
ICEBP writing group Rob Baker
Jeremiah Brown Donny Likosky
Consensus Statement writing group
Summary of Recommendations:
1, Mandatory description of CPB equipment and perfusion techniques used. See Table 1.
2, Report a minimum of 3 criteria (3 major criteria or 2 major and 1 minor). See Tables 2 & 3:
i.e. 3 major (2 inflammatory and 1 clinical end-point or marker of organ injury)
or
2 major (1 inflammatory and 1 clinical end-point or marker of organ injury) and 1 minor criteria.
OUTCOMES XIII MAY 27-30 2009
systemic local
heart brain kidney gut lung vein grafts X-clamp
• vessel trauma • endothelial denudation
• ischemic injury • endothelial activation
intrinsic coagulation
classical complement
white cell adhesion
fibrinolysis
bleeding humoral, white cell & vascular activation
hemolysis/ RBC transf.
oxidative stress
systemic local
systemic factors
local trigger
Fluid shifts in the brain
“Fixing the heart: must the brain pay the price?” Mark Newman, Circulation 2004
Whole blood PAR1 function assay
FL3
CD14
(M
onoc
yte)
FL1 CD45 (pan-leukocyte)
monocytes
neutrophils
lymphocytes
Blood samples taken before, during and after CPB
Platelet binding to leukocytes used as a surrogate for platelet activation
FL2 CD42b (platelet)
7.01 % 2. Determine % of platelets in the leukocyte gate
84.01%
TRAP-6
FL2 CD42b (platelet)
1. Gate on leukocyte subpopulation
3. Assess ability of platelets to be activated via PAR1 by adding PAR1 agonist TRAP-6
( After: Ferraris, V.A., et al. (1998) Ann Thorac Surg 65:352-8)
Aprotinin has a weak Ki for thrombin
Aprotinin Ki (M)
trypsin 6 x 10-11
plasmin 9 x 10-11
plasma kallikrein
3 x 10-8
tissue kallikrein
3 x 10-10
Factor XIIa > 1 x 10-6
Factor XIa 1 x 10-7
elastase > 1 x 10-6
thrombin > 1 x 10-6
Conclusions on mechanism of action
Aprotinin inhibits binding of thrombin to the hirudin-like binding site on PAR1.
Leads to a reduced rate of PAR1 hydrolysis by thrombin.
Fits the inhibitory profile of aprotinin.