Intensive care unit interventions to promote sleep and circadian biology in reducing incident delirium: a scoping review.

RATIONALE/OBJECTIVES: Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU. METHODS: A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified. RESULTS: Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging. CONCLUSIONS: This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation.

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

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.

Study protocol for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study.

BACKGROUND: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. METHODS: The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. DISCUSSION: Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02447692 . Prospectively registered on May 19, 2015.

Clinical characteristics, multiorgan dysfunction and outcomes of patients with COVID-19: a prospective case series.

BACKGROUND: Characterizing the multiorgan manifestations and outcomes of patients hospitalized with COVID-19 will inform resource requirements to address the long-term burden of this disease. We conducted a descriptive analysis using prospectively collected data to describe the clinical characteristics and spectrum of organ dysfunction, and in-hospital and longer-term clinical outcomes of patients hospitalized with COVID-19 during the first wave of the pandemic at a Canadian centre. METHODS: We conducted a prospective case series involving adult patients (aged ≥ 18 yr) with COVID-19 admitted to 1 of 2 hospitals in London, Ontario, from Mar. 17 to June 18, 2020, during the first wave of the pandemic. We recorded patients' baseline characteristics, physiologic parameters, measures of organ function and therapies administered during hospitalization among patients in the intensive care unit (ICU) and in non-ICU settings, and compared the characteristics of hospital survivors and nonsurvivors. Finally, we recorded follow-up thoracic computed tomography (CT) and echocardiographic findings after hospital discharge. RESULTS: We enrolled 100 consecutive patients (47 women) hospitalized with COVID-19, including 32 patients who received ICU care and 68 who received treatment in non-ICU settings. Respiratory sequelae were common: 23.0% received high-flow oxygen by nasal cannula, 9.0% received noninvasive ventilation, 24.0% received invasive mechanical ventilation and 2.0% received venovenous extracorporeal membrane oxygenation. Overall, 9.0% of patients had cerebrovascular events (3.0% ischemic stroke, 6.0% intracranial hemorrhage), and 6.0% had pulmonary embolism. After discharge, 11 of 19 patients had persistent abnormalities on CT thorax, and 6 of 15 had persistent cardiac dysfunction on echocardiography. INTERPRETATION: This study provides further evidence that COVID-19 is a multisystem disease involving neurologic, cardiac and thrombotic dysfunction, without evidence of hepatic dysfunction. Patients have persistent organ dysfunction after hospital discharge, underscoring the need for research on long-term outcomes of COVID-19 survivors.

The physiological underpinnings of life-saving respiratory support.

Treatment of respiratory failure has improved dramatically since the polio epidemic in the 1950s with the use of invasive techniques for respiratory support: mechanical ventilation and extracorporeal respiratory support. However, respiratory support is only a supportive therapy, designed to "buy time" while the disease causing respiratory failure abates. It ensures viable gas exchange and prevents cardiorespiratory collapse in the context of excessive loads. Because the use of invasive modalities of respiratory support is also associated with substantial harm, it remains the responsibility of the clinician to minimize such hazards. Direct iatrogenic consequences of mechanical ventilation include the risk to the lung (ventilator-induced lung injury) and the diaphragm (ventilator-induced diaphragm dysfunction and other forms of myotrauma). Adverse consequences on hemodynamics can also be significant. Indirect consequences (e.g., immobilization, sleep disruption) can have devastating long-term effects. Increasing awareness and understanding of these mechanisms of injury has led to a change in the philosophy of care with a shift from aiming to normalize gases toward minimizing harm. Lung (and more recently also diaphragm) protective ventilation strategies include the use of extracorporeal respiratory support when the risk of ventilation becomes excessive. This review provides an overview of the historical background of respiratory support, pathophysiology of respiratory failure and rationale for respiratory support, iatrogenic consequences from mechanical ventilation, specifics of the implementation of mechanical ventilation, and role of extracorporeal respiratory support. It highlights the need for appropriate monitoring to estimate risks and to individualize ventilation and sedation to provide safe respiratory support to each patient.

The PROMIZING trial enrollment algorithm for early identification of patients ready for unassisted breathing.

BACKGROUND: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study. METHODS: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (FiO2) 40% for 30-120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. RESULTS: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1-49] hours. Only 7 (8%) patients required reintubation. CONCLUSION: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h.

Liberation from Mechanical Ventilation: Established and New Insights.

A substantial proportion of critically ill patients require ventilator support with the majority requiring invasive mechanical ventilation. Timely and safe liberation from invasive mechanical ventilation is a critical aspect of patient care in the intensive care unit (ICU) and is a top research priority for patients and clinicians. In this article, we discuss how to (1) identify candidates for liberation from mechanical ventilation, (2) conduct spontaneous breathing trials (SBTs), and (3) optimize patients for liberation from mechanical ventilation. We also discuss the roles for (4) extubation to noninvasive ventilation and (5) newer modes of mechanical ventilation during liberation from mechanical ventilation. We conclude that, though substantial progress has been made in identifying patients who are likely to be liberated (e.g., through the use of SBTs) and management strategies that speed liberation from the ventilator (e.g., protocolized SBTs, lighter sedation, and early mobilization), many important questions regarding liberation from mechanical ventilation in clinical practice remain unanswered.

Proportional-assist ventilation with load-adjustable gain factors for mechanical ventilation: a cost-utility analysis.

BACKGROUND: Mechanical ventilation is an important component of patient critical care, but it adds expense to an already high-cost setting. This study evaluates the cost-utility of 2 modes of ventilation: proportional-assist ventilation with load-adjustable gain factors (PAV+ mode) versus pressure-support ventilation (PSV). METHODS: We adapted a published Markov model to the Canadian hospital-payer perspective with a 1-year time horizon. The patient population modelled includes all patients receiving invasive mechanical ventilation who have completed the acute phase of ventilatory support and have entered the recovery phase. Clinical and cost inputs were informed by a structured literature review, with the comparative effectiveness of PAV+ mode estimated via pragmatic meta-analysis. Primary outcomes of interest were costs, quality-adjusted life years (QALYs) and the (incremental) cost per QALY for patients receiving mechanical ventilation. Results were reported in 2017 Canadian dollars. We conducted probabilistic and scenario analyses to assess model uncertainty. RESULTS: Over 1 year, PSV had costs of $50 951 and accrued 0.25 QALYs. Use of PAV+ mode was associated with care costs of $43 309 and 0.29 QALYs. Compared to PSV, PAV+ mode was considered likely to be cost-effective, having lower costs (-$7642) and increased QALYs (+0.04) after 1 year. In cost-effectiveness acceptability analysis, 100% of simulations would be cost-effective at a willingness-to-pay threshold of $50 000 per QALY gained. INTERPRETATION: Use of PAV+ mode is expected to benefit patient care in the intensive care unit (ICU) and be a cost-effective alternative to PSV in the Canadian setting. Canadian hospital payers may therefore consider how best to optimally deliver mechanical ventilation in the ICU as they expand ICU capacity.

Extracorporeal Life Support for Respiratory Failure in Patients With Electronic Cigarette or Vaping Product Use-Associated Lung Injury.

OBJECTIVES: Electronic cigarette or vaping product use-associated lung injury is a clinical entity that can lead to respiratory failure and death. Despite the severity of electronic cigarette or vaping product use-associated lung injury, the role of extracorporeal life support in its management remains unclear. Our objective was to describe the clinical characteristics and outcomes of patients with electronic cigarette or vaping product use-associated lung injury who received extracorporeal life support. DESIGN: We performed a retrospective review of records of electronic cigarette or vaping product use-associated lung injury patients who received extracorporeal life support. Standardized data were collected via direct contact with extracorporeal life support centers. Data regarding presentation, ventilatory management, extracorporeal life support details, and outcome were analyzed. SETTING: This was a multi-institutional, international case series with patients from 10 different institutions in three different countries. PATIENTS: Patients who met criteria for confirmed electronic cigarette or vaping product use-associated lung injury (based on previously reported diagnostic criteria) and were placed on extracorporeal life support were included. Patients were identified via literature review and by direct contact with extracorporeal life support centers. MEASUREMENTS AND MAIN RESULTS: Data were collected for 14 patients ranging from 16 to 45 years old. All had confirmed vape use within 3 months of presentation. Nicotine was the most commonly used vaping product. All patients had respiratory symptoms and radiographic evidence of bilateral pulmonary opacities. IV antibiotics and corticosteroids were universally initiated. Patients were intubated for 1.9 days (range, 0-6) prior to extracorporeal life support initiation. Poor oxygenation and ventilation were the most common indications for extracorporeal life support. Five patients showed evidence of ventricular dysfunction on echocardiography. Thirteen patients (93%) were placed on venovenous extracorporeal life support, and one patient required multiple rounds of extracorporeal life support. Total extracorporeal life support duration ranged from 2 to 37 days. Thirteen patients survived to hospital discharge; one patient died of septic shock. CONCLUSIONS: Electronic cigarette or vaping product use-associated lung injury can cause refractory respiratory failure and hypoxemia. These data suggest that venovenous extracorporeal life support can be an effective treatment option for profound, refractory respiratory failure secondary to electronic cigarette or vaping product use-associated lung injury.

Acute Hemorrhagic Encephalitis Related to COVID-19.

PURPOSE OF REVIEW: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most critical public health challenge in recent history. In this report, we present a case of suspected acute hemorrhagic encephalitis with bilateral intracranial hemorrhages associated with coronavirus disease 2019 (COVID-19) infection. RECENT FINDINGS: A 48-year-old female COVID-19-positive patient developed acute changes in her neurologic status. A head CT with CT angiography demonstrated extensive bilateral parietal and occipital intraparenchymal hemorrhage with intraventricular extension and acute hydrocephalus. The patient was treated with an external ventricular drain, and a CSF sample was tested for SARS-CoV-2 but was found to be negative. SUMMARY: The underlying mechanism for developing acute hemorrhagic encephalitis in viral illnesses may be autoimmune in nature and warrants further investigation. The initial neurologic presentation of COVID-19-related hemorrhagic encephalitis is altered level of consciousness, which may prompt further neurologic examination and imaging to exclude this feature.

Knowledge translation tools to guide care of non-intubated patients with acute respiratory illness during the COVID-19 Pandemic.

Providing optimal care to patients with acute respiratory illness while preventing hospital transmission of COVID-19 is of paramount importance during the pandemic; the challenge lies in achieving both goals simultaneously. Controversy exists regarding the role of early intubation versus use of non-invasive respiratory support measures to avoid intubation. This review summarizes available evidence and provides a clinical decision algorithm with risk mitigation techniques to guide clinicians in care of the hypoxemic, non-intubated, patient during the COVID-19 pandemic. Although aerosolization of droplets may occur with aerosol-generating medical procedures (AGMP), including high flow nasal oxygen and non-invasive ventilation, the risk of using these AGMP is outweighed by the benefit in carefully selected patients, particularly if care is taken to mitigate risk of viral transmission. Non-invasive support measures should not be denied for conditions where previously proven effective and may be used even while there is suspicion of COVID-19 infection. Patients with de novo acute respiratory illness with suspected/confirmed COVID-19 may also benefit. These techniques may improve oxygenation sufficiently to allow some patients to avoid intubation; however, patients must be carefully monitored for signs of increased work of breathing. Patients showing signs of clinical deterioration or high work of breathing not alleviated by non-invasive support should proceed promptly to intubation and invasive lung protective ventilation strategy. With adherence to these principles, risk of viral spread can be minimized.

Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation.

OBJECTIVES: Coronavirus disease 2019 is caused by the novel severe acute respiratory syndrome coronavirus 2 virus. Patients admitted to the ICU suffer from microvascular thrombosis, which may contribute to mortality. Our aim was to profile plasma thrombotic factors and endothelial injury markers in critically ill coronavirus disease 2019 ICU patients to help understand their thrombotic mechanisms. DESIGN: Daily blood coagulation and thrombotic factor profiling with immunoassays and in vitro experiments on human pulmonary microvascular endothelial cells. SETTING: Tertiary care ICU and academic laboratory. SUBJECTS: All patients admitted to the ICU suspected of being infected with severe acute respiratory syndrome coronavirus 2, using standardized hospital screening methodologies, had daily blood samples collected until testing was confirmed coronavirus disease 2019 negative on either ICU day 3 or ICU day 7 if the patient was coronavirus disease 2019 positive. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Age- and sex-matched healthy control subjects and ICU patients that were either coronavirus disease 2019 positive or coronavirus disease 2019 negative were enrolled. Cohorts were well balanced with the exception that coronavirus disease 2019 positive patients were more likely than coronavirus disease 2019 negative patients to suffer bilateral pneumonia. Mortality rate for coronavirus disease 2019 positive ICU patients was 40%. Compared with healthy control subjects, coronavirus disease 2019 positive patients had higher plasma von Willebrand factor (p < 0.001) and glycocalyx-degradation products (chondroitin sulfate and syndecan-1; p < 0.01). When compared with coronavirus disease 2019 negative patients, coronavirus disease 2019 positive patients had persistently higher soluble P-selectin, hyaluronic acid, and syndecan-1 (p < 0.05), particularly on ICU day 3 and thereafter. Thrombosis profiling on ICU days 1-3 predicted coronavirus disease 2019 status with 85% accuracy and patient mortality with 86% accuracy. Surface hyaluronic acid removal from human pulmonary microvascular endothelial cells with hyaluronidase treatment resulted in depressed nitric oxide, an instigating mechanism for platelet adhesion to the microvascular endothelium. CONCLUSIONS: Thrombosis profiling identified endothelial activation and glycocalyx degradation in coronavirus disease 2019 positive patients. Our data suggest that medications to protect and/or restore the endothelial glycocalyx, as well as platelet inhibitors, should be considered for further study.

Pulmonary Functional MRI and CT in a Survivor of Bronchiolitis and Respiratory Failure Caused by e-Cigarette Use.

Although nearly 3,000 e-cigarette-related hospitalizations have been reported in North America, the long-term outcomes in these patients have not been described. We followed an 18-year-old boy who survived acute critical illness and respiratory failure related to 5 months of e-cigarette use. Chronic irreversible airflow obstruction and markedly abnormal 129Xe MRI ventilation heterogeneity was observed and persisted 8 months after hospital discharge, despite improvement in quality-of-life and chest CT findings. Lung clearance index and oscillometry measures were also highly abnormal at 8 months postdischarge. Although 129Xe MRI ventilation abnormalities were dominant in the lung apices and central lung regions, the pattern of ventilation defects was dissimilar to ventilation heterogeneity observed in patients with obstructive lung disease, such as asthma and COPD. Our findings underscore the long-term functional impacts of e-cigarette-related lung injury in survivors of critical illness; longitudinal evaluations may shed light on the pathophysiologic mechanisms that drive e-cigarette-related lung disease.

A Systematic Review of Risk Factors for Sleep Disruption in Critically Ill Adults.

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.

Life-threatening bronchiolitis related to electronic cigarette use in a Canadian youth.

BACKGROUND: Although electronic cigarettes (e-cigarettes) were initially marketed as a potential smoking-cessation aid and a safer alternative to smoking, the long-term health effect of e-cigarette use ("vaping") is unknown. Vaping e-liquids expose the user to several potentially harmful chemicals, including diacetyl, a flavouring compound known to cause bronchiolitis obliterans with inhalational exposure ("popcorn worker's lung"). CASE DESCRIPTION: We report the case of a 17-year-old male who presented with intractable cough, progressive dyspnea and malaise after vaping flavoured e-liquids and tetrahydrocannabinol intensively. Initial physical examination showed fever, tachycardia, hypoxemia, and bibasilar inspiratory crackles on lung auscultation. Computed tomography of the chest showed diffuse centrilobular "tree-inbud" nodularity, consistent with acute bronchiolitis. Multiple cultures, including from 2 bronchoalveolar lavage samples, and biopsy stains, were negative for infection. He required intubation, invasive mechanical ventilation and venovenous extracorporeal membrane oxygenation (ECMO) for refractory hypercapnia. The patient's condition improved with high-dose corticosteroids. He was weaned off ECMO and mechanical ventilation, and discharged home after 47 days in hospital. Several months after hospital discharge, his exercise tolerance remained limited and pulmonary function tests showed persistent, fixed airflow obstruction with gas trapping. The patient's clinical picture was suggestive of possible bronchiolitis obliterans, thought to be secondary to inhalation of flavouring agents in the e-liquids, although the exact mechanism of injury and causative agent are unknown. INTERPRETATION: This case of severe acute bronchiolitis, causing near-fatal hypercapnic respiratory failure and chronic airflow obstruction in a previously healthy Canadian youth, may represent vaping-associated bronchiolitis obliterans. This novel pattern of pulmonary disease associated with vaping appears distinct from the type of alveolar injury predominantly reported in the recent outbreak of cases of vaping-associated pulmonary illness in the United States, underscoring the need for further research into all potentially toxic components of e-liquids and tighter regulation of e-cigarettes.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

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.

A Pilot Randomized Trial Comparing Weaning From Mechanical Ventilation on Pressure Support Versus Proportional Assist Ventilation.

OBJECTIVES: Despite protocols incorporating spontaneous breathing trials, 31% of ICU patients experience difficult or prolonged weaning from mechanical ventilation. Nonfatiguing modes such as pressure support ventilation are recommended. Proportional assist ventilation provides assistance in proportion to patient effort, which may optimize weaning. However, it is not known how proportional assist ventilation performs relative to pressure support ventilation over a prolonged period in the complex ICU setting. The purpose of this study was to compare the physiologic and clinical performance (failure rate), safety, and feasibility of protocols using daily spontaneous breathing trial plus pressure support ventilation versus proportional assist ventilation until ventilation discontinuation. DESIGN: Single-center, unblinded pilot randomized controlled trial. SETTING: Medical-surgical ICU of a tertiary-care hospital. PATIENTS: Adult patients intubated greater than 36 hours were randomized if they met eligibility criteria for partial ventilatory support, tolerated pressure support ventilation greater than or equal to 30 minutes, and either failed or did not meet criteria for a spontaneous breathing trial. INTERVENTIONS: Patients were randomized to the pressure support ventilation or proportional assist ventilation protocol (PAV+, Puritan Bennett 840; Covidien, Boulder, CO). Both protocols used progressive decreases in level of assistance as tolerated, coupled with daily assessment for spontaneous breathing trials. MEASUREMENTS AND MAIN RESULTS: Of 54 patients randomized, outcome data are available for 50 patients; 27 were randomized to receive proportional assist ventilation and 23 to receive pressure support ventilation. There were no adverse events linked to the study interventions, and protocol violations were infrequent. Recruitment was slower than projected (1.3 patients per month). The median (interquartile range) time from randomization to successful extubation was 3.9 days (2.8-8.4 d) on proportional assist ventilation versus 4.9 days (2.9-26.3 d) on pressure support ventilation (p = 0.39). Time to live ICU discharge was 7.3 days (5.2-11.4 d) on proportional assist ventilation versus 12.4 days (7.5-30.8 d) on pressure support ventilation (p = 0.03). CONCLUSION: This pilot study demonstrates the utility, safety, and feasibility of the weaning protocols and provides important information to guide the design of a future randomized controlled trial comparing weaning from mechanical ventilation on pressure support ventilation versus proportional assist ventilation.

Cholesterol-mediated surfactant dysfunction is mitigated by surfactant protein A.

The ability of pulmonary surfactant to reduce surface tension at the alveolar surface is impaired in various lung diseases. Recent animal studies indicate that elevated levels of cholesterol within surfactant may contribute to its inhibition. It was hypothesized that elevated cholesterol levels within surfactant inhibit human surfactant biophysical function and that these effects can be reversed by surfactant protein A (SP-A). The initial experiment examined the function of surfactant from mechanically ventilated trauma patients in the presence and absence of a cholesterol sequestering agent, methyl-ß-cyclodextrin. The results demonstrated improved surface activity when cholesterol was sequestered in vitro using a captive bubble surfactometer (CBS). These results were explored further by reconstitution of surfactant with various concentrations of cholesterol with and without SP-A, and testing of the functionality of these samples in vitro with the CBS and in vivo using surfactant depleted rats. Overall, the results consistently demonstrated that surfactant function was inhibited by levels of cholesterol of 10% (w/w phospholipid) but this inhibition was mitigated by the presence of SP-A. It is concluded that cholesterol-induced surfactant inhibition can actively contribute to physiological impairment of the lungs in mechanically ventilated patients and that SP-A levels may be important to maintain surfactant function in the presence of high cholesterol within surfactant.

Management of necrotizing pneumonia and pulmonary gangrene: a case series and review of the literature.

BACKGROUND: Necrotizing pneumonia is an uncommon but severe complication of bacterial pneumonia, associated with high morbidity and mortality. The availability of current data regarding the management of necrotizing pneumonia is limited to case reports and small retrospective observational cohort studies. Consequently, appropriate management for these patients remains unclear. OBJECTIVE: To describe five cases and review the available literature to help guide management of necrotizing pneumonia. METHODS: Cases involving five adults with respiratory failure due to necrotizing pneumonia admitted to a tertiary care centre and infected with Streptococcus pneumoniae (n=3), Klebsiella pneumoniae (n=1) and methicillin-resistant Staphylococcus aureus (n=1) were reviewed. All available literature was reviewed and encompassed case reports and retrospective reviews dating from 1975 to the present. RESULTS: All five patients received aggressive medical management and consultation by thoracic surgery. Three patients underwent surgical procedures to debride necrotic lung parenchyma. Two of the five patients died in hospital. CONCLUSIONS: Necrotizing pneumonia often leads to pulmonary gangrene. Computed tomography of the thorax with contrast is recommended to evaluate the pulmonary vascular supply. Further study is necessary to determine whether surgical intervention, in the absence of pulmonary gangrene, results in better outcomes.