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 Table of Contents  
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 19-24

Inhaled nitric oxide therapy for pulmonary arterial hypertension of newborn: Eight-year experience of a level IIIB unit

Department of Neonatology, Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, India

Date of Submission04-Oct-2021
Date of Acceptance03-Dec-2021
Date of Web Publication08-Feb-2022

Correspondence Address:
Dr. Femitha Pournami
Department of Neonatology, Kerala Institute of Medical Sciences, Thiruvananthapuram - 695 029, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/arwy.arwy_57_21

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Background: Inhaled nitric oxide (iNO) has been in use for several decades now in neonates with hypoxic respiratory failure (HRF) associated with pulmonary hypertension (PH). Its requirement is uncommon, and is considered as an advanced form of support that is not widely available. Analysis of outcomes in specific settings, notably from low-middle income countries, is crucial. Objectives: To evaluate the patient profile and outcomes of neonates treated with iNO in our Level IIIB unit. Methods: This retrospective observational study describes the clinical diagnosis, management strategies and short-term outcomes of all neonates who received iNO in the years between 2013 and 2021. Details were retrieved from Electronic Medical Records and systematically analysed. Observation: Of 35 infants who received iNO during the study period, 31 (88.6%) were >34 weeks. The median and interquartile range (IQR) of oxygenation index at which iNO was started was 28 (20,33). The median (IQR) duration of iNO therapy was 48 (23,95) hours. Overall, 18 neonates (51.4%) survived till hospital discharge. Therapeutic response was best observed in infants with HRF secondary to meconium aspiration syndrome or congenital pneumonia (100% survival). Though the benefits of iNO use in congenital diaphragmatic hernia and bronchopulmonary dysplasia associated with PH are debatable, its use continues as a rescue measure. Conclusion: iNO is used in severe HRF associated with PH in neonates and can improve survival rates in select patient profiles without any major adverse outcomes.

Keywords: Hypoxic respiratory failure, inhaled nitric oxide, oxygenation index, pulmonary hypertension of newborn

How to cite this article:
Anand V, Pournami F, Prithvi AK, Nandakumar A, Prabhakar J, Jain N. Inhaled nitric oxide therapy for pulmonary arterial hypertension of newborn: Eight-year experience of a level IIIB unit. Airway 2022;5:19-24

How to cite this URL:
Anand V, Pournami F, Prithvi AK, Nandakumar A, Prabhakar J, Jain N. Inhaled nitric oxide therapy for pulmonary arterial hypertension of newborn: Eight-year experience of a level IIIB unit. Airway [serial online] 2022 [cited 2023 Jun 4];5:19-24. Available from: https://www.arwy.org/text.asp?2022/5/1/19/337415

  Introduction Top

There is probably no event in a human being's life span that is more dramatic than birth itself. Aeration of lungs with the first breaths leads to a multitude of changes that eventually result in smooth transition from intrauterine to extrauterine existence. One of the most crucial changes is the decrease in pulmonary arterial pressure. Blood flow to the lungs after birth must increase by nearly 8-fold with oxygenation of the alveoli.[1] However, there are several factors (not always identifiable) whose consequence can be persistent pulmonary hypertension of the neonate (PPHN). PPHN is typically secondary to underlying severe hypoxic respiratory failure (HRF) due to various aetiologies, multiorgan failure or systemic disease such as sepsis.[2] Idiopathic PPHN is a dilemma, and the role of genetics is being increasingly recognised. Infants with PPHN are often very sick. Various modalities of advanced supports are hence directed to reverse the pathophysiology. As is the case with most neonatal intensive care therapies, the physician aims at maximising benefits while minimising risks. Many drugs are used for PPHN either serially or consecutively.[3] Nitric oxide is an endogenous signalling molecule with several biological functions. Its role in PPHN is in the regulation of pulmonary vascular tone.[4]

When therapeutically administered, inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator which binds quickly to haemoglobin and therefore has negligible systemic effects. iNO has been in use for several decades now after its approval for use in late preterm and term neonates.[2] There is controversy surrounding its use in preterm infants, but off-label use continues across the world in extremely sick neonates as rescue therapy even in this group.[5] It is notable that this form of therapy is not widely available across India, where (ironically) the most deserving sick babies are not uncommon.[6] Scientific literature pertaining to its use in low-middle income countries could contribute to advocacy towards its availability in units which care for sick neonates.

Ours is a Level IIIB unit (National Neonatology Forum India accredited) which cares for sick inborn neonates, as well as those referred from middle to south Kerala, nearby districts of Tamil Nadu and Maldives. This manuscript describes our experience with the use of iNO from 2013 to 2021 and discusses literature regarding current patterns of use.

  Methods Top

The unit has the facility to provide advanced ventilation including high-frequency oscillatory ventilation (HFOV) and iNO therapy. It also has the capability of providing extracorporeal membrane oxygenation (ECMO) in infants. iNO is commenced as rescue therapy in late preterm and term neonates who have HRF and clinical indicators of PPHN.

Echocardiography was performed by a cardiologist before or at least within 12 h of initiation of therapy (we did not wait for an echocardiography diagnosis for commencement of therapy if the clinical setting was strongly suggestive of PPHN). iNO was used if response of HRF to high degree of support from conventional ventilation or HFOV was suboptimal). Details of the clinical diagnosis, management strategies and short-term outcomes were systematically analysed.

  Results Top

During the study duration, there were 7681 admissions to the Neonatal Intensive Care Unit (NICU). Of these, 35 infants received iNO therapy for pulmonary hypertension (PH). Baseline characteristics are presented in [Table 1]. It is important to note that 65.7% of these were referred with refractory HRF from other units. We used iNO in only four babies who were <34 weeks gestation at birth.
Table 1: Baseline maternal and neonatal data (n=35)

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The overall survival among these 35 infants till hospital discharge was 51.4%. The outcome was remarkably different based on the primary cause for PH/indication for use of iNO [Table 2]. All those who were diagnosed with meconium aspiration syndrome (MAS) or congenital pneumonia had an extremely favourable outcome (100% survived).
Table 2: Aetiologies of pulmonary hypertension for which inhaled nitric oxide was used and survival

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Particulars relevant to iNO use and other supportive therapies in these sick neonates are presented in [Table 3]. The median interquartile range (IQR) of oxygenation index (OI = [FIO2 × Mean airway pressure/PaO2] × 100) at which iNO was started was 28 (20,33). There were 4 babies where the OI was ≥40 at the start of therapy, 3 of whom died. While one of these infants had severe perinatal asphyxia, 2 had sepsis with multiorgan dysfunction syndrome. All 4 had features of disseminated intravascular coagulopathy and could not be considered for ECMO. In 37.1% cases, the unit commenced the therapy on day 1 of life. Most of the others were received in the unit after several hours of ventilation/oxygen therapy was tried in the referring units. The median (IQR) of duration of iNO therapy was 48 (23,95) hours. One neonate was planned for ECMO, but the parents refused consent in view of risk of stroke/intracerebral bleed. She eventually improved on prolonged ventilation with iNO therapy and was discharged home.
Table 3: Particulars relevant to pulmonary hypertension and use of inhaled nitric oxide

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In none of the situations did we need to discontinue therapy for high nitrogen dioxide alarms or suspected methemoglobinaemia.

In the last available follow-up of the 18 survivors, 2 were lost to follow-up. Normal neurodevelopmental outcome was noted in 12 infants at 2 years of age; 3 had gross motor delay in development and 1 had cerebral palsy.

  Discussion Top

In our case series covering a period of 8 years, iNO was used in 35 neonates (0.46% of all neonatal admissions during the study period). Most larger reports of the use of iNO are either based on National data or multicentre statistics.[7],[8],[9] Units from India and Thailand reported 26 and 55 neonates, respectively.[10],[11] This observation substantiates the contention that just like ECMO, use of advanced therapies is uncommon. Yet, these may be the crucial supports that decide outcomes if patients are selected appropriately. Reports from teaching medical institutes in the country emphasise the lack of availability of iNO therapy, even though there are admissions of neonates with PPHN who could potentially benefit.[6]

PPHN is the failure of decrease of pulmonary vascular resistance at and soon after birth. This could be due to acute onset diseases such as MAS, infection (pneumonia/sepsis), hypoxic ischaemic encephalopathy and severe respiratory distress syndrome (RDS).[1] Approximately 0.2% of all neonates >34 weeks develop PPHN characterised by labile arterial saturations and differential cyanosis (higher preductal SpO2 than in lower limbs) due to bidirectional shunts across the patent ductus arteriosus. In our unit, we relied on an echocardiogram confirmation of PPHN in less than half the cases (40%) before instituting therapy. Although imaging by a cardiologist or a neonatologist trained in functional ECHO plays a role in the diagnosis of PH, neonatologists have reflected on the real-world situation where treatment could be started based on clinical judgement in these acutely sick neonates.[8]

Sound evidence supports iNO use for those >34 weeks with HRF and PH due to pulmonary maladaptation unresponsive to other therapy.[7] Its use has also been supported by no increase in neurodevelopmental impairments at 18–24 months postnatal age.[12]

In our unit, overall survival in those who received iNO was 51.4%. It is crucial to emphasise two important facts; first, survival varies remarkably based on the aetiology and underlying cause of HRF [Table 2], and second, these are critically ill neonates with several other advanced ongoing therapies [Table 3]. In maladaptation type of PPHN due to MAS or early onset pneumonia (congenital pneumonia), the use of iNO for HRF was beneficial with a 100% survival.

Razak et al. reported their experience of its use in India. Although 70% of 26 neonates showed response to iNO in terms of improvement in oxygenation, overall survival rate was 42%. Similar to our finding, HRF secondary to MAS responded well to the therapy. Their study differed in that only those >35 weeks of gestation were analysed.[10] Authors from Thailand have reported a survival rate of 76.4%. MAS was the most common underlying cause of PPHN amongst 55 infants described by them too.[11]

However, there are conditions such as congenital diaphragmatic hernia (CDH), other lung malformations and HRF in preterm infants (acute RDS, evolving or established bronchopulmonary dysplasia [BPD]) where PH is a significant comorbidity. Stakeholders advise exercising caution while selecting CDH patients for iNO use. Pathophysiology in CDH is unique and heterogenous. The presence of left ventricular (LV) compromise may be one of the key determinants of response to iNO. Use in those with pulmonary venous hypertension due to LV hypoplasia/failure may lead to worsening.[13] Although the overall survival of our CDH admissions is >80%, amongst those who were given a trial of iNO therapy, only about 33% survived. This itself would emphasise that iNO is given only to those with HRF not responding to conventional modes of intensive care support.

The National Institutes of Health consensus panel (2011) and the American Academy of Pediatrics Committee on Fetus and Newborn (2014) suggest that available evidence is insufficient to recommend the use of iNO in those <34 weeks gestation for prevention of BPD.[14],[15] There are exceptions to this recommendation. Available evidence suggests that rescue use of iNO may be considered for preterms in the acute setting of PH, especially if pulmonary hypoplasia due to prolonged premature rupture of membranes, and severe oligamnios and sepsis is a component of the HRF.[16],[17] In established BPD, the pathophysiology differs. Developing lungs of an extreme preterm undergo changes related to mechanical ventilation, which affect not only alveoli but also vascular compliance, calibre and remodeling. This process can lead to PH much later, demonstrable even on cardiac catheterisation.[18] The treatment for patients with BPD-PH is not clearly defined. Nonetheless, recent recommendations allow iNO use for acute PH crises in established BPD after deliberate evaluation and treatment for other offending agents such as viral/bacterial infections or airways issues; and should be weaned after stabilisation.[19]

A large Japanese Registry compared the use of iNO in those <34 weeks gestational age with those born late preterm and term and found survival rates were similar in both groups of gestation.[8] Our experience with the use of iNO in those <34 weeks gestation at birth is limited to only 4 neonates, of whom 2 survived. Both of the survivors did not show adequate response of BPD-PH to iNO, and the therapy was therefore discontinued.

Weismann et al. demonstrated that preterms with PH had increased mortality as compared to those without PH.[20] Nees et al. reported that 33% of patients who received targeted therapy for BPD-PH died during their study period. However, only 10% were directly attributable to worsening PH occurring due to intercurrent illness or aspiration events.[18]

Actual reports of patterns of use suggest that even after guidelines described above for off-label use were published, the proportion of iNO-treated neonates with CDH remained relatively constant, and the proportion of those with RDS increased.[7] The major shift has been in the significant increased off-label use of iNO in premature neonates. These probably reflect the principle of “desperate times calling for desperate measures”. Neonatologists at the bedside of a critically ill infant are aware of the well-described physiologic effect of iNO in increasing oxygenation. It is interesting to note that the history of ECMO is not dissimilar. There was a time when ECMO was used based on less than adequate evidence. It is now considered life-saving therapy in adults, older children and select neonates alike.[21]

Our study has the inherent limitations of it being a retrospective analysis of a small number of patients. However, iNO is used as advanced therapy in very sick neonates, and our data supports its benefits in at least a select group of neonates with HRF (MAS, congenital pneumonia). This life-saving drug could be made available in settings caring often for such sick infants. The costs involved may be considered while these decisions are made.

  Conclusions Top

In our case series, 51.4% of 35 neonates who received iNO survived. Survival was 100% in MAS or congenital pneumonia associated with PPHN. Response to therapy in CDH and preterm infants with BPD-PH was not remarkable. Although the need for iNO in treatment of PPHN in the NICU is rare, benefits in terms of survival in select patient profiles are commendable. Units that care for neonates with these diagnoses could have better outcomes if iNO therapy is available.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lakshminrusimha S. Neonatal and postneonatal pulmonary hypertension. Children (Basel) 2021;8:131.  Back to cited text no. 1
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Fortas F, Di Nardo M, Yousef N, Humbert M, De Luca D. Life-threatening PPHN refractory to nitric oxide: Proposal for a rational therapeutic algorithm. Eur J Pediatr 2021;180:2379-87.  Back to cited text no. 3
DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: Inhaled nitric oxide for neonates with acute hypoxic respiratory failure. Respir Care 2010;55:1717-45.  Back to cited text no. 4
Baczynski M, Ginty S, Weisz DE, McNamara PJ, Kelly E, Shah P, et al. 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:F508-14.  Back to cited text no. 5
Sardar S, Pal S, Mishra R. A retrospective study on the profile of persistent pulmonary hypertension of newborn in a tertiary care unit of Eastern India. J Clin Neonatol 2020;9:18-26.  Back to cited text no. 6
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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;46:657-63.  Back to cited text no. 8
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Razak A, Nagesh K, Desai S, Venkatesh HA. Inhaled nitric oxide in neonates with severe hypoxic respiratory failure – Early Indian experience. J Neonatol 2013;27:1-3.  Back to cited text no. 10
Chotigeat U, Khorana M, Kanjanapattanakul W. Inhaled nitric oxide in newborns with severe hypoxic respiratory failure. J Med Assoc Thai 2007;90:266-71.  Back to cited text no. 11
Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: Neurodevelopmental follow-up. J Pediatr 2007;150:235-40.  Back to cited text no. 12
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  [Table 1], [Table 2], [Table 3]


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