This study was conducted in the NICU of Ankara City Hospital between January 2020 and June 2021. Infants who were less than 30 weeks of gestational age, required intubation and mechanical ventilation in the first 24 hours of life, received surfactant at least once, and were clinically stable at postnatal 24 hours were included in the study. Written informed consent was obtained from the patients’ families. Patients whose families did not provide consent, who had major congenital anomalies at admission, or had congenital heart disease were excluded. The study was approved by the Ankara City Hospital Ethics Committee (E1-19-198) and prospectively registered at clinicaltrials.gov (NCT04191239).
Gestational age was determined based on the mother’s last menstrual period, first trimester prenatal ultrasound (US) data, or estimated postnatally using the New Ballard Score . Respiratory distress syndrome (RDS) was defined as early postnatal symptoms of respiratory distress accompanied by tachypnea, retraction, moans, and cyanosis and supported by blood gas and chest X-ray findings [9, 10].
In accordance with unit protocols, surfactant therapy for RDS was administered prophylactically at NICU admission or as early rescue therapy in the first two hours according to the following criteria: As per the recommendations of the Turkish Neonatal Society, preterm infants at gestational age < 26 weeks that did not receive antenatal steroid therapy and preterm infants that required intubation in the delivery room received prophylactic surfactant; infants with signs of RDS findings and FiO2 requirement > 40% received early rescue surfactant therapy. All patients in the study received surfactant (poractant alfa 200 mg/kg) within the first 2 hours of NICU admission and were monitored using GE® Carescape R860 model ventilators.
This study was designed as a prospective, randomized crossover study. Patients who met the selection criteria were randomized after the first surfactant administration to crossover ventilation with bilevel VG and PRVC for 2 hours each using the sealed envelope method with grouping by weight.
Group 1 (PRVC): Bilevel VG mode first, PRVC mode second, then continued with PRVC
Group 2 (bilevel VG): PRVC mode first, bilevel VG mode second, then continued with bilevel VG.
In block randomization, weight stratification categories were determined as 500–750 g, 751–1000 g, and 1001–1250 g. As blinding was not possible due to the nature of the study, the sealed envelope method was used to help ensure balance and reduce bias.
After group assignment, the infants were monitored with the designated ventilation mode. The following ventilator parameters were set in PRVC mode: FiO2, positive end-expiratory pressure (PEEP), pressure support (PS), VT, respiratory rate, inspiratory time (Tins), inspiratory pressure minimum (Pmin) and maximum (Pmax). In bilevel VG mode, FiO2, VT, PEEP, respiratory rate, Tins, and Pmax were set. VT was set to 5 mL/kg and the target blood gas values were pH 7.25–7.35, PaCO2 45–55 mmHg, and PaO2 50–70 mmHg.
Operating Principles Of The Ventilation Modes
In SIMV PRVC mode, the ventilator delivers synchronized pressure-regulated, volume-controlled breaths at the set respiratory rate. For each mechanical breath, the ventilator adjusts the inspiration pressure to the lowest pressure needed to provide the target VT. All spontaneous efforts trigger pressure-assisted breaths.
The ventilator provides volume-controlled ventilation for 10 seconds or two breaths (whichever is longer when the mode is initiated) to determine the patient’s lung compliance. Inspiratory pressure is determined according to lung compliance and used for subsequent breaths.
When adjusting inspiratory pressure, the ventilator uses PEEP + Pmin as the lower limit and Pmax − 5 cmH2O as the upper limit. The difference in inspiratory pressure between breaths does not exceed ± 3 cmH2O. If a high airway pressure alarm is activated for the current breath, the target pressure for the next breath is reduced by 0.5 cmH2O.
In Bilevel VG mode, if the patient initiates a breath at the PEEP level, a pressure-supported breath is provided at the set PS. The ventilator switches between PEEP and minimum pressure to maintain the target VT according to the set respiratory rate and Tins values. As in PRVC mode, the ventilator determines lung compliance by providing volume-controlled ventilation over 10 seconds or two breaths (whichever is longer when the mode is initiated) and this is used to determine inspiratory pressure for subsequent breaths. Inspiratory pressure limits and adjustments are also the same as in PRVC mode.
All patients were monitored with a GE® Carescape R860 model ventilator. After randomization, initial ventilator settings were adjusted for each patient and recorded as the starting point. Respiratory rate, heart rate, and pulse oximetry (SpO2 90–94%) values were continuously monitored in all patients. After the first 2 hours of ventilation, the patients were switched to the other ventilator mode for 2 hours. Ventilator parameters, vital signs, and blood gas values were evaluated at the beginning of the study, after the first ventilation mode, and after the second ventilation mode (Fig. 1). Infants with oxygen requirements greater than 35% received a second dose of surfactant 8–12 hours after the first dose.
Follow-up ventilation management and other supportive treatments were provided by the attending neonatologist in accordance with unit protocols. In our unit, feeding and care of preterm infants and the diagnosis and management of RDS, BPD, patent ductus arteriosus (PDA), and retinopathy of prematurity (ROP) are carried out in accordance with Turkish Neonatology Society guidelines [10–14].
BPD in a preterm infant < 32 weeks of gestational age is defined as radiographically confirmed persistent parenchymal lung disease and is classified according to oxygen requirement at postmenstrual 36 weeks as follows [12, 15]:
Mild BPD, nasal cannula oxygen < 2 L/min, FiO2 ≥ 21
Moderate BPD, nasal cannula oxygen > 2 L/min or nCPAP or NIPPV, FiO2 ≥ 21
Severe BPD, invasive PPV, FiO2 ≥ 21
PDA refers to nonclosure of the ductus arteriosus after the first 72 hours of life. The diagnosis of hemodynamically significant PDA is made by demonstrating high volume flow through the PDA on echocardiography. The first choice of medical treatment for PDA in our clinic is ibuprofen in two doses, 10 mg/kg/day followed by 5 mg/kg/day, administered 24 hours apart .
ROP screening is performed in all infants born at a gestational age of < 34 weeks and birth weight of < 1700 g, as well as infants with a gestational age of ≥ 34 or birth weight of > 1700 g who received cardiopulmonary supportive treatment or is considered by the attending clinician to be at risk of ROP. The first ophthalmological examination is performed at postnatal 4 weeks. In our unit, the criteria specified by the multicenter ETROP (Early Treatment for Retinopathy of Prematurity) study group are used for in the application of laser photocoagulation for ROP [14, 16].
Proven sepsis is defined as the presence of clinical and laboratory findings consistent with sepsis and a demonstrated causative pathogen. Clinical sepsis is defined as the presence of clinical and laboratory findings consistent with sepsis for which a causative pathogen could not be demonstrated [17, 18].
Intraventricular hemorrhage (IVH) is evaluated using bedside cranial ultrasound (US) and staged according to the Papile classification .
Data regarding the patients’ survival to discharge, any stage of BPD, PDA requiring medical treatment, any stage of ROP, grade 3–4 IVH, and clinical or proven sepsis was recorded from the patients’ records.
The data were analyzed using SPSS for Windows. Descriptive statistics are shown as frequency and percentage, mean and standard deviation, or median and range. Paired samples t-test was used for comparisons of repeated measures within subjects and Mann-Whitney U test was used for comparisons between the two different groups. Statistical significance was accepted at p < 0.05.