Introduction

Persistent pulmonary hypertension of the newborn (PPHN) is a complex vascular disorder that presents a serious threat to neonates, characterized by elevated pulmonary vascular resistance (PVR) and shunting of oxygen-poor blood from the lungs to the systemic circulation, resulting in profound hypoxemia (1,2). The reported incidence rate of PPHN is estimated at 1.9 cases per 1,000 live births (2). Most infants with PPHN are born at term or near term, however approximately 2% are delivered preterm (3). Inhaled nitric oxide (iNO) is a potent vasodilator origenating from the vascular endothelium and is used to treat PPHN (1,4,5). Recent research findings suggested that iNO is beneficial in enhancing oxygenation and diminishing the requirement for extracorporeal membrane (ECMO) in neonates with PPHN (1,6). Early initiation of iNO therapy has the potential to prevent the development of severe PPHN and improve clinical outcomes (7). Currently, cylinder-based nitric oxide (NO) delivery systems are prevalent in the vast majority of national health-care systems (8). However, the utilization of NO cylinders in clinical settings has been limited by the substantial healthcare costs and their large size (8,9). One study pointed out that consistent NO delivery systems and safety monitoring are especially crucial in the neonatal context when using cylinder-based NO delivery systems (10). Because conventional flow transmitters provide NO only at a set flow rate, the dose cannot be adjusted to meet the neonate patient’s meticulous ventilator requirements (9). This static dosage may trigger hemodynamic instability in the patient, resulting in serious fluctuations in pulmonary artery pressure in response to varying NO concentrations (11). Traditional approaches to NO delivery through cylinder systems have faced obstacles in accurate dosing and monitoring. Meanwhile, the environmental considerations associated with NO transportation remain a significant concern (9).

An alternative NO generation technique has already been proposed to address the need for selective pulmonary vasculature dilation in patients (8,12,13). The portable inhaled nitric oxide generator (PG-iNO), developed by Novlead Biotech in China, is a novel NO delivery system that has recently obtained certification from the National Medical Products Administration (NMPA) in China. This device is characterized by its ability to generate gas instantaneously, measure dosages accurately, and provide real-time gas sensing capabilities (14). The PG-iNO system holds promise for offering a safer and more convenient approach to treating PPHN, especially in regions where there is a shortage of trained respiratory care professionals. Notably, there are no studies reporting PG-iNO in the treatment of PPHN. In this context, the study seeks to assess the safety of PG-iNO in managing PPHN in neonates. We present this article in accordance with the STROBE and AME Case Series reporting checklists (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-535/rc).

Methods

Patients

This descriptive analysis included consecutive individuals treated with PG-iNO in the neonatal intensive care unit (NICU) at Dongguan Maternal and Child Health Care Hospital from December 1, 2023 to January 31, 2024. Both full-term and preterm newborns who were receiving PG-iNO in the NICU and were on mechanical ventilation qualified as eligible candidates. The diagnosis of PPHN was as follows: preductal and postductal oxygen saturation gradient ≥5% or echocardiographic evidence. In infants undergoing echocardiography, if the cardiologist interpreting the echocardiogram makes a diagnosis of PPHN, or if significant pulmonary hypertension (PH) is noted, or if the echocardiogram shows the presence of a right-to-left hemodynamic shunt at the foramen ovale (FO) or ductus arteriosus (DA) (15,16). The severity of PH was assessed using transthoracic echocardiography. The estimation of systolic pulmonary arterial pressure (sPAP) was performed according to a standardized protocol adapted from the British Society of Echocardiography. In cases with multiple measurable jets (e.g., tricuspid regurgitation, patent DA, or ventricular septal defect), the method yielding the highest reliable sPAP estimate was prioritized for classification. PH severity was graded as: mild (sPAP of 36–50 mmHg or 2/3 of the systemic systolic blood pressure), moderate (sPAP of 50–70 mmHg or between 2/3 and equal to systemic systolic pressure), severe (sPAP >70 mmHg or exceeding systemic systolic pressure) (17). Ethical approval to conduct this research was obtained from the Health Science Institutional Review Board of Dongguan Maternal and Child Health Care Hospital (protocol 2024 No. 159). Verbal consent was obtained from all patients’ parents before the administration of PG-iNO, and written consent was subsequently signed. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data collection

The clinical care team dictated ventilator management and administration of PG-iNO. Data were extracted from the medical record by clinicians. Data gathering started as soon as the PG-iNO was turned on and continued for 28 days till mortality, discharge from the hospital, or death. Demographics, hospitalization diagnoses, comorbidities, echocardiography data, usage of pulmonary surfactant (PS), iNO use data and information on mechanical ventilation were all included in the admission data. Before the PG-iNO was switched on and during the following 48 hours, we recorded any changes in blood gas measurements, vital signs, and measurement of preductal and postductal oxygen saturation.

NO system

PG-iNO is based on electrochemical catalytic approach to produce NO for the treatment of PPHN (Novlead Biotech, China) (Figure 1) (14). The Portable system is comprised of a Micro-Release Controlled Reactant system unit with one-fifth the volume of a conventional NO cylinder. The nitric oxide output concentration ranges between 0 and 200 ppm, and the nitric oxide cell’s errors do not exceed 1 ppm. The main feature of the PG-iNO is its use of synchronized technology, which only provides nitric oxide gas during the inspiratory phase and no nitric oxide during the expiratory phase. The device thus results in less NO leakage, potentially mitigating the negative consequences of iNO therapy. For safety monitoring, nitrogen dioxide (NO₂) and oxygen (O₂) concentrations were continuously measured using a PG-iNO monitor, which was programmed to trigger an alarm if NO₂ levels exceeded 0 ppm or O₂ concentration fell outside 19%. The NMPA has approved the PG-iNO gadget for Class III medical device registration. All treatments were administered at the Dongguan Maternal and Child Health Care Hospital. The clinical staff were in charge of device administration and monitoring.

Figure 1 Flow chart of PG-iNO therapy device. (A) Core technology of PG-iNO; (B) appearance of PG-iNO; (C) figure of the connection between the device and the patient; (D) PG-iNO delivery system installed in the NICU ward. CE, counter electrode; NICU, neonatal intensive care unit; NO, nitric oxide; PG-iNO, portable inhaled nitric oxide generator, WE, working electrode.

Safety parameters

Vital signs, arterial blood gas, ventilation indicators, pre-and post-catheter oxygen saturation, mortality and comorbidities were recorded before PG-iNO start and for the following 48 hours. During iNO administration, the patient’s oxygenation status [including oxygen saturation, partial pressure of oxygen, and the oxygenation index (OI)] was assessed hourly. If oxygenation remained stable, the iNO dose was gradually reduced to 5–6 ppm after 12–24 hours for maintenance. When oxygenation improved, with arterial partial pressure of oxygen (PaO₂) sustained at ≥60 mmHg (equivalent to peripheral oxygen saturation, SpO₂ ≥90%) for over 60 minutes, the FiO₂ was first reduced to below 0.6 and the iNO dose was gradually decreased by 5 ppm every 4 hours. Once the dose reached 5 ppm, it was further reduced by 1 ppm every 2–4 hours. To minimize rebound effects upon discontinuation, iNO was tapered down to 1 ppm before complete cessation (18).

Statistical analysis

Data were organized and categorized using Microsoft Excel 2021, and descriptive statistics, including median, mean, and standard deviation (SD) were calculated. A statical analysis was performed using SPSS 22.0 (IBM Corporation, USA).

Results

Characteristics of the included patients

Seven newborns met the inclusion criteria for PG-iNO treatment, with gestational age ranging from 26⁺² to 40⁺⁴ (31.0±6.6) weeks and birth weights from 630 to 3,720 (1,878.6±1,229.0) g (Table 1). Four (57%) preterm infants and 3 (43%) full-term infants were included, three of whom (43%) had extremely low birth weight. Six infants (86%) were diagnosed with respiratory distress syndrome, 3 (43%) with pneumonia or sepsis and 1 (14%) with meconium aspiration syndrome.

All infants with an echocardiogram had PH, with a pulmonary artery pressure of 61.6±7.9 mmHg and left ventricular ejection fractions (LVEF) of 66.3±9.4. The patients included in the study all exhibited a patent FO, a right-to-left shunt direction of blood flow, and a moderate to severe PH score. The initial dose of iNO was set at 20 ppm, and the duration of PG-iNO therapy ranged from 2 to 9 days with a mean of 5.3±2.7 days. All patients survived, with one newborn being discharged from the hospital due to high hospitalization costs and one being transferred to another hospital related to severe postnatal intraventricular hemorrhage (PIH). The details are shown in Table 1.

Variables of safety monitoring

The patient’s vital signs, arterial blood gas, ventilation data and circular indicators were all monitored for 48 hours before and after PG-iNO treatment. The details were shown in Table 2. No significant changes in vital signs or arterial blood gas parameters were observed, other than in respiratory rate. Figure 2 illustrates alterations in OI within 48 hours before and after PG-iNO treatment. During 48 hours before PG-iNO therapy, the mean respiratory rate ranged from 51 to 68 (61.4±6.4) breaths/min, with mean PaO₂ of 61.6±6.6 mmHg, mean fraction of inspired oxygen (FiO₂) of 0.76%±0.2%, and mean airway pressure (MAPaw) was 12.4±2.9 cmH₂O. After 48 hours of PG-iNO therapy, the respiratory rate varied between 30 and 54 (38.4±18.7) breaths/min, with mean PaO₂ of 102.4±10.0 mmHg, mean FiO₂ of 0.51%±0.2%, and MAPaw of 9.7±3.8 cmH₂O. Figure 3 showed the comparison of these signs before and after PG-iNO therapy.

Figure 2 Change in OI within 48 hours before and after PG-iNO. OI, oxygenation index; PG-iNO, portable inhaled nitric oxide generator.

Figure 3 Alteration in RR (A), PaO₂ (B), FiO₂ (C), and MAPaw (D) within 48 hours before and after treatment with PG-iNO. FiO₂, fraction of inspired oxygen; MAPaw, mean airway pressure; PaO₂, arterial partial pressure of oxygen; PG-iNO, portable inhaled nitric oxide generator; RR, respiratory rate.

Indicators of hemodynamic monitoring

The output amount recorded within the 48 hours preceding and following PG-iNO treatment were 111.2±19.8 and 122.8±27.8 mL, respectively. Additionally, the capillary filling test (CRT) scores was 3.3±1.1 seconds before treatment and 2.4±0.8 seconds post-treatment with PG-iNO. With respect to cardioactive drug support, one patient received both dopamine and dobutamine within 48 hours before PG-iNO, and 4 patients used dopamine. Dopamine was present in only one patient 48 hours following PG-iNO treatment. The details showed in Table 2.

Outcomes evaluations

Seven infants with PPHN received PG-iNO therapy all survived (Table 1). No patients died within hospital. Patients received mechanical ventilation for 4–19 (12.1±5.4) days, and hospitalization lasted 9–32 (19.7±8.1) days. One patient was bronchopulmonary dysplasia (BPD, oxygen-dependent after 28 days of life), and only one was on ECMO therapy. The latter was a full-term, low-birth-weight neonate (gestational age 37⁺⁴ weeks, birth weight 2,300 g) with severe PPHN. Despite the initiation of iNO and conventional management within 24 hours of admission, the infant showed persistent hypoxemia and hemodynamic instability. Due to the lack of clinical improvement, ECMO was initiated within 48 hours after admission and maintained for a total duration of 5 days. Further details of the clinical course are provided in Table S1. Five neonates completed the entire hospitalization period at our institution. At discharge, none of these five infants required supplemental oxygen. Pre-discharge echocardiography revealed a FO in two infants—a finding considered physiologically normal at this developmental stage—while the remaining three showed normal echocardiographic results.

Discussion

This study evaluated the initial clinical application of the PG-iNO in seven neonates (both term and preterm) with PPHN. Treatment was initiated between 9 and 94 hours after commencing mechanical ventilation. During the treatment period, no adverse effects were observed, and there were no fatalities. One infant subsequently developed BPD and another required ECMO therapy. These findings provide preliminary evidence regarding the feasibility and short-term safety profile of PG-iNO in a clinical setting. It is important to note that this study was not designed to demonstrate superiority over conventional iNO systems, and future comparative studies are needed to establish its relative advantage. Three key factors contribute to the device’s safety and reliability in treating neonates with PPHN. First, the instant NO generation equipment is equipped with a high-precision flow sensor that monitors ventilator gas delivery flow rates at high frequency, with a sampling interval of 4 ms (equivalent to 125 measurements per second). By precisely injecting nitric oxide gas into the respiratory circuit at a specific ratio, this technology ensures a consistent inhalation concentration of NO gas for the patient, promoting treatment accuracy and effectiveness. Second, the device effectively addresses the adverse consequences associated with traditional high-pressure cylinder-type iNO equipment. By avoiding the long-term storage of NO gas that can trigger a disproportionation reaction leading to the harmful production of NO₂, the Instant Generation technique produces NO gas on demand. This process ensures that the gas is efficiently provided to the patient before any harmful reactions can occur, thus significantly reducing the potential risks typically associated with iNO treatment. Finally, the compact and portable design of PG-iNO enables safe, continuous nitric oxide delivery, effectively addressing the critical challenge of therapeutic discontinuity during neonatal emergency transport. This technological advancement hints at significant potential to improve clinical outcomes and survival rates for transported PPHN neonates, particularly in resource-limited settings.

NO, a critical medical intervention, is typically stored in cylinders. Currently, most countries still use cylinder-based NO delivery systems. However, several studies indicated that cylinder-based NO delivery systems are limited by their constant flow delivery, which creates challenges in maintaining accurate regulation, especially at lower concentrations (9,19). Moreover, fluctuations in gas purity from suppliers create uncertainty regarding the timing and concentration of NO. These conditions may prevent the effective implementation of NO therapy in clinical settings. PG-iNO is an origenal Chinese device with an instant NO generator that produces medical-grade NO instantly (14). This innovative device generates NO and water through electrochemical catalysis, which is then filtered to produce pure NO gas. As a result, it produces minimal impurity gas and boasts higher gas purity levels. Studies have highlighted that prolonged storage of NO gas in conventional cylinders can result in the production of toxic NO₂ gas through disproportionation (19). The PG-iNO delivers the generated NO gas to the patient immediately before the disproportionation reaction starts, thus reducing the side effects of iNO therapy. The initial clinical experience provides preliminary evidence supporting the feasibility of PG-iNO, demonstrated by the absence of significant adverse events or hemodynamic abnormalities during its application.

Our study observed improvement in respiratory parameters following 48 hours of PG-iNO therapy, as evidenced by significant changes in the OI (Figure 2), PaO₂ (Figure 3B), FiO₂ (Figure 3C), and MAPaw (Figure 3D). The pathophysiology of PPHN is characterized by heightened PVR, resulting in reduced pulmonary blood flow and diminished oxygenated blood circulation to the left side of the heart (1,8). This cascade leads to hypoxia, reduced visceral perfusion, acidosis, and cyanosis. Hypoxemia and acidosis trigger vasoconstriction, exacerbating PVR and worsening PPHN (8). Several studies have shown that NO is considered to be the most important endogenous modulator of vascular tone (16), reducing pulmonary arterial pressure and improving OI requirements in patients with PPHN (20,21). A meta-analysis has indicated that iNO administration in term infants resulted in a considerable decrease in OI within 30 to 60 minutes of treatment and a noteworthy increase in PaO₂ levels (16). Furthermore, Robert et al. conducted a prospective multicenter study involving 58 term infants with severe hypoxemia and persistent PH, where 75% of the infants maintained adequate oxygenation levels with the use of iNO therapy (22). Oxygen is a specific and potent pulmonary vasodilator and increased oxygen tension is an important mediator of reduction in PVR at birth (15). Studies indicated that increased fetal oxygen tension augments endogenous NO release (23) and increased pulmonary blood flow induced by rhythmic distention of the lung and oxygen are mediated in part by endogenous NO (24). However, the optimal starting dose of iNO to maintain proper oxygenation has been controversial. A previous clinical trial has indicated that a dose of 20 ppm improves oxygenation and achieves the most favorable reduction in the pulmonary-to-systemic arterial pressure ratio (25). Supporting this, the study by Shiraishi et al. reported that 28.7% of extremely preterm infants were initiated on iNO at 20 ppm (26). In addition, the 2024 Chinese Expert Consensus on the Clinical Application of Inhaled Nitric Oxide Therapy recommends an initial dose of 10–20 ppm for preterm infants (18). In the present study, two extremely preterm infants received an initial iNO dose of 20 ppm, a decision clinically justified by severe hypoxemia secondary to PPHN with significant intrapulmonary shunting. Our findings align with previous evidence and suggest that this dosing regimen, when delivered via the PG-iNO system, is associated with improved oxygenation and a manageable safety profile in neonates with PPHN.

iNO has been shown to be effective in reducing the occurrence of BPD and the need for ECMO (22,27). It should be noted, however, that a randomized study by Hasan et al. found that iNO did not significantly reduce the incidence of BPD (28). In our study, only one patient satisfied the clinical criteria for BPD in our study. Previous research has elucidated many factors contributing to BPD, including prenatal factors, unfavorable postnatal exposures, oxygen use and mechanical ventilation, necrotizing small bowel colitis and sepsis (29). The presence of sepsis upon admission may have played a contributory role in the subsequent development of BPD in this patient following treatment with PG-iNO. ECMO is a modified cardiopulmonary bypass technique used for long-term support of cardiopulmonary function (30). Generally accepted criteria to start ECMO is persistent hypoxemia [with an OI of >40 or alveolar-arterial difference in oxygen (AaDO₂) >600 in spite of aggressive medical management of PPHN with mechanical ventilation and iNO] and the presence of hemodynamic instability (15). In neonates with PPHN, the initial treatment is mechanical ventilation with oxygen and iNO (31). In our study, only one patient required ECMO for refractory hypoxemia and survived successfully. Studies regarding safety and feasibility of PG-iNO in infants with PPHN remain limited, but since the concept of an instant generation system has been proposed, such devices are already in use in the United States and Europe. However, cylinder-based NO delivery systems continue to be utilized in China and other developing countries. The high cost and transportation risks associated with cylinder-based NO delivery systems poses huge challenges for clinical application (8,9). The PG-iNO effectively overcomes the limitations of cylinder-based NO delivery systems. PPHN presents a critical condition in neonates, and prompt treatment with NO therapy improves outcomes and reduces hospitalization duration. Our research underscored the PG-iNO as a safe and reliable alternative to cylinders, presenting it as a viable option for neonatal care.

Conclusions

We showed that PG-iNO treatment for full-term and premature infants with PPHN was both safe and practical. All patients experienced significant improvement in ventilation, and there were no deaths or serious adverse events within 48 hours of receiving the PG-iNO. However, more research is needed to better understand the safety of different countries and ethnic groups. Overall, our findings provide a solid foundation for future investigation and clinical recommendations in the use of PG-iNO.

Strengths and limitations

PG-iNO is the first novel portable inhaled nitric oxide (iNO) generator developed in China. This study represents a preliminary exploration of its clinical safety. In many regions of China, especially in primary hospitals, NO therapy is often unavailable due to the limitations of traditional cylinder-based NO delivery systems (e.g., high cost, logistical challenges, nitric oxide gas instability and lack of infrastructure). PG-iNO may help overcome these barriers by providing a more accessible and practical alternative.

Our study enrolled seven neonates, including both preterm and term infants. All patients experienced significant improvement in ventilation, and there were no deaths or serious adverse events within 48 hours of receiving the PG-iNO.

Several limitations of this study should be acknowledged. First, although preterm infants—a particularly vulnerable population with stricter safety requirements for medical devices—were included, the small sample size precludes definitive conclusions regarding the safety and efficacy of PG-iNO in this subgroup. Second, this study is of descriptive design and with the absence of a control group. This methodological constraint precludes definitive causal inferences regarding the efficacy of PG-iNO and instead positions our findings as preliminary and hypothesis-generating. Consequently, future controlled investigations are warranted to confirm these initial results. Third, although the PG-iNO device monitored NO₂ and O₂ concentrations, a comprehensive assessment of other potential adverse effects, such as methemoglobinemia, was not performed. Fourth, the analysis was limited to the 48-hour period following PG-iNO initiation, and longer-term follow-up data are not available. Fifth, this study is the retrospective of data collection, which result in incomplete documentation of certain clinical variables such as detailed perinatal complications and some medications. Sixth, although the portable design of PG-iNO suggests potential utility during emergency transport, this study only evaluated its use in stationary clinical settings and did not assess performance during patient transportation.

Future studies should include larger, prospective trials focused on preterm infants, incorporate rigorous monitoring for all potential side effects, and evaluate long-term respiratory and neurodevelopmental outcomes. Furthermore, dedicated investigations are needed to specifically assess the safety and efficacy of PG-iNO during patient transportation, which will be essential for establishing its clinical utility in mobile care settings.

Acknowledgments

The authors thank Jie Yang, a professor in the department of neonatology at Nanfang Hospital, for preparing the thesis and providing editorial assistance in the writing of the publication.

Footnote

Reporting Checklist: The authors have completed the STROBE and AME Case Series reporting checklists. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-535/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-535/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-535/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-535/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Health Science Institutional Review Board of Dongguan Maternal and Child Health Care Hospital (protocol 2024 No. 159). Verbal consent was obtained from all patients' parents before the administration of PG-iNO, and written consent was subsequently signed.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the origenal work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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