The systemic inflammatory response to cardiopulmonary bypass
Collaborators: Ken Taylor, Dorian Haskard, Anna Randi, Clive Landis
Cardiopulmonary Bypass (CPB) has been associated with some degree of major organ
dysfunction since the earliest days of cardiac surgery. In the absence of infection or
ischaemia, the concept of the “post-pump syndrome” or “Systemic Inflammatory
Response Syndrome (SIRS)” is used 1. The clinical consequences of the inflammatory
response vary from increased duration of hospital stay, to neurocognitive disorders,
stroke, acute lung injury, multiple organ failure and death. The severity of SIRS
attributable to CPB and the organs involved differ widely between patients, but the
ischaemic lung appears to be particularly susceptible. The life threatening
complication, Adult Respiratory Distress Syndrome (ARDS), occurs in 0.5 – 1.7% of
CPB patients and can be associated with multiple organ failure, which carries a
mortality of 50 – 92% 2.
The mechanism of the inflammatory response in CPB is multifactorial. It combines
operative trauma with contact activation of circulating blood components by the
artificial surface of the bypass circuit, ischemia to major organs and endotoxin release
from the gut. Systemic activation of complement, platelets, leukocytes and EC in turn
leads to secretion of inflammatory mediators, such as IL-1, IL-6, IL-8 and TNF 3, 4
and generation of complement factors C3a, C5a and C5b-C9 (the membrane attack
complex) 5. These are thought to lead to systemic vascular endothelial activation and
leukocyte sequestration in organs 6, although direct evidence for these steps in
humans is limited. Neutrophils and mononuclear phagocytes are thought to play an
important role in lung injury by populating the affected organ and discharging their
histotoxic contents. Activation of the circulating neutrophil pool has been
demonstrated by elevated expression of Mac-1 (CD11b), and this occurs within 15
minutes of the commencement of bypass 7.
Therapeutic effects of aprotinin
Aprotinin (Trasylol) is a broad-spectrum serine protease inhibitor that has been in
clinical use since the late 1980s to reduce blood loss during CPB surgery 8-10. It is an
anti-fibrinolytic agent that inhibits the activity of plasmin 11. A significant additional
benefit of aprotinin compared to other anti-fibrinolytic agents (eg. tranexamic acid) is
that it appears to blunt the systemic inflammatory response to CPB 12, 13. A metaanalysis studying the cost and duration of hospital stay following CPB surgery has
shown that aprotinin was the most effective treatment in high risk patients, compared
to other state-of-the-art regimes, including leukocyte filtration, methylprednisolone
administration or heparin-bonded circuitry 14. Clinically the effects of aprotinin are
known to be mediated, at least in part, via reduced contact-activation of platelets and
leukocytes 11, 15 and reduced inflammatory cytokine synthesis 16. Furthermore, during
the 1995-1999 period, our in vitro and preclinical in vivo studies had suggested that
aprotinin inhibits EC activation 17 and neutrophil transendothelial migration 18.
Currently, Betsy Evans (BHF Clinical Research Fellow) is investigating the ability of
aprotinin to prevent trapping of leukocytes in tissues during CPB, using cantharadininduced skin blisters 19.
Changes in monocyte phenotype in response to CPB
Cells of the monocyte/macrophage lineage are activated between 2-24h post-bypass,
as demonstrated by elevated monocyte:platelet conjugate formation 20 and elevated
expression of CD11b 21. In the context of our interest in monocyte-macrophage
differentiation and anti-inflammatory function (see above), we have further explored
the changes in monocyte surface phenotype induced by CPB. Our results suggest a
change in monocyte function in response to surgery lasting for at least 2-3 days, such
that monocytes post-operatively are more capable of interacting with immunecomplexes and scavenging Hb:Hp complexes 19, 22. We are currently exploring the
putative anti-inflammatory phenotype of post-operative monocytes in more detail.
References
(1) Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary
bypass. Ann Thorac Surg 1993 February;55(2):552-9.
(2) Asimakopoulos G, Smith PL, Ratnatunga CP, Taylor KM. Lung injury and
acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac
Surg 1999 September;68(3):1107-15.
(3) Lahat N, Zlotnick AY, Shtiller R, Bar I, Merin G. Serum levels of IL-1, IL-6
and tumour necrosis factors in patients undergoing coronary artery bypass
grafts or cholecystectomy. Clin Exp Immunol 1992 August;89(2):255-60.
(4) McBride WT, Armstrong MA, Crockard AD, McMurray TJ, Rea JM.
Cytokine balance and immunosuppressive changes at cardiac surgery:
contrasting response between patients and isolated CPB circuits. Br J Anaesth
1995 December;75(6):724-33.
(5) Chennoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin
JW. Complement activation during cardiopulmonary bypass: evidence for the
generation of C3a and C5a anaphylatoxins. N Engl J Med 1981;304:497-503.
(6) Dreyer WJ, Michael LH, Millman EE, Berens KL, Geske RS. Neutrophil
sequestration and pulmonary dysfunction in a canine model of open heart
surgery with cardiopulmonary bypass. Evidence for a CD18-dependent
mechanism. Circulation 1995 October 15;92(8):2276-83.
(7) Asimakopoulos G, Kohn A, Stefanou DC, Haskard DO, Landis RC, Taylor
KM. Leukocyte integrin expression in patients undergoing cardiopulmonary
bypass. Ann Thorac Surg 2000 April;69(4):1192-7.
(8) Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on
need for blood transfusion after repeat open- heart surgery. L 1987 December
5;2(8571):1289-91.
(9) Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss
after cardiopulmonary bypass using high dose aprotinin (Trasylol): studies in
patients undergoing coronary bypass surgery, reoperations and valve
replacement for endocarditis. Thorac and Cardiovasc Surg 1989;97:373-8.
(10) Bidstrup BP, Harrison J, Royston D, Taylor KM, Treasure T. Aprotinin
therapy in cardiac operations: a report on use in 41 cardiac centers in the
United Kingdom. Ann Thorac Surg 1993 April;55(4):971-6.
(11) van OW, Jansen NJ, Bidstrup BP, Royston D, Westaby S, Neuhof H,
Wildevuur CR. Effects of aprotinin on hemostatic mechanisms during
cardiopulmonary bypass. Ann Thorac Surg 1987 December;44(6):640-5.
(12) Blauhut B, Harringer W, Bettelheim P, Doran JE, Spath P, LundsgaardHansen P. Comparison of the effects of aprotinin and tranexamic acid on
blood loss and related variables after cardiopulmonary bypass. J Thorac
Cardiovasc Surg 1994 December;108(6):1083-91.
(13) Royston D. Aprotinin versus lysine analogues: the debate continues. Ann
Thorac Surg 1998 April;65(4 Suppl):S9-19.
(14) 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 antiinflammatory strategies. Ann Thorac Surg 1998
September;66(3):747-53.
(15) Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman
RW, Edmunds LH, Jr. Aprotinin inhibits the contact, neutrophil, and platelet
activation systems during simulated extracorporeal perfusion. J Thorac
Cardiovasc Surg 1993 July;106(1):1-9.
(16) Tassani P, Augustin N, Barankay A, Braun SL, Zaccaria F, Richter JA. Highdose aprotinin modulates the balance between proinflammatory and antiinflammatory responses during coronary artery bypass graft surgery. J
Cardiothorac Vasc Anesth 2000 December;14(6):682-6.
(17) Asimakopoulos G, Lidington EA, Mason J, Haskard DO, Taylor KM, Landis
RC. Effect of aprotinin on endothelial cell activation. J Thorac Cardiovasc
Surg 2001 July;122(1):123-8.
(18) Asimakopoulos G, Thompson R, Nourshargh S, Lidington EA, Mason JC,
Ratnatunga CP, Haskard DO, Taylor KM, Landis RC. An anti-inflammatory
property of aprotinin detected at the level of leukocyte extravasation. J Thorac
Cardiovasc Surg 2000 August;120(2):361-9.
(19) Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, Landis
RC. Hemoglobin Scavenger Receptor CD163 Mediates Interleukin-10 Release
and Heme Oxygenase-1 Synthesis: AntiInflammatory Monocyte-Macrophage
responses in vitro, in Resolving Skin Blisters in vivo and Postoperatively
Following Cardio-Pulmonary Bypass. Circulation Research 2004;94:119-26.
(20) Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR.
Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood
1992;79:1201-5.
(21) Mathew JP, Rinder CS, Tracey JB, Auszura LA, O'Connor T, Davis E, Smith
BR. Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in
vivo cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995
March;109(3):448-56.
(22) Stefanou DC, Asimakopoulos G, Yagnik DR, Haskard DO, Anderson JR,
Philippidis P, Landis RC, Taylor KM. Monocyte Fc gamma receptor
expression in patients undergoing coronary artery bypass grafting. Ann Thorac
Surg 2004 March;77(3):951-5.