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Observational Study
. 2024 Aug:271:114042.
doi: 10.1016/j.jpeds.2024.114042. Epub 2024 Apr 2.

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

Sherry L Kausch  1 , Douglas E Lake  2 , Juliann M Di Fiore  3 , Debra E Weese-Mayer  4 , Nelson Claure  5 , Namasivayam Ambalavanan  6 , Zachary A Vesoulis  7 , Karen D Fairchild  8 , Phyllis A Dennery  9 , Anna Maria Hibbs  3 , Richard J Martin  3 , Premananda Indic  10 , Colm P Travers  6 , Eduardo Bancalari  5 , Aaron Hamvas  11 , James S Kemp  12 , John L Carroll  13 , J Randall Moorman  2 , Brynne A Sullivan  8 ; Prematurity-Related Ventilatory Control (Pre-Vent) Investigators
Affiliations
Observational Study

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

Sherry L Kausch et al. J Pediatr. 2024 Aug.

Abstract

Objective: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation.

Study design: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, 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 >72 hours after birth and ≥5-day 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 events with oxygen saturation <80% (IH80) 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 including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve 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.

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Conflict of interest statement

Declaration of Competing Interest Some authors have financial conflicts of interest. JRM and DEL own stock in Medical Prediction Sciences Corporation. JRM is a consultant for Nihon Kohden Digital Health Solutions, proceeds donated to the University of Virginia. ZAV is a consultant for Medtronic. All other authors have no financial conflicts to disclose. No authors have any nonfinancial conflicts of interest to disclose. Funding Support: We acknowledge the following NIH grants for funding the work presented in this manuscript. University of Virginia (NCT03174301): U01 HL133708, K23 HD097254, HL133708-05S1. Case Western Reserve University: U01 HL133643. Northwestern University: U01 HL133704. University of Alabama at Birmingham: U01 HL133536, K23 HL157618. University of Miami: U01 HL133689. Washington University: U01 HL133700, F.

Figures

Figure 1.
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.
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.
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.
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