Jean Louis Leclerc

Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass

Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8, and anti unflammatory cytokines, such as interleukin-10, may play an important role in patient responses to cardiopulmonary bypass. We sought to define whether the myocardium and the lungs serve as important sources of these cytokines under conditions of cardiopulmonary bypass. Ten patients (age 64 +/- 3 years, mean +/- standard error of the mean) undergoing elective coronary artery bypass grafting were monitored with an arterial catheter, a coronary sinus catheter, and pulmonary artery catheter. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured simultaneously in peripheral arterial blood, coronary sinus blood, and mixed venous blood before heparin administration, 1 minute before aortic crossclamping, 5 minutes after aortic declamping, and at 0.5, 1, 1.5 and 2 hours after aortic declamping. The durations of cardiopulmonary bypass and aortic crossclamping were 114 +/- 9 and 64 +/- 5 minutes, respectively. Levels of tumor necrosis factor-alpha and interleukin-6 were significantly higher in coronary sinus blood than in arterial blood after aortic declamping. Tumor necrosis factor-alpha and interleukin-6 levels were also higher in mixed venous blood than in arterial blood within 1 hour after declamping. There were no significant differences among the three sampling sites with respect to interleukin-8 and interleukin-10 levels. In one patient who had postoperative myocardial infarction, however, interleukin-8 levels were three times as high as in coronary sinus blood than in arterial blood. These data indicate that the myocardium is a major source of tumor necrosis factor-alpha and interleukin-6 in patients undergoing cardiopulmonary bypass. The lungs may consume rather than release proinflammatory cytokines in the early phase of reperfusion. The source under these conditions of the antünflammatory cytokine interleukin-10 remains to be determined.

Cytokine Responses to Cardiopulmonary Bypass: Lessons Learned From Cardiac Transplantation

BACKGROUND A growing body of evidence relates the release during cardiopulmonary bypass (CPB) of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, to the postoperative systemic inflammatory response syndrome. Antiinflammatory cytokines, such as IL-10, however, may also play an important role in limiting these complications. METHODS The English-language literature was reviewed. Emphasis was placed on cytokine responses during clinical CPB for cardiac operations and, in particular, for heart and heart-lung transplantation. RESULTS The recent data indicate that (1) although cytokine release can be triggered by many factors during CPB, ischemia-reperfusion may play the most important role; (2) the levels of tumor necrosis factor-alpha, IL-6, and IL-8 are correlated with the duration of cardiac ischemia and the myocardium is a major source of these three cytokines during CPB; (3) IL-10 levels are correlated with the duration of CPB and the liver is a major source of IL-10 during CPB; and (4) steroid pretreatment is an effective intervention to inhibit the release of proinflammatory cytokines and enhance IL-10 production. CONCLUSIONS The improved knowledge of cytokine responses to CPB may help to develop interventions aimed at reducing postoperative morbidity and mortality.

Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men

BACKGROUND Interleukin (IL)-10 is a potent antiinflammatory cytokine inhibiting the release of tumor necrosis factor--alpha (TNF-alpha) and IL-8 by activated macrophages and polymorphonuclear leukocytes. Cardiopulmonary bypass (CPB) represents a unique situation where an inflammatory reaction is predictably induced. The present study examined the influence of CPB on the release of TNF-alpha, IL-1 beta, IL-8, and IL-10 and also defined the effects of pretreatment with corticosteroids on the release of these cytokines. METHODS The study included 22 patients undergoing coronary artery bypass graft operations, including eight control patients and seven patients who received dexamethasone, and seven patients who received methylprednisolone 4 hours before the operation. Cytokines were measured with the enzyme-linked immunosorbent assay technique before treatment, before anesthesia induction, immediately before heparin administration, before aorta declamping, 10 minutes and 90 minutes after aorta declamping, and 4 hours after the end of CPB. RESULTS In the control patients the TNF-alpha levels and especially the IL-8 levels increased during CPB and reached their maximal levels 4 hours after CPB. IL-10 levels rose moderately and transiently, reaching peak values 90 minutes after aorta declamping. Notably, administration of corticosteroids prevented IL-8 release but increased IL-10 levels, which were tenfold higher than in the control group 90 minutes after aorta declamping (dexamethasone, 271 +/- 128 pg/ml; methylprednisolone, 312 +/- 213 pg/ml; control, 17 +/- 12 pg/ml, p < 0.05). IL-1 beta was not detected in any group of patients. CONCLUSIONS The present data indicate that IL-10 is released together with proinflammatory cytokines during and after CPB and that pretreatment with corticosteroids markedly enhances this release. The release of IL-10 may play an important role in the antiinflammatory effects of corticosteroids.

Human cytokine responses to cardiac transplantation and coronary artery bypass grafting

Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8. To elucidate the pathophysiology of this cytokine response, we explored the possible differences in cytokine responses between patients undergoing heart transplantation and those undergoing coronary artery bypass grafting. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured in eight patients undergoing heart transplantation (mean age 44 years) and eight patients undergoing coronary artery bypass grafting (mean age 61 years). Duration of cardiopulmonary bypass and ischemic time were both longer in the heart transplantation group than in the coronary artery bypass grafting group (133 +/- 26 min vs 100 +/- 31 min, p < 0.05, and 130 +/- 47 min vs 58 +/- 21 min, p < 0.005, respectively). Samples were collected before heparin administration, at aortic crossclamping and declamping, and at 0.5, 1, 1.5, 2, 4, 12, and 24 hours after declamping. Tumor necrosis factor-alpha levels were significantly higher 30 minutes after aortic declamping in the heart transplantation group than in the coronary artery bypass grafting group (68 +/- 30 vs 18 +/- 5 pg/ml, p < 0.05). Interleukin-6 and interleukin-8 levels were also significantly higher 90 minutes after declamping in patients undergoing heart transplantation than in those undergoing coronary artery bypass grafting (310 +/- 63 vs 169 +/- 24 pg/ml, p < 0.05, and 73 +/- 17 vs 24 +/- 5 pg/ml, p < 0.01, respectively). Furthermore, interleukin-6 and interleukin-8 values 90 minutes after declamping were significantly correlated with the ischemic time (r = 0.72 and r = 0.82, respectively, both p < 0.05). Interleukin-10 levels in both groups rose to reach a peak value of around 115 pg/ml 1 hour after declamping. Patients undergoing heart transplantation exhibited a second peak of tumor necrosis factor-alpha, interleukin-8, and interleukin-10 levels 12 hours after declamping, probably related to the administration of rabbit antihuman thymocyte immunoglobulin (Thymoglobuline) 3 hours after declamping. Interleukin-6 levels decreased more significantly 12 and 24 hours after declamping in patients undergoing heart transplantation, probably related to methylprednisolone therapy. In conclusion, cardiopulmonary bypass is associated with the production of both proinflammatory and antiinflammatory cytokines. The production of proinflammatory cytokines in patients undergoing heart transplantation is higher than that in patients undergoing coronary artery bypass grafting, and this increase could be related to the longer duration of ischemia in the former group. The later course of cytokine levels after heart transplantation may be further influenced by immunosuppressive therapy.

Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients☆☆☆★★★♢

With its antiinflammatory properties, interleukin (IL)-10 may play an important role in limiting complications associated with cardiopulmonary bypass (CPB). We previously demonstrated that pretreatment with steroids can significantly increase IL-10 production during CPB, but neither the heart nor the lung was found to be its main source. To define whether the liver is the source of IL-10, hepatic venous cannulation was performed in 12 patients undergoing CPB. Each patient received 30 mg/kg of methylprednisolone before operation. Plasma levels of IL-10 were simultaneously measured in peripheral arterial blood and hepatic venous blood before heparin administration, before aortic cross-clamping, and 5, 30, 60, 90, and 120 minutes after aortic declamping. The duration of CPB and aortic cross-clamping was 113 +/- 7 minutes and 75 +/- 6 minutes (mean +/- SEM), respectively. IL-10 levels 30 minutes after declamping were significantly higher in hepatic venous blood than in arterial blood (1187 +/- 573 pg/ml vs 911 +/- 405 pg/ml, p < 0.01 by Wilcoxons signed-rank test). To determine whether steroids can also induce the release of another antiinflammatory cytokine, IL-4, plasma IL-4 levels were measured simultaneously. IL-4 was detected in the arterial blood of only 4 of the 12 patients, transiently after aortic declamping. IL-4 was not detected in hepatic venous blood. In conclusion, the liver is a major source of IL-10 during CPB. However, steroid-treated patients do not show an increase in IL-4, and the liver is not the source of IL-4 during and after CPB.

Cardiac Tamponade Due to Spontaneous Rupture of Right Coronary Artery Aneurysm

A case of acute cardiac tamponade caused by spontaneous rupture of a right coronary artery aneurysm is reported. The aneurysm, which was present distally, was ligated during operation. Postoperative angiography suggested the aneurysm was congenital. The patient is doing well 5 months after operation.

Steroid administration in heart and heart—lung transplantation: Is the timing adequate?

BACKGROUND The release of cytokines after cardiopulmonary bypass may play an important role in postoperative morbidity. The release of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-6 and IL-8, is even greater in patients undergoing heart transplantation (HTx) than coronary artery grafting. We tested the hypothesis that in HTx patients the earlier administration of steroids, before rather than after cardiopulmonary bypass as usual, can reduce the inflammatory response. METHODS In 20 consecutive patients who underwent HTx or heart-lung transplantation (HLTx), plasma levels of tumor necrosis factor alpha, IL-6, IL-8, and anti-inflammatory cytokine IL-10 were measured before heparin administration, at aortic cross-clamping and declamping, and 0.5, 1, 1.5, 2, 4, 12, and 24 hours after aortic declamping. In 10 patients (group I, 6 HTx and 4 HLTx), 500 mg of methylprednisolone was first given as usual at 1.5 hours after aortic declamping (at the end of cardiopulmonary bypass). In the next 10 patients (group II, 6 HTx and 4 HLTx), the first doses of methylprednisolone were given 1 hour before operation. In both groups, 125 mg of methylprednisolone were given every 8 hours thereafter during the first postoperative day. RESULTS The ischemic time and cardiopulmonary bypass time were similar in the two groups (166 +/- 16 minutes versus 157 +/- 13 minutes, and 192 +/- 21 minutes versus 186 +/- 20 minutes, respectively, mean +/- standard error of the mean). At 30 minutes after aortic declamping and throughout the next 4 hours, tumor necrosis factor alpha levels were significantly lower in group II than in group I (all p < 0.03). Interleukin-8 values 1 hour after declamping were also lower in group II than in group I (49 +/- 15 pg/mL versus 130 +/- 38 pg/mL, p < 0.02). Interleukin-10 levels were significantly higher in group II than in group I from 30 minutes after declamping through 2 hours after (all p < 0.03). Interleukin-6 levels were similar in the two groups. CONCLUSIONS Earlier steroid administration in the immunosuppressive protocol for HTx or HLTx may be preferable to reduce the inflammatory response to cardiopulmonary bypass, as reflected by a lower production of tumor necrosis factor alpha and IL-8, and a greater release of IL-10.

Heparin-coated circuits reduce myocardial injury in heart or heart-lung transplantation: a prospective, randomized study

BACKGROUND The effects of heparin-coated (HC) circuits have been primarily investigated in routine cardiac operations with limited duration of cardiopulmonary bypass (CPB) and ischemia. Their benefits have not been conclusively proven but could be more significant when CPB and ischemic times are longer, such as during heart transplantation (HTx) or heart-lung transplantation (HLTx). METHODS In a 22-month period, 29 patients undergoing HTx and HLTx were randomly divided into two groups using HC (Duraflo II, n = 14, 10 HTx and 4 HLTx) or uncoated but identical circuits (NHC group, n = 15, 10 HTx and 5 HLTx). All patients received full systemic heparinization (3 mg/kg) during CPB. Plasma endotoxin, interleukin (IL)-6, IL-8, IL-10, IL-12, and cardiac troponin-I were measured before heparin administration, immediately after aortic cross-clamping, 5, 30, 60, 90, 120 minutes, and 12 and 24 hours after aortic declamping. The intensive care unit (ICU) staff and the laboratory technologists were blinded as to the use of HC circuits. RESULTS No statistically significant differences between groups were found with respect to all baseline values, duration of CPB and aortic cross-clamping, graft ischemic time, doses of heparin, postoperative blood loss and transfusion, peak lactate and creatine kinase-MB isoenzyme values, duration of mechanical ventilation, or length of ICU stay. One patient in each group died during the hospital stay. Patients in the HC group needed more protamine sulfate after CPB. Although endotoxin levels were similar in the two groups, significantly lower IL-6, IL-8, and IL-10 levels were observed 1 hour after aortic declamping in the HC group. The release of cardiac troponin-I was also significantly reduced in the HC group 12 and 24 hours after reperfusion. CONCLUSIONS The use of HC circuit limits both pro- and anti-inflammatory responses to CPB. It may also reduce myocardial injury after prolonged duration of CPB and ischemia.

Administration of nebivolol after coronary artery bypass in patients with altered left ventricular function.

Summary: This prospective, double-blind study used invasive monitoring and echo-Doppler techniques to compare the hemodynamic effects of nebivolol, a new β1-selective β-blocking agent with those of atenolol in patients recovering from coronary artery bypass grafting surgery. Five milligrams nebivolol and 50 mg atenolol equally decreased heart rate (HR) and blood pressure (BP) but, nebivolol, in contrast to atenolol, caused no decrease in stroke index (SI), cardiac index (CI), and right ventricular ejection fraction (RVEF). These differences appeared to be related in part to different peripheral effects of the two agents because nebivolol administration was associated with a reduction in systemic vascular resistance (SVR). After ≤10 days of treatment, acceleration of aortic flow velocity increased and isovolumic relaxation time decreased with nebivolol but not with atenolol treatment. Both drugs were equally well tolerated. Therefore, nebivolol shares most of its effects with classical β1-blockers but is devoid of the potentially harmful effects on cardiac output (CO) and peripheral resistance.

Hypophosphatemia after cardiothoracic surgery

The incidence of hypophosphatemia during the first 48 h following cardiothoracic surgery was prospectively studied in 74 patients. Hypophosphatemia, defined by a serum phosphate below 2.50 mg/dl, was observed in 19 of 34 (56%) patients after thoracic surgery and in 20 of 40 (50%) patients after cardiac surgery. As a whole, hypophosphatemia occurred earlier after thoracic than after cardiac surgery. After thoracic surgery, hypophosphatemia was milder for patients in whom bleeding was more severe. The anticoagulant solution CPD used in stored blood was identified as an important source of phosphate. These results indicate hypophosphatemia is a common finding after cardiothoracic surgery. Since severe hypophosphatemia can be related to phosphate depletion, phosphate supplements could be warranted especially during thoracic surgery when blood transfusions are less than 1000 ml.