Local and systemic effects of a silver nitrate coated indwelling pleural catheter in an animal model of pleurodesis.

Purpose/Aim of the study: This study assessed the safety and potential toxicity of a silver nitrate coated indwelling pleural catheter (SNCIPC) designed to create pleurodesis in a large animal model. MATERIALS AND METHODS: Sixteen animals underwent insertion of either a SNCIPC or an uncoated silicone catheter. Half of the animals were sacrificed at day 7 and the others at day 30. Animal weight and assessment of well-being, pleural fluid and blood collection were performed at regular intervals. Pleurodesis was assessed at necropsy and histopathological examination of organs performed. RESULTS: No mortality or significant clinical findings were observed throughout the experiment. SNCIPC treated animals had increased pleural fluid drainage overall (p < 0.001) and specifically on days 1-4. No differences in hemoglobin, white blood cell count or neutrophil counts were detected between groups. No treatment related histological findings were observed in any of the evaluated tissues outside of the treated area. Serum silver levels in SNCIPC catheter treated animals peaked on Day 4 (0.185 µg/mL, 30 day group) then gradually decreased for the remainder of the study period. The highest tissue silver concentrations were noted in the SNCIPC groups in tissues close to the treatment site in addition to the liver (59.8ug/g +/- 8.6 and 73.3ug/g +/- 25). Pleurodesis scores were significantly higher in SNCIPC treated animals for both the 7 day (median 6.5 vs. 1.0, p = 0.029) and 30 day cohorts (median 7.0 vs. 1.5, p = 0.029). CONCLUSIONS: SNCIPC are well tolerated and not associated with any significant signs of toxicity. Silver levels were elevated in local tissues, serum and liver but without evidence of pathological impact. Effective pleurodesis was present by day 7 and more established by day 30. Clinical studies to investigate the safety and efficacy of this device in patients with malignant pleural effusions appear warranted.

Silver Nitrate-coated versus Standard Indwelling Pleural Catheter for Malignant Effusions: The SWIFT Randomized Trial.

Rationale: Tunneled, indwelling pleural catheters (IPCs) have been demonstrated to be an effective method of managing malignant pleural effusions. However, they allow pleurodesis and can therefore be removed in only a subset of patients. A novel, silver nitrate-coated IPC was developed with the intention of creating a rapid, effective chemical pleurodesis to allow more frequent and earlier catheter removal. This study represents the pivotal clinical trial evaluating that catheter versus the standard IPC. Objectives: To compare the efficacy of a novel silver nitrate-eluting indwelling pleural catheter (SNCIPC) with that of a standard, uncoated catheter. Methods: The SWIFT [A Pivotal Multi-Center, Randomized, Controlled, Single-Blinded Study Comparing the Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) to the Uncoated PleurX® Pleural Catheter for the Management of Symptomatic, Recurrent, Malignant Pleural Effusions] trial was a multicenter, parallel-group, randomized, controlled, patient-blind trial. Central randomization occurred according to a computer-generated schedule, stratified by site. Recruitment was from 17 secondary or tertiary care hospitals in the United States and 3 in the United Kingdom and included adult patients with malignant pleural effusion needing drainage, without evidence of lung entrapment or significant loculation. The intervention group underwent insertion of an SNCIPC with maximal fluid drainage, followed by a tapering drainage schedule. The control group received a standard, uncoated catheter. Follow-up was conducted until 90 days. The primary outcome measure was pleurodesis efficacy, measured by fluid drainage, at 30 days. Results: A total of 119 patients were randomized. Five withdrew before receiving treatment, leaving 114 (77 SNCIPC, 37 standard IPC) for analysis. The mean age was 66 years (standard deviation, 11). More patients in the SNCIPC group were inpatients (39% vs. 14%; P = 0.009). For the primary outcome, pleurodesis rates were 12 (32%) of 37 in the control group and 17 (22%) of 77 in the SNCIPC group (rate difference, -0.10; 95% confidence interval, -0.30 to 0.09). Median time to pleurodesis was 11 days (interquartile range, 9 to 23) in the control group and 4 days (interquartile range, 2 to 15) in the SNCIPC group. No significant difference in treatment-related adverse event rates was noted between groups. Conclusions: The SNCIPC did not improve pleurodesis efficacy compared with a standard IPC. This study does not support the wider use of the SNCIPC device. Clinical trial registered with www.clinicaltrials.gov (NCT02649894).

Interaction of Critical Care Practitioners With a Decision Support Tool for Weaning Mechanical Ventilation in Children.

BACKGROUND: There is evidence that ventilator weaning protocols provide benefit to children receiving mechanical ventilation, but many protocols do not include explicit instructions for decreasing ventilator support from maximal settings. We evaluated care provider opinions on ventilator weaning recommendations made by a computerized decision support tool. METHODS: Recommendations for ventilator adjustment were generated using a computerized decision support tool based on the ARDSNet protocol using data from children with acute hypoxemic respiratory failure admitted to the pediatric ICU (PICU). Attending physicians, fellows, nurse practitioners, and respiratory therapists (RTs) caring for these patients answered a brief survey to assess whether recommendations were reasonable and whether the practitioner believed they could be implemented. RESULTS: RTs completed 99 surveys and ICU providers completed 96 surveys based on data from 10 patients. RTs and ICU providers found 63.9% and 65.3% of recommendations reasonable, respectively. There were 5 instances of disagreement between RTs and ICU providers. The percent of recommendations that RTs thought could be implemented was 29.9%, whereas this figure for ICU providers was 26.3%, with 4 instances of disagreement. Free-text responses indicated that many RTs and ICU providers were concerned about disrupting current patient stability and low tidal volumes. CONCLUSIONS: On initial evaluation, the decision support tool did not appear to be highly acceptable to RTs and ICU providers in our setting because recommendations were rarely implemented. In addition, acceptability did not increase over time as patients generally improved. Most respondents preferred to make no ventilator changes and felt the recommendations were too aggressive. The notable barrier to use was a perception of potential patient instability with weaning.

Physiologic Effects of 3 Different Neonatal Volume-Targeted Ventilation Modes in Surfactant-Deficient Juvenile Rabbits.

BACKGROUND: Different brands of volume-targeted modes may vary the location of tidal volume (VT) monitoring and whether peak inspiratory pressure is adjusted based on inspiratory, expiratory, or leak-compensated VT. These variables may result in different levels of support provided to patients, especially when an endotracheal tube (ETT) leak is present. We hypothesized that there would be no differences in gas exchange, triggering, or work of breathing between volume-targeted modes of 3 different brands of equipment in a surfactant-deficient, spontaneously breathing animal model with and without an ETT leak. METHODS: Twelve rabbits (mean ± SD 1.61 ± 0.20 kg) were sedated, anesthetized, intubated, lavaged with 0.9% saline solution, and randomized in a crossover design so that each animal was supported by 3 different volume-targeted modes at identical settings with and without an ETT leak. After 30 min, arterial blood gas, VT, and esophageal and airway pressure were recorded for each condition, and pressure-rate product and percentage of successfully triggered breaths were calculated. RESULTS: Gas exchange and the pressure-rate product were not different between the ventilators in the absence of an ETT leak. When an ETT leak was introduced, volume-guarantee modes allowed a higher percentage of triggered breaths and peak inspiratory pressure, which resulted in higher minute ventilation, pH, and lower PaCO2 than the pressure-regulated volume control mode (P < .05). CONCLUSIONS: When a moderate ETT leak was present, volume-targeted modes that used proximal VT monitoring and triggering with adaptive leak compensation capabilities appeared more effective in providing ventilation support than did a ventilator that used measurements obtained from the back at the ventilator and does not have leak compensation.

Nitric oxide delivery by neonatal noninvasive respiratory support devices.

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 <1.5 ppm with all forms of noninvasive support, except nasal intermittent mandatory ventilation at 40 ppm 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.

Marked structural and functional heterogeneity in CXCR4: separation of HIV-1 and SDF-1alpha responses.

CXCR4, the chemotactic cell receptor for SDF-1alpha, 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-1alpha-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-1alpha. 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-1alpha responses and may indicate therapeutic possibilities.