All patients will be premedicated the night before surgery with bromazepam 3 mg PO, and 0.1 mg/Kg morphine sulphate IM one hour preoperatively. Upon arrival to the pre-induction room, the patient will receive supplementary oxygen via a nasal cannula, and will be monitored with ECG, Non invasive blood pressure and pulse oximeter. Under local infiltration anesthesia (lidocaine 2%) a peripheral venous cannula (14 or 16 G) and a 20 G arterial cannula will be inserted. Induction of anesthesia will be accomplished with fentanyl (7-10 μg/Kg), propofol 0.5 - 1.0 mg/Kg and pancuronium (0.08 - 0.12 mg/Kg). After intubation a triple lumen central venous catheter will be inserted in a central vein. The temperature probe will be inserted in the nasopharynx; the TEE probe will be also inserted after decompression of the stomach with a nasogastric tube.
All patients will be mechanically ventilated with a tidal volume of 6-8 mL/kg and a respiratory rate of 12 - 14 to achieve end-tidal CO2 30 - 35 mmHg . A PEEP of 5 cm H2O is also added. FiO2 will be adjusted to achieve a PaO2 between 200 and 300 mmHg. Isoflurane will be adjusted to 1 - 1.5 expired MAC , as well as fentanyl increments of 2 μg/Kg will be used to control adequate level of anesthesia and to maintain hemodynamic stability. Incremental doses of pancuronium will be administered as needed.
Before starting CPB anticoagulation with 400IU/kg heparin iv will be administered and activated clotting time (ACT) will be used to check proper anticoagulation throughout CPB aiming at ACT \>400s.
Cardiopulmonary bypass flow rate of 2.2 - 2.4 l/min/m2 is maintained aiming to keep MAP of 50-80 mmHg together with the use of vasopressors and vasodilators when needed. After Initiation of CPB mild hypothermia (34-35℃) will be performed . During weaning from CPB, volume and pharmacological therapy with inotropes and vasodilators will be used as needed to maintain hemodynamic stability. All blood on the CPB machine will be re-infused into the patient and protamine will be administered in a dose of 4 mg/kg to return ACT to baseline values.
Using a computer-generated random sequence of numbers, patients will be allocated to one of the following two study groups:
\- Control group (Group C): During bypass, patients in this group will receive propofol infusion 50 - 70 mcg/kg/min plus normal saline infusion
\- Group Dexmedetomidine (Group DEX): During bypass, patients in this group will receive propofol infusion 50 - 70 mcg/kg/min plus dexmedetomidine infusion 0.5 mcg/kg/hr Patients and investigators performing the study and assessing its outcomes will all be blinded to the study group allocation. The study drugs will be prepared by a separate investigator not involved in either study performance or analysis.
Data collection Microcirculation will be studied with side-stream dark field (SDF) imaging (Microscan; MicroVision Medical, Amsterdam, Netherlands) at three times; Immediately before starting CBP (T0) , 30 min after initiation of bypass (T1), and 30 min after weaning from bypass (T2) Side stream dark field imaging is equipped with sterile caps to avoid contamination. Briefly, after gentle cleansing by isotonic-saline-drenched gauze, avoiding pressure artefacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done by two investigators. A previously validated semiquantitative score will be used . It distinguishes between no flow (0), intermittent flow (1), sluggish flow (2), and continuous flow (3). A value is assigned to each individual vessel. The overall score, called the microvascular flow index (MFI), is the average of the individual values. For each patient, the values from 5 videos will be averaged. In addition, vascular density will be quantified as the number of vessels per millimeters squared. To determine heterogeneity of perfusion, the flow heterogeneity index will be calculated as the highest MFI minus the lowest MFI divided by the mean MFI. Finally, the percent of perfused vessels and the total and capillary perfused vascular densities will be calculated. The percent of perfused vessels will be calculated as the number of vessels with flows 2 and 3 divided by the total number of vessels and multiplied by 100. The perfused vascular density will be calculated as the number of vessels multiplied by the fraction of perfused vessels. These quantifications of flow were made per group of vessel diameter: small (capillaries), 10 to 20 μm; medium, 21 to 50 μm; and large, 51 to 100 μm Sample size (number of participants included) 68 patients (34 in each group) Power analysis was performed using Student's t-test for independent samples with MFI as the primary outcome. A previous study demonstrated that MFI during cardiopulmonary bypass was approximately 2.6 + 1. Sample size was calculated to detect a 25% difference in MFI between the two groups with a power of 0.8 and an alpha error of 0.5. A minimum of 62 patients (31 in each group) would be necessary, and this was increased to 68 (34 in each group) to compensate for dropouts.
Statistical analysis Data will expressed as mean + SD, median (range), or frequency as appropriate. Categorical variables will be compared using Chi-square or Fisher's exact test as appropriate. Normally distributed data will be compared using Student's t-test while non-normally distributed data will be compared using Mann-Whitney test or the Kruskal-Wallis test as appropriate. Intergroup comparisons will be done using analysis of variance with repeated measures and post-hoc Dunnett test. A P-value \< 0.05 will be considered statistically significant.
