Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and ...glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.
To develop and validate a real-time subclassification method for septic shock.
Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).
The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval CI95 = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).
We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
Purpose
Acute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is ...unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS.
Methods
This was a single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests.
Results
Direct ARDS had lower severity of illness (
p
< 0.001) but worse oxygenation (
p
< 0.001), relative to indirect. Predictors of mortality were similar for direct and indirect ARDS. When comparing infectious and non-infectious ARDS, infectious ARDS had lower severity of illness (
p
< 0.001), worse oxygenation (
p
= 0.014), and lower mortality (
p
= 0.013). In multivariable analysis, immunocompromised status demonstrated effect modification between infectious and non-infectious ARDS (
p
= 0.005 for interaction), with no association with mortality in non-infectious ARDS.
Conclusions
In children, direct and indirect ARDS have distinct clinical characteristics, but similar outcomes and similar predictors of mortality. In contrast, infectious and non-infectious ARDS demonstrate heterogeneity of clinical characteristics, mortality, and predictors of mortality, with traditional predictors of ARDS mortality only applicable to infectious ARDS.
Both oxygenation and peak inspiratory pressure are associated with mortality in pediatric acute respiratory distress syndrome. Since oxygenation and respiratory mechanics are linked, it is difficult ...to identify which variables, pressure or oxygenation, are independently associated with outcome. We aimed to determine whether respiratory mechanics (peak inspiratory pressure, positive end-expiratory pressure, ΔP PIP minus PEEP, tidal volume, dynamic compliance Cdyn) or oxygenation (PaO2/FIO2) was associated with mortality.
Prospective, observational, cohort study.
University affiliated PICU.
Mechanically ventilated children with acute respiratory distress syndrome (Berlin).
None.
Peak inspiratory pressure, positive end-expiratory pressure, ΔP, tidal volume, Cdyn, and PaO2/FIO2 were collected at acute respiratory distress syndrome onset and at 24 hours in 352 children between 2011 and 2016. At acute respiratory distress syndrome onset, neither mechanical variables nor PaO2/FIO2 were associated with mortality. At 24 hours, peak inspiratory pressure, positive end-expiratory pressure, ΔP were higher, and Cdyn and PaO2/FIO2 lower, in nonsurvivors. In multivariable logistic regression, PaO2/FIO2 at 24 hours and ΔPaO2/FIO2 (change in PaO2/FIO2 over the first 24 hr) were associated with mortality, whereas pressure variables were not. Both oxygenation and pressure variables were associated with duration of ventilation in multivariable competing risk regression.
Improvements in oxygenation, but not in respiratory mechanics, were associated with lower mortality in pediatric acute respiratory distress syndrome. Future trials of mechanical ventilation in children should focus on oxygenation (higher PaO2/FIO2) rather than lower peak inspiratory pressure or ΔP, as oxygenation was more consistently associated with outcome.
Although all definitions of acute respiratory distress syndrome use some measure of hypoxemia, neither the Berlin definition nor recently proposed pediatric-specific definitions proposed by the ...Pediatric Acute Lung Injury Consensus Conference utilizing oxygenation index specify which PaO2/FIO2 or oxygenation index best categorizes lung injury. We aimed to identify variables associated with mortality and ventilator-free days at 28 days in a large cohort of children with acute respiratory distress syndrome.
Prospective, observational, single-center study.
Tertiary care, university-affiliated PICU.
Two-hundred eighty-three invasively ventilated children with the Berlin-defined acute respiratory distress syndrome.
None.
Between July 1, 2011, and June 30, 2014, 283 children had acute respiratory distress syndrome with 37 deaths (13%) at the Children's Hospital of Philadelphia. Neither initial PaO2/FO2 nor oxygenation index at time of meeting acute respiratory distress syndrome criteria discriminated mortality. However, 24 hours after, both PaO2/FIO2 and oxygenation index discriminated mortality (area under receiver operating characteristic curve, 0.68 0.59-0.77 and 0.66 0.57-0.75; p < 0.001). PaO2/FIO2 at 24 hours categorized severity of lung injury, with increasing mortality rates of 5% (PaO2/FIO2, > 300), 8% (PaO2/FIO2, 201-300), 18% (PaO2/FIO2, 101-200), and 37% (PaO2/FIO2, ≤ 100) across worsening Berlin categories. This trend with 24-hour PaO2/FIO2 was seen for ventilator-free days (22, 19, 14, and 0 ventilator-free days across worsening Berlin categories; p < 0.001) and duration of ventilation in survivors (6, 9, 13, and 24 d across categories; p < 0.001). Similar results were obtained with 24-hour oxygenation index.
PaO2/FIO2 and oxygenation index 24 hours after meeting acute respiratory distress syndrome criteria accurately stratified outcomes in children. Initial values were not helpful for prognostication. Definitions of acute respiratory distress syndrome may benefit from addressing timing of oxygenation metrics to stratify disease severity.
Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to ...determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock.
Retrospective observational study.
PICU at an academic medical center.
One hundred thirty patients treated for severe sepsis or septic shock.
None.
We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure-free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74-277 min) and to first appropriate antimicrobial was 177 minutes (90-550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27-12.06) and 3.59 (95% CI, 1.09-11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45-16.2) and 4.92 (95% CI, 1.30-18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure-free days (16 interquartile range, 1-23 vs 20 interquartile range, 6-26; p = 0.04).
Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.
Limited data exist about the international burden of severe sepsis in critically ill children.
To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive ...care units to better inform interventional trials.
A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality.
Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range IQR, 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 corrected patients per group.
Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.
Planets are born in protostellar disks, which are now observed with enough resolution to address questions about internal gas flows. Magnetic forces are possibly drivers of the flows, but ionization ...state estimates suggest that much of the gas mass decouples from magnetic fields. Thus, hydrodynamical instabilities could play a major role. We investigate disk dynamics under conditions typical for a T Tauri system, using global 3D radiation-hydrodynamics simulations with embedded particles and a resolution of 70 cells per scale height. Stellar irradiation heating is included with realistic dust opacities. The disk starts in joint radiative balance and hydrostatic equilibrium. The vertical shear instability (VSI) develops into turbulence that persists up to at least 1600 inner orbits (143 outer orbits). Turbulent speeds are a few percent of the local sound speed at the midplane, increasing to 20%, or 100 m s−1, in the corona. These are consistent with recent upper limits on turbulent speeds from optically thin and thick molecular line observations of TW Hya and HD 163296. The predominantly vertical motions induced by the VSI efficiently lift particles upward. Grains 0.1 and 1 mm in size achieve scale heights greater than expected in isotropic turbulence. We conclude that while kinematic constraints from molecular line emission do not directly discriminate between magnetic and nonmagnetic disk models, the small dust scale heights measured in HL Tau and HD 163296 favor turbulent magnetic models, which reach lower ratios of the vertical kinetic energy density to the accretion stress.
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