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STUDY OBJECTIVES: To review our experience with diagnostic bronchoscopy in the evaluation of pulmonary infiltrates in adult hematopoietic stem cell transplantation (HSCT) recipients in the era of Pneumocystis prophylaxis and cytomegalovirus antigen testing. The study focused on diagnostic yields and the influence of bronchoscopic findings on pharmacologic therapy and mortality, comparing allogeneic (allo) HSCT patients to autologous (auto) HSCT patients. DESIGN: Case series review. SETTING: Tertiary care academic urban medical centers. PATIENTS: All adult allo-HSCT and auto-HSCT patients undergoing bronchoscopy for the evaluation of pulmonary infiltrates from January 1997 to September 2001. MEASUREMENTS AND RESULTS: The review identified 169 bronchoscopies that had been performed on HSCT patients, representing 12.5% of all HSCT patients (allo-HSCT patients, 125 bronchoscopies; auto-HSCT patients, 44 bronchoscopies). Bronchoscopy was requested more often in allo-HSCT patients (18.7%) compared to auto-HSCT patients (6.6%). Findings at bronchoscopy provided a specific diagnosis more frequently in allo-HSCT patients (50%) compared to auto-HSCT patients (34%). For both allo-HSCT and auto-HSCT patients, most diagnoses were obtained by BAL alone, whereas transbronchial biopsy (TBBx) provided additional specific information in < 10% of cases. For select patients (n = 27), surgical lung biopsy following bronchoscopy provided unique diagnoses in 47 to 50% of cases. Information from bronchoscopy influenced clinical decisions more often in allo-HSCT patients (50%) than in auto-HSCT patients (36%), and allowed for the discontinuation or addition of antimicrobial, corticosteroid, or antineoplastic agents to treatment. Complications from bronchoscopy occurred in 9% of all HSCT patients (n = 15), and were associated with higher in-hospital mortality rates in allo-HSCT patients (82%; n = 9) compared to auto-HSCT patients (50%; n = 2). The overall in-hospital mortality rates for allo-HSCT and auto-HSCT patients having bronchoscopy was similar (38% vs 27%, respectively; p = 0.25), and establishing a specific diagnosis by bronchoscopy did not improve the in-hospital mortality rate for allo-HSCT or auto-HSCT patients. CONCLUSIONS: Bronchoscopy may provide clinically useful information in the evaluation of adult allo-HSCT and auto-HSCT recipients with pulmonary infiltrates. The results of testing BAL fluid samples alone suggested an etiology in most cases, whereas the findings of TBBx provided unique diagnoses infrequently. Further studies are warranted to improve the utility of diagnostic bronchoscopy in the evaluation of HSCT patients. [ABSTRACT FROM AUTHOR]

Introduction: The management of severe hemoptysis mainly consists of invasive interventional procedures, including angiographic bronchial artery embolization, various endobronchial interventions, and sometimes surgery. However, there are limited effective noninvasive medical therapies available. The objective of this analysis was to evaluate the effectiveness and safety of nebulized tranexamic acid (TXA) administration compared with conventional management in patients with hemoptysis. Methods: This Institutional Review Board-approved, single-center, retrospective matched cohort study was performed from January 1, 2018 to March 31, 2021. Electronic health record data were used to identify all adult inpatients with hemoptysis (International Classification of Diseases, Tenth Revision, code R04.2). All patients who received ≥1 dose of nebulized TXA were matched with up to five controls based on available severity criteria (hemoptysis severity, need for mechanical ventilation, and sequential organ failure assessment score at the time of hemoptysis diagnosis) with coarsened exact matching. The primary outcome was the need for invasive interventions for the management of hemoptysis. Secondary outcomes included time to hemoptysis resolution, duration of mechanical ventilation, hemoptysis recurrence, and hospital length of stay. Results: A total of 14 patients were treated with nebulized TXA; they were matched with 58 controls. Patients were 59.7% male, had a median age of 65.5 years, with airway disease (36.1%) being the major etiology of hemoptysis. There was no difference in the number of patients who required an invasive intervention between the TXA (35.7%) versus control group (56.9%), p  = 0.344. Additionally, no difference was found in the time to hemoptysis resolution ( p  = 0.050), duration on mechanical ventilation ( p  = 0.128), hemoptysis recurrence ( p  = 1.000), or hospital length of stay ( p  = 0.139). Conclusions: In patients with hemoptysis, nebulized TXA may be considered as a noninvasive option for the management of hemoptysis. However, a larger analysis is warranted to determine the impact of nebulized TXA on invasive interventions for management.

Purpose: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP., Methods and Materials: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual., Results: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism., Conclusions: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Sleep is a biological mandate with an integral role in optimizing functions that maintain psychological and physical health. During critical illness, however, sleep may be disrupted at best and elusive at worst. Sleep improvement efforts and research endeavors evaluating interventions to improve sleep in critically ill adults are hampered by limited methods available to measure sleep in this setting. This narrative review summarizes available modalities for sleep assessment in the ICU, describes new ICU sleep assessment methods under development, and highlights features of the ideal ICU sleep measurement tool., Data Sources: The most relevant literature and author experiences were assessed for inclusion from PubMed and textbooks., Study Selection: The authors selected studies for inclusion by consensus., Data Extraction: The authors reviewed each study and selected appropriate data for inclusion by consensus., Data Synthesis: Currently available tools to measure sleep in critically ill adults have important flaws. Subjective measurements are limited by recall bias, the inability of many patients to communicate, and poorly correlate with objective measures when completed by surrogates. Actigraphy does not consider the effects of sedating medications or myopathy leading to an over estimation of sleep time. Polysomnography, the gold standard for sleep assessment, is limited by interpretation issues and practical application concerns. Single and multiple channel electroencephalogram devices offer real-time physiologic data and are more practical to use than polysomnography but are limited by the scope of sleep-specific information they can measure and poorly characterize the circadian system., Conclusions: A measurement tool that offers real-time sleep and circadian assessment and is practical for broad application in the ICU does not exist. Newer sleep assessment devices have shown promise in measuring physiologic data in real time; when used in combination with other assessment modalities, and analyzed by computational techniques, they may revolutionize sleep monitoring in the ICU., Competing Interests: Dr. Devlin has received funding from the National Institute of Aging, the Canadian Institute of Health Research, and Bioexcel Therapeutics; he is on the editorial board of Critical Care Medicine. Dr. Kimchi has received funding from the National Institute of Mental Health. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: To evaluate the impact of Sars-Cov-2 infection on mortality and immune checkpoint inhibitor (ICI) toxicity in patients with cancer receiving ICIs compared to those not receiving ICIs., Methods: We conducted a retrospective matched cohort study of 25 patients receiving ICIs within 1 year of coronavirus disease 2019 (COVID-19) diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute/Mass General Brigham. Cases were matched 1:1 with controls based on age, sex, and anticancer therapy within the prior 6 months., Results: Seven of 25 (28%) patients receiving ICIs died from COVID-19 as compared with nine of 25 (36%) controls. Through multivariable analysis adjusting for age, sex, and anticancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR [odds ratio] 0.36, 95% CI 0.07-1.87). Determinants of mortality included age (OR 1.14, 95% CI 1.03-1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76-85.14). Statin use was protective against mortality (OR 0.08, 95% CI 0.01-0.63). Two patients experienced persistent immune-related adverse events (irAEs) (hypophysitis); one had new-onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICIs had significantly higher platelet ( p = 0.017) and D-dimer ( p = 0.037) levels. Elevated troponin levels ( p = 0.01) were associated with COVID-19 death in patients using ICI., Conclusion: There is insufficient evidence to conclude COVID-19-related outcomes are associated with ICIs, and we did not observe an increased risk of COVID-19-related death associated with ICIs. The potential protective effect of statin therapy and role of laboratory biomarkers warrant further investigation., Competing Interests: Conflict of Interest: Isaac A. Klein is a shareholder and member of the Scientific Advisory Board of Dewpoint Therapeutics, a shareholder in Infinite MD, and consultant to Day-to-Day Health. Shilpa Grover is an editor in gastroenterology at UpToDate, Wolters Kluwer Inc. Nicole R. LeBoeuf is a consultant and has received honoraria from Bayer, Seattle Genetics, and Sanofi. Osama Rahma has received research support from Merck; serves as a speaker for activities supported by educational grants from BMS and Merck; consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, and Sobi; and has a pending patent titled “Methods of Using Pembrolizumab and Trebananib.” The remaining authors had nothing to disclose., (© Innovative Healthcare Institute 2021.)

We retrospectively characterized scheduled, newly initiated, nocturnal neuroactive medication use, and related clinician documentation, in a cohort of consecutive adults admitted greater than or equal to 24 hours to seven different medical/surgical ICUs at two academic centers who had not received a scheduled nocturnal neuroactive medication prior to admission, over a 5-month period (April 1, 2017, to August 31, 2017). A total of 207 different newly initiated, scheduled nocturnal neuroactive medication orders were written (melatonin agonist 101 [48.8%], antipsychotic 80 [38.6%], antidepressant 17 [8.2%], benzodiazepine 9 [4.3%]) in 189 (9.7%) of the 1,955 patients. Among the 1,553 nights, the 189 patients spent in the ICU, a scheduled nocturnal neuroactive medication was administered on 1,103 (71%), an "as needed" nocturnal neuroactive medication was solely administered on 183 (11.8%), delirium occurred on 736 (47.4%), and nurses were twice as likely as physicians (28.8% vs 11.4%; p < 0.0001) to document a note about sleep quality. Among the 69.8% of patients discharged to the floor, and the 64.5% from the hospital, the scheduled nocturnal neuroactive medication was continued in 85.6% and 87.3%, respectively. Scheduled nocturnal neuroactive medication initiation is common, often continued beyond hospital discharge, and poorly documented., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Critical Illness Recovery Programs report low attendance. We aimed to provide information about postintensive care syndrome and to learn which patients would pursue help in a Critical Illness Recovery Clinic. All patients who checked in to our Lung Center were given a survey regarding their ICU experience and offered information about postintensive care syndrome and an appointment in the clinic. Nine hundred and twenty respondents reported having had an ICU experience: 37% of former ICU patients reported difficulty returning to their normal lives afterward compared with 21% who were family or close friends of a former ICU patient. Only 5% requested information and less than 1% requested a dedicated appointment. More than one of three former ICU patients and one in five close friends or relatives of former ICU patients reported difficulty returning to their normal lives after their ICU experience. Very few pursued the opportunity to learn more about it or seek help., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: The objectives of this study were to evaluate the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019., Design: Retrospective single-center study., Setting: ICUs at a large academic medical center in the United States., Patients: Thirty-eight adult critically ill patients with coronavirus disease 2019 and refractory hypoxemia treated with either inhaled epoprostenol or inhaled nitric oxide for at least 1 hour between March 1, 2020, and June 30, 2020., Interventions: Electronic chart review., Measurements and Main Results: Of 93 patients screened, 38 were included in the analysis, with mild (4, 10.5%), moderate (24, 63.2%), or severe (10, 26.3%), with acute respiratory distress syndrome. All patients were initiated on inhaled epoprostenol as the initial pulmonary vasodilator and the median time from intubation to initiation was 137 hours (68-228 h). The median change in Pao 2 /Fio 2 was 0 (-12.8 to 31.6) immediately following administration of inhaled epoprostenol. Sixteen patients were classified as responders (increase Pao 2 /Fio 2 > 10%) to inhaled epoprostenol, with a median increase in Pao 2 /Fio 2 of 34.1 (24.3-53.9). The mean change in Pao 2 and Spo 2 was -0.55 ± 41.8 and -0.6 ± 4.7, respectively. Eleven patients transitioned to inhaled nitric oxide with a median change of 11 (3.6-24.8) in Pao 2 /Fio 2 . A logistic regression analysis did not identify any differences in outcomes or characteristics between the responders and the nonresponders. Minimal adverse events were seen in patients who received either inhaled epoprostenol or inhaled nitric oxide., Conclusions: We found that the initiation of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019, on average, did not produce significant increases in oxygenation metrics. However, a group of patients had significant improvement with inhaled epoprostenol and inhaled nitric oxide. Administration of inhaled epoprostenol or inhaled nitric oxide may be considered in patients with severe respiratory failure secondary to coronavirus disease 2019., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: Numerous risk factors for sleep disruption in critically ill adults have been described. We performed a systematic review of all risk factors associated with sleep disruption in the ICU setting., Data Sources: PubMed, EMBASE, CINAHL, Web of Science, Cochrane Central Register for Controlled Trials, and Cochrane Database of Systematic Reviews., Study Selection: English-language studies of any design published between 1990 and April 2018 that evaluated sleep in greater than or equal to 10 critically ill adults (> 18 yr old) and investigated greater than or equal to 1 potential risk factor for sleep disruption during ICU stay. We assessed study quality using Newcastle-Ottawa Scale or Cochrane Risk of Bias tool., Data Extraction: We abstracted all data independently and in duplicate. Potential ICU sleep disruption risk factors were categorized into three categories based on how data were reported: 1) patient-reported reasons for sleep disruption, 2) patient-reported ratings of potential factors affecting sleep quality, and 3) studies reporting a statistical or temporal association between potential risk factors and disrupted sleep., Data Synthesis: Of 5,148 citations, we included 62 studies. Pain, discomfort, anxiety/fear, noise, light, and ICU care-related activities are the most common and widely studied patient-reported factors causing sleep disruption. Patients rated noise and light as the most sleep-disruptive factors. Higher number of comorbidities, poor home sleep quality, home sleep aid use, and delirium were factors associated with sleep disruption identified in available studies., Conclusions: This systematic review summarizes all premorbid, illness-related, and ICU-related factors associated with sleep disruption in the ICU. These findings will inform sleep promotion efforts in the ICU and guide further research in this field.

Bronchoscopy is the safest procedure for lung cancer diagnosis when an invasive evaluation is required after imaging procedures. However, its sensitivity is relatively low, especially for small and peripheral lesions. We assessed benefits and costs of introducing a bronchial gene-expression classifier (BGC) to improve the performance of bronchoscopy and the overall diagnostic process for early detection of lung cancer. We used discrete-event simulation to compare clinical and economic outcomes of two different strategies with the standard practice in former and current smokers with indeterminate nodules: (i) location-based strategy-integrated the BGC to the bronchoscopy indication; (ii) simplified strategy-extended use of bronchoscopy plus BGC also on small and peripheral lesions. Outcomes modeled were rate of invasive procedures, quality-adjusted-life-years (QALYs), costs and incremental cost-effectiveness ratios. Compared to the standard practice, the location-based strategy (i) reduced absolute rate of invasive procedures by 3.3% without increasing costs at the current BGC market price. It resulted in savings when the BGC price was less than $3,000. The simplified strategy (ii) reduced absolute rate of invasive procedures by 10% and improved quality-adjusted life expectancy, producing an incremental cost-effectiveness ratio of $10,109 per QALY. In patients with indeterminate nodules, both BGC strategies reduced unnecessary invasive procedures at high risk of adverse events. Moreover, compared to the standard practice, the simplified use of BGC for central and peripheral lesions resulted in larger QALYs gains at acceptable cost. The location-based is cost-saving if the price of classifier declines., (© 2019 UICC.)

Objective: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU., Design: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017., Methods: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified., Results: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation., Conclusions: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Objectives: To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults., Design: We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges., Setting/subjects: Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff., Interventions: Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps., Measurements and Main Results: Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps., Conclusions: Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.

Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.

Purpose: The objective of this study was to evaluate the use of sedative, analgesic, and neuromuscular blocking agents (NMBAs) in patients undergoing extracorporeal membrane oxygenation (ECMO) support., Materials and Methods: This was a 2-year, prospective, observational study of adult intensive care unit patients on ECMO support for more than 48hours., Results: We analyzed 32 patients, including 15 receiving VA (venoarterial) ECMO and 17 VV (venovenous) ECMO. The median daily dose of benzodiazepines (midazolam equivalents) was 24mg, and the median daily dose of opioids (fentanyl equivalents) was 3875 μg. There was a moderate negative correlation between the day of ECMO and the median daily benzodiazepine dose (r=-0.5515) and a very weak negative correlation for the median daily opioid dose (r=-0.0053). On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and -1. Continuous infusions of opioids, benzodiazepines, propofol, dexmedetomidine, and NMBAs were administered on 404 (85.1%), 199 (41.9%), 95 (20%), 32 (6.7%), and 60 (12.6%) ECMO days, respectively. Patients in the VA arm received a continuous infusion opioid (96.4% vs 81.6% days; P<.001) and benzodiazepine (58.2% vs 37.0% days; P<.001) more frequently., Conclusions: Patients received relatively low doses of sedatives and analgesics while at a light level of sedation on average. Patients rarely required neuromuscular blockade., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study aimed to assess whether interventions targeted at improving sleep in the ICU were associated with reductions in ICU delirium. Secondary outcomes include duration of delirium and ICU length of stay., Data Sources: MEDLINE, CINAHL, Web of Science, Scopus, WorldCat, and International Pharmaceutical Abstracts were searched from inception to January 2016., Study Selection: Studies investigating any type of sleep intervention (nonpharmacologic or pharmacologic) and assessing the impact on ICU delirium were included. Any type of study design was permitted so long as the delirium assessment was made at least daily with a validated delirium assessment tool., Data Extraction: The following data were extracted: first author, year of publication, study design, ICU type, components of sleep intervention, use of sleep assessment tool, patient age, sex, severity of illness, sleep measures, delirium assessment tool, incidence of delirium, duration of delirium, and ICU length of stay. The incidence of delirium was used to compare rates of ICU delirium across studies. Methodologic quality of included studies was evaluated using the Effective Public Health Practice Project quality assessment tool., Data Synthesis: Of 488 citations screened, 10 studies were identified for inclusion in the final review; six of which demonstrated a statistically significant reduction in the incidence of ICU delirium associated with sleep intervention. Four studies assessed duration of delirium; of which, three reported a shorter duration of delirium with sleep intervention. Two studies associated sleep intervention with a reduced ICU length of stay. In regard to quality assessment and risk of bias, only one study was assessed as strong. Multiple identified confounders and the significant qualitative assessment of heterogeneity limit both the conclusions that can be drawn from these findings and the quantitative pooling of data., Conclusions: Although sleep interventions seem to be a promising approach for improving delirium-related outcomes, studies are limited by bias issues, varying methodologies, and multiple confounders, making the evidence base for this conclusion limited at best. Future studies would benefit from a systematic approach to studying the link between sleep intervention and delirium-related outcomes, which is outlined in the context of reviewing the existing literature.

Background: Extracorporeal membrane oxygenation (ECMO) is associated with a significant risk of bleeding and thrombosis. Despite high rates of bleeding and bleeding-related mortality in patients on ECMO, there is little evidence available to guide clinicians in the management of ECMO-associated bleeding., Methods: We report the use of aminocaproic acid in four patients with bleeding on ECMO and a review of the literature., Results: High D-dimer levels and low fibrinogen levels suggested that an antifibrinolytic agent may be effective as an adjunct to control bleeding. After aminocaproic acid administration, bleeding was controlled in each patient as evidenced by clinical and laboratory parameters. One patient suffered a cardiac arrest and care was withdrawn., Conclusions: In patients on ECMO with evidence of fibrinolysis, aminocaproic acid may be an effective option to control bleeding and to stabilize clot formation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sleep is an important physiologic process, and lack of sleep is associated with a host of adverse outcomes. Basic and clinical research has documented the important role circadian rhythm plays in biologic function. Critical illness is a time of extreme vulnerability for patients, and the important role sleep may play in recovery for intensive care unit (ICU) patients is just beginning to be explored. This concise clinical review focuses on the current state of research examining sleep in critical illness. We discuss sleep and circadian rhythm abnormalities that occur in ICU patients and the challenges to measuring alterations in circadian rhythm in critical illness and review methods to measure sleep in the ICU, including polysomnography, actigraphy, and questionnaires. We discuss data on the impact of potentially modifiable disruptors to patient sleep, such as noise, light, and patient care activities, and report on potential methods to improve sleep in the setting of critical illness. Finally, we review the latest literature on sleep disturbances that persist or develop after critical illness.

Purpose of Review: Delirium in the ICU affects as many as 60-80% of mechanically ventilated patients and a smaller but substantial percentage of other critically ill patients. Poor sleep quality has been consistently observed in critically ill patients. These problems are associated with worse ICU outcomes and, in many cases, delirium and poor sleep quality may be related. This review will summarize the recent literature relevant to both the problems and provide a potential pathway toward improvement., Recent Findings: Many cases of delirium and the poor sleep experienced by ICU patients may be iatrogenic. How critical care practitioners prescribe sedatives and analgesics and, perhaps more broadly, how all medications are administered to critically ill patients, may be at the root of some of these problems. Reducing the administration of some commonly used ICU medications, especially some sedatives and anticholinergic medications, and keeping patients more awake and actively engaged in their care during the day may lead to better outcomes., Summary: It is our responsibility to apply the best available, evidence-based medicine to our practice. Adherence to new guidelines for the treatment of pain, agitation, and delirium may be the best pathway toward reducing delirium, improving sleep quality, and improving related outcomes.

Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t-test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48-2067) after HSCT. Eighty-six (97%) of our BOS cohort had extra-pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan-based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD., (Copyright © 2013 Wiley Periodicals, Inc.)

Rationale: Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). There is minimal data published on quantitative radiologic characterization of airway remodeling in these subjects., Objectives: To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS., Methods: All adult patients who underwent allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n = 1854) between January 1st 2000 and June 30th 2010 were screened for the development of BOS. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. For each subjects discrete measures of airway wall area were performed and the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated., Measurements and Main Results: We identified 88 cases of BOS, and 37 of these patients had available HRCT. On CT scans obtained after BOS diagnosis, the Pi10 decreased (consistent with airway dilation) as compared with pre-BOS values (p < 0.001). After HSCT the Pi10 correlated with FEV(1)% predicted (r = 0.636, p < 0.0001), and RV/TLC% predicted (r = -0.736, p < 0.0001), even after adjusting for age, sex and total lung capacity (p < 0.0001 for both)., Conclusions: On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. This is opposite of what has been previously demonstrated in COPD and asthma that quantitative measure of proximal airway wall thickening directly correlate with pulmonary function. Our data suggests that the pathologic process affecting the central airways is different from the pathology observed in the distal airways. Further work is needed to determine if such change can be used as a sensitive and specific tool for the future diagnosis and staging of BOS., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Sedation in the ICU is, paradoxically, both a cause and a potential treatment for the sleep disruption almost universally observed in the critically ill. A patient-focused sedation strategy that minimizes unnecessary medication, avoids medication withdrawal, addresses the specific impediments to sleep, and serves as an adjunct to attentive environmental control may ultimately serve patients best., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Noninvasive positive pressure ventilation (NPPV) can improve outcomes of critically ill patients. Early and simple predictors of NPPV outcome could improve clinical management of patients with respiratory failure., Materials and Methods: A prospective observational study was conducted in a medical intensive care unit of a tertiary medical center. Patients requiring NPPV were included and followed. Clinical data including respiratory mechanics at the time of NPPV initiation, and clinical outcomes were recorded. Data were analyzed to identify variables that distinguished NPPV success or failure., Results: A total of 133 patients were included in the study. Noninvasive positive pressure ventilation success rate was 41%. Patients diagnosed with malignancy had only 29% NPPV success rate. Among patients without malignancy, higher oxygen saturation, oxygen saturation/fraction of inspired oxygen (SF) ratios, and SF/minute ventilation ratios were associated with NPPV success. Receiver operating characteristic curve analyses identify SF ratio less than 98.5 to be a specific (89% specificity, P = .013) predictor of NPPV failure. Furthermore, for patients requiring at least 24 hours of NPPV support, tidal volume/predicted body weight ratio negatively correlated with respiratory improvement., Conclusions: For patients without malignancy, SF ratios at the time of NPPV initiation discriminated NPPV success and failure, and could be used to help guide the management of critically ill patients who require ventilatory support., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Tracheostomies have become a typical component of the management of patients with prolonged respiratory failure. There are, however, relatively few studies from which to establish an accepted standard of care with regard to the specific features, daily care, and removal of tracheostomy tubes. Consequently, these decisions are sometimes guided by myth and misconception. In this article, we review the different types of tracheostomy tubes with their respective advantages and disadvantages, basic principles of care, recognition of complications, speech with a tracheostomy tube, and the process by which they may sometimes be removed.

The need for compassionate care of the critically ill often compels clinicians to treat these patients with pharmacologic sedation. Although patients may appear to be asleep under the influence of these sedating medications, the relationship between sleep and sedation is complex and not fully understood. These medications exert their effects at different points along the central nervous system's natural sleep pathway, leading to similarities and differences between the two states. This relationship is important because critically ill patients sleep poorly and this phenomenon has been linked to poor intensive care unit outcomes. Therefore, greater awareness of the effects of these medications on sleep may lead to sedation protocols that further improve outcomes. This article reviews the relationship between sedation and sleep from physiologic and clinical perspectives.

Delirium occurs frequently in critically ill patients and has been associated with both short-term and long-term consequences. Efforts to decrease delirium prevalence have been directed at identifying and modifying its risk factors. One potentially modifiable risk factor is sleep deprivation. Critically ill patients are known to experience poor sleep quality with severe sleep fragmentation and disruption of sleep architecture. Poor sleep while in the intensive care unit is one of the most common complaints of patients who survive critical illness. The relationship between delirium and sleep deprivation remains controversial. However, studies have demonstrated many similarities between the clinical and physiologic profiles of patients with delirium and sleep deprivation. This article aims to review the literature, the clinical and neurobiologic consequences of sleep deprivation, and the potential relationship between sleep deprivation and delirium in intensive care unit patients. Sleep deprivation may prove to be a modifiable risk factor for the development of delirium with important implications for the acute and long-term outcome of critically ill patients.

Critically ill patients are almost universally administered medications to treat their acute illnesses and to maximize their comfort. The effects of many of these medications on their sleep, however, may be important. It is known that critically ill patients have severely disrupted sleep and that this disrupted sleep has a negative impact on ICU outcomes. This article reviews how some commonly used ICU medications may affect patients' sleep.

Vascular endothelial cells (EC) are one of the initial cells exposed to decreases in blood oxygen tension. Bovine EC respond not only by altering secretion of vasoactive, mitogenic, and thrombogenic substances, but also by developing adaptive mechanisms in order to survive acute and chronic hypoxic exposures. EC exposed to hypoxia in vitro upregulate a unique set of stress proteins of Mr 34, 36, 39, 47, and 56 kD. Previous studies have shown that these proteins are cell associated, upregulated in a time and oxygen-concentration dependent manner, and are distinct from heat shock (HSPs) and glucose-regulated proteins (GRPs). To further characterize these hypoxia-associated proteins (HAPs), we investigated their upregulation in human EC from various vascular beds and compared this to possible HAP upregulation in other cell types. Human aortic, pulmonary artery, and microvascular EC upregulated the same set of proteins in response to hypoxia. In comparison, neither lung fibroblasts, pulmonary artery smooth muscle cells, pulmonary alveolar type II cells, nor renal tubular epithelial cells upregulated proteins of these Mr. Instead, most of these cell types induced synthesis of proteins of Mrs corresponding to either HSPs, GRPs, or both. Further studies demonstrated that exposure of EC to related stresses such as cyanide, 2-deoxyglucose, hydrogen peroxide, dithiothreitol, and glucose deprivation did not cause upregulation of HAPs. Evaluation of cellular damage during hypoxia using phase-contrast microscopy, trypan blue exclusion, chromium release, and adherent cell counts showed that EC survived longer with less damage than any of the above cell types. The induction of HAPs, and the lack of induction of HSPs or GRPs, by EC in response to hypoxia may be related to their unique ability to tolerate hypoxia for prolonged periods.

Exposure to hypoxia alters many aspects of endothelial cell metabolism and function; however, changes in surface glycoconjugates under these conditions have not been extensively evaluated. In the current studies, we examined surface glycoproteins of cultured bovine aortic (BAEC) and pulmonary arterial (BPAEC) endothelial cells under standard culture conditions (21% oxygen) and following exposure to hypoxia (0% oxygen) for varying time periods (30 min to 18 h) using a system of biotinylation, lectin binding (concanavalin A, Con A; Griffonia simplicifolia, GSA; Arachis hypogaea, PNA; Ricinus communis, RCA; or Triticum vulgaris, WGA), subsequent strep-avidin binding, and staining. Using these methods, we identified differences in lectin binding between the two cell types cultured in 21% oxygen with all lectins except PNA. With exposure to 0% oxygen, there was no change in lectin binding to most surface glycoproteins. Several surface glycoproteins, including glycoprotein IIIa on both cell types, demonstrated a time-dependent decrease in lectin binding; in addition, there was an increase in lectin binding to a few specific surface glycoproteins on each cell type within 30-60 min of exposure to 0% oxygen. These changes in specific surface glycoproteins were confirmed in both cell types by 125I labeling. Increased lectin binding was observed for Con A binding BAEC glycoproteins at molecular weight (MW) 116, 130, and 205 kDa, GSA binding BAEC glycoproteins at MW 120 and 205 kDa, and RCA binding BPAEC glycoproteins at MW 140 and 205 kDa. Increased binding of WGA or PNA was not observed during exposure to hypoxia. The specificity of lectin binding was further confirmed by competitive inhibition with the appropriate sugar. These studies demonstrate that there are baseline differences between BAEC and BPAEC cell surface glycoproteins and that exposure to hypoxia is associated with little change in lectin binding to most surface glycoproteins. There is, however, increased surface expression of a few glycoproteins that differ depending of the origin of the endothelial cell. Although the mechanism of this increase in lectin binding is not yet clear, subsequent studies suggested that it is due to increased availability of select carbohydrate moieties. The time course of these alterations suggests a possible role in the endothelial cell response to decreases in ambient oxygen tension.