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Supplemental Digital Content is available in the text., OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28–29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants’ reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

The role of non-invasive respiratory support (high-flow nasal oxygen and noninvasive ventilation) in the management of acute hypoxemic respiratory failure and acute respiratory distress syndrome is debated. The oxygenation improvement coupled with lung and diaphragm protection produced by non-invasive support may help to avoid endotracheal intubation, which prevents the complications of sedation and invasive mechanical ventilation. However, spontaneous breathing in patients with lung injury carries the risk that vigorous inspiratory effort, combined or not with mechanical increases in inspiratory airway pressure, produces high transpulmonary pressure swings and local lung overstretch. This ultimately results in additional lung damage (patient self-inflicted lung injury), so that patients intubated after a trial of noninvasive support are burdened by increased mortality. Reducing inspiratory effort by high-flow nasal oxygen or delivery of sustained positive end-expiratory pressure through the helmet interface may reduce these risks. In this physiology-to-bedside review, we provide an updated overview about the role of noninvasive respiratory support strategies as early treatment of hypoxemic respiratory failure in the intensive care unit. Noninvasive strategies appear safe and effective in mild-to-moderate hypoxemia (PaO2/FiO2 > 150 mmHg), while they can yield delayed intubation with increased mortality in a significant proportion of moderate-to-severe (PaO2/FiO2 ≤ 150 mmHg) cases. High-flow nasal oxygen and helmet noninvasive ventilation represent the most promising techniques for first-line treatment of severe patients. However, no conclusive evidence allows to recommend a single approach over the others in case of moderate-to-severe hypoxemia. During any treatment, strict physiological monitoring remains of paramount importance to promptly detect the need for endotracheal intubation and not delay protective ventilation.

OBJECTIVES We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN Prospective observational study. SETTING Large academic medical center between 2013 and 2019. SUBJECTS Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

Purpose In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. Methods We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. Results The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2–PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. Conclusion Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

Rationale:Early mobilization and physical rehabilitation improve functional outcomes and are essential to high quality critical care. Despite its importance, it is common for rehabilitation to be deferred in the critically ill due to a variety of barriers, including infection with SARS-CoV-2. We present a single academic center's experience providing physical and occupational therapy to critically ill patients infected with SARS-CoV-2. Methods:All patients with Coronavirus Disease 2019 (COVID-19) associated illness admitted to the intensive care unit (ICU) from March 1st to July 31st, 2020 were identified in this retrospective chart review. Patients who received at least one therapy treatment session were included in the study. Results:Three-hundred and seventy-nine physical and occupational therapy sessions were conducted with 116 patients. The majority (85%) of patients were admitted to the ICU for hypoxemic respiratory failure. The median number of treatment sessions during ICU admission per patient was 2, (IQR: 1-4). The median time from ICU admission to first PT session was 4 days (IQR, 3-5). The median percentage of ICU days with physical and occupational therapy treatment was 33% (IQR, 21-50). The median session length was 25 minutes (IQR, 25-30min). Sitting was achieved in 353 sessions, (93%) standing was achieved in 261 sessions (69%), walking was achieved in 185 sessions (48%), and sitting in the bedside chair 118 times (31%).Patients with respiratory failure completed therapy sessions while receiving mechanical ventilation (21% of sessions), high flow nasal cannula (45% of sessions), non-invasive positive pressure ventilation by helmet and facemask (7% of sessions), and ECMO (12% of sessions). Patients requiring vasoactive medications (4%) and continuous renal replacement therapy (6%) were also treated by physical and occupational therapy. Delirium, determined by confusion assessment method (CAM-ICU), was frequently encountered by the physical and occupational therapy teams and was not an absolute barrier (32%) (Table 1). Discharge destinations included: home (n=57, 61%), acute rehabilitation units (n=16, 17%), long term acute care hospitals (n=9, 10%), sub-acute care centers (n=8, 8%), and skilled nursing facilities (n=4, 4%). No members of the therapy team were diagnosed with SARS-CoV-2 during the study period. Conclusions:This report demonstrates the feasibility of conducting physical and occupational therapy in COVID-19 specific ICUs. Providing therapy services appeared to be safe for patients and members of the therapy team, as adverse events were rare and no therapist was diagnosed with COVID-19.

Rationale:Patients with COVID-19 frequently develop severe respiratory disease and may require invasive mechanical ventilation. A study of primarily white patients intubated for COVID-19 associated respiratory failure found predictors of 28-day mortality to be respiratory system compliance, age, tidal volume, arterial pH and heart rate. Little is known about the outcomes of minority populations with severe COVID-19 pneumonia. Therefore, we present an analysis of the predictors of mortality in a group of primarily African American patients with COVID-19 associated respiratory failure. Methods:All adult patients admitted to the University of Chicago COVID-19 intensive care unit receiving invasive mechanical ventilation between March 1st and June 31st, 2020 were identified. Patients were included in the study if they had at least one recorded measure of plateau airway pressure while receiving volume-controlled ventilation allowing determination of driving pressure and lung compliance. Univariable analysis was conducted comparing survivors with those who died in-hospital followed by construction of a multivariable logistic regression model predicting in-hospital mortality based on significant factors from univariable analysis, excluding colinear variables. Results:Eighty-five patients were included in this retrospective study. Patients were primarily African American (n=73, 86%). Among all study patients, median tidal volume was 6.0 cc/kg ideal body weight (IQR 5.8-6.2), PEEP was 8 cm H2O (IQR 5.0-10), and driving pressure was 14 cm H2O (IQR 11-16). Median respiratory system compliance was 27 ml/cm H2O (IQR 21-34). Salvage therapies for refractory hypoxemia in the cohort included prone positioning (27%), paralysis (27%), inhaled pulmonary vasodilators (19%), and extracorporeal membrane oxygenation (1%). In the multivariable logistic regression model, age (OR 1.077, 95% CI 1.031 to 1.125, p=0.001) and driving pressure (OR 1.174, 95% CI 1.009 to 1.366, p=0.038) were found to be independent predictors of mortality. Conclusions:In a predominantly African American patient population with COVID-19 pneumonia requiring invasive mechanical ventilation, higher driving pressure was predictive of overall mortality. These finding are consistent with the work of Botta et al (2020), who demonstrated reduced lung compliance was predictive of mortality among a largely white group of patients with severe COVID-19 pneumonia. While minority populations infected with COVID-19 have been found worse outcomes, early lung mechanics appear to be comparable to white patients. These findings support that higher driving pressures and low lung compliance are indicative of serious lung injury which may lead to death.

Purpose Functional electrical stimulation-assisted cycle ergometry (FESCE) enables in-bed leg exercise independently of patients’ volition. We hypothesised that early use of FESCE-based progressive mobility programme improves physical function in survivors of critical care after 6 months. Methods We enrolled mechanically ventilated adults estimated to need >7 days of intensive care unit (ICU) stay into an assessor-blinded single centre randomised controlled trial to receive either FESCE-based protocolised or standard rehabilitation that continued up to day 28 or ICU discharge. Results We randomised in 1:1 ratio 150 patients (age 61±15 years, Acute Physiology and Chronic Health Evaluation II 21±7) at a median of 21 (IQR 19–43) hours after admission to ICU. Mean rehabilitation duration of rehabilitation delivered to intervention versus control group was 82 (IQR 66–97) versus 53 (IQR 50–57) min per treatment day, p

Background Lidocaine is used to alleviate procedural pain but paradoxically increases pain during injection. Pain perception can be modulated by non-noxious stimuli such as temperature or touch according to the gate control theory of pain. We postulated that lidocaine dripped onto the skin prior to injection would cool or add the sensation of touch at the skin surface to reduce pain perception from the procedure. Methods A randomized clinical trial of patients referred to the procedure service from February 2011 through March 2015 was conducted. All patients received 1% subcutaneous lidocaine injection. Patients randomized to the intervention group had approximately 1 to 2 ml of lidocaine squirted onto the skin surface prior to subcutaneous lidocaine injection. Patients were blinded to the details of the intervention and were surveyed by a blinded investigator to document the primary outcome (severity of pain from the procedure) using a visual analog scale. Results A total of 481 patients provided consent and were randomized to treatment. There was a significant improvement in the primary outcome of procedural pain (control, 16.6 ± 24.8 mm vs 12.2 ± 19.4 mm; P = .03) with the intervention group as assessed by using the visual analog scale score. Pain scores were primarily improved for peripherally inserted central catheters (control, 18.8 ± 25.6 mm vs 12.2 ± 18.2 mm; P = .02) upon subgroup analysis. Conclusions Bedside procedures are exceedingly common. Data regarding the severity of procedural pain and strategies to mitigate it are important for the informed consent process and patient satisfaction. Overall, pain reported from common bedside procedures is low, but pain can be further reduced with the addition of lidocaine onto the skin surface to modulate pain perception. Trial Registry ClinicalTrials.gov; No.: NCT01330134; URL: www.clinicaltrials.gov.

Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert panel was convened to produce a “state-of-the-art” article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an “ABCDEF-R” bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity.

Background Convalescent plasma therapy for COVID‐19 relies on transfer of anti‐viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID‐19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial. Methods Multivariable analysis of clinical and serological parameters in 103 confirmed COVID‐19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed‐effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID‐19. Results Donor antibody titres ranged from 0 to 1 : 3892 (anti‐receptor binding domain (RBD)) and 0 to 1 : 3289 (anti‐spike). Higher anti‐RBD and anti‐spike titres were associated with increased age, hospitalization for COVID‐19, fever and absence of myalgia (all P

BackgroundConvalescent plasma therapy for COVID-19 relies on the transfer of anti-viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID-19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial.MethodsMultivariable analysis of clinical and serological parameters in 103 confirmed COVID-19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID-19.FindingsMean symptom duration of plasma donors was 11.9±5.9 days and 7.8% (8/103) had been hospitalized. Antibody titers ranged from 0 to 1:3,892 (anti-receptor binding domain (RBD)) and 0 to 1:3,289 (anti-spike). Multivariable analysis demonstrated that higher anti-RBD and anti-spike titer were associated with increased age, hospitalization for COVID-19, fever, and absence of myalgia (all pInterpretationAdvanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titer to COVID-19. Despite variability in donor titer, 80% of convalescent plasma recipients showed significant increase in antibody levels post-transfusion. A more complete understanding of the dose-response effect of plasma transfusion among COVID-19 patients is needed to determine the clinical efficacy of this therapy.Trial RegistrationNCT04340050FundingDepartment of Surgery University of Chicago, National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051

Background: Convalescent plasma is a potential therapy for COVID-19 Using existing resources at a single academic medical center, we established an integrated

Background: Enteral nutrition (EN) increases hyperglycemia due to high carbohydrate concentrations while providing insufficient protein. The study tested whether an EN formula with very high‐protein‐ and low‐carbohydrate‐facilitated glucose control delivered higher protein concentrations within a hypocaloric protocol. Methods: This was a multicenter, randomized, open‐label clinical trial with parallel design in overweight/obese mechanically ventilated critically ill patients prescribed 1.5 g protein/kg ideal body weight/day. Patients received either an experimental very high‐protein (37%) and low‐carbohydrate (29%) or control high‐protein (25%) and conventional‐carbohydrate (45%) EN formula. Results: A prespecified interim analysis was performed after enrollment of 105 patients (52 experimental, 53 control). Protein and energy delivery for controls and experimental groups on days 1–5 were 1.2 ± 0.4 and 1.1 ± 0.3 g/kg ideal body weight/day (P = .83), and 18.2 ± 6.0 and 12.5 ± 3.7 kcals/kg ideal body weight/day (P < .0001), respectively. The combined rate of glucose events outside the range of >110 and ≤150 mg/dL were not different (P = .54, primary endpoint); thereby the trial was terminated. The mean blood glucose for the control and the experimental groups were 138 (−SD 108, +SD 177) and 126 (−SD 99, +SD 160) mg/dL (P = .004), respectively. Mean rate of glucose events >150 mg/dL decreased (Δ = −13%, P = .015), whereas that of 80–110 mg/dL increased (Δ = 14%, P = .0007). Insulin administration decreased 10.9% (95% CI, −22% to 0.1%; P = .048) in the experimental group relative to the controls. Glycemic events ≤80 mg/dL and rescue dextrose use were not different (P = .23 and P = .53). Conclusions: A very high‐protein and low‐carbohydrate EN formula in a hypocaloric protocol reduces hyperglycemic events and insulin requirements while increasing glycemic events between 80–110 mg/dL.

Objectives Many survivors of acute respiratory distress syndrome have poor long-term outcomes possibly due to supportive care practices during "invasive" mechanical ventilation. Helmet noninvasive ventilation in acute respiratory distress syndrome may reduce intubation rates; however, it is unknown if avoiding intubation with helmet noninvasive ventilation alters the consequences of surviving acute respiratory distress syndrome. Design Long-term follow-up data from a previously published randomized controlled trial. Patients Adults patients with acute respiratory distress syndrome enrolled in a previously published clinical trial. Setting Adult ICU. Intervention None. Measurements and main results The primary outcome was functional independence at 1 year after hospital discharge defined as independence in activities of daily living and ambulation. At 1 year, patients were surveyed to assess for functional independence, survival, and number of institution-free days, defined as days alive spent living at home. The presence of ICU-acquired weakness and functional independence was also assessed by a blinded therapist on hospital discharge. On hospital discharge, there was a greater prevalence of ICU-acquired weakness (79.5% vs 38.6%; p = 0.0002) and less functional independence (15.4% vs 50%; p = 0.001) in the facemask group. One-year follow-up data were collected for 81 of 83 patients (97.6%). One-year mortality was higher in the facemask group (69.2% vs 43.2%; p = 0.017). At 1 year, patients in the helmet group were more likely to be functionally independent (40.9% vs 15.4%; p = 0.015) and had more institution-free days (median, 268.5 [0-354] vs 0 [0-323]; p = 0.017). Conclusions Poor functional recovery after invasive mechanical ventilation for acute respiratory distress syndrome is common. Helmet noninvasive ventilation may be the first intervention that mitigates the long-term complications that plague survivors of acute respiratory distress syndrome managed with noninvasive ventilation.

Item does not contain fulltext 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.

Background This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society (ATS) and the American College of Chest Physicians (CHEST). Methods A multidisciplinary panel posed six clinical questions in a population, intervention, comparator, outcomes (PICO) format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, confidence in the evidence, certainty about how much the public values the main outcomes, magnitude and balance of desirable and undesirable outcomes, resources and costs associated with the intervention, impact on health disparities, and acceptability and feasibility of the intervention. Results Evidence-based recommendations were formulated and graded initially by subcommittees and then modified following full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. Conclusions The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and CHEST.

Background An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator. Methods Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation. Results Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence. Conclusions The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.

Background: Interventions that lead to earlier liberation from mechanical ventilation can improve patient outcomes. This guideline, a collaborative effort between the American Thoracic Society and the American College of Chest Physicians, provides evidence-based recommendations to optimize liberation from mechanical ventilation in critically ill adults. Methods: Two methodologists performed evidence syntheses to summarize available evidence relevant to key questions about liberation from mechanical ventilation. The methodologists appraised the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach and summarized the results in evidence profiles. The guideline panel then formulated recommendations after considering the balance of desirable consequences (benefits) versus undesirable consequences (burdens, adverse effects, and costs), the certaintyintheevidence,andthefeasibilityandacceptabilityofvarious interventions. Recommendations were rated as strong or conditional. Results:Theguidelinepanelmadefourconditionalrecommendations related to rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. The recommendations were for acutely hospitalized adults mechanically ventilated for more than 24 hours to receive protocolized rehabilitation directed toward early mobilization, be managed with a ventilator liberation protocol, be assessed with a cuff leak test if they meet extubation criteria but are deemed high risk for postextubation stridor, and be administered systemic steroids for at least 4 hours before extubation if they fail the cuff leak test. Conclusions: The American Thoracic Society/American College of Chest Physicians recommendations are intended to support healthcare professionals in their decisions related to liberating critically ill adults from mechanical ventilation.

Background: This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society and the American College of Chest Physicians. Methods: A multidisciplinary panel posed six clinical questions in a Population, Intervention, Comparator, and Outcomes format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, the confidence in the evidence, the certainty about how much the public values the main outcomes, the magnitude and balance of desirable and undesirable outcomes, the resources and costs associated with the intervention, the impact on health disparities, and the acceptability and feasibility of the intervention. Results: Evidence-based recommendations were formulated and graded initially by subcommittees and then modified after full-panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. Conclusions: The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and Chest.

Patients who are critically ill and hospitalized often require invasive procedures as a part of their medical care. Each procedure carries a unique set of risks and associated complications, but common to all of them is the risk of hemorrhage. Central venous catheterization, arterial catheterization, paracentesis, thoracentesis, tube thoracostomy, and lumbar puncture constitute a majority of the procedures performed in patients who are hospitalized. In this article, the authors will discuss the risk factors for bleeding complications from each of these procedures and methods to minimize risk. Physicians often correct coagulopathy prior to procedures to decrease bleeding risk, but there is minimal evidence to support this practice.

Immunocompromised patients are at high risk for developing severe sepsis. Currently, there are no validated strategies for identifying this group of patients in large administrative databases.We set out to define and validate a method that could be used to identify immunocompromised patients with severe sepsis in administrative databases.Patients were categorized as immunocompromised based on the presence of International Classification of Diseases, 9th revision discharge diagnosis codes and medication data. We validated this strategy by comparing the discriminatory ability of the search algorithm to that of manual chart review.We identified 4,438 patients at a single academic center with severe sepsis using a definition applied to administrative data described by Angus and colleagues. There were 1,185 (26.7%) who were categorized as immunocompromised based on our novel administrative data search strategy. Compared with identification by medical record review, the new administrative data search strategy had positive and negative predictive values of 94.4% (95% confidence interval [CI], 88.8-97.7%) and 94.3% (95% CI, 91.0-96.6%). The sensitivity and specificity were 87.4% (95% CI, 80.6-92.5%) and 97.6% (95% CI, 95.0-99.9%).Patients who are immunosuppressed are a large subgroup of those with severe sepsis. Following its validation as a search strategy using other large databases, and its adaptation for International Classification of Diseases, 10th revision, this novel method may allow researchers to account for a patient's immune state when examining outcomes.

Immunosuppressive medical conditions are risk factors for mortality from severe infections. It is unknown whether hospital characteristics affect this risk.To determine whether the odds of death for an immunosuppressed patient with sepsis relative to a nonimmunosuppressed patient with sepsis varies according to the hospital's yearly case volume of immunosuppressed patients with sepsis.Patients with sepsis at hospitals in the Vizient database were characterized as immunosuppressed or not immunosuppressed on the basis of diagnosis codes and medication use. Hospitals were grouped into quartiles based on their average volumes of immunosuppressed patients with sepsis per year. Multilevel logistic regression with clustering of patients by hospital was used to determine whether the odds of in-hospital death from sepsis owing to a suppressed immune state varied by hospital quartile.There were 350,183 patients with sepsis at 60 hospitals in the Vizient database from 2010 to 2012. Immunosuppressed patients with sepsis at the 15 hospitals in the lowest quartile (64 to 224 immunosuppressed patients with sepsis per year) had an increased odds of in-hospital death relative to nonimmunosuppressed patients with sepsis at these hospitals (adjusted odds ratio, 1.38; 95% confidence interval, 1.27-1.50; P 0.001). The odds of in-hospital death for immunosuppressed patients with sepsis relative to nonimmunosuppressed patients with sepsis was similar for patients at hospitals in the second, third, and fourth quartiles (225 to 1,056 immunosuppressed patients with sepsis per year). The adjusted odds of death from sepsis owing to a suppressed immune state of 1.21 (95% confidence interval, 1.18-1.25; P 0.001) for patients at these 45 hospitals was significantly less than for patients at the 15 hospitals in the lowest quartile (P = 0.004 for difference).The risk of death from sepsis owing to a suppressed immune state was greatest at hospitals with the lowest volume of immunosuppressed patients with sepsis. Further study is needed to determine whether this finding is related to differences in patient characteristics or in care delivery at hospitals with different amounts of exposure to immunosuppressed patients.

Background The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. Methods Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. Results Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17–3.17, p = 0.01; and HR 1.13, 95% CI 1.01–1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69–11.5, p

Background Vasoactive medications are commonly used in the treatment of critically ill patients, but their impact on the development of ICU-acquired weakness is not well described. The objective of this study is to evaluate the relationship between vasoactive medication use and the outcome of ICU-acquired weakness. Methods This is a secondary analysis of mechanically ventilated patients (N = 172) enrolled in a randomized clinical trial of early occupational and physical therapy vs conventional therapy, which evaluated the end point of ICU-acquired weakness on hospital discharge. Patients underwent bedside muscle strength testing by a therapist blinded to study allocation to evaluate for ICU-acquired weakness. The effects of vasoactive medication use on the incidence of ICU-acquired weakness in this population were assessed. Results On logistic regression analysis, the use of vasoactive medications increased the odds of developing ICU-acquired weakness (odds ratio [OR], 3.2; P = .01) independent of all other established risk factors for weakness. Duration of vasoactive medication use (in days) (OR, 1.35; P = .004) and cumulative norepinephrine dose (μg/kg/d) (OR, 1.01; P = .02) (but not vasopressin or phenylephrine) were also independently associated with the outcome of ICU-acquired weakness. Conclusions In mechanically ventilated patients enrolled in a randomized clinical trial of early mobilization, the use of vasoactive medications was independently associated with the development of ICU-acquired weakness. Prospective trials to further evaluate this relationship are merited. Trial Registry ClinicalTrials.gov; No.: NCT01777035; URL: www.clinicaltrials.gov

Author(s): Devlin, John W; Skrobik, Yoanna; Gelinas, Celine; Needham, Dale M; Slooter, Arjen JC; Pandharipande, Pratik P; Watson, Paula L; Weinhouse, Gerald L; Nunnally, Mark E; Rochwerg, Bram; Balas, Michele C; van den Boogaard, Mark; Bosma, Karen J; Brummel, Nathaniel E; Chanques, Gerald; Denehy, Linda; Drouot, Xavier; Fraser, Gilles L; Harris, Jocelyn E; Joffe, Aaron M; Kho, Michelle E; Kress, John P; Lanphere, Julie A; McKinley, Sharon; Neufeld, Karin J; Pisani, Margaret A; Payen, Jean-Francois; Pun, Brenda T; Puntillo, Kathleen A; Riker, Richard R; Robinson, Bryce RH; Shehabi, Yahya; Szumita, Paul M; Winkelman, Chris; Centofanti, John E; Price, Carrie; Nikayin, Sina; Misak, Cheryl J; Flood, Pamela D; Kiedrowski, Ken; Alhazzani, Waleed

Aims: Central venous catheter access in an acute setting can be a challenge given underlying disease and risk for venous thrombosis. Peripherally inserted central venous catheters (PICCs) are commonly placed but limit sites for fistula creation in patients with chronic renal failure (CKD). The aim of this study is to determine the incidence of venous thrombosis from small bore internal jugular (SBIJ) and PICC line placement. This investigation identifies populations of patients who may not be ideal candidates for a PICC and highlights the importance of peripheral vein preservation in patients with renal failure. Materials and methods: A venous Doppler ultrasound was performed at the time of SBIJ insertion and removal to evaluate for thrombosis in the internal jugular vein. Data was collected pre- and post-intervention to ascertain if increased vein preservation knowledge amongst the healthcare team led to less use of PICCs. Demographic factors were collected in the SBIJ and PICC groups and risk factor analysis was completed. Results: 1,122 subjects had PICC placement and 23 had SBIJ placement. The incidence of thrombosis in the PICC group was 10%. One patient with an SBIJ had evidence of central vein thrombosis when the catheter was removed. Univariate and multivariate analysis demonstrated a history of transplant, and the indication of total parenteral nutrition was associated with thrombosis (p

As the prevalence of obesity increases, so too does the number of obese patients being cared for in the critical care setting. Many patients will require the administration of analgesics and sedative medications during the course of their critical illness. Therefore, it is important for clinicians to recognize not only the effect of critical illness on the pharmacokinetics and pharmacodynamics of these medications but also how obesity further alters these effects. A lack of knowledge in these areas may lead to excessive or inadequate sedation.

Intensive care unit (ICU) costs have doubled since 2000, totalling 108 billion dollars per year. Acute respiratory distress syndrome (ARDS) has a prevalence of 10.4% and a 28-day mortality of 34.8%. Noninvasive ventilation (NIV) is used in up to 30% of cases. A recent randomized controlled trial by Patel et al. (2016) showed lower intubation rates and 90-day mortality when comparing helmet to face mask NIV in ARDS. The population in the Patel et al. trial was used for cost analysis in this study. Projections of cost savings showed a decrease in ICU costs by $2527 and hospital costs by $3103 per patient, along with a 43.3% absolute reduction in intubation rates. Sensitivity analysis showed consistent cost reductions. Projected annual cost savings, assuming the current prevalence of ARDS, were $237538 in ICU costs and $291682 in hospital costs. At a national level, using yearly incidence of ARDS cases in American ICUs, this represents $449 million in savings. Helmet NIV, compared to face mask NIV, in nonintubated patients with ARDS, reduces ICU and hospital direct-variable costs along with intubation rates, LOS, and mortality. A large-scale cost-effectiveness analysis is needed to validate the findings.

Background ICU-acquired weakness (ICU-AW) has immediate and long-term consequences for critically ill patients. Strategies for the prevention of weakness include modification of known risk factors, such as hyperglycemia and immobility. Intensive insulin therapy (IIT) has been proposed to prevent critical illness polyneuropathy. However, the effect of insulin and early mobilization on clinically apparent weakness is not well known. Methods This is a secondary analysis of all patients with mechanical ventilation (N = 104) previously enrolled in a randomized controlled trial of early occupational and physical therapy vs conventional therapy, which evaluated the end point of functional independence. Every patient had IIT and blinded muscle strength testing on hospital discharge to determine the incidence of clinically apparent weakness. The effects of insulin dose and early mobilization on the incidence of ICU-AW were assessed. Results On logistic regression analyses, early mobilization and increasing insulin dose prevented the incidence of ICU-AW (OR, 0.18, P = .001; OR, 0.001, P = .011; respectively) independent of known risk factors for weakness. Early mobilization also significantly reduced insulin requirements to achieve similar glycemic goals as compared with control patients (0.07 units/kg/d vs 0.2 units/kg/d, P Conclusions The duel effect of early mobilization in reducing clinically relevant ICU-AW and promoting euglycemia suggests its potential usefulness as an alternative to IIT.

Background Interventions that reduce delirium duration may also lower short-term mortality. We reviewed randomized trials of adult ICU patients of interventions hypothesized to reduce delirium burden to determine whether interventions that are more effective at reducing delirium duration are associated with a reduction in short-term mortality.

Many patients who are evaluated and treated for sepsis have histories of recent infections. The prognostic implications of surviving an infectious process are not well understood. We undertook this study to determine the clinical impact of prior infections among patients with hematological malignancies, a population at high risk for developing and dying from sepsis. The medical records of 203 patients with hematological malignancies and blood-stream infections admitted over a 3-year period to an urban teaching hospital were retrospectively reviewed. The 30-day mortality after blood-stream infection in these high-risk patients was 24 %. There were 46 patients (23 %) who had inpatient infections in the 90 days prior to the index blood-stream infection. History of recent infection portended worse prognosis from blood-stream infection under multivariable analysis [odds ratio (OR) 2.60, p = 0.04, 95 % confidence interval (CI) 1.04-6.47]. There were 86 patients (42 %) who had subsequent infections in the first 90 days after the index blood-stream infection. Patients with subsequent infections had greater mortality during days 91-365 than patients without subsequent infections [hazard ratio (HR) 1.97, p = 0.02, 95 % CI 1.13-3.44]. Recent infections prognosticate worse outcomes from subsequent blood-stream infections for this high-risk population. Further research into the clinical and biochemical reasons for this observation may lead to targets for intervention, and, ultimately, improvements in long-term mortality from sepsis.

Stays in intensive care units are commonly accompanied by muscle weakness. This article reviews the basis for these changes and provides guidance on how to prevent, diagnose, and treat this condition.

Rationale: Intensive care unit (ICU) delirium is associated with ventilator, ICU, and hospital days; discharge functional status; and mortality. Whether rapidly reversible, sedation-related delirium (delirium that abates shortly after sedative interruption) occurs with the same frequency and portends the same prognosis as persistent delirium (delirium that persists despite a short period of sedative interruption) is unknown.Objectives: To compare rapidly reversible, sedation-related delirium and persistent delirium.Methods: This was a prospective cohort study of 102 adult, intubated medical ICU subjects in a tertiary care teaching hospital. Confusion Assessment Method for the ICU evaluation was performed before and after daily interruption of continuous sedation (DIS). Investigators were blinded to each other’s assessments and as to whether evaluations were before or after DIS. The primary outcome was proportion of days with no delirium versus rapidly reversible, sedation-related delirium versus persisten...

Research supports the provision of physical therapy intervention and early mobilization in the management of patients with critical illness. However, the translation of care from that of well-controlled research protocols to routine practice can be challenging and warrants further study. Discussions in the critical care and physical therapy communities, as well as in the published literature, are investigating factors related to early mobilization such as transforming culture in the intensive care unit (ICU), encouraging interprofessional collaboration, coordinating sedation interruption with mobility sessions, and determining the rehabilitation modalities that will most significantly improve patient outcomes. Some variables, however, need to be investigated and addressed specifically by the physical therapy profession. They include assessing and increasing physical therapist competence managing patients with critical illness in both professional (entry-level) education programs and clinical settings, determining and providing an adequate number of physical therapists for a given ICU, evaluating methods of prioritization of patients in the acute care setting, and adding to the body of research to support specific functional outcome measures to be used with patients in the ICU. Additionally, because persistent weakness and functional limitations can exist long after the critical illness itself has resolved, there is a need for increased awareness and involvement of physical therapists in all settings of practice, including outpatient clinics. The purpose of this article is to explore the issues that the physical therapy profession needs to address as the rehabilitation management of the patient with critical illness evolves.