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The influence of physiological parameters on long term heart rate variability in healthy preterm infants Conny M. A. van Ravenswaaij-Arts, Jeroen C. W. Hopman, Louis A. A. Kollee, and Gerard B. A. Stoelinga
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands
1
Introduction
Curriculum vitae
The spontaneous cardiac rhythm is modified by the activity of autonomic nerves and by neurotransmitters [18, 29]. The major cardioregulatory mechanisms behind this phenomenon of heart rate variability (HRV) are related to respiration (respiratory sinus arrhytmia (RSA), blood pressure (BP) (baroreceptor reflex) and thermoregulation (peripheral vascular resistance) [10, 29]. Each mechanism causes heart rate fluctuations with a specific frequency. Fast fluctuations (beatto-beat or short term variability (STV), mainly caused by RSA) are mediated by the parasympathetic system, slow fluctuations (long term variability (LTV), caused by changes in vascular resistance) by both the parasympathetic and sympathetic system [3, 25].
CONNY VAN RAVENSWAAIJ-ARTS was born on June 24th, 1961 and finished medical graduation from the University of Leiden, The Netherlands, in 1986. In the same year she was admitted as a research fellow to the. Department of Pediatrics, Division Neonatology of the University Hospital Nijmegen. She is mainly interested in the physiological background and clinical applicability of neonatal heart rate variability.
In obstetrics HRV is considered to reflect fetal well-being. Lack of variation in basal fetal heart rate is known to be related to high risk of poor fetal outcome [15, 19]. HRV has also been considered to be a measure of neonatal condition [4, 13, 14, 23], but neonatal HRV is influenced by different physiological mechanisms. The question whether HRV can be a valuable monitoring tool in neonatal intensive care can only be solved if the relative importance of these mechanisms is known.
rate, respiration rate, transcutaneous pO2 and behaviour) on HRV in four preterm infants with an uncomplicated neonatal course will be discussed. This preliminary study was performed to get insight into interrelations between these parameters before starting a large scale study in high risk preterm infants.
2 Patients
In four healthy preterm newborns with a gestational age of 34 to 35 weeks (birth weight 1765 to 2735 g), four tunes a day a measurement series was performed during the first five days of life. All infants breathed spontaneously, had normal blood gases, and did not suffer from complicaIn this article the results of a study regarding the tions like respiratory distress syndrome, periventricular hemorrhage, ductus arteriosus influence of physiological parameters (age, heart Brought to you by | New York University Bobst patent Library Technical Services or
Hitherto most studies regarding HRV are performed in the fetus, in adults and in animal models. A small number of studies were performed in full term [4, 8, 11, 17] or sick preterm newborns [4, 14, 17, 23].
1990 by Walter de Gruyter & Co. Berlin · New York
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congenital abnormalties. No drugs except antibiotics were given. Apgar scores were above six at one minute and above eight at five minutes after birth. Informed parental consent was obtained for each infant. 3 Methods During the measurement series instantaneous heart rate (iHR) and respiration rate (RR) were recorded from a neonatal monitor (HP 78801B) and transcutaneous pO2 (tc pO2) from a Novametrix tcO2mette (809A) on a FM-recorder (HP 3968A instrumentation recorder) for at least 40 minutes. Every four minutes systolic, diastolic and mean blood pressure (BP) were measured with a microprocessor-controlled Dinamap 1486 SX non-invasive BP monitor. After each BP measurement a marker signal was sent to the recorder as a time reference. During the measurements the infants were not disturbed and not allowed to suck. The behavioural state was scored according to PRECHTL [26]. 4 Data analysis The signals of iHR, RR and tc pO2 were stored on a DEC PDP-11/23 microcomputer using a sampling frequency of 80 Hz and a tape speed eight times the recording speed, offering an effective sample interval time of 0.1 sec. The information on tape was sampled in periods of three minutes between BP measurements. For each period, containing 1800 samples of iHR, RR and tc pO2, the median (p50) was calculated as central parameter and the difference between p95 and p5 as an index for the range. With this method from the first five days of life, four times a day, 10 sets of the following parameters were obtained for each child: median and range of
iHR, RR, and tc pO2 (all over three minutes), systolic, diastolic and mean BP (at the end of each three minute period) and behavioural state (scored during each three minute period). The range of iHR was chosen as index for long term variability (LTV). This index resembles the LTVindex used by JENKINS [14] and CABAL [4]. For statistical evaluation Pearson or Spearman correlation coefficients were calculated. 5 Results The age at the first measurement was 8 to 12 hours and at the last measurement 109 to 119 hours. So the four infants underwent 18 to 20 measurement series. Behavioural states during measurements were distributed as follows: quiet sleep 10% (5-24%), REM sleep 66% (6170%), quiet awake 0.3% (0-0.5%), active awake 7% (5-9%) and crying 16% (2-23%). To exclude the effects of behavioural state differences, the influence of other physiological parameters on HRV was analysed only during REM sleep. Results are summarized in tables I and II. The most remarkable results are illustrated with examples in figures 1 to 3. In table I for several parameters the Spearman correlation coefficients with age are given. In all infants there was a small but significant positive correlation between LTV and age. An example is given in figure 1. There also appeared to be a weak negative correlation of RR and tc pO2 and a weak positive correlation of BP with age. There was no clear relationship between heart rate and age. Table II summarizes the Pearson correlation coefficients of the neonatal parameters with LTV. Except for patient 1 there was no correlation between median iHR and LTV. There appears to be a negative correlation between RR and
Table I. Spearman correlation coefficients with age during active sleep pat.
median iHR
LTV
median RR
range RR
median tcp0 2
range tcpO 2
syst. BP
1 2 3 4
-0.18* -0.01 -0.15 0.31***
0.62*** 0.47*** 0.60*** 0.44***
-0.11 -0.23** -0.31*** -0.35***
-0.18* -0.10 -0.06 0.12
-0.45*** -0.48*** 0.05 -0.32**
0.35*** 0.04 0.07 0.12
0.19* 0.32*** 0.24** 0.54***
Brought you by | New York University Bobst Library Technical Services = p < 0.05; ** = p < 0.01; *** = p to < 0.001 Authenticated Download Date | 5/21/15 9:38 PM
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van Ravenswaaij-Arts et al, Heart rate variability Table Π. Pearson correlation coefficients with LTV during active sleep
pat.
median iHR
median RR
range RR
median tcpO 2
range tc P 21)
syst. BP
diast. BP
1 2 3 4
-0.23** 0.06 0.08 0.02
-0.00 -0.21* -0.46*** -0.47***
-0.02 0.19* 0.19* 0.17
-0.13 -0.28** -0.15 0.06
0.23* 0.40*** 0.06 -0.02
0.15 0.05 0.17 0.31***
0.05 0.04 0.18 0.24**
*) the range of tc pO2 was not normally distributed, therefore a log-transformation has been performed before calculation of correlation coefficients. * = p < 0.05; ** = p < 0.01; *** = p < 0.001
s:
I
·.·· -.-...V·'. :·· :
>*>
'„. „.*«*·. V
10 Ο
10 20 30 40 50 60 70 80 90 100 110 120
Age in hours after birth
Figure 1. Long term heart rate variability during active sleep in one patient plotted against age. r = 0.62, p = 0.0001 (Spearman).
0
***
* * ·'
10 20 30 40 50 60 70 80 90 100 110 120
Age in hours after birth STATE.. .Quiet Steep *«« Active Steep
Figure 3. Long term heart rate variability during quiet and active sleep in all patients plotted against age.
60 50
i
40
No consistent correlation between LTV and range or median of tc pO2 and BP was found (table II). After correction of LTV for age the correlation coefficients even became less.
As already mentioned the infants were asleep during most of the measurements (70 — 90%). Median Respiration Frequency Although LTV seemed to be higher during awake Figure 2. Long term heart rate variability during active behavioural states this could not be confirmed sleep in one patient plotted against respiration rate, statistically because of the small number of measr = 0.47, ρ = 0.0001 (Pearson). urements during awake behaviour. In figure 3 LTV during quiet and REM sleep is plotted against age. The LTV is clearly higher during LTV. An example is shown in figure 2. From REM sleep (overall mean ± SD: quiet sleep 14.2 linear regression the relation of LTV and RR ± 5.9; REM sleep 24.2 ± 10.6 bpm). Also difwith age was found for each patient. After cor- ferences in RR (50.5 ± 9.9; 41.4 ± 9.2/min), rection of both LTV and RR for age the corre- RR range (23.1 ± 12.5; 28.9 ± 8.5/min) and tc lation between LTV and RR was still significant pO2 range (4.5 ± 3.1; 7.6 ± 5.4 mmHg) between in patient 3 and 4 (r = —0.31 and —0.35 re- both sleep states were found. These differences spectively; ρ < 0.001). There was no obvious in- remained significant at the 0.05 level after corfluence of RR range on LTV. Brought to you by | New rection for age. Bobst Library Technical Services York University 20
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6 Discussion In this study we have tried to gain some preliminary insight into the relationship between HRV and other physiological parameters. The advantage of this study is the great amount of measurements per infant in such a manner that statistics per infant could be performed, ignoring inter-patient differences. A disadvantage is the limitation to a simple LTVindex with no possibility to calculate short term variability (STV). However, LTV is more pronounced than STV in newborns [8] and appears to be more related to neonatal well-being [4,14]. This is due to the immaturity of the parasympathetic system and the dominance of the sympathetic system in the newborn [24]. Since HRV is caused by the autonomic cardioregulatory mechanisms one of the physiological factors influencing neonatal HRV is the maturity of the autonomic nervous system. An increase of HRV with gestational age has been reported from fetal [6] and neonatal studies [13]. Also during early neonatal life and increase of HRV with age is found [4,14]. We were able to confirm this influence of age in healthy preterm infants. From fetal studies it is known that periods with body and respiration movements are accompanied by an increase in LTV [5, 18]. During fetal REM-sleep a decrease of STV occurs that is ascribed to an increase in sympathetic activity in expense of parasympathetic activity [7, 28, 31, 33]. We found a clear increase of LTV during REM-sleep in newborns. This is in accordance with an increase in sympathetic activity.
and, synchronous with these waves, in iHR oscillations with a frequency of 0.1 Hz in adults [29] and 0.06-0.08 Hz in newborns [18]. According to our data the baroreceptor reflex oscillations are not influenced by the level of blood pressure (table II). An important phenomenon with respect to HRV in adults, especially in relationship with RSA, is the entrainment between oscillations of different frequencies [16]. If respiration frequency approaches 0.1 Hz HRV tends to be enhanced [29]. Therefore, in adults STV is maximal at a breathing frequency of 5.5 to 7 per minute (0.09 — 0.12 Hz). Above this frequency there is a linear decrease of STV with RR [12, 21]. In newborns RR is elevated, the parasympathetic system is immature, and the sensitive HRV frequency regarding entrainment is around 0.06 to 0.08 Hz. So few influence of RR on HRV can be expected [10]. Nevertheless ROTHER et al [27] found a strong negative correlation between STV and RR in neonates. We found a negative correlation between RR and LTV, which persisted after correction of both LTV and RR for age. A simple explanation could be that although RR is very high in newborns, entrainment occurs and not only results in an increase of STV but secondary also in an increase of LTV. According to this explanation it seems that the LTV index used by us is not independent of STV.
Another explanation is possible if we suppose that tidal volume and changes in tidal volume decrease as RR increases. DYKES [8] demonstrated in full term newborns that respiration and heart rate are less related by RR (which Respiration causes fast fluctuations in HR which effects STV), than by changes in respiration amare well known as respiratory sinus arrhythmia plitude or tidal volume (which modulates LTV). (RSA). This phenomenon has been ascribed to HATHORN [11] has stated that oscillations in tidal several mechanisms including Bainbridge reflex, volume originate from the delay in the respiralung mechanoreceptor activity and a centrally tory feed-back control system involving the automediated attenuation of the cardioinhibitory nomic nervous system mediation of chemoregubaroreceptorreflex during inspiration resulting in lation. These oscillations have a frequency of a fluctuation in heart rate and blood pressure approximately 0.10 Hz during REM sleep and (Traube-Hering waves) synchronous with respi0.115 Hz during quiet sleep. The tidal volume ration [9, 22]. oscillations cause low frequency oscillations in Another fluctuation in heart rate and blood pres- heart rate near the sensitive region of 0.06 to sure is caused by the baroreceptor reflex itself. 0.08 Hz [8]. A rise in LTV, e. g. during REM Due to a delay in the baroreceptor loop, caused sleep in comparison to quiet sleep, may be caused by neural conduction time and the response time by an increase of oscillation amplitude [11] or a of effector organs, an oscillation in the blood decrease of oscillation frequency which results in pressure control system occurs. This oscillation more entrainment. We found an increase of LTV, results in the Mayer-waves Brought of blood pressure RR University range and tc pO andServices a decrease of 2 range, to you by | New York Bobst Library Technical Authenticated Download Date | 5/21/15 9:38 PM
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van Ravenswaaij-Arts et al, Heart rate variability RR during REM sleep. The increase in both RR range and tc pO2 range suggest an increase of oscillation amplitude of tidal volume during REM sleep. So, besides the decrease of tidal volume oscillation frequency also the increase of tidal volume oscillation amplitude might explain the increase of LTV during REM sleep. In our study group only patient 1 showed a negative correlation between LTV and heart rate and this correlation disappeared after correction of LTV for age. This confirms the results of other studies [1, 9] in which no correlation between HR and LTV could be established, in contrast to a wellknown negative correlation between HR
and STV [20, 32].
Some studies have been performed regarding the relationship between blood gases and HRV. Acute hypoxia causes an activation of the sympathetic system with a subsequent increase of HRV [30]. Chronic hypoxia, hypercapnia and acidosis cause a decrease of HRV through central depression of the autonomic nervous system. In
neonates with respiratory distress syndrome especially respiratory acidosis causes a decrease of HRV. AÄRIMAA described a negative correlation between HRV and tc pCO2, probably due to a decrease of pH in the medulla oblongata [1]. We only measured tc pO2, within physiological ranges no relationship between LTV and tc pO2 could be detected. In conclusion it can be stated that in healthy preterm infants LTV is mainly influenced by age, respiration and behaviour. No influence of blood pressure, heart rate and transcutaneous pO2 within physiological ranges could be detected in this study. A relationship of HRV with mortality [14], respiratory distress syndrome [2, 4,17, 27] asphyxia [23] and intracranial hemorrhage [13] has been reported. However, before the value of HRV as a monitoring tool in neonatal intensive care can be investigated extensive research on the influence of physiological parameters on neonatal HRV has to be performed.
Abstract
The instantaneous heart rate shows a variation around the mean heart rate caused by cardioregulatory mechanisms which are mediated through the sympathetic and vagal autonomic nervous system. To gain more insight into the influence of physiological parameters on neonatal heart rate variability a study was performed in four healthy preterm newborns during the first five days of life. Instantaneous heart rate, respiration rate, transcutaneous pO2, blood pressure and behaviour were recorded during 40 minutes four times a day. Long term heart rate variability was calculated as the difference between p95 and p5 of instantaneous
heart rate values sampled during three minutes. A clear relationship between long term variability and age (maturity of the autonomic nervous system), respiration rate (respiratory sinus arrhythmia or a tidal volume mediated effect) and behaviour (increase of sympathetic tone during REM sleep) was found. No influence of blood pressure, heart rate, and transcutaneous pC>2 within physiological ranges could be detected. The relative influence of the different physiological parameters on heart rate variability has to be established before the value of heart rate variability as a monitoring tool in neonatal intensive care can be investigated.
Keywords: Heart rate variability, long term variability, neonatal monitoring, preterm infant, respiratory sinus arrhythmia. Zusammenfassung
medizin überprüften, waren einige Voruntersuchungen notwendig, um den Einfluß verschiedener physiologiDie Herzfrequenzvariabilität wird gesteuert durch car- scher Parameter auf die HRV von Frühgeborenen zu dioregulatorische Mechanismen, die durch die Atmung erfassen. (respiratorische Sinusarrhythmie (RSA), den Barore- Bei vier gesunden Frühgeborenen (Gestationsalter zwizeptorreflex und die Thermoregulation (peripherer Ge- schen 34 und 35 Wochen) wurden viermal am Tag die laßwiderstand) beeinflußt werden. Neben diesen wich- momentane Herzfrequenz (instantaneous heart rate tigsten Mechanismen haben andere physiologische und (iHR)), die Atemfrequenz (respiration rate (RR)) und pathologische Faktoren ihre Wirkung auf die neona- der transcutane pC>2 über einen Zeitraum von mindetale Herzfrequenzvariabilität (heart rate variability stens 40 min kontinuierlich auf Band aufgezeichnet. (HRV)). Bevor wir die Brauchbarkeit der HRV als Alle vier min wurden der Blutdruck (BP) non-invasiv Überwachungsparameter in der neonatalen gemessen sowie das Verhalten KindesServices registriert. Brought Intensivto you by | New York University Bobst Library des Technical Einfluß physiologischer Parameter auf die Langzeitvariabilität der Herzfrequenz bei gesunden Frühgeborenen
J. Perinat. Med. 18 (1990)
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Die Informationen auf dem Band wurden über Zeitabschnitte von drei min zwischen den BP-Messungen digitalisiert, wobei 1800 Samples der iHR, RR und des tc pO2 für jeden Zeitabschnitt zustande kamen. Für jedes Set dieser 1800 Samples wurden die Medianwerte (p50) sowie die Streubreite (p95 — p5) ermittelt. Als Langzeitvariabilität (long term variability, LTV) wurde die Streuung der iHR innerhalb von drei min definiert. Für jeden Patienten wurden die statistischen Parameter separat berechnet, entweder während des „aktiven" oder des REM-Schlafes. Bei allen Kindern gab es eine geringe, jedoch signifikante Korrelation zwischen LTV und Alter (Tab. I). Zwischen LTV und RR schien eine negative Korrelation vorzuliegen (Tab. II), was wahrscheinlich nicht durch eine respiratorische Sinusarrhytmie bedingt ist, denn die Atemfrequenz bei Neugeborenen ist zu schnell, um mit den langsamen Baroreflexoszillationen (0.06 — 0.08 Hz) zu interferieren. Als Erklärungen können eher die Ergebnisse von DYKES [8] herangezogen werden, der auf die Bedeutung von Volumenänderun-
gen hinweist, die bei Neugeborenen mit einer Frequenz dieses empfindlichen Bereiches von 0.06 — 0.08 Hz auftreten. Diese Erklärung wird gestützt durch die Unterschiede, die wir zwischen Tiefschlaf- und REMPhasen fanden. Die Zunahme der LTV während des REM-Schlafes kann durch eine Erhöhung des Sympathikustonus erklärt werden. Jedoch tritt auch eine Abnahme der Atemfrequenz und eine Zunahme der Streuung von RR und tc pO2, was eine Zunahme von wellenförmigen Volumenänderungen nahelegt. In unserem Untersuchungskollektiv konnten wir keinen Einfluß des BP, der iHR und des tc pO2 innerhalb der physiologischen Grenzen feststellen. Zusammenfassend kann man sagen, daß bei gesunden Frühgeborenen die LTV hauptsächlich durch das Alter, die Respiration und das Verhalten beeinflußt wird. Die Bedeutung dieser physiologischen Faktoren muß bekannt sein, bevor man Untersuchungen über die Wertigkeit der HRV als Überwachungsinstrument in der neonatalen Intensivmedizin beginnt.
Schlüsselwörter: Frühgeborenes, Herzfrequenzvariabilität, Langzeitvariabilität, neonatale Überwachung, respiratorische Sinusarrhythmie. Resume L'influence des parametres physiologiques sur la variabilite a long terme du rythme cardiaque chez les enfants prematures en bonne sante
La variabilite du rythme cardiaque (VRC) est le resultat net des mecanismes cardioregulateurs lies ä la respiration (arythmie sinusale respiratoire), aux reflexes barorecepteurs et a la thermoregulation (resistances vasculaires peripheriques). A cote de ces mecanismes principaux, il est d'autres facteurs physiologiques et pathologiques qui influencent la VRC neonatale. Avant d'explorer la valeur de la VRC comme Instrument de surveillance pour les soins intensifs neonataux, nous avons cherche a obtenir des donnees preliminaires concernant les effets de divers parametres physiologiques sur la VRC chez les prematures. On a enregistre en continu sur bände pendant au moins 40 minutes, 4 fois par jour, le rythme cardiaque instantane (RCI), le rythme respiratoire (RR) et la pO2 transcutanee chez 4 enfants prematures en bonne sante (d'äge gestationnel de 34 ä 35 semaines de gestation). Toutes les 4 minutes on a mesure la pression sanguine (PS) de fagon non invasive ainsi que Fetat comportemental. Les informations sur la bände etaient numerisees sur des periodes de 3 minutes entre les mesures de la PS, fournissant ainsi pour chaque periode 1800 valeurs du RCI, du RR et de la tcpO2. On calcule pour chaque ensemble de 1800 valeurs les valeurs moyennes (p 50) et les variations (p95—p 5). La variabilite ä long terme (VLT) a ete definie comme les variations du RCI par periode de 3 minutes. Toutes les analyses statistiques ont ete effectuees pour chaque patient se-
parement, au cours du sommeil actif ou avec ReM. Chez tous les enfants il existe une correlation positive faible mais significative entre la VLT et Tage (tableau I). II y a une correlation negative entre la VLt et le RR (tableau II). Cela est vraisembleblement secondaire a Parythmie sinusale respiratoire puisque le RR est trop rapide pour interferer avec les faibles oscillations baroreflexes (0,06 — 0,08 Hz). Une explication plus pointue est fondee sur les donnees de Dykes [8] qui a etabli l'importance des variations periodiques de volume pour une frequence proche de la region sensible de 0,06 — 0,08 Hz chez les nouveaux nes. Cette idee est confortee par les differences que nous avons trouvees entre le sommeil REM et le sommeil calme. On peut expliquer Paugmentation de la VLT au cours du sommeil REM par une augmentation du tonus sympathique. Neanmoins, il existe egalement une diminution du RR ainsi qu'une augmentation des variations du RR, ainsi que des variations de la tcpO2 pendant le sommeil REM ce qui suggere une augmentation des variation de volume periodiques. Dans notre grpupe d'etude, nous n'avons pas pu detecter d'influence de la PS, ou du RCI ni de la tcpO2 dans les limites des variations physiologiques. En conclusion, on peut etablir que chez les prematures bien portants, la VLT est influencee de fa^on predominante par Page, la respiration et le comportement. L'importance relative de ces facteurs physiologiques doit etre connue avant que Pon puisse explorere la valeur de la VLT comme instrument de surveillance au cours des soins intensifs neonataux.
Mots-cles: Arythmie sinusale respiratoire, premature, surveillance neonatale, variabilite a long terme, variabilite du rythme cardiaque.Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 5/21/15 9:38 PM
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[31] VAN GEIJN HP, HW JONGSMA, J DE HAAN, TKAB ESKES, HFR PRECHTL: Heart rate as an indicator of the behavioral state: studies in the newborn infant and prospects for fetal heart rate monitoring. Am J Obstet Gynecol 136 (1980) 1061 [32] VAN GEIJN HP, HW JONGSMA, J DE HAAN, TKAB ESKES: Analysis of heart rate and beat-to-beat variability: interval difference index. Am J Obstet Gynecol 138 (1980) 246
[33] ZHU Y, HH SZETO: Cyclic variation in fetal heart rate and sympathetic activity. Am J Obstet Gynecol 156 (1987) 1001 Received December 6, 1989. Accepted December 9, 1989. Conny M. A. van Ravenswaaij-Arts Dept. of Pediatrics University Hospital Nijmegen P.O. Box 9101 6500 HB Nijmegen The Netherlands
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van Ravenswaaij-Arts et al, Heart rate variability
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The influence of physiological parameters on long term heart rate variability in healthy preterm infants Conny M. A. van Ravenswaaij-Arts, Jeroen C. W. Hopman, Louis A. A. Kollee, and Gerard B. A. Stoelinga
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands
1
Introduction
Curriculum vitae
The spontaneous cardiac rhythm is modified by the activity of autonomic nerves and by neurotransmitters [18, 29]. The major cardioregulatory mechanisms behind this phenomenon of heart rate variability (HRV) are related to respiration (respiratory sinus arrhytmia (RSA), blood pressure (BP) (baroreceptor reflex) and thermoregulation (peripheral vascular resistance) [10, 29]. Each mechanism causes heart rate fluctuations with a specific frequency. Fast fluctuations (beatto-beat or short term variability (STV), mainly caused by RSA) are mediated by the parasympathetic system, slow fluctuations (long term variability (LTV), caused by changes in vascular resistance) by both the parasympathetic and sympathetic system [3, 25].
CONNY VAN RAVENSWAAIJ-ARTS was born on June 24th, 1961 and finished medical graduation from the University of Leiden, The Netherlands, in 1986. In the same year she was admitted as a research fellow to the. Department of Pediatrics, Division Neonatology of the University Hospital Nijmegen. She is mainly interested in the physiological background and clinical applicability of neonatal heart rate variability.
In obstetrics HRV is considered to reflect fetal well-being. Lack of variation in basal fetal heart rate is known to be related to high risk of poor fetal outcome [15, 19]. HRV has also been considered to be a measure of neonatal condition [4, 13, 14, 23], but neonatal HRV is influenced by different physiological mechanisms. The question whether HRV can be a valuable monitoring tool in neonatal intensive care can only be solved if the relative importance of these mechanisms is known.
rate, respiration rate, transcutaneous pO2 and behaviour) on HRV in four preterm infants with an uncomplicated neonatal course will be discussed. This preliminary study was performed to get insight into interrelations between these parameters before starting a large scale study in high risk preterm infants.
2 Patients
In four healthy preterm newborns with a gestational age of 34 to 35 weeks (birth weight 1765 to 2735 g), four tunes a day a measurement series was performed during the first five days of life. All infants breathed spontaneously, had normal blood gases, and did not suffer from complicaIn this article the results of a study regarding the tions like respiratory distress syndrome, periventricular hemorrhage, ductus arteriosus influence of physiological parameters (age, heart Brought to you by | New York University Bobst patent Library Technical Services or
Hitherto most studies regarding HRV are performed in the fetus, in adults and in animal models. A small number of studies were performed in full term [4, 8, 11, 17] or sick preterm newborns [4, 14, 17, 23].
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congenital abnormalties. No drugs except antibiotics were given. Apgar scores were above six at one minute and above eight at five minutes after birth. Informed parental consent was obtained for each infant. 3 Methods During the measurement series instantaneous heart rate (iHR) and respiration rate (RR) were recorded from a neonatal monitor (HP 78801B) and transcutaneous pO2 (tc pO2) from a Novametrix tcO2mette (809A) on a FM-recorder (HP 3968A instrumentation recorder) for at least 40 minutes. Every four minutes systolic, diastolic and mean blood pressure (BP) were measured with a microprocessor-controlled Dinamap 1486 SX non-invasive BP monitor. After each BP measurement a marker signal was sent to the recorder as a time reference. During the measurements the infants were not disturbed and not allowed to suck. The behavioural state was scored according to PRECHTL [26]. 4 Data analysis The signals of iHR, RR and tc pO2 were stored on a DEC PDP-11/23 microcomputer using a sampling frequency of 80 Hz and a tape speed eight times the recording speed, offering an effective sample interval time of 0.1 sec. The information on tape was sampled in periods of three minutes between BP measurements. For each period, containing 1800 samples of iHR, RR and tc pO2, the median (p50) was calculated as central parameter and the difference between p95 and p5 as an index for the range. With this method from the first five days of life, four times a day, 10 sets of the following parameters were obtained for each child: median and range of
iHR, RR, and tc pO2 (all over three minutes), systolic, diastolic and mean BP (at the end of each three minute period) and behavioural state (scored during each three minute period). The range of iHR was chosen as index for long term variability (LTV). This index resembles the LTVindex used by JENKINS [14] and CABAL [4]. For statistical evaluation Pearson or Spearman correlation coefficients were calculated. 5 Results The age at the first measurement was 8 to 12 hours and at the last measurement 109 to 119 hours. So the four infants underwent 18 to 20 measurement series. Behavioural states during measurements were distributed as follows: quiet sleep 10% (5-24%), REM sleep 66% (6170%), quiet awake 0.3% (0-0.5%), active awake 7% (5-9%) and crying 16% (2-23%). To exclude the effects of behavioural state differences, the influence of other physiological parameters on HRV was analysed only during REM sleep. Results are summarized in tables I and II. The most remarkable results are illustrated with examples in figures 1 to 3. In table I for several parameters the Spearman correlation coefficients with age are given. In all infants there was a small but significant positive correlation between LTV and age. An example is given in figure 1. There also appeared to be a weak negative correlation of RR and tc pO2 and a weak positive correlation of BP with age. There was no clear relationship between heart rate and age. Table II summarizes the Pearson correlation coefficients of the neonatal parameters with LTV. Except for patient 1 there was no correlation between median iHR and LTV. There appears to be a negative correlation between RR and
Table I. Spearman correlation coefficients with age during active sleep pat.
median iHR
LTV
median RR
range RR
median tcp0 2
range tcpO 2
syst. BP
1 2 3 4
-0.18* -0.01 -0.15 0.31***
0.62*** 0.47*** 0.60*** 0.44***
-0.11 -0.23** -0.31*** -0.35***
-0.18* -0.10 -0.06 0.12
-0.45*** -0.48*** 0.05 -0.32**
0.35*** 0.04 0.07 0.12
0.19* 0.32*** 0.24** 0.54***
Brought you by | New York University Bobst Library Technical Services = p < 0.05; ** = p < 0.01; *** = p to < 0.001 Authenticated Download Date | 5/21/15 9:38 PM
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van Ravenswaaij-Arts et al, Heart rate variability Table Π. Pearson correlation coefficients with LTV during active sleep
pat.
median iHR
median RR
range RR
median tcpO 2
range tc P 21)
syst. BP
diast. BP
1 2 3 4
-0.23** 0.06 0.08 0.02
-0.00 -0.21* -0.46*** -0.47***
-0.02 0.19* 0.19* 0.17
-0.13 -0.28** -0.15 0.06
0.23* 0.40*** 0.06 -0.02
0.15 0.05 0.17 0.31***
0.05 0.04 0.18 0.24**
*) the range of tc pO2 was not normally distributed, therefore a log-transformation has been performed before calculation of correlation coefficients. * = p < 0.05; ** = p < 0.01; *** = p < 0.001
s:
I
·.·· -.-...V·'. :·· :
>*>
'„. „.*«*·. V
10 Ο
10 20 30 40 50 60 70 80 90 100 110 120
Age in hours after birth
Figure 1. Long term heart rate variability during active sleep in one patient plotted against age. r = 0.62, p = 0.0001 (Spearman).
0
***
* * ·'
10 20 30 40 50 60 70 80 90 100 110 120
Age in hours after birth STATE.. .Quiet Steep *«« Active Steep
Figure 3. Long term heart rate variability during quiet and active sleep in all patients plotted against age.
60 50
i
40
No consistent correlation between LTV and range or median of tc pO2 and BP was found (table II). After correction of LTV for age the correlation coefficients even became less.
As already mentioned the infants were asleep during most of the measurements (70 — 90%). Median Respiration Frequency Although LTV seemed to be higher during awake Figure 2. Long term heart rate variability during active behavioural states this could not be confirmed sleep in one patient plotted against respiration rate, statistically because of the small number of measr = 0.47, ρ = 0.0001 (Pearson). urements during awake behaviour. In figure 3 LTV during quiet and REM sleep is plotted against age. The LTV is clearly higher during LTV. An example is shown in figure 2. From REM sleep (overall mean ± SD: quiet sleep 14.2 linear regression the relation of LTV and RR ± 5.9; REM sleep 24.2 ± 10.6 bpm). Also difwith age was found for each patient. After cor- ferences in RR (50.5 ± 9.9; 41.4 ± 9.2/min), rection of both LTV and RR for age the corre- RR range (23.1 ± 12.5; 28.9 ± 8.5/min) and tc lation between LTV and RR was still significant pO2 range (4.5 ± 3.1; 7.6 ± 5.4 mmHg) between in patient 3 and 4 (r = —0.31 and —0.35 re- both sleep states were found. These differences spectively; ρ < 0.001). There was no obvious in- remained significant at the 0.05 level after corfluence of RR range on LTV. Brought to you by | New rection for age. Bobst Library Technical Services York University 20
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6 Discussion In this study we have tried to gain some preliminary insight into the relationship between HRV and other physiological parameters. The advantage of this study is the great amount of measurements per infant in such a manner that statistics per infant could be performed, ignoring inter-patient differences. A disadvantage is the limitation to a simple LTVindex with no possibility to calculate short term variability (STV). However, LTV is more pronounced than STV in newborns [8] and appears to be more related to neonatal well-being [4,14]. This is due to the immaturity of the parasympathetic system and the dominance of the sympathetic system in the newborn [24]. Since HRV is caused by the autonomic cardioregulatory mechanisms one of the physiological factors influencing neonatal HRV is the maturity of the autonomic nervous system. An increase of HRV with gestational age has been reported from fetal [6] and neonatal studies [13]. Also during early neonatal life and increase of HRV with age is found [4,14]. We were able to confirm this influence of age in healthy preterm infants. From fetal studies it is known that periods with body and respiration movements are accompanied by an increase in LTV [5, 18]. During fetal REM-sleep a decrease of STV occurs that is ascribed to an increase in sympathetic activity in expense of parasympathetic activity [7, 28, 31, 33]. We found a clear increase of LTV during REM-sleep in newborns. This is in accordance with an increase in sympathetic activity.
and, synchronous with these waves, in iHR oscillations with a frequency of 0.1 Hz in adults [29] and 0.06-0.08 Hz in newborns [18]. According to our data the baroreceptor reflex oscillations are not influenced by the level of blood pressure (table II). An important phenomenon with respect to HRV in adults, especially in relationship with RSA, is the entrainment between oscillations of different frequencies [16]. If respiration frequency approaches 0.1 Hz HRV tends to be enhanced [29]. Therefore, in adults STV is maximal at a breathing frequency of 5.5 to 7 per minute (0.09 — 0.12 Hz). Above this frequency there is a linear decrease of STV with RR [12, 21]. In newborns RR is elevated, the parasympathetic system is immature, and the sensitive HRV frequency regarding entrainment is around 0.06 to 0.08 Hz. So few influence of RR on HRV can be expected [10]. Nevertheless ROTHER et al [27] found a strong negative correlation between STV and RR in neonates. We found a negative correlation between RR and LTV, which persisted after correction of both LTV and RR for age. A simple explanation could be that although RR is very high in newborns, entrainment occurs and not only results in an increase of STV but secondary also in an increase of LTV. According to this explanation it seems that the LTV index used by us is not independent of STV.
Another explanation is possible if we suppose that tidal volume and changes in tidal volume decrease as RR increases. DYKES [8] demonstrated in full term newborns that respiration and heart rate are less related by RR (which Respiration causes fast fluctuations in HR which effects STV), than by changes in respiration amare well known as respiratory sinus arrhythmia plitude or tidal volume (which modulates LTV). (RSA). This phenomenon has been ascribed to HATHORN [11] has stated that oscillations in tidal several mechanisms including Bainbridge reflex, volume originate from the delay in the respiralung mechanoreceptor activity and a centrally tory feed-back control system involving the automediated attenuation of the cardioinhibitory nomic nervous system mediation of chemoregubaroreceptorreflex during inspiration resulting in lation. These oscillations have a frequency of a fluctuation in heart rate and blood pressure approximately 0.10 Hz during REM sleep and (Traube-Hering waves) synchronous with respi0.115 Hz during quiet sleep. The tidal volume ration [9, 22]. oscillations cause low frequency oscillations in Another fluctuation in heart rate and blood pres- heart rate near the sensitive region of 0.06 to sure is caused by the baroreceptor reflex itself. 0.08 Hz [8]. A rise in LTV, e. g. during REM Due to a delay in the baroreceptor loop, caused sleep in comparison to quiet sleep, may be caused by neural conduction time and the response time by an increase of oscillation amplitude [11] or a of effector organs, an oscillation in the blood decrease of oscillation frequency which results in pressure control system occurs. This oscillation more entrainment. We found an increase of LTV, results in the Mayer-waves Brought of blood pressure RR University range and tc pO andServices a decrease of 2 range, to you by | New York Bobst Library Technical Authenticated Download Date | 5/21/15 9:38 PM
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van Ravenswaaij-Arts et al, Heart rate variability RR during REM sleep. The increase in both RR range and tc pO2 range suggest an increase of oscillation amplitude of tidal volume during REM sleep. So, besides the decrease of tidal volume oscillation frequency also the increase of tidal volume oscillation amplitude might explain the increase of LTV during REM sleep. In our study group only patient 1 showed a negative correlation between LTV and heart rate and this correlation disappeared after correction of LTV for age. This confirms the results of other studies [1, 9] in which no correlation between HR and LTV could be established, in contrast to a wellknown negative correlation between HR
and STV [20, 32].
Some studies have been performed regarding the relationship between blood gases and HRV. Acute hypoxia causes an activation of the sympathetic system with a subsequent increase of HRV [30]. Chronic hypoxia, hypercapnia and acidosis cause a decrease of HRV through central depression of the autonomic nervous system. In
neonates with respiratory distress syndrome especially respiratory acidosis causes a decrease of HRV. AÄRIMAA described a negative correlation between HRV and tc pCO2, probably due to a decrease of pH in the medulla oblongata [1]. We only measured tc pO2, within physiological ranges no relationship between LTV and tc pO2 could be detected. In conclusion it can be stated that in healthy preterm infants LTV is mainly influenced by age, respiration and behaviour. No influence of blood pressure, heart rate and transcutaneous pO2 within physiological ranges could be detected in this study. A relationship of HRV with mortality [14], respiratory distress syndrome [2, 4,17, 27] asphyxia [23] and intracranial hemorrhage [13] has been reported. However, before the value of HRV as a monitoring tool in neonatal intensive care can be investigated extensive research on the influence of physiological parameters on neonatal HRV has to be performed.
Abstract
The instantaneous heart rate shows a variation around the mean heart rate caused by cardioregulatory mechanisms which are mediated through the sympathetic and vagal autonomic nervous system. To gain more insight into the influence of physiological parameters on neonatal heart rate variability a study was performed in four healthy preterm newborns during the first five days of life. Instantaneous heart rate, respiration rate, transcutaneous pO2, blood pressure and behaviour were recorded during 40 minutes four times a day. Long term heart rate variability was calculated as the difference between p95 and p5 of instantaneous
heart rate values sampled during three minutes. A clear relationship between long term variability and age (maturity of the autonomic nervous system), respiration rate (respiratory sinus arrhythmia or a tidal volume mediated effect) and behaviour (increase of sympathetic tone during REM sleep) was found. No influence of blood pressure, heart rate, and transcutaneous pC>2 within physiological ranges could be detected. The relative influence of the different physiological parameters on heart rate variability has to be established before the value of heart rate variability as a monitoring tool in neonatal intensive care can be investigated.
Keywords: Heart rate variability, long term variability, neonatal monitoring, preterm infant, respiratory sinus arrhythmia. Zusammenfassung
medizin überprüften, waren einige Voruntersuchungen notwendig, um den Einfluß verschiedener physiologiDie Herzfrequenzvariabilität wird gesteuert durch car- scher Parameter auf die HRV von Frühgeborenen zu dioregulatorische Mechanismen, die durch die Atmung erfassen. (respiratorische Sinusarrhythmie (RSA), den Barore- Bei vier gesunden Frühgeborenen (Gestationsalter zwizeptorreflex und die Thermoregulation (peripherer Ge- schen 34 und 35 Wochen) wurden viermal am Tag die laßwiderstand) beeinflußt werden. Neben diesen wich- momentane Herzfrequenz (instantaneous heart rate tigsten Mechanismen haben andere physiologische und (iHR)), die Atemfrequenz (respiration rate (RR)) und pathologische Faktoren ihre Wirkung auf die neona- der transcutane pC>2 über einen Zeitraum von mindetale Herzfrequenzvariabilität (heart rate variability stens 40 min kontinuierlich auf Band aufgezeichnet. (HRV)). Bevor wir die Brauchbarkeit der HRV als Alle vier min wurden der Blutdruck (BP) non-invasiv Überwachungsparameter in der neonatalen gemessen sowie das Verhalten KindesServices registriert. Brought Intensivto you by | New York University Bobst Library des Technical Einfluß physiologischer Parameter auf die Langzeitvariabilität der Herzfrequenz bei gesunden Frühgeborenen
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Die Informationen auf dem Band wurden über Zeitabschnitte von drei min zwischen den BP-Messungen digitalisiert, wobei 1800 Samples der iHR, RR und des tc pO2 für jeden Zeitabschnitt zustande kamen. Für jedes Set dieser 1800 Samples wurden die Medianwerte (p50) sowie die Streubreite (p95 — p5) ermittelt. Als Langzeitvariabilität (long term variability, LTV) wurde die Streuung der iHR innerhalb von drei min definiert. Für jeden Patienten wurden die statistischen Parameter separat berechnet, entweder während des „aktiven" oder des REM-Schlafes. Bei allen Kindern gab es eine geringe, jedoch signifikante Korrelation zwischen LTV und Alter (Tab. I). Zwischen LTV und RR schien eine negative Korrelation vorzuliegen (Tab. II), was wahrscheinlich nicht durch eine respiratorische Sinusarrhytmie bedingt ist, denn die Atemfrequenz bei Neugeborenen ist zu schnell, um mit den langsamen Baroreflexoszillationen (0.06 — 0.08 Hz) zu interferieren. Als Erklärungen können eher die Ergebnisse von DYKES [8] herangezogen werden, der auf die Bedeutung von Volumenänderun-
gen hinweist, die bei Neugeborenen mit einer Frequenz dieses empfindlichen Bereiches von 0.06 — 0.08 Hz auftreten. Diese Erklärung wird gestützt durch die Unterschiede, die wir zwischen Tiefschlaf- und REMPhasen fanden. Die Zunahme der LTV während des REM-Schlafes kann durch eine Erhöhung des Sympathikustonus erklärt werden. Jedoch tritt auch eine Abnahme der Atemfrequenz und eine Zunahme der Streuung von RR und tc pO2, was eine Zunahme von wellenförmigen Volumenänderungen nahelegt. In unserem Untersuchungskollektiv konnten wir keinen Einfluß des BP, der iHR und des tc pO2 innerhalb der physiologischen Grenzen feststellen. Zusammenfassend kann man sagen, daß bei gesunden Frühgeborenen die LTV hauptsächlich durch das Alter, die Respiration und das Verhalten beeinflußt wird. Die Bedeutung dieser physiologischen Faktoren muß bekannt sein, bevor man Untersuchungen über die Wertigkeit der HRV als Überwachungsinstrument in der neonatalen Intensivmedizin beginnt.
Schlüsselwörter: Frühgeborenes, Herzfrequenzvariabilität, Langzeitvariabilität, neonatale Überwachung, respiratorische Sinusarrhythmie. Resume L'influence des parametres physiologiques sur la variabilite a long terme du rythme cardiaque chez les enfants prematures en bonne sante
La variabilite du rythme cardiaque (VRC) est le resultat net des mecanismes cardioregulateurs lies ä la respiration (arythmie sinusale respiratoire), aux reflexes barorecepteurs et a la thermoregulation (resistances vasculaires peripheriques). A cote de ces mecanismes principaux, il est d'autres facteurs physiologiques et pathologiques qui influencent la VRC neonatale. Avant d'explorer la valeur de la VRC comme Instrument de surveillance pour les soins intensifs neonataux, nous avons cherche a obtenir des donnees preliminaires concernant les effets de divers parametres physiologiques sur la VRC chez les prematures. On a enregistre en continu sur bände pendant au moins 40 minutes, 4 fois par jour, le rythme cardiaque instantane (RCI), le rythme respiratoire (RR) et la pO2 transcutanee chez 4 enfants prematures en bonne sante (d'äge gestationnel de 34 ä 35 semaines de gestation). Toutes les 4 minutes on a mesure la pression sanguine (PS) de fagon non invasive ainsi que Fetat comportemental. Les informations sur la bände etaient numerisees sur des periodes de 3 minutes entre les mesures de la PS, fournissant ainsi pour chaque periode 1800 valeurs du RCI, du RR et de la tcpO2. On calcule pour chaque ensemble de 1800 valeurs les valeurs moyennes (p 50) et les variations (p95—p 5). La variabilite ä long terme (VLT) a ete definie comme les variations du RCI par periode de 3 minutes. Toutes les analyses statistiques ont ete effectuees pour chaque patient se-
parement, au cours du sommeil actif ou avec ReM. Chez tous les enfants il existe une correlation positive faible mais significative entre la VLT et Tage (tableau I). II y a une correlation negative entre la VLt et le RR (tableau II). Cela est vraisembleblement secondaire a Parythmie sinusale respiratoire puisque le RR est trop rapide pour interferer avec les faibles oscillations baroreflexes (0,06 — 0,08 Hz). Une explication plus pointue est fondee sur les donnees de Dykes [8] qui a etabli l'importance des variations periodiques de volume pour une frequence proche de la region sensible de 0,06 — 0,08 Hz chez les nouveaux nes. Cette idee est confortee par les differences que nous avons trouvees entre le sommeil REM et le sommeil calme. On peut expliquer Paugmentation de la VLT au cours du sommeil REM par une augmentation du tonus sympathique. Neanmoins, il existe egalement une diminution du RR ainsi qu'une augmentation des variations du RR, ainsi que des variations de la tcpO2 pendant le sommeil REM ce qui suggere une augmentation des variation de volume periodiques. Dans notre grpupe d'etude, nous n'avons pas pu detecter d'influence de la PS, ou du RCI ni de la tcpO2 dans les limites des variations physiologiques. En conclusion, on peut etablir que chez les prematures bien portants, la VLT est influencee de fa^on predominante par Page, la respiration et le comportement. L'importance relative de ces facteurs physiologiques doit etre connue avant que Pon puisse explorere la valeur de la VLT comme instrument de surveillance au cours des soins intensifs neonataux.
Mots-cles: Arythmie sinusale respiratoire, premature, surveillance neonatale, variabilite a long terme, variabilite du rythme cardiaque.Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 5/21/15 9:38 PM
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[33] ZHU Y, HH SZETO: Cyclic variation in fetal heart rate and sympathetic activity. Am J Obstet Gynecol 156 (1987) 1001 Received December 6, 1989. Accepted December 9, 1989. Conny M. A. van Ravenswaaij-Arts Dept. of Pediatrics University Hospital Nijmegen P.O. Box 9101 6500 HB Nijmegen The Netherlands
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