Outi Aikio

Transient Defect in Nitric Oxide Generation after Rupture of Fetal Membranes and Responsiveness to Inhaled Nitric Oxide in Very Preterm Infants with Hypoxic Respiratory Failure

OBJECTIVE To study antenatal risk factors and inflammatory responses during hypoxic respiratory failure (HRF) in infants of very low gestational age (VLGA, ≤32.0 weeks). STUDY DESIGN Of a cohort of 765 VLGA infants, 144 required mechanical ventilation. Airway specimens from these patients were prospectively studied. Infants who developed HRF (oxygenation index >25) with echocardiographic diagnosis of pulmonary hypertension were treated with inhaled nitric oxide (iNO). Three gestation comparison groups were formed on the basis of specific antenatal complications: prolonged preterm rupture of membranes (PPROM), spontaneous preterm birth, and preeclampsia. Chest radiographs were studied and airway specimens were analyzed for concentrations of tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-10, IL-12p70, IL-1β, and nitrite + nitrate over 4 days. RESULTS Seventeen (2.2% of all VLGA infants) developed HRF. In all 17 cases, PPROM complicated the antenatal course; these infants responded to iNO, regardless of infection or PPROM. The chest radiographs of HRF and non-HRF PPROM infants were similar. Airway proinflammatory cytokines and nitrite + nitrate levels were low in infants with HRF, but they increased during iNO treatment and remained elevated after discontinuation of iNO. Each of the 3 comparison groups had different and characteristic patterns of airway cytokines and nitrite + nitrate levels. CONCLUSIONS Seven percent of VLGA infants with preterm rupture of membranes and 15% of those with PPROM developed HRF, characterized by pulmonary hypertension that acutely responds to iNO. These infants may have a transient deficiency in the inflammatory response, including a defect in nitric oxide generation in airspaces.

Exhaled and nasal nitric oxide in mechanically ventilated preterm and term newborns.

Aim: Nitric oxide (NO) is an important mediator required for neonatal pulmonary circulatory adaptation and for pulmonary defence. Both deficient and excessive NO production have been proposed to play a role in neonatal lung disease. This study aimed to establish a method that allows direct measurement of exhaled and nasal NO concentrations in newborn infants who require intubation and ventilation. Methods: A rapid‐response chemiluminescence NO analyser was used. Gas was sampled from the endotracheal intubation tube, and tidal volumes and flow rates were measured. The nasal NO was sampled from the non‐intubated nostril. The accuracy of the method was validated using a lung model. NO levels from six preterm and six term/near‐term newborns were studied. Measurements were performed on a daily basis during the first week. Results: An expiration >0.2 s in duration with a flow rate >1.7mls−1 could be accurately analysed for the presence of >1 parts per billion of NO. The very preterm infants with neonatal lung disease had a different postnatal NO output pattern from the lower and upper airways compared with the ventilated term/near‐term infants.

Nitric oxide treatment and acute pulmonary inflammatory response in very premature infants with intractable respiratory failure shortly after birth

Aim: Premature infants with respiratory failure and early‐onset pneumonia have low inducible nitric oxide synthase (NOS2) and no evidence of nitric oxide (NO) toxicity. However, inhalation of NO may not be indicated in sepsis because excessive NO generation has been reported. This prospective study was designed to test the hypothesis that inhaled NO is effective in a select group of small premature infants and that the responsiveness to NO is associated with low NOS2 enzyme. Methods: 246 very low birthweight infants (birthweight <1500 g, VLBW) were screened for severe, intractable respiratory failure (oxygenation index >40, arterial‐alveolar ratio for oxygen tension <0.10) that does not respond to two doses of surfactant within 5 h from birth. Infants with severe cardiac failure or a bleeding disorder were excluded. Five of the nine eligible cases received inhaled NO. They all had prolonged rupture of foetal membranes, early‐onset pneumonia and persistent pulmonary hypertension. Results: All five responded strikingly, survived and appeared normal in follow‐up. Airway specimens during the first day of life revealed very low NOS2, interleukin‐1β and surfactant protein A, compared with VLBW infants who had no acute infection despite histological chorioamnionitis. In early‐onset pneumonia, NOS2 and other inflammatory mediators increased first during the recovery 1–2 d after birth.

Nitric oxide in critical respiratory failure of very low birth weight infants

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. In randomised trials, iNO increased gas exchange modestly and had no effect on the outcome (survival, chronic lung disease, CLD) in very low birth-weight (VLBW) infants. NO is an important component of the innate immune system and a lipid- soluble free radical scavenger that interacts with the surfactant system. VLBW infants with pneumonia and therapy-resistant, severe respiratory failure soon after birth were studied. Despite their infection, there was no detectable alveolar inducible NO synthase or nitrotyrosine, which is a toxic oxidation product of NO. These infants do not respond to exogenous surfactant and demonstrate severe pulmonary hypertension. However, they require exogenous surfactant prior to iNO. In most cases the disease is complicated by pneumonia and prolonged rupture of fetal membranes. We have shown evidence that iNO given within a few hours after birth reverses the progressive course of respiratory failure and pulmonary hypertension in VLBW infants.

Intravenous paracetamol was associated with closure of the ductus arteriosus in extremely premature infants

Symptomatic patent ductus arteriosus may lead to serious complications in extremely preterm and extremely low birthweight infants and is often resistant to medication. We evaluated early intravenous paracetamol for pain prevention during respiratory therapy, in an attempt to understand the ductal treatment of such infants.

Follow-up study of the early, randomised paracetamol trial to preterm infants, found no adverse reactions at the two-years corrected age

We examined the long‐term outcomes and safety of early intravenous paracetamol for ductus arteriosus closure at a corrected age of two years.