Tracheostomy Is Associated With a Decrease in Delirium and Sedation for Intubated COVID-19 Patients.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome can experience prolonged periods of ventilation, high incidence of delirium, and require high amounts of sedation. Tracheostomy has been associated with earlier ventilator liberation, decreased sedation needs, and lower rates of delirium but optimal timing of tracheostomy remains unknown. Is tracheostomy associated with lower sedation requirements and lower incidence of delirium in patients with COVID-19 that are intubated? METHODS: We retrospectively reviewed the first 32 patients at a large urban tertiary referral center that underwent tracheostomy for prolonged respiratory failure. We obtained Richmond Agitation Sedation-Scale scores and Confusion Assessment Method for Intensive Care Unit data along with amount(s) and type(s) of sedating medications given, in the 7 days before and after tracheostomy. Proportion of days delirious and sedating medications were compared in the 7 days before and after tracheostomy. RESULTS: There was a significant decrease in the amount of opioids and benzodiazepines in the 7-day period following tracheostomy. Opioid dosing decreased by 157.5 morphine equivalents (SD=339, P =0.01) and benzodiazepine dosing decreased by 18 mg lorazepam equivalents (SD=34, P =0.01). There was no significant difference in antipsychotic or other sedative-hyponotic drug doses. There was a significant decrease in the proportion of days of coma or delirium (mean decrease in proportion=0.16, SD=0.32, P =0.008) following tracheostomy. CONCLUSION: Tracheostomy was associated with a significant decrease amount of sedating medications and with a decrease in proportion of days delirious following tracheostomy.

Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study.

BACKGROUND: Combination intrapleural fibrinolytic and enzyme therapy (IET) has been established as a therapeutic option in pleural infection. Despite demonstrated efficacy, studies specifically designed and adequately powered to address complications are sparse. The safety profile, the effects of concurrent therapeutic anticoagulation, and the nature and extent of nonbleeding complications remain poorly defined. RESEARCH QUESTION: What is the bleeding complication risk associated with IET use in pleural infection? STUDY DESIGN AND METHODS: This was a multicenter, retrospective observational study conducted in 24 centers across the United States and the United Kingdom. Protocolized data collection for 1,851 patients treated with at least one dose of combination IET for pleural infection between January 2012 and May 2019 was undertaken. The primary outcome was the overall incidence of pleural bleeding defined using pre hoc criteria. RESULTS: Overall, pleural bleeding occurred in 76 of 1,833 patients (4.1%; 95% CI, 3.0%-5.0%). Using a half-dose regimen (tissue plasminogen activator, 5 mg) did not change this risk significantly (6/172 [3.5%]; P = .68). Therapeutic anticoagulation alongside IET was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; P = .017). As well as systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of < 100 × 109/L were associated with a significant increase in bleeding risk. However, only RAPID score and use of systemic anticoagulation were independently predictive. Apart from pain, non-bleeding complications were rare. INTERPRETATION: IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided. Parameters related to higher IET-related bleeding have been identified that may lead to altered risk thresholds for treatment.

Pleural Effusions in the Critically Ill and "At-Bleeding-Risk" Population.

Thoracentesis is a common bedside procedure, which has a low risk of complications when performed with thoracic ultrasound and by experienced operators. In critically ill or mechanically ventilated patients, or in patients with bleeding risks due to medications or other coagulopathies, the complication rate remains low. Drainage of pleural effusion in the intensive care unit has diagnostic and therapeutic utility, and perceived bleeding risks should be one part of an individualized and comprehensive risk-benefit analysis.

Physician Practice Patterns for Performing Thoracentesis in Patients Taking Anticoagulant Medications.

BACKGROUND: Patients undergoing thoracentesis often have comorbid conditions or take medications that potentially put them at higher bleeding risk. Direct oral anticoagulant (DOAC) use has also increased significantly. There are no published guidelines or consensus on when to perform thoracentesis in patients on anticoagulants. Recent studies support the safety of a more liberal approach for thoracentesis among patients with coagulopathy. METHODS: We conducted a survey to ascertain the practices of physicians regarding thoracentesis in patients with increased bleeding risk. The survey was administered to the email distribution lists of the American Association of Bronchology and Interventional Pulmonology and of the American Thoracic Society. RESULTS: The survey was completed by 256 attending physicians. Most of them were general pulmonologists practicing at academic medical centers. Most of them would perform a thoracentesis in patients receiving acetylsalicylic acid or prophylactic doses of unfractionated heparin or low molecular weight heparin (96%, 89%, and 88%, respectively). Half of the respondents would perform a thoracentesis in patients on antiplatelet medications (clopidogrel and ticagrelor, 51%; ticlopidine, 53%). A minority would perform thoracentesis in patients on direct oral anticoagulants or infused thrombin inhibitors (19% and 12%, respectively). The only subgroup that had a higher proclivity for performing thoracentesis without holding medications were attending physicians practicing for under 10 years. Relative to noninterventional pulmonologists, there were no significant differences in the responses of interventional pulmonologists. CONCLUSION: There was variation in the practice patterns of attending physicians in performing thoracentesis in patients with elevated bleeding risk. Further data and guidelines regarding the safety of thoracentesis in these patients are needed.

Improved Diagnostic Yield and Specimen Quality With Endobronchial Ultrasound-Guided Forceps Biopsies: A Retrospective Analysis.

BACKGROUND: Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) has a high diagnostic yield when evaluating mediastinal and hilar lymphadenopathy (LAD). Having previously demonstrated the safety of EBUS-guided cautery-assisted transbronchial nodal forceps biopsy (ca-TBFB), we report disease-specific improvements in diagnostic yield and tissue acquisition when supplementing the EBUS-TBNA-based standard of care (SOC) with ca-TBFB. METHODS: We retrospectively reviewed 213 patients who sequentially underwent SOC and ca-TBFB during the same procedure. We determined 3 clinical scenarios of interest based on preprocedural imaging: isolated mediastinal/hilar LAD, LAD associated with a nodule or mass suspicious for malignancy, and LAD associated with parenchymal findings suggestive of sarcoidosis. Using validated methods, we assessed diagnostic yield on a per-patient basis and specimen quality on a per-node basis on the 136 patients meeting diagnostic criteria. RESULTS: Administration of disease-specific SOC with ca-TBFB yielded gains that varied by diagnosis. Diagnostic yields of SOC and its supplementation with ca-TBFB were 91.8% and 93.4% (P = .50) of the 61 patients diagnosed with solid-organ malignancy, 62.7% and 94.9% (P < .001) of the 59 patients diagnosed with sarcoidosis, and 62.5% and 93.8% (P = .042) of the 16 patients diagnosed with lymphoma, the. For each disease process, specimens obtained with ca-TBFB exhibited statistically higher quality. CONCLUSIONS: We suggest that relative to SOC, ca-TBFB improves diagnostic yield for sarcoidosis and lymphoma while providing uniformly better tissue quality and cellularity. We propose a protocol for use of this innovative technique.

Advances and Controversies in Thoracentesis and Medical Thoracoscopy.

Pleural effusions are common and associated with high morbidity and mortality. Whereas thoracentesis can assist in achieving a diagnosis or therapy, advances in education and in the technique may prevent morbidity associated with the procedure. Medical thoracoscopy is often useful for undiagnosed effusions, as well as for therapeutic purposes. There is much enthusiasm about techniques for biopsies that extend beyond forceps. These include biopsies using a diathermic knife as well as cryoprobes. Similarly, adhesiolysis or other techniques to improve therapy in multiloculated effusions using medical thoracoscopy are contested. This review attempts to synthesize recent advances and controversies in thoracentesis and medical thoracoscopy as clinicians head into the next decade of treatment.

The utility of bronchoscopy in immunocompromised patients: a review.

Bronchoscopy is an important tool for the diagnosis of pulmonary disorders in immunocompromised patients. The addition of biopsies to bronchoalveolar lavage improves the diagnostic yield of non-infectious etiologies, although the underlying etiology of the immunocompromised state must be considered and may be influential. Certain unknowns remain, including timing of bronchoscopy and its impact on medical management and mortality. The ongoing role of non-invasive testing for infectious complications prior to bronchoscopy also remains to be defined. This review addresses the role of bronchoscopy in immunocompromised states related to underlying hematologic malignancies, prescription drug use or chemotherapy, and other disorders that predispose patients to infectious or non-infectious pulmonary diseases.

Safety and Tolerability of Vacuum Versus Manual Drainage During Thoracentesis: A Randomized Trial.

BACKGROUND: Pleural effusions may be aspirated manually or via vacuum during thoracentesis. This study compares the safety, pain level, and time involved in these techniques. METHODS: We randomized 100 patients receiving ultrasound-guided unilateral thoracentesis in an academic medical center from December 2015 through September 2017 to either vacuum or manual drainage. Without using pleural manometry, the effusion was drained completely or until the development of refractory symptoms. Measurements included self-reported pain before and during the procedure (from 0 to 10), time for completion of drainage, and volume removed. Primary outcomes were rates of all-cause complications and of early termination of the procedure with secondary outcomes of change in pain score, drainage time, volume removed, and inverse rate of removal. RESULTS: Patient characteristics in the manual (n=49) and vacuum (n=51) groups were similar. Rate of all-cause complications was higher in the vacuum group (5 vs. 0; P=0.03): pneumothorax (n=3), surgically treated hemothorax with subsequent death (n=1) and reexpansion pulmonary edema causing respiratory failure (n=1), as was rate of early termination (8 vs. 1; P=0.018). The vacuum group exhibited greater pain during drainage (P<0.05), shorter drainage time (P<0.01), no association with volume removed (P>0.05), and lower inverse rate of removal (P≤0.01). CONCLUSION: Despite requiring less time, vacuum aspiration during thoracentesis was associated with higher rates of complication and of early termination of the procedure and greater pain. Although larger studies are needed, this pilot study suggests that manual aspiration provides greater safety and patient comfort.

Bronchoscopic lung volume reduction: recent updates.

Emphysema causes significant morbidity and mortality, incurring both financial and psychosocial costs. Alternatives to medical therapy and surgical lung volume reduction surgery (LVRS) have increased interest in bronchoscopic techniques. Bronchoscopic lung volume reduction (BLVR) is still in its infancy and additional trials and follow-up are critical. However, several new randomized clinical trials (RCTs) have demonstrated improvement in lung function, quality of life and exercise capacity in select patients receiving endobronchial valves and coil therapy. This article highlights recent data regarding bronchoscopic treatment of emphysema.

A novel endobronchial approach to massive hemoptysis complicating silicone Y-stent placement for tracheobronchomalacia: A case report.

RATIONALE: Airway stabilization for severe, symptomatic tracheobronchomalacia (TBM) may be accomplished by silicone Y-stent placement. Common complications of the Y-stent include mucus plugging and granulation tissue formation. PATIENT CONCERNS: We describe a rare case of massive hemoptysis originating from a silicone Y-stent placed for TBM. DIAGNOSES: An emergent bronchoscopy showed an actively bleeding, pulsatile vessel at the distal end of the left bronchial limb of the Y-stent. It was felt that the bleeding was caused by, or at least impacted by, the distal left bronchial limb of the Y-stent eroding into the airway wall. INTERVENTIONS: We hypothesized that placement of oxidized regenerated cellulose (ORC) would provide initial hemostasis, and the subsequent placement of a biocompatible surgical sealant would lead to definitive resolution. OUTCOMES: ORC provided sufficient hemostasis and the subsequent synthetic polymer reinforced the tissue for complete cessation of the bleed. LESSONS: The combined use of ORC and a biocompatible surgical sealant provided long-term management for life-threatening hemoptysis, and potentially morbid procedures such as embolization or surgery were avoided by advanced endobronchial therapy.

Indwelling Pleural Catheter Placement for Nonmalignant Pleural Effusions.

Pleural effusions account for significant symptoms and morbidity. Recent studies demonstrate a high mortality in patients with "benign" pleural effusions, now better characterized as nonmalignant pleural effusions (NMPEs) based on their prognosis. The most common nonmalignant clinical conditions with recurrent pleural effusions are congestive heart failure and hepatic hydrothorax, although many other diseases exist in isolation or as comorbid conditions. When conventional therapy fails, thoracentesis is often performed for relief of dyspnea. Many times, however, the effusions recur despite maximal medical therapy. Placement of tunneled or indwelling pleural catheters provides an effective therapeutic strategy for recurrent NMPEs when other medical therapy fails.

Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-ß1 (TGF-ß1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF. OBJECTIVES: We aimed to define an association between mtDNA and fibroblast responses in IPF. METHODS: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-ß1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects. MEASUREMENTS AND MAIN RESULTS: Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-ß1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival. CONCLUSIONS: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.

RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT.

PURPOSE/OBJECTIVE(S): Appropriate use of invasive mediastinal staging in patients with clinically node-negative NSCLC staged by PET-CT is critical in selecting patients for curative-intent therapy such as surgery or SBRT, but little data exists to guide this decision-making. We examined a large population of patients with clinical stage I NSCLC referred for mediastinoscopy or EBUS to find risk factors for occult N2 lymph nodes and determine which patients benefit from invasive staging. MATERIALS/METHODS: We identified consecutive clinical T1-2N0 NSCLC patients being evaluated for curative-intent therapy between 2011 and 2015. None had evidence of nodal disease by PET-CT; the endpoint was pathologic confirmation of occult N2 disease by EBUS or mediastinoscopy. Tumor size, location, histology, SUVmax, and radiographic appearance were evaluated as determinants of occult N2 disease. Two group comparisons of continuous variables were done with independent t-tests and categorical variables were compared with χ2 or Fisher's exact test. RESULTS: In 284 patients with PET-CT-staged clinical T1-2N0 disease, the prevalence of occult N2 metastases was 7.0%. The negative predictive value of PET-CT was 92.9% and the negative predictive value of mediastinoscopy/EBUS was 96.3%. T2 tumors were more likely to have occult N2 disease than T1 tumors (11.8% v 3.6% p=0.009). Pure solid tumors had greater involvement of N2 nodes than tumors with any ground glass component (12.6% v 3.1%, p<0.001). 17.5% of central tumor cases were found to have occult N2 metastases while 4.4% of patients with peripheral tumors (P<0.001). 33.3% of patients with solid central T2 tumors had occult N2 metastases whereas 2.0% of patients with peripheral T2 tumors with a ground glass component, 1.2% of patients with peripheral T1 tumors with a ground glass component and 3.6% of patients with peripheral T1 solid tumors had N2 metastases. CONCLUSIONS: Invasive mediastinal staging should be strongly encouraged in central tumors and solid T2 tumors because the risk of occult nodal involvement is greater than 10% in these cohorts. However, for patients with peripheral T1 tumors or peripheral T2 tumors with a significant ground glass component, the yield of invasive staging after a negative PET-CT is very low and invasive staging may not be warranted.

Pulmonary Manifestations of Solid Non-Pulmonary Malignancies.

The lungs are a common site of metastatic disease. Pulmonary metastases develop due to local blood flow and cellular or biochemical properties of tumor cells. Metastases develop from any type of malignancy and may occur via hematogenous, lymphatic, aerogenous, and/or direct spread. Metastatic disease may present with symptoms indistinguishable from primary lung cancer, including dyspnea, hemoptysis, and chest pain. Radiographically, these may present as parenchymal lung disease, mediastinal lymphadenopathy, airway obstruction, or pleural and vascular disease. No part of the thorax is spared from metastatic potential. This review highlights complications of non-pulmonary solid malignancies based on sites of anatomic metastases.

Recent Advances in Bronchoscopic Treatment of Peripheral Lung Cancers.

The detection of peripheral lung nodules is increasing because of the expanded use of CT imaging and implementation of lung cancer screening recommendations. Although surgical resection of malignant nodules remains the treatment modality of choice at present, many patients are not surgical candidates, thus prompting the need for other therapeutic options. Stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation are emerging as viable alternatives to surgical resection. For safety, efficacy, and cost-effectiveness purposes, however, alternative bronchoscopic methods for treatment of peripheral lung cancer are currently under active exploration. We searched the Cochrane Library and MEDLINE from 1990 to 2015 to provide the most comprehensive review of bronchoscopic treatment of malignant lung nodules. We used the following search terms: bronchoscopy, lung nodule, peripheral lung lesion, and bronchoscopic treatment. We focused on peripheral pulmonary nodules that are confirmed or highly likely to be malignant. Seventy-one articles were included in this narrative review. We have provided an overview of advanced bronchoscopic modalities that have been used or are under active investigation for definitive treatment of malignant pulmonary nodules. We have concisely discussed the use of direct intratumoral chemotherapy or gene therapies, transbronchial brachytherapy, bronchoscopy-guided radiofrequency ablation (RFA), placement of markers to guide real time-radiation and surgery, cryotherapy, and photodynamic therapy. We have also briefly reported on emerging technologies such as vapor ablation of lung parenchyma for lung cancers. Advances in bronchoscopic therapy will bring additional treatment options to patients with peripheral lung malignancies, with putative advantages over other minimally invasive modalities.

Randomized Trial of Pleural Fluid Drainage Frequency in Patients with Malignant Pleural Effusions. The ASAP Trial.

RATIONALE: Patients with malignant pleural effusions have significant dyspnea and shortened life expectancy. Indwelling pleural catheters allow patients to drain pleural fluid at home and can lead to autopleurodesis. The optimal drainage frequency to achieve autopleurodesis and freedom from catheter has not been determined. OBJECTIVES: To determine whether an aggressive daily drainage strategy is superior to the current standard every other day drainage of pleural fluid in achieving autopleurodesis. METHODS: Patients were randomized to either an aggressive drainage (daily drainage; n = 73) or standard drainage (every other day drainage; n = 76) of pleural fluid via a tunneled pleural catheter. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of autopleurodesis following the placement of the indwelling pleural catheters. The rate of autopleurodesis, defined as complete or partial response based on symptomatic and radiographic changes, was greater in the aggressive drainage arm than the standard drainage arm (47% vs. 24%, respectively; P = 0.003). Median time to autopleurodesis was shorter in the aggressive arm (54 d; 95% confidence interval, 34-83) as compared with the standard arm (90 d; 95% confidence interval, 70 to nonestimable). Rate of adverse events, quality of life, and patient satisfaction were not significantly different between the two arms. CONCLUSIONS: Among patients with malignant pleural effusion, daily drainage of pleural fluid via an indwelling pleural catheter led to a higher rate of autopleurodesis and faster time to liberty from catheter. Clinical trial registered with www.clinicaltrials.gov (NCT 00978939).

Convex probe EBUS for centrally located parenchymal lesions without a bronchus sign.

BACKGROUND: Convex probe endobronchial ultrasound (CP-EBUS) has proven safe and accurate for identifying malignancy and granulomatous disease affecting the mediastinum and hilum. For the diagnosis of parenchymal lung lesions, conventional techniques such as transbronchial biopsy, brush and lavage are useful, particularly when an airway leads directly to the lesion. For centrally located intraparenchymal lesions, CP-EBUS has been shown to be efficacious. OBJECTIVE: To expand on the existing literature in an effort to highlight the important diagnostic role of CP-EBUS in centrally located lesions, particularly those without a bronchus sign. METHODS: In our cohort of 430 patients undergoing CP-EBUS between 03/2009-03/2012, we retrospectively identified 32 who underwent transbronchial needle aspiration (TBNA) of a centrally located parenchymal lung lesion. All lesions were completely surrounded by lung parenchyma and not visualized during white light bronchoscopy. Diagnostic yield was determined and compared to conventional bronchoscopic biopsy techniques, when performed. RESULTS: The mean lesion size was 25.6 mm and 24/32 (75%) lesions were located in the lower lobes. A definitive diagnosis was obtained in 27/32 (84.4%) of parenchymal lesions without a bronchus sign biopsied using CP-EBUS. CP-EBUS provided the exclusive method of diagnosis in 15/32 (46.9%) patients in this cohort. Most lesions (26/32) were diagnosed as non-small cell carcinoma. There were no procedural complications. CONCLUSION: CP-EBUS is useful for diagnosing parenchymal lung abnormalities without a bronchus sign, extending its scope beyond mediastinal and hilar lymph nodes. It is imperative that physicians performing EBUS maintain this tool as a complement to conventional bronchoscopic techniques.