Treatment with inhaled Argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect.

BACKGROUND: Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols. METHODS: Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. In vivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while in vitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation. FINDINGS: The systematic review detected 60 experimental studies (16 in vitro, 7 ex vivo, 31 in vivo, 6 with both in vitro and in vivo) investigating the role of Ar. Only one clinical study was found. Data from six in vitro and nineteen in vivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events). INTERPRETATION: This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design. FUNDING: This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416.

Agreement between the thromboelastography reaction time parameter using fresh and citrated whole blood during extracorporeal membrane oxygenation with Teg®5000 and Teg®6s.

PURPOSE: We aimed at assessing the correlation between TEG reaction time (TEG-R) in citrated and fresh blood samples with TEG5000 and TEG 6S during heparin administration in patients with and without ECMO support. MATERIALS AND METHODS: Paired TEG5000 (fresh and citrated whole blood, kaolin and kaolin-heparinase) and TEG6S (citrated whole blood) samples were obtained, together with standard coagulation laboratory tests. Bland-Altman analysis and Lin's concordance correlation coefficient were used to assess agreement. RESULTS: Thirteen consecutive ECMO patients and eight consecutive non-ECMO patients were enrolled and TEG was performed for a total of 84 paired samples. ECMO patients received 19.2 (12.6-25.8) U/kg/h of heparin. Five of the non-ECMO patients did not receive heparin, two of them received a very low prophylactic dose (1.6 and 2.9 IU/kg/h, respectively), and one of them 13.1 U/kg/h of heparin. Using TEG®5000, TEG-R was 21.0 (-23.4; 65.5) min longer on fresh compared to citrated blood in patients receiving heparin while only 1.58 (-5.5; 8.7) min longer in patients not-receiving heparin. These differences were reverted by heparinase. CONCLUSIONS: Using citrated-recalcified blood to perform TEG might lead to underestimation of the effect of heparin.

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) may act as a driver or propagator of systemic inflammation. In turn, cytokine release can modify thromboelastographic (TEG) tests which are commonly used for anticoagulation monitoring. In this context, antithrombin (AT) supplementation might further modify TEG. METHODS: This is a pre-specified sub-study of the "Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation" study (investigator-initiated, randomized, single-blind, two-arm trial) conducted in two Italian ECMO referral ICUs. Adult patients requiring vv-ECMO for respiratory failure and undergoing unfractioned heparin (UFH) administration were enrolled and randomized whether to receive AT supplementation. Plasma samples for cytokine assay (IL-8, IL-10, IL-6, IL-1ß, TNF-α and Pro-ADM) and heparinase TEG were collected from every patient before ECMO start, 24 h and 72 h after ECMO start, before ECMO removal, and 7 days after ECMO removal or upon ICU discharge whichever happened first. AT concentration, coagulation and clinical data were collected before ECMO start and at pre-fixed time points. RESULTS: Thirty-nine patients were enrolled (21 treatments, 18 controls). TEG-R had a weak-to-moderate positive correlation with IL-8, IL-6, IL-10 and TNF-α and a moderate positive correlation with Pro-ADM. TEG-ANG showed a weak negative correlation with IL-8, IL-6 and TNF-α, while TEG-MA negatively correlated with IL-8, TNF-α and Pro-ADM. AT supplementation seemed to modify the association between TEG-MA and IL-8, IL-10 and Pro-ADM; conversely, AT did not affect the relationship among TEG-R or TEG-ANG and the studied cytokines. CONCLUSIONS: High concentrations of systemic cytokines correlated with longer reaction times and decreased angle and amplitude at TEG, suggesting that an increase in inflammation is related with hypocoagulability as revealed by thromboelastography.

Lung donor bronchoalveolar lavage positivity: Incidence, risk factors, and lung transplant recipients' outcome.

BACKGROUND: Inconsistent data exists regarding the risk factors for bronchoalveolar lavage (BAL) positivity in lung donors, the incidence of donor-derived infections (DDI), and the effect of BAL positivity on lung transplant (LuTx) recipients' outcome. METHODS: A retrospective analysis was conducted on consecutive LuTx at a single center from January 2016 to December 2022. Donors' data, including characteristics, graft function and BAL samples were collected pre-procurement. Recipients underwent BAL before LuTx and about the 3rd, 7th and 14th day after LuTx. A DDI was defined as BAL positivity (bacterial growth ≥104 colony forming units) for identical bacterial species between donor and recipient. Recipients' pre-operative characteristics, intra-operative management, and post-operative outcomes were assessed. Two recipient cohorts were identified based on lung colonization status before undergoing LuTx. RESULTS: Out of 188 LuTx procedures performed, 169 were analyzed. Thirty-six percent of donors' BAL tested positive. Donors' characteristics and graft function at procurement were not associated with BAL positivity. Fourteen DDI were detected accounting for 23% of recipients receiving a graft with a positive BAL. Only among uncolonized recipients, receiving a graft with positive BAL is associated with higher likelihood of requiring invasive ventilation at 72 hours after LuTx on higher positive end-expiratory pressure levels having lower PaO2/FiO2, prolonged duration of mechanical ventilation and longer ICU stay. No difference in hospital length of stay was observed. CONCLUSIONS: Receiving a graft with a positive BAL, which is poorly predicted by donors' characteristics, carries the risk of developing a DDI and is associated to a worse early graft function among uncolonized recipients.

Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Portal hypertension-like pattern in coronavirus disease 2019 acute respiratory distress syndrome.

OBJECTIVES: Although respiratory failure is the most common feature in coronavirus disease 2019 (COVID-19), abdominal organ involvement is likewise frequently observed. To investigate visceral and thoracic circulation and abdominal organ damage in COVID-19 patients. MATERIALS AND METHODS: A monocentric observational study was carried on. In COVID-19 patients affected by acute respiratory distress syndrome (ARDS) (n = 31) or mild pneumonia (n = 60) thoracoabdominal circulation was evaluated using Doppler-ultrasound and computed tomography. The study also included non-COVID-19 patients affected by ARDS (n = 10) or portal hypertension (n = 10) for comparison of the main circulatory changes. RESULTS: Patients affected by COVID-19 ARDS showed hyperdynamic visceral flow and increased portal velocity, hepatic artery resistance-index, and spleen diameter relative to those with mild-pneumonia (p = 0.001). Splanchnic circulatory parameters significantly correlated with the main respiratory indexes (p < 0.001) and pulmonary artery diameter (p = 0.02). The chest and abdominal vascular remodeling pattern of COVID-19 ARDS patients resembled the picture observed in the PH group, while differed from that of the non-COVID ARDS group. A more severe COVID-19 presentation was associated with worse liver dysfunction and enhanced inflammatory activation; these parameters both correlated with abdominal (p = 0.04) and chest imaging measures (p = 0.03). CONCLUSION: In COVID-19 ARDS patients there are abdominal and lung vascular modifications that depict a portal hypertension-like pattern. The correlation between visceral vascular remodeling, pulmonary artery enlargement, and organ damage in these critically ill patients is consistent with a portal hyperlfow-like syndrome that could contribute to the peculiar characteristics of respiratory failure in these patients. CLINICAL RELEVANCE STATEMENT: our data suggest that the severity of COVID-19 lung involvement is directly related to the development of a portal hyperflow-like syndrome. These observations should help in defining the need for a closer monitoring, but also to develop dedicated therapeutic strategies.

Physiologic Effects of ECMO in Patients with Severe Acute Respiratory Distress Syndrome.

RATIONALE: Blood flow rate affects mixed venous oxygenation (SvO2) during venovenous extracorporeal membrane oxygenation (ECMO), with possible effects on the pulmonary circulation and the right heart function. OBJECTIVES: We aimed at describing the physiologic effects of different levels of SvO2 obtained by changing ECMO blood flow, in patients with severe ARDS receiving ECMO and controlled mechanical ventilation. METHODS: Low (SvO2 target 70-75%), intermediate (SvO2 target 75-80%) and high (SvO2 target > 80%) ECMO blood flows were applied for 30 minutes in random order in 20 patients. Mechanical ventilation settings were left unchanged. The hemodynamic and pulmonary effects were assessed with pulmonary artery catheter and electrical impedance tomography (EIT). MEASUREMENTS AND MAIN RESULTS: Cardiac output decreased from low to intermediate and to high blood flow/SvO2 (9.2 [6.2-10.9] vs 8.3 [5.9-9.8] vs 7.9 [6.5-9.1] L/min, p = 0.014), as well as mean pulmonary artery pressure (34 ± 6 vs 31 ± 6 vs 30 ± 5 mmHg, p < 0.001), and right ventricle stroke work index (14.2 ± 4.4 vs 12.2 ± 3.6 vs 11.4 ± 3.2 g*m/beat/m2, p = 0.002). Cardiac output was inversely correlated with mixed venous and arterial PO2 values (R2 = 0.257, p = 0.031 and R2 = 0.324, p = 0.05). Pulmonary artery pressure was correlated with decreasing mixed venous PO2 (R2 = 0.29, p <0.001) and with increasing cardiac output (R2 = 0.378 p < 0.007). Measures of ventilation/perfusion mismatch did not differ between the three steps. CONCLUSIONS: In severe ARDS patients, increased ECMO blood flow rate resulting in higher SvO2 decreases pulmonary artery pressure, cardiac output, and right heart workload. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society (ERS) and the European Society of Intensive Care Medicine (ESICM). Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVES: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN: Retrospective observational cohort study. SETTING: Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS: Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society and the European Society of Intensive Care Medicine. Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Transthoracic impedance variability to assess quality of chest compression in out-of-hospital cardiac arrest.

BACKGROUND: Chest compression is a lifesaving intervention in out-of-hospital cardiac arrest (OHCA), but the optimal metrics to assess its quality have yet to be identified. The objective of this study was to investigate whether a new parameter, that is, the variability of the chest compression-generated transthoracic impedance (TTI), namely ImpCC , which measures the consistency of the chest compression maneuver, relates to resuscitation outcome. METHODS: This multicenter observational, retrospective study included OHCAs with shockable rhythm. ImpCC variability was evaluated with the power spectral density analysis of the TTI. Multivariate regression model was used to examine the impact of ImpCC variability on defibrillation success. Secondary outcome measures were return of spontaneous circulation and survival. RESULTS: Among 835 treated OHCAs, 680 met inclusion criteria and 565 matched long-term outcomes. ImpCC was significantly higher in patients with unsuccessful defibrillation compared to those with successful defibrillation (p = .0002). Lower ImpCC variability was associated with successful defibrillation with an odds ratio (OR) of 0.993 (95% confidence interval [95% CI], 0.989-0.998, p = .003), while the standard chest compression fraction (CCF) was not associated (OR 1.008 [95 % CI, 0.992-1.026, p = .33]). Neither ImpCC nor CCF was associated with long-term outcomes. CONCLUSIONS: In this population, consistency of chest compression maneuver, measured by variability in TTI, was an independent predictor of defibrillation outcome. ImpCC may be a useful novel metrics for improving quality of care in OHCA.

Regional Ventilation-Perfusion Matching by Electrical Impedance Tomography After Single Lung Transplant.

Single lung transplantation (LUTX) can be the last therapeutic option for a growing cohort of patients suffering from end-stage respiratory failure. Postoperative ventilatory management of single LUTX recipients is challenged by the coexistence of the diseased native lung and a healthy-but fragile-graft. In this case report, in a single LUTX recipient with idiopathic pulmonary fibrosis, regional ventilation ( ), perfusion ( ), and / matching and subsequent measurement of shunt fraction ( Qs / Qt ) and alveolar dead space ( Vd / Vt ) were obtained by integrating electrical impedance tomography (EIT) with volumetric capnography and pulmonary thermodilution technique. Although the preoperative pulmonary scintigraphy showed predominant right lung perfusion (79.8% vs. 20.2%), the EIT documented the postoperative re-establishment of between the lungs (demonstrating the adequate functioning of vascular anastomoses), the diversion of to the graft and similar global Qs / Qt (17%) and Vd / Vt (29%) between native and graft lung. Electrical impedance tomography mapping allowed regional Qs / Qt and Vd / Vt assessment: the native right lung had a completely deranged distribution of and ( Qs / Qt 25%, Vd / Vt 46%), whereas the graft showed normal coupling of and ( Qs / Qt 8%, Vd / Vt 12%). Electrical impedance tomography may allow noninvasive, repeatable, bedside assessments of the lung / coupling after single LUTX.

Anticoagulation and Bleeding during Veno-Venous Extracorporeal Membrane Oxygenation: Insights from the PROTECMO Study.

Rationale: Definitive guidelines for anticoagulation management during veno-venous extracorporeal membrane oxygenation (VV ECMO) are lacking, whereas bleeding complications continue to pose major challenges. Objectives: To describe anticoagulation modalities and bleeding events in adults receiving VV ECMO. Methods: This was an international prospective observational study in 41 centers, from December 2018 to February 2021. Anticoagulation was recorded daily in terms of type, dosage, and monitoring strategy. Bleeding events were reported according to site, severity, and impact on mortality. Measurements and Main Results: The study cohort included 652 patients, and 8,471 days on ECMO were analyzed. Unfractionated heparin was the initial anticoagulant in 77% of patients, and the most frequently used anticoagulant during the ECMO course (6,221 d; 73%). Activated partial thromboplastin time (aPTT) was the most common test for monitoring coagulation (86% of days): the median value was 52 seconds (interquartile range, 39 to 61 s) but dropped by 5.3 seconds after the first bleeding event (95% confidence interval, -7.4 to -3.2; P < 0.01). Bleeding occurred on 1,202 days (16.5%). Overall, 342 patients (52.5%) experienced at least one bleeding event (one episode every 215 h on ECMO), of which 10 (1.6%) were fatal. In a multiple penalized Cox proportional hazard model, higher aPTT was a potentially modifiable risk factor for the first episode of bleeding (for 20-s increase; hazard ratio, 1.07). Conclusions: Anticoagulation during VV ECMO was a dynamic process, with frequent stopping in cases of bleeding and restart according to the clinical picture. Future studies might explore lower aPTT targets to reduce the risk of bleeding.