Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Extremely Preterm Infants

Abstract

Objectives: Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks' gestational age (GA)) on versus off invasive mechanical ventilation.

Study design: Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, SD 1.71). Monitoring data were available and analyzed for 719 infants (47,512 patient-days), of whom 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72h after birth and ≥5d antibiotics).

Results: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer IH80 events and more bradycardia events before sepsis. IH events were associated with higher sepsis risk, but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model predicted sepsis with an AUC of 0.783.

Conclusion: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Keywords: Apnea; Bradycardia; Intermittent hypoxia; Neonatal Late-Onset Sepsis; Prematurity.

Figure 1.. Sepsis risk based on clinical predictors.

Depiction of associations of predictors in each univariate logistic regression model for times (A) off- ventilator (No Vent) and (B) on-ventilator (Vent). Each tile is a plot of the relative risk of sepsis as a function of the predictor across its range, where 1 on the y-axis indicates risk equal to the overall sepsis event rate. The event rate for on-ventilator times was 0.0188 and for off-ventilator times was 0.0036. The translucent ribbon represents the 95% confidence interval. The vertical dashed lines indicate the 2.5 and 97.5 percentile of data. The red line highlights the range where the confidence intervals do not include 1. In these ranges, the variable can be considered a predictor of significantly increased sepsis risk. The major finding is increased sepsis risk at lower PMA.

Figure 2.. Sepsis risk based on cardiorespiratory predictors, on and off invasive mechanical ventilation.

Associations of predictors in each univariate logistic regression model for times (A) off-ventilator and (B) on-ventilator. Brady count is the number of bradycardia events per day; IH is intermittent hypoxemia; DPE is duration per event in seconds; PB is periodic breathing exposure in minutes per day. The rate of sepsis per day for times on-ventilator are 0.0188 and for times off-ventilator 0.0036. The major findings are increased sepsis risk when cardiorespiratory measures are increased.

Figure 3.. Cardiorespiratory events around sepsis diagnosis, on and off invasive mechanical ventilation.

Panels show the time courses of cardiorespiratory events 5 days before and after diagnosis of sepsis at day zero (A) off-ventilator and (B) on-ventilator. Solid lines represent the median value; gray dashed lines represent the 25th and 75th percentiles; horizontal red lines represent the median value for all times irrespective of sepsis. Brady count is the number of bradycardia events per day; IH is intermittent hypoxemia; DPE is duration per event in seconds; PB is periodic breathing exposure in minutes per day. The major finding is of dynamic changes in bradycardia, apnea and periodic breathing but not in IH events. Daily median bradycardia counts and the median IH80 and IH90 DPE are shown for times on- and off-ventilator (A, B). Additionally, for times off- ventilator (A), median daily number of apnea events and median duration per event for PB are shown.