Chasing Zero: Increasing Infection Control Compliance on an Inpatient Cystic Fibrosis Unit.

Patients with cystic fibrosis have increased risk of pulmonary infections, and reducing spread of microorganisms is critical. To improve hospital-staff adherence to infection control guidelines, we implemented brightly colored Safe Zone floor decals, staff compliance contracts, and an infection control in-service video. Audits of staff adherence conducted pre and postintervention demonstrated an increased and sustainable improvement among each group (P < .05). These effective measures may be implemented to improve infection control compliance elsewhere.

Safety of non-cuffed tunneled central venous catheters in adults with cystic fibrosis.

BACKGROUND: Peripherally inserted central catheters (PICCs) are the most common route of intravenous (I.V.) access for treatment of cystic fibrosis (CF) pulmonary exacerbations, but repeated PICC placement can result in upper extremity peripheral venous stenosis. Once peripheral stenosis develops, a non-cuffed tunneled central venous catheter (NcTCVC) is an alternative route for IV access. While these are regularly used at some CF centers, the safety and complication rate compared to PICCs in adults with CF has not been reported. This study aims to describe the safety of NcTCVCs in adults with CF. METHODS: A retrospective cohort study was performed at a CF Foundation accredited institution including adults with CF who received NcTCVCs in interventional radiology from 7/19/2007 to 3/09/2020. Complications analyzed included catheter related deep venous thrombosis (DVT), central line associated blood stream infection (CLABSI), and catheter related central venous stenosis. Complications were considered attributable if they occurred while the catheter was in place or within 30 days of catheter removal. RESULTS: During the study duration, 386 NcTCVCs were placed in 60 unique patients (55 % female) with a mean of 6.4 catheters per patient. Majority of NcTCVCs placed were 4 French (61.4 %). Average duration of indwelling NcTCVC was 16.2 days. No patients demonstrated catheter attributable symptomatic DVT. The incidence of DVT, CLABSI, and central venous stenosis was 0 (0 %), 4 (1 %), and 1 (0.3 %), respectively. CONCLUSIONS: Many adults with CF have required insertion of numerous PICCs for the treatment of recurrent pulmonary exacerbations. In those adults that develop PICC-associated peripheral vein stenosis precluding PICC placement, these results indicate NcTCVCs are a safe alternative.

Complications and Practice Variation in the Use of Peripherally Inserted Central Venous Catheters in People With Cystic Fibrosis: The Prospective Study of Peripherally Inserted Venous Catheters in People With Cystic Fibrosis Study.

BACKGROUND: Peripherally inserted central catheters (PICCs) are used commonly to administer antibiotics to people with cystic fibrosis (CF), but their use can be complicated by venous thrombosis and catheter occlusion. RESEARCH QUESTION: Which participant-, catheter-, and catheter management-level attributes are associated with increased risk of complications of PICCs among people with CF? STUDY DESIGN AND METHODS: This was a prospective observational study of adults and children with CF who received PICCs at 10 CF care centers in the United States. The primary end point was defined as occlusion of the catheter resulting in unplanned removal, symptomatic venous thrombosis in the extremity containing the catheter, or both. Three categories of composite secondary outcomes were identified: difficult line placement, local soft tissue or skin reactions, and catheter malfunction. Data specific to the participant, catheter placement, and catheter management were collected in a centralized database. Risk factors for primary and secondary outcomes were analyzed by multivariate logistic regression. RESULTS: Between June 2018 and July 2021, 157 adults and 103 children older than 6 years with CF had 375 PICCs placed. Patients underwent 4,828 catheter-days of observation. Of the 375 PICCs, 334 (89%) were ≤ 4.5 F, 342 (91%) were single lumen, and 366 (98%) were placed using ultrasound guidance. The primary outcome occurred in 15 PICCs for an event rate of 3.11 per 1,000 catheter-days. No cases of catheter-related bloodstream infection occurred. Other secondary outcomes developed in 147 of 375 catheters (39%). Despite evidence of practice variation, no risk factors for the primary outcome and few risk factors for secondary outcomes were identified. INTERPRETATION: This study affirmed the safety of contemporary approaches to inserting and using PICCs in people with CF. Given the low rate of complications in this study, observations may reflect a widespread shift to selecting smaller-diameter PICCs and using ultrasound to guide their placement.

HMG-CoA Reductase Inhibitors for Prevention and Treatment of Severe Sepsis.

HMG-CoA reductase inhibitors, or statins, are among the most commonly prescribed pharmaceuticals in the world, especially among the elderly. The remarkable conjuncture of this fact with the rising incidence of severe sepsis among people over age 65 could prove to be of serendipitous benefit, because numerous actions of the statins make them of potential use in the prevention and treatment of severe sepsis. Severe sepsis continues to be a highly lethal condition, for which there are, as yet, no effective pharmacological treatments, save antibiotics. We explore the biological plausibility of statins as prophylaxis agents and as treatment for severe sepsis and thoroughly review the preclinical and clinical studies that have explored the effects of statins in infected and septic patients. Statins remain only promising treatments for severe sepsis, without convincing evidence that they reduce patient mortality. Ongoing randomized trials may provide conclusive evidence, whether positive or negative.

Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling.

BACKGROUND: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. METHODS: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB. RESULTS: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB. CONCLUSION: In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.

High-Frequency Percussive Ventilation in Cystic Fibrosis Patients With Acute Respiratory Failure: A Case Series.

Acute respiratory failure in cystic fibrosis carries a high risk of mortality. The optimal mode of mechanical ventilation (MV) in this population is not well established. In this case series, we identified patients with cystic fibrosis who were ventilated with high-frequency percussive ventilation (HFPV) at our institution and describe their characteristics and outcomes. The use of high-frequency percussive ventilation has been sparsely described in the literature. This case series could serve as hypothesis-generating for future research.

Physical Activity Level and Perception of Exercise in Cystic Fibrosis.

BACKGROUND: More patients with cystic fibrosis (CF) are living longer, and lifestyle-related behavior is becoming increasingly important for improving morbidity and mortality. Declining levels of exercise leads to low cardiorespiratory fitness, which is a strong, independent predictor of mortality in patients with CF. As a result, exercise training has become a commonly accepted form of treatment for patients with CF. The purpose of this study was to determine physical activity levels and perception of exercise in adult patients with CF. METHODS: Adult patients from an in-patient CF unit were recruited to participate. A structured interview and self-report questionnaires were used to collect information on levels of physical activity and exercise perception including preferences, readiness, and barriers. RESULTS: Forty-six adult patients with CF consented to participate in the interview and completed self-report questionnaires. Subjects self-reported that the majority (84%) of their time was spent performing physical activity at a moderate level, with mean ± SD of 11.8 ± 12.2 h per week of moderate physical activity. Vigorous physical activity was described as hard and very hard physical activity, with a mean ± SD of 1.8 ± 4.6 h (13%) and 0.4 ± 1.6 h (3%), respectively. Most of the adult subjects with CF preferred walking, and 65% of them felt that exercise was very important. Lack of energy, lack of good health, lack of self-discipline, and lack of time were noted as the most frequent barriers to exercise. CONCLUSIONS: In this study, adult subjects with CF self-reported performing an adequate amount of moderate physical activity, although only a small proportion of time was spent at a vigorous level of physical activity. Clinicians providing rehabilitation have an opportunity to improve adherence to prescribed exercise by understanding the impact that physiological and psychological factors have on patients with CF. Further, motivating patients with CF to engage in more vigorous physical activity may provide a stimulus that improves clinical outcomes and potentially survival.

Aztreonam Lysine Inhalation Solution in Cystic Fibrosis.

Patients with cystic fibrosis (CF) develop pulmonary disease secondary to airway infection and dysregulated inflammation. Therapeutic innovations such as nebulized antimicrobial therapy targeting specific pathogens have resulted in improvements in quality of life and life expectancy. Aztreonam lysine for inhalation (AZLI) solution was initially approved to improve respiratory symptoms in CF patients with Pseudomonas aeruginosa (PA) in 2010 by the Food and Drug Administration. Since then, research broadening labeling and clinical application has been developed. In this review, we analyze published and ongoing research regarding AZLI therapy in CF. A search of the Cochrane Database of Systematic Reviews and the PubMed and ClinicalTrials.gov databases was conducted to identify publications about AZLI. Three pre-approval studies were identified and assessed. Two are Phase 3, placebo-controlled trials, assessing a variety of safety and efficacy endpoints, leading to FDA approval. The third is an open-label extension of the two previous trials. An additional seven post-approval, completed trials were identified and are included in this review. They represent a variety of study designs including safety and efficacy in patients with mild lung disease and young patients, an active comparator trial vs inhaled tobramycin, an eradication study, a study among patients with Burkholderia cepacia, and a study assessing continuous alternating antibiotic therapy. Finally, five ongoing clinical trials are discussed. Overall, studies demonstrated that inhaled aztreonam is a safe and effective antimicrobial treatment for the eradication of newly acquired P. aeruginosa and long-term suppressive therapy of chronic endobronchial infection among people with cystic fibrosis.

Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics.

BACKGROUND: Recently, it has been shown that increasing body mass index (BMI) in asthma is associated with reduced exhaled NO. Our objective in this study was to determine if the BMI-related changes in exhaled NO differ across asthmatics and controls, and to determine if these changes are related to increased airway oxidative stress and systemic levels of leptin and adiponectin. METHODS: Observational study of the association of BMI, leptin, and adiponectin with exhaled nitric oxide (NO) and exhaled 8-isoprostanes in 67 non-smoking patients with moderate to severe persistent asthma during baseline conditions and 47 controls. Measurements included plasma levels of leptin, adiponectin, exhaled breath condensates for 8-isoprostanes, exhaled NO, pulmonary function tests, and questionnaires regarding asthma severity and control. RESULTS: In asthmatics, BMI and the ratio of leptin to adiponectin were respectively associated with reduced levels of exhaled NO (beta = -0.04 [95% C.I. -0.07, -0.1], p < 0.003) and (beta = -0.0018 [95% C.I. -0.003, -0.00034], p = 0.01) after adjusting for confounders. Also, BMI was associated with increased levels of exhaled 8-isoprostanes (beta = 0.30 [95% C.I. 0.003, 0.6], p = 0.03) after adjusting for confounders. In contrast, we did not observe these associations in the control group of healthy non-asthmatics with a similar weight distribution. CONCLUSION: In adults with stable moderate to severe persistent asthma, but not in controls, BMI and the plasma ratio of leptin/adiponectin is associated with reduced exhaled NO. Also, BMI is associated with increased exhaled 8-isoprostanes. These results suggest that BMI in asthmatics may increase airway oxidative stress and could explain the BMI-related reductions in exhaled NO.

NanoCluster budesonide formulations enable efficient drug delivery driven by mechanical ventilation.

Agglomerates of budesonide nanoparticles (also known as 'NanoClusters') are fine dry powder aerosols that were hypothesized to enable drug delivery through ventilator circuits. These engineered powders were delivered via a Monodose inhaler or a novel device, entrained through commercial endotracheal tubes, and analyzed by cascade impaction. Inspiration flow rates and other parameters such as inspiration patterns and inspiration volumes were controlled by a ventilator. NanoCluster budesonide (NC-Bud) formulations had a higher efficiency of aerosol delivery compared to micronized budesonide with NC-Bud showing a much higher percent emitted fraction (%EF). Different inspiration patterns (sine, square, and ramp) did not affect the powder performance of NC-Bud when applied through a 5.0 mm endotracheal tube. The aerosolization of NC-Bud also did not change with the inspiration volume (1.5-2.5 L) nor with the inspiration flow rate (20-40 L/min) suggesting fast emptying times for budesonide capsules. The %EF of NC-Bud was higher at 51% relative humidity compared to 82% RH. The novel device and the Monodose showed the same efficiency of drug delivery but the novel device fit directly to a ventilator and endotracheal tubing connections. The new device combined with NanoCluster formulation technology allowed convenient and efficient drug delivery through endotracheal tubes.

HIV-1/cocaine induced oxidative stress disrupts tight junction protein-1 in human pulmonary microvascular endothelial cells: role of Ras/ERK1/2 pathway.

Intravenous drug use (IVDU) is the major risk factor in the development of HIV-related pulmonary arterial hypertension (HRPAH); however, the pathogenesis of HRPAH in association with IVDU has yet to be characterized. Endothelial injury is considered to be an initiating factor for pulmonary vascular remodeling in animal models of PAH. Our previous study shows that simultaneous exposure to HIV-Trans-activator of transcription (Tat) and cocaine exacerbates both disruption of tight junction proteins and permeability of human pulmonary artery endothelial cells compared with either treatment alone. We here now demonstrate that this HIV-Tat and cocaine mediated endothelial dysfunction accompanies with increase in hydrogen peroxide and superoxide radicals generation and involves redox sensitive signaling pathway. Pretreatment with antioxidant cocktail attenuated the cocaine and Tat mediated disassembly of Zonula Occludens (ZO)-1 and enhancement of endothelial monolayer permeability. Furthermore, inhibition of NADPH oxidase by apocynin or siRNA-mediated knockdown of gp-91(phox) abolished the Tat/cocaine-induced reactive oxygen species (ROS) production, suggesting the NADPH oxidase mediated generation of oxidative radicals. In addition, ROS dependent activation of Ras and ERK1/2 Kinase was observed to be mediating the TJP-1 disassembly, and endothelial dysfunction in response to cocaine and Tat exposure. In conclusion, our findings demonstrate that Tat/cocaine -mediated production of ROS activate Ras/Raf/ERK1/2 pathway that contributes to disruption of tight junction protein leading to pulmonary endothelial dysfunction associated with pulmonary vascular remodeling.

Quality improvement initiative to reduce deep vein thrombosis associated with peripherally inserted central catheters in adults with cystic fibrosis.

RATIONALE: Peripherally inserted central catheters (PICCs) are common in the treatment of patients with cystic fibrosis (CF). Previous reports suggest that patients with CF are at increased risk for PICC-associated deep vein thrombosis (DVT). OBJECTIVES: We assessed potential risk factors for symptomatic PICC-associated DVT with subsequent implementation of a quality improvement (QI) initiative to reduce PICC-associated DVT in patients with CF. METHODS: This was a 5-year retrospective cohort study with subsequent 21-month prospective observation following implementation of a QI intervention in adults (aged 18 yr or older) with CF. All patients with a PICC inserted from July 2006 to March 2013 at our CF Foundation-accredited center were included. Symptomatic DVT was diagnosed by Doppler ultrasound. PICC insertions were analyzed, and nine risk factors for DVT were analyzed to formulate a QI initiative to reduce risk of PICC-associated DVT. The QI program focused on staff education and included modification to PICC order entry with a 4 French (F) single-lumen (SL) catheter as standard for all patients with CF. MEASUREMENTS AND MAIN RESULTS: A total of 369 PICCs were analyzed in 117 unique patients for a total of 5,437 PICC-days of placement. Symptomatic DVT was diagnosed in 28 (7.6%) of the 369 PICCs analyzed. Using regression analysis, the strongest predictors for DVT occurrence were warfarin use (odds ratio [OR] = 9.2, P = 0.006) and history of PICC-associated DVT (OR = 2.97, P = 0.08). Insertion of a 4F SL PICC resulted in zero symptomatic DVT. Zero episodes of DVT associated with 4F PICC insertion prevented use of PICC size in regression analysis. However, univariate analysis revealed that insertion of a 4F SL PICC instead of either 5F double lumen or 6F triple lumen was associated with a reduction in PICC-associated DVT (P = 0.001). After the QI intervention, 4F SL catheter insertion substantially increased to 65.8% of all PICCs inserted, whereas 6F triple-lumen catheter insertion declined to 6.8% of PICCs inserted. The QI initiative resulted in an absolute risk reduction in DVT per PICC placed of 6.1% (P = 0.055). CONCLUSIONS: To reduce risk of PICC-associated DVT in patients with CF, QI strategies should focus on insertion of smaller-diameter 4F PICCs and reduction in PICC use in high-risk patients when possible.