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.

Safety and feasibility of above cuff vocalisation for ventilator-dependant patients with tracheostomies.

INTRODUCTION: Temporary tracheostomy is commonly used in patients admitted to intensive care units. Cuffed tubes prevent laryngeal airflow, preventing vocalisation. Sub-glottic suction tubes such as the 'Blue Line Ultra Suctionaid™' are used primarily to remove sub-glottic secretions, but retrograde gas flows via the suction port can facilitate above cuff vocalisation. The aims were to assess whether patients could achieve an audible voice using above cuff vocalisation, to demonstrate the safe use of the Blue Line Ultra Suctionaid™ tracheostomy tube for above cuff vocalisation, and to assess potential benefits of above cuff vocalisation for communication, secretion management and swallowing. METHODS: Our study (Reference 15/NW/0464, IRAS 178997) recruited adult intensive care unit patients who were alert, able to participate in an above cuff vocalisation trial and dependent on an inflated Blue Line Ultra Suctionaid™ cuff for ventilatory support. Consenting participants underwent fibreoptic endoscopic assessment of swallow by experienced Speech & Language Therapy staff with and without above cuff vocalisation. Clinical and fibreoptic endoscopic assessment of swallow, assessment of voice quality, swallowing and secretion management were recorded and scored. Median differences between paired observations and scores were analysed with and without above cuff vocalisation. Adverse events were identified by follow up fibreoptic endoscopic assessment of swallow and patient accounts. RESULTS: Ten patients completed the study. Above cuff vocalisation was used for a median of 15 min, during a median of nine episodes, over a median of three days. Above cuff vocalisation resulted in an audible voice in eight of the 10 patients, during 66 out of 91 above cuff vocalisation attempts. There improvements in unstimulated dry cough and swallow frequency and aspiration ratings measured by fibreoptic endoscopic assessment of swallow. No complications were reported or observed in 66 attempts with only one episode terminated prematurely. CONCLUSIONS: Above cuff vocalisation can achieve effective, safe, well-tolerated vocalisation in ventilator-dependant intensive care unit patients. Above cuff vocalisation has the potential to aid earlier, more effective communication and may improve laryngeal function and rehabilitation.

Long-term non-invasive ventilation in cystic fibrosis -- experience over two decades.

BACKGROUND: Non-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting. METHODS: We reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010. RESULTS: Of 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16 months (range 2-90). Mean FEV(1) fell by 212 ml over the year before NIV but increased by 18 ml in the following year (p<0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV(1). From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted. CONCLUSIONS: NIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre.

Can a score derived from the Critical Care Minimum Data Set be used as a marker of organ dysfunction? - a pilot study.

BACKGROUND: The aim of this study was to develop a simple organ score derived from the Critical Care Minimum Data Set (CCMDS) to compare with the Sequential Organ Failure Assessment (SOFA) score, a previously validated score of organ dysfunction. FINDINGS: The CCMDS collects data regarding the support of seven organ systems. To create a CCMDS derived score each level of organ support was allocated a numerical value. SOFA scores were collected retrospectively from each patient in the study. Data was collected in 50 sequential admissions over the first 5 days of their admission. This generated a total of 147 pairs of data for comparison.Scatter plots and Spearman's rank correlation coefficient suggest a weak positive association between our CCMDS-derived score and the SOFA score. Daily Bland-Altman plots reveal minimal bias between the score but wide limits of agreement. CONCLUSION: Our CCMDS-derived score cannot be regarded as an indicator of severity of organ dysfunction and cannot replace SOFA scores when a daily marker of organ dysfunction is required.