Transient tachypnea of the newborn (TTNB) is a respiratory condition frequently encountered in late preterm and term babies, characterized by delayed resorption of fetal lung fluid post-delivery. ¹ This compromises pulmonary gas exchange, manifesting clinically as respiratory distress with signs including tachypnea (respiratory rate >60 breaths per minute), nasal flaring, grunting, and chest indrawings. ² TTNB affects up to 13% of neonates delivered via caesarean section within the first few hours of life, highlighting its relevance as a common cause of early respiratory morbidity in this population. ³ Although typically self-limiting, TTNB requires vigilant monitoring and appropriate respiratory support to prevent complications such as hypoxemia, extended hospitalization, and, in very rare instances, serious outcomes including pneumothorax or persistent pulmonary hypertension. ^{4– 6}

Standard oxygen therapy (SOT), delivered via a nasal cannula, hood, or mask, has traditionally been the first-line intervention for TTNB. However, its efficacy in addressing impaired alveolar fluid clearance is limited in literature. ⁷ Hence, there has been a marked shift in its management with the emergence of noninvasive respiratory strategies, mostly continuous positive airway pressure (CPAP) and nasal intermittent positive pressure ventilation (NIPPV). These approaches offer the advantage of stabilizing functional residual capacity and reducing extra effort for breathing, thereby avoiding invasive ventilation, which further shortens the symptomatic period and hospital stay. ^{4, 8, 9} A Cochrane review (2020) including three trials (150 infants) comparing either CPAP to free-flow oxygen, NIPPV to CPAP, or nasal high-frequency ventilation versus CPAP, highlighted the low quality of evidence to determine the safety or effectiveness of non-invasive respiratory support in treating TTNB, with no significant differences observed in clinically relevant outcomes despite some reduction in symptom duration. ⁴

Heated humidified high-flow nasal cannula (HHHFNC) has recently garnered traction in various neonatal respiratory conditions. ^{10– 12} By delivering warmed, humidified oxygen at high flow rates, HHHFNC can help reduce airway resistance, flush nasopharyngeal dead space, and provide positive airway pressure. ¹³ Furthermore, its user-friendliness, enhanced infant well-being, and reduced nasal injuries compared to CPAP make it an attractive alternative in neonates. ^{14, 15} Although it has shown benefits in reducing care escalation and intubation rates in pediatric respiratory conditions such as bronchiolitis, its specific effectiveness in TTNB remains unproven. ^{16, 17} This novel study aimed to compare HHHFNC and SOT as initial respiratory support modalities in managing TTNB, focusing on the efficacy, duration of respiratory support, hospital stay, and rates of treatment failure or complications to inform and improve neonatal care.

This open-label, non-blinded, randomized controlled trial was conducted in the neonatal unit of the Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, India for a period of two years (between March 2023 and February 2025). This study was approved by the Institutional Ethics Committee of Kalinga Institute of Medical Sciences, Kalinga Institute of Industrial Technology Deemed University (KIIT/KIMS/IEC/1267/2023) and registered with the Clinical Trial Registry of India (CTRI/2024/06/069504). Written informed consent was obtained from all parents or guardians prior to enrolment.

Given limited prior data on HHHFNC versus standard oxygen therapy in Transient tachypnea of the newborn, this study was conducted as a pilot randomized controlled trial using consecutive sampling during the study period. Thus the sample size was feasibility-based rather than power-calculated, which may limit detection of less frequent but clinically important outcomes. This study included neonates with gestational age ≥ 34 weeks presenting with TTNB, that is, respiratory distress within six hours after birth (respiratory rate >60 breaths/min, presence of subcostal and/or intercostal indrawings, nasal flaring, grunting) and supported by chest radiograph or lung ultrasound for TTNB. Neonates with major congenital anomalies, presence of thick meconium-stained fluid, and/or diagnosis of meconium aspiration syndrome, antenatal diagnosis of major congenital pulmonary or cardiac anomalies, or severe respiratory distress scores were excluded from the study. The severity of respiratory distress in neonates was evaluated using the Downe Score, performed by the attending neonatologist at presentation and at 1, 6, and 12 hours thereafter. It comprises five elements: respiratory rate, cyanosis, air entry, grunting, and chest retractions, each scored on a scale of 0 to 2. The total score ranges from 0 to 10, with a score ≤3 indicating mild distress, 4–6 indicating moderate distress, and ≥7 signifying severe respiratory distress.

Eligible neonates diagnosed with TTNB were randomly assigned to either the HHHFNC or SOT (through nasal cannula) group using computer-generated simple randomization. Allocation concealment was ensured via sequentially numbered sealed envelopes that opened post-enrolment. Baseline demographic profiles, including birth weight, gestational age, mode of delivery, APGAR score, and Downe score, were recorded. Neonates in both arms were nursed under a radiant warmer and attached to the pulse oximeter probe of a multipara monitor. Neonates in the HHHFNC arm were placed on Fisher & Paykel Airvo 2 with Optiflow nasal cannula (neonatal size), and those in the SOT arm were administered oxygen via an intersurgical neonatal nasal cannula. In the HHHFNC group, treatment was initiated at a flow rate of 4 L/min, with the fraction of inspired oxygen (FiO ₂) adjusted to maintain oxygen saturation between 91% and 95%. Flow settings differed due to inherent device characteristics, as HHHFNC requires a minimum flow to wash out nasopharyngeal dead space and provide mild distending pressure, leading to a higher starting flow than conventional oxygen therapy. Escalation was defined as any increase in flow rate or FiO ₂ beyond initial settings to maintain target SpO ₂ (91–95%) and was duly noted in both groups by the research team members. Time-keeping and serial recordings of the events were performed by a dedicated staff nurse. Neonates who needed respiratory support for more than two hours were shifted to the NICU, and the rest were shifted to the mother side. Neonates who did not respond to the assigned respiratory support, despite reaching the maximum escalation as per the mentioned protocol, were designated as treatment failure cases and upgraded to CPAP or mechanical ventilation if needed. Neonates in both arms received standard respiratory nursing care throughout the period of respiratory support provided by trained staff nurses and attending neonatologists. Neonates were monitored for complications such as nasal blockage, crusting, nasal injury, feeding difficulty, or air leaks (pneumothorax).

Data were recorded using Microsoft Excel and analyzed using SPSS v25.0. Continuous variables are expressed as mean ± standard deviation and were compared using unpaired t-tests. Categorical variables are presented as frequencies (percentages) and analyzed using chi-square or Fisher’s exact tests. Statistical significance was set at p < 0.05.

Within the study timeframe, 8 out of 68 neonates were excluded (3 had thick meconium-stained liquor, 3 had severe respiratory distress score, 1 had congenital cardiac anomaly,1 baby died), and 60 neonates were randomly assigned to the HHHFNC and SOT groups ( Figure 1).

Baseline demographic profiles were comparable between the two groups ( Table 1). Majority of neonates in both groups were delivered via caesarean section (73% vs. 76%; p = 1.000), with a slight overall male predominance. There was no statistically significant difference in the initial Downe Score between the HHHFNC and oxygen groups (4.36 ± 0.93 vs. 4.43 ± 0.68; p = 0.74).

The mean maximum flow rate achieved (L/min) in HHHFNC vs SOT was 5.00 ± 1.26 vs 1.88 ± 0.87 respectively, p=0.001. The higher flow rates observed in the HHHFNC group is consistent with its expected physiological and clinical application. A significant number of neonates in the oxygen arm needed escalation of support in terms of an increase in the flow rate compared to the HHHFNC arm (29(96.7%) vs. 14(46.7%), p = 0.001) ( Table 2). The improvement in the Downe score at the end of one hour in the HHHFNC group vs. the SOT group (1.97 ± 1.42 vs 2.73 ± 1.14, p = 0.03) was also statistically significant. Ten neonates from each group were transferred to the NICU for stabilization. Treatment failure, requiring upgrade to CPAP, occurred in two infants in the HHHFNC group and three infants in the oxygen group, while none of the infants required mechanical ventilation. Neonates in the HHHFNC arm needed respiratory support for a significantly shorter duration [Median(Q1,Q3)- 0.36 (0.25,0.91) hours vs 0.7 (0.35,3) hours, p=0.03]. Though the duration of hospital stay was also reduced in the HHHFNC group compared to the oxygen arm (4.67 ± 1.65 days vs 5.83 ± 3.42 days, p=0.10), the difference was not statistically significant.

While no serious complications such as pneumothorax, feeding intolerance, or nasal injuries were observed in either group, nasal crusting occurred exclusively in 20% of neonates in the standard oxygen arm. All crusting cases were managed with saline nasal drops. Additionally, repeated suctioning was required in seven (23.3%) neonates in the HHHFNC group compared to 11 (36.7%) in the SOT group ( Table 3).

The present study offers novel insights into the comparative efficacy of a heated humidified high-flow nasal cannula and standard oxygen therapy in the management of transient tachypnea in newborns. Notably, this is one of the few prospective studies that directly compared these two modalities in a head-to-head design, addressing gaps in the existing literature regarding their clinical utility and safety in neonates. Our findings indicate that HHHFNC is associated with a lower need for escalation of respiratory support, a more rapid improvement in respiratory distress, and a reduction in nasal crusting than standard oxygen therapy.

TTNB is more frequently observed in late preterm and early term neonates, particularly in those delivered via caesarean section. The absence of labor-related mechanical compression and hormonal stimuli, such as the catecholamine surge that activates alveolar sodium channels for lung fluid absorption, increases the risk of respiratory distress. ^{18, 19} This trend was also evident in our study, where caesarean deliveries predominated, around 70%, among affected neonates in both arms.

The significant decrease in the need for escalation of support (14 vs. 29 cases), along with notable improvement in respiratory distress scores in the HHHFNC group, indicates that high-flow therapy offers more effective respiratory support, potentially leading to earlier stabilization of the affected neonates. These findings are consistent with those of a randomized controlled trial conducted by Sitthikarnkha et al., involving infants and children aged between one month and five years with respiratory distress. The study found that high-flow therapy significantly improved clinical respiratory scores, heart rate, and respiratory rate compared to conventional oxygen therapy. ²⁰ Aligning with our study’s observation of lower treatment failure in the HHHFNC group (though not statistically significant), Mozun et al. reported that in infants under two years with hypoxemic bronchiolitis, high-flow oxygen therapy significantly reduced treatment failure rates and the need for escalation compared to standard oxygen therapy. ²¹ A recently conducted randomized controlled trial in preterm neonates found that HHHFNC had comparable efficacy and safety to NCPAP for delivery room support. ²² Although HHHFNC demonstrated early clinical improvement, the cost of equipment and availability of high-flow systems may limit its widespread use in resource-constrained settings. Therefore, careful consideration of cost-effectiveness and infrastructure is necessary before routine implementation.

In our study, although the HHHFNC group spent a significantly shorter time on oxygen support but the shorter hospitalization duration was not statistically significant than the standard oxygen group. The PARIS-2 Randomized Clinical Trial concluded that early initiation of nasal high-flow oxygen therapy in 1 to 4 years old children with acute hypoxemic respiratory failure did not result in a shorter hospital stay than standard oxygen therapy. ²³ These differences in the findings could be explained by variations in patient demographics, disease conditions, and clinical environments in which the studies were conducted.

The complete absence of nasal crusting in the HHHFNC group contrasts sharply with SOT, in which 20% of neonates required saline drops for mucosal dryness. Inadequate humidification and the provision of cold oxygen at higher flow rates in standard oxygen therapy cause drying of the nasal mucosa and increase moisture evaporation. This leads to thickened mucus that forms crusts, especially in neonates with delicate mucosal linings. ²⁴ Although manageable, this complication adds to nursing workload and parental anxiety. In contrast, the heating and humidification inherent to HHHFNC keep the nasal passages moist, which inhibits mucosal drying and reduces irritation. ²⁵

This study had several limitations. The modest sample size (30 neonates per group) limits the statistical power and generalizability of our findings, although it provides valuable preliminary data for future research. As this was a single-center study, uniformity in protocols and data collection was maintained; however, this setting may limit applicability to broader neonatal populations. That said, our institute being a referral center helps mitigate the potential diversity bias. The short follow-up period restricted the assessment to short-term outcomes. Blinding was impossible owing to medical-device-based interventions, which may introduce performance or detection bias, although it reflects real-world clinical conditions. Additionally, the duration of hospitalization could not be solely attributed to TTNB, as comorbidities such as hypoglycemia, sepsis, neonatal jaundice, prematurity, and feeding establishment also contributed to a prolonged stay in a few cases.

HHHFNC showed significant decrease in duration of respiratory support, early clinical improvement and reduced need for escalation of support compared with standard oxygen therapy; however, differences in other clinical outcomes such as CPAP requirement, and hospital stay were not statistically significant. Larger adequately powered trials are required before recommending HHHFNC as routine first-line therapy in TTNB.

Institutional Ethics Committee of Kalinga Institute of Medical Sciences, Kalinga Institute of Industrial Technology University (KIIT/KIMS/IEC/1267/2023) -

Clinical trial registry of India (CTRI/2024/06/069504).

Written informed consent was obtained from all parents or guardians prior to enrolment.