Nasal and lower airway levels of nitric oxide in prematurely born infants
Introduction
Chronic lung disease (CLD) is a common adverse outcome of premature birth [1]. It is an inflammatory disorder; nitrates and breakdown products of nitric oxide (NO) have been shown to be present in the bronchoalveolar lavage fluid of prematurely born infants developing CLD [2]. In children and adults with airway inflammation, exhaled nitric oxide (eNO) levels are increased and can be reduced by the administration of corticosteroids [3]. Measurement of eNO levels might then identify infants at risk of CLD development and may be used to monitor their progress. If such a technique is to be useful, it must be accurate. In older patients, when measuring eNO, it is essential to avoid nasal contamination. Nitric oxide is produced by various cells in the respiratory tract, but the majority are released from the paranasal sinuses in adults [4]. Instillation of l-NAME, an NO synthase inhibitor, results in a greater reduction of NO levels if instilled directly into the nasal sinuses, than simply given intranasally [5]. In addition, immunohistochemical studies and in situ hybridisation have shown dense staining for nitric oxide synthase and its RNA in the sinus epithelium, but only weak staining in the nasal epithelium [5]. Nitric oxide appears to be higher in exhaled nasal gas compared to gas from lower airways in infants [6], but few data are available and the paranasal sinuses in infants are only partially pneumatised. Thus, nasal NO would be predicted to be low in infants measured soon after birth and/or born very prematurely. It is important to test that hypothesis, as it has implications for both the methodology used to measure eNO and the interpretation of the results obtained. The aims, therefore, of this study were to determine whether nasal NO could be detected in very immature infants, particularly soon after birth, and whether nasal or lower airway NO levels were influenced by gestational age or postnatal age.
Section snippets
Patients and methods
Fifteen infants, with a median gestational age of 27 weeks (range 25–32 weeks) and birth weight of 820 g (range 616–2330 g), were entered into the study after informed written parental consent had been obtained. The study was approved by the King's College Hospital National Health Service Research Ethics Committee. All of the infants had received antenatal dexamethasone and none was receiving postnatal dexamethasone. Caffeine was given to facilitate extubation and only after NO sampling had
Statistical analysis
Differences between nasal and lower airway NO levels were assessed for statistical significance using the paired Wilcoxon sign rank test. Spearman's correlation coefficients were calculated to determine the strength of the relationship between NO levels and gestational age and postnatal age.
Results
Nasal NO was detected in all infants on all study occasions. Nasal NO levels were higher than lower airway NO levels on all study days in all infants (Table 1), including day 1 (Fig. 1). On day 1, transitory high nasal NO levels (median 395, range 182–1800 ppb) were recorded in eight infants. No significant correlations with gestational age were found with either nasal (r=0.31, p=0.29) or lower airway (r=0.29, p=0.40) NO levels (Fig. 2, Table 2). Significant correlations with postnatal age were
Discussion
We have demonstrated that nasal NO levels were higher than lower airway NO levels, even on the first day after birth and in infants born very prematurely. The differences were not significant on all study occasions, but after day 1, smaller numbers of infants could be examined. Nevertheless, on all study occasions, nasal NO levels were higher than lower airway NO levels in each infant. This was particularly apparent when the transitory high nasal NO levels noted at the onset of sampling were
Acknowledgments
Dr. Olivia Williams is supported by the Children Nationwide Medical Research Fund. We thank Ms. Sue Williams for secretarial assistance and Dr. Paul Cheeseman for statistical advice.
References (20)
- et al.
Exhaled nitric oxide in pre-term infants
Respir. Physiol.
(1998) - et al.
Gas trapping during high frequency positive pressure ventilation using conventional ventilators
Early Hum. Dev.
(1990) - et al.
Nitric oxide and the respiratory system in health and disease
Respir. Med.
(1998) - et al.
Corticosteroids decrease exhaled nitric oxide in children with acute asthma
J. Pediatr.
(1997) - et al.
Mixed exhaled nitric oxide and plasma nitrates and nitrites in newborn infants
Life Sci.
(2001) High frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity
N. Engl. J. Med.
(2002)- et al.
Concentration of nitric oxide products in bronchoalveolar fluid obtained from infants who develop chronic lung disease of prematurity
Arch. Dis. Child.
(1999) - et al.
Exhaled nitric oxide concentrations during treatment of wheezing exacerbations in infants and young children
Am. J. Respir. Crit. Care Med.
(1999) - et al.
Nasally exhaled nitric oxide in humans originates mainly in the paranasal sinuses
Acta Physiol. Scand.
(1994) - et al.
High nitric oxide production in human paranasal sinuses
Nat. Med.
(1995)
Cited by (28)
Exhaled nitric oxide in premature and mature infants during the first months of life: Exhaled Nitric Oxide in neonates – a review
2021, Nitric Oxide - Biology and ChemistryCitation Excerpt :However, there is still some heterogeneity in methods, as well as the periods of included samples differ. When measuring FeNO with a facemask, it is impossible to eliminate the nasal and upper airways' contribution, where the NO concentration is considerably higher than in the lower airways [42]. Although the neonatal sinuses are less developed, neonates are nose-breathers, and we cannot rule out that there is a contribution from the upper airways.
6q12 and 11p14 variants are associated with postnatal exhaled nitric oxide levels and respiratory symptoms
2017, Journal of Allergy and Clinical ImmunologyCitation Excerpt :There are no data supporting a difference between strictly oral or nasal NO in term infants.27,45 However, such differences could be demonstrated for premature infants very early in life and before any possible significant bacterial colonization and pneumatization of paranasal sinuses, with much higher levels for nasal NO, predominantly under inducible NOS influence,17 than for bronchial eNO.46,47 The link to the already mentioned role of NO metabolism in cell signaling, vascular endothelial growth factor−mediated airway development,10-13 lung epithelial-mesenchymal crosstalk,14 and epithelial function is striking.
The Role of Nitric Oxide in Lung Growth and Function
2012, The Newborn Lung: Neonatology Questions and Controversies Expert ConsultThe Role of Nitric Oxide in Lung Growth and Function
2012, The Newborn LungAdvances in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn
2009, Pediatric Clinics of North AmericaCitation Excerpt :These properties make iNO the ideal pulmonary vasodilator in neonatal respiratory failure. Recent studies have demonstrated that NO levels in the nasal cavity of premature infants can reach 50 to 100 parts per billion.80,81 Significant exhaled NO concentrations are measured in these neonates, suggesting that inhalation of NO occurs physiologically during tidal respiration.80
Inhaled Nitric Oxide for Preterm Neonates
2009, Clinics in PerinatologyCitation Excerpt :Recent studies show that NO is normally present in the upper airway from synthesis in the airway mucosa, however, and is inhaled during tidal respiration in neonates. The breath NO levels in the nasal cavity of preterm neonates approach 100 parts per billion (0.1 ppm).40,41 These data suggest that iNO has a physiologic role in gas exchange and lung protection in neonates.