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.

Effect of early mobilisation on long-term cognitive impairment in critical illness in the USA: a randomised controlled trial.

BACKGROUND: Patients who have received mechanical ventilation can have prolonged cognitive impairment for which there is no known treatment. We aimed to establish whether early mobilisation could reduce the rates of cognitive impairment and other aspects of disability 1 year after critical illness. METHODS: In this single-centre, parallel, randomised controlled trial, patients admitted to the adult medical-surgical intensive-care unit (ICU), at the University of Chicago (IL, USA), were recruited. Inclusion criteria were adult patients (aged ≥18 years) who were functionally independent and mechanically ventilated at baseline and within the first 96 h of mechanical ventilation, and expected to continue for at least 24 h. Patients were randomly assigned (1:1) via computer-generated permuted balanced block randomisation to early physical and occupational therapy (early mobilisation) or usual care. An investigator designated each assignment in consecutively numbered, sealed, opaque envelopes; they had no further involvement in the trial. Only the assessors were masked to group assignment. The primary outcome was cognitive impairment 1 year after hospital discharge, measured with a Montreal Cognitive Assessment. Patients were assessed for cognitive impairment, neuromuscular weakness, institution-free days, functional independence, and quality of life at hospital discharge and 1 year. Analysis was by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01777035, and is now completed. FINDINGS: Between Aug 11, 2011, and Oct 24, 2019, 1222 patients were screened, 200 were enrolled (usual care n=100, intervention n=100), and one patient withdrew from the study in each group; thus 99 patients in each group were included in the intention-to-treat analysis (113 [57%] men and 85 [43%] women). 65 (88%) of 74 in the usual care group and 62 (89%) of 70 in the intervention group underwent testing for cognitive impairment at 1 year. The rate of cognitive impairment at 1 year with early mobilisation was 24% (24 of 99 patients) compared with 43% (43 of 99) with usual care (absolute difference -19·2%, 95% CI -32·1 to -6·3%; p=0·0043). Cognitive impairment was lower at hospital discharge in the intervention group (53 [54%] 99 patients vs 68 [69%] 99 patients; -15·2%, -28·6 to -1·7; p=0·029). At 1 year, the intervention group had fewer ICU-acquired weaknesses (none [0%] of 99 patients vs 14 [14%] of 99 patients; -14·1%; -21·0 to -7·3; p=0·0001) and higher physical component scores on quality-of-life testing than did the usual care group (median 52·4 [IQR 45·3-56·8] vs median 41·1 [31·8-49·4]; p<0·0001). There was no difference in the rates of functional independence (64 [65%] of 99 patients vs 61 [62%] of 99 patients; 3%, -10·4 to 16·5%; p=0·66) or mental component scores (median 55·9 [50·2-58·9] vs median 55·2 [49·5-59·7]; p=0·98) between the intervention and usual care groups at 1 year. Seven adverse events (haemodynamic changes [n=3], arterial catheter removal [n=1], rectal tube dislodgement [n=1], and respiratory distress [n=2]) were reported in six (6%) of 99 patients in the intervention group and in none of the patients in the usual care group (p=0·029). INTERPRETATION: Early mobilisation might be the first known intervention to improve long-term cognitive impairment in ICU survivors after mechanical ventilation. These findings clearly emphasise the importance of avoiding delays in initiating mobilisation. However, the increased adverse events in the intervention group warrants further investigation to replicate these findings. FUNDING: None.

Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure.

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

Physicians' attitudes and perceptions of neuromuscular blocker infusions in ARDS.

PURPOSE: The perceptions and practices of ICU physicians regarding initiating neuromuscular blocker infusions (NMBI) in acute respiratory distress syndrome (ARDS) may not be evidence-based amidst the surge of severe ARDS during the SARS-CoV-2 pandemic and new practice guidelines. We identified ICU physicians' perspectives and practices regarding NMBI use in adults with moderate-severe ARDS. MATERIALS AND METHODS: After extensive development and testing, an electronic survey was distributed to 342 ICU physicians from three geographically-diverse U.S. health systems(n = 12 hospitals). RESULTS: The 173/342 (50.5%) respondents (75% medical) somewhat/strongly agreed a NMBI should be reserved until: after a trial of deep sedation (142, 82%) or proning (59, 34%) and be dose-titrated based on train-of-four monitoring (107, 62%). Of 14 potential NMBI risks, 2 were frequently reported to be of high/very high concern: prolonged muscle weakness with steroid use (135, 79%) and paralysis awareness due to inadequate sedation (114, 67%). Absence of dyssychrony (93, 56%) and use ≥48 h (87, 53%) were preferred NMBI stopping criteria. COVID-19 + ARDS patients were twice as likely to receive a NMBI (56 ± 37 vs. 28 ± 19%, p < 0.01). CONCLUSIONS: Most intensivists agreed NMBI in ARDS should be reserved until after a deep sedation trial. Stopping criteria remain poorly defined. Unique considerations exist regarding the role of paralysis in COVID-19+ ARDS.

Performance Characteristics of a Novel 3D-Printed Bubble Intermittent Mandatory Ventilator (B-IMV) for Adult Pulmonary Support.

The COVID-19 pandemic has brought attention to the need for developing effective respiratory support that can be rapidly implemented during critical surge capacity scenarios in healthcare settings. Lung support with bubble continuous positive airway pressure (B-CPAP) is a well-established therapeutic approach for supporting neonatal patients. However, the effectiveness of B-CPAP in larger pediatric and adult patients has not been addressed. Using similar principles of B-CPAP pressure generation, application of intermittent positive pressure inflations above CPAP could support gas exchange and high work of breathing levels in larger patients experiencing more severe forms of respiratory failure. This report describes the design and performance characteristics of the BubbleVent, a novel 3D-printed valve system that combined with commonly found tubes, hoses, and connectors can provide intermittent mandatory ventilation (IMV) suitable for adult mechanical ventilation without direct electrification. Testing of the BubbleVent was performed on a passive adult test lung model and compared with a critical care ventilator commonly used in tertiary care centers. The BubbleVent was shown to deliver stable PIP and PEEP levels, as well as timing control of breath delivery that was comparable with a critical care ventilator.

Immediate Effect of Mechanical Ventilation Mode and Sedative Infusion on Measured Diaphragm Thickness.

Rationale: In patients who are mechanically ventilated, diaphragm thinning on ultrasound is thought to correlate with diaphragm atrophy and has been associated with prolonged intubation. Factors other than atrophy, however, may cause changes in diaphragm thickness, which may confound studies examining changes in diaphragm thickness over time. Objectives: To determine if changes in the mode of mechanical ventilation or an interruption of sedatives have immediate effects on diaphragm thickness measurements in adult patients in the intensive care unit who are mechanically ventilated. Methods: Adult patients receiving invasive mechanical ventilation for less than 48 hours were included. Diaphragm thickness was measured at end-expiration and peak inspiration using ultrasound while patients were receiving both volume assist-control and pressure-support modes in a randomized crossover fashion. In patients receiving sedatives, additional measurements were taken after an interruption of sedatives. Measurements were compared between modes and on assist-control before and after an interruption of sedatives. Results: Of 85 patients enrolled, 66 had measurements on assist-control and spontaneous modes, and 40 had measurements before and after an interruption of sedatives. End-expiratory diaphragm thickness increased by a median of 0.08 mm after an interruption of sedatives (95% confidence interval [CI], 0.002 mm to 0.164 mm; P = 0.017), corresponding to a median increase of 6.5%. No difference was seen when comparing measurements taken on volume assist-control and pressure support (median difference, 0 mm; 95% CI, -0.07 mm to 0.08 mm; P = 0.98). Conclusions: End-expiratory diaphragm thickness increased by 6.5% after an interruption of sedatives. The effect of sedatives on measured diaphragm thickness should be considered in future studies examining changes in diaphragm thickness over time. Clinical trial registered with Clinicaltrials.gov (NCT04319939).

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.

Non-invasive ventilatory support and high-flow nasal oxygen as first-line treatment of acute hypoxemic respiratory failure and ARDS.

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.

Emergency Department-initiated High-flow Nasal Cannula for COVID-19 Respiratory Distress.

INTRODUCTION: Patients with coronavirus disease 2019 (COVID-19) can develop rapidly progressive respiratory failure. Ventilation strategies during the COVID-19 pandemic seek to minimize patient mortality. In this study we examine associations between the availability of emergency department (ED)-initiated high-flow nasal cannula (HFNC) for patients presenting with COVID-19 respiratory distress and outcomes, including rates of endotracheal intubation (ETT), mortality, and hospital length of stay. METHODS: We performed a retrospective, non-concurrent cohort study of patients with COVID-19 respiratory distress presenting to the ED who required HFNC or ETT in the ED or within 24 hours following ED departure. Comparisons were made between patients presenting before and after the introduction of an ED-HFNC protocol. RESULTS: Use of HFNC was associated with a reduced rate of ETT in the ED (46.4% vs 26.3%, P <0.001) and decreased the cumulative proportion of patients who required ETT within 24 hours of ED departure (85.7% vs 32.6%, P <0.001) or during their entire hospitalization (89.3% vs 48.4%, P <0.001). Using HFNC was also associated with a trend toward increased survival to hospital discharge; however, this was not statistically significant (50.0% vs 68.4%, P = 0.115). There was no impact on intensive care unit or hospital length of stay. Demographics, comorbidities, and illness severity were similar in both cohorts. CONCLUSIONS: The institution of an ED-HFNC protocol for patients with COVID-19 respiratory distress was associated with reductions in the rate of ETT. Early initiation of HFNC is a promising strategy for avoiding ETT and improving outcomes in patients with COVID-19.

Analgesia and sedation in patients with ARDS.

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.

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.

Dietary Management of Blood Glucose in Medical Critically Ill Overweight and Obese Patients: An Open-Label Randomized Trial.

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.

Impact of Vasoactive Medications on ICU-Acquired Weakness in Mechanically Ventilated Patients.

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.