Normal values and correlation of age and the Heart Rate Variability in healthy children younger than 18 months

doi:10.21203/rs.3.rs-2760542/v1

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Normal values and correlation of age and the Heart Rate Variability in healthy children younger than 18 months

https://doi.org/10.21203/rs.3.rs-2760542/v1

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Purpose

A normal heart rate variability (HRV) is the result of a balanced relation between the sympathetic and parasympathetic system. Epilepsy, as one of the most common diseases worldwide, is thought to have an impact on the autonomic nervous system and could therefore lead to an imbalance. But anyway, there are no available normal values for HRV in children, especially in infants. The current study is aimed to create reference values for the HRV in children aged younger than 18 months.

Methods

We analyzed ECG curves of 30 infants, who had a routine EEG due to non-epileptic paroxysmal events. To evaluate the HRV we calculated the RMSSD (root mean square of the successive differences) and the SDNN (standard deviation of all normal sinus R/R intervals). Analyses were performed for each patient and in a second step separately for patients from 0 - <12 months and from 12 - <18 months.

Results

We found no significant differences in the different age groups regarding the HRV. Using linear regression, it was also shown that there were no other significant differences in HRV in children under 18 months of age.

Conclusions

Our results also indicate age-dependent differences when compared to previous findings in the literature and show that it is important to have age-matching normal values.

Heart rate variability (HRV)

normal values

infants

children

A normal HRV is the result of a balanced relation between the sympathetic and parasympathetic system.
Little is known about normal HRV in infants and small children.
Several diseases are thought to have an impact on the autonomic nervous system and could lead to an imbalance, but also the medication which is administered has to be taken into account.

We could present normal values of HRV in infants aged younger than 18 months.
Our results indicate age-dependent differences in HRV.

A normal heart rate variability (HRV) is the result of a balanced relation between the sympathetic and parasympathetic system. Therefore, a reduced HRV could be a sign of inadequate adaptability of the autonomic nervous system [1]–[3]. To take one of the most common diseases worldwide as an example, epilepsy is thought to have an impact on the autonomic nervous system and could lead to such an imbalance [2], [3]. There is no distinctness concerning the effect of antiepileptic treatment on a reduced HRV. Lotufo et al. could not observe an improvement of a reduced HRV after establishing an antiepileptic drug therapy [2]. Other studies found a decrease in HRV in epilepsy patients with and without antiepileptic drug therapy compared to a control group [4]. In contrast, Berilgen et al. could show a positive effect of treatment on autonomic dysfunction in epilepsy patients [5]. Møller et al. found reduced HRV in patients with West syndrome when hypsarrhythmia is present in the electroencephalography (EEG) [6]. Thus, it is evident that changes in HRV can be subject to a disease, but also to the medication which is administered. The knowledge about this is essential to inform the patients and families adequately about possible increased morbidity or mortality (e.g. due to SUDEP – sudden unexpected death in epilepsy patients [1], [4], [6]) and about side effects of the medication.

However, there are no available normal values for HRV in children, especially in infants. All mentioned studies compared their data to a distinct control group. Therefore, we aimed to create reference values for the HRV in children aged younger than 18 months to improve the explanatory power of future studies. To this end, we analyzed the correlation between age and HRV in the first 18 months of life.

This retrospective study was conducted on 30 infants aged younger than 18 months, who had a routine EEG (electroencephalogram) due to non-epileptic paroxysmal events. All examinations were carried out at the epilepsy unit of the Department of Pediatrics and Adolescent Medicine, Kepler University Hospital Linz between 03. February 2021 and 08. April 2022.

During the EEG-Monitoring the heartrate was documented using ECG (electrocardiogram) electrodes. We analyzed a period of 60s of ECG for each patient. This was done by a single investigator (A.P.) by analyzing the recorded ECG curves in the used EEG program “Natus Database”. The most artifact-free and calm phase possible was selected for this purpose. All R/R intervals were measured manually over 60 seconds and entered into an Excel file.

To evaluate the HRV we calculated the RMSSD (root mean square of the successive differences) using the definition of the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology (ESC/NASPE) 1996: “The square root of the mean of the sum of the squares of differences between adjacent R/R intervals”. This was performed for each patient. In a second step, we also calculated the mean RMSSD, both for the whole study collective and separately for patients from 0 - <12 months and from 12 - <18 months.

Because the SDNN (standard deviation of all normal sinus R/R intervals) is the “gold standard” for medical stratification of cardiac risk, we also calculated this value for each patient. Likewise, the mean SDNN was calculated for the whole study collective and separately for patients from 0 - <12 months and from 12 - <18 months.

All demographic data were collected from patient records. We assessed age, gender, and the indication for EEG examination.

To reduce inter-observer variability, the calculation and analysis were done by the same author (A.P.) for all participants under the supervision of author G.G. The intra-rater variability was a priori tested on a sample of four participants.

For data analysis, we used SPSS 28. On the one hand, we determined the mean and the standard deviation by t-test. To describe the differences between the age groups regarding the HRV we used the chi-squared test. To better represent the relationship between age and HRV we used the linear regression analysis model.

In total 30 patients younger than 18 months who had a routine EEG were retrospectively analyzed. The mean age was 8.7 months (± 4.83), range 1 to 17 months. 13 patients were male (43.33%) and 17 were female (56.67%). Of all patients, 20 were aged younger than 12 months and 10 were aged between 12 and < 18 months. For these subgroups, the mean age was 5.9 months (± 3.06) and 14.3 months (± 1.77) respectively. There were various indications for performing the EEG examination: shuddering attacks, gastroesophageal reflux, BRUE (brief resolved unexplained event), rhythmic movement disorder, transient loss of tonus, breath-holding spells, vasovagal syncope, movement stereotypes, apnea, benign myoclonus of infancy, shaking chills, striking eye movements, paroxysmal movement disorder, emotional excitement, tonic upward gaze, pain-induced twitching and pronounced VitB12 deficiency. For a detailed presentation of indications and demographic data, see Table 1.

The median RMSSD in our study collective was 15.49 ± 5.25 ms (12.99–32.28 ms; 25% 14.0 ms – 75% 21.7 ms). For patients aged < 12 months, we found a median RMSSD of 15.28 ± 3.99 ms (12.99–27.66 ms; 25% 13.77 ms – 75% 18.77 ms) and 18.72 ± 6.60 ms (13.61–32.28 ms; 25% 14.62 ms – 75% 26.04 ms) for patients aged 12 to 17 months. SDNN values were 20.94 ± 7.49 ms (9.22–44.97 ms; 25% 18.82 ms – 75% 27.97 ms) for all patients, 19.98 ± 6.72 ms (9.22–34.55 ms; 25% 17.02 ms -75% 26.29 ms) for patients aged < 12 months, and 24.62 ± 8.43 ms (15.57–44.97 ms; 25% 18.87 ms – 75% 29.15 ms) for patients aged 12 to < 18 months. A graphical presentation of these data can be seen in Fig. 1A-C.

We found no significant differences in the different age groups regarding the HRV (RMSSD p = 0.414 and SDNN p = 0.414). Using linear regression analysis and t-test, it was also shown that there were no other significant differences in HRV in children under 18 months of age (p = 0.252). A difference regarding gender could not be found.

It was previously shown, that age is an important parameter with a strong influence on HRV [7], [8]. For this reason, it is essential to obtain normal values in infancy and early childhood. Changes in HRV might be a cause of SUDEP [1], [4], [6]. Attention is now being paid to this in various studies [9], [10]. However, the value of the data collected can only be interpreted in conjunction with normal values. The aim of our study was on the one hand the correlation of HRV with age in the first 18 months of life and on the other hand the evaluation of normal values in this age group. In our study, we could show a median RMSSD of 15.49 96 ± 5.25 ms and the median SDNN value was 20.94 ± 7.49 ms in healthy children aged younger than 18 months. In the age group we studied, there were no further gradations of HRV with age. A difference regarding gender could not be found. Other studies have already described HRV in healthy children, but not yet in a structured way in this age group. Hallioglu et al. reported RMSSD values of 70.4 ± 47.6 ms and SDNN values of 66.4 ± 33.7 ms in children with a mean age of 8.1 years [4]. Evrengül et al. found an RMSSD of 46.6 ± 33.2 ms and an SDNN of 91.7 ± 34.0 ms in healthy adults [3]. We showed that small children younger than 18 months have a lower HRV (RMSSD and SDNN) compared with older children or adults mentioned in other studies (RMSSD 15.5 vs 46.6 vs 70.4 ms, SDNN 20.9 vs 91.7 66.4 ms) [3], [4]. The reason why the children in the study of Hallioglu et al. score highest would not be explained in more detail.

The main limitation of this study is that the calculations were performed manually by a single investigator. So there might be a bias due to manual imprecision. For further studies evaluating HRV in infants, an automated measurement should be preferred. This could ease the whole analysis and therefore, a larger sample size could be investigated. Studies on healthy subjects are difficult at this age because parents do not make their healthy children available for examination. For this reason, we used the ECG channels recorded during the EEG examination. Furthermore, the recording or measurement of 60 seconds is quite short. A longer recording, maybe over 24 hours might be constructive, especially as there might be changes in the HRV during different states of awareness. This could be particularly important to explain the underlying pathophysiology of SUDEP, which mostly occurs during sleep [1]. But there is also a benefit of the short measurement. Due to the short measurement, we were able to create relatively uniform test conditions. Thus, variations due to different physical activities could be excluded compared to a longer measurement in daily life.

We could present normal values of HRV in infants aged younger than 18 months. Furthermore, a subanalysis shows corresponding data for children from 0 - <12 months and 12 - <18 months of age. Our results also indicate age-dependent differences when compared to previous findings in the literature and show that it is important to have age-matching normal values.

BRUE: brief resolved unexplained event

ECG: electrocardiogram

EEG: electroencephalogram

HRV: heart rate variability

RMSSD: root mean square of the successive differences

SDNN: standard deviation of all normal sinus R/R intervals

SUDEP: sudden unexpected death in epilepsy patients

Ethical Approval:

This study was supported by the Ethics Committees of Kepler University Hospital Linz affiliated with the medical faculty of Johannes Kepler University Linz, Austria.

Competing interests:

The authors declare no competing interests.

Funding:

None.

Author contributions:

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Anna Peherstorfer. The first draft of the manuscript was written by Anna Peherstorfer and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

Table1.docx

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Normal values and correlation of age and the Heart Rate Variability in healthy children younger than 18 months

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Abstract

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Methods

Results

Conclusions

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What Is Known

What Is New

Introduction

Material And Methods

Results

Discussion

Conclusion

Abbreviations

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table

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Supplementary Files

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