Mesenchymal stem cells - a promising therapy for Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) constitutes a spectrum of severe acute respiratory failure in response to a variety of inciting stimuli that is the leading cause of death and disability in the critically ill. Despite decades of research, there are no therapies for ARDS, and management remains supportive. A growing understanding of the complexity of the pathophysiology of ARDS, coupled with advances in stem cell biology, has lead to a renewed interest in the therapeutic potential of mesenchymal stem cells for ARDS. Recent evidence suggests that mesenchymal stem cells can modulate the immune response to reduce injury and also increase resistance to infection, while also facilitating regeneration and repair of the injured lung. This unique combination of effects has generated considerable excitement. We review the biological characteristics of mesenchymal stem cells that underlie their therapeutic potential for ARDS. We also summarise existing pre-clinical evidence, evaluate the potential and pitfalls of using mesenchymal stem cells for treatment, and examine the likely future directions for mesenchymal stem cells in ARDS

Bench-to-bedside review: Carbon dioxide

Carbon dioxide is a waste product of aerobic cellular respiration in all aerobic life forms. PaCO2 represents the balance between the carbon dioxide produced and that eliminated. Hypocapnia remains a common - and generally underappreciated - component of many disease states, including early asthma, high-altitude pulmonary edema, and acute lung injury. Induction of hypocapnia remains a common, if controversial, practice in both adults and children with acute brain injury. In contrast, hypercapnia has traditionally been avoided in order to keep parameters normal. More recently, advances in our understanding of the role of excessive tidal volume has prompted clinicians to use ventilation strategies that result in hypercapnia. Consequently, hypercapnia has become increasingly prevalent in the critically ill patient. Hypercapnia may play a beneficial role in the pathogenesis of inflammation and tissue injury, but may hinder the host response to sepsis and reduce repair. In contrast, hypocapnia may be a pathogenic entity in the setting of critical illness. The present paper reviews the current clinical status of low and high PaCO2 in the critically ill patient, discusses the insights gained to date from studies of carbon dioxide, identifies key concerns regarding hypocapnia and hypercapnia, and considers the potential clinical implications for the management of patients with acute lung injury

Pressure ulcers in patients with COVID ‐19 acute respiratory distress syndrome undergoing prone positioning in the intensive care unit: a pre‐ and post‐intervention study

Background: Prone positioning has been widely used to improve oxygenation and reduce ventilator‐induced lung injury in patients with severe COVID‐19 acute respiratory distress syndrome (ARDS). One major complication associated with prone positioning is the development of pressure ulcers (PUs). Aim: This study aimed to determine the impact of a prevention care bundle on the incidence of PUs in patients with COVID‐19 ARDS undergoing prone positioning in the intensive care unit. Study Design: This was a single‐centre pre and post‐test intervention study which adheres to the Standards for Reporting Implementation Studies (StaRI) guidelines. The intervention included a care bundle addressing the following: increasing frequency of head turns, use of an open gel head ring, application of prophylactic dressings to bony prominences, use of a pressure redistribution air mattress, education of staff in the early identification of evolving PUs through regular and rigorous skin inspection and engaging in bedside training sessions with nursing and medical staff. The primary outcome of interest was the incidence of PU development. The secondary outcomes of interest were severity of PU development and the anatomical location of the PUs. Results: In the pre‐intervention study, 20 patients were included and 80% (n = 16) of these patients developed PUs, comprising 34 ulcers in total. In the post‐intervention study, a further 20 patients were included and 60% (n = 12) of these patients developed PUs, comprising 32 ulcers in total. This marks a 25% reduction in the number of patients developing a PU, and a 6% decrease in the total number of PUs observed. Grade II PUs were the most prevalent in both study groups (65%, n = 22; 88%, n = 28, respectively). In the post‐intervention study, there was a reduction in the incidence of grade III and deep tissue injuries (pre‐intervention 6%, n = 2 grade III, 6% n = 2 deep tissue injuries; post‐intervention no grade III ulcers, grade IV ulcers, or deep tissues injuries were recorded). However, there was an increase in the number of unstageable PUs in the post‐intervention group with 6% (n = 2) of PUs being classified as unstageable, meanwhile there were no unstageable PUs in the pre‐intervention group. This is an important finding to consider as unstageable PUs can indicate deep tissue damage and therefore need to be considered alongside PUs of a more severe grade (grade III, grade IV, and deep tissue injuries). Conclusion: The use of a new evidence‐based care bundle for the prevention of PUs in the management of patients in the prone position has the potential to reduce the incidence of PU development. Although improvements were observed following alterations to standard practice, further research is needed to validate these findings. Relevance to Clinical Practice: The use of a new, evidence‐based care bundle in the management of patients in the prone position has the potential to reduce the incidence of PUs

Preventing facial pressure injuries among health care staff working in diverse COVID‐19 care environments

The aim of this study was to determine the impact of a specially designed care bundle on the development of facial pressure injuries among frontline health care workers wearing personal protective equipment (PPE) during the COVID-19 pandemic. This was a mixed methods study. First, a pre-posttest observational design was employed to evaluate the impact of the pre-piloted intervention, a care bundle including skin cleansing and hydration, protective material use, facemask selection and skin inspection, developed in line with international best practice guidelines. Data were collected using survey methodology. Frontline COVID-19 staff working in acute, community and ambulance services were invited to participate. Then, judgemental and volunteer sampling was used to select participants to undertake semi-structured interviews to elicit feedback on their perceptions of the care bundle. The sample included 120 acute hospital staff, 60 Ambulance staff, 24 Community Hub staff and 20 COVID-19 testing centre staff. A survey response rate of 61% was realised (n = 135/224). Of the participants, 32% (n = 43) had a facial pressure ulcer (FPI) pre-intervention and 13% (n = 18) developed an FPI while using the care bundle. The odds ratio (OR) was 0.33 (95% CI: 0.18 to 0.61; P = .0004), indicating a 77% reduction in the odds of FPI development with use of the care bundle. Analysis of the qualitative data from 22 interviews identified three key themes, the context for the care bundle, the ease of use of the care bundle and the care bundle as a solution to FPI development. The care bundle reduced the incidence of FPI among the participants and was found to be easy to use. Implementation of skin protection for frontline staff continues to be important given the persistently high incidence of COVID-19 and the ongoing need to wear PPE for protracted durations

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial):A Multicentre, Randomised, Controlled Trial

RationaleMesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).ObjectivesWe investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.MethodsThis multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MeasurementsThe primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit 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 day 0, 4 and 7.Main results60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.ConclusionORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Severity of COVID-19 in children with cancer : Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project

BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment

COVID-19 in children with haematological malignancies

BACKGROUND: Children with cancer are not at increased risk of severe SARS-CoV-2 infection; however, adults with haematological malignancies have increased risk of severe infections compared with non-haematological malignancies. METHODS: We compared patients with haematological and non-haematological malignancies enrolled in the UK Paediatric Coronavirus Cancer Monitoring Project between 12 March 2020 and 16 February 2021. Children who received stem cell transplantation were excluded. RESULTS: Only 2/62 patients with haematological malignancy had severe/critical infections, with an OR of 0.5 for patients with haematological compared with non-haematological malignancies. INTERPRETATION: Children with haematological malignancies are at no greater risk of severe SARS-CoV-2 infection than those with non-haematological malignancies

The 1921 European drought: impacts, reconstruction and drivers

The European drought of 1921 is assessed in terms of its impacts on society and in terms of its physical characteristics. The development of impacts of the drought are categorized by a systematic survey of newspaper reports from five European newspapers covering the area from England to the Czech Republic and other parts of Europe. This is coupled to a reconstruction of daily temperature and precipitation based on meteorological measurements to quantify the drought severity and extent, and reanalysis data are used to identify its drivers. This analysis shows that the first impacts of the drought started to appear in early spring and lingered on until well into autumn and winter, affecting water supply and agriculture and livestock farming. The dominant impact in western Europe is on agriculture and livestock farming while in central Europe the effects of wildfires were reported on most often. The peak in the number of reports is in late summer. Preceding the first impacts was the dry autumn of 1920 and winter 1920–1921. The area hardest hit by the drought in the following spring and summer was the triangle between Brussels, Paris and Lyon, but a vast stretch of the continent, from Ireland to the Ukraine, was affected. The reported impacts on water supply and water-borne transport in that region were matched by an analysis of the hydrological situation over the Seine catchment. On average, the 1921 summer was not particularly hot, but the heatwave which was observed at the end of July saw temperatures matching those of the heatwaves in modern summers. Similar to modern droughts, an anticyclone was present roughly over the British Isles, maintaining sunny and dry weather in Europe and steering away cyclones to the north. Its persistence makes it exceptional in comparison to modern droughts. The 1921 drought stands out as the most severe and most widespread drought in Europe since the start of the 20th century. The precipitation deficit in all seasons was large, but in none of the seasons in 1920 and 1921 was the precipitation deficit the largest on record. The severity of the 1921 drought relates to the conservative nature of drought which amplifies the lack of precipitation in autumn and winter into the following spring and summer