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BACKGROUND: Inhaled nitric oxide (INO) has been used with heated and humidified high-flow nasal cannula (HFNC), nasal CPAP and several forms of noninvasive ventilation (NIV). This study was designed to evaluate the delivered dose of INO, level of NO2 generation, and effect of net gas delivery (addition of INO to the ventilator circuit - gas removed for sampling) on lung pressure at different NO doses during noninvasive respiratory support. METHODS: An infant lung model was supported with the different noninvasive modes during INO therapy. NO and NO2 were measured from within the patient circuit of the noninvasive devices and simulated neonatal trachea at several NO levels. Lung pressures were compared with and without INO and at several INO settings. RESULTS: Accuracy of NO delivery was determined to be within the stated accuracy by the manufacturer with nasal CPAP and NIV, but accuracy was compromised during HFNC. INO and NO2 measured by the INOmax DSIR (Ikaria, Hampton, New Jersey) did not consistently reflect the delivered dose of NO or formation of NO2 across all types of neonatal noninvasive respiratory support. Tracheal NO2 levels were <1.5ppm with all forms of noninvasive support, except nasal intermittent mandatory ventilation at 40ppm INO. Lung model mean airway pressures were mildly affected by gas sampling/delivery during combined INO therapy/HFNC at certain flows but remained stable with all other forms of noninvasive support. CONCLUSIONS: Clinicians cannot always assume that the set INO level results in a similar lung dose when using all forms of neonatal noninvasive support. Clinical decisions regarding ways to improve INO delivery may need to include changing settings or placing patients on a different form of noninvasive support. The NO2 level delivered to the patient could be greater than the value recorded by the INO delivery system. [ABSTRACT FROM AUTHOR]

CXCR4, the chemotactic cell receptor for SDF-1α, is essential for immune trafficking and HIV infection. CXCR4 is remarkably heterogeneous and the purpose of this study was to better identify the isoforms expressed by cells and compare their structure and function. We found that cells express either a predominant isoform or multiple isoforms. These were best resolved on SDS-PAGE using sucrose-gradient-fractionated, triton-insoluble, membrane extracts. We hypothesized that glycosyl modification may underpin some of this heterogeneity and that cell isoform(s) differences may underscore CXCR4's multiple cell functions. A comparison of wild-type (WT) and dual N-linked glycosylation site, N11A/N176A, mutant CXCR4 expressed in 3T3 and HEK-293 cells served to implicate variabilities in glycosylation and oligomerization in almost half of the isoforms. Immunoprecipitation of CXCR4 revealed monomer and dimer non-glycosylated forms of 34 kDa and 68 kDa from the N11A/N176A mutant, compared with glycosylated 40 kDa and 47 kDa and 73 kDa and 80 kDa forms from WT. The functional specificity of isoform action was also implicated because, despite CEMT4 cells expressing high levels of CXCR4 and 11 different isoforms, a single 83 kDa form was found to bind gp120 for HIV-1 IIIB infection. Furthermore, comparative studies found that in contrast to SDF-1α-responsive Nalm-6 cells that expressed similar levels of a single isoform, CEMT4 cells did not show a Ca++ flux or a chemotactic response to SDF-1α. Thus, CXCR4 can differ both structurally and functionally between cells, with HIV-1 infection and chemotaxis apparently mediated by different isoforms. This separation of structure and function has implications for understanding HIV-1 entry and SDF-1α responses and may indicate therapeutic possibilities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neonatal volume-targeted modes adjust peak inspiratory pressure (PIP) in response to a measured tidal volume (VT). Several ventilator manufacturers offer these modes but there are differences per brand about location of VT monitoring and whether the PIP is adjusted based on measured inspiratory, expiratory, or a leak compensated VT. We hypothesized that there would be no differences in PIP, PEEP, mean airway pressure, inspiratory work of breathing, and gas exchange in surfactant-deficient, spontaneously breathing juvenile rabbits (with and without ET tube leak) between modes that regulate PIP based on inspiratory, expiratory, or leak corrected VT measurements. METHODS: Rabbits (1.61 ± 0.20 kg, n=12) were sedated, anesthetized, intubated, and favaged, and then stabilized on mechanical ventilation. The trachea was dissected and umbilical tape was used to adjust the size of the ET tube leak. An esophageal balloon was placed to estimate pleural pressure. Animals were randomized and in a crossover design to be supported by AVEA (Carefusion, Yorba Linda, CA), VN500 (Draeger, Lubeck, Germany), and Servo I (Maquet, Solna, Sweden) with and without an induced ET tube leak (50% at PIP 20 cmH2O). These ventilators use expiratory VT (proximal), leak-corrected VT (proximal) and inspiratory V (at ventilator) measurements, respectively to guide PIP adjustment. After 20 min, ABG, pressure rate product, VT and pressures were recorded at each condition. RESULTS: When an ET Tube leak was not present, the AVEA had lower PEEP than the VN500 and Servo I (P<0.05) and lower PIP and Vr than the Servo-I (P<0.05). There were no other differences in the other physiologic parameters. When a mpderate tube leak was implemented, the AVEA and VN500 ventilators modes increased PIP; whereas the Servo 1 reduced PIP by -4 cmHTO. V, and pH were greater with the AVEA and VN500 and pressure rate product lower with the VNS00 than the Servo-I (P<0.05) with an ET Tube leak. DISCUSSION/CONCLUSION: A major finding from this study is that all subjects were able to be supported similarly without an ET tube leak. Modes that allow VT monitoring using a proximal flow sensor placed at the airway to guide PIP adjustments during volume-targeted ventilation may be more effective in providing ventilation when ET Tube leaks exist. Studies in human infants need to be conducted to validate these findings and guide development in future ventilator mode designs. Sponsored Research - Draeger provided the research funding but had no input into study design, equipment, lab space, or writing of this abstract. [ABSTRACT FROM AUTHOR]

BACKGROUND: Infants with hypoxic lung disease and pulmonary hypertension may require W-ECLS to support gas exchange. In the clinical setting, iNO therapy is commonly discontinued once a neonate is placed on W-ECLS. Depending on the severity of lung disease and degree of lung inflation, gas exchange may still occur at the alveolar-capillary membrane. As such, there is potential for iNO to be an effective treatment option. We hypothesized that iNO therapy at 20 ppm would result in no differences in gas exchange and hemodynamic parameters in juvenile piglets with thromboxane-induced pulmonary hypertension supported by W-ECLS. METHODS: Sedated piglets (n=4) were rracheotomized, supported by a mechanical ventilator, and instrumented with hemodynamic catheters to monitor mean arterial pressure (MAP), central venous pressure (CVP), pulmonary arterial pressure (PAP), and arterial gas exchange. Piglets were then cannulated for W-ECLS using a catheter placed into the IVC and right atrium. ECLS support was initiated and VT was maintained at 5 ml./kg (~40% of a piglet's resting spontaneous VT). Thromboxane was administered to induce pulmonary hypertension by doubling the mean pulmonary artery pressure (MPAP) from baseline. The iNOvent (Ikaria, Hampton, NJ) was placed inline with the ventilator. Following a 30 min stabilization period, hemodynamic parameters and blood gases were obtained without iNO therapy. The iNO therapy was initiated at 20 ppm and physiologic measurements were obtained after 15 minutes. RESULTS: The use of iNO at 20 ppm during W ECLS resulted in lower PAP and greater PaO2 (p<0.05) than when no iNO was administered. There were no differences in HR (p=0.44), MAP (p=0.56), CVP (p-0.26), pH (p=0.97) and PaCO2 (p=0.98). DISCUSSION/CONCLUSION: Lung-injured piglets from the current study experienced a 40% reduction in MPAP which resulted in a modest improvement in oxygenarion with iNO therapy. Based on these findings, iNO therapy coupled with W-ECLS maybe a useful adjunct in pediatric patients experiencing severe pulmonary hypertension. It is unclear if these findings could be translated into improved outcomes or appreciable reduction in ECLS duration at this time. These findings should guide future studies that would be required in order to suggest that this costly inhaled drug should be used in infants with different forms of ECLS. Disclosure: Mallinkrodt provided study drug and no other funding Sponsored Research - Nitric Oxide gas was donated by Mallinckrodt. [ABSTRACT FROM AUTHOR]