Cytokine screening identifies NICU patients with Gram-negative bacteremia.

Infants in the neonatal intensive care unit (NICU) are highly susceptible to late-onset sepsis, with rates as high as 25% among preterm very-low-birth-weight infants. This is an important public health problem because mortality and morbidity are substantial (1), and survivors are at increased risk for neurodevelopmental impairment (2). The standard paradigm for diagnosing and treating late-onset sepsis is to perform a blood culture and initiate empiric two-antibiotic therapy after an infant displays signs possibly attributable to sepsis. With this approach, mortality is high, particularly in cases of Gram-negative septicemia. Discovering ways to detect sepsis in its early phases and to tailor antibiotic therapy to the likely causative organism could improve outcomes. On the other hand, avoidance of unnecessary antibiotic therapy is also a worthy goal. To this end, biomarkers and physiomarkers associated with neonatal sepsis have been investigated. Cytokines have been proposed as promising biomarkers because some of them rise very early in the course of bacteremia (3) and thus are more sensitive for detecting the early phase of sepsis than acute-phase proteins such as C-reactive protein (CRP) (4). This was demonstrated by Kuster et al. in a prospective study of preterm infants in which blood levels of interleukin (IL)-6 and IL-1 receptor antagonist (IL-1ra) rose 1–2 d before the clinical presentation of blood culture–proven sepsis (5). Performing routine biomarker screening of asymptomatic NICU patients is not practicable, yet waiting for overt signs of sepsis to develop can lead to unfavorable outcomes. To address this problem, our group developed a system for continuous physiomarker (heart rate characteristics (HRC)) screening for sepsis in NICU patients. Abnormal HRC have been identified in NICU patients with sepsis and often occur prior to clinical deterioration (6–8). Bacteremia can trigger a systemic inflammatory response with release of cytokines and subsequent physiologic changes in multiple organs including the heart. Two such changes identified in septic neonates are decreased beat-to-beat variability and repetitive transient decelerations in heart rate (9) similar to the changes seen in fetuses in the settings of asphyxia or chorioamnionitis (10,11). Our group has shown in a rodent model that pathogen toxins induce heart rate decelerations and decreased variability, in part through increased production of cytokines such as tumor necrosis factor (TNF)-α In NICU patients, abnormal HRC associated with sepsis are not apparent to clinicians using conventional cardiorespiratory monitoring, prompting development of a monitor that detects HRC predictive of impending clinical deterioration. Through analysis of electrocardiogram data from hundreds of preterm infants, an HRC index was derived that incorporates decreased variability and decelerations to calculate the fold increase in risk that a patient will be diagnosed with sepsis in the next 24 h (7,8,12–14). After testing and validating the HRC index for sepsis detection, the impact of continuous HRC index monitoring on outcomes of very-low-birth-weight preterm infants was tested in a randomized clinical trial of 2,989 patients in eight centers, completed in 2010. This trial showed a significant decrease in mortality in preterm infants whose HRC index was continuously displayed to clinicians (15). Further refinement is essential for optimizing biomarker and physiomarker screening for sepsis in NICU patients. We undertook this study for two purposes: (i) to determine if cytokine screening could discriminate between patients with sepsis ruled out and those with clinical or blood culture–positive sepsis, and (ii) to determine the relationship between abnormal HRC index and elevated cytokine levels in NICU patients with clinically suspected late-onset sepsis.