Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

Dietary intake and bio-activation of nitrite and nitrate in newborn infants.

Nitrate and nitrite are commonly thought of as inert end products of nitric oxide (NO) oxidation, possibly carcinogenic food additives, or well-water contaminants. However, recent studies have shown that nitrate and nitrite play an important role in cardiovascular and gastrointestinal homeostasis through conversion back into NO via a physiological system involving enterosalivary recirculation, bacterial nitrate reductases, and enzyme-catalyzed or acidic reduction of nitrite to NO. The diet is a key source of nitrate in adults; however, infants ingest significantly less nitrate due to low concentrations in breast milk. In the mouth, bacteria convert nitrate to nitrite, which has gastro-protective effects. However, these nitrate-reducing bacteria are relatively inactive in infants. Swallowed nitrite is reduced to NO by acid in the stomach, affecting gastric blood flow, mucus production, and the gastric microbiota. These effects are likely attenuated in the less acidic neonatal stomach. Systemically, nitrite acts as a reservoir of NO bioactivity that can protect against ischemic injury, yet plasma nitrite concentrations are markedly lower in infants than in adults. The physiological importance of the diminished nitrate→nitrite→NO axis in infants and its implications in the etiology and treatment of newborn diseases such as necrotizing enterocolitis and hypoxic/ischemic injury are yet to be determined.

Inhaled nitric oxide therapy increases blood nitrite, nitrate, and s-nitrosohemoglobin concentrations in infants with pulmonary hypertension.

OBJECTIVE: To measure the circulating concentrations of nitric oxide (NO) adducts with NO bioactivity after inhaled NO (iNO) therapy in infants with pulmonary hypertension. STUDY DESIGN: In this single center study, 5 sequential blood samples were collected from infants with pulmonary hypertension before, during, and after therapy with iNO (n = 17). Samples were collected from a control group of hospitalized infants without pulmonary hypertension (n = 16) and from healthy adults for comparison (n = 12). RESULTS: After beginning iNO (20 ppm) whole blood nitrite levels increased approximately two-fold within 2 hours (P<.01). Whole blood nitrate levels increased to 4-fold higher than baseline during treatment with 20 ppm iNO (P<.01). S-nitrosohemoglobin increased measurably after beginning iNO (P<.01), whereas iron nitrosyl hemoglobin and total hemoglobin-bound NO-species compounds did not change. CONCLUSION: Treatment of pulmonary hypertensive infants with iNO results in increases in levels of nitrite, nitrate, and S-nitrosohemoglobin in circulating blood. We speculate that these compounds may be carriers of NO bioactivity throughout the body and account for peripheral effects of iNO in the brain, heart, and other organs.

Nitrate reductase activity of bacteria in saliva of term and preterm infants.

The salivary glands of adults concentrate nitrate from plasma into saliva where it is converted to nitrite by bacterial nitrate reductases. Nitrite can play a beneficial role in adult gastrointestinal and cardiovascular physiology. When nitrite is swallowed, some of it is converted to nitric oxide (NO) in the stomach and may then exert protective effects in the gastrointestinal tract and throughout the body. It has yet to be determined either when newborn infants acquire oral nitrate reducing bacteria or what the effects of antimicrobial therapy or premature birth may be on the bacterial processing of nitrate to nitrite. We measured nitrate and nitrite levels in the saliva of adults and both preterm and term human infants in the early weeks of life. We also measured oral bacterial reductase activity in the saliva of both infants and adults, and characterized the species of nitrate reducing bacteria present. Oral bacterial conversion of nitrate to nitrite in infants was either undetectable or markedly lower than the conversion rates of adults. No measurable reductase activity was found in infants within the first two weeks of life, despite the presence of oral nitrate reducing bacteria such as Actinomyces odontolyticus, Veillonella atypica, and Rothia mucilaginosa. We conclude that relatively little nitrite reaches the infant gastrointestinal tract due to the lack of oral bacterial nitrate reductase activity. Given the importance of the nitrate-nitrite-NO axis in adults, the lack of oral nitrate-reducing bacteria in infants may be relevant to the vulnerability of newborns to hypoxic stress and gastrointestinal tract pathologies.

Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator.

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction ( approximately 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.

Effect of inhaled nitric oxide on cerebrospinal fluid and blood nitrite concentrations in newborn lambs.

Inhaled nitric oxide (iNO) has many extrapulmonary effects. As the half-life of nitric oxide (NO) in blood is orders of magnitude less than the circulation time from lungs to the brain, the mediator of systemic effects of iNO is unknown. We hypothesized that concentrations of nitrite, a circulating byproduct of NO with demonstrated NO bioactivity, would increase in blood and cerebrospinal fluid (CSF) during iNO therapy. iNO (80 ppm) was given to six newborn lambs and results compared with six control lambs. Blood and CSF nitrite concentrations increased 2-fold in response to iNO. cGMP increased in blood but not CSF suggesting brain guanylate cyclase activity was not increased. When sodium nitrite was infused i.v. blood and CSF nitrite levels increased within 10 min and reached similar levels of 14.6 +/- 1.5 microM after 40 min. The reactivity of nitrite in Hb-free brain homogenates was investigated, with the findings that nitrite did not disappear nor did measurable amounts of s-nitroso, n-nitroso, or iron-nitrosyl-species appear. We conclude that although nitrite diffuses freely between blood and CSF, due to its lack of reactivity in the brain, nitrite's putative role as the mediator of the systemic effects of iNO is limited to intravascular reactions.

Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants.

OBJECTIVE: To compare the incidence of low free T4 values reported by a direct equilibrium dialysis method to their incidence reported by 2 non-dialysis methods. STUDY DESIGN: Ninety-five infants, < or = 33 weeks gestational age at birth, admitted to Loma Linda University Children's Hospital before day 3 of life were studied. Infants were grouped by gestational age ranges: < or = 27, 28-30, and 31-33 weeks. Free T4 determinations were measured at 3, 7, and 14 days of life with 3 different free T4 methods. Gestational age-specific newborn reference ranges were available for the direct equilibrium dialysis method only. The only reference ranges available for the non-dialysis free T4 methods were not gestational age specific. Using available reference ranges we classified free T4 values as either low or not low. The incidence of low free T4 values was compared at 3, 7, and 14 days of life. RESULTS: Low direct equilibrium dialysis free T4 values were substantially less frequent than non-dialysis free T4 values. CONCLUSION: Substantial free T4 inconsistencies occur between dialysis and non-dialysis free T4 methods in preterm infants. It is unclear how much of this inconsistency is method dependent and how much is reference range dependent.

The use of ECMO for gastroschisis and omphalocele: Two decades of experience.

PURPOSE: The aim was to review the respiratory failure causes and outcomes of infants with omphalocele or gastroschisis receiving ECMO and reported to the Extracorporeal Life Support Organization (ELSO). METHODS: Gastroschisis and omphalocele infants supported with ECMO and reported to the ELSO Registry between 1992 and 2015 were retrospectively reviewed. Clinical variables, diagnosis of respiratory failure (pulmonary hypertension (PHN), congenital heart defects (CHD), congenital diaphragmatic hernia (CDH), and sepsis), and outcomes were recorded. Univariate analysis was performed using Student's t-test for continuous or Fisher's exact test for categorical variables. RESULTS: Fifty-two infants with gastroschisis (41) (79%) or omphalocele (11) (21%) were identified. The survival to discharge rate of 51% for gastroschisis remained stable and was significantly higher (P=0.05). The overall mortality rate for omphalocele was 82%. Omphalocele had significantly more PHN (P<0.01), CDH (P<0.01), and multiple anomalies (P=0.04) had significantly more sepsis (P=0.02), and none had a CDH. CONCLUSION: Infants with gastroschisis requiring ECMO support have significantly better survival than omphaloceles, and respiratory failure is significantly associated with sepsis. The majority of omphalocele infants die despite ECMO, and respiratory failure is associated PHN and CDH. The association of omphalocele, PHN, and CDH merits further investigation. STUDY TYPE AND EVIDENCE LEVEL: Retrospective comparative study of Registry Database, Level 3.

Comparison of 2 iron doses in infants receiving recombinant human erythropoietin therapy.

OBJECTIVE: To compare iron sufficiency in premature infants receiving high-dose recombinant human erythropoietin (r-HuEPO), 1200 IU/kg per week, supplemented with 6 or 12 mg/kg per day of enteral iron. DESIGN: We conducted a prospective, double-blind, controlled study of premature infants receiving r-HuEPO therapy, randomly assigned to receive 2 different doses of iron. Measurements of ferritin, iron, total iron-binding capacity, reticulocyte count, hemoglobin level, and hematocrit were obtained at baseline, 4, and 6 weeks. Transferrin saturation was calculated; the number of blood transfusions and the incidences of sepsis were recorded. SETTING: This study was performed in the neonatal intensive care unit at Loma Linda University Children's Hospital, Loma Linda, Calif. SUBJECTS: Infants with a gestational age of 32 weeks or younger, older than 7 days, and receiving r-HuEPO therapy from March 1, 1997, to June 30, 1998, were eligible for the study. Infants were randomly assigned to receive 6 mg/kg per day or 12 mg/kg per day of enteral iron during a course of r-HuEPO therapy for 4 to 6 weeks. RESULTS: Sixty-four infants were enrolled in the study. Twelve infants did not complete the study; 52 completed 4 weeks and 41 completed 6 weeks of the study. While ferritin levels and transferrin saturation decreased in both groups over the study period, there were no differences between the 2 study groups. CONCLUSIONS: Infants receiving high-dose r-HuEPO therapy (1200 IU/kg per week) decrease their ferritin levels (measure of iron stores) even when receiving high enteral iron supplementation. Given that the ferritin levels were similar between the 2 groups, we speculate that the additional iron either was not absorbed or was not stored.

Cerebral blood flow and oxygenation during venoarterial and venovenous extracorporeal membrane oxygenation in the newborn lamb.

BACKGROUND: Concern exists that extracorporeal membrane oxygenation (ECMO) may decrease cerebral blood flow (CBF), impair cerebral autoregulation, and thereby increase the risk of neurologic injury. OBJECTIVE: This study was undertaken in newborn lambs to compare the effects of initiation of venoarterial and venovenous ECMO on CBF and cerebral oxygen delivery as measured by laser-Doppler flowmetry. This study also evaluates the effects of carotid artery and jugular vein ligation on CBF. DESIGN: CBF, arterial blood pressure, sagittal sinus pressure, heart rate, cardiac output, arterial blood gases, and hemoglobin saturation were measured. After anesthesia, instrumentation, and a 1-2 hr stabilization period, values were recorded during a 30-min control period, and the carotid artery or jugular vein was cannulated. The animals were then studied during venoarterial or venovenous ECMO for 1 hr. MAIN RESULTS: Carotid ligation resulted in a transient decrease in right cortex CBF that resolved within 60 secs. Next, during a 60-min period of venoarterial ECMO (flow rate of 100 mL.min(-1).kg(-1), n = 11), cerebral resistance to flow increased, CBF decreased 25%, and cerebral oxygen delivery decreased by 30%. Native cardiac output and Paco(2) remained constant. Pulsatility in the lingual artery, representing the pulsatility of arterial flow to the brain, decreased throughout venoarterial ECMO. In contrast, in those lambs receiving ECMO in the venovenous mode (n = 7), resistance to flow, CBF, cerebral oxygen delivery, and pulsatility did not change. CONCLUSIONS: There was no sustained decrease in CBF after ligation of either the carotid artery or jugular vein. Venoarterial but not venovenous ECMO induced decreases of CBF that could not be attributed to changes in blood gases or blood pressure but that may relate to diminished pulsatility in cerebral resistance vessels or to differences in levels of circulating vasoactive compounds.

QTc interval in infants receiving cisapride.

OBJECTIVE: To examine the effect of cisapride on the corrected QT (QTc) interval in infants over a 14-day period. STUDY DESIGN: A prospective cohort study of infants receiving cisapride (0.8 mg/kg per day). Twelve-lead electrocardiograms were obtained before and 3, 5, 7, and 14 days after cisapride initiation. RESULTS: Fifty infants completed the study; none had arrhythmias. Fifteen of 50 infants (30%) developed QTc interval > or =450 msec; QTc interval normalized in 13 of 15 infants. Infants with QTc interval on day 3 > or =2 standard deviations above the mean baseline QTc interval (401+40 msec) were more likely to develop prolonged QTc interval (p<0.0001). CONCLUSION: QTc interval prolongation was noted in 30% of infants. Subsequently, the majority of those infants had QTc interval normalization by day 14 of cisapride therapy. QTc interval 3 days following cisapride initiation may identify infants at risk for transient QTc interval prolongation. With appropriate monitoring, hospitalized infants receiving cisapride may have improved gastrointestinal motility without cardiac morbidity.

Incidence of low free T4 values in premature infants as determined by direct equilibrium dialysis.

BACKGROUND: The incidence of transient reductions in serum free T(4) (FT(4)) in premature infants may be overestimated because certain FT(4) analytical methods underestimate FT(4) concentrations. Transient reductions of FT(4) measurements have been reported in the majority of premature newborn infants. Direct equilibrium dialysis (DED) does not underestimate FT(4) concentrations and is the best available technique to measure serum FT(4) in the premature infant. OBJECTIVE: To evaluate the incidence of low FT(4) concentrations in premature infants using DED to measure FT(4). DESIGN/METHOD: We measured FT(4) by DED in infants with birth weight <1500 g. Infants were excluded if the following conditions were present: congenital anomalies or maternal thyroid disorders. Free T(4) was measured at 14 days of life. Low FT(4) was defined using a statistical definition of FT(4) measurements <10.3 pmol/l (0.8 ng/dl). RESULTS: Free T(4) was measured by DED in 114 infants. Low FT(4) levels were seen in nine infants (7.9%). CONCLUSION: The incidence of low FT(4) was much lower than previously reported when FT(4) was measured using DED indicating that methodological issues are involved in the variability among estimates of the frequency of transient reduction in FT(4).

Nitrite and nitrate concentrations and metabolism in breast milk, infant formula, and parenteral nutrition.

Dietary nitrate and nitrite are sources of gastric NO, which modulates blood flow, mucus production, and microbial flora. However, the intake and importance of these anions in infants is largely unknown. Nitrate and nitrite levels were measured in breast milk of mothers of preterm and term infants, infant formulas, and parenteral nutrition. Nitrite metabolism in breast milk was measured after freeze-thawing, at different temperatures, varying oxygen tensions, and after inhibition of potential nitrite-metabolizing enzymes. Nitrite concentrations averaged 0.07 ± 0.01 µM in milk of mothers of preterm infants, less than that of term infants (0.13 ± 0.02 µM) (P < .01). Nitrate concentrations averaged 13.6 ± 3.7 µM and 12.7 ± 4.9 µM, respectively. Nitrite and nitrate concentrations in infant formulas varied from undetectable to many-fold more than breast milk. Concentrations in parenteral nutrition were equivalent to or lower than those of breast milk. Freeze-thawing decreased nitrite concentration ~64%, falling with a half-life of 32 minutes at 37°C. The disappearance of nitrite was oxygen-dependent and prevented by ferricyanide and 3 inhibitors of lactoperoxidase. Nitrite concentrations in breast milk decrease with storage and freeze-thawing, a decline likely mediated by lactoperoxidase. Compared to adults, infants ingest relatively little nitrite and nitrate, which may be of importance in the modulation of blood flow and the bacterial flora of the infant GI tract, especially given the protective effects of swallowed nitrite.

Pharmacokinetic analysis of 14C-ursodiol in newborn infants using accelerator mass spectrometry.

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of (14) C-ursodiol: 8 ng (1.0 nCi), 26 ng (3.3 nCi), and 80 ng (10 nCi) 48 hours apart. Three additional infants with cholestasis were administered a single 80 ng (10.0 nCi) oral dose of (14) C-ursodiol together with a therapeutic dose of 40 mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research.