NAVA-synchronized compared to nonsynchronized noninvasive ventilation for apnea, bradycardia, and desaturation events in VLBW infants.

Neurally adjusted ventilatory assistance (NAVA) can overcome technical difficulties with synchronizing noninvasive ventilation breaths with the patient, a modality often used in very low birthweight infants (VLBW) with apnea of prematurity (AOP). This study is a retrospective single-center investigation into whether NAVA-synchronized noninvasive (niNAVA) ventilation is better than nonsynchronized (nasal intermittent positive pressure ventilation [nIPPV]) for symptomatic apnea in VLBW infants. Nursing records of apnea, bradycardia, and/or desaturations were abstracted from the electronic medical records of 108 VLBW infants admitted to the neonatal intensive care unit (NICU) from 2015 to 2017 who received either of the two modalities, 61 epochs of niNAVA totaling 488 days and 103 epochs of nIPPV totaling 886.5 days. niNAVA was associated with a significant reduction in the number of isolated bradycardic events/day (0.48 ± 0.14 vs 1.35 ± 0.27; P = .019) and overall bradycardias/day (2.42 ± 0.47 vs 4.02 ± 0.53; P = .042) and there were more epochs with no events with niNAVA compared with nIPPV (23.0% vs 6.8%; P = .004). These results justify a prospective trial of NAVA-synchronized noninvasive ventilation for VLBW infants with caffeine-resistant AOP.

Impact of Caffeine Boluses and Caffeine Discontinuation on Apnea and Hypoxemia in Preterm Infants.

Background: Apnea of prematurity often occurs during and following caffeine therapy. We hypothesized that number of apnea events would be impacted by adjustments in caffeine therapy. Materials and Methods: An automated algorithm was used in all infants ≤32 weeks gestation admitted to a level IV Neonatal Intensive Care Unit from 2009 to 2014 to analyze chest impedance, electrocardiogram, and oxygen saturation data around the time of serum caffeine levels, caffeine boluses while on maintenance therapy, and caffeine discontinuation. Episodes of central apnea/bradycardia/desaturation (ABDs), and percent time with SpO2 <88% and <75% were measured. Results: ABDs were analyzed in 302 preterm infants (mean gestational age 27.6 weeks) around the time of 485 serum caffeine levels, 90 caffeine boluses, and 273 episodes of caffeine discontinuation. Higher serum caffeine levels were not associated with fewer ABDs or higher heart rate. For caffeine boluses given due to clinically recognized spells, hypoxemia and algorithm-detected ABDs decreased day 1-2 after the bolus compared to the day before and day of the bolus (mean 4.4 events/day after vs. 6.6 before, p = 0.004). After caffeine discontinuation, there was no change in hypoxemia and a small increase in ABDs (2 events/day 3-5 days after discontinuation vs. 1 event/day before and >5 days after, p < 0.01). This increase in ABDs occurred irrespective of gestational age, respiratory support, or postmenstrual age at the time caffeine was stopped. Conclusions: In this retrospective analysis, caffeine boluses and caffeine discontinuation were associated with a small change in the number of ABD events in preterm infants.

Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254).

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.