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.
The ratio of tidal volume to functional residual capacity (FRC), defined as "volumetric" strain, causes physical lung deformation. The corresponding change in transpulmonary pressure at end inspiration, defined as stress, is directly applied to the alveolus [1]. Both stress and strain may cause global or local lung deformation and microscopic or macroscopic tissue damage, representing significant determinants of ventilator-induced lung injury [1]. A modified nitrogen washout/washin technique, measuring end-expiratory lung volume (EELV), correlated well with computed tomography and was proposed as a valuable tool to optimize ventilator settings, improving lung protective ventilation [2]. The aim of this study was to evaluate the effect of positive end-expiratory pressure (PEEP) on EELV, compliance of the respiratory system (Crs), and stress/strain in children with acute respiratory distress syndrome (ARDS), and compare it with children "at risk of ARDS" and those with no lung injury using the modified nitrogen washout/washin technique (see electronic supplementary material). To monitor the effects of the disease evolution on the PEEP-induced increases in lung stress/strain, measurements were repeated at predetermined time points. We hypothesized that PEEP escalation increases EELV, Crs, strain, and stress in mechanically ventilated children, potentially influenced by disease severity and timing. A total of 700 measurements were recorded in 25 mechanically ventilated critically ill children (ARDS, n = 8; at risk of ARDS, n = 5; without lung injury, n = 12). ARDS patients had higher oxygenation index (OI > 4) and PaCO 2 , lower PaO 2 /FiO 2 , PaO 2 , and prolonged length of
Background Mechanical power is a composite variable for energy transmitted to the respiratory system over time that may better capture risk for ventilator-induced lung injury than individual ventilator management components. We sought to evaluate if mechanical ventilation management with a high mechanical power is associated with fewer ventilator-free days (VFD) in children with pediatric acute respiratory distress syndrome (PARDS). Methods Retrospective analysis of a prospective observational international cohort study. Results There were 306 children from 55 pediatric intensive care units included. High mechanical power was associated with younger age, higher oxygenation index, a comorbid condition of bronchopulmonary dysplasia, higher tidal volume, higher delta pressure (peak inspiratory pressure—positive end-expiratory pressure), and higher respiratory rate. Higher mechanical power was associated with fewer 28-day VFD after controlling for confounding variables (per 0.1 J·min−1·Kg−1 Subdistribution Hazard Ratio (SHR) 0.93 (0.87, 0.98), p = 0.013). Higher mechanical power was not associated with higher intensive care unit mortality in multivariable analysis in the entire cohort (per 0.1 J·min−1·Kg−1 OR 1.12 [0.94, 1.32], p = 0.20). But was associated with higher mortality when excluding children who died due to neurologic reasons (per 0.1 J·min−1·Kg−1 OR 1.22 [1.01, 1.46], p = 0.036). In subgroup analyses by age, the association between higher mechanical power and fewer 28-day VFD remained only in children < 2-years-old (per 0.1 J·min−1·Kg−1 SHR 0.89 (0.82, 0.96), p = 0.005). Younger children were managed with lower tidal volume, higher delta pressure, higher respiratory rate, lower positive end-expiratory pressure, and higher PCO2 than older children. No individual ventilator management component mediated the effect of mechanical power on 28-day VFD. Conclusions Higher mechanical power is associated with fewer 28-day VFDs in children with PARDS. This association is strongest in children < 2-years-old in whom there are notable differences in mechanical ventilation management. While further validation is needed, these data highlight that ventilator management is associated with outcome in children with PARDS, and there may be subgroups of children with higher potential benefit from strategies to improve lung-protective ventilation. Take Home Message: Higher mechanical power is associated with fewer 28-day ventilator-free days in children with pediatric acute respiratory distress syndrome. This association is strongest in children <2-years-old in whom there are notable differences in mechanical ventilation management.
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 (C RS) 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, C RS , 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 5 15 subjects with ARDS; n 5 17 subjects at risk for ARDS). EELV correlated positively with strain or stress in the ARDS group (r 5 0.30, P < .001) and the at risk group (r 5 0.60, P < .001). C RS correlated with strain (r 5 0.40, P < .001) only in subjects at risk for ARDS. EELV increased over time as PEEP rose from 4 to 10 cm H 2 O in subjects with ARDS (P 5 .001). In the at risk group, EELV only increased at 48 h (P 5 .001). Longitudinally, C RS (P 5 .001) and EELV (P 5 .002) were lower and strain and stress were higher in subjects with ARDS compared to those at risk for ARDS (P 5 .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 H 2 O (P 5 .02). In the at risk group, strain and stress declined from 6 h to 72 h at a PEEP of 10 cm H 2 O (P 5 .001). CONCLUSIONS: Longitudinally, C RS 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 H 2 O. At these PEEP levels, strain and stress remained within safe limits in both groups.
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