Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.

2020

5174-5183

2020 Oct 27

2473-9537

<p>Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.</p>

10.1182/bloodadvances.2020002592

Blood Adv

33095872

Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury.

2020

2020 Jul 25

1432-198X

<p><strong>OBJECTIVE: </strong>To determine how hypotension in the first 48 h of sepsis management impacts acute kidney injury (AKI) development and persistence.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective study of patients &gt; 1 month to &lt; 20 years old with sepsis in a pediatric ICU between November 2012 and January 2015 (n = 217). All systolic blood pressure (SBP) data documented within 48 h after sepsis recognition were collected and converted to percentiles for age, sex, and height. Time below SBP percentiles and below pediatric advanced life support (PALS) targets was calculated by summing elapsed time under SBP thresholds during the first 48 h. The primary outcome was new or persistent AKI, defined as stage 2 or 3 AKI present between sepsis day 3-7 using Kidney Disease: Improving Global Outcomes creatinine definitions. Secondary outcomes included AKI-free days (days alive and free of AKI) and time to kidney recovery.</p>

<p><strong>RESULTS: </strong>Fifty of 217 sepsis patients (23%) had new or persistent AKI. Patients with AKI spent a median of 35 min under the first SBP percentile, versus 4 min in those without AKI. After adjustment for potential confounders, the odds of AKI increased by 9% with each doubling of minutes spent under this threshold (p = 0.03). Time under the first SBP percentile was also associated with fewer AKI-free days (p = 0.02). Time spent under PALS targets was not associated with AKI.</p>

<p><strong>CONCLUSIONS: </strong>The duration of severe systolic hypotension in the first 48 h of pediatric sepsis management is associated with AKI incidence and duration when defined by age, sex, and height norms, but not by PALS definitions. Graphical abstract.</p>

10.1007/s00467-020-04704-2

Pediatr. Nephrol.

32710239

Utility of Procalcitonin as a Biomarker for Sepsis in Children.

2020

2020 Apr 29

1098-660X

<p>Sepsis is a complex process defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is associated with significant morbidity and mortality in both adults and children, and emphasis has been placed on its early recognition and prompt provision of antimicrobials. Owing to limitations of current diagnostic tests (i.e. poor sensitivity, delayed results), significant research has been conducted to identify sepsis biomarkers. Ideally, a biomarker could reliably and rapidly distinguish bacterial infection from other, non-infectious causes of systemic inflammatory illness. In doing so, a sepsis biomarker could be used for earlier identification of sepsis, risk stratification/prognostication, and/or guidance of antibiotic decisions. In this Minireview, we review one of the most commonly clinically used sepsis biomarkers, procalcitonin, and its roles in sepsis management in these three areas. We highlight key findings in the adult literature, but focus the bulk of this review on pediatric sepsis. The challenges and limitations of procalcitonin measurement in sepsis are also discussed.</p>

10.1128/JCM.01851-19

J. Clin. Microbiol.

32350044

Identification of Pediatric Sepsis for Epidemiologic Surveillance Using Electronic Clinical Data.

2020

113-121

2020 Feb

1529-7535

<p><strong>OBJECTIVES: </strong>A method to identify pediatric sepsis episodes that is not affected by changing diagnosis and claims-based coding practices does not exist. We derived and validated a surveillance algorithm to identify pediatric sepsis using routine clinical data and applied the algorithm to study longitudinal trends in sepsis epidemiology.</p>

<p><strong>DESIGN: </strong>Retrospective observational study.</p>

<p><strong>SETTING: </strong>Single academic children's hospital.</p>

<p><strong>PATIENTS: </strong>All emergency and hospital encounters from January 2011 to January 2019, excluding neonatal ICU and cardiac center.</p>

<p><strong>EXPOSURE: </strong>Sepsis episodes identified by a surveillance algorithm using clinical data to identify infection and concurrent organ dysfunction.</p>

<p><strong>INTERVENTIONS: </strong>None.</p>

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>A surveillance algorithm was derived and validated in separate cohorts with suspected sepsis after clinician-adjudication of final sepsis diagnosis. We then applied the surveillance algorithm to determine longitudinal trends in incidence and mortality of pediatric sepsis over 8 years. Among 93,987 hospital encounters and 1,065 episodes of suspected sepsis in the derivation period, the surveillance algorithm yielded sensitivity 78% (95% CI, 72-84%), specificity 76% (95% CI, 74-79%), positive predictive value 41% (95% CI, 36-46%), and negative predictive value 94% (95% CI, 92-96%). In the validation period, the surveillance algorithm yielded sensitivity 84% (95% CI, 77-92%), specificity of 65% (95% CI, 59-70%), positive predictive value 43% (95% CI, 35-50%), and negative predictive value 93% (95% CI, 90-97%). Notably, most "false-positives" were deemed clinically relevant sepsis cases after manual review. The hospital-wide incidence of sepsis was 0.69% (95% CI, 0.67-0.71%), and the inpatient incidence was 2.8% (95% CI, 2.7-2.9%). Risk-adjusted sepsis incidence, without bias from changing diagnosis or coding practices, increased over time (adjusted incidence rate ratio per year 1.07; 95% CI, 1.06-1.08; p &lt; 0.001). Mortality was 6.7% and did not change over time (adjusted odds ratio per year 0.98; 95% CI, 0.93-1.03; p = 0.38).</p>

<p><strong>CONCLUSIONS: </strong>An algorithm using routine clinical data provided an objective, efficient, and reliable method for pediatric sepsis surveillance. An increased sepsis incidence and stable mortality, free from influence of changes in diagnosis or billing practices, were evident.</p>

10.1097/PCC.0000000000002170

Pediatr Crit Care Med

32032262

Neonatal sepsis registry: Time to antibiotic dataset.

2019

104788

2019 Dec

2352-3409

<p>This article describes the process of extracting electronic health record (EHR) data into a format that supports analyses related to the timeliness of antibiotic administration. The de-identified data that accompanies this article were collected from a cohort of infants who were evaluated for possible sepsis in the Neonatal Intensive Care Unit (NICU) at the Children's Hospital of Philadelphia (CHOP). The interpretation of findings from these data are reported in a separate manuscript [1]. For purposes of illustration for interested readers, scripts written in the R programming language related to the creation and use of the dataset have also been provided. Interested researchers are encouraged to contact the research team to discuss opportunities for collaboration.</p>

10.1016/j.dib.2019.104788

Data Brief

31799346

A National Approach to Pediatric Sepsis Surveillance.

2019

2019 Nov 27

1098-4275

<p>Pediatric sepsis is a major public health concern, and robust surveillance tools are needed to characterize its incidence, outcomes, and trends. The increasing use of electronic health records (EHRs) in the United States creates an opportunity to conduct reliable, pragmatic, and generalizable population-level surveillance using routinely collected clinical data rather than administrative claims or resource-intensive chart review. In 2015, the US Centers for Disease Control and Prevention recruited sepsis investigators and representatives of key professional societies to develop an approach to adult sepsis surveillance using clinical data recorded in EHRs. This led to the creation of the adult sepsis event definition, which was used to estimate the national burden of sepsis in adults and has been adapted into a tool kit to facilitate widespread implementation by hospitals. In July 2018, the Centers for Disease Control and Prevention convened a new multidisciplinary pediatric working group to tailor an EHR-based national sepsis surveillance approach to infants and children. Here, we describe the challenges specific to pediatric sepsis surveillance, including evolving clinical definitions of sepsis, accommodation of age-dependent physiologic differences, identifying appropriate EHR markers of infection and organ dysfunction among infants and children, and the need to account for children with medical complexity and the growing regionalization of pediatric care. We propose a preliminary pediatric sepsis event surveillance definition and outline next steps for refining and validating these criteria so that they may be used to estimate the national burden of pediatric sepsis and support site-specific surveillance to complement ongoing initiatives to improve sepsis prevention, recognition, and treatment.</p>

10.1542/peds.2019-1790

Pediatrics

31776196

Surviving Sepsis in a Referral Neonatal Intensive Care Unit: Association between Time to Antibiotic Administration and In-Hospital Outcomes.

2019

2019 Oct 08

1097-6833

<p><strong>OBJECTIVE: </strong>To determine if time to antibiotic administration is associated with mortality and in-hospital outcomes in a neonatal intensive care unit (NICU) population.</p>

<p><strong>STUDY DESIGN: </strong>We conducted a prospective evaluation of infants with suspected sepsis between September 2014 and February 2018; sepsis was defined as clinical concern prompting blood culture collection and antibiotic administration. Time to antibiotic administration was calculated from time of sepsis identification, defined as the order time of either blood culture or an antibiotic, to time of first antibiotic administration. We used linear models with generalized estimating equations to determine the association between time to antibiotic administration and mortality, ventilator-free and inotrope-free days, and NICU length of stay in patients with culture-proven sepsis.</p>

<p><strong>RESULTS: </strong>Among 1946 sepsis evaluations, we identified 128 episodes of culture-proven sepsis in 113 infants. Among them, prolonged time to antibiotic administration was associated with significantly increased risk of mortality at 14&nbsp;days (OR, 1.47; 95% CI, 1.15-1.87) and 30&nbsp;days (OR, 1.47; 95% CI, 1.11-1.94) as well as fewer inotrope-free days (incidence rate ratio, 0.91; 95% CI, 0.84-0.98). No significant associations with ventilator-free days or NICU length of stay were demonstrated.</p>

<p><strong>CONCLUSIONS: </strong>Among infants with sepsis, delayed time to antibiotic administration was an independent risk factor for death and prolonged cardiovascular dysfunction. Further study is needed to define optimal timing of antimicrobial administration in high-risk NICU populations.</p>

10.1016/j.jpeds.2019.08.023

J. Pediatr.

31604632

PRagMatic Pediatric Trial of Balanced versus nOrmaL Saline FlUid in Sepsis: the PRoMPT BOLUS Randomized Controlled Trial Pilot Feasibility Study.

2019

2019 Jun 10

1553-2712

<p><strong>BACKGROUND: </strong>Resuscitation with crystalloid fluid is a cornerstone of pediatric septic shock treatment. However, the optimal type of crystalloid fluid is unknown. We aimed to determine the feasibility of conducting a pragmatic randomized trial to compare balanced (lactated Ringer's [LR]) with 0.9% normal saline (NS) fluid resuscitation in children with suspected septic shock.</p>

<p><strong>METHODS: </strong>Open-label pragmatic randomized controlled trial (RCT) at a single academic children's hospital from January - August 2018. Eligible patients were &gt;6 months to &lt;18 years-old who were treated in the emergency department for suspected septic shock, operationalized as blood culture, parenteral antibiotics, and fluid resuscitation for abnormal perfusion. Screening, enrollment, and randomization were carried out by the clinical team as part of routine care. Patients were randomized to receive either LR or NS for up to 48 hours following randomization. Other than fluid type, all treatment decisions were at the clinical team's discretion. Feasibility outcomes included proportion of eligible patients enrolled, acceptability of enrollment via the U.S. federal exception from informed consent (EFIC) regulations, and adherence to randomized study fluid administration.</p>

<p><strong>RESULTS: </strong>Of 59 eligible patients, 50 (85%) were enrolled and randomized. Twenty four were randomized to LR and 26 to NS. Only one (2%) of 44 patients enrolled using EFIC withdrew before study completion. Total median crystalloid fluid volume received during the intervention window was 107 (IQR 60, 155) mL/kg and 98 (IQR 63, 128) mL/kg in the LR and NS arms, respectively (p=0.50). Patients randomized to LR received a median of only 20% (IQR 13, 32) of all study fluid as NS compared to 99% (IQR 64,100%) of study fluid as NS in the NS arm (absolute difference 79%, 95% CI 48,85).</p>

<p><strong>CONCLUSIONS: </strong>A pragmatic study design proved feasible to study comparative effectiveness of LR versus NS fluid resuscitation for pediatric septic shock. This article is protected by copyright. All rights reserved.</p>

10.1111/acem.13815

Acad Emerg Med

31183919

Major Adverse Kidney Events in Pediatric Sepsis.

2019

2019 Apr 18

1555-905X

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Major adverse kidney events, a composite of death, new kidney replacement therapy, or persistent kidney dysfunction, is a potential patient-centered outcome for clinical trials in sepsis-associated kidney injury. We sought to determine the incidence of major adverse kidney events within 30 days and validate this end point in pediatric sepsis.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>We conducted a retrospective observational study using the Pediatric Health Information Systems Plus database of patients &gt;6 months to &lt;18 years old with a diagnosis of severe sepsis/septic shock; orders for bacterial blood culture, antibiotics, and at least one fluid bolus on hospital day 0/1; and known hospital disposition between January 2007 and December 2011. The primary outcome was incidence of major adverse kidney events within 30 days. Major adverse kidney events within 30 days were validated against all-cause mortality at hospital discharge, hospital length of stay, total hospital costs, hospital readmission within 30 days and 1 year, and lowest eGFR between 3 months and 1 year after discharge. We reported incidence of major adverse kidney events within 30 days with 95% confidence intervals using robust SEM and used multivariable logistic regression to test the association of major adverse kidney events within 30 days with hospital costs and mortality.</p>

<p><strong>RESULTS: </strong>Of 1685 admissions, incidence of major adverse kidney events within 30 days was 9.6% (95% confidence interval, 8.1% to 11.0%), including 4.5% (95% confidence interval, 3.5% to 5.4%) death, 1.7% (95% confidence interval, 1.1% to 2.3%) kidney replacement therapy, and 5.8% (95% confidence interval, 4.7% to 6.9%) persistent kidney dysfunction. Patients with versus without major adverse kidney events within 30 days had higher all-cause mortality at hospital discharge (28% versus 1%; &lt;0.001), higher total hospital costs ($61,188; interquartile range, $21,272-140,356 versus $28,107; interquartile range, $13,056-72,697; &lt;0.001), and higher proportion with eGFR&lt;60 ml/min per 1.73 m between 3 months and 1 year after discharge (19% versus 4%; =0.001). Major adverse kidney events within 30 days was not associated with length of stay or readmissions.</p>

<p><strong>CONCLUSIONS: </strong>In children with sepsis, major adverse kidney events within 30 days are common, feasible to measure, and a promising end point for future clinical trials.</p>

<p><strong>PODCAST: </strong>This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_18_CJASNPodcast_…;

10.2215/CJN.12201018

Clin J Am Soc Nephrol

31000518

Is chloride worth its salt?

2018

2018 Nov 28

1432-1238

10.1007/s00134-018-5477-1

Intensive Care Med

30488168