The study protocol was approved by the Local Ethics Committee of The First Affiliated Hospital of Dalian Medical University (KY2009-38; Dalian, China), and written informed consent was obtained from all the participating patients. The present investigation was designed as a single-center, randomized controlled trial on patients scheduled to undergo open-heart cardiac surgery with CPB at the Department of Cardiovascular Surgery in the First Affiliated Hospital of Dalian Medical University.

Patients were included in the current study if they met the following criteria: i) Age between 40 and 80 years; ii) patients undergoing elective primary cardiac surgery, including coronary artery bypass graft (CABG) or heart valvular replacement (HVR); iii) a cardiac function of New York Heart Association class II or III; and iv) no evidence of myocardial ischemia or elevation of serum levels of myocardial markers (troponin I [TnI], creatine kinase [CK] or CK-MB fraction [CK-MB]) within the last 24 h prior to surgery. The exclusion criteria were as follows: i) A diagnosis of acute myocardial infarction within the last 4 weeks prior to the scheduled surgery; ii) an activated phase of rheumatic diseases; iii) left ventricular ejection fraction of <40%; iv) preoperatively confirmed intra-cardiac shunt; v) a hematocrit of <30%; and vi) severe systemic diseases, including pulmonary diseases, hepatic, renal, musculoskeletal diseases or immune system illnesses. Additionally, patients receiving oral hypoglycemic agents or theophyllines were excluded since these medications are known to influence the process of ischemia-reperfusion injury (14).

Eligible patients were assigned to one of the two study arms on the basis of a computer-generated randomization list: One group was administered the conventional care (control group; n=12), while the other was administered conventional care plus intravenous esmolol infusion (esmolol group; n=12; Sanlian Pharmacy, Harbin, China). The mean age of the patients was 60.5 years old and 14 of the enrolled patients were male.

All patients included were administered intramuscular injections of scopolamine (0.6 µg/kg; Minsheng Pharmacy, Hangzhou, China), morphine (0.1 mg/kg) and pethidine (1 mg/kg) (both purchased from Shenyang 1st Pharmacy of Northeastern China, Shenyang, China) 30 min prior to the induction of anesthesia. Preoperative sedation and anesthesia were achieved with the intravenous injection of midazolam (0.1 mg/kg; Enhua Pharmacy, Jiangsu, China), fentanyl (10 µg/kg; Renfu Pharmacy, Yichang, China), etomidate (0.2–0.3 mg/kg; Enhua Pharmacy) and cisatracurium besilate (0.2 mg/kg; Hengrui Pharmacy, Jiangsu, China), and these drugs were administered during the surgery in order to maintain a stable hemodynamic status. Following tracheal intubation, the patients were placed on artificial ventilation such that the end-tidal carbon dioxide pressure was maintained at 30–35 mmHg and the airway pressure at 8–18 cm H₂O. Anesthesia was maintained using the standard method with continuous administration of propofol at 3–6 mg/kg/h.

Patients in the esmolol group were administered intravenous esmolol (70 µg/kg/min) during the incision until the initiation of CPB, and the dosages of esmolol were titrated every 2 min to maintain the heart rate (HR) of each patient within 80% of the baseline level. Patients assigned to the control group were administered equal volumes of 0.9% saline.

All patients underwent cardiac surgery under CPB according to the standard method using a roller pump and a membrane oxygenator with a priming solution (Jinyao Pharmacy, Tianjin, China). During CPB, pump flow was set such that the mean arterial pressure (MAP) was maintained between 50 and 80 mmHg. The blood temperature was allowed to drop to <30°C and restored back to 36°C with active rewarming at the end of CPB. Myocardial protection was ensured with the induction of cardioplegia by administration of cold potassium solution (10–15 ml/kg) and by placement of ice chips in the pericardial region to maintain the heart in a hypothermic condition. Moreover, cardioplegia was achieved using the single-clamp technique in an anterograde fashion. Following the establishment of CPB, vasoactive medications, including dopamine, nitroglycerin and norepinephrine, were administered to maintain the arterial blood pressure at a relatively stable level.

The aortic cross-clamp was completely released, followed by the placement of the epicardial atrial or ventricular pacing wires. The aortic and venous cannulas were removed following the administration of the appropriate test dose of protamine such that the activated clotting time was maintained at 110–140 sec, and the surgery was continued with the closure of the pericardium and sternum. Following surgery, the patients were closely monitored during their stay in the intensive care unit (ICU) at The First Affiliated Hospital of Dalian Medican University for at least 12 h.

The primary outcomes analyzed in the present study were perioperative changes in the concentrations of the serum markers of myocardial injury, including TnI, CK and CK-MB. Briefly, arterial blood samples (3 ml for each time point) of the patients were collected from the radial artery or from the arterial catheters during CPB at the following time points: Baseline (prior to the start of the CPB procedure), prior to aortic cannulation, 30 min prior to the placement of the aortic cross-clamp at the time of releasing the aortic cross-clamp, and 120 min after the release of the aortic cross-clamp. The levels of the markers of myocardial injury were measured using the Roche Biochemical Analyzer (ADVIA centaur-CP; Siemens AG, Munich, Germany) according to the manufacturer's instructions. The secondary outcomes analyzed were the changes in the levels of the hemodynamic parameters, including HR, MAP and central venous pressure (CVP), during the surgery and during the 12-h ICU follow-up. In addition to the abovementioned parameters, other related clinical outcomes were also evaluated, including the characteristics of CPB, usage of vasoactive medications, rebeating status of the heart and the incidence of postoperative adverse events.

The results are presented as mean values with standard deviation. Significant intergroup differences at the different time points were analyzed using the Student's t–test. Moreover, one-way analysis of variance was used for intragroup comparison of the values of the hemodynamic parameters if the data were normally distributed; if the distribution was abnormal, the Friedman test was used. P<0.05 was used to indicate a statistically significant difference. All the statistical analyses were performed using SPSS Software (version 13.0; SPSS, Inc., Chicago, IL, USA).

In total, 14 patients enrolled underwent CABG, while 10 patients underwent HVR. All the surgical procedures were executed successfully, and the patients were closely monitored during their 12-h postoperative ICU follow-up period. The baseline characteristics of the patients included are listed in Table I. The two study groups were well balanced in terms of the demographic characteristics, prevalence of hypertension, diabetes, types of surgery and class of cardiac function.

The two groups did not differ significantly in terms of the characteristics of the surgery and CPB procedure (CPB time, aortic cross-clamp time, surgical duration and quantity of potassium cardioplegic solution used) (Table II). Furthermore, no significant differences were detected between the two groups with respect to the following parameters: Perioperative fluid infusion, urinary volumes, usage of vasoactive medications during the surgery and status of the heart rebeating. Similarly, no significant intergroup differences were noted in the length of the ICU stay, decannulation times and urinary volumes during the ICU stay (Table II).

The mean MAP of the patients in both groups was gradually reduced from the baseline levels (esmolol group, 105.4±18.9 mmHg; control group, 106.1±17.1 mmHg; P=0.464 between groups), and remained at relatively low levels throughout the surgical procedures (60–70 mmHg for both groups) (Fig. 1A). Furthermore, no significant differences were noted between the two groups in the measurement of MAP at the aforementioned 6 time points of assessment. Although CVP (at the time of tracheal intubation) in the patients of the esmolol group was found to be significantly greater than that in the control group (6.4±3.5 vs. 4.2±2.2 cm H₂O; P=0.039), the values at the other time points did not show any significant difference (Fig. 1B). Moreover, the HR in the esmolol group appeared to be lower than that in the control group at the majority of time-points, which may partially reflect the potential negative chronotropic effects of esmolol; however, these differences were not statistically significant (Fig. 1C). These observations suggest that preprocedural administration of esmolol did not induce any significant changes in the levels of venous and arterial hemodynamic parameters during the perioperative period in patients who underwent elective cardiac surgery with CPB.

As shown in Fig. 2A, the baseline levels of serum TnI did not differ significantly in the two groups (esmolol group, 0.048±0.064 ng/ml; control group, 0.064±0.056 ng/ml; P=0.282). However, prior to aortic cannulation (~30 min after esmolol administration) and at 120 min after the release of the aortic cross-clamp, the serum TnI levels were significantly lower in the esmolol group than in the control group (esmolol group, 6.114±2.864 ng/ml and 0.072±0.058 ng/ml, respectively; control group, 9.709±6.146 ng/ml and 0.188±0.094 ng/ml, respectively; P=0.039 and P<0.001, respectively). Similarly, the TnI levels in the esmolol group were lower than those in the control group at 30 min prior to the aortic cross-clamp and at the time of release of the aortic cross-clamp, although the difference was not significant (P=0.099 and P=0.163, respectively). The serum levels of CK (Fig. 2B) did not show any significant difference between the two groups at four of the five time points (baseline, before aortic cannulation, before aortic cross-clamp and 120 min after the release of aortic cross-clamp); however, the levels were significantly higher in the esmolol group compared with the control group (esmolol group, 125.67±30.81 IU/ml; control group, 89.67±23.31 IU/ml; P=0.002). With regard to the serum levels of CK-MB, which is an isoenzyme considered to be more specifically reflective of myocardial injury than CK, no significant intergroup differences were detected (Fig. 2C).

The dynamic changes in the MAP, CVP and HR in both groups during the 12-h ICU follow-up period are presented in Fig. 3A-C, respectively. The levels of all three parameters were similar in the two groups, except for significantly higher levels of MAP at the 5th and the 10th hour in the esmolol group compared with the control group (P=0.026). This indicates that the preprocedural administration of esmolol did not have any significant effect on the postoperative hemodynamic status.

The incidences of the most common complications and adverse events occurring in the two groups are provided in Table III. Postoperative pulmonary infection was noted in two patients in the esmolol group and in three patients in the control group. Furthermore, one patient in the control group had neurological complications manifesting as delayed postoperative recovery. No other instances of infection of incision, pericardial tamponade, open-chest hemostasis or mortality were recorded in the present study.