Treatment for Neonatal Abstinence Syndrome using Nonpharmacological Interventions.

OBJECTIVE: Management of neonatal abstinence syndrome includes nonpharmacological interventions, but their effectiveness may not be verified before implemented. The objective of this study is to evaluate the effectiveness of a type of bassinet in the treatment of infants with neonatal abstinence syndrome. STUDY DESIGN: This is a retrospective observational cohort study. Study setting involved a 24-bed open-bay Level III neonatal intensive care unit located in a metropolitan academic trauma facility. Participant inclusion criteria involved prenatally opioid-exposed infants ≥ 35 weeks with confirmed maternal opioid urine toxicology, required pharmacological treatment for withdrawal symptoms, and were admitted to the neonatal intensive care unit. Three subsets of study participants were analyzed over three different time periods: Group 1 were infants admitted during 2019 without nonpharmacological intervention, Group 2 who were admitted from September 2021 to February 2022 and received nonpharmacological interventions, and Group 3 included those admitted from February 2022 to March 2023 who received the same interventions as Group 2 but were managed in bassinets being used in other local facilities for neonatal abstinence syndrome. RESULTS: Group 3 had significant increases in length of stay compared with Group 1 (p = 0.006) and Group 2 (p = 0.013). Group 3 had a significantly greater length of treatment than Group 1 (p = 0.041) and a significantly higher total mg/kg morphine exposure than Group 1 (p = 0.006). CONCLUSION: Addition of the bassinet for nonpharmacological management of infants with neonatal abstinence syndrome appeared to prolong length of stay, length of treatment, and increase total mg/kg morphine exposure. As a retrospective nonrandomized study, weakness of low certainty of causality is of concern but findings strongly warrant further research before devices such as the bassinet used in this study are adopted for routine neonatal abstinence syndrome care. KEY POINTS: · Special bassinets are promoted to enhance sleep and decrease agitation.. · Such bassinets may assist infants undergoing drug withdrawal.. · Study of the bassinet failed to show benefit to this population..

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Implementing an exclusive human milk diet for preterm infants: real-world experience in diverse NICUs.

BACKGROUND: Human milk-based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk-based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines. METHODS: Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population. RESULTS: Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution's size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution. CONCLUSIONS: The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

Prevalence and Risk Factors for Kidney Disease and Elevated BP in 2-Year-Old Children Born Extremely Premature.

BACKGROUND AND OBJECTIVES: Extremely low gestational age neonates born <28 weeks gestation are at risk for chronic disease. We sought to describe the prevalence of kidney outcomes by gestational age and determine risk factors for their development. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Recombinant Erythropoietin for Protection of Infant Renal Disease (REPAIReD) study examined kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo NeuroProtection Trial (PENUT) study. Kidney function, urine albumin, and BP were measured at 2-year (24±2 months) corrected gestational age. We compared outcomes across gestational age categories and evaluated associations between kidney-related outcomes and neonatal and maternal characteristics. The primary outcome was eGFR <90 ml/min per 1.73 m2 (CKD); secondary outcomes were spot urine albumin-creatinine ratio ≥30 mg/g (albuminuria) and either systolic BP or diastolic BP >90th percentile for height, age, and sex. RESULTS: A total of 832 survived to 2 years, and 565 (68%) had at least one outcome measured. Overall, 297 (53%) had one abnormal kidney outcome; 61 (18%) had an eGFR <90 ml/min per 1.73 m2, 155 (36%) had albuminuria, 65 (22%) had elevated systolic BP, and 128 (44%) had elevated diastolic BP. Gestational age (odds ratio, 0.94; 95% confidence interval, 0.89 to 0.99), birth weight z-score (odds ratio, 0.92; 95% confidence interval, 0.85 to 0.98), and prenatal steroids (odds ratio, 1.23; 95% confidence interval, 1.08 to 1.39) were associated with an eGFR <90 ml/min per 1.73 m2. An elevated systolic BP was associated with indomethacin use (odds ratio, 1.18; 95% confidence interval, 1.04 to 1.33) and Black race (odds ratio, 1.19; 95% confidence interval, 1.01 to 1.39); elevated diastolic BP was associated with male sex (odds ratio, 1.29; 95% confidence interval, 1.12 to 1.49), severe AKI (odds ratio, 1.24; 95% confidence interval, 1.04 to 1.48), and indomethacin use (odds ratio, 1.16; 95% confidence interval, 1.01 to 1.33). CONCLUSIONS: Approximately 18% of extremely low gestational age neonates have CKD, 36% have albuminuria, 22% have an elevated systolic BP, and 44% have an elevated diastolic BP at 2 years of age. Gestational age, birthweight z-score, and prenatal steroids were associated with CKD. Male sex, Black race, indomethacin use, and severe AKI were associated with elevated BP. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_19_CJN15011121.mp3.

A quality improvement project improving the value of iNO utilization in preterm and term infants.

OBJECTIVE: Inhaled NO (iNO) is used in the NICU for management of hypoxemic respiratory failure. The cost of iNO is significant and does not consistently improve outcomes in infants <34 weeks. PROJECT DESIGN: Our team used The Model for Improvement to design a quality improvement project to utilize iNO for appropriate indications, ensure response to therapy and initiate timely weaning. The project was carried out at a Level IV NICU and successful interventions spread to a smaller Level III NICU. RESULTS: This project demonstrated significant improvement in all measures; total iNO hours per month, average iNO hours per patient, and the percentage of prolonged iNO courses. With an estimated cost of $115/h, the cost per patient for iNO use declined by half from $21,620 to $10,580. CONCLUSIONS: Our team improved the value of iNO utilization at our institution and spread successful interventions to another NICU in our network.

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. Objectives: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. Design, Setting, and Participants: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. Interventions: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. Main Outcomes and Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. Results: A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). Conclusions and Relevance: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions.

Pulmonary ischemia-reperfusion (IR) injury may result from trauma, atherosclerosis, pulmonary embolism, pulmonary thrombosis and surgical procedures such as cardiopulmonary bypass and lung transplantation. IR injury induces oxidative stress characterized by formation of reactive oxygen (ROS) and reactive nitrogen species (RNS). Nitric oxide (NO) overproduction via inducible nitric oxide synthase (iNOS) is an important component in the pathogenesis of IR. Reaction of NO with ROS forms RNS as secondary reactive products, which cause platelet activation and upregulation of adhesion molecules. This mechanism of injury is particularly important during pulmonary IR with increased iNOS activity in the presence of oxidative stress. Platelet-endothelial interactions may play an important role in causing pulmonary arteriolar vasoconstriction and post-ischemic alveolar hypoperfusion. This review discusses the relationship between ROS, RNS, P-selectin, and platelet-arteriolar wall interactions and proposes a hypothesis for their role in microvascular responses during pulmonary IR.

Hypothermia and the treatment of the term gestation infant with perinatal hypoxic-ischemic encephalopathy.

Although hypoxic-ischemic encephalopathy (HIE) is relatively rare, it commonly results in devastating long-term mortality and death. Intervention against this condition has been limited and frustrating. As research in this area progresses, a tremendous growth of knowledge about mechanisms involved with HIE is now contributing to the development of neuroprotective strategies. Hypothermia as a therapeutic intervention for HIE appears to be promising, as evident from recent human trials that suggest selective head cooling or total body cooling decreases the incidence of disability and death. Many questions, however, still remain unanswered about the use of hypothermia. Long-term efficacy and safety of hypothermia needs to be established before it can be recommended "as standard of care" for the treatment of neonatal HIE.

Inhibition of inducible nitric oxide synthase attenuates platelet adhesion in subpleural arterioles caused by lung ischemia-reperfusion in rabbits.

Oxidative stress, induced by lung ischemia-reperfusion, leads to platelet and leukocyte activation and may contribute to decreased alveolar perfusion by platelet adhesion to the arteriolar wall. We investigated the hypothesis that ischemia-reperfusion injury increases inducible nitric oxide synthase (iNOS) activity and subsequent generation of reactive nitrogen species with P-selectin-dependent platelet-endothelial interactions and vasoconstriction during lung reperfusion. Subpleural arterioles, labeled platelets, and leukocytes were examined in anesthetized, open-chest rabbits by intravital fluorescence microscopy. Ischemia was caused by reversible occlusion of the right pulmonary artery for 1 or 2 h (1IR and 2IR groups). During 2 h of reperfusion, postischemic platelet rolling and adhesion were independent from leukocyte-arteriolar wall interactions and correlated with pulmonary arteriolar constriction in proportion to the length of ischemia. In rabbits treated with an iNOS inhibitor (1400W) before occlusion (2IR + 1400W group), platelet-arteriolar wall interactions and vasoconstriction were prevented. iNOS expression and activity in ischemic lung tissue were markedly greater than control and also were proportional to ischemia duration. NOS activity, immunochemically detected P-selectin, and nitrotyrosine expression in ischemic lung tissue from animals subjected to ischemia-reperfusion, as well as the plasma level of soluble P-selectin, were significantly higher than in nonischemic lungs and were inhibited by pretreatment with 1400W. These results show that platelet adhesion and arteriolar constriction during early reperfusion in the ventilated lung can result from increased iNOS activity and is highly correlated with reactive nitrogen species and P-selectin expression.

Effects of exogenous surfactant on gas exchange and compliance in rabbits after meconium aspiration.

Success in using adjunctive surfactant therapy for meconium aspiration has been inconsistent. We tested the hypothesis that the ability of exogenous surfactant to improve gas exchange and pulmonary compliance after meconium aspiration is related to the method of surfactant administration. In anesthetized rabbits (2.4 +/- 0.16 kg body weight), an endotracheal tube (ETT) was placed in the lower trachea, and the lungs were ventilated mechanically. After a control period, filtered meconium (3-5 mL/kg) was instilled through the ETT. Group 1 (n = 5) was not given surfactant. Thirty minutes after meconium instillation, group 2 (n = 5) was given a bolus of bovine surfactant (Beractant, 4 mL/kg) through the ETT, and group 3 (n = 5) was given an infusion of Beractant (4 mL/kg for 1 hr) through the side-port of the ETT. Thirty minutes after meconium instillation, tracheal pressure increased by 8 +/- 1 cm H(2)O (mean +/- SEM), dynamic compliance decreased by 0.36 +/- 0.07 mL/cm H(2)O/kg, arterial PO(2) (PaO(2)) decreased by 49 +/- 6.0 mmHg, arterial PCO(2) (PaCO(2)) increased by 12 +/- 2.4 mmHg, and arterial pH (pHa) decreased by 0.09 +/- 0.02. After 3 hr of exposure to meconium, tracheal pressure was significantly (P < 0.001) lower in group 3 compared to groups 1 or 2. PaO(2) remained below baseline in all groups. Group 3 had a significantly (P = 0.001) higher dynamic compliance than groups 1 or 2. Likewise, static compliance was higher for group 3 compared to groups 1 or 2, with the greatest difference at low lung volume. Mean arterial blood pressure, pulse rate, PaCO(2), and pHa were not significantly different between groups. These results suggest that continuous infusion of exogenous surfactant is more effective than bolus administration in improving pulmonary function after meconium aspiration.

Effects of pulmonary ischemia-reperfusion on platelet adhesion in subpleural arterioles in rabbits.

Reperfusion of the ischemic lung is associated with increased pulmonary vascular resistance and reduced alveolar perfusion in conjunction with an inflammatory response. To determine the contribution of platelet-endothelial interactions, we examined effects of pulmonary ischemia-reperfusion (IR) on platelet adhesion and diameter of arterioles and investigated the hypothesis that this process is P-selectin mediated. In anesthetized rabbits with open-chest and ventilated lungs, we examined subpleural arterioles by fluorescence microscopy. Ischemia was caused by reversibly occluding the right pulmonary artery for 2 h. Fluorescently labeled platelets were injected into the right atrium and the right lung was observed after 0.5, 1.0, and 2.0 h of reperfusion. Platelets rolling and adherence along arterioles occurred with a decrease in diameter that was significant during IR, but not after 3- to 5-min occlusion (control). Systemic pretreatment with Fucoidan (a ligand to P- and L-selectin) inhibited platelet rolling, adherence, and the decrease in diameter. Pretreatment of only exogenously labeled platelets with monoclonal antibody (MoAb) to P-selectin prevented platelet rolling and adherence, but not the decrease in diameter. These results indicate that in the intact lung, pulmonary IR causes platelet rolling and adhesion along arteriolar walls, and suggest that this process, which is mediated by P-selectin, contributes to vasoconstriction and hypoperfusion. Thus, it appears that platelet-endothelial interactions may contribute to the development of pulmonary IR injury.