Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy

Al-Shargabi, Tareq; Govindan, Rathinaswamy B.; Dave, Rhiya; Metzler, Marina; Wang, Y; Plessis, Adré du; Massaro, An N.

doi:10.1038/jp.2017.15

Cited by 31 publications

(29 citation statements)

References 37 publications

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“…The appropriateness of our model of mild NEC and vagotomy as grade≥2 is supported by the observation that we did not measure significant differences in plasma TNF‐α levels between control and NEC rats. This is consistent with previous studies showing that TNF‐α is involved in systemic inflammation, while NEC is associated with more localized changes within the GI tract . We additionally found no difference in the levels of IFN‐γ between groups, most likely due to the role of IFN‐γ in viral replication, which is not a part of NEC etiology .…”

Section: Discussionsupporting

confidence: 92%

“…This is consistent with previous studies showing that TNF-α is involved in systemic inflammation, while NEC is associated with more localized changes within the GI tract 50,51,[54][55][56][57][58]. We additionally found no difference in the levels of IFN-γ between groups, most likely due to the role of IFN-γ in viral replication, which is not a part of NEC etiology 51,52,[54][55][56][57][58]. Finally, we report no significant differences in the anti-inflammatory cytokine IL-10 between groups, consistent with our hypothesis that NEC affects pro-inflammatory cytokines such as IL-1 and IL-6.…”

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confidence: 93%

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Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats

Meister

Doheny

Travagli

2018

Neurogastroenterology Motil

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Background We have shown previously that a decreased high‐frequency spectrum of heart rate variability (HF‐HRV), indicative of reduced vagal tone, shows promise in predicting neonates likely to develop necrotizing enterocolitis (NEC) before its clinical onset. We hypothesized that NEC induction in rat pups decreases HF‐HRV power; subdiaphragmatic vagotomy worsens the severity of the NEC phenotype, increases levels of pro‐inflammatory cytokines, and alters the myenteric phenotype. Methods Newborn Sprague‐Dawley rats, representative of preterm human neonates, were subjected to 7‐8 days of brief periods of cold stress and hypoxia to induce NEC with or without unilateral subdiaphragmatic vagotomy. HRV was measured at postnatal days one and five, pups were sacrificed at day 8/9, and gastrointestinal tissues and blood were collected for immunohistochemical, corticosterone, and cytokine analysis. Key Results Compared to control, NEC‐induced rats showed the following: (a) typical histological signs of grade 2 NEC, which were more severe in rats that underwent vagotomy; (b) reduced developmental increases in time (RMSSD) and frequency (HF) HRV spectra when combined with the stress of laparotomy/vagotomy; (c) increases in nitric oxide synthase‐immunoreactivity in the myenteric plexus of jejunum and ileum; furthermore, compared to mild NEC and controls, vagotomized NEC rats had increased plasma values of pro‐inflammatory cytokines IL‐1β and IL‐6. Conclusions and Inferences Our data suggest that in rodents, similar to neonatal observations, NEC induction attenuated developmental HF‐HRV increases, furthermore, subdiaphragmatic vagotomy worsened the histological severity, increased pro‐inflammatory cytokines, and altered the nitrergic myenteric phenotype, suggesting a role of the vagus in the development of NEC pathology.

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Section: Discussionsupporting

confidence: 92%

supporting

confidence: 93%

Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats

Meister

Doheny

Travagli

2018

Neurogastroenterology Motil

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“…Systemic inflammation‐modulating cytokine expression may be inversely related to HF power or parasympathetic control of HRV (Al‐Shargabi et al. ). Preliminary data indicates that levels of inflammatory biomarkers may help distinguish groups of neonates with poor outcomes from neonates with good outcomes after cooling.…”

Section: Discussionmentioning

confidence: 99%

Heart rate variability and inflammatory markers in neonates with hypoxic‐ischemic encephalopathy

et al. 2019

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To examine heart rate variability (HRV) and inflammatory markers as predictors for neurological injury in neonates undergoing therapeutic hypothermia for hypoxic‐ischemic encephalopathy (HIE). We hypothesized that HRV would differentiate between infants with no/mild injury and infants with moderate/severe injury observed on MRI. Because HRV can be associated with the inflammatory cascade, cytokine concentrations were compared with the severity of brain injury indicated by MRI. Further, we studied the effect of temperature, sex, and mechanical ventilation on HRV. HRV was prospectively collected on neonates with HIE using spectral analysis for low and high frequency components (n = 16). A subset (n = 10) of neonates had serum available for inflammatory cytokine analysis obtained during cooling. Neonates were stratified into no/mild or moderate/severe injury based on MRI obtained after rewarming. Differences in HRV were identified; lower low frequency power predicted more injury on MRI. Additionally, in neonates with HIE after cooling procedure, HRV differed by gender. Elevated RANTES (CCL5) and decreased GM‐CSF (Granulocyte‐macrophage colony‐stimulating factor) at 96 hours predicted less severe injury. In this small study, HRV differs between no/mild and moderate/severe injury in neonates with HIE. With further study, this may aid the clinician in real‐time decision making. HRV differs by gender. Finally, inflammatory biomarkers may help elucidate the pathophysiology of HIE.

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“…Since HRV modifications correlated with inflammatory cytokine levels (Al-Shargabi et al, 2017), real-time HRV could be a useful marker of clinical acuity: indeed, HRV alterations-a decrease in RMS S , RMS L , DFA α S , LF, HF, and TP or an increase in HRC index-correlated with the pathology severity (Sullivan et al, 2014;Al-Shargabi et al, 2018). Variations in LF, HF, and LF/HF correlated with HIE severity, although more studies are needed to resolve conflicting results between studies (Andersen et al, 2019).…”

Section: Hrv As An Index To Monitor Clinical Improvementmentioning

confidence: 99%

Heart Rate Variability in the Perinatal Period: A Critical and Conceptual Review

Chiera¹,

Cerritelli²,

Casini³

et al. 2020

Front. Neurosci.

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Neonatal intensive care units (NICUs) greatly expand the use of technology. There is a need to accurately diagnose discomfort, pain, and complications, such as sepsis, mainly before they occur. While specific treatments are possible, they are often timeconsuming, invasive, or painful, with detrimental effects for the development of the infant. In the last 40 years, heart rate variability (HRV) has emerged as a noninvasive measurement to monitor newborns and infants, but it still is underused. Hence, the present paper aims to review the utility of HRV in neonatology and the instruments available to assess it, showing how HRV could be an innovative tool in the years to come. When continuously monitored, HRV could help assess the baby's overall wellbeing and neurological development to detect stress-/painrelated behaviors or pathological conditions, such as respiratory distress syndrome and hyperbilirubinemia, to address when to perform procedures to reduce the baby's stress/pain and interventions, such as therapeutic hypothermia, and to avoid severe complications, such as sepsis and necrotizing enterocolitis, thus reducing mortality. Based on literature and previous experiences, the first step to efficiently introduce HRV in the NICUs could consist in a monitoring system that uses photoplethysmography, which is low-cost and non-invasive, and displays one or a few metrics with good clinical utility. However, to fully harness HRV clinical potential and to greatly improve neonatal care, the monitoring systems will have to rely on modern bioinformatics (machine learning and artificial intelligence algorithms), which could easily integrate infant's HRV metrics, vital signs, and especially past history, thus elaborating models capable to efficiently monitor and predict the infant's clinical conditions. For this reason, hospitals and institutions will have to establish tight collaborations between the obstetric, neonatal, and pediatric departments: this way, healthcare would truly improve in every stage of the perinatal period (from conception to the first years of life), since information about patients' health would flow freely among different professionals, and high-quality research could be performed integrating the data recorded in those departments.

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Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy

Cited by 31 publications

References 37 publications

Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats

Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats

Heart rate variability and inflammatory markers in neonates with hypoxic‐ischemic encephalopathy

Heart Rate Variability in the Perinatal Period: A Critical and Conceptual Review

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