Search

Background The relationship between the presence of pleural and pericardial effusion in reference to hemodynamic parameters remains unclear in ambulatory patients with pulmonary hypertension (PH). Methods Consecutive patients who underwent right catheterization (RHC) for the evaluation of pulmonary hypertension were enrolled. Point-of- care ultrasound was performed prior to the RHC to determine the presence of pleural effusion and pericardial effusion. We conducted a cross-sectional study to determine the association between presence of pericardial and pleural effusion with pulmonary hemodynamic variables. Results Twenty-five (78.1%) of 32 patients had evidence of PH by RHC. Mean pulmonary artery pressure of the population was 40.6 mmHg, and 68% (17/25) had WHO group I PH. Six (24.0%) of 25 PH patients had pleural effusions identified, of which 4 out of 6 (66.7%) had a pulmonary artery wedge pressure >15 mmHg. Eleven (44.0%) of the 25 PH patients were also found to have pericardial effusions, and most of those patients 10/11(90.9%) had an elevated right atrial pressure >10 mmHg. The presence of a pleural effusion was associated with a pulmonary artery wedge pressure >15 mmHg (p = 0.032) and the presence of a pericardial effusion was associated with a right atrial pressure >10 mmHg (p = 0.004). Detection of pleural effusion had a poor positive predictive value (67%) for the presence of pulmonary venous hypertension, whereas presence of a pericardial effusion was highly predictive (89%) of the presence of systemic venous hypertension. Conclusions Systemic venous hypertension was associated with the presence of pericardial effusions, while pulmonary venous hypertension is associated with pleural effusion development in ambulatory patients with pulmonary hypertension.

Background There are limited data examining the diagnostic accuracy of thoracic ultrasonography (TUS) in distinguishing transudative from exudative pleural effusions. Research Question What is the diagnostic accuracy of TUS in distinguishing transudative from exudative effusions in consecutive patients with pleural effusion? Study Design and Methods Consecutive patients who underwent TUS and subsequently a diagnostic thoracentesis with a pleural fluid analysis were identified. TUS images of the pleural effusions were interpreted by previously published criteria. We evaluated the diagnostic performance of TUS findings in predicting a transudative vs exudative pleural effusions and specific pleural diagnoses. Results We evaluated 300 consecutive pleural effusions in 285 patients. The pleural effusions were classified as exudative in 229 of 300 cases (76%). TUS showed anechoic effusions in 122 of 300 cases (40%) and complex effusions in 178 of 300 cases (60%). An anechoic appearance on TUS was associated with exudative effusions (68/122; 56%) as compared with transudative effusions (54/122; 44%). The presence of a complex-appearing effusion on TUS was highly predictive of an exudative effusion (positive predictive value of 90%). However, none of the four TUS characteristics were highly specific of a pleural diagnosis. Interpretation Thoracic ultrasonography is inadequate to diagnose a transudative pleural effusion reliably. Although the TUS findings of a complex effusion may suggest an exudative pleural effusion, specific pleural diagnoses cannot be predicted confidently.

Pleural manometry (PM) is a novel tool that allows direct measurement of the pressure in the pleural space in the presence of either a pleural effusion or a pneumothorax. Originally it was used to guide therapy for tuberculosis (TB) before the development of anti-TB medications. It was relegated to highly specialized centers for thoracoscopies until Light used it to investigate pleural effusions in the 1980s. However, there remains lack of robust data to support the routine use of PM. Recently additional published studies have generated renewed interest supporting the use of PM in specialized cases of complex pleural disorders. In this paper we summarize the current different techniques, applications, and pitfalls for the use of PM.

Background Thoracentesis can be accomplished by active aspiration or drainage with gravity. This trial investigated whether gravity drainage could protect against negative pressure-related complications such as chest discomfort, re-expansion pulmonary edema, or pneumothorax compared with active aspiration. Methods This prospective, multicenter, single-blind, randomized controlled trial allocated patients with large free-flowing effusions estimated ≥ 500 mL 1:1 to undergo active aspiration or gravity drainage. Patients rated chest discomfort on 100-mm visual analog scales prior to, during, and following drainage. Thoracentesis was halted at complete evacuation or for persistent chest discomfort, intractable cough, or other complication. The primary outcome was overall procedural chest discomfort scored 5 min following the procedure. Secondary outcomes included measures of discomfort and breathlessness through 48 h postprocedure. Results A total of 142 patients were randomized to undergo treatment, with 140 in the final analysis. Groups did not differ for the primary outcome (mean visual analog scale score difference, 5.3 mm; 95% CI, –2.4 to 13.0; P = .17). Secondary outcomes of discomfort and dyspnea did not differ between groups. Comparable volumes were drained in both groups, but the procedure duration was significantly longer in the gravity arm (mean difference, 7.4 min; 95% CI, 10.2 to 4.6; P Conclusions Thoracentesis via active aspiration and gravity drainage are both safe and result in comparable levels of procedural comfort and dyspnea improvement. Active aspiration requires less total procedural time. Trial Registry ClinicalTrials.gov; No.: NCT03591952; URL: www.clinicaltrials.gov.

Rationale: Prolonged air leak (PAL) after partial lung resection can occur due to surgical complications or in the presence of residual thoracic space. The former type results in drainage-independe...

Objective Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) (scleroderma) and the leading cause of scleroderma-related deaths. There exists an unmet need for a new drug therapy for ILD-complicated SSc. Substantial evidence supports an important role for thrombin in the pathogenesis of SSc-associated ILD (hereafter SSc-ILD), and targeting thrombin with a direct thrombin inhibitor could prove to be a novel and effective treatment strategy. As a first step toward designing a clinical trial to test the efficacy of thrombin inhibition in SSc-ILD, we conducted this study to test the safety and tolerability of dabigatran in patients with SSc-ILD. Methods We performed a prospective, single-center, open-label treatment trial with the direct thrombin inhibitor, dabigatran, in patients with SSc-ILD. Any patient with a history of gastrointestinal hemorrhage or gastric antral vascular ectasia was excluded. Blood monitoring was performed monthly, and patient-reported outcomes, pulmonary function tests, and skin scores were obtained at baseline and at 3- and 6-month visits. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at baseline and at 6 months for measurement of lung thrombin activity. Results Of 15 patients with SSc-ILD, 14 completed 6 months of treatment with dabigatran at 75 mg taken orally twice daily. Adverse events were uncommon and usually mild or unrelated to the study medication. No serious adverse event was observed. Dabigatran was well tolerated, and we observed no significant gastrointestinal, pulmonary, or other safety issues or intolerability. BAL fluid thrombin activity decreased or remained stable in 13 of 14 (92.8%) subjects. Conclusion Dabigatran appears to be safe and well tolerated in patients with SSc-ILD. A larger randomized controlled trial to test the efficacy of direct thrombin inhibition with dabigatran can be considered.

Background In patients with non-expandable lung, removal of pleural fluid can result in excessively negative pleural pressure, which is associated with chest discomfort, pneumothorax, and re-expansion pulmonary oedema. Pleural manometry is widely used to safeguard against pressure-related complications during thoracentesis despite little evidence to support the approach. We investigated whether monitoring of pleural pressure with manometry during thoracentesis could protect against complications compared with assessment of symptoms alone. Methods We did a prospective randomised single-blind trial involving patients with large pleural effusions at two academic medical centres in, Nashville, TN, and Baltimore, MD, USA. Eligible patients were adults with free-flowing effusions estimated to be at least 0·5 L who could remain seated throughout the procedure. Patients were randomly assigned 1:1 to receive thoracentesis guided by symptoms only (control) or by symptoms plus manometry at timepoints based on volume drained. The randomisation schedule was computer generated, used permuted blocks of four and six, and was stratified by participating institution. Patients, who were masked to study-group assignment, were asked to rate chest discomfort on 100 mm visual analogue scales before, during, and after drainage. In both groups drainage was discontinued before complete evacuation of pleural fluid if patients developed persistent chest discomfort, intractable cough, or other complications. In the manometry group, an additional criterion for stopping was if end-expiratory pleural pressure was lower than −20 cm H2O or declined by more than 10 cm H2O between two measurements to a value less than or equal to −10 cm H2O. The primary outcome was overall chest discomfort from before the start to after the procedure measured by patients 5 min after the end of drainage. Analysis was by modified intention to treat (ie, included all patients with any procedure or outcome data). This trial is registered with ClinicalTrials.gov, number NCT02677883. Findings Between March 4, 2016, and Sept 8, 2017, 191 patients were screened, of whom 128 were randomly assigned treatment and 124 were included in the final analysis (62 in each group). Four patients were excluded because of manometer malfunction (n=2), inability to access effusion due to pleural tumour burden (n=1), and inability to remain seated (n=1). Groups did not differ for the primary outcome (mean difference in chest discomfort score 2·4 mm, 95% CI −5·7 to 10·5, p=0·56). Six (10%) of 62 patients in the control group had asymptomatic pneumothorax ex vacuo compared with none in the manometry group (p=0·01). No serious complications occurred in either group. Interpretation Measurement of pleural pressure by manometry during large-volume thoracentesis does not alter procedure-related chest discomfort. Our findings do not support the routine use of this approach.

Background In the INPULSIS® trials, nintedanib reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing of disease progression. We characterised the effects of nintedanib on physiologic outcomes using pooled data from the INPULSIS® trials. Methods Post-hoc analyses included changes in FVC over time, cumulative distribution of patients by change in FVC % predicted, and annual rate of decline in FVC in subgroups by diffusing capacity of the lung for carbon monoxide (DLco) and composite physiologic index (CPI) at baseline. Changes from baseline in DLco and oxygen saturation by pulse oximetry (SpO2) were pre-specified. Results Nintedanib significantly reduced FVC decline versus placebo from week 12. A higher proportion of patients treated with nintedanib than placebo had an improvement or no decline in FVC % predicted, whereas a smaller proportion had absolute declines in FVC ≥5% or ≥10% predicted from baseline to week 52. The effect of nintedanib on FVC decline was similar in patients with baseline DLco >40% versus ≤40% predicted or CPI ≤45 versus >45. There were no significant differences between nintedanib and placebo in change from baseline in DLco % predicted, CPI, or SpO2 at week 52. However, change (deterioration) in CPI was significantly lower with nintedanib versus placebo in patients with CPI > 45 at baseline (1.0 versus 2.9) and CPI >55 at baseline (−1.2 versus 3.3). Conclusions A range of physiologic outcome measures in the INPULSIS® trials support the effect of nintedanib on reducing disease progression in patients with IPF.

BACKGROUND: The clinical features and outcomes of mechanically ventilated patients with COVID-19 infection who develop a pneumothorax has not been rigorously described or compared to those who do not develop a pneumothorax. PURPOSE: To determine the incidence, clinical characteristics, and outcomes of critically ill patients with COVID-19 infection who developed pneumothorax. In addition, we compared the clinical characteristics and outcomes of mechanically ventilated patients who developed a pneumothorax with those who did not develop a pneumothorax. METHODS: This study was a multicenter retrospective analysis of all adult critically ill patients with COVID-19 infection who were admitted to intensive care units in 4 tertiary care centers in the United States. RESULTS: A total of 842 critically ill patients with COVID-19 infection were analyzed, out of which 594 (71%) were mechanically ventilated. The overall incidence of pneumothorax was 85/842 (10%), and 80/594 (13%) in those who were mechanically ventilated. As compared to mechanically ventilated patients in the non-pneumothorax group, mechanically ventilated patients in the pneumothorax group had worse respiratory parameters at the time of intubation (mean PaO2:FiO2 ratio 105 vs 150, P

ImportanceSARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2.ObjectiveTo determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19.Design, setting, and participantsThe Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021.InterventionsPatients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone.Main outcomes and measuresThe composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days.ResultsThe trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns.Conclusions and relevanceIn this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity.Trial registrationClinicalTrials.gov Identifier: NCT04397718.

Unexpandable lung is a common complication of malignant pleural effusions and inflammatory pleural diseases, such as pleural infection (e.g. empyema and complicated parapneumonic effusion) and noninfectious fibrinous pleuritis. Unexpandable lung due to pleural disease may be because of an active pleural process, and is referred to as malignant or inflammatory lung entrapment. An unexpandable lung may also be encountered in the setting of remote pleural inflammation resulting in a mature fibrous membrane overlying the visceral pleura preventing full expansion of the lung. This condition is termed trapped lung and may be understood as a form of defective healing of the pleural space. Trapped lung typically presents as a chronic, stable pleural effusion without evidence of active pleural disease. An unexpandable lung most often manifests itself as an inability of fully expanding the lung with pleural space drainage. Patients will either develop chest pain preventing complete drainage of the pleural space or develop a post-procedure pneumothorax. Pleural manometry and radiological imaging are useful in the assessment of an unexpandable lung. Pleural manometry can demonstrate abnormal lung expansion during drainage and imaging will demonstrate abnormal visceral pleural thickening found in trapped lung or malignant and inflammatory lung entrapment.

Response to: 'Considering the Duration of Lung Collapse When Comparing Thoracentesis Techniques', Chest, Vol. 158, Issue 1, and 'Gravity vs Active Aspiration for Thoracentesis', Chest, Vol. 158, Issue 1, based on the initial article: 'The Impact of Gravity vs Suction-driven Therapeutic Thoracentesis on Pressure-related Complications', Chest, Vol. 157, Issue 3.

Background Both elevated pleural elastance (E-PEL) and radiographic evidence of incomplete lung expansion following thoracentesis have been used to exclude patients with a malignant pleural effusion (MPE) from undergoing pleurodesis. This article reports on a cohort of patients with MPE in whom complete drainage was attempted with pleural manometry to determine the frequency of E-PEL and its relation with postthoracentesis radiographic findings. Methods Seventy consecutive patients with MPE who underwent therapeutic pleural drainage with pleural manometry were identified. The pressure/volume curves were constructed and analyzed to determine the frequency of E-PEL and the relation of PEL to the postthoracentesis chest radiographic findings. Results E-PEL and incomplete lung expansion were identified in 36 of 70 (51.4%) and 38 of 70 (54%) patients, respectively. Patients with normal PEL had an OR of 6.3 of having complete lung expansion compared with those with E-PEL (P = .0006). However, 20 of 70 (29%) patients exhibited discordance between postprocedural chest radiographic findings and the pleural manometry results. Among patients who achieved complete lung expansion on the postdrainage chest radiograph, 9 of 32 (28%) had an E-PEL. In addition, PEL was normal in 11 of 38 (34%) patients who had incomplete lung expansion as detected according to the postthoracentesis chest radiograph. Conclusions E-PEL and incomplete lung expansion postthoracentesis are frequently observed in patients with MPE. Nearly one-third of the cohort exhibited discordance between the postprocedural chest radiographic findings and pleural manometry results. These findings suggest that a prospective randomized trial should be performed to compare both modalities (chest radiograph and pleural manometry) in predicting pleurodesis outcome.

Thoracentesis can be accomplished by active aspiration or drainage with gravity. This trial investigated whether gravity drainage could protect against negative pressure-related complications such as chest discomfort, re-expansion pulmonary edema, or pneumothorax compared with active aspiration.This prospective, multicenter, single-blind, randomized controlled trial allocated patients with large free-flowing effusions estimated ≥ 500 mL 1:1 to undergo active aspiration or gravity drainage. Patients rated chest discomfort on 100-mm visual analog scales prior to, during, and following drainage. Thoracentesis was halted at complete evacuation or for persistent chest discomfort, intractable cough, or other complication. The primary outcome was overall procedural chest discomfort scored 5 min following the procedure. Secondary outcomes included measures of discomfort and breathlessness through 48 h postprocedure.A total of 142 patients were randomized to undergo treatment, with 140 in the final analysis. Groups did not differ for the primary outcome (mean visual analog scale score difference, 5.3 mm; 95% CI, -2.4 to 13.0; P = .17). Secondary outcomes of discomfort and dyspnea did not differ between groups. Comparable volumes were drained in both groups, but the procedure duration was significantly longer in the gravity arm (mean difference, 7.4 min; 95% CI, 10.2 to 4.6; P .001). There were no serious complications.Thoracentesis via active aspiration and gravity drainage are both safe and result in comparable levels of procedural comfort and dyspnea improvement. Active aspiration requires less total procedural time.ClinicalTrials.gov; No.: NCT03591952; URL: www.clinicaltrials.gov.

Summary Background The efficacy and safety of nintedanib, an intracellular tyrosine kinase inhibitor, in patients with idiopathic pulmonary fibrosis were assessed in two phase 3, placebo-controlled INPULSIS trials. Patients who completed the 52-week treatment period in an INPULSIS trial could receive open-label nintedanib in the extension trial, INPULSIS-ON. We aimed to assess the long-term efficacy and safety of nintedanib in INPULSIS-ON. Methods Patients who completed the 52-week treatment period of INPULSIS, and the follow-up visit 4 weeks later, were eligible for INPULSIS-ON. The off-treatment period between INPULSIS and INPULSIS-ON could be 4–12 weeks. Patients receiving nintedanib 150 mg twice daily or placebo at the end of an INPULSIS trial received nintedanib 150 mg twice daily in INPULSIS-ON. Patients receiving nintedanib 100 mg twice daily or placebo at the end of an INPULSIS trial could receive nintedanib 100 mg twice daily or 150 mg twice daily in INPULSIS-ON. Spirometric tests were done at baseline, at weeks 2, 4, 6, 12, 24, 36, 48, and then every 16 weeks. The primary outcome of INPULSIS-ON was to characterise the long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis, and this was analysed in patients who received at least one dose of nintedanib in INPULSIS-ON. This study is registered with ClinicalTrials.gov, number NCT01619085, and with EudraCT, number 2011-002766-21. Findings The first patient was enrolled into INPULSIS-ON in July 2, 2012. Of 807 patients who completed the INPULSIS trials, 734 (91%) were treated in INPULSIS-ON. 430 (59%) patients had received nintedanib in INPULSIS and continued nintedanib in INPULSIS-ON, and 304 (41%) had received placebo in INPULSIS and initiated nintedanib in INPULSIS-ON. Median exposure time for patients treated with nintedanib in both the INPULSIS and INPULSIS-ON trials was 44·7 months (range 11·9–68·3). The safety profile of nintedanib in INPULSIS-ON was consistent with that observed in INPULSIS. Diarrhoea was the most frequent adverse event in INPULSIS-ON (60·1 events per 100 patient exposure-years in patients who continued nintedanib, 71·2 events per 100 patient exposure-years in patients who initiated nintedanib). 20 (5%) of 430 patients who continued nintedanib and 31 (10%) of 304 patients who initiated nintedanib permanently discontinued nintedanib because of diarrhoea. The adverse event that most frequently led to permanent discontinuation of nintedanib was progression of idiopathic pulmonary fibrosis (51 [12%] patients continuing nintedanib and 43 [14%] patients initiating nintedanib). The event rate of bleeding was 8·4 events per 100 patient exposure-years in patients who continued nintedanib and 6·7 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of major adverse cardiovascular events was 3·6 events per 100 patient exposure-years in patients who continued nintedanib and 2·4 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of myocardial infarction using the broad scope (ie, all possible cases) was 1·3 events per 100 patient exposure-years in patients who continued nintedanib and 0·7 events per 100 patient exposure-years in patients who initiated nintedanib. Interpretation These findings suggest that nintedanib has a manageable safety and tolerability profile over long-term use, with no new safety signals. Patients with idiopathic pulmonary fibrosis could use nintedanib over the long-term to slow disease progression. Funding Boehringer Ingelheim.

The management of patients with cirrhosis along with acute kidney injury is complex and depends in large part on accurate assessment of intravascular volume status. Assessment of intravascular volume status by point-of-care echocardiography often relies solely on inferior vena cava size and variability evaluation; however, this parameter should be interpretated with an understanding of right ventricular function integrated with stroke volume and flow. Attempts to optimize intra-abdominal hemodynamics favorably are clearly problematic when physical examination findings or rudimentary assessments of central venous pressure or change in central venous pressure are used. Here, we have demonstrated the potential utility of point-of-care echocardiography to optimize the hemodynamic state in patients with decompensated cirrhosis along with acute kidney injury. This case is very unique and describes how this technique may have great promise in optimizing the intra-abdominal hemodynamics and predict the timing of large-volume paracentesis in patients with decompensated cirrhosis, which in turn can aid in promoting favorable renal recovery.

Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available., SCOPUS: re.j, info:eu-repo/semantics/published

In the INPULSISPost-hoc analyses included changes in FVC over time, cumulative distribution of patients by change in FVC % predicted, and annual rate of decline in FVC in subgroups by diffusing capacity of the lung for carbon monoxide (DLco) and composite physiologic index (CPI) at baseline. Changes from baseline in DLco and oxygen saturation by pulse oximetry (SpONintedanib significantly reduced FVC decline versus placebo from week 12. A higher proportion of patients treated with nintedanib than placebo had an improvement or no decline in FVC % predicted, whereas a smaller proportion had absolute declines in FVC ≥5% or ≥10% predicted from baseline to week 52. The effect of nintedanib on FVC decline was similar in patients with baseline DLco40% versus ≤40% predicted or CPI ≤45 versus45. There were no significant differences between nintedanib and placebo in change from baseline in DLco % predicted, CPI, or SpOA range of physiologic outcome measures in the INPULSIS

Background: In patients with non-expandable lung, pleural fluid removal can result in excessively negative pleural pressure, associated with chest discomfort, pneumothorax, and reexpansion pulmonary edema. Monitoring pleural pressure during thoracentesis may reduce discomfort and protect against complications. Methods: In this prospective randomized single-blind trial, subjects with large pleural effusions at two academic medical centers were randomly assigned (1:1 ratio) to symptom-guided ("control") versus symptom-plus-manometry-guided ("manometry") thoracentesis. All had free-flowing effusions meeting pre-specified criteria suggesting volume of at least 500 milliliters. Subjects, who were blinded to assignment, rated chest discomfort on visual analog scales before, during, and after drainage. Pleural pressure was measured at regular intervals in the manometry group. Drainage was discontinued before complete evacuation for persistent chest discomfort, incessant cough, complication, rapidly falling pleural pressure, or end-expiratory pleural pressure lower than -20 cm H2O (latter two only in the manometry group). We performed a modified intention-to-treat analysis. The primary outcome was overall procedural chest discomfort through 5 minutes post-procedure. Findings: Between March 4, 2016 and September 8, 2017, 191 patients were screened. One hundred twenty-eight eligible subjects were randomized with four excluded from the final analysis of 62 subjects per group due to manometer malfunction (n=2), inability to access effusion due to pleural tumor burden (n=1), and inability to remain seated (n=1). There was no difference in the primary outcome of overall procedural chest discomfort between groups (mean difference 2.4, 95% CI -5.7-10.5; p = 0.78). Six asymptomatic pneumothoraces ex-vacuo occurred in the control group; no serious complications occurred in either group. Interpretation: Measurement of pleural pressure during large-volume thoracentesis does not alter procedure-related chest discomfort. This is the first study to directly assess the impact of pleural manometry on important patient-centered clinical outcomes during thoracentesis, and does not support its routine use. This trial was registered at clinicaltrials.gov, NCT02677883 Funding: Centurion Medical Products Declaration of Interest: No authors report any financial or non-financial conflicts of interest pertinent to this work outside the declared funding source for this trial (see below re: role of funding source). Ethics Approval Statement: This randomized single-blind trial recruited inpatient and outpatient subjects at two academic medical centers (Vanderbilt University Medical Center, Nashville, TN, USA and Johns Hopkins Hospital, Baltimore, MD, USA). Institutional Review Boards of both institutions approved this trial (VUMC IRB number 151492; JHU IRB number 00119664).

Introduction: Patients with IPF who completed one of the two Phase III INPULSIS trials could receive open-label nintedanib in the extension trial INPULSIS-ON. Patients treated with placebo in INPULSIS initiated nintedanib in INPULSIS-ON, while patients treated with nintedanib in INPULSIS continued nintedanib in INPULSIS-ON. Aim: We examined patterns of permanent discontinuation of nintedanib in INPULSIS-ON. Methods: The first patient was enrolled in INPULSIS-ON in July 2012 and the trial ended in September 2017. The timing of and reasons for permanent discontinuation of nintedanib in INPULSIS-ON were analysed descriptively based on the final analysis. Results: Mean (SD) duration of exposure to nintedanib in INPULSIS-ON was 29.0 (16.4) months; maximum exposure was 56.3 months. Of 734 patients treated with open-label nintedanib in INPULSIS-ON, 514 patients (70.0%) discontinued treatment during the trial. Patients discontinued nintedanib due to adverse events related to IPF (n=81, 11.0%), adverse events not related to IPF (n=188, 25.6%), death (n=86, 11.7%), lung transplant (n=20, 2.7%) and other reasons such as availability of commercial drug (n=139, 18.9%). Discontinuations were most frequent in the first year (figure). Conclusion: In INPULSIS-ON, the most common reason for discontinuing nintedanib was adverse events not related to IPF. These occurred most frequently in the first year of INPULSIS-ON.

Background Safety data on combined pirfenidone and nintedanib use are limited. Methods A single-arm, open-label study (NCT02598193) assessed safety and tolerability of 24 weeks’ pirfenidone (1602–2403 mg/day) and nintedanib (200–300 mg/day) in patients with idiopathic pulmonary fibrosis (IPF) with forced vital capacity (FVC) ≥50% and diffusing capacity of the lung for carbon monoxide (DLco) ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg/day pirfenidone for ≥28 days. Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. Change from baseline FVC, DLco and King’s Brief Interstitial Lung Disease (K-BILD) score were assessed at 24 weeks. The study is monitored by a data monitoring committee. Results Eighty-nine patients were enrolled. A pre-specified interim analysis was conducted once 63 patients (mean age 68.7 years, 85.7% male) completed (n=50) or discontinued (n=13) 24 weeks’ combination treatment. Fifty patients had 330 treatment-related TEAEs (Table); 11 patients discontinued due to TEAEs. Two patients had serious treatment-related TEAEs (Table) but none led to death. Final Results for all 89 patients, including change from baseline FVC, DLco and K-BILD score, will be presented at BTS. Conclusions Combined pirfenidone and nintedanib use for 24 weeks did not reveal a different safety profile to that expected for either treatment alone. Patients had tolerated a stable dose of pirfenidone before initiation of nintedanib, which may explain why investigators attributed more TEAEs to nintedanib than pirfenidone. Funding F. Hoffmann-La Roche, Ltd./Genentech, Inc.

Introduction: In the two INPULSIS trials in patients with IPF, the annual rate of decline in FVC was reduced in patients treated with nintedanib 150 mg twice daily versus placebo. Patients who completed an INPULSIS trial could receive open-label nintedanib in the extension trial INPULSIS-ON. The influence of medications commonly prescribed to treat comorbid conditions on the effect of nintedanib is unknown. Aim: To assess whether concomitant medication use at the start of INPULSIS and INPULSIS-ON influenced the effect of nintedanib on FVC decline. Methods: The annual rate of decline in FVC over 52 weeks in INPULSIS and over 48 weeks in INPULSIS-ON in subgroups defined by concomitant medication use at baseline was assessed descriptively. Results: The annual rates of decline in FVC over 52 weeks in INPULSIS and over 48 weeks in INPULSIS-ON were consistent across subgroups by concomitant medication use at baseline, including anti-acid therapy and corticosteroids (Table). There was a numerical difference in the annual rate of decline in FVC between subgroups defined by use of N-acetylcysteine or bronchodilators in INPULSIS-ON; however, as the number of patients in some subgroups was small, these results should be interpreted with caution. Conclusion: Data from INPULSIS and INPULSIS-ON demonstrated a consistent effect of nintedanib on the annual rate of decline in FVC in patients with IPF irrespective of concomitant medication use at baseline.

Unexpandable lung is a common complication of malignant pleural effusions and inflammatory pleural diseases, such as pleural infection (e.g. empyema and complicated parapneumonic effusion) and noninfectious fibrinous pleuritis. Unexpandable lung due to pleural disease may be because of an active pleural process, and is referred to as malignant or inflammatory lung entrapment. An unexpandable lung may also be encountered in the setting of remote pleural inflammation resulting in a mature fibrous membrane overlying the visceral pleura preventing full expansion of the lung. This condition is termed trapped lung and may be understood as a form of defective healing of the pleural space. Trapped lung typically presents as a chronic, stable pleural effusion without evidence of active pleural disease. An unexpandable lung most often manifests itself as an inability of fully expanding the lung with pleural space drainage. Patients will either develop chest pain preventing complete drainage of the pleural space or develop a post-procedure pneumothorax. Pleural manometry and radiological imaging are useful in the assessment of an unexpandable lung. Pleural manometry can demonstrate abnormal lung expansion during drainage and imaging will demonstrate abnormal visceral pleural thickening found in trapped lung or malignant and inflammatory lung entrapment.

Urinothorax is an uncommon thoracic complication of genitourinary (GU) tract disease, which is most frequently caused by obstructive uropathy, but may also occur as a result of iatrogenic or traumatic GU injury. It is underrecognized because of a perceived notion as to the rarity of the diagnosis and the absence of established diagnostic criteria. Urinothorax is typically described as a paucicellular, transudative pleural effusion with a pleural fluid/serum creatinine ratio1.0. It is the only transudate associated with pleural fluid acidosis (pH7.40). When the pleural fluid analysis demonstrates features of a transudate, pH7.40 and a pleural fluid/serum creatinine ratio1.0, a confident clinical diagnosis of urinothorax can be established. A technetium 99m renal scan can be considered a confirmatory test in patients who lack the typical pleural fluid analysis features or fail to demonstrate evidence of obstructive uropathy that can be identified via conventional radiographic modalities. Management of a urinothorax requires a multidisciplinary approach with an emphasis on the correction of the underlying GU tract pathology, and once corrected, this often leads to a rapid resolution of the pleural effusion.

Yellow nail syndrome (YNS) can be associated with a pleural effusion (PE) but the characteristics of these patients are not well defined.We performed a systematic review across four electronic databases for studies reporting clinical findings, PE characteristics, and most effective treatment of YNS. Case descriptions and retrospective studies were included, unrestricted by year of publication. We reviewed 112 studies (150 patients), spanning a period of nearly 50 years. The male/female ratio was 1.2/1. The median age was 60 years (range: 0-88). Seventy-eight percent were between 41-80 years old. All cases had lymphoedema and 85.6% had yellow nails.PEs were bilateralin68.3%. The appearance of the fluid was serous in 75.3%, milky in 22.3% and purulent in 3.5%.The PE was an exudate in 94.7% with lymphocytic predominance in 96% with a low count of nucleated cells. In 61 of 66 (92.4%) of patients, pleural fluid protein values were >3 g/dL, and typically higher than pleural fluid LDH. Pleurodesis and decortication/pleurectomy were effective in 81.8% and 88.9% of cases, respectively, in the treatment of symptomatic PEs. The development of YNS and PE occurs between the fifth to eighth decade of life and is associated with lymphoedema. The PE is usually bilateral and behaves as a lymphocyte-predominant exudate. The most effective treatments appear to be pleurodesis and decortication/pleurectomy.

Background In individual patients, especially those who are hospitalized, several conditions often coexist that may be responsible for the development of a pleural effusion and may affect the pleural fluid analysis (PFA). The objective of this study was to investigate the effects of end-stage renal disease and pneumonia on PFA in patients with hydrostatic pleural effusion. Methods In a retrospective analysis of 1,064 consecutive patients who underwent thoracentesis at a university hospital, cell counts and pleural fluid protein, lactate dehydrogenase, pH, and glucose levels were examined in those (n = 300) with clinical evidence of hydrostatic pleural effusion. Results The 300 patients (28.1%) with pleural effusions had congestive heart failure (CHF), circulatory overload (CO), or both. Expert consensus was achieved in 66 (22%) for CHF as the sole diagnosis (SCHF), 30 (10%) for CHF and coexisting pneumonia (PCHF), and 26 (8.7%) for end-stage renal disease (ESRD) with coexisting CO or CHF. The remaining 178 patients were excluded because of complicating conditions. There were minor, but statistically significant differences in pleural fluid/serum protein ratios in patients with ESRD with coexisting CO or CHF compared with SCHF. Compared with SCHF, there were statistically significant tendencies for higher protein and lactate dehydrogenase concentrations and lower pH levels in those with PCHF. The total nucleated cell count and the absolute neutrophil count were significantly higher in PCHF. Conclusions ESRD in patients with hydrostatic pleural effusions has a minimal effect on the PFA. Coexisting pneumonia most often results in an exudative effusion in patients with CHF.

Although a pleural effusion (PE) is a common condition in clinical practice (with a prevalence of slightly >400 patients/100,000), a definitive diagnosis is not established in approximately 20% of cases. In the classic publications, thoracentesis provided a definitive or presumptive diagnosis in 73%

Rickettsiosis, Q fever, tularemia, and anthrax are all bacterial diseases that can affect the pleura. Rocky Mountain Spotted Fever (RMSF) and Mediterranean Spotted Fever (MSF) are caused by Rickettsia rickettsii and Rickettsia conorii, respectively. Pleural fluid from a patient with MSF had a neutrophil-predominant exudate. Coxiella burnetii is the causative agent of Q fever. Of the two cases described in the literature, one was an exudate with a marked eosinophilia while the other case was a transudate due to a constrictive pericarditis. Francisella tularensis is the causative agent of tularemia. Pleural fluid from three tularemia patients showed a lymphocyte predominant exudate. Bacillus anthracis is the causative agent of anthrax. Cases of inhalational anthrax from a recent bioterrorist attack evidenced the presence of a serosanguineous exudative pleural effusion. These four bacterial microorganisms should be suspected in patients presenting with a clinical history, exposure to known risk factors and an unexplained pleural effusion.

Background There are limited published data defining complete pleural fluid analysis, echocardiographic characteristics, or the presence or absence of ascites on sonographic or CT imaging in patients with hepatic hydrothorax. Methods We reviewed pleural fluid analysis and radiographic, sonographic, and echocardiographic findings in 41 consecutive patients with hepatic hydrothorax referred to the Pleural Procedure Service for thoracentesis. Results Ascites was detected on sonographic or CT imaging in 38 of 39 patients (97%). Diastolic dysfunction was found in 11 of 21 patients (52%). Contrast echocardiography with agitated saline demonstrated an intrapulmonary shunt in 18 of 23 cases (78%). Solitary hepatic hydrothorax had a median pleural fluid pH of 7.49 (fifth to 95th percentile, 7.40-7.57), total protein level of 1.5 g/dL (0.58-2.34), and lactate dehydrogenase (LDH) level of 65 IU/L (36-138). The median pleural fluid/serum protein ratio and pleural LDH/upper limit of normal serum LDH ratio were 0.25 (0.10-0.43) and 0.27 (0.14-0.57), respectively. The median absolute neutrophil count (ANC) was 26 cells/μL (1-230). Only a single patient had a protein discordant exudate despite 83% of patients receiving diuretics. When comparing solitary hepatic hydrothorax and spontaneous bacterial pleuritis, there was no statistically significant difference among pleural fluid total protein (P = .99), LDH (P = .33), and serum albumin (P = .47). ANC was higher in patients with spontaneous bacterial pleuritis (P Conclusions Hepatic hydrothorax virtually always presents with ascites that is detectable on sonographic or CT imaging. The development of an "exudate" from diuretic therapy is a rare phenomenon in hepatic hydrothorax. In contrast, diastolic dysfunction and intrapulmonary shunting are common in patients with hepatic hydrothorax. There was no statistically significant change in pleural fluid parameters with spontaneous bacterial pleuritis, except an increased ANC.

Study objectives: To review the pleural fluid characteristics, pleural manometry, and radiographic data of patients who received a diagnosis of trapped lung in our pleural diseases service. Design: Retrospective case series. Methods: The procedure records of 247 consecutive patients who underwent pleural manometry at the Medical University of South Carolina between October 2002 and November 2005 were reviewed. Eleven patients in whom a diagnostic pneumothorax was introduced were identified. Manometry data, radiographic findings, pleural fluid analysis, final clinical diagnosis, and information regarding the initial pleural insult were retrieved from the medical record. Results: All 11 patients had a clinical diagnosis of trapped lung. The causes of trapped lung were attributed to coronary artery bypass graft surgery, uremia, thoracic radiation, pericardiotomy, spontaneous bacterial pleuritis and repeated thoracentesis, and complicated parapneumonic effusion. Mean pleural fluid pH was 7.30, pleural fluid lactate dehydrogenase (LDH) was 124 IU/L, and pleural fluid total protein was 2.9 g/dL. Pleural fluid was paucicellular with mononuclear cell predominance. Pleural space elastance was increased in all cases and ranged from 19 to 149 cm H 2 O/L of pleural fluid removed. All demonstrated abnormal visceral pleural thickness on air-contrast chest CT. Conclusions: Trapped lung is a clinical entity characterized by the presence of a restrictive visceral pleural peel that was first described in 1967. The pleural fluid is paucicellular, LDH is low, and protein may be in the exudative range. The elevated total pleural fluid protein may be related to factors other than active pleural inflammation or malignancy and does not exclude the diagnosis.

Introduction To describe the incidence of discordant exudate (DE) effusions, their underlying etiologies and their effect on the accuracy of the Light's criteria to diagnose exudate effusions. Methods A retrospective review of pleural fluid analysis (PFA) from a cohort of patients with pleural effusion (PE) who underwent thoracentesis. PEs were defined as exudative based on the Light's criteria. The effusions were further classified in concordant or DE. Results From 847 PE samples, 611 (72.1%) were diagnosed as an exudate and 236 (27.9%) as a transudate. In 10.3% of cases ( n = 87), there was discordancy between the final pleural fluid diagnosis and the PFA defined by Light's criteria. 281 (33.2%) of the 632 effusions classified as an exudate by Light's criteria were DE (52 transudates and 229 exudates). 182 (65%) of the 281 DE were found to be protein discordant (37 transudates and 145 exudates), and 99 (35.2%) were lactate dehydrogenase discordant (15 transudates and 84 exudates). The positive predictive value and positive likelihood ratio of Light's criteria for the diagnosis of an exudate effusion decreased from 99.4% and 67.4%, respectively, when the exudates were concordant to 81.5% and 1.7, respectively, if they were discordant. Conclusions In a significant percentage of patients, there is discordancy between the results of the PFA and the final clinical diagnosis. DE decreased the accuracy of Light's criteria to identify exudate PE, increasing the risk of misclassifying a transudate as an exudate. Concordant exudates almost universally established the presence of an exudative PE.

Introduction: To describe the incidence of discordant exudate effusions, their underlying etiologies and their impact on the accuracy of the Light9s criteria to diagnose exudate effusions. Methods: A retrospective review of pleural fluid analysis from a cohort of patients who underwent thoracentesis. Pleural effusions were defined as exudative based on the Light9s criteria. The effusions were further classified in concordant or discordant exudates. Results: From 847 pleural effusion analysis, 588 (69.4%) were finally diagnosed as exudate and 259 (30.6%) as transudate. In the 13% of cases there was discordancy between the final diagnosis and the pleural fluid analysis by the Light9s criteria. 281 (44%) of the effusions classified as exudate by Light9s criteria were discordant exudates (62 transudates and 219 exudates). 182 (75%) were protein discordant (44 transudates and 138 exudates), and 99 (35%) were LDH discordant (18 transudates and 81 exudates). The positive predicted value and positive likelihood ratio of the Light9s criteria for the diagnosis of exudate effusion decreased from 95.7% and 12 respectively when the exudates were concordant to 77.9% and 3.4 respectively if they were discordant. Conclusions: In a significant percentage of patients, there is discordancy between the results of the pleural fluid analysis and the final clinical diagnosis. The decrease in the accuracy of Light9s criteria to identify exudate effusions when they are discordant exudates suggest that, in these cases, physicians should look aggressively to identify the underlying etiology of the effusion, taking in account the clinical history and presentation.

The goals of therapeutic thoracentesis are to remove the maximum amount of pleural fluid to improve dyspnea and to facilitate the diagnostic evaluation of large pleural effusions. Pleural manometry may be useful for immediately detecting an unexpandable lung, which may coexist when any pleural fluid accumulates. Pleural manometry may improve patient safety when removing large amounts of pleural fluid. The basics of pleural space mechanics are discussed as they apply to the normal pleural space and to pleural effusion associated with expandable and unexpandable lung. This article also discusses the instrumentation required to perform bedside manometry, how manometry may decrease the risk of re-expansion pulmonary edema when large amounts of fluid are removed, and the diagnostic capabilities of manometry.

Introduction: Pleural manometry during large-volume thoracentesis can prevent the development of excessively negative pleural pressures, which have been associated with re-expansion pulmonary edema; can diagnose an unexpandable lung; and can predict pleurodesis success. We currently perform pleural manometry simultaneously with both a vertical-column water manometer with an interposed resistive element, and a hemodynamic transducer connected to a standard physiologic system. We present the technique as well as the advantages and disadvantages of both systems in measuring pleural liquid pressures. Technique: A flexible thoracentesis catheter is inserted in the most dependent portion of the pleural effusion. The water manometer consists of two lengths of IV tubing connected through a 22-gauge needle inserted into an injection terminal. The system is connected to the zeroing port of the pressure transducer, and both are carefully purged of air. The electronic system is zeroed at the level the thoracentesis catheter is introduced into the patient. Measurements are performed initially and after each 250 mL of fluid that is withdrawn. Accuracy of the water manometer: Forty consecutive patients who underwent therapeutic thoracentesis had pressure measurements. Pleural fluid removed ranged from 50 to 4,200 mL (mean, 1,445 mL). A total of 291 pressure measurements were acquired and analyzed. Mean pleural liquid pressure obtained by the water manometer had a strong positive correlation with the values obtained by a standard physiologic system ( r = 0.97, p Conclusion: An overdamped water manometer is a valid method to measure mean pleural liquid pressure. Coughing invalidates pressure measurements with the water manometer; however, with the electronic method, periods of quiet breathing can be identified, allowing for the measurement of pleural pressure.

The development of pleural fibrosis follows severe pleural space inflammation which is typically associated with an exudative pleural effusion. The response of the mesothelial cell to injury and its ability, along with the basement membrane, to maintain its integrity, is vital in determining whether there is normal healing or pleural fibrosis. The formation of a fibrinous intrapleural matrix is critical to the development of pleural fibrosis. This matrix is the result of disordered fibrin turnover, whereby fibrin formation is up-regulated and fibrin dissolution is down-regulated. Cytokines, such as TGF-β and TNF-α, facilitate the fibrin matrix formation. A complete understanding of the pathogenesis of pleural fibrosis and why abnormal pleural space remodeling occurs in some and not in others, remains unknown. Clinically significant pleural fibrosis requires involvement of the visceral pleura. Isolated parietal pleural fibrosis, as with asbestos pleural plaques, does not cause restriction or respiratory impairment. The causes of visceral pleural fibrosis include asbestos-associated diffuse pleural thickening, coronary bypass graft surgery, pleural infection (including tuberculous pleurisy), drug-induced pleuritis, rheumatoid pleurisy, uraemic pleurisy, and haemothorax. Systemic and intrapleural corticosteroids administered during the initial presentation of rheumatoid pleurisy in small series may decrease the incidence of pleural fibrosis. Several randomised control trials using corticosteroids in tuberculous pleurisy have not shown efficacy in reducing residual pleural fibrosis. Decortication is effective in treating symptomatic patients regardless of the cause of pleural fibrosis as long as chronicity has been documented and significant underlying parenchymal disease has been excluded.

We compared the accuracy of pleural ultrasound versus chest CT versus chest radiograph (CXR) to determine radiographic complexity in predicting a complicated parapneumonic effusion (CPPE) defined by pleural fluid analysis. 66 patients with parapneumonic effusions were identified with complete data. Pleural ultrasound had a sensitivity of 69.2% (95% CI 48.2% to 85.7%) and specificity of 90.0% (95% CI 76.3% to 97.2%). Chest CT had a sensitivity of 76.9% (95% CI 56.3% to 91.0%) and specificity of 65.0% (95% CI 48.3% to 79.4%). CXR had a sensitivity of 61.5% (95% CI 40.6% to 79.8%) and specificity of 60.0% (95% CI 43.3% to 75.1%). Pleural ultrasound appears to be a superior modality to rule in a CPPE when compared with chest CT and CXR.