The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis.

Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein-DNA interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis and COVID-19, this reduction is primarily attributed to a redistribution process associated with the inflammatory response. In this response, hepatic metallothionein production increases in reaction to cytokine release, which is linked to inflammation, and this protein effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc levels are associated with increasing severity of organ dysfunction, prolonged hospital stay and increased mortality in septic and COVID-19 patients. Results of recent studies focusing on these topics are summarized and discussed in this narrative review. Existing evidence currently does not support pharmacological zinc supplementation in patients with sepsis or COVID-19. Complementation and repletion should follow current guidelines for micronutrients in critically ill patients. Further research investigating the pharmacological mechanism of zinc in programmed cell death caused by invasive infections and its therapeutic potential in sepsis and COVID-19 could be worthwhile.

Severe and Atypical Presentation of Takotsubo Cardiomyopathy in a Pediatric Patient after a Serious Crash Injury-Case Report and Literature Review.

Takotsubo cardiomyopathy is an uncommon clinical entity in children, resulting in severe but sometimes reversible systolic dysfunction of the left ventricle. This condition is triggered by multiple emotional or physical stressors, while neurogenic stress cardiomyopathy after brain injuries has become increasingly recognized in children over the past few years. We report the case of an 11-year-old child with an atypical clinical presentation after a serious car crash accident. An initial computed tomography scan revealed an acute epidural hematoma, which was immediately treated by an emergency craniotomy. During the patient's following pediatric intensive care unit hospitalization, severe hemodynamic instability was observed, leading to gradually higher doses of vasopressors for circulatory support. On echocardiography, the patient had signs of severe cardiac contractility compromise, with characteristic pattern of regional wall motion abnormalities of the left ventricle, which, in combination with seriously elevated cardiac enzymes, electrocardiographic (ECG) abnormalities and continuous thermodilution hemodynamic monitoring (PICCO) findings, led to intensification of inotropic support and to the diagnosis of takotsubo cardiomyopathy. Despite supportive measures, the patient developed multiorgan failure and succumbed to their serious illness. For this atypical case, extracorporeal membrane oxygenation (ECMO) was addressed as an option for the seriously failing heart, but due to the extremely high risk of intracranial bleeding, it could not be used for this patient's treatment. In conclusion, Takotsubo cardiomyopathy should be suspected in pediatric cases of cardiac dysfunction after serious injuries or stress conditions.

Inflammation biomarkers IL­6 and IL­10 may improve the diagnostic and prognostic accuracy of currently authorized traumatic brain injury tools.

Traumatic brain injury (TBI) is currently one of the leading causes of mortality and disability worldwide. At present, no reliable inflammatory or specific molecular neurobiomarker exists in any of the standard models proposed for TBI classification or prognostication. Therefore, the present study was designed to assess the value of a group of inflammatory mediators for evaluating acute TBI, in combination with clinical, laboratory and radiological indices and prognostic clinical scales. In the present single-centre, prospective observational study, 109 adult patients with TBI, 20 adult healthy controls and a pilot group of 17 paediatric patients with TBI from a Neurosurgical Department and two intensive care units of University General Hospital of Heraklion, Greece were recruited. Blood measurements using the ELISA method, of cytokines IL-6, IL-8 and IL-10, ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein, were performed. Compared with those in healthy control individuals, elevated IL-6 and IL-10 but reduced levels of IL-8 were found on day 1 in adult patients with TBI. In terms of TBI severity classifications, higher levels of IL-6 (P=0.001) and IL-10 (P=0.009) on day 1 in the adult group were found to be associated with more severe TBI according to widely used clinical and functional scales. Moreover, elevated IL-6 and IL-10 in adults were found to be associated with more serious brain imaging findings (rs<0.442; P<0.007). Subsequent multivariate logistic regression analysis in adults revealed that early-measured (day 1) IL-6 [odds ratio (OR)=0.987; P=0.025] and UCH-L1 (OR=0.993; P=0.032) are significant independent predictors of an unfavourable outcome. In conclusion, results from the present study suggest that inflammatory molecular biomarkers may prove to be valuable diagnostic and prognostic tools for TBI.

Impact of Intracranial Hypertension on Outcome of Severe Traumatic Brain Injury Pediatric Patients: A 15-Year Single Center Experience.

Background: Intracranial hypertension (IC-HTN) is significantly associated with higher risk for an unfavorable outcome in pediatric trauma. Intracranial pressure (ICP) monitoring is widely becoming a standard of neurocritical care for children. Methods: The present study was designed to evaluate influences of IC-HTN on clinical outcomes of pediatric TBI patients. Demographic, injury severity, radiologic characteristics were used as possible predictors of IC-HTN or of functional outcome. Results: A total of 118 pediatric intensive care unit (PICU) patients with severe TBI (sTBI) were included. Among sTBI cases, patients with GCS < 5 had significantly higher risk for IC-HTN and for mortality. Moreover, there was a statistically significant positive correlation between IC-HTN and severity scoring systems. Kaplan−Meier analysis determined a significant difference for good recovery among patients who had no ICP elevations, compared to those who had at least one episode of IC-HTN (log-rank chi-square = 11.16, p = 0.001). A multivariable predictive logistic regression analysis distinguished the ICP-monitored patients at risk for developing IC-HTN. The model finally revealed that higher ISS and Helsinki CT score increased the odds for developing IC-HTN (p < 0.05). Conclusion: The present study highlights the importance of ICP-guided clinical practices, which may lead to increasing percentages of good recovery for children.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

Survivin and caspases serum protein levels and survivin variants mRNA expression in sepsis.

Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases' responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n = 107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n = 75) and to healthy controls (n = 89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ΔEx3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -ΔΕx3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p < 0.05). Survivin correlated with IL-8 and caspase-9 (p < 0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.

Longitudinal PEEP Responses Differ Between Children With ARDS and at Risk for ARDS.

BACKGROUND: It is unknown whether lung mechanics differ between patients with pediatric ARDS and at risk for ARDS. We aimed to examine the hypothesis that, compared to ARDS, subjects at risk of ARDS are characterized by higher end-expiratory lung volume (EELV) or respiratory system compliance (CRS) and lower distending pressure (stress) applied on the lung or parenchymal deformation (strain) during mechanical ventilation. METHODS: Consecutively admitted subjects fulfilling the PALICC ARDS criteria were considered eligible for inclusion in this study. A ventilator with an integrated gas exchange module was used to calculate EELV, CRS, strain, and stress after a steady state had been achieved based on nitrogen washout/washin technique. All subjects were subjected to incremental PEEP trials at 0, 6, 12, 24, 48, and 72 h. RESULTS: A total of 896 measurements were longitudinally calculated in 32 mechanically ventilated subjects (n = 15 subjects with ARDS; n = 17 subjects at risk for ARDS). EELV correlated positively with strain or stress in the ARDS group (r = 0.30, P < .001) and the at risk group (r = 0.60, P < .001). CRS correlated with strain (r = 0.40, P < .001) only in subjects at risk for ARDS. EELV increased over time as PEEP rose from 4 to 10 cm H2O in subjects with ARDS (P = .001). In the at risk group, EELV only increased at 48 h (P = .001). Longitudinally, CRS (P = .001) and EELV (P = .002) were lower and strain and stress were higher in subjects with ARDS compared to those at risk for ARDS (P = .002), remaining within safe limits. Strain and stress increased by 24 h but declined by 72 h in subjects with ARDS at a PEEP of 4 cm H2O (P = .02). In the at risk group, strain and stress declined from 6 h to 72 h at a PEEP of 10 cm H2O (P = .001). CONCLUSIONS: Longitudinally, CRS and EELV were lower and strain and stress were higher in subjects with ARDS compared to subjects at risk for ARDS. These parameters behaved differently over time at PEEP values of 4 or 10 cm H2O. At these PEEP levels, strain and stress remained within safe limits in both groups.

Central line-associated bloodstream infection in childhood malignancy: Single-center experience.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a common complication in children with malignancy, often leading to prolonged hospitalization, delay in chemotherapy or catheter removal. This retrospective epidemiological study reviewed 91 children with malignancy over a 5 year period between 2011 and 2015 and analyzed potential risk factors for CLABSI. METHODS: Symptoms, laboratory and microbiology characteristics, subsequent treatment and outcome were recorded and analyzed. All the collected data were processed through SPSS for statistical analysis. RESULTS: Among 40 episodes of CLABSI recorded in 30 patients, the rate of CLABSI was estimated as 2.62 episodes per 1,000 days of central venous catheter (CVC) carriage. Most of the bacterial pathogens isolated in CLABSI episodes were Gram positive, including different strains of staphylococci, while Gram-negative bacteria were involved in 30% of episodes. Invasive mycosis was isolated in 7.5% of episodes, accounting for the highest catheter removal rate. Intensive chemotherapy and prolonged hospitalization proved to be independent risk factors for CVC infection. In children with neutropenia, the risk for CLABSI was also fourfold greater (P = 0.001). Children with leukemia had a fivefold greater risk for CLABSI (P = 0.005). Finally, although 36% of patients received antibiotic lock therapy, in 15% of these patients catheter replacement could not be avoided due to persistent serious infection. CONCLUSIONS: Younger age, neutropenia, hematologic malignancy and longer catheterization are important risk factors for CLABSI, but further research is required for the prevention of catheter-related infection in children with malignancy.