CEREBROVASCULAR CONTROL IN HEALTHY TERM INFANTS SLEEPING PRONE http://dx.doi.org/10.5665/sleep.3228

Cerebrovascular Control is Altered in Healthy Term Infants When They Sleep Prone Flora Wong, MBBS, PhD1,2,3; Stephanie R. Yiallourou, PhD1; Alexsandria Odoi, BNS (Honours)1; Pamela Browne, BSc1; Adrian M. Walker, PhD1; Rosemary S. C. Horne, PhD1,3

1 The Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia; 2Monash Newborn, Monash Medical Centre, Melbourne, Victoria, Australia; 3Department of Paediatrics, Monash University, Melbourne, Victoria, Australia

Study Objectives: Sudden infant death syndrome (SIDS) is a leading cause of infant death, and prone sleeping is the major risk factor. Prone sleeping impairs arousal from sleep and cardiovascular control in infants at 2-3 months, coinciding with the highest risk period for SIDS. We hypothesized that prone sleeping would also alter cerebrovascular control, and aimed to test this hypothesis by examining responses of cerebral oxygenation to head-up tilts (HUTs) over the first 6 months after birth. Study Design and Participants: Seventeen healthy full-term infants were studied at 2-4 weeks, 2-3 months, and 5-6 months of age using daytime polysomnography, with the additional measurements of blood pressure (BP, FinometerTM, Finometer Medical Systems, The Netherlands) and cerebral tissue oxygenation index (TOI, NIRO 200, Hamamatsu Photonics KK, Japan). HUTs were performed in active sleep (AS) and quiet sleep (QS) in both prone and supine positions. Results: When infants slept in the prone position, a sustained increase in TOI (P < 0.05) occurred following HUTs, except in QS at 2-3 months when TOI was unchanged. BP was either unchanged or fell below baseline during the sustained TOI increase, signifying cerebro-vasodilatation. In contrast, when infants slept supine, TOI did not change after HUTs, except in QS at 2-3 and 5-6 months when TOI dropped below baseline (P < 0.05). Conclusions: When infants slept in the prone position, cerebral arterial vasodilation and increased cerebral oxygenation occurred during head-up tilts, possibly as a protection against cerebral hypoxia. Absence of the vasodilatory response during quiet sleep at 2-3 months possibly underpins the decreased arousability from sleep and increased risk for sudden infant death syndrome at this age. Keywords: Blood pressure, cerebral blood flow, cerebral oxygenation, cerebrovascular circulation Citation: Wong F; Yiallourou SR; Odoi A; Browne P; Walker AM; Horne RSC. Cerebrovascular control is altered in healthy term infants when they sleep prone. SLEEP 2013;36(12):1911-1918.

INTRODUCTION In developed countries, sudden infant death syndrome (SIDS) remains the leading cause of death in infants aged 1 mo to 1 y. Ninety percent of these infants die during the first 6 mo of life, with a distinct peak incidence at 2-3 mo of age.1 Although the cause of SIDS remains unknown, cardiovascular instability leading to hypotension and a failure to arouse from sleep is thought to play a major role.2-4 Epidemiological studies have identified that the major SIDS risk factor is the prone sleeping position,5 which we have previously shown to be associated with reduced blood pressure,6 impaired baroreflex control of blood pressure,7 and reduced arousal from sleep,8,9 with all these effects being maximal at 2-3 mo of age. The deficits in the control of the systemic circulation associated with prone sleeping during the high-risk period for SIDS may also include impairments in control of cerebral circulation. Sleep related instability in cerebrovascular control and cerebral blood flow has been demonstrated in newborn animal studies.10 Recent studies by our group have also shown that cerebral oxygenation, assessed by near-infrared spectroscopy, is reduced in the prone sleeping position,11 suggesting that relative hypoxia might underpin the deficits in arousal responses

Submitted for publication January, 2013 Submitted in final revised form June, 2013 Accepted for publication June, 2013 Address correspondence to: Professor Rosemary S. C. Horne, PhD, The Ritchie Centre, Level 5, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC, Australia; Tel: +61 3 9594 5100; Fax: +61 3 9594 6811; E-mail: [email protected] SLEEP, Vol. 36, No. 12, 2013 1911 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

associated with this sleeping position.8,9 Reduced cerebral oxygenation11 and blood pressure 6 while sleeping prone may place an infant at particular risk of an adverse event, such as acute hypotension or hypoxia, lowering the margin of safety against cerebral hypoxic ischemia. However, to date the effect of sleeping position on cerebrovascular control and oxygenation during a circulatory challenge has not been assessed during infancy. We have previously applied the head-up tilt (HUT) test to assess cardiovascular control during early infancy, and reported that prone sleeping alters blood pressure responses to this cardiovascular challenge at 2-3 mo of age when, instead of increasing blood pressure as it does in the supine position, it causes an exaggerated fall in blood pressure.12 We therefore hypothesized that cerebrovascular control would also be impaired in the prone position, leading to a further reduction in cerebral oxygenation in response to a HUT. As the impairment of sleep arousal responses peaks at 2-3 mo of age when SIDS risk is greatest, we predicted that cerebral oxygenation impairment would also be maximal at this age. Accordingly, we assessed the effects of prone sleeping, sleep state, and postnatal age on cerebrovascular control, in response to a cardiovascular challenge in healthy term infants over the first 6 mo after birth. METHODS Ethical approval for this project was obtained from the Southern Health and Monash University Human Research Ethics Committees. No monetary incentive was provided for participation and written parental consent was obtained prior to commencement of the study. Cerebral Oxygenation in Infants during Sleep—Wong et al

Subjects Seventeen healthy full-term infants (eight females, nine males) born at 38-42 w gestation were studied. All infants had normal birth weights ranging from 2,900 g to 4,615 g (mean 3,666 ± 105 g) and Apgar scores ranging from 9-10 (median 9) at 5 min. Infants were born to nonsmoking mothers, routinely slept supine at home, and were breastfed. Each infant was studied longitudinally using daytime polysomnography on three occasions across the first 6 mo of life, at 2-4 w, 2-3 mo, and 5-6 mo postnatal age. Data on baseline measurements of cerebral oxygenation have previously been published from this group of infants.11 Polysomnography Polysomnography was performed between 09:00 and 16:00 in a sleep laboratory. Polysomnographic recordings included continuous monitoring of two channels of electroencephalogram (EEG; (C4/A1; O2/A1); electrooculogram, submental electromyogram, electrocardiogram (ECG), thoracic and abdominal breathing movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian VA, USA), arterial blood oxygen saturation (SpO2) (Masimo Radical Oximeter, Masimo Corporation, Irvine, CA, USA), and abdominal skin temperature (ADInstruments, Sydney, Australia). All electrodes and measuring devices for polysomnography were attached during the infant’s morning feeding. Infants were then allowed to sleep naturally in a pram in a darkened room at constant temperature (22-23°C). Infants were visually monitored continuously via an infra-red camera placed above the pram; behavioral changes, such as body movements and crying, were recorded. Infants slept in both the prone and supine positions, with the initial starting position randomized. Sleeping position was changed between morning and afternoon sleep periods that were interrupted by a midday feed. Blood Pressure Measurements Blood pressure was measured using a noninvasive photoplethysmographic cuff (FinometerTM, FMS, Finapres Medical Systems, The Netherlands) placed around the infant’s wrist13,14 as previously described by our group in term infants.6,12 Cerebral Oxygenation Measurements Near-infrared spectroscopy (Spatially Resolved Spectroscopy, NIRO 200 spectrophotometer, Hamamatsu Photonics KK, Japan) was used to assess cerebral oxygenation as previously described.11 Briefly, spatially resolved spectroscopy continuously measures the cerebral tissue oxygenation index (TOI, %), which represents the mixed oxygen saturation in all cerebrovascular compartments. Quantification of TOI is achieved via a continuous wave light and light detection at multiple distances. A near-infrared light of wavelengths 775, 810, and 850 nm is transmitted and delivered to the infant via a fiberoptic bundle terminating in an emission probe. Two aligned photodetectors separated by 4 mm are housed within the detection probe, spaced 4 cm from the emission probe. Both the emission and detection probes were placed over the frontal region of the head and covered with light proof dressing. The NIRO 200 spectrophotometer automatically calculates TOI using the spatially resolved spectroscopy algorithm, which uses the slopes of SLEEP, Vol. 36, No. 12, 2013 1912 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

near-infrared light attenuation versus the different distances of the two photodetectors from the emission probe and continuously computes the ratio of concentrations of oxyhemoglobin to total hemoglobin, and hence the absolute TOI.15,16 All physiological data were recorded at a sampling frequency of 512 Hz using a Compumedics E-Series Sleep Recording system with ProFusion PSG 2 software (Compumedics Limited, Abbortsford, Vic, Australia). At the completion of the study, data were exported via European Data Format to analysis software (LabChart 7.2, ADInstruments). Sleep state was defined as quiet sleep (QS) or active sleep (AS) using electroencephalographic patterns, heart rate (HR), breathing patterns, and behavioral criteria.17 Head-Up Tilt To assess cerebrovascular control in response to a circulatory challenge, each infant underwent repeated HUT testing. In each infant, in both sleep states and sleeping positions replicate 15° HUTs (n = 3) were performed manually over 2-3 sec in each infant, as previously described.12,18 Each HUT measurement consisted of a baseline period and a tilt period, each of 1 min duration. All HUTs were commenced when the infants were physiologically stable and no movement was present. Data Analysis HUTs that were interrupted by movement, arousal, sigh, or apneic pauses within the pre-HUT or HUT phases were excluded from analysis. For each HUT beat-beat values of TOI, changes in oxyhemoglobin (OxyHb), changes in deoxyhemoglobin (DeoxyHb), and mean arterial pressure (MAP) were obtained (LabChart 7.2, ADInstruments) for the 30 beats prior to the HUT and the 90 beats following the HUT. MAP and TOI data were expressed as the percentage change (Δ%) from baseline values averaged over 30 beats prior to the HUT. HUT responses were assessed using methods adapted from our previous studies,12,18 which have shown that a typical infant response to a HUT is biphasic, consisting of (1) initial increases in HR and MAP, each rising rapidly to a peak; (2) decreases in HR and MAP either to or below baseline; and (3) a subsequent return to baseline HR accompanied by a sustained decrease or return to baseline in MAP. To quantify the response, the HUT was divided into three phases: an initial phase occurring 0-30 beats post-HUT; a middle phase occurring 31-60 beats post-HUT; and a late phase occurring 61-90 beats post-HUT. The period of 30 beats is equivalent to ~ 15 sec, a period sufficient to elicit cardiovascular reflex responses; we emphasize that 30- beat phases were successfully used in infant studies by ourselves and by others.12,19,20 HUT responses were averaged in each infant in each sleep state and each sleeping position. Statistical Analysis Statistical analysis was performed using SigmaPlot 12.0 (Systat Software Inc, Richmond, CA, USA). All data were first tested for normality and equal variance. Baseline data for MAP, TOI, SpO2, and HR (averaged 30 beats prior to the HUT) were compared between sleep states and sleep positions using a two-way repeated-measures analysis of variance (RM ANOVA) at each age. The effect of postnatal age on baseline data was compared using a two-way RM ANOVA in each sleep state. For Cerebral Oxygenation in Infants during Sleep—Wong et al

Table 1—Baseline values for tissue oxygenation index, mean arterial pressure, oxygen saturation, and heart rate 2-4 weeks MAP (mmHg) TOI (%) SpO2 (%) HR (beats/min)

QS-supine (n = 14) 62 ± 2 69 ± 2 97.7 ± 0.3 138 ± 2

QS-prone (n = 16) 65 ± 3 66 ± 2a 96.8 ± 0.4 142 ± 2

MAP (mmHg) TOI (%) SpO2 (%) HR (beats/min)

QS-supine (n = 17) 68 ± 3 65 ± 2e 97.9 ± 0.2 135 ± 3

QS-prone (n = 16) 71 ± 3b 63 ± 1e 98.2 ± 0.2e 140 ± 3

AS-supine (n = 12) 70 ± 3 68 ± 2 97.3 ± 0.4 141 ± 4

AS-prone (n = 12) 74 ± 3b 63 ± 2a,b 96.8 ± 0.3 142 ± 3

2-3 months AS-supine (n = 10) 74 ± 2 63 ± 2 97.4 ± 0.8 139 ± 3

AS-prone (n = 11) 79 ± 4b 62 ± 1 99.0 ± 0.2a 136 ± 2

5-6 months MAP (mmHg) TOI (%) SpO2 (%) HR (beats/min)

QS-supine (n = 17) 72 ± 4 61 ± 2c 96.5 ± 0.4c,d 125 ± 2c,d

QS-prone (n = 16) 73 ± 3 58 ± 1c 97.4 ± 0.3a 126 ± 2c,d

AS-supine (n = 12) 73 ± 5 63 ± 2 96.5 ± 0.4 127 ± 3c,d

AS-prone (n = 13) 76 ± 4 61 ± 2 97.7 ± 0.4 130 ± 3b,c

Effects of sleep state, sleeping position and postnatal age on baseline values (averaged 30 beats prior to HUT) for MAP, TOI, SpO2 and HR assessed during QS and AS in both the supine and prone sleeping position at 2-4 w, 2-3 mo, and 5-6 mo postnatal age. aP < 0.05 supine versus prone. bP < 0.05 QS versus AS. cP < 0.05 2-4 w versus 5-6 mo. dP < 0.05 2-3 mo versus 5-6 mo. eP < 0.05 2-4 w versus 2-3 mo. AS, active sleep; HR, heart rate; MAP, mean arterial pressure; QS, quiet sleep; SpO2, arterial oxygen saturation; TOI, tissue oxygenation index.

all baseline comparisons, Student Newman Keuls post hoc analysis was applied. For HUT responses, the initial, middle, and late phases of the HUT response were compared to pre-HUT baseline values using one-way RM ANOVA with Bonferroni post hoc analysis. Statistical significance was taken at the P < 0.05 level. Values are presented as mean ± standard error of the mean. RESULTS Baseline TOI, MAP SpO2, and HR Effect of Sleeping Position

At all three ages, TOI averaged lower in the prone compared to the supine position, with this difference reaching statistical significance in post hoc analysis at 2-4 w during both AS (P = 0.035) and QS (P = 0.043). MAP and HR tended to be higher in the prone position in both sleep states at all three ages; however, these did not reach statistical significance. There was no effect of sleeping position on SpO2, except for 2-3 mo during AS (P = 0.011) and 5-6 mo during QS (P = 0.024), where SpO2 was higher in the prone compared to the supine position (+0.9 to 1.6%). This information is presented in Table 1. Effect of Sleep State

At both 2-4 w and 2-3 mo, TOI averaged lower in AS compared to QS, with this difference reaching statistical significance at 2-4 w in the prone position (P = 0.003). At 5-6 mo, TOI averaged 2-3% higher in AS compared to QS; however, this difference did not reach statistical significance. MAP was higher in AS compared to QS at 2-4 w in the prone position (P = 0.036), and 2-3 mo in both the supine (P = 0.016) and SLEEP, Vol. 36, No. 12, 2013 1913 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

prone positions (P = 0.035). HR was higher in AS compared to QS at 5-6 mo in the prone position (P = 0.017). There was no effect of sleep state on SpO2. Effect of Postnatal Age

TOI decreased by 8% between 2-4 w and 5-6 mo during QS in both the supine (P < 0.001) and prone (P = 0.003) sleeping positions; however, there was no effect of postnatal age in AS in either sleep position. HR decreased with advancing postnatal age in both sleeping positions during AS (supine, P < 0.001; prone, P = 0.008) and QS (P < 0.001 for both positions). There was a small but significant decrease (1.2%) in SpO2 between 2-4 w and 5-6 mo during QS in the supine position (P = 0.039), whereas there was an increase in SpO2 between 2-4 w and 2-3 mo during QS in the prone position (P = 0.038). There was no effect of postnatal age on MAP in either sleep state or sleeping position. Response to the HUT Figure 1 illustrates a typical recording of blood pressure, SpO2, OxyHb, DeoxyHb, TOI, and HR in response to a HUT in the supine and prone sleeping positions. Overall, in the supine position, TOI did not change in response to the HUT despite an increase in blood pressure (Figure 1A). In contrast, in the prone position TOI increased in response to the HUT (Figure 1B) due largely to an increase in OxyHb. In this position, blood pressure exhibited a biphasic response with a small initial rise, followed by a decrease back to or below baseline. TOI and MAP Responses to HUT QS

The grouped responses to a HUT of TOI and MAP during QS are presented in Figure 2. In the supine position (Figure Cerebral Oxygenation in Infants during Sleep—Wong et al

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Figure 1—Typical recording of the blood pressure (BP), oxygen saturation (SpO2), oxygenated hemoglobin (OxyHB), deoxygenated hemoglobin (DeoxyHb), tissue oxygenation index (TOI), and heart rate (HR) responses to a head-up tilt (HUT) in the supine and prone positions during quiet sleep in a 2- 4 w old infant. The HUT onset is indicated by the line at beat zero. Note that the rise in TOI post-HUT in the prone position is absent when the infant is supine.

2 A-C), TOI remained close to baseline values after the HUT at all three ages, with a small (~2%) but significant TOI fall in the initial and middle phases at both 2-3 mo (initial phase, P = 0.002 and in middle phase, P < 0.001) and 5-6 mo (initial phase; P < 0.001). The lowest TOIs reached were 64% and 59% at 2-3 mo and 5-6 mo, respectively. In contrast, in the prone position (Figure 2 D-F) at both 2-4 w and 5-6 mo, TOI did not decrease but increased 2-3% from baseline, reaching a peak within the initial phase (2-4 w and 5-6 mo, P < 0.001) and remaining above baseline for the duration of the HUT in the middle (2-4 w and 5-6 mo, P < 0.001) and late phases (2-4 w and 5-6 mo, P = 0.007). The maximum TOIs reached were 68% and 60% at 2-4 w and 5-6 mo, respectively. Notably, this increase in TOI was absent during QS at 2-3 mo in the prone position (Figure 2E). During QS in the supine position, MAP increased by 2-4% in the initial phase and returned to baseline in the late phase of the HUT at both 2-4 w (initial phase, P < 0.001) and 2-3 mo (initial phase, P < 0.001), at 5-6 mo it fell 3-4% below baseline (middle phase, P = 0.04, late phase P < 0.001). The pattern was similar in the prone position at all ages studied, except that MAP fell below baseline after the initial increase. TOI and MAP Response to HUT- AS

The grouped HUT responses of TOI and MAP for AS are presented in Figure 3. In the supine position, TOI responded in a similar fashion to that in QS, with no change from baseline SLEEP, Vol. 36, No. 12, 2013 1914 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

observed after the HUT at all three ages. In contrast in the prone position, as observed in QS, there was a marked increase in TOI (~4%) at 2-4 w (initial phase P < 0.001 and middle phase P = 0.010), 2-3 mo (initial phase P < 0.001 and middle phase P = 0.005) and at 5-6 mo (initial phase P < 0.001 and late phase P < 0.001). The MAP response to a HUT during AS was more variable than that observed during QS. There were no significant differences from baseline for MAP post-HUT, except at 5-6 mo in the prone position, when MAP fell 4% below baseline in the late phase of the HUT (P < 0.001). In all sleep states, sleeping positions, and postnatal ages, the changes in SpO2 in response to the HUT was less than 1.5% from the baseline. DISCUSSION To our knowledge, this is the first study to take into account the effects of both sleeping position and sleep state, while examining developmental changes in cerebrovascular control in healthy term infants longitudinally over the first 6 mo after birth. In response to a cardiovascular challenge we found consistent and statistically significant changes in cerebral oxygenation, which varied with sleeping position, postnatal age, and sleep state. When infants slept in the supine position, cerebral oxygenation was maintained after the HUT, with the exception of QS at 2-3 mo and 5-6 mo of age when it fell transiently. In contrast, when infants slept in the prone position, a significant and sustained increase in cerebral oxygenation occurred following the HUT, with the sole exception of 2-3 mo of age in QS when TOI remained unchanged from baseline values. TOI represents oxygen saturation in all cerebrovascular compartments but is most influenced by the venous compartment, which comprises approximately 75% of total cerebral blood volume.21 Accordingly, a lower TOI represents a relative reduction of cerebral blood flow compared to cerebral oxygen consumption with increased oxygen extraction. As the HUT was performed over a short period of time, during which significant change of cerebral oxygen consumption is unlikely, changes in TOI can be assumed to represent parallel responses in cerebral blood flow. Prone Sleeping, Cerebrovascular Control, and Tissue Oxygenation Consistent with our previous report,11 baseline TOI was lower in the prone sleeping position compared to the supine position. The lower TOI could be due to position-dependent perturbations in cerebral arterial blood flow and venous drainage, related to head rotation in prone sleeping.22,23 In addition, adult studies suggest that prone positioning causes an increase in intrathoracic pressure leading to a decrease in arterial filling and cardiac index,24 which may potentially impede cerebral perfusion and oxygenation. Nevertheless, the difference in TOI we observed between supine and prone sleeping is relatively small and the TOI values are still within what is generally accepted as normal range, compared to previous reports in sick preterm infants undergoing intensive care25 and newborn animals subjected to severe hypoxia-ischemia.26-28 However, the infants in our study are all healthy term infants recruited from home and are unlikely to display TOI changes similar to sick preterm infants. Cerebral Oxygenation in Infants during Sleep—Wong et al

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Figure 2—Mean arterial pressure (MAP, open circles) and tissue oxygenation index (TOI, solid circles) responses to head-up tilt (HUT) recorded during quiet sleep (QS) in the supine sleeping position (A-C) and prone sleeping position (D-F) at 2-4 w (top panel), 2-3 mo (middle panel), and 5-6 mo (bottom panel). The HUT onset is indicated by the dotted line at beat zero. *P < 0.05 MAP versus pre-HUT baseline; †P < 0.05 TOI versus pre-HUT baseline.

The prolonged increased TOI during the HUT in these healthy infants, observed only in the prone sleeping position, indicates that a rise in cerebral blood flow occurs even when blood pressure has returned to baseline levels. This is likely to be due to cerebral arterial vasodilation, as shown by the increase in OxyHb (Figure 1B). The mediating factor for arterial cerebrovasodilation in the prone sleeping position during the HUT is intriguing, as cerebral blood flow is usually tightly regulated by mechanisms sensitive to oxygen, carbon dioxide, neuronal requirements (metabolic and functional activation), and blood pressure. However, none of these mechanisms offers a physiological explanation for the sustained cerebrovasodilation after the HUT in the prone sleeping position, especially because the infants did not show SLEEP, Vol. 36, No. 12, 2013 1915 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

any arousal response or change in respiratory parameters. The increase in TOI precedes the upward trend in blood pressure, indicating that it is not due to an increase in cerebral perfusion pressure operating within a pressure-passive cerebral circulation.29 Rather, cerebral vasodilatation may be related to vestibular mechanisms that have been suggested to alter systemic vascular resistance during movements and postural changes in infants.12 In support of this idea, animal studies have shown that labyrinthine signals participate in setting basal rates of blood flow to the head to compensate for orthostatic challenges.30 Additionally, vestibular impairment disrupts basal cerebral blood flow while causing labile blood pressure during postural changes.30 As the blood pressure decreases in the middle and late phases of the HUT, reduction in the transmural pressure in Cerebral Oxygenation in Infants during Sleep—Wong et al

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Figure 3—Mean arterial pressure (MAP, open circles) and tissue oxygenation index (TOI, solid circles) responses to head-up tilt (HUT) recorded during active sleep in the supine sleeping position (A-C) and prone sleeping position (D-F) at 2-4 w (top panel), 2-3 mo (middle panel), and 5-6 mo (bottom panel). The HUT onset is indicated by the dotted line at beat zero. *P < 0.05 MAP versus pre-HUT baseline; †P < 0.05 TOI versus pre-HUT baseline.

cerebral vessels would normally induce the myogenic reflex, to vasodilate cerebral blood vessels in order to maintain constant cerebral blood flow.31 However, the sustained rise in TOI in the middle and late phases of the HUT suggests that this vasodilation has been exaggerated. Among the possibilities to explain this, sympathetic nerves that richly innervate cerebral blood vessels in early life and powerfully modulate cerebral blood flow32 may play a role and provide a possible explanation for this exaggerated vasodilation. Withdrawal of sympathetic influences on cerebral blood vessels increases cerebral blood flow33 and would elevate TOI. The sustained higher level of TOI in the prone position may be due to reduced vestibulosympatheticcerebrovascular reflex activity during the HUT,34 possibly as a compensatory mechanism for the low baseline TOI in this SLEEP, Vol. 36, No. 12, 2013 1916 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

position.11 We speculate that this is a protective response in the vulnerable prone position to prevent cerebral hypoxia. Of great importance is that such compensatory mechanisms of increased cerebral oxygenation in the prone position are absent at 2-3 mo of age in QS, coinciding with the nadir in baseline TOI in the same sleeping position, postnatal age, and sleep state.11 These findings suggest a developmental characteristic that may contribute to the decreased arousability that is well described in prone sleeping and during QS at the high-risk age.9,35 Interestingly, the arousal response to our HUT of 15° was not reduced by prone sleeping in infants,12 in contrast to the arousal response to other stimuli or HUTs of greater magnitudes.8,9,35-37 Our results show that at all ages studied, the TOI values during the HUT, relative to baseline, were higher in the Cerebral Oxygenation in Infants during Sleep—Wong et al

prone position compared to the supine position. The absence of a positional difference on the arousal response to a HUT in the prone position may be explained by the compensatory increase in TOI. This finding further supports the possible relationship between cerebral oxygenation and arousability in infants. Further studies to delineate the relationship should involve testing arousal thresholds to different stimuli, together with cerebral TOI measurements. Supine Sleeping and Cerebrovascular Control Baseline TOI was higher in the supine sleeping position compared with the prone sleeping position in both sleep states and at all postnatal ages. In contrast to prone sleeping, TOI in the supine position during the HUT was maintained consistently, except in QS at 2-3 mo and 5-6 mo of age when it dropped below baseline. Note that at both ages TOI was well maintained during the initial increase in blood pressure, and subsequently decreased transiently with the decrease in blood pressure. The restoration of TOI to baseline values took 19 heartbeats (equivalent to ~8 sec) and 4 heartbeats (equivalent to ~2 sec) at 2-3 mo and 5-6 mo of age, respectively. The timing of the TOI and blood pressure changes suggest that cerebral blood flow was maintained initially by cerebrovasoconstriction during the period of increased blood pressure, but later decreased transiently with the decreased blood pressure, possibly due to the response time required for cerebral autoregulation and cerebrovasodilation to restore cerebral blood flow.38 Our longitudinal data revealed that this response time was longest at 2-3 mo of age. These findings suggest a developmental characteristic of cerebrovascular control in QS at 2-3 mo of age, with subsequent restoration later during infancy. QS is the Vulnerable Sleep State at the High-Risk Age The new findings of this study have important implications for understanding the mechanisms of SIDS. For both prone and supine sleeping, there was a different developmental “characteristic” of cerebrovascular control in QS at 2-3 mo of age, the age when the SIDS risk is greatest. Previously we also demonstrated that TOI decreases with age in QS in both sleep positions.11 Our new result lends additional support to the idea of QS being a particularly vulnerable state after the neonatal period, as arousal responses are also significantly reduced during QS compared to AS, with the difference most marked at 2-3 mo of age.9,12,37,39 Notably, the altered cerebrovascular control in QS at this age may represent a diminished capacity for compensatory increases in oxygen extraction to the brain should there be coincident hypoxic stress, hypotension, or hypoperfusion. CONCLUSION We have identified that cerebrovascular control in normal healthy term infants during sleep is different in the prone compared to the supine sleeping position. In prone sleeping, when baseline blood pressure and cerebral oxygenation are low, cerebral arterial vasodilation and increased cerebral oxygenation occur during a cardiovascular challenge, possibly as a protective mechanism to maintain cerebral oxygen delivery. However, such a putatively protective vasodilatory response is absent during QS at 2-3 mo of age. Most prominently in supine sleeping, also during QS at 2-3 mo of age, cerebral oxygenation SLEEP, Vol. 36, No. 12, 2013 1917 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

in response to a cardiovascular challenge drops below the baseline. In summary, the altered cerebrovascular control in QS at 2-3 mo of age may underpin decreased arousability from sleep and place infants at risk when faced with circulatory challenges, thus representing a critical mechanism that may underpin the increased risk of SIDS at this age. ACKNOWLEDGMENTS Drs. Wong and Yiallourou are co-first authors of this paper. The authors acknowledge all the parents and infants who participated in this study and the support of staff of the Melbourne Children’s Sleep Centre. DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest. This project was supported by Scottish Cot Death Trust, the National Health and Medical Research Council of Australia project number 1006647 and the Victorian Government’s Operational Infrastructure Support Programme. Dr. Wong was supported by a National Health and Medical Research Council of Australia Health Professional Research Fellowship. Dr. Yiallourou was partially supported by the Kaarene Fitzgerald Fellowship, SIDS and Kids, Victoria. Professor Horne was supported by a National Health and Medical Research Council of Australia Senior Research Fellowship. REFERENCES

1. Moon RY. SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics 2011;128:1030-9. 2. Matthews T. Sudden infant death syndrome--a defect in circulatory control? Child Care Health Dev 2002;28:41-3. 3. Ledwidge M, Fox G, Matthews T. Neurocardiogenic syncope: a model for SIDS. Arch Dis Child 1998;78:481-3. 4. Harper RM. Sudden infant death syndrome: a failure of compensatory cerebellar mechanisms? Pediatr Res 2000;48:140-2. 5. Blair PS, Sidebotham P, Berry PJ, Evans M, Fleming PJ. Major epidemiological changes in sudden infant death syndrome: a 20-year population-based study in the UK. Lancet 2006;367:314-9. 6. Yiallourou SR, Walker AM, Horne RS. Effects of sleeping position on development of infant cardiovascular control. Arch Dis Child 2008;93:868-72. 7. Yiallourou S, Sands SA, Walker AM, Horne RS. Baroreflex sensitivity during sleep in infants: impact of sleeping position and sleep state. Sleep 2011;34:725-32. 8. Franco P, Pardou A, Hassid S, Lurquin P, Groswasser J, Kahn A. Auditory arousal thresholds are higher when infants sleep in the prone position. J Pediatr 1998;132:240-3. 9. Horne RS, Ferens D, Watts AM, et al. The prone sleeping position impairs arousability in term infants. J Pediatr 2001;138:811-6. 10. Grant DA, Franzini C, Wild J, Eede KJ, Walker AM. Autoregulation of the cerebral circulation during sleep in newborn lambs. J Physiol 2005;564:923-30. 11. Wong FY, Witcombe NB, Yiallourou SR, et al. Cerebral oxygenation is depressed during sleep in healthy term infants when they sleep prone. Pediatrics 2011;127:e558-65. 12. Yiallourou SR, Walker AM, Horne RS. Prone sleeping impairs circulatory control during sleep in healthy term infants: implications for SIDS. Sleep 2008;31:1139-46. 13. Drouin E, Gournay V, Calamel J, Mouzard A, Roze J. Feasibility of using finger arterial pressure in neonates. Arch Dis Child 1997;77:139-40. 14. Yiallourou SR, Walker AM, Horne RSC. Validation of a new non-invasive method to measure blood pressure and assess baroreflex sensitivity in preterm infants during sleep. Sleep 2006;29:1083-8.

Cerebral Oxygenation in Infants during Sleep—Wong et al

15. Matcher SJ, Kirkpatrick P, Nahid K, Cope M, Delpy D. Absolute quantification methods in tissue near infrared spectroscopy. Proc SPIE 1995;2389:486-9. 16. Suzuki S TS, Ozaki T, Kobayashi Y. A tissue oxygenation monitor using NIR spatially resolved spectroscopy. Proc SPIE 1999;3597:582-92. 17. Anders T, Emde R, Parmelee A. A manual of standardized terminology, techniques and criteria for scoring of states of sleep and wakefulness in newborn Infants. Los Angeles: BRI Publications, 1971. 18. Witcombe NB, Yiallourou SR, Walker AM, Horne RS. Delayed blood pressure recovery after head-up tilting during sleep in preterm infants. J Sleep Res 2010;19:93-102. 19. Harrington C, Kirjavainen T, Teng A, Sullivan CE. Cardiovascular responses to three simple, provocative tests of autonomic activity in sleeping infants. J Appl Physiol 2001;91:561-8. 20. Kirjavainen T, Viskari S, Pitkanen O, Jokinen E. Infants with univentricular heart have reduced heart rate and blood pressure responses to side motion and altered responses to head-up tilt. J Appl Physiol 2005;98:518-25. 21. An H, Lin W. Cerebral venous and arterial blood volumes can be estimated separately in humans using magnetic resonance imaging. Magn Reson Med 2002;48:583-8. 22. Pamphlett R, Raisanen J, Kum-Jew S. Vertebral artery compression resulting from head movement: a possible cause of the sudden infant death syndrome. Pediatrics 1999;103:460-8. 23. Watson GH. Effect of head rotation on jugular vein blood flow. Arch Dis Child 1974;49:237-9. 24. Edgcombe H, Carter K, Yarrow S. Anaesthesia in the prone position. Br J Anaesth 2008;100:165-83. 25. van Bel F, Lemmers P, Naulaers G. Monitoring neonatal regional cerebral oxygen saturation in clinical practice: value and pitfalls. Neonatology 2008;94:237-44. 26. Hou X, Ding H, Teng Y, Zhou C, Tang X, Li S. Research on the relationship between brain anoxia at different regional oxygen saturations and brain damage using near-infrared spectroscopy. Physiol Meas 2007;28:1251-65. 27. Kurth CD, Levy WJ, McCann J. Near-infrared spectroscopy cerebral oxygen saturation thresholds for hypoxia-ischemia in piglets. J Cereb Blood Flow Metab 2002;22:335-41.

SLEEP, Vol. 36, No. 12, 2013 1918 Downloaded from https://academic.oup.com/sleep/article-abstract/36/12/1911/2709416 by guest on 06 June 2018

28. Hagino I, Anttila V, Zurakowski D, Duebener LF, Lidov HG, Jonas RA. Tissue oxygenation index is a useful monitor of histologic and neurologic outcome after cardiopulmonary bypass in piglets. J Thorac Cardiovasc Surg 2005;130:384-92. 29. Soul JS, Hammer PE, Tsuji M, et al. Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatr Res 2007;61:467-73. 30. Wilson TD, Cotter LA, Draper JA, et al. Effects of postural changes and removal of vestibular inputs on blood flow to the head of conscious felines. J Appl Physiol 2006;100:1475-82. 31. McHedlishvili GI, Nikolaishvili LS, Antia RV. Are the pial arterial responses dependent on the direct effect of intravascular pressure and extravascular and intravascular PO2, PCO2, and pH? Microvasc Res 1975;10:298-311. 32. Cassaglia PA, Griffiths RI, Walker AM. Cerebral sympathetic nerve activity has a major regulatory role in the cerebral circulation in REM sleep. J Appl Physiol 2009;106:1050-6. 33. Cassaglia PA, Griffiths RI, Walker AM. Sympathetic withdrawal augments cerebral blood flow during acute hypercapnia in sleeping lambs. Sleep 2008;31:1729-34. 34. Cooke WH, Carter JR, Kuusela TA. Human cerebrovascular and autonomic rhythms during vestibular activation. Am J Physiol Regul Integr Comp Physiol 2004;286:R838-43. 35. Richardson HL, Walker AM, Horne RS. Sleep position alters arousal processes maximally at the high-risk age for sudden infant death syndrome. J Sleep Res 2008;17:450-7. 36. Horne RS, Bandopadhayay P, Vitkovic J, Cranage SM, Adamson TM. Effects of age and sleeping position on arousal from sleep in preterm infants. Sleep 2002;25:746-50. 37. Galland BC, Reeves G, Taylor BJ, Bolton DP. Sleep position, autonomic function, and arousal. Arch Dis Child Fetal Neonatal Ed 1998;78:F189-94. 38. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke 1989;20:45-52. 39. Parslow PM, Harding R, Adamson TM, Horne RS. Effects of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants. Sleep 2004;27:105-9.

Cerebral Oxygenation in Infants during Sleep—Wong et al