Inroduction

The obligatory systemic inflammatory response to cardiac surgery with cardiopulmonary bypass (CPB) has been associated with significant perioperative and long-term morbidity and mortality. Cardiac surgery with CPB initiates a profound systemic inflammatory response, characterized by increased level of inflammatoryry mediators and Oxidative stress mediators which have been shown to be correlated with the incidence of organ dysfunction and adverse clinical outcome [1]. The pro inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 are associated with anti-inflammatory mediators such as IL-10 and TGF-β [2]. However, the net effect of these circulating inflamatory mediators seems to be distorted as inhibition of innate immune cells, the molecular and cellular mechanisms responsible for suppression of the immune system after cardiac surgery with CPB [3]. In addition generation of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide and malondialdehyde occurs upon reperfusion following CPB and these may be important contributors to tissue injury [4]. Furthermore, post-CPB coronary endothelial dysfunction appears to be partially mediated by ROS [5]. Opioids have been widely used as anesthic agents for various types of surgery including cardiac surgery. Several studies found opioid preconditioning had a protective effect on the postiscthemic heart [6-8]. Also, exogenous activation of μ-opioid receptor has been shown to ameliorate inflammation in experimental colitis [9], supporting the concept that μ-opioid receptor agonists might act as regulatory modulators of gut inflammatory processes. However, no study has examined the direct role of opioids in the expression of ƉrŽͲŝnŇĂmmĂƚŽry mediators (including IL-6, and IL- 8) and malondialdehyde (MDA) in cardiac surgery with CPB. These ŽbƐĞrvĂƟŽnƐ provided the background for our hypothesis that exogenous opioids might Ä‚Æ©ÄžnƵĂƚĞ the ŝnŇĂmmĂƚŽry response induced by cardiac surgery with CPB. To test our hypothesis, we used fentanyl and remifentanil as Ä‚nĞƐƚŚĞƟc agents for cardiac surgery with CPB. The aim of our study was to ŝnvĞƐƟŐĂƚĞ the ĞīĞcÆš of exogenous Ä‚ÄšmŝnŝƐƚrĂƟŽn of opioids on the systemic ŝnŇĂmmĂƚŽry response induced by cardiac surgery with CPB. We assessed the changes of ƉrŽ ÅnŇĂmmĂƚŽry mediators including IL-6, and IL-8, ŽxŝĚĂƟvÄž stress mediator (MDA) and myocardial damage markers such as cardiac troponin T and crĞĂƟnÄž kinase MB in the ƉĂƟĞnƚƐ undergoing cardiac surgery with CPB.

Materials and Methods

Patients and study protocol

The study was approved by Chonnam EĂƟŽnĂů University Hospital’s /nƐƟƚƵƟŽnĂů Review Board and wrŝƩĞn informed consent was obtained. This ƉrŽƐƉĞcÆŸvĞ͕ randomized study was performed on 60 ƉĂƟĞnƚƐ undergoing ĞůĞcÆŸvÄž valve replacement using CPB. WÄ‚ÆŸÄžnƚƐ with ASA cůĂƐƐŝĮcĂƟŽn more than 4, coronary disease requiring surgical rÄžvĂƐcƵůĂrŝnjĂƟŽnÍ• unstable cardiac ĨƵncƟŽn with the need for medical or mechanical inotropic supports, severe ŚĞƉĂƟc or renal disease, malignancy, ƉrĞĞxŝƐƟnŐ lung parenchymal disease and acute ŝnŇĂmmĂƚŽry response were excluded. WÄ‚ÆŸÄžnƚƐ were randomly divided into either the fentanyl group (n=30) who received fentanyl for Ä‚nĞƐƚŚĞƟc ŝnĚƵcƟŽn (3-10 µg/kg) and maintenance (0.03-0.1 µg/kg/min), and the remifentanil group (n=30) who received remifentanil for Ä‚nĞƐƚŚĞƟc ŝnĚƵcƟŽn (0.5-1.0 µg/kg) and maintenance (0.05-0.1 µg/kg/min). WrĞĂnĞƐƚŚĞƟc mĞĚŝcĂƟŽn included midazolam (0.1 mg/kg, PO) and ĨĂmŽƟĚŝnÄž (0.3 mg/kg, IV). Anesthesia was induced with midazolam (0.05-0.15 mg/kg, IV), fentanyl or remifentanil and tracheal ŝnƚƵbĂƟŽn were facilitated with rocuronium (0.8 mg/kg). WÄ‚ÆŸÄžnƚƐ were mechanically vÄžnƟůĂƚĞĚ with 50% oxygen with air to maintained normocarbic (PaCO2 35 ± 5 mmHg). Anesthesia was maintained with ƐĞvŽŇƵrÄ‚nÄž (0.5-1 vol%), and fentanyl or remifentanil. The cardiac surgeon and anesthesiologists were blinded to group assignment. CPB was established using a twostage venous drainage and ascending ĂŽrÆŸc return. ŌĞr Ä‚ÄšmŝnŝƐƚrĂƟŽn of heparin (300 IU/kg), standard CPB was started with the priming volume. Body temperature was maintained under mild hypothermia (32-33) with cold blood cardioplegic ƐŽůƵƟŽn͘ Pump ŇŽw rate was maintained at 2.0-2.5 L/min/m2 of body surface area with mean arterial blood pressure of 50-80 mmHg using nŽnͲƉƵůƐĂƟůĞ ŇŽw͘ All ƉĂƟĞnƚƐ underwent cŽnÆŸnƵŽƵƐ monitoring with radial artery and pulmonary artery catheters about hemodynamic variables such as mean arterial blood pressure, heart rate, mean pulmonary artery pressure, central venous pressure, pulmonary capillary wedge pressure, systemic vascular resistance and cardiac index were measured cŽnÆŸnƵŽƵƐůy͘ Blood was sampled from the radial artery at the following points: ƉrĞŝnĚƵcƟŽn (T1), just before ĂŽrÆŸc clamping (T2), just before ĂŽrÆŸc declamping (T3), 5 (T4), 30 (T5), and 60 (T6) minutes (min) ĂŌĞr ĂŽrÆŸc declamping. Myocardial cell damage as assessed by plasma level of troponin T and crĞĂƟnÄž kinase-MB (CK-MB) were measured before and 24 hours ĂŌĞr surgery.