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Complicated parapneumonic effusions and empyemas are associated with significant morbidity and mortality. When managing a potentially infected pleural space, current guidelines support performing diagnostic thoracentesis prior to consideration of chest tube insertion. We present a case demonstrating our clinical approach to the management of complicated parapneumonic effusions and empyemas, with patient presentation and initial point-of-care thoracic ultrasound assessment guiding consideration of immediate insertion of small-bore (14 F) chest tube.

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Point-of-care ultrasound is a bedside tool that is increasingly being used as part of the physical examination to evaluate fluid status. Cardiac ultrasound for assessment of volume status focuses on evaluating left ventricular ejection fraction, presence of pericardial effusion, right ventricular size, inferior vena cava size and collapsibility, and stroke volume measurement at the left ventricular outflow tract. Another way in which POCUS can be used to assess for fluid overload is the use of mitral inflow doppler to measure early diastolic transmitral flow velocity (E) and tissue doppler to measure early diastolic mitral annular velocity (e'). The ratio of E/e' is then used as an estimation of left ventricular filling pressure. This is a case where a 54-year-old female with end stage renal disease presents with hypoxic respiratory failure and is found to have diffuse bilateral airspace opacities on chest radiograph. E/e' was used to determine the etiology of the patient's undifferentiated pulmonary infiltrates and guide fluid removal through ultrafiltration. Ultrafiltration was performed with subsequent improvement in E/e' and the patient was successfully weaned off mechanical ventilation.

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Disorders of the pleural space are quite common in the critically ill patient. They are generally associated with the underlying illness. It is sometimes difficult to assess for pleural space disorders in the ICU given the instability of some patients. Although the portable chest X-ray remains the primary modality of diagnosis for pleural disorders in the ICU. It can be nonspecific and may miss subtle findings. Ultrasound has become a useful tool to the bedside clinician to aid in diagnosis and management of pleural disease. The majority of pleural space disorders resolve as the patient's illness improves. There remain a few pleural processes that need specific therapies. While uncomplicated parapneumonic effusions do not have their own treatments. Those that progress to become a complex infected pleural space can have its individual complexity in therapy. Chest tube drainage remains the cornerstone in therapy. The use of intrapleural fibrinolytics has decreased the need for surgical referral. A large hemothorax or pneumothorax in patients admitted to the ICU represent medical emergencies and require emergent action. In this review we focus on the management of commonly encountered complex pleural space disorders in critically ill patients such as complicated pleural space infections, hemothoraces and pneumothoraces.

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Systemic sclerosis (SSc), also referred to as scleroderma, is a rare autoimmune disease associated with vasculopathy, inflammation, and fibrosis of the skin and/or internal organs. Interstitial lung disease (ILD) is a frequent complication and is the leading cause of death in patients with SSc. Although economic data are limited, available data suggest that SSc-ILD is associated with significant cost implications. Treatment of SSc-ILD has historically been with immunosuppressive agents. In 2019, however, the treatment landscape expanded with the FDA approval of the tyrosine kinase inhibitor nintedanib. A lack of codified treatment guidelines for patients with SSc-ILD creates significant challenges in improving outcomes at the patient level and, more generally, in reducing disease burden to the health care system. As the treatment landscape continues to evolve, it is likely that to reduce lung volume loss in patients, a combination of immunosuppressive and antifibrotic approaches will need to be used. Additionally, a greater emphasis on risk-stratification strategies may allow for more efficient follow-up, monitoring, and assessment of treatment response.

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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.

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INTRODUCTION: Fulfillment of the diagnostic criteria for -hepatorenal syndrome type 1 (HRS-1) requires prior failure of 2 days of intravenous volume expansion and/or diuretic withdrawal. However, no parameter of volume status is used to guide the need for volume expansion in patients with suspected HRS-1. We hypothesized that point-of-care echocardiography (POCE) may better characterize the volume status in patients with acute kidney injury (AKI) and cirrhosis to ascertain or disprove the diagnosis of HRS-1. METHODS: A pilot observational study was conducted to determine the clinical utility of POCE-based examination of inferior vena cava diameter (IVCD) and collapsibility index (IVCCI) to assess intravascular volume status in patients with cirrhosis and AKI who had been deemed adequately volume-repleted and thereby assigned a clinical diagnosis of HRS-1. Early improvement in kidney function was defined as ≥20% decrease in serum creatinine (sCr) at 48-72 h. RESULTS: A total of 53 patients were included. The mean sCr at the time of volume assessment was 3.2 ± 1.5 mg/dL, and the mean Model for End-Stage Liver Disease score was 29 ± 8. Fifteen (23%) patients had an IVCD <1.3 cm and IVCCI >40% and were reclassified as fluid-depleted, 11 (21%) had an IVCD >2 cm and IVCCI <40% and were reclassified as fluid-expanded, and 8 (15%) had and IVCD <1.3 cm and IVCCI <40% and were reclassified as having intra-abdominal hypertension (IAH). Twelve (23%) patients exhibited early improvement in kidney function following a POCE-guided therapeutic maneuver, that is, volume expansion, diuresis, or paracentesis for those deemed fluid-depleted, fluid-expanded or having IAH, respectively. CONCLUSION: POCE-based assessment of volume status in cirrhotic individuals with AKI reveals marked heterogeneity. Unguided volume expansion in these patients may lead to premature or delayed diagnosis of HRS-1.

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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by irreversible loss of lung function and an unpredictable course of disease progression. METHODS: The safety data for patients with IPF who received placebo in 6 clinical trials were pooled to examine the categories and frequencies of serious adverse events (SAEs) in this population. RESULTS: In 1082 patients with IPF who received placebo, 673 SAEs were reported. Of these, 93 SAEs resulted in death (8.6% of patients). Respiratory-related conditions were the most frequently reported SAE (225 events, 16.33 per 100 patient-exposure years [PEY]), followed by infections and infestations (136 events, 9.87 per 100 PEY) and cardiac disorders (79 events, 5.73 per 100 PEY); these categories also had the most fatal outcomes (60, 10, and 10 deaths, respectively). The most frequently reported fatal respiratory-related SAEs were IPF and respiratory failure (38 and 11 patients, respectively), and the most frequently reported fatal infections and infestations and cardiac disorders were pneumonia (5 patients) and myocardial infarction (3 patients), respectively. CONCLUSIONS: This pooled analysis has value as a comparator for safety in future studies of IPF and provides insights in the natural evolution of both IPF and common comorbidities.

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OBJECTIVES: The aims of this study are (1) to characterize factors influencing self-management behaviors and quality of life in adolescent and young adult (AYA) patients with childhood-onset systemic lupus erythematosus (cSLE) and (2) to identify barriers and facilitators of treatment adherence via focus groups. METHODS: AYAs with cSLE ages 12-24 years and primary caregivers of the adolescents participated in this study. Recruitment occurred during pediatric rheumatology clinic visits at a Midwestern children's hospital or the hospital's cSLE active clinic registry. Information about disease severity was obtained from patient health records. Pain and fatigue questionnaires were administered. Descriptive statistics were used to analyze data. RESULTS: Thirty-one AYA patients and caregivers participated in six focus groups. Ten major themes emerged from sessions; four were expressed both by the AYA and caregiver groups: knowledge deficits about cSLE, symptoms limiting daily function, specifically mood and cognition/learning, barriers and facilitators of adherence, and worry about the future. Themes unique to AYA participants included symptoms limiting daily functioning-pain/fatigue, self-care and management, impact on personal relationships, and health care provider communication/relationship. For caregiver groups unique themes included need for school advocacy, disruption of family schedule, and sense of normalcy for their adolescent. CONCLUSION: AYAs with cSLE face a lifelong disease characterized by pervasive pain, fatigue, organ damage, isolation-social and/or physical-and psycho-socioeducational challenges. This study confirmed that continued psychosocial support, health information education, adherence interventions, and personalized treatment plans are necessary to increase self-management and autonomy in AYAs with cSLE.

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PURPOSE: Physiological markers that estimate sympathetic activation may be used to infer pain and stress in humans. To date, effective reproducible methods are invasive and pose an undesired risk to participants. Previous work in animal models has used infrared thermography to measure the temperature of the lacrimal caruncle region and may be a promising method for measuring stress and pain non-invasively. The current study aimed to determine whether this method is useful in humans. METHODS: Sixteen young healthy participants (age: 18-35) were recruited and underwent sympathetic activation using a cold pressor test (CPT) and a muscle chemoreflex (MCR), and completed a control trial. Throughout all trials, infrared thermographic imaging of the lacrimal caruncle, heart rate, heart rate variability, mean arterial blood pressure and pulse transit time were measured. RESULTS: Heart rate (MCR: 4 ± 3 bpm, CPT: 17 ± 4 bpm p < 0.01) and mean arterial pressure increased (MCR: 6 ± 2, CPT: 5 ± 2 mmHg, p < 0.01) and pulse transit time decreased (p = 0.03) with both sympathetic activation interventions. However, lacrimal caruncle temperature did not vary under any condition remaining at 35.2 ± 0.2 °C which was similar to baseline. CONCLUSIONS: Our findings suggest infrared thermographic monitoring of eye temperature in humans does not reliably relate to sympathetic activation. This could be due to hemodynamic responses at the lacrimal caruncle that may be more complex than previously proposed with sympathetic activation. Alternatively, pulse transit time seems like a promising non-invasive measure of changes in sympathetic activation in humans.

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We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day-1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.

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BACKGROUND: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. METHODS: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. RESULTS: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. CONCLUSIONS: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. CLINICAL TRIAL REGISTRATION: NCT0061015.

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OBJECTIVE: Typically, clinical measures of cognition require motor or speech responses. Thus, a significant percentage of people with disabilities are not able to complete standardized assessments. This situation could be resolved by employing a more accessible test administration method, such as a brain-computer interface (BCI). A BCI can circumvent motor and speech requirements by translating brain activity to identify a subject's response. By eliminating the need for motor or speech input, one could use a BCI to assess an individual who previously did not have access to clinical tests. APPROACH: We developed an asynchronous, event-related potential BCI-facilitated administration procedure for the peabody picture vocabulary test (PPVT-IV). We then tested our system in typically developing individuals (N = 11), as well as people with cerebral palsy (N = 19) to compare results to the standardized PPVT-IV format and administration. MAIN RESULTS: Standard scores on the BCI-facilitated PPVT-IV, and the standard PPVT-IV were highly correlated (r = 0.95, p < 0.001), with a mean difference of 2.0 ± 6.4 points, which is within the standard error of the PPVT-IV. SIGNIFICANCE: Thus, our BCI-facilitated PPVT-IV provided comparable results to the standard PPVT-IV, suggesting that populations for whom standardized cognitive tests are not accessible could benefit from our BCI-facilitated approach.

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In this review we critically analyze pulmonary, gastrointestinal and cardiac manifestations of childhood-onset systemic lupus erythematosus (cSLE). Clinical manifestations of these organ systems may be the initial manifestation of cSLE; frequently occur with very active cSLE; and are potential life-threatening manifestations often presenting to the emergency department and requiring admission to the intensive care unit. Early recognition and treatment of the pulmonary, gastrointestinal and cardiac manifestations of cSLE will result in improved prognosis and better outcomes.

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Assistive technology control interface theory describes interface activation and interface deactivation as distinct properties of any control interface. Separating control of activation and deactivation allows precise timing of the duration of the activation. Objective. We propose a novel P300 brain-computer interface (BCI) functionality with separate control of the initial activation and the deactivation (hold-release) of a selection. Approach. Using two different layouts and off-line analysis, we tested the accuracy with which subjects could (1) hold their selection and (2) quickly change between selections. Main results. Mean accuracy across all subjects for the hold-release algorithm was 85% with one hold-release classification and 100% with two hold-release classifications. Using a layout designed to lower perceptual errors, accuracy increased to a mean of 90% and the time subjects could hold a selection was 40% longer than with the standard layout. Hold-release functionality provides improved response time (6-16 times faster) over the initial P300 BCI selection by allowing the BCI to make hold-release decisions from very few flashes instead of after multiple sequences of flashes. Significance. For the BCI user, hold-release functionality allows for faster, more continuous control with a P300 BCI, creating new options for BCI applications.

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OBJECTIVE: To assess whether pleural fluid analysis (PFA) can confidently diagnose tuberculous pleural effusion (TPE). METHODS: PFA of 548 TPEs was performed between January 1991 and December 2011. The control group consisted of patients with malignant PE (MPE), complicated parapneumonic/empyema (infectious) PE (IPE), miscellaneous PE (MisPE) and transudative PE (TrPE). RESULTS: The PFA of 548 histologically or culture-positive consecutive cases of TPE was compared with that of 158 consecutive cases of MPE, 113 cases of IPE, 37 cases of MisPE and 115 cases of TrPE. Statistically significant differences were noted in pleural fluid glucose, pH, cholesterol, triglycerides, adenosine deaminase (ADA), and total percentages of lymphocytes, neutrophils and macrophages when TPEs were compared to all other groups. Of the TPEs, 99.1% were exudates. Pleural fluid protein ≥ 5.0 g/dl, lymphocytes > 80% and ADA > 45 U/l were diagnostic of TPE, with a specificity of 100%, a sensitivity of 34.9% and an area under the curve of 0.975. CONCLUSION: PFA alone was diagnostic in one third of the TPE cases, with a high probability in nearly 60%.

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Numerous intrapleural therapies have been adopted to treat a vast array of pleural diseases. The first intrapleural therapies proposed focused on the use of fibrinolytics and DNase to promote fluid drainage in empyema. Numerous case series and five randomized controlled trials have been published to determine the outcomes of fibrinolytics in empyema treatment. In the largest randomized trial, the use of streptokinase had no reduction in mortality, decortication rates or hospital days compared with placebo in the treatment of empyema. Criticism over study design and patient selection may have potentially affected the outcomes in this study. The development of dyspnoea is common in the setting of malignant pleural effusions. Pleural fluid evacuation followed by pleurodesis is often attempted. Numerous sclerosing agents have been studied, with talc emerging as the most effective agent. Small particle size of talc should be avoided because of increased systemic absorption potentiating toxicity, such as acute lung injury. Over the past several years, the use of chronic indwelling pleural catheters have emerged as the preferred modality in the treating a symptomatic malignant pleural effusion. For patients with malignant-related lung entrapment, pleurodesis often fails due to the presence of visceral pleural restriction; however, chronic indwelling pleural catheters are effective in palliation of dyspnoea. Finally, the use of staphylococcal superantigens has been proposed as a therapeutic model for the treatment of non-small lung cancer. Intrapleural instillation of staphylococcal superantigens increased median survival by 5 months in patients with non-small cell lung cancer with a malignant pleural effusion.

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PURPOSES: Reliable staging of the mediastinum determines TNM classification and directs therapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate predictors of mediastinal lymph node metastasis in patients undergoing endobronchial ultrasound (EBUS). METHODS: Patients with known or suspected lung cancer undergoing EBUS for staging were included. Lymph node radiographic characteristics on chest CT/PET scan and ultrasound characteristics of size, shape, border, echogenicity, and number were correlated with rapid on-site evaluation (ROSE) and final pathology. Logistic regression (estimated with generalized estimating equations to account for correlation across nodes within patients) was used with cancer (vs normal pathology) as the outcome. ORs compare risks across groups, and testing was performed with two-sided α of 0.05. RESULTS: Two hundred twenty-seven distinct lymph nodes (22.5% positive for malignancy) were evaluated in 100 patients. Lymph node size, by CT scan and EBUS measurements, and round and oval shape were predictive of mediastinal metastasis. Increasing size of lymph nodes on EBUS was associated with increasing malignancy risk (P = .0002). When adjusted for CT scan size, hypermetabolic lymph nodes on PET scan did not predict malignancy. Echogenicity and border contour on EBUS and site of biopsy were not significantly associated with cancer. In 94.8% of lymph nodes with a clear diagnosis, the ROSE of the first pass correlated with subsequent passes. CONCLUSIONS: Lymph node size on CT scan and EBUS and round or oval shape by EBUS are predictors of malignancy, but no single characteristic can exclude a visualized lymph node from biopsy. Further, increasing the number of samples taken is unlikely to significantly improve sensitivity.

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Phocid herpesvirus-1 (PhHV-1, subfamily Alphaherpesvirinae) was isolated from harbor seals (Phoca vitulina vitulina) in the Netherlands in 1985, and was subsequently identified in Pacific harbor seals (Phoca vitulina richardsi) from California, USA in the 1990s. PhHV-1-associated pathology was first recognized in harbor seal carcasses submitted to a veterinary diagnostic laboratory in Abbotsford, British Columbia, Canada in 2000, and 63 cases were identified by 2008. A review of these cases indicated that PhHV-1-associated disease is widespread in harbor seals in the wild and within rehabilitation facilities in the coastal northeastern Pacific (including British Columbia, Canada, and Washington, USA). Morbidity and mortality occurred primarily in neonatal and weanling seal pups, and was due to PhHV-1 alone, or in combination with other disease processes. All cases occurred between July and October, corresponding to the pupping and weaning seasons in this area. Although previous publications have described the prevalence of antibody to PhHV-1 in harbor seals from British Columbia, Canada and Washington, USA this is the first study to focus on the epidemiology and pathology of the virus in this region.

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