Sepsis Huddles in the Neonatal Intensive Care Unit: A Retrospective Cohort Study of Late-onset Infection Recognition and Severity Assessment.

OBJECTIVE: To analyze relationships between provider-documented signs prompting sepsis evaluations, assessments of illness severity, and late-onset infection (LOI). STUDY DESIGN: Retrospective cohort study of all infants receiving a sepsis huddle in conjunction with a LOI evaluation. Participants were ≥3 days old and admitted to a level IV neonatal intensive care unit (NICU) from September 2018 through May 2021. Data were extracted from standardized sepsis huddle notes in the electronic health record, including clinical signs prompting LOI evaluations, illness severity assessments (from least to most severe: green, yellow, and red), and management plans. To analyze relationships of sepsis huddle characteristics with the detection of culture-confirmed LOI (bacteremia, urinary tract infection, or meningitis), we utilized diagnostic test statistics, area under the receiver-operator characteristic analyses, and multivariable logistic regression. RESULTS: We identified 1209 eligible sepsis huddles among 604 infants. There were 111 culture-confirmed LOI episodes (9% of all huddles). Twelve clinical signs of infection poorly distinguished infants with and without LOI, with sensitivity for each ranging from 2% to 36% and area under the receiver-operator characteristic ranging 0.49-0.53. Multivariable logistic regression identified increasing odds of infection with higher perceived illness severity at the time of sepsis huddle, adjusted for gestational age and receipt of intensive care supports. CONCLUSIONS: Clinical signs prompting sepsis huddles were nonspecific and not predictive of concurrent LOI. Higher perceived illness severity was associated with presence of infection, despite some misclassification based on objective criteria. In level IV NICUs, antimicrobial stewardship through development of criteria for antibiotic noninitiation may be challenging, as presenting signs of LOI are similar among infants with and without confirmed infection.

Acute Kidney Injury Associated with Late-Onset Neonatal Sepsis: A Matched Cohort Study.

OBJECTIVES: To determine incidence and severity of acute kidney injury (AKI) within 7 days of sepsis evaluation and to assess AKI duration and the association between AKI and 30-day mortality. STUDY DESIGN: Retrospective, matched cohort study in a single-center level IV neonatal intensive care unit. Eligible infants underwent sepsis evaluations at ≥72 hours of age during calendar years 2013-2018. Exposed infants (cases) were those with culture-proven sepsis and antimicrobial duration ≥5 days. Nonexposed infants (controls) were matched 1:1 to exposed infants based on gestational and corrected gestational age, and had negative sepsis evaluations with antibiotic durations <48 hours. AKI was defined by modified neonatal Kidney Disease Improving Global Outcomes criteria. Statistical analysis included Mann-Whitney and χ2 tests, multivariable logistic regression, and Kaplan-Meier time-to-event analysis. RESULTS: Among 203 episodes of late-onset sepsis, 40 (20%) developed AKI within 7 days after evaluation, and among 193 episodes with negative cultures, 16 (8%) resulted in AKI (P = .001). Episodes of sepsis also led to greater AKI severity, compared with nonseptic episodes (P = .007). The timing of AKI onset and AKI duration did not differ between groups. Sepsis was associated with increased odds of developing AKI (aOR, 3.0; 95% CI, 1.5-6.2; P = .002). AKI was associated with increased 30-day mortality (aOR, 4.5; 95% CI, 1.3-15.6; P = .017). CONCLUSIONS: Infants with late-onset sepsis had increased odds of AKI and greater AKI severity within 7 days of sepsis evaluation, compared with age-matched infants without sepsis. AKI was independently associated with increased 30-day mortality. Strategies to mitigate AKI in critically ill neonates with sepsis may improve outcomes.

Performance of Pediatric Systemic Inflammatory Response Syndrome and Organ Dysfunction Criteria in Late-Onset Sepsis in a Quaternary Neonatal Intensive Care Unit: A Case-Control Study.

OBJECTIVES: To evaluate accuracy of systemic inflammatory response syndrome (SIRS) criteria in identifying culture-proven late-onset neonatal sepsis and to assess prevalence of organ dysfunction and its relationship with SIRS criteria. STUDY DESIGN: This was a retrospective case-control study of patients in the Children's Hospital of Philadelphia level IV neonatal intensive care unit undergoing sepsis evaluations (concurrent blood culture and antibiotics). During calendar years 2016-2017, 77 case and 77 control sepsis evaluations were identified. Cases included infants who had sepsis evaluations with positive blood cultures and antibiotic duration ≥7 days. Controls were matched by gestational and postmenstrual age, and had sepsis evaluations with negative blood cultures and antibiotic duration ≤48 hours. SIRS criteria were determined at time of sepsis evaluation, and organ dysfunction evaluated in the 72 hours following sepsis evaluation. Statistical analysis included descriptive statistics, Mann-Whitney tests, and χ2 (Fisher exact) tests. RESULTS: At time of sepsis evaluation, 42% of cases and 26% of controls met SIRS criteria. Among infants of ≤37 weeks postmenstrual age, SIRS criteria were met in only 17% of sepsis evaluations (4 of 23 in both cases and controls). Test characteristics for SIRS at diagnosis of culture-proven sepsis included sensitivity 42% and specificity 74%. Cases had higher rates of new organ dysfunction within 72 hours (40% vs 21%); however, 58% of cases developing organ dysfunction did not meet SIRS criteria at time of sepsis evaluation. Of 6 deaths (all cases with organ dysfunction), 2 did not meet SIRS criteria at sepsis evaluation. CONCLUSIONS: SIRS criteria did not accurately identify culture-proven late-onset sepsis, with poorest accuracy in preterm infants. SIRS criteria did not predict later organ dysfunction or mortality.

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

OBJECTIVE: To determine if time to antibiotic administration is associated with mortality and in-hospital outcomes in a neonatal intensive care unit (NICU) population. STUDY DESIGN: 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. RESULTS: 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 days (OR, 1.47; 95% CI, 1.15-1.87) and 30 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. CONCLUSIONS: 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.

Risk factors associated with laboratory-confirmed bloodstream infections in a tertiary neonatal intensive care unit.

BACKGROUND: Bloodstream infections (BSI) remain a leading cause of morbidity and mortality among infants admitted to neonatal intensive care units (NICUs). At the time of evaluation for suspected BSI, presenting signs may be nonspecific. We sought to determine the clinical signs and risk factors associated with laboratory-confirmed BSI among infants evaluated for late-onset sepsis in a tertiary NICU. METHODS: This prospective cohort study included infants >3 days of age admitted to a level 4 NICU from July 2006 to October 2009 for whom a blood culture was drawn for suspected sepsis. Clinicians documented presenting signs at the time of culture. Laboratory-confirmed BSI was defined as per the National Healthcare Safety Network. Multivariate analyses were performed using a logistic regression random effects model. RESULTS: Six-hundred and eighty eligible episodes of suspected BSI were recorded in 409 infants. Enteral contrast within the preceding 48 hours was the most significant risk factor for laboratory-confirmed BSI [Odds Ratio: 9.58 (95% confidence interval: 2.03-45.19)] followed by presence of a central venous catheter. Apnea and hypotension were the most strongly associated presenting signs. CONCLUSION: Among infants evaluated in a tertiary NICU, recent exposure to enteral contrast was associated with increased odds of developing BSI. Apnea and hypotension were the most strongly associated clinical signs of infection.

Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants.

OBJECTIVES: To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC). STUDY DESIGN: Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation. RESULTS: A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC. CONCLUSIONS: We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.

Traumatic lumbar punctures in infants hospitalized in the neonatal intensive care unit.

Traumatic lumbar punctures occur frequently in the neonatal intensive care unit, making the interpretation of cerebrospinal fluid values difficult. We report correction factors for cerebrospinal fluid protein and white blood cells in the face of red blood cell contamination. These correction factors should facilitate the diagnosis of bacterial meningitis in highrisk hospitalized infants.

Cerebrospinal fluid reference ranges in term and preterm infants in the neonatal intensive care unit.

OBJECTIVE: To determine reference ranges of cerebrospinal fluid (CSF) laboratory findings in term and preterm infants in the neonatal intensive care unit. STUDY DESIGN: Data were collected prospectively as part of a multisite study of infants aged <6 months undergoing lumbar puncture for evaluation of suspected sepsis. Infants with a red blood cell count >500 cells/µL or a known cause of CSF pleocytosis were excluded from the analysis. RESULTS: A total of 318 infants met the inclusion criteria. Of these, 148 infants (47%) were preterm, and 229 (72%) received antibiotics before undergoing lumbar puncture. The upper reference limit of the CSF white blood cell (WBC) count was 12 cells/µL in preterm infants and 14 cells/µL in term infants. CSF protein levels were significantly higher in preterm infants (upper reference limit, 209 mg/dL vs 159 mg/dL in term infants; P < .001), and declined with advancing postnatal age in both groups (preterm, P = .008; term, P < .001). CSF glucose levels did not differ in term and preterm infants. Antibiotic exposure did not significantly affect CSF WBC, protein, or glucose values. CONCLUSIONS: CSF WBC counts are not significantly different in preterm and term infants. CSF protein levels are higher and decline more slowly with postnatal age in preterm infants compared with term infants. This study provides CSF reference ranges for hospitalized preterm and term infants, particularly in the first month of life.

Fumonisin mycotoxin contamination of corn-based foods consumed by potentially pregnant women in southern California.

OBJECTIVE: To evaluate a sample of locally available corn-based foods for fumonisin contamination. STUDY DESIGN: We analyzed 38 corn tortilla and masa flour samples from Los Angeles, San Diego and Tijuana, Mexico,for fumonisin contamination. Retail sources were diverse and not limited to Hispanic neighborhoods. RESULTS: Fumonisins were found in all samples. The median fumonisin B1 mycotoxin level was 84 ng/g, with a range of 1-729 (n = 38). The median total fumonisin level was 231 ng/g, with a range of 2.8-1,863. Levels of fumonisins differed by geographic site. CONCLUSION: Fumonisin contamination of corn-based foods in southern California is common. At levels of contamination > 1,000 ng/g, a 60-kg potentially pregnant woman could exceed the World Health Organization recommendations by eating 120 g (dry weight) of corn products daily. Fumonisin contamination may constitute a preventable risk for NTDs among susceptible reproductive-age women and their progeny.

Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality.

OBJECTIVE: To test the hypothesis that cytokines might distinguish critically ill infants with bacterial sepsis or necrotizing enterocolitis (NEC) from those with sepsis syndrome and that these elevations would be correlated with clinical variables of inflammation and mortality. STUDY DESIGN: We measured plasma and tracheal aspirate (TA) levels of interleukin-8 (IL-8), epithelial neutrophil activating peptide (ENA-78), IL-10, and IL-18 in 84 neonates with suspected sepsis or NEC. Thirty-one infants had bacterial sepsis, 19 had NEC, and 34 infants with negative results on cultures had sepsis syndrome. RESULTS: Plasma IL-8 and IL-10 levels were significantly increased in infants with bacterial sepsis compared with those in infants with sepsis syndrome. Plasma IL-8, ENA-78, and IL-10 levels were elevated in infants with NEC compared with those in infants with sepsis syndrome. TA IL-8 and IL-10 levels were also increased in infants with bacterial sepsis; TA ENA-78, and IL-18 were not elevated in infants with sepsis or NEC when compared with infants with sepsis syndrome. Plasma and TA cytokine levels correlated with hematologic parameters. Plasma cytokine levels were higher in infants who did not survive than in infants who did survive. CONCLUSIONS: Plasma and TA cytokine levels are elevated in critically ill infants with bacterial sepsis or NEC compared with those in infants with sepsis syndrome. Our results suggest distinct patterns of cytokine elaboration in different disease states.