Extracellular vesicles in disorders of hemostasis following traumatic brain injury.

Traumatic brain injury (TBI) is a global health priority. In addition to being the leading cause of trauma related death, TBI can result in long-term disability and loss of health. Disorders of haemostasis are common despite the absence of some of the traditional risk factors for coagulopathy following trauma. Similar to trauma induced coagulopathy, this manifests with a biphasic response consisting of an early hypocoagulable phase and delayed hypercoagulable state. This coagulopathy is clinically significant and associated with increased rates of haemorrhagic expansion, disability and death. The pathophysiology of TBI-induced coagulopathy is complex but there is biologic plausibility and emerging evidence to suggest that extracellular vesicles (EVs) have a role to play. TBI and damage to the blood brain barrier result in release of brain-derived EVs that contain tissue factor and phosphatidylserine on their surface. This provides a platform on which coagulation can occur. Preclinical animal models have shown that an early rapid release of EVs results in overwhelming activation of coagulation resulting in a consumptive coagulopathy. This phenomenon can be attenuated with administration of substances to promote EV clearance and block their effects. Small clinical studies have demonstrated elevated levels of procoagulant EVs in patients with TBI correlating with clinical outcome. EVs represent a promising opportunity for use as minimally invasive biomarkers and potential therapeutic targets for TBI patients. However, additional research is necessary to bridge the gap between their potential and practical application in clinical settings.

The impact of brain tissue oxygenation monitoring on the Glasgow Outcome Scale/Glasgow Outcome Scale Extended in patients with moderate to severe traumatic brain injury: A systematic review.

BACKGROUND: Traumatic brain injuries (TBIs) are one of the leading causes of death or long-term disability around the world. As a result of improvements in supportive care, patients are surviving more severe insults with more pronounced dependency on their families, hospitals, and long-term care facilities. The introduction of brain tissue oxygenation (PbtO2) monitoring aims to recognize episodes of reduced cerebral perfusion with and without associated increased intracranial pressure (ICP). AIM: The aim of this review is to determine the impact of PbtO2 on the Glasgow Outcome Scale/Glasgow Outcome Scale Extended (GOS/GOSE) in patients with moderate to severe TBI. DESIGN: Systematic review with narrative and meta-analysis. All original research in which adult patients undergoing PbtO2 were compared with a control group of traditional ICP/cerebral perfusion pressure (CPP) monitoring. Both randomized controlled trials and observational studies were included in this review. METHODS: Databases were searched in September 2022. The primary outcome of the review was the impact of PbtO2 monitoring on GOS/GOSE, while secondary outcomes were mortality and length of stay (LOS) in the intensive care unit (ICU). RESULTS: Seven studies with a combined number of 770 patients were included in the review. These patients were adults ≥16 years of age. Only two of the studies included found a statistically significant association between PbtO2 monitoring and improved long-term neurological outcomes in patients with TBI (p = .01, p < .01). A meta-analysis of the secondary outcomes identified an associated reduction of mortality in favour of the group treated with PbtO2 monitoring (p < .0001). Results from studies examining LOS in ICU have demonstrated an associated increase of LOS in ICU in patients treated with PbtO2-guided therapy. CONCLUSION: From the studies included in this review, only two found a statistically significant association between PbtO2 monitoring and long-term outcomes. It is unclear whether PbtO2 goal-directed therapy has a positive impact on the long-term neurological functions and mortality of patients suffering from TBI. A multicentre randomized controlled trial may provide further evidence, but not necessarily conclusive. RELEVANCE TO CLINICAL PRACTICE: Further research is warranted to determine the efficacy of the introduction of this new monitoring system to guide local policy change.

Biomarkers for the early detection of pressure ulcers in the intensive care setting: A comparison between sub-epidermal moisture measurements and interleukin-1α.

Pressure ulcer (PU) prevention in the intensive care unit (ICU) is an important clinical issue as critically unwell patients are at high risk of developing PUs. However, current methods of PU detection are limited, especially for early detection. This study aimed to establish the correlation between Interleukin-1α (IL-1α)/total protein (TP) and sub-epidermal moisture (SEM) measurements in the early identification of PUs in ICU patients. This study employed an observational research design using the STROBE guidelines. Following ethical approval, 53 participants were recruited and sebum was obtained using Sebutape from weight-bearing areas (sacrum, heels and a control site). SEM measurements were taken from the same anatomical sites. Both measures were taken at the same time and participants were followed up for 5 days, or until discharge or death. Correlations between SEM delta measurements, IL-1α, TP and PU incidence and other demographic information were explored using Spearman's correlation for data not normally distributed, and Pearson's R correlation coefficient for normally distributed data. Mean baseline SEM delta measurements indicate abnormal readings for all anatomical sites except the control site, consistent with previous studies. Mean baseline IL-1α/TP readings were higher for the sacrum versus both heels and, on average, readings were higher for the control site versus all other anatomical locations. This is conflicting, given that the control site was non-weight bearing. There were very weak or weak correlations between SEM delta measurements and IL-1α/TP readings. SEM measurements are quick and easy to obtain and results are instant, however Sebutape sampling takes significantly longer and is challenging to conduct among haemodynamically unstable patients. Obtaining SEM measurements is more practical and feasible than Sebutape sampling to assess for the presence of inflammation.

Effects of vasopressor agents on the development of pressure ulcers in critically ill patients: a systematic review.

OBJECTIVE: The primary objective of this systematic review was to determine the effect of vasopressor agents on the development of pressure ulcers (PUs) among critically ill patients in intensive care units (ICUs). The secondary outcome of interest was length of stay in the ICU. METHOD: A systematic review was undertaken using the databases searched: Medline, Embase, CINAHL and The Cochrane Library. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to formulate the review. Data were extracted using a predesigned data extraction table and analysed as appropriate using RevMan. Quality appraisal was undertaken using the EBL Critical Appraisal Tool. RESULTS: The inclusion criteria were met by 13 studies. Two studies provided sufficient data to compare the number of patients who developed a PU with and without the use of vasopressors. Consistently, within these two studies, being treated with a vasopressor increased the likelihood of PU development. RevMan analysis identified that shorter duration of administration of vasopressors was associated with less PU development (mean difference (MD) 65.97 hours, 95% confidence interval (CI): 43.47-88.47; p=0.0001). Further, a lower dose of vasopressors was also associated with less PU development (MD: 8.76µg/min, 95% CI: 6.06-11.46; p<0.00001). Mean length of stay increased by 11.46 days for those with a PU compared to those without a PU (MD: 11.46 days; 95% CI: 7.10-15.82; p<0.00001). The overall validities of the studies varied between 45-90%, meaning that there is potential for bias within all the included studies. CONCLUSION: Vasopressor agents can contribute to the development of PUs in critically ill patients in ICUs. Prolonged ICU stay was also associated with pressure ulcers in this specific patient group. Given the risk of bias within the included studies, further studies are needed to validate the findings of this review paper.

Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.

BACKGROUND: Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. METHODS: Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. FINDINGS: AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. INTERPRETATION: There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. FUNDING: NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

Emerging pharmacological therapies for ARDS: COVID-19 and beyond.

ARDS, first described in 1967, is the commonest form of acute severe hypoxemic respiratory failure. Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of lung injury and repair, and advances in supportive care, particularly ventilatory management, there remains no effective pharmacological therapy for this syndrome. Hospital mortality at 40% remains unacceptably high underlining the need to continue to develop and test therapies for this devastating clinical condition. The purpose of the review is to critically appraise the current status of promising emerging pharmacological therapies for patients with ARDS and potential impact of these and other emerging therapies for COVID-19-induced ARDS. We focus on drugs that: (1) modulate the immune response, both via pleiotropic mechanisms and via specific pathway blockade effects, (2) modify epithelial and channel function, (3) target endothelial and vascular dysfunction, (4) have anticoagulant effects, and (5) enhance ARDS resolution. We also critically assess drugs that demonstrate potential in emerging reports from clinical studies in patients with COVID-19-induced ARDS. Several therapies show promise in earlier and later phase clinical testing, while a growing pipeline of therapies is in preclinical testing. The history of unsuccessful clinical trials of promising therapies underlines the challenges to successful translation. Given this, attention has been focused on the potential to identify biologically homogenous subtypes within ARDS, to enable us to target more specific therapies 'precision medicines.' It is hoped that the substantial number of studies globally investigating potential therapies for COVID-19 will lead to the rapid identification of effective therapies to reduce the mortality and morbidity of this devastating form of ARDS.