Efficacy of acute administration of inhaled argon on traumatic brain injury in mice.

BACKGROUND: Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI. METHODS: Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry. RESULTS: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. CONCLUSIONS: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue.

Organ donation: from diagnosis to transplant.

PURPOSE OF REVIEW: Organ transplantation has largely expanded over the last decades and despite several improvements have been made in the complex process occurring between the identification of organ donors and organ transplant, there is still a chronic inability to meet the needs of patients. Consequently, the optimization of the transplant process through its different steps is crucial, and the role of the intensivists is fundamental as it requires clinical, managerial and communication skills to avoid the loss of potential donors. The purpose of this review is to provide an update on the transplant process from the early identification of the donor, to transplant. The two main pathways of organ donation will be discussed: donation after death by neurologic criteria and the donation after cardiac death (DCD). RECENT FINDINGS: Recent evidence demonstrates that appropriate intensive care management is fundamental to increase organ availability for transplantation. The expansion of pool donation requires a strong legal framework supporting ethical and organizational considerations in each country, together with the implementation of physicians' technical expertise and communication skills for family involvement and satisfaction. New evidence is available regarding organ donor's management and pathway. The importance of checklists is gaining particular interest according to recent literature. Recent clinical trials including the use of naloxone, simvastatin and goal directed hemodynamic therapies were not able to demonstrate a clear benefit in improving quality and number of transplanted organs. Ethical concerns about DCD are recently being raised, and these will be discussed focusing on the differences of outcome between controlled and uncontrolled procedure. SUMMARY: The major change in the process of organ donation has been to implement parallel DCD and donation after brain death pathways. However, more research is needed for improving quality and number of transplanted organs.

Prone Positioning during Venovenous Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome. A Multicenter Cohort Study and Propensity-matched Analysis.

Rationale: Prone positioning reduces mortality in patients with severe acute respiratory distress syndrome (ARDS). To date, no evidence supports the use of prone positioning (PP) during venovenous extracorporeal oxygenation (ECMO).Objectives: The aim of the study was to assess the feasibility, safety, and effect on oxygenation and lung mechanics of PP during ECMO. As a secondary exploratory aim, we assessed the association between PP and hospital mortality.Methods: We performed a multicenter retrospective cohort study in six Italian ECMO centers, including patients managed with PP during ECMO support (prone group; four centers) and patients managed in the supine position (control group; two centers). Physiological variables were analyzed at four time points (supine before PP, start of PP, end of PP, and supine after PP). The association between PP and hospital mortality was assessed by multivariate analysis and propensity score-matching.Results: A total of 240 patients were included, with 107 in the prone group and 133 in the supine group. The median duration of the 326 pronation cycles was 15 (12-18) hours. Minor reversible complications were reported in 6% of PP maneuvers. PP improved oxygenation and reduced intrapulmonary shunt. Unadjusted hospital mortality was lower in the prone group (34 vs. 50%; P = 0.017). After adjusting for covariates, PP remained significantly associated with a reduction of hospital mortality (odds ratio, 0.50; 95% confidence interval, 0.29-0.87). Sixty-six propensity score-matched patients were identified in each group. In this matched sample, patients who underwent pronation had higher ECMO duration (16 vs. 10 d; P = 0.0344) but lower hospital mortality (30% vs. 53%; P = 0.0241).Conclusions: PP during ECMO improved oxygenation and was associated with a reduction of hospital mortality.

Emergently planned exclusive hub-and-spoke system in the epicenter of the first wave of COVID-19 pandemic in Italy: the experience of the largest COVID-19-free ICU hub for time-dependent diseases.

BACKGROUND: Lombardy was the epicenter in Italy of the first wave of COVID-19 pandemic. To face the contagion growth, from March 8 to May 8, 2020, a regional law redesigned the hub-and-spoke system for time-dependent diseases to better allocate resources for COVID-19 patients. METHODS: We report the reorganization of the major hospital in Lombardy during COVID-19 pandemic, including the rearrangement of its ICU beds to face COVID-19 pandemic and fulfill its role as extended hub for time-dependent diseases while preserving transplant activity. To highlight the impact of the emergently planned hub-and-spoke system, all patients admitted to a COVID-19-free ICU hub for trauma, neurosurgical emergencies and stroke during the two-month period were retrospectively collected and compared to 2019 cohort. Regional data on organ procurement was retrieved. Observed-to-expected (OE) in-ICU mortality ratios were computed to test the impact of the pandemic on patients affected by time-dependent diseases. RESULTS: Dynamic changes in ICU resource allocation occurred according to local COVID-19 epidemiology/trends of patients referred for time-dependent diseases. The absolute increase of admissions for trauma, neurosurgical emergencies and stroke was roughly two-fold. Patients referred to the hub were older and characterized by more severe conditions. An increase in crude mortality was observed, though OE ratios for in-ICU mortality were not statistically different when comparing 2020 vs. 2019. An increase in local organ procurement was observed, limiting the debacle of regional transplant activity. CONCLUSIONS: We described the effects of a regional emergently planned hub-and-spoke system for time-dependent diseases settled in the epicenter of COVID-19 pandemic in Italy.

Neuroprotection in Traumatic Brain Injury: Mesenchymal Stromal Cells can Potentially Overcome Some Limitations of Previous Clinical Trials.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In the last 30 years several neuroprotective agents, attenuating the downstream molecular and cellular damaging events triggered by TBI, have been extensively studied. Even though many drugs have shown promising results in the pre-clinical stage, all have failed in large clinical trials. Mesenchymal stromal cells (MSCs) may offer a promising new therapeutic intervention, with preclinical data showing protection of the injured brain. We selected three of the critical aspects identified as possible causes of clinical failure: the window of opportunity for drug administration, the double-edged contribution of mechanisms to damage and recovery, and the oft-neglected role of reparative mechanisms. For each aspect, we briefly summarized the limitations of previous trials and the potential advantages of a newer approach using MSCs.

Intracranial pressure monitor insertion in traumatic brain injury: a single center, retrospective decision process analysis.

BACKGROUND: Evidence-based indications for intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI) are lacking. The aim of this study was to analyze the main factors that guided the decision-making of invasive ICP monitoring in a large cohort of TBI patients from our institution. METHODS: This is a retrospective, single centre, observational study including adult TBI patients consecutively admitted to our NeuroIntensive Care Unit over 20 years. Logistic regression analyses were performed to identify potential factors associated with the decision for ICP monitor insertion. A decision tree was developed to identify the combination of factors with the highest statistical power to predict the decision for ICP monitor insertion. RESULTS: A total of 857 adult patients were included in the analysis. The decision to monitor ICP was strongly related to different factors, including Glasgow Coma Scale (GCS), Computed Tomography (CT) scan classification, pupils' reactivity, and patients' prognosis at the admission calculated by the International Mission on Prognosis in Traumatic Brain Injury (IMPACT) score (p<0.01). Results from the decision tree showed an overall ability of the 72% in the prediction of ICP monitoring and that, among the factors analysed, CT findings had the primarily and strongest discrimination power. CONCLUSIONS: The decision to insert an invasive ICP monitoring in patients with TBI is multifactorial. Among the different factors analysed in our cohort of TBI patients, prognostication factors as for IMPACT score and in particular CT findings could potentially explain the decision making for ICP monitoring.

Blood Component Therapy and Coagulopathy in Trauma: A Systematic Review of the Literature from the Trauma Update Group.

BACKGROUND: Traumatic coagulopathy is thought to increase mortality and its treatment to reduce preventable deaths. However, there is still uncertainty in this field, and available literature results may have been overestimated. METHODS: We searched the MEDLINE database using the PubMed platform. We formulated four queries investigating the prognostic weight of traumatic coagulopathy defined according to conventional laboratory testing, and the effectiveness in reducing mortality of three different treatments aimed at contrasting coagulopathy (high fresh frozen plasma/packed red blood cells ratios, fibrinogen, and tranexamic acid administration). Randomized controlled trials were selected along with observational studies that used a multivariable approach to adjust for confounding. Strict criteria were adopted for quality assessment based on a two-step approach. First, we rated quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Then, this rating was downgraded if other three criteria were not met: high reporting quality according to shared standards, absence of internal methodological and statistical issues not detailed by the GRADE system, and absence of external validity issues. RESULTS: With few exceptions, the GRADE rating, reporting and methodological quality of observational studies was "very low", with frequent external validity issues. The only two randomized trials retrieved were, instead, of high quality. Only weak evidence was found for a relation between coagulopathy and mortality. Very weak evidence was found supporting the use of fibrinogen administration to reduce mortality in trauma. On the other hand, we found high evidence that the use of 1:1 vs. 1:2 high fresh frozen plasma/packed red blood cells ratios failed to obtain a 12% mortality reduction. This does not exclude lower mortality rates, which have not been investigated. The use of tranexamic acid in trauma was supported by "high" quality evidence according to the GRADE classification but was downgraded to "moderate" for external validity issues. CONCLUSIONS: Tranexamic acid is effective in reducing mortality in trauma. The other transfusion practices we investigated have been inadequately studied in the literature, as well as the independent association between mortality and coagulopathy measured with traditional laboratory testing. Overall, in this field of research literature quality is poor.

Utility of interferon-γ release assay results to monitor anti-tubercular treatment in adults and children.

BACKGROUND: Interferon-γ release assays (IGRAs), including the commercially available T-SPOT.TB, QuantiFERON-TB Gold (QFT-G), and QuantiFERON-TB Gold In-Tube (QTF-G-IT), enable detection of circulating T lymphocytes responsive to specific Mycobacterium tuberculosis antigens. Studies of the potential role of serial IGRAs for assessment of response to anti-tubercular therapy are accumulating. OBJECTIVE: The objective of this systematic review was to evaluate the potential clinical utility of serial IGRAs in anti-tubercular therapy. METHODS: We conducted a literature search of the Cochrane Library and MEDLINE by PubMed, from database inception through October 1, 2011, for serial IGRA results in anti-tubercular therapy, in adults and children, using commercial stardardized assays. All types of articles in the English language were included. Meta-analysis was performed to estimate the pooled percentage of reversion from a positive to a negative IGRA value at 3- to 6-month follow-up. RESULTS: According to inclusion and exclusion criteria, three T-SPOT.TB-based (n = 319 patients), three QFT-G-based (n = 75 patients), and seven QFT-G-IT-based (n = 558 patients) longitudinal studies were included. The percentage of patients with reversion from a positive to a negative IGRA value ranged from 5.71% to 13.93% for T-SPOT.TB, 5.26% to 71.05% for QFT-G, and 14.28% to 41.89% for QFT-G-IT assays. Meta-analysis estimation of reversion was feasible only for the QFT-G-IT assay, at 30.54% (95% CI, 22.89-38.75). In two pediatric studies, which were QFT-G-IT based (n = 122 children), the reported reversion rates were 14.28% and 20.33%, respectively. CONCLUSIONS: Because IGRAs require time and cost resources, and reversion from positive to negative IGRA values occurs in a minority of treated patients, monitoring IGRA changes over time seems to have only speculative value in adults. Data in children are poor, but are in line with results reported in adults.