Introduction of oral feeding in premature infants on high flow nasal cannula in a level IV neonatal intensive care unit: a quality improvement initiative.

BACKGROUND: Failure to reach full oral feeding remains a significant barrier for premature infants to discharge home. Postmenstrual age (PMA) at first oral feeding is significantly associated with the length of hospital stay (LOS). METHODS: Single-center QI to introduce oral feeding to infants on high-flow nasal cannula (HFNC) by reducing the flow to 2 L during feeds. GLOBAL AIM: To reduce PMA at first oral feeding and reduce the LOS. SMART AIM: To introduce oral feeds in 40% of infants who are on ≤4 L HFNC by the end of 12 months. RESULTS: Over 12 months, SMART aim reached with 100% enrollment. PMA at first oral feeding decreased from a median of 42.4w ((IQR) (40,46.6) to 37.8w (35.8,43.2), PMA at discharge decreased from 47w (44.6,50.7) to 42.6w (41.3,48.8). CONCLUSION: Allowing oral feeding in infants while on HFNC is feasible. This approach can significantly reduce PMA at first and full oral feeding.

Efficacy of recombinant erythropoietin for the late treatment of anemia of prematurity in a level IV neonatal intensive care unit: a retrospective single-center cohort study.

OBJECTIVE: To describe the population to which we administered recombinant erythropoietin and to determine the effectiveness of this treatment as quantified by the change in hematocrit. STUDY DESIGN: This retrospective chart review study included infants who received erythropoietin for the treatment of anemia of prematurity. RESULTS: There were 132 infants representing 162 unique treatment courses included in the study. The average duration of therapy was 9 days (±7) and 6 doses (±2). The average change in hematocrit (Hct) was 6.2% (SD 3.9%, p < 0.001). Rise in Hct was associated with a higher number of rEPO doses (p < 0.001) and higher postmenstrual age (p < 0.001). In our small cohort we did not find an association between the number of rEPO doses and retinopathy of prematurity (ROP) requiring treatment. CONCLUSION: Erythropoietin is safe and effective at treating anemia of prematurity as evidenced by a clinically and statistically significant increase in Hct from baseline.

The spectrum of pneumonia among intubated neonates in the neonatal intensive care unit.

We review the pathophysiology, epidemiology, diagnosis, treatment, and prevention of ventilator-associated pneumonia (VAP) in neonates. VAP has been studied primarily in adult ICU patients, although there has been more focus on pediatric and neonatal VAP (neo-VAP) in the last decade. The definition as well as diagnosis of VAP in neonates remains a challenge to date. The neonatal intensivist needs to be familiar with the current diagnostic tools and prevention strategies available to treat and reduce VAP to reduce neonatal morbidity and the emergence of antibiotic resistance. This review also highlights preventive strategies and old and emerging treatments available.

Predicting iatrogenic adrenal insufficiency in neonates exposed to prolonged steroid courses: do cortisol levels help?

OBJECTIVE: To determine whether random cortisol levels obtained in neonates to assess for secondary adrenal insufficiency (AI) after prolonged steroid exposure are predictive of central AI. STUDY DESIGN: Data were collected on neonates born 2017-2022 who received ≥10 consecutive days of systemic steroids and had cortisol measured thereafter. Data were then collected on whether those neonates developed signs of AI or had a failed adrenocorticotropic hormone (ACTH) stimulation test. RESULTS: Of the 71 cortisol levels (in 67 neonates) that were analyzed, there was no difference in cortisol levels between neonates who developed AI (median cortisol level of 6.5 mcg/dl) and those who did not (median of 9.2 mcg/dl), or between those who failed their ACTH stimulation test or passed it, using Wilcoxon ranked sum tests. CONCLUSION: These findings demonstrate that cortisol levels may not be helpful in identifying AI in neonates exposed to prolonged steroids.

Use of surfactant beyond respiratory distress syndrome, what is the evidence?

Surfactant replacement therapy is currently approved by the United States Food and Drug Administration (FDA) for premature infants with respiratory distress syndrome (RDS) caused by surfactant deficiency due to immaturity. There is strong evidence that surfactant decreases mortality and air leak syndromes in premature infants with RDS. However, surfactant is also used "off-label" for respiratory failure beyond classic RDS. This review discusses current evidence for the use of off-label surfactant therapy for (1) term infants with lung disease such as meconium aspiration syndrome (MAS), pneumonia/sepsis, and congenital diaphragmatic hernia (2) premature infants after 72 h for acute respiratory failure, and (3) the use of surfactant lavage. At last, we briefly describe the use of surfactants for drug delivery and the current evidence on evaluating infants for surfactant deficiency.

Pharmacotherapy of BPD: Current status & future perspectives.

Bronchopulmonary dysplasia (BPD) is a disease exclusive to prematurity and has changed in its definition since Northway first described it in 1967. There have been countless clinical trials evaluating the efficacy of drugs in the treatment and prevention of BPD in human subjects, and an even larger number of animal studies. Despite these, only a handful of drugs are used at the bedside today, primarily due to the lack of consistent efficacy seen in clinical trials or due to reports of adverse effects. This review summarizes the list of the most commonly used drugs and emerging new therapies which target BPD and BPD-related pulmonary hypertension (BPD-PH), including those which have shown promise in human trials but are not yet used routinely.

Infrared light elicits endothelium-dependent vasodilation in isolated occipital arteries of the rat via soluble guanylyl cyclase-dependent mechanisms.

The left and right occipital arteries provide blood supply to afferent cell bodies in the ipsilateral nodose and petrosal ganglia. This supply is free of an effective blood-ganglion barrier, so changes in occipital artery blood flow directly affect the access of circulating factors to the afferent cell bodies. The application of infrared (IR) light to modulate neural and other cell processes has yielded information about basic biological processes within tissues and is gaining traction as a potential therapy for a variety of disease processes. To address whether IR can directly modulate vascular function, we performed wire myography studies to determine the actions of IR on occipital arteries isolated from male Sprague-Dawley rats. Based on our previous research that functionally-important differences exist between occipital artery segments close to their origin at the external carotid artery (ECA) and those closer to the nodose ganglion, the occipital arteries were dissected into two segments, one closer to the ECA and the other closer to the nodose ganglion. Segments were constricted with 5-hydroxytryptamine to a level equal to 50% of the maximal response generated by the application of a high (80 mM) concentration of K+ ions. The direct application of pulsed IR (1,460 nm) for 5 s produced a rapid vasodilation in occipital arteries that was significantly more pronounced in segments closest to the ECA, although the ECA itself was minimally responsive. The vasodilation remained for a substantial time (at least 120 s) after cessation of IR application. The vasodilation during and following cessation of the IR application was markedly diminished in occipital arteries denuded of the endothelium. In addition, the vasodilation elicited by IR in endothelium-intact occipital arteries was substantially reduced in the presence of a selective inhibitor of the nitric oxide-sensitive guanylate cyclase, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ). It appears that IR causes endothelium-dependent, nitric-oxide-mediated vasodilation in the occipital arteries of the rat. The ability of IR to generate rapid and sustained vasodilation may provide new therapeutic approaches for restoring or improving blood flow to targeted tissues.

The Pandemic Allocation of Ventilators Model Penalizes Infants with Bronchopulmonary Dysplasia.

During the COVID-19 pandemic, institutions developed ventilator allocation models. In one proposed model, neonates compete with adults for ventilators using a scoring system. Points are given for conditions that increase one- and five-year (y) mortality. For example, comparable points were added for adult conditions with mortality of 71.3% and for neonates with moderate or severe bronchopulmonary dysplasia (mod/sBPD). We hypothesized that this model overestimates mortality in neonates with BPD and would penalize these infants unfairly. There was little information available on 1 y and 5 y mortality risk for mod/sBPD. To evaluate this allocation protocol, a retrospective chart review was performed on infants born ≥22 weeks and weighing <1500 g admitted to Rainbow Babies and Children's Hospital in 2015 to identify babies with BPD. The main outcomes were 1 and 5 y mortality. In 2015, 28 infants were diagnosed with mod/s BPD based on NIH 2001 definition; 4 infants had modBPD and 24 had sBPD. All infants (100%) with modBPD survived to 5 y; 2 infants with sBPD died by 1 y (8%) and 22 survived (92%) to 1 y; 3 died (12.5%) by 5 y; and at least 13 survived (54%) to 5 y. Infants with mod/s BPD had lower-than-predicted 1 and 5 y mortality, suggesting the points assigned in the model are too high for these conditions. We believe this model would unfairly penalize these babies.

RDS-NExT workshop: consensus statements for the use of surfactant in preterm neonates with RDS.

OBJECTIVE: To provide the best clinical practice guidance for surfactant use in preterm neonates with respiratory distress syndrome (RDS). The RDS-Neonatal Expert Taskforce (RDS-NExT) initiative was intended to add to existing evidence and clinical guidelines, where evidence is lacking, with input from an expert panel. STUDY DESIGN: An expert panel of healthcare providers specializing in neonatal intensive care was convened and administered a survey questionnaire, followed by 3 virtual workshops. A modified Delphi method was used to obtain consensus around topics in surfactant use in neonatal RDS. RESULT: Statements focused on establishing RDS diagnosis and indicators for surfactant administration, surfactant administration methods and techniques, and other considerations. After discussion and voting, consensus was achieved on 20 statements. CONCLUSION: These consensus statements provide practical guidance for surfactant administration in preterm neonates with RDS, with a goal to contribute to improving the care of neonates and providing a stimulus for further investigation to bridge existing knowledge gaps.

Patent Ductus Arteriosus Response to Treatment by Course and Associations with Perinatal and Clinical Factors.

OBJECTIVE: The objective of this study is to examine patent ductus arteriosus (PDA) response by treatment course and investigate associations with postmenstrual age (PMA), chronological age (CA), gestational age (GA), antenatal steroid exposure (ANS), birthweight (BW), weight at treatment initiation (WT), and PDA/left pulmonary artery (LPA) ratio. STUDY DESIGN: This is a single-center retrospective cohort study of preterm infants less than 37 weeks' GA born January 1, 2016 to December 31, 2018 who received acetaminophen and/or indomethacin for PDA treatment. Cox proportional hazards regression models were used to determine whether factors of interest were associated with PDA response to medical treatment. RESULTS: In total, 289 treatment courses were administered to 132 infants. Thirty-one (23%) infants experienced treatment-associated PDA closure. Ninety-four (71%) infants had evidence of PDA constriction following any treatment course. Ultimately, 84 (64%) infants experienced definitive PDA closure. For each 7-day increase in CA at the time of treatment initiation, the PDA was 59% less likely to close (p = 0.04) and 42% less likely to respond (i.e., constrict or close) to treatment (p < 0.01). PDA/LPA ratio was associated with treatment-associated PDA closure (p = 0.01). For every 0.1 increase in the PDA/LPA ratio, the PDA was 19% less likely to close in response to treatment. CONCLUSION: In this cohort, PDA closure is independent of PMA, GA, ANS, BW, and WT; however, CA at treatment initiation predicted both treatment-associated PDA closure and PDA response (i.e., constriction or closure), and PDA/LPA ratio was associated with treatment-associated closure. Most infants experienced PDA constriction rather than closure, despite receiving up to four treatment courses. KEY POINTS: · Detailed PDA responses for up to four treatment courses provide a novel perspective.. · Chronological age at the start of treatment predicted treatment-associated PDA closure and response.. · For each 7-day increase in chronological age, the PDA was 59% less likely to close..

2022 Year in review: Neonatal pulmonology.

This review outlines some of the major contributions to Neonatal Pulmonology published in 2022 in Pediatric Pulmonology in the areas of lung ultrasound, prevention and treatment of bronchopulmonary dysplasia, and pulmonary function outcomes of neonatal lung disease.

Evaluation of Intravenous Immunoglobulin Administration for Hyperbilirubinemia in Newborn Infants with Hemolytic Disease.

The primary objective of this research was to evaluate the use of intravenous immunoglobulin (IVIG) in infants with hemolytic disease, to assess compliance with the American Academy of Pediatrics (AAP) guideline recommendations, and to review the data on which the guidelines were based. This retrospective study evaluated all infants in the NICU (neonatal intensive care unit) who received IVIG between January 2018 and December 2020 (n = 71). Total serum bilirubin (TSB) levels surrounding the time of IVIG administration, rate of rise of bilirubin, and direct antiglobulin test (DAT) status were evaluated to determine the appropriateness of IVIG use based on the 2004 AAP recommendations that was current at the time of the study. Fifty-nine infants received IVIG for hyperbilirubinemia. Of them, 80% had an ABO mismatch, 19% had Rh mismatch, and 71% were DAT-positive. Phototherapy was started at an average of 7 h of age, and the first IVIG dose was administered at an average of 13 h of life; nearly 25% received a second IVIG dose. One infant (1.6%) met all three AAP guideline criteria of being DAT-positive, bilirubin within 3 of exchange level, and rising bilirubin despite intensive phototherapy. Twenty-five (42%) babies were DAT positive and met one of the other two criteria. Only 12% (n = 7) had a bilirubin within 3 of exchange level. Most infants who received IVIG for hyperbilirubinemia did not meet the AAP criteria, prompting us to develop an institution-specific IVIG clinical practice guideline. The 2022 AAP guideline was published after our study was completed, but it confirmed our belief that IVIG usage should be more restricted and the criteria more explicit.

The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester.

This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency of breathing, expiratory time, tidal volume, minute ventilation, or expiratory drive but pronounced changes in inspiratory time, end-inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF50, relaxation time, apneic pause, inspiratory drive and non-eupneic breathing index, (b) minimal changes in arterial blood-gas (ABG) chemistry (pH, pCO2, pO2, SO2) and Alveolar-arterial (A-a) gradient (index of alveolar gas exchange), and (c) minimal changes in antinociception (tail-flick latency). Subsequent injection of morphine (10 mg/kg, IV) elicited markedly smaller effects on the above parameters, ABG chemistry, and A-a gradient in rats receiving L-CYSee, whereas morphine antinociception was not impaired. Infusions of L-cysteine or L-serine ethyl ester (oxygen rather than sulfur moiety), did not affect morphine actions on ABG chemistry or A-a gradient. L-CYSee (250 µmol/kg, IV) injection elicited dramatic changes in ventilatory parameters given 15 min after injection of morphine in rats receiving L-CYSee. Our findings suggest that (a) L-CYSee acts in neurons that drive ventilation, (b) L-CYSee reversal of the adverse actions of morphine on ventilation, ABG chemistry and A-a gradient may be via modulation of intracellular signaling pathways activated by morphine rather than by direct antagonism of opioid receptors since morphine antinociception was not diminished by L-CYSee, and (c) the thiol moiety of L-CYSee is vital to efficacy, (d) intracellular conversion of L-CYSee to an S-nitrosylated form may be part of its mechanism of action.

A quality improvement initiative to standardize time to initiation of enteral feeds after non-surgical necrotizing enterocolitis using a consensus-based guideline.

BACKGROUND: Recent evidence demonstrates that earlier feeding may be beneficial after non-surgical necrotizing enterocolitis (NEC). We aimed to decrease time to reach full enteral feeds by 20% post-NEC by standardizing time to reinitiate feeds. METHODS: We implemented a consensus-based guideline for earlier feeding post-NEC. Outcome measures included days to initiate enteral feeds and reach full enteral feeds. Central venous line days and length of stay were also evaluated. Balancing measures were NEC recurrence and post-NEC stricture. Statistical analysis used process control methodology and standard comparison statistical testing. RESULTS: Average days infants with Stage II NEC began feeding decreased from 9.4 to 5.1 days and average days to reach full feeds was decreased by 35% from 24.0 to 15.7 days. We observed no change in our balancing measures. CONCLUSION: A multidisciplinary consensus-based NEC earlier feeding guideline decreased time to reach full enteral feeds and reduced central line days without adverse events.

A predictive model for preterm babies born < 30 weeks gestational age who will not attain full oral feedings.

OBJECTIVE: Develop a model to predict gastrostomy tube (GT) for feeding at discharge in infants born < 30 weeks' (w) gestational age (GA). STUDY DESIGN: A single-center retrospective study at academic NICU. Total of 391 (78 GT, 313 non-GT) infants < 30 w GA admitted in 2015-2018 split into test (15-16) and validation (17-18) cohorts. Classification and regression tree analysis was used to identify predictive factors for GT. RESULTS: Several factors were associated with GT requirements. Four factors included in the model were postmenstrual age (PMA) at first oral feeding, birth GA, high-frequency ventilation exposure, necrotizing enterocolitis stage II/III. Area under the receiver operator characteristic curve was 0.944 in the test cohort, 0.815 in the validation cohort. Implementation plan based on the model was developed. CONCLUSIONS: We developed a predictive model to risk-stratify infants born < 30 w GA for failing full oral feeding. We hope implementation at 38 w PMA will result in earlier placement of needed GT and discharge.

Oxygen and steroids affect the regulatory role of natriuretic peptide receptor-C on surfactant secretion by type II cells.

Atrial natriuretic peptide (ANP) and its receptors natriuretic peptide receptor (NPR)-A and NPR-C are all highly expressed in alveolar epithelial type II cells (AEC2s) in the late-gestation ovine fetal lung and are dramatically decreased postnatally. However, of all the components, NPR-C stimulation inhibits ANP-mediated surfactant secretion. Since alveolar oxygen increases dramatically after birth, and steroids are administered to mothers antenatally to enhance surfactant lung maturity, we investigated the effects of O2 concentration and steroids on NPR-C-mediated surfactant secretion in AEC2s. NPR-C expression was highest at 5% O2 while being suppressed by 21% O2, in cultured mouse lung epithelial cells (MLE-15s) and/or human primary AEC2s. Surfactant protein-B (SP-B) was significantly elevated in media from both in vitro and ex vivo culture at 13% O2 versus 21% O2 in the presence of ANP or terbutaline (TER). Both ANP and C-ANP (an NPR-C agonist) attenuated TER-induced SP-B secretion; this effect was reversed by dexamethasone (DEX) pretreatment in AEC2s and by transfection with NPR-C siRNA in MLE-15 cells. DEX markedly reduced AEC2 NPR-C expression, and pregnant ewes treated with betamethasone showed reduced ANP in fetal sheep lung fluid. These data suggest that elevated O2 downregulates AEC2 NPR-C and that steroid-mediated NPR-C downregulation in neonatal lungs may provide a novel mechanism for their effect on perinatal surfactant production.

Severity of respiratory disease is correlated with time of first oral feeding and need for a gastrostomy tube at discharge in premature infants born at <30 weeks of gestation.

BACKGROUND: Premature infants who cannot achieve full oral feeds may need a gastrostomy tube (GT) to be discharged from the neonatal intensive care unit (NICU). We previously developed a model to predict which infants born <30 weeks (w) gestational age (GA) will require a GT before discharge. Here we report the detailed respiratory variable data to describe the general respiratory course for infants in the NICU < 30 w GA at birth and the association between different levels of respiratory support with postmenstrual age (PMA) at the time of first oral feeding attempt (PMAff), including later need for GT for discharge. METHODS: Retrospective chart review of 391 NICU admissions comprising test (2015-2016) and validation (2017-2018) cohorts. Data, including respiratory support, were collected on 204 infants, 41 GT and 163 non-GT, in the test cohort, and 187 infants, 37 GT, and 150 non-GT, in the validation cohort. RESULTS: Respiratory data were significantly different between GT and non-GT infants. Infants who required GT for discharge were on significantly higher respiratory support at 30 days of age, 32 w PMA, and 36 w PMA. Respiratory parameters were highly correlated with PMAff. CONCLUSION: Respiratory status predicts PMAff, which was the variable in our previously described model that was most predictive of failure to achieve full oral feeding. These data provide a catalyst to develop strategies for improving oral feeding outcome for infants requiring prolonged respiratory support in the NICU.

Dexamethasone Alters Tracheal Aspirate T-Cell Cytokine Production in Ventilated Preterm Infants.

Postnatal corticosteroids improve respiratory status and facilitate respiratory support weaning in preterm infants with bronchopulmonary dysplasia (BPD). Older literature describes characteristic cytokine profiles in tracheal aspirates (TA) of BPD patients which are altered with corticosteroids. Corticosteroids also influence peripheral blood T-cell presence. However, little is known regarding TA T-cell phenotype and cytokine production before or after exogenous corticosteroids. We hypothesized that postnatal dexamethasone alters the TA T-cell cytokine profiles of preterm infants. TA samples were collected from 14 infants born from 23 0/7 to 28 6/7 weeks who were mechanically ventilated for at least 14 days. Samples were collected up to 72 h before a ten-day dexamethasone course and again 1 to 3 calendar days after dexamethasone initiation. The primary outcome was change in T cell populations present in TA and their intracellular cytokine profile after dexamethasone treatment, ascertained via flow cytometry. Following dexamethasone treatment, there were significant decreases in respiratory severity score (RSS), percent CD4+IL-6+ cells, CD8+IL-6+ cells, CXCR3+IL-6+ cells, and CXCR3+IL-2+ cells and total intracellular IFN-γ in TA. RSS significantly correlated with TA percent CD4+IL-6+ cells. To our knowledge, this is the first study demonstrating that dexamethasone reduced T-cell IL-6 and this reduction was associated with improved RSS in pre-term infants with evolving BPD.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. METHODS: AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. RESULTS: AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. CONCLUSIONS: These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.