Maturational effect of leptin on CO2 chemosensitivity in newborn rats.

BACKGROUND: Leptin augments central CO2 chemosensitivity and stabilizes breathing in adults. Premature infants have unstable breathing and low leptin levels. Leptin receptors are on CO2 sensitive neurons in the Nucleus Tractus Solitarius (NTS) and locus coeruleus (LC). We hypothesized that exogenous leptin improves hypercapnic respiratory response in newborn rats by improving central CO2 chemosensitivity. METHODS: In rats at postnatal day (p)4 and p21, hyperoxic and hypercapnic ventilatory responses, and pSTAT and SOCS3 protein expression in the hypothalamus, NTS and LC were measured before and after treatment with exogenous leptin (6 µg/g). RESULTS: Exogenous leptin increased the hypercapnic response in p21 but not in p4 rats (P ≤ 0.001). At p4, leptin increased pSTAT expression only in the LC, and SOCS3 expression in the NTS and LC; while at p21 pSTAT and SOCS3 levels were higher in the hypothalamus, NTS, and LC (P ≤ 0.05). CONCLUSIONS: We describe the developmental profile of the effect of exogenous leptin on CO2 chemosensitivity. Exogenous leptin does not augment central CO2 sensitivity during the first week of life in newborn rats. The translational implication of these findings is that low plasma leptin levels in premature infants may not be contributing to respiratory instability. IMPACT: Exogenous leptin does not augment CO2 sensitivity during the first week of life in newborn rats, similar to the developmental period when feeding behavior is resistant to leptin. Exogenous leptin increases CO2 chemosensitivity in newborn rats after the 3rd week of life and upregulates the expression of pSTAT and SOC3 in the hypothalamus, NTS and LC. Low plasma leptin levels in premature infants are unlikely contributors to respiratory instability via decreased CO2 sensitivity in premature infants. Thus, it is highly unlikely that exogenous leptin would alter this response.

Ultrasonographic assessment of diaphragmatic function in preterm infants on non-invasive neurally adjusted ventilatory assist (NIV-NAVA) compared to nasal intermittent positive-pressure ventilation (NIPPV): a prospective observational study.

NIV-NAVA mode for respiratory support in preterm infants is not well-studied. This study aimed to describe the diaphragmatic function, diaphragmatic excursion (DE), and thickness fraction (DTF), in preterm infants < 30 weeks' gestation supported by NIV-NAVA compared to NIPPV using bedside ultrasonography. In this consecutive prospective study, DE, diaphragmatic thickness at end of expiration (DTexp), end of inspiration (DTins), and DTF were assessed using bedside ultrasound. Lung aeration evaluation using lung ultrasound score (LUS) was performed for the two groups. Diaphragmatic measurements and LUS were compared for the 2 groups (NIV-NAVA group versus NIPPV group). Statistical analyses were conducted using the SPSS software version 22. Out of 70 infants evaluated, 40 were enrolled. Twenty infants were on NIV-NAVA and 20 infants on NIPPV with a mean [SD] study age of 25.7 [0.9] weeks and 25.1 [1.4] weeks respectively (p = 0.15). Baseline characteristics and respiratory parameters at the time of the scan showed no significant difference between groups. DE was significantly higher in NIV-NAVA with a mean SD of 4.7 (1.5) mm versus 3.5 (0.9) mm in NIPPV, p = 0.007. Additionally, the mean (SD) of DTF for the NIV-NAVA group was 81.6 (30) % vs 78.2 (27) % for the NIPPV group [p = 0.71]. Both groups showed relatively high LUS but no significant difference between groups [12.8 (2.6) vs 12.6 (2.6), p = 0.8].  Conclusion: Preterm infants managed with NIV-NAVA showed significantly higher DE compared to those managed on NIPPV. This study raises the hypothesis that NIV-NAVA could potentially improve diaphragmatic function due to its synchronization with patients' own breathing. Longitudinal studies to assess diaphragmatic function over time are needed.  Trial registry: Clinicaltrials.gov (NCT05079412). Date of registration September 30, 2021. What is Known: • NIV-NAVA utilizes diaphragmatic electrical activity to provide synchronized breathing support. • Evidence for the effect of NIV-NAVA on diaphragmatic thickness fraction (DTF) and excursion (DE) is limited. What is New: • Ultrasonographic assessment of diaphragmatic function (DTF and DE) is feasible. • In preterm infants, DE was significantly higher in infants supported with NIV-NAVA compared to those supported with NIPPV.

Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat.

BACKGROUND: Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. METHOD: We measured the acetaminophen dose-response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. RESULTS: Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with L-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone CONCLUSIONS: In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.

Chronic Intermittent Hypoxia in Premature Infants: The Link Between Low Fat Stores, Adiponectin Receptor Signaling and Lung Injury.

Premature infants have chronic intermittent hypoxia (CIH) that increases morbidity, and the youngest and the smallest premature infants are at the greatest risk. The combination of lung injury from inflammation/oxidative stress causing low functional residual capacity combined with frequent short apneas leads to CIH. Adiponectin (APN) is an adipose-derived adipokine that protects the lung from inflammation and oxidative stress. Premature and small for gestational age (SGA) infants have minimal body fat and low levels of circulating APN. To begin to understand the potential role of APN in lung protection during lung development, we characterized the developmental profile of APN and APN receptors (AdipoR1 and AdipoR2) protein and mRNA expression in the newborn rat lung at fetal day (FD) 19, and postnatal days (PD) 1, 4, 7, 10, 14, 21, and 28. Protein levels in lung homogenates were measured by western blot analyses; relative mRNA expression was detected by quantitative PCR (qPCR); and serum high molecular weight (HMW) APN was measured using enzyme-linked immunosorbent assay (ELISA). Results: APN protein and mRNA levels were lowest at FD19 and PD1, increased 2.2-fold at PD4, decreased at PD10, and then increased again at PD21. AdipoR1 protein and mRNA levels peaked at PD1, followed by a threefold drop by PD4, and remained low until PD21. AdipoR2 protein and mRNA levels also peaked at PD1, but remained high at PD4, followed by a 1.7-fold drop by PD10 that remained low by PD21. Serum APN levels detected by ELISA did not differ from PD4 to PD28. To date, this is the first report characterizing APN and APN receptor protein and mRNA expression in the rat lung during development. The developmental stage of the newborn rat lung models that of the premature human infant; both are in the saccular stage of lung development. In the newborn rat lung, alveolarization begins at PD4, peaks at PD10, and ends at PD21. Importantly, we found that AdipoR1 receptor protein and mRNA expression is lowest during lung alveolarization (PD4 to PD21). Thus, we speculate that low levels of AdipoR1 during lung alveolarization contributes to the increased susceptibility to developing acute lung edema and chronic lung injury such as bronchopulmonary dysplasia (BPD) in premature human infants.

Elevated Baseline Cortisol Levels Are Predictive of Bad Outcomes in Critically Ill Children.

OBJECTIVE: The definition of an adequate adrenal response in critically ill children continues to be controversial. We aimed to evaluate the cortisol levels at baseline and after adrenocorticotropin (ACTH) stimulation and determine their association to clinical outcome of critically ill children. METHODS: All children who underwent an ACTH test in the pediatric intensive care unit (PICU) in a tertiary medical center between 2006 and 2013 were included in the study. Data on age, sex, diagnosis, vasoactive-inotropic score, length of pediatric intensive care unit stay, and mortality were obtained. Laboratory variables included hematologic and chemistry data, arterial lactate, and total plasma cortisol levels at baseline and after ACTH stimulation. RESULTS: Ninety-nine patients (61 males; median [range] age, 2 [0-204] months) were enrolled. The mortality rate of children with a baseline cortisol level of 600 nmol/L or greater was 36% (12/33 patients) versus 18% (12/66 patients) for children with a baseline cortisol level of less than 600 nmol/L (odds ratio, 2.6 [95% confidence interval, 1-6.6]; P = 0.05). There was a positive correlation between baseline cortisol and lactate levels (r = 0.40, P < 0.0001), vasoactive-inotropic scores (r = 0.24, P = 0.02), and mortality (P = 0.05). There was no correlation between peak cortisol measured at the ACTH test or the delta increment of cortisol from baseline and mortality. CONCLUSIONS: A high baseline cortisol level in critically ill children was associated with more severe illness, higher lactate level, and a higher mortality rate. Routine baseline cortisol assessment is recommended to identify patients at high mortality risk.

Follow-up of newborns of mothers with Graves' disease.

BACKGROUND: Overt neonatal Graves' disease is rare, but may be severe, even life threatening, with deleterious effects on neural development. The main objective of this study was to describe the course of thyrotropin (TSH) and free thyroxin (fT4) levels, as well as postnatal weight gain in relation to fT4 levels, in neonates born to women with Graves' disease without overt neonatal thyrotoxicosis. Such information is important to deduce the optimal schedule for evaluation. METHODS: We conducted a retrospective chart review of neonates born to mothers with Graves' disease between January 2007 and December 2012. The records were reviewed for sex, gestational age, birth weight, maternal treatment during pregnancy, and maternal thyroid stimulating immunoglobulin (TSI) level. For each visit in the clinic, the data included growth parameters, presence of symptoms suspected for hyperthyroidism, blood test results (levels of TSH, fT4, and TSI), and treatment. RESULTS: Ninety-six neonates were included in the study (49 males), with a total of 320 measurements of thyroid function tests (TSH and fT4). Four neonates (4%) had overt neonatal Graves' disease; one of them along with nine others were born preterm. In 77 (92.9%) of the remaining 83 neonates (the subclinical group), fT4 levels were above the 95th percentile on day 5. All had normal fT4 on day 15. A negative association was found between fT4 and weight gain during the first two weeks. CONCLUSIONS: In this cohort, most neonates born to mothers with Graves' disease had a subclinical course with abnormal fT4 levels that peaked at day 5. After day 14, all measurements of fT4 returned to the normal range, although measurements of TSH remained suppressed for up to three months. Elevated fT4 was associated with poor weight gain.