Abnormal heart rate variability at school age in survivors of neonatal hypoxic-ischemic encephalopathy managed with therapeutic hypothermia

https://doi.org/10.1016/j.ejpn.2020.08.004Get rights and content

Highlights

  • Heart rate variability is a reliable measure of autonomic function in children.

  • Plethysmography informs on heart rate variability changes at school-age, in survivors of hypoxic-ischemic encephalopathy.

  • Frequency analysis of heart rate variability highlighted autonomic over activation in patients compared to healthy peers.

  • In the absence of major neurological disability, autonomic dysfunction point to neurobiological vulnerability.

Abstract

Background and objective

Major deficits in the autonomic nervous system function, detected by measuring heart rate variability (HRV), are reported in neonatal hypoxic-ischemic encephalopathy (HIE)). However, it is unknown if they will recover in the long-term. Because of the possible implications for the neurological outcome, this study aimed to evaluate the HRV at school age, in a cohort of children who survived HIE managed with therapeutic hypothermia.

Methods

A cross-sectional study of HRV in 40 children: 20 HIE survivors and 20 healthy peers. All underwent 5-min plethysmography using the PPG Stress Flow device (BioTekna Italy). Absolute and normalized HRV spectral power in the very low frequency (VLF), low frequency (LF), and high frequency (HF) bands and total power were compared between patients and healthy children. The outcome evaluation included neurological, cognitive (WISC-IV), and psychosocial (Parent Stress Index-Short Form-PSI-SF and psychosocial interview) measures.

Results

All mean HRV values were significantly higher in survivors of HIE, compared to healthy peers, with the larger effect size for the HF band (Total Power 8.57 ± 0.59 vs 7.82 ± 0.77 ms2, p .003 ES 0.21; HF 7.82 + 0.77 vs 8.57 + 0.59 ms2, p .001 EF 0.24). None of the children had major health, neurological and psychosocial (PSI-SF/interview) problems. The IQ (WISC-IV) was normal in 17/20 patients, borderline in 2, and <70 in 1.

Conclusions

HRV measures highlight autonomic dysfunction at school age in survivors of neonatal HIE, in the absence of major neurodevelopmental and psychosocial problems. The significance of this finding for children's future life needs further neuropsychiatric investigations and longer follow-up.

Introduction

Heart rate variability (HRV) refers to changes over time in beat-to-beat intervals. It is regulated by the sympathetic and parasympathetic branches of the autonomic nervous system (ANS), giving a good measure of its function [1]. ANS plays a major role in the regulation of the body functions such as heart rate, breathing, blood pressure, and temperature contributing to the constancy of internal environment and the adaptation to external perturbations, and it is crucial for homeostasis and body health [2,3]. The ANS regulatory action is controlled by a complex network (the so-called central autonomic network) involving the brainstem, forebrain, and prefrontal cortex [4,5].

Hypoxic-ischemic encephalopathy (HIE) is a major cause of brain injury in the neonatal period, and brain regions crucial for the central autonomic control such as the prefrontal cortex, hippocampus, and brainstem [4,5] are affected in HIE [6]. ANS involvement, in hypoxic-ischemic brain injury, is further supported by observations during complicated labor [7] and by the occurrence of autonomic symptoms in moderate and severe HIE encephalopathy [8].

An easy and non-invasive way to measure ANS activity is the analysis of heart rate variability [1]. Analogous to the EEG, power spectral analysis can be used to separate HRV into its component rhythms that operate within different frequency ranges supplying both frequency and amplitude information [9]. The total frequency power informs on the general ANS activation while the three frequency bands measurable in a short term recording (5 min), high-frequency (HF) low-frequency (LF), and very low frequency (VLF) represent the parasympathetic and sympathetic modulation of the heart rate [1].

In health, sympathovagal balance reflects physical and psychological adaptability to a changing environment [10]. By contrast, ANS imbalance has been related, in the adult population, to health threats and disease [11]. In childhood, ANS dysfunction has been implicated in a variety of conditions, including gastrointestinal and connective tissue disorders, diabetes, chronic fatigue syndrome, and neuropsychiatric disorders [12,13]. In neonatal HIE, abnormalities of HRV have been reported only in the perinatal period and were associated with EEG and MRI severity [[14], [15], [16], [17]]. Moreover neonatal HRV measures were only correlated with the outcome at 2 y of age [18]. Goulding and colleagues showed that HRV tested at 48 h of life had a positive predictive value of 100% for an abnormal outcome defined as death, cerebral palsy, or a Griffith's Quotient lower than 87 [18].

The ability of HRV to recover after neonatal imbalance and/or severe depression is still unknown. However, to study ANS developmental trajectory and outcome could be particularly important, in HIE survivors. In fact, therapeutic hypothermia increased survival, free of major neurological handicaps, but the risk of neurodevelopmental disorders with onset later in life remains high [19].

Azzopardi and colleagues found that,even in the cooled group, a significant proportion of children evaluated at six to seven years of age had intellectual disability, impairment in specific neuropsychological domains, motor impairment, attention deficit hyperactivity disorder and/or sensory deficits [19].

We choose to focus on the school-age period since the beginning of the learning period, that corresponds to school entry, is an important developmental landmark. At this stage, a latent neurobiological vulnerability may allow neurodevelopmental disorders to emerge, even in the absence of severe brain damage. In fact, at school age, cerebral maturation makes a considerable growth spurt in its complexity, involving neurotransmitters systems [20] and higher-order neuropsychological functions [21].

The aim of this study was, therefore, to measure the HRV at school age in a cohort of children surviving neonatal HIE managed with therapeutic hypothermia and to compare HRV data between HIE survivors and healthy age-matched children.

Section snippets

Participants

All term and near-term neonates (≥35 gestational weeks) delivered at the Obstetric Clinic of an Italian University Hospital between January 2010 and December 2013, who underwent therapeutic hypothermia for HIE at the third level neonatal intensive care unit were eligible. In agreement with international guidelines and as previously reported [22,23], entry criteria for hypothermia at our institution were: age ≥ 35 weeks; (ii) any of the following: arterial umbilical cord or first blood gas

Results

The study cohort consisted of 40 children, 20 HIE survivors patients (mean age 6.3 years, range 5.9–7.3, 12 males), and 20 healthy children (mean age 6.5 years, range 5.8–7, 11 males).

Discussion

This study found significant differences in HRV measures between school-aged children with a neurodevelopmental risk because of neonatal HIE and age-matched healthy peers. The total power and the power of all HRV frequency bands (VLF, LV and HF), was significantly higher in the HIE survivors compared to healthy children, with the largest effect size for the HF band.

This is the first study that examined HRV a long time after the acute phase of neonatal HIE. Because of the emerging understanding

Conclusions

In conclusion, this study adds new information on the long term outcome of ANS function (as measured by HRV) in a specific type of perinatal adversity that is neonatal HIE. In fact, we demonstrated, for the first time, significant differences in ANS function between school-aged patients with a history of neonatal HIE managed with hypothermia and age-matched healthy children. These consisted of significantly increased power of all HRV bands suggesting ANS over activation and parasympathetic

Contributors’ statement

Agnese Suppiej conceptualized and designed the study, coordinated and supervised data collection, carried out the neurological evaluations, wrote the final version of the manuscript, reviewed and revised the manuscript.

Luca Vedovelli participated in data collection, performed the statistical analysis of the data, conceptualized and drafted tables and figures and reviewed and revised the manuscript.

Dario Boschiero contributed to the original idea of the study and reviewed the manuscript.

Moreno

Funding sources

This research was supported by the University of Ferrara (Incentives for research funds - FIR- 2018). BIOTEKNA Biomedical Technologies provided the PPG Stress Flow Photopletismography device. BIOTEKNA Biomedical Technologies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Declaration of competing interest

Dario Boschiero is the scientific director of BIOTEKNA Biomedical Technologies. A.S., L.V., M.B., E.C. declare no conflict of interest.

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