A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects.

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% w/w lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients.

Interventional Pulmonology Fellowship Accreditation Standards: Executive Summary of the Multisociety Interventional Pulmonology Fellowship Accreditation Committee.

Interventional pulmonology (IP) is a rapidly evolving subspecialty of pulmonary medicine. In the last 10 years, formal IP fellowships have increased substantially in number from five to now > 30. The vast majority of IP fellowship trainees are selected through the National Resident Matching Program, and validated in-service and certification examinations for IP exist. Practice standards and training guidelines for IP fellowship programs have been published; however, considerable variability in the environment, curriculum, and experience offered by the various fellowship programs remains, and there is currently no formal accreditation process in place to standardize IP fellowship training. Recognizing the need for more uniform training across the various fellowship programs, a multisociety accreditation committee was formed with the intent to establish common accreditation standards for all IP fellowship programs in the United States. This article provides a summary of those standards and can serve as an accreditation template for training programs and their offices of graduate medical education as they move through the accreditation process.

Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis.

OBJECTIVE: To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. DESIGN: This study was a secondary data analysis of a prospective cohort study. SETTING: Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. PATIENTS: Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. INTERVENTIONS: None. MEASUREMENTS: Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. MAIN RESULTS: Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. CONCLUSIONS: High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.

Use of ultrasound guidance for central venous catheterization: a national survey of intensivists and hospitalists.

PURPOSE: The purpose of the study is to evaluate the frequency and barriers to use of ultrasound guidance for central venous catheter (CVC) insertion by physicians specializing in critical care and hospital medicine. MATERIALS AND METHODS: A national cross-sectional electronic survey of intensivists and hospitalists was administered from November 2014 to January 2015. RESULTS: The survey response rate was 5.9% (1013/17 233). Moderate to very frequent use of ultrasound guidance varied by site: internal jugular vein (80%), subclavian vein (31%), and femoral vein (45%). Nearly all physicians (99%) who insert internal jugular CVCs daily use ultrasound guidance, whereas only 46% of physicians who insert subclavian CVCs daily use ultrasound guidance. Use of real-time ultrasound guidance varied by insertion site: internal jugular vein (73%), subclavian vein (28%), and femoral vein (42%). Most physicians (59%) reported not being comfortable with real-time needle tracking at the subclavian site. The most frequently reported barriers to use of ultrasound guidance were (1) limited availability of ultrasound equipment (28%), (2) perception of increased total procedure time (22%), and (3) concern for loss of landmark skills (13%). CONCLUSIONS: Most intensivists routinely use ultrasound guidance to insert internal jugular CVCs but not subclavian CVCs. The most commonly reported barrier to ultrasound use was limited access to an ultrasound machine.

Chromogranin A levels and mortality in patients with severe sepsis.

CONTEXT: Chromogranin A (CgA) is a novel biomarker with potential to assess mortality risk of patients with severe sepsis. OBJECTIVE: Assess association of CgA levels and mortality risk of severely septic patients. METHODS: Serum CgA levels were measured in 50 hospitalized, severely septic patients with organ failure <48 h. RESULTS: Higher CgA levels trended toward higher ICU and hospital mortality. Patients without cardiovascular disease who died in the ICU had higher median (IQR) CgA levels 602.3 (343.3, 1134.3) ng/ml versus 205.5 (130.7, 325.9) ng/ml, p = 0.01. CONCLUSIONS: High CgA levels predict ICU mortality in severely septic patients without prior cardiovascular disease.

Understanding the Concept of Health Care-Associated Pneumonia in Lung Transplant Recipients.

BACKGROUND: Limited data are available regarding the etiologic impact of health care-associated pneumonia (HCAP) in lung transplant recipients. Therefore, our aim was to evaluate the microbiologic differences between HCAP and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in lung transplant recipients with a radiographically confirmed diagnosis of pneumonia. METHODS: We performed a retrospective cohort study of lung transplant recipients with pneumonia at one transplant center over a 7-year period. Eligible patients included lung transplant recipients who developed a first episode of radiographically confirmed pneumonia ≥ 48 h following transplantation. HCAP, HAP, and VAP were classified according to the American Thoracic Society/Infectious Diseases Society of America 2005 guidelines. χ² and Student t tests were used to compare categorical and continuous variables, respectively. RESULTS: Sixty-eight lung transplant recipients developed at least one episode of pneumonia. HCAP (n = 42; 62%) was most common, followed by HAP/VAP (n = 26; 38%) stratified in HAP (n = 20; 77%) and VAP (n = 6; 23%). Pseudomonas aeruginosa was the predominantly isolated organism (n = 22; 32%), whereas invasive aspergillosis was uncommon (< 10%). Multiple-drug resistant (MDR) pathogens were less frequently isolated in patients with HCAP compared with HAP/VAP (5% vs 27%; P = .009). Opportunistic pathogens were less frequently identified in lung transplant recipients with HCAP than in those with HAP/VAP (7% vs 27%; P = .02). Lung transplant recipients with HCAP had a similar mortality at 90 days (n = 9 [21%] vs n = 4 [15%]; P = .3) compared with patients with HAP/VAP. CONCLUSIONS: HCAP was the most frequent infection in lung transplant recipients. MDR pathogens and opportunistic pathogens were more frequently isolated in HAP/VAP. There were no differences in 30- and 90-day mortality between lung transplant recipients with HCAP and those with HAP/VAP.

Mechanical ventilatory support in potential lung donor patients.

Lung transplantation reduces mortality in patients with end-stage lung disease; however, only approximately 21% of lungs from potential donor patients undergo transplantation. A large number of donor lungs become categorized as unsuitable for lung transplantation as a result of lung injury around the time of brain death. Limiting this injury is key to increasing the number of successful lung procurements and subsequent transplants. This narrative review by a working group of pulmonologists, respiratory therapists, and lung transplant specialists elucidates principles of mechanical ventilatory support that can be used to limit lung injury in potential lung donor patients and examines the implementation of protocolized strategies in enhancing the procurement of donor lungs for transplantation.

Lung transplant infection.

Lung transplantation has become an accepted therapeutic procedure for the treatment of end-stage pulmonary parenchymal and vascular disease. Despite improved survival rates over the decades, lung transplant recipients have lower survival rates than other solid organ transplant recipients. The morbidity and mortality following lung transplantation is largely due to infection- and rejection-related complications. This article will review the common infections that develop in the lung transplant recipient, including the general risk factors for infection in this population, and the most frequent bacterial, viral, fungal and other less frequent opportunistic infections. The epidemiology, diagnosis, prophylaxis, treatment and outcomes for the different microbial pathogens will be reviewed. The effects of infection on lung transplant rejection will also be discussed.

Management of asthma during pregnancy.

Asthma is an inflammatory lung condition that is the most common chronic disease affecting pregnancy. The changes in pulmonary physiology during pregnancy include increased minute ventilation, decreased functional residual capacity, increased mucus production, and airway mucosa hyperemia and edema. Pregnancy is also associated with a physiological suppression of the immune system. Many studies have described the heterogeneous immune system response in women with asthma during pregnancy, which partly explains why asthma has been shown to worsen, improve, or remain stable in equal proportions of women during pregnancy. Asthma may be associated with poor maternal and fetal outcomes. However, better maternal and fetal outcomes are observed with better asthma control. Asthma controller medications are generally thought to be safe during pregnancy, but limited data are available for some of the medicines. Newer medications like omalizumab open avenues for the treatment of asthma, but also pose a challenge, as there is limited experience with their use. Therefore, a multidisciplinary approach, including obstetricians, asthma specialists, and pediatricians should collaborate with the patient to carefully weigh the risks and benefits to determine an optimal management plan for each individual patient. The aim of this review article is to summarize the most recent literature about the immunological changes that occur during pregnancy, physiological and clinical implications of asthma on pregnancy, and asthma management and medication use in pregnant women.

Technologic advances in endotracheal tubes for prevention of ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is associated with high morbidity, mortality, and costs. Interventions to prevent VAP are a high priority in the care of critically ill patients requiring mechanical ventilation (MV). Multiple interventions are recommended by evidence-based practice guidelines to prevent VAP, but there is a growing interest in those related to the endotracheal tube (ETT) as the main target linked to VAP. Microaspiration and biofilm formation are the two most important mechanisms implicated in the colonization of the tracheal bronchial tree and the development of VAP. Microaspiration occurs when there is distal migration of microorganisms present in the secretions accumulated above the ETT cuff. Biofilm formation has been described as the development of a network of secretions and attached microorganisms that migrate along the ETT cuff polymer and inside the lumen, facilitating the transfer to the sterile bronchial tree. Therefore, our objective was to review the literature related to recent advances in ETT technologies regarding their impact on the control of microaspiration and biofilm formation in patients on MV, and the subsequent impact on VAP.

Lung transplantation for Williams-Campbell syndrome with a probable familial association.

Williams-Campbell syndrome is a rare disorder characterized by deficiency of subsegmental bronchial cartilage and development of airway collapse and bronchiectasis that may subsequently progress to respiratory failure and death. There are only 2 published reports suggesting a familial association, and only one report of lung transplantation being used as a therapeutic modality. Due to postoperative airway complications, transplantation has not been recommended for this disease. We report the first lung transplant with prolonged survival, approaching 10 years, in a patient with Williams-Campbell syndrome, and provide further evidence to support a familial association.

Status asthmaticus in the medical intensive care unit: a 30-year experience.

OBJECTIVES: To investigate the characteristics, trends in management (permissive hypercapnia; mechanical ventilation (MV); neuromuscular blockade) and their impact on complications and outcomes in Status Asthmaticus (SA). METHODS: We performed a retrospective observational study of subjects admitted with SA to a single multidisciplinary MICU over a 30-year period. All laboratory, radiologic, respiratory care, physician notes and orders were extracted from an electronic medical record (EMR) maintained during the entire duration of the study. RESULTS: Two hundred and twenty-seven subjects were admitted with 280 episodes of SA. While subjects reflected our regional population (52% Hispanic), African Americans were over-represented (22%) and Caucasians under-represented (21%). Thirty-eight percent reported childhood asthma, 27% were steroid dependent (10% in the last 10 years), and 18% had a recent steroid taper. One hundred and thirty-nine (61.2%) required intubation. The duration of hospitalization was similar between mechanically ventilated and non-ventilated subjects (5.8±4.41 vs. 6.8±7.22 days; p=0.07). The overall complication rate remained low irrespective of the use of permissive hypercapnia or mode of mechanical ventilation (overall mortality 0.4%; pneumothorax 2.5%; pneumonia 2.9%). The frequency of SA declined significantly in the last 10 years of the study (12.4 vs. 3.2 cases/year). CONCLUSIONS: Despite the frequent use of mechanical ventilation, mortality/complication rates remained extremely low. MV did not significantly increase the duration of hospitalization. At our institution, the frequency of SA significantly decreased despite an increase in emergency room visits for asthma.