Eur J Cardio-thorac Surg (1991) 5:211-217

C: SpringGVerlag 199 1

The role of different types of corticosteroids on the inflammatory mediators

in cardiopulmonary bypass
N. J. G. Jansen q2, W. van Oeveren I, M. van Vliet 3, C. P. Stoutenbeek 3, L. Eysman 3, and C. R. H. Wildevuur 1
Departments of Cardio-Pulmonary Surgery, Research Division, and Pediatrics, University Hospital Groningen. The Netherlands
3 Departments of Anesthesiology and Intensive Treatment, Hematology and Cardio-Pulmonary Surgery, Onze Lieve Vrouwe Gasthuis,
Amsterdam, The Netherlands

Abstract. In a placebo-controlled double-blind study on patients undergoing cardiopulmonary bypass (CPB) we studied the
inhibiting effects of dexamethasone, a high dose of methylprednisolone, and a low dose of prednisolone on the inflammatory
reaction induced by CPB. During CPB two episodes of blood activation were noticed. First, the blood-material interaction
caused a significant increase in complement C3a and elastase concentrations after the start of bypass (p c 0.01). Secondly,
the reperfusion of the ischemic heart, lungs, and peripheral tissue, after release of the aortic cross-clamp, caused an
additional increase in C3a and elastase concentration and a statistically significant increase in leukotriene B, (LTB,)
concentration and tissue plasminogen activator (t-PA) activity (p < 0.01, p < 0.05, respectively). Dexamethasone treatment
effectively inhibited the increase in LTB, concentration and t-PA activity after release of the cross-clamp (significant
differences to the placebo group, p < 0.01, p < 0.05, respectively). High-dose methylprednisolone treatment was almost as
effective as dexamethasone treatment, whereas low-dose prednisolone treatment was less effective than methylprednisolone
in the inhibition of the inflammatory mediators (DM > MP > P). None of the corticosteroid regimens was able to inhibit
the increase in complement C3a and elastase. We therefore conclude that corticosteroids do not have an effect on
complement activation during CPB. However, leukocyte activation and t-PA activity after release of the aortic cross-clamp
are effectively inhibited by corticosteroid treatment, in a dose-dependent way. The inhibition of this inflammatory reaction
will have a favourable effect on the postoperative course in patients who have undergone CPB. [Eur J Cardio-thorac Surg
(1991) 5:211-2171
Key words: Inflammatory reaction - Reperfusion - Corticosteroids - Cardiopulmonary bypass

The extracorporeal circulation of blood during car-
diopulmonary bypass (CPB) induces a whole-body in-
flammatory reaction [18], which might lead to a postper-
fusion syndrome (PPS), a syndrome comprised of pul-
monary and renal dysfunction and hemorrhagic diathesis
[34]. The activation of the complement system by blood-
material contact is considered to be one of the most im-
portant mediators of PPS [3]. However, in a recent study
we showed that the release of the aortic cross-clamp is
followed by a strong leukocyte inflammatory reaction
which plays an important role in the hemodynamic insta-
bility after CPB [16].
In vivo and in vitro studies have shown that cortico-
steroids are able to inhibit the inflammatory reaction by
inhibition of the complement [14, 331 and fibrinolytic
system [ll]. Corticosteroid treatment also inhibits poly-
morphonuclear leukocyte (PMN) aggregation, especially
Received for publication: October 30, 1990
Accepted for publication: November 15, 1990
by receptor down-regulation on the PMNs [28], and has
a direct inhibitory effect on the leukocyte arachidonic
acid system, by inhibition of the phospholipase A, activ-
ity [15]. For this reason, corticosteroid treatment is rec-
ommended during CPB to inhibit the activation of the
different plasmatic systems and blood cells and reduce
the risk of a post perfusion syndrome [2, 221. However,
there is little agreement as to which corticosteroid regi-
men is the most effective. This can be explained by the
fact that the corticosteroids investigated are of different
types (dexamethasone or methylprednisolone), that dif-
ferent doses are used, and that the observations were
made at different moments during CPB [2, 4, 22, 231.
Although corticosteroids act in a dose-dependent man-
ner, a high dose may be disadvantageous because of
simultaneous inhibition of the host defense against infec-
tion.
The purpose of this study was to determine which of
the selected corticosteroid regimens most frequently used
in CPB had sufficient inhibitory effect on the release of
212
inflammatory mediators during CPB. Patients were
therefore treated with dexamethasone, high-dose methyl-
prednisolone, low-dose prednisolone, or a placebo.
Patients and methods
Patients
Forty-eight patients undergoing elective coronary artery bypass
grafting procedures were studied in a randomized double-blind
trial. All patients gave their informed consent. Patients with insulin-
dependent diabetes mellitus or chronic obstructive disease or who
had used corticosteroids preoperatively were not included. Twelve
patients (group 1) received dexamethasone (Department of Phar-
macology, Onze Lieve Vrouwe Gasthuis, Amsterdam) 1 mg/kg
body wt., 12 patients (group 2) received methylprednisolone
30 mg/kg body wt., 12 patients (group 3) received prednisolone
1 mg/kg body wt., and 12 others (group 4) received a placebo (sa-
line) after induction of anesthesia.
Technique of cardiopulmonary bypass
The extracorporeal circuit consisted of a Bard hollow-fiber mem-
brane oxygenator (Model HF 4000) 3, a Bard cardiotomy reservoir
with filter (Model-H-705 F) and a Bard arterial line filter (Model
H-625). Polyvinyl chloride tubing was used, except for the pump
tubing which was silicon rubber. The extracorporeal circuit was
primed with 2.2 1 Ringers lactate, 0.2 1 20% human albumin4 and
50 mg heparin5. A nonpulsatile flow of 3.0 l/min/m at normother-
mia and 2.4 l/min/m during hypothermia (28-30C) was used.
Heparin (300 IU/kg) was given intravenously before cannulation of
the aorta and repeated at a dose of 25 mg whenever the activated
clotting time was shorter than 400 s. Heparin was neutralized by an
intravenous injection of 300 IU protamine sulfate within 5 min after
the end of perfusion.
When the distal coronary artery anastomosis was established,
the aorta was cross-clamped and cardioplegia was achieved with a
0C isotonic solution containing 15 mmol K+, 15 mm01 Mg + and
1.5 g procaine HCI. Cardioplegic fluid was administered every
20 min. On average, about 2 1 cardioplegic fluid was used.
Technique of anesthesia
Anesthesia was induced with a bolus of alfentanil (50 lg/kg per
minute) and etomidate (0.1 mg/kg) followed by pancuronium
(0.1 mg/kg). Prior to CPB anesthesia was maintained with a contin-
uous infusion of etomidate 10 pg/kg per minute and alfentani13 pLg/
kg per minute; during and after CPB the maintenance dosages of
these drugs were 5 pg/kg per minute and 1.5 pg/kg per minute re-
spectively. When blood pressures increased the alfentanil concen-
tration was changed and a nitroglycerin infusion was started. At
termination of CPB inotropic drugs were given if necessary. All
patients were ventilated to normocapnia (PaCO, 4.5-5 kPa) with
an air/oxygen mixture (FiO,) of 0.5.
Methods
Blood samples were taken from the radial artery or arterial line of
the extracorporeal circuit after induction of anesthesia, 5 min before
1 Solu-Medrol, Upjohn, Puurs, Belgium
2 Di-Adreson-F aquosum, Organon, Oss, The Netherlands
Bard Inc., William Harvey, Santa Ana, California, USA
4 CLB, Amsterdam, The Netherlands
5 Leo, Emmen, The Netherlands
CPB, 5 and 30 min after the start of CPB, at the end of CPB, and
30 min after protamine sulfate administration. In addition, blood
was collected 5 min before and 5 min after release of the aortic
cross-clamp. On the first postoperative day an additional blood
sample was collected for determination of leukocyte and platelet
count and CRP concentration:
- 2 ml blood, anticoagulated with EDTA (0.01 M final concentra-
tion), was collected for hematocrit, platelet, and leukocyte count
using a Cell Counterj. Cell numbers were corrected for hemodilu-
tion, the hematocrit values after induction of anesthesia being used
as a standard.
- 3 ml blood, anticoagulated with EDTA (0.01 M), was centrifuged
and stored at -70C for C3a assay. C3a des arg concentrations were
determined by radioimmunoassay7.
- 4 ml blood, anticoagulated with 0.318% citrate, was collected for
determination of the leukotriene B4 (LTB4), elastase, and C-reac-
tive protein (CRP) concentration and tissue plasminogen activator/
plasminogen activator inhibitor (t-PA/PAI) activity in plasma.
LTB4 generation was determined by radioimmunoassay
(Leukotriene B4 (3H) assay reagents system)*. Prior to the assay,
plasma samples were acidified to pH 3.5 and extracted with ethyl-
acetate. The ethylacetate fraction was collected and dried under
nitrogen. The extract was solved in 0.05 M Tris-HCl buffer
(pH 8.6). These specimens were used for the radioimmunoassay.
Elastase release was quantitated in complex with cc,-proteinase
inhibitor by enzyme-linked immunosorbent assay.
CRP was determined by an immunoassay (Melisa C-reactive
protein kit) lo with a spectrophotometer at 492 nm.
t-PA and PA1 activity were determined by the conversion of
plasminogen and by the amidolytic activity of plasmin on chro-
mogenic substrate (Coa-set t-PA/PAI) I1 with a spectrophotometer
at 405 nm.
Statistical analysis
For comparison of values between the four groups the Mann-Whit-
ney U test was used. Students paired t test was used for comparison
within groups. Statistical significance was assumed when thep value
was less than 0.05.
Results
Patients
The characteristics of all 48 patients are shown in Table 1.
No significant differences in age, body weight, bypass
time, or aortic cross-clamp time were observed between
the four groups. None of the patients developed infection
postoperatively.
Complement activation
After the initial drop in C3a concentrations, due to
hemodilution at the onset of CPB, C3a concentrations
increased steadily during CPB in all four groups, reach-
Hemolog, Coulter Electronics, UK
7 Upjohn, Kalamazoo, Michigan, USA
* Amersham, Buckinghamshire, UK
v Merck, Darmstadt, FRG
lo Walker Laboratories Ltd., Angel Drove, Cambridgeshire, UK
I1 Kabi Diagnostica, Stockholm, Sweden
 213

Table 1. Characteristics of the patients in the four groups (n = 12 in

each) 12cNl1 _ T, T
Group 1 Group 2 Group 3 Group 4

Steroid DM MP P Placebo
Drug concentration 1 30 1 _
(mg/kg)
Age (years) 64k3 59+2 55+4 61+3
Body surface area (m) 1.9 1.9 1.9 1.9
Body weight (kg) 78k3 76k4 76+3 81+3
Bypass time (min) 115k9 93+10 93*9 109&-11
Cross-clamp time (min) 72&6 60*6 59*5 67+8 200 - P
X-clamp
DM = dexamethasone; MP = methylprednisolone; P = prednisolone
0 CPB
Data are means + SEM , I I I I 9
-30 0 30 60 90 120 150
There are no sig&icant differences between the four groups
Time (min)
Fig. 1. Complement C3a concentration in plasma during and after
cardiopulmonary bypass (CPB) in patients treated with dexa-
ing a plateau after about 70 min CPB. No significant methasone (w), methylprednisolone (o), prednisolone (n), or a
differences were seen between the four groups (Fig. 1). placebo (0). During CPB, C3a concentrations increased steadily,
reaching a plateau after about 70 min CPB. No significant differ-
ences were seen between the four groups
Leukocytes
20
The leukocyte numbers (corrected for hemodilution) re- 1
mained stable during the cross-clamp period but in-
* *
creased at the end of CPB in all groups. At the end of 16 - *
zi
OF
l

CPB and after CPB the leukocyte count was higher in the 0
l *

three treated groups than in the placebo group, with a =h

significant difference between the prednisolone and the I 12-

placebo group (~~0.05). At the 1st postoperative day ::
s
leukocytosis was seen in the three treated groups, with a s
significant difference between the dexamethasone and the 6-

methylprednisolone group and the placebo group

(p<O.Oi in both cases; Fig. 2).

Platelets X-clamp 1
I CPB I
0 1 1 I
-30 0 30 60 90 120 Ii0 'Ida;l
At the onset of CPB there was a slight increase in platelet
numbers (corrected for hemodilution) to a similar extent Tiye (min)

in all four groups. The platelet numbers did not change
upon release of the cross-clamp. After release of the aor-
tic cross-clamp and at the end of CPB there was a signif-
icant difference between the prednisoione and the
placebo group (p ~0.05). At the end of CPB and after
protamine sulfate administration the platelet numbers
were significantly higher in the dexamethasone group
than in the placebo group (p < 0.05). On the 1st postoper-
ative day platelet numbers slightly increased in the dexa-
methasone group (Fig. 3).
Leukotriene B4
Upon start of CPB the LTB4 concentrations decreased
in all four groups, but most obviously in the dexa-
methasone-treated group, which was significantly differ-
ent to the placebo group (~~0.05). During the cross-
clamp period the LTB4 concentration reached about
Fig. 2. Leukocyte count in blood during and after cardiopul-
monary bypass (CPB) in patients treated with dexamethasone (m),
methylprednisolone (o), prednisolone (o), or a placebo (0). At the
end of CPB the leukocyte count rose in all groups and remained
higher in the three corticosteroid-treated groups than in the placebo
group. At the 1st postoperative day leukocytosis was seen in the
three corticosteroid-treated groups. * =p < 0.05; ** =p < 0.01
baseline values again in all groups. After release of the
cross-clamp LTB4 concentrations increased significantly
in the placebo group (p < O.Ol), whereas in the corticos-
teroid-treated groups concentrations decreased and were
significantly lower than in the placebo group 0, < 0.01 for
the dexamethasone group, ~~0.05 for the methylpred-
nisolone and prednisolone groups). LTB4 concentrations
remained significantly lower in the dexamethasone group
until the end of CPB (p ~0.05; Fig. 4). The LTB4 concen-
trations at start of CPB were expressed as loo%, to focus
on the effect of the start of CPB and of the release of the
214

1
300

01 X-clamp
X-clamp 1
CPB CPB
100 , I 4 I I I I I I I I
-30 0 30 60 90 120 do 'G -30 0 30 60 90 120 150

Time (min) Time (min)

Fig. 3. Platelet count in blood during and after cardiopulmonary
bypass (CPB) in patients treated with dexamethasone (m), methyl-
prednisolone (o), prednisolone (o), or a placebo (0). During CPB
the platelet count was higher in all four groups; it dropped again
after the end of CPB. At the 1st postoperative day the platelet count
was highest in the dexamethasone group. * =p < 0.05
Fig. 5. Elastase concentrations in plasma during and after cardio-
pulmonary bypass (CPB) in patients treated with dexamethasone
(m), methylprednisolone (o), prednisolone (o), or a placebo (0).
After 30 min CPB the elastase concentrations started to increase
until 30 min after protamine administration. There were no signifi-
cant differences between the four groups

60

60
g 100

z
A

75

50

X-clamp
CPB
25 I I I I I
0 30 60 90 120 150 -30 0 30 60 90 120 150

Time (min) Time(min)

Fig. 4. Leukotriene B, (LTB,) percentages in plasma during and
after cardiopulmonary bypass (CPB) in patients treated with
dexamethasone (w), methylprednisolone (o), prednisolone (o), or a
placebo (0). Upon start of CPB, LTB, concentrations decreased in
all groups, most markedly in the dexamethasone group. After re-
lease of the cross-clamp, the LTB, concentration increased in the
placebo-treated group, whereas it decreased in the corticosteroid-
treated groups. At the end of CPB, LTB, remained lower in the
dexamethasone group. * =p < 0.05; ** =p < 0.01
Fig. 6. Tissue plasminogen activator (t-PA) activity in plasma dur-
ing and after cardiopulmonary bypass (CPB) in patients treated
with dexamethasone (N), methylprednisolone (o), prednisolone (o),
or a placebo (0). After release of the cross-clamp, t-PA activity
increased significantly in the placebo group, with a significant dif-
ference to all the corticosteroid-treated groups. At the end of CPB,
t-PA activity decreased further in the dexamethasone and methyl-
prednisolone groups, remaining lower than in the placebo group.
*=p<o.o5; **=p<o.o1

cross-clamp, and because of some individual variation in end of CPB were in all groups significantly higher than at
baseline values (range 2.4-12.9 ngjml). the start of CPB (pt0.01). No significant differences
were seen between the four groups (Fig. 5).
Elastase
C-reactive protein
The elastase concentrations started to increase after
30 min CPB in all groups and increased further after re- The CRP concentrations remained stable during and im-
lease of the cross-clamp. Elastase concentrations at the mediately after CPB in all four groups. At day 1 there was
 21.5

Table 2. Comparison of CRP and PAI concentrations (mean + SEM) during and after CPB in the four groups

Time CRP (mg/I) PA1 (AU/l)

DM MP P Placebo DM MP P Placebo

Anesthesia 4_tl 5*2 4+2 2+1 163kll 16Ok18 158& 8 158k13

5 min before 4*1 3*1 4+2 2,l 153*11 156+ 6 137*13 155+12
5 min after 142+10 141+ 7 129+ 10 142+11
30 min after 311 2*1 4*1 2+1 139113 139+ 7 1305 8 145*11
Before cross-clamp 138+13 145+ 5 123* 10 142kll
After cross-clamp 135*14 14Orl: 6 121* 7 136k 13
End of CPB 2+0 2+1 3+1 I*1 138+11 151+ 6 125k 6 127+ 14
30 min of protamine 2*1 1*1 4,l 2*1 156kll 159k 6 153k22 153512
Day 1 32&-8 47$11 52+8 62k6

DM = dexamethasone; MP = methylprednisolone; P = prednisolone

Data are mean f SEM
There are no significant differences between the four groups

a significant increase in CRP concentrations in all four
groups, with the highest concentration in the placebo
group and the lowest in the dexamethasone-treated
group. There were no significant differences between the
four groups (Table 2).
t-PA activity
Five minutes before start of CPB there was a steep in-
crease in t-PA activity in all four groups, followed by a
rapid drop 5 min after start of CPB. After release of the
cross-clamp t-PA activity increased significantly in the
placebo group (JJ< 0.05) and remained high until the end
of CPB. In the corticosteroid-treated groups t-PA activity
was significantly lower after release of the cross-clamp
than in the placebo group (p<O.O5 in comparison with
the dexamethasone and prednisolone groups and p < 0.01
in comparison with the methylprednisolone-treated
group). At the end of CPB t-PA activity decreased further
in the dexamethasone and methylprednisolone groups,
both to significantly lower activities than in the placebo
group (~~~0.05; Fig. 6).
Plasminogen activator inhibitor
Upon start of CPB the PA1 concentrations decreased
slightly in all four groups and remained stable until the
end of CPB. After CPB, PA1 concentrations increased
slightly in all groups. No significant differences were seen
between the groups (Table 2).
Discussion
None of the corticosteroid regimens in this study inhib-
ited either complement activation or elastase release dur-
ing CPB. High-dose methylprednisolone treatment in
particular has been described as inhibiting complement
activation in CPB [2, 141, but we and others have been
unable to confirm these findings [8, IO]. The failure to
inhibit complement activation in this study may also be
related to the ineffectiveness of the corticosteroid regi-
mens in preventing release of elastase. It can therefore be
concluded that corticosteroid treatment is not able to
inhibit the material-dependent blood activation seen
upon start of CPB. However, corticosteroids were able to
inhibit the leukocyte inflammatory reaction after release
of the aortic cross-clamp, as is shown by the inhibition of
the leukocyte arachidonic acid metabolism, as quanti-
tated by LTB4 activity. Of the three corticosteroid regi-
mens, dexamethasone treatment had the strongest inhib-
itory effect on the inflammatory reaction. Dexameth-
asone is the glucocorticosteroid with the strongest anti-
inflammatory response and longest duration of action
[21]. Methylprednisolone and prednisolone both have a
shorter duration of action, but because of the high dose
administered, methylprednisolone was almost as effective
as dexamethasone. Low-dose prednisolone inhibited the
inflammatory reaction less effectively than dexameth-
asone and methylprednisolone, which could be due to the
dose-related shorter half-time [21].
The leukocyte inflammatory reaction seen after reper-
fusion of the heart, lungs, and peripheral tissues could be
due to washout of release products of PMNs that were
activated in the stagnant circulation during the period of
cross-clamping [7], or due to leukocyte sequestration in
the lung, which occurs after release of the cross-clamp [9,
251. Corticosteroid treatment can inhibit leukocyte aggre-
gation [28], which also explains the leukocytosis on the
1st postoperative day, and can decrease the superoxide and
hydrogen peroxide production of activated leukocytes
[18]. Together with the inhibition of LTB4, this could
prevent plasma leakage through the endothelial barrier
[19, 271.
The higher platelet numbers at the end of CPB and on
the 1st postoperative day in the corticosteroid-treated
groups can also be explained in part by the inhibitory
effect of corticosteroids on activated leukocytes; the re-
216
lease of thromboxane A, and platelet activating factor
from activated PMNs is known to cause irreversible
platelet aggregation [ 12, 321.
The increase in t-PA activity after release of the cross-
clamp may be due to release from endothelial cells during
stagnant circulation and by activated PMNs [6]. t-PA is
known to deteriorate the endothelial barrier and can in-
duce respiratory distress by generation of fibrin degrada-
tion products [20, 261. Dexamethasone and methylpred-
nisolone and to a lesser extent prednisolone, were able to
reduce t-PA activity, which was not due to the release of
a PA1 [5], because we observed no significant changes in
PA1 concentrations during and after CPB in any group.
It is therefore more likely that the reduced t-PA activity
in the corticosteroid-treated patients may be due to a
direct protective effect on endothelial cells [29] and/or
reduced leukocyte enzyme release.
Corticosteroid treatment is described to have a favour-
able effect on CPB patients postoperative course 1221,
which agrees with the CRP concentrations at day 1 in this
study. CRP is an acute-phase protein, known to increase
upon tissue lesion and inflammation and by stimulation
of interleukin 1 (IL-l) [13, 241. Therefore, lower CRP
concentrations at day 1 might correlate with a better
postoperative clinical course. High-dose corticosteroid
treatment (especially dexamethasone and methylpred-
nisolone) resulted in a significantly better hemodynamic
course during the first postoperative days in the intensive
care unit following CPB [22, 301, whereas low-dose corti-
costeroid treatment only had a favourable effect in the
first 3 h after CPB [30]. This suggests that low-dose pred-
nisolone treatment could be effective in the first period of
CPB, but should be repeated until the activation process
is discontinued. This might in some circumstances be
the preferred treatment, since recent studies have shown
that high-dose methylprednisolone given to patients suf-
fering from sepsis did not improve the survival rate, be-
cause there was an increase in infectious complications
due to immunosuppression caused by the steroid treat-
ment [l, 311.
In conclusion: corticosteroids cannot inhibit biomate-
rial-induced complement activation during CPB. How-
ever, they can reduce the inflammatory reaction, as is
clearly shown by the decrease in LTB4 concentrations
and t-PA activity upon reperfusion of the heart, lungs,
and peripheral tissue in this study. Prophylactic cortico-
steroid treatment with sufficient duration of action, espe-
cially dexamethasone 1 mg/kg body wt., inhibits the for-
mation of inflammatory mediators most effectively and is
therefore recommended for routine use during CPB pro-
cedures.
Acknowledgements. We thank the anesthetists and perfusionists of
the Onze Lieve Vrouwe Gasthuis for their cooperation during this
study. We want especially to thank Dr. van der Linden (Pharmacol-
ogy) for her support in this study. We also thank J. Haan for his
technical assistance in performing the assays.
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