Amiodarone and inflammation after cardiopulmonary bypass

It is well documented, that cardiopulmonary bypass (the "heart lung machine") and operative trauma during cardiac surgery induces a systemic inflammatory response. This proinflammatory response causes significant morbidity or may even cause mortality. Postoperative low output syndrome, postoperative low vascular resistance and organ failure have been attributed to this proinflammatory response. Amelioration or inhibition of this reaction could reduce or obviate the use of catecholamines, improve abnormal gas exchange after cardiac surgery, shorten the time to extubation and shorten the stay on the intensive care unit. Amiodarone is a class III antiarrhythmic drug with outstanding properties. Numerous studies have ascertained that it does not increase mortality in highly compromised populations as do other antiarrhythmic substances. Recent studies have also shown, that amiodarone is able to inhibit the production of tumor necrosis factor-a [TNF] in vitro. This ability has been implicated in the apparent benefits of amiodarone in heart failure patients. These patients may have elevated TNF-a levels and amiodarone has been shown to reduce the combined end point of cardiac death and hospitalization for heart failure. Thus, amiodarone might be able to reduce TNF-a levels and to abrogate the cytokine cascade initiated by the production of TNF-a in response to exogen surfaces and surgical trauma during cardiopulmonary bypass. TNF-a is the first mediator in a chain of events during SIRS and sepsis. Clinically relevant levels of amiodarone may reduce TNF-a production in vitro by up to 50%. Amiodarone has been used to reduce the postoperative incidence of atrial fibrillation in patients undergoing cardiac surgery with good results and a low complication rate. Whether antiinflammatory properties of the compound played a major role in achieving these results is unclear. The antiinflammatory actions of amiodarone have not been investigated in vivo. The aim of this prospective, double blinded, randomized study is to investigate the antiinflammatory properties of amiodarone during open heart surgery. Patients aged 40 -75 years, undergoing aortocoronary bypass operation with the use of cardiopulmonary bypass will be randomized to receive amiodarone or placebo. Treatment will start orally 7 days prior to cardiac surgery and will be continued during the operation and for 48 hours thereafter. The main outcome variable is the postoperative course of the C reactive protein [CRP](area under the curve). Secondary endpoints evaluated are fever, leukocyte count, fibrinogen, TNF-a, IL-1 and IL-6. We hypothesize, that the postoperative CRP response will be significantly reduced. Since the antiinflammatory actions of amiodarone have not been investigated in vivo and the magnitude of any antiinflammatory effect is essentially unknown, an interim analysis will be performed following inclusion of 40 patients.

Background: Systemic inflammation during open heart surgery causes significant morbidity and mortality. Low cardiac output, low systemic vascular resistance and organ failure have been attributed to systemic inflammation. Systemic inflammation is also one hallmark of critical illness. The present study investigated open heart surgery with use of cardiopulmonary bypass as model of well defined and clearly timed systemic inflammation. Amiodarone is a widely use antiarrhythmic agent with potent action against ventricular and supraventricular arrhythmias. Recently, in vivo studies suggested an inhibition of tumor necoris factor release and amelioration of interleukin 2 release. On the other hand, the toxicity of amiodarone encompasses lung-tocicity wich is thought to represent inflammation and is treated with corticosteroids. Amiodarone is widely used to treat postoperative atrial fibrillation. Two large, randomized, controlled studies demonstrated a reduction in the incidence of postoperative atrial fibrillation with the pre and periooperative use of the substance. Aim: Aim of the present study was to assess any anti-inflammatory property of pretreatment with amiodarone and to investigate whether amiodarone is able to ameliorate perioperative inflammation. On the other hand, it is important to know and characterize any pro-inflammatory effect of the compound, if any, given ist widespread use to treat peroperative atrial fibrillation. Design: double blind, randomized, placebo controlled pilot study, intention to treat Methods: We screened 1211 patients sceduled for open heart surgery during a two-years period. Twenty three fulfilled all inclusion criteria and were randomly assigned to treatment with amiodarone or placeb. Primary endpoint was the c-reactive protein (CRP) and secondary endpoints were leucocyte count, fibrinogen, and tumor necrosis factor alpha and interleukin 2. The course of the parameters was assessed for 96 and 48 hours, respectively. Results: CRP increased more slowly until hour 4 after operation in the amiodarone group but showed a somewhat higher and earlyer peak until 72 hours after the operation. At 96 hours after surgery, CRP levels were already lower in the amiodarone group. The groups did not differ significantly with respect to the area under the CRP and when comparing courves by ANOVA. Also, no significant difference in the course of leucocyte count, fibrinogen, tumor necrosis factor and interleukine were found. Conclusion: Data of these pilot series do not show a significant amelioration of post cardiopulmonary bypass inflammatory response. No pro-inflammatory action of amiodarone was noted in this study.