Study design and patients
This is a retrospective, observational, case-control analysis, conducted from January 2015 to June 2019. Ethical Committee of Fuwai Cardiovascular Hospital approved the protocol (Approval NO. 2015-682), and informed consent was obtained from participant’ parents before enrolment.
The study was conducted in a PICU (40 beds) at a 1521-bedded tertiary medical care center in China. Patients entry criteria included: (1) less than 1 year old; (2) complete repair of CHD with CPB; (3) PaO2/FiO2 lowered than 150 and had been mechanically ventilated for more than 48 hours. Exclusion criteria: (1) residual cardiac malformation that must be treated surgically; (2) ECMO; (3) cardiopulmonary resuscitation; (4) airway anomalies that will delay extubation; (5) ejection fracture < 45% (every patient received an ECHO when ARDS was diagnosed); (6) left atrial pressure>12 (Left atrial pressure of every infant was measured by placing a special catheter into the right atrium then punching through the interatrial septum).
The primary endpoint was the improvement in OI after 24-hour of surfactant treatment; and secondary endpoints were ventilator time and PICU time. A sample size calculation with power analysis was performed for this study. Based on the primary outcome-improvement in OI after 24-hour of surfactant treatment, 4 differences in OI between surfactant group and control group is considered significant, an SD of 4 was used. This SD is based on a previous study of infants suffering ARDS after cardiac surgery . At 80% power and an alpha of 0.05, at least 16 subjects would be required in each group.
There were 2 different strategies to deal with these infants in our center. Some patients preferred to adopt surfactant, who met the criteria. Other patients preferred to use standard treatment, for worrying about the potential complications such as airway obstruction, or for disliking extra economic burden. Everyone was offered surfactant at the beginning, but surfactant is not a part of our standard treatment protocol.
During the 42-month study, 7569 children that had cardiac surgery were admitted to PICU, and 3414 of them were infants. 343 infants used mechanical ventilation above 2 days. 78 infants were diagnosed with moderate to severe ARDS (PaO2/FiO2), and who matched inclusion and exclusion criteria. 22 infants who received surfactant in addition to standard care constituted surfactant group. In order to minimize potential bias caused by differences in baseline characteristics between groups, patients were matched in a 1:1 ratio using the following baseline features: age (±30d), weight (±3kg), RACHS-1, and initial PaO2/FiO2 (±10). These 22 controls were also offered surfactant but declined (high cost 5, guardians’ preference to use standard treatment 5, and guardians’ refusal for worrying about the potential complications 12). It was a comparative study evaluating the changes in clinical status and outcome between the two groups.
Surfactant (Calf Pulmonary Surfactant for injection, produced by Shuang he Inc, Beijing, CN) is a modified natural lung surfactant. It is produced by extracting the phospholipids, cholesterol, triglycerides, free fatty acids, surfactant protein B and surfactant protein C from bovine lung surfactant of newborn calf lungs. China Food and Drug Administration approved surfactant for neonatal respiratory distress syndrome.
Surfactant is a routine therapeutic choice for pre-term newborns suffering respiratory distress syndrome. The standard dose of surfactant is 50-100mg/kg [14,15], some patients may have side effects such as intense instant hemodynamic fluctuation and hypoxemia. Due to high cost and concern for dangerous acute side effects, we are cautious about surfactant dosage. Considering that the native surfactant system of these infants was nearly normal before operation, and self-repairing systems of epithelial cells could replenish surfactant after CPB, a low dose of 20 mg/kg nature surfactant as the treatment dosage was used.
All operations were performed by 2 senior surgeons. Patients in both groups had received standard care according to the hospital protocol. The basic care contained fluid resuscitation, enteral feeds and pain management, and other treatments including cardiac, diuretic, anti-inflammatory. Vital signs, oximetry and hemodynamic parameters would be continuously monitored. The cardiac functions and circulatory blood volume status were obtained by pumping multiple vasoactive agents mainly including catecholamine drugs and giving adequate fluid supplement. Rescue protocol for any severe hemodynamic ﬂuctuation would be prepared. Sedation and mechanical ventilation treatment would be strictly controlled. Supportive management and antibiotics were given as per unit policy. ARDS was diagnosed based on the standard recommended by the North American-European Consensus Conference Committee . The diagnosis of ARDS was confirmed by clinical, radiological and laboratory findings.
Lung protective ventilation strategy was applied to all infants before enrollment. All infants were intubated and supported by mechanical ventilation with synchronized intermittent mandatory ventilation mode of the ventilator (PB 840®). Ventilator settings were adjusted to arterial blood gas results. The peak inspiratory pressure was adjusted to reach a tidal volume goal of 6 ml/kg to 8 ml/kg. To keep the PaCO2 below 45 mmHg, the inspiratory time would be set at approximately 0.5s, with respiratory rate 25-40/min, PEEP 4-8 cmH2O. Also, to maintain arterial oxygen saturation above 85% and PaO2 above 50 mmHg, peak inspiratory pressure and FiO2 needed to be adjusted.
Natural surfactant (bovine) would be given 20mg/Kg (35mg/ml). After receiving the written parental permission, surfactant would be instilled into the trachea via an endotracheal tube using a small catheter in 4 equal aliquots, which would be instilled in four different positions (left, head up then down, right). Manual ventilation with 100% O2 would be applied for 5 minutes after the treatment. With concomitant sedation and muscle relaxation, the next tracheal suctioning would be performed at least 4 hours later. The acute effects of surfactant therapy would be evaluated 24- hour after the treatment. Vital signs were monitored continuously and recorded for 60 minutes after the intervention. Chest radiographs were acquired before and after surfactant administration every day.
Data was entered on a pre-designed case record form from the patients' archived files. The data extracted included patient demographics, blood gases, ventilator settings, complication, total time on ventilator, total time in PICU and clinical outcomes. Ventilator days were counted from the first day that a patient received mechanical ventilation. Ventilator parameters were recorded before the start of surfactant administration. After surfactant treatment, OI and VI were derived from the measured data. OI was calculated via mean airway pressure * FiO2 *100/PaO2 and VI was calculated via PaCO2 * peak inspiratory pressure * respiratory rate/1000.
The baseline demographic and clinical characteristics that were collected were age, weight, sex, RACHS-1, total on-pump time, aortic clamping time, OI, VI, PaO2/FiO2, PaO2 and the status of the patient within the time of inclusion (Table 1). In addition, the severity of illness at the time of inclusion was recorded and assessed by using the SOFA score . Moreover, the daily vital signs, urine output, laboratory data, ventilator settings, vasopressor dosage were extracted.
Qualitative data were presented as frequencies and percentages, whereas quantitative data were presented as mean, standard deviation. The unpaired t-test was used for comparison between patients in surfactant group and control group (or
the Fisher exact test when there were counts of <5). The cumulative percentages of extubated patients were analyzed using Kaplan-Meier survival analysis with the log-rank test. The data was analyzed using SPSS version 20.0. The p-value of <0.05 was considered as statistically significant.