To determine whether treatment with a protocolized sepsis guideline in the emergency department was associated with a lower burden of organ dysfunction by hospital day 2 compared to nonprotocolized ...usual care in pediatric patients with severe sepsis.
Retrospective cohort study.
Tertiary care children's hospital from January 1, 2012, to March 31, 2014.
Patients older than 56 days old and younger than 18 years old with international consensus defined severe sepsis and who required PICU admission within 24 hours of emergency department arrival were included.
The exposure was the use of a protocolized emergency department sepsis guideline. The primary outcome was complete resolution of organ dysfunction by hospital day 2. One hundred eighty nine subjects were identified during the study period. Of these, 121 (64%) were treated with the protocolized emergency department guideline and 68 were not. There were no significant differences between the groups in age, sex, race, number of comorbid conditions, emergency department triage level, or organ dysfunction on arrival to the emergency department. Patients treated with protocolized emergency department care were more likely to be free of organ dysfunction on hospital day 2 after controlling for sex, comorbid condition, indwelling central venous catheter, Pediatric Index of Mortality-2 score, and timing of antibiotics and IV fluids (adjusted odds ratio, 4.2; 95% CI, 1.7-10.4).
Use of a protocolized emergency department sepsis guideline was independently associated with resolution of organ dysfunction by hospital day 2 compared to nonprotocolized usual care. These data indicate that morbidity outcomes in children can be improved with the use of protocolized care.
We investigated the effects of transcranial alternating current stimulation (tACS) targeted to the bilateral medial prefrontal cortex (mPFC) and administered at either delta or alpha frequencies, on ...brain activity and apathy in people with Huntington's disease (HD) (n = 17). Given the novelty of the protocol, neurotypical controls (n = 20) were also recruited. All participants underwent three 20-min sessions of tACS; one session at alpha frequency (Individualised Alpha Frequency (IAF), or 10 Hz when an IAF was not detected); one session at delta frequency (2 Hz); and a session of sham tACS. Participants completed the Monetary Incentive Delay (MID) task with simultaneous recording of EEG immediately before and after each tACS condition. The MID task presents participants with cues signalling potential monetary gains or losses that increase activity in key regions of the cortico-basal ganglia-thalamocortical networks, with dysfunction of the latter network being implicated in the pathophysiology of apathy. We used the P300 and Contingent Negative Variation (CNV) event-related potentials elicited during the MID task as markers of mPFC engagement. HD participants' CNV amplitude significantly increased in response to alpha-tACS, but not delta-tACS or sham. Neurotypical controls' P300 and CNV were not modulated by any of the tACS conditions, but they did demonstrate a significant decrease in post-target response times following alpha-tACS. We present this as preliminary evidence of the ability of alpha-tACS to modulate brain activity associated with apathy in HD.
•Proof-of-concept study targeting mPFC with tACS in people with HD and controls.•P300 and CNV on the MID task used as neurophysiological markers of apathy.•Compared 20 min sessions of tACS at alpha and delta frequencies as well as sham.•Amplitude of the CNV on the MID task was increased by alpha-tACS in the HD group.•The control group's response times on the MID task were decreased by alpha-tACS.
We explored the utility of the Monetary Incentive Delay (MID) task with concurrent encephalography (EEG) as a marker of apathy in people with Huntington's disease (HD) as well as neurotypical ...controls. Specifically, we assessed between and within-group differences in the amplitude of the P300 and Contingent Negative Variation (CNV) event-related potentials as a function of motivational salience. In contrast to neurotypical controls, HD participants' ERP amplitudes were not differentially modulated by motivationally salient cues (i.e., signalling potential ‘gain’ or ‘loss’) compared to ‘neutral’ cues. Difference waves isolating amplitude specific to the motivationally salient cues were calculated for the P300 and CNV. Only the difference waves for ERPs elicited by ‘gain’ cues differentiated the groups. The CNV difference wave was also significantly correlated with clinical measures of apathy and processing speed in the HD group. These findings provide initial support for the use of the MID with EEG as a marker of apathy in HD, and its potential as a sensitive outcome measure for novel treatment development.
•We explored the EEG version of the Monetary Incentive Delay task in people with HD.•The HD group's ERP amplitudes did not change following motivationally salient cues.•Neurotypical controls' ERPs were enhanced following motivationally salient cues.•Apathy and processing speed correlated with the CNV difference wave in the HD group.•The EEG version of the MID is a potential sensitive marker of apathy in HD.
•We examined EEG oscillatory power and functional connectivity as potential correlates of non-motor symptoms in Huntington’s disease (HD).•The HD group had lower theta power, higher delta power and ...connectivity, and theta power was correlated with processing speed.•Our findings support the use of quantitative EEG metrics as a potential marker of processing speed for clinical research in HD.
To find sensitive neurophysiological correlates of non-motor symptoms in Huntington’s disease (HD), which are essential for the development and assessment of novel treatments.
We used resting state EEG to examine differences in oscillatory activity (analysing the isolated periodic as well as the complete EEG signal) and functional connectivity in 22 late premanifest and early stage people with HD and 20 neurotypical controls. We then assessed the correlations between these neurophysiological markers and clinical measures of apathy and processing speed.
Significantly lower theta and greater delta resting state power was seen in the HD group, as well as significantly greater delta connectivity. There was a significant positive correlation between theta power and processing speed, however there were no associations between the neurophysiological and apathy measures.
We speculate that these changes in oscillatory power and connectivity reflect ongoing, frontally concentrated degenerative and compensatory processes associated with HD.
Our findings support the potential utility of quantitative EEG as a proximate marker of processing speed, but not apathy in HD.
Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein ...receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction.
Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified.
A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype.
We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.
Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of ...at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock.
To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on Day 3 (D
SA-AKI) in pediatric septic shock.
We performed secondary analysis of a prospective observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk.
Among 379 patients, 65 (17%) developed severe D
SA-AKI. The proportion of patients developing severe D
SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D
SA-AKI after adjustment for age and illness severity (odds ratio, 1.4; 95% confidence interval, 1.2-1.7;
< 0.001). Similar associations were found between increasing PERSEVERE-II mortality probability and the need for renal replacement therapy. Lower PERSEVERE-II mortality probability was independently associated with increased odds of renal recovery among patients with early AKI. A newly derived model incorporating the PERSEVERE biomarkers and Day 1 AKI status predicted severe D
SA-AKI with an area under the received operating characteristic curve of 0.95 (95% confidence interval, 0.92-0.98).
Among children with septic shock, the PERSEVERE biomarkers predict severe D
SA-AKI and identify patients with early AKI who are likely to recover.
Acute kidney injury is common in critically ill children; however, the frequency of septic shock-associated acute kidney injury and impact on functional status are unknown. We evaluated functional ...outcomes of children with septic shock-associated acute kidney injury.
Secondary analysis of patients with septic shock from the prospective Life after Pediatric Sepsis Evaluation study. We defined acute kidney injury using Kidney Disease Improving Global Outcomes criteria, comparing patients with absent/Stage 1 acute kidney injury to those with Stage 2/3 acute kidney injury (severe acute kidney injury). Our primary outcome was a composite of mortality or new functional morbidity at day 28 of hospitalization or discharge. We also assessed poor long-term outcome, defined as mortality or a persistent, serious deterioration in health-related quality of life at 3 months.
Twelve academic PICUs in the United States.
Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.
None.
More than 50% of patients (176/348) developed severe acute kidney injury; of those, 21.6% (38/176) required renal replacement therapy. Twice as many patients with severe acute kidney injury died or developed new substantive functional morbidity (38.6 vs 16.3%; p < 0.001). After adjustment for age, malignancy, and initial illness severity, severe acute kidney injury was independently associated with mortality or new substantive morbidity (adjusted odds ratio, 2.78; 95% CI, 1.63-4.81; p < 0.001). Children with severe acute kidney injury had poorer health-related quality of life at 3 months (adjusted effect size 2.46; 95% CI, 1.44-4.20; p = 0.002). Children with severe acute kidney injury required longer duration of mechanical ventilation (11.0 vs 7.0 d; p < 0.001) and PICU stay (11.7 vs 7.1 d; p < 0.001).
Among children with septic shock, severe acute kidney injury was independently associated with increased risk of death or new substantive functional morbidity. Survivors of sepsis with severe acute kidney injury were more likely to have persistent, serious health-related quality of life deterioration at 3 months.
OBJECTIVES:Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a ...challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.
DESIGN:We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype.
MEASUREMENTS AND MAIN RESULTS:Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01–0.54; p = 0.007).
CONCLUSIONS:A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.
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