Survey of the national clinical practice of inhaled nitric oxide in preterm infants in China

doi:10.21203/rs.3.rs-3272515/v1

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Survey of the national clinical practice of inhaled nitric oxide in preterm infants in China

https://doi.org/10.21203/rs.3.rs-3272515/v1

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Background

To help understand the current clinical practice and provide a reference for the quality improvement of iNO in preterm infants in China.

Methods

A survey on iNO use in preterm infants in neonatal intensive care units was sent to healthcare providers and conducted from January to February 2021.

Results

Of 678 people participated in this survey, 638 were finally included in the analysis. There was no statistical difference (P > 0.05) in iNO use in infants with a gestational age of 28–36 weeks among different types of hospitals; however, iNO use significantly differed in infants with a gestational age of < 28 weeks (P < 0.001). The younger the gestational age of preterm infants, the fewer the respondents who agreed with its use, with only 26.15% of respondents choosing to use iNO in neonates with a gestational age of < 28 weeks. Hypoxic respiratory failure combined with persistent pulmonary hypertension was the main indication for iNO. The majority of investigators (70.77%) used 20 ppm as the initial concentration of iNO therapy in preterm infants.

Conclusion

iNO has been used on preterm infants in some hospitals in China. High-quality clinical evidence is needed to further evaluate the dose, procedure, effectiveness, and safety of iNO in preterm infants.

neonatal pulmonary hypertension

newborns

nitric oxide inhalation therapy

preterm infants

questionnaire

Inhaled nitric oxide (iNO) is the only pulmonary vasodilator approved by the United States Food and Drug Administration (FDA) for persistent pulmonary hypertension of newborns (PPHN) in term, preterm, or near-term infants [1]. Although an article published by the National Institutes of Health concludes that NO needs to be used with caution in preterm infants, the American Thoracic Society and Pediatric Pulmonary Hypertension Guidelines support the individualized use of iNO in preterm infants [2–7]. Indeed, the use of iNO in preterm infants has been increasing since 2000 [3]. A study published in the United States in 2010 reported a 6-fold increase in iNO use between 2000 and 2008 in infants with less than 34 weeks gestation, and the largest increase was observed among infants with 23–26 weeks gestation [8]. There was also a significant increase in the use of iNO in preterm infants in the United States between 2011 and 2016 [9]. Moreover, a survey also showed increasing use of iNO in preterm infants admitted to neonatal units in the United Kingdom between 2010 and 2015 [10].

There are no absolute indications for iNO in preterm infants, and no evidence-based guidelines are available to guide clinical practice regarding the timing and use of iNO. In a Japanese survey on iNO in extremely preterm infants, the investigators used the concentration of inhaled oxygen (FiO₂), the difference in oxygen saturation between the upper and lower extremities, and the oxygenation index as initiation criteria for iNO treatment in extremely preterm infants, and the concentrations and gradients chosen for the continued or discontinued use of iNO varied [11].

However, in China, there are few national studies on iNO treatment in preterm infants, and there is no detailed expert consensus as those available for term infants. Thus, the Neonatologists Branch of the Chinese Medical Association organized a national survey to help understand the current clinical practice of iNO in preterm infants in China. The study aims to understand the process, indications, contraindications, and other relevant information regarding the use of iNO in preterm infants in various provinces and levels of hospitals in China, to determine the practices of health care professionals at all levels of hospitals, and thus to understand the current status of iNO use in preterm infants in China and to infer differences in the methods of use. It can then provide an understanding of the current clinical practice, which may provide a reference for the quality improvement of iNO therapy in preterm infants.

After a comprehensive literature review and discussions with three experts with ≥ 20 years of neonatal intensive care unit (NICU) experience, we designed a questionnaire using an online survey platform (Questionnaire Star), which was sent by the Neonatologists Branch of the Chinese Medical Association to neonatologists nationwide via Wechat.

This questionnaire comprises three main sections: basic information about the respondent, current opinions of using iNO in preterm infants with different gestational ages, and the application and treatment process of iNO in preterm infants. The survey was conducted between January and February 2021, and the link to the questionnaire was posted on social platforms such as WeChat. A total of 678 questionnaires were distributed; after excluding questionnaires from investigators who did not work in the NICU, a total of 638 valid questionnaires were collected, with a valid return rate of 94.1% (638/678).

The results of the collected questionnaire were sent to five respiratory therapists who had bedside work experience for at least one year and used iNO for ≥ 5 neonatal patients per year, and the feedbacks were combined. Questionnaires were collected regarding the diagnosis of pulmonary hypertension in preterm infants, the use of iNO in different hospitals for preterm infants with different gestational ages, and the indications and procedures for iNO use. De-identified demographic information was also collected (the questionnaire can be found in the supplementary material [appendix 1]). Some questions had multiple choices, allowing the investigator to select one or more answers as needed.

All statistical analyses were performed using SPSS. Descriptive statistics were computed to present qualitative data as the total number, percentage of those who responded, and percentage of total responses (for multi-selection questions) to each question. Thus, the total number of responses for each question may differ from the total number of participants. Chi-square test was used to examine differences between categories, and p-values < 0.05 were considered statistically significant.

Demographics

Of the 638 participants included, 351 (55.0%) worked in units without iNO devices, and 27 (4.2%) worked in units with iNO devices that were never used; thus, they completed only the first part of the questionnaire. In total, 260 (40.8%) completed the entire questionnaire.

The 260 respondents came from 26 provinces and 65 cities (Fig. 1), and the first-tier cities accounted for 66.9%. Furthermore, of these 260 respondents, 96.92% were from grade-A tertiary hospitals, 76.92% (200/260) were doctors, 21.92% (57/260) were nurses, and only 1.15% (3/260) were respiratory therapists. Moreover, 93.08% (242/260) worked in teaching hospitals, 54.62% (142/260) were senior-level healthcare workers, and 53.46% (139/260) were postgraduates (Table 1).

FIGURE 1 Sample statistics by province

TABLE 1 Factors influencing the current status of iNO use among preterm infants [persons (%)]

Proportions of children with different gestational ages who used iNO

For infants with a gestational age of 34–36 weeks, 91.92% (239/260) of the respondents chose to use iNO, and for preterm infants with a gestational age of 28–33^+ 6 weeks, 70.38% (183/260) of the respondents used iNO. However, for extremely preterm infants with a gestational age of < 28 weeks, only 28.15% of the respondents used iNO. The lower the gestational age, the lower the choice of use. The use of iNO in infants of different gestational ages had no statistical difference between teaching and non-teaching hospitals (p > 0.05). Moreover, among infants with a gestational age of < 28 weeks, the use of iNO was slightly different in different types of hospitals, including general hospitals, children's hospitals, women's and children's specialty hospitals, and maternal and child health hospitals (Tables 2–5).

Table 2 Use of nitric oxide in children of different gestational ages in teaching and non-teaching hospitals [persons (%)]

Table 3 Use of nitric oxide in children < 28 weeks in different types of hospitals [persons (%)]

Table 4 Nitric oxide use among children at 28–33 weeks in different types of hospitals [persons (%)]

Table 5 Nitric oxide use among children at 34–36 weeks in different types of hospitals [persons (%)]

Diagnosis of pulmonary hypertension and assessment of outcomes

In total, 97.69% (254/260) of the respondents diagnosed pulmonary hypertension based on echocardiography, 93.08% (242/260) based on pre-ductal and post-ductal oxygen saturation (SpO₂) differences, 92.31% (240/260) based on the clinical presentation of the patient, and 78.85% (205/260) based on the patient's oxygenation index (OI).

Furthermore, echocardiography was used to assess the efficacy during iNO treatment. Approximately 6.9% (18/260) of the respondents chose to repeat echocardiography within 12 h, 24.49% (64/260) once every 12–24 h, and 22.86% (59/260) once every 24–48 h; 5.71% (15/260) of the respondents chose to repeat echo once every 48–72 h, and 40% (104/260) chose to decide the frequency of ultrasound according to the patient's clinical condition.

Respondents' opinions on the indications for iNO

The top 4 indications for iNO were hypoxic respiratory failure in the presence of PPHN (98.08%, 255/260), PPHN secondary to meconium aspiration syndrome (95.0%, 247/260), PPHN secondary to respiratory distress syndrome in preterm infants (80.0%, 208/260), and PPHN secondary to birth asphyxia (70.46%, 183/260) (Table 6).

Table 6 Respondents' views on iNO indications[persons (%)]

Respondents' opinions on contraindications for iNO

The top four contraindications for iNO were severe haemorrhages, such as intracranial haemorrhage, intraventricular haemorrhage, and pulmonary haemorrhage (87.31%, 227/260); congenital methemoglobinemia (79.62%, 207/260); fatal congenital defects and congestive heart failure (78.85%, 205/260); and severe left heart dysplasia or arterial catheter-dependent congenital heart disease (78.85%, 205/260). Notably, 53.46% (139/260) of the investigators considered gestational age ≤ 28 weeks as a contraindication for the use of iNO, and 23.46% (61/260) considered gestational age ≤ 34 weeks as a contraindication for iNO (Table 7).

Table 7 Respondents' views on iNO contraindications[persons (%)]

Selection of different medications in the treatment of pulmonary hypertension

The results of the survey on the use of iNO and other medications for the treatment of pulmonary hypertension in preterm infants showed that 91.2% (237/260) of the investigators had used sildenafil, followed by iNO (84.6%, 220/260), and other drugs used included milrinone (70.0%, 182/260), prostacyclin (26.5%, 69/260), magnesium sulphate (24.6%, 64/260), phentolamine (24.2%, 63/260), and bosentan (17.7%, 46/260). Notably, the proportion of sildenafil use was even higher than that of iNO use (91.2% vs. 84.6%).

Current status of the process for investigators using iNO

In total, 82.4% (214/260) of the respondents' hospitals had a protocol for iNO use. For the initial iNO concentration used for preterm infants, 70.77% (184/260) of the investigators chose 20 ppm, and 16.54% (43/260) chose 10 ppm.

For weaning NO criteria, 74.36% (193/260) of the respondents chose pulse oxygen saturation between 90–94%, 65.0% (193/260) chose no difference between pre- and post-ductal oxygen saturation, 58.08% (151/260) chose arterial partial pressure of oxygen (PaO₂) greater than 60–80 mmHg, 48.46% (126/260) chose ultrasound clarification of normal pulmonary artery pressure, 41.54% (108/260) chose OI < 10 when PaO₂ reached 80–100 mm Hg, and 27.69% (72/260) opted for PaO₂ > 80–100 mm Hg. Others chose FiO₂ concentration < 60% (2.89%, 75/260), FiO₂ concentrations < 40% (1.92%, 50/260), and improvement of primary disease (0.96%, 25/260).

For weaning NO, 61.92% (161/260) of the respondents preferred to decrease FiO₂ concentration, and 66.46% (173/260) chose to decrease iNO concentration when the inhalation oxygen concentration was decreased to 0.4–0.6. Moreover, 38.08% (99/260) preferred to decrease NO concentration first, and approximately half of the respondents (50.51% [131/260]) chose to decrease FiO₂ when the iNO concentration was weaned down to 6–10 ppm.

Most of the respondents (93.08%, 242/260) chose to decrease iNO in increments of 1–5 ppm, 4.62% (12/260) chose to decrease iNO in increments of 6–10 ppm, 0.38% (1/260) chose to decrease iNO in increments of 11–5 ppm, and 1.92% (50/260) of the respondents chose to reduce from 20 to 10, then to 5, and thereafter by 1 ppm each time.

When treatment with iNO remained ineffective for 12 h, 36.15% (94/260) would consider withdrawing it, 33.46% (87/260) after 6 h, 14.62% (38/260) after 1 h, and 5.38% (140/260) after 30 minutes; however, 10.38% (27/260) would choose to continue using it regardless of its effectiveness (Fig. 2).

iNO has been demonstrated to improve oxygenation and reduce mortality or the incidence of extracorporeal membrane pulmonary oxygenation in near-term infants with hypoxic respiratory failure who do not respond to conventional therapy [12–17]. iNO has been approved by the FDA for use in newborns with a gestational age of < 35 weeks who have hypoxic respiratory failure due to pulmonary hypertension [1]. This study showed that 91.9% of respondents had used iNO in infants with a gestational age of 34–37 weeks.

Studies in the United States and Europe showed that 40–46% of all infants treated with NO had a gestational age of < 34 weeks [18, 19]. A study in British found that 31% of all iNO was applied to infants with a gestational age of < 29 weeks, and 18% was used for infants with a gestational age of 29–33 weeks [10]. The majority of preterm infants with iNO use in the United States during 2004–2016 were those with a gestational age of < 27 weeks, and the use of iNO among infants with a gestational age of ≤ 24 weeks increased from 19.8–22.7% during 2011–2016 compared with 2004–2010.[9] The Canadian Neonatal Collaborative Network reported in 2015 that The proportion of neonates who received iNO in the 22–25, 26–29, and 30–33 weeks' GA groups was 16.1, 6.0, and 1.3%, respectively [20]. Our results showed that the younger the gestational age, the lower the number of people who had used it; only approximately 26.2% (68/260) used iNO in infants with a gestational age of < 28 weeks, and gestational ages < 34 and < 28 weeks were considered contraindications for iNO by 23% and 53% of the investigators, respectively.

Regarding the safety of iNO in preterm infants, accumulating evidence suggests that neither rescue nor routine NO use improves survival in preterm infants with respiratory failure, but NO treatment is effective and safe in preterm infants with combined PPHN [21]. For example, a study published in 2005 showed that iNO did not reduce mortality or the incidence of bronchopulmonary dysplasia (BPD) in preterm infants with a gestational age of < 34 weeks who had severe respiratory failure [22]. A study published by Cochrane in 2017 found that iNO used within 3 days of birth or after 3 days did not significantly decrease mortality or BPD incidence in preterm infants [23]. However, these studies did not specifically address PPHN; therefore, the results were limited. In infants with combined PPHN, guidelines published by the American Heart Association and the American Thoracic Society in 2015 mention that iNO may be effective for hypoxemia due to PPHN, especially in preterm infants with combined premature rupture of membranes and low amniotic fluid [4]. The 2016 Pediatric PPHN Collaborative Network also mentions that NO is safer for preterm infants than other pulmonary vasodilators [2]. Moreover, in preterm infants with severe respiratory distress syndrome combined with PPHN and respiratory failure combined with PPHN, there was a significant improvement in oxygenation after NO treatment [24, 25]. Therefore, we should explore the application and long-term prognosis of iNO in preterm infants with combined PPHN in the future.

Data from the NO-CLD (nitric oxide [to prevent] chronic lung disease) trial suggested that iNO is safe and does not increase lung inflammation or oxidative stress [26–29]. Moreover, one study found that in preterm infants, methemoglobinemia (MetHb > 5%) hardly occurred at iNO < 10 ppm; methaemoglobin could be maintained in a safe range (< 2.5%) when iNO < 8 ppm, and blood sampling for MetHb assessment could be avoided.[30] If therapeutic concentrations of iNO < 20 ppm in term or near-term infants and iNO < 10 ppm in preterm infants are followed, the level of methaemoglobin will be low [30].

For the diagnostic criteria of pulmonary hypertension, most respondents used ultrasound findings, clinical manifestations, pre- and post-ductal oxygen saturation/partial pressure difference, and oxygenation index. Diagnosis by echocardiography alone can be difficult because preterm infants have patent foramen ovale and patent ductus arteriosus, may have shunts, and are more hemodynamically unstable than full-term infants [31]. It has been suggested that pulmonary hypertension in preterm infants needs to be diagnosed with a combination of the clinical presentation (e.g., > 10% pre- and post-ductal oxygen saturation difference) and ultrasound findings [32]. The findings are similar to ours.

For preterm infants who developed pulmonary hypertension, our results showed that a higher proportion of respondents chose sildenafil for initial treatment than iNO (91.15% vs. 84.62%). This finding may be related to the fact that the indications, safety, and efficacy of iNO in preterm infants are still unclear, and iNO is expensive and not easily accessible [33].Moreover, some studies have shown that approximately 40% of preterm infants do not respond to iNO or have unimproved oxygenation [33]. Therefore, clinicians use pharmacologic alternatives, including systemic and inhaled vasodilators (i.e., prostaglandin E1, prostacyclin), endothelin antagonists, milrinone, magnesium sulphate, and phosphodiesterase type 5 inhibitors (i.e., sildenafil[34, 35]). Among these potential medications, sildenafil is widely used as an alternative to iNO in less developed countries [36]. However, the FDA issued safety recommendations against the use of sildenafil in paediatric patients aged 1–17 years in 2012 but did not mention the risks of using sildenafil in neonates, especially in preterm infants [37]. Several meta-analyses have confirmed the efficacy of sildenafil in neonates, suggesting that sildenafil may be an alternative to iNO for the rescue of term and preterm infants with PPHN, especially in resource-limited areas [34, 38–40]. Moreover, three randomized controlled trials (RCTs) showed a significant reduction in mortality in the sildenafil group compared with the blank control group [41–43], and two RCTs revealed improved oxygenation in the sildenafil group [42, 43]. he third most selected drug choice (70%) is milrinone, which improves oxygenation and right and left ventricular function. in infants with severe PPHN [44–46]. However, milrinone may lower systemic blood pressure and cause systemic hypotension [47], which may further impair myocardial perfusion and worsen cardiac function. Thus, these complications need to be closely monitored in users of milrinone.

We found that 82.4% of the survey respondents' hospitals had a protocol for iNO use; this may be related to the reference protocol provided in the Guidelines for the Use of Nitric Oxide Inhalation Therapy in the Neonatal Intensive Care Unit. In addition, a study proposed a process in which evacuation would not be attempted in neonates until PaO₂ > 50 mmHg and pulse oximetry > 90% 10 to 14 h after the start of iNO therapy; the finding is consistent with that in this study, which showed that 74.36% of respondents chose to achieve a pulse oxygen saturation of 90–94% [22]. If the oxygenation index was ≤ 5, an evacuation was attempted every 4 to 8 h [22]. A successful evacuation was defined as a decrease in PaO2 of ≤ 20 mmHg and a value of ≥ 50 mmHg with oxygen saturation greater than 90%, 30 minutes after the attempted evacuation [22]. Several studies found that most preterm infants had an onset of action 30 min–6 h after iNO [7, 48–51]. For infants with ineffective NO therapy, sudden evacuation may be an option within 30 min of exposure and does not cause a decrease in oxygenation [52]. In contrast, 36.15% of respondents in this study would consider the evacuation of NO when it was still ineffective after 12 h of use, which may be related to the lack of knowledge about the onset of NO. Moreover, there is no common standard for the initial concentration of iNO when used in preterm infants; several current retrospective studies found that the minimum starting concentration was 5 ppm, the highest starting concentration was 30 ppm, and the maximum setting concentration for use was 40 ppm [5, 48, 49, 53]. These findings suggest that the starting concentration varies from 5 ppm to > 20 ppm, and this inconsistent variation warrants further investigation in a high-quality study.

In summary, although there is a lack of high-quality evidence to support the use of iNO in preterm infants, it is still being used in some hospitals in different ways in China. More robust longitudinal studies and RCTs are needed to further evaluate the efficacy, dosage, process, and safety of iNO to support the use of iNO in preterm infants.

This study has several limitations. Because this study did not have a strict sampling design and mainly investigated medical and nursing staff in tertiary care hospitals, with a smaller proportion in secondary care hospitals, the results might not be fully representative of the current status of iNO use among preterm infants in China. To compensate for the lack of timeliness, we plan to conduct a survey every five years to dynamically track the changes in iNO use among preterm infants in China.

iNO inhaled nitric oxide

FDA Food and Drug Administration

PPHN persistent pulmonary hypertension of newborns

NICU neonatal intensive care unit

OI oxygenation index

PaO₂ arterial partial pressure of oxygen

BPD bronchopulmonary dysplasia

NO-CLD nitric oxide [to prevent] chronic lung disease

RCT randomized controlled trial

Ethics approval and consent to participate

The study was approved by the ethics committee of the West China Second University Hospital of Sichuan University (Ethics approval number: 2021–011). Verbal consent was obtained from all participants. All respondents participated voluntarily and were informed that the survey data would be used for publication. The completion of the questionnaire means that the verbal consent is signed. The study does not involve individual privacy and it is not harmful to the individual. The procedures for verbal consent were approved by the ethics committee of the West China Second University Hospital of Sichuan University.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declared that they have not competing interest.

Funding

The authors have not declared a specific grant for this research from any fund- ing in the public, commercial or not-for-profit sectors.

Authors' contributions

Tian Ke conceptualized, designed, analyzed and wrote the first draft and prepared all the figures and tables. Gong Lingyue, Huang Yi and Tang Jun reviewed and revised the manuscript. All authors read and approved the final manuscript.

Mandell E, Kinsella JP, Abman SH: Persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 2021, 56(3):661-669.
Kinsella JP, Steinhorn RH, Krishnan US, Feinstein JA, Adatia I, Austin ED, Rosenzweig EB, Everett AD, Fineman JR, Hanna BD et al: Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. J Pediatr 2016, 170:312-314.
Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV et al: NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 2011, 127(2):363-369.
Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D et al: Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation 2015, 132(21):2037-2099.
Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE, Stevenson DK: Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol 2009, 26(4):317-322.
de Waal K, Kluckow M: Prolonged rupture of membranes and pulmonary hypoplasia in very preterm infants: pathophysiology and guided treatment. J Pediatr 2015, 166(5):1113-1120.
Baczynski M, Ginty S, Weisz DE, McNamara PJ, Kelly E, Shah P, Jain A: Short-term and long-term outcomes of preterm neonates with acute severe pulmonary hypertension following rescue treatment with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed 2017, 102(6):F508-f514.
Clark RH, Ursprung RL, Walker MW, Ellsbury DL, Spitzer AR: The changing pattern of inhaled nitric oxide use in the neonatal intensive care unit. J Perinatol 2010, 30(12):800-804.
Peluso AM, Othman HF, Karnati S, Sammour I, Aly HZ: Epidemiologic evaluation of inhaled nitric oxide use among neonates with gestational age less than 35 weeks. Pediatr Pulmonol 2022, 57(2):427-434.
Subhedar NV, Jawad S, Oughham K, Gale C, Battersby C: Increase in the use of inhaled nitric oxide in neonatal intensive care units in England: a retrospective population study. BMJ Paediatr Open 2021, 5(1):e000897.
Shiraishi J, Kusuda S, Cho K, Nakao A, Hiroma T, Sugiura H, Suzuki S, Oshiro M, Yoshimoto S, Watabe S: Standardization of nitric oxide inhalation in extremely preterm infants in Japan. Pediatr Int 2019, 61(2):152-157.
Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997, 336(9):597-604.
Wang X, Li B, Ma Y, Zhang H: Effect of NO inhalation on ECMO use rate and mortality in infants born at or near term with respiratory failure. Medicine (Baltimore) 2019, 98(41):e17139.
Hoffman GM, Ross GA, Day SE, Rice TB, Nelin LD: Inhaled nitric oxide reduces the utilization of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Crit Care Med 1997, 25(2):352-359.
Barrington KJ, Finer N, Pennaforte T, Altit G: Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017, 1(1):Cd000399.
Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, Fenton AC, Subhedar N, Ahluwalia J, Halliday HL, Stocks J et al: Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005, 115(4):926-936.
Christou H, Van Marter LJ, Wessel DL, Allred EN, Kane JW, Thompson JE, Stark AR, Kourembanas S: Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Crit Care Med 2000, 28(11):3722-3727.
Ellsworth MA, Harris MN, Carey WA, Spitzer AR, Clark RH: Off-label use of inhaled nitric oxide after release of NIH consensus statement. Pediatrics 2015, 135(4):643-648.
Dewhurst C, Ibrahim H, Göthberg S, Jónsson B, Subhedar N: Use of inhaled nitric oxide in the new born period: results from the European Inhaled Nitric Oxide Registry. Acta Paediatr 2010, 99(6):854-860.
Soraisham AS, Harabor A, Shivananda S, Alvaro R, Ye XY, Lee SK, Shah PS: Trends and Variations in the Use of Inhaled Nitric Oxide in Preterm Infants in Canadian Neonatal Intensive Care Units. Am J Perinatol 2016, 33(7):715-722.
Kumar P: Use of inhaled nitric oxide in preterm infants. Pediatrics 2014, 133(1):164-170.
Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, Higgins RD, Oh W, Hudak ML et al: Inhaled Nitric Oxide for Premature Infants with Severe Respiratory Failure. N Engl J Med 2005, 353(1):13-22.
Barrington KJ, Finer N, Pennaforte T: Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2017, 1(1):Cd000509.
Dani C, Corsini I, Cangemi J, Vangi V, Pratesi S: Nitric oxide for the treatment of preterm infants with severe RDS and pulmonary hypertension. Pediatr Pulmonol 2017, 52(11):1461-1468.
Suzuki S, Togari H, Potenziano JL, Schreiber MD: Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience. J Perinat Med 2018, 46(6):657-663.
Truog WE, Ballard PL, Norberg M, Golombek S, Savani RC, Merrill JD, Parton LA, Cnaan A, Luan X, Ballard RA: Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics 2007, 119(4):670-678.
Ballard PL, Merrill JD, Truog WE, Godinez RI, Godinez MH, McDevitt TM, Ning Y, Golombek SG, Parton LA, Luan X et al: Surfactant function and composition in premature infants treated with inhaled nitric oxide. Pediatrics 2007, 120(2):346-353.
Ballard PL, Truog WE, Merrill JD, Gow A, Posencheg M, Golombek SG, Parton LA, Luan X, Cnaan A, Ballard RA: Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants. Pediatrics 2008, 121(3):555-561.
Posencheg MA, Gow AJ, Truog WE, Ballard RA, Cnaan A, Golombek SG, Ballard PL: Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. J Perinatol 2010, 30(4):275-280.
Hamon I, Gauthier-Moulinier H, Grelet-Dessioux E, Storme L, Fresson J, Hascoet JM: Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr 2010, 99(10):1467-1473.
Vieira F, Makoni M, Szyld E, Sekar K: The Controversy Persists: Is There a Qualification Criterion to Utilize Inhaled Nitric Oxide in Pre-term Newborns? Front Pediatr 2021, 9:631765.
Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ: Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr Res 2017, 82(6):901-914.
Ahmed MS, Giesinger RE, Ibrahim M, Baczynski M, Louis D, McNamara KP, Jain A, Weisz DE, McNamara PJ: Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxic preterm neonates. J Paediatr Child Health 2019, 55(7):753-761.
Unegbu C, Noje C, Coulson JD, Segal JB, Romer L: Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors. Pediatrics 2017, 139(3).
Stultz JS, Puthoff T, Backes C, Jr., Nahata MC: Intermittent intravenous sildenafil for pulmonary hypertension management in neonates and infants. Am J Health Syst Pharm 2013, 70(5):407-413.
Trottier-Boucher MN, Lapointe A, Malo J, Fournier A, Raboisson MJ, Martin B, Moussa A: Sildenafil for the Treatment of Pulmonary Arterial Hypertension in Infants with Bronchopulmonary Dysplasia. Pediatr Cardiol 2015, 36(6):1255-1260.
Jiang L, Sun W, Zhang K, Zhou B, Kong X: Perioperative Sildenafil Therapy in Pediatric Congenital Cardiac Disease Patients. Int Heart J 2018, 59(6):1333-1339.
Perez KM, Laughon M: Sildenafil in Term and Premature Infants: A Systematic Review. Clin Ther 2015, 37(11):2598-2607.e2591.
Gao XF, Zhang JJ, Jiang XM, Ge Z, Wang ZM, Li B, Mao WX, Chen SL: Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials. Patient Prefer Adherence 2017, 11:871-885.
Kelly LE, Ohlsson A, Shah PS: Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2017, 8(8):Cd005494.
Al Omar S, Salama H, Al Hail M, Al Rifai H, Bunahia M, El Kasem W, Siddiqui FJ, Dilawar M, Yassin H, Masud F et al: Effect of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. A feasibility study. J Neonatal Perinatal Med 2016, 9(3):251-259.
Baquero H, Soliz A, Neira F, Venegas ME, Sola A: Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006, 117(4):1077-1083.
Vargas-Origel A, Gómez-Rodríguez G, Aldana-Valenzuela C, Vela-Huerta MM, Alarcón-Santos SB, Amador-Licona N: The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010, 27(3):225-230.
Bassler D, Choong K, McNamara P, Kirpalani H: Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate 2006, 89(1):1-5.
McNamara PJ, Laique F, Muang-In S, Whyte HE: Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 2006, 21(2):217-222.
James AT, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF: The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension. Cardiol Young 2016, 26(1):90-99.
Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL: Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995, 23(11):1907-1914.
Favilli S, De Simone L, Pollini I, Bettuzzi MG, Cianfrini D, Crepaz R, Santillo V, Trevisanuto D, Vignati G, Manetti A: 145. G Ital Cardiol 1998, 28(11):1247-1252.
Rallis D, Deierl A, Atreja G, Chaban B, Banerjee J: The efficacy of inhaled nitric oxide treatment in premature infants with acute pulmonary hypertension. Early Hum Dev 2018, 127:1-5.
Kettle R, Subhedar NV: Nitric Oxide in Pulmonary Hypoplasia: Results from the European iNO Registry. Neonatology 2019, 116(4):341-346.
Rhine WD, Suzuki S, Potenziano JL, Escalante S, Togari H: An Analysis of Time to Improvement in Oxygenation in Japanese Preterm and Late Preterm or Term Neonates With Hypoxic Respiratory Failure and Pulmonary Hypertension. Clin Ther 2019, 41(5):910-919.
Carriedo H, Rhine W: Withdrawal of inhaled nitric oxide from nonresponders after short exposure. J Perinatol 2003, 23(7):556-558.
Uga N, Ishii T, Kawase Y, Arai H, Tada H: Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr Int 2004, 46(1):10-14.

Tables are available in the Supplementary Files section.

No competing interests reported.

questionaire.docx
Appendix 1
TABLE1.xlsx
TABLE 1 Factors influencing the current status of iNO use among preterm infants [persons (%)]
TABLE2.xlsx
TABLE 2 Use of nitric oxide in children of different gestational ages in teaching and non-teaching hospitals [persons (%)]
TABLE3.xlsx
TABLE 3 Use of nitric oxide in children <28 weeks in different types of hospitals [persons (%)]
TABLE4.xlsx
TABLE 4 Nitric oxide use among children at 28-33 weeks in different types of hospitals [persons (%)]
TABLE5.xlsx
TABLE 5 Nitric oxide use among children at 34-36 weeks in different types of hospitals [persons (%)]
TABLE6.xlsx
TABLE 6 Respondents' views on iNO indications[persons (%)]
TABLE7.xlsx
TABLE 7 Respondents' views on iNO contraindications[persons (%)]

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Survey of the national clinical practice of inhaled nitric oxide in preterm infants in China

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