Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial.

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FiO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

Quantifying allo-grooming in wild chacma baboons (Papio ursinus) using tri-axial acceleration data and machine learning.

Quantification of activity budgets is pivotal for understanding how animals respond to changes in their environment. Social grooming is a key activity that underpins various social processes with consequences for health and fitness. Traditional methods use direct (focal) observations to calculate grooming rates, providing systematic but sparse data. Accelerometers, in contrast, can quantify activity budgets continuously but have not been used to quantify social grooming. We test whether grooming can be accurately identified using machine learning (random forest model) trained on labelled acceleration data from wild chacma baboons (Papio ursinus). We successfully identified giving and receiving grooming with high precision (81% and 91%) and recall (87% and 79%). Giving grooming was associated with a distinct rhythmical signal along the surge axis. Receiving grooming had similar acceleration signals to resting, and thus was more difficult to assign. We applied our machine learning model to n = 680 collar data days from n = 12 baboons and found that grooming rates obtained from accelerometers were significantly and positively correlated with direct observation rates for giving but not receiving grooming. The ability to collect continuous grooming data in wild populations will allow researchers to re-examine and expand upon long-standing questions regarding the formation and function of grooming bonds.

Multiple Organ Dysfunction in Older Major Trauma Critical Care Patients: A Multicenter Prospective Observational Study.

The objective was to explore the characteristics and outcomes of multiple organ dysfunction syndrome (MODS) in older trauma patients. Background: Severely injured older people present an increasing challenge for trauma systems. Recovery for those who require critical care may be complicated by MODS. In older trauma patients, MODS may not be predictable based on chronological age alone and factors associated with its development and resolution are unclear. Methods: Consecutive adult patients (aged ≥16 years) admitted to 4 level 1 major trauma center critical care units were enrolled and reviewed daily until discharge or death. MODS was defined by a daily total sequential organ failure assessment score of >5. Results: One thousand three hundred sixteen patients were enrolled over 18 months and one-third (434) were aged ≥65 years. Incidence of MODS was high for both age groups (<65 years: 64%, ≥65 years: 70%). There were few differences in severity, patterns, and duration of MODS between cohorts, except for older traumatic brain injury (TBI) patients who experienced a prolonged course of MODS recovery (TBI: 9 days vs no TBI: 5 days, P < 0.01). Frailty rather than chronological age had a strong association with MODS development (odds ratio [OR], 6.9; 95% confidence intervals [CI], 3.0-12.4; P < 0.001) and MODS mortality (OR, 2.1; 95% CI, 1.31-3.38; P = 0.02). Critical care resource utilization was not increased in older patients, but MODS had a substantial impact on mortality (<65 years: 17%; ≥65 years: 28%). The majority of older patients who did not develop MODS survived and had favorable discharge outcomes (home discharge ≥65 years NoMODS: 50% vs MODS: 15%; P < 0.01). Conclusions: Frailty rather than chronological age appears to drive MODS development, recovery, and outcome in older cohorts. Early identification of frailty after trauma may help to predict MODS and plan care in older trauma.

Open versus percutaneous tracheostomy in COVID-19: a multicentre comparison and recommendation for future resource utilisation.

PURPOSE: The COVID-19 pandemic placed an unprecedented demand on critical care services for the provision of mechanical ventilation. Tracheostomy formation facilitates liberation from mechanical ventilation with advantages for both the patient and wider critical care resource, and can be performed using both percutaneous dilatational and surgical techniques. We compared outcomes in those patients undergoing percutaneous dilatational tracheostomy to those undergoing surgical tracheostomy and make recommendations for provision of tracheostomy services in any future surge. METHODS: Multicentre multidisciplinary retrospective observational cohort study including 201 patients with COVID-19 pneumonitis admitted to an ICU in one of five NHS Trusts within the South London Adult Critical Care Network who required mechanical ventilation and subsequent tracheostomy. RESULTS: Percutaneous dilatational tracheostomy was performed in 124 (62%) of patients, and surgical tracheostomy in 77 (38%) of patients. There was no difference between percutaneous dilatational tracheostomy and surgical tracheostomy in either the rate of peri-operative complications (16.9 vs. 22.1%, p = 0.46), median [IQR(range)] time to decannulation [19.0 (15.0-30.2 (5.0-65.0)] vs. 21.0 [15.5-36.0 (5.0-70.0) days] or mortality (13.7% vs. 15.6%, p = 0.84). Of the 172 patients that were alive at follow-up, two remained ventilated and 163 were decannulated. CONCLUSION: In patients with COVID-19 pneumonitis that require tracheostomy to facilitate weaning from mechanical ventilation, there was no difference in outcomes between those patients that had percutaneous dilatational tracheostomy compared with those that had surgical tracheostomy. Planning for future surges in COVID-19-related critical care demands should utilise all available resource and expertise.

Transient Receptor Potential Cation Channels and Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

BACKGROUND: Until recently, the mechanism for the malignant hyperthermia crisis has been attributed solely to sustained massive Ca release from the sarcoplasmic reticulum on exposure to triggering agents. This study tested the hypothesis that transient receptor potential cation (TRPC) channels are important contributors to the Ca dyshomeostasis in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the mechanisms responsible for Ca dyshomeostasis in RYR1-p.G2435R mouse muscles and muscle cells using calcium and sodium ion selective microelectrodes, manganese quench of Fura2 fluorescence, and Western blots. RESULTS: RYR1-p.G2435R mouse muscle cells have chronically elevated intracellular resting calcium and sodium and rate of manganese quench (homozygous greater than heterozygous) compared with wild-type muscles. After exposure to 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3/6 activator, increases in intracellular resting calcium/sodium were significantly greater in RYR1-p.G2435R muscles (from 153 ± 11 nM/10 ± 0.5 mM to 304 ± 45 nM/14.2 ± 0.7 mM in heterozygotes P < 0.001] and from 251 ± 25 nM/13.9 ± 0.5 mM to 534 ± 64 nM/20.9 ± 1.5 mM in homozygotes [P < 0.001] compared with 123 ± 3 nM/8 ± 0.1 mM to 196 ± 27 nM/9.4 ± 0.7 mM in wild type). These increases were inhibited both by simply removing extracellular Ca and by exposure to either a nonspecific (gadolinium) or a newly available, more specific pharmacologic agent (SAR7334) to block TRPC6- and TRPC3-mediated cation influx into cells. Furthermore, local pretreatment with SAR7334 partially decreased the elevation of intracellular resting calcium that is seen in RYR1-p.G2435R muscles during exposure to halothane. Western blot analysis showed that expression of TRPC3 and TRPC6 were significantly increased in RYR1-p.G2435R muscles in a gene-dose-dependent manner, supporting their being a primary molecular basis for increased sarcolemmal cation influx. CONCLUSIONS: Muscle cells in knock-in mice expressing the RYR1-p.G2435R mutation are hypersensitive to TRPC3/6 activators. This hypersensitivity can be negated with pharmacologic agents that block TRPC3/6 activity. This reinforces the working hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia-susceptible muscle, both at rest and during the malignant hyperthermia crisis.

Neurally adjusted ventilatory assist versus pressure support ventilation: a randomized controlled feasibility trial performed in patients at risk of prolonged mechanical ventilation.

BACKGROUND: The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV). METHODS: An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary-≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality. RESULTS: In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0-97.1%) and 100% (100-100%), and protocol compliance was 66.7% (50.3-80.0%) and 100% (89.0-100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0-11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2-0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality. CONCLUSIONS: This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01826890. Registered 9 April 2013.

Late HIV diagnosis is a major risk factor for intensive care unit admission in HIV-positive patients: a single centre observational cohort study.

BACKGROUND: HIV positive patients are at risk of infectious and non-infectious complications that may necessitate intensive care unit (ICU) admission. While the characteristics of patients requiring ICU admission have been described previously, these studies did not include information on the denominator population from which these cases arose. METHODS: We conducted an observational cohort study of ICU admissions among 2751 HIV positive patients attending King's College Hospital, South London, UK. Poisson regression models were used to identify factors associated with ICU admission. RESULTS: The overall incidence rate of ICU admission was 1.0 [95% CI 0.8, 1.2] per 100 person-years of follow up, and particularly high early (during the first 3 months) following HIV diagnosis (12.4 [8.7, 17.3] per 100 person-years compared to 0.37 [0.27, 0.50] per 100 person-years thereafter; incidence rate ratio 33.5 [23.4, 48.1], p < 0.001). In time-updated analyses, AIDS and current CD4 cell counts of less than 200 cells/mm3 were associated with an increased incidence of ICU admission while receipt of combination antiretroviral therapy (cART) was associated with a reduced incidence of ICU admission. Late HIV diagnosis (initial CD4 cell count <350 or AIDS within 3 months of HIV diagnosis) applied to 81% of patients who were first diagnosed HIV positive during the study period and who required ICU admission. Late HIV diagnosis was significantly associated with ICU admission in the first 3 months following HIV diagnosis (adjusted incidence rate ratio 8.72, 95% CI 2.76, 27.5). CONCLUSIONS: Late HIV diagnosis was a major risk factor for early ICU admission in our cohort. Earlier HIV diagnosis allowing cART initiation at CD4 cell counts of 350 cells/mm3 is likely to have a significant impact on the need for ICU care.

Use of inspiratory strength training to wean six patients who were ventilator-dependent.

BACKGROUND AND PURPOSE: Patients who are unable to wean from mechanical ventilation (MV) after resolution of critical illness or surgery risk increased morbidity and death and consume a disproportionate amount of intensive care unit resources. Decreased inspiratory muscle strength is often cited as a major factor contributing to prolonged MV. The purpose of this case report is to describe the rationale and application of inspiratory strength training (IST) as an adjunct to lengthen unassisted breathing trials and to ultimately wean patients with chronic mechanical ventilator dependency. CASE DESCRIPTION: Six patients who had been ventilator-dependent for 18 to 221 days (mean of 72 days) after surgery and were diagnosed with "failure to wean" performed low-repetition, high-resistance breathing exercises that were coupled with increasing time off the ventilator. OUTCOMES: All 6 patients were weaned from the ventilator in 9 to 28 days (mean of 17 days). The patients' training pressure increased from a mean of 9.3 cm/H2O to 27.5 cm/H2O, for an increase of 195%. The volitional maximum inspiratory pressure (MIP) increased from a mean of 22.5 cm/H2O to 54 cm/H2O, for a 140% gain in pressure. DISCUSSION: Although it is not clear why the patients appeared to benefit from IST, possible explanations include: (1) addressing inspiratory muscle pump dysfunction, (2) standardization of breathing patterns, 3) routinization of the patients' unassisted breathing trials, and (4) nonspecific training effects. Future research should address these possibilities when attempting to understand the effects of IST in the weaning of patients with chronic ventilator dependency.