Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study.

RESEARCH QUESTION: Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? BACKGROUND: Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. METHODS: Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. RESULTS: Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. CONCLUSIONS: Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.

A 72-Year-Old Woman With Dyspnea, Multiple Pulmonary Nodules, and Mediastinal Lymphadenopathy.

CASE PRESENTATION: A 72-year-old woman presented to our institution with gradually worsening shortness of breath and bilateral lower extremity edema of 3 weeks' duration. She had associated complaints of cough and intermittent hemoptysis. Her medical history was significant for hypertension and hypothyroidism. She was a former cigarette smoker with a 35 pack-year smoking history. She had no recent travel history and had a pet dog at home. Six months before the current hospitalization, evaluation for cough had revealed mediastinal lymphadenopathy at an outside institution. She underwent evaluation with an endobrachial ultrasound procedure at an outside facility 8 weeks before the current admission. The procedure demonstrated both acute and chronic inflammation, with one specimen showing few atypical cells on cytopathology and no growth on bacterial, fungal, and mycobacterial cultures. She was treated empirically with oral steroids for presumed sarcoidosis. However, this did not result in clinical benefit, and because of progressive symptoms, she presented to our institution.

A 34-Year-Old Man With Lightheadedness and Dyspnea.

CASE PRESENTATION: A 34-year-old man presented to our institution with lightheadedness and dyspnea on exertion. His medical history included chronic pancreatitis, juvenile rheumatoid arthritis (JRA), gastroesophageal reflux disease, hypertension, lumbar degenerative disc disease, seizure disorder, anterior uveitis, and multiple vertebral fractures. In addition, he was a cigarette smoker with a 10-pack-year smoking history.

Robotic Bronchoscopy for Peripheral Pulmonary Lesion Biopsy: Evidence-Based Review of the Two Platforms.

Despite many advancements in recent years for the sampling of peripheral pulmonary lesions, the diagnostic yield remains low. Initial excitement about the current electromagnetic navigation platforms has subsided as the real-world data shows a significantly lower diagnostic sensitivity of ~70%. "CT-to-body divergence" has been identified as a major limitation of this modality. In-tandem use of the ultrathin bronchoscope and radial endobronchial ultrasound probe has yielded only comparable results, attributable to the limited peripheral reach, device maneuverability, stability, and distractors like atelectasis. As such, experts have identified three key steps in peripheral nodule sampling-navigation (to the lesion), confirmation (of the correct location), and acquisition (tissue sampling by tools). Robotic bronchoscopy (RB) is a novel innovation that aspires to improve upon these aspects and consequently, achieve a better diagnostic yield. Through this publication, we aim to review the technical aspects, safety, feasibility, and early efficacy data for this new diagnostic modality.

A 41-Year-Old Man Presenting With Shortness of Breath, Nausea, Vomiting, and Diarrhea.

CASE PRESENTATION: A 41-year-old man presented to our institution with shortness of breath for 1 day, and nausea, vomiting, and diarrhea for 10 days. He has a medical history of gastroesophageal reflux disease, migraines, and anxiety. He is a 10 pack-year former cigarette smoker and an active vaper. He quit smoking cigarettes in 2013 but reports vaping flavored nicotine from 2013 to 2018. Since 2018, he has been vaping tetrahydrocannabinol products of different flavors and brands. A few weeks prior to admission, the subject had changed the brand of his vaping product to "Cookies High Flyers" with a "Biscotti" flavor. The new product contains 1,000 mg (883 mg tetrahydrocannabinol and 117 mg cannabidiol) in a 0.04 oz cartridge. He vapes five times a day, taking two to three puffs every time. He had recently traveled to Texas and had a sick contact with his 18-month-old daughter. She recently recovered from a diarrheal illness of presumed viral origin. Prior to admission, the subject tested negative for influenza and completed outpatient antibiotic treatment, with no improvement.

Using a Facebook group to facilitate faculty-student interactions during preclinical medical education: a retrospective survey analysis.

BACKGROUND: Strong learner-teacher relationships are associated with more successful learning outcomes. With shortened modular curricula and increased availability of online resources, fostering faculty interaction with preclinical medical students has become more challenging. We sought to enhance learner-teacher relationships by engaging in discussion with preclinical medical students in their own online space. METHODS: We utilized a closed Facebook discussion group, where faculty and students voluntarily joined in informal discussions and shared announcements related to their courses. The closed discussion group allowed only participating students and faculty to see others' posts within the group. This provided a platform to freely interact within the confines of the group while maintaining privacy for the personal Facebook accounts of both faculty and students. We utilized the discussion group through three separate organ system-based modules for 14 weeks. Afterward, students were asked to complete an anonymous, voluntary online survey about their experience. RESULTS: 94.1% (160/170) of enrolled second-year medical students joined the voluntary FB discussion group. There were 214 posts, 628 comments, and 4166 reactions in this discussion group during the three modules. Of the students in the group, 74.4% (119/160) responded to the online survey. Overall, students strongly agreed that the Facebook discussion group fostered better rapport with faculty, helped content learning, and improved emotional well-being. Also, they felt more comfortable seeking academic help after using the discussion group. They reported a slight preference for Facebook over email as a medium for asking questions, but no preference for either as a medium for distributing announcements. Students overwhelmingly recommended that the discussion group should be continued in future years. CONCLUSION: The Facebook discussion group was a free, efficient, and effective method of cultivating the learner-teacher relationship with the preclinical medical students, resulting in reported enhancement of learning and morale.

The Performance of Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

OBJECTIVE: The diagnostic criteria for secondary hemophagocytic lymphohistiocytosis (HLH) have not been validated in the critically ill adult population. We set out to evaluate the performance of diagnostic criteria and determine the ferritin cutoff in critically ill adults. DESIGN: A retrospective single-center study. SETTING AND PATIENTS: Patients admitted to intensive care unit between 2008 and March 2010. Data were collected on consecutive patients who had ferritin measured. Charts were reviewed for the diagnostic criteria of HLH and components of Hscore. MEASUREMENTS AND MAIN RESULTS: A total of 445 patients had a ferritin level measured during the study period. A diagnosis of HLH was made for 10 patients. Having 5 of 6 criteria had a specificity of 97% and a sensitivity of 70%. Hemophagocytosis was found in 41 (47.1%) of 87 bone marrow biopsies. Two hundred thirty-one patients had a ferritin level above 500 ng/dL. When determining the odds of HLH being clinically diagnosed, the optimal cut point for ferritin was 1197 ng/dL. When determining the odds of HLH based on the Hscore, the best cutoff was 143.5 (sensitivity of 90% and specificity of 90%) and patients who had HLH in our study population had an Hscore of 203.8 ± 64.9. CONCLUSION: In this cohort of critically ill patients, the HLH criteria are specific for HLH but not sensitive. Critically ill patients can have a higher incidence of hemophagocytosis without HLH. A higher ferritin cutoff in combination with 5 other clinical criteria is comparable to the Hscore for the recognition of HLH in the critically ill population.

Cocaine Use and Pulmonary Hypertension.

Evidence linking cocaine to the risk of pulmonary hypertension (PH) is limited and inconsistent. We examined whether cocaine use, in the absence of other known causes of PH, was associated with elevated systolic pulmonary artery pressure (sPAP) and increased probability of PH. We compared patients with documented cocaine use to a randomly selected age, sex, and race-matched control group without history of cocaine use. All participants had no known causes of PH and underwent echocardiography for noninvasive estimation of sPAP. We used routinely reported echocardiographic parameters and contemporary guidelines to grade the probability of PH. In 88 patients with documented cocaine use (mean age ± standard deviation 51.7 ± 9.5 years), 33% were women and 89% were of Black race. The commonest route of cocaine use was smoking (74%). Cocaine users compared with the control group had significantly higher sPAP (mean ± standard deviation, 30.1 ± 13.1 vs 22.0 ± 9.8 mm Hg, p <0.001) and greater likelihood of PH (25% vs 10%, p = 0.012). In multivariable analyses adjusted for potential confounders including left ventricular diastolic dysfunction, cocaine use conferred a fivefold greater odds of echocardiographic PH (p = 0.006). Additionally, a stepwise increase in the likelihood of PH was noted across cocaine users with negative or no drug screen on the day of echocardiography to cocaine users with a positive drug screen (multivariable p for trend = 0.008). In conclusion, cocaine use was associated with a higher sPAP and an increased likelihood of echocardiographic PH with a probable acute-on-chronic effect.

Optimizing the Approach to Patients With Pleural Effusion and Radiologic Findings Suspect for Cancer.

BACKGROUND: When patients present with pleural effusion and structural abnormalities consistent with malignancy on imaging, the traditional approach has been to perform a thoracentesis and await the results before proceeding to more invasive diagnostic procedures. The objective of this study was to evaluate whether concurrent thoracentesis and tissue biopsy is superior to sequential sampling. METHODS: Retrospective chart review was performed for patients who had a pleural cytology from May 2014 until January 2017. Patients without parenchymal, pleural, or mediastinal abnormalities and those with a prior primary thoracic malignancy were excluded. Patients with an effusion and additional suspect findings were grouped based upon whether initial approach was concurrent versus sequential. The following outcomes were documented: lag time to diagnosis from thoracentesis, lag time to hematology/oncology (HONC) service consult, time to molecular study results, lag time to therapy, and time to death. RESULTS: Of 565 cases, 45 met criteria, 28 (62%) having undergone concurrent and 17 (38%) sequential sampling. The median lag time to biopsy for the concurrent group, 3 days, was significantly shorter than the 9-day lag time for the sequential group (P=0.006). Five patients in the sequential group and one in the concurrent group were lost to follow-up. Patients in the concurrent group had earlier diagnosis and oncology visits (2 d, 7 d) than those in the sequential group (6.5 d, 16 d) (P<0.001 and <0.039, respectively). Time from diagnosis to death did not differ for the 2 groups. CONCLUSION: For patients presenting with pleural effusion accompanied by additional suspect findings, concurrent tissue sampling, and thoracentesis may both reduce loss to follow up and accelerate care.

A bronchoscopic approach to benign subglottic stenosis.

OBJECTIVES: Subglottic stenosis is an abnormal narrowing of the tracheal lumen at the level of subglottis (the area in between the vocal cords and the cricoid cartilage). It can cause significant symptoms due to severe attenuation of airflow. We describe our experience in alleviating symptoms by addressing the stenosis using fibreoptic bronchoscopic methods. METHODS: We report all concurrent cases performed between September 2015 and July 2016. We use a combination of balloon dilation, electro-surgery knife to dilate and incise stenotic segments followed by steroid injection to modulate healing. RESULTS: We treated 10 patients in the study period, 8 of which were women. A total of 39 procedures were performed on these patients during this period. Gastro-esophageal reflux was the most common comorbidity associated with stenosis. The majority of the patients required more than 2 therapeutic procedures, but none required more than 4 procedures. There were no complications. CONCLUSION: Tracheal stenosis and in particular subglottic stenosis is a recurrent process and its management requires extensive collaboration amongst treating specialties. Our technique of steroid injection after dilation of the stenosis was effective in symptom control and decreased the number of repeat procedures.

Mitral valve vegetation diagnosed with oesophageal ultrasound with bronchoscope (EUS-B).

Oesophageal ultrasound with bronchoscope (EUS-B) is designed to evaluate mediastinal structures. We describe a case of a 78-year-old woman who presented with altered mental status for 2 weeks. CT head revealed a subacute infarct in the right middle cerebral artery distribution. She was also found to have a lung mass on chest imaging. EUS-B-guided fine needle aspiration demonstrated the presence of adenocarcinoma in station 7 lymph node and in the mass. Immunohistochemistry confirmed it to be a lung primary as the Thyroid Transcription Factor-1 (TTF-1) was strongly positive. During the procedure, the cardiac valves were evaluated, and a mitral valve vegetation was noted. Formal echocardiography confirmed the presence of the vegetation. During hospital stay, the patient developed fever. Her blood cultures grew oxacillin-resistant Staphylococcus aureus. She was subsequently treated for infective endocarditis. We suggest that the use of EUS-B to routinely scan adjacent structures during a procedure may help obtain additional clinical information that may be critical to patient management.

Association of Obesity With In-Hospital Mortality of Cardiogenic Shock Complicating Acute Myocardial Infarction.

Several previous studies have shown obesity to be counterintuitively associated with more favorable mortality in patients with acute myocardial infarction (AMI); however, the association of obesity with in-hospital mortality of cardiogenic shock complicating AMI has not been previously examined. We queried the 2004 to 2013 National Inpatient Sample databases to identify all patients ≥18 years hospitalized with the principal diagnosis of AMI. Multivariable regression models adjusting for demographics, hospital characteristics, and co-morbidities were used to examine differences in incidence and in-hospital mortality of cardiogenic shock complicating AMI between obese and nonobese patients. Of 6,097,817 patients with AMI, 290,894 (4.8%) had cardiogenic shock. There was no difference in risk-adjusted incidence of cardiogenic shock between obese and nonobese patients (adjusted odds ratio 1.00, 95% CI 0.98 to 1.01; p = 0.46). Of the patients with cardiogenic shock complicating AMI, 8.9% had a documented diagnosis of obesity. Obese patients were on average 6 years younger and had higher prevalence of most cardiovascular co-morbidities. Obese patients were more likely to receive revascularization (73.0% vs 63.4%, p <0.001) and had lower risk-adjusted in-hospital mortality compared with nonobese patients (28.2% vs 36.5%; adjusted odds ratio 0.89, 95% CI 0.86 to 0.92; p <0.001). Similar findings were seen in subgroups of patients with cardiogenic shock complicating ST elevation or non-ST elevation MI. In conclusion, this large retrospective analysis of a nationwide cohort of patients with cardiogenic shock complicating AMI demonstrated that obese patients were younger, more likely to receive revascularization, and had modestly lower risk-adjusted in-hospital mortality compared with nonobese patients.

Acute Eosinophilic Pneumonia: Pyrethroid Exposure & Change In Smoking Habit!

We report a case of Acute Eosinophilic Pneumonia (AEP) in a 29-year-old white woman with recent use of a'flea bomb' (containing pyrethroids) at home while remaining indoors, about 48 hours prior to presentation, and recent change in smoking habit (restarted 2 weeks prior after quitting for 10 years). She presented with two days of worsening fever, shortness of breath, productive cough, developed hypoxemic respiratory failure and ARDS. She required a PEEP of 20 and 100% FiO2 to maintain oxygenation. Bronchoalveolar lavage showed 36% Eosinophils. She was given IV steroids with dramatic clinical and radiological improvement. To the best of our knowledge, this is the second report associating AEP with pyrethroid exposure.

Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study.

STUDY OBJECTIVE: The combination of vancomycin and piperacillin-tazobactam has been associated with an increased risk of acute kidney injury (AKI) in non-critically ill patient populations, but it is still unknown if this association exists in critically ill patients. The objective of this study was to compare the incidence of AKI development during therapy or within 72 hours after completion of therapy in adult critically ill patients who received vancomycin with concomitant piperacillin-tazobactam or cefepime. DESIGN: Retrospective cohort study. SETTING: Medical, surgical, and neuroscience intensive care units (ICUs) within a single tertiary care hospital. PATIENTS: A total of 122 critically ill patients who received at least 48 hours of combination therapy with vancomycin and piperacillin-tazobactam (49 patients) or vancomycin and cefepime (73 patients) during an ICU admission between September 2012 and December 2014. MEASUREMENTS AND MAIN RESULTS: The primary outcome was AKI development, as determined by the Acute Kidney Injury Network criteria, during combination therapy or within 72 hours of completion of combination therapy. The inverse probability of the treatment-weighting (IPTW) approach was used to account for potential treatment selection bias. AKI incidence was assessed in the unadjusted and propensity score-weighted cohorts. Of the 122 patients, 37 patients (30.3%) developed AKI. In the unadjusted analysis, the incidence of AKI was similar in the piperacillin-tazobactam group compared with the cefepime group (32.7% vs 28.8%, p=0.647). The average treatment effect between the groups was not significant, showing no association between ß-lactam choice and AKI (ß = -0.004, p=0.958). Secondary outcomes were ICU length of stay, hospital length of stay, AKI duration, and need for renal replacement therapy. The choice of ß-lactam was not a significant predictor of any of these outcomes: ICU length of stay (ß = 0.436, p=0.780), hospital length of stay (ß = 3.819, p=0.125), AKI duration (ß = -4.027, p=0.283), and need for renal replacement therapy (ß = 2.828, p=0.161). CONCLUSION: After adjusting for propensity to receive each of the treatment choices, no significant difference was found in the incidence of AKI development or other outcomes between the groups. The previously described finding that concomitant vancomycin and piperacillin-tazobactam increases AKI in non-critically ill patients may not be generalizable to the critically ill population. Prospective evaluation of this hypothesis is warranted.

How Long Is Too Long? Trials and Tribulations of an Indolent Tumor.

A 31-year-old African American man presented for workup of a right hilar and tracheal mass. Stability of the mass when compared with a computed tomographic scan performed 3 years prior suggested an indolent process. On bronchoscopy, there were 2 separate although morphologically similar endobronchial lesions, one in the distal trachea and the second at the level of the right upper lobe bronchus. Biopsies of both lesions demonstrated granular cell tumors. Subsequent rigid bronchoscopy with ablation led to resolution of wheeze, decrease in dyspnea, and documented improvements in both ventilation and perfusion to the right lung. This case illustrates both a rare disease (multifocal endobronchial granular cell tumor) and the physiological impact of reducing large airway obstruction.

Intrapleural cisplatin for management of malignant pleural effusion in a patient with plasma cell leucaemia.

Plasma cell leucaemia (PCL) is a rare aggressive form of multiple myeloma. It occasionally involves the pleura, causing malignant pleural effusion (MPE). MPE presents a management dilemma for physicians, given the different treatment options available with varying efficacy and side effects. We report a case of a 64-year-old man with MPE due to PCL, successfully managed with intrapleural cisplatin and a tunnelled pleural catheter. We believe this to be the first report of management of PCL-associated MPE with intrapleural cisplatin.

Nodular trachea: tracheobronchopathia osteochondroplastica.

Tracheobronchopathia osteochondroplastica (TPO) is a rare disorder characterised by development of cartilaginous and bony nodules in the trachea. It usually affects elderly males with total prevalence of disease reported to be around 0.1%. Even though multiple theories and associations have been described, the exact cause of the disease remains unknown. Its presentation is non-specific with many cases being diagnosed incidentally. Chronic cough and dyspnoea are the most common presenting symptoms, but some cases may present with severe airway compromise. We present a case of a 70-year-old man with IgA λ multiple myeloma, who was diagnosed with TPO by flexible bronchoscopy.