Sleep state changes associated with cerebral blood volume changes in healthy term newborn infants

Early Human Development 52 (1998) 27–42

Sleep state changes associated with cerebral blood volume changes in healthy term newborn infants *, Hans Ulrich Bucher, Gabriel Duc ¨ Daniel Martin Munger Clinic for Neonatology, University Hospital of Zurich, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland Received 9 April 1997; received in revised form 15 October 1997; accepted 11 December 1997

Abstract In order to assess the possible effects of sleep states on cerebral haemodynamics in healthy term infants, we measured cerebral oxyhaemoglobin, deoxyhaemoglobin and total haemoglobin concentration using near infrared spectroscopy. Thirty-seven sleep state changes in seventeen infants (gestational age: 37 to 41 4 / 7 weeks), aged between two and eight days were continuously registrated during 1–3 h. Transcutaneous PaO 2 , PaCO 2 , arterial O 2 saturation and heart rate were simultaneously recorded and sleep states were clinically defined. There was a close relationship between sleep state changes and changes in total cerebral haemoglobin concentration, which increased from active to quiet sleep and decreased from quiet to active sleep. Changes in total cerebral haemoglobin were due, in the most part, to changes in the cerebral oxyhaemoglobin concentration. In conclusion, sleep states influence the cerebral haemoglobin concentration. Studies on cerebral haemodynamics should take sleep state into account in term newborn infants.  1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Healthy term newborn infants; Sleep state changes; Near infrared spectroscopy; Cerebral haemoglobin concentration

1. Introduction Sleep states, i.e. quiet (QS or state I) and active sleep (AS or state II) of the newborn are distinct physiological conditions, each reflecting a special mode of *Corresponding author. 0378-3782 / 98 / $19.00  1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0378-3782( 98 )00002-4

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Table 1 Clinical criteria for definition of behavioural states (after [37,51,52]) Behavioural state

Eyes open

Respiration regular

Gross movements

Voc.

REM a

Muscle tonus a

I, quiet sleep II, active sleep III, quiet awake IV, active awake V, crying

2 2 1 1 6

1 2 1 2 2

2 6 2 1 1

2 2 2 2 1

2 1

1 2

Signs: 1 5 present; 2 5 absent; 6 5 may be present or absent; Voc. 5 vocalisation a Clinical criteria of REM (rapid eye movement) and muscle tonus were added by us.

central nervous activity (Table 1). The normal term newborn infant spends up to 20 h per day sleeping. Studies of physiological functions and cerebral haemodynamics during the first days of life are therefore mainly in sleep states. Comparisons of cerebral haemodynamic parameters between different behavioural states in newborns and adults have been obtained with venous occlusion plethysmography [32,34,40], doppler ultrasonography [16,25,41] and the 133 Xenon clearance method [18,53]. With the exceptions of refs. [16,18], these studies revealed significant differences in cerebral blood flow (CBF) and cerebral blood flow velocity (CBFV) between the different behavioural states. In general, CBF in newborn infants was increased during AS compared to QS, analogous to adult individuals comparing REM and non-REM sleep [53]. Near infrared spectroscopy (NIRS) has not yet been applied to measure cerebral haemodynamics during sleep state changes (SSCs). NIRS has the advantage of being able to measure cerebral haemodynamic parameters continuously and non-invasively, and is easy to apply at the cotside [14]. We measured cerebral haemoglobin concentration changes reflecting cerebral blood volume (CBV) changes during different sleep states. The following questions were asked: Do sleep states influence cerebral haemoglobin concentration as measured by NIRS in healthy term newborn infants during the first days of life? If yes, what is the time relationship between these changes and sleep state changes?

2. Subjects and methods

2.1. Subjects Seventeen healthy term infants (seven female, ten male), aged from two to eight days (mean, four days) were investigated. All babies were born in the Frauenklinik of the University Hospital of Zurich. Gestational age ranged from 37 to 41 4 / 7 weeks post menstruationem (mean, 39 5 / 7 weeks); birth weight ranged from 2570 to 4150 g (mean, 3335 g). Head circumference, birth weight and length were between 10. and 90. centile.

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Table 2 Clinical information on studied infants Infant number

Sex

Gestational age (wk)

Birth weight (g)

Postnatal age (d)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

f m m m m f m m m f m f m m f f f

38 39 40 39 39 39 37 41 39 39 38 41 39 40 41 40 39

3170 3300 3490 3890 3260 2830 3010 4150 3620 3690 3740 2800 2930 3340 3180 3720 2570

2 1.5 8.3 5 3 3.5 3.5 3 2 1.5 6 6.5 2 2 8.5 3 4

3/7 1/7 1/7 3/7 5/7 1/7 0/7 2/7 1/7 3/7 6/7 4/7 3/7 3/7 4/7 1/7 6/7

Clinical data for the infants are listed in Table 2. There were no complications during pregnancy. Five infants were delivered by caesarean section, two by forceps and ten spontaneously. APGAR score one minute post partum was $ 4, 5 min p.p. $ 7 and 10 min p.p. $ 9. All infants had pH values in the umbilical artery of more than 7.15, except for one infant, who had a pH of 7.04. This newborn infant and another one showed a transient respiratory distress syndrome due to wet lungs following caesarean section without any further clinical signs 3 h after delivery. All babies were clinically normal at the time of the study. Besides vitamin K supplementation on day three, no other drugs were given to the babies.

2.2. Measurement procedure Infants were taken from the maternity ward to a half darkened, quiet room at the neonatal unit. The temperature of the room was 20 to 218C. After installation procedures, which lasted for about 15 to 20 min, the infants were left untouched in either a prone or lateral position, dressed and under coverlet to the hips (Fig. 1, photograph). Measurements lasted for 1–3 h and were done at different times of the day. Informed consent was obtained from one or both parents. The mother was present during measurements. The study protocol was approved by the ethical committee of the Children’s Hospital of Zurich.

2.3. Behavioural state definition Infants were closely observed at the cotside and the behavioural state was clinically defined according to Prechtl [37] and Thoman [51,52] (Table 1). SSCs were defined

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Fig. 1. Photograph of measurement arrangement which shows ends of light conveying bundles and head of the baby shielded from background light by an opaque cap.

as periods of QS followed by periods of AS and the reverse. The time between sleep states, clinically a behavioural state characteristic for neither QS nor AS, was called sleep state transition (SST), in accordance with others [35,37,45,51,52].

2.4. Continuous recording Changes in cerebral oxyhaemoglobin (D[O 2 Hb]) and deoxyhaemoglobin (D[HHb]) were recorded and averaged over 5 s by NIRS (NIR 1000 spectrophotometer, Hamamatsu Photonics KK). Arterial oxygen saturation (SaO 2 ) and heart rate were recorded by a pulse oximeter (Nellcor 200) with a sensor fixed on the infants’ hand. Transcutaneous carbon dioxide tension (PaCO 2 ) and oxygen tension (PaO 2 ) were measured by an oxycapnomonitor (Hellige, Freiburg Germany) from the posterior chest of the newborn infant.

2.5. Principles of the near infrared spectroscopy technique Near infrared light (wavelength of 700 to 1000 nm) penetrates biological tissue very well, up to 7 cm, in contrast to visible light (400 to 700 nm), which is absorbed

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after a few mm. The ability of chromophores like haemoglobin to absorb light in the near infrared region allows measurements in vivo by transmission spectroscopy [10,23]. Oxyhaemoglobin and deoxyhaemoglobin can be differentiated because of their different absorption spectra [6,11,57]. Changes in measured cerebral haemoglobin concentrations reflect changes in cerebral haemodynamics and can be monitored by this method continuously at the cotside [14,58,59]. Changes in cerebral haemoglobin concentration are expressed as mmol / l total brain tissue. In our study, light-conveying bundles were positioned lateral fronto-temporal and on the same side parieto-occipital of the infant’s head. Measuring through the biparietal diameter is not possible in term infants, because the distance is too far for enough light to emerge. The head of the infant and the ends of the fibres were shielded from background light by an opaque cap (Fig. 1). NIRS offers the opportunity to measure CBF intermittently using a sudden increase of [O 2 Hb] [14] or an injection of a dye as a tracer [36]. These methods were not applied in the present study as the necessary intervention was considered not to be ethical in healthy newborn infants. Gross turns or movements of the head of the newborn can provoke artefacts in NIRS data registrations, which have to be recognised during continuous clinical observations.

2.6. Data analysis NIRS data, blood gas and heart rate values were transfered to a personal computer (IBM PS2). Mean cerebral haemoglobin concentration values were calculated over each sleep state period. Data recordings with artefacts in near infrared measurements, quiet and active awake (states III and IV) and crying (state V) were excluded from the final analysis. To make the graph more representable, [Hb] values are averaged over 15 s and the heart rate over 5 s. Sleep state after a SST was divided into an overshooting ‘‘initial condition’’ (ic) and a ‘‘stable condition’’ (sc) period (Fig. 2). This division is based on differences in cerebral haemodynamics between the initial time of a new sleep period and the latter as described by others [4,45,48]. The duration of the initial condition was defined as from the beginning of the new sleep state period to the beginning of a clearly visible more stable cerebral haemoglobin concentration trace. During overshooting ic, a time-frame of 30 s was taken as a reference, named ‘‘initial condition peak’’ (ic peak), for allowing quantitative comparisons (Fig. 2). Quantitative changes in cerebral haemodynamics during SSC, i.e. between the two sleep states, were analysed and calculated (Fig. 3, Table 3). In addition, qualitative aspects of cerebral haemodynamic changes during sleep state transitions were described (Fig. 2). Changes in total cerebral haemoglobin concentration (D[Hb]) were calculated in summing up the changes in [O 2 Hb] and [HHb]. The differences between ic, sc and ic peak to stable condition of the previous sleep state were analysed separately. SaO 2 , PaO 2 , PaCO 2 and heart rate were analysed likewise. The statistical significance of group differences was evaluated with the Wilcoxon matched pairs signed-ranks. P values , 0.05 were considered to be significant.

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Fig. 2. Examples of changes in cerebral haemoglobin concentrations and heart rate during sleep state changes in two infants (no. 13 and 15). ——— [O 2 Hb] 1 [HHb] 5 total cerebral haemoglobin concentration. – – – [O 2 Hb] 5 cerebral oxyhaemoglobin concentration. ——— [HHb] 5 cerebral deoxyhaemoglobin concentration.

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Fig. 3. Individual event values (d) of cerebral haemoglobin concentration changes during sleep state changes. AS 5 active sleep; QS 5 quiet sleep; ic 5 initial condition and sc 5 stable condition of the new sleep state; D[O 2 Hb] 5 cerebral oxyhaemoglobin concentration change. D[HHb] 5 cerebral desoxyhaemoglobin concentration change.

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Table 3 Changes in cerebral haemoglobin concentration during sleep state changes (values are differences from the original sc and in mmol / l) From QS to AS

From AS to QS

ic

(ic-peak)

sc

ic

(ic-peak)

sc

D([O 2 Hb 1 HHb])

median min max

2 5.74** 2 12.15 10.57

(28.28**) (212.72) (4.9)

2 4.95** 2 10.84 9.23

7.17** 2 26.23 27.53

(11.07**) (224.02) (29.86)

6.02** 2 31.83 24.22

D[O 2 Hb]

median min max

2 7.81** 2 16.45 5.47

(211.16**) (219.99) (4.23)

2 6.25** 2 12.51 2.36

8.69** 2 22.11 18.35

(12.09**) (220.97) (21.54)

7.23** 2 26.96 13.11

D[HHb]

median min max

3.04 2 1.42 7.81

(3.62**) (25.09) (10.93)

1.24* 2 3.71 10.22

2 2.67 2 5.88 9.34

(22.96) (26.35) (8.31)

2 0.75 2 5.52 12.65

D[O 2 Hb] 5 cerebral oxyhaemoglobin concentration change; D[HHb] 5 cerebral deoxyhaemoglobin concentration change. AS 5 active sleep; QS 5 quiet sleep; ic 5 initial condition; ic-peak 5 peak reference value during initial condition; sc 5 stable condition. Significance: *p 5 0.05–0.01; **p , 0.01.

3. Results

3.1. Cerebral haemoglobin concentration during sleep state change Twenty-one SSCs from QS to AS (sixteen infants) and sixteen SSCs from AS to QS (fourteen infants) were analyzed. Two registrations of cerebral haemoglobin concentration and heart rate are given in Fig. 2. Graphical representations of the individual data values are shown in Fig. 3 and median values are listed in Table 3. The changes in cerebral haemoglobin concentration during SSCs are remarkable. The cerebral haemoglobin concentration increased significantly from active to quiet sleep and decreased from quiet to active sleep. Fig. 2 shows typical patterns of overshooting ic, followed by the more stable condition, which was still different from the original state. There was no time delay from the beginning of a new sleep state to the change in cerebral haemoglobin concentration. Sometimes the [Hb] changed even during the SST, before onset of a new clinically well defined sleep state (Fig. 2b). The duration of periods are listed in Table 4. Figs. 2, 3 and Table 3 show that the initial change period was characterized by opposite changes of [O 2 Hb] and [HHb], while more was represented by changes in [O 2 Hb]. During stable conditions, the concentration change of cerebral haemoglobin was almost completely represented by the oxyhaemoglobin. All differences are highly significant for D[Hb] and D[O 2 Hb]. D[HHb] was only significant during SSCs from QS to AS. As in healthy neonates, no peripheral haematocrit was measured, no absolute CBV change could be calculated. With a hypothetical haematocrit of 45 to 55% changes of

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Table 4 Duration of all calculated periods and sleep state transitions (minutes) QS

Sleep periods Median Range (n)

AS

8 4–25 (21)

AS

ic

sc

3.5 1.5–6.5 (21)

10 2–22 (17)

QS

9 2.3–29 (17)

Sleep state transition periods Median 2 Range 1–4 (n) (21)

ic

sc

4.0 2–6.5 (17)

9.5 4–25 (16)

2 0.8–7 (17)

AS 5 active sleep; QS 5 quiet sleep; ic 5 initial condition; sc 5 stable condition; n 5 number of calculated periods.

cerebral heamoglobin concentration reflect a change of total CBV of about 5–10% during SSC.

3.2. Heart rate and blood gases during sleep state change Graphs of heart rate versus time are shown in Fig. 2. Mean values of heart rate and blood gases are listed in Table 5. Transcutaneous PaO 2 , PaCO 2 and oxygen saturation were increased in QS compared to AS, while heart rate was decreased. Differences were not statistically significant. Changes in cerebral haemoglobin concentration did not correlate neither with blood gas changes nor with heart rate changes.

Table 5 Absolute values of blood gases and heart rate during sleep state changes (values are median). Differences are not significant statistically QS

PaO 2 (kPa) (n) PaCO 2 (kPa) (n) SaO 2 (%) (n) Heart rate (bpm) (n)

9.7 (12) 8.0 (11) 93 (16) 120 (16)

AS

AS

ic

ic-peak

sc

9.3 (12) 7.8 (11) 92 (14) 124 (16)

9.2 (12) 7.8 (11) 94 (11) 130 (16)

9.4 (10) 7.8 (9) 92 (11) 125 (12)

9.3 (7) 7.6 (6) 91 (14) 125 (14)

QS ic

ic-peak

sc

9.9 (6) 8.1 (6) 92 (14) 122 (14)

9.5 (6) 8.2 (6) 95 (12) 121 (13)

10.6 (6) 8.2 (6) 94 (13) 122 (13)

AS 5 active sleep; QS 5 quiet sleep; ic 5 initial condition; ic-peak 5 peak reference value during ic; sc 5 stable condition. PaO 2 5 transcutaneous PaO 2 ; PaCO 2 5 transcutaneous PaCO 2 ; SaO 2 5 arterial oxygen saturation. n 5 number of calculated periods.

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3.3. Cerebral haemodynamics during sleep state change in relation to time after last meal, postnatal age and clinical data Median time after the last meal (breast or bottle feeding) was 2 h 5 min for both QS to AS and AS to QS (range, from QS to AS 30 min to 7 h; from AS to QS, 20 min to 4 h). Changes in the cerebral haemoglobin concentration tended to be inversely proportional to the time after the last meal, and were more prominent in the SSC from QS to AS. There was also a non-statistically significant inverse relation between [Hb] change and postnatal age in SSC from AS to QS, but not from QS to AS. There was no statistically significant association between postnatal age, birth, weight, mode of delivery, APGAR score, umbilical artery pH, disease or whether or not the mother smoked during pregnancy and cerebral haemoglobin concentration changes during SSC.

4. Discussion This study shows that sleep state changes in term newborn infants are associated with characteristic changes in cerebral haemoglobin concentration, mainly due to changes in oxyhaemoglobin. Cerebral haemoglobin concentration increased from AS to QS, persisted during QS and decreased when QS changed to AS. Cerebral haemoglobin concentration changed simultaneously with a sleep state change and showed a pattern consisting of two distinct periods. Increased values of transcutaneous PaCO 2 , PaO 2 and SaO 2 and decreased heart rate in QS compared to AS were observed. No correlation was found between blood gases and cerebral haemoglobin concentration. The methodological and physiological aspects are discussed separately in the following section.

4.1. Methodological aspects In contrast to our findings, other studies using different techniques (venous occlusion plethysmography in term infants [32,34,40]; doppler ultrasonography in term and preterm infants [25,41]) revealed that cerebral blood perfusion is lower in QS than in AS. One doppler ultrasonography investigation in term infants showed no difference in CBFV [16]. One study performed in preterm infants with the 133 Xenon clearance method showed an insignificant increase in CBF in QS compared to AS [18]. There are several explanations for these differences: 1. NIRS measures the change in [O 2 Hb] and [HHb] continuously, which is summed up to give the total change in [Hb]. Concentrations are expressed per liter brain, with vascular bed and brain tissue included. Total [Hb] reflects cerebral blood volume, including arterial and venous compartments [58,59]. Changes in total [Hb] are either due to changes in arterial inflow or changes of venous outflow of the brain. Therefore, changes in total [Hb] do not necessarily reflect changes in CBF as measured by 133 Xenon and NIRS [8,14,60] and venous occlusion

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2.

3.

4.

5.

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plethysmography [32,34,40] or changes in CBFV as measured by Doppler ultrasonography [16,25,41]. As near infrared light scatters widely in cerebral tissue, concentration changes in [Hb] measured by NIRS give information about global changes in the blood distribution in brain and not about regional changes. Therefore, a comparison with regional flow measurements or measurement of flow velocity in specific vessels is not feasible. Several environmental factors, such as noise, lighting and temperature, may affect the response of [Hb] to sleep state changes [30,56]. We tried to control these confounding factors by studying the infants in the same quiet, semi-dark room with constant air temperature and humidity. Parents were asked not to influence measurements by speaking. Sleep state control and related [Hb] response may depend on age. We measured healthy term newborn infants, whose sleep state and behavioural pattern [37,50– 52,56] differ considerably from that in preterm infants [35,44,45,48], older children or adults [3,26,53]. Therefore, differences in postnatal and gestational age and health status may explain our discordant results. Behavioural state was defined by a trained observer using clinical criteria [37]. In contrast, many studies based sleep state definition on EEG recordings. This methodological difference is unlikely to be of significance, as good agreement between clinical and EEG-supported definitions of sleep states have been shown [37,45,48].

4.2. Physiological aspects The most striking finding was the biphasic pattern of change in cerebral haemoglobin concentration after transition from QS to AS and from AS to QS. We speculate that this phenomenon is the summation of two overlapping different mechanisms, both beginning during SST. The first mechanism has its greatest influence during the initial period after a SST, caused by neuronal activity, influencing directly and suddenly local vessel tone and intracranial blood volume. The second mechanism is more dependent on metabolism and ventilation; it lasts longer, continuing its influence into the stable condition period to the next sleep state (Fig. 2). Both mechanisms point to a close relationship between the mode of cerebral activity and the regulation of its blood supply. Detection of these short-term effects were possible with the continuously measuring NIRS method. The first physiological mechanism can be explained by the ‘‘redistribution condition’’, and the second can be explained by the ‘‘new metabolic condition’’. In summary, four main factors are responsible for ‘‘sleep state change–cerebral haemodynamic coupling’’ and for differences in cerebral haemoglobin concentrations between the two sleep states: 1. Nervous cell activity and autonomic regulation of the brain vessels 2. The resulting activity pattern – mediated by sympathicotone / parasympathicotone

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– to different distribution patterns of total body blood volume (this parameter is closely related to the first). 3. O 2 consumption 4. CO 2 - and O 2 response of the brain vessels An attempt to discuss physiologic mechanisms during the initial overshooting conditions (a) and the later stable condition (b) is made separately in the following two sections.

4.2.1. (a) [ Hb] change during initial condition (‘‘ redistribution condition’’) The initial period of a new sleep state is characterized by a sudden redistribution of oxidised and deoxidised cerebral haemoglobin concentration (Fig. 2). Possible explanations are as follows: 4.2.1.1. Cerebral vascular regulation. Cerebral vascular regulation, determined by arteriolar tone, is directly influenced by the perivascular nerves, which are closely related to cerebral activity. Increased CBV, PaO 2 and SaO 2 in QS compared to AS is supposed to increase O 2 supply to the cell. It is still unclear if increased O 2 supply means an increased O 2 need and increased O 2 consumption in QS. Another explanation is luxurious O 2 -perfusion in QS. The O 2 supply of the brain could be more ‘‘actively’’ regulated in AS compared to QS, corresponding to our knowledge that AS is the phylogenetically older and more developed state of sleep in the human newborn [35]. To answer these questions, cerebral O 2 consumption has to be measured. 4.2.1.2. Body movements, sympathetic activity. Redistribution between cerebral blood volume and whole body blood volume seems to be an obvious physiological phenomenon. Reduced muscle tone between movements and gross movements in AS could both lead to a relative fall in cerebral [Hb] and an increased blood supply to the muscles at this time. The increased frequency of general body movements during the initial few minutes of a new sleep state [37,45], especially in AS, could additionally provoke the typical prominent initial change in [Hb]. In addition, increased intrathoracal pressure is known to decrease central venous return, resulting in increased CBV in preterm infants [7]. The relationship between sympathicus activity and the CO 2 response of the brain vessels has also been investigated in newborn animals [21,54,55], where it was found that increased sympathicus activity causes a decrease in the CO 2 response, resulting in decreased CBF. This hypothesis is supported by other studies [9], showing vasodilatation of brain vessels following parasympathetic activities, which were estimated to be in QS. Increased sympathicotone in AS in newborn infants could lead to a decreased CO 2 response, with a resulting fall in CBV. 4.2.1.3. Heart rate and blood pressure. Changes in heart rate and blood pressure during SSC cause a change in central venous return, influencing cerebral blood volume and haemoglobin concentration. Nevertheless, there is some evidence that

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cerebral perfusion pressure, CBV or CBF, is independent of blood pressure in healthy newborn infants with intact cerebral autoregulation [2,12,20,42]. The biphasic pattern, observed in our study, seems to be independent of cyclic variations in physiological parameters such as blood pressure, heart rate and cerebral blood flow velocity that were observed by several groups [1,13,22,29,61].

4.2.1.4. Time after last meal. There is some evidence from cited literature [4,37,40,47,54,56] that there is a relationship between physiological responses of the newborn infant and the time after their last meal and postnatal age. These physiological responses were also observed in our study, however, they were not considered to be significant. 4.2.2. ( b) [ Hb] change during the stable condition (‘‘ new metabolic condition’’) The ‘‘stable condition’’ period begins 3–4 min after ending of the SST and persists throughout the sleep state (Fig. 2). In contrast to the initial condition, mainly [O 2 Hb] and not [HHb] was changed in the stable condition. This ‘‘stable’’ nervous cell activity and metabolism probably reflects a change due to several factors, such as local general metabolites as blood gases and hormones (i.e. prostanoids, angiotensin, nitric oxide and catecholamines) [39]. 4.2.2.1. Transcutaneous PaCO2 . Transcutaneous PaCO 2 , known for a long time as a potent vasodilator of cerebral vessels [27], was increased in QS. It has been shown that increased ventilation rate [4], O 2 consumption [49] and minute volume [5,17,48] cause a fall in PaCO 2 during AS [25,43,46]. A change of 2 kPa would be needed to explain a change in total [Hb] of 5 mmol / l (own results, [38,60]). In newborn piglets, CBF [19], and in rats, extraparenchymal CBV and CBF increased, while intraparenchymal CBV did not change significantly during hypercapnia [28]. The trend to higher CO 2 in QS compared with AS would support this relation. However, the change in CO 2 is too small to fully explain the change in [Hb] and does not allow to establish a correlation between the two. 4.2.2.2. Transcutaneous PaO2 . Transcutaneous PaO 2 decreased during a SSC from QS to AS. Different rates of ventilation in different sleep states could explain this phenomenon [25,31,33]. Decreased PaO 2 is supposed to increase CBF in the lamb, whereby the relationship between PaO 2 and CBV or cerebral [Hb] was not studied [24]. The ventilatory effects observed reflect long term changes over several minutes and do not explain the breath-to-breath changes in [Hb] as described in adults using NIRS [15].

5. Conclusions Sleep states influence the concentration of cerebral haemoglobin, which increases from active to quiet sleep and decreases from quiet to active sleep. These changes reflect differences in nervous cell activity and autonomic regulation between the

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different sleep states. In active sleep, regulation of cerebral blood distribution seems to be more ‘‘active’’ compared to a more ‘‘passive’’ one during quiet sleep. Studies of cerebral haemodynamics with near infrared spectroscopy in term newborn infants must account for the various sleep states.

Acknowledgements ¨ This work is dedicated to my wife, Sandra E. Munger-Flaitz. Special thanks to Prof. H.U. Bucher and Prof. G. Duc for their permanent support of this work. I also thank the staff of the Clinic for Neonatology and the Department of Obstetrics for their help, parents for giving their consent for investigations and Dr. A.C. Eichenberger for his contribution. The study was supported by the Swiss national fond (SNF: Nr. 3.814.087) for research at the neonatal unit of University Hospital of Zurich.

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