Cardiopulmonary Bypass Induced Inflammatory Response Pathophysiology & Impact on Postoperative Course Ronald Bronicki, MD, FCCM, FACC Texas Children’s Hospital Different motif, more science Text xxx00.#####.ppt 10/31/2017 1:20:37 AM

Objectives History of CPB induced inflammation Pathophysiology of CPB induced inflammation Clinical sequelae Treatment Text xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

Upon exposure of the blood elements to the non endothelialized surface Complement activation, transpulmonary neutropenia xxx00.#####.ppt 10/31/2017 1:20:37 AM

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. xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

Cas--pase are involved in the induction of apoptosis xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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. xxx00.#####.ppt 10/31/2017 1:20:37 AM

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

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

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

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 Text xxx00.#####.ppt 10/31/2017 1:20:37 AM

Glucocorticoids & Pediatric CPB GC vs. Placebo  serum and myocardial inflammatory mediator release Decrease myocardial injury (troponin) & decrease vasoactive support Text xxx00.#####.ppt 10/31/2017 1:20:37 AM

Large PRCT n = 140 Decrease troponin release Improved fluid balance No impact on outcome measures

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 . xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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. xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

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 xxx00.#####.ppt 10/31/2017 1:20:37 AM

B – type natriuretic peptide levels A pilot study with 16 patients; Troponin levels B – type natriuretic peptide levels xxx00.#####.ppt 10/31/2017

Trend toward improved fluid balance despite significantly less diuretic usage xxx00.#####.ppt 10/31/2017

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 Text xxx00.#####.ppt 10/31/2017 1:20:37 AM