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Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control
Early Human Development 91 (2015) 351–356
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control Zuzana Uhrikova a, Mirko Zibolen a, Kamil Javorka b, Lenka Chladekova b, Michal Javorka b,⁎ a b
Clinic of Neonatology, Comenius University, Jessenius Faculty of Medicine and University Hospital, Kollarova 2, 03601 Martin, Slovakia Department of Physiology, Comenius University, Jessenius Faculty of Medicine, Mala Hora 4, 03601 Martin, Slovakia
a r t i c l e
i n f o
Article history: Received 12 June 2014 Received in revised form 18 December 2014 Accepted 23 March 2015 Available online xxxx Keywords: Heart rate variability Sympatho-vagal balance Neonates Hyperbilirubinemia Phototherapy Nonlinear analysis
a b s t r a c t Background: Neonatal jaundice and its phototherapeutic treatment can lead to several side effects involving activation of autonomic control mechanisms. Aim: The aims of this study are to investigate the autonomic nervous system changes in icteric neonates using heart rate variability (HRV) and to assess the effect of phototherapy on short-term heart rate dynamics as an indicator of autonomic nervous control of cardiovascular system. Methods: HRV recordings from 20 icteric full-term neonates before, during and after phototherapy and from 20 healthy controls were analyzed. In addition to traditional time and frequency domain measures, heart rate complexity parameters including normalized complexity index (NCI), normalized unpredictability index (NUPI), pattern classification indices (0 V%, 1 V%, 2LV%, 2UV%) and irreversibility index (P%) on four time scales were evaluated. All measures were derived from data segments of 1000 RR intervals. Results: The analysis revealed higher values of 1 V%, 2LV%, and lower P% in neonates with hyperbilirubinemia compared to controls. While HRV magnitude did not change, mean heart rate increased during and after the phototherapy. Nonlinear analysis showed a decrease of complexity, unpredictability and pattern classification measures 2LV% and 2UV%. In contrast, 0 V% and irreversibility index P% were increased during and at least 30 min after phototherapy. Conclusion: The results suggest a shifted autonomic balance in icteric neonates compared to the controls and its further alterations during phototherapy. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neonatal jaundice is one of the most common conditions requiring medical intervention shortly after birth [1]. Although the positive effects of elevated serum bilirubin are currently widely discussed, it is still regarded as a dangerous neurotoxic metabolic waste product and hyperbilirubinemia needs to be identified and treated [2]. Phototherapy is commonly used to treat neonatal jaundice [3]. Although it is usually regarded as a safe intervention, it can be associated with several side effects including changes in hemodynamics, represented by a reduced cardiac output resulting from the blood redistribution [4]. Concommitant decrease in arterial blood pressure causes the activation of autonomic reflexes aimed to compensate for the evoked hemodynamic changes [5,6]. We hypothesize that the hyperbilirubinemia itself via neurotoxicity of bilirubin on autonomic centers and its treatment by phototherapy ⁎ Corresponding author at: Department of Physiology, Comenius University, Jessenius Faculty of Medicine, Mala Hora Str. N. 4, 036 01 Martin, Slovakia. Tel.: +421 43 2633404. E-mail addresses: [email protected] (Z. Uhrikova), [email protected] (M. Zibolen), [email protected] (K. Javorka), [email protected] (M. Javorka).
http://dx.doi.org/10.1016/j.earlhumdev.2015.03.009 0378-3782/© 2015 Elsevier Ireland Ltd. All rights reserved.
could influence the cardiovascular control by autonomic nervous system in newborns. Since the data on these effects are very limited, the aims of our study were: 1) to investigate an effect of hyperbilirubinemia on the heart rate autonomic control by comparing the icteric neonates with healthy control subjects; and 2) to investigate an effect of phototherapy on heart rate dynamics reflecting its autonomic nervous control in jaundiced neonates. 2. Methods 2.1. Subjects We analyzed spontaneous oscillations of heart rate – heart rate variability (HRV) – reflecting autonomic cardiac control in two groups of neonates: icteric group with hyperbilirubinemia (ICT) and healthy matched control group (CON). Into our study, only spontaneously delivered newborns with a 1-minute Apgar score N 7, and 5-minute Apgar score N 8 were included. The newborns with inappropriate postnatal adaptation, perinatal infections, congenital abnormalities and those with hyperbilirubinemia due to hemolytic disease or other disorders were excluded.
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ICT group consisted of 20 eutrophic full-term infants [median gestational age 39.5 (38 – 40) (interquartile range) weeks, 9 female/11 male, birth weight: 3395 (3030 – 3640) g, length: 51.5 (50 – 53) cm]. The total serum bilirubin concentration was measured by direct spectrophotometry 48 – 72 h after the birth before the phototherapy [249.5 (239 – 255) μmol l− 1] and 12 – 20 h after the phototherapy [241 (230 – 266) μmol l− 1]. The criteria for inclusion of a newborn into ICT group and for the treatment by phototherapy were based on the recommendation of American Academy of Pediatrics [2]. CON group consisted of 20 healthy eutrophic full-term gender matched infants [11 female/9 male, birth weight: 3305 (3050 – 3500) g, length: 51 (50 – 53) cm] with gestational age of 39 (39 – 40) weeks, without any symptom of icterus. The blood bilirubin level 48 – 72 h after birth [70 (11 – 120) μmol l−1] was significantly lower in CON compared to ICT group (Mann–Whitney U test, p b 0.0001). The study was approved by the Ethics Committee of Jessenius Faculty of Medicine, Comenius University, in accordance with the Declaration of Helsinki. All parents of the infants enrolled in the study gave their written informed consent prior to the examination. 2.2. Protocol During the measurement, all newborns were placed into the incubator (Isolette®8000, Dräger, Germany) with a temperature controlled within thermoneutral range (29.7 – 32.7 °C), blindfolded and left resting in the supine position for 30 min. The stabilization period was followed by ECG recording. In newborns from CON group, 40 min lasting recording was obtained. In ICT group, three recordings (before, during and after phototherapy; 40 min each) were obtained. As a phototherapy in ICT group, the conventional phototherapeutic lamp (FL-222, ALFAMEDIC, Czech Republic) with the spectral irradiance of 15 μW/cm2/nm was used. The wavelength of emitted light from fluorescent tube producing blue light ranged approximately from 400 to 580 nm with the maximum corresponding to 426 – 470 nm. The phototherapeutic lamp was placed 30 cm from the newborn's body surface and whole body surface (except areas of diaper and eye shield) was irradiated. To avoid influence of body temperature changes, the rectal temperature of the newborn was measured regularly during study protocol by the standard thermometer and maintained in the normal range (36.5 – 37.5 °C), i.e.: during measurement, if the rectal temperature of the newborn has a tendency to decrease or increase outside this range (occuring only very rarely in our group of full-term infants), the preset temperature inside the incubator was manually decreased or increased, respectively, to hold the body temperature inside a normal range. The newborns were 1 – 2 h after last feeding and the external visual and acoustic stimuli were minimized during study protocol. The behavioral state of the newborn was monitored and classified visually during whole recording according to Stefanski [7]. 2.3. Data recording and pre-processing The neonatal ECG signal was recorded by the bipolar horizontal thoracic ECG lead of portable devices for continuous heart rate recording VarCor PF6 and VarCor PF7 (Dimea, Czech Republic) with a sampling frequency of 1000 Hz. The RR interval was defined as the time interval between two consecutive R peaks after their automatic detection within QRS complex in the ECG signal. The recordings were visually checked and rarely occurring ectopic beats were interpolated linearly. From the 40-min recordings, 1000 heart beats long segments with the newborn in quite state (according to Stefanski criteria, patterns 2 – 3) were selected and analyzed. 2.4. Data analysis Analysis of HRV was performed on RR intervals time series – 1000 heart beats long segments – obtained during each condition in ICT
group (before – PT1, during – PT2, and after the phototherapy – PT3 segment) and in the control group (1 segment) – using custom-made software. HRV was analyzed by standard linear time and frequency domain measures [8], and nonlinear approach including measures derived by symbolic dynamics approach [9] and time irreversibility analysis [10]. 2.4.1. Linear analysis 2.4.1.1. Time domain analysis. We computed three commonly used measures (expressed in ms): - meanNN—mean length of normal RR interval as an index related to average heart rate - SDNN—standard deviation of normal RR intervals length reflecting the overall HRV magnitude - rMSSD—root-mean-square of successive beat-to-beat differences in normal RR interval duration reflecting the average magnitude of changes between two consecutive beats regarded as a marker of vagal heart rate control 2.4.1.2. Frequency domain analysis. We computed the spectral powers of HRV using fast Fourier transform in two frequency bands: - low frequency band (LF: 0.04 – 0.15 Hz) reflecting the parasympathetic, sympathetic and baroreflex activity - high frequency band (HF: 0.15 – 1.4 Hz) determined mainly by the respiratory sinus arrhythmia; regarded as a marker of the cardiac vagal control. 2.4.2. Nonlinear analysis Firstly, we analyzed the complexity, unpredictability and measures quantifying patterns distribution of the time series using the symbolic dynamics method [9]: - normalized complexity index (NCI)—a measure of the oscillations complexity, it ranges from zero (maximum regularity of the time series) to one (maximum complexity of the time series). - normalized unpredictability index (NUPI) measures the unpredictability of the heart rate oscillations—the larger NUPI indicates the more unpredictable heart rate time series. - pattern classification in HRV. Three beats long sequences in heart rate oscillations encoded into symbols were grouped into: 1) patterns with no variation (0 V, all three symbols are equal); 2) patterns with one variation (1 V, two consecutive symbols are equal and the remaining one is different); 3) patterns with two like variations (2LV, three symbols form an ascending or descending ramp), and 4) patterns with two unlike variations (2UV, three symbols form a peak or a valley). The rates of occurrence of these patterns in HRV recording were indicated as 0 V%, 1 V%, 2LV% and 2UV%. These indices are proposed to follow the changes of the sympatho-vagal balance—an increase of 0 V% was associated with an increase of sympathetic activity, while a decrease in 2LV% accompanied the vagal withdrawal during orthostatic test (head-up tilt) in adults [11]. 2.4.2.1. Time irreversibility. Time irreversibility or time asymmetry is a recently described phenomenon in heart rate (or RR intervals) time series characterized by the non-equal number and different steepness of increases compared to decreases within the spontaneous variability. In our study, we used Porta's index (P%) [12,13] to quantify time irreversibility of RR intervals time series on four different time scales using multiscale approach employing a coarse-graining procedure [14]. 2.5. Statistical analysis We used nonparametric tests due to non-gaussian distribution of HRV parameters. Comparisons between groups were performed by the Mann–Whitney U-test. The changes in the HRV measures in ICT group assessed before, during and after the phototherapy (PT1 vs PT2
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Fig. 1. Box-and-whisker plots representing linear time domain parameters: mean normal RR interval—meanNN (left), SDNN and rMSSD (middle) and frequency domain parameters (right) derived from the HRV time series of the icteric (ICT) and control (CON) neonates. Asterisks and circles correspond to outliers.
vs PT3) were analyzed by Friedman test. A p value (two-tailed) b 0.05 was considered statistically significant. All values are presented as median and interquartile range. 3. Results 3.1. Effect of hyperbilirubinemia—between groups comparison 3.1.1. Linear analysis The statistical analysis did not reveal any significant betweengroups difference in linear time domain (meanNN, SDNN, rMSSD) and frequency domain (LF, HF) measures (Fig. 1). 3.1.2. Nonlinear analysis Analysis of the complexity (NCI) and unpredictability (NUPI) of the HRV series revealed no significant between-group differences. Pattern classification analysis showed significantly higher values of 1 V% (p = 0.026) and 2LV% (p = 0.009) in the group with hyperbilirubinemia (ICT) compared to the control group (Fig. 2). We observed lower P% in ICT group compared to the controls for time scales 2 (p = 0.044) and 4 (p = 0.022) (Fig. 3). 3.2. Effect of phototherapy 3.2.1. Linear analysis The statistical analysis revealed a decrease in the mean RR interval length during and after phototherapy while other linear measures (SDNN, rMSSD, LF, HF) remained unchanged (Fig. 4).
3.2.2. Nonlinear analysis Statistical analysis showed a significant reduction in the complexity (NCI, p = 0.041) and unpredictability (NUPI, p = 0.015) of the HRV series during and after the phototherapy. In addition, the 0 V% index increased (p = 0.026), while 2LV% (p = 0.008) and 2UV% (p = 0.006) decreased during and after the treatment (Fig. 5). The analysis showed increased P% during and after the phototherapy on scales 2 (p = 0.021) and 4 (p = 0. 001) (Fig. 6). 4. Discussion Our study revealed subtle differences in cardiovascular control as the effects of hyperbilirubinemia and its treatment by phototherapy. These differences were detectable by novel nonlinear methods of heart rate variability analysis only. 4.1. Effect of hyperbilirubinemia The adverse effects of bilirubin on central nervous system in newborns are based on the ability of free bilirubin to pass through immature blood–brain barrier. Therefore, considering the neurotoxicity of bilirubin, its increasing level could be also related to the impairment of cardiovascular autonomic control mechanisms [15]. Our study was focused on the mathematical analysis of spontaneous oscillations in heart rate (heart rate variability—HRV). Analysis of HRV recorded under standardized conditions is a rapid, noninvasive, sensitive and reproducible method to assess cardiac autonomic regulation
Fig. 2. Box-and-whisker plots representing complexity (NCI) and unpredictability indices (NUPI) (left) and pattern classification indices 0 V%, 1 V%, 2LV%, 2UV% (right) in the icteric (ICT) and control (CON) neonates. Asterisks and circles correspond to outliers. #: significant between groups difference.
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studies analyzing the effect of orthostasis as a maneuver shifting the sympatho-vagal balance towards sympathetic dominance on symbolic dynamics and time irreversibility measures in adults [26,27], we suggest that – using novel HRV analysis methods – we were able to detect a subtle shift in the cardiovascular control system towards parasympathetic activity increase and/or sympathetic activity decrease in icteric newborns. The children were assigned into two groups (icteric and control) having all conditions and characteristics similar except blood bilirubin level. Taken together, we suggest that increased bilirubin level in icteric newborns could influence the cardiac autonomic control mechanisms. The heart rate dynamics changes were not detected by linear measures indicating the higher sensitivity of nonlinear measures to detect subtle abnormalities/changes within heart rate dynamics. 4.2. Effect of phototherapy Fig. 3. Box-and-whisker plots representing irreversibility index P% derived from the HRV time series for multiple time scales (τ = 1, 2, 3, 4) in the icteric (ICT) and control (CON) groups. #: Significant between-groups difference of the corresponding index value.
[8]. Traditionally used linear analysis in the time and frequency domains quantifies the magnitude of heart rate oscillations [8]. In our study, conventional linear analysis of HRV did not reveal any significant difference between icteric and control newborns. It indicates that pathologically increased bilirubin level in icteric newborns does not have a significant effect on the magnitude of HRV. Since the HRV is predominantly influenced by vagal innervation [16] it could indicate that parasympathetic activity is not significantly changed by hyperbilirubinemia. However, recent studies have shown that HRV analysis should also include novel nonlinear measures quantifying various qualitative aspects of the HRV maximizing the information obtained from HRV recording [14,17]. This recommendation is based on the fact that healthy neonatal, as well as the adult heart rate, is controlled by a very complex nonlinear control system where output is disproportional to the system inputs. The nonlinear analysis of HRV has a potential to provide more appropriate, precise and sensitive information as it reflects the complex dynamics of the heart rate modulation [18–21]. The qualitative characteristics of the oscillations represented by the methods focused on complexity, unpredictability, irregularity or time irreversibility of HRV are independent from the oscillations magnitude. Therefore, the combination of linear and nonlinear HRV analysis could describe the neurocardiac control more comprehensively and concisely than traditionally used linear (time and frequency domain) measures [22–25]. Our results confirmed this assumption: several indices based on nonlinear dynamics (1LV%, 2LV%, P% on scales 2 and 4) were able to detect subtle between groups differences not detectable by conventional analysis. Comparing our findings with the results of previous
Phototherapy used as a treatment of neonatal jaundice has several side effects including hemodynamic and behavioral changes [4]. Despite the controlled temperature in incubator, a conventional phototherapy can induce profound vasodilation in the skin vessels via increased nitric oxide production [28,29] accompanied by an increase in skin surface temperature by 0.3 – 0.6 °C [30]. Peripheral vasodilation and reduced motor activity of an infant lead to a reduction in cardiac output 30 min after phototherapy followed by an activation of autonomic compensatory mechanisms via baroreflex resulting in blood flow redistribution and heart rate changes [5]. Despite the large number of studies investigating short- and longterm effects of phototherapy, information on the autonomic nervous system changes during phototherapy are very sparse. To our knowledge, only one study was performed so far to investigate the changes in cardiovascular autonomic control during phototherapy [30]. We have observed a borderline significant increase in heart rate during and after phototherapy. Magnitude of HRV oscillations quantified by time and frequency domain indices was not significantly changed by phototherapy. In contrast to Weissman et al. [30], we have not observed any decrease in overall and beat-to-beat HRV magnitude. The application of nonlinear dynamics approach in our study has shown significant changes in symbolic dynamics and time irreversibility indices during and after phototherapy. From symbolic dynamics measures, 2LV%, 2UV% decreased and 0 V% increased, while heart rate oscillations complexity and unpredictability (NCI and NUPI) decreased during and after phototherapy. These changes indicate that the response of autonomic nervous system expressed in chronotropic cardiac regulation during and after phototherapy could be characterized by a shift in sympatho-vagal balance towards sympathetic dominance and this modification persists at least 30 min after phototherapy.
Fig. 4. Box-and-whisker plots representing linear time domain parameters: meanNN (left), SDNN and rMSSD (middle); and frequency domain parameters (right) in icteric neonates before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
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Fig. 5. Box-and-whisker plots representing complexity (NCI) and unpredictability (NUPI) (left) and pattern classification indices 0 V%, 1 V%, 2LV%, 2UV% (right) in icteric neonates before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
The major limitation of our study is the lacking information about the skin surface temperature changes during the experimental protocol. Therefore, we cannot exclude the possibility of enhanced vasodilation in skin vasculature associated with the potentially increased body surface temperature. Additionally, the heating effect of conventional phototherapy could enhance insensible water loss [3]. These effects could lead to blood redistribution evoking a shift in cardiovascular autonomic nervous system balance. Our goal was to observe the effects of conventional phototherapy where potential effect of the heating by infrared radiation generated by the lamp could not be excluded. The LED technology based phototherapy (used mostly for intensive phototherapy with the possibility to increase light intensity used for phototherapy up to irradiation of N30 μW/cm2/nm) where the infrared radiation is almost completely suppressed is now available. The effect of LED based phototherapy on cardiovascular autonomic nervous system could differ from the observations in our study but it requires further study. We tried to minimize the overall thermic effect of the phototherapeutic lamp. Since in our study we applied conventionally used fluorescence tube lamp emitting a limited amount of radiation also in the infrared part of the electromagnetic spectrum, the core body temperature of the newborn was monitored during phototherapy and any deviation from the normal range was counterbalanced by the changes of preset temperature inside incubator. It resulted in stable body temperature of the subjects in our study. Therefore, we suggest that the changes in body temperature did not contribute to observed ANS changes during phototherapy. Our study provided an observation of the ANS changes related to hyperbilirubinemia and its treatment by phototherapy. However, the
exact mechanism(s) of observed shifts in sympatho-vagal balance need further study. It would be of benefit not only to measure body surface temperature but the information about the time course of bilirubin degradation products concentration during and after phototherapy could be helpful in understanding the exact mechanisms of found effects. The importance of cardiovascular/autonomic nervous system changes during and after phototherapy is stressed by the fact that autonomic dysregulation could lead to serious consequences including severe ventricular arrhythmia and sudden death. Knowledge on cardiovascular control system response is very important to prevent potential adverse effects. However, based on our results, we cannot conclude if the observed subtle autonomic nervous system changes are of any clinical importance and they require further study. In conclusion, our study revealed subtle differences in resting cardiac autonomic control in newborns with hyperbilirubinemia using nonlinear measures. In addition, we found mean heart rate and its variability changes during and after phototherapy. Our observations point towards mildly increased parasympathetic activity associated with hyperbilirubinemia, and a shift in sympatho-vagal balance associated with vagal withdrawal and/or sympathetic activation during phototherapy persisting at least 30 min after this intervention. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgments This study was supported by grants VEGA N. 1/0223/12, 1/0059/13 and APVV-0235-12. References
Fig. 6. Box-and-whisker plots representing time irreversibility index P% derived from the RR intervals time series for multiple time scales (τ = 1, 2, 3, 4) in the icteric group before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
[1] Rennie J, Burman-Roy S, Murphy MS. Guideline Development Group. Neonatal jaundice: summary of NICE guidance. BMJ 2010;340:c2409. [2] American Academy of Pediatrics. Management of hyperbilirubinemia in newborn infant 35 or more week of gestation. Pediatrics 2004;114:297–316. [3] Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008; 358:920–8. [4] Xiong T, Tang J, Mu DZ. Side effects of phototherapy for neonatal hyperbilirubinemia. Chin J Contemp Pediatr 2012;14:396–400. [5] Benders MJ, Van Bel F, Vande Bor M. Haemodynamic consequences of phototherapy in term infants. Eur J Pediatr 1999;158:323–8. [6] Pezzati M, Fusi F, Dani C, Piva D, Bertini G, Rubaltelli FF. Changes in skin temperature of hyperbilirubinemic newborns under phototherapy: conventional versus fibrooptic device. Am J Perinatol 2002;19:439–43.
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[7] Stefanski M, Schulze K, Bateman D, Kairam R, Pedley TA, Masterson J, et al. A scoring system for states of sleep and wakefulness in term and preterm infants. Pediatr Res 1984;18:58–63. [8] Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–65. [9] Porta A, Guzzetti S, Montano N, Furlan R, Pagani M, Malliani A, et al. Entropy, entropy rate, and pattern clasification as tools to typify complexity in short heart period variability series. IEEE Trans Biomed Eng 2001;48:1282–91. [10] Chladekova L, Czippelova B, Turianikova Z, Tonhajzerova I, Calkovska A, Baumert M, et al. Multiscale time irreversibility of heart rate and blood pressure variability during orthostasis. Physiol Meas 2012;33:1747–56. [11] Porta A, Faes L, Mase M, D`Addio G, Pinna GD, Maestri R, et al. Symbolic analysis of short-term heart period variability during graded head-uptilt. Comput Cardiol 2006;33:109–12. [12] Porta A, Casali KR, Gnecchi-Ruscone T, Tobaldini E, Montano N, Lange S, et al. Temporal asymmetries of short-term heart period variability are linked to autonomic regulation. Am J Physiol Regul Integr Comp Physiol 2008;295:R550–7. [13] Hou F, Zhuang J, Bian C, Tong T, Chen Y, Yin J, et al. Analysis of heartbeat asymmetry based on multi-scale time irreversibility test. Phys A 2010;389:754–60. [14] Costa MD, Peng CK, Goldberger AL. Multiscale analysis of heart rate dynamics: entropy and time irreversibility measures. Cardiovasc Eng 2008;8:88–93. [15] Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concept in bilirubin encephalopahy. Eur J Clin Invest 2003;33:988–97. [16] Beckers F, Verheyden B, Ramaekers D, Swynghedauw B, Aubert AE. Effects of autonomic blockade on non-linear cardiovascular variability indices in rats. Clin Exp Pharmacol Physiol 2006;33:431–9. [17] Batchinsky AI, Cooke WH, Kuusela T, Cancio LC. Loss of complexity characterizes the heart rate response to experimental hemorrhagic shock in swine. Crit Care Med 2007;35:519–25. [18] Friedman BH. An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone. Biol Psychol 2007;74:185–99. [19] Goldberger AL, Rigney DR, West BJ. Chaos and fractals in human physiology. Sci Am 1990;262:42–9.
[20] Maestri R, Pinna GD, Porta A, Balocchi R, Sassi R, Signorini MG, et al. Assessing nonlinear properties of heart rate variability from short-term recordings: are these measurements reliable? Physiol Meas 2007;28:1067–77. [21] McNames J, Aboy M. Reliability and accuracy of heart rate variability metrics versus ECG segment duration. Med Biol Eng Comput 2006;44:747–56. [22] Cysarz D, Linhard M, Edelhauser F, Langler A, Van Leeuwen P, Henze G, et al. Symbolic patterns of heart rate dynamics reflect cardiac autonomic changes during childhood and adolescence. Auton Neurosci 2013;178:37–43. [23] Voss A, Schulz S, Schroeder R, Baumert M, Caminal P. Methods derived from nonlinear dynamics for analysing heart rate variability. Philos Transact A Math Phys Eng Sci 2009;367:277–96. [24] Doyle OM, Korotchikova I, Lightbody G, Marnane W, Kerins D, Boylan GB. Heart rate variability during sleep in healthy term newborns in the early postnatal period. Physiol Meas 2009;30:847–60. [25] Longin E, Gerstner T, Schaible T, Lenz T, König S. Maturation of the autonomic nervous system: differences in heart rate variability in premature vs. term infant. J Perinat Med 2006;34:303–8. [26] Porta A, Tobaldini E, Guzzetti S, Furlan R, Montano N, Gnecchi-Ruscone T. Assessment of cardiac autonomic modulation during graded head-up tilt by symbolic analysis of heart rate variability. Am J Physiol Heart Circ Physiol 2007;293:H702–8. [27] Chladekova L, Turianikova Z, Tonhajzerova I, Calkovska A, Javorka M. Time irreversibility of heart rate oscillations during orthostasis. Acta Med Mart 2011(Suppl. 1): 41–5. [28] Jahnukainen T, Lindqvist A, Jalonen J, Kero P, Valimaki I. Responsiveness of cutaneous vasculature to thermal stimulation during phototherapy in neonatal jaundice. Eur J Pediatr 1999;158:757–60. [29] Liu GS, Wu H, Wu BQ, Huang RZ, Zhao LH, Wen Y. Effect of phototherapy on blood endothelin and nitric oxide levels: clinical significance in preterm infants. World J Pediatr 2008;4:31–5. [30] Weissman A, Berkowitz E, Smolkin T, Blazer S. Effect of phototherapy on neonatal heart rate variability and complexity. Neonatology 2009;95:41–6.
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control Zuzana Uhrikova a, Mirko Zibolen a, Kamil Javorka b, Lenka Chladekova b, Michal Javorka b,⁎ a b
Clinic of Neonatology, Comenius University, Jessenius Faculty of Medicine and University Hospital, Kollarova 2, 03601 Martin, Slovakia Department of Physiology, Comenius University, Jessenius Faculty of Medicine, Mala Hora 4, 03601 Martin, Slovakia
a r t i c l e
i n f o
Article history: Received 12 June 2014 Received in revised form 18 December 2014 Accepted 23 March 2015 Available online xxxx Keywords: Heart rate variability Sympatho-vagal balance Neonates Hyperbilirubinemia Phototherapy Nonlinear analysis
a b s t r a c t Background: Neonatal jaundice and its phototherapeutic treatment can lead to several side effects involving activation of autonomic control mechanisms. Aim: The aims of this study are to investigate the autonomic nervous system changes in icteric neonates using heart rate variability (HRV) and to assess the effect of phototherapy on short-term heart rate dynamics as an indicator of autonomic nervous control of cardiovascular system. Methods: HRV recordings from 20 icteric full-term neonates before, during and after phototherapy and from 20 healthy controls were analyzed. In addition to traditional time and frequency domain measures, heart rate complexity parameters including normalized complexity index (NCI), normalized unpredictability index (NUPI), pattern classification indices (0 V%, 1 V%, 2LV%, 2UV%) and irreversibility index (P%) on four time scales were evaluated. All measures were derived from data segments of 1000 RR intervals. Results: The analysis revealed higher values of 1 V%, 2LV%, and lower P% in neonates with hyperbilirubinemia compared to controls. While HRV magnitude did not change, mean heart rate increased during and after the phototherapy. Nonlinear analysis showed a decrease of complexity, unpredictability and pattern classification measures 2LV% and 2UV%. In contrast, 0 V% and irreversibility index P% were increased during and at least 30 min after phototherapy. Conclusion: The results suggest a shifted autonomic balance in icteric neonates compared to the controls and its further alterations during phototherapy. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neonatal jaundice is one of the most common conditions requiring medical intervention shortly after birth [1]. Although the positive effects of elevated serum bilirubin are currently widely discussed, it is still regarded as a dangerous neurotoxic metabolic waste product and hyperbilirubinemia needs to be identified and treated [2]. Phototherapy is commonly used to treat neonatal jaundice [3]. Although it is usually regarded as a safe intervention, it can be associated with several side effects including changes in hemodynamics, represented by a reduced cardiac output resulting from the blood redistribution [4]. Concommitant decrease in arterial blood pressure causes the activation of autonomic reflexes aimed to compensate for the evoked hemodynamic changes [5,6]. We hypothesize that the hyperbilirubinemia itself via neurotoxicity of bilirubin on autonomic centers and its treatment by phototherapy ⁎ Corresponding author at: Department of Physiology, Comenius University, Jessenius Faculty of Medicine, Mala Hora Str. N. 4, 036 01 Martin, Slovakia. Tel.: +421 43 2633404. E-mail addresses: [email protected] (Z. Uhrikova), [email protected] (M. Zibolen), [email protected] (K. Javorka), [email protected] (M. Javorka).
http://dx.doi.org/10.1016/j.earlhumdev.2015.03.009 0378-3782/© 2015 Elsevier Ireland Ltd. All rights reserved.
could influence the cardiovascular control by autonomic nervous system in newborns. Since the data on these effects are very limited, the aims of our study were: 1) to investigate an effect of hyperbilirubinemia on the heart rate autonomic control by comparing the icteric neonates with healthy control subjects; and 2) to investigate an effect of phototherapy on heart rate dynamics reflecting its autonomic nervous control in jaundiced neonates. 2. Methods 2.1. Subjects We analyzed spontaneous oscillations of heart rate – heart rate variability (HRV) – reflecting autonomic cardiac control in two groups of neonates: icteric group with hyperbilirubinemia (ICT) and healthy matched control group (CON). Into our study, only spontaneously delivered newborns with a 1-minute Apgar score N 7, and 5-minute Apgar score N 8 were included. The newborns with inappropriate postnatal adaptation, perinatal infections, congenital abnormalities and those with hyperbilirubinemia due to hemolytic disease or other disorders were excluded.
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ICT group consisted of 20 eutrophic full-term infants [median gestational age 39.5 (38 – 40) (interquartile range) weeks, 9 female/11 male, birth weight: 3395 (3030 – 3640) g, length: 51.5 (50 – 53) cm]. The total serum bilirubin concentration was measured by direct spectrophotometry 48 – 72 h after the birth before the phototherapy [249.5 (239 – 255) μmol l− 1] and 12 – 20 h after the phototherapy [241 (230 – 266) μmol l− 1]. The criteria for inclusion of a newborn into ICT group and for the treatment by phototherapy were based on the recommendation of American Academy of Pediatrics [2]. CON group consisted of 20 healthy eutrophic full-term gender matched infants [11 female/9 male, birth weight: 3305 (3050 – 3500) g, length: 51 (50 – 53) cm] with gestational age of 39 (39 – 40) weeks, without any symptom of icterus. The blood bilirubin level 48 – 72 h after birth [70 (11 – 120) μmol l−1] was significantly lower in CON compared to ICT group (Mann–Whitney U test, p b 0.0001). The study was approved by the Ethics Committee of Jessenius Faculty of Medicine, Comenius University, in accordance with the Declaration of Helsinki. All parents of the infants enrolled in the study gave their written informed consent prior to the examination. 2.2. Protocol During the measurement, all newborns were placed into the incubator (Isolette®8000, Dräger, Germany) with a temperature controlled within thermoneutral range (29.7 – 32.7 °C), blindfolded and left resting in the supine position for 30 min. The stabilization period was followed by ECG recording. In newborns from CON group, 40 min lasting recording was obtained. In ICT group, three recordings (before, during and after phototherapy; 40 min each) were obtained. As a phototherapy in ICT group, the conventional phototherapeutic lamp (FL-222, ALFAMEDIC, Czech Republic) with the spectral irradiance of 15 μW/cm2/nm was used. The wavelength of emitted light from fluorescent tube producing blue light ranged approximately from 400 to 580 nm with the maximum corresponding to 426 – 470 nm. The phototherapeutic lamp was placed 30 cm from the newborn's body surface and whole body surface (except areas of diaper and eye shield) was irradiated. To avoid influence of body temperature changes, the rectal temperature of the newborn was measured regularly during study protocol by the standard thermometer and maintained in the normal range (36.5 – 37.5 °C), i.e.: during measurement, if the rectal temperature of the newborn has a tendency to decrease or increase outside this range (occuring only very rarely in our group of full-term infants), the preset temperature inside the incubator was manually decreased or increased, respectively, to hold the body temperature inside a normal range. The newborns were 1 – 2 h after last feeding and the external visual and acoustic stimuli were minimized during study protocol. The behavioral state of the newborn was monitored and classified visually during whole recording according to Stefanski [7]. 2.3. Data recording and pre-processing The neonatal ECG signal was recorded by the bipolar horizontal thoracic ECG lead of portable devices for continuous heart rate recording VarCor PF6 and VarCor PF7 (Dimea, Czech Republic) with a sampling frequency of 1000 Hz. The RR interval was defined as the time interval between two consecutive R peaks after their automatic detection within QRS complex in the ECG signal. The recordings were visually checked and rarely occurring ectopic beats were interpolated linearly. From the 40-min recordings, 1000 heart beats long segments with the newborn in quite state (according to Stefanski criteria, patterns 2 – 3) were selected and analyzed. 2.4. Data analysis Analysis of HRV was performed on RR intervals time series – 1000 heart beats long segments – obtained during each condition in ICT
group (before – PT1, during – PT2, and after the phototherapy – PT3 segment) and in the control group (1 segment) – using custom-made software. HRV was analyzed by standard linear time and frequency domain measures [8], and nonlinear approach including measures derived by symbolic dynamics approach [9] and time irreversibility analysis [10]. 2.4.1. Linear analysis 2.4.1.1. Time domain analysis. We computed three commonly used measures (expressed in ms): - meanNN—mean length of normal RR interval as an index related to average heart rate - SDNN—standard deviation of normal RR intervals length reflecting the overall HRV magnitude - rMSSD—root-mean-square of successive beat-to-beat differences in normal RR interval duration reflecting the average magnitude of changes between two consecutive beats regarded as a marker of vagal heart rate control 2.4.1.2. Frequency domain analysis. We computed the spectral powers of HRV using fast Fourier transform in two frequency bands: - low frequency band (LF: 0.04 – 0.15 Hz) reflecting the parasympathetic, sympathetic and baroreflex activity - high frequency band (HF: 0.15 – 1.4 Hz) determined mainly by the respiratory sinus arrhythmia; regarded as a marker of the cardiac vagal control. 2.4.2. Nonlinear analysis Firstly, we analyzed the complexity, unpredictability and measures quantifying patterns distribution of the time series using the symbolic dynamics method [9]: - normalized complexity index (NCI)—a measure of the oscillations complexity, it ranges from zero (maximum regularity of the time series) to one (maximum complexity of the time series). - normalized unpredictability index (NUPI) measures the unpredictability of the heart rate oscillations—the larger NUPI indicates the more unpredictable heart rate time series. - pattern classification in HRV. Three beats long sequences in heart rate oscillations encoded into symbols were grouped into: 1) patterns with no variation (0 V, all three symbols are equal); 2) patterns with one variation (1 V, two consecutive symbols are equal and the remaining one is different); 3) patterns with two like variations (2LV, three symbols form an ascending or descending ramp), and 4) patterns with two unlike variations (2UV, three symbols form a peak or a valley). The rates of occurrence of these patterns in HRV recording were indicated as 0 V%, 1 V%, 2LV% and 2UV%. These indices are proposed to follow the changes of the sympatho-vagal balance—an increase of 0 V% was associated with an increase of sympathetic activity, while a decrease in 2LV% accompanied the vagal withdrawal during orthostatic test (head-up tilt) in adults [11]. 2.4.2.1. Time irreversibility. Time irreversibility or time asymmetry is a recently described phenomenon in heart rate (or RR intervals) time series characterized by the non-equal number and different steepness of increases compared to decreases within the spontaneous variability. In our study, we used Porta's index (P%) [12,13] to quantify time irreversibility of RR intervals time series on four different time scales using multiscale approach employing a coarse-graining procedure [14]. 2.5. Statistical analysis We used nonparametric tests due to non-gaussian distribution of HRV parameters. Comparisons between groups were performed by the Mann–Whitney U-test. The changes in the HRV measures in ICT group assessed before, during and after the phototherapy (PT1 vs PT2
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Fig. 1. Box-and-whisker plots representing linear time domain parameters: mean normal RR interval—meanNN (left), SDNN and rMSSD (middle) and frequency domain parameters (right) derived from the HRV time series of the icteric (ICT) and control (CON) neonates. Asterisks and circles correspond to outliers.
vs PT3) were analyzed by Friedman test. A p value (two-tailed) b 0.05 was considered statistically significant. All values are presented as median and interquartile range. 3. Results 3.1. Effect of hyperbilirubinemia—between groups comparison 3.1.1. Linear analysis The statistical analysis did not reveal any significant betweengroups difference in linear time domain (meanNN, SDNN, rMSSD) and frequency domain (LF, HF) measures (Fig. 1). 3.1.2. Nonlinear analysis Analysis of the complexity (NCI) and unpredictability (NUPI) of the HRV series revealed no significant between-group differences. Pattern classification analysis showed significantly higher values of 1 V% (p = 0.026) and 2LV% (p = 0.009) in the group with hyperbilirubinemia (ICT) compared to the control group (Fig. 2). We observed lower P% in ICT group compared to the controls for time scales 2 (p = 0.044) and 4 (p = 0.022) (Fig. 3). 3.2. Effect of phototherapy 3.2.1. Linear analysis The statistical analysis revealed a decrease in the mean RR interval length during and after phototherapy while other linear measures (SDNN, rMSSD, LF, HF) remained unchanged (Fig. 4).
3.2.2. Nonlinear analysis Statistical analysis showed a significant reduction in the complexity (NCI, p = 0.041) and unpredictability (NUPI, p = 0.015) of the HRV series during and after the phototherapy. In addition, the 0 V% index increased (p = 0.026), while 2LV% (p = 0.008) and 2UV% (p = 0.006) decreased during and after the treatment (Fig. 5). The analysis showed increased P% during and after the phototherapy on scales 2 (p = 0.021) and 4 (p = 0. 001) (Fig. 6). 4. Discussion Our study revealed subtle differences in cardiovascular control as the effects of hyperbilirubinemia and its treatment by phototherapy. These differences were detectable by novel nonlinear methods of heart rate variability analysis only. 4.1. Effect of hyperbilirubinemia The adverse effects of bilirubin on central nervous system in newborns are based on the ability of free bilirubin to pass through immature blood–brain barrier. Therefore, considering the neurotoxicity of bilirubin, its increasing level could be also related to the impairment of cardiovascular autonomic control mechanisms [15]. Our study was focused on the mathematical analysis of spontaneous oscillations in heart rate (heart rate variability—HRV). Analysis of HRV recorded under standardized conditions is a rapid, noninvasive, sensitive and reproducible method to assess cardiac autonomic regulation
Fig. 2. Box-and-whisker plots representing complexity (NCI) and unpredictability indices (NUPI) (left) and pattern classification indices 0 V%, 1 V%, 2LV%, 2UV% (right) in the icteric (ICT) and control (CON) neonates. Asterisks and circles correspond to outliers. #: significant between groups difference.
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studies analyzing the effect of orthostasis as a maneuver shifting the sympatho-vagal balance towards sympathetic dominance on symbolic dynamics and time irreversibility measures in adults [26,27], we suggest that – using novel HRV analysis methods – we were able to detect a subtle shift in the cardiovascular control system towards parasympathetic activity increase and/or sympathetic activity decrease in icteric newborns. The children were assigned into two groups (icteric and control) having all conditions and characteristics similar except blood bilirubin level. Taken together, we suggest that increased bilirubin level in icteric newborns could influence the cardiac autonomic control mechanisms. The heart rate dynamics changes were not detected by linear measures indicating the higher sensitivity of nonlinear measures to detect subtle abnormalities/changes within heart rate dynamics. 4.2. Effect of phototherapy Fig. 3. Box-and-whisker plots representing irreversibility index P% derived from the HRV time series for multiple time scales (τ = 1, 2, 3, 4) in the icteric (ICT) and control (CON) groups. #: Significant between-groups difference of the corresponding index value.
[8]. Traditionally used linear analysis in the time and frequency domains quantifies the magnitude of heart rate oscillations [8]. In our study, conventional linear analysis of HRV did not reveal any significant difference between icteric and control newborns. It indicates that pathologically increased bilirubin level in icteric newborns does not have a significant effect on the magnitude of HRV. Since the HRV is predominantly influenced by vagal innervation [16] it could indicate that parasympathetic activity is not significantly changed by hyperbilirubinemia. However, recent studies have shown that HRV analysis should also include novel nonlinear measures quantifying various qualitative aspects of the HRV maximizing the information obtained from HRV recording [14,17]. This recommendation is based on the fact that healthy neonatal, as well as the adult heart rate, is controlled by a very complex nonlinear control system where output is disproportional to the system inputs. The nonlinear analysis of HRV has a potential to provide more appropriate, precise and sensitive information as it reflects the complex dynamics of the heart rate modulation [18–21]. The qualitative characteristics of the oscillations represented by the methods focused on complexity, unpredictability, irregularity or time irreversibility of HRV are independent from the oscillations magnitude. Therefore, the combination of linear and nonlinear HRV analysis could describe the neurocardiac control more comprehensively and concisely than traditionally used linear (time and frequency domain) measures [22–25]. Our results confirmed this assumption: several indices based on nonlinear dynamics (1LV%, 2LV%, P% on scales 2 and 4) were able to detect subtle between groups differences not detectable by conventional analysis. Comparing our findings with the results of previous
Phototherapy used as a treatment of neonatal jaundice has several side effects including hemodynamic and behavioral changes [4]. Despite the controlled temperature in incubator, a conventional phototherapy can induce profound vasodilation in the skin vessels via increased nitric oxide production [28,29] accompanied by an increase in skin surface temperature by 0.3 – 0.6 °C [30]. Peripheral vasodilation and reduced motor activity of an infant lead to a reduction in cardiac output 30 min after phototherapy followed by an activation of autonomic compensatory mechanisms via baroreflex resulting in blood flow redistribution and heart rate changes [5]. Despite the large number of studies investigating short- and longterm effects of phototherapy, information on the autonomic nervous system changes during phototherapy are very sparse. To our knowledge, only one study was performed so far to investigate the changes in cardiovascular autonomic control during phototherapy [30]. We have observed a borderline significant increase in heart rate during and after phototherapy. Magnitude of HRV oscillations quantified by time and frequency domain indices was not significantly changed by phototherapy. In contrast to Weissman et al. [30], we have not observed any decrease in overall and beat-to-beat HRV magnitude. The application of nonlinear dynamics approach in our study has shown significant changes in symbolic dynamics and time irreversibility indices during and after phototherapy. From symbolic dynamics measures, 2LV%, 2UV% decreased and 0 V% increased, while heart rate oscillations complexity and unpredictability (NCI and NUPI) decreased during and after phototherapy. These changes indicate that the response of autonomic nervous system expressed in chronotropic cardiac regulation during and after phototherapy could be characterized by a shift in sympatho-vagal balance towards sympathetic dominance and this modification persists at least 30 min after phototherapy.
Fig. 4. Box-and-whisker plots representing linear time domain parameters: meanNN (left), SDNN and rMSSD (middle); and frequency domain parameters (right) in icteric neonates before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
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Fig. 5. Box-and-whisker plots representing complexity (NCI) and unpredictability (NUPI) (left) and pattern classification indices 0 V%, 1 V%, 2LV%, 2UV% (right) in icteric neonates before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
The major limitation of our study is the lacking information about the skin surface temperature changes during the experimental protocol. Therefore, we cannot exclude the possibility of enhanced vasodilation in skin vasculature associated with the potentially increased body surface temperature. Additionally, the heating effect of conventional phototherapy could enhance insensible water loss [3]. These effects could lead to blood redistribution evoking a shift in cardiovascular autonomic nervous system balance. Our goal was to observe the effects of conventional phototherapy where potential effect of the heating by infrared radiation generated by the lamp could not be excluded. The LED technology based phototherapy (used mostly for intensive phototherapy with the possibility to increase light intensity used for phototherapy up to irradiation of N30 μW/cm2/nm) where the infrared radiation is almost completely suppressed is now available. The effect of LED based phototherapy on cardiovascular autonomic nervous system could differ from the observations in our study but it requires further study. We tried to minimize the overall thermic effect of the phototherapeutic lamp. Since in our study we applied conventionally used fluorescence tube lamp emitting a limited amount of radiation also in the infrared part of the electromagnetic spectrum, the core body temperature of the newborn was monitored during phototherapy and any deviation from the normal range was counterbalanced by the changes of preset temperature inside incubator. It resulted in stable body temperature of the subjects in our study. Therefore, we suggest that the changes in body temperature did not contribute to observed ANS changes during phototherapy. Our study provided an observation of the ANS changes related to hyperbilirubinemia and its treatment by phototherapy. However, the
exact mechanism(s) of observed shifts in sympatho-vagal balance need further study. It would be of benefit not only to measure body surface temperature but the information about the time course of bilirubin degradation products concentration during and after phototherapy could be helpful in understanding the exact mechanisms of found effects. The importance of cardiovascular/autonomic nervous system changes during and after phototherapy is stressed by the fact that autonomic dysregulation could lead to serious consequences including severe ventricular arrhythmia and sudden death. Knowledge on cardiovascular control system response is very important to prevent potential adverse effects. However, based on our results, we cannot conclude if the observed subtle autonomic nervous system changes are of any clinical importance and they require further study. In conclusion, our study revealed subtle differences in resting cardiac autonomic control in newborns with hyperbilirubinemia using nonlinear measures. In addition, we found mean heart rate and its variability changes during and after phototherapy. Our observations point towards mildly increased parasympathetic activity associated with hyperbilirubinemia, and a shift in sympatho-vagal balance associated with vagal withdrawal and/or sympathetic activation during phototherapy persisting at least 30 min after this intervention. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgments This study was supported by grants VEGA N. 1/0223/12, 1/0059/13 and APVV-0235-12. References
Fig. 6. Box-and-whisker plots representing time irreversibility index P% derived from the RR intervals time series for multiple time scales (τ = 1, 2, 3, 4) in the icteric group before (PT1), during (PT2) and after phototherapy (PT3). #: Significant change during protocol (Friedman test).
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