0. Cardiopulmonary Bypass Induced Inflammatory Response
Pathophysiology & Impact on Postoperative Course
Ronald Bronicki, MD, FCCM, FACC
Texas Children’s Hospital
Different motif, more science
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1. Objectives History of CPB induced inflammation
Pathophysiology of CPB induced inflammation
Clinical sequelae
Treatment
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2. Advent of inflammatory mediator assay, becoming more readliy available
Immunologic response leading to a systemic inflammatory response triggered by non infectious stimuli
Advent of inflammatory mediator assay, becoming more readliy available
Lead to a greater understanding of other disease processes such as trauma, chronic HF, inflammatory response to CPB
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3. Upon exposure of the blood elements to the non endothelialized surface
Complement activation, transpulmonary neutropenia
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4. CPB & CPB - Induced Inflammation & Organ Dysfunction
Kirklin & colleagues were the 1st to demonstrate a positive relationship between inflammation & cardiac & pulmonary dysfunction
They also demonstrated age (younger) & duration of CPB (longer) were associated with the development of organ dysfunction
Kirklin JK et al J Thorac Cardiovasc Surg 1983; 86: 845.
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5. Systemic Inflammatory Response to CPB
Non-endothelialized
circuit 
Membrane oxygenator
Heparin – protamine
complexes
Neutrophil mediated
tissue injury
Impaired organ function
Upon exposure of plasma proteases to the non endothelialized surface of the CPB circuit, alternate pathway of complement is activated, as is the contact system which activates the classical pathway of complement—all of which leads to the generation of cellular derived inflammatory mediations such as arachindonic acid metabolites(prostaglandins, leukotrienes)
Virtually every inflammatory pathway and nucleated cell are activated, contributing to the systemic inflammatory cascade
Culminates with activation of neutrohils and endothelail cells, the expression of ICAM, extravasation of PMNs into the interstitium and release of tissue destructive proteases
And ultimately organ injury and dysfunction, which as Kirklin and others have shown to contribute to morbidity following cardiac surgery
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6. Myocardial Ischemia – Reperfusion Injury
A period of ischemia followed by re introduction of oxygen leads to an inflammatory response most notably the generation of ROS and cytokines; neutrophil mediated injury as well as programmed cell death results in impaired organ function;
Included is damage to the endothelium and impaired NO production leading to a pro coagulant and pro inflammatory mileu
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7. Reperfusion injury characterized by the release of cytokines
It is not until myocardial and pulmonary perfusion is re-established that we see elevations in serum cytokines such as TNF, IL-1, 6 for example.
DC represents sampling 5” after removal of the aortic cross clamp
A, aortia; CS coronary sinus; PA, pulmonary artery; sill over into the systemic circulation
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8. Organ Injury Cardiopulmonary Bypass Induced
To what extent is it the generalized inflammatory response to the non-
endothelialized surface versus myocardial and pulmonary reperfusion injury

9. Animal model of CPB to tease out the relative importance of each…
AQP are aquaporins or transmembrane proteins that function as water channels, AQP mRNA and myocardial water content
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10. Cas--pase are involved in the induction of apoptosis
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11. Animal model of cpb: group A: CPB without PA perfusion; and B with PA perfusion
The primary mech responsible for increases in pulm vasc reactivity following CPB is IRI
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12. Ultrastructural changes like those seen in ALI/ARDS: air blood barrier breakdown; increase in EVLW; impaired surfactant production and function; increase in lung elastic recoil forces, greater risk for loss of lung volume; and impaired oxygenation from edema and lung volume loss
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13. The Role of Polymorphisms in the Inflammatory Response to CPB
Grunenfelder J et al J Thorac Cardiovasc Surg 2004; 128: 92.
Polymorphisms in the inflammatory response to bypass and IRI
Gaudino M et al J Thorac Cardiovasc Surg 2003; 126: 1107.
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14. Clinical Sequelae
Interstitial edema formation, fever & increase in VO2
Pulmonary injury:  compliance & impaired oxygenation
Impaired pulmonary vascular function &  reactivity
Impaired myocardial function: diastolic & systolic function
Circulatory arrest: reperfusion injury elsewhere

15. Immune Modulatory Therapies
Glucocorticoids
Ultrafiltration (conventional and modified)
Heparin-coated circuits
Nitric oxide

16. Glucocorticoids Clinical experience Readily available & inexpensive
Widely effective immune suppressing agents
Prime the immune system prior to the stimuli
Immunesuppression is dose-responsive

17. Glucocorticoids & Pediatric CPB GC vs. Placebo
Decrease serum inflammatory mediator levels (TNF, IL-6)
Improved fluid balance, greater preservation of renal function &  duration of CMV
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18. Glucocorticoids & Pediatric CPB GC vs. Placebo
 serum and myocardial inflammatory mediator release
Decrease myocardial injury (troponin) & decrease vasoactive support
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19. Large PRCT n = 140
Decrease troponin release
Improved fluid balance
No impact on outcome measures

20. Glucocorticoids & Pediatric CPB GC vs. Placebo
All studies have shown decrease in the inflammatory response but clnical impact has varied
Decrease inflammatory mediator release but no improve- ment in the post operative course
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21. Glucocorticoids Dose - Response
Several studies have evaluated the dose response of GC on ameliorating the …Abstract 2000 Circulation
No further reduction in inflammation except for complement – which has been shown in in vitro studies but no clinical benefit
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22. Glucocorticoids Dose - Response
Graham EM et al (JTCVS 2011; 142: 1523)
 inflammatory mediator release
No improvement in post operative parameters
Perhaps  risk for post operative renal dysfunction
Varan B et al (Pediatr Cardiol 2002; 23:437)
No impact on mediators or outcomes
Schroeder VA et al (Circulation 2003; 107: 2823)
 myocardial & systemic inflammation
 circulatory function & trend toward  incidence LCOS
Improved fluid balance .
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23. Meta-Analysis of Glucocorticoids & Pediatric Cardiopulmonary Bypass
Its absolutely clear that GCs suppress the inflammatory response and Less clear what the impact is on the postoperative period
The majority of centers use GC prior to CPB and virtually all centers use GCs for virtually all neonatal surgeries
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25. UF has been shown to improve cardiac and pulmonary function
Ultrafiltration does remove substantial amounts of inflammatory mediators
UF has been shown to improve cardiac and pulmonary function
Great review of CUF and MUF by Wang; some 75% of centers conduct MUF following CPB
Effective in removing water but also inflammatory mediators
And evidence that it leads to improved cardiopulmonary function (water v. mediator removal)
Perfusion 2012; 27: 438.
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26. Peritoneal Dialysis & Inflammatory Mediator Removal
PD removes inflammatory mediators and has been shown to improve outcomes and again how much is water removal v mediator removal
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27. 41 PRCT met inclusion criteria, > 3400 patients (adult studies)
Decrease need for blood transfusion, duration of CMV
Some 75% of pediatric centers use a heparin bonded circuit
Limited positive results on clinical outcomes in children
Decreased
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28. B – type natriuretic peptide levels
A pilot study with 16 patients;
Troponin levels
B – type natriuretic peptide levels
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29. Trend toward improved fluid balance despite significantly less diuretic usage
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30. Summary CPB results in a systemic inflammatory response, which
is compounded by cardiopulmonary reperfusion injury
CPB contributes to organ dysfunction & post
operative morbidity
Immune modulatory strategies ameliorate the
inflammatory response to CPB & more likely than not
Improve the post-operative course
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