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International audience; Objectives: The aim of the present study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration.Design: Prospective nonrandomized study.Setting: Patients hospitalized in ICU for COVID-19 infection.Patients: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU.Interventions: None.Measurements and main results: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status.Conclusions: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.

Microaspiration of subglottic secretions is the main pathogenic mechanism for ventilator-associated pneumonia (VAP). Adequate inflation of the endotracheal cuff is pivotal to providing an optimal seal of the extraluminal airway. However, cuff pressure substantially fluctuates due to patient or tube movements, which can induce microaspiration. Therefore, devices for continuous cuff pressure control (CCPC) have been developed in recent years. The purpose of this systematic review and meta-analysis is to assess the effectiveness of CCPC in VAP prevention.A systematic search of Embase, the Cochrane Central Register of Controlled Trials, and the International Clinical Trials Registry Platform was conducted up to February 2022.Eligible studies were randomized controlled trials (RCTs) and quasi-RCTs comparing the impact of CCPC versus intermittent cuff pressure control on the occurrence of VAP.Random-effects meta-analysis was used to calculate odds ratio (OR) and 95% CI for VAP incidence between groups. Secondary outcome measures included mortality and duration of mechanical ventilation (MV) and ICU stay. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.Eleven RCTs with 2,092 adult intubated patients were included. The use of CCPC was associated with a reduced risk of VAP (OR, 0.51). Meta-analyses of secondary endpoints showed no significant difference in mortality but significant differences in durations of MV (mean difference, -1.07 d) and ICU stay (mean difference, -3.41 d) in favor of CCPC. However, the risk of both reporting and individual study bias was considered important. The main issues were the lack of blinding, potential commercial conflicts of interest of study authors and high heterogeneity due to methodological differences between studies, differences in devices used for CCPC and in applied baseline preventive measures. Certainty of the evidence was considered "very low."The use of CCPC was associated with a reduction in VAP incidence; however, this was based on very low certainty of evidence due to concerns related to risk of bias and inconsistency.

To determine the safety and efficacy of probiotics or synbiotics on morbidity and mortality in critically ill adults and children.We searched MEDLINE, EMBASE, CENTRAL, and unpublished sources from inception to May 4, 2021.We performed a systematic search for randomized controlled trials (RCTs) that compared enteral probiotics or synbiotics to placebo or no treatment in critically ill patients. We screened studies independently and in duplicate.Independent reviewers extracted data in duplicate. A random-effects model was used to pool data. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development, and Evaluation approach.Sixty-five RCTs enrolled 8,483 patients. Probiotics may reduce ventilator-associated pneumonia (VAP) (relative risk [RR], 0.72; 95% CI, 0.59 to 0.89 and risk difference [RD], 6.9% reduction; 95% CI, 2.7-10.2% fewer; low certainty), healthcare-associated pneumonia (HAP) (RR, 0.70; 95% CI, 0.55-0.89; RD, 5.5% reduction; 95% CI, 8.2-2.0% fewer; low certainty), ICU length of stay (LOS) (mean difference [MD], 1.38 days fewer; 95% CI, 0.57-2.19 d fewer; low certainty), hospital LOS (MD, 2.21 d fewer; 95% CI, 1.18-3.24 d fewer; low certainty), and duration of invasive mechanical ventilation (MD, 2.53 d fewer; 95% CI, 1.31-3.74 d fewer; low certainty). Probiotics probably have no effect on mortality (RR, 0.95; 95% CI, 0.87-1.04 and RD, 1.1% reduction; 95% CI, 2.8% reduction to 0.8% increase; moderate certainty). Post hoc sensitivity analyses without high risk of bias studies negated the effect of probiotics on VAP, HAP, and hospital LOS.Low certainty RCT evidence suggests that probiotics or synbiotics during critical illness may reduce VAP, HAP, ICU and hospital LOS but probably have no effect on mortality.

Objectives: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without.Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation.Setting: Thirty-one PICUs in the United States.Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index >= 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation).Interventions: NMBA for the entire duration of days 1 and 2 after intubation.Measurements and Main Results: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline PaO2/FIO2 less than 150.Conclusions: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics.

To evaluate the impact of the additional use of early neuromuscular electrical stimulation (NMES) on an early mobilization (EM) protocol.Randomized controlled trial.ICU of the Clinical Hospital of Ribeirão Preto, University of São Paulo, Brazil.One hundred and thirty-nine consecutive mechanically ventilated patients were included in the first 48 hours of ICU admission.The patients were divided into two groups: EM and EM+NMES. Both groups received EM daily. In the EM+NMES group, patients additionally received NMES 5 days a week, for 60 minutes, starting in the first 48 hours of ICU admission until ICU discharge.Functional status, muscle strength, ICU and hospital length of stay (LOS), frequency of delirium, days on mechanical ventilation, mortality, and quality of life were assessed. Patients in the EM+NMES group presented a significant higher score of functional status measured by the Functional Status Score for the ICU scale when compared with the EM group in the first day awake: 22 (15-26) versus 12 (8-22) (p = 0.019); at ICU discharge: 28 (21-33) versus 18 (11-26) (p = 0.004); and hospital discharge: 33 (27-35) versus 25 (17-33) (p = 0.014), respectively. They also had better functional status measured by the Physical Function Test in the ICU scale, took less days to stand up during the ICU stay, and had a significant shorter hospital LOS, lower frequency of ICU-acquired weakness, and better global muscle strength.The additional application of early NMES promoted better functional status outcomes on the first day awake and at ICU and hospital discharge. The patients in the EM+NMES group also took fewer days to stand up and had shorter hospital LOS, lower frequency of ICU-acquired weakness, and better muscle strength. Future studies are still necessary to clarify the effects of therapies associated with EM, especially to assess long-term outcomes.

Deep sedation in the emergency department (ED) is common, increases deep sedation in the ICU, and is negatively associated with outcome. Limiting ED deep sedation may, therefore, be a high-yield intervention to improve outcome. However, the feasibility of conducting an adequately powered ED-based clinical sedation trial is unknown. Our objectives were to assess trial feasibility in terms of: 1) recruitment, 2) protocol implementation and practice change, and 3) safety. Patient-centered clinical outcomes were assessed to better plan for a future large-scale clinical trial.Pragmatic, multicenter ( n = 3), prospective before-after pilot and feasibility trial.The ED and ICUs at three medical centers.Consecutive, adult mechanically ventilation ED patients.An educational initiative aimed at reliable ED sedation depth documentation and reducing the proportion of deeply sedated patients (primary outcome).Sedation-related data in the ED and the first 48 ICU hours were recorded. Deep sedation was defined as a Richmond Agitation-Sedation Scale of -3 to -5 or a Sedation-Agitation Scale of 1-3. One thousand three hundred fifty-six patients were screened; 415 comprised the final population. Lighter ED sedation was achieved in the intervention group, and the proportion of deeply sedated patients was reduced from 60.2% to 38.8% ( p0.01). There were no concerning trends in adverse events (i.e., inadvertent extubation, device removal, and awareness with paralysis). Mortality was 10.0% in the intervention group and 20.4% in the preintervention group ( p0.01). Compared with preintervention, the intervention group experienced more ventilator-free days [22.0 (9.0) vs 19.9 (10.6)] and ICU-free days [20.8 (8.7) vs 18.1 (10.4)], p0.05 for both.This pilot trial confirmed the feasibility of targeting the ED in order to improve sedation practices and reduce deep sedation. These findings justify an appropriately powered clinical trial regarding ED-based sedation to improve clinical outcomes.

OBJECTIVES Availability of long-term acute care hospitals has been associated with hospital discharge practices. It is unclear if long-term acute care hospital availability can influence patient care decisions. We sought to determine the association of long-term acute care hospital availability at different hospitals with the likelihood of tracheostomy. DESIGN Retrospective cohort study. SETTING California Patient Discharge Database, 2016-2018. PATIENTS Adult patients receiving mechanical ventilation for respiratory failure. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Using the California Patient Discharge Database 2016-2018, we identified all mechanically ventilated patients and those who received tracheostomy. We determine the association between tracheostomy and the distance between each hospital and the nearest long-term acute care hospital and the number of long-term acute care hospital beds within 20 miles of each hospital. Among 281,502 hospitalizations where a patient received mechanical ventilation, 22,899 (8.1%) received a tracheostomy. Patients admitted to a hospital closer to a long-term acute care hospital compared with those furthest from a long-term acute care hospital had 38.9% (95% CI, 33.3-44.6%) higher odds of tracheostomy (closest hospitals 8.7% vs furthest hospitals 6.3%, adjusted odds ratio = 1.65; 95% CI, 1.40-1.95). Patients had a 32.4% (95% CI, 27.6-37.3%) higher risk of tracheostomy when admitted to a hospital with more long-term acute care hospital beds in the immediate vicinity (most long-term acute care hospital beds within 20 miles 8.9% vs fewest long-term acute care hospital beds 6.7%, adjusted odds ratio = 1.54; 95% CI, 1.31-1.80). Distance to the nearest long-term acute care hospital was inversely correlated with hospital risk-adjusted tracheostomy rates (ρ = -0.25; p < 0.0001). The number of long-term acute care hospital beds within 20 miles was positively correlated with hospital risk-adjusted tracheostomy rates (ρ = 0.22; p < 0.0001). CONCLUSIONS Proximity and availability of long-term acute care hospital beds were associated with patient odds of tracheostomy and hospital tracheostomy practices. These findings suggest a hospital effect on tracheostomy decision-making over and above patient case-mix. Future studies focusing on shared decision-making for tracheostomy are needed to ensure goal-concordant care for prolonged mechanical ventilation.

To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.Hospitals in North America and Europe.Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo.Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

To evaluate and synthesize the available literature on sex differences in the treatment of adult ICU patients.MEDLINE and EMBASE.Two reviewers independently screened publications to identify observational studies of adult ICU patients that explicitly examined the association between sex and ICU treatment-specifically, mechanical ventilation, renal replacement therapy, and length of stay.We extracted data independently and in duplicate: mean age, illness severity, use of mechanical ventilation and renal replacement therapy, and length of stay in ICU and hospital. We assessed risk of bias using the Newcastle-Ottawa Scale. We used a DerSimonian-Laird random-effects model to calculate pooled odds ratios (ORs) and mean differences between women and men.We screened 4,098 publications, identifying 21 eligible studies with 545,538 participants (42.7% women). The study populations ranged from 246 to 261,255 participants (median 4,420). Most studies (76.2%) were at high risk of bias in at least one domain, most commonly representativeness or comparability. Women were less likely than men to receive invasive mechanical ventilation (OR, 0.83; 95% CI, 0.77-0.89; I2 = 90.4%) or renal replacement therapy (OR, 0.79; 95% CI, 0.70-0.90; I2 = 76.2%). ICU length of stay was shorter in women than men (mean difference, -0.24 d; 95% CI, -0.37 to -0.12; I2 = 89.9%). These findings persisted in meta-analysis of data adjusted for illness severity and other confounders and also in sensitivity analysis excluding studies at high risk of bias. There was no significant sex difference in duration of mechanical ventilation or hospital length of stay.Women were less likely than men to receive mechanical ventilation or renal replacement therapy and had shorter ICU length of stay than men. There is substantial heterogeneity and risk of bias in the literature; however, these findings persisted in sensitivity analyses.

Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients.Prospective observational study.Two tertiary critical care units in Paris, France, between April and December 2020.Adult critically ill patients with COVID-19 acute respiratory distress syndrome.Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation.Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia.Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

To characterize clusters of double triggering and ineffective inspiratory efforts throughout mechanical ventilation and investigate their associations with mortality and duration of ICU stay and mechanical ventilation.Registry-based, real-world study.Asynchronies during invasive mechanical ventilation can occur as isolated events or in clusters and might be related to clinical outcomes.Adults requiring mechanical ventilation greater than 24 hours for whom greater than or equal to 70% of ventilator waveforms were available.We identified clusters of double triggering and ineffective inspiratory efforts and determined their power and duration. We used Fine-Gray's competing risk model to analyze their effects on mortality and generalized linear models to analyze their effects on duration of mechanical ventilation and ICU stay.We analyzed 58,625,796 breaths from 180 patients. All patients had clusters (mean/d, 8.2 [5.4-10.6]; mean power, 54.5 [29.6-111.4]; mean duration, 20.3 min [12.2-34.9 min]). Clusters were less frequent during the first 48 hours (5.5 [2.5-10] vs 7.6 [4.4-9.9] in the remaining period [p = 0.027]). Total number of clusters/d was positively associated with the probability of being discharged alive considering the total period of mechanical ventilation (p = 0.001). Power and duration were similar in the two periods. Power was associated with the probability of being discharged dead (p = 0.03), longer mechanical ventilation (p0.001), and longer ICU stay (p = 0.035); cluster duration was associated with longer ICU stay (p = 0.027).Clusters of double triggering and ineffective inspiratory efforts are common. Although higher numbers of clusters might indicate better chances of survival, clusters with greater power and duration indicate a risk of worse clinical outcomes.

Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context.Monocenter, retrospective, observational cohort study.A French tertiary center.All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients.None.Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04).Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.

Supplemental Digital Content is available in the text., Objective: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock. Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020. Study Selection: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms “sepsis,” “septicemia,” or “septic shock” in the title or abstract. Data Extraction: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed. Data Synthesis: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001). Conclusions: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

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.

Supplemental Digital Content is available in the text., OBJECTIVES: We performed a comprehensive health assessment in mechanically ventilated coronavirus disease 2019 survivors to assess the impact of respiratory and skeletal muscle injury sustained during ICU stay on physical performance at 3 months following hospital discharge. DESIGN: Preregistered prospective observational cohort study. SETTING: University hospital ICU. PATIENTS: All mechanically ventilated coronavirus disease 2019 patients admitted to our ICU during the first European pandemic wave. MEASUREMENTS AND MAIN RESULTS: At 3 months after hospital discharge, 46 survivors underwent a comprehensive physical assessment (6-min walking distance, Medical Research Council sum score and handgrip strength), a full pulmonary function test, and a chest CT scan which was used to analyze skeletal muscle architecture. In addition, patient-reported outcomes measures were collected. Physical performance assessed by 6-minute walking distance was below 80% of predicted in 48% of patients. Patients with impaired physical performance had more muscle weakness (Medical Research Council sum score 53 [51–56] vs 59 [56–60]; p < 0.001), lower lung diffusing capacity (54% [44–66%] vs 68% of predicted [61–72% of predicted]; p = 0.002), and higher intermuscular adipose tissue area (p = 0.037). Reduced lung diffusing capacity and increased intermuscular adipose tissue were independently associated with physical performance. CONCLUSIONS: Physical disability is common at 3 months in severe coronavirus disease 2019 survivors. Lung diffusing capacity and intermuscular adipose tissue assessed on CT were independently associated with walking distance, suggesting a key role for pulmonary function and muscle quality in functional disability.

Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation.Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620).Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites).Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization.Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy.The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: plt; 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments.The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.

International audience; Objectives: Prone position is used in acute respiratory distress syndrome and in coronavirus disease 2019 acute respiratory distress syndrome. However, it is unclear how responders may be identified and whether an oxygenation response improves outcome. The objective of this study was to quantify the response to prone position, describe the differences between coronavirus disease 2019 acute respiratory distress syndrome and acute respiratory distress syndrome, and explore variables associated with survival.Design: Retrospective, observational, multicenter, international cohort study.Setting: Seven ICUs in Italy, United Kingdom, and France.Patients: Three hundred seventy-six adults (220 coronavirus disease 2019 acute respiratory distress syndrome and 156 acute respiratory distress syndrome).Intervention: None.Measurements and main results: Preproning, a greater proportion of coronavirus disease 2019 acute respiratory distress syndrome patients had severe disease (53% vs 40%), worse Pao2/Fio2 (13.0 kPa [interquartile range, 10.5-15.5 kPa] vs 14.1 kPa [interquartile range, 10.5-18.6 kPa]; p = 0.017) but greater compliance (38 mL/cm H2O [interquartile range, 27-53 mL/cm H2O] vs 31 mL/cm H2O [interquartile range, 21-37 mL/cm H2O]; p < 0.001). Patients with coronavirus disease 2019 acute respiratory distress syndrome had a longer median time from intubation to prone position (2.0 d [interquartile range, 0.7-5.0 d] vs 1.0 d [interquartile range, 0.5-2.9 d]; p = 0.03). The proportion of responders, defined by an increase in Pao2/Fio2 greater than or equal to 2.67 kPa (20 mm Hg), upon proning, was similar between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome (79% vs 76%; p = 0.5). Responders had earlier prone position (1.4 d [interquartile range, 0.7-4.2 d] vs 2.5 d [interquartile range, 0.8-6.2 d]; p = 0.06)]. Prone position less than 24 hours from intubation achieved greater improvement in oxygenation (11 kPa [interquartile range, 4-21 kPa] vs 7 kPa [interquartile range, 2-13 kPa]; p = 0.002). The variables independently associated with the "responder" category were Pao2/Fio2 preproning (odds ratio, 0.89 kPa-1 [95% CI, 0.85-0.93 kPa-1]; p < 0.001) and interval between intubation and proning (odds ratio, 0.94 d-1 [95% CI, 0.89-0.99 d-1]; p = 0.019). The overall mortality was 45%, with no significant difference observed between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome. Variables independently associated with mortality included age (odds ratio, 1.03 yr-1 [95% CI, 1.01-1.05 yr-1]; p < 0.001); interval between hospital admission and proning (odds ratio, 1.04 d-1 [95% CI, 1.002-1.084 d-1]; p = 0.047); and change in Pao2/Fio2 on proning (odds ratio, 0.97 kPa-1 [95% CI, 0.95-0.99 kPa-1]; p = 0.002).Conclusions: Prone position, particularly when delivered early, achieved a significant oxygenation response in ~80% of coronavirus disease 2019 acute respiratory distress syndrome, similar to acute respiratory distress syndrome. This response was independently associated with improved survival.

OBJECTIVES We aim to describe the use of continuous infusion of neuromuscular blocking agents in mechanically ventilated critically ill children and to test its association with in-hospital mortality. DESIGN Multicenter, registry-based, observational, two-cohort-comparison retrospective study using prospectively collected data from a web-based national registry. SETTING Seventeen PICUs in Italy. PATIENTS We included children less than 18 years who received mechanical ventilation and a neuromuscular blocking agent infusion from January 2010 to October 2017. A propensity score-weighted Cox regression analysis was used to assess the relationship between the use of neuromuscular blocking agents and in-hospital mortality. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of the 23,227 patients admitted to the PICUs during the study period, 3,823 patients were included. Patients who received a continuous infusion of neuromuscular blocking agent were more likely to be younger (p < 0.001), ex-premature (p < 0.001), and presenting with less chronic respiratory insufficiency requiring home mechanical ventilation (p < 0.001). Reasons for mechanical ventilation significantly differed between patients who received a continuous infusion of neuromuscular blocking agent and patients who did not receive a continuous infusion of neuromuscular blocking agent, with a higher frequency of respiratory and cardiac diagnosis among patients who received neuromuscular blocking agents compared with other diagnoses (all p < 0.001). The covariates were well balanced in the propensity-weighted cohort. The mortality rate significantly differed among the two cohorts (patients who received a continuous infusion of neuromuscular blocking agent 21% vs patients who did not receive a continuous infusion of neuromuscular blocking agent 11%; p < 0.001 by weighted logistic regression). Patients who received a continuous infusion of neuromuscular blocking agent experienced longer mechanical ventilation and PICU stay (both p < 0.001 by weighted logistic regression). A weighted Cox regression analysis found the use of neuromuscular blocking agents to be a significant predictor of in-hospital mortality both in the unadjusted analysis (hazard ratio, 1.7; 95% CI, 1.3-2.2) and in the adjusted one (hazard ratio, 1.6; 95% CI, 1.2-2.1). CONCLUSIONS Thirteen percent of mechanically ventilated children in PICUs received neuromuscular blocking agents. When adjusting for selection bias with a propensity score approach, the use of neuromuscular blocking agent was found to be a significant predictor of in-hospital mortality.

OBJECTIVE: To describe mechanical ventilation management and factors associated with non-adherence to lung protective ventilation principles in pediatric acute respiratory distress syndrome (PARDS). DESIGN: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6-hour measurements) during PARDS days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume (V(T)) recommendations (

Supplemental Digital Content is available in the text., OBJECTIVES: Fluid therapy is an important component of intensive care management, however, optimal fluid management is unknown. The relationship between fluid balance and ventilator-associated events has not been well established. This study investigated the dose-response relationship between fluid balance and ventilator-associated events. DESIGN: Nested case-control study. SETTING: The study was based on a well-established, research-oriented registry of healthcare-associated infections at ICUs of West China Hospital system (Chengdu, China). PATIENTS: A total of 1,528 ventilator-associated event cases with 3,038 matched controls, who consistently underwent mechanical ventilation for at least 4 days from April 1, 2015, to December 31, 2018, were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We calculated cumulative fluid balance within 4 days prior to ventilator-associated event occurrence. A weighted Cox proportional hazards model with restricted cubic splines was used to evaluate the dose-response relationship. A nonlinear relationship between fluid balance and all three tiers of ventilator-associated events, patients with fluid balance between –1 and 0 L had the lowest risk (p < 0.05 for nonlinear test). The risk of ventilator-associated event was significantly higher in patients with positive fluid balance (4 d cumulative fluid balance: 1 L: 1.19; 3 L: 1.92; 5 L: 2.58; 7 L: 3.24), but not in those with negative fluid balance (–5 L: 1.34; –3 L: 1.14; –1 L: 0.98). CONCLUSIONS: There was nonlinear relationship between fluid balance and all three tiers of ventilator-associated event, with an fluid balance between –1 and 0 L corresponding to the lowest risk. Positive but not negative fluid balance increased the risk of ventilator-associated events, with higher positive fluid balance more likely to lead to ventilator-associated events.

Objectives Patients suffering from spontaneous subarachnoid hemorrhage frequently require mechanical ventilation. Here, we aimed to identify factors associated with prolonged mechanical ventilation in subarachnoid hemorrhage patients and to create a new predictive score for prolonged mechanical ventilation. Design Prospective cohort study with retrospective data analysis. Setting Neurocritical care unit at a tertiary academic medical center. Patients Two hundred ninety-seven consecutive nontraumatic adult subarachnoid hemorrhage patients. Methods In patients with mechanical ventilation, we identified factors associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days compared with mechanical ventilation less than or equal to 48 hours, less than or equal to 7 days, or less than or equal to 14 days in multivariable generalized linear models. Ventilated patients who died before 48 hours, 7 days, or 14 days and those never ventilated were excluded from the respective analysis. We incorporated those factors into a new prognostic score (the RAISE score) to predict prolonged mechanical ventilation greater than 7 days. The calculation was based on a random dataset of 60% of subarachnoid hemorrhage patients and was internally validated. Interventions None. Measurements and main results Patients were 57 years old (interquartile range, 47-68 yr) and presented with a median Hunt and Hess grade of 3 (1-5). Two hundred forty-two patients (82%) required mechanical ventilation for 9 days (2-20 d). In multivariable analysis, a higher Acute Physiology Score was associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days, a higher Hunt and Hess grade with greater than 7 days and greater than 14 days. Early neuroimaging findings were associated with mechanical ventilation greater than 48 hours (hydrocephalus; high-grade Subarachnoid Hemorrhage Early Brain Edema Score), greater than 7 days (high-grade Subarachnoid Hemorrhage Early Brain Edema Score, co-occurrence of intracerebral bleeding) but not with prolonged mechanical ventilation greater than 14 days. The RAISE score, including age, Acute Physiology Score, Hunt and Hess grade, Subarachnoid Hemorrhage Early Brain Edema Score, and the co-occurrence of intracerebral hemorrhage accurately stratified patients by prolonged mechanical ventilation greater than 7 days (C-statistic 0.932). A RAISE score of 12 predicted 60% likelihood of mechanical ventilation greater than 7 days. Conclusions Initial disease severity and neuroimaging findings detected within 24 hours after ICU admission were associated with the need for prolonged mechanical ventilation in patients with subarachnoid hemorrhage. These results may be helpful for patient families and caregivers to better anticipate the course of therapy.

OBJECTIVES: Previous case series reported an association between dexmedetomidine use and hyperthermia. Temperature data have not been systematically reported in previous randomized controlled trials evaluating dexmedetomidine. A causal link between dexmedetomidine administration and elevated temperature has not been demonstrated. DESIGN: Post hoc analysis. SETTING: Four ICUs in Australia and New Zealand. PATIENTS: About 703 mechanically ventilated ICU patients. INTERVENTIONS: Early sedation with dexmedetomidine versus usual care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean daily body temperature. Secondary outcomes included the proportions of patients with body temperatures greater than or equal to 38.3°C and greater than or equal to 39°C, respectively. Outcomes were recorded for 5 days postrandomization in the ICU. The mean daily temperature was not different between the dexmedetomidine (n = 351) and usual care (n = 352) groups (36.84°C ± sd vs 36.78°C ± sd; p = 0.16). Over the first 5 ICU days, more dexmedetomidine group (vs usual care) patients had a temperature greater than or equal to 38.3°C (43.3% vs 32.7%, p = 0.004; absolute difference 10.6 percentage points) and greater than or equal to 39.0°C (19.4% vs 12.5%, p = 0.013; absolute difference 6.9 percentage points). Results were similar after adjusting for diagnosis, admitting temperature, age, weight, study site, sepsis occurrence, and the time from dexmedetomidine initiation to first hyperthermia recorded. There was a significant dose response relationship with temperature increasing by 0.30°C ±0.08 for every additional 1 μg/kg/hr of dexmedetomidine received p < 0.0002. CONCLUSIONS: Our study suggests potentially important elevations in body temperature are associated with early dexmedetomidine sedation, in adults who are mechanically ventilated in the ICU.

Postoperative pulmonary complications (PPCs) are a leading cause of morbidity and mortality following upper abdominal surgery. Applying either noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) in the early postoperative period is suggested to prevent PPC. We aimed to assess whether postoperative NIV or CPAP or both prevent PPCs compared with standard care in adults undergoing upper abdominal surgery, including in those identified at higher PPC risk. Additionally, the different interventions used were evaluated to assess whether there is a superior approach.We searched PubMed, Embase' CINAHL, CENTRAL, and Scopus from inception to May 17, 2021.We performed a systematic search of the literature for randomized controlled trials evaluating prophylactic NIV and/or CPAP in the postoperative period.Two authors independently performed study selection and data extraction. Individual study risk of bias was assessed using the PEDro scale, and certainty in outcomes was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.We included 17 studies enrolling 6,108 patients. No significant benefit was demonstrated for postoperative NIV/CPAP to reduce PPC (risk ratio [RR], 0.89; 95% CI, 0.78-1.01; very low certainty), including in adults identified at higher PPC risk (RR, 0.91; 95% CI, 0.77-1.07; very low certainty). No intervention approach was identified as superior, and no significant benefit was demonstrated when comparing: 1) CPAP (RR, 0.90; 95% CI, 0.79-1.04; very low certainty), 2) NIV (RR, 0.68; 95% CI, 0.41-1.13; very low certainty), 3) continuous NIV/CPAP (RR, 0.90; 95% CI, 0.77-1.05; very low certainty), or 4) intermittent NIV/CPAP (RR, 0.66; 95% CI, 0.39-1.10; very low certainty) to standard care.These findings suggest routine provision of either prophylactic NIV or CPAP following upper abdominal surgery may not be effective to reduce PPCs' including in those identified at higher risk.

We aimed to identify which set of components differentiates the ICU diaries that were effective in reducing psychologic symptoms after critical illness.We searched the online databases MEDLINE, OVID, Embase, and EBSCOhost from inception to December 2021.Randomized controlled trials (RCTs) of the ICU diary were included, irrespective of the language, with samples of adult patients (≥ 18 yr old) and/or their relatives hospitalized in an ICU for more than 24 hours. Two qualitative syntheses on patients' and healthcare providers' perceptions on the ICU diary were included.Four findings were extracted from the qualitative synthesis of patients' perspectives on the ICU diary. From the RCTs, we extracted the components of the ICU diary and whether the patients were ventilated for at least 3 days. We reported the outcome as effective or not, regardless of the psychiatric symptoms and diagnostic tools used for evaluation. We built a matrix in which each column represented a recommendation for an intervention component derived from the qualitative review, and each row represented whether the components of an individual trial's intervention matched any of the recommendations.Eight RCTs were included in the final analysis. The sample of five studies consisted of patients under mechanical ventilation (MV) for at least 3 days. Two were positive trials. Three RCTs included family members, and two of those were positive trials.For patients under MV for at least 3 days, the ICU diaries that were effective in preventing psychiatric symptoms after critical illness were written by the ICU staff, delivered after hospital discharge, and read with a healthcare professional in order to better understand the diary and the ICU stay. For family members, the presence of photographs was the only characteristic identified a successful ICU diary.