carmeda® bioactive surface

Transcription

carmeda bioactive surface
®
Clinical and Scientific Information
Improving health care quality for patients
undergoing extracorporeal circulation
procedures is a high priority today as patient
outcomes measures are increasingly, and
often publicly, scrutinized.
Today’s leading cardiovascular surgery teams
strategically apply teamwork, techniques and
technologies to achieve the best possible
outcomes for their patients undergoing
extracorporeal circulation. Around the world,
Carmeda®* BioActive Surface is an important
component of these comprehensive strategies.
Blood is meant to contact the healthy vascular
endothelium that lines the blood vessels and
heart, not artificial surfaces. The activation of
the blood’s formed and unformed elements,
which occurs when blood contacts the
extracorporeal circuit’s artificial surfaces,
is associated with an induction of two highly
interconnected events: coagulation and
inflammation. These events may affect
the body’s organ systems and compromise
clinical outcomes.
The important role of Carmeda® BioActive
Surface is to provide thromboresistance
and biocompatibility by reducing the impact
of blood contact with the circuit’s artificial
surfaces. A large body of published clinical
and scientific evidence reports the beneficial
impact of Carmeda® BioActive Surface on
the body’s defense systems and on clinical
outcomes for both adult and pediatric patients.
*Manufactured under license from Carmeda AB, Sweden.
Carmeda is a registered trademark of Carmeda AB.
This compendium of clinical and scientific information
describes the role of Carmeda® BioActive Surface
during extracorporeal circulation procedures, reviews
the evolution of heparin biosurface technology,
highlights Carmeda® BioActive Surface’s technological
characteristics and theory of function, and summarizes
the large body of published supporting clinical and
scientific evidence for this End Point Attached
heparin technology.
OVERVIE W
Today’s Strategies to Reduce Extracorporeal
Circulation-related Morbidity: The Role of
Carmeda® BioActive Surface
Extracorporeal circulation procedures help save lives
and enhance the quality of life. They can also make
patients ill.
Carmeda® BioActive Surface was developed to minimize one
contributor to extracorporeal circulation-related morbidity: the
contact-initiated activation of the blood’s coagulation system and
the subsequent activation of platelets that occurs when blood
comes in contact with the artificial materials lining extracorporeal
circuits. Activation of the blood’s formed and unformed elements
is associated with an inflammatory response that may affect the
body’s organ systems, disturb blood coagulation processes and
compromise clinical outcomes.
Carmeda® BioActive Surface provides
thromboresistance and biocompatibility to
extracorporeal circuit surfaces.
For pediatric patients to adults, Carmeda® BioActive Surface
bonded circuits are used for routine as well as complex
procedures requiring extracorporeal circulation.
Carmeda® BioActive Surface is a critical component
of comprehensive strategies to reduce extracorporeal
circulation-related morbidity.
Besides blood-surface interactions, there are several other
potential contributors to extracorporeal circulation-related
morbidity. Therefore, leading clinical teams strategically apply
teamwork, techniques and technologies that carefully consider
the many surface-, flow-, and blood-related issues that may
impact patient outcomes (Figure 1). Heparin biocompatible
surfaces are an important component of these comprehensive
strategies for achieving the best possible outcomes for patients
undergoing extracorporeal circulation (Table 1).
Table 1
Strategies for Reducing Extracorporeal
Circulation-Related Morbidity
Published evidence suggests that extracorporeal circulation-related
morbidity may be reduced by:
•Using a heparin biocompatible surface for blood-contacting areas
on the circuit1,2,3,4,5,6,7
• Preventing excessive hemodilution8,9,10,11,12,13,14
• Reducing shear, stasis and turbulence15
•Using closed-to-air systems and other techniques and technologies
to limit air-blood interface16,17
• Minimizing manipulation of the aorta18
•Avoiding direct reinfusion of unprocessed cardiotomy suction
blood19,20,21
• Providing precise, patient-specific hemostasis
management22,23,24,25,26,27,28
Technology Highlights
Description
Carmeda® BioActive Surface is a non-leaching, covalently bonded,
End Point Attached heparin biosurface applied to the bloodcontacting surfaces of Medtronic extracorporeal circulation
technologies.
Clinical need addressed
• The patient’s blood is exposed to the artificial materials of the
circuit during extracorporeal circulation procedures.
• The blood recognizes the materials on the inner surfaces of
the circuit as “foreign,” triggering coagulation and inflammatory
events that may lead to adverse clinical outcomes.
• Carmeda® BioActive Surface is bonded to extracorporeal
circuit components to mimic critical characteristics of the
vascular endothelium that naturally lines the circulatory system
to reduce coagulation and inflammation responses due to
blood-material surface interaction.
Figure 1
Teamwork – Technique – Technology
Strategies for Improving Extracorporeal Circulation Outcomes
•Minimize:
- Shear
- Stasis
- Turbulence
Improving
Extracorporeal
Circulation
• Prevent excessive hemodilution
• Prevent emboli
• Avoid direct reinfusion of cardiotomy suction blood
• Optimal pharmacological management
• Precise, patient-specific hemostasis management
• Heparin biocompatible surfaces
• Avoid air-blood interfaces
• Minimize circuit surface area
Carmeda® BioActive Surface is an important component of comprehensive strategies for reducing extracorporeal circulation-related morbidity.
2
OVERVIE W
Clinical applications
• Extracorporeal circulation procedures for patients of all ages
and sizes, pediatric to adult
Materials bonded
• Plastic and metal materials that line the blood-contacting
surfaces of the extracorporeal circuit components
Carmeda® BioActive Surface Mimics Critical
Characteristics of the Vascular Endothelium
Figure 2
Carmeda® BioActive Surface: a schematic
Extracorporeal technologies bonded
•Oxygenators
• Resting Heart® System
• Centrifugal blood pumps
• Custom tubing sets
• Cardioplegia delivery systems • Closed chest support system
• Arterial filters
• Hemodynamic support system
•Reservoirs
• Cannulae
•Flow probes
• Cannulae adapters
•O2 saturation cells
Clinical and scientific findings
Carmeda® BioActive Surface is the most extensively researched
biosurface for today’s extracorporeal circulation technologies,
with extensive publication of clinical and scientific evidence in
peer-reviewed cardiovascular surgery, perfusion and scientific
literature, including:
• Less blood product
use1,2,3,29,30,31,32
• Less perioperative blood
loss6,30,31,32,33,34,35,36
• Shorter ventilator time2,31,33,37,38 and reduced post-operative
peak airway pressures39
• Shorter
ICU3,4
and
hospital2,3,33
length of stay
• Less postoperative body temperature rise33,40
• Fewer postoperative neurocognitive deficits5,33,41
Heparin
• H
igh degree of bioactivity is consistently delivered, due to the
unique Carmeda® BioActive Surface chemistry and its sophisticated
manufacturing process.
• End Point Attached heparin bonding process assures that the
heparin molecules’ active binding sites remain free to participate
in biological reactions with the blood components.
• Durable, non-leaching heparin surface that does not wash off is
provided by the strong covalent bonding process used to immobilize
the End Point Attached heparin on the device surface.
Negative charge
• Similar to the negative charge of the vascular endothelium, the
heparin in Carmeda® BioActive Surface is negatively charged.
Hydrophilicity
• Hydrophilic, or “water loving,” characteristics are provided by
Carmeda® BioActive Surface’s heparin and priming layer.
• Hydrophilic surfaces adsorb less blood protein compared to
hydrophobic, or “water hating,” surfaces; this protein adsorption
is also more readily reversible.67,68,69
• Significantly greater urine output during CPB31,37
• Lower costs, as related to improved clinical outcomes3
• Less negative impact on the body’s defense systems,
including the:
– contact system42,43,44,45,46,47
– coagulation system5,35,43,48,49,50,51,52,53,54,55,56
– fibrinolytic system4,31,48,57,58
– complement system4,5,34,36,38,39,50,54,59,60,61,62,63,64
– cytokine proteins4,38,39,51,60,64
Figure 3
Impact of Carmeda® BioActive Surface on the Human
Body Defense Systems
• Reduced impact on the blood’s formed elements, including:
– platelets34,43,51,54,55,62,64,65
– red blood cells31,35,46,50,57,66
– leukocytes4,38,46,51,54,55,61,62,63
Research indicates mitigating effects by Carmeda® BioActive Surface
3
Table of Contents
Today’s strategies to reduce extracorporeal circulation-related morbidity: the role of Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . 2
Technology highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Blood is naturally compatible with vascular endothelium, not artificial circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
All heparin biosurfaces are not created equal: the history of End Point Attached heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Mimicking critical characteristics of the vascular endothelium with Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Theory of function of Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
End Point Attached heparin bonding process: an overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Pediatric patients to adults: Carmeda® BioActive Surface’s broad clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Can extracorporeal circulation be improved? Clinical and scientific evidence on the impact of Carmeda® BioActive Surface . . . . . . . . . . . 16
Experimental in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Experimental in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Adult – clinical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Pediatric – clinical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Reducing patient exposure to DEHP: the impact of Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Common clinical topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figures
1Teamwork-Technique-Technology: Strategies for Improving Extracorporeal Circulation Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2Carmeda® BioActive Surface: a Schematic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3Impact of Carmeda® BioActive Surface on the Human Body Defense Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4Responses to Blood-Material Contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5Carmeda® BioActive Surface: Impact on Surface Deposition of Blood Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
6Ionically Bonded Heparin: A Schematic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
7Covalently Linked Heparin: A Schematic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
8Carmeda® BioActive Surface End Point Attached Heparin: a Schematic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
9Orientation of Heparan Sulfate and End Point Attached Heparin (Carmeda® BioActive Surface): Schematics . . . . . . . . . . . . . . . . . . . . . 9
10Theory of Function: End Point Attached Heparin-Antithrombin-Coagulation Factor Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
11Inhibition of Factor XIIa on High Affinity® Heparinized Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
12Carmeda® BioActive Surface Reduces Thrombogenicity of the Extracorporeal Circuit: Ex vivo Experiment . . . . . . . . . . . . . . . . . . . . . . . 11
13 Plasma Coagulation Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
14Impact of Carmeda® BioActive Surface on the Human Body Defense Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
15Complement Activation Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
16 Hemocompatibility of Carmeda® BioActive Surface: Comparison of Soluble and Surface Adsorbed Markers of Hemocompatibility . . 13
17End Point Attached Heparin Bonding Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
18Carmeda® BioActive Surface’s Role During Extracorporeal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
19DEHP Leaching Test Circuit Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
20Total DEHP Leached from PVC Circuits Circulating Undiluted Bovine Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Tables
1Strategies for Reducing Extracorporeal Circulation-Related Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2Biological Pathways Impacted by Blood-Material Contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3Blood Cell Types Impacted by Blood-Material Contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4Systemic Inflammatory Response Syndrome: Potential Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5 “Bioactive” Surfaces: a Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
6 Heparin Stability and Activity Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
7Medtronic Extracorporeal Circulation Technologies Available with Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
8Clinical and Scientific Findings: Carmeda® BioActive Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9Summary of DEHP Leaching Data from Three Types of PVC Tubing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
10 Percent Reduction in DEHP Leaching from PVC Tubing Attributed to Heparin Biosurfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4
Blood is naturally compatible with vascular
endothelium, not artificial circuits.
Healthy vascular endothelium: The ultimate
biocompatible surface
Inside the human body, blood is compatible with the healthy
vascular endothelium. In contrast, outside the body, blood is not
compatible with artificial surfaces, including the materials that
line the blood pathway of extracorporeal circuits and the air found
in open reservoir systems.
The endothelium is a monolayer of cells that lines all blood vessels
and the heart. Complex biologic mechanisms within the vascular
endothelium maintain blood within the vessels without causing
thrombosis or clotting (coagulation). The healthy, uninjured
endothelium layer produces inhibitors of blood coagulation and
platelet aggregation.70 Vascular endothelium modulates vascular
tone and permeability and provides a protective envelope
that separates hemostatic blood components from reactive
subendothelial structures70 that could lead to platelet adhesion
and activation of the coagulation system. Endothelial cells are
highly negatively charged, a characteristic that may repel the
negatively charged platelets and be important in limiting the
hemostatic reaction.70
The endothelium plays an active biological role in maintaining
homeostasis, or a balance, among the various body defense
systems in a manner that provides a state of readiness and
simultaneously avoids the trigger of adverse responses.67,71 These
defense systems initiate hemostasis to maintain vessel integrity,
stimulate fibrinolysis to dispose of fibrin and consequently
dissolve clots, attack foreign bodies, activate the immune
systems, and perform other roles to maintain or restore the
balance among the defense systems.
Blood contact with artificial surfaces may trigger
an inflammatory response that can lead to
patient morbidity.
When foreign material comes in contact with a body tissue, the
body recognizes it as “foreign” and initiates an inflammatory
response. The general response that occurs when blood tissue
contacts an artificial material is depicted in Figure 4 .
The blood is a fluid tissue with a composition that includes
formed elements, such as platelets and various types of blood
cells (red blood cells or “erythrocytes;” white blood cells or
“leukocytes”), and unformed soluble elements, such as the
plasma proteins. During extracorporeal circulation, activation of
the blood’s formed and unformed elements, due to contact with
the circuit’s artificial surfaces, initiates a number of the biological
pathways and elements involved in the inflammatory response,
including the coagulation, fibrinolysis, kallikrein and complement
activation cascades as well as the cytokine proteins (Table 2).72, 73
Figure 4
Responses to Blood-Material Contact
Blood—Surface Contact
Protein adsorption onto surface
Protein alterations
Coagulation
Fibrinolysis
Kallikrein/Kinin
Complement
Cytokines
Cellular alterations
Platelets
Red blood cells
White blood cells
Systemic Inflammatory Response
Table 2
Biological Pathways Impacted by Blood-Material Contact
Coagulation system: responsible for forming blood clots at the site
of injury in order to control blood loss
Fibrinolytic system: dissolves a blood clot once the injury has
healed and the body no longer needs the blood clot, thereby
maintaining hemostasis
Kallikrein system: composed of a group of enzymes; reacts with other
elements of the coagulation, fibrinolytic and complement systems to
enable the body to maintain hemostasis
Complement system: closely related to the immune system; fights
infections and reacts to foreign objects
Cytokines: a diverse group of proteins produced by different types
of cells; play various roles, including the regulation and modulation of
immunologic and inflammatory processes72,74
Table 3
Blood Cell Types Impacted by Blood-Material Contact
Platelets: participate in the formation of blood clots
Red blood cells: transport oxygen and carbon dioxide through the
blood vessels between the lungs and tissues
White blood cells: participate in defense against foreign materials;
types of white blood cells include granulocytes (neutrophils,
eosinophils, basophils), monocytes and lymphocytes
Within seconds of blood exposure to these artificial, nonendothelial surfaces, there is rapid adsorption of proteins, such
as the coagulation protein fibrinogen, from the blood onto the
surface of the material.75 The final composition of this very thin
protein layer is specific for each type of material and is affected
by many factors, including the chemical and physical nature of
the material, the concentrations of various proteins in the blood
and the affinities of these proteins for a specific surface.71 For
example, hydrophilic, or “water loving” surfaces adsorb less blood
protein compared to hydrophobic, or “water hating,” surfaces;
hydrophilic protein adsorption is more readily reversible.67,68,69
5
Adsorption onto a surface may result in protein denaturation, such
as the denaturation of adsorbed fibrinogen,67 and lead to activation
of the plasma proteolytic systems. Subsequent events, including
cell adhesion, are mediated by the adsorbed protein layer.67
Table 4
Systemic Inflammatory Response Syndrome:
Potential Clinical Manifestations74,78
Following the general protein response, blood cells and other
specific protein groups in the blood that are associated with the
body’s defense systems may interact with the material and its
new protein layer67,71 (Tables 2 and 3).
• Organ dysfunction:
– Pulmonary
– Renal
– Gut
– Central nervous system
– Cardiac
Ultimately, the biological reactions associated with the defense
systems may affect the heart, lungs, brain and other organs,
causing conditions that have been described as the “postperfusion syndrome,”76 the “systemic inflammatory response
syndrome”77 (SIRS) or the “whole body inflammatory response.”75
Clinical manifestations of SIRS are highlighted in Table 4 .
End Point Attached heparin mimics critical
characteristics of the vascular endothelium.
Due to the vascular endothelium’s active role in maintaining the
checks and balances of the body’s defense systems, the harmful
biologic reactions that are generated during extracorporeal
circulation do not occur when normal blood circulates through
intact blood vessels lined by healthy endothelial cells.67,71
• Increased susceptibility to
infections
•Capillary permeability
– Transcapillary plasma loss
– Increased interstitial fluid
• Coagulation disorders
•Vasodilatation or
vasoconstriction
• Leukocytosis
• Hemodynamic instability
• Fever
Figure 5
Carmeda® BioActive Surface:
Impact on Surface Deposition of Blood Elements
Carmeda® BioActive
Surface Bonded
Heparan sulfate, a proteoglycan that is structurally and
functionally similar to the anticoagulant heparin, is naturally found
on the endothelial cell surface of the vascular wall.79 Its structure
consists of a central protein core to which polysaccharide chains
are bound.79,80
Heparan sulfate molecules are linked to endothelial cells in a
manner that exposes the polysaccharide chains, making the
chains highly accessible to protein molecules in the blood.79
Particular binding sequences on the heparan sulfate molecules
bind with proteins in the blood. 80 Heparan sulfate activates
plasma serine protease antithrombin (AT), a type of blood
protein, catalyzing the inhibition of thrombin and factor Xa,70,81
two other types of blood proteins, or enzymes, that play a role
in the blood coagulation process.
Uncoated
End Point Attached heparin mimics the orientation of the heparan
sulfate molecule on the vascular endothelium so the surfaceimmobilized heparin’s active sequence is exposed and available to
interact with blood elements. In other heparin bonding methods,
the active sequence often becomes part of the bond between
the heparin molecule and the surface, resulting in unavailability
of the active sequence for interactions with blood.
The evolution of heparin biosurfaces and the development of
End Point Attached heparin technology will be discussed in
greater detail in the following section. Specific information on
the manner in which Carmeda® BioActive Surface mimics critical
characteristics of the vascular endothelium can be found on page 9.
Scanning electron micrographs of oxygenator fiber surfaces after
one hour of in vitro circulation in a closed system using heparinized,
diluted human blood (100x magnification)
6
All heparin biosurfaces are not created equal:
the history of End Point Attached heparin.
Carmeda® BioActive Surface End Point Attached heparin was
developed to overcome the limitations of earlier heparin binding
methods, providing a durable heparin biosurface while preserving
the key structural and biological relationships of heparin essential
to its activity.
Heparin and heparin biosurfaces - background
Anticoagulation using unfractionated heparin has made
cardiopulmonary bypass possible since John Gibbon’s first
successful procedure more than five decades ago. The concept
of coating blood contact surfaces with heparin first originated
because of the molecule’s anticoagulant properties. Attempts
to heparinize surfaces eventually led to development of the End
Point Attached heparin method of bonding heparin to the inner
surface of extracorporeal circuits, as is used with Carmeda®
BioActive Surface.
Heparin is a polysaccharide that is naturally found in mast cells
of connective tissue.80 Although it has anticoagulant properties,
heparin is not naturally found in the circulation,79 unlike the
similarly structured heparan sulfate molecules attached to
endothelial cells lining the vascular walls. Commercial heparin
preparations are isolated from animal tissues such as porcine
intestinal mucosa.
Heparin’s anticoagulant effect is attributed to its ability to bind
to antithrombin (AT),82 a protease inhibitor found in the plasma.
AT inactivates thrombin and enzymes responsible for the generation
of thrombin. 83 When heparin binds to AT, the AT molecule
configuration is altered, increasing the rate of enzyme-inhibitor
complex formation by a factor of 1,000 or more. 84 The enzymeinhibitor complex then detaches from the heparin molecule,
leaving the heparin molecule available to interact with another
AT molecule.79 Heparin is not consumed in this process, but rather
acts as a catalyst.79
Heparin biosurfaces for extracorporeal circulation have evolved
using three basic types of heparin attachment:
•Ionic bonding
Ionically bonded heparin:
an early attempt at heparin immobilization
Ionic bonding processes were developed during earlier attempts
at surface immobilization of heparin. An ionic bond is an electrical
attraction between two oppositely charged atoms. The formation
of an ionic bond requires that one substance give up electrons
to the other substance, leaving one negatively-charged and one
positively-charged ion. In the case of heparin coating and the
cardiopulmonary bypass (CPB) circuit surface, the CPB circuit
surface gives up electrons to the coating and the two attract
to form an ionic bond (Figure 6).
The ionic bond leaves the anticoagulant active sequence of
the heparin free. However, an ionic bond, because it is between
two essentially unstable ions, is not very stable, and the coating
tends to wash off when blood flows through the CPB circuit. 85
Later methods of ionic bonding attempted to stabilize the
relatively weak bond of ionically bound heparin biosurfaces by
using surfactants or by incorporating crosslinking reagents such
as glutaraldehyde. While this combination was better, leaching
continued to be an issue when the coating came into contact
with blood, because proteins such as albumin break the ionic
bond, releasing heparin into the bloodstream. Heparin leaching
can result in increased levels of circulating heparin in the systemic
circulation. Also, heparin leached into the blood is no longer
available on the device surface to provide thromboresistance
and biocompatibility.
Figure 6
Ionically Bonded Heparin: a Schematic
Ionically bonded heparin is less stable and tends to wash off when
blood flows through the CPB Circuit.
•Covalent bonding
•End Point Attachment
7
Covalently bonded heparin: improved stability but
limited bioavailability of immobilized heparin
Covalent bonding techniques were later developed to overcome
limitations of ionic bonding, such as instability and heparin
leaching. A covalent bond is created when two atoms share
one or more pairs of bonding electrons. Each atom donates
the electrons for one half of the pair(s).
Atoms in covalent bonds are more stable than ionic bonds.
Covalent bonds are therefore stronger than ionic bonds and
prevent heparin leaching from the coating on CPB surfaces.
An issue with most covalent bonding processes is that the
orientation of the heparin molecule is not controlled. Consequently,
the heparin molecule’s anticoagulant active sequence may
become part of the bond between the heparin molecule and
the surface, therefore becoming unavailable to interact with the
blood circulating through the CPB circuit (Figure 7). In addition,
the heparin’s chain conformation may become restricted so
that it cannot attain the proper conformation required to bond
with blood proteins. The End Point Attached method of heparin
bonding was subsequently developed to address this issue.
Figure 7
Covalently Linked Heparin: a Schematic
Covalent bonds are more stable but the heparin’s anticoagulant
active sequence may become involved in the bond and therefore
unavailable to interact with blood.
Figure 8
End Point Attached Heparin: a Schematic
End Point Attached heparin: a breakthrough
in bioavailability and durability of surface
immobilized heparin
As heparin surface immobilization technology evolved, the
importance of preserving specific binding sites on the heparin
complex and keeping the sites available to achieve maximum
reactivity became evident. For example, it became known that
the active binding site on heparin for binding antithrombin
is a specific sequence of five saccharide residues.
Larm et al. 86 first described a method of attaching heparin
in which reactive aldehyde groups on heparin molecules were
covalently bonded to amine groups on a prepared material surface.
With this process, the aldehyde group on each heparin molecule
is covalently bound to the prepared artificial surface (End Point
Attached) and the remainder of the molecule, including the
active binding sequence, is free to interact with the blood and
not involved in the surface attachment mechanism (Figure 8).
This leaves the active binding sequences available for biological
reactions during extracorporeal circulation. Because its End Point
Attachment technique incorporatesa covalent bond, the heparin
surface immobilization in Carmeda® BioActive Surface is stable,
durable and does not wash off during extracorporeal circulation.
End Point Attached heparin bonding technology provides a surface
that is “bioactive” (Table 5) to reduce coagulation and inflammation
responses due to the blood-material surface interaction described
on pages 5-6. It mimics critical characteristics of the vascular
endothelium and its active role, discussed in greater detail
beginning on page 9.
Medtronic has exclusive licenses to Carmeda®
BioActive Surface Endpoint Attached heparin
technology for extracorporeal circulation applications.
Medtronic has exclusive licenses for use of Carmeda® BioActive
Surfaces for extracorporeal membrane oxygenation systems
and additional license rights to certain other applications from
Carmeda® AB, Sweden (www.carmeda.com), the developer of
Carmeda® BioActive Surface.
Carmeda® BioActive Surface also has an extensive history of use
across several additional medical applications** offered by other
manufacturers, including vascular grafts, ventricular assist devices,
stents, intraocular lenses and diagnostic devices.87
** Note: Certain device applications may not be available in the United States.
8
The End Point Attached heparin bonding process uses a stable covalent
bond and orients the heparin molecule so that its anticoagulant active
sequence is free to participate in biological interactions with the blood.
Table 5
“Bioactive” Surfaces: a Definition
Surfaces that “are intended to actively support natural control
mechanisms in order to prevent unwanted and uncontrolled responses
of the host to the foreign material.”79
Mimicking critical characteristics of
the vascular endothelium with
The durable, non-leaching, covalent bonding process
results in thromboresistance and biocompatibility
throughout the extracorporeal circulation procedure.
Carmeda® BioActive Surface provides thromboresistance and
biocompatibility for the blood-contacting surfaces of extracorporeal
circulation circuits to address the foreign body response that
is initiated when blood comes in contact with non-endothelial
surfaces. Its End Point Attached heparin technology mimics critical
characteristics of the vascular endothelium and its active role.
• The covalent bonds of the End Point Attached heparin bonding
process include a shared electron of the heparin biosurface and
a shared electron of the device material (Figure 9).
Heparin’s antithrombin (AT) binding sequence is
critical for biological interactions with the blood.
• Heparin is a heterogeneous, heavily sulfated polysaccharide
compound that is more specifically described as a
glycosaminoglycan.79,82 The AT binding sequence, a
pentasaccharide consisting of five sugar residues of exactly
defined structure within the heparin molecule, is required
for interaction between the heparin molecule and the plasma
protease inhibitor antithrombin.79
• This AT binding sequence is present only in approximately
one out of three unbound heparin molecules and accounts
for essentially all of the anticoagulant activity of heparin. 88
• A covalent bond is created when two atoms share one or more
pairs of bonding electrons.
• The Carmeda® BioActive Surface covalent bonds are strong
and stable, resulting in a heparin biosurface that does not wash
off during extracorporeal circulation.46,51,85,86 This ensures that
End Point Attached heparin molecules are available to provide
thromboresistance and biocompatibility throughout the
extracorporeal procedure.
Figure 9
Orientation of Heparan Sulfate and End Point Attached
Heparin (Carmeda® BioActive Surface): Schematics
Heparan Sulfate
Molecule
• Heparin binding to antithrombin results in approximately a
1,000-fold acceleration of enzyme-inhibitor complex formation.84
• In addition to thrombin inactivation, antithrombin has also
been found to inactivate other hemostatic enzymes of the
intrinsic coagulation cascade, including factors IXa, Xa, XIa and
XIIa.84,89,90,91,92 Heparin accelerates each of these proteaseprotease inhibitor reactions.84
Polysaccharide Chains
Endothelial
Membrane
End Point Attached
Heparin Molecule
Carmeda® BioActive Surface heparin preserves this
important AT binding sequence.
• The special preparation of heparin for the End Point Attached
bonding process preserves the high affinity binding site. It is
present in one out of four Carmeda® BioActive Surface heparin
molecules93 and therefore available for biological interactions
with the blood.
By orienting heparin molecules and preserving active
sites, End Point Attached heparin is able to participate
in biological reactions with the blood, similar to
heparan sulfate on the vascular endothelium.
• Heparan sulfate’s structure consists of a central protein
core to which polysaccharide chains are bound.79,80 Heparan
sulfate chains are linked to the endothelial cells in a manner
that exposes the chains so they are highly accessible to the
molecules in the blood.79 Like heparin, a particular area of
heparan sulfate, called the antithrombin binding sequence,
interacts with the blood.79
• Carmeda® BioActive Surface End Point Attached heparin
molecules are oriented to the blood in a manner similar to that
of heparan sulfate on the vascular endothelium (Figure 9).
The heparin molecules protrude into the blood in a manner that
allows their AT binding sequences to interact with the blood.
End Point Attached heparin is oriented in the same manner as
heparan sulfate on the cell membrane of vascular endothelial cells.
This orientation ensures that the molecules’ AT binding sequences
are exposed to the blood elements. Other heparin-binding methods
are limited because the AT binding sequences may become part
of the bond itself, resulting in their unavailability to interact with
blood elements.
Carmeda® BioActive Surface mimics additional
characteristics of the vascular endothelium.
• Negative charge. Similar to the vascular endothelium, Carmeda®
BioActive Surface is negatively charged due to the negative
charge of its heparin molecules.
• Hydrophilicity. Heparin is a hydrophilic, or water-attracting,
molecule. Heparin molecules provide Carmeda® BioActive
Surface with hydrophilic characteristics, as does the biosurface’s
hydrophilic priming layer.
• A limitation of other types of heparin binding processes is that
this important AT-binding sequence may become part of the
bond between the heparin molecule and the device surface,
preventing the AT-binding sequence from interacting with
the blood.
9
Theory of function of
By orienting heparin molecules and preserving active
sites, End Point Attached heparin is able to interact
with blood.
Figure 10
Theory of Function: End Point Attached HeparinAntithrombin-Coagulation Factor Binding
The End Point Attached heparin
bonding method preserves the active
sequence of immobilized heparin so it
can interact with the blood elements,
including antithrombin (AT).
• One of the best known roles of heparin is binding with
antithrombin (AT), a normal physiological inhibitor of the
coagulation cascade (Figure 10A).
• Not only is AT a well known inhibitor of thrombin, it also inhibits
other hemostatic enzymes of the intrinsic coagulation cascade,
including factors IXa, Xa, XIa and XIIa.84,89,90,91,92
• Antithrombin in the blood can inhibit coagulation factors
without heparin, but at relatively slow rates. When AT binds to
heparin at its active site, it increases its affinity for coagulation
factors in the coagulation cascade by at least one thousand
times84 (Figure 10B).
• Attachment of the activated coagulation factor to AT forms
harmless inactive complexes, which are no longer available
to participate in or trigger other events in the coagulation
cascade (Figure 10C).
Reconformation
1,000X increase
in reaction rate
• Inactive AT coagulation factor complexes are then released
from the immobilized heparin and swept away from the site
by flowing blood (Figure 10D).
When heparin binds to AT, the nature
of AT changes. The resulting
heparin-AT complex has a much
higher affinity for coagulation factors
than AT alone. The rate at which
the heparin-AT complex increases
its affinity for coagulation factors
is 1,000 times faster than AT alone.
For example, the coagulation factor
thrombin (Factor II) in the blood
flowing through the circuit binds to
the heparin-AT complex and becomes
inactivated (Factor IIa).
• The End Point Attached heparin molecule is not consumed
in this reaction and remains on the surface, available to repeat
this cycle (Figure 10E).
Like vascular endothelium, End Point Attached heparin
inhibits Factor XII at the initiation, or “contact phase,”
of the coagulation cascade.
•Carmeda® BioActive Surface’s high affinity heparin binds
Factor XII and inhibits its conversion to activated Factor XIIa47
(Figure 11).
•End Point Attached heparin mediates inhibition of the coagulation
cascade prior to prothrombin activation, as suggested by
research finding no clotting and no measurable amounts of
thrombin-antithrombin complex (TAT) in closed test loops
of End Point Attached heparin bonded tubing circulating
recalcified blood plasma. 56
TAT
Inactive
Complex
•Experiments with endothelial lining in segments of harvested
human saphenous vein demonstrated binding of FXII and
inhibition of its activated form in the presence of AT.94
Similar to naturally occurring heparan
sulfate on the vascular endothelium,
the immobilized heparin molecule
is not consumed by this cycle and
remains bonded intact to the material
surface. Its anticoagulant active
sequence is then free to attach
to another AT molecule.
Inhibiting the coagulation cascade at its start may
have a more profound effect on thrombus formation
than inhibiting factors toward the cascade’s end by
mitigating the amplifying effect of the coagulation
cascade.
• FXII adsorption, activation and almost instantaneous AT binding
occur on End Point Attached heparin, resulting in rapid
inhibition of a-FXIIa by the AT bound to the surface. This has
been found to prevent formation of kallikrein and b-FXIIa,
which subsequently prevents feedback triggering of FXII and
activation of adsorbed FXI.95
• Inhibiting Factor XII is a more efficient means of preventing
thrombus than inhibiting thrombin after the amplifying effect
has greatly increased Factor XII concentration.
10
The thrombin-AT complex detaches
from the heparin molecule and
continues to flow through the circuit.
This complex is eventually metabolized
by the body.
E
Legend
• Reduced thrombogenicity has been demonstrated with
Carmeda® BioActive Surface bonded extracorporeal circulation
circuits52 (Figure 12).
• In addition to activation of the intrinsic coagulation system
(Figure 13), the plasma contact activation system is involved
with triggering other enzymatic systems such as the fibrinolytic,
complement and kallikrein/kinin systems79 (Figure 14). The
angiotensin/renin systems are also affected.79
• Inhibition of Factor XII therefore not only inhibits thrombus
formation, it also inhibits other body defense systems. This
helps explain how Carmeda® BioActive Surface may improve
the broader mechanism of overall biocompatibility, which
ultimately may reduce the whole body inflammatory response.
Like systemically administrated heparin, End Point
Attached heparin inactivates thrombin and Factor Xa
in the presence of AT.
• End Point Attached heparin inactivates thrombin and Factor Xa
in the presence of AT. 56,96
• Similar to systemic heparin, End Point Attached heparin’s
inhibitory capacity is not observed in the absence of AT. 56
Figure 11
Inhibition of Factor XIIa on
High-Affinity Heparinized Surfaces47
2–
Factor XII
N=6
Factor XIIa
N=6
Delta A 405 nm
1.5 –
Figure 12
Carmeda® BioActive Surface Reduces Thrombogenicity
of the Extracorporeal Circuit: Ex vivo Experiment52
16 –
Fibrinopeptide A (nM)
Inhibition of Factor XII not only inhibits thrombosis,
it inhibits other body defense systems.
Uncoated Circuit 1
Uncoated Circuit 2
CBAS bonded Circuit 1
CBAS bonded Circuit 2
12 –
Uncoated:
Heparin
disappeared
8–
4–
CBAS: Heparin disappeared
0–
Pre10 30
operative
Heparin
administered
60
90 120 150 180 210 240 270 300 330 360
Time (minutes)
• The thromboresistance of Carmeda® BioActive Surface (CBAS)
applied to the entire extracorporeal circuit during 6 hours of
extracorporeal support was studied in an ex vivo experiment with
calves undergoing partial bypass (flow rate 2 l/min) receiving either
a CBAS bonded circuit (n=2) or an uncoated circuit (n=2).
• Animals received only one bolus injection of heparin (250 IU/kg)
before cannulation with no further heparin administered.
• Findings:
–Uncoated group: Heparin activity disappeared at 250 minutes of
bypass. Plasma fibrinopeptide A (FPA) levels started increasing
after 60 min and continued to increase to 9 nM at which point
the experiments were terminated at 255 minutes because the
oxygenator was occluded with fibrin clots. Lung tissue biopsy
indicated that most of the blood vessels in the sample were
partially or completely occluded with fibrin. An accumulation of
neutrophils was noted.
– CBAS group: Heparin activity disappeared at 180 minutes.
FPA levels started to increase at a runtime of 150 minutes and
reached 4.5 nM at the scheduled termination of the experiment,
360 minutes. Lung tissue biopsy showed no fibrin deposition.
An accumulation of neutrophils was found.
• Findings suggest that Carmeda® BioActive Surface bonding greatly
reduced the thrombogenicity of the extracorporeal circulation circuit.
1–
Figure 13
Plasma Coagulation Pathways
.5 –
Intrinsic Pathway
(Contact Activation)
0–
High Affinity Heparin (CBAS)
Low Affinity Heparin
Tissue Factor + VII
XII
XIIa
Mean surface adsorbed Factor XII and Factor XIIa on tubing samples
bonded with 1.) End Point Attached heparin, including both high and
low affinity molecules or 2.) End Point Attached heparin containing
low affinity molecules only. Samples were incubated in vitro with
200 ml normal citrated human plasma. (Y-axis represents adsorbance
units after 5 minutes incubation with a chromogenic substrate).
•Both heparin surfaces similarly adsorbed FXII from plasma but
on the low affinity heparin surface, a major portion of surfacebound FXII was recovered in its enzymatically active form FXIIa.
In contrast, only trace amounts of FXIIa were recovered from
the surfaces bonded with both high and low affinity heparin.
•Surface-associated enzymatic activity was not detected when
FXII-deficient plasma was used in experiments.
•Conversion of FXII to FXIIa was not prevented when standard
heparin or low molecular weight heparin was added to the plasma.
•Findings suggest that high affinity heparin applied using the End
Point Attached bonding method:
– Binds Factor XII
– Prevents Factor XII from becoming activated (FXIIa)
Extrinsic Pathway
(Tissue Factor Pathway)
XI
HMWK
IX
TF - VIIa
PL
Common Pathway
X
XIa
IXa
II (Prothrombin)
PL
VIIIa
Xa
PL
Va
Thrombin
(IIa)
Fibrinogen
Fibrin
Clot
Carmeda® BioActive Surface’s beneficial impact is associated with
reduced activation of the coagulation system’s intrinsic, or “contact
activation,” pathway. Measures to reduce activation of both the
intrinsic and extrinsic pathways are considered in comprehensive
strategies to reduce CPB-related morbidity.
• The intrinsic pathway is activated when blood comes into contact
with a non-endothelial surface.
• Extrinsic pathway activation occurs when tissue factor is released
into the circulation from damaged tissue.
• For each pathway, a series of reactions occurs that result in the
activation of Factor X.
• The intrinsic and extrinsic pathways converge with the activation
of Factor X and form a common pathway. Additional reactions
occur that result in the formation of thrombin, which then cleaves
fibrinogen to form fibrin, resulting in clot formation.
11
Unlike the response to systemically administered
heparin, thrombin inactivation by End Point Attached
heparin occurs at the device surface and not
in the bulk of the blood circulating through the
extracorporeal circuit.
• Thromboresistant properties of End Point Attached heparin
depend, in part, on the inhibition of initially formed trace
amounts of locally produced thrombin that are necessary
for propagation of the blood coagulation process. 97
• While End Point Attached heparin inhibits the initial contact
activation enzymes through antithrombin-mediated mechanisms,
heparin in solution does not have this beneficial effect on
contact activation. 98
• Contribution of End Point Attached heparin to neutralization
of fluid phase thrombin has been found to be negligible.97
Both high- and low-affinity heparin molecules play a
role in End Point Attached heparin’s inhibitory function.
Figure 15
Complement Activation Pathways
Classical Pathway
Alternative Pathway
Blood exposure to Blood exposure to
antigen/antibody complex
foreign surface
C1C3b (uncleaved)
C2
C4
C3 cleavage
Terminal pathway
C3
C5
C6
C7
C8
C9
Terminal Complement Complex (TCC)
Lysis
• The density of AT on both the high and low affinity heparin
molecules determines the Factor Xa inhibition capacity.93
Several published studies report that Carmeda® BioActive Surface
reduces complement activation.
• The amount of AT on high affinity heparin sites limits the
rate of Factor Xa inhibition.93
•The alternative pathway for complement is most affected by
extracorporeal circulation.
• These findings suggest that during the inhibition of Factor Xa,
there is continuous surface diffusion of AT from low affinity
sites to high affinity sites.93
• Complement activation during extracorporeal circulation is
associated with inflammation that can negatively impact
clinical outcomes.
Improved complement compatibility is associated
with End Point Attached heparin.
Reduced leukocyte activation is found with End Point
Attached heparin bonded surfaces.
• Blood exposure to artificial circuits results in activation of the
complement system (Figure 15), mainly through the alternative
pathway.77 Complement system activation plays a role in the
inflammatory response67 and is associated with CPB patient
morbidity.99
• Leukocytes play a role in the inflammatory response and
may become activated with exposure to artificial surfaces.67,73
Leukocyte activation occurs by a number of pathways,
including the complement cascade and the contact system.105
• End Point Attached heparin has been found to reduce
complement activation in both clinical4,5,39,58,63,64,100,101
and laboratory51,54,102,103,104 studies.
Figure 14
Impact of Carmeda® BioActive Surface on the
Human Body Defense Systems
• End Point Attached heparin has been found to reduce
activation of leukocytes in clinical and laboratory investigations,
including granulocytes, 51,54,55,62,103,106,107,108,109,110 such as
neutrophils,4,38,42,61,63,64,111,112 eosinophils113 and monocytes.103,114
End Point Attached heparin bonded surfaces are
platelet-friendly, with improved platelet preservation
and less platelet activation.
• Platelet activation during extracorporeal circulation is caused by
platelet interaction with thrombin, contact with non-endothelial
surfaces and contact with platelet-activating factor produced
by a variety of cells.71 Increased postoperative bleeding times
are associated with loss of platelet numbers and function.71
• Better platelet count preservation and reduced platelet activation
have been demonstrated in clinical and laboratory investigations
of End Point Attached heparin surfaces. 34,40,42,51,54,55,65,115,116
Reduced platelet adhesion has also been noted.117,118
Research indicates mitigating effects by Carmeda® BioActive Surface
A simplified diagram of the human body defense systems affected by
extracorporeal circulation of the blood shows the extensive relationships
and cross-activations between them and the general areas where
published research indicates Carmeda® BioActive Surface has influence.
12
Figure 16
Hemocompatibility of Carmeda® BioActive Surface:51
Comparison of Soluble and Surface Adsorbed Markers of Hemocompatibility
Complement System
Coagulation System
Terminal Complement Complex (soluble marker)
Significantly less terminal
ng/ml
2100 –
complement complex
1800 –
formation occurred with
1500 –
Carmeda® BioActive
1200 –
Surface bonding, indicating
900 –
less complement activation.
Prothrombin Fragment 1+2 (soluble marker)
600 –
(p <0.05)
300 –
7–
6–
5–
4–
3–
2–
(p <0.01)
1–
0–
0–
control
CBAS-bonded
control
60 min
120 min
Mean ± SD (n = 7)
Non-coated
CBAS-bonded
C3-Complement (surface adsorbed marker)
O.D.405nm
1.2 –
1.0 –
0.8 –
0.6 –
0.4 –
0.2 –
0.0 –
Less coagulation activation
occurred with Carmeda®
BioActive Surface bonding,
suggested by significantly
lower prothrombin
fragment F1+2 levels.
nmol/l
8–
control
5’
CBAS-bonded
15’
30’
60’
Mean ± SD (n = 4)
Non-coated
120’
60 min
120 min
Mean ± SD (n = 7)
Non-coated
Fibrinogen (surface adsorbed marker)
Significantly reduced
complement activation
occurred with End Point
Attached heparin,
suggested by reduced
surface adsorption of
complement protein C3 on
the Carmeda® BioActive
Surface bonded samples.
O.D.405nm
2.0 –
1.6 –
1.2 –
0.8 –
0.4 –
0.0 –
control
(p <0.01)
Neutrophils
5’
CBAS-bonded
15’
30’
60’
Mean ± SD (n = 4)
Non-coated
120’
Platelets
b-Thromboglobulin (soluble marker)
PMN-elastase-alpha 1-PI (soluble marker)
The Carmeda® BioActive
Surface group had
significantly lower PMNelastase release, indicating
less neutrophil activation.
(ng/ml)
160 –
120 –
80 –
(p <0.05)
40 –
>J$ba
(%%%Ä
'*%%Ä
'%%%Ä
&*%%Ä
&%%%Ä
*%%Ä
%#%Ä
0–
control
CBAS-bonded
Significantly lower
adsorption of fibrinogen
on the Carmeda® BioActive
Surface bonded surfaces
occurred, compared to
uncoated surfaces, also
provided evidence of
reduced thrombogenicity
with End Point Attached
heparin.
(p <0.01)
Xdcigda
60 min
120 min
Mean ± SD (n = 7)
Non-coated
876H"WdcYZY
+%b^c
&'%b^c
BZVc¥H9c2,
Cdc"XdViZY
Levels of bTG were five
times greater in the
uncoated samples compared
to the Carmeda® BioActive
Surface bonded samples,
suggesting less platelet
activation with use of End
Point Attached heparin
surfaces.
(p <0.01)
Kallikrein System
High-molecular-weight-kininogen (surface adsorbed marker)
Improved hemocompatibility,
suggested by significantly
greater surface adsorption
of the contact factor
high-molecular-weight
Kininogen (HMWK), was
found with Carmeda®
BioActive Surface bonding.
O.D.405nm
1.2 –
0.9 –
0.6 –
0.3 –
0.0 –
control
5’
15’
30’
60’
Mean ± SD (n = 4)
CBAS-bonded
Non-coated
120’
(p <0.05)
Fibronectin (surface adsorbed marker)
Reduced thrombogenicity
on Carmeda® BioActive
Surface bonded surfaces
was suggested by
significantly lower
adsorption of the plasma
protein fibronectin.
O.D.405nm
1.0 –
0.8 –
0.6 –
0.4 –
0.2 –
0.0 –
(p <0.01)
control
5’
CBAS-bonded
15’
30’
60’
Mean ± SD (n = 4)
Non-coated
120’
Cytokines
Interleukin 1-b (soluble marker)
Blood cell secretion of the
pro-inflammatory cytokine
IL-1b was significantly
reduced in the Carmeda®
BioActive Surface samples.
pg/ml
3.0 –
2.5 –
2.0 –
1.5 –
(p <0.01)
1.0 –
0.5 –
0.0 –
control
CBAS-bonded
Mean ± SD (n = 5)
Comparison of soluble markers and surface adsorbed markers
of blood activation measured in samples taken from Carmeda®
BioActive Surface bonded and uncoated test loops through which
heparinized human whole blood was circulated for up to 120 minutes.
Carmeda® BioActive Surface (CBAS) was found to favorably alter
the composition of surface adsorbed proteins and was also
associated with a reduction in complement, coagulation, neutrophil
and platelet activation (Weber N. Biomaterials 2002; 23:429-439).
120 min
Non-coated
13
End Point Attached heparin bonding process:
an overview
Heparin bonding is carefully performed to provide the unique
features of Carmeda® BioActive Surface that are important to
its biological role:
1.) Heparin is covalently bonded, preventing its release, or
“leaching,” from the surface
2.)The End Point Attachment bonding process allows the
polymeric molecules of heparin to achieve conformations
necessary for their anticoagulant function so they can
perform in a predictable and reliable manner.
Sophisticated End Point Attached heparin
bonding process
Prime coat
• Alternating layers of high molecular weight ionic polymers
polyethyleneimine (PEI) and dextran sulfate are deposited on
the device surface via electrostatic adsorption. This provides
a consistent substrate that allows the Carmeda® BioActive
Surface to be applied to a variety of device materials, including
plastics and metals.
• Uncrosslinked polyethyleneimine is laid over the prime coat
via electrostatic aqueous adsorption. It tenaciously attaches
to the artificial surface and provides a large number of amine
binding sites for covalent attachment of heparin.
• Heparin isolated from porcine mucosa is prepared for End
Point Attachment by controlled and selective cleavage of
the molecules, giving rise to formation of chemically reactive
aldehyde groups. The aldehyde groups are located at the
reducing terminus of the heparin molecules, thereby preserving
the heparin molecule’s biologically active structures.
• At this point, the heparin is covalently bound to the artificial
surface on one end via the polyethyleneimine layer. The other
end is in a sterically “free” state so that it is “available” to
interact with the antithrombin in the circulating blood. The
surface immobilization of heparin by End Point Attachment
through a covalent bond allows maximum exposure of the
blood elements to its anticoagulant active sequence.
Aqueous, solvent-free manufacturing methods
The Carmeda® BioActive Surface process uses aqueous solutions,
mild pH and moderate temperatures. No organic solvents are
involved. Coating processes are designed and controlled to ensure
that coated devices are uncompromised in meeting their
established performance standards.
Table 6
Heparin Stability and Activity Assessment
Medtronic uses two tests during manufacturing to verify both the
stability and activity of the Carmeda® BioActive Surface heparin
bonding process.
Qualitative testing
A heparin-sensitive O-toluidine blue dye is flushed through treated
devices to qualitatively assess the uniformity of the heparin bonding
process. When the blue dye is picked up by the heparin, it turns a
distinctive purple color, indicating heparin on the surface.
Quantitative testing
A quantitative assay is performed in which human thrombin and
antithrombin are used to measure the units of thrombin inhibited per
square centimeter of the surface area treated. This test, performed
using a spectrophotometer to measure thrombin, can
be used as a direct measure of heparin activity.
• The prepared heparin with its aldehyde end-groups is reacted
with the primary amino groups on the prepared surface to
form a Schiff’s base which undergoes chemical reduction,
converting to a stable covalent bond.
Figure 17
End Point Attached Heparin Bonding Process
End Point Attached
NAD heparin
Adsorbed alternating
cationic/anionic base
coating for later
heparin coupling
The device surface is first pre-treated with alternating layers of polyethyleneimine and dextran
sulfate to provide an exposed, or available, amine group. Commercial heparin derived from porcine
mucosa is specifically prepared to form chemically reactive aldehyde groups at the heparin molecule’s
reducing terminus. The heparin’s aldehyde groups react with the base layer’s amine groups to form
a covalent bond, linking end-to-end, allowing maximum exposure of the heparin’s anticoagulant
active sequence to the blood pathway.
14
Pediatric patients to adults: Carmeda®
BioActive Surface’s broad clinical applications
For pediatric patients to adults, Carmeda® BioActive Surface
is an important component of life-saving and life-enhancing
procedures performed using extracorporeal circulation.
Its non-leaching, durable End Point Attached heparin provides
thromboresistance and biocompatibility during routine as well
as complex procedures.
Table 7
Medtronic Extracorporeal Circulation Technologies
Available with Carmeda® BioActive Surface
•Oxygenators
•Resting Heart® System
•Centrifugal blood pumps
•Custom tubing sets
•Cardioplegia delivery systems •Closed chest support system
•Arterial filters
• Hemodynamic support system
•Reservoirs
•Cannulae
•Flow probes
•Cannulae adapters
•O2 saturation cells
15
Can extracorporeal circulation be improved?
Clinical and scientific evidence on the impact
of Carmeda® BioActive Surface
Figure 18
Carmeda® BioActive Surface’s Role
During Extracorporeal Circulation
Numerous clinical and scientific studies highlight the favorable
impact of Carmeda® BioActive Surface on interactions between
blood and artificial surfaces of extracorporeal circuits as well as
its associated benefits for improved clinical outcomes (Table 8).
Due to this extensive body of evidence, leading clinical teams
around the world incorporate Carmeda® BioActive Surface into
their comprehensive strategies for improving extracorporeal
circulation procedure outcomes.
Carmeda® BioActive Surface was developed to minimize one
contributor to extracorporeal circulation-related morbidity:
the activation of blood when it comes in contact with artificial
materials that line extracorporeal circuits. However, it does not
mitigate the effects of other potential sources of extracorporeal
circulation-related morbidity, such as the return of unprocessed
cardiotomy suction blood directly to a pump. Differences in
reported efficacy and associated clinical outcomes for heparin
bonded circuits may be due to variations in cardiopulmonary
bypass techniques.20
Carmeda® BioActive Surface: Bibliography of published
clinical and scientific studies on End Point Attached
heparin technology
Carmeda® BioActive Surface is used in comprehensive strategies for
reducing CPB-related morbidity by providing thromboresistance and
biocompatibility where blood comes in contact with artificial surfaces.
Table 8
Clinical and Scientific Findings:
Experimental in vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Carmeda® BioActive Surface is the most extensively researched
biosurface for today’s extracorporeal circulation technologies, with
extensive publication of clinical and scientific evidence in peerreviewed cardiovascular surgery, perfusion and scientific literature,
including:
• Less blood product use1,2,3,29,30,31,32
Experimental in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
• Less perioperative blood loss 6,30,31,32,33,34,35,36
Adult clinical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
• Shorter ventilator time2,31,33,37,38 and reduced post-operative
peak airway pressures39
Pediatric clinical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
• Shorter ICU3,4 and hospital2,3,33 length of stay
• Less postoperative body temperature rise33,40
• Fewer postoperative neurocognitive deficits5,33,41
• Significantly greater urine output during CPB31,37
• Lower costs, as related to improved clinical outcomes3
•
Less negative impact on the body’s defense systems, including the:
– Contact system42,43,44,45,46,47
– Coagulation system5,35,43,48,49,50,51,52,53,54,55,56
– Fibrinolytic system4,31,48,57,58
– Complement system4,5,34,36,38,39,50,54,59,60,61,62,63,64
– Cytokine proteins4,38,39,51,60,64
• Reduced impact on the blood’s formed elements, including:
– Platelets34,43,51,54,55,62,64,65
– Red blood cells31,35,46,50,57,66
– Leukocytes4,38,46,51,54,55,61,62,63
16
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These published clinical and scientific studies on End Point
Attached heparin technology report findings from controlled in
vitro and in vivo experiments as well as from clinical studies on
the use of Carmeda® BioActive Surface bonded circuits during
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17
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18
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heparin-coated circuits. Thorac Cardiovasc Surg. 1997;45(4):163-167.
19
Gott JP, Cooper WA, Schmidt FE, Jr., Brown WM, III, Wright CE,
Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk
for extracorporeal circulation: trial of four anti-inflammatory
strategies. Ann Thorac Surg. 1998;66(3):747-753.
Ljunghusen O, Cederholm I, Lundahl J, Nilsson B, Olin C, Sjogren F,
Stendahl. Phenotypic alterations in circulating monocytes induced
by open heart surgery using heparinized and nonheparinized
cardiopulmonary bypass systems. Artif Organs. 1997;21(10):1091-1097.
Lundblad R, Moen O, Fosse E. Endothelin-1 and neutrophil activation
during heparin-coated cardiopulmonary bypass. Ann Thorac Surg.
1997;63(5):1361-1367.
Mahoney CB. Heparin-bonded circuits: clinical outcomes and costs.
Perfusion. 1998;13(3):192-204.
Misoph M, Babin-Ebell J, Schwender S. A comparative evaluation
of the effect of pump type and heparin-coated surfaces on
platelets during cardiopulmonary bypass. Thorac Cardiovasc Surg.
1997;45(6):302-306.
Misoph M, Schwender S, Babin-Ebell J. Response of the cellular
immune system to cardiopulmonary bypass is independent of the
applied pump type and of the use of heparin-coated surfaces.
Thorac Cardiovasc Surg. 1998;46(4):222-227.
Rao SK, Palazzo RS, Metz HN et al. Redox potential measurements
of plasma in patients undergoing coronary artery bypass graft and
its clinical significance. J Pharmacol Toxicol Methods. 1997;38(3):151-156.
Spiess BD, Vocelka C, Cochran RP, Soltow L, Chandler WL. Heparincoated bypass circuits (Carmeda) suppress the release of tissue
plasminogen activator during normothermic coronary artery bypass
graft surgery. J Cardiothorac Vasc Anesth. 1998;12(3):299-304.
Svenmarker S, Sandstrom E, Karlsson T, Jansson E, Haggmark S,
Lindholm R, Appelblad M, Aberg T. Clinical effects of the heparin
coated surface in cardiopulmonary bypass. Eur J Cardiothorac Surg.
1997;11(5):957-964.
Gorman RC, Ziats N, Rao AK, Gikakis N, Ling S, Khan MMH,
Stenach N, Suneeti S, Vibhuti C, Gormann JH, Niewiarowshi S,
Colman RW, Anderson JM, Edmunds LH, Khuri SF, Magovern GJ,
Hill RC, von Segesser LK. Surface-bound heparin fails to reduce
thrombin formation during clinical cardiopulmonary bypass. J Thorac
Cardiovasc Surg. 1996;111(1):1-11.
Moen O, Fosse E, Brockmeier V, Andersson C, Mollnes TE,
Hogasen K, Venge P. Disparity in blood activation by two different
heparin-coated cardiopulmonary bypass systems. Ann Thorac Surg.
1995;60(5):1317-1323.
Moen O, Fosse E, Dregelid E, Brockmeier V, Andersson C, Hogasen K,
Venge P, Mollnes TE, Kierulf P. Centrifugal pump and heparin
coating improves cardiopulmonary bypass biocompatibility. Ann
Thorac Surg. 1996;62(4):1134-1140.
Nilsson L, Peterson C, Venge P, Borowiec JW, Thelin S. Eosinophil
granule proteins in cardiopulmonary bypass with and without
heparin coating. Ann Thorac Surg. 1995;59(3):713-716.
Ovrum E, Brosstad F, Am HE, Tangen G, Abdelnoor M, Oystese R.
Complete heparin-coated (CBAS) cardiopulmonary bypass and
reduced systemic heparin dose; effects on coagulation and
fibrinolysis. Eur J Cardiothorac Surg. 1996;10(6):449-455.
Ovrum E, Fosse E, Mollnes TE, Am Holen E, Tangen G, Abdelnoor M,
Ringdal MA, Oystese R, Venge P. Complete heparin-coated
cardiopulmonary bypass and low heparin dose reduce complement
and granulocyte activation. Eur J Cardiothorac Surg. 1996;10(1):54-60.
Ovrum E, Mollnes TE, Fosse E, Am Holen E, Tangen G, Abdelnoor M,
Ringdal ML, Oystese R, Venge P. Complement and granulocyte
activation in two different types of heparinized extracorporeal
circuits. J Thorac Cardiovasc Surg. 1995;110(6):1623-1632.
1996 - 1995
Saenz A, Larranaga G, Alvarez L, Greco E, Marrero A, Lunar M,
Elosegui C, Ubago JL, Gallo I. Heparin-coated circuit in coronary
surgery. A clinical study. Eur J Cardiothorac Surg. 1996;10(1):48-53.
Aldea GS, Doursounian M, O'Gara P, Treanor P, Shapira OM, Lazar HL,
Shemin RJ. Heparin-bonded circuits with a reduced anticoagulation
protocol in primary CABG: a prospective, randomized study. Ann
Thorac Surg. 1996;62(2):410-417.
Shapira OM, Aldea GS, Zelingher J, Volpe C, Fitzgerald C,
DeAndrade K, Lazar HL, Shemin RJ. Enhanced blood conservation and
improved clinical outcome after valve surgery using heparin-bonded
cardiopulmonary bypass circuits. J Card Surg. 1996;11(5):307-317.
Aldea GS, Shapira OM, Treanor PR, Lazar HL, Shemin RJ. Effective
use of heparin-bonded circuits and lower anticoagulation for
coronary artery bypass grafting in Jehovah's Witnesses. J Card Surg.
1996;11(1):12-17.
Steinberg BM, Grossi EA, Schwartz DS, McLoughin DE, Aguinaga M,
Bizekis C, Greenwald J, Flisser A, Spencer FC, Galloway AC, Colvin SB.
Heparin bonding of bypass circuits reduces cytokine release during
cardiopulmonary bypass. Ann Thorac Surg. 1995;60(3):525-529.
Aldea GS, Zhang X, Memmolo CA, Shapira OM, Treanor PR,
Kupferschmid P, Lazar HL, Shemin RJ. Enhanced blood conservation
in primary coronary artery bypass surgery using heparin-bonded
circuits with lower anticoagulation. J Card Surg. 1996;11(2):85-95.
Borowiec JW, Hagman L, Totterman TH, Pekna M, Venge P, Thelin S.
Circulating cytokines and granulocyte-derived enzymes during
complex heart surgery. A clinical study with special reference to
heparin-coating of cardiopulmonary bypass circuits. Scand J Thorac
Cardiovasc Surg. 1995;29(4):167-174.
Bozdayi M, Borowiec J, Nilsson L, Venge P, Thelin S, Hansson HE.
Effects of heparin coating of cardiopulmonary bypass circuits on
in vitro oxygen free radical production during coronary bypass
surgery. Artif Organs. 1996;20(9):1008-1016.
Ernofsson M, Thelin S, Siegbahn A. Thrombin generation during
cardiopulmonary bypass using heparin-coated or standard circuits.
Scand J Thorac Cardiovasc Surg. 1995;29(4):157-165.
Fukutomi M, Kobayashi S, Niwaya K, Hamada Y, Kitamura S.
Changes in platelet, granulocyte, and complement activation during
20
cardiopulmonary bypass using heparin-coated equipment. Artif
Organs. 1996;20(7):767-776.
1994 - 1993
Belboul A, al-Khaja N, Gudmundsson M, Karlsson H, Uchino T, Liu B,
El-Gatit A, Bjell A, Roberts D, William-Olsson G. The influence
of heparin-coated and uncoated extracorporeal circuits on
blood rheology during cardiac surgery. J Extra Corpor Technol.
1993;25(2):40-46.
Borowiec JW, Bylock A, van der LJ, Thelin S. Heparin coating
reduces blood cell adhesion to arterial filters during coronary
bypass: a clinical study. Ann Thorac Surg. 1993;55(6):1540-1545.
Fosse E, Moen O, Johnson E, Semb G, Brockmeier V, Mollnes TE,
Fagerhol MK, Venge P. Reduced complement and granulocyte
activation with heparin-coated cardiopulmonary bypass. Ann
Thorac Surg. 1994;58(2):472-477.
Hatori N, Yoshizu H, Haga Y, Kusama Y, Takeshima S, Segawa D,
Tanaka S. Biocompatibility of heparin-coated membrane oxygenator
during cardiopulmonary bypass. Artif Organs. 1994;18(12):904-910.
Horikoshi S, Makano M, Hashimoto K, Emoto H, Koyanagi K,
Kanazawa T, Kurosara H. Alterations in coagulation, fibrinolysis and
complement during cardiopulmonar bypass with a heparin-coated
oxygenator. Artif Organs Today. 1994;3(4):239-252.
Jones DR, Hill RC, Vasilakis A, Hollingsed MJ, Graeber GM,
Gustafson RA, Cruzzavala JL, Murray GF. Safe use of heparincoated bypass circuits incorporating a pump-oxygenator. Ann
Thorac Surg. 1994;57(4):815-818.
Pediatric—clinical
2004 - 2003
Boning A, Scheewe J, Ivers T. Friedrich C, Stieh J, Freitag S, Cremer J.
Phosphorylcholine or heparin coating for pediatric extracorporeal
circulation causes similar biologic effects in neonates and infants.
J Thorac Cardiovasc Surg. 2004;127(5):1458-1465.
Pekna M, Borowiec J, Fagerhol MK, Venge P, Thelin S.
Biocompatibility of heparin-coated circuits used in cardiopulmonary
bypass. Scand J Thorac Cardiovasc Surg. 1994;28(1):5-11.
Jensen E, Andreasson S, Bengtsson A, Berggren H, Ekroth R,
Larsson E, Ouchterlony J. Changes in hemostasis during pediatric
heart surgery: impact of a biocompatible heparin-coated perfusion
system. Ann Thorac Surg. 2004;77(3):962-967.
Sellevold OF, Berg TM, Rein KA, Levang OW, Iversen OJ, Bergh K.
Heparin-coated circuit during cardiopulmonary bypass. A
clinical study using closed circuit, centrifugal pump and reduced
heparinization. Acta Anaesthesiol Scand. 1994;38(4):372-379.
Jensen E, Andreasson S, Bengtsson A, Berggren H, Ekroth R,
Lindholm L, Ouchterlony J. Influence of two different perfusion
systems on inflammatory response in pediatric heart surgery. Ann
Thorac Surg. 2003;75(3):919-925.
Shigemitsu O, Hadama T, Takasaki H, Mori Y, Kimura T, Miyamoto S,
Sako H, Soeda T, Kawawaki Y, Uchida Y. Biocompatibility of a
heparin-bonded membrane oxygenator (Carmeda MAXIMA) during
the first 90 minutes of cardiopulmonary bypass: clinical comparison
with the conventional system. Artif Organs. 1994;18(12):936-941.
von Segesser LK, Garcia E, Turina MI. Low-dose heparin versus
full-dose heparin with high-dose aprotinin during cardiopulmonary
bypass. A preliminary report. Tex Heart Inst J. 1993;20(1):28-32.
Wagner WR, Johnson PC, Thompson KA, Marrone GC. Heparincoated cardiopulmonary bypass circuits: hemostatic alterations and
postoperative blood loss. Ann Thorac Surg. 1994;58(3):734-740.
1992 - 1991
2000 - 1997
Ashraf S, Tian Y, Cowan D, Entress A, Martin PG, Watterson KG.
Release of proinflammatory cytokines during pediatric
cardiopulmonary bypass: heparin-bonded versus nonbonded
oxygenators. Ann Thorac Surg. 1997;64(6):1790-1794.
Grossi EA, Kallenbach K, Chau S, Derivaux C, Aguinaga MG,
Steinberg BM, Kim D, Iyer S, Tayyarah M, Artman M, Galloway AC,
Colvin SB. Impact of heparin bonding on pediatric cardiopulmonary
bypass: a prospective randomized study. Ann Thorac Surg.
2000;70(1):191-196.
Kagisaki K, Masai T, Kadoba K, Sawa Y, Nomura F, Fukushima N.
Biocompatibility of heparin-coated circuits in pediatric
cardiopulmonary bypass. Artif Organs. 1997;21(7):836-840.
Borowiec J, Thelin S, Bagge L, Hultman J, Hansson HE. Decreased
blood loss after cardiopulmonary bypass using heparin-coated
circuit and 50% reduction of heparin dose. Scand J Thorac
Cardiovasc Surg. 1992;26(3):177-185.
Miyaji K, Hannan RL, Ojito J, Jacobs JP, White JA, Burke RP. Heparincoated cardiopulmonary bypass circuit: clinical effects in pediatric
cardiac surgery. J Card Surg. 2000;15(3):194-198.
Borowiec J, Thelin S, Bagge L, Nilsson L, Venge P, Hansson HE.
Heparin-coated circuits reduce activation of granulocytes during
cardiopulmonary bypass. A clinical study. J Thorac Cardiovasc Surg.
1992;104(3):642-647.
Olsson C, Siegbahn A, Henze A, Nilsson B, Venge P, Joachimsson PO,
Thelin S. Heparin-coated cardiopulmonary bypass circuits reduce
circulating complement factors and interleukin-6 in paediatric
heart surgery. Scand Cardiovasc J. 2000;34(1):33-40.
Borowiec J, Thelin S, Bagge L, van der LJ, Thorno E, Hansson HE.
Heparin-coated cardiopulmonary bypass circuits and 25%
reduction of heparin dose in coronary artery surgery–a clinical
study. Ups J Med Sci. 1992;97(1):55-66.
Schreurs HH, Wijers MJ, Gu YJ, van Oeveren W, van Domburg RT,
de Boer JH, Bogers JJC. Heparin-coated bypass circuits: effects on
inflammatory response in pediatric cardiac operations. Ann Thorac
Surg. 1998;66(1):166-171.
Mollnes TE, Videm V, Gotze O, Harboe M, Oppermann M.
Formation of C5a during cardiopulmonary bypass: inhibition by
precoating with heparin. Ann Thorac Surg. 1991;52(1):92-97.
Videm V, Svennevig JL, Fosse E, Semb G, Osterud A, Mollnes TE.
Reduced complement activation with heparin-coated oxygenator
and tubings in coronary bypass operations. J Thorac Cardiovasc Surg.
1992;103(4):806-813.
21
Reducing patient exposure to DEHP:
the impact of Carmeda® BioActive Surface
Carmeda® BioActive Surface reduces patient exposure
to DEHP during extracorporeal circulation, in addition to
providing thromboresistance and biocompatibility.
Extracorporeal circulation procedures, including extracorporeal
membrane oxygenation (ECMO) and cardiopulmonary bypass
(CPB), result in large exposures of patients to DEHP.119,120 DEHP
[di(2-ethylhexyl) phthalate] is a plasticizer, which is frequently
added to the PVC (polyvinyl chloride) material used in medical
devices to provide critical characteristics such as softness and
flexibility. PVC without a plasticizer is hard and rigid.
Certain procedures pose the highest risk of patient exposure
to DEHP, including ECMO in pediatrics and cardiac surgery
procedures using cardiopulmonary bypass.119,120 The male fetus,
male neonate and the peripubertal male have been identified as
high risk for exposure to DEHP.119,120,121 This risk determination
is based on laboratory studies that have found an association
between DEHP exposure and abnormal development of the male
reproductive system and production of normal sperm in young
animals of certain types of rodents.119,120,121 Controversy exists
regarding the applicability of these animal models and study
findings to humans.119,120,121,122
Limiting DEHP exposures in patient populations considered to
be at risk has been recommended by the U.S. Food and Drug
Administration (FDA) and by Health Canada.119,120 However, both
organizations caution that procedures with a high risk for DEHP
exposure should not be avoided simply due to the possibility of
health risks associated with DEHP exposure, as the risk of not
doing a needed procedure is far greater than the risk associated
with exposure to DEHP.123,124
22
Heparin biosurfaces: an option to reduce DEHP
leaching from extracorporeal circulation circuits.
Clinical and laboratory studies suggest that the use of heparin
coatings, particularly covalently bonded heparin coatings,
significantly reduces leaching of DEHP from PVC components
used for extracorporeal circulation procedures.125,126
• Karle, et, al. (1997).125 Almost no DEHP leaching was detected
in blood samples taken from infants undergoing ECMO therapy
using circuits made with tubing coated with Carmeda® BioActive
Surface. In contrast, DEHP was extracted from blood samples
taken from infants undergoing ECMO using uncoated circuits.
• Haishima Y, et, al. (2004).126 DEHP release into circulating bovine
blood was significantly suppressed in test circuits made with
PVC tubing coated with covalently bonded heparin. A considerable
amount of DEHP was released from test circuits made using
two different manufacturers’ uncoated PVC tubing and also
from a test circuit made using PVC tubing coated with an
ionically bonded heparin.
While research finds that heparin biocompatible surfaces reduce
leaching from DEHP, it also suggests there may be differences
between types of heparin biocompatible surfaces. In testing
conducted by scientists and engineers in the laboratories of
the Medtronic Energy and Component Center and Medtronic
Perfusion Systems (Minneapolis, Minnesota, USA), the impact
of Medtronic’s heparin biosurfaces Carmeda® BioActive Surface
and Trillium® Biosurface on DEHP leaching from PVC tubing
commonly used in extracorporeal circulation circuits was
measured and compared.
Determination of reduction in DEHP leaching from PVC
tubing attributed to Carmeda® and Trillium® Heparin
Biocompatible Surfaces.
Figure 19
DEHP Leaching Test Circuit Diagram
Objective: To quantitatively determine the reduction in leaching
of di(2-ethylhexyl) phthalate (DEHP) plasticizer from PVC tubing
attributed to the use of Carmeda® BioActive Surface or Trillium®
Biosurface.
Peristaltic Pump
Silicone Tubing
Test materials/methods: Test circuits were constructed that
each contained a sample of one of four types of tubing (length:
20 feet, inner diameter 3/8 inch, wall thickness 3/32 inch):
uncoated PVC, Carmeda® BioActive Surface coated PVC, Trillium®
Biosurface coated PVC or silicone.
Glass Reservoir
Heat
Exchanger
Each test circuit also included additional silicone tubing for
placement in the peristaltic roller pump raceway, a silicone shunt
(used to re-circulate blood in the non-PVC parts of the circuit
until a temperature of 37°C was reached), polycarbonate
connectors, a heat exchanger and a 1-liter glass reservoir with
an HDPE (high density polyethylene) tubing insert (Figure 19).
Silicone
Tubing
Silicone Tubing
Results: DEHP concentrations, measured in parts per million
(ppm), increased over time in all PVC test circuits but were
lower in the test circuits coated with heparin biosurfaces
(Figure 20; Table 9). DEHP leaching was reduced by 95% or more
in Carmeda® BioActive Surface coated tubing compared to
uncoated PVC Tubing, with significantly less leaching found in
samples studied at all time points (Table 10). A reduction in DEHP
leaching of 1%-12% was measured in the Trillium® Biosurface
circuit samples (Table 10), with significant differences from
uncoated PVC tubing noted only at 24 hr (Table 9). The highest
DEHP levels were detected in the uncoated PVC tubing circuit
samples. As expected, no DEHP was detected in the samples
from silicone circuits.
Conclusion: Carmeda® BioActive Surface is a significant barrier
to DEHP leaching from flexible PVC. DEHP reduction due to the
Trillium® Biosurface was not substantially or significantly different
than that found with uncoated tubing. It cannot automatically
be assumed that all heparin coatings have the same impact on
DEHP leach reduction. Each coating, including heparin coatings
and other types of coatings, must be evaluated separately to
determine its abilities as a barrier to DEHP.
Table 9
Summary of DEHP Leaching Data from
Three Types of PVC Tubing
mean ± standard deviation (ppm)
Interval (hr)
Uncoated
Carmeda®
Trillium®
2
5.87 ± 0.62
0.20 ± 0.05*
5.84 ± 0.63
6
19.93 ± 2.20
0.42 ± 0.07*
18.20 ± 1.44
24
70.57 ± 9.57
1.64 ± 0.23*
62.41 ± 8.10*
Heater/Cooler
Unit
Silicone Tubing Shunt
Silicone Tubing
Six circuits were tested for each tubing type. For each test circuit,
1 liter of undiluted blood from an individual donor animal was
circulated using a peristaltic roller pump for 24 hr (4 L/min, 37°C).
Blood from each donor animal was used for a test of each circuit.
Blood samples were collected from each circuit at 2 hr, 6 hr and
24 hr of circulation time. The blood samples were extracted
and analyzed for DEHP content using high performance liquid
chromatography (HPLC) with mass spectral detection.
Water
Lines
Test Tubing
Figure 20
Total DEHP Leached from PVC Circuits Circulating
Undiluted Bovine Blood
Table 10
Percent Reduction in DEHP Leaching from PVC Tubing
Attributed to Heparin Biosurfaces
Interval (hr)
Carmeda®
Trillium®
2
96.6%
0.5%
6
97.9%
8.7%
24
97.7%
11.6%
* Statistically significant difference compared to uncoated PVC tubing
(p <0.05)
23
Common clinical topics
Patient size and weight restrictions. . . . . . . . . . . . . . . . . . . . . . . 24
Oxygenator gas transfer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Duration of use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Antifibrinolytics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Reprocessing/resterilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Anticoagulation protocols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Shelf life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Protamine interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Bonded circuit component selection. . . . . . . . . . . . . . . . . . . . . . 24
Heparin-induced thrombocytopenia (HIT) patients. . . . . . . . 25
Compatibility with other types of
coated circuit components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Heparin source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Patient size and weight restrictions
Bonded circuit component selection
There are no size or weight restrictions for use of Carmeda®
BioActive Surface. Pediatric patients to adults may receive
the benefits of extracorporeal circulation procedures using
technologies covalently bonded with non-leaching Carmeda®
BioActive Surface Endpoint Attached heparin.
In order to maximize the benefits of improved biocompatibility,
all blood contact surfaces should be exclusively heparin bonded
with Carmeda® BioActive Surface.
In contrast, labeling for devices coated with ionically bonded
heparin have included patient size restrictions.127 Ionically bonded
heparin leaches over time, contributing to heparin in systemic
circulation.85,128,129
Duration of use
In the United States, Medtronic Perfusion Systems’ extracorporeal
circulation technologies, with the exception of silicone membrane
oxygenators, are indicated for up to six hours of use. Extracorporeal
circulation technologies bonded with Carmeda® BioActive Surface
are accordingly indicated for use up to six hours.
In countries outside the United States, consult your Medtronic
Representative and product labeling for more specific information
about the duration of use for a particular product in your area.
Reprocessing/resterilization
Devices bonded with Carmeda® BioActive Surface are intended
for single use only and should not be reprocessed or resterilized.
The integrity and performance of Carmeda® BioActive Surface,
as well as the coated device, may become compromised if
subjected to reprocessing.
Shelf life
Medtronic Perfusion Systems technologies, including Carmeda®
BioActive Surface bonded technologies, should never be used
beyond their labeled expiration date. This date is established after
carefully evaluating device design, material characteristics and
performance requirements and after rigorous tests have been
performed to establish that the technology meets requirements
for safe and effective use within its stated shelf life parameters.
Shelf life may differ from device to device.
Devices that have reached their labeled expiration date should be
discarded. They should never be used, reprocessed or resterilized.
A Medtronic Representative may be consulted for information
on Carmeda® BioActive Surface bonded extracorporeal circuit
component availability.
Compatibility with other types of coated
circuit components
Medtronic offers two non-leaching heparin biocompatible surfaces
for our extracorporeal technologies: Carmeda® BioActive Surface
and Trillium® Biosurface. Based on Medtronic’s knowledge of
the characteristics and performance of these two biocompatible
surfaces, components coated with Carmeda® BioActive Surface
and Trillium® Biosurface may be combined within the same
extracorporeal circuit.
Because Medtronic does not have control over the quality, safety
or performance of other manufacturer’s devices, we cannot
comment on the use of Medtronic’s heparin bonded technologies
with other manufacturers’ devices.
Oxygenator gas transfer
All oxygenators manufactured by Medtronic must meet
performance requirements for safe and effective clinical use,
including oxygenators with coated fiber bundles. As demonstrated
during hundreds of thousands of hours of successful patient use,
Carmeda® BioActive Surface does not have a clinically significant
impact on gas transfer performance requirements for safe and
effective cardiopulmonary bypass.
Information on any Medtronic oxygenator’s gas transfer
performance characteristics may be found in the device’s
product labeling.
Antifibrinolytics
Reports describing use of antifibrinolytic agents such as
aprotinin45,115,130,131,132 or aminocaproic acid29,48,133 in clinical
and experimental studies with Carmeda® BioActive Surface
bonded devices have been published in the literature.
Medtronic, as a medical device manufacturer, does not make
specific recommendations regarding the use of antifibrinolytic
agents with Carmeda® BioActive Surface bonded extracorporeal
technologies. This decision is to be made by a physician, based
on clinical judgment of the requirements for a particular patient
in a particular clinical situation.
24
Anticoagulation protocols
Medtronic, as a manufacturer of Carmeda® BioActive Surface
bonded extracorporeal technologies, does not recommend or
promote specific heparin regimens for use with any of our
technologies. The amount of heparin used during extracorporeal
circulation is strictly a physician decision based upon the benefits
and risks for a specific patient and procedure.
A strict anticoagulation protocol should be followed, and
anticoagulation routinely monitored, during all extracorporeal
procedures using Carmeda® BioActive Surface bonded
technologies. The benefits of extracorporeal support must be
weighed against the risks of systemic anticoagulation and must
be assessed by the prescribing physician. Adequate heparinization
must be maintained before and during the extracorporeal
procedure. Use of a heparin management system may be
considered for determining precise, patient-specific heparin
and protamine requirements.
Protamine interactions
Protamine inactivates heparin, including the heparin in Carmeda®
BioActive Surface. Immobilized heparin that has been reversed by
protamine is not fully able to interact with the blood and may not
provide its full benefits for thromboresistance and biocompatibility.
Heparin-induced thrombocytopenia (HIT) patients
The use of Carmeda® BioActive Surface technologies for patients
with heparin-induced thrombocytopenia (HIT) is a physician
decision based on the patient’s specific clinical condition and
the clinical team’s comprehensive patient management strategy.
Institutions rarely encounter patients with HIT who require
cardiac surgery on an emergent basis. Accordingly, large,
controlled investigations of the use of Carmeda® BioActive
Surface during extracorporeal circulation procedures for HIT
patients have not been published to date. Published case reports
have described the use of Carmeda® BioActive Surface bonded
devices with alternative anticoagulation protocols for patients
with HIT.134,135 However, findings from individual case studies
cannot be generalized to all patients.
Heparin source
Carmeda® BioActive Surface is manufactured using porcine
heparin. Porcine heparin has always been used for the manufacture
of Carmeda® BioActive Surface.
25
References
1 Kreisler KR, Vance RA, Cruzzavala J, Mahnken JD. Heparin-bonded
cardiopulmonary bypass circuits reduce the rate of red blood cell
transfusion during elective coronary artery bypass surgery.
2 Mahoney CB, Lemole GM. Transfusion after coronary artery bypass
surgery: the impact of heparin-bonded circuits. Eur J Cardiothorac
Surg. 1999;16(2):206-210.
3 Mahoney CB. Heparin-bonded circuits: clinical outcomes and costs.
Perfusion. 1998;13(3):192-204.
4 Lindholm L, Westerberg M, Bengtsson A, Ekroth R, Jensen E, Jeppsson A.
A closed perfusion system with heparin coating and centrifugal pump
improves cardiopulmonary bypass biocompatibility in elderly patients.
Ann Thorac Surg. 2004;78(6):2131-2138.
5 Heyer EJ, Lee KS, Manspeizer HE, et al. Heparin-bonded
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29
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