Electrophysiological neuromuscular alterations and severe fatigue predict long-term muscle weakness in survivors of COVID-19 acute respiratory distress syndrome.

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits. Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control. Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT. Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Use of a Novel Three-Dimensional Model to Teach Ultrasound-guided Subclavian Vein Cannulation.

Background: Central venous cannulation is an essential skill in perioperative and critical care medicine. Ultrasound guidance is the standard of care for femoral and internal jugular vein access, with the subclavian vein being perceived to be less amenable to ultrasound-guided (UG) insertion, resulting in a lack of procedural competency and low cannulation rate. There is a paucity of resources and a lack of experience among staff physicians to effectively instruct trainees. Simulation-based medical education has the potential to help maintain high-stakes, infrequently performed skills and counteract possible unrecognized skill decline. We aimed to create a novel, low-cost, high-fidelity three-dimensional (3D) model for UG subclavian vein (UG-SCV) access with an accompanying curriculum to improve this important skill. Methods: A curriculum was created consisting of preparatory material reviewing UG-SCV access, followed by an in-person didactic lecture focusing on ultrasound use and management of complications and a deliberate practice session scanning volunteers and practicing UG vascular puncture on a 3D model. A qualitative usability test design was used to assess the validity of the curriculum in trainees with advanced vascular access skills (anesthesiologists). Participants were second-year anesthesia residents, anesthesia fellows, and staff physicians. Focus groups conducted after each session explored the face validity of the model and curriculum. By applying a usability design, the curriculum was optimized and finalized. Results: Between September 2020 and February 2021, 28 participants tested the curriculum. The focus groups ensured that the curriculum achieved its objective, with iterative changes made after each session in a quality improvement framework Plan-Do-Study-Act approach. After the third cycle, minimal changes were suggested, and the curriculum and 3D model were finalized. An additional group of participants was used to ensure that no new input would help improve the curriculum further. Conclusions: A focused curriculum for enhancing skills in UG-SCV cannulation using a novel 3D model was successfully implemented and validated through a usability test design. This curriculum is better targeted for practitioners experienced in central venous access to master a subclavian approach and maintain their skill level.

Mono- and bi-plane sonographic approach for difficult accesses in the emergency department - A randomized trial.

BACKGROUND: The insertion of peripheral intravenous (PIV) catheters is one of the most performed invasive procedures in acute healthcare settings. However, peripheral difficult vascular access (PDVA) is not uncommon and can lead to delays in administering essential medications. Ultrasound (US) has emerged as a valuable tool for facilitating PIV cannulation. Advancements in technology have introduced a technique known as bi-plane imaging, allowing the simultaneous display of both longitudinal and transverse views of vessels. We aimed to investigate whether the utilization of bi-plane imaging, as opposed to the single-plane approach, would yield superior results for PDVA in the emergency department (ED). METHODS: This study was a single-center randomized controlled trial. We included adult patients admitted to the ED who required PIV cannulation. Patients were randomly assigned to undergo cannulation using either the mono-plane or bi-plane approach, both performed by skilled providers. The primary outcome of the study was to compare the first attempt success rates between the two techniques. RESULTS: A total of 442 patients were enrolled, with 221 undergoing cannulation attempts using the mono-plane approach. Successful placement of a functioning PIV catheter was achieved in a single attempt for 313 out of 442 patients (70.8%). There was no significant difference in the success rates between the two study groups: 68.3% in the mono-plane group and 73.3% in the bi-plane group (p = 0.395). The median time required for a successful attempt differed between the groups, with 45 s (range 18-600) in the mono-plane group and 35 s (range 20-600) in the bi-plane group (p = 0.03). CONCLUSIONS: Our study confirms that US is a highly effective tool for facilitating PIV cannulation in patients with PDVA presenting to the ED. However, our investigation into the use of bi-plane imaging did not reveal a significant improvement when compared to mono-plane imaging.

Lung ultrasound: A comparison of image interpretation accuracy between curvilinear and phased array transducers.

Introduction: Both curvilinear and phased array transducers are commonly used to perform lung ultrasound (LUS). This study seeks to compare LUS interpretation accuracy of images obtained using a curvilinear transducer with those obtained using a phased array transducer. Methods: We invited 166 internists and trainees to interpret 16 LUS images/cineloops of eight patients in an online survey: eight curvilinear and eight phased array, performed on the same lung location. Images depicted normal lung, pneumothorax, pleural irregularities, consolidation/hepatisation, pleural effusions and B-lines. Primary outcome for each participant is the difference in image interpretation accuracy scores between the two transducers. Results: A total of 112 (67%) participants completed the survey. The mean paired accuracy score difference between the curvilinear and phased array images was 3.0% (95% CI: 0.6 to 5.4%, P = 0.015). For novices, scores were higher on curvilinear images (mean difference: 5.4%, 95% CI: 0.9 to 9.9%, P = 0.020). For non-novices, there were no differences between the two transducers (mean difference: 1.4%, 95% CI: -1.1 to 3.9%, P = 0.263). For pleural-based findings, the mean of the paired differences between transducers was higher in the novice group (estimated mean difference-in-differences: 9.5%, 95% CI: 0.6 to 18.4%; P = 0.036). No difference in mean accuracies was noted between novices and non-novices for non-pleural-based pathologies (estimated mean difference-in-differences: 0.6%, 95% CI to 5.4-6.6%; P = 0.837). Conclusions: Lung ultrasound images obtained using the curvilinear transducer are associated with higher interpretation accuracy than the phased array transducer. This is especially true for novices interpreting pleural-based pathologies.

Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity.

In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMBs) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved in areas of lung injury (edema and atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful USMB-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed downregulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5 overexpression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines, and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach to the treatment of lung injury.NEW & NOTEWORTHY Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS.

Long-term physical impairments in survivors of COVID-19-associated ARDS compared with classic ARDS: A two-center study.

PURPOSE: This work aimed to compare physical impairment in survivors of classic ARDS compared with COVID-19-associated ARDS (CARDS) survivors. MATERIAL AND METHODS: This is a prospective observational cohort study on 248 patients with CARDS and compared them with a historical cohort of 48 patients with classic ARDS. Physical performance was evaluated at 6 and 12 months after ICU discharge, using the Medical Research Council Scale (MRCss), 6-min walk test (6MWT), handgrip dynamometry (HGD), and fatigue severity score (FSS). We also assessed activities of daily living (ADLs) using the Barthel index. RESULTS: At 6 months, patients with classic ARDS had lower HGD (estimated difference [ED]: 11.71 kg, p < 0.001; ED 31.9% of predicted value, p < 0.001), 6MWT distance (ED: 89.11 m, p < 0.001; ED 12.96% of predicted value, p = 0.032), and more frequent significant fatigue (OR 0.35, p = 0.046). At 12 months, patients with classic ARDS had lower HGD (ED: 9.08 kg, p = 0.0014; ED 25.9% of predicted value, p < 0.001) and no difference in terms of 6MWT and fatigue. At 12 months, patients with classic ARDS improved their MRCss (ED 2.50, p = 0.006) and HGD (ED: 4.13 kg, p = 0.002; ED 9.45% of predicted value, p = 0.005), while those with CARDS did not. Most patients in both groups regained independence in ADLs at 6 months. COVID-19 diagnosis was a significant independent predictor of better HGD (p < 0.0001) and 6MWT performance (p = 0.001), and lower prevalence of fatigue (p = 0.018). CONCLUSIONS: Both classic ARDS and CARDS survivors experienced long-term impairments in physical functioning, confirming that post-intensive care syndrome remains a major legacy of critical illness. Surprisingly, however, persisting disability was more common in survivors of classic ARDS than in CARDS survivors. In fact, muscle strength measured with HGD was reduced in survivors of classic ARDS compared to CARDS patients at both 6 and 12 months. The 6MWT was reduced and fatigue was more common in classic ARDS compared to CARDS at 6 months but differences were no longer significant at 12 months. Most patients in both groups regained independent function in ADLs at 6 months.

Predictors of ICU Mortality among Mechanically Ventilated Patients: An Inception Cohort Study from a Tertiary Care Center in Addis Ababa, Ethiopia.

Background: Mechanical ventilation is a life-saving intervention for patients with critical illnesses, yet it is associated with higher mortality in resource-constrained settings. This study intended to determine factors associated with the mortality of mechanically ventilated adult intensive care unit (ICU) patients. Methods: A one-year retrospective inception cohort study was conducted using manual chart review in ICU patients (age >13) admitted to Tikur Anbessa Specialized Hospital (Addis Ababa, Ethiopia) from September 2019 to September 2020; mechanically ventilated patients were followed to hospital discharge. Demographic, clinical, and outcome data were collected; logistic regression was used to determine mortality predictors in the ICU. Result: A total of 160 patients were included; 85/160 (53.1%) were females and the mean (SD) age was 38.9 (16.2) years. The commonest indication for ICU admission was a respiratory problem (n = 97/160, 60.7%). ICU and hospital mortality were 60.7% (n = 97/160) and 63.1% (n = 101/160), respectively. Coma (Glasgow Coma Score <8 or 7 with an endotracheal tube (7T)) (adjusted odds ratio [AOR] 6.3, 95% confidence interval 1.19-33.00), cardiovascular diagnosis (AOR 5.05 [1.80-14.15]), and a very low serum albumin level (<2 g/dl) (AOR 4.9 [1.73-13.93]) were independent predictors of mortality (P < 0.05). The most commonly observed complication was ICU acquired infection (n = 48, 30%). Conclusions: ICU mortality in ventilated patients is high. Coma, a very low serum albumin level (<2 g/dl), and cardiovascular diagnosis were independent predictors of mortality. A multifaceted approach focused on developing and implementing context appropriate guidelines and improving skilled healthcare worker availability may prove effective in reducing mortality.

Occurrence and Effects on Weaning From Mechanical Ventilation of Intensive Care Unit Acquired and Diaphragm Weakness: A Pilot Study.

Purpose: Limb intensive care unit (ICU)-acquired weakness (ICUAW) and ICU acquired diaphragm weakness (DW) occur frequently in mechanically ventilated (MV) patients; their coexistence in cooperative and uncooperative patients is unknown. This study was designed to (1) describe the co-occurrence of the two conditions (2) evaluate the impact of ICUAW and DW on the ventilator-free days (VFDs) at 28 days and weaning success, and (3) assess the correlation between maximal inspiratory pressure (MIP) and thickening fraction (TFdi) in patients with DW. Methods: This prospective pilot study was conducted in a single-center on 73 critically ill MV patients. Muscle weakness was defined as a Medical Research Council score < 48 in cooperative patients or a bilateral mean simplified peroneal nerve test < 5.26 mV in uncooperative patients. Diaphragm dysfunction was defined as MIP < 30 cm H2O or as a TFdi < 29%. Weaning success was defined according to weaning according to a new definition (WIND). Results: Fifty-seven patients (78%) had ICUAW and 59 (81%) had DW. The coexistence of the two conditions occurred in 48 patients (65%), without association (χ2 = 1.06, p = 0.304). In the adjusted analysis, ICUAW was independently related to VFDs at 28-days (estimate difference 6 days, p = 0.016), and WIND (OR of 3.62 for having WIND different than short weaning), whereas DW was not. The linear mixed model showed a significant but weak correlation between MIP and TFdi (p < 0.001). Conclusion: This pilot study is the first to explore the coexistence of ICUAW and DW in both cooperative and uncooperative patients; a lack of association was found between DW and ICUAW when considering both cooperative and uncooperative patients. We found a strong correlation between ICUAW but not DW with the VFDs at 28 days and weaning success. A future larger study is warranted in order to confirm our results, and should also investigate the use of transdiaphragmatic twitch pressure measurement during bilateral anterior magnetic phrenic nerve stimulation for the diagnosis of DW.

Seeking the Light in Intensive Care Unit Sedation: The Optimal Sedation Strategy for Critically Ill Patients.

The clinical approach to sedation in critically ill patients has changed dramatically over the last two decades, moving to a regimen of light or non-sedation associated with adequate analgesia to guarantee the patient's comfort, active interaction with the environment and family, and early mobilization and assessment of delirium. Although deep sedation (DS) may still be necessary for certain clinical scenarios, it should be limited to strict indications, such as mechanically ventilated patients with Acute Respiratory Distress Syndrome (ARDS), status epilepticus, intracranial hypertension, or those requiring target temperature management. DS, if not indicated, is associated with prolonged duration of mechanical ventilation and ICU stay, and increased mortality. Therefore, continuous monitoring of the level of sedation, especially when associated with the raw EEG data, is important to avoid unnecessary oversedation and to convert a DS strategy to light sedation as soon as possible. The approach to the management of critically ill patients is multidimensional, so targeted sedation should be considered in the context of the ABCDEF bundle, a holistic patient approach. Sedation may interfere with early mobilization and family engagement and may have an impact on delirium assessment and risk. If adequately applied, the ABCDEF bundle allows for a patient-centered, multidimensional, and multi-professional ICU care model to be achieved, with a positive impact on appropriate sedation and patient comfort, along with other important determinants of long-term patient outcomes.

Criteria, Processes, and Determination of Competence in Basic Critical Care Echocardiography Training: A Delphi Process Consensus Statement by the Learning Ultrasound in Critical Care (LUCC) Initiative.

BACKGROUND: With the paucity of high-quality studies on longitudinal basic critical care echocardiography (BCCE) training, expert opinion guidelines have guided BCCE competence educational standards and processes. However, existing guidelines lack precise detail due to methodological flaws during guideline development. RESEARCH QUESTIONS: To formulate methodologically robust guidelines on BCCE training using evidence and expert opinion, detailing specific criteria for every step, we conducted a modified Delphi process using the principles of the validated AGREE-II tool. Based on systematic reviews, the following domains were chosen: components of a longitudinal BCCE curriculum; pass-grade criteria for image-acquisition and image-interpretation; and formative/summative assessment and final competence processes. STUDY DESIGN AND METHODS: Between April 2020 and May 2021, a total of 21 BCCE experts participated in four rounds. Rounds 1 and 2 used five web-based questionnaires, including branching-logic software for directed questions to individual panelists. In round 3 (videoconference), the panel finalized the recommendations by vote. During the journal peer-review process, Round 4 was conducted as Web-based questionnaires. Following each round, the agreement threshold for each item was determined as ≥ 80% for item inclusion and ≤ 30% for item exclusion. RESULTS: Following rounds 1 and 2, agreement was reached on 62 of 114 items. To the 49 unresolved items, 12 additional items were added in round 3, with 56 reaching agreement and five items remaining unresolved. There was agreement that longitudinal BCCE training must include introductory training, mentored formative training, summative assessment for competence, and final cognitive assessment. Items requiring multiple rounds included two-dimensional views, Doppler, cardiac output, M-mode measurement, minimum scan numbers, and pass-grade criteria. Regarding objective criteria for image-acquisition and image-interpretation quality, the panel agreed on maintaining the same criteria for formative and summative assessment, to categorize BCCE findings as major vs minor and a standardized approach to errors, criteria for readiness for summative assessment, and supervisory options. INTERPRETATION: In conclusion, this expert consensus statement presents comprehensive evidence-based recommendations on longitudinal BCCE training. However, these recommendations require prospective validation.

Rocuronium as Neuromuscular Blockade in Tetanus Patients With Methamphetamine Use Disorder: A Case Report.

BACKGROUND: Spasm control is essential in the management of tetanus. Benzodiazepines are administered as initial treatment of tetanic spasms; however, sedation may be difficult to attain among patients with methamphetamine use disorder. Neuromuscular blocking agents, which act on an entire different mechanism, can be given to induce paralysis. METHODS: We describe 2 cases of patients with methamphetamine use disorder who were diagnosed with severe tetanus and our experience in the use of rocuronium to control their spasms. We performed a systematic review of the SCOPUS and PubMed databases for case reports and case series describing the use of rocuronium in tetanus patients who also have methamphetamine use disorder. We discussed the clinical features and treatment outcomes. RESULTS: A total of 4 cases of patients with substance abuse disorder who had severe tetanus were reported in the literature, including the current cases. The mean age was 28.8 years; all of them male. Trismus, generalized limb and abdominal rigidity were the most common presentation. Three patients underwent emergency tracheostomy. Rocuronium was given as 0.008mg/kg bolus in 1 patient; 2 patients received an intravenous bolus dose of 0.6mg/kg. Infusion dose ranged from 5 to 10 mcg/kg/min. Spasms were controlled within 24-48 hours after giving rocuronium in 3 out of 4 patients. One patient died from complications of dysautonomia and immobility. CONCLUSION: Rocuronium demonstrates a potential role as neuromuscular blocking agent of choice for patients with chronic methamphetamine use disorder and severe tetanus. Management challenges and complications of severe tetanus were also highlighted in this study.

Basic ultrasound head-to-toe skills for intensivists in the general and neuro intensive care unit population: consensus and expert recommendations of the European Society of Intensive Care Medicine.

PURPOSE: To provide consensus, and a list of experts' recommendations regarding the basic skills for head-to-toe ultrasonography in the intensive care setting. METHODS: The Executive Committee of the European Society of Intensive Care (ESICM) commissioned the project and supervised the methodology and structure of the consensus. We selected an international panel of 19 expert clinicians-researchers in intensive care unit (ICU) with expertise in critical care ultrasonography (US), plus a non-voting methodologist. The panel was divided into five subgroups (brain, lung, heart, abdomen and vascular ultrasound) which identified the domains and generated a list of questions to be addressed by the panel. A Delphi process based on an iterative approach was used to obtain the final consensus statements. Statements were classified as a strong recommendation (84% of agreement), weak recommendation (74% of agreement), and no recommendation (less than 74%), in favor or against. RESULTS: This consensus produced a total of 74 statements (7 for brain, 20 for lung, 20 for heart, 20 for abdomen, 7 for vascular Ultrasound). We obtained strong agreement in favor for 49 statements (66.2%), 8 weak in favor (10.8%), 3 weak against (4.1%), and no consensus in 14 cases (19.9%). In most cases when consensus was not obtained, it was felt that the skills were considered as too advanced. A research agenda and discussion on training programs were implemented from the results of the consensus. CONCLUSIONS: This consensus provides guidance for the basic use of critical care US and paves the way for the development of training and research projects.

Teaching Ultrasound at the Point of Care in Times of Social Distancing.

Point-of-care ultrasound has become an integral aspect of critical care training. The Bedside Assessment by Sonography In Critical Care Medicine Curriculum was established at the University of Toronto to train critical care trainees in basic echocardiography and general critical care ultrasound. During the coronavirus disease (COVID-19) pandemic, our program needed to adapt quickly to ensure staff safety and adherence to infection-control protocols. In this article, we share our experience and reflect on the challenges and benefits of shifting from a primarily in-person teaching model to a hybrid model of remote and in-person teaching. Curricular changes were threefold: the transition to entirely web-based interactive didactic teaching and online imaging interpretation modules, the recruitment of sonographers at multiple academic sites as instructors to facilitate in-person practices with lower instructor to trainee ratio, and the use of a mobile application for informal group case-based discussions. Challenges included lost opportunities for scanning healthy volunteers, variability in attendance at online lectures, and a lower number of study submissions for review. However, curricular changes enabled maintenance of directly observed practice, high levels of engagement with recorded content, and an expansion of our reach to a global audience. We believe that future curricula should combine high-quality online curriculum and resources with the ongoing in-person delivery of key elements of curriculum to allow for direct observation and feedback as well as the maintenance of self-directed point-of-care ultrasound portfolios.

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.