Efficacy of inhaled nitric oxide under different oxygenation indexes in neonatal pulmonary hypertension

Efficacy of inhaled nitric oxide under different oxygenation indexes in neonatal pulmonary hypertension | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of inhaled nitric oxide under different oxygenation indexes in neonatal pulmonary hypertension YiJin Wang, Ying Pan, Jian Ming Li, Guofeng Lan, Xiao He, XueKai Shi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4445013/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives To analyze the efficacy of inhaled nitric oxide (iNO) in the treatment of neonatal pulmonary hypertension under different oxygenation indexes (OI). Methods In this retrospective analysis, 51 neonates diagnosed with PPHN and treated with invasive mechanical ventilation at The Second People's Hospital of Nanning and Maternal and Child Health Hospital of Nanning from January 1, 2021, to December 31, 2023, were selected as the study subjects. According to different values of OI, the neonates were divided into three groups; subjects with OI ≤ 12 were categorized into group A (n = 20), 12 16 into group C (n = 15). The OI, oxygen saturation (SaO 2 ), pulmonary artery pressure (PAP), duration of iNO treatment, and the time and cure rate of invasive mechanical ventilation were compared between groups A, B, and C after treatment. Results Comparison of OI between the three groups indicated significant changes in group A at 6 h and 24 h after treatment; whereas, there were no significant changes in group B and C at 6 h after treatment, and changes were visible only 24 h after treatment. Among the three groups, the degree of decrease of OI in group A was the highest, followed by group B, and group C was the least, with the differences being statistically significant ( P < 0.05). Moreover, there were no significant differences in PAP and SaO 2 in the three groups before treatment; whereas, after treatment, group A showed the greatest decrease in PAP and the greatest increase in SaO 2 , followed by groups B and C, and the differences were statistically significant ( P < 0.05). Furthermore, a comparison of the durations of NO treatment, mechanical ventilation, and prognosis of children in groups A, B, and C revealed that children in group A needed iNO and mechanical ventilation for the lowest time, followed by those in group B, while children in group C needed iNO and mechanical ventilation for the longest time, with the differences being statistically significant ( P < 0.05). The cure rate of group A was 85.0%, that of group B was 75.0%, and group C was 46.7% (x 2 = 6.161; P < 0.05). Conclusions Under different OI conditions, iNO treatment for pulmonary hypertension may produce different curative effects. When OI ≤ 12, iNO treatment can timely improve SaO 2 , reduce PAP, improve the cure rate, shorten the time on the machine, and decrease the treatment cost. When OI > 12, iNO treatment cannot increase SaO 2 significantly or decrease PAP and PaCO 2 timely; mortality rates increased significantly, and the time needed on a ventilator was longer. Therefore, when the OI of children with PPHN reaches 12, iNO should be used as soon as possible to improve the cure rate. Persistent pulmonary hypertension of the newborn inhaled nitric oxide oxygenation index Introduction persistent pulmonary hypertension of the newborn ( PPHN) refers to the failure of the normal circulatory transition that occurs after birth, characterized by marked pulmonary hypertension that causes hypoxemia secondary to right-to-left shunting of blood at the foramen ovale and ductus arteriosus. Its clinical signs can be manifested as persistent hypoxemia [ 1 ] . As a recommended basic treatment for PPHN, inhaled nitric oxide (iNO) is currently the only pulmonary vasodilator approved by the United States Food and Drugs Administration (USFDA) [ 2 , 3 ] . Oxygenation indexes (OI) are an important indicator in mechanical ventilation to assess whether organ tissues can obtain enough oxygen for normal function. They are also important indicators for evaluating the need for iNO and extracorporeal membrane oxygenation (ECMO) therapy in children with PPHN. In this study, according to the Guidelines for the Application of Nitric Oxide Inhalation in Neonatal Intensive Care Units (NICUs) published by the Neonatal Doctors Branch of the Chinese Medical Doctor Association in 2019, the indications for iNO treatment for PPHN are mainly the timely use of iNO during mechanical ventilation in case of an OI of 16 [ 4 ] . A randomized controlled trial (RCT) found that when neonates with PPHN had an OI between 15 and 25, early iNO therapy decreased the need for ECMO support and mortality compared with those with an OI of 30 [ 5 ] . Due to the increased rate of birth of premature infants, the incidence of neonatal PPHN is increasing. However, existing literature does not report whether it is appropriate to use iNO when OI > 16 or whether iNO can quickly reduce pulmonary artery pressure (PAP), decrease the occurrence of neonatal acute respiratory distress syndrome, and improve the cure rate. This study aims to investigate the efficacy of iNO for the treatment of PPHN under different OIs and provide more reference ideas for the optimal timing of iNO intervention in PPHN therapy. Materials and Methods Study subjects and groups This retrospective study included 51 children diagnosed with PPHN at the Department of Neonatology of Nanning Maternal and Child Health Hospital from January 01, 2021, to December 31, 2023. Inclusion criteria The inclusion criteria followed the diagnosis and treatment guidelines formulated by the Neonatal Group of Pediatrics Branch of the Chinese Medical Association in 2017 [ 6 ] . PPHN was diagnosed as arterial pressure of oxygenpressure difference of 10–20 mmHg between the right-upper limb (anterior catheterization) and the lower limb, or oxygen saturation (SaO 2 ) of 5%, significant hypoxemia, and not proportional to the extent of lung disease shown in the x-ray, except for patients with pneumothorax or congenital heart disease. For ultrasound diagnosis, pulmonary artery systolic pressure was calculated based on tricuspid valve regurgitation, PAP of > 35 mmHg, or systemic circulatory systolic pressure of 2/3, calculated as right ventricular systolic pressure = right atrial pressure + (4 tricuspid valve regurgitation velocity2) [ 7 ] , or the presence of right-to-left shunt at the level of the atrium or ductus arteriosus. All included children received invasive mechanical ventilation. Exclusion criteria The exclusion criteria were severe congenital diseases or serious genetic diseases; right-to-left shunt-type congenital cardiovascular malformations such as complete pulmonary venous ectopic drainage, aortic constriction, and pulmonary capillary dysplasia; congenital heart disease; cardiac insufficiency with increased diastolic pressure in the left atrium and ventricular and pulmonary veins; serious pulmonary disease such as severe pulmonary dysplasia; congenital methemoglobinemia, and chromosomal abnormal genetic disease; and children with a gestational age of < 28 weeks. Grouping The 51 children with iNO were divided into three groups, namely, groups A, B, and C, according to the value of pre-treatment OI, calculated as OI = inhaled oxygen concentration (fraction of inspired oxygen, FiO 2 ) mean airway pressure (mean airway pressure, Pmean) 100/PaO 2 . The value of OI in group A was 12 (n = 20), between 12 and 16 in group B (n = 16), and > 16 in group C (n = 15). Clinical observation indicators The clinical observation indicators were SaO 2 and OI of the three groups of children before iNO treatment and 6 h, 24 h, 48 h, and 72 h after treatment, partial pressure of carbon dioxide (PaCO 2 ), PAP, iNO treatment duration, mechanical ventilation duration, and cure rate. Statistical analysis The statistical software SPSS 24.0 was used for statistical analyses. For categorical data, the chi-square test was used to compare groups. The measurement data were presented as mean ± standard deviation. The t -test was adopted to compare the mean values of samples between two groups, while a one-way analysis of variance was performed for comparisons among multiple groups. A P -value of < 0.05 indicated statistically significant differences between groups. Results Comparison of the general data of children in the three groups Among the 20 children in group A, 8 were female (40%), 12 were male (60%); 5 were term (25%), 15 were premature (75%); 16 (80%) had neonatal respiratory distress syndrome (NRDS), 3 (15%) had meconium aspiration syndrome (MAS), and 1 (5%) had bronchopulmonary dysplasia (BPD). Among the 16 children in group B, 5 were female (31.3%), 11 were male (68.8%); 7 were term (43.7%), and 9 were premature (56.3%); 15 had NRDS (93.8%), and 1 had MAS (6.3%). Among the 15 children in group C, 7 were female (46.7%) and 8 were male (53.3%); 6 were term (40%) and 9 were premature (60%); 9 had NRDS (60%), 5 had MAS (33.3%), and 1 had BPD (6.7%) (Table 1 ). Table 1 Comparison of general data among the three groups Groups n sex Fetal age (weeks) premature birth Primary disease woman man NRDS MAS BPD group A 20 8 (40%) 12 (60%) 34.221 ± 3.949 15 (75%) 16 (80%) 3 (15%) 1 (5%) group B 16 5 (31.3%) 11 (68.8%) 36.045 ± 3.131 9 (56.3%) 15 (93.8%) 1 (6.3%) 0 (0) group C 15 7 (46.7%) 8 (53.3%) 35.210 ± 4.277 9 (60%) 9 (60%) 5 (33.3%) 1 (6.7%) χ 2 /F value χ 2 = 0.780 F = 1.025 χ 2 = 1.574 χ 2 = 5.458 P value 0.677 0.366 0.455 0.243 NRDS, neonatal respiratory distress syndrome; MAS, meconium aspiration syndrome; BPD, bronchopulmonary dysplasia. Comparison of the OI in the three groups OI was compared between the three groups before treatment and at different treatment intervals. When compared across different treatment times, the OI varied significantly after 6 h of iNO treatment in group A ( P 0.05). At the same treatment interval, the highest decrease in OI was observed in group A, followed by group B, with the decrease in group C being significantly lower than that in group A ( P < 0.05) (Table 2 ). Table 2 Comparison of OI in patients between the three groups Groups n pretherapy Six hours after treatment Twenty-four hours after treatment group A 20 10.690 ± 0.620 7.415 ± 0.593 ① 4.040 ± 0.410 ①② group B 16 14.513 ± 1.011 a 14.456 ± 0.998 a 8.231 ± 0.448 a ①② group C 15 20.167 ± 3.211 ab 20.093 ± 3.255 ab 16.973 ± 2.981 ab ①② group F = 110.74, P < 0.001 ③ F = 188.296, P < 0.001 Time - F = 2016.426, P < 0.001 Time * group - F = 140.892, P < 0.001 Note: (a) P < 0.05 compared with group A; (b) P < 0.05; ① P < 0.05 compared with group B; ① P < 0.05 compared with pre-treatment; ② P < 0.05 within group compared with 6 h after treatment; ③ P 0.05). In group A, the PAP decreased the most at 6 h and 24 h after iNO treatment, followed by group B. The children in group C showed the least change in PAP, which was significantly lower than that in group A ( P < 0.05) (Table 3 ). Table 3 Comparison of PAP among the three groups Groups n pretherapy Six hours after treatment Twenty-four hours after treatment group A 20 36.100 ± 1.021 18.950 ± 1.849 ① 10.050 ± 1.986 ①② group B 16 36.313 ± 1.078 35.063 ± 2.645 a 24.063 ± 1.982 a ①② group C 15 36.600 ± 1.183 36.467 ± 1.187 a 23.400 ± 1.639 a ①② group F = 0.905, P = 0.411* F = 333.083, P < 0.001 time - F = 2601.871, P < 0.001 Time * group - F = 320.625, P < 0.001 Note: (a) P < 0.05 compared with group A; P < 0.05. (b) P < 0.05 compared with group B; ① P < 0.05 compared with before treatment; ② P 0.05. Comparison of SaO 2 among children in the three subgroups SaO 2 was compared between groups at the same interval before and after treatment. Before treatment with iNO, the difference in SaO 2 between the three groups was not statistically significant ( P > 0.05). After initiation of treatment with iNO, the SaO 2 in the three groups started increasing. Children in group A showed the highest increase in SaO 2 at 6 h and 24 h after treatment, followed by those in group B. Children in group C showed the least change, which was significantly lower than that in the other groups ( P < 0.05) (Table 4 ). Table 4 Comparison of SaO 2 among the three groups Groups n pretherapy Six hours after treatment Twenty-four hours after treatment group A 20 89.200 ± 0.951 92.850 ± 0.671 ① 95.100 ± 0.968 ①② group B 16 88.500 ± 0.632 a 88.688 ± 0.602 a 93.188 ± 1.167 a ①② group C 15 88.067 ± 0.594 a 88.267 ± 0.884 a 92.133 ± 0.743 ab ①② group F = 9.824, P < 0.001 ③ F = 106.932, P < 0.001 time - F = 713.689, P < 0.001 Time * group - F = 41.861, P < 0.001 Note: * P < 0.05 within the group compared with before treatment, a P < 0.05; ① P < 0.05 within the group compared with before treatment; ② P < 0.05 within group compared with 6 h after treatment. SaO 2 , blood oxygen saturation. ③ Significant difference between groups before treatment with iNO, P < 0.05. Comparison of cure rates in the three groups The cure rate of children in group A was 85%, followed by group B (75%), whereas the lowest cure rate was observed in group C (46.7%). The difference was statistically significant ( P < 0.05) (Table 5 ). Table 5 Comparison of cure rates among the three groups Groups n cure Uncured group A 20 17 (85%) 3 (15%) group B 16 12 (75%) 4 (25%) group C 15 7 (46.7%) 8 (53.3%) χ 2 value 6.161 P value 0.046 Discussion As one of the most common critical diseases in NICUs, the incidence of PPHN is related to the economic level of the region. In Western developed countries, the incidence of PPHN is about 1.8–1.9 per 1000, while that in Asian countries is about 0.5–4.6 per 1000, with the mortality rate being as high as 20.6% [ 8 ] . Therefore, the diagnosis and treatment of PPHN are among the most popular research priorities today. Effect of iNO on SaO 2 Multiple clinical data indicate that iNO plays a significant role in the treatment of PPHN, improvement of OI, and reduction in the rate of ECMO demand. The study of Wan et al. [ 9 ] shows that compared with conventional treatment, children with iNO have shorter mechanical ventilation and aerobic treatment and significantly improved blood-gas index, which can more effectively improve the respiratory function of children with PPHN. The study of Yan Xiaoya et al. [ 10 ] showed that the PaCO 2 and the mean arterial pressure in children with PPHN were significantly lower than those before treatment with iNO,. The results of these studies corroborate can effectively improve oxygenation and SaO 2 after 6 h of treatment with iNO, as well as reduce PAP. Clinically, iNO has become the preferred method for the treatment of PPHN, mainly because it can selectively dilate blood vessels, decrease pulmonary artery pressure, and improve oxygenation [ 11 – 12 ] . Impact on the PAP . In the treatment of PPHN, Nitric oxide acts as a vasodilator and regulates PAP mainly. After entering the body, it interacts with nitric oxide synthase (NOS) in the lungs to reduce PAP rapidly."Studies have shown that the conventional treatment of PPHN children using mechanical ventilation began to show obvious changes within 12 h, whereas the use of iNO for the treatment of children significantly decreased PAP within 1 h of treatment [ 13 – 14 ] . Therefore, NO plays a significant role in regulating the vascular tone and reducing PAP. However, contrary to that study, in groups B and C in our study showed an effective reduction in PAP after 6 hours of iNO treatment. This could be attributed to the higher proportion of preterm infants in these groups and the possibility that iNO had a lower effect on infants with a lower gestational age. Analysis of the efficacy of iNO on PPHN under different OI indexes According to the Guidelines for the Application of Nitric Oxide Inhalation Therapy in NICUs, published by the Neonatologists Branch of the Chinese Medical Doctor Association in 2019, neonates with hypoxemic respiratory failure due to PPHN should be prioritized for iNO treatment at an OI value of 16. OI can be used to assess the severity of hypoxic respiratory failure and is closely related to the prognosis of PPHN. When the OI of neonates with respiratory failure is between 15 and 25, early iNO therapy can alleviate the need for ECMO support or even death compared with children with OI progressing to 30 [ 15 ] . Due to the lack of ECMO therapy in our hospital, the condition of some patients worsened, and ECMO cannot be used when OI reaches 40. Moreover, due to the increase in the birth rate of premature infants, they accounted for 66.67% of all cases of PPHN in this study. Therefore, it remains unclear whether iNO therapy can improve the cure rate. Thus, the current recommendation of choosing iNO therapy in premature infants when OI exceeds 16 needs further study. This study investigated whether choosing early intervention with iNO when OI reached 12 could more effectively reduce PAP, or whether timely treatment could increase the cure rate and reduce the time of mechanical ventilation before pulmonary hypertension aggravated further and evolved into acute lung injury. A study found that iNO reduced the accumulation of lung neutrophils, as well as the expression of TNF-A and the ratio of IL-10, thereby decreasing lung inflammation and the development of acute respiratory distress [ 16 ] . As can be seen from the retrospective analysis in this study, children in group A showed the highest decrease in OI after 6 h of iNO treatment. However, the decrease in OI was not obvious in children of groups B and C until 24 h after treatment, suggesting that the effect of iNO treatment was lower at 6 h when OI was > 12. Meanwhile, at OI of 12, the effect of iNO treatment was obvious, when the values of SaO 2 and PAP were compared before and after treatment in the three groups. Group A children treated with iNO showed the most increase in SaO 2 at 6 h and 12 h, the PAP showed the highest decrease, and hypoxemia improved significantly at the same treatment time. Moreover, iNO therapy has led to the requirement of mechanical ventilation in a shorter time. Also, the cure rate in group A was significantly higher than that in groups B and C. Therefore, it is reasonable to assume that for preterm infants with a gestational age > 28 weeks, iNO therapy at an OI of 12 can more effectively reduce the PAP. The iNO therapy was also fast-acting, with significant improvement in the oxygenation evident within 6 h [ 17 ] . When OI > 12, the effect was slower and no effect was observed within 6 h. Therefore, in PPHN cases, iNO treatment should be performed as soon as possible, when OI ≤ 12, to decrease the occurrence of acute lung distress, shorten the duration of treatment and hospitalization, and improve the cure rate. Declarations Funding This study was supported by Guangxi Science and Technology Major Project （Grant Number. Guike AA22096032） Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. We got the approval of the Third Affiliated Hospital of Guangxi Medical University. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of Interests Authors’ declaration of personal interests: Yijin Wang has no conflicts of interest to report with this study. Ying Pan has no conflicts of interest to report with this study. Jian Ming Li has no conflicts of interest to report with this study. Guofeng Lan has no conflicts of interest to report with this study. Xiao He has no conflicts of interest to report with this study. Xuekai Shi has no conflicts of interest to report with this study. Author statement Yijin Wang: Conceptualization, Methodology, Investigation, Formal Analysis, Writing - Original Draft . Ying Pan: Date Curation, Writing - Original Draft . Jian Ming: Funding Acquisition,project adiministration . Guofeng Lan: Data curation . Xiao He :Visualization, Writing - Review. Xuekai Shi (Corresponding Author):Conceptualization, Funding Acquisition, Resources, Supervision, Writing - Review & Editing. 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Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure [J]. J Perinatol, 2013,33(12): 944-949. Ding Dan, Wang Shijie, Pan Jiahua. Prognostic risk factors affecting nitric oxide inhalation in neonatal treatment of persistent pulmonary hypertension [J]. Chinese General Medicine, 2019, (07): 1157-1160. BARRINGTON K J, FINER N, PENNAFORTE T. Inhaled nitric oxide for respiratory failure in preterm infants [J]. Cochrane Database Syst Rev, 2017,1(1): 509. Zhao Min, Li Xianghong, Yin Xiangyun, etc. Comparison of clinical effects of NO inhalation in preterm infants versus term infants [J]. Maternal and Child Health in China, 2023,38 (24): 4842-4846. Wan Yang, Zhang Shuqing, Left Jingye, and other clinical effects of nitric oxide inhalation in neonatal treatment of persistent pulmonary hypertension [J]. Practical drugs and clinical, 2019,22 (12): 1288-1291. Yan Xiaoyan, Si Xin, Quan Yanhua, etc. The relationship between serum CXCL 8, CXCL12 and the clinical outcome of nitric oxide inhalation therapy in newborns with persistent pulmonary hypertension [J]. Joint Logistic Military Medicine, 2024,38 (01): 26-30. SUN Z, SUN B, WANG X, et al. Anti-inflammatory effects of inhaled nitric oxide are optimized at lower oxygen concentration in experimental Klebsiella pneumoniae pneumonia [J]. Inflammation research : official journal of the European Histamine Research Society ...[et al.], 2016,55(10): 430. Yan Chen Yan, Chong Zhang, Manor, etc. Effect of nitric oxide inhalation combined with mechanical ventilation therapy on clinical effect, oxygenation index and disease outcome in children with persistent pulmonary hypertension [J]. PLA Medical Journal, 2021,33 (12): 56-59. STEINHORN R H, FINEMAN J, KUSIC-PAJIC A, et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4445013","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":324205019,"identity":"03a11872-5a86-4bcf-a699-566ae87339c6","order_by":0,"name":"YiJin Wang","email":"","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"YiJin","middleName":"","lastName":"Wang","suffix":""},{"id":324205021,"identity":"99200b85-39e4-47ee-8397-db5459ab1646","order_by":1,"name":"Ying Pan","email":"","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Pan","suffix":""},{"id":324205022,"identity":"d92a8edf-b18c-4ee3-92f6-d7971ceadd2a","order_by":2,"name":"Jian Ming Li","email":"","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"Ming","lastName":"Li","suffix":""},{"id":324205023,"identity":"cfa7aef9-71f1-4278-96fc-7ba3ce992ba5","order_by":3,"name":"Guofeng Lan","email":"","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guofeng","middleName":"","lastName":"Lan","suffix":""},{"id":324205024,"identity":"ee3c3597-169b-4631-a6b6-353298e027ae","order_by":4,"name":"Xiao He","email":"","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"He","suffix":""},{"id":324205025,"identity":"75fe5f3e-ee5c-4587-ab3a-8f00a23b78f4","order_by":5,"name":"XueKai Shi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIie3QMQuCUBDA8Xs4m1s8aXhfQQmaxL6KIvgZHA3CSWg1+hKOjfd44HTtQovS2iC0NiSOEfnaGt5vvj/cHYBh/CmWIw8dUIhDpp8EibtrYlmRfpKyWtFa2XuNcXGgjVuRsqChAe0chLPE74nXpolft2rBykuN7hn84ymaSbgl+25QlsXHxCeIvOtMIg4yl2PCCnHvMC40EsBE9nWbshIIUOok0y0VBQmHxpM58flbpo+VDQ+3qG6PZxYIZzW32Bv+27hhGIbx2QsrJlQmhJlSqAAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Nanning People's Hospital,The Third Affiliated Hospital of Guangxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"XueKai","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2024-05-19 16:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4445013/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4445013/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66252821,"identity":"a25cb6fe-f54e-408a-bfeb-a6f9ff2e2487","added_by":"auto","created_at":"2024-10-09 09:17:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":501441,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4445013/v1/a7f79c46-7ea2-4c83-8006-0ac87299a464.pdf"},{"id":61024251,"identity":"092bd72d-d469-4fc9-b115-029c738bb733","added_by":"auto","created_at":"2024-07-24 17:04:08","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":12867,"visible":true,"origin":"","legend":"","description":"","filename":"useNOpatientinformation.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4445013/v1/ce269a44a57befb4bb56511f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of inhaled nitric oxide under different oxygenation indexes in neonatal pulmonary hypertension","fulltext":[{"header":"Introduction","content":"\u003cp\u003epersistent pulmonary hypertension of the newborn ( PPHN) refers to the failure of the normal circulatory transition that occurs after birth, characterized by marked pulmonary hypertension that causes hypoxemia secondary to right-to-left shunting of blood at the foramen ovale and ductus arteriosus. Its clinical signs can be manifested as persistent hypoxemia\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs a recommended basic treatment for PPHN, inhaled nitric oxide (iNO) is currently the only pulmonary vasodilator approved by the United States Food and Drugs Administration (USFDA)\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Oxygenation indexes (OI) are an important indicator in mechanical ventilation to assess whether organ tissues can obtain enough oxygen for normal function. They are also important indicators for evaluating the need for iNO and extracorporeal membrane oxygenation (ECMO) therapy in children with PPHN. In this study, according to the Guidelines for the Application of Nitric Oxide Inhalation in Neonatal Intensive Care Units (NICUs) published by the Neonatal Doctors Branch of the Chinese Medical Doctor Association in 2019, the indications for iNO treatment for PPHN are mainly the timely use of iNO during mechanical ventilation in case of an OI of 16\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. A randomized controlled trial (RCT) found that when neonates with PPHN had an OI between 15 and 25, early iNO therapy decreased the need for ECMO support and mortality compared with those with an OI of 30\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Due to the increased rate of birth of premature infants, the incidence of neonatal PPHN is increasing. However, existing literature does not report whether it is appropriate to use iNO when OI\u0026thinsp;\u0026gt;\u0026thinsp;16 or whether iNO can quickly reduce pulmonary artery pressure (PAP), decrease the occurrence of neonatal acute respiratory distress syndrome, and improve the cure rate. This study aims to investigate the efficacy of iNO for the treatment of PPHN under different OIs and provide more reference ideas for the optimal timing of iNO intervention in PPHN therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eStudy subjects and groups\u003c/p\u003e \u003cp\u003eThis retrospective study included 51 children diagnosed with PPHN at the Department of Neonatology of Nanning Maternal and Child Health Hospital from January 01, 2021, to December 31, 2023.\u003c/p\u003e \u003cp\u003eInclusion criteria\u003c/p\u003e \u003cp\u003eThe inclusion criteria followed the diagnosis and treatment guidelines formulated by the Neonatal Group of Pediatrics Branch of the Chinese Medical Association in 2017\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. PPHN was diagnosed as arterial pressure of oxygenpressure difference of 10\u0026ndash;20 mmHg between the right-upper limb (anterior catheterization) and the lower limb, or oxygen saturation (SaO\u003csub\u003e2\u003c/sub\u003e) of 5%, significant hypoxemia, and not proportional to the extent of lung disease shown in the x-ray, except for patients with pneumothorax or congenital heart disease. For ultrasound diagnosis, pulmonary artery systolic pressure was calculated based on tricuspid valve regurgitation, PAP of \u0026gt;\u0026thinsp;35 mmHg, or systemic circulatory systolic pressure of 2/3, calculated as right ventricular systolic pressure\u0026thinsp;=\u0026thinsp;right atrial pressure + (4 tricuspid valve regurgitation velocity2)\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, or the presence of right-to-left shunt at the level of the atrium or ductus arteriosus. All included children received invasive mechanical ventilation.\u003c/p\u003e \u003cp\u003eExclusion criteria\u003c/p\u003e \u003cp\u003eThe exclusion criteria were severe congenital diseases or serious genetic diseases; right-to-left shunt-type congenital cardiovascular malformations such as complete pulmonary venous ectopic drainage, aortic constriction, and pulmonary capillary dysplasia; congenital heart disease; cardiac insufficiency with increased diastolic pressure in the left atrium and ventricular and pulmonary veins; serious pulmonary disease such as severe pulmonary dysplasia; congenital methemoglobinemia, and chromosomal abnormal genetic disease; and children with a gestational age of \u0026lt;\u0026thinsp;28 weeks.\u003c/p\u003e \u003cp\u003eGrouping\u003c/p\u003e \u003cp\u003eThe 51 children with iNO were divided into three groups, namely, groups A, B, and C, according to the value of pre-treatment OI, calculated as OI\u0026thinsp;=\u0026thinsp;inhaled oxygen concentration (fraction of inspired oxygen, FiO\u003csub\u003e2\u003c/sub\u003e) mean airway pressure (mean airway pressure, Pmean) 100/PaO\u003csub\u003e2\u003c/sub\u003e. The value of OI in group A was 12 (n\u0026thinsp;=\u0026thinsp;20), between 12 and 16 in group B (n\u0026thinsp;=\u0026thinsp;16), and \u0026gt;\u0026thinsp;16 in group C (n\u0026thinsp;=\u0026thinsp;15).\u003c/p\u003e \u003cp\u003eClinical observation indicators\u003c/p\u003e \u003cp\u003eThe clinical observation indicators were SaO\u003csub\u003e2\u003c/sub\u003e and OI of the three groups of children before iNO treatment and 6 h, 24 h, 48 h, and 72 h after treatment, partial pressure of carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e), PAP, iNO treatment duration, mechanical ventilation duration, and cure rate.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical software SPSS 24.0 was used for statistical analyses. For categorical data, the chi-square test was used to compare groups. The measurement data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. The \u003cem\u003et\u003c/em\u003e-test was adopted to compare the mean values of samples between two groups, while a one-way analysis of variance was performed for comparisons among multiple groups. A \u003cem\u003eP\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 indicated statistically significant differences between groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eComparison of the general data of children in the three groups\u003c/p\u003e\n\u003cp\u003eAmong the 20 children in group A, 8 were female (40%), 12 were male (60%); 5 were term (25%), 15 were premature (75%); 16 (80%) had neonatal respiratory distress syndrome (NRDS), 3 (15%) had meconium aspiration syndrome (MAS), and 1 (5%) had bronchopulmonary dysplasia (BPD). Among the 16 children in group B, 5 were female (31.3%), 11 were male (68.8%); 7 were term (43.7%), and 9 were premature (56.3%); 15 had NRDS (93.8%), and 1 had MAS (6.3%). Among the 15 children in group C, 7 were female (46.7%) and 8 were male (53.3%); 6 were term (40%) and 9 were premature (60%); 9 had NRDS (60%), 5 had MAS (33.3%), and 1 had BPD (6.7%) (Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of general data among the three groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003esex\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eFetal age (weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003epremature birth\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003ePrimary disease\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ewoman\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eman\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNRDS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMAS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.221\u0026nbsp;\u0026plusmn; 3.949\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (31.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (68.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.045\u0026nbsp;\u0026plusmn; 3.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (93.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (6.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.210\u0026nbsp;\u0026plusmn; 4.277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e/F value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e =\u0026nbsp;0.780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF =\u0026nbsp;1.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e =\u0026nbsp;1.574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e =\u0026nbsp;5.458\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.455\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eNRDS, neonatal respiratory distress syndrome; MAS, meconium aspiration syndrome; BPD, bronchopulmonary dysplasia.\u003c/p\u003e\n\u003cp\u003eComparison of the OI in the three groups\u003c/p\u003e\n\u003cp\u003eOI was compared between the three groups before treatment and at different treatment intervals. When compared across different treatment times, the OI varied significantly after 6 h of iNO treatment in group A (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and after 24 h in groups B and C (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At the same treatment interval, the highest decrease in OI was observed in group A, followed by group B, with the decrease in group C being significantly lower than that in group A (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of OI in patients between the three groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epretherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSix hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTwenty-four hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.690\u0026nbsp;\u0026plusmn; 0.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.415\u0026nbsp;\u0026plusmn; 0.593\u003csup\u003e①\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.040\u0026nbsp;\u0026plusmn; 0.410\u003csup\u003e①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.513\u0026nbsp;\u0026plusmn; 1.011\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.456\u0026nbsp;\u0026plusmn; 0.998\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.231\u0026nbsp;\u0026plusmn; 0.448\u003csup\u003ea ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.167\u0026nbsp;\u0026plusmn; 3.211\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.093\u0026nbsp;\u0026plusmn; 3.255\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.973\u0026nbsp;\u0026plusmn; 2.981\u003csup\u003eab ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF =\u0026nbsp;110.74, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003csup\u003e③\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;188.296, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;2016.426, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTime * group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;140.892, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNote: (a) \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with group A; (b) \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; ① \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with group B; ① \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with pre-treatment; ② \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 within group compared with 6 h after treatment; ③ \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Between-group ratio. OI, oxygenation index.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n\u003c/div\u003e\n\u003cp\u003eComparison of PAP among the three pediatric groups\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in PAP between the three groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In group A, the PAP decreased the most at 6 h and 24 h after iNO treatment, followed by group B. The children in group C showed the least change in PAP, which was significantly lower than that in group A (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of PAP among the three groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epretherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSix hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTwenty-four hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.100\u0026nbsp;\u0026plusmn; 1.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.950\u0026nbsp;\u0026plusmn; 1.849\u003csup\u003e①\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.050\u0026nbsp;\u0026plusmn; 1.986\u003csup\u003e①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.313\u0026nbsp;\u0026plusmn; 1.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.063\u0026nbsp;\u0026plusmn; 2.645\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.063\u0026nbsp;\u0026plusmn; 1.982\u003csup\u003ea ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.600\u0026nbsp;\u0026plusmn; 1.183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.467\u0026nbsp;\u0026plusmn; 1.187\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.400\u0026nbsp;\u0026plusmn; 1.639\u003csup\u003ea ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;0.905, \u003cem\u003eP\u003c/em\u003e =\u0026nbsp;0.411*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;333.083, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003etime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;2601.871, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTime * group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;320.625, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNote: (a) \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with group A; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. (b) \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with group B; ① \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with before treatment; ② \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with 6 h after treatment. PAP, pulmonary artery partial pressure. * comparison between groups before the intervention, not statistically significant, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eComparison of SaO\u003csub\u003e2\u003c/sub\u003e among children in the three subgroups\u003c/p\u003e\n\u003cp\u003eSaO\u003csub\u003e2\u003c/sub\u003e was compared between groups at the same interval before and after treatment. Before treatment with iNO, the difference in SaO\u003csub\u003e2\u003c/sub\u003e between the three groups was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After initiation of treatment with iNO, the SaO\u003csub\u003e2\u003c/sub\u003e in the three groups started increasing. Children in group A showed the highest increase in SaO\u003csub\u003e2\u003c/sub\u003e at 6 h and 24 h after treatment, followed by those in group B. Children in group C showed the least change, which was significantly lower than that in the other groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of SaO\u003csub\u003e2\u003c/sub\u003e among the three groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epretherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSix hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTwenty-four hours after treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89.200\u0026nbsp;\u0026plusmn; 0.951\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92.850\u0026nbsp;\u0026plusmn; 0.671\u003csup\u003e①\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95.100\u0026nbsp;\u0026plusmn; 0.968\u003csup\u003e①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.500\u0026nbsp;\u0026plusmn; 0.632\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.688\u0026nbsp;\u0026plusmn; 0.602\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93.188\u0026nbsp;\u0026plusmn; 1.167\u003csup\u003ea ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.067\u0026nbsp;\u0026plusmn; 0.594\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.267\u0026nbsp;\u0026plusmn; 0.884\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92.133\u0026nbsp;\u0026plusmn; 0.743\u003csup\u003eab ①②\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;9.824, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003csup\u003e③\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;106.932, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003etime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;713.689, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTime * group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u0026nbsp;=\u0026nbsp;41.861, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNote: * \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 within the group compared with before treatment, \u003csup\u003ea\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; ① \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 within the group compared with before treatment; ② \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 within group compared with 6 h after treatment. SaO\u003csub\u003e2\u003c/sub\u003e, blood oxygen saturation. ③ Significant difference between groups before treatment with iNO, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eComparison of cure rates in the three groups\u003c/p\u003e\n\u003cp\u003eThe cure rate of children in group A was 85%, followed by group B (75%), whereas the lowest cure rate was observed in group C (46.7%). The difference was statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab7\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 5\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of cure rates among the three groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ecure\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUncured\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e6.161\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs one of the most common critical diseases in NICUs, the incidence of PPHN is related to the economic level of the region. In Western developed countries, the incidence of PPHN is about 1.8\u0026ndash;1.9 per 1000, while that in Asian countries is about 0.5\u0026ndash;4.6 per 1000, with the mortality rate being as high as 20.6%\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Therefore, the diagnosis and treatment of PPHN are among the most popular research priorities today.\u003c/p\u003e \u003cp\u003eEffect of iNO on SaO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMultiple clinical data indicate that iNO plays a significant role in the treatment of PPHN, improvement of OI, and reduction in the rate of ECMO demand. The study of Wan \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e shows that compared with conventional treatment, children with iNO have shorter mechanical ventilation and aerobic treatment and significantly improved blood-gas index, which can more effectively improve the respiratory function of children with PPHN. The study of Yan Xiaoya \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e showed that the PaCO\u003csub\u003e2\u003c/sub\u003e and the mean arterial pressure in children with PPHN were significantly lower than those before treatment with iNO,. The results of these studies corroborate can effectively improve oxygenation and SaO\u003csub\u003e2 after\u003c/sub\u003e 6 h of treatment with iNO, as well as reduce PAP. Clinically, iNO has become the preferred method for the treatment of PPHN, mainly because it can selectively dilate blood vessels, decrease pulmonary artery pressure, and improve oxygenation \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImpact on the PAP\u003c/p\u003e \u003cp\u003e. In the treatment of PPHN, Nitric oxide acts as a vasodilator and regulates PAP mainly. After entering the body, it interacts with nitric oxide synthase (NOS) in the lungs to reduce PAP rapidly.\"Studies have shown that the conventional treatment of PPHN children using mechanical ventilation began to show obvious changes within 12 h, whereas the use of iNO for the treatment of children significantly decreased PAP within 1 h of treatment \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Therefore, NO plays a significant role in regulating the vascular tone and reducing PAP. However, contrary to that study, in groups B and C in our study showed an effective reduction in PAP after 6 hours of iNO treatment. This could be attributed to the higher proportion of preterm infants in these groups and the possibility that iNO had a lower effect on infants with a lower gestational age.\u003c/p\u003e \u003cp\u003eAnalysis of the efficacy of iNO on PPHN under different OI indexes\u003c/p\u003e \u003cp\u003e According to the Guidelines for the Application of Nitric Oxide Inhalation Therapy in NICUs, published by the Neonatologists Branch of the Chinese Medical Doctor Association in 2019, neonates with hypoxemic respiratory failure due to PPHN should be prioritized for iNO treatment at an OI value of 16. OI can be used to assess the severity of hypoxic respiratory failure and is closely related to the prognosis of PPHN. When the OI of neonates with respiratory failure is between 15 and 25, early iNO therapy can alleviate the need for ECMO support or even death compared with children with OI progressing to 30\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Due to the lack of ECMO therapy in our hospital, the condition of some patients worsened, and ECMO cannot be used when OI reaches 40. Moreover, due to the increase in the birth rate of premature infants, they accounted for 66.67% of all cases of PPHN in this study. Therefore, it remains unclear whether iNO therapy can improve the cure rate. Thus, the current recommendation of choosing iNO therapy in premature infants when OI exceeds 16 needs further study.\u003c/p\u003e \u003cp\u003eThis study investigated whether choosing early intervention with iNO when OI reached 12 could more effectively reduce PAP, or whether timely treatment could increase the cure rate and reduce the time of mechanical ventilation before pulmonary hypertension aggravated further and evolved into acute lung injury. A study found that iNO reduced the accumulation of lung neutrophils, as well as the expression of TNF-A and the ratio of IL-10, thereby decreasing lung inflammation and the development of acute respiratory distress\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. As can be seen from the retrospective analysis in this study, children in group A showed the highest decrease in OI after 6 h of iNO treatment. However, the decrease in OI was not obvious in children of groups B and C until 24 h after treatment, suggesting that the effect of iNO treatment was lower at 6 h when OI was \u0026gt;\u0026thinsp;12. Meanwhile, at OI of 12, the effect of iNO treatment was obvious, when the values of SaO\u003csub\u003e2\u003c/sub\u003e and PAP were compared before and after treatment in the three groups. Group A children treated with iNO showed the most increase in SaO\u003csub\u003e2\u003c/sub\u003e at 6 h and 12 h, the PAP showed the highest decrease, and hypoxemia improved significantly at the same treatment time. Moreover, iNO therapy has led to the requirement of mechanical ventilation in a shorter time. Also, the cure rate in group A was significantly higher than that in groups B and C. Therefore, it is reasonable to assume that for preterm infants with a gestational age\u0026thinsp;\u0026gt;\u0026thinsp;28 weeks, iNO therapy at an OI of 12 can more effectively reduce the PAP. The iNO therapy was also fast-acting, with significant improvement in the oxygenation evident within 6 h \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. When OI\u0026thinsp;\u0026gt;\u0026thinsp;12, the effect was slower and no effect was observed within 6 h. Therefore, in PPHN cases, iNO treatment should be performed as soon as possible, when OI\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;12, to decrease the occurrence of acute lung distress, shorten the duration of treatment and hospitalization, and improve the cure rate.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported \u0026nbsp;by \u0026nbsp; Guangxi Science and Technology Major Project （Grant Number. Guike AA22096032）\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWe\u0026nbsp;got the approval\u0026nbsp;of\u0026nbsp;the Third Affiliated Hospital of Guangxi Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; declaration of personal interests:\u003c/p\u003e\n\u003cp\u003eYijin Wang \u0026nbsp;has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Ying Pan \u0026nbsp;has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Jian Ming Li has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003eGuofeng Lan \u0026nbsp;has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003eXiao He \u0026nbsp;has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Xuekai Shi has no conflicts of interest to report with this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYijin Wang: \u0026nbsp;Conceptualization, Methodology, \u0026nbsp;Investigation, Formal Analysis, Writing - Original Draft .\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Ying Pan: \u0026nbsp;Date Curation,\u0026nbsp;Writing - Original Draft .\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Jian Ming: \u0026nbsp;Funding Acquisition,project adiministration \u0026nbsp;.\u003c/p\u003e\n\u003cp\u003eGuofeng Lan: \u0026nbsp;Data curation \u0026nbsp;.\u003c/p\u003e\n\u003cp\u003eXiao He :Visualization, Writing - Review.\u003c/p\u003e\n\u003cp\u003eXuekai Shi\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(Corresponding Author):Conceptualization, Funding Acquisition, Resources, Supervision, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eQian Aimin, Zhu Wen, Yang Yang, etc. Analysis of the early impact factors of death in neonatal infants with persistent pulmonary hypertension treated with nitric oxide inhalation [J]. Chinese Journal of Contemporary Pediatrics, 2022,24 (05): 507-513.\u003c/li\u003e\n\u003cli\u003e. Progress in the diagnosis and treatment of persistent pulmonary hypertension [J]. Jilin Medical, 2021,42 (01): 207-210.\u003c/li\u003e\n\u003cli\u003e. Fangsay, progress in the treatment of persistent pulmonary hypertension in newborn ates [J]. Chinese Electronic Journal of Critical Care Medicine (online edition), 2019,5 (03): 268-273.\u003c/li\u003e\n\u003cli\u003e. Hong Xiaoyang, Hua Shaodong, Kong Xiangyi, and other guidelines for the application of nitric oxide inhalation therapy in neonatal intensive care units (2019 edition) [J]. Electronic Journal of Developmental Medicine, 2019,7 (04): 241-248.\u003c/li\u003e\n\u003cli\u003eKONDURI G G, SOKOL G M, Van MEURS K P, et al. Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure [J]. J Perinatol, 2013,33(12): 944-949.\u003c/li\u003e\n\u003cli\u003eDing Dan, Wang Shijie, Pan Jiahua. Prognostic risk factors affecting nitric oxide inhalation in neonatal treatment of persistent pulmonary hypertension [J]. Chinese General Medicine, 2019, (07): 1157-1160.\u003c/li\u003e\n\u003cli\u003eBARRINGTON K J, FINER N, PENNAFORTE T. Inhaled nitric oxide for respiratory failure in preterm infants [J]. Cochrane Database Syst Rev, 2017,1(1): 509.\u003c/li\u003e\n\u003cli\u003eZhao Min, Li Xianghong, Yin Xiangyun, etc. Comparison of clinical effects of NO inhalation in preterm infants versus term infants [J]. Maternal and Child Health in China, 2023,38 (24): 4842-4846.\u003c/li\u003e\n\u003cli\u003eWan Yang, Zhang Shuqing, Left Jingye, and other clinical effects of nitric oxide inhalation in neonatal treatment of persistent pulmonary hypertension [J]. Practical drugs and clinical, 2019,22 (12): 1288-1291.\u003c/li\u003e\n\u003cli\u003eYan Xiaoyan, Si Xin, Quan Yanhua, etc. The relationship between serum CXCL 8, CXCL12 and the clinical outcome of nitric oxide inhalation therapy in newborns with persistent pulmonary hypertension [J]. Joint Logistic Military Medicine, 2024,38 (01): 26-30.\u003c/li\u003e\n\u003cli\u003eSUN Z, SUN B, WANG X, et al. Anti-inflammatory effects of inhaled nitric oxide are optimized at lower oxygen concentration in experimental Klebsiella pneumoniae pneumonia [J]. Inflammation research : official journal of the European Histamine Research Society ...[et al.], 2016,55(10): 430.\u003c/li\u003e\n\u003cli\u003eYan Chen Yan, Chong Zhang, Manor, etc. Effect of nitric oxide inhalation combined with mechanical ventilation therapy on clinical effect, oxygenation index and disease outcome in children with persistent pulmonary hypertension [J]. PLA Medical Journal, 2021,33 (12): 56-59.\u003c/li\u003e\n\u003cli\u003eSTEINHORN R H, FINEMAN J, KUSIC-PAJIC A, et al. Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial [J]. Journal of Pediatrics, 2016: 90-96.\u003c/li\u003e\n\u003cli\u003e. Wang Weiguo, Zhou Bisheng, Tang Jun female, the effect of nitric oxide inhalation combined with high-frequency oscillatory ventilation in the treatment of neonatal pulmonary hypertension [J]. Clinical Medicine, 2019,39 (11): 29-31.\u003c/li\u003e\n\u003cli\u003e. Progress of Luo Gang, Pantlin ECMO in neonatal persistent pulmonary hypertension [J]. Chinese Journal of Practical Clinical Pediatrics, 2018,33 (02): 157-160.\u003c/li\u003e\n\u003cli\u003eZhao Yanan, Zhang Xiuying, Dong Jing, et al. Effects of nitric oxide inhalation on PaO _ 2, PaCO _ 2, SaO _ 2, SPAP and SBP in neonatal infants with severe pulmonary hypertension [J]. Journal of Rare Diseases, 2023,30 (05): 4-5.\u003c/li\u003e\n\u003cli\u003eBOBBY, MATHEW, SATYAN, et al.Persistent Pulmonary Hypertension in the Newborn.[J].Children, 2017.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Persistent pulmonary hypertension of the newborn, inhaled nitric oxide, oxygenation index","lastPublishedDoi":"10.21203/rs.3.rs-4445013/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4445013/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo analyze the efficacy of inhaled nitric oxide (iNO) in the treatment of neonatal pulmonary hypertension under different oxygenation indexes (OI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective analysis, 51 neonates diagnosed with PPHN and treated with invasive mechanical ventilation at The Second People's Hospital of Nanning and Maternal and Child Health Hospital of Nanning from January 1, 2021, to December 31, 2023, were selected as the study subjects. According to different values of OI, the neonates were divided into three groups; subjects with OI ≤ 12 were categorized into group A (n = 20), 12 \u0026lt; OI ≤ 16 into group B (n = 16), and OI \u0026gt; 16 into group C (n = 15). The OI, oxygen saturation (SaO\u003csub\u003e2\u003c/sub\u003e), pulmonary artery pressure (PAP), duration of iNO treatment, and the time and cure rate of invasive mechanical ventilation were compared between groups A, B, and C after treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparison of OI between the three groups indicated significant changes in group A at 6 h and 24 h after treatment; whereas, there were no significant changes in group B and C at 6 h after treatment, and changes were visible only 24 h after treatment. Among the three groups, the degree of decrease of OI in group A was the highest, followed by group B, and group C was the least, with the differences being statistically significant (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). Moreover, there were no significant differences in PAP and SaO\u003csub\u003e2\u003c/sub\u003e in the three groups before treatment; whereas, after treatment, group A showed the greatest decrease in PAP and the greatest increase in SaO\u003csub\u003e2\u003c/sub\u003e, followed by groups B and C, and the differences were statistically significant (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). Furthermore, a comparison of the durations of NO treatment, mechanical ventilation, and prognosis of children in groups A, B, and C revealed that children in group A needed iNO and mechanical ventilation for the lowest time, followed by those in group B, while children in group C needed iNO and mechanical ventilation for the longest time, with the differences being statistically significant (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). The cure rate of group A was 85.0%, that of group B was 75.0%, and group C was 46.7% (x\u003csup\u003e2 =\u003c/sup\u003e 6.161; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnder different OI conditions, iNO treatment for pulmonary hypertension may produce different curative effects. When OI ≤ 12, iNO treatment can timely improve SaO\u003csub\u003e2\u003c/sub\u003e, reduce PAP, improve the cure rate, shorten the time on the machine, and decrease the treatment cost. When OI \u0026gt; 12, iNO treatment cannot increase SaO\u003csub\u003e2\u003c/sub\u003e significantly or decrease PAP and PaCO\u003csub\u003e2\u003c/sub\u003e timely; mortality rates increased significantly, and the time needed on a ventilator was longer. Therefore, when the OI of children with PPHN reaches 12, iNO should be used as soon as possible to improve the cure rate.\u003c/p\u003e","manuscriptTitle":"Efficacy of inhaled nitric oxide under different oxygenation indexes in neonatal pulmonary hypertension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-24 17:04:03","doi":"10.21203/rs.3.rs-4445013/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ff96595b-b577-4b64-bb06-e35fcdd068a1","owner":[],"postedDate":"July 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-09T09:09:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-24 17:04:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4445013","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4445013","identity":"rs-4445013","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}