Decreasing Continuous Positive Airway Pressure Failure in Preterm Infants.

BACKGROUND AND OBJECTIVES: Many preterm infants stabilized on continuous positive airway pressure (CPAP) at birth require mechanical ventilation (MV) during the first 72 hours of life, which is defined as CPAP failure. Our objective was to decrease CPAP failure in infants ≤29 weeks' gestational age (GA). METHODS: A quality improvement bundle named OPTISURF was implemented for infants ≤29 weeks' GA admitted on CPAP, consisting of stepwise escalation of CPAP and less invasive surfactant administration guided by fractional inspired oxygen concentration ≥0.3. The CPAP failure rate was tracked by using control charts. We compared practice and outcomes of a pre-OPTISURF cohort (January 2017 to September 2018) to a post-OPTISURF cohort (October 2018 to December 2019). RESULTS: Of the 216 infants ≤29 weeks' GA admitted to NICU on CPAP, 125 infants belonged to the pre-OPTISURF cohort (OSC) and 91 to the post-OSC. Compared with the pre-OSC, a higher proportion of infants in the post-OSC received CPAP 7 cm H2O within 4 hours of life (7% vs 32%; P < .01). The post-OSC also had lower rates of CPAP failure (54% vs 11%; P < .01), pneumothoraces (8% vs 1%; P < .03), need for MV (58% vs 31%; P < .01), and patent ductus arteriosus treatment (21% vs 9%; P = .02). Additionally, in a subgroup analysis, CPAP failure was lower in the post-OSC among infants 23 to 26 weeks (79% vs 27%; P < .01) and 27 to 29 weeks' GA (46% vs 3%; P < .01). CONCLUSIONS: Implementation of a quality improvement bundle including CPAP optimization and less invasive surfactant administration decreased CPAP failure and need for MV in preterm infants.

Prompt control of an outbreak caused by extended-spectrum ß-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit.

OBJECTIVES: To assess the effectiveness of a set of multidisciplinary interventions aimed at limiting patient-to-patient transmission of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae (ESBL-KP) during a neonatal intensive care unit (NICU) outbreak, and to identify risk factors associated with ESBL-KP colonization and disease in this setting. STUDY DESIGN: A 61-infant cohort present in the NICU during an outbreak of ESBL-KP from April 26, 2011, to May 16, 2011, was studied. Clinical characteristics were compared in infected/colonized infants and unaffected infants. A multidisciplinary team formulated an outbreak control plan that included (1) staff reeducation on recommended infection prevention measures; (2) auditing of hand hygiene and environmental services practices; (3) contact precautions; (4) cohorting of infants and staff; (5) alleviation of overcrowding; and (6) frequent NICU-wide screening cultures. Neither closure of the NICU nor culturing of health care personnel was instituted. RESULTS: Eleven infants in this level III NICU were infected/colonized with ESBL-KP. The index case was an 18-day-old infant born at 25 weeks' gestation who developed septicemia from ESBL-KP. Two other infants in the same room developed sepsis from ESBL-KP within 48 hours; both expired. Implementation of various infection prevention strategies resulted in prompt control of the outbreak within 3 weeks. The ESBL-KP isolates presented a single clone that was distinct from ESBL-KP identified previously in other units. Being housed in the same room as the index infant was the only risk factor identified by logistic regression analysis (P = .002). CONCLUSION: This outbreak of ESBL-KP affected 11 infants and was associated with 2 deaths. Prompt control with eradication of the infecting strain from the NICU was achieved with multidisciplinary interventions based on standard infection prevention practices.

SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter.

ABCA1 transport of cholesterol and phospholipids to nascent HDL particles plays a central role in lipoprotein metabolism and macrophage cholesterol homeostasis. ABCA1 activity is regulated both at the transcriptional level and at the post-translational level. To explore mechanisms involved in the post-translational regulation of the transporter, we have used affinity purification and mass spectrometry to identify proteins that bind ABCA1 and influence its activity. Previously, we demonstrated that an interaction between beta1-syntrophin stimulated ABCA1 activity, at least in part, be slowing the degradation of the transporter. This work demonstrates that one subunit of the serine palmitoyltransferase enzyme, SPTLC1, but not subunit 2 (SPTLC2), is copurified with ABCA1 and negatively regulates its function. In human THP-I macrophages and in mouse liver, the ABCA1-SPTLC1 complex was detected by co-immunoprecipitation, demonstrating that the interaction occurs in cellular settings where ABCA1 activity is critical for HDL genesis. Pharmacologic inhibition of SPTLC1 with myriocin, which resulted in the disruption of the SPTLC1-ABCA1 complex, and siRNA knockdown of SPTLC1 expression both stimulated ABCA1 efflux by nearly 60% ( p < 0.05). In contrast, dominant-negative mutants of SPTLC1 inhibited ABCA1 efflux, indicating that a reduced level of sphingomyelin synthesis could not explain the effect of myriocin on ABCA1 activity. In 293 cells, the SPTLC1 inhibition of ABCA1 activity led to the blockade of the exit of ABCA1 from the endoplasmic reticulum. In contrast, myriocin treatment of macrophages increased the level of cell surface ABCA1. In composite, these results indicate that the physical interaction of ABCA1 and SPTLC1 results in reduction of ABCA1 activity and that inhibition of this interaction produces enhanced cholesterol efflux.

ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol.

The highly branched mammalian lung relies on surfactant, a mixture of phospholipids, cholesterol, and hydrophobic proteins, to reduce intraalveolar surface tension and prevent lung collapse. Human mutations in the ABCA3 transporter have been associated with childhood respiratory disease of variable severity and onset. Here, we report the generation of Abca3 null mice, which became lethargic and cyanotic and died within 1 h of birth. Tissue blots found ABCA3 expression was highest in lung but was also detectable in other tissues, including the kidney. Gross development of kidney and lung was normal in neonatal Abca3(-/-) pups, but the mice failed to inflate their lungs, leading to death from atelectatic respiratory failure. Ultrastructural analysis of the Abca3(-/-) lungs revealed an absence of surfactant from the alveolar space and a profound loss of mature lamellar bodies, the intracellular storage organelle for surfactant. Mass spectrometry measurement of >300 phospholipids in lung tissue taken from Abca3(-/-) mice showed a dramatic reduction of phosphatidylglycerol (PG) levels as well as selective reductions in phosphatidylcholine species containing short acyl chains. These results establish a requirement of ABCA3 for lamellar body formation and pulmonary surfactant secretion and suggest a unique and critical role for the transporter in the metabolism of pulmonary PG. They also demonstrate the utility of the Abca3 null mouse as a model for a devastating human disease.