Antioxidant defence during cardiopulmonary bypass surgery

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European Journal of Cardio-thoracic Surgery 27 (2005) 611–616
www.elsevier.com/locate/ejcts
Antioxidant defence during cardiopulmonary bypass surgery
Chris R. Luytena, Frans J. van Overvelda, Lieve A. De Backera, Anna M. Sadowskaa,*,
Inez E. Rodrigusb, Stefan G. De Hertc, Wilfried A. De Backera
a
Department of Respiratory Medicine, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen-Wilrijk, Belgium
b
Department of Cardiac Surgery, University Hospital Antwerp, Antwerpen-Wilrijk, Belgium
c
Department of Anesthesiology, University Hospital Antwerp, Antwerpen-Wilrijk, Belgium
Received 15 July 2004; received in revised form 3 December 2004; accepted 13 December 2004; Available online 13 January 2005
Abstract
Objective: Cardiac surgery may lead to severe oxidative stress due to formation of oxidation products generated during ischemia and
reperfusion. We investigated to which extent oxidative stress influences a number of endogenous antioxidants and markers of cellular
activation. Methods: At six time points blood was withdrawn from patients undergoing coronary artery bypass grafting, using the on-pump
procedure. Results: Both glutathione peroxidase and superoxide dismutase show a gradual and strong increase in activity during surgery (40 and
30%, respectively), returning to baseline values 24 h after surgery. The total antioxidant capacity has a maximum increase of 60%. Markers of
cellular activation, such as eosinophil cationic protein and tryptase also increase during the procedure. Conclusion: Cardiac surgery results in
systemic inflammation accompanied or caused by severe oxidative stress. The human body has a strong innate oxidative defence screen, which
is probably not sufficient to fully compensate for the total amount of oxidative damage.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Bypass surgery; Antioxidants; Glutathione peroxidase; Superoxide dismutase; Oxidative stress
1. Introduction
Although open cardiac coronary artery by-pass grafting
(CABG) surgery has become a routine procedure worldwide,
patient morbidity and mortality due to adverse postoperative complications are still unacceptably high. The
endothelial injury and/or cardiac, renal, hepatic or pulmonary dysfunction associated with CABG surgery have been
linked to the inflammatory responses and systemic oxidative
stress directly caused by this procedure but the underlying
mechanisms have not been fully elucidated yet.
It has been suggested that in addition to the damage
caused directly in the myocardium, a significant proportion
of the adverse outcomes may also be caused by the systemic
effects of cardiopulmonary bypass (CPB) [1]. It has moreover
been demonstrated that on-pump procedure gives rise to a
more pronounced systemic inflammation and oxidative
stress than the off-pump procedure [2]. The mechanisms
explaining these observations may be related to several
deleterious events occurring during CPB [3] which are either
material-dependent (caused by exposure of blood to nonphysiologic surfaces and conditions during the extracorporeal circulation, ECC) or material-independent (caused by
* Corresponding author. Tel: C32 3 820 2591; fax: C32 3 820 2590.
E-mail address: [email protected] (A.M. Sadowska).
1010-7940/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejcts.2004.12.013
surgical trauma, ischemia-reperfusion and changes in body
temperature). One of the most damaging consequences of
these events is the formation of reactive oxygen species
(ROS) and radicals, which originate from various cellular and
enzymatic sources such as myocardial cells, activated
neutrophils [4] or endothelial xanthine oxidase. These are
closely linked to inflammatory responses, including complement activation, release of cytokines and leukocyte
activation, along with expression of adhesion molecules
[5]. Many studies have described the nature of these ROS and
the time course of their formation during CPB [6]. The nature
of these oxidative events leads to depletion of plasma
antioxidants, increased lipid peroxidation and formation of
other damaging metabolites [7–9]. In order to counterbalance this sequence of events and to diminish oxidative
injury, several studies have investigated the use of antioxidant supplements during ECC [10,11]. Less is known about
the consequences of CPB on the endogenous antioxidant
capacity that is derived from the activity of antioxidant
enzymes such as glutathione peroxidase (GPx) and superoxide dismutase (SOD), responsible for the clearance of
peroxides and superoxide, respectively.
In order to investigate this question, our study focused on
the time course of innate antioxidant activity (antioxidant
enzymes and global antioxidant capacity in plasma) in
patients undergoing cardiopulmonary bypass surgery. In
particular, we were interested in analysing to which extent
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C.R. Luyten et al. / European Journal of Cardio-thoracic Surgery 27 (2005) 611–616
antioxidants were being generated or activated during CPB.
In order to elucidate the relationship between the changes in
antioxidant status and the activation of inflammatory cells
during CPB, we also monitored markers of leukocyte
activation such as tryptase and eosinophil cationic protein.
were measured in every blood sample. In order to take
dilution with the priming solution of the CBP system into
account, the value of the first blood sample (pre-surgery)
was set as a reference baseline value. All obtained data were
then corrected for haemodilution using the hematocrit
values to calculate the appropriate correction factor.
2. Materials and methods
2.4. Antioxidant measurements
2.1. Study population
Trolox equivalent antioxidant capacity (TEAC) was
measured in plasma according to the method of Rice-Evans
and Miller. TEAC is a measure that is indicative for the whole
pool of antioxidants in plasma and thus for the total
antioxidant capacity of plasma. Trolox is a synthetic vitamin
E analog with antioxidant activity, which is able to prevent
radical generation by H2O2 in a reaction mixture containing
metmyoglobine and 2, 2 0 -azino-bis (3-ethylbenzthiazoline-6sulfonic acid (ABTS). When antioxidant activity in the milieu
is depleted, ABTS forms stable coloured radicals that can be
measured by spectrophotometry (absorption at 734 nm).
Plasma antioxidant capacity is compared with a calibration
curve of trolox concentration and thus trolox equivalent
antioxidant capacity can be calculated. Intra and inter-assay
CV was 5 and 14%.
Glutathione peroxidase (GPx) in full blood was measured
with a Ransel Glutathione Peroxidase kit (Randox Laboratories Ltd), and is based on the method of Paglia and
Valentine: GPx catalyses the oxidation of glutathione (GSH)
by cumene hydroperoxide. In the presence of glutathione
reductase and the oxidized glutathione (GSSG) is immediately converted to the reduced form with a concomitant
oxidation of nicotinamide adenine dinucleotide phosphate,
reduced form (NADPH) to NADPC. The decrease in absorbance of NADPH can be measured at 340 nm. Intra- and
inter-assay CV was 2 and 6%.
Superoxide dismutase (SOD) was measured with a RanSOD
superoxide dismutase kit (Randox Laboratories Ltd). The
role of SOD is to accelerate the dismutation of the toxic
superoxide radical OK
2 to hydrogen peroxide and molecular
oxygen. The Randox method uses xanthine and xanthine
oxidase to generate superoxide radicals that react with 2-(4iodophenyl)-3-(4-nitrophenol)-5-phenyltetrazolium (I.N.T.)
to form a red formazan dye. The SOD activity is then
calculated from the degree of inhibition of this reaction
compared to a standard curve of SOD. Intra- and inter-assay
CV was 6 and 15%.
Alpha-tocoferol and retinol in serum were measured by
High Performance Liquid Chromatography (Dionex, HPLC
with a 100% methanol mobile phase) with detection at 292
and 325 nm, respectively. Intra- and inter-assay CV was 5
and 13%.
Ten patients (6 males, 4 females, mean age 68.4 yrsG
7.7 SD) undergoing elective coronary artery bypass grafting
were included in this study. Perioperative data are shown in
Table 1. This study was in accordance to the principles
outlined in the Declaration of Helsinki. Patients were
informed of the procedure and the ethical committee of
the University Hospital of Antwerp approved the study
protocol.
2.2. Cardiopulmonary bypass
Anaesthesia with endotracheal intubation and balanced
administration of premedication and transfusions was
uniform in all cases. The CPB equipment consisted of a
Bentley membrane oxygenator (Bentley Oxygenation system
CM50, Baxter, Ivina CA, USA). The pump-oxygenator system
was primed with 1800 ml crystalloid solution (Plasma-Lyte A,
Baxter) and 6% HetaStarch. Anticoagulation was achieved by
300 U/kg heparin (Leo Pharma, Denmark). All patients were
cooled to 28 8C. Surgery was performed using the intermittent cross-clamp technique. Fifteen minutes after
decannulation, heparin was neutralised with protamine
chloride (1:1 ratio; Roche, Belgium). Patients only received
autologous transfusion with residual blood left in the pump
after CPB.
2.3. Blood sampling
Blood samples were collected into sterile Lithium-heparin
tubes and SST-tubes with clotting activator (Vacutainer,
Becton Dickinson) at several time points during and after
cardiac surgery: (a) 10 min after induction of anaesthesia
(left radial artery), (b) 10 min after start of ECC (arterial side
of pump), (c) at the end of ECC (arterial side of pump), (d)
10 min after protamine administration (left radial artery),
(e) 4 h and (f) 24 h after surgery (left radial artery). Blood
samples were processed within 10 min after sampling to
avoid auto-oxidation of antioxidants. Hematocrit values
Table 1
Patient characteristics, operative and postoperative data
Number of patients
Male/female
Age (yrs)
BMI (kg/m2)
Elective/urgent
Graft/patient
Cardiopulmonary bypass time (min)
Cross-clamp time (min)
Fluid balance (mL)
10
6/4
72 (56–77)
26.4G3.4
10/0
4 (2–5)
119 (83–186)
52 (35–126)
648G446
Data presented as meanGSD or median (minimum–maximum).
2.5. Markers of cellular activation
Eosinophil cationic protein (ECP) was measured in serum
using a fluoroenzymeimmunoassay provided by Pharmacia
(Uppsala, Sweden). Anti-ECP, covalently coupled to ImmunoCAP, reacts with the ECP in the patient’s serum specimen.
After washing, enzyme-labelled antibodies against ECP are
added to form a complex. After incubation, unbound
enzyme-anti-ECP is washed away and the bound complex is
C.R. Luyten et al. / European Journal of Cardio-thoracic Surgery 27 (2005) 611–616
Fig. 1. Levels of glutathione peroxidase (GPx) in full blood before, during, and
after cardiopulmonary bypass surgery. *P!0.05 when compared to the value
before surgery.
613
Fig. 3. Concentrations of a-tocopherol (vitamin E) in serum before, during,
and after cardiopulmonary bypass surgery. *P!0.05 when compared to the
value before surgery.
3. Results
then incubated with a developing agent. After stopping the
reaction, the fluorescence is measured. The fluorescence is
inversely correlated with the concentration of ECP in the
serum sample. Measuring range is 2–200 mg/l. Within assay
CV is 3.8%.
Tryptase is a serine protease released by mast cells upon
activation. It can be measured in serum applying an
immunoassay from Pharmacia, according to the same
principle as described for ECP. Measuring range for undiluted
sample is 1–200 mg/l. Within assay CV is 3%.
2.6. Statistical analysis
Data are shown as meanGSEM. Analysis of variance for
repeated measures was used to compare changes in time.
Differences were considered significant at P value less than
0.05.
The power of the primary end-points (GPX, SOD and
TEAC) was O0.7.
Fig. 2. Levels of superoxide dismutase (SOD) from red blood cells before,
during, and after cardiopulmonary bypass surgery. *P!0.05 when compared
to the value before surgery.
Enzyme activity of the antioxidants GPx and SOD in full
blood increased significantly in the initial stages of
surgery. When looking at the changes within each individual
(in-patient), GPx rose by an average of 20% at 10 min after
starting the ECC compared to pre-surgery values, and
reached a maximum average increase of 40% at the end of
cross-clamp circulation (Fig. 1). SOD reached a 30%
maximum rise in activity at the end of surgery, after the
administration of protamine (Fig. 2).
Serum concentration of retinol and a-tocopherol varied
rather widely between patients in all measurements. We saw
that both retinol (data not shown) and a-tocopherol
remained constant during CBP (Fig. 3). It is only from 4 h
after surgery that serum concentration of these antioxidants
decreased significantly.
Total antioxidant capacity of plasma (TEAC) (Fig. 4)
increased from 0.9 mM Trolox equivalents to 1.45 mM at
10 min of ECC, corresponding to an increase of plasma
antioxidant capacity of 60%.
Fig. 4. The total antioxidant capacity (TEAC) of plasma before, during, and
after cardiopulmonary bypass surgery. *P!0.05 when compared to the value
before surgery.
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Fig. 5. Levels of serum tryptase before, during, and after cardiopulmonary
bypass surgery. *P!0.05 when compared to the value before surgery.
Tryptase levels in serum increased markedly (by 60%,
P!0.05) during ECC (Fig. 5), gradually returning to baseline
values after surgery. As for ECP, serum concentration was up
to 4 times higher at the end of ECC (P!0.01) (Fig. 6),
decreasing again to baseline values towards the end and
after the procedure. An artefact in two blood samples
caused the seemingly high values at 24 h after surgery.
4. Discussion
The systemic increase in oxidative stress during CABG is
well-documented [5,7] but the various components of the
oxidant-antioxidant balance and the contribution of the
various mechanisms involved have not been fully evaluated
yet. This study aimed at describing the changes in
endogenous antioxidant capacity in patients undergoing
CABG under procedures which are known to enhance
production and release of oxidants. Firstly, the intermittent
clamp technique used under the CPB is a direct cause of
ischemia-reperfusion with, as a consequence, release of
superoxide by the xanthine-oxidase system [2]. In addition,
extracorporeal circulation, by increasing contact of blood
Fig. 6. Concentrations of eosinophil cationic protein (ECP) in serum before,
during, and after cardiopulmonary bypass surgery. *P!0.05, **P!0.01 when
compared to the value before surgery.
with foreign substances, will induce systemic inflammatory
responses associated with complement activation, cytokine
release and cellular activation of neutrophils [1]. These are
all sources of ROS production [12] which will ultimately lead
to depletion of plasma antioxidants [8]. In a previous study
we already described a decrease in plasma glutathione
during CPB [9]. In the present study, we used TEAC as a
marker for total antioxidant capacity in plasma. Unexpectedly, we did not document a decrease of TEAC value, or—in
other words—a depletion of plasma antioxidants, but an
almost twofold increase. The nature of this increase is not
known. Two abundant plasma molecules with antioxidant
activity, namely albumin and uric acid are the main
determinants of the TEAC value. Albumin concentration in
plasma, however, did not increase significantly during CPB
(data not shown) and could therefore, not have contributed
to the increase of TEAC value. The contribution of uric acid
herein could not be assessed, due to technical limitations.
Another possible cause of increased TEAC value could have
been haemolysis of red blood cells during or after sampling.
Hemoglobin has been shown to interfere with the TEAC
measurements. Thus the impact of free hemoglobin and uric
acid in plasma should be taken into account when measuring
global antioxidant capacity in future studies.
The activity of the enzymatic antioxidants glutathione
peroxidase (GPx) and superoxide dismutase (SOD) increased
significantly during ECC. This could explain the time course
of depletion of GSH we observed previously, because GPx
uses GSH as a cofactor [10]. Moreover, when comparing our
time course of GPx activation and the time course of TBAreactive peroxides as described by Davies [6], we see a close
match. This parallelism suggests that glutathione peroxidase
forms a first barrier against the reactive oxygen species
being formed during the operation. Our findings confirm the
results obtained by Arduini et al. [13], who also found an
increase in GPx activity. Others studies, however, observed
a decrease in GPx activity [14], or no change during CPB [15].
Most of these studies, however, were performed on animal
models, which may explain part of the discrepancy between
our study and the ones just mentioned.
SOD, the enzyme responsible for converting superoxide
anion into hydrogen peroxide, was also strongly activated, a
fairly acute response lasting from early CPB until after
protamine administration. This can be explained by the fact
that contact of blood with polymers of the CPB circuit
releases cytokines and activates neutrophils [12], independent of heparin coating. Activated neutrophils will via the
respiratory burst generate superoxide anion which is
detoxified by SOD. These two findings illustrate that GPx
and SOD form a strong first line of defence against reactive
oxygen species. Moreover, GPx and SOD are enzymatic
antioxidants which are not consumed during their detoxification activities. In contrast, antioxidants which act as
free radical scavengers are consumed during oxidative
processes and the time courses of depletion vary depending
on the nature of the antioxidant.
Retinol is not considered to be a very potent antioxidant,
although its precursors of the carotenoid group are. Alphatocopherol on the other hand is well known for its
antioxidative capacity. However, its role is rather controversial, for some studies find supplementation of patients
C.R. Luyten et al. / European Journal of Cardio-thoracic Surgery 27 (2005) 611–616
with a-tocopherol prior to CPB to be beneficial [16], while
several big-scale studies such as the Heart Outcomes
Prevention Evaluation (HOPE) study, clearly demonstrated
that vitamin E supplementation, independently of surgery,
had no apparent effect on cardiovascular outcomes [11].
Also, the role and consumption of a-tocopherol during CPB
are debatable. Some studies state that a-tocopherol level
decreases during and after CPB [17], while others find a
slight or non-significant decrease in serum a-tocopherol
concentration [18]. Our results, after correction for haemodilution, are similar to the ones published by Barsacchi et al.
[17] who found a decrease of a-tocopherol concentration
under conditions of ischemia and reoxygenation. However,
the decrease observed in our study was only significant after
surgery. This time course suggests that it can be the result of
post-ischemic repair of (membrane) lipid peroxides. An
added cause can be the depletion of vitamin C during CPB.
Since vitamin C is able to regenerate vitamin E from its
radical intermediate, consumption of a-tocopherol is more
likely if vitamin C is depleted [19]. Ballmer et al. have shown
that vitamin C is strongly depleted after CPB [20]. These
observations suggest that the oxidative burden during CPB
would, in a first instance, consume vitamin C, together with
reduced glutathione, which are the most effective watersoluble non-enzymatic antioxidants under conditions of
oxidative stress. Their ensuing depletion and, as a consequence, that of a-tocopherol, may seriously alter the rest of
the anti-oxidative cascade and result in systemic whole-body
inflammation which then increases the risk of post-ischemic
damage.
In order to elucidate the relationship between the changes
in antioxidant status and the activation of inflammatory cells
during CABG, we also monitored markers of leukocyte
activation. Evidence of neutrophil activation during ECC has
been provided by other authors [4]. In addition, in a previous
study performed at our institution by Jorens et al. [21], IL-8
response was monitored and found to be significantly
increased during CPB, returning to normal values 20 h postoperative. In the present study we found a peri-operative
increase in serum eosinophil cationic protein (ECP) and
tryptase levels. This suggests that both eosinophils and mast
cells were activated during or after CABG and points out to a
possible anaphylactoid reaction. Nevertheless, ECP release is
not only a sign of eosinophil activation as it is supposed to be
transported by neutrophils [22]. Moreover, despite the fact
that ECP is of eosinophilic origin, in some studies in asthma
patients no relationship was found between eosinophil
number and ECP levels in sputum [23]. This observation
suggests that the ECP sputum concentrations are not merely a
function of the eosinophil numbers but could also be an
indirect marker of neutrophil activation.
With regard to the activation of mast cells during CABG,
several underlying mechanisms could explain this observation. Mast cells are heavily granulated wandering cells
found in connective tissue and are abundant beneath
epithelial surfaces. The release of their granule content
(heparin, histamine and many proteases such as tryptase)
can be triggered by physical factors (mechanical trauma,
changes in temperature), toxins, endogenous mediators
(proteins, tissue proteases) and immune mechanisms (IgE
dependent and independent). Also complement activation
615
can cause mast cell degranulation (anaphylotoxins C5a, C3a
and C4a are formed during complement activation) [24]. All
these processes can occur during the ischemia-reperfusion
and ECC of the CPB procedure and can, moreover, be linked
to the oxidative activity. For example, activation of C5a
receptors on mast cells during CPB may trigger degranulation. Furthermore, tryptase released from mast cells can
further stimulate the release of IL-8 and up-regulate ICAM-1
on epithelial cells [24]. Based on these facts, the activation
of mast cells during CPB is not necessarily a sign of allergy
but could just be a consequence of complement activation.
There is also a growing body of evidence that mast cells are
activated during ischemia-reperfusion. The increased influx
of oxidants occurring at the onset of reperfusion may thus
also be responsible for mast cell activation [25]. It has
already been reported that superoxide is known to activate
these cells [26] which in turn play a role in neutrophil
activation and infiltration into the lung [27], thus, in their
turn, further aggravating the release of ROS.
In summary, this study, performed in a small number of
selected patients, showed that there was a strong innate
antioxidant response under the conditions of acute
oxidative stress occurring during CABG. However, it is
well documented that post-ischemic oxidative damage still
occurs. This indicates that this antioxidant response is not
sufficient to counteract the heavy oxidant burden of these
surgical procedures. It would be interesting to investigate
whether supplementation with antioxidant mixtures such
as vitamin C plus glutathione could, in a first instance,
prevent their depletion during CPB, and, in a second
instance, suppress the post-ischemic inflammatory
response.
This study also showed that there was a significant and
parallel release of markers of anaphylaxis. The role played
herein by mast cell and eosinophil activation needs further
investigation. The information collected in such studies will
aid in the search for effective systemic measures to prevent
post-ischemic damage and thus ensure a better outcome for
patients undergoing cardiac surgery.
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