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Ann Thorac Surg 2003;76:S2220-S2223
© 2003 The Society of Thoracic Surgeons
a Harrison Department of Surgical Research, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
* Address reprint requests to Dr Edmunds, Department of Surgery, 5000 Ravdin Court, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104-4283, USA
e-mail: hank.edmunds{at}uphs.upenn.edu
Presented at the symposium, "Gibbon & His Heart-Lung Machine: 50 Years & Beyond," Philadelphia, PA, May 2, 2003.
In July 1934 John and Mary Gibbon started to create, build, and test the first extracorporeal perfusion circuit using ingenuity, tenacity, assorted laboratory paraphernalia, and newly available heparin [1]. Much hard work, animal studies, and steady refinements finally produced the IBM machine, which was used May 6, 1953, to successfully close a large atrial septal defect in a young woman [2]. The door of opportunity opened but much more was needed before heart surgery became safe and effective.
The first decade after John Gibbon's triumph was spent learning about the pathologic anatomy of the heart; how to make an accurate diagnosis during life; how to stop, start, incise, suture, and patch the heart; what to monitor and how to do it; refining the heart-lung machine; creating new hardware; manipulating oxygen supply and demand by changing flows, temperature, and hematocrit; and finding materials compatible with blood. The goal was survivors and the means were trial and error. Surgeons and cardiologists learned from their mistakes and nobody paid any attention to annoying hemolysis or thrombocytopenia that seemed unrelated to success or failure.
In 1960 Jim Maloney's group at the University of California, Los Angeles, raised an alarm in a presentation documenting denatured plasma proteins and fat emboli produced by bubble oxygenators [3]. Subsequent studies verified the production of fat and fibrin emboli and identified the bubble oxygenator as the source of countless gas emboli [4]. Autopsies showed fibrin and fat emboli in brains of the dead (Fig 1) and tests showed neurocognitive deficits in the living [5, 6]. Despite huge doses of heparin it became apparent that blood was not compatible with the heart-lung machine.
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The development of artificial heart valves in the late 1960s and myocardial revascularization in the early 1970s produced an almost overwhelming demand for cardiac surgery, which by that time had overcome many of the challenges encountered after the Gibbon demonstration. Surgeons realized that heart operations were different from other forms of surgery in that blood in contact with nonendothelial cell surfaces was constantly recirculated through the patient. Bleeding was greater and more difficult to manage; fluids shifted more freely between the vascular and interstitial compartments; and function of nearly every organ including the heart was temporarily compromised. Since blood and priming solutions were the only link between the heart-lung machine and the patient, surgeons at last began to study the interaction between heparinized blood and the biomaterial surfaces and rheology of the heart-lung machine.
This problem had already attracted the interests of chemical engineers and hematologists. Initially the hope was to discover a nonthrombogenic material or coating but this hope vanished when it became apparent that the endothelial cell, which is the only known nonthrombogenic surface, was found to produce both anticoagulants and procoagulants, which maintain a dynamic equilibrium between the fluid and gel forms of blood. Early studies of the interaction of heparinized blood and biomaterial surfaces showed that plasma proteins are instantly adsorbed onto the surface but in amounts that differ from those in circulating plasma [9]. Subsequent work revealed that surface adsorbed plasma proteins form a dense monolayer of selected plasma proteins, which are irreversibly bound, immobile and 100 to 1,000 times more densely packed than circulating plasma proteins [10]. The mosaic of absorbed proteins is related to the chemical and physical characteristics of the biomaterial and to bulk concentrations of each protein in plasma but cannot be predicted [10]. Different concentrations of circulating plasma proteins produce different topography on a given biomaterial and amounts of surface adsorbed proteins from the same plasma differ on different biomaterials. In addition adsorbed proteins often undergo limited conformational changes [11, 12] that may expose "receptor" amino acid sequences that are recognized by specific blood cells or circulating plasma proteins. Conformational changes of adsorbed factor XII activate the contact and intrinsic coagulation pathways; adsorbed fibrinogen triggers platelet adhesion; and changes in complement protein 3 activate the complement cascade [10]. Heparinized blood therefore interacts with its own reactive plasma proteins that are different for every biomaterial and for every patient.
During clinical cardiac surgery using cardiopulmonary bypass (CPB) five plasma protein systems and five blood "cells" are activated to produce an acute, massive defense reaction that produces a consumptive coagulopathy [13]; circulates more than 70 hormones, cytokines, chemokines, vasoactive substances, cytotoxins, reactive oxygen species and proteases of the coagulation and fibrinolytic systems [14]; induces mild to huge interstitial fluid shifts; generates a host of microemboli (<500 µ); and causes temporary dysfunction of nearly every organ [15]. The pathology of CPB is primarily due to the interaction between blood and nonendothelial surfaces; nonpulsatile flow and varying physiologic conditions contribute a relatively minor component to the disruption of the homeostasis of the "internal milleau."
For practical purposes this defense reaction involves two components that are interrelated and overlapping but are best described and understood if separated. The first is the "coagulation response" involving four plasma protein systems, platelets, monocytes, and endothelial cells [13]. The second component is the "inflammatory response," which primarily involves complement and neutrophils, monocytes, endothelial cells, and platelets [14]. Lymphocytes are primarily involved in the immune response and do not materially participate in the acute defense reaction.
Heparin fails to inhibit thrombin formation; consequently thrombin, which has a half life in plasma around 30 seconds, is continuously generated and circulated during all applications of extracorporeal perfusion [16]. Heparin inhibits thrombin by accelerating plasma antithrombin after it is formed and does not inhibit thrombin in clots. The protein fragment, F1.2 produced by the cleavage of prothrombin progressively increases during CPB and documents continuous thrombin formation (Fig 2). Thrombin activates platelets through a specific thrombin receptor [17]; this activation causes some platelets to adhere to surface adsorbed fibrinogen in the perfusion circuit, to form aggregates with other platelets and white cells, and to release granular contents. Activation of platelets and dilution with priming solutions reduces the number and quality of circulating platelets and causes prolongation of bleeding times, which measure overall platelet function. In addition thrombin stimulates endothelial cells to produce tissue plasminogen activator (t-PA), which cleaves plasminogen into the fibrinolytic enzyme, plasmin. Plasmin cleaves fibrin to produce a fragment, d-dimer, which also progressively increases during CPB [18]. The simultaneous production of thrombin and plasmin is the definition of a consumptive coagulopathy. Together with fewer and dysfunctional platelets this consumptive coagulopathy is the cause of the bleeding and thrombotic complications associated with CPB, circulatory assist devices, and extracorporeal life support (ECLS).
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Activation of complement, endothelial cells, neutrophils, monocytes, and platelets produces a host of vasoactive, cell signaling, and cytotoxic substances during extracorporeal perfusion [14]. These products of the acute defense reaction cause inappropriate vasoconstriction and vasodilatation of regional vascular territories; endothelial cell contraction and relaxation; increased interstitial edema (but not intracellular edema); expression of integrins and other cellular receptors; and migration of neutrophils and monocytes into tissues. Production and circulation of reactive oxygen species, cytotoxins and microemboli are responsible for temporary organ dysfunction of nearly every organ and for deaths of scattered cells and nests of cells throughout the entire body [15].
Complement is activated in the perfusion circuit and by reperfusion of the ischemic heart by both the classic and alternative pathways and is activated by the heparin-protamine complex by the classic pathway alone. The alternative pathway predominates during CPB but both pathways generate C3a and C3b. The C3b cleaves C5 into C5a and C5b. The C5b progresses to form the terminal attack complex, C5b-9, which is cytotoxic and which with C5a is a major agonist for other participants in the inflammatory response [14].
C5a and kallikrein are major activators of neutrophils during CPB but neutrophils are also activated by many other agonists and respond to the CXC family of chemokines [14]. The inflammatory cytokines interleukin (IL)1-ß, tumor necrosis factor (TNF)-
, and IL-8 activate neutrophils and are produced by a variety of nonblood cells and both monocytes and neutrophils. The inflammatory cytokines, platelet-activating factor (PAF) and activated complement proteins all stimulate endothelial cells to produce P and E-selectins and to eventually promote neutrophil migration into the interstitial space.
A variety of agonists that include C5a, IL-1ß, platelet factor 4 (PF-4), thrombin and C-C chemokines activate monocytes during CPB. Monocytes also respond to many chemokines including leukotriene 4, cathepsin G (from neutrophils), C5a, PF-4, PAF, and C-C chemokines. Monocytes are a major source of the early response inflammatory cytokines, IL-1ß, TNF-, and IL-8, and also produce other cytokines including IL-6 and IL-10. Monocytes also express several integrin receptors that facilitate endothelial cell adhesion and migration into the interstitial space.
Neutrophils and monocytes are storehouses of chemotactic and cytotoxic substances. Both monocytes and neutrophils are major producers of reactive oxygen species, which are usually employed internally during phagocytosis but which may circulate during extracorporeal perfusion. Neutrophils particularly produce and secrete multiple cytotoxins, which include reactive oxygen and nitrogen species, many potent proteases, lysozymes, phospholipase, and eicosanoids.
Thrombin, C5a, IL-1ß, and TNF- primarily activate endothelial cells during CPB. The two inflammatory cytokines induce endothelial ICAM-1 and VCAM-1 receptors, which bind neutrophils and monocytes; initiate transvascular trafficking; and stimulate production of IL-1, IL-6, IL-8, MCP-1, nitric oxide, PAF, prostacyclin, and the vasoconstrictor endothelin-1.
Platelets contribute to the inflammatory response by synthesis and release of eicosanoids, serotonin, IL-1ß, IL-8, CXC and C-C chemokines, PF4, neutrophil activating protein, endothelial cell neutrophil attractant (ENA-78), and acid hydrolases. Platelets are primarily activated by thrombin but other agonists such as epinephrine, PAF, vasopressin, cathepsin G, ADP, and serotonin may also participate.
Many variables affect the intensity of the coagulation and inflammatory responses to extracorporeal perfusion and these variables largely determine the morbidity of clinical applications of the technology [14]. Patient factors such as age, preoperative organ function, infection, cachexia, hepatic and renal function, anemia, genetic profiles, and cardiac performance profoundly affect the intensity of the defense reaction to extracorporeal perfusion and the patient's ability to recover. Duration of perfusion, surface area of the perfusion circuit, amount of recirculated wound blood, blood loss, number of allogenic transfusions, organ ischemia and reperfusion injury, duration of circulatory arrest, rheology of blood flow within the extracorporeal circuit, endotoxin, and use of corticosteroids and other pharmacologic agents are other variables that affect the intensity of the inflammatory response to CPB and all other applications of extracorporeal perfusion.
Many variables affecting the coagulation and inflammatory components of the defense reaction are beyond the clinician's control but some can be manipulated. Revascularization without CPB is now widespread and effective. Patient selection is another effective method of avoiding or ameliorating the complications of CPB and extracorporeal perfusion. However increasingly sicker, older patients with more comorbid conditions and compromised organ function are referred for intracardiac operations that require CPB. Well-planned and managed expeditious surgery decreases bleeding and the duration of CPB and reduces the intensity of the patient's defense reaction. Increasing evidence now suggests that not adding blood from the pericardial wound directly to the perfusion circuit may substantially reduce the amount of circulating thrombin and the severity of the consumptive coagulopathy associated with CPB. Using a cell-saving device and returning wound blood as packed cells may also reduce the concentrations of circulating vasoactive substances and cytotoxins and perhaps some forms of microemboli. The jury is still out regarding the efficacy of specific inhibitors of protein and cellular agonsits involved in the defense reaction; surface coatings; and the use of corticosteroids and other pharmacologic agents. But in reality 50 years after the first successful use of the heart-lung machine and the extension of millions of lives, blood and the heart-lung machine remain incompatible.
Acknowledgments
This work was supported by HL47186 from the National Heart Lung Blood Institute, National Institutes of Health, Bethesda, Maryland.
References
This article has been cited by other articles:
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  A. K Darwazah, R. A. A. Sham'a, I. Isleem, B. Hanbali, and B. Jaber Off-Pump Coronary Artery Bypass for Emergency Myocardial Revascularization Asian Cardiovasc Thorac Ann, April 1, 2009; 17(2): 133 - 138. [Abstract] [Full Text] [PDF]
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S. G Raja and G. D Dreyfus Current Status of Off-pump Coronary Artery Bypass Surgery Asian Cardiovasc Thorac Ann, April 1, 2008; 16(2): 164 - 178. [Abstract] [Full Text] [PDF]
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S. G Raja, S. Yousufuddin, F. Rasool, A. Nubi, M. Danton, and J. Pollock Impact of modified ultrafiltration on morbidity after pediatric cardiac surgery. Asian Cardiovasc Thorac Ann, August 1, 2006; 14(4): 341 - 350. [Abstract] [Full Text] [PDF]
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S. G Raja and G. D Dreyfus Modulation of Systemic Inflammatory Response after Cardiac Surgery Asian Cardiovasc Thorac Ann, December 1, 2005; 13(4): 382 - 395. [Abstract] [Full Text] [PDF]
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 S. G Raja and G. D Dreyfus Will off-pump coronary artery surgery replace conventional coronary artery surgery? J R Soc Med, June 1, 2004; 97(6): 275 - 278. [Full Text] [PDF]
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p less than 0.001 PERC versus PERF. (HEP = after heparin, before CPB; PERF = perfusate sample taken 30 to 45 minutes after the start of CPB; PERC = sample taken simultaneously with PERF from the pericardial wound; POST = 5 minutes after stopping CPB; PROT = sample from the patient 15 minutes after protamine infusion.) (Reprinted with permission from Chung JH, et al. Circulation 1996;93:2014–8.)