Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs.

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147-150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

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

Inhaled nitric oxide (iNO) use in premature newborns remains controversial among clinicians. In 2014, the American Academy of Pediatrics, Committee on Fetus and Newborn released a statement that the available data do not support routine iNO use in pre-term newborns. Despite the absence of significant benefits, 2016 California data showed that clinicians continue to utilize iNO in pre-term infants. With studies as recent as January 2017, the Cochrane review confirmed no major advantages of iNO in pre-term newborns. Still, it recognized that a subset of pre-term infants with pulmonary hypertension (PHTN) had not been separately investigated. Furthermore, recent non-randomized controlled trials have suggested that iNO may benefit specific subgroups of pre-term newborns, especially those with PHTN, prolonged rupture of membranes, and antenatal steroid exposure. Those pre-term infants who showed a clinical response to iNO had increased survival without disability. These findings underscore the need for future studies in pre-term newborns with hypoxemic respiratory failure and PHTN. This review will discuss the rationale for using iNO, controversies regarding the diagnosis of PHTN, and additional novel approaches of iNO treatment in perinatal asphyxia and neonatal resuscitation in the pre-term population < 34 weeks gestation.

The Effect of a Continuous Milk Warming System on Weight Gain in Very Low Birth-Weight Infants: A Randomized Controlled Trial.

BACKGROUND: Few studies support the practice of warming human milk before feeding. No studies have compared the method of warming milk and its effect on growth, particularly in preterm infants. PURPOSE: To evaluate growth in preterm infants receiving continuously warmed human milk as compared with infants receiving human milk warmed in a hot water bath before feeding. METHODS: Forty-four infants less than 32 weeks' gestation admitted to a regional referral level IV neonatal intensive care unit in south central United States were randomly assigned to either the experimental group (continuous warming: n = 22) or the control group (hot water bath: n =22) for 10 days. All infants were on full human milk feedings (120-130 kcal/kg/d) as part of a standardized feeding protocol. Tolerance and weight gain over the 10-day period were used to evaluate the effectiveness of continuous milk warming. RESULTS: There was a significant difference in weight gain for infants receiving continuously warmed milk compared with infants receiving standard warmed milk (203.73 ± 70.71 vs 271.95 ± 67.40, P = .002). IMPLICATIONS FOR PRACTICE: The use of continuous milk warming improves weight gain in very low birth-weight infants.

Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.

Volume Targeted Ventilation and High Frequency Ventilation as the Primary Modes of Respiratory Support for ELBW Babies: What Does the Evidence Say?

Respiratory management of the extremely low birth weight (ELBW) newborn has evolved over time. Although non-invasive ventilation is being increasingly used for respiratory support in these ELBW infants, invasive ventilation still remains the primary mode in this population. Current ventilators are microprocessor driven and have revolutionized the respiratory support for these neonates synchronizing the baby's breath to ventilator breaths. High frequency ventilators with the delivery of tidal volumes less than the dead space have been introduced to minimize barotrauma and chronic lung disease. Despite these advances, the incidence of chronic lung disease has not decreased. There is still controversy regarding which mode is ideal as the primary mode of ventilation in ELBW infants. The most common modes seem to be pressure targeted conventional ventilation, volume targeted conventional ventilation and high frequency ventilation which includes high frequency oscillatory ventilation, high frequency jet ventilation and high frequency flow interrupter. In recent years, several randomized controlled trials and meta-analyses have compared volume vs. pressure targeted ventilation and high frequency ventilation. While volume targeted ventilation and high frequency ventilation does show promise, substantial practice variability among different centers persists. In this review, we weighed the evidence for each mode and evaluated which modes show promise as the primary support of ventilation in ELBW babies.

Inhaled nitric oxide as an adjunct to neonatal resuscitation in premature infants: a pilot, double blind, randomized controlled trial.

BACKGROUND: Nitric oxide (NO) plays an important role in normal postnatal transition. Our aims were to determine whether adding inhaled NO (iNO) decreases supplemental oxygen exposure in preterm infants requiring positive pressure ventilation (PPV) during resuscitation and to study iNO effects on heart rate (HR), oxygen saturation (SpO2), and need for intubation during the first 20 min of life. METHODS: This was a pilot, double-blind, randomized, placebo-controlled trial. Infants 25 0/7-31 6/7 weeks' gestational age requiring PPV with supplemental oxygen during resuscitation were enrolled. PPV was initiated with either oxygen (FiO2-0.30) + iNO at 20 ppm (iNO group) or oxygen (FiO2-0.30) + nitrogen (placebo group). Oxygen was titrated targeting defined SpO2 per current guidelines. After 10 min, iNO/nitrogen was weaned stepwise per protocol and terminated at 17 min. RESULTS: Twenty-eight infants were studied (14 per group). The mean gestational age in both groups was similar. Cumulative FiO2 and rate of exposure to high FiO2 (>0.60) were significantly lower in the iNO group. There were no differences in HR, SpO2, and need for intubation. CONCLUSIONS: Administration of iNO as an adjunct during neonatal resuscitation is feasible without side effects. It diminishes exposure to high levels of supplemental oxygen.

Health Economics and Outcomes of Surfactant Treatments for Respiratory Distress Syndrome Among Preterm Infants in US Level III/IV Neonatal Intensive Care Units.

OBJECTIVE: To compare length of stay (LOS), costs, mechanical ventilation (MV), and mortality in preterm infants treated in the Neonatal Intensive Care Unit (NICU) with beractant (BE), calfactant (CA), and poractant alfa (PA) for Respiratory Distress Syndrome (RDS). METHODS: This study evaluated preterm infants born between 2010 and 2013 with RDS diagnosis, gestational age of 25 to 36 weeks, birthweight of ≥500 g, and age of ≤2 days on first surfactant administration. Multivariable regression was used to evaluate all NICU outcomes. RESULTS: Of 13,240 infants meeting the study criteria, 4136 (31.2%) received BE, 2502 (18.9%) received CA, and 6602 (49.9%) received PA. Adjusted analyses estimated similar mean LOS (BE 26.7 days, CA 27.8 days, and PA 26.2 days) and hospital costs (BE: $50,929; CA: $50,785; and PA: $50,212). Compared to PA, BE and CA were associated with greater odds of MV use on day 3 (OR = 1.56 and 1.60, respectively) and day 7 (OR = 1.39 and 1.28, respectively; all p < 0.05). Adjusted NICU mortality was significantly higher only with CA vs PA (OR = 1.51; p = 0.015). CONCLUSION: Adjusted NICU LOS and costs were similar among BE, CA, and PA. Infants receiving PA were less likely to be on MV at 3 and 7 days, and PA treatment was associated with lower odds of NICU mortality when compared to CA.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 µg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [µg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Neonatal distraction surgery for micrognathia reduces obstructive apnea and the need for tracheotomy.

The objective of the study was to assess the effectiveness of neonatal mandibular distraction in treatment of obstructive sleep apnea in the perinatal period in preventing a tracheotomy. This was a prospective study of 17 infants at two centers with severe micrognathia who demonstrated obstructive sleep apnea refractory to conservative therapy. Age at surgery varied from 5 to 120 days. Distraction was performed at a rate of 2 mm/d. After distraction, callus consolidation was allowed for 4 to 6 weeks, and the device was then removed. Each child underwent a three-dimensional computed tomography scan before surgery and approximately 3 months after surgery. Of the 17 patients, 14 successfully underwent extubation and demonstrated significant improvement in the obstructive sleep apnea. Postoperative horizontal ramus length increased from 23.3 to 34.8 mm after surgery. Mean maxillary mandibular discrepancy was 8.28 mm before surgery and 2.2 mm after surgery. Ten infants who underwent pre- and postoperative polygraphic studies showed improvement in obstructive apnea. Three patients had postoperative polysomnographic studies only; the results were also within the normal range. The mean follow-up interval was 16.5 months (range: 8-48 months). Neonatal distraction is an effective method for treatment of micrognathia with obstructive sleep apnea in the perinatal period in preventing a tracheotomy.

A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants.

We compared the onset of clinical response and safety of two surfactants, poractant alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n = 293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of poractant alfa or 100 ( n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (F IO(2)) between 0 and 6 hours measured using the area under the curve (F IO(2) AUC (0-6)); other outcomes were assessed for the entire cohort at 28 days and for infants born at < or = 32 weeks gestation at 36 weeks postconceptional age. We found that the mean F IO(2) AUC (0-6) values for the 100 and 200 mg/kg poractant alfa groups were both significantly lower than the mean F IO(2) AUC (0-6) values for the beractant group ( p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at < or = 32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg poractant alfa group than in either the beractant group (3% versus 11%; p = 0.034) or in the 100 mg/kg poractant alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg poractant alfa in comparison to the beractant-treated group ( p < 0.002). Treatment with poractant alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality ( p <0.05) than either beractant or poractant alfa (100 mg/kg dosing) in infants < or =32 weeks gestation with RDS.

A Cost Minimization Comparison of Two Surfactants-Beractant and Poractant alfa-Based Upon Prospectively Designed, Comparative Clinical Trial Data.

OBJECTIVES: To compare the pharmacoeconomic profiles of beractant (Survanta(®), Ross Laboratories, Columbus, Ohio) and poractant alfa (Curosurf(®), DEY LP, Napa, CA) via a cost-minimization analysis. METHODS: This analysis was based upon clinical data from two previously published studies (Speer C, et al. Arch Dis Child 1995;72: F8-13; and Ramanathan R, et al. Am J Perinatol 2004; 21:109-19) where investigators found significant differences in the number of doses required to achieve a similar clinical response. Our analyses employed several models based upon single-use or multiple-use of single-use vial scenarios, average wholesale pricing, and costs computed on a per-patient basis. Model 1 involved single-dose vials and mean weight of the infants (both trials). Models 2 and 3, based on individual patient weights, assessed single-dose and multiple-use of single-dose vials cost scenarios, respectively. Individual patient weights allowed for statistical evaluation in Models 2 and 3. RESULTS: Model 1 savings with poractant alfa treatment was $949.67 (53%) based upon Speer and $617.90 (46%) based upon Ramanathan. Models 2 and 3 reported savings for poractant alfa of $220.50 (20%) (P = 0.11) and $180 (20%) (P = 0.018), respectively over beractant. CONCLUSIONS: These analyses would suggest poractant alfa may offer a less costly, clinically-equivalent option. Savings may vary with vial usage and mix, patient weight distribution, and how surfactants are used in practice. Institutions utilizing surfactants may wish to examine usage patterns, dosing protocols, and patient mix to determine what potential savings may exist.

A multicenter, randomized, controlled trial comparing Surfaxin (Lucinactant) lavage with standard care for treatment of meconium aspiration syndrome.

OBJECTIVE: Infants with meconium aspiration syndrome (MAS) have marked surfactant dysfunction. Airways and alveoli of affected neonates contain meconium, inflammatory cells, inflammatory mediators, edema fluid, protein, and other debris. The objective of this study was to compare treatment with bronchoalveolar lavage using dilute Surfaxin with standard therapy in a population of newborn infants with MAS. METHODS: Inclusion criteria were 1) gestational age > or =35 weeks, 2) enrollment within 72 hours of birth, 3) diagnosis of MAS, 4) need for mechanical ventilation, and 5) an oxygenation index > or =8 and < or =25. Subjects were randomized to either lavage with Surfaxin or standard care (2:1 proportion). In lavaged infants, a volume of 8 mL/kg dilute Surfaxin (2.5 mg/mL) was instilled into each lung over approximately 20 seconds followed by suctioning after 5 ventilator breaths. The procedure was repeated twice. The third and final lavage was with a more concentrated solution (10 mg/mL) of Surfaxin. RESULTS: Twenty-two infants were enrolled (15 Surfaxin and 7 control). Demographic characteristics were similar. There were trends (not significant) for Surfaxin-lavaged infants to be weaned from mechanical ventilation earlier (mean of 6.3 vs 9.9 days, respectively), as well as to have a more rapid decline in their oxygenation indexes compared with control infants, the latter difference persisting for the 96-hour-long study period. The therapy was safe and generally well tolerated by the infants. CONCLUSIONS: Dilute Surfaxin lavage seems to be a safe and potentially effective therapy in the treatment of MAS. Data from this investigation support future prospective, controlled clinical trials of bronchoalveolar lavage with Surfaxin in neonates with MAS.