Patient enrollment and study design. We performed a randomized-, prospective-, controlled clinical study. This investigation conforms to the principles outlined in the Declaration of Helsinki after receiving the Medical Ethics Committee approval at Beijing Anzhen Hospital, Capital Medical University. Written informed consent was obtained from all patients prior to inclusion. This study is registered in the www.chictr.org.cn database (ID: ChiCTR1900023576),, Clinical trial date of registration was 02/06/2019.
100 children with American Society of Anesthesiologists (ASA) scores between class II and III who underwent correction of congenital heart disease whit right vertical infra-axillary thoracotomy under general anaesthesia gave written informed consent to participate in this randomized controlled study. Inclusion criteria were >6 months and <3 years of age, and preoperative diagnosis of atrial septal defect (ASD), ventricular septal defect (VSD) and partial atrioventricular septal defects (PAVSD). Exclusion criteria were refusal to give consent, BMI < 18 kg/m2 or > 35 kg/m2, significant cardiac dysfunction (left ventricular ejection fraction ,40%) asthma requiring bronchodilator therapy, pulmonary infection and emergency surgery.
Subjects. Seventy-eight children were divided into the control group (group C, n = 19); the ulinastatin group (group U, n = 20); the alveolar recruitment maneuver group (ARM, group A, n = 20) and the ulinastatin combined with alveolar recruitment maneuver group (group U + A, n = 19). In group U, children were intravenously infused with ulinastatin (Techpool, Guangdong, China) at a rate of 10,000 U/ kg/hour for the first hour after anesthesia induction and then at a rate of 5,000 U/kg/hour (diluted into 20 mL using normal saline) until the conclusion of surgery. In group A, immediately after the end of cardiopulmonary bypass, lung recruitment was achieved by sequential increases in PEEP in three steps from 10 cm H2O (for 3 breaths), 15 cm H2O (for 3 breaths), and 20 cm H2O PEEP (for 3 breaths). Following ARM, volume control was established using Vt 6 mL/kg and reductions in PEEP to 10 cmH2O. The ARM lasted about 30–60 seconds and was repeated at 30 min after the first recruitment. In group U + A, children were intravenously infused with ulinastatin and alveolar recruitment maneuver. Group C did not accept any additional interventions during surgery.
Anesthesia and Surgery. Standard monitoring was achieved in all children. Anesthesia was induced with sufentanil (1µg/kg), midazolam (0.2 mg/kg), pipecuronium bromide (0.1mg/kg) and maintained with hypnotics (propofol), pipecuronium bromide, and opioid (sufentanil). Patient monitoring included continuous 5-lead electrocadiographic registration with ST-segment analysis, peripheral oxygen saturation by pulse oximetry, radial arterial blood pressure, central venous pressure, capnography, rectal temperature, and urine output. The radial artery catheter was connected to a monitor for pulse contour analysis (MostCare system, Vygon-Vytech, Padova, Italy) and the resulting signal processed for determination of hemodynamic variables.
Children received volume-controlled mechanical ventilation using a tidal volume (VT) of 6–8 mL/kg of body weight, inspiratory/ expiratory time ratio (I: E) 1:1.5 and an O2/air mixture (FiO2 of 0.5) of 2 L/min. The respiration rate was adjusted to maintain an end-tidal CO2 tension of 35 to 40 mmHg. At the end of the surgery, a recruitment maneuver (applying a continuous positive airway pressure of 30 cm of water for 30 seconds), repeated 3 times for lung re-expansion after one-lung ventilation (OLV) to avoid atelectasis.
Surgical technique. Children were canted to the right at an angle of 60°. The right arm was placed on the head with a 120° abduction from the shoulder. Skin incision was started from the third intercostal space in the midaxillary line and applied until the fifth intercostal space. The right lung was pushed back with a wet sponge and a malleable retractor. Therefore, the intraoperative operation caused the right lung to be trapped.
Surgeon placed standard purse sutures on right side of the ascending aorta, the superior vena cava, and the right aortocaval junction. After heparinization, surgeon cannulated the ascending aorta, the superior vena cava and the inferior vena cava. Then, a standard CPB was initiated and aortic cross-clamp was performed in the same incision. The same VSD closure or ASD closure was done as used in other procedures. Finally, the pericardium was partially closed and a chest drainage was placed in the right thorax.
CPB management. The dose of heparin used for anticoagulation during CPB was 300 U/kg plus additional doses to achieve and maintain an activated clotting time more than 480 seconds.
During CPB, minimum rectal temperature was maintained at 30–32°C. Management of CPB included alpha-stat pH management, MAP in the range of 50–80 mmHg, hematocrit of 20–25%, and a non-pulsatile flow rate of 2.0–2.4 L/min/m2. Protamine sulfate was used to reverse heparin-induced anticoagulation after separation from CPB.
Postoperative care. All children were transferred to the ICU after cardiac surgery, where they underwent management according to our institutional protocols. Volume-pressure controlled ventilation was applied with a tidal volume of 6–8 mL/kg, PEEP of 5 to 7 mmHg, FiO2 of 50% and respiratory rate of 10 to 25/min to maintain an end-tidal CO2 tension of 35 to 45 mmHg. Pressure support ventilation with a 10-cmH2O pressure support level and 5-cmH2O PEEP was performed upon recovery of spontaneous respiration.
The extubation criteria was a respiratory rate of 15 to 30 breaths/min, heart rate within 20% of baseline for at least for 1 h, PaO2 of > 70 mmHg, PaCO2 of < 48 mmHg, and pH of 7.35 to 7.50 on an arterial blood gas analysis.
Primary and Secondary Outcomes. Ventilation time, pulmonary collapse, hospital mortality, duration of ICU and postoperative hospital stays and postoperative lung complications were recorded after surgical.
Other clinical outcomes evaluated included HR, MBP, CI and arterial blood gas analysis. Arterial blood gas analysis was calculated at the following time points:5 minutes prior to incision (T1), 3 min after the first ARM (T2), 3 min after the second ARM (T3), 2 h after weaning from CPB (T4). Global hemodynamic variables (HR, MBP, CI) were recorded at regular time points: T1, T2, T3, T4. In all groups, the same measurements were recorded at the same time points.
The oxygenation index (OI) during surgery were calculated according to the following formulas: OI = PaO2/FiO2.
The children’s plasma levels of IL-6 and TNF-α were determined at T1 and T4. Blood samples were drawn into the tubes containing ethylenediaminetetraacetic acid via the central venous catheter and centrifuged at 3,000 rpm for 20 min. The extracted plasma was stored in polypropylene tubes at -80℃ until further analysis and then analyzed for IL-6 and TNF-α by a quantitative sandwich enzyme immunoassay (Quantikine ELISA; R&D Systems, Inc., Minneapolis, MN, USA). All enzyme immunoassays were performed with a V-MAX 220 VAC ELISA reader (Molecular Devices, Palo Alto, CA, USA).
Statistical analysis. Descriptive analysis was performed using mean ± SD for continuous variables and frequencies (percentages) for categorical data. For comparisons of categorical variables Chi-square analysis was used. Student’s t-test was used to compare the means of two samples. The arterial blood gas analysis variables were analyzed using repeated measures analysis of variance (ANOVA). All of the collected data were stored electronically and analyzed using SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov and normal-quantile plots were used to determine whether the continuous variables were normally distributed. Graphics were produced by use of GraphPad Prism 5 (GraphPad Software, San Diego, CA).