Effects of Inhaled Nitric Oxide on Preterm Infants with Respiratory Diseases

Result and Discussion
Inhaled nitric oxide (iNO) is effective on preterm infants suffering from respiratory diseases where its potential risks and pathophysiology respiratory failure differ significantly. Nitric oxide is said to help in regulating the muscle tone of the pulmonary arteries, thereby reducing pulmonary hypertension. Inhaled nitric oxide (iNO) has been shown to be effective in treating preterm infants affected by severe respiratory failure. Nevertheless, the effect of iNO on preterm infants remains unclear [1, 2].

Premature babies suffering from respiratory distress syndrome (RDS) are increasingly required to use inhaled nitric oxide (iNO). Most of this off-label use occurs in the first week of life. Nitric oxide contributes to smooth muscle relaxation through various mechanisms. The stimulation of NOS activity will increase the release of NO, which is then released into adjacent smooth muscle cells and bind to the heme unit of cytoplasmic guanylate cyclase. The activation of guanylate cyclase increases the concentration of cyclic guanosine monophosphate in the cell, resulting in smooth muscle relaxation. After release, NO is rapidly inactivated by binding to hemoglobin, producing methemoglobin, and finally forming nitrite5 and inorganic nitrate [4, 5].

Background
Premature babies in need of assisted ventilation are at risk of severe lung and brain injuries. Nitric oxide is an effective treatment for hypoxic respiratory failure and pulmonary hypertension for premature infants. The results showed that in two studies of routine use of iNO in intubated preterm infants, the combined outcome of death or chronic lung disease (CLD) was statistically significantly lower.

However, uncertainty still exists with another study showing that iNO has no obvious benefit to this combined result. Studies on severely ill infants have also shown no obvious benefit. A study on iNO treatment in the late postnatal period reported that the incidence of CLD decreased. The purpose of the separate patient meta-analysis was to confirm or refute the potentially conflicting outcomes, and to determine how patient or treatment characteristics get various results from inhaled nitric oxide [8, 9].

About 8 to 13% of babies are born before they are mature in developed countries. Preterm births account for 75 to 80% of the entire mortality and neonatal morbidity. Survival rates have however improved significantly in recent decades, premature infants who require assisted ventilation still have a significant risk of getting lung and brain injuries.
It is estimated that 75% of infants born with less than 1,000 grams suffer from respiratory distress syndrome. Almost 30% of patients still rely on oxygen. The most common report of chronic lung disease (CLD) is dependent on oxygen or support for the respiratory tract at 36 weeks postmenstrual era. Babies with severe CLD still have a high risk of lung disease and death in the first two years after birth.

In addition, long-term neurodevelopmental disorders related to cerebral palsy, sensorineural hearing loss, visual impairment, and mental retardation are often observed in infants with CLD [4, 5]. The occurrences of these neurodevelopmental disorders increase with a decrease in birth weight. The incidence of newborns with a birth weight of 1501 to 2500 grams is 8%, and the incidence of infants with a weight of less than 1000 g is 25% [6, 7].

Practice implications
In severely ill premature infants who meet the criteria for insufficient oxygen supply, iNO rescue therapy cannot improve survival without BPD or brain damage, although oxygen supply can be enhanced in the short term. Indeed, some proofs show that the combined results of severe intracranial hemorrhage and severe periventricular leukomalacia or intraventricular haemorrhage may increase. As a result, iNO should not be routinely applied to premature infants as a rescue therapy for hypoxic respiratory failure [2, 3].

Routine early use of iNO seems to be ineffective in ventilated preterm infants who do not have a serious condition but still have a risk of severe brain damage or BPD. Although some studies have shown potential benefits, a meta-analysis of trials did not confirm the overall benefit. Only one study in the group reported showed longer neurodevelopmental outcomes, and the study suggested beneficial effects. Presently, data does not support widespread conventional iNO therapy to stop brain damage or BPD.

The use of iNO in premature infants who still need respiratory support after 5-21 days does not appear to minimize BPD. It was determined by subgroup analysis that this effect appeared to be most pronounced in infants who were less ill, and in infants who had received previous treatment (i.e., 7 to 14 days old).

Condition description
Pulmonary hypertension can make respiratory failure in premature babies more difficult. Conventional therapies for pulmonary hypertension involve airway support, including assisted ventilation and continuous stretching pressure, administration of surfactants and tranquilizers, and muscle relaxation when necessary. The systemic circulation of sick babies is usually supported by inotropic drugs. Since the introduction of surfactants, the mortality rate of respiratory failure in premature infants has been greatly reduced. However, some babies did not show sufficient oxygen supply after surfactant treatment. Premature babies that get mechanical airway support face higher risks of bronchopulmonary dysplasia (BPD) due to lung injury, which can have major long-term effects [8, 9].

Intervention description
Nitric oxide (NO) regulates vascular muscle tension at the cellular level. Nitric oxide is enzymatically produced by L-arginine through one of three NO synthase enzymes. NO activates guanylate cyclase by attaching to its heme component, resulting in the generating of cyclic guanosine monophosphate (cGMP), hence there is vasodilation. NO gas can combine with inhaled gas and is directly delivered to the surrounding respiratory tract where local vasodilation may occur [6, 7].

How the intervention works
Although the pulmonary artery pressure in premature infants increases with respiratory arrest, the elevation in pulmonary artery pressure is not usually enough for the ductal shunt reversal. Therefore, its hemodynamic characteristics are different from newborns. ECMO is used because of concerns about bleeding complications and its requirement can't be utilized as a result criterion.

Animal models of BPD indicate that long-term treatment of iNO can change lung injury. Inhalation of nitric oxide has the effect of reducing lung pneumonia in premature infants during acute attacks and improving vascular remodeling [9, 10].
Premature babies are in danger of long-term lung dysfunction associated with BPD. The significance of stopping or improving BPD is related to the relationship between BPD and subsequent neurodevelopmental disorders, chronic diseases, and rehospitalization. If iNO therapy can reduce the need for ventilation assistance, reducing lung damage can prevent or improve BPD. Nitric oxide is involved in the production and protection from oxidative damage. Therefore, before introducing iNO into clinical practice, the effects of iNO treatment on the developing lungs should be carefully evaluated.

Discussion
This review showed that there is no clear evidence when preterm infants inhale nitric oxide (iNO). Earlier versions of this review proposed that early treatment may be beneficial. , but with the increase in results, the reduction in bronchopulmonary dysplasia (BPD) or death that may have occurred before and the reduction in brain damage aren't major issues. The heterogeneity of these outcomes is still unexplainable, and further research into the causes of the heterogeneity might not be helpful.

Early rescue treatment seems to be ineffective and may lead to an insignificant increase in brain damage. However, preterm infants with clear proof of pulmonary hypertension haven't been individually identified in these studies, and may form a subgroup with different responses [5, 6].

Mortality
Except in some cases, none of the other trials portrayed minimization in mortality. A meta-analysis of the first two studies evaluating the routine application of iNO in intubated infants shows that there may be differences, but another similar trail found no significant effect [3, 4].

Survival without bronchopulmonary dysplasia
Studies examining iNO as a routine treatment for preterm infants have not shown any impact on the combined results of bronchopulmonary dysplasia or death. Studies on the admission of three-day-old infants to hospitals based on oxygenation standards show that iNO has no obvious benefit.

It was however shown that the combined BPD scores or death in a big multi-center study have declined after using multi-output techniques to plan and analyze data. The pre-planned subgroup analysis of the infant subgroup of 7-14 days at admission and the infant subgroup who were less well (respiratory severity <3.5) recorded the greatest benefits. Before, another study specifically looked at such children and revealed that in contrast, iNO did not bring any benefits [8, 9]. The overall effect of preventing BPD found in subsequent treatment studies showed that the danger ratio of "BPD or death" was 0.92, and the 95% confidence interval (CIs) only indicated the no effect possibility (0.85 to 1, 01).

Brain Injury
Three studies of routine early use of iNO in intubated premature infants have shown no effect on ultrasound-diagnosed severe brain damage-a combined result of periventricular leukomalacia or severe haemorrhage. Early rescue studies revealed that it may have an impact on the results. A 20% increase in heavy bleeding is important because the researchers did not show any benefit [4, 5].

Developmental and neurological outcomes
There was an abnormal neurodevelopmental score reduction at the age of two which was mainly caused by mental development. Another study showed that the use of ultrasound can improve the appearance of the brain but no long-term results have been reported. Some trials reported head abnormalities through ultrasound examination prior to enrollment and found that the new lesions in the iNO treatment group were lower than that of the control group [3, 4].

Comprehensive
Further analysis of patient characteristics related to possible beneficial reactions would be helpful. It was also said that maternal ethnicity can as well influence the findings. The researchers used a variety of methods, such as Generalized Estimation Equations (GEE) with various output techniques and sensitivity analysis described above. They also conducted a meta-analysis of individual participants using all data. But one of the relevant trials confirmed the original conclusions of the authors on these techniques [6, 7].

Conclusion
iNO therapy in preterm infants with severe IBS and respiratory failure can improve oxygen supply without short-term side effects (such as pulmonary hemorrhage, pneumothorax, acute exacerbation, or intracranial hemorrhage). However, iNO treatment does not significantly reduce death rates or incidences of PDA, ROP, CLD, or ICH [5, 6].

References
(1) Ballard PL, Keller RL, Black DM, Durand DJ, Merrill JD, Eichenwald EC, et al. PS-205 Inhaled Nitric Oxide Increases Urinary Nitric Oxide Metabolites And Cgmp In Premature Infants: Relationship To Pulmonary Outcome. Arch Dis Child 2014 10;99. (3) Shen W, Du J, Wang B, Zeng Q.
(2) Soll RF. Inhaled Nitric Oxide for Respiratory Failure in Preterm Infants. Neonatology 2012 11;102(4):251-3.
(3) Sivasli E, Babaoglu M, Yasar Ü, Yurdakök M, Bozkurt A, Korkmaz A, et al. Association between the Glu298Asp and T(-786)C polymorphisms of the endothelial nitric oxide synthase gene and respiratory distress in preterm neonates. Turk J Pediatr 2010 Mar;52(2):145-9.
(4) Ballard RA, M.D., Truog WE, M.D., Cnaan A, PhD., Martin RJ, M.D., Ballard, Philip L,M.D., PhD., Merrill JD, M.D., et al. Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation. N Engl J Med 2006 Jul 27;355(4):343-53.
(5) Stark AR, M.D. EDITORIALS: Inhaled NO for Preterm Infants - Getting to Yes? N Engl J Med 2006 Jul 27;355(4):404-6.
(6) Dani C, Bertini G, Rubaltelli FF, Hasan SU, al e. Inhaled Nitric Oxide/DR. VAN MEURS AND A COLLEAGUE REPLY/DR. SCHREIBER AND COLLEAGUES REPLY/DRS. MARTIN AND WALSH REPLY. N Engl J Med 2005 Oct 13;353(15):1626-8; author reply 1626-8.
(7) Martin, Richard J,M.B., F.R.A.C.P., Walsh MC, M.D. EDITORIAL: Inhaled Nitric Oxide for Preterm Infants - Who Benefits? N Engl J Med 2005 Jul 07;353(1):82-4.
(8) Van Meurs, Krisa P, MD, Wright LL, M.D., Ehrenkranz RA, M.D., Lemons JA, M.D., Ball MB, Poole WK, et al. Inhaled Nitric Oxide for Premature Infants with Severe Respiratory Failure. N Engl J Med 2005 Jul 07;353(1):13-22.
(9) Martin, Richard J,M.B., F.R.A.C.P. Nitric oxide for preemies - not so fast. N Engl J Med 2003 Nov 27;349(22):2157-9.
(10) Kinsella JP, Walsh WF, Bose CL, Gerstmann DR, al e. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. The Lancet 1999 Sep 25;354(9184):1061-5.