Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

BACKGROUND: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. OBJECTIVE: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. METHODS: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. RESULTS: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). CONCLUSIONS AND RELEVANCE: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Bedside estimates of dead space using end-tidal CO2 are independently associated with mortality in ARDS.

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.

Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis.

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.

One-Year Outcomes in Patients With Acute Respiratory Distress Syndrome Enrolled in a Randomized Clinical Trial of Helmet Versus Facemask Noninvasive Ventilation.

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.

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.

Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality.

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 < 0.01). This type of immune response was most common among patients who were not immunocompromised. In contrast, among immunocompromised patients who died, a decreasing Th1/Treg response was most common. CONCLUSIONS: The association of both increased Th17 responses and increased neutrophil counts relative to lymphocyte counts with mortality suggests that an overwhelming inflammatory response is detrimental. However, the differential responses of patients according to immune state suggest that immune status is an important clinical indicator that should be accounted for in the management of septic patients, as well as in the development of novel immunomodulatory therapies.

Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling.

RATIONALE: Acute respiratory distress syndrome (ARDS) is caused by widespread endothelial barrier disruption and uncontrolled cytokine storm. Genome-wide association studies (GWAS) have linked multiple genes to ARDS. Although mechanosensitive transcription factor Krüppel-like factor 2 (KLF2) is a major regulator of endothelial function, its role in regulating pulmonary vascular integrity in lung injury and ARDS-associated GWAS genes remains poorly understood. OBJECTIVES: To examine KLF2 expression in multiple animal models of acute lung injury and further elucidate the KLF2-mediated pathways involved in endothelial barrier disruption and cytokine storm in experimental lung injury. METHODS: Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow. KLF2 manipulation, permeability measurements, small GTPase activity, luciferase assays, chromatin immunoprecipitation assays, and network analyses were used to determine the mechanistic roles of KLF2 in regulating endothelial monolayer integrity, ARDS-associated GWAS genes, and lung pathophysiology. MEASUREMENTS AND MAIN RESULTS: KLF2 is significantly reduced in several animal models of acute lung injury. Microvascular endothelial KLF2 is significantly induced by capillary flow but reduced by pathologic cyclic stretch and inflammatory stimuli. KLF2 is a novel activator of small GTPase Ras-related C3 botulinum toxin substrate 1 by transcriptionally controlling Rap guanine nucleotide exchange factor 3/exchange factor directly activated by cyclic adenosine monophosphate, which maintains vascular integrity. KLF2 regulates multiple ARDS GWAS genes related to cytokine storm, oxidation, and coagulation in lung microvascular endothelium. KLF2 overexpression ameliorates LPS-induced lung injury in mice. CONCLUSIONS: Disruption of endothelial KLF2 results in dysregulation of lung microvascular homeostasis and contributes to lung pathology in ARDS.

An Official American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Rehabilitation Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests.

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 certainty in the evidence, and the feasibility and acceptability of various interventions. Recommendations were rated as strong or conditional. RESULTS: The guideline panel made four conditional recommendations 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.

Official Executive Summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults.

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.

Effect of Noninvasive Ventilation Delivered by Helmet vs Face Mask on the Rate of Endotracheal Intubation in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

IMPORTANCE: Noninvasive ventilation (NIV) with a face mask is relatively ineffective at preventing endotracheal intubation in patients with acute respiratory distress syndrome (ARDS). Delivery of NIV with a helmet may be a superior strategy for these patients. OBJECTIVE: To determine whether NIV delivered by helmet improves intubation rate among patients with ARDS. DESIGN, SETTING, AND PARTICIPANTS: Single-center randomized clinical trial of 83 patients with ARDS requiring NIV delivered by face mask for at least 8 hours while in the medical intensive care unit at the University of Chicago between October 3, 2012, through September 21, 2015. INTERVENTIONS: Patients were randomly assigned to continue face mask NIV or switch to a helmet for NIV support for a planned enrollment of 206 patients (103 patients per group). The helmet is a transparent hood that covers the entire head of the patient and has a rubber collar neck seal. Early trial termination resulted in 44 patients randomized to the helmet group and 39 to the face mask group. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who required endotracheal intubation. Secondary outcomes included 28-day invasive ventilator-free days (ie, days alive without mechanical ventilation), duration of ICU and hospital length of stay, and hospital and 90-day mortality. RESULTS: Eighty-three patients (45% women; median age, 59 years; median Acute Physiology and Chronic Health Evaluation [APACHE] II score, 26) were included in the analysis after the trial was stopped early based on predefined criteria for efficacy. The intubation rate was 61.5% (n = 24) for the face mask group and 18.2% (n = 8) for the helmet group (absolute difference, -43.3%; 95% CI, -62.4% to -24.3%; P < .001). The number of ventilator-free days was significantly higher in the helmet group (28 vs 12.5, P < .001). At 90 days, 15 patients (34.1%) in the helmet group died compared with 22 patients (56.4%) in the face mask group (absolute difference, -22.3%; 95% CI, -43.3 to -1.4; P = .02). Adverse events included 3 interface-related skin ulcers for each group (ie, 7.6% in the face mask group had nose ulcers and 6.8% in the helmet group had neck ulcers). CONCLUSIONS AND RELEVANCE: Among patients with ARDS, treatment with helmet NIV resulted in a significant reduction of intubation rates. There was also a statistically significant reduction in 90-day mortality with helmet NIV. Multicenter studies are needed to replicate these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01680783.

New-onset atrial fibrillation is an independent predictor of mortality in medical intensive care unit patients.

BACKGROUND: Atrial fibrillation (AF) has been extensively studied in postoperative critically ill surgical patients, but little literature exists to describe the outcomes of patients in the medical intensive care unit (ICU). OBJECTIVES: To determine the incidence of new-onset AF in patients admitted to a medical ICU and if new-onset AF was associated with adverse clinical outcomes. METHODS: This was a single-center, retrospective study of all adult patients admitted to the medical ICU at an academic medical center for >24 hours between December 2008 and April 2010. Collected data included past medical history, incidence of new-onset AF, Acute Physiology and Chronic Health Evaluation II scores, organ failure, length of stay in the ICU and hospital, and in-hospital and 60-day survival. RESULTS: A total of 741 patients were included. New-onset AF occurred in 53 patients (7.2%). In-hospital mortality was significantly greater for patients with new-onset AF (45% vs 16%; adjusted odds ratio [OR] = 2.21, 95% CI 1.07-4.54, P = 0.032), as was 60-day mortality (51% vs 23%; adjusted OR = 1.99, 95% CI = 1.01-3.91, P = 0.047). Patients with new-onset AF experienced greater ICU (6 ± 10.2 days vs 3 ± 3.6 days, P < 0.01) and hospital (15 ± 19 days vs 7 ± 9 days, P < 0.01) lengths of stay. CONCLUSIONS: Medical ICU patients who developed new-onset AF experienced a 2-fold increase in the odds of in-hospital mortality and death at 60 days. Further research investigating contributing factors to new-onset AF and potential treatments is warranted.

Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit.

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 persistent delirium. Secondary outcomes were ventilator, ICU, and hospital days; discharge disposition; and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: The median proportion of ICU days with delirium was 0.57 before versus 0.50 after DIS (P < 0.001). The Confusion Assessment Method for the ICU indicated patients are 10.5 times more likely to have delirium before DIS versus after (P < 0.001). Rapidly reversible, sedation-related delirium showed fewer ventilator (P < 0.001), ICU (P = 0.001), and hospital days (P < 0.001) than persistent delirium. Subjects with no delirium and rapidly reversible, sedation-related delirium were more likely to be discharged home (P < 0.001). Patients with persistent delirium had increased 1-year mortality versus those with no delirium and rapidly reversible, sedation-related delirium (P < 0.001). CONCLUSIONS: Rapidly reversible, sedation-related delirium does not signify the same poor prognosis as persistent delirium. Degree of sedation should be considered in delirium assessments. Coordinating delirium assessments with daily sedative interruption will improve such assessments' ability to prognosticate ICU delirium outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00919698).

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults.

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.

Randomized ICU trials do not demonstrate an association between interventions that reduce delirium duration and short-term mortality: a systematic review and meta-analysis.

OBJECTIVES: 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. DATA SOURCES: We searched CINHAHL, EMBASE, MEDLINE, and the Cochrane databases from 2001 to 2012. STUDY SELECTION: Citations were screened for randomized trials that enrolled critically ill adults, evaluated delirium at least daily, compared a drug or nondrug intervention hypothesized to reduce delirium burden with standard care (or control), and reported delirium duration and/or short-term mortality (≤ 45 d). DATA EXTRACTION: In duplicate, we abstracted trial characteristics and results and evaluated quality using the Cochrane risk of bias tool. We performed random effects model meta-analyses and meta-regressions. DATA SYNTHESIS: We included 17 trials enrolling 2,849 patients which evaluated a pharmacologic intervention (n = 13) (dexmedetomidine [n = 6], an antipsychotic [n = 4], rivastigmine [n = 2], and clonidine [n = 1]), a multimodal intervention (n = 2) (spontaneous awakening [n = 2]), or a nonpharmacologic intervention (n = 2) (early mobilization [n = 1] and increased perfusion [n = 1]). Overall, average delirium duration was lower in the intervention groups (difference = -0.64 d; 95% CI, -1.15 to -0.13; p = 0.01) being reduced by more than or equal to 3 days in three studies, 0.1 to less than 3 days in six studies, 0 day in seven studies, and less than 0 day in one study. Across interventions, for 13 studies where short-term mortality was reported, short-term mortality was not reduced (risk ratio = 0.90; 95% CI, 0.76-1.06; p = 0.19). Across 13 studies that reported mortality, meta-regression revealed that delirium duration was not associated with reduced short-term mortality (p = 0.11). CONCLUSIONS: A review of current evidence fails to support that ICU interventions that reduce delirium duration reduce short-term mortality. Larger controlled studies are needed to establish this relationship.

Relationship between ICU bed availability, ICU readmission, and cardiac arrest in the general wards.

OBJECTIVE: The decision to admit a patient to the ICU is complex, reflecting patient factors and available resources. Previous work has shown that ICU census does not impact mortality of patients admitted to the ICU. However, the effect of ICU bed availability on patients outside the ICU is unknown. We sought to determine the association between ICU bed availability, ICU readmissions, and ward cardiac arrests. DESIGN: In this observational study using data collected between 2009 and 2011, rates of ICU readmission and ward cardiac arrest were determined per 12-hour shift. The relationship between these rates and the number of available ICU beds at the start of each shift (accounting for census and nursing capacity) was investigated. Grouped logistic regression was used to adjust for potential confounders. SETTING: Five specialized adult ICUs comprising 63 adult ICU beds in an academic medical center. PATIENTS: Any patient admitted to a non-ICU inpatient unit was counted in the ward census and considered at risk for ward cardiac arrest. Patients discharged from an ICU were considered at risk for ICU readmission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were available for 2,086 of 2,190 shifts. The odds of ICU readmission increased with each decrease in the overall number of available ICU beds (odds ratio = 1.06; 95% CI, 1.00-1.12; p = 0.03), with a similar but not statistically significant association demonstrated in ward cardiac arrest rate (odds ratio = 1.06; 95% CI, 0.98-1.14; p = 0.16). In subgroup analysis, the odds of ward cardiac arrest increased with each decrease in the number of medical ICU beds available (odds ratio = 1.26; 95% CI, 1.06-1.49; p = 0.01). CONCLUSIONS: Reduced ICU bed availability is associated with increased rates of ICU readmission and ward cardiac arrest. This suggests that systemic factors are associated with patient outcomes, and flexible critical care resources may be needed when demand is high.

Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report.

INTRODUCTION: Pain assessment is associated with important outcomes in ICU patients but remains challenging, particularly in non-communicative patients. Use of a reliable tool is paramount to allow any implementation of sedation/analgesia protocols in a multidisciplinary team. This study compared psychometric properties (inter-rater agreement primarily; validity, responsiveness and feasibility secondarily) of three pain scales: Behavioural Pain Scale (BPS/BPS-NI, that is BPS for Non-Intubated patients), Critical Care Pain Observation Tool (CPOT) and Non-verbal Pain Scale (NVPS), the pain tool routinely used in this 16-bed medical ICU. METHODS: Pain was assessed by at least one of four investigators and one of the 20 bedside nurses before, during and 10 minutes after routine care procedures in non-comatose patients (Richmond Agitation Sedation Scale ≥ -3) who were unable to self-report their pain intensity. The Confusion Assessment Method for the ICU was used to assess delirium. Non-parametric tests were used for statistical analysis. Quantitative data are presented as median (25th to 75th). RESULTS: A total of 258 paired assessments of pain were performed in 30 patients (43% lightly sedated, 57% with delirium, 63% mechanically ventilated). All three scales demonstrated good psychometric properties. However, BPS and CPOT exhibited the best inter-rater reliability (weighted-κ 0.81 for BPS and CPOT) and the best internal consistency (Cronbach-α 0.80 for BPS, 0.81 for CPOT), which were higher than for NVPS (weighted-κ 0.71, P <0.05; Cronbach-α 0.76, P <0.01). Responsiveness was significantly higher for BPS compared to CPOT and for CPOT compared to NVPS. For feasibility, BPS was rated as the easiest scale to remember but there was no significant difference in regards to users' preference. CONCLUSIONS: BPS and CPOT demonstrate similar psychometric properties in non-communicative intubated and non-intubated ICU patients.