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.

The Impact of Estimated Energy and Protein Balances on Extrauterine Growth in Preterm Infants.

BACKGROUND: Nutritional support of preterm infants remains a field of debate in the literature and clinical practice varies significantly. Adequate nutrition should promote growth and aim for optimal later neurodevelopment. However, it is often impaired by prematurity-associated morbidity and the physiologic immaturity of preterm infants. This study assessed the impact of energy and macronutrient provision on growth velocity and outcome and explored differences attributed to the heterogeneity of the preterm population. METHODS: We retrospectively collected clinical and nutritional data from neonates hospitalized in two separate Neonatal Intensive Care Units (NICUs). Estimated energy and protein balance were calculated based on the ESPGHAN guidelines and their association with the growth outcome was explored. Growth assessment was based on somatometry Delta (Δ) z-scores at discharge. RESULTS: In total, 174 neonates were included in the study. By day 14, most preterm infants were exclusively enterally fed, whereas there were infants in the <28 and 28-31+6 subgroups fed exclusively parenterally. Energy balance was positive for all gestational age (GA) subgroups except for those born <28 weeks. Protein balance was consistently positive for extremely premature but negative for late preterms. Cumulative substrates provisions were strong predictors of a positive energy or protein balance in the <34 weeks GA preterms on days 14 (ROC analyses, p < 0.001) and 7 (p < 0.05). A higher GA (p = 0.013) and enteral nutrition (p = 0.005) were additional predictors of a positive energy balance. All GA subgroups had a negative Δ z-score of weight at discharge. In the <34 GA subcohorts, a positive protein balance on day 14 (p = 0.009) and a short time to regain birth weight (exp(B) 3.1 (p = 0.004)) were independently associated with a positive Δ z-score of weight at discharge. CONCLUSIONS: Early achievement of a positive energy and protein balance, based on the ESPGHAN guidelines, is crucial to ensure optimal postnatal growth and prevent extrauterine growth restriction, a relatively common occurrence in preterm infants.

Suicidality Prevalence in a Pediatric Psychiatric Clinic: Relation to Social and Environmental Risk Factors.

Suicidality is a growing public health problem in children and adolescents. The aim of this retrospective data analysis study was to estimate the prevalence of suicidality in pediatric patients admitted to an academic Pediatric Psychiatric Clinic (PPC) and to analyze social and environmental risk factors associated with suicide. Suicidal ideation was assessed by the Self-Injurious Thoughts and Behaviors Interview. Using established psychometric scales, social and stressful events were analyzed. During the four-year study, 249 episodes of care were experienced by 152 individuals (mean age 15.2 ± 2 years, girls/boys 107/45). Twenty-eight patients (11.2%) were admitted from the Pediatric Intensive Care Unit and the Department of Pediatrics, 162 (65.1%) from the Pediatric Emergency Department, and 59 (23.7%) from other Hospitals (p = 0.003). A significant longitudinal increase in admissions to PPC, with increasing trends of suicidal ideation, suicide attempts, and suicidality, was recorded. Suicidal behavior, bullying, internet addiction, friends quarreling, and family problems were risk factors for suicide attempts and suicidality. Our results have implications for prevention programs, highlighting an increasing need for care for suicide attempts and suicidal ideation, related to specific stressful events and contextual socio-environmental status.

Point of care transthoracic echocardiography for the prediction of post - spinal anesthesia hypotension in elderly patients with cardiac diseases and left ventricular dysfunction : Inferior vena cava and post-spinal anesthesia hypotension in elderly patients.

In elderly patients with cardiac diseases, changes in cardiovascular physiology diminish cardiovascular reserve and predispose to hemodynamic instability after spinal anesthesia; hence, such patients could be at risk of postoperative complications. Additionally, transthoracic echocardiography (TTE) is used in clinical practice to evaluate cardiovascular hemodynamics. Therefore, we hypothesized that echocardiographic measurements could display significant diagnostic power in the prediction of post - spinal anesthesia hypotension in elderly patients with cardiac diseases and reduced left ventricular ejection fraction (LV-EF). Therefore, sixty-one elderly orthopedic-trauma patients were recruited. Prior to spinal anesthesia a TTE examination was performed. The LV-EF, the stroke volume index (SVI), the peripheral vascular resistance (PVR), the LV filling pressures (E/Em ratio), the right ventricular function [tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TASV) and fractional area change (FAC)], as well as inferior vena cava (IVC) measurements, such as IVCCI (collapsibility index of the IVC) and dIVCmax (maximum diameter of IVC)-to-IVCCI ratio were assessed. Twenty-six out of sixty-one patients manifested hypotension. Preoperative dIVCmax-to-IVCCI ratio demonstrated the greatest performance amongst echocardiographic indices in predicting post - spinal anesthesia hypotension. The dIVCmax-to-IVCCI ratio < 48 had significantly higher diagnostic power than IVCCI > 0.28, FAC > 42, E/Em ratio < 9 and SVI < 32 (receiver operator characteristic curve analysis). The gray zone for the dIVCmax-to-IVCCI ratio (40-49) showed the lowest number of inconclusive measurements among echocardiographic variables. The preoperative dIVCmax-to-IVCCI ratio could be a reliable echocardiographic index to predict post - spinal anesthesia hypotension in elderly patients with left ventricular dysfunction.

Ex Vivo Evaluation of Glutamine Treatment in Sepsis and Trauma in a Human Peripheral Blood Mononuclear Cells Model.

We aimed to assess the lipopolysaccharide (LPS), or heat shock (HS) induction, and glutamine-modulating effects on heat shock protein-90α (HSP90α) and cytokines in an ex vivo model using peripheral blood mononuclear cells (PBMCs). The PBMCs of patients with septic shock, trauma-related systemic inflammatory response syndrome (SIRS), and healthy subjects were incubated with 1 µg/mL LPS at 43 °C (HS). Glutamine 10 mM was added 1 hour before or after induction or not at all. We measured mRNA HSP90α, monocyte (m) and lymphocyte (l) HSP90α proteins, interleukin (IL)-1b, -6, -8, -10, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) supernatant levels. Heat shock increased the HSP90α mRNA and mHSP90α in all groups (10-fold in sepsis, p < 0.001 and p = 0.047, respectively). LPS induced the mHSP90α and lHSP90α in healthy (p < 0.001) and mHSP90α in SIRS (p = 0.004) but not in sepsis. LPS induced the cytokines at 24 and 48 h in all groups, especially in trauma (p < 0.001); HS only induced the IL-8 in healthy (p = 0.003) and septic subjects (p = 0.05). Glutamine at 10 mM before or after stimulation did not alter any induction effect of LPS or HS on HSP90α mRNA and mHSP90α protein in sepsis. In SIRS, glutamine before LPS decreased the mHSP90α but increased it when given after HS (p = 0.018). Before or after LPS (p = 0.049) and before HS (p = 0.018), glutamine decreased the lHSP90α expression in sepsis but increased it in SIRS when given after HS (p = 0.003). Regarding cytokines, glutamine enhanced the LPS-induced MCP-1 at 48 h in healthy (p = 0.011), SIRS (p < 0.001), and sepsis (p = 0.006). In conclusion, glutamine at 10 mM, before or after LPS and HS, modulates mHSP90α and lHSP90α in sepsis and SIRS differently and unpredictably. Although it does not alter the stimulation effect on interleukins, glutamine enhances the LPS induction effect on supernatant MCP-1 in all groups. Future research should seek to elucidate better the impact of glutamine and temperature modulation on HSP90α and MCP-1 pathways in sepsis and trauma.

External Validation of Equations to Estimate Resting Energy Expenditure in Critically Ill Children and Adolescents with and without Malnutrition: A Cross-Sectional Study.

We evaluated the validity of sixteen predictive energy expenditure equations for resting energy expenditure estimation (eREE) against measured resting energy expenditure using indirect calorimetry (REEIC) in 153 critically ill children. Predictive equations were included based on weight, height, sex, and age. The agreement between eREE and REEIC was analyzed using the Bland−Altman method. Precision was defined by the 95% limits of the agreement; differences > ±10% from REEIC were considered clinically unacceptable. The reliability was assessed by the intraclass correlation coefficient (Cronbach's alpha). The influence of anthropometric, nutritional, and clinical variables on REEIC was also assessed. Thirty (19.6%) of the 153 enrolled patients were malnourished (19.6%), and fifty-four were overweight (10.5%) or obese (24.8%). All patients received sedation and analgesia. Mortality was 3.9%. The calculated eREE either underestimated (median 606, IQR 512; 784 kcal/day) or overestimated (1126.6, 929; 1340 kcal/day) REEIC compared with indirect calorimetry (928.3, 651; 1239 kcal/day). These differences resulted in significant biases of −342 to 592 kcal (95% limits of agreement (precision)−1107 to 1380 kcal/day) and high coefficients of variation (up to 1242%). Although predicted equations exhibited moderate reliability, the clinically acceptable ±10% accuracy rate ranged from only 6.5% to a maximum of 24.2%, with the inaccuracy varying from −31% to +71.5% of the measured patient's energy needs. REEIC (p = 0.017) and eREE (p < 0.001) were higher in the underweight compared to overweight and obese patients. Apart from a younger age, malnutrition, clinical characteristics, temperature, vasoactive drugs, neuromuscular blockade, and energy intake did not affect REEIC and thereby predictive equations' accuracy. Commonly used predictive equations for calculating energy needs are inaccurate for individual patients, either underestimating or overestimating REEIC compared with indirect calorimetry. Altogether these findings underscore the urgency for measuring REEIC in clinical situations where accurate knowledge of energy needs is vital.

External Validation with Accuracy Confounders of VCO2-Derived Predicted Energy Expenditure Compared to Resting Energy Expenditure Measured by Indirect Calorimetry in Mechanically Ventilated Children.

Optimal energy provision, guided by measured resting energy expenditure (REE) and determined by indirect calorimetry (IC), is fundamental in Intensive Care Units (ICU). Because IC availability is limited, methods to predict REE based on carbon dioxide production (VCO2) measurements (REEVCO2) alone have been proposed as a surrogate for REE measured by IC (REEIC). The study aimed at externally and internally validating the accuracy of the REEVCO2 as an alternative to REEIC in mechanically ventilated children. A ventilator's integrated gas exchange module (E-COVX) was used to prospectively measure REEIC and predict REEVCO2 on 107 mechanically ventilated children during the first 24 h of admission. The accuracy of the REEVCO2 compared to REEIC was assessed through the calculation of bias and precision, paired median differences, linear regression, and ROC analysis. Accuracy within ±10% of the REEIC was deemed acceptable for the REEVCO2 equation. The calculated REEVCO2 based on respiratory quotient (RQ) 0.89 resulted in a mean bias of −72.7 kcal/day (95% limits of agreement −321.7 to 176.3 kcal/day) and a high coefficient of variation (174.7%), while 51.4% of the calculations fell outside the ±10% accuracy rate. REEVCO2 derived from RQ 0.80 or 0.85 did not improve accuracy. Only measured RQ (Beta 0.73, p < 0.001) and no-recorded neuromuscular blocking agents (Beta −0.13, p = 0.044) were independently associated with the REEVCO2−REEIC difference. Among the recorded anthropometric, metabolic, nutrition, or clinical variables, only measured RQ was a strong predictor of REEVCO2 inaccuracy (p < 0.001). Cutoffs of RQ = 0.80 predicted 89% of underestimated REEIC (sensitivity 0.99; specificity 0.89) and RQ = 0.82 predicted 56% of overestimated REEIC (sensitivity of 0.99; specificity 0.56). REEVCO2 cannot be recommended as an alternative to REEIC in mechanically ventilated children, regardless of the metabolic, anthropometric, or clinical status at the time of the evaluation.

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.

Specific characteristics and current diagnostic and treatment modalities performance of super refractory status epilepticus in children: A comparative study.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is associated with significant morbidity and mortality in children. We explored the clinical spectrum, specific characteristics, and outcome in SRSE patients admitted in a pediatric intensive care unit (PICU) and investigated how well current diagnostic or treatment modalities perform compared to Status Epilepticus (SE) and Refractory SE (RSE) patients. METHODS: Retrospective analysis of PICU patients admitted with convulsive SE during 2009-2019. Eighty-six patients were classified as SE, RSE, and SRSE. New-onset RSE (NORSE) and febrile infection-related epilepsy syndrome (FIRES) were also identified. Functional outcome was evaluated by the modified Rankin scale. RESULTS: Patients with SRSE (n = 20) had longer weaning off anesthetics (p = 0.014), length of stay, mechanical ventilation duration, higher illness severity scores, and poorer outcome compared to SE (n = 13) or RSE (n = 53) patients (all p < 0.001). Diagnosis, mainly expressed by high prevalence of NORSE (n = 13) and FIRES (n = 9), was independently associated with SRSE (p = 0.024). Abnormal MRI findings (p = 0.005), and epilepsy-related pathogenic variants identified by whole-exome sequencing (WES) were mostly found in SRSE patients. Compared to intravenous immunoglobulins and steroid pulses, plasmapheresis and ketogenic diet, more often used in SRSE (p < 0.01), contributed better to seizure control. Only SRSE (AUROC > 0.80, 95% CI = 0.68-0.94, p < 0.001) and diagnosis (AUROC > 0.70, 95% CI = 0.55-0.83, p = 0.02) could predict a poor outcome. CONCLUSION: The majority of SRSE patients are characterized by considerable functional decline and morbidity. WES analysis may reveal epilepsy-related pathogenic variants while early aggressive immunotherapy and/or ketogenic diet might prove beneficial. Multicenter studies for prediction models of outcome are needed.

Active Surveillance of Healthcare-associated Infections in Pediatric Intensive Care Units: Multicenter ECDC HAI-net ICU Protocol (v2.2) Implementation, Antimicrobial Resistance and Challenges.

BACKGROUND: Surveillance is essential to all aspects of management of healthcare-associated infections (HAIs) in critically ill children, where data are limited. We conducted an active surveillance study to elucidate epidemiology, resistance, antimicrobial treatment practices and outcomes of pediatric intensive care unit-acquired HAIs in a southern European country. METHODS: Four Greek pediatric intensive care unit encounters (153 patients, 2183 patient-days) during a 6-month period participated using the European Centre for Disease Prevention and Control HAI-net ICU (v2.2) protocol. Bloodstream infections and device-associated HAIs were recorded. Clinical severity, isolated pathogens, antimicrobial resistance and antibiotic prescriptions were collected on a daily basis. Mortality and excess length of stay due to HAI were also assessed. RESULTS: Overall rate of HAIs was 18.3 per 1000 patient-days. Aggregate rates for device-associated HAI were: catheter-related bloodstream infection 2.32, intubation-associated pneumonia 10.5, and catheter-associated urinary tract infection 4.6 per 1000 device-days. Children with HAI (n = 28, 18.3%) had higher severity of illness (Pediatric Risk Mortality Score 7.5 vs. 4, P < 0.001), longer hospitalization (23 vs. 6 days, P < 0.001), but not higher mortality, compared with those without. Most frequent recovered pathogens were Klebsiella pneumoniae (40%), Pseudomonas aeruginosa (22.5%), Acinetobacter baumannii (12.5%), with respective carbapenem resistance 50%, 44% and 80%, and Staphylococcus aureus (12.5%). Total antibiotic use was 2142 days of treatment per 1000 patient-days. CONCLUSIONS: Our study, based on the updated ECDC HAI-net ICU (v2.2) protocol, effectively addresses the significant burden of HAIs in critically ill children in Greece. Using a well-standardized system facilitates inter- and intra-countries reliable recordings and comparative assessments of infection control programs.

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.