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The Systemic Inflammatory
Response to Cardiac Surgery
Aims and Objectives
To provide an overview of:
• Pathophysiology of the inflammatory response in cardiac
• Factors influencing the extent of the inflammatory
response .
• Clinical implications .
• Therapeutic strategies.
SIRS: Systemic Inflammatory Response Syndrome
• A nonspecific, generalised inflammatory response,
independent of causative factors but an indicator of injury.
• Symptoms of “sepsis” can arise in the absence of an infection.
• A frequent complication of SIRS is the development of organ
• Long term survival of patients developing SIRS may be
adversely affected.
Clinical Implications of the Inflammatory
Response to Cardiac Surgery
• Beneficial? :
Immune system priming may help prevent perioperative infection and
promote wound healing.
• An uncontrolled inflammatory response contributes to the pathogenesis
* Acute pulmonary dysfunction
* Cardiovascular dysfunction
* Neurologic dysfunction
* Renal dysfunction
* Splanchnic dysfunction
* Hematologic dysfunction
Factors That Activate the Inflammatory
• Surgical trauma.
• Blood loss, haemodilution and transfusion.
• Hypothermia.
• Anaesthetic drugs
• CPB.
CPB and The Activation of the
Inflammatory Response
• Contact activation: exposure of blood to foreign
surfaces of the circuit.
• Ischemia, hypoperfusion / reperfusion injury to all
• Endotoxemia: Splanchnic hypoperfusion may
damage mucosal barrier allowing translocation of
endotoxin. (Other sources of endotoxin include
priming fluid and cardioplegia)
Complement Activation and Cardiac Surgery
• Contact activation: exposure of blood to foreign surfaces of
the circuit. (Blood-gas interface may play a part).
(Alternative pathway)
• Ischemia, hypoperfusion / reperfusion injury to all organs.
(Alternative pathway)
• Heparin neutralisation with protamine. Delayed activation of
complement appears to be mediated by CRP in response to
large heparin-protamine complexes.
(Classical pathway)
Cytokines and Cardiac Surgery
• Proinflammatory cytokines stimulate the inflammatory response; plasma
concentrations of specific cytokines are predictive of outcome in critically
ill patients.
• Tumour necrosis factor α (TNF α) and Interleukin 1β (IL-1 β) are elevated
early following cardiac surgery, with IL-6 and IL-8 peaking later.
• Direct cause and effect are not fully understood however elevations of
proinflammatory cytokines are associated with adverse events. Patients
who develop SIRS have significant elevations in cytokine levels compared
to patients who have an uncomplicated recovery following surgery.
Coagulation-Fibrinolytic Cascades
• The coagulation-fibrinolytic cascades and the inflammatory
response are separate processes however they are closely
• Haemostasis is mediated by a balance of procoagulant and
anticoagulant properties which are tightly controlled.
• Coagulation factors including the activation of tissue factor
are initiated in response to inflammatory stimulus, oxidative
or shear stress during CPB.
• The endothelium is intricately involved in both processes.
Heparin and Protamine
• Drugs used to modulate coagulation during cardiac surgery.
• Heparin appears to possess important anti-inflammatory effects however
protamine neutralisation results in significant cardiovascular effects. (Note
caution and speed of delivery of protamine during surgery).
• Although protamine itself has adverse effects, it is the heparin protamine
interaction that activates the inflammatory response.
* Complement activation
* Histamine release
* Thromboxane, nitric acid production and
antibody formation
In a minority of patients severe anaphylactic reactions may result from the
heparin-protamine interaction.
The Endothelium
• The vascular endothelium is a dynamic participant in cellular
and organ function rather than a static barrier.
• The inflammatory response to CPB is characterised by a state
of widespread endothelial activation and injury.
• The endothelium controls vascular tone and permeability,
regulates coagulation and thrombosis and directs the passage
of leukocytes into areas of inflammation.
• Inflammatory mediators including TNFα and IL-1β bind to
specific receptors on the endothelium.
This schematic diagram depicts the role of the endothelium in the
regulation of vascular tone and illustrates important early events known to
occur in systemic inflammatory response syndrome (SIRS).
The endothelium regulates local vascular tone and adapts organ blood
flow to metabolic needs, by altering the balance of 4 key mediators: nitric
oxide (NO), prostacyclin (PGI2), thromboxane (TXA2), and endothelin (ET)
Endothelial Damage
• Vascular endothelium damage plays a central role in the
pathogenesis of microcirculatory derangement following CPB.
• An increased pulmonary vascular resistance (PVR) following CPB is
attributed to reduced Nitric Oxide (NO) release from dysfunctional
pulmonary endothelium. (Reversed by NO supplementation).
• Loss of vasodilator and antithrombotic effects of NO may alter
myocardial perfusion.
• Endothelial dysfunction and associated inflammatory response may
alter long term survival; patency of grafts, progression of
atherosclerosis. (Recruits leukocytes and platelets to the arterial
Illustration of Neutrophil-Endothelium Interaction
Each neutrophil represents a key event within the capillary, from right to left.
* Initially the freely moving neutrophil is converted to the “rolling” state.
* The neutrophil loosely interacts with the endothelium via the expression of selectins (adhesion
molecules) on both membranes.
* The expression of integrin receptors result in tighter binding to the capillary wall.
* In the third stage the neutrophil becomes tightly bound to the endothelium and transmigrates
out of the circulation, triggering activation, degranulation and further endothelial injury.
Factors Influencing the Extent of the
Inflammatory Response
• Preoperative:
* Disorders of cytokine balance.
* Diabetic patients- impaired micro circulation may effect immune response.
• Anaesthetic Techniques:
* Anaesthetic drugs- Many of the drugs used possess immunomodulatory
* Lung management –Apnea is associated with enzyme production and Acute
Lung Injury (ALI).
• Surgical Factors:
* Type of operation ( length of ischemic time)
* Inflammation appears to correlate with severity of illness; ventricular
dysfunction increases cytokine concentrations.
CPB and Immunological Response
The composition of the priming solution
Pulsatile or nonpulsatile flow
Roller or centrifugal pump
Type of circuit (biocompatible)
Blood transfusion
Cardiotomy suction
Inflammatory Response to CPB
Early Phase
“Contact Activation”
Cellular Components
• Endothelial cells
• Neutrophils
• Monocytes
• Lymphocytes
• Platelets
Humoral Components
• Contact
• Intrinsic Coagulation
• Extrinsic coagulation
• Complement
• Fibrinolysis
Late Phase
I/R Injury
• Neutrophil- EC interaction
• Reactive O2 species
• Arachadonic Acid Metabolites
• Cytokine Release
• Complement activation
• Cytokine release
• Nitric Oxide release
• Increase O2 consumption
CPB and Immunological Response
• The release of inflammatory mediators appears to be
temperature dependent. Warm CPB is associated with an
increased inflammatory response compared to hypothermic
CPB. However hypothermic CPB may simply delay cytokine
release and neutrophil activation.
• Evidence suggests tepid CPB (32-34°C) most effectively
attenuates the inflammatory response.
CPB and Immunological Response
Circuit adaptation:
• Heparin-coated circuits reduce complement and
proinflammatory cytokine release. More evidence is required
to analyse clinical significance.
• Some studies demonstrate that centrifugal pumps result in
less activation of the inflammatory response.
CPB and Immunological Response
Shear Stress:
• Excessive shear stress may develop during CPB as a result of
pressure changes across the circuit. Damage to blood
constituents activates the inflammatory response.
• Shear stress appears to be particularly significant at the tip of
the arterial cannula and is associated with haemolysis.
• Leukocyte adhesiveness is increased, with neutrophil
degranulation and release of cytotoxic products further
inducing endothelial damage and immune response.
Blood Transfusion
• Restrictive Transfusion Strategies?!
• Do we know the exact content of a bag of
packed cells?
CPB and Immunological Response
Blood Transfusions:
• Blood transfusions are associated with an increased morbidity and
mortality in cardiac surgery patients.
• The immunomodulatory effects of blood transfusions are
increasingly recognised.
• Packed red cells directly increase the concentration of inflammatory
mediators and indirectly stimulate the inflammatory response.
• Aged packed cells contain a high proportion of deformed
erythrocytes and debris which cause microcirculation occlusion,
damage and tissue ischemia in some organs.
CPB and Immunological Response
• Why do we use hemofiltration therapy? Modify
immune response?
• Hemofiltration appears to remove TNF α and IL-1β
and their inhibitors from the plasma of patients
with SIRS.
• The advantage that comes with the removal of
inflammatory mediators must be balanced against
the removal of clotting factors and other useful
metabolites. It is critical to always treat the patient
as a whole and not to focus on one aspect.
CPB and Immunological Response
Cardiotomy Suction:
• Do all surgeons use them?
• Shear stress and negative pressure in
conjunction with air/blood interface
activation leads to immunologically
activated blood.
• Separate reservoir.
• Cell salvage
• Sucker bypass scenario?
CPB and Immunological Response
• Hypoperfusion and inflammation effect the permeability of
the mucus membrane within the gut.
• Translocation of Endotoxins from the gut increases the
immune response. Endotoxins are present elsewhere.
• Strategies to reduce endotoxemia are done routinely for
gastric surgery;
Selective Digestive Decontamination (SDD): Oral
nonabsorbable antibiotics reduce the gut content of
Schematic diagram of potentially useful
strategies and therapies to control the
inflammatory response in cardiac
• Cardiac surgery evokes a generalised inflammatory
response in all patients, with serious clinical
consequences in a minority.
• A balanced, controlled inflammatory response is
potentially beneficial however a loss of control may
lead to SIRS and consequently organ dysfunction.
• We can make a difference!
• Research is on going into strategies and therapies to
reduce the immune response