Sepsis and Mortality Prediction in Very Low Birth Weight Infants: Analysis of HeRO and nSOFA

Abstract

Objective Scores to predict sepsis or define sepsis severity could improve care for very low birth weight (VLBW) infants. The heart rate characteristics (HRC) index (HeRO score) was developed as an early warning system for late-onset sepsis (LOS), and also rises before necrotizing enterocolitis (NEC). The neonatal sequential organ failure assessment (nSOFA) was developed to predict sepsis-associated mortality using respiratory, hemodynamic, and hematologic data. The aim of this study was to analyze the HRC index and nSOFA near blood cultures in VLBW infants relative to diagnosis and sepsis-associated mortality.

Study Design Retrospective, single-center study of VLBW infants from 2011 to 2019. We analyzed HRC index and nSOFA around blood cultures diagnosed as LOS/NEC. In a subgroup of the cohort, we analyzed HRC and nSOFA near the first sepsis-like illness (SLI) or sepsis ruled-out (SRO) compared with LOS/NEC. We compared scores by diagnosis and mortality during treatment.

Results We analyzed 179 LOS/NEC, 93 SLI, and 96 SRO blood culture events. In LOS/NEC, the HRC index increased before the blood culture, while nSOFA increased at the time of culture. Both scores were higher in nonsurvivors compared with survivors and in LOS/NEC compared with SRO. The nSOFA 12 hours after the time of blood culture predicted mortality during treatment better than any other time point analyzed (area under the curve 0.91).

Conclusion The HRC index provides earlier warning of imminent sepsis, whereas nSOFA after blood culture provides better prediction of mortality.

Key Points

• The HRC index and nSOFA provide complementary information on sepsis risk and sepsis-related mortality risk.

• This study adds to existing literature evaluating these risk scores independently by analyzing them together and in cases of not only proven but also suspected infections.

• The impact of combining risk models could be improved outcomes for premature infants.

Keywords

prematurity - predictive analytics - necrotizing enterocolitis - neonatal sepsis

• References

• 1 Greenberg RG, Kandefer S, Do BT. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Late-onset sepsis in extremely premature infants: 2000-2011. Pediatr Infect Dis J 2017; 36 (08) 774-779
• 2 Stoll BJ, Hansen NI, Adams-Chapman I. et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292 (19) 2357-2365
• 3 Bright HR, Babata K, Allred EN. et al; ELGAN Study Investigators. Neurocognitive outcomes at 10 years of age in extremely preterm newborns with late-onset bacteremia. J Pediatr 2017; 187: 43-49.e1
• 4 Griffin MP, Moorman JR. Toward the early diagnosis of neonatal sepsis and sepsis-like illness using novel heart rate analysis. Pediatrics 2001; 107 (01) 97-104
• 5 Fairchild KD, O'Shea TM. Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010; 37 (03) 581-598
• 6 Moorman JR, Carlo WA, Kattwinkel J. et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011; 159 (06) 900-6.e1
• 7 Fairchild KD, Schelonka RL, Kaufman DA. et al. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013; 74 (05) 570-575
• 8 Fairchild KD, Srinivasan V, Moorman JR, Gaykema RPA, Goehler LE. Pathogen-induced heart rate changes associated with cholinergic nervous system activation. Am J Physiol Regul Integr Comp Physiol 2011; 300 (02) R330-R339
• 9 Fairchild KD, Saucerman JJ, Raynor LL. et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009; 297 (04) R1019-R1027
• 10 Sullivan BA, Grice SM, Lake DE, Moorman JR, Fairchild KD. Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants. J Pediatr 2014; 164 (04) 775-780
• 11 Alonzo CJ, Fairchild KD. Dexamethasone effect on heart rate variability in preterm infants on mechanical ventilation. J Neonatal Perinatal Med 2017; 10 (04) 425-430
• 12 Sullivan BA, Fairchild KD. Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock. Semin Fetal Neonatal Med 2015; 20 (04) 255-261
• 13 Griffin MP, O'Shea TM, Bissonette EA, Harrell Jr FE, Lake DE, Moorman JR. Abnormal heart rate characteristics are associated with neonatal mortality. Pediatr Res 2004; 55 (05) 782-788
• 14 Sullivan BA, McClure C, Hicks J, Lake DE, Moorman JR, Fairchild KD. Early heart rate characteristics predict death and morbidities in preterm infants. J Pediatr 2016; 174: 57-62
• 15 Wynn JL, Polin RA. Progress in the management of neonatal sepsis: the importance of a consensus definition. Pediatr Res 2018; 83 (1-1): 13-15
• 16 Vincent JL, Moreno R, Takala J. et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22 (07) 707-710
• 17 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 18 Sweeney TE, Wynn JL, Cernada M. et al. Validation of the sepsis metascore for diagnosis of neonatal sepsis. J Pediatric Infect Dis Soc 2018; 7 (02) 129-135
• 19 Wynn JL, Polin RA. A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants. Pediatr Res 2020; 88 (01) 85-90
• 20 Wynn JL, Kelly MS, Benjamin DK. et al. Timing of multiorgan dysfunction among hospitalized infants with fatal fulminant sepsis. Am J Perinatol 2017; 34 (07) 633-639
• 21 Fleiss N, Coggins SA, Lewis AN. et al. Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection. JAMA Netw Open 2021; 4 (02) e2036518
• 22 Patel AL, Panagos PG, Silvestri JM. Reducing incidence of necrotizing enterocolitis. Clin Perinatol 2017; 44 (03) 683-700
• 23 Boghossian NS, Page GP, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr 2013; 162 (06) 1120-1124 , 1124.e1
• 24 Zozaya C, García González I, Avila-Alvarez A. et al. Incidence, treatment, and outcome trends of necrotizing enterocolitis in preterm infants: a multicenter cohort study. Front Pediatr 2020; 8: 188
• 25 Horbar JD, Carpenter JH, Badger GJ. et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012; 129 (06) 1019-1026
• 26 Griffin MP, Lake DE, Bissonette EA, Harrell Jr FE, O'Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005; 116 (05) 1070-1074
• 27 Lake DE, Fairchild KD, Moorman JR. Complex signals bioinformatics: evaluation of heart rate characteristics monitoring as a novel risk marker for neonatal sepsis. J Clin Monit Comput 2014; 28 (04) 329-339
• 28 Stone ML, Tatum PM, Weitkamp JH. et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J Perinatol 2013; 33 (11) 847-850
• 29 Griffin MP, O'Shea TM, Bissonette EA, Harrell Jr FE, Lake DE, Moorman JR. Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness. Pediatr Res 2003; 53 (06) 920-926
• 30 Aviles-Otero N, Ransom M, Weitkamp J. et al. Urinary tract infections in very low birthweight infants: a two-center analysis of microbiology, imaging and heart rate characteristics. J Neonatal Perinatal Med 2020; (x): 1-8
• 31 Weissman A, Zimmer EZ, Aranovitch M, Blazer S. Heart rate dynamics during acute pain in newborns. Pflugers Arch 2012; 464 (06) 593-599
• 32 Coggins SA, Weitkamp J-H, Grunwald L. et al. Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience. Arch Dis Child Fetal Neonatal Ed 2016; 101 (04) F329-F332
• 33 Seymour CW, Liu VX, Iwashyna TJ. et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 762-774
• 34 Coggins S, Harris MC, Grundmeier R, Kalb E, Nawab U, Srinivasan L. 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. J Pediatr 2020; 219: 133-139.e1
• 35 Hofer N, Zacharias E, Müller W, Resch B. Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates. J Perinat Med 2012; 40 (05) 587-590
• 36 Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet 2017; 390 (10104): 1770-1780
• 37 Mukhopadhyay S, Puopolo KM. Antibiotic use and mortality among premature infants without confirmed infection-perpetrator or innocent bystander?. JAMA Pediatr 2016; 170 (12) 1144-1146
• 38 Sullivan BA, Nagraj VP, Berry KL. et al. Clinical and vital sign changes associated with late-onset sepsis in very low birth weight infants at 3 NICUs. J Neonatal Perinatal Med 2021; (x): 1-9
• 39 Stoll BJ, Hansen N, Fanaroff AA. et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110 (2 Pt 1): 285-291