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Echocardiographic Changes and Clinical Outcomes During Invasive and Non-Invasive Ventilatory Sup-port in Neonates: A Prospective Cohort Study

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01 November 2026

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03 November 2026

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Abstract
Background: Different modes of respiratory support may affect cardiovascular performance and systemic hemodynamics differently in neonates. Objective: The study aimed to evaluate the effects of invasive and non-invasive respiratory support on hemodynamic status and clinical outcomes in neonates. Methods: This prospective observational cohort study was conducted in the NICU. We enrolled 90 neonates and allocated them to three groups: invasive ventilation, non-invasive ventilation, and a control. Echocardiographic measurements were performed, including stroke volume (SV), cardiac output (CO), cardiac index (CI), mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (FAC), pulmonary artery systolic pressure (PASP), and myocardial performance indices for the left and right ventricles, as well as Doppler evaluation of the superior mesenteric and renal arteries. Assessments were conducted one hour after initiation of respiratory support and repeated after three days of ventilation. Results: After three days, invasive ventilation was associated with significantly lower SV, CO, CI, MAPSE, TAPSE, FAC, right ventricular SV, and pulmonary acceleration time, together with higher pulmonary artery systolic pressure compared with the non-invasive group (p=0.001, 0.001, 0.001, 0.002, 0.002, 0.006), respectively. The invasive group showed a significant reduction in Vmax values in the studied arteries. Neonates who developed acute kidney injury or died exhibited significantly impaired biventricular performance. Conclusions: Invasive mechanical ventilation is associated with lower cardiac output and evidence of greater impairment in both left and right ventricular functional indices over time, accompanied by higher rates of adverse clinical outcomes.
Keywords: 
acute kidney injury
;  
Doppler US
;  
echocardiography
;  
hemodynamics
;  
neonatal mortality
;  
non-invasive ventilation
;  
neonatal intensive care unit
;  
mechanical ventilation
Subject: 
Medicine and Pharmacology  -   Pediatrics, Perinatology and Child Health

1. Introduction

Hemodynamics refers to the normal functioning of the target organ facilitated by the cardiovascular system (CVS), the blood's capacity to transport oxygen, and the tissue's autoregulatory capabilities. The preservation of neonatal circulatory homeostasis is a significant challenge, owing to the intricate physiology during postnatal transition and the intrinsic immaturity of the cardiovascular system and other relevant organs [1]. Neonatal hemodynamic compromise may arise in diverse clinical situations, including but not limited to maladaptation during the initial transitional phase, sepsis, congenital cardiac anomalies, hemodynamically significant patent ductus arteriosus, persistent pulmonary hypertension of the newborn, systemic inflammatory conditions such as necrotizing enterocolitis, perinatal asphyxia, sepsis, the necessity for respiratory assistance, and dehydration [2]. Abnormal cardiovascular function in newborn infants increased the hazard of morbidity and mortality. It is important to recognize the properties of the neonatal circulation to be able to improve hemodynamic interventions [3]. The afflicted organs include the brain, gut, kidney, and adrenal gland. Previous research has demonstrated changes in blood flow and resistance index (RI) in the superior mesenteric, renal, and pancreatic arteries of ill infants [4]. Ventilatory assistance for ill infants may also enhance hemodynamic status. Invasive mechanical ventilation can lead to changes in cardiac output and arterial blood pressure, potentially altering blood flow distribution. Ventilation may elicit these hemodynamic alterations by modifying systemic venous return to the right ventricle, pulmonary arterial pressure, ventricular interdependence (left ventricular preload), or transmural left ventricular ejection pressure (left ventricular afterload) [5]. To our knowledge, there are limited data regarding traditional echocardiographic indices such as ejection fraction, fractional shortening, TAPSE, MAPSE, tissue Doppler velocities, and myocardial performance index, and organ perfusion in newborn infants during invasive and non- invasive respiratory support, as the field has historically focused on hemodynamic physiology and ventricular output measurements rather than conventional echocardiographic function metrics. We hypothesized that early identification of cardiovascular dysfunction may help precision management of vulnerable neonates in the NICU [6]. This study aimed to evaluate the effects of invasive and non-invasive respiratory support on hemodynamic status and clinical outcomes in neonates using Echocardiography and Doppler Ultrasound.

2. Materials and Methods

2.1. Study design and setting

This observational prospective cohort study was conducted in the neonatal intensive care unit (NICU) from February 2023 to December 2025. The study included 60 neonates assigned according to their need for respiratory support to invasive mechanical ventilation (30) and non-invasive ventilation (30). They were assessed against 30 stable neonates, matched for sex, gestational age, and postnatal age. The newborn infants who needed both types of support and/or phototherapy were excluded. Sample size estimation was performed using a two-sided α level of 0.05 and a power of 80%, assuming a 20% effect size. The minimum required sample size was 86 neonates; therefore, 90 participants were included in the study.

2.2. Inclusion and exclusion criteria:

All neonates admitted to the NICU) who required respiratory support were eligible. The causes of respiratory distress in the studied neonates included respiratory distress syndrome (RDS), meconium aspiration syndrome (MAS), transient tachypnea of the newborn (TTN), or congenital pneumonia. Neonates were excluded if they required both invasive and noninvasive respiratory support during the 3-day study period. Additional exclusion criteria included hyperbilirubinemia requiring phototherapy, congenital anomalies, congenital infections, metabolic disorders, and death before completion of the third study day. A control group consisting of neonates who did not require ventilatory support was also included. The invasive ventilation group comprised neonates receiving mechanical ventilation using synchronized intermittent mandatory ventilation (SIMV) or pressure-control (PC) modes. The noninvasive ventilation group included infants supported with continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), or bilevel positive airway pressure (BiPAP).

2.3. Intervention

All studied neonates were subjected to detailed history taking and received comprehensive clinical and diagnostic assessment. Clinical evaluation included assessment of vital signs, capillary refill, and blood pressure. Blood pressure centiles were used; measurements above the 97th centile were considered hypertensive, below the 3rd centile were considered hypotensive, and otherwise were normal. Laboratory investigations included complete blood count, arterial blood gases, serum electrolytes, blood glucose, and liver and renal function tests. Radiological examinations were performed as clinically indicated. Ventilator parameters at the time of echocardiographic assessment were recorded. Recorded variables included ventilation mode (SIMV or PC ventilation), mean airway pressure (MAP), positive end-expiratory pressure (PEEP), and fraction of inspired oxygen (FiO2). The ventilator settings for both study groups are presented in Supplementary Tables S1 and S2.

2.4. Echocardiography

Echocardiographic examination was performed on the first and third day of respiratory support for the study groups and on the first day for the control group. Philips Affiniti 30 cardiovascular ultrasound machine with an 8-12 MHz electronic sector transducer (made in the United States) was used. Serial number |(US419E1412). All cases were subjected to an echocardiography study for assessment of both systolic and diastolic function. Echo-Doppler imaging (including M-mode, 2D echocardiography, colour flow, and Doppler flow modalities, and tissue velocity imaging using all accessible windows and different views for assessment of the left and right ventricles. The echocardiographic parameters for the right and left ventricles were recorded. They included stroke volume (SV), cardiac output (COP), cardiac index (CI), and mitral annular plane systolic excursion (MAPSE). Pulsed-wave Doppler was employed to evaluate left ventricular diastolic function by detecting blood flow velocities across valves, utilizing tissue Doppler imaging, and assessing parameters including ejection fraction (EF), fractional shortening (%FS), E wave, A wave, E/A ratio, and MV E/e. The evaluation of right ventricular function included tricuspid annular plane systolic excursion (TAPSE), right ventricular output, and right ventricular fractional area change (RV FAC), as well as estimations of pulmonary pressure (PASP). Advanced Doppler imaging was employed to assess RV longitudinal strain, RV outflow tract velocity time integral, myocardial performance index (MPI), RV filling pattern, and acceleration time, tricuspid valve Ejection/Accélération ratio (TV E/A ), early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity (TV E/a), right ventricular Tie index (RV Tie), time: pulmonary valve acceleration time ( PV acc ), right ventricular stroke volume ( RVSV), and right ventricular cardiac output (Rv/COP). Tissue Doppler imaging was utilized to assess myocardial performance.

2.5. Doppler ultrasound

Doppler ultrasonography was performed using an ESAOTE SPA ultrasound machine (Italy; serial number: SN 03192) equipped with a high-resolution micro-convex transducer (3-11 MHz). Superior mesenteric, and renal blood flow velocities were assessed. The measured Doppler parameters included timed average velocities (Vmax), pulsatility index (PI), and resistance index (RI). These measurements were obtained in newborn infants requiring respiratory support, including both invasive mechanical ventilation and noninvasive ventilation. Echocardiography and Doppler investigations for superior mesenteric, and renal arteries were performed at two time points: on the first day of ventilation, after 60 minutes of respiratory support, and again on the third day of ventilation. To minimize inter-observer variability, all examinations were conducted by a single experienced operator. The radiologist and cardiologist were blind to the clinical details. The maneuvers were performed in a thermoneutral environment, and the neonates were quiet. Controls were assessed only at baseline.

2.6. Statistical analysis:

All data were collected, coded, and analyzed using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normality and are presented as mean ± standard deviation (SD). The independent-t test was used for comparisons between two independent groups, while one-way analysis of variance (ANOVA) was used to compare more than two groups, followed by Tukey's post hoc test for pairwise comparisons. Categorical variables are presented as frequencies and percentages and were compared using the chi-square test. Fisher's exact test was applied when the expected cell count was less than five. Paired-samples t tests were used to compare repeated echocardiographic and Doppler measurements within the same group over time. To identify factors independently associated with cardiac output, univariable and multivariable linear regression analyses were performed. Variables showing statistical significance in univariable analysis were entered into the multivariable model. Potential confounding factors, including gestational age and baseline acidosis, were considered in the adjusted analyses. Results are presented as regression coefficients (β) with corresponding standard errors (SE). Two-tailed p-value < 0.05 was considered statistically significant.

2.7. Ethical considerations:

This study was approved by the Ethics Committee of the Department of Pediatrics and the Research Ethics Committee of the Faculty of Medicine for Girls, Al-Azhar University (Approval No. 1544; October 12, 2022). The study was conducted in accordance with the principles of the Declaration of Helsinki and its subsequent amendments.
Informed consent was obtained from the parents or legal guardians of all enrolled neonates after explaining the study objectives and procedures. Participation was voluntary, and parents retained the right to withdraw their infants from the study at any time without prejudice to their medical care. Patients' information was handled confidentially and used only for research purposes.

3. Results

The results are shown in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9 and Table 10 and Supplements 1 - 3.

3.1. Characteristics of the Study Groups:

There were no statistically significant differences among the three groups regarding sex distribution or body surface area. Nevertheless, the invasive ventilation group had a significantly higher percentage of preterm neonates (p = 0.003). Regarding clinical parameters, neonates in the invasive ventilation group exhibited significantly higher heart rates and respiratory rates compared with both the non-invasive ventilation and control groups (p = 0.001 for both comparisons). Additionally, lower blood pressure values were detected in the invasive ventilation group (p = 0.011). Analysis of arterial blood gas parameters demonstrated a significantly higher prevalence of acidosis among neonates receiving invasive ventilation (p = 0.001). Table 1
Table 1. Comparison between invasive and noninvasive ventilation and control groups regarding demographic, clinical data and blood gases of the studied groups at the 1st hour.
Table 1. Comparison between invasive and noninvasive ventilation and control groups regarding demographic, clinical data and blood gases of the studied groups at the 1st hour.
History Control Group
(n=30)		 Invasive Group
(n=30)		 Non-invasive Group
(n=30)		 P
GA (weeks) 37.33 ±1.62 35.37±1.43 37.00±1.61 0.024
Postnatal age (days)
Median (IQR) 		2(1-3) 1 (1-2) 1(1-1) 0.004
Gender (N %)
Male 16(53.3%) 17(56.7%) 18(60.0%) 0.873a
Female 14(46.7%) 13(43.3%) 12(40.0%)
BSA (m2) Mean ±SD 0.20±0.01 0.19±0.01 0.19±0.01 0.428
Preterm (N %) 10(33.3%) 23(76.7%) 14(46.7%) 0.003a
Full term (N %) 20(66.7%) 7(23.3%) 16(53.3%)
Heart rate (beats/min) Mean ± SD 136.47±6.83 161.83±9.92 157.40±8.92 0.001
Blood pressure (mmHg) (N %)
Normal 30(100.0%) 23(76.7%) 28(93.3%) 0.011b
Hypotension 0(0.0%) 5(16.7%) 0(0.0%)
Hypertension 0(0.0%) 2(6.7%) 2(6.7%)
Respiratory rate (cycle/min) Mean ±SD 47.30±5.05B 69.07±4.68A 64.90±5.63A
0.001
Temperature oC (N %) 0.015b
Normal 30(100) 26 ( 86.7%) 30(100%)
Abnormal 0(0.0%) 4(13.3%) 0(0.0%)
Capillary refill time sec (N %) 0.015b
Normal 30(100.0%) 26(86.7%) 30(100.0%)
Delayed 0 (0.0%) 4(13.3%) 0(0.0%)
Non survival (N %) 0 (0.0%) 9(30%) 3(10%) 0.002
pH 7.19±0.16 7.24±0.14 0.001
PaCO2(mmHg) 57.07±7.09 51.10±8.62 0.001
PaO2(mmHg) 75.63±5.48 76.70±4.67 0.001
HCO3(mmol/L) 17.92±2.49 20.22±5.39 0.036
O2Sat (%) 78.13±4.34 78.80±4.37 0.001
Acidosis (N %) 0.001
No 4(13.3%) 12(40.0%)
Yes 26(86.7%) 18(60.0%)
ANOVA: one-way analysis of variance test, followed by Tukey’s post hoc test; BSA: body surface area; GA: gestational age; SD: standard deviation; pH: potential of hydrogen; PaO2: partial pressure of oxygen; PaCO2: partial pressure of carbon dioxide; HCO3: bicarbonate; O2 Sat: oxygen saturation; a Chi-square test; b Fisher’s exact test.

3.2. Echocardiographic assessment of left Ventricular function

As shown in Table 2, significant differences among the study groups were observed at 1 hour after initiation of ventilatory support with respect to cardiac output (COP) (p = 0.001), cardiac index (CI) (p = 0.001), MAPSE (p = 0.016), and mitral valve E/e′ ratio (p = 0.041). After 3 days of ventilation, neonates in the invasive ventilation group had significantly lower SV (p = 0.001), COP (p = 0.001), CI (p = 0.001), and MAPSE (p = 0.002) compared with the non-invasive ventilation group. These findings indicate progressive impairment of left ventricular performance in neonates receiving invasive mechanical ventilation.
Table 2. Comparison of echocardiographic parameters of the left ventricle between invasive, non-invasive ventilation, and control groups at the 1st hour and between the invasive and non-invasive groups on the 3rd day.
Table 2. Comparison of echocardiographic parameters of the left ventricle between invasive, non-invasive ventilation, and control groups at the 1st hour and between the invasive and non-invasive groups on the 3rd day.
Echo left ventricle at 1hr Control Group (n=30) Invasive Group (n=30) Non-invasive Group (n=30) P
EF% 69.01±6.17 70.68±6.31 70.16±5.22 0.539
FS% 35.68±6.15 35.68±3.94 36.02±3.80 0.950
SV (ml) 6.07±1.23 5.32±1.57 5.97±1.47 0.093
COP (ml/kg/min) 284.75±53.46 319.76±63.08 344.63±59.55 0.001
CI (ml/kg/min)/m2 1424.67±278.78 1680.29±279.76 1797.96±291.24 0.001
MAPSE (cm) 0.78±0.10 0.71±0.10 0.76±0.11 0.016
LV_Tei 0.36±0.02 0.37±0.02 0.37±0.02 0.541
E/A ratio 0.88±0.10 0.84±0.09 0.85±0.11 0.363
MV E/e 9.70±1.25 8.88±1.37 8.99±1.39 0.041
Echo left ventricle on the 3rd day Invasive group Non-invasive group P
EF% 66.98±5.42 67.70±4.16 0.568
FS% 32.90±6.77 34.37±2.55 0.268
SV (ml) 3.38±0.98 5.17±1.50 0.001
COP (ml/kg/min) 204.28±59.24 295.04±85.56 0.001
CI (ml/kg/min)/m2 1077.24±312.4 1533.49±444.71 0.001
MAPSE (cm) 0.60±0.16 0.73±0.16 0.002
LV_Tei 0.41±0.06 0.39±0.06 0.157
E/A ratio 1.02±0.21 0.99±0.22 0.536
MV E/e 10.58±2.64 10.51±2.11 0.927
One-way Analysis of Variance test : multiple comparisons between groups through Post Hoc test: Tukey's, Independent t-test. EF: Ejection fraction; FS: Fraction shorting; SV: Stroke volume; COP: cardiac output; CI: cardiac index; MAPSE: mitral annular plane systolic excursion; LV Tie: left ventricular Tei index; E/A: Ejection/Accélération ratio; MV E/e: Early diastolic mitral inflow velocity to early diastolic mitral annulus velocity.

3.3. Echocardiographic assessment of right ventricular function

As presented in Table 3, TAPSE at 1 hour was significantly lower in the invasive ventilation group compared with the non-invasive ventilation group and the control group (p = 0.002). After 3 days of ventilatory support, neonates receiving invasive ventilation exhibited significantly lower TAPSE (p = 0.002), FAC (p = 0.006), RV stroke volume (p = 0.001), RV cardiac output (p = 0.001), and pulmonary valve acceleration time (p = 0.026) compared with the non-invasive ventilation group. Conversely, pulmonary artery systolic pressure was significantly higher in the invasive ventilation group (p = 0.022). These findings suggest progressive deterioration of right ventricular function and pulmonary hemodynamics among neonates managed with invasive mechanical ventilation.
Table 3. Comparison of echocardiographic parameters of the right ventricle between invasive, non-invasive ventilation, and control groups at the 1st hour and between the invasive and non-invasive groups on the 3rd day.
Table 3. Comparison of echocardiographic parameters of the right ventricle between invasive, non-invasive ventilation, and control groups at the 1st hour and between the invasive and non-invasive groups on the 3rd day.
Echo right ventricle at 1 hr. Control Group (n=30) Invasive Group (n=30) Non-invasive Group (n=30) p
TAPSE (cm) 0.83±0.11 0.72±0.11 0.80±0.13 0.002
FAC% 0.32±0.04 0.31±0.04 0.34±0.05 0.117
TV EA. ratio 0.86±0.08 0.88±0.08 0.85±0.07 0.287
PASP (mm Hg) 19.50±4.27 21.70±5.41 21.27±5.15 0.198
TV/E/e 8.48±1.33 8.02±1.41 8.81±1.31 0.077
RV Tei 0.38±0.05 0.40±0.03 0.39±0.05 0.211
PV. acc. time (ms) 91.97±8.04 89.53±6.93 90.23±8.94 0.483
RVSV (ml) 5.87±1.05 5.33±1.52 5.82±1.37 0.230
Echo right ventricle on the 3rd day Invasive Group Non-invasive Group p
TAPSE (cm) 0.60±0.15 0.76±0.20 0.002
FAC% 0.27±0.07 0.33±0.08 0.006
TV EA ratio 0.80±0.16 0.87±0.09 0.252
PASP (mm Hg) 25.47 ± 8.26 20.67±5.17 0.022
TV/E/e 8.04±2.01 9.34±1.93 0.050
RV Tei 0.45±0.09 0.42±0.06 0.086
PV Acc. time (ms) 78.30±16.15 86.97±12.98 0.026
RVSV (ml) 3.16±0.79 5.05±1.26 0.001
Rv/COP (ml/kg/min) 191.03±47.76 288.45±72.11 0.001
One-way analysis of Variance test & multiple comparisons between groups through Post Hoc test: Tukey's test shows significant difference in invasive group. TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; FAC: Fractional area change ;TV E/A : tricuspid valve Ejection/Acceleration ratio; TV E/a: Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity; RV Tei: Right ventricule Tei index; PV. acc. time: pulmonary valve acceleration time; RVSV: Right ventricular stroke volume; Rv/COP: Right ventricular cardiac output.

3.4. Longitudinal changes in echocardiographic parameters

Table 4 shows the longitudinal changes in echocardiographic parameters after 3 days of invasive and non-invasive ventilation. Regarding the left ventricular parameters, both ventilation groups demonstrated a significant decline in left ventricular systolic performance after 3 days. In the invasive ventilation group, EF, FS, stroke volume, cardiac output, cardiac index, and MAPSE decreased significantly, while the LV Tei index increased significantly (all p≤0.032), indicating deterioration of global left ventricular performance. Similar reductions in EF, FS, SV, CO, and CI were observed in the non-invasive group (all p≤0.024). However, MAPSE and LV Tei index remained unchanged, suggesting relative preservation of longitudinal and global LV function compared with the invasive group. Concerning the diastolic function, both groups demonstrated significantly higher E/A ratio and mitral E/e′ ratio after 3 days, proposing distorted ventricular filling and a trend toward higher left ventricular filling pressures.
Right ventricular parameters in the invasive ventilation group exhibited significant deterioration in right ventricular function after 3 days, evidenced by reductions in TAPSE (p=0.001), FAC (p=0.006), RV stroke volume (p=0.001), and RV cardiac output (p=0.001). In addition, PASP increased significantly, PV acceleration time shortened, and RV Tei index increased significantly, collectively indicating worsening right ventricular performance and increased pulmonary vascular load. In contrast, non-invasive ventilation was associated with minimal changes in most right ventricular parameters. TAPSE, FAC, TV E/A ratio, PASP, TV E/e′ ratio, and pulmonary valve acceleration time remained statistically unchanged. Although RV Tei index increased modestly (p=0.022), and RV stroke volume and RV cardiac output decreased significantly (both p=0.001), the magnitude of these changes was considerably smaller than that observed in the invasive ventilation group.
Table 4. The longitudinal changes in echocardiographic parameters after 3 days of invasive and non-invasive ventilation.
Table 4. The longitudinal changes in echocardiographic parameters after 3 days of invasive and non-invasive ventilation.
Echo left ventricle on the 3rd day Invasive at 1 hr.
Mean ±SD		 Invasive Group
After 3days
Mean ±SD		 p Non -Invasive
At 1hr.
Mean ±SD		 Non-Invasive
After 3days
Mean ±SD		 P
EF% 70.68±6.31 66.98±5.42 0.005 70.16±5.22 67.70±4.16 0.024
FS% 35.68±3.94 32.90±6.77 0.032 36.02±3.80 34.37±2.55 0.024
SV (ml) 5.32±1.57 3.38±0.98 0.001 5.97±1.47 5.17±1.50 0.001
COP (ml/kg/min) 319.76±63.08 204.28±59.24 0.001 344.63±59.55 295.04±85.56 0.001
CI (ml/kg/min)/m2 1680.29±279.76 1077.24±312.40 0.001 1797.96±291.24 1533.49±444.71 0.001
MAPSE (cm) 0.71±0.10 0.60±0.16 0.001 0.76±0.11 0.73±0.16 0.113
LV_Tei 0.37±0.02 0.41±0.06 0.001 0.37±0.02 0.39±0.06 0.174
E/A ratio 0.84±0.09 1.02±0.21 0.001 0.85±0.11 0.99±0.22 0.008
MV E/e 8.88±1.37 10.58±2.64 0.008 8.99±1.39 10.51±2.11 0.002
Echo right ventricle on the 3rd day
TAPSE (cm) 0.72±0.11 0.60±0.15 0.001 0.80±0.13 0.76±0.20 0.108
FAC% 0.31±0.04 0.27±0.07 0.006 0.34±0.05 0.33±0.08 0.840
TV EA ratio 0.88±0.08 0.80±0.16 0.015 0.85±0.07 0.87±0.09 0.586
PASP (mm Hg) 21.70±5.41 25.47 ± 8.26 0.016 21.27±5.15 20.67±5.17 0.708
TV/E/e 8.02±1.41 8.04±2.01 0.961 8.81±1.31 9.34±1.93 0.241
RV Tei 0.40±0.03 0.45±0.09 0.007 0.39±0.05 0.42±0.06 0.022
PV Acc. time (ms) 89.53±6.93 78.30±16.15 0.002 90.23±8.94 86.97±12.98 0.149
RVSV (ml) 5.33±1.52 3.16±0.79 0.001 5.82±1.37 5.05±1.26 0.001
Rv/COP (ml/kg/min) 320.70±59.46 191.03±47.76 0.001 336.29±55.80 288.45±72.11 0.001
Paired t-test EF: Ejection fraction; FS: Fraction shorting ;SV: Stroke volume; COP: cardiac output ,CI :cardiac index; MAPSE: mitral annular plane systolic excursion; LV Tie: left ventricular Tie index; E/A : Ejection/Acceleration ratio; MV E/e : Early diastolic mitral inflow velocity to early diastolic mitral annulus velocity;TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure ;FAC: Fractional area change ;TV E/A : tricuspid valve Ejection/Acceleration ratio; TV E/a: Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity;RV Tei: Right ventricular Tei index; PV. acc. time: pulmonary valve acceleration time; RVSV: Right ventricular stroke volume; Rv/COP: Right ventricular cardiac output.

3.5. Comparison Between Preterm and Full-Term Infants in the Invasive Ventilation Group

As shown in Table 5, preterm infants in the invasive ventilation group demonstrated significantly lower SV (p = 0.001), COP (p = 0.003), CI (p = 0.018), and MAPSE (p = 0.001) compared with full-term infants after 3 days of ventilation. In addition, the left ventricular Tei index was significantly higher among preterm neonates (p=0.015). Regarding right ventricular function, preterm infants exhibited significantly lower TAPSE (p = 0.001), FAC (p = 0.001), tricuspid E/A ratio (p = 0.028), RV stroke volume (p = 0.001), and RV cardiac output (p = 0.007) than full-term infants. Furthermore, the RV Tei index was significantly higher in preterm neonates (p = 0.034). Prematurity was related to less favorable echocardiographic indices among neonates treated by invasive mechanical ventilation.

3.6. Comparison Between Preterm and Full-Term Infants in the Non-Invasive Ventilation Group

As shown in Table 5, preterm infants receiving non-invasive ventilation had significantly lower fractional shortening (p = 0.031), stroke volume (p = 0.001), cardiac output (p = 0.001), cardiac index (p = 0.001), and MAPSE (p = 0.001) than full-term infants. In contrast, the left ventricular Tei index was significantly higher in preterm neonates (p = 0.014). Assessment of right ventricular parameters showed significantly lower TAPSE (p = 0.001), FAC (p = 0.003), tricuspid E/A ratio (p = 0.012), RV stroke volume (p = 0.001), and RV cardiac output (p = 0.001) in preterm compared with full-term infants. These findings suggest that gestational maturity was associated with differences in both left and right ventricular functional indices, even among neonates receiving non-invasive respiratory support.
Table 5. Comparison of Echocardiographic Parameters Between Preterm and Full Term Neonates in the Invasive and Non - Invasive Ventilation Groups After 3 Days of Ventilation.
Table 5. Comparison of Echocardiographic Parameters Between Preterm and Full Term Neonates in the Invasive and Non - Invasive Ventilation Groups After 3 Days of Ventilation.
Variable Invasive Invasive P Non-Invasive Non-Invasive P
Preterm Full term Preterm Full term
Mean ±SD Mean ±SD Mean ±SD Mean ±SD
Echo left ventricle on 3rd day
EF% 66.24±5.24 69.41±5.68 0.179 66.25±4.78 68.97±3.16 0.074
FS% 32.13±7.35 35.40±3.74 0.271 33.31±2.49 35.30±2.28 0.031
SV (ml) 2.76±0.80 5.42±1.57 0.001 3.27±0.95 6.83±0.77 0.001
COP (ml/kg/min) 180.49±52.34 282.45±81.91 0.003 210.78±61.13 368.77±22.52 0.001
CI (ml/kg/min)/m2 980.74±284.42 1394.32±404.35 0.018 1148.97±333.20 1869.95±150.54 0.001
MAPSE (cm) 0.55±0.12 0.77±0.17 0.001 0.60±0.14 0.85±0.05 0.001
LV_Tei 0.42±0.06 0.36±0.03 0.015 0.41±0.07 0.36±0.02 0.014
E/A ratio 1.05±0.22 0.93±0.15 0.187 1.10±0.26 0.89±0.13 0.007
MV E/e 10.43±3.02 11.07±3.21 0.652 11.61±2.39 9.55±1.25 0.005
Echo right ventricle on the 3rd day
TAPSE (cm) 0.53±0.15 0.80±0.18 0.001 0.59±0.15 0.91±0.07 0.001
FAC% 0.24±0.07 0.37±0.04 0.001 0.29±0.08 0.37±0.03 0.003
TV EA ratio 0.76±0.16 0.91±0.06 0.028 0.82±0.11 0.91±0.06 0.012
PASP (mm Hg) 21.52±6.24 25.86±7.50 0.238 21.43±6.21 20.00±5.80 0.614
TV/E/e 7.59±2.20 9.51±2.76 0.145 8.67±2.23 9.93±1.45 0.073
RV Tei 0.44±0.10 0.35±0.06 0.034 0.43±0.07 0.41±0.03 0.318
PV. Acc. time (ms) 75.39±14.78 87.86±17.94 0.073 82.79±16.46 90.63±7.76 0.100
RVSV (ml) 2.60±0.76 4.97±1.44 0.001 3.19±0.93 6.68±0.77 0.001
Rv/COP (ml/kg/min) 170.34±49.40 259.01±75.11 0.007 205.69±59.65 360.86±26.16 0.001
Independent-samples t-test. EF: Ejection fraction; FS: Fraction shorting; SV: Stroke volume; COP: cardiac output; CI: cardiac index; MAPSE: mitral annular plane systolic excursion; LV Tie: left ventricular Tie index; E/A: Ejection/Acceleration ratio; MV E/e: Early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; FAC: Fractional area change; TV E/A: tricuspid valve Ejection/Acceleration ratio; TV E/a: Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity; RV Tei: Right ventricular Tei index; PV. acc. time: pulmonary valve acceleration time; RVSV: Right ventricular stroke volume; Rv/COP: Right ventricular cardiac output.

3.7. Clinical Outcomes

As shown in Table 6, the frequency of seizures, necrotizing enterocolitis (NEC), late-onset sepsis, and mortality differed significantly among the study groups. Neonates in the invasive ventilation group exhibited higher rates of seizures (p = 0.001), NEC (p = 0.002), late-onset sepsis (p = 0.001), and mortality (p = 0.002) compared with the non-invasive ventilation and control groups.
Table 6. Comparison of Complications and Mortality Between the Invasive and Non-Invasive Ventilation Groups.
Table 6. Comparison of Complications and Mortality Between the Invasive and Non-Invasive Ventilation Groups.
Complications Invasive Group (n=30) Non -Invasive
Group (n=30)		 P
Seizure 14(46.7%) 7(23.3%) 0.001
Shock 1(3.3%) 0(0.0%) 0.364b
IVH 3(10.0%) 1(3.3%) 0.160b
NEC 10(33.3%) 5(16.7%) 0.002
AKI 4(13.3%) 3(10.0%) 0.133b
Late-onset sepsis 15(50.0%) 10(33.3%) 0.001b
Dehydration 4(13.3%) 3(10.0%) 0.133b
Mortality 9(30.0%) 3(10.0%) 0.002b
x2: Chi-square test – b Fisher’s exact test.

3.7.1. Acute kidney injury:

Table 7 demonstrates that neonates who developed AKI exhibited significantly impaired left and right ventricular performance compared with those without AKI in both invasive and non-invasive ventilation groups. In the invasive and non-invasive ventilation neonates developed AKI had significantly lower SV (p=0.039, p=0.003), COP (p=0.031, 0.001), CI (p=0.032,0.001), MAPSE (p=0.023, 0.006), TAPSE (p=0.013, 0.015), FAC (p=0.009), RV stroke volume (p=0.030, p=0.002), and RV cardiac output (p=0.021,0.001), while EF and FS did not differ significantly between groups. Whereas in the invasive group, the AKI patients also demonstrated a prolonged LV Tei index (p=0.004, a significantly lower TV E/A ratio (p=0.049), higher PASP (p=0.002), prolonged RV Tei index (p=0.017), and decreased pulmonary artery acceleration time (p=0.002).In the non-invasive ventilation group, AKI was associated with significantly higher LV Tei index (p=0.001), RV Tei index (p=0.001), transmitral E/A ratio (p=0.008), and MV E/e′ ratio (p=0.003). These findings indicate a close association between AKI and biventricular systolic and global myocardial dysfunction. Conventional measures of myocardial performance appeared less sensitive than cardiac output-derived indices in identifying renal impairment.
Table 7. Comparison of Day-3 Echocardiographic Parameters According to Acute Kidney Injury Status in Invasively and Non-Invasively Ventilated Neonates.
Table 7. Comparison of Day-3 Echocardiographic Parameters According to Acute Kidney Injury Status in Invasively and Non-Invasively Ventilated Neonates.
Variable Invasive Invasive P Non - Invasive Non - Invasive P
Non -AKI AKI Non -AKI AKI
Mean ±SD Mean ±SD Mean ±SD Mean ±SD
Echo left ventricle on the 3rd day
EF% 67.59±5.52 63.05±2.45 0.120 67.93±4.30 65.60±1.97 0.366
FS% 33.15±7.22 31.23±2.17 0.604 34.51±2.62 33.17±1.51 0.397
SV (ml) 3.63±1.05 1.77±0.33 0.039 5.54±1.61 1.87±0.15 0.003
COP (ml/kg/min) 217.22±62.99 120.18±19.06 0.031 314.23±81.86 122.35±14.14 0.001
CI (ml/kg/min)/m2 1140.28±330.68 667.48±87.72 0.032 1629.79±389.94 666.81±87.77 0.001
MAPSE (cm) 0.62±0.16 0.43±0.05 0.023 0.76±0.14 0.50±0.10 0.006
LV_Tei 0.40±0.05 0.48±0.05 0.004 0.37±0.05 0.48±0.07 0.001
E/A ratio 1.00±0.21 1.18±0.14 0.106 0.95±0.20 1.30±0.17 0.008
MV E/e 10.37±2.99 11.93±3.46 0.374 10.15±1.80 13.82±2.10 0.003
Echo right ventricle on the 3rd day
TAPSE (cm) 0.63±0.19 0.38±0.10 0.013 0.79±0.19 0.50±0.00 0.015
FAC% 3rd 0.29±0.08 0.18±0.02 0.009 0.35±0.07 0.20±0.02 0.001
TV EA ratio 0.82±0.15 0.65±0.12 0.049 0.89±0.08 0.70±0.02 0.001
PASP (mm Hg) 20.77±5.85 34.00±9.86 0.002 21.04±6.10 17.33±3.21 0.430
TV/E/e 8.23±2.39 6.82±1.98 0.397 9.56±1.86 7.33±1.58 0.056
RV Tei 0.40±0.10 0.53±0.07 0.017 0.41±0.05 0.51±0.01 0.001
PV. Acc. time (ms) 81.73±14.31 56.00±7.12 0.002 88.26±13.05 75.33±1.15 0.103
RVSV (ml) 3.40±0.98 1.59±0.34 0.030 5.42±1.57 1.74±0.16 0.002
Rv/COP (ml/kg/min) 203.84±59.11 107.77±16.89 0.021 307.80±81.48 114.29±12.33 0.001
Independent t-test. EF: Ejection fraction; FS: Fraction shorting; SV: Stroke volume; COP: cardiac output; CI: cardiac index; MAPSE: mitral annular plane systolic excursion; LV Tie: left ventricular Tie index; E/A: Ejection/Acceleration ratio; MV E/e: Early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; FAC: Fractional area change ;TV E/A: tricuspid valve Ejection/Acceleration ratio; TV E/a: Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity; RV Tei: Right ventricular Tei index; PV. acc. time: pulmonary valve acceleration time; RVSV: Right ventricular stroke volume; Rv/COP: Right ventricular cardiac output.

3.7.2. Mortality

In the invasive group, there was impaired left ventricular performance in the non-survivors; they showed significantly lower EF% (p=0.025), SV (p=0.003), COP (p=0.001), CI (p=0.001), and significantly higher LV Tei index (p=0.001). Evaluation of right ventricular function revealed significantly lower TAPSE (p=0.016), FAC (p=0.001), TV E/A ratio (p=0.012), RV stroke volume (p=0.002), and RV cardiac output (p=0.001) among non-survivors. In contrast, PASP and RV Tei index were significantly higher in non-survivors ( p=0.049 and p=0.006, respectively), while pulmonary artery acceleration time was significantly shorter ( p=0.013). All significant variables demonstrated large to very large effect sizes (g > 0.9). The strongest associations with mortality were LV Tei index (g = 2.19, 95% CI 1.21-3.18), RV cardiac output (g = 2.01, 95% CI 1.05-2.96), RV stroke volume (g = 1.96, 95% CI 1.01-2.91), stroke volume (g = 1.95, 95% CI 1.00-2.90) and cardiac output (g = 1.88, 95% CI 0.95-2.81). Mortality was associated with obvious derangement in both left and right ventricular systolic function, reduced cardiac output, and evidence of diastolic impairment in the non-invasive group.
In the non-invasive group, non-survivors had significantly lower left ventricular parameters of cardiac performance, which were confirmed by effect size analysis. Most significant variables exceeded 1.5-2.5, indicating clinically important differences between survivors and non-survivors. These included SV (p=0.003; g ≈ 2.44), COP (p=0.001; g ≈ 2.42), CI (p=0.001; g ≈ 2.45), and MAPSE (p=0.006). Furthermore, non-survivors showed evidence of impaired left ventricular diastolic function, with a higher LV Tei index (p=0.001; g ≈ 2.06), E/A ratio (p=0.008), MV E/e′ ratio (p=0.003) . These findings suggest deteriorating global myocardial function and elevated left ventricular filling pressures among non-survivors.
The right ventricular parameters in the non –invasive group, of the non-survivors showed significant worsening in right ventricular function, proved by lower TAPSE (p=0.015), FAC (p=0.001) (g ≈ 2.25), tricuspid valve E/A ratio (p=0.001) (g ≈ 2.46), right ventricular stroke volume (RVSV) (p=0.002) (g ≈ 2.46) and right ventricular cardiac output (p=0.001) (g ≈ 2.42). On the contrary, the RV Tei index was significantly higher in non-survivors (p=0.001), indicating impaired global right ventricular performance. Table 8
Table 8. Comparison of Day-3 Echocardiographic Parameters Between Survivors and Non-Survivors in the Invasive and Non-Invasive Ventilation Groups.
Table 8. Comparison of Day-3 Echocardiographic Parameters Between Survivors and Non-Survivors in the Invasive and Non-Invasive Ventilation Groups.
Invasive Survival Non Survival Size Effect p-value
Mean ±SD Mean ± SD Hedges'g 95% CI
Echo left ventricle on the 3rd day
EF% 68.41±5.71 63.66±2.65 2.373 0.94 0.13 to 1.75 0.025
FS% 33.46±7.99 31.58±1.91 0.692 0.27 0.50-1.04 0.494
SV (ml) 3.96±1.15 2.02±0.42 3.311 1.95 1.00 to 2.90 0.003
COP (ml/kg/min) 236.48±68.58 129.14±15.92 3.859 1.88 0.95 to 2.81 0.001
CI (ml/kg/min)/m2 1238.06±359.04 701.99±75.42 3.971 1.76 0.86 to 2.66 0.001
MAPSE (cm) 0.64±0.15 0.51±0.15 1.986 0.84 0.01-1.69 0.057
LV_Tei 0.38±0.04 0.47±0.04 5.209 2.19 1.21 to 3.18 0.001
E/A ratio 0.97±0.18 1.13±0.23 2.009 0.8 1.64 to 0.04 0.054
MV E/e 10.60±2.82 10.51±3.05 0.071 0.03 0.75 to 0.81 0.944
Echo right ventricle on the 3rd day
TAPSE (cm) 0.65±0.18 0.47±0.14 2.567 1.05 0.21 to 1.89 0.016
FAC% 0.31±0.07 0.20±0.05 4.330 1.73 0.84 to 2.62 0.001
TV EA ratio 0.84±0.15 0.69±0.12 2.703 1.03 0.21-1.85 0.012
PASP (mm Hg) 20.57±5.97 27.11±7.86 2.062 0.96 0.15 to 1.77 0.049
TV/E/e 8.22±2.38 7.63±2.21 0.482 1.04 0.20 to 1.88 0.633
RV Tei 0.39±0.10 0.49±0.07 2.972 1.09 0.24 to 1.93 0.006
PV. Acc. time (ms) 82.95±15.63 67.44±12.07 2.647 1.02 0.18 to 1.86 0.013
RVSV (ml) 3.71±1.08 1.86±0.35 3.480 1.96 1.01 to 2.91 0.002
Rv/COP (ml/kg/min) 221.94±64.36 118.92±17.08 4.056 2.01 1.05 to 2.96 0.001
Non-invasive Survival Non Survival Size effect p-value
Mean ±SD Mean ± SD Hedges'g 95% CI
Echo left ventricle on the 3rd day
EF% 67.93±4.30 65.60±1.97 0.56 -0.65 to 1.77 0.366
FS% 34.51±2.62 33.17±1.51 0.53 -0.68 to 1.74 0.397
SV (ml) 5.54±1.61 1.87±0.15 2.33 0.88 to 3.79 0.003
COP (ml/kg/min) 314.23±81.86 122.35±14.14 2.39 0.91 to 3.87 0.001
CI (ml/kg/min)/m2 1629.79±389.94 666.81±87.77 2.48 0.96 to 3.99 0.001
MAPSE (cm) 0.76±0.14 0.50±0.10 1.91 0.62 to 3.19 0.006
LV_Tei 0.37±0.05 0.48±0.07 1.94 0.64 to 3.24 0.001
E/A ratio 0.95±0.20 1.30±0.17 1.80 0.54 to 3.06 0.008
MV E/e 10.15±1.80 13.82±2.10 2.11 0.75 to 3.46 0.003
Echo right ventricle on the 3rd day
TAPSE (cm) 0.79±0.19 0.50±0.00 1.56 0.38 to 2.74 0.015
FAC% 0.35±0.07 0.20±0.02 2.18 0.79 to 3.57 0.001
TV EA ratio 0.89±0.08 0.70±0.02 2.47 0.95 to 3.98 0.001
PASP (mm Hg) 21.04±6.10 17.33±3.21 0.62 -0.60 to 1.83 0.430
TV/E/e 9.56±1.86 7.33±1.58 1.20 0.10 to 2.31 0.056
RV Tei 0.41±0.05 0.51±0.01 2.06 0.72 to 3.40 0.001
PV. Acc. time (ms) 88.26±13.05 75.33±1.15 1.01 -0.04 to 2.07 0.103
RVSV (ml) 5.42±1.57 1.74±0.16 2.35 0.89 to 3.81 0.002
Rv/COP (ml/kg/min) 307.80±81.48 114.29±12.33 2.42 0.93 to 3.91 0.001
Independent t-test. EF: Ejection fraction; FS: Fraction shorting; SV: Stroke volume; COP: cardiac output; CI: cardiac index; MAPSE: mitral annular plane systolic excursion; LV Tei: left ventricular Tei index; E/A: Ejection/Acceleration ratio; MV E/e: Early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; FAC: Fractional area change; TV E/A: tricuspid valve Ejection/Acceleration ratio; TV E/a: Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity; RV Tei: Right ventricular Tei index; PV. acc. time: pulmonary valve acceleration time; RVSV: Right ventricular stroke volume; Rv/COP: Right ventricular cardiac output.

3.8. Regarding the Doppler results,

The non-survivors in the invasive group showed significantly lower peak systolic flow velocities in the middle cerebral artery, superior mesenteric artery, and renal artery compared with survivors (p=0.001, p=0.001, and p=0.002, respectively). Likewise, in the non-invasive group, non-survivors displayed significantly reduced MCA and SMA Vmax values (p=0.007 and p=0.008, respectively). On the contrary, the vascular resistance indices of the MCA PI and RI and renal artery PI and RI did not differ significantly between survivors and non-survivors. Besides statistical significance, mortality was associated with large to very large effect sizes for MCA, SMA, and renal artery Vmax measurements, indicating high discriminatory ability for mortality. These findings suggest that absolute organ perfusion (Vmax) may have been more important than vascular resistance measurements in predicting adverse outcomes and mortality in ventilated neonates. Table 9 and Supplement 3
Table 9. Comparison of Doppler parameters according to survival status in the invasive and non-invasive ventilation groups after 3 days of ventilation.
Table 9. Comparison of Doppler parameters according to survival status in the invasive and non-invasive ventilation groups after 3 days of ventilation.
Variable Invasive
survival		 Invasive non-
survival 		Size
Effect and CI		 p Non-Invasive Survival Non-
Invasive
non-survival 		Size Effect and CI P
Mean ±SD Mean ±SD Mean ±SD Mean ±SD
SMA
Vmax (cm/s) 34.65±10.05 17.51±4.13 1.99
1.02 -2.96		 0.001 41.17±11.94 16.47±3.05 3
1.55 -4.45		 0.008
PI 1.49±0.25 1.47±0.23 0.08
-0.70 - 0.86		 0.904 1.36±0.22 1.07±0.12 1.32
0.07 -2.56		 0.034
RI 0.74±0.07 0.77±0.08 -0.40
-1.19 -0.39		 0.241 0.71±0.09 0.67±0.12 0.42
-0.78 -1.62		 0.456
RA
Vmax (cm/s) 36.77±10.66 22.14±6.42 1.49
0.62 - 2.37		 0.002 37.34±10.66 18.47±0.40 1.76
0.49 -3.04		 0.005
PI 1.53±0.19 1.38±0.24 0.71
-0.09 - 1.51		 0.077 1.44±0.27 1.50±0.10 0.50
0.70 - 1.70		 0.698
RI 0.75±0.08 0.77±0.08 -0.24
-1.03 - 0.54		 0.698 0.73±0.12 0.67±0.15 -0.60
-1.81 -0.61		 0.406
SMA: superior mesenteric artery; Vmax: maximum velocity (peak velocity) ; PI: pulsatility index ; RI: resistivity index; RA: renal artery.

3.9. Determinants of cardiac output

Univariable regression analysis found significant associations of cardiac output with pH, PaCO2, PaO2, oxygen saturation, acidosis, gestational age, systolic blood pressure, mean arterial pressure, PEEP and ventilation modality. Multivariable analysis showed an independent association of pH, PaCO2, PaO2, oxygen saturation, acidosis, gestational age, and ventilation modality with cardiac output after correction for other covariates. Table 10
Table 10. Independent Predictors of Cardiac Output Identified by Univariate and Multivariable Linear Regression Analyses.
Table 10. Independent Predictors of Cardiac Output Identified by Univariate and Multivariable Linear Regression Analyses.
Parameters Univariate Multiple linear regression
Unstandardized
Coefficients		 Standardized
Coefficients		 P Unstandardized
Coefficients		 Standardized
Coefficients		 P
β ±SE Beta β ±SE Beta
Ventilation hrs. -6.048 54.086 -0.057 0.522
PEEP -4.839 43.269 -0.045 0.029* -8.3504 14.924 -0.10516 0.580
MAP 1.273 9.469 0.037 0.432
pH -6.574 58.789 -0.062 <0.001** 92.291 27.674 0.722 0.019*
Paco2 11.588 22.706 1.181 0.008* -15.083 6.718 -1.259 0.039*
PaO2 46.430 83.787 3.572 0.016* 1.926 6.579 0.124 0.033*
Hco3 -28.205 26.683 -0.526 0.606
O2 sat 1.018 7.575 0.030 0.018* 6.616 2.721 0.339 0.045*
Acidosis -22.564 21.346 -0.421 0.010* -61.472 14.809 -0.250 0.027*
GA 25.803 49.205 1.735 <0.001** 123.496 44.133 0.626 0.013*
SBP (mmHg) 12.596 24.681 1.283 0.017* 1.207169 1.423132 0.158283 0.403494
DBP (mmHg) 37.144 67.030 2.858 0.540
MBP (mmHg) 1.384 10.292 0.040 0.043*
Type of ventilation -0.731 5.104 -0.028 0.016* -2.022 6.908 -0.131 0.012*
β: Regression coefficient; SE: Standard error; *p-value <0.05 is significant.

4. Discussion

Hemodynamic stability is a critical determinant of neonatal outcomes, yet it remains challenging to maintain because of the immaturity of the cardiovascular system and the complex physiological adaptations that occur during the transition from fetal to neonatal life. Respiratory support itself may influence cardiovascular performance by altering preload, afterload, cardiac output, and systemic blood flow [7.8]. Very few studies specifically compare echocardiographic parameters of left and right ventricles during invasive mechanical ventilation and non-invasive ventilation in neonates, given limited data regarding traditional echocardiographic indices such as ejection fraction, fractional shortening, TAPSE, MAPSE, tissue Doppler velocities, and myocardial performance index (MPI). Also, the relationship between cardiac output and organ-specific perfusion and complications during different modes of respiratory support in newborn infants was not fully studied. Most published data are derived from adult or animal studies, whereas neonatal-specific evidence remains limited. The studies have focused on hemodynamic physiology and ventricular output measurements rather than conventional echocardiographic function metrics. The current study was undertaken to evaluate the effects of invasive and non-invasive respiratory support on hemodynamic status and clinical outcomes in neonates using echocardiography and Doppler.
In the current study, neonates receiving invasive ventilation showed significant changes in several hemodynamic and clinical parameters, more than the non-invasive group. These findings may be associated with cardiovascular adjustments and changes in autonomic regulation among mechanically ventilated neonates [5,9].Blood gas analysis indicated a considerably higher prevalence of acid-base disturbances in the invasive ventilation group, defined by lower pH values, lower PaO2, and higher PaCO2 levels. These abnormalities may reflect the greater severity of respiratory dysfunction among infants requiring invasive mechanical ventilation [10].

4.1. Echocardiographic changes during respiratory support

The invasive and non-invasive ventilation groups had significantly higher cardiac output and cardiac index values compared with controls during the first hour of ventilation. These findings may indicate an adaptive cardiovascular response to maintain systemic oxygen delivery during acute respiratory dysfunction. Regardless of these hemodynamic changes, conventional indices of left ventricular systolic function, including ejection fraction, fractional shortening, stroke volume, and E/A ratio, remained comparable among groups, proposing preservation of myocardial contractility during the early phase of respiratory support. Similar explanations have been reported in neonatal studies revealing maintenance of cardiac function during early cardiopulmonary adaptation [5,11].
Notably, MAPSE was significantly lower in the invasive ventilation group, regardless of maintained conventional systolic indices. MAPSE may identify subtle ventricular impairment before abnormalities become apparent, so it could be used as a sensitive marker of longitudinal myocardial function. Likewise, the lower MV E/e′ ratio observed in invasively ventilated infants may reflect early alterations in preload and ventricular filling dynamics induced by positive-pressure ventilation. Together, these findings suggest that invasive respiratory support may affect myocardial mechanics even before overt impairment of global systolic performance becomes evident [5,12,13].
Assessment of right ventricular performance during the first hour of ventilation demonstrated a similar pattern. Mostly, right ventricular parameters were maintained; however, in the invasive ventilation group, TAPSE was significantly reduced. TAPSE is known as a sensitive indicator of right ventricular systolic performance. The results may indicate an initial hemodynamic response to elevated intrathoracic pressure, decreased venous return, and changes in pulmonary vascular resistance. There is plausible evidence related to the susceptibility of the neonatal right ventricle during early life. Previous reports showed that right ventricular function is sensitive to the effects of positive-pressure ventilation and greatly dependent on pulmonary vascular conditions [5,13].
Longitudinal assessment after three days of respiratory support showed reductions in ejection fraction, fractional shortening, stroke volume, cardiac output, and cardiac index in both ventilation groups, indicating a progressive decline in left ventricular systolic performance over time after 3 days. However, more marked significant reductions in MAPSE were associated with an increase in the LV Tei index in the invasive group, proving impairment of both longitudinal and global left ventricular function. Simultaneous increases in mitral E/A and E/e′ ratios point to changes in ventricular relaxation and filling dynamics. This finding possibly shows increased filling pressures and reduced ventricular compliance. These findings validate the notion that prolonged respiratory support influences both systolic and diastolic cardiac function, with a greater effect during invasive ventilation [14,15,16].
Right ventricular performance exhibited the most significant differences between ventilation strategies. TAPSE, FAC, RV SV, and RV COP values were significantly decreased after three days of invasive ventilation. These changes were augmented by increased pulmonary artery systolic pressure, shortened pulmonary valve acceleration time, and a higher mean value of the RV Tei index. All these changes are markers of deteriorating right ventricular systolic function, as well as increased pulmonary vascular load, and aggravated right ventricular-pulmonary arterial coupling. The right ventricle of the newborn is sensitive to changes in pulmonary vascular resistance. Exposure to positive-pressure ventilation for a long duration may lead to more hemodynamic impairment of right ventricular performance [5,17]. On the other hand, the newborn infants of the non-invasive group displayed relative preservation of the majority of right ventricular parameters such as TAPSE, FAC, PASP, tricuspid E/e′ ratio, and pulmonary acceleration time during the study period. These results imply that non-invasive ventilation may decrease adverse effects on ventricular performance [18,19,20].
Overall, the current findings indicate that invasive mechanical ventilation is associated with progressive impairment of both left and right ventricular performance, whereas non-invasive respiratory support is characterized by a more favorable hemodynamic profile. Evidence from this study suggests that the right ventricle may show earlier adverse effects from positive pressure ventilation than the left ventricle due to earlier changes in TAPSE. With continued respiratory support, however, evidence of dysfunction became apparent in both ventricles, highlighting the complex interaction between mechanical ventilation, pulmonary vascular physiology, and neonatal myocardial performance.
A substantial proportion of infants in the invasive ventilation group developed significant clinical complications, including seizures, necrotizing enterocolitis, late-onset sepsis, and mortality. These findings are consistent with previous studies showing that adverse outcomes of invasive ventilation are multifactorial due to disease severity, systemic inflammation, infection, and prolonged ventilation [21,22]. As revealed in the study, infants who need invasive ventilation are more severely sick; thus, these associations should not be interpreted as invasive ventilation directly causing these complications. The lower percentage of complications observed in the non-invasive ventilation group supports that, when clinically possible, it is better to use non- invasive ventilation.
The present study determined that neonates who developed AKI had significantly impaired cardiac performance in both studied groups by Day 3, evidenced by lower stroke volume, cardiac output, cardiac index, MAPSE, TAPSE, and FAC. AKI was diagnosed according to the neonatal modified KDIGO criteria [23]. However, EF and FS remained comparable with non-AKI groups. These findings suggest that the systolic indices may not be sensitive to detect early myocardial dysfunction, whereas longitudinal monitoring as well as output-based parameters may help to identify the hemodynamic variations correlated with AKI. Impaired cardiac function may contribute to reduced renal perfusion and subsequent kidney injury. Global myocardial dysfunction involving both systolic and diastolic components is indicated by the increase in LV and RV Tei indices. The right ventricular dysfunction was more evident among invasively ventilated neonates; this could be due to increased RV afterload and reduced forward flow, which contribute to renal hypoperfusion. Although evidence directly linking these echocardiographic abnormalities to neonatal AKI remains limited, similar cardiorenal mechanisms have been described in pediatric and adult populations [24]. To our knowledge, few neonatal studies have directly evaluated comprehensive echocardiographic measures of biventricular performance in relation to AKI. The observed decrease in cardiac output, cardiac index, MAPSE, TAPSE, and FAC, with increased ventricular Tei indices, is supported by the theory that impaired cardiovascular function may contribute to renal hypoperfusion and AKI development. This is in agreement with previous neonatal studies that identified cardiac performance measures as sensitive markers of hemodynamic instability and highlighted inadequate systemic perfusion as a major contributor to renal injury [13,25,26,27].
Mortality was linked to a significant deterioration of cardiac function, marked by reduced stroke volume, cardiac output, cardiac index, TAPSE, FAC, and right ventricular stroke volume, and elevated LV and RV Tei indices, as well as increased pulmonary artery systolic pressure. These results indicate that both reduced systemic blood circulation and biventricular dysfunction play a role in negative outcomes for critically ill neonates. Due to the small number of AKI and non–survival cases, we apply the effect sizes and results reinforced significant values of cardiac output, cardiac index, right ventricular cardiac output, fractional area change, left ventricular Tei index, and regional Doppler velocities. These validated the clinical importance of inadequate systemic perfusion and biventricular dysfunction in negative outcomes. Comparable results were noted in the group receiving non-invasive ventilation. Mortality was found to be more strongly associated with diminished forward flow and overall ventricular dysfunction than with traditional indicators of systolic contractility by themselves.
The study proposed that a comprehensive evaluation of cardiac output, ventricular performance indicators, and regional organ perfusion could provide more precise prognostic information than ejection fraction or fractional shortening in recognizing ventilated newborns with a greater risk of death. Previous research on neonatal hemodynamics has highlighted the importance of cardiac output, ventricular function, and pulmonary vascular load as predictive factors. Moreover, elevated Tei indices are known as established markers of general myocardial dysfunction [8,13,27,28].
The study also demonstrated a reduction in mesenteric and renal arterial blood flow velocities during invasive ventilation compared to non-invasive ventilation. Doppler flow velocities in the superior mesenteric and renal arteries showed a significant reduction in non-surviving neonates; this was further documented by large to very large effect sizes. The PI and RI showed non-significant changes. Earlier, we demonstrated a decrease in the middle cerebral artery flow velocity among the invasive group and non-surviving neonates [4]. These findings suggest that impaired regional organ perfusion is more closely linked to mortality than changes in vascular resistance alone. Also, the reduction in end-organ blood flow and cardiac performance among non-survivors supports the hypothesis that mortality in ventilated neonates is enhanced by impaired systemic circulation and tissue perfusion rather than by changes in vascular resistance. [4,29]
Regression analysis identified acid-base status, gestational age, blood pressure, and mode of ventilation as independent elements of cardiac output. Better acid-base status and higher gestational age were associated with improved cardiac performance, likely reflecting more favorable myocardial function and cardiovascular maturation of myocardial structure, ventricular compliance, and cardiovascular regulatory mechanisms with advancing gestation. These findings are similar to studies documenting better cardiovascular adaptation among full-term infants [29].
Although causality cannot be inferred due to the observational nature of our study, lower cardiac output in invasive ventilation compared with non-invasive respiratory support after adjustment for potential confounders may reflect the hemodynamic effects of positive-pressure ventilation on venous return, ventricular preload, and pulmonary vascular dynamics and/or greater illness severity among infants requiring invasive respiratory support. Collectively, these findings suggest that neonatal cardiovascular function is influenced by both developmental and clinical factors and highlight the importance of comprehensive hemodynamic assessment in ventilated neonates. Although ventilatory mode is one of several factors affecting neonatal cardiac output, we advocate non-invasive respiratory support when clinically appropriate [31].
Finally, these findings suggest that invasive mechanical ventilation is associated with less favorable cardiovascular adaptation than non-invasive respiratory support, particularly when prolonged over several days. The observed impairments in ventricular function and cardiac output, together with higher rates of adverse clinical outcomes, emphasize the importance of comprehensive hemodynamic monitoring in ventilated neonates.

4.2. Strengths and Limitations

The present study has several important strengths. First, its prospective design with serial assessments supported detailed evaluation of progressive changes of cardiovascular and perfusion changes during neonatal respiratory support. This approach provides a more comprehensive understanding of hemodynamic adjustment than single-time measurements and provides a more accurate description of changes occurring during both the early and later phases of respiratory support.
Second, the study utilized a comprehensive multiple hemodynamic assessment, integrating functional echocardiography with Doppler evaluation of the mesenteric, and renal perfusion. This allowed simultaneous assessment of biventricular function, cardiac output, and end-organ blood flow, providing a more complete picture of neonatal cardiovascular adaptation than studies focusing solely on cardiac parameters.
Third, the study provides novel insights into the differential cardiovascular effects of invasive and non-invasive ventilation. To our knowledge, few neonatal studies have prospectively evaluated serial changes in both left and right ventricular performance together with organ perfusion during different modes of respiratory support. A particularly important observation was the apparent earlier impairment of right ventricular function, evidenced by reduced TAPSE before significant abnormalities became evident in conventional left ventricular systolic indices, advocating higher susceptibility of the right ventricle to the hemodynamic effects of positive-pressure ventilation.
Fourth, the combination of mortality and detailed cardiac output, cardiac index, TAPSE, FAC, Tei measurements appears relatively novel.
Fifth and finally, the study extends current knowledge regarding the cardio-renal interaction in ventilated neonates. The evaluation of AKI in relation to echocardiographic and perfusion parameters demonstrated associations between AKI, TAPSE, MAPSE, Tei, CO in neonates, impaired biventricular performance, and altered organ perfusion despite relatively preserved conventional systolic indices. These findings highlight the potential value of advanced echocardiographic measures and organ-specific perfusion assessment as early markers of cardiovascular compromise and cardio-renal dysfunction in critically ill neonates.
However, several limitations should be acknowledged. First, the observational design does not allow causal relationships to be established between ventilation mode and hemodynamic alterations. Second, neonates requiring invasive ventilation may have had greater baseline illness severity, which could have contributed to differences in cardiovascular function and clinical outcomes. Third, the study was conducted at a single center with a relatively limited sample size, which may affect the generalizability of the findings. Fourth, the higher percentage of preterm infants among the invasive group may affect the overall hemodynamic status. Fifth, and finally, unmeasured confounding variables, including differences in underlying respiratory pathology, fluid management, and vasoactive medication use, may have influenced the results. Given the exploratory nature of multiple secondary analyses, findings should be interpreted cautiously and require confirmation in larger multicenter studies.
Future multicenter studies with larger sample sizes and careful adjustment for disease severity are needed to further clarify the relationship and independent influence of respiratory support modalities on neonatal cardiovascular dysfunction, organ perfusion, and clinical outcomes in critically ill neonates. Also, to confirm whether the right ventricle consistently demonstrates greater vulnerability to the hemodynamic effects of invasive respiratory support in neonates.

5. Conclusions

In this cohort of neonates requiring respiratory support, invasive mechanical ventilation was associated with less favorable echocardiographic and Doppler hemodynamic profiles compared with non-invasive ventilation. Infants receiving invasive ventilation demonstrated lower cardiac output and evidence of greater impairment in both left and right ventricular functional indices over time, accompanied by higher rates of adverse clinical outcomes. Assessment of neonatal AKI risk should extend beyond renal biomarkers alone and include hemodynamic evaluation, particularly cardiac output, ventricular performance indices, and longitudinal ventricular function. However, given the observational design of the study and the potential influence of baseline illness severity and other confounding factors, these findings should be interpreted as associations rather than causal relationships. Further prospective multicenter studies are needed to better define the effects of different respiratory support modalities on neonatal cardiovascular function and organ perfusion.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/doi/s1; Table S1: Supplement 1. Invasive ventilation modes and parameters; Table S2: Supplement 2. Non-invasive ventilation modes and parameters; Table S3: Comparison of SMA, and renal artery Doppler parameters between invasive, non-invasive ventilation, and control groups at the 1st hour and between the invasive and non-invasive groups on the 3rd day.

Author Contributions

Conceptualization, S.E. and D.A.; methodology, D.A.; and A.E.; validation, A.E., S.E. and D.A.; formal analysis, N.A.; investigation, N.A.; and A.M. resources, A.M.; data curation, A.E.; writing—original draft preparation, S.A.; writing—review and editing, D.A.; visualization, A.E.; supervision, S.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Faculty of Medicine for Girls, Al-Azhar University (Approval No. 1544; October 12, 2022).

Data Availability Statement

The data presented in this study are available on request from the corresponding author on reasonable request due to privacy and ethical reasons.

Acknowledgments

We would like to thank all the parents of the studied cases for their cooperation.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

EF Ejection fraction
FS Fraction shorting
SV Stroke volume
COP Cardiac output
CI Cardiac index
MAPSE Mitral annular plane systolic excursion
LV Tie Left ventricular
E/A Ejection/Acceleration ratio
MV E/e MV E/e: Early diastolic mitral inflow velocity to early diastolic
mitral annulus velocity
TAPSE Tricuspid annular plane systolic excursion;
PASP Pulmonary artery systolic pressure
FAC Fractional area change
TV E/A Tricuspid valve Ejection/Acceleration ratio
TV E/a Early diastolic tricuspid inflow velocity to early diastolic tricuspid annulus velocity
RV Tei Right ventricule Tei index
PV. acc. time Pulmonary valve acceleration time
RVSV Right ventricular stroke volume
Rv/COP Right ventricular cardiac output

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