Study design
This was a retrospective study, conducted by reviewing medical records and data. The study protocol was approved by the institutional research ethics committee of Shenzhen Children’s Hospital (2,022,062).
Patients
This retrospective study was performed on data from 462 premature infants with a gestational age(GA) of < 32 weeks who were hospitalized between January 2019 and December 2021 in the NICU at Shenzhen Children’s Hospital.
The inclusion criteria were as follows
(1)GA at birth < 32 weeks; (2)admitted to hospital within one day after birth; (3)the hospital stay was longer than 28 days; (4)echocardiography was performed on DOL 1、DOL 7、 and DOL 14; (5)platelet tests were performed on DOL 1、DOL 7 and DOL 14.
The exclusion criteria were as follows
(1) severe congenital constructional or chromosome malformations, such as congenital heart or lung disease(infants with patent foramen ovale(PFO) and no hemodynamically significant patent ductus arterious(no hsPDA) were excluded), diaphragmatic hernia, genetic metabolic disease, or chromosomal disease; (2) blood exchange treatment or suffering from hematological diseases; (3) neonatal sepsis and neonatal severe asphyxia; (4)severe arrhythmia; (5)poor echocardiography image quality or incomplete clinical medical records.
Diagnostic criteria
According to the consensus definition of the National Institute of Child Health and Human Development [20], BPD is diagnosed when supplemental oxygen is required for more than 28 days. BPD severity was assessed according to the oxygen concentration required at 36 weeks PMA or at discharge.
We enrolled 220 premature infants in the study including 85 and 135 infants in the BPD group and non-BPD group respectively (Fig. 1).
Flowchart of cases selection and analysis. 220 premature infants were enrolled in this study. NICU, neonatal intensive care unit; GA, gestational age; BPD, bronchopulmonary dysplasia
Clinical data collection
Data on the following variables were retrieved from the electronic medical records: GA, birth weight(BW), delivery method, Apgar score at 1 min, sex, multiple births, surfactant treatment, duration of invasive mechanical ventilation, neonatal pneumonia and neonatal respiratory distress syndrome (NRDS), maternal age, antenatal steroid use, antibiotics use, incidence of premature prelabor rupture of membranes, gestational diabetes mellitus and high blood pressure during pregnancy.
Echocardiographic measurements
Echocardiographic evaluation was performed using a Vivid E9 (GE Health care, Horten, Norway) with an M6S probe. All infants were in a state of quiet sleep cooperation at the time of examination. All images and measurements were obtained from standard views according to the recommendations of the American Society of Echocardiography for chamber quantification [21]. When the two-dimensional image section was stable, clear and standard, dynamic images of three cardiac cycles were stored and the original data were measured again.
All measurements were taken by two senior cardiac sonographers.
Traditional ultrasonic indices
The detection rate of tricuspid regurgitation jet velocity (TRJV), ventricular septal flattening, pulmonary artery widening, right ventricular dilation and right atrial enlargement were analyzed on DOL7 in the two groups (Table 2).
①TRJV was measured using continuous doppler. The modified Bernoullik method was used to estimate right ventricular systolic pressure (RVSP), and in the absence of right ventricular outflow tract obstruction, RVSP was equal to pulmonary systolic pressure (PASP): PASP = RVSP = 4TRJV 2+RAP (Fig. 2-a).
Measurement of the traditional ultrasonic indices. (a) tricuspid regurgitation jet velocity was measured using continuous doppler; (b) The white line represents “D1” and the red line represents “D2” ,left ventricular eccentricity index(LVEI) was obtained through D1 / D2 calculations; (c-d) The inner diameter of right atrium and right ventricle were measured in the four-chamber section of the apex; (e) The inner diameter of pulmonary arteries were measured in the short axis of the aorta
②Ventricular septal flattening can be quantified using the left ventricular eccentricity index(LVEI). The left ventricular long diameter D1 parallel to the interventricular septum and the left ventricular short diameter D2 perpendicular to the septum were measured on the parastericular short-axis section. LVEI was obtained through D1 / D2 calculations (Fig. 2-b).
③The inner diameter of right atrium and right ventricle were measured in the four-chamber section of the apex (Fig. 2-c and 2-d ) and determines whether dilated according to the normal reference value [22].
④The inner diameter of the main pulmonary artery and left and right pulmonary arteries were measured in the short axis of the aorta (Fig. 2-e) and determines whether dilated according to the normal reference value [22].
Right ventricular function indices
We performed transthoracic echocardiography on DOL 1,DOL 7 and DOL 14.
①TAPSE was measured through M-mode from the four-chamber view. M sampling lines are parallel to the direction of movement of the tricuspid annulus of the sidewall. The distance between the end-diastolic and end-systolic represents TAPSE (Fig. 3).
Measurement of TAPSE. The distance between the end-diastolic and end-systolic represents TAPSE
②RIMP was measured with conventional pulsed Doppler using the method proposed by Tei et al. Pulsed-Doppler waveforms of the tricuspid inflow were recorded from the parasternal four-chamber view and the “a’’” interval was the time from tricuspid closing to opening. The right ventricular outflow patterns were visualized from the parasternal short-axis view, and the “b’’” interval was measured between onset and cessation of the right ventricle outflow and RIMP was calculated as (a’-b’)/b’. To minimize variations in heart rate, mean values were obtained by averaging a minimum of three consecutive cardiac cycles (Fig. 4).
Measurement of RIMP. The “a’” interval was the time from tricuspid closing to opening.the “b’” interval was measured between onset and cessation of the right ventricle outflow and RIMP was calculated as (a’-b’)/b’
Measurement of platelet parameters
Platelet parameters were recorded on DOL 1,DOL 7, and DOL 14, including platelet (PLT) count, mean platelet volume (MPV), platelet hematocrit (PCT) level, and platelet distribution width (PDW). The blood cell analyzer SysmexXN350 and the supporting reagent of Micron Hisen were used for parameter detection.
Statistical analysis
Statistical analysis was performed using SPSS 26.0 software. The normality of continuous variable distribution assumption was tested. Normally distributed variables were presented as the mean ± standard deviation, and non-normally distributed variables were presented as the median and quartile range. Comparisons between the continuous variables were performed using an independent sample t-test or Mann-Whiteny U-test. Categorical variables were presented as the frequency and percentage and were compared using the chi-squared test. The Friedman test was used to investigate the age dependency of TAPSE and RIMP. Multivariate logistic regression was performed to determine the independent risk factors of BPD. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in logistic regression analysis. A receiver operating characteristics (ROC) curve was used to analyze the accuracy of echocardiographic indices of the right ventricular function combined with platelet parameters in predicting BPD. P-values of < 0.05 were considered statistically significant.
To ensure the stability of the Logistic regression model, a multicollinearity test was conducted on the variables included in the regression. Blant-Altman analysis was used to test the inter-group and intra-group repeatability of TAPSE and RIMP.
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