Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxic preterm neonates

Abstract

Aim To evaluate the clinical and echocardiography modulators of treatment response in hypoxemic preterm infants exposed to inhaled nitric oxide (iNO). Methods In this multicentre retrospective study, clinical parameters, including oxygenation, ventilation and haemodynamics, were collected for preterm infants <36 weeks gestation before and 2 h after initiation of iNO for acute hypoxemia. Comprehensive echocardiography, performed near the time iNO initiation, was analysed by experts blind to the clinical course. Multiple logistic regression analysis was used to identify factors associated with iNO response as defined by a reduction in the fraction of inspired oxygen by >0.20. Results A total of 213 infants met eligibility criteria, of which 73 had echocardiography data available and formed the study cohort. Response to iNO was demonstrated in 56% of patients. Younger post‐natal age (odds ratio (OR) 0.94; 95% confidence interval (CI) 0.89, 0.99) and the presence of pulmonary hypertension (PH) (OR 4.47; 95% CI 1.23–11.9) were independently predictive of iNO response regardless of gestational age. Among neonates <72 h old with documented PH, iNO response was seen in 82%. The onset of a new diagnosis of severe (grade III/IV) intraventricular haemorrhage (IVH) after iNO treatment was seen in 6 of 40 patients <28 weeks' gestational age, with a greater frequency in responders (32 vs. 0%, P = 0.02). Conclusions Positive response to iNO is greatest in the first 3 days of life and in patients with echo‐confirmed PH, independent of gestational age. The association between critical illness, iNO administration and IVH in extremely premature infants may merit prospective delineation.

The Off-Label Use of Inhaled Nitric Oxide as a Rescue Therapy in Neonates with Refractory Hypoxemic Respiratory Failure: Therapeutic Response and Risk Factors for Mortality

“…Therefore, we defined the use of iNO in hypoxemic neonates with diagnoses other than PPHN as “off-label rescue use”. In contrast to most of the published randomized controlled trials that focused on infants less than 34 weeks of gestation and early use of iNO during the few days of life [10,11,12,13,14,16,26,27,28], we were the first to investigate the rescue use of iNO in the late treatment of neonates who already had BPD and secondary pulmonary hypertension. We found that the rescue use of iNO improved initial oxygenation in over half of the preterm neonates with refractory hypoxemia.…”

“…In animal studies of hypoxia pulmonary injury, iNO has been found to have anti-inflammatory effects, promotion of angiogenesis, apoptosis inhibition and anti-oxidative injury [23,24,25]. The beneficial effects of iNO on extremely preterm infants have been increasingly investigated [10,11,12,13,14,16,18,26,27,28,29,30]. Recently, the American Heart Association, American Thoracic Society and Pediatric Pulmonary Hypertension Network have considered iNO to be superior to other pulmonary vasodilators in the treatment of preterm infants with severe pulmonary hypertension [31,32].…”

“…Recent studies have also demonstrated that a significant proportion of preterm infants with severe hypoxemia can be rescued by iNO therapy during their critical stage, especially during the first 3 days of life [10,18,22,26,27,28]. The better response of exogenous iNO administration in preterm infants in the early life may be due to the underlying mechanism of transient deficiency of endogenous nitric oxide generation, especially in those with prolonged preterm rupture of membranes [14,34].…”

The Controversy Persists: Is There a Qualification Criterion to Utilize Inhaled Nitric Oxide in Pre-term Newborns?

“…This patient's overall evaluation provided novel physiologic insights and permitted individualized care of these neonates. For example, Ahmed et al developed a scoring system using echocardiogram findings associated with clinical findings to better diagnose PHTN in pre-term newborns in a cohort study, specifically using the relationship between right ventricular and systolic pressure (123). Such a scoring system requires bedside evaluation of the neonatologist from the TnEcho team.…”

“…Other retrospective studies suggested that newborns>1,000 g were more likely to benefit from iNO (136,145). Conversely, three studies reported that newborns as small as 750 grams could still benefit from iNO, likely because of receiving surfactant before iNO initiation (123,135,147). Since most studies focused on birthweight, few studies mentioned GA as a limiting factor.…”