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Perfusion 2003; 18: 7 ¡/12
A review of anti-in ammatory strategies in
cardiac surgery
George Asimakopoulos1 and Terence Gourlay2
1
Cardiothoracic Surgery, West London Rotation, UK;
2
Cardiothoracic Surgery, NHLI Imperial College Faculty of Medicine, London, UK
It is generally accepted that cardiac surgery is frequently published literature concerning the use of anti-inflam-
associated with the development of systemic inflamma- matory techniques and pharmacological agents in car-
tory response. This phenomenon is very variable clini- diac surgery. In particular, the anti-inflammatory effects
cally, and can be detected by measuring plasma of off-pump surgery, leukocyte filtration, corticosteroids,
concentrations of certain inflammatory markers. Com- aprotinin, phosphodiesterase inhibitors, dpoexamine, H2
plement component, cytokines and adhesion molecules antagonists and ACE inhibitors are reviewed. The overall
are examples of these markers. Systemic inflammation conclusion is that although certain strategies reduce
can be potentially damaging to major organs. Several plasma levels of inflammatory mediators, convincing
anti-inflammatory strategies have been used in recent evidence of significant clinical benefits is yet to come.
years, aiming to attenuate the development of systemic Perfusion (2003) 18, 7 ¡/12.
inflammatory response. This article summarizes recently
Systemic inflammatory response in cardiac The role of inflammatory markers in the study of
surgery systemic inflammation in cardiac surgery was re-
cognized over 20 years ago and has been reviewed
extensively.1 ¡ 3 Briefly, plasma levels of several
Cardiac surgery is associated with a complex net- ‘acute phase proteins’ increase during the systemic
work of phenomena that can be summarized under inflammatory response. Well-investigated examples
the term ‘systemic inflammatory response’. Non- include interleukin-(IL-)6, IL-1, C-reactive protein
clinicians use the nearly synonymous term ‘acute and complement components C3 and C4. Contact
phase response’. This condition can be detected by activation of Factor XII occurs once this is bound to
measuring the concentration of certain molecules, negatively charged surfaces; in particular, within the
‘inflammatory mediators’, in plasma and tissues. CPB circuit. Activation of Factor XII leads to the
The clinical relevance of the systemic inflammatory formation of bradykinin via conversion of prekallik-
response can be assessed by measuring the perio- rein to kallikrein. Products of the bradykinin-form-
perative dysfunction, which affects most major ing cascade bind to the surface of endothelial cells,
organs. Systemic inflammatory response occurs in neutrophils and platelets and contribute to the
relation to many different types of clinical injury, activation of these cells. Furthermore, cell activation
such as major trauma, major noncardiac surgery, is also facilitated through the action of ‘cytokines’.
infection, burns or pancreatitis. It is particularly This general term includes a large number of small
frequent in cardiac surgery, however, possibly as a proteins with proinflammatory and anti-inflamma-
result of the fact that more than one major inflam- tory properties. Cytokines such as IL-I, IL-6 and also
matory insult takes place simultaneously. These tumour necrosis factor-a (TNF-a ), IL-8, transforming
include the mechanical effects of intraoperative growth factor-b and many others are produced by
tissue manipulation, ischaemia and subsequent cells and cause further cell activation. They mediate
reperfusion of lungs and myocardium, and the their inflammatory actions by binding to specific
potentially inflammatory effects of the cardiopul- cell-surface cytokine receptors. Inflammatory activa-
monary bypass (CPB). tion of leukocytes and endothelial cells and inter-
action between the two groups are critical steps in
inflammation.
Address for correspondence: Mr George Asimakopoulos,
Cardiothoracic Department, St George’s Hospital, Blackshaw
It has been shown, conclusively, that cardiac
Road, London SW17 0QT, UK surgery is associated with increased plasma concen-
E-mail: geoasi@hotmail.com trations of several inflammatory mediators.1 Activa-
# Arnold 2003 10.1191/0267659103pf623oa
Review of anti-inflammatory strategies in cardiac surgery
G Asimakopoulos and T Gourlay
8
tion of the complement cascade takes place and has been examined in several clinical trials over the
secretion of IL-6, IL-8 and TNF-a also occurs. last five years, whereby plasma levels of inflamma-
Specific adhesion molecules increase their expres- tory mediators were measured in patients under-
sion on the surface of leukocytes and endothelial going OPCAB (or MIDCAB) and compared with
cells. Intensified interaction between these cell patients undergoing conventional CABG. A review
groups leads to leukocyte sequestration in tissues, of the subject was published recently,4 and the
migration into subendothelial areas and, often, to following conclusions were drawn:
leukocyte-led tissue damage. The specific role of
leukocytes and, in particular, neutrophils will be . CPB appears to be responsible for the activation of
discussed in one of the following paragraphs. complement during cardiac surgery.
. CPB specifically promotes secretion of the pro-
inflammatory cytokines IL-8 and TNF-a and of
the anti-inflammatory cytokine IL-10.
Anti-inflammatory strategies
. Plasma levels of the acute phase proteins C-
reactive protein and IL-6 are raised equally in
Dysfunction of lungs, kidneys, myocardium, intes- both patient groups. IL-6 levels, however, were
tine and brain is common after cardiac surgery. reduced when MIDCAB patients were compared
Although the dysfunction is usually temporary, it with OPCAB patients in one study. This suggests
coincides strongly with activation of inflammatory that operative trauma, rather than CPB, initiates
cascades. Pathological conditions, such as bacterial the release of IL-6.
infections, acute ischaemia or embolic events are
. CPB promotes activation of neutrophils.
often at the forefront of organ dysfunction. It is
likely, however, that systemic inflammatory re- OPCAB is being practised with various degrees of
sponse also plays a significant role. Different anti- enthusiasm around the world. Although, admit-
inflammatory strategies have been used over the tedly, there is still controversy with regards to its
years with various degrees of success. In general, it clinical benefits, it appears to be less proinflamma-
has been easier to demonstrate success in reducing tory than cardiac surgery with CPB.
plasma concentrations of specific inflammatory
mediators than to prove significant clinical benefit.
This is probably due to the fact that most rando- leukocyte filtration
mized trials were severely underpowered to show Activation of leukocytes and their mobilization
reduction in morbidity and mortality. Some of the towards injured tissues are critical steps in inflam-
anti-inflammatory strategies, such as leukocyte fil- mation. Neutrophils, in particular, play a major role
tration and the perioperative administration of in conquering insults, such as bacterial invasion.
corticosteroids, have been used extensively. Certain Activated neutrophils, however, may exert dama-
others, such as the use of angiotensin-converting ging effects on tissues of the host organism, indir-
enzyme (ACE) inhibitors, are relatively new con- ectly by releasing inflammatory mediators and
cepts. The following paragraphs present an over- directly by damaging endothelial cells with proteo-
view of commonly used anti-inflammatory methods lytic enzymes.
and pharmacological agents in cardiac surgery. Specific receptors on the neutrophil surface can
be activated by proinflammatory cytokines, inter-
Off-pump CABG feron-g (IFN-g ), platelet activating factor (PAF) or
Cardiac surgery without the use of CPB [off-pump complement components C3a and C5a. Neutrophils,
coronary artery bypass grafting (CABG) or OPCAB] subsequently, secrete further inflammatory media-
has been practised in many centres in recent years. tors (IL-1, TNF-a , IL-6, IL-8, IFN-g ), a process which
OPCAB, on certain occasions, can be performed leads to amplification of leukocyte activation.5 The
without the use of midline sternotomy, thus redu- damaging potential of the activated neutrophils
cing operative trauma (minimally invasive direct depends on their ability to adhere to the endothe-
coronary artery bypass or MIDCAB). The potential lium. Neutrophil-endothelial cell adhesion may be
benefits are related to reduced manipulation of the followed by generation of oxidizing agents and by
ascending aorta in high-risk cases, avoidance of release of several toxic substances from intracellular
global ischaemia and reperfusion in the heart and granules of the neutrophils. Molecules such as
lungs, avoidance of cardioplegic arrest and its oxygen-derived free radicals and proteolytic en-
damaging effects on the endothelium, reduced cost zymes (e.g., elastase and metalloproteinases) cause
and, last but not least, avoidance of the potentially extracellular damage in order to facilitate their
inflammatory effects of the CPB. The latter concept migration into tissues.6
Review of anti-inflammatory strategies in cardiac surgery
G Asimakopoulos and T Gourlay
9
In cardiac surgery, there is a positive correlation cocorticoids is exerted through their ability to
between elastase plasma concentrations after CPB control the patterns of synthesis of proteins.
and postoperative respiratory dysfunction, as shown The effects of corticosteroids on organ function
by changes in the respiratory index and increase of and systemic inflammatory response in patients
the intrapulmonary shunt.7 In CPB-associated lung undergoing cardiac surgery have been investigated
injury, neutrophils appear to play a significant role. since the early 1960s. A recent article by Chatney
After the administration of protamine, the neutro- presented an exhaustive review of published clin-
phil count in the pulmonary artery exceeds the ical investigations using corticosteroids, mainly
count in the systemic arterial blood, suggesting that methylprednisolone, in cardiac surgery.13 Chatney’s
neutrophils are sequestrated in the lungs.8 Concen- review is comprehensive and renders repetition in
trations of neutrophils in bronchial lavage fluid are this article unnecessary. The overall conclusion is
higher after CPB in comparison with control pa- that, while the use of corticosteroids is associated
tients.9 with a significant reduction in plasma levels of a
In view of the role leukocytes play in inflamma- large variety of inflammatory mediators, there is no
tion, removal of activated leukocytes by intraopera- proven clinical advantage. On the contrary, corti-
tive filtration has been used as an anti-inflammatory costeroids may be detrimental to the operative out-
strategy in cardiac surgery. Several trials using come.
leukocyte filtration have been carried out since the
mid-1990s. Results were reviewed in two recent
Aprotinin
articles.10,11 Filters have been mainly inserted in the
Aprotinin (Trasylol® ) is a nonspecific serine pro-
arterial, but also in the venous CPB line, the
tease inhibitor that has been used extensively in
cardioplegia line and the suction system. Filters in
cardiac surgery since its efficacy in reducing post-
the arterial line reduced postoperative leucocytosis
operative bleeding was discovered in the mid-
in some studies and were particularly efficient in
1980s.14 It possesses broad haemostatic properties
reducing leukocyte counts when inserted in the that are mediated by blocking pathways of comple-
venous part of the circuit. There appears to be no ment activation and fibrinolysis, as well as inhibit-
difference with regards to plasma levels of inflam- ing the action of proteinases such as trypsin,
matory mediators, but a minority of trials reported plasmin and kallikrein. 15 Although used mainly
improved lung function when filters were used. for its haemostatic effects, aprotinin is also thought
leukocyte-depleted cardioplegia is associated with to modify the inflammatory response to major
reduced plasma levels of CK-MB. Despite some surgery through a general ability to inhibit neutro-
promising results, the use of leukocyte filtration phil activation. Diminished activation of neutro-
still remains limited to certain institutions. Further phils associated with aprotinin therapy has been
optimization of timing, material and patient selec- demonstrated in previous clinical trials and in vitro
tion might improve outcome further. studies, which studied markers of leukocyte activa-
tion, such as expression of cell surface proteins and
release of elastase, TNF-a and IL-8. 16,17
Corticosteroids Aprotinin has been in clinical use for over 30
Corticosteroids can be divided into mineralocorti- years and, although several in vitro and in vivo
coids and glucocorticoids. The latter have a variety studies have investigated its anti-inflammatory ef-
of metabolic, immunosuppressing and anti-inflam- fects, the exact mechanism of action remains un-
matory actions. Their anti-inflammatory effects in- known. Recognition of aprotinin’s antiplasmin
clude decreased production of prostaglandins and effects led to its use as an antifibrinolytic agent.
cytokines, decreased expression of surface adhesion Although Tice et al. 18 reported the use of aprotinin
molecules, suppression of neutrophil adhesion and to reduce bleeding in cardiac surgery as early as
phagocytosis, and also decreased proliferation of 1963, the drug’s potential role in postoperative
lymphocytes. Glucocorticoids bind to specific cyto- haemostasis remained initially unrecognized. The
plasmic receptors. The receptors have glucocorti- serendipitous discovery at the Hammersmith Hos-
coid-binding domains and DNA-binding domains. pital that aprotinin, given at certain doses, signifi-
The binding of the glucocorticoid to its receptor cantly reduces bleeding after cardiac surgery drew
results in translocation of the receptor-glucocorti- wide attention to the drug and resulted in its
coid complex into the nucleus. The subsequent extensive worldwide use.15,19
binding of the complex to the promoter region of Aprotinin is a basic polypeptide with a molecular
specific genes results in altered gene activation and weight of 6512 Da. Its activity is often expressed as
transcription.12 The physiological influence of glu- kallikrein inactivator units (KIU) or trypsin inacti-
Review of anti-inflammatory strategies in cardiac surgery
G Asimakopoulos and T Gourlay
10
vator units (TIU), based on aprotinin’s biological matory mediators in cardiac surgical patients.
action properties. Clinically, aprotinin in used as a Enoximone reduced plasma levels of inflammatory
continuous infusion following a loading dose. The cytokines and soluble adhesion molecules when
full Hammersmith dose aims to suppress kallikrein used intraoperatively in patients aged over 80 years
activity and consists of: 1) a loading dose of 2 ½/106 undergoing CABG.25 Milrinone was associated with
KIU (280 mg); 2) a CPB pump prime dose of 2 ½/106 reduced secretion of the acute phase proteins
KIU; and 3) a maintenance infusion of 0.5½/106 amyloid A and IL-6 after CPB.26 The use of the
KIU/hour until the end of the operation. The newly developed olprinone was associated with
concentration of aprotinin regarded as necessary to reduced IL-10 levels and moderate reduction in
block kallikrein action under laboratory conditions gastric acidosis intraoperatively.27
is ~ /200 KIU/mL of plasma.15,19 Pentoxifylline, a methyl xanthine derivative, is
A metaanalysis, however, of trials investigating known for its protective effects on endothelium.
the influence of aprotinin on clinical outcome after When given to cardiac surgical patients in the
cardiac surgery demonstrated decreased mortality in perioperative period, its use was associated with
patients treated with aprotinin. 20 It is unclear, of reduced production of cytokines, reduced leukocyte
course, whether this favourable result is primarily activation and sequestration in the lungs and im-
attributable to the haemostatic or the anti-inflam- provement in indices of pulmonary injury.28 ¡ 30
matory effects of aprotinin. Previous studies in
cardiac surgery showed that aprotinin is related to Dopexamine
decreased proinflammatory cytokine production, Dopexamine is used as an intravenous infusion for
increased IL-10 production21 and decreased NO its inotropic and vasodilatory properties. It acts on
production.22 beta-2 receptors in cardiac muscle and on peripheral
dopamine receptors. It produces vasodilatation in
Phosphodiesterase inhibitors the renal and splachnic microcirculation and is,
Phosphodiesterase inhibitors inhibit cyclic adeno- therefore, regarded as protective towards the gut
sine 3?,5?-monophosphate phosphodiesterase mucosal barrier, causing subsequent reduction in
(cAMP) and have been used over the last two ischaemia-induced endotoxaemia and inflammatory
decades for their positive inotropic effects. Phos- response.
phodiesterase converts cAMP into the physiologi- Two small randomized trials suggested that do-
cally inactive 5?-AMP by hydrolysis. cAMP acts as a pexamine is associated with reduced secretion of
hormonal and, also, inflammatory messenger by acute phase proteins in patients undergoing CPB.
activating protein kinase A, which alters the activity There was increased creatinine clearance but no
of proteins. An increase in intracellular cAMP measurable effect on splachnic blood flow. 31,32
enhances Ca2 » influx, resulting in a positive ino-
tropic effect. Similarly, increase in intracellular H2 antagonists
cyclic guanosine monophosphate (cGMP) also pro- Histamine is a biogenic amine, synthesized in hu-
duces physiological effects. Nitric oxide, an impor- man mast cells, which plays a significant role as
tant vasodilator and anti-inflammatory molecule, mediator in the immediate hypersensitivity reaction
increases intracellular cGMP concentrations. and the acute inflammatory response. Histamine is
Drugs such as enoximone, milrinone and olpri- stored in secretory granules and exerts its actions
none inhibit selectively a subgroup of phosphodies- after degranulation and release into extracellular
terases, the phosphodiesterase III. This leads to an space. Its biological effects are mediated through its
increase in the tissue concentration of cAMP only. interaction with cellular H receptors. H2 receptors
On the other hand, the earlier ‘classic’ phosphodies- mediate gastric acid secretion, but also activation of
terase inhibitors, such as pentoxiphyllin, are less lymphocytes, neutrophils and endothelial cells.
selective and also cause an increase in cGMP within These effects may stem from an increase in intra-
the cardiac myocyte. Phosphodiesterase inhibitors cellular cAMP concentrations.33,34 The most impor-
have a peripheral vasodilatory effect in addition to tant role of peripheral H2 receptors in humans
their potential anti-inflammatory properties. appears to be the regulation of gastric acid secretion
Although the exact mechanism of their anti-inflam- and H2 antagonists, such as cimetidine, were devel-
matory effect is not entirely clear, they inhibit oped primarily for the treatment of peptic ulcers.
leukocyte, macrophage and endothelial activa- Protamine is a small positively charged protein
tion. 23,24 that constitutes the only known effective antidote to
Published trials demonstrated that phosphodies- heparin. The formation of protamine/heparin com-
terase III inhibitors reduce plasma levels of inflam- plexes after administration of heparin in cardiac
Review of anti-inflammatory strategies in cardiac surgery
G Asimakopoulos and T Gourlay
11
surgical procedures can lead to a form of anaphy- sure lowering effect and is possibly due to direct
lactic reaction, involving release of histamine.35 tissue action.41 Furthermore, results from the Heart
This is the theoretical basis for the use of H2 Outcomes Prevention Evaluation (HOPE) trial de-
antagonists as potential anti-inflammatory agents monstrated that ACE inhibition, using ramipril,
in cardiac surgery. Two early publications reported reduces the risk of cardiovascular death and myo-
that the use of cimetidine during CPB reduces cardial infarction in patients at risk.42 Consequently,
haemodynamic instability after administration of ACE inhibitors are regarded as potential anti-inflam-
protamine.36,37 In a recent trial, cimetidine infusion matory agents in acute inflammatory conditions
was associated with reduced plasma levels of IL-8 such as cardiac surgery. A recently published non-
and neutrophil elastase levels.38 randomized study showed that IL-6 plasma levels
after cardiac surgery were lower in patients who
ACE inhibitors received ACE inhibitors preoperatively.43
ACE splits off histidyl-leucine from the physiologi- In conclusion, there is wide recognition of the fact
cally inactive angiotensin I, forming the octapeptide that systemic inflammatory response takes place in
angiotensin II. This is an extremely potent vasocon- association with cardiac surgery. Postoperative mor-
strictor, which also promotes release of aldosterone bidity is often related to inflammatory phenomena,
and norepinephrine.39 ACE is widely distributed in prompting basic scientists and clinicians to develop
the body, but it is particularly active in the pulmon- anti-inflammatory strategies that aim to attenuate
ary endothelium. ACE inhibitors reduce blood the damaging effects of systemic inflammation.
pressure by lowering angiotensin II plasma concen- Several methods and drugs are currently used in
trations and also through a diuretic effect. It has also trials with various degrees of success. While
been recognized that angiotensin II affects cell reduction in plasma levels of inflammatory media-
growth, inflammation, fibrosis and coagulation.40 tors has been achieved on many occasions, no single
Numerous recent trials provide evidence that ACE anti-inflammatory method has been shown to re-
inhibition reduces cardiovascular events via a me- duce convincingly postoperative morbidity and
chanism that is independent from the blood pres- mortality.
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