(Circulation. 1995;92:347-353.)
© 1995 American Heart Association, Inc.
Articles |
Steroid Inhibition of Cytokine-Mediated Vasodilation After Warm Heart Surgery
From the Departments of Medicine and Surgery and Pathology, McMaster University, and the Hamilton Civic Hospitals, Hamilton, Ontario, Canada.
Correspondence to Kevin H.T. Teoh, MD, 293 Wellington St N, Suite 132, Hamilton, Ontario L8L 8E7, Canada.
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Abstract |
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Background Peripheral vasodilation, a potentially adverse effect of warm heart surgery, may be mediated by the perioperative release of cytokines. Corticosteroids may abolish cytokine production and vasodilation. We investigated cytokine production and its inhibition by steroids in patients undergoing elective coronary bypass surgery.
Methods and Results Twenty-five patients undergoing coronary bypass surgery with normothermic cardiopulmonary bypass received either preoperative steroid (Solumedrol 250 mg IV, n=16) or no steroid (n=9, control group). Blood samples were obtained serially for 24 hours and assayed for interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-8 (IL-8). In the control patients, the IL-6, TNF, and IL-8 levels were elevated postoperatively and peaked between 3 and 6 hours after surgery (IL-6, 1330±295 [mean±SEM] pg/mL; TNF, 18.4±9.8 pg/mL; and IL-8, 150±51 pg/mL). Cytokine release was abolished in patients receiving preoperative corticosteroid (IL-6, 75±38 pg/mL; TNF, 2.6±0.5 pg/mL; and IL-8, 33±6.7 pg/mL; P<.05). Patients receiving steroid premedication had higher arterial pressure, lower cardiac index, and higher systemic vascular resistance, indicating less vasodilation.
Conclusions Our findings demonstrate that cytokine production occurs after normothermic cardiopulmonary bypass. Preoperative administration of steroids abolishes cytokine release and vasodilation.
Key Words: cytokines • cardiopulmonary bypass • steroids
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Introduction |
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Cardiopulmonary bypass (CPB) is associated with an inflammatory systemic reaction. In its most severe form, this inflammatory reaction, also called post–pump perfusion syndrome, is characterized by increased capillary permeability, increased interstitial fluid, peripheral vasoconstriction, fever, myocardial edema, diffuse cerebral edema, and a diffuse bleeding diathesis.1 Although most patients convalesce normally after cardiac surgery, all patients are thought to experience these damaging effects to some degree.1
The pathogenic mechanism responsible for the post–pump perfusion syndrome has not been elucidated fully. Generation of complements, specifically C3a, C4a, and C5a, has been demonstrated by several investigators.2 3 4 5 6 Both C3a and C5a anaphylatoxins can induce a systemic inflammatory reaction manifested by increased capillary permeability, histamine release from mast cells, and organ dysfunction.
Injury or trauma to the body triggers this cascade of events, known as the acute phase reaction.7 8 The nature of this noxious stimulus is not well known, and the cells subsequently activated include monocytes, macrophages, fibroblasts, endothelial cells, T lymphocytes, and epithelial cells. It has been shown that the acute phase response is mediated by cytokines derived from these activated cells. The cytokines include tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6.7 It has been shown in animal models that ischemic reperfusion injury in the liver is followed by the release of TNF and subsequently by a systemic inflammatory reaction.
After CPB, levels of TNF, IL-6, and IL-1 all have been shown to increase. These cytokines are recognized as critical early mediators of organ injury, and thus they may play a role in initiating the cascade that leads to the post–pump perfusion syndrome that is observed clinically. During CPB and cardioplegic arrest, the heart essentially is undergoing an ischemic reperfusion injury.
After removal of the aortic cross-clamp, there is pulmonary sequestration of neutrophils.9 10 11 Complement certainly has been implicated as one of the initiators of this phenomenon9 10 11 ; however, the other inflammatory cytokines, including TNF and IL-6, also may play a role.9 Recently, a cytokine called IL-8, which belongs to a family of neutrophil-attacking and neutrophil-activating peptides, was discovered.12 13 14 15 In vitro work has shown that IL-8 can produce neutrophil sequestration in the lungs,16 and thus it may be one of the stimuli for the acute microvascular lung injury identified after CPB.
Administration of corticosteroids during CPB was shown to improve the postoperative course, and to improve survival in two randomized but small studies.9 17 Steroids also have been shown to decrease the generation of TNF during CPB.9 If cytokine generation is an important mediator of post–pump perfusion syndrome, steroid administration may play an important role in attenuating the clinical response, although further clinical studies are needed to substantiate this hypothesis.
Warm heart surgery recently was introduced as an alternative method of myocardial protection. Normothermic CPB is an integral component of warm heart surgery. Previous studies have reported lower systemic vascular resistance with normothermic versus hypothermic CPB.18 Enhanced cytokine release after normothermic CPB may cause the vasodilation associated with normothermic CPB. Knowledge of cytokine production after normothermic CPB is limited.
We propose that the cytokines TNF, IL-6, and IL-8 are released after normothermic CPB and that they mediate postoperative vasodilation. Corticosteroids may abolish cytokine release after normothermic CPB and reduce postoperative vasodilation. This study prospectively looked at the release of TNF, IL-6, and IL-8 in patients undergoing CPB, both with and without pretreatment with methylprednisolone.
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Methods |
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Patient Population
Twenty-five patients who were undergoing elective coronary artery bypass surgery enrolled in the study. These patients signed a consent form that was approved by the Institutional Review Board. Patients who had diabetes mellitus or who were steroid dependent were excluded. Sixteen patients received preoperative steroid medication; 9 patients served as controls and did not receive steroids.
Steroid Administration
Patients assigned to the steroid group
received 250 mg IV
Solumedrol (methylprednisolone) before anesthetic induction and
surgery. Patients in the control group did not receive steroid
medication.
Operative Technique
Radial and pulmonary arterial catheters
were
introduced under local anesthesia. Anesthesia
was induced and maintained with either fentanyl or sufentanil. Muscle
relaxation was achieved with either pancuronium bromide or vecuronium
bromide. CPB was instituted with an ascending aortic cannula and a
two-stage right-atrial cannula. The extracorporeal circuit
consisted of a roller pump, a cardiotomy reservoir, and a
semiporous-membrane oxygenator (CML, COBE Laboratories Inc). The
circuit was primed with 2.5 L Ringer's lactate solution. Heparin was
given at an initial dose of 400 U/kg body wt to achieve an
activated clotting time of >400 seconds before CPB was
instituted. A pump flow rate of 2.5
L · min-1 · m-2 was used.
Normothermia was maintained during CPB. Cold blood potassium
cardioplegia was used for myocardial protection. After discontinuation
of CPB, heparin was reversed with protamine sulfate by heparin-ACT
dose-response curve.
Measurements
Blood samples were obtained before surgery and
serially after
surgery for measurement of IL-6, TNF, and IL-8. The blood samples were
taken before operation (before anesthetic induction), during CPB (30
minutes), after aortic-cross-clamp release (5 minutes), and
after operation at 1, 3, 6, 12, and 24 hours. Blood was withdrawn from
the radial artery catheter and collected into vacuum tubes.
Platelet-poor plasma was prepared by
centrifugation at 2000g for 15 minutes. The
plasma was stored in polypropylene tubes at -70°C until use.
Cytokine Assays
IL-6 Bioassay
IL-6 bioactivity
was tested with a B9 hybridoma cell assay as
described.17 Human sera were
heat-inactivated (60°C, 1 hour) before assay. The
assay is sensitive to 1 pg/mL and is standardized against purified
recombinant human IL-6. Antibody to recombinant human IL-6 is used to
neutralize bioactivity to confirm the specificity of the assay.
Human
TNF-
enzyme immunoassay. The human TNF enzyme
immunoassay, BIOTRAK product code RPN-2148, distributed by Amersham
Canada was used. Recombinant human IL-8 standards cover the range of
23.4 to 6000 pg/mL.
Human IL-8 enzyme immunoassay. Human IL-8 enzyme immunoassay, BIOTRAK product code RPN-2147, distributed by Amersham Canada was used. Recombinant human IL-8 standards cover the range 23.4 to 600 pg/mL.
Hemodynamic Measurements
Mean arterial pressure, cardiac
index (by
thermodilution), and systemic vascular resistance were recorded
during and after surgery. Serial temperature measurements
(pulmonary artery) were also obtained.
Statistics
2 analysis was used to
analyze categorical data. The nonparametric
Mann-Whitney U test was used to compare continuous data.
Tests that compare means, such as the t and F
tests, require that the data are distributed normally and that the
variances are equal. The data in this study, particularly IL-6
measurements, were unsuitable for analysis by these tests
because the variances between the treatment and control groups were so
different (Fig 1
). Nonparametric testing was
chosen because these tests do not have any requirements regarding
distribution of the data. Correlation between postoperative
cytokine levels and hemodynamics was
established by linear regression models. Significance was established
at a value of P<.05. Given that statistical tests were
performed at each time point that the cytokines were measured,
an adjusted probability value with the Bonferroni correction for
multiple testing would establish a more conservative level of
significance at P<.01. In each figure, the level of
statistical significance (P<.05 or P<.01) of
cytokine results was depicted. Results are expressed as
mean±SEM.
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Results |
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Patients
The clinical characteristics and operative procedures for the patients are shown in the Table
. The patients were
similar with regard to age, sex, and body surface area. CPB and
aortic-cross-clamp times were similar. The temperature during
CPB was 34.0±0.9°C in the steroid group and 34.5±0.7°C
in the
control group. All the patients recovered uneventfully. Plasma glucose
concentrations were significantly higher in the steroid group (7.7±0.6
versus 6.6±1.7 mmol/L) only during the measurement 1 hour after
surgery. No patients required insulin.
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Cytokines
IL-6
For both study and control
patients, plasma IL-6 concentrations
were low before and during CPB (Fig 1
). IL-6 levels rose after
surgery
and peaked at 6 hours (1330±295 pg/mL). IL-6 levels remained elevated
for 24 hours after surgery. IL-6 was not detectable for up to 3 hours
after surgery in patients receiving steroids; IL-6 levels measured at
6, 12, and 24 hours were low compared with control measurements.
TNF
In the control patients, TNF concentrations
rose postoperatively,
reaching peak levels between 1 and 3 hours after surgery (16.9±8.4 and
18.4±9.8 pg/mL, respectively, Fig 2). Patients
receiving steroids had low TNF levels during and after surgery. Peak
concentrations at 1 and 3 hours after surgery were 2.6±0.4 and
2.6±0.5 pg/mL, respectively. These values were significantly lower
than the TNF levels in the control patients.
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IL-8
IL-8 concentrations in the control patients rose after surgery and
peaked 3 hours after surgery (150±51 pg/mL). IL-8 levels were
significantly lower during and after CPB in patients receiving steroids
(Fig 3).
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Hemodynamics
Postoperative mean arterial pressure, cardiac
index,
and systemic vascular resistance were significantly different between
the groups, suggesting less vasodilation in patients receiving steroids
(Figs 4 through 6).
Postoperative hemodynamics correlated significantly
with cytokine levels. The relation between cardiac index and
systemic vascular resistance and IL-6 concentrations at 3 hours is
illustrated in Figs 7 and 8.
Postoperative temperatures were also higher in the control group
despite similar temperatures on CPB, suggesting a greater inflammatory
response (Fig 9). Postoperative temperature also
correlated significantly with IL-6 levels (Fig
10).
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Discussion |
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During normothermic CPB, we found an increase in cytokine release. Cytokine IL-6 was detected 1 hour after clamp release and peaked at 6 hours, returning to normal levels within 24 hours. Both IL-8 and TNF peaked earlier at 3 hours and then again decreased within 24 hours. These results certainly support that in the literature. The release of IL-6 and IL-8 has been described in both normothermic and hypothermic CPB.19 20 21 22 23 24 The elevation of IL-6 is very similar to that shown previously in normothermic CPB,19 although the peak in this study occurred 4 hours after surgery, whereas the peak in our study was 6 hours after surgery. As noted by the authors in the previous study, the IL-6 peak is earlier than that observed after moderate hypothermic CPB. The effect of temperature may play a role; it has been shown in in vitro studies that hypothermia can delay the release of activated complement as well as IL-1.25 26 A similar pattern of IL-8 generation after CPB was demonstrated by Frering et al.19 They also showed that the levels remained significantly elevated until up to 6 hours after surgery and then returned to normal levels. The literature, however, is inconsistent with respect to TNF levels after CPB: some studies noted identifying measurable levels, and others did not.19 21 23 27 28 29 30 31 32 In the control group, TNF concentrations rose after surgery, reaching peak levels between 1 and 3 hours after surgery. This is very similar to the measurements of TNF made by Jansen and associates9 who also showed elevation of TNF after CPB. The peak in their study, however, came within 3 hours after CPB compared with the peak in our study at
1 hour. The
differences here may have occurred because their study was performed in
hypothermic patients, whereas we studied normothermic
patients. Thus, concentrations of IL-6, TNF, and IL-8 increased within 6 hours after removal of the cross-clamp. Levels of none of these cytokines increased during surgery, and thus the stimulus probably was not surgery alone. The initiation occurred after removal of the cross-clamp, and thus myocardial ischemia and reperfusion may play a role in the generation of these cytokines.
We demonstrated that the administration of methylprednisolone after CPB was sufficient to repress the release of IL-6, IL-8, and TNF to undetectable amounts. When steroids were administered before CPB, the levels of TNF both during and after surgery were extremely low. Although there was a relative peak at 1 and 3 hours after surgery in these patients, similar to the non–steroid-treated patients, the values compared with those in patients not administered steroids were relatively negligible. This effect also was shown in the study by Jansen et al,9 whose dexamethasone administration also decreased the value of TNF to negligible levels.
Normothermic CPB has been associated with lower systemic vascular resistance compared with hypothermia,18 33 and it has been proposed that enhanced cytokine release may be responsible for this phenomenon. This proposal is supported by in vitro studies demonstrating that hypothermia delays both release of cytokines as well as their peak levels.25 We previously demonstrated reduced systemic vascular resistance and mean blood pressure with an increased cardiac index in normothermic CPB patients compared with hypothermic CPB patients. Although cytokine generation was implicated as a cause, the baseline temperature difference also could have made a significant hemodynamic difference. In this study, all patients were operated at the same temperature. There was a significant difference in cytokine generation in the group of patients who had received methylprednisolone. This group had undetectable levels of IL-6, IL-8, and TNF. Clinically, this steroid-treated group demonstrated significantly less reduction in mean blood pressure and systemic vascular resistance compared with the control group that did not receive steroids. Similarly, there was a significant reduction in the increase in cardiac index as well as a significant reduction in the increased temperature in the methylprednisolone-treated group.
Postoperative temperatures were higher in the control group, despite
similar temperatures on CPB. We acknowledge that steroid administration
is well known to reduce temperature response through inhibition of the
IL-1 pathway. IL-1 was not measured in these patients, although it has
been shown by other workers25 to be increased after CPB.
Thus, the lower temperature in the steroid-treated group may well
suggest a diminished inflammatory response, although one of the
cytokines that we measured may not be directly responsible.
Generation of IL-6 occurs in conjunction with IL-1 and TNF, and
certainly our postoperative temperatures correlated significantly with
IL-6 levels (Fig 10). The febrile response also may be
mediated by the
release of arachidonic acid metabolites. Steroid
administration also can modulate arachidonic acid
metabolism.34
A significant association was demonstrated between the IL-6 levels and the cardiac index (r=.76, P<.001) as well as the systemic vascular resistance (r=.49, P=.028). The temperature elevations also correlated with IL-6 levels (r=.664, P=.005). A significant correlation of IL-6 levels with clinical outcomes has not been described before. Other studies, however, have shown a relation between the levels of IL-6 and IL-8 with the postoperative myocardial ischemia and segmental wall abnormalities that have been described after CPB.35 They propose a relation between the level of cytokines and the myocardial abnormalities. Our results further support that cytokine release during normothermic CPB contributes to the inflammatory-like response identified. Steroid administration suppresses the cytokines, and we have shown clinical stability in this group of patients. Other studies17 also have shown improved postoperative course as well as improved survival rates with steroids, although cytokines were not measured during these studies.
Neutrophil activation has been implicated in the postperfusion inflammatory response.20 36 37 38 39 40 Certainly, the neutropenia identified after CPB is ameliorated by pretreatment with methylprednisolone; in the past, this effect has been attributed to an inhibition of the complement mediation of neutrophil activation.41 Cytokine IL-8 is a potent neutrophil chemotactic and activation factor42 and thus may initiate the cascade following neutrophil activation. Certainly, IL-8 has been implicated in reperfusion injury43 and in the post–perfusion pump syndrome.2 44 Methylprednisolone pretreatment has been shown by other studies to ameliorate the microvascular lung injury found after CPB.41 Other workers45 also found that steroid treatment depressed the levels of IL-8. They found a significant decrease in IL-8 production when the cross-clamp was released. The other time points did not show any difference between the steroid and the nonsteroid treatment groups, but when we compare it with our data, those time points were either before significant IL-8 production was present, ie, before and at the beginning of CPB, or at the 24-hour period. No measurements were done by Jorens et al45 at 3 and 6 hours after CPB, when we found our major increases. They found a significantly greater production of IL-8 at removal of the cross-clamp; this is contrary to our findings, which is difficult to explain. They used a similar method of measuring IL-8, but there may have been differences in the technique of CPB grafting because they used an intermittent cross-clamp method, whereas we used a single cross-clamp technique. No detrimental clinical effect was noted with short-term steroid use.
In conclusion, with normothermic CPB, we showed a cytokine pulse and documented physiological clinical parameters that are consistent with such a pulse. Pretreatment with low-dose methylprednisolone inhibits the production of cytokines in the circulation and dramatically alters the physiological parameters in the immediate postoperative phase and the beneficial clinical outcomes. The cytokine response to hypothermic CPB was not examined in this study. Therefore, the generalization of these results to patients exposed to hypothermia during cardiac surgery is limited. Further studies are currently under way to delineate the cytokine response to hypothermic CPB.
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Acknowledgments |
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This study was supported by the Hamilton Civic Hospitals Foundation. We wish to thank our anesthetists, cardiovascular perfusionists, and nurses for their technical assistance in cytokine measurements. We wish to thank Paul Stetsko for his assistance in the cytokine measurements. We wish to thank Judy Hukezalie for her assistance in preparation of the article.
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