Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury.

BACKGROUND: The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS: HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS: The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS: Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.

Rapidly improving acute respiratory distress syndrome in COVID-19: a multi-centre observational study.

BACKGROUND: Before the pandemic of coronavirus disease (COVID-19), rapidly improving acute respiratory distress syndrome (ARDS), mostly defined by early extubation, had been recognized as an increasingly prevalent subphenotype (making up 15-24% of all ARDS cases), associated with good prognosis (10% mortality in ARDSNet trials). We attempted to determine the prevalence and prognosis of rapidly improving ARDS and of persistent severe ARDS related to COVID-19. METHODS: We included consecutive patients with COVID-19 receiving invasive mechanical ventilation in three intensive care units (ICU) during the second pandemic wave in Greece. We defined rapidly improving ARDS as extubation or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO2:FiO2 of equal to or less than 100 on the second day following intubation. RESULTS: A total of 280 intubated patients met criteria of ARDS with a median PaO2:FiO2 of 125.0 (interquartile range 93.0-161.0) on day of intubation, and overall ICU-mortality of 52.5% (ranging from 24.3 to 66.9% across the three participating sites). Prevalence of rapidly improving ARDS was 3.9% (11 of 280 patients); no extubation occurred on the first day following intubation. ICU-mortality of patients with rapidly improving ARDS was 54.5%. This low prevalence and high mortality rate of rapidly improving ARDS were consistent across participating sites. Prevalence of persistent severe ARDS was 12.1% and corresponding mortality was 82.4%. CONCLUSIONS: Rapidly improving ARDS was not prevalent and was not associated with good prognosis among patients with COVID-19. This is starkly different from what has been previously reported for patients with ARDS not related to COVID-19. Our results on both rapidly improving ARDS and persistent severe ARDS may contribute to our understanding of trajectory of ARDS and its association with prognosis in patients with COVID-19.

Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients With COVID-19: An Observational Study and Subsequent Meta-Analysis.

BACKGROUND: Whether vitamin C provides any benefit when administered in critically ill patients, including those with coronavirus disease (COVID-19), is controversial. We endeavored to estimate the effect of administration of vitamin C on clinical outcomes of critically ill patients with COVID-19 by performing an observational study and subsequent meta-analysis. METHODS: Firstly, we conducted an observational study of critically ill patients with laboratory-confirmed COVID-19 who consecutively underwent invasive mechanical ventilation in an academic intensive care unit (ICU) during the second pandemic wave. We compared all-cause mortality of patients receiving vitamin C ("vitamin C" group) or not ("control" group) on top of standard-of-care. Subsequently, we systematically searched PubMed and CENTRAL for relevant studies, which reported on all-cause mortality (primary outcome) and/or morbidity of critically ill patients with COVID-19 receiving vitamin C or not treatment. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO. RESULTS: In the observational study, baseline characteristics were comparable between the two groups. Mortality was 20.0% (2/10) in the vitamin C group vs. 47.6% (49/103; p = 0.11) in the control group. Subsequently, the meta-analysis included 11 studies (6 observational; five randomized controlled trials) enrolling 1,807 critically ill patients with COVID-19. Mortality of patients receiving vitamin C on top of standard-of-care was not lower than patients receiving standard-of-care alone (25.8 vs. 34.7%; RR 0.85, 95% CI 0.57-1.26; p = 0.42). CONCLUSIONS: After combining results of our observational cohort with those of relevant studies into a meta-analysis of data from 1,807 patients, we found that administration vitamin C as opposed to standard-of-care alone might not be associated with lower of mortality among critically ill patients with COVID-19. Additional evidence is anticipated from relevant large randomized controlled trials which are currently underway. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021276655.

Description of a Recovery Model in Rabbits for the Study of the Late Phase of Liver Ischemia-Reperfusion Injury.

AIM: Description of an anesthetic recovery model with endotracheal intubation in rabbits which provides metabolic stability for the study of the late phase of liver ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: Two groups of New Zealand rabbits, n=7 in each, were used: Ischemia/reperfusion (I/R) group (45 min of partial liver ischemia/reperfusion) and no intervention (sham) group. Blood alanine aminotransferase, lactate, pH values, mean arterial pressure and pCO2 were calculated at baseline, and at 2 and 24 h post reperfusion. Tissue samples from left (ischemic) and right (non-ischemic) liver lobes were examined at 2 and 24 h after reperfusion. RESULTS: The I/R group presented significantly higher levels of alanine aminotransferase (p=0.001) at 2 and 24 h, and of lactate (p=0.016) at 2 h post reperfusion. No differences were documented for pH, mean arterial pressure and pCO2 Histological exanimation revealed significant injury at 24 h post reperfusion for the I/R group. CONCLUSION: This anesthetic recovery model permitted avoidance of hypoxia and respiratory acidosis, allowing the study of the late phase of I/R injury.

Elderly adults with COVID-19 admitted to intensive care unit: A narrative review.

BACKGROUND: In the context of the Coronavirus disease 2019 (COVID-19) pandemic, it has been reported that elderly patients are particularly at risk of developing severe illness and exhibiting increased mortality. While many studies on hospitalized elderly patients with COVID-19 have been published, limited information is available on the characteristics and clinical outcomes of those elderly patients admitted to intensive care unit (ICU). AIM: To review the available evidence of the clinical data of elderly patients admitted to the ICU due to COVID-19. METHODS: We searched for published articles available in English literature to identify those studies conducted in critically ill patients admitted to the ICU due to COVID-19, either exclusively designed for the elderly or for the whole ICU population with COVID-19, provided that analyses according to the patients' age had been conducted. RESULTS: Only one study exclusively focusing on critically ill elderly patients admitted to the ICU due to COVID-19 was found. Eighteen additional studies involving 17011 ICU patients and providing information for elderly patients as a subset of the whole study population have also been included in the present review article. Among the whole patient population, included in these studies, 8310 patients were older than 65 years of age and 2630 patients were older than 70 years. Clinical manifestations were similar for all patients; however, compared to younger ones, they suffered from more comorbidities and showed a varied, albeit high mortality. CONCLUSION: In summary, at present, although elderly patients constitute a considerable proportion of critically ill patients admitted to the ICU due to severe COVID-19, studies providing specific information are limited. The evidence so far suggests that advanced age and comorbidities are associated with worse clinical outcome. Future studies exclusively designed for this vulnerable group are needed.

Does Route of Full Feeding Affect Outcome among Ventilated Critically Ill COVID-19 Patients: A Prospective Observational Study.

The outbreak of the new coronavirus strain SARS-CoV-2 (COVID-19) highlighted the need for appropriate feeding practices among critically ill patients admitted to the intensive care unit (ICU). This study aimed to describe feeding practices of intubated COVID-19 patients during their second week of hospitalization in the First Department of Critical Care Medicine, Evaggelismos General Hospital, and evaluate potential associations with all cause 30-day mortality, length of hospital stay, and duration of mechanical ventilation. We enrolled adult intubated COVID-19 patients admitted to the ICU between September 2020 and July 2021 and prospectively monitored until their hospital discharge. Of the 162 patients analyzed (52.8% men, 51.6% overweight/obese, mean age 63.2 ± 11.9 years), 27.2% of patients used parenteral nutrition, while the rest were fed enterally. By 30 days, 34.2% of the patients in the parenteral group had died compared to 32.7% of the patients in the enteral group (relative risk (RR) for the group receiving enteral nutrition = 0.97, 95% confidence interval = 0.88-1.06, p = 0.120). Those in the enteral group demonstrated a lower duration of hospital stay (RR = 0.91, 95% CI = 0.85-0.97, p = 0.036) as well as mechanical ventilation support (RR = 0.94, 95% CI = 0.89-0.99, p = 0.043). Enteral feeding during second week of ICU hospitalization may be associated with a shorter duration of hospitalization and stay in mechanical ventilation support among critically ill intubated patients with COVID-19.