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Effects of sleep position, sleep state and age on heart rate responses following provoked arousal in term infants
Early Human Development 71 (2003) 157 – 169 www.elsevier.com/locate/earlhumdev
Effects of sleep position, sleep state and age on heart rate responses following provoked arousal in term infants Rita Tuladhar a, Richard Harding b, Susan M. Cranage a, T. Michael Adamson a, Rosemary S.C. Horne a,* a
Department of Paediatrics and Ritchie Centre for Baby Health Research, Monash Medical Centre, Monash University, 246 Clayton Road, Melbourne, Victoria 3168, Australia b Department of Physiology, Monash University, Melbourne, Victoria 3168, Australia Accepted 23 December 2002
Abstract Previous studies have suggested that autonomic dysfunction may be involved in Sudden Infant Death Syndrome (SIDS). The major risk factors for SIDS are the prone sleeping position and maternal smoking. Our aim was to examine the effects of sleeping position and maternal smoking on the postnatal maturation of autonomic function by examining heart rate responses following arousal in healthy term infants. Twenty-four infants (11 born to mothers who smoked during pregnancy and 13 to mother who did not smoke) were studied using daytime polysomnography and multiple measurements of arousal threshold (cm H2O) in response to air-jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS). We demonstrated no difference between smoking and non-smoking groups of infants in any of our measurements, and thus combined data from the groups. Baseline (BHR) was elevated in the prone compared to the supine position in quiet sleep (QS) at 2 – 3 weeks ( p < 0.001) and 5 – 6 months ( p < 0.001), and in active sleep (AS) at 2 – 3 and 5 – 6 months ( p < 0.05). BHR was significantly elevated in AS compared to QS in the supine position at all ages ( p < 0.01) and in the prone position at 2 – 3 ( p < 0.001) and 5 – 6 months ( p < 0.05). Increases in heart rate (DHR%) following arousal were significantly greater in the supine compared to the prone position in QS at 2 – 3 weeks ( p < 0.05) and in AS at both 2 – 3 ( p < 0.01) and 5 – 6 months ( p < 0.05). DHR% was significantly greater in AS compared to QS in both supine ( p < 0.05) and prone ( p < 0.001) positions at 2 – 3 weeks and in the supine position at 2 – 3 months ( p < 0.001). We conclude that sleep state, sleep position and postnatal age affect the cardiac responses following arousal from sleep in healthy term
* Corresponding author. Tel.: +61-3-95944504; fax: +61-3-95946259. E-mail address: [email protected] (R.S.C. Horne). 0378-3782/03/$ - see front matter D 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0378-3782(03)00005-7
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infants. Impairment of heart rate control in the prone position may be important in understanding the increased risk for SIDS in this position. D 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Sleep; Heart rate; Arousal; Infant
1. Introduction The control of the cardiorespiratory system undergoes functional maturation after birth, and until this process is completed, the control of breathing and the cardiovascular system is unstable, placing infants at risk for cardiorespiratory disturbances, especially during sleep [1]. Evidence of autonomic dysfunction or autonomic maturational delay is a feature of some infants who succumb to Sudden Infant Death Syndrome (SIDS). Infants dying of SIDS exhibited a higher heart rate, lower overall heart rate variability and disturbed longterm coordination of cardiac and respiratory measures when compared with age matched control infants [2– 4]. Despite the dramatic decline in the incidence of SIDS over recent years, it is still the major cause of death in infants between 1 month and 1 year of age [5]. Recent data recorded from infants dying whilst being monitored has demonstrated that infants appear to loose the ability to integrate cardiac and respiratory function. Initially, bradycardia occurs in the presence of continued respiration followed by gasping, but heart rate does not recover [6,7]. The prone sleeping position and maternal smoking have been demonstrated in a number of studies in different countries to be two of the major risk factors for SIDS [8 –15]. It has been hypothesised that the ability to arouse from sleep is an important survival mechanism, which may be impaired in SIDS infants [16]. In support of this idea, studies have now demonstrated that arousal responses are impaired in the prone position [17 – 19] and also in infants whose mothers smoked during pregnancy [20 – 22]. In addition, it has been suggested that sleep position [17,18] and maternal smoking [20,23] alter autonomic control in infants. In this study, we examined the effects of sleeping position and maternal smoking on the postnatal maturation of autonomic function by examining heart rate responses following arousal in healthy term infants. Our hypothesis was that the prone sleeping position and maternal smoking would impair changes in heart rate at arousal, and these would be most marked at 2 – 3 months of age, when SIDS incidence is highest.
2. Methods The Monash Medical Centre Human Ethics Committee granted ethical approval for this project. All subjects were volunteers recruited from the maternity wards and Jessie McPherson Private Hospital, Monash Medical Centre, Melbourne. Written informed consent was obtained from parents prior to commencement of the study, and no monetary incentive was provided for participation.
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3. Subjects We recruited 24 infants born at term with normal birth weights and Apgar scores and without any congenital abnormalities (Table 1). All 24 infants were studied at 2– 3 weeks postnatal age, 22 infants were studied at 2 – 3 months of age and 18 infants were studied at 5 –6 months of age. Mothers were asked to complete a questionnaire regarding their smoking habits at the first study detailing the number of cigarettes smoked during and after pregnancy and whether or not other members of the household smoked. Samples of infant urine were collected at 2 –3 months of age using sterile paediatric urine collection bags. Samples were frozen immediately and stored at 20 jC until analysis. Because nicotine has a relatively short serum half-life (f 2 h) and is excreted as cotinine (and 3OH cotinine) in the urine, we analysed these metabolites as an indicator of maternal smoking [24]. Urinary cotinine was analysed using a chemiluminescent enzyme immunometric assay kit (Diagnostic Products) for the Immulite automated analyser. Results were correlated with an HPLC cotinine method [25] by Passing Bablok regression (r = 0.925).
4. Recording methods Infants were studied using daytime polysomnography. Electrodes for recording physiological variables were attached to each infant during feeding and, when drowsy, the infant was placed in a bassinet under dim lighting and constant room temperature (22 – 23 jC). Infants generally had both a morning and afternoon sleep interrupted by a midday feed, when sleep position was changed. Each infant slept both prone and supine during each study, the initial sleep position was randomised both between infants and studies. Using a polygraph (Grass Instrument, Quincey, MA, USA), we recorded electroencephalogram (EEG), electrooculogram (EOG), submental electromyogram (EMG) and electrocardiogram (ECG), instantaneous heart rate, thoracic and abdominal breathing Table 1 Demographics of infant study groups
Number of infants Gestation (weeks) Birth weight (g) Apgar score at 1 min Apgar score at 5 min Maternal age (years) Age at Study 1 (days) Weight at Study 1 (g) Age at Study 2 (days) Weight at Study 2 (g) Age at Study 3 (days) Weight at Study 3 (g)
Non-smoking
Smoking
13 40 F 0.3 (38 – 41) 3498 F 102 (2765 – 4015) 9 (5 – 10) 9 (7 – 10) 28 F 2 (18 – 39) 14 F 1 (8 – 19) 3709 F 129 (2750 – 4390) 74 F 2 (63 – 83) 5453 F 213 (4423 – 6480) 189 F 5 (175 – 213) 7865 F 359 (6200 – 9335)
11 40 F 0.4 (38 – 42) 3598 F 129 (3015 – 4190) 9 (5 – 10) 9 (6 – 10) 32 F 2 (26 – 42) 15 F 1 (10 – 21) 3886 F 140 (3155 – 4536) 75 F 2 (68 – 84) 5805 F 227 (4536 – 7000) 176 F 5 (155 – 200) 7935 F 223 (6804 – 8800)
Values are mean F S.E.M. with range in brackets.
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movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian, VA, USA), expired CO2 (CO2/O2 Analyser, Engstrom Eliza MC, Bromma, Sweden), blood oxygen saturation (SpO2) (Biox 3700e Pulse Oximeter, Ohmeda, Louisville, CO, USA) and abdominal skin and rectal temperature (Yellow Springs Instruments, Yellow Springs, OH, USA). Sleep state was assessed as either QS, AS or indeterminate sleep using EEG, behavioral, heart rate and breathing pattern criteria [26].
Fig. 1. Mean heart rate response at 2 – 3 months following arousal in (A) AS and (B) QS in 22 infants sleeping prone and supine. Stimulus onset is indicated by the arrow.
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5. Stimulus and arousal criteria A pulsatile air-jet (frequency 3 Hz for 5 s) delivered to the nostrils of the infant was used to induce arousal both in active sleep (AS) and quiet sleep (QS) [27,28]. The stimulus was presented alternately to the left and right nostrils; if the infant failed to arouse, the air-jet pressure was increased when the stimulus was again presented to that nostril. Whenever an arousal response occurred, the pressure was decreased. In determining whether a presentation elicited an arousal response, four criteria were used: change in ventilation pattern of more than two breaths, an observed behavioral response, a heart rate acceleration of greater than 10% above the baseline and an increase in submental EMG activity [27,28].
6. Data analysis Baseline heart rate (BHR) data were collected over 20 beats prior to each stimulus presentation that induced arousal. Heart rate typically increased following the arousing stimulus, and data for 30 beats after the stimulus were analysed to measure the maximum heart rate (Max HR) (Fig. 1). Maximum heart rate was the average of three beats prior to and three beats after peak heart rate. The increase in heart rate (DHR%) was calculated as the difference between maximum heart rate and baseline heart rate ([Max HR BHR]/ [BHR] 100). The number of heartbeats to reach the maximum heart rate (Max HB) was also counted. Data for smoking and non-smoking groups were compared with two-way ANOVA. The effects of sleep state and sleep position at each age were compared using twoway ANOVA for repeated measures. At 5– 6 months of age, only 15 infants had complete data for this analysis. For the analysis of maturational effects, 11 infants in AS and 15 infants in QS had complete data for all three postnatal ages and these were compared using two-way ANOVA for repeated measures. All values are expressed as mean F S.E.M. and a p-value of < 0.05 was considered significant.
7. Results There was no significant difference between the smoking and non-smoking groups for any of the demographic measures recorded (Table 1).
8. Maternal smoking Mothers of the non-smoking group (n = 13) reported that they did not smoke and that no one else in the household smoked. This was confirmed by infant urinary cotinine levels measured at the 2 –3 months study, which were all < 10 ng/ml. Eight of these infants were breast-fed. In the maternal smoking group (n = 11), mothers reported routinely smoking 3 – 20 cigarettes/day (mean 15 F 6/day). Seven of the infants were breast-fed. Two mothers reported stopping smoking when pregnancy was confirmed at 6 – 8 weeks gestation; however, they started smoking 10 – 15 cigarettes/day as soon as the infants were born.
162 R. Tuladhar et al. / Early Human Development 71 (2003) 157–169 Fig. 2. (A – D) Effect of sleep position on (A) baseline heart rate, (B) maximum heart rate, (C) percentage change in heart rate (DHR%) and (D) number of heartbeats to reach maximum heart rate. *p < 0.05, **p < 0.01, ***p < 0.001. ( ) Supine AS, (n) Prone AS, ( ) Supine QS, ( ) Prone QS.
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One of these infants, who was bottle-fed, had < 10 ng/ml cotinine in the urine. In the remaining infants (n = 10), urinary cotinine levels ranged between 10.6 and 286 ng/ml (mean 82.5 ng/ml). Data were first analysed separately and compared between the smoking and nonsmoking groups. We found no difference between the smoking and non-smoking groups in BHR, Max HR, DHR or Max HB in either sleep state at any study age with the exception of BHR at 5– 6 months in QS in the prone position when BHR was elevated by 7 beats/ min ( p < 0.05) in the non-smoking group compared to the smoking group. As we did not consider this difference to be of physiological significance, we have combined the data for the two groups for all subsequent analyses. There were no significant differences in respiratory rates, oxygen saturation or rectal temperature between sleeping positions in either sleep state at any of the ages studied. Abdominal skin temperature was significantly elevated by 0.3 –0.7 jC when infants slept prone in both AS and QS at the three ages studied.
9. Baseline heart rate 9.1. Effects of sleeping position BHR was elevated in the prone compared to the supine position in QS at 2– 3 weeks and 5– 6 months ( p < 0.001) and in AS at 2– 3 and 5 –6 months ( p < 0.05) (Fig. 2A). 9.2. Effects of sleep state BHR was significantly elevated in AS compared to QS when infants slept in the supine position at 2– 3 weeks, 2 – 3 and 5– 6 months of age ( p < 0.01). In the prone sleeping Table 2 Effects of sleep state on heart rate (beats/min) before and following arousal 2 – 3 Weeks (N = 24)
Total no. tests BHR Max HR DHR% Max HB
AS QS AS QS AS QS AS QS AS QS
2 – 3 Months (N = 22)
5 – 6 Months (N = 15)
Supine
Prone
Supine
Prone
Supine
Prone
228 114 137 F 2** 133 F 2 157 F 2*** 147 F 2 15 F 1* 11 F 2 20 F 1*** 15 F 1
261 165 139 F 2 139 F 2 156 F 1*** 149 F 2 13 F 1*** 7F1 19 F 1*** 14 F 1
184 135 131 F 2** 128 F 2 151 F 2*** 142 F 2 15 F 1*** 12 F 1 19 F 1** 15 F 1
216 181 134 F 2*** 130 F 2 149 F 2* 146 F 2 11 F 1 12 F 1 18 F 1 17 F 1
41 73 125 F 2** 120 F 2 145 F 2** 136 F 3 16 F 2 13 F 1 19 F 1 15 F 1
57 99 131 F 3* 129 F 2 145 F 3 143 F 3 11 F 1 11 F 1 16 F 1 18 F 1
N = number of infants. *p < 0.05 AS vs. QS. **p < 0.01 AS vs. QS. ***p < 0.001 AS vs. QS.
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Table 3 Effects of postnatal age on heart rate (beats/min) before and following arousal Postnatal age
Supine
Prone
2 – 3 Weeks 2 – 3 Months 5 – 6 Months 2 – 3 Weeks
2 – 3 Months 5 – 6 Months
AS (N = 11) BHR Max HR DHR% Max HB QS (N = 15) BHR Max HR DHR% Max HB
135 F 3* 157 F 3* 17 F 2 20 F 0.8* 132 F 2*** 148 F 3** 12 F 2 17 F 1.2
134 F 3 149 F 4 11 F 2 16 F 1.0 132 F 2 148 F 2 12 F 1 18 F 1.0
131 F 3 151 F 4 15 F 2 19 F 0.8 129 F 3yy 145 F 2yy 12 F 2 17 F 1.0
126 F 2 145 F 3 16 F 1 16 F 1.4 120 F 1 136 F 1 14 F 1 17 F 0.8
138 F 3 157 F 2**k 14 F 1.0 19 F 0.9 139 F 2***k 149 F 3*y 8 F 1k 15 F 1.4
132 F 4 145 F 4 10 F 1 19 F 1.4 127 F 2 142 F 2 12 F 2 15 F 1.2
*p < 0.05, **p < 0.01, ***p < 0.001 2 – 3 weeks vs. 5 – 6 months. yp < 0.05, yyp < 0.01, yyyp < 0.001 2 – 3 months vs. 5 – 6 months. kp < 0.05 2 – 3 weeks vs. 2 – 3 months. N = number of infants.
position, BHR was elevated in AS compared to QS at 2 –3 ( p < 0.001) and 5 – 6 months ( p < 0.05) (Table 2). 9.3. Effects of postnatal age In the supine position, BHR was significantly greater at 2 – 3 weeks compared to 5– 6 months in both AS ( p < 0.05) and QS ( p < 0.001). BHR was significantly elevated at 2– 3 months compared to 5 – 6 months ( p < 0.01) in QS when infants slept supine. In the prone position, BHR was significantly elevated at 2 –3 weeks compared to 2 –3 ( p < 0.05) and 5– 6 months ( p < 0.001) in QS (Table 3). There was no significant maturation in AS when infants slept prone. 10. Maximum heart rate at arousal 10.1. Effects of sleeping position Max HR was higher in the prone compared to the supine position in QS at 2– 3 ( p < 0.01) and 5 –6 months ( p < 0.05) (Fig. 2B). 10.2. Effects of sleep state Max HR was higher in AS compared to QS at all three ages when infants slept supine (2– 3 weeks p < 0.001, 2– 3 months p < 0.001, 5 – 6 months p < 0.01) and at 2 –3 weeks p < 0.001 and 2 –3 months p < 0.05) when infants slept prone (Table 2). 10.3. Effects of postnatal age In AS, Max HR was significantly greater at 2 – 3 weeks compared to 5– 6 months in both supine ( p < 0.05) and prone positions ( p < 0.01). Max HR was also significantly
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elevated at 2 –3 weeks compared to 2– 3 months ( p < 0.05) in AS when infants slept prone. In QS, Max HR was significantly elevated at 2 –3 weeks compared to 5 –6 and 2 –3 months compared to 5 –6 months in both supine ( p < 0.01) and prone positions ( p < 0.05) (Table 3).
11. Change in heart rate at arousal (DHR%) 11.1. Effects of sleeping position DHR% was significantly greater in the supine compared to the prone position in QS at 2– 3 weeks ( p < 0.05) and in AS at both 2– 3 ( p < 0.01) and 5– 6 months ( p < 0.05) (Fig. 2C). 11.2. Effects of sleep state DHR% was significantly greater in AS compared to QS in both supine ( p < 0.05) and prone ( p < 0.001) positions at 2 –3 weeks. At 2 – 3 months, the difference between sleep states was only seen when infants slept supine ( p < 0.001). There was no significant difference in either position at 5 –6 months (Table 2). 11.3. Effects of postnatal age DHR% was significantly greater at 2– 3 months compared to 2– 3 weeks in QS when infants slept prone ( p < 0.05) (Table 3).
12. Number of heart-beats to reach peak heart rate (Max HB) 12.1. Effects of sleeping position Max HB was significantly elevated in the prone position in QS at 2– 3 months ( p < 0.05) and at 5 –6 months ( p < 0.05) compared to the supine position (Fig. 2D). 12.2. Effects of sleep state Max HB was significantly elevated in AS compared to QS at 2– 3 weeks when infants slept in both supine ( p < 0.001) and prone positions ( p < 0.001), and at 2– 3 months in the supine position ( p < 0.01) (Table 2). 12.3. Effects of postnatal age Max HB was elevated at 2– 3 weeks compared to 5– 6 months when infants slept supine ( p < 0.05) in AS (Table 3).
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13. Discussion This study has demonstrated that cardiac responses of sleeping infants when aroused are altered by sleep state, sleep position and postnatal age. However, we found that maternal smoking did not affect cardiac responses in either sleeping position, in contrast to previous studies suggesting that maternal smoking alters autonomic function in infants, as assessed by power spectral analysis of R – R interval [20,23]. Alterations in autonomically mediated cardiovascular function may indicate subtle developmental anomalies, which might contribute to increased susceptibility to SIDS in the infants of smokers [23,29]. Our findings that maternal smoking did not affect cardiac responses is perhaps not surprising, as the two groups of infants were not different in either birth weight or Apgar scores at birth, indicating that they had not suffered significant stress in utero. Galland et al. [30] also demonstrated no smoking-related effects on autonomic function in infants studied in the first month of life and at 3 months of age with similar levels of exposure to maternal smoking. 13.1. Effect of sleep position Previous studies have demonstrated that the prone sleeping position affects basal heart rate, with healthy term infants exhibiting a higher heart rate in the prone compared to the supine position [19,30 –34]. In addition, heart rate variability in AS has been shown to be decreased in the prone position, together with a decrease in cardiac parasympathetic tone [35] and in both AS and QS [18,30]. Our study supports these findings and extends them by determining the effects at increasing postnatal ages. We found that in both AS and QS, BHR was elevated in the prone position at all three ages studied, although this achieved statistical significance only at 2– 3 weeks and 5– 6 months in QS and 2 –3 and 5– 6 months in AS. Arousal from sleep is accompanied by increases in heart rate, and arterial pressure [36]. In this study, we hypothesised that increases in heart rate following arousal would be depressed in the prone position. We found that the maximum HR following arousal (Max HR) was not different between sleep positions in either sleep state at 2 –3 weeks. However, at 2– 3 and 5– 6 months, Max HR was significantly greater in QS when infants slept prone, reflecting the higher BHR in this position. When data were normalised, DHR% was greater in the supine position than in the prone position in both AS and QS at all three ages, with the exception of QS at 2 – 3 months. This difference reached statistical significance in QS at 2 –3 weeks and in AS at both 2– 3 and 5 – 6 months, thereby supporting our hypothesis that the prone position depresses heart rate responses. Our studies support those of Franco et al. [35], who also demonstrated that term infants aged between 8 and 15 weeks exposed to auditory challenges during sleep had smaller changes in heart rate in the prone position than in the supine position; these studies were, however, only carried out at one age and only in AS. The finding that the number of heart beats taken to reach maximum heart rate (Max HB) was significantly greater in the prone position than in the supine position in QS at 2– 3 and 5– 6 months, despite the higher baseline heart rate and smaller changes in DHR% in the prone position, is of interest and may reflect depressed autonomic responsiveness in this position.
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13.2. Effect of sleep state BHR was elevated in AS compared to QS when infants slept supine at all three ages, and also in the prone position at 2 –3 and 5– 6 months of age (Table 2). This sleep state effect on basal heart rate has been demonstrated previously in a number of studies [19,37]. Our study has expanded these findings by demonstrating that sleep state also has a marked influence on heart rate responses following arousal. Max HR, DHR% and HB were all more pronounced in AS compared to QS, although these effects were also altered by postnatal age and sleeping position. It has been suggested that the sleep-state differences reflect a predominant parasympathetic control of heart rate in QS and a predominant sympathetic influence during AS [1]. 13.3. Effects of postnatal age In healthy full term infants, heart rate increases from 1 week to 1 month, decreases rapidly between 1 and 3 months and falls more slowly between 3 and 6 months [1,37]. In our study, we also demonstrated maturational changes, with Max HR gradually decreasing with increasing postnatal age in both supine and prone positions and in both AS and QS and BHR following similar patterns with the exception of AS in the prone position. This may indicate that the prone position slows down maturation of heart rate in AS. In summary, we have demonstrated that the prone sleeping position has a marked influence on both baseline heart rate and cardiac responses following arousal. The usual increase in heart rate following arousal was most significantly damped in AS at 2 –3 months of age, an age at which SIDS risk is highest. Our study supports the hypothesis that autonomic control of heart rate is impaired in the prone position and this may explain the increased risk for SIDS when infants sleep prone. Acknowledgements The authors wish to thank the staff of the maternity wards at the Monash Medical Centre and Jessie McPherson Private Hospital and the parents and infants who participated in this study. References [1] Gaultier C. Cardiovascular adaptation during sleep in infants and children. Pediatr Pulmonol 1995;19: 105 – 17. [2] Taylor BJ, Williams SM, Mitchell EA, Ford RPK. Symptoms, sweating and reactivity of infants who die of SIDS compared to community controls. J Paediatr Child Health 1996;32:316 – 22. [3] Schechtman VL, Raetz SL, Harper RK, Garfinkle A, Wilson AJ, Southall DP, et al. Dynamic analysis of cardiac R – R intervals in normal infants and in infants who subsequently succumbed to the sudden infant death syndrome. Pediatr Res 1992;1:606 – 12. [4] Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti R, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709 – 14. [5] Byard RW. Sudden infant death syndrome: a ‘diagnosis’ in search of a disease. J Clin Forensic Med 1995;2:121 – 8.
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Effects of sleep position, sleep state and age on heart rate responses following provoked arousal in term infants Rita Tuladhar a, Richard Harding b, Susan M. Cranage a, T. Michael Adamson a, Rosemary S.C. Horne a,* a
Department of Paediatrics and Ritchie Centre for Baby Health Research, Monash Medical Centre, Monash University, 246 Clayton Road, Melbourne, Victoria 3168, Australia b Department of Physiology, Monash University, Melbourne, Victoria 3168, Australia Accepted 23 December 2002
Abstract Previous studies have suggested that autonomic dysfunction may be involved in Sudden Infant Death Syndrome (SIDS). The major risk factors for SIDS are the prone sleeping position and maternal smoking. Our aim was to examine the effects of sleeping position and maternal smoking on the postnatal maturation of autonomic function by examining heart rate responses following arousal in healthy term infants. Twenty-four infants (11 born to mothers who smoked during pregnancy and 13 to mother who did not smoke) were studied using daytime polysomnography and multiple measurements of arousal threshold (cm H2O) in response to air-jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS). We demonstrated no difference between smoking and non-smoking groups of infants in any of our measurements, and thus combined data from the groups. Baseline (BHR) was elevated in the prone compared to the supine position in quiet sleep (QS) at 2 – 3 weeks ( p < 0.001) and 5 – 6 months ( p < 0.001), and in active sleep (AS) at 2 – 3 and 5 – 6 months ( p < 0.05). BHR was significantly elevated in AS compared to QS in the supine position at all ages ( p < 0.01) and in the prone position at 2 – 3 ( p < 0.001) and 5 – 6 months ( p < 0.05). Increases in heart rate (DHR%) following arousal were significantly greater in the supine compared to the prone position in QS at 2 – 3 weeks ( p < 0.05) and in AS at both 2 – 3 ( p < 0.01) and 5 – 6 months ( p < 0.05). DHR% was significantly greater in AS compared to QS in both supine ( p < 0.05) and prone ( p < 0.001) positions at 2 – 3 weeks and in the supine position at 2 – 3 months ( p < 0.001). We conclude that sleep state, sleep position and postnatal age affect the cardiac responses following arousal from sleep in healthy term
* Corresponding author. Tel.: +61-3-95944504; fax: +61-3-95946259. E-mail address: [email protected] (R.S.C. Horne). 0378-3782/03/$ - see front matter D 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0378-3782(03)00005-7
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infants. Impairment of heart rate control in the prone position may be important in understanding the increased risk for SIDS in this position. D 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Sleep; Heart rate; Arousal; Infant
1. Introduction The control of the cardiorespiratory system undergoes functional maturation after birth, and until this process is completed, the control of breathing and the cardiovascular system is unstable, placing infants at risk for cardiorespiratory disturbances, especially during sleep [1]. Evidence of autonomic dysfunction or autonomic maturational delay is a feature of some infants who succumb to Sudden Infant Death Syndrome (SIDS). Infants dying of SIDS exhibited a higher heart rate, lower overall heart rate variability and disturbed longterm coordination of cardiac and respiratory measures when compared with age matched control infants [2– 4]. Despite the dramatic decline in the incidence of SIDS over recent years, it is still the major cause of death in infants between 1 month and 1 year of age [5]. Recent data recorded from infants dying whilst being monitored has demonstrated that infants appear to loose the ability to integrate cardiac and respiratory function. Initially, bradycardia occurs in the presence of continued respiration followed by gasping, but heart rate does not recover [6,7]. The prone sleeping position and maternal smoking have been demonstrated in a number of studies in different countries to be two of the major risk factors for SIDS [8 –15]. It has been hypothesised that the ability to arouse from sleep is an important survival mechanism, which may be impaired in SIDS infants [16]. In support of this idea, studies have now demonstrated that arousal responses are impaired in the prone position [17 – 19] and also in infants whose mothers smoked during pregnancy [20 – 22]. In addition, it has been suggested that sleep position [17,18] and maternal smoking [20,23] alter autonomic control in infants. In this study, we examined the effects of sleeping position and maternal smoking on the postnatal maturation of autonomic function by examining heart rate responses following arousal in healthy term infants. Our hypothesis was that the prone sleeping position and maternal smoking would impair changes in heart rate at arousal, and these would be most marked at 2 – 3 months of age, when SIDS incidence is highest.
2. Methods The Monash Medical Centre Human Ethics Committee granted ethical approval for this project. All subjects were volunteers recruited from the maternity wards and Jessie McPherson Private Hospital, Monash Medical Centre, Melbourne. Written informed consent was obtained from parents prior to commencement of the study, and no monetary incentive was provided for participation.
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3. Subjects We recruited 24 infants born at term with normal birth weights and Apgar scores and without any congenital abnormalities (Table 1). All 24 infants were studied at 2– 3 weeks postnatal age, 22 infants were studied at 2 – 3 months of age and 18 infants were studied at 5 –6 months of age. Mothers were asked to complete a questionnaire regarding their smoking habits at the first study detailing the number of cigarettes smoked during and after pregnancy and whether or not other members of the household smoked. Samples of infant urine were collected at 2 –3 months of age using sterile paediatric urine collection bags. Samples were frozen immediately and stored at 20 jC until analysis. Because nicotine has a relatively short serum half-life (f 2 h) and is excreted as cotinine (and 3OH cotinine) in the urine, we analysed these metabolites as an indicator of maternal smoking [24]. Urinary cotinine was analysed using a chemiluminescent enzyme immunometric assay kit (Diagnostic Products) for the Immulite automated analyser. Results were correlated with an HPLC cotinine method [25] by Passing Bablok regression (r = 0.925).
4. Recording methods Infants were studied using daytime polysomnography. Electrodes for recording physiological variables were attached to each infant during feeding and, when drowsy, the infant was placed in a bassinet under dim lighting and constant room temperature (22 – 23 jC). Infants generally had both a morning and afternoon sleep interrupted by a midday feed, when sleep position was changed. Each infant slept both prone and supine during each study, the initial sleep position was randomised both between infants and studies. Using a polygraph (Grass Instrument, Quincey, MA, USA), we recorded electroencephalogram (EEG), electrooculogram (EOG), submental electromyogram (EMG) and electrocardiogram (ECG), instantaneous heart rate, thoracic and abdominal breathing Table 1 Demographics of infant study groups
Number of infants Gestation (weeks) Birth weight (g) Apgar score at 1 min Apgar score at 5 min Maternal age (years) Age at Study 1 (days) Weight at Study 1 (g) Age at Study 2 (days) Weight at Study 2 (g) Age at Study 3 (days) Weight at Study 3 (g)
Non-smoking
Smoking
13 40 F 0.3 (38 – 41) 3498 F 102 (2765 – 4015) 9 (5 – 10) 9 (7 – 10) 28 F 2 (18 – 39) 14 F 1 (8 – 19) 3709 F 129 (2750 – 4390) 74 F 2 (63 – 83) 5453 F 213 (4423 – 6480) 189 F 5 (175 – 213) 7865 F 359 (6200 – 9335)
11 40 F 0.4 (38 – 42) 3598 F 129 (3015 – 4190) 9 (5 – 10) 9 (6 – 10) 32 F 2 (26 – 42) 15 F 1 (10 – 21) 3886 F 140 (3155 – 4536) 75 F 2 (68 – 84) 5805 F 227 (4536 – 7000) 176 F 5 (155 – 200) 7935 F 223 (6804 – 8800)
Values are mean F S.E.M. with range in brackets.
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movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian, VA, USA), expired CO2 (CO2/O2 Analyser, Engstrom Eliza MC, Bromma, Sweden), blood oxygen saturation (SpO2) (Biox 3700e Pulse Oximeter, Ohmeda, Louisville, CO, USA) and abdominal skin and rectal temperature (Yellow Springs Instruments, Yellow Springs, OH, USA). Sleep state was assessed as either QS, AS or indeterminate sleep using EEG, behavioral, heart rate and breathing pattern criteria [26].
Fig. 1. Mean heart rate response at 2 – 3 months following arousal in (A) AS and (B) QS in 22 infants sleeping prone and supine. Stimulus onset is indicated by the arrow.
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5. Stimulus and arousal criteria A pulsatile air-jet (frequency 3 Hz for 5 s) delivered to the nostrils of the infant was used to induce arousal both in active sleep (AS) and quiet sleep (QS) [27,28]. The stimulus was presented alternately to the left and right nostrils; if the infant failed to arouse, the air-jet pressure was increased when the stimulus was again presented to that nostril. Whenever an arousal response occurred, the pressure was decreased. In determining whether a presentation elicited an arousal response, four criteria were used: change in ventilation pattern of more than two breaths, an observed behavioral response, a heart rate acceleration of greater than 10% above the baseline and an increase in submental EMG activity [27,28].
6. Data analysis Baseline heart rate (BHR) data were collected over 20 beats prior to each stimulus presentation that induced arousal. Heart rate typically increased following the arousing stimulus, and data for 30 beats after the stimulus were analysed to measure the maximum heart rate (Max HR) (Fig. 1). Maximum heart rate was the average of three beats prior to and three beats after peak heart rate. The increase in heart rate (DHR%) was calculated as the difference between maximum heart rate and baseline heart rate ([Max HR BHR]/ [BHR] 100). The number of heartbeats to reach the maximum heart rate (Max HB) was also counted. Data for smoking and non-smoking groups were compared with two-way ANOVA. The effects of sleep state and sleep position at each age were compared using twoway ANOVA for repeated measures. At 5– 6 months of age, only 15 infants had complete data for this analysis. For the analysis of maturational effects, 11 infants in AS and 15 infants in QS had complete data for all three postnatal ages and these were compared using two-way ANOVA for repeated measures. All values are expressed as mean F S.E.M. and a p-value of < 0.05 was considered significant.
7. Results There was no significant difference between the smoking and non-smoking groups for any of the demographic measures recorded (Table 1).
8. Maternal smoking Mothers of the non-smoking group (n = 13) reported that they did not smoke and that no one else in the household smoked. This was confirmed by infant urinary cotinine levels measured at the 2 –3 months study, which were all < 10 ng/ml. Eight of these infants were breast-fed. In the maternal smoking group (n = 11), mothers reported routinely smoking 3 – 20 cigarettes/day (mean 15 F 6/day). Seven of the infants were breast-fed. Two mothers reported stopping smoking when pregnancy was confirmed at 6 – 8 weeks gestation; however, they started smoking 10 – 15 cigarettes/day as soon as the infants were born.
162 R. Tuladhar et al. / Early Human Development 71 (2003) 157–169 Fig. 2. (A – D) Effect of sleep position on (A) baseline heart rate, (B) maximum heart rate, (C) percentage change in heart rate (DHR%) and (D) number of heartbeats to reach maximum heart rate. *p < 0.05, **p < 0.01, ***p < 0.001. ( ) Supine AS, (n) Prone AS, ( ) Supine QS, ( ) Prone QS.
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One of these infants, who was bottle-fed, had < 10 ng/ml cotinine in the urine. In the remaining infants (n = 10), urinary cotinine levels ranged between 10.6 and 286 ng/ml (mean 82.5 ng/ml). Data were first analysed separately and compared between the smoking and nonsmoking groups. We found no difference between the smoking and non-smoking groups in BHR, Max HR, DHR or Max HB in either sleep state at any study age with the exception of BHR at 5– 6 months in QS in the prone position when BHR was elevated by 7 beats/ min ( p < 0.05) in the non-smoking group compared to the smoking group. As we did not consider this difference to be of physiological significance, we have combined the data for the two groups for all subsequent analyses. There were no significant differences in respiratory rates, oxygen saturation or rectal temperature between sleeping positions in either sleep state at any of the ages studied. Abdominal skin temperature was significantly elevated by 0.3 –0.7 jC when infants slept prone in both AS and QS at the three ages studied.
9. Baseline heart rate 9.1. Effects of sleeping position BHR was elevated in the prone compared to the supine position in QS at 2– 3 weeks and 5– 6 months ( p < 0.001) and in AS at 2– 3 and 5 –6 months ( p < 0.05) (Fig. 2A). 9.2. Effects of sleep state BHR was significantly elevated in AS compared to QS when infants slept in the supine position at 2– 3 weeks, 2 – 3 and 5– 6 months of age ( p < 0.01). In the prone sleeping Table 2 Effects of sleep state on heart rate (beats/min) before and following arousal 2 – 3 Weeks (N = 24)
Total no. tests BHR Max HR DHR% Max HB
AS QS AS QS AS QS AS QS AS QS
2 – 3 Months (N = 22)
5 – 6 Months (N = 15)
Supine
Prone
Supine
Prone
Supine
Prone
228 114 137 F 2** 133 F 2 157 F 2*** 147 F 2 15 F 1* 11 F 2 20 F 1*** 15 F 1
261 165 139 F 2 139 F 2 156 F 1*** 149 F 2 13 F 1*** 7F1 19 F 1*** 14 F 1
184 135 131 F 2** 128 F 2 151 F 2*** 142 F 2 15 F 1*** 12 F 1 19 F 1** 15 F 1
216 181 134 F 2*** 130 F 2 149 F 2* 146 F 2 11 F 1 12 F 1 18 F 1 17 F 1
41 73 125 F 2** 120 F 2 145 F 2** 136 F 3 16 F 2 13 F 1 19 F 1 15 F 1
57 99 131 F 3* 129 F 2 145 F 3 143 F 3 11 F 1 11 F 1 16 F 1 18 F 1
N = number of infants. *p < 0.05 AS vs. QS. **p < 0.01 AS vs. QS. ***p < 0.001 AS vs. QS.
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Table 3 Effects of postnatal age on heart rate (beats/min) before and following arousal Postnatal age
Supine
Prone
2 – 3 Weeks 2 – 3 Months 5 – 6 Months 2 – 3 Weeks
2 – 3 Months 5 – 6 Months
AS (N = 11) BHR Max HR DHR% Max HB QS (N = 15) BHR Max HR DHR% Max HB
135 F 3* 157 F 3* 17 F 2 20 F 0.8* 132 F 2*** 148 F 3** 12 F 2 17 F 1.2
134 F 3 149 F 4 11 F 2 16 F 1.0 132 F 2 148 F 2 12 F 1 18 F 1.0
131 F 3 151 F 4 15 F 2 19 F 0.8 129 F 3yy 145 F 2yy 12 F 2 17 F 1.0
126 F 2 145 F 3 16 F 1 16 F 1.4 120 F 1 136 F 1 14 F 1 17 F 0.8
138 F 3 157 F 2**k 14 F 1.0 19 F 0.9 139 F 2***k 149 F 3*y 8 F 1k 15 F 1.4
132 F 4 145 F 4 10 F 1 19 F 1.4 127 F 2 142 F 2 12 F 2 15 F 1.2
*p < 0.05, **p < 0.01, ***p < 0.001 2 – 3 weeks vs. 5 – 6 months. yp < 0.05, yyp < 0.01, yyyp < 0.001 2 – 3 months vs. 5 – 6 months. kp < 0.05 2 – 3 weeks vs. 2 – 3 months. N = number of infants.
position, BHR was elevated in AS compared to QS at 2 –3 ( p < 0.001) and 5 – 6 months ( p < 0.05) (Table 2). 9.3. Effects of postnatal age In the supine position, BHR was significantly greater at 2 – 3 weeks compared to 5– 6 months in both AS ( p < 0.05) and QS ( p < 0.001). BHR was significantly elevated at 2– 3 months compared to 5 – 6 months ( p < 0.01) in QS when infants slept supine. In the prone position, BHR was significantly elevated at 2 –3 weeks compared to 2 –3 ( p < 0.05) and 5– 6 months ( p < 0.001) in QS (Table 3). There was no significant maturation in AS when infants slept prone. 10. Maximum heart rate at arousal 10.1. Effects of sleeping position Max HR was higher in the prone compared to the supine position in QS at 2– 3 ( p < 0.01) and 5 –6 months ( p < 0.05) (Fig. 2B). 10.2. Effects of sleep state Max HR was higher in AS compared to QS at all three ages when infants slept supine (2– 3 weeks p < 0.001, 2– 3 months p < 0.001, 5 – 6 months p < 0.01) and at 2 –3 weeks p < 0.001 and 2 –3 months p < 0.05) when infants slept prone (Table 2). 10.3. Effects of postnatal age In AS, Max HR was significantly greater at 2 – 3 weeks compared to 5– 6 months in both supine ( p < 0.05) and prone positions ( p < 0.01). Max HR was also significantly
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elevated at 2 –3 weeks compared to 2– 3 months ( p < 0.05) in AS when infants slept prone. In QS, Max HR was significantly elevated at 2 –3 weeks compared to 5 –6 and 2 –3 months compared to 5 –6 months in both supine ( p < 0.01) and prone positions ( p < 0.05) (Table 3).
11. Change in heart rate at arousal (DHR%) 11.1. Effects of sleeping position DHR% was significantly greater in the supine compared to the prone position in QS at 2– 3 weeks ( p < 0.05) and in AS at both 2– 3 ( p < 0.01) and 5– 6 months ( p < 0.05) (Fig. 2C). 11.2. Effects of sleep state DHR% was significantly greater in AS compared to QS in both supine ( p < 0.05) and prone ( p < 0.001) positions at 2 –3 weeks. At 2 – 3 months, the difference between sleep states was only seen when infants slept supine ( p < 0.001). There was no significant difference in either position at 5 –6 months (Table 2). 11.3. Effects of postnatal age DHR% was significantly greater at 2– 3 months compared to 2– 3 weeks in QS when infants slept prone ( p < 0.05) (Table 3).
12. Number of heart-beats to reach peak heart rate (Max HB) 12.1. Effects of sleeping position Max HB was significantly elevated in the prone position in QS at 2– 3 months ( p < 0.05) and at 5 –6 months ( p < 0.05) compared to the supine position (Fig. 2D). 12.2. Effects of sleep state Max HB was significantly elevated in AS compared to QS at 2– 3 weeks when infants slept in both supine ( p < 0.001) and prone positions ( p < 0.001), and at 2– 3 months in the supine position ( p < 0.01) (Table 2). 12.3. Effects of postnatal age Max HB was elevated at 2– 3 weeks compared to 5– 6 months when infants slept supine ( p < 0.05) in AS (Table 3).
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13. Discussion This study has demonstrated that cardiac responses of sleeping infants when aroused are altered by sleep state, sleep position and postnatal age. However, we found that maternal smoking did not affect cardiac responses in either sleeping position, in contrast to previous studies suggesting that maternal smoking alters autonomic function in infants, as assessed by power spectral analysis of R – R interval [20,23]. Alterations in autonomically mediated cardiovascular function may indicate subtle developmental anomalies, which might contribute to increased susceptibility to SIDS in the infants of smokers [23,29]. Our findings that maternal smoking did not affect cardiac responses is perhaps not surprising, as the two groups of infants were not different in either birth weight or Apgar scores at birth, indicating that they had not suffered significant stress in utero. Galland et al. [30] also demonstrated no smoking-related effects on autonomic function in infants studied in the first month of life and at 3 months of age with similar levels of exposure to maternal smoking. 13.1. Effect of sleep position Previous studies have demonstrated that the prone sleeping position affects basal heart rate, with healthy term infants exhibiting a higher heart rate in the prone compared to the supine position [19,30 –34]. In addition, heart rate variability in AS has been shown to be decreased in the prone position, together with a decrease in cardiac parasympathetic tone [35] and in both AS and QS [18,30]. Our study supports these findings and extends them by determining the effects at increasing postnatal ages. We found that in both AS and QS, BHR was elevated in the prone position at all three ages studied, although this achieved statistical significance only at 2– 3 weeks and 5– 6 months in QS and 2 –3 and 5– 6 months in AS. Arousal from sleep is accompanied by increases in heart rate, and arterial pressure [36]. In this study, we hypothesised that increases in heart rate following arousal would be depressed in the prone position. We found that the maximum HR following arousal (Max HR) was not different between sleep positions in either sleep state at 2 –3 weeks. However, at 2– 3 and 5– 6 months, Max HR was significantly greater in QS when infants slept prone, reflecting the higher BHR in this position. When data were normalised, DHR% was greater in the supine position than in the prone position in both AS and QS at all three ages, with the exception of QS at 2 – 3 months. This difference reached statistical significance in QS at 2 –3 weeks and in AS at both 2– 3 and 5 – 6 months, thereby supporting our hypothesis that the prone position depresses heart rate responses. Our studies support those of Franco et al. [35], who also demonstrated that term infants aged between 8 and 15 weeks exposed to auditory challenges during sleep had smaller changes in heart rate in the prone position than in the supine position; these studies were, however, only carried out at one age and only in AS. The finding that the number of heart beats taken to reach maximum heart rate (Max HB) was significantly greater in the prone position than in the supine position in QS at 2– 3 and 5– 6 months, despite the higher baseline heart rate and smaller changes in DHR% in the prone position, is of interest and may reflect depressed autonomic responsiveness in this position.
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13.2. Effect of sleep state BHR was elevated in AS compared to QS when infants slept supine at all three ages, and also in the prone position at 2 –3 and 5– 6 months of age (Table 2). This sleep state effect on basal heart rate has been demonstrated previously in a number of studies [19,37]. Our study has expanded these findings by demonstrating that sleep state also has a marked influence on heart rate responses following arousal. Max HR, DHR% and HB were all more pronounced in AS compared to QS, although these effects were also altered by postnatal age and sleeping position. It has been suggested that the sleep-state differences reflect a predominant parasympathetic control of heart rate in QS and a predominant sympathetic influence during AS [1]. 13.3. Effects of postnatal age In healthy full term infants, heart rate increases from 1 week to 1 month, decreases rapidly between 1 and 3 months and falls more slowly between 3 and 6 months [1,37]. In our study, we also demonstrated maturational changes, with Max HR gradually decreasing with increasing postnatal age in both supine and prone positions and in both AS and QS and BHR following similar patterns with the exception of AS in the prone position. This may indicate that the prone position slows down maturation of heart rate in AS. In summary, we have demonstrated that the prone sleeping position has a marked influence on both baseline heart rate and cardiac responses following arousal. The usual increase in heart rate following arousal was most significantly damped in AS at 2 –3 months of age, an age at which SIDS risk is highest. Our study supports the hypothesis that autonomic control of heart rate is impaired in the prone position and this may explain the increased risk for SIDS when infants sleep prone. Acknowledgements The authors wish to thank the staff of the maternity wards at the Monash Medical Centre and Jessie McPherson Private Hospital and the parents and infants who participated in this study. References [1] Gaultier C. Cardiovascular adaptation during sleep in infants and children. Pediatr Pulmonol 1995;19: 105 – 17. [2] Taylor BJ, Williams SM, Mitchell EA, Ford RPK. Symptoms, sweating and reactivity of infants who die of SIDS compared to community controls. J Paediatr Child Health 1996;32:316 – 22. [3] Schechtman VL, Raetz SL, Harper RK, Garfinkle A, Wilson AJ, Southall DP, et al. Dynamic analysis of cardiac R – R intervals in normal infants and in infants who subsequently succumbed to the sudden infant death syndrome. Pediatr Res 1992;1:606 – 12. [4] Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti R, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709 – 14. [5] Byard RW. Sudden infant death syndrome: a ‘diagnosis’ in search of a disease. J Clin Forensic Med 1995;2:121 – 8.
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