Abstract
Although it is well known that neonatal sepsis can induce important alterations in cardiorespiratory control, their detailed early features and the mechanisms involved remain poorly understood. As a first step in resolving this issue, the main goal of this study was to characterize these alterations more extensively by setting up a full-term newborn lamb model of systemic inflammation using lipopolysaccharide (LPS) injection. Two 6-h polysomnographic recordings were performed on two consecutive days on eight full-term lambs: the first after an IV saline injection (control condition, CTRL); the second, after an IV injection of 2.5 μg/kg Escherichia coli LPS 0127:B8 (LPS condition). Rectal temperature, locomotor activity, state of alertness, arterial blood gases, respiratory frequency and heart rate, mean arterial blood pressure, apneas and cardiac decelerations, and heart-rate and respiratory-rate variability (HRV and RRV) were assessed. LPS injection decreased locomotor activity (p = 0.03) and active wakefulness (p = 0.01) compared to the CTRL. In addition, LPS injection led to a biphasic increase in rectal temperature (p = 0.01 at ∼30 and 180 min) and in respiratory frequency and heart rate (p = 0.0005 and 0.005, respectively), and to an increase in cardiac decelerations (p = 0.05). An overall decrease in HRV and RRV was also observed. Interestingly, the novel analysis of the representations of the horizontal and vertical visibility network yielded the most statistically significant alterations in HRV structure, suggesting its potential clinical importance for providing an earlier diagnosis of neonatal bacterial sepsis. A second goal was to assess whether the reflexivity of the autonomic nervous system was altered after LPS injection by studying the cardiorespiratory components of the laryngeal and pulmonary chemoreflexes. No difference was found. Lastly, preliminary results provide proof of principle that brainstem inflammation (increased IL-8 and TNF-α mRNA expression) can be shown 6 h after LPS injection. In conclusion, this full-term lamb model of systemic inflammation reproduces several important aspects of neonatal bacterial sepsis and paves the way for studies in preterm lambs aiming to assess both the effect of prematurity and the central neural mechanisms of cardiorespiratory control alterations observed during neonatal sepsis.
Highlights
Sepsis is defined as a systemic inflammation caused by a bacterial, viral, or fungal infection (Hotchkiss et al, 2016; Singer et al, 2016)
Microglial cells serve as resident macrophages in the nervous system and can be activated, e.g., by LPS, to produce various inflammatory mediators, such as interleukine 8 (IL-8) and TNF-α
Body Core Temperature Contrarily to control condition (CTRL), LPS injection induced a biphasic increase in body core temperature in 7/8 lambs with a first peak at approximately 30 min ( T = 1.3◦C; p = 0.01) followed by a second, longer increase peaking around 3 h ( T = 1.3◦C; p = 0.01)
Summary
Sepsis is defined as a systemic inflammation caused by a bacterial, viral, or fungal infection (Hotchkiss et al, 2016; Singer et al, 2016). The currently available monitoring of heart-rate variability (HRV) allows earlier diagnosis of LOS (Griffin et al, 2005; Bohanon et al, 2015), with a reported decrease in death rate of 20% (Fairchild, 2013). This approach is, hampered by low specificity, which limits its clinical usefulness. The use of HRV analysis methods with better diagnostic accuracy are needed to further improve the early LOS detection and prognosis (Coggins et al, 2016). A better understanding of the altered cardiorespiratory control during neonatal sepsis is needed
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