- Email: [email protected]
Cerebral blood flow and sleep state in the normal newborn infant
Early Human Development, 1979, 314, 321-328 o Elsevier/North-Holland Biomedical Press
321
Cerebral blood flow and sleep state in the normal newborn
infant
DAVID W.A. MILLIGAN* Neonatal Research Group, London United Kingdom
Hospital Medical College, Turner Street, London El,
Accepted for publication 16 August 1979
~_____
___
~~
~___
SUMMARY
The cerebral blood flow (CBF) index measured by venous occlusion plethysmography in 12 normal newborn infants was found to vary significantly with sleep state. Criteria for definition of sleep state are described. The cerebral blood flow index in active sleep was 23% higher than in quiet sleep, and there were smaller, but consistent and significant, differences between intermediate and active or quiet sleep. sleep; CBF index; autoregulation
INTRODUCTION
The development of a non-invasive method for measurement of cerebral blood flow in the newborn infant [ 5,6] has provided a means of investigating a previously uncharted area of normal neonatal physiology. Sleep state has been shown to influence cerebral blood flow in animals [9,19] and adult man [ 16,241. The newborn infant spends 17-20 hours sleeping in a 24-hour period during the first week of life, of which about half is spent in sleep associated with rapid eye movements (REM) [ 1,131, so that physiological changes with sleep state assume greater importance than in adulthood. In addition, the method of measurement is most easily employed with a sleeping infant so that, if significant changes in cerebral blood flow with sleep state occurred, it would be critical to take these into account when interpreting results obtained using the method. In a preliminary study on 9 normal full-term newborn infants in the first week of life, the cerebral blood flow index in REM sleep was found to be consistently higher than in sleep without rapid eye movements (NREM). *Address for reprints: Department St., London WCl, U.K.
of Pediatrics,
University College Hospital, Huntley
322
The mean difference was 16% (P < 0.005 on paired t-test). This study was undertaken to document changes in the cerebral blood flow index with more closely defined sleep states.
Sleep state Sleep state was defined using a combination of behavioral [ 181 and electroencephalographic criteria. Four EEG patterns were differentiated by visual inspection of a tracing recorded from C3-C4 (Fig. 1). Stage 1 consisted of fast, low voltage (20-50 pV) activity. Stage 2 included some higher amplitude (75-100 pV) waves on a background of fast low voltage activity. Stage 3 consisted of high amplitude (100-150 pV) slow waves. Stage 4 contained bursts of high amplitude (150-200 pV) waves separated by intervals of very low voltage activity (trach alternant). These patterns were found to correspond closely to those described by Dreyfus Brisac [7] . It was not possible to make consistent distinctions on behavioral grounds between stage 3 and stage 4, and the two patterns would sometimes alternate over a period of about one minute. Three sleep states were therefore defined. Active sleep consisted of rapid eye movements, frequent small body movements and a stage 1 EEG. Intermediate sleep was associated with infrequent body movements, a stage 2 EEG and, sometimes, with slow eye movements. Quiet sleep was defined when there were no eye movements, no body movements apart from an occasional startle or sigh, and a stage 3 or stage 4 EEG.
‘“;;t
10set I
I
stage 1 lcovvIr+crrrrLuurh
stage
4
Fig. 1. Single channel biparietal (C,-C,) EEG, taken from a 3.day-old illustrating the 4 patterns described in the text.
MATERIALS
full-term
infant,
AND METHODS
The study group consisted of 12 normal full-term infants (6 male, 6 female) born at the London Hospital. The study was approved by the ethical com-
323
mittee of the London Hospital, and informed consent was obtained from one or both parents. The mother was always present at some time during the study on her infant. The mean age of the infants at the time of the study was 3.4 days, and their mean weight was 3.36 kg. No study commenced sooner than 50 minutes after the end of the preceding feed (mean start time 78 minutes). Eleven infants were breast fed and one was formula fed. A single channel EEG was recorded from C3-C4 using Beckman electrodes and a Hewlett-Packard Bioelectric amplifier 8811A, using a time constant of 0.3 seconds and an upper frequency cut-off at 30 Hz. A three-lead ECG was recorded using another Bioelectric amplifier. A mercury in Silastic* strain gauge [6] (length 60 cm, I.D. 0.76 mm, E.D. 1.65 mm) arranged in four 15cm strands was positioned around the occipitofrontal circumference of the infant’s head, and adjusted to a predetermined tension. A consistent gauge tension was ensured for each infant by first balancing the Wheatstone bridge circuit for zero output when the gauge was loaded with 150 g on the bench. The gauge tension was then adjusted on the infant’s head until balance was again achieved. Calibration was effected on the infant’s head by means of a pneumatically operated calibrating block with a fixed movement of 1 mm. The output from the Wheatstone bridge circuit was amplified using a Hewlett-Packard low level amplifier (88038). Eye movements and body movements were noted by the observers and recorded on the chart. Sleep state was defined as described above. The infant was allowed to settle in a supine position on the assistant’s lap, the gauge was calibrated and the first series of about 10 jugular compressions was performed. If the infant was not in quiet sleep at this time, no further compressions were performed until the criteria for quiet sleep were met, as it was felt that repeated tactile stimuli might disrupt the sleep cycle. Subsequent experience has shown that this does not usually occur. When quiet sleep was established a series of compressions was performed every 5-10 minutes until the infant again entered an epoch of active sleep, when one or more further series of measurements were made. It was hoped in this way to obtain measurements on either side of the quiet to active transition which were relatively close together, as the transition in this direction is usually more abrupt than the gradual change from active to quiet sleep. The rate of skull circumference increase was calculated from the slope of a straight line drawn through the diastolic nadirs (pulse minima) of the first pulsation following jugular occlusion (points 0 and 1 in Fig. 2). The results presented here are the means of about 10 consecutive compression waveforms. The occipitofrontal circumference was measured, and the rate of volume increase computed using the formula V = C3/89, where V is volume and C head circumference [6] . Brain weight was calculated from head circumference [4] , and the rate of skull volume increase expressed as an index of cerebral blood flow in nominal units of ml/min/lOO g brain. Heart rate was counted for 10 second periods from the ECG recording. *Dow
Corning
silicone
rubber
tubing.
324
Fig. 2. Recording from the strain gauge during internal jugular occlusion, showing the increase in head circumference (vertical scale) with time (horizontal scale). Jugular compression was applied at time 0 and released at 4.95 sec. The straight line described in the text passes through the pulse minima at points 0 and 1.
RESULTS
Measurements were obtained from all 12 infants in active and quiet sleep and from 7 in intermediate sleep. The cerebral blood flow index was consistently higher in active sleep (mean 37, SD 4.3) than in quiet sleep (mean 30, SD 4.1). The differences were significant (P < 0.001 on paired t-test) (Fig. 3).
40
5 D
40
35
35
::
z 2
:
%
U
U
30
303
25
25. ACTIVE
ACTIVE
QUIET
Fig. 3. CBF index in active active sleep in all 12 infants.
and quiet
Fig. 4. CBF index vs. sleep between the 3 sleep states.
state
sleep.
in 7 infants.
A consistently
There
higher
is a consistent
INTERMEDIATE
QUIET
value is obtained
gradation
in
of CBF
325
There were smaller but consistent differences between active sleep and intermediate sleep (mean 33, SD 3.8, P < O.OOl), and between intermediate and quiet sleep (P < 0.02) (Fig. 4). Differences did not vary significantly with direction of sleep state change, but sequential measurements in active sleep were found to vary more than those in quiet sleep. The mean coefficient of variation for all infants was 9.0% in active sleep, 7.9% in intermediate sleep, and 6.5% in quiet sleep. There was a significant difference between the variation in quiet sleep and the variation in active and intermediate sleep (P < 0.001 by paired t-test). The values obtained within infants during the same sleep state in the subsequent sleep cycle were within 10% of the first measurement (mean 4.3, SEM 0.64). Measurements in two infants who were awake yielded values similar to and slightly lower than those obtained in active sleep. Heart rate was consistently higher and more variable in active sleep (mean 118 beats/min) than in quiet sleep (mean 106 beats/min). The difference was significant (P < 0.001 on paired t-test). There was no significant difference in heart rate between intermediate and quiet sleep.
Defence
of method
of analysis
It has been pointed out that the method of measurement described only estimates jugular venous blood flow [6], and that, if total intracranial flow is to be obtained, a more sophisticated method of analysis must be used. Essentially, this involves the fitting of exponential curves to the inflow and outflow portions of the compression waveform so that allowance may be made for the progressive steal of blood through the vertebral veins. In order to obtain an adequate number of points for a satisfactory curve fit, a compression lasting about 10 cardiac cycles is needed (Fig. 2). In the present study the mean length of compression was 4 cardiac cycles, which precludes any
IO
IV
10
Fig. from and sion
50 STRAIGHT
I
I
I
30 CBF INDEX
70 LINE
5. The relationship between results from a curve-fitting analysis (ordinate) and those a straight line construction (abscissa). Jugular flow is represented by closed circles the regression line ‘j’. Total intracranial flow is shown as open circles and the regresline ‘c’. ‘i’ is the line of identity.
326
but a straight line analysis. Agreement between results obtained using the two methods are, however, close, and differences will be obtained only in magnitude, and not direction of change, especially if comparisons are made only between changes within infants. Figure 5 illustrates the relationship between the results obtained by the different methods of analysis on 279 waveforms from 33 experiments on normal term newborn infants. The regression equation for jugular blood flow [6] is y = 0.93&+0.857, I”= 0.892 , and for total intracranial flow [6] it is y = 1.21&-1.259, r = 0.867. Thus, the mean values for total intracranial flow in the present study would be 44 ml/min/lOO g brain for active sleep, 39 for intermediate sleep, and 35 for quiet sleep. The proportionate difference between active and quiet sleep is little changed at 24%.
DISCUSSION
The finding of a higher cerebral blood flow index in active sleep than in quiet sleep is in accordance with other published work on sleep and cerebral blood flow. Direct comparison of results is not possible because each author has used different methods, and the criteria for sleep state definition do not always coincide. Cerebral blood flow measured by a thermal technique was found to be from 30 to 50% higher in desynchronized (REM) sleep in unanesthetized unrestrained cats [9]. Reivich et al. [19] used an autoradiographic technique to measure regional CBF in cats, and found an increase of 62-173s in flow compared with the waking state. They also found small increases in some regions in slow wave sleep. Cerebral impedance pulsations were reported to resemble those of awake cats when the animals were in paradoxical (REM) sleep (21. Invasive techniques have largely confined measurement in man to individuals with an already compromised cerebral circulation, Normal healthy adult males have been studied by the nitrous oxide technique [ 161 and the inhaled 133Xe method [24]. The former group found an increase in blood flow during sleep of about 10% compared with the waking state. Townsend et al. [24] found a 3-12s increase in REM sleep and a 6-14s decrease during slow wave sleep compared with waking levels. The changes could not be accounted for by alterations in blood gas tensions or arterial blood pressure. The increased CBF index found in active sleep in the present study could be secondary to changes in cardiorespiratory status, or could be a response to increased cerebral metabolism. Arterial blood gases are not available for this study group, but other authors have reported a slight fall in both PaO, and PaCOz during active sleep [17,20]. The CBF response of the neonate to changes in arterial blood gas tensions [14] (Milligan, unpublished data and P.M. Rahilly, personal communication) is similar to that seen in adults [ll]. Arterial blood pressure is higher and less stable in active sleep than in slow wave sleep in adults [ 12,221, and is accompanied by an increase in cardiac
327
output, which is probably secondary to an increased heart rate as stroke volume remains unchanged [12]. The change in heart rate, and thus cardiac output, between active and quiet sleep in this study was about half of the observed change in CBF index, although there was not the same parallel trend between intermediate and quiet sleep. Few measurements of blood pressure in infants have been related to sleep state, but in one study [8] the blood pressure fell in infants, “who became quietly asleep”. In order to accept a rise in arterial blood pressure or an increase in cardiac output as an explanation for the increase in flow index found, it would be necessary to postulate a loss of autoregulation such as has been described in sick infants [ 151. There is some evidence that this may occur in the cat [9], but this has not been confirmed, and the usual pattern in the cat is for CBF to rise and blood pressure to fall. To avoid disturbance of the infant, blood pressure was not measured in this present study. Indirect evidence for increased metabolic rate in active sleep has been obtained in rabbits [lo] and cats [21] using measurements of brain temperature. Similar studies have not been reported in man, but total oxidative metabolism increases by from 4 to 10% in adults [3] and newborn infants [23] during REM sleep, and a major proportion of this increase is probably accounted for by the brain. The estimate of the difference found in this study is likely to be a conservative one for two reasons. Central venous pressure usually falls slightly in quiet sleep [ 121. This would have the effect of allowing the head to collapse more in diastole and placing it lower on its compliance curve, so that the first pulsatile increase with jugular occlusion will be steeper and the measured CBF index higher. Conversely, in active sleep the measurement is likely to underestimate the flow, as the concomitant rise in CSF pressure which probably occurs will mean that head expansion starts from a less compliant baseline. Further investigation is needed into the relationship between cerebral blood flow, intracranial pressure and arterial blood pressure. The possibility of a partial loss of autoregulation in a system where the expansile skull damps alterations in the transmural pressure of cerebral vessels is not inconceivable, and is most likely to occur in active sleep, when homeostasis is known to be compromised.
ACKNOWLEDGEMENTS
I would like to thank Professor K.W. Cross for his support, Ms. Norma Cullen for technical assistance and Dr. Nestor Muller for translating reference no. 9. REFERENCES 1
Aserinsky, E. and Kleitman, N. (1953): Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science, 118, 273-274.
328 2 3 4
5 6
7
8 9
10
11
12 13 14
15 16
17 18 19 20 21 22
23 24
Birzis, L. and Tachibana, S. (1964): Local cerebral impedance and blood flow during sleep and arousal. Exp. Neurol., 9, 269-285. Brebbia, D.R. and Altshuler, K.Z. (1965): Oxygen consumption rate and electroencephalographic stage of sleep. Science, 150, 1621-1623. Cooke, R.W.L., Lucas, A., Yudkin, P.L.N. and Pryce-Davies, J. (1977): Head circumference as an index of brain weight in the fetus and newborn. Early Hum. Dev., 1,145-149. Cross, K.W., Dear, P.R.F., Warner, R.M. et al. (1976): An attempt to measure cerebral blood flow in the newborn infant. J. Physiol. (London), 260,42p--43~. Cross, K.W., Dear, P.R.F., Hathorn, M.K.S., Hyams, A., Kerslake, D.McK., Milligan, D.W.A., Rahilly, P.M. and Stothers, J.K. (1979): An estimation of intracranial blood flow in the newborn infant. J. Physiol. (London), 289, 329-345. Dreyfus Brisac, C. (1964): In: Neurological and Electroencephalographic Studies in Infancy, pp. 186-207. Editors: Kellaway and Petersen, Grune and Stratton, New York. Gupta, J.M. and Scopes, J.W. (1965): Observations on blood pressure in newborn infants. Arch. Dis. Child., 40, 637-644. Kanzow, E., Krause, D. and Kuhnel, H. (1962): Die vasomotorik der Hirnrinde in den Phasen desynchronisierter EEG-Aktivitlt in naturlichen Schlaf der Katze. Pflugers Arch. Gesamte Physiol., 274, 593-607. Kawamura, H., Whitmoyer, D.I. and Sawyer, C.H. (1966): Temperature changes in the rabbit brain during paradoxical sleep. Electroenceph. Clin. Neurophysiol., 21, 469-477. Kety, S.S. and Schmidt, C.F. (1948): The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J. Clin. Invest., 27, 484-492. Khatri, I.M. and Freis, E.D. (1967): Hemodynamic changes during sleep. J. Appl. Physiol., 22, 867-873. Kleitman, N. and Engelmann, T.G. (1953): Sleep characteristics of infants. J. Appl. Physiol., 6, 269-282. Leahy, F., Sankaran, K., Cates, D. et al. (1978): Changes in cerebral blood flow (CBF) in preterm infants during inhalation of CO, and 100% 0,. Clin. Res., 26, 879A. Lou, H.C., Lassen, N.A. and Friis Hansen, B. (1979): Impaired autoregulation of CBF in the distressed newborn infant. J. Pediatr., 94, 118-121. Mangold, R., Sokoloff, L., Conner, E. et al. (1955): The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J. Clin. Invest., 34, 1092-1100. Martin, R.J., Okker, A. and Rubin, D. (1979): Arterial oxygen tension during active and quiet sleep in the normal neonate. J. Pediatr., 94, 271-274. Prechtl, H.F.R. and Beintema, D. (1964): The Neurological Examination of the Newborn Infant. In: Little Club Clinics, Vol. 12, p. 6. Reivich, M., Isaacs, G., Eva&, E. and Kety, S. (1968): The effect of slow wave sleep and REM sleep on regional cerebral blood flow in cats. J. Neurochem., 15, 301-306. Rigatto, H., David, M., Sankaran, K. et al. (1978): The effect of CO, on sleep state and chest distortion. J. Pediatr., 93, 315. Satoh, T. (1968): Brain temperature of the cat during sleep. Arch. Ital. Biol., 106, 73-82. Snyder, F., Hobson, J.A., Morrison, D.F. and Goldfrank, F. (1964): Changes in respiration, heart rate and systolic blood pressure in human sleep. J. Appl. Physiol., 19,417-422. Stothers, J.K. and Warner, R.M. (1978): Oxygen consumption and neonatal sleep states. J. Physiol. (London), 278, 435-440. Townsend, R.E., Prinz, P.N. arid Gbrist, -W.D. (1973): Humance@rebr&b~~So-\;i during sleep and waking. J. Appl. Physiol., 35, 620-625.
321
Cerebral blood flow and sleep state in the normal newborn
infant
DAVID W.A. MILLIGAN* Neonatal Research Group, London United Kingdom
Hospital Medical College, Turner Street, London El,
Accepted for publication 16 August 1979
~_____
___
~~
~___
SUMMARY
The cerebral blood flow (CBF) index measured by venous occlusion plethysmography in 12 normal newborn infants was found to vary significantly with sleep state. Criteria for definition of sleep state are described. The cerebral blood flow index in active sleep was 23% higher than in quiet sleep, and there were smaller, but consistent and significant, differences between intermediate and active or quiet sleep. sleep; CBF index; autoregulation
INTRODUCTION
The development of a non-invasive method for measurement of cerebral blood flow in the newborn infant [ 5,6] has provided a means of investigating a previously uncharted area of normal neonatal physiology. Sleep state has been shown to influence cerebral blood flow in animals [9,19] and adult man [ 16,241. The newborn infant spends 17-20 hours sleeping in a 24-hour period during the first week of life, of which about half is spent in sleep associated with rapid eye movements (REM) [ 1,131, so that physiological changes with sleep state assume greater importance than in adulthood. In addition, the method of measurement is most easily employed with a sleeping infant so that, if significant changes in cerebral blood flow with sleep state occurred, it would be critical to take these into account when interpreting results obtained using the method. In a preliminary study on 9 normal full-term newborn infants in the first week of life, the cerebral blood flow index in REM sleep was found to be consistently higher than in sleep without rapid eye movements (NREM). *Address for reprints: Department St., London WCl, U.K.
of Pediatrics,
University College Hospital, Huntley
322
The mean difference was 16% (P < 0.005 on paired t-test). This study was undertaken to document changes in the cerebral blood flow index with more closely defined sleep states.
Sleep state Sleep state was defined using a combination of behavioral [ 181 and electroencephalographic criteria. Four EEG patterns were differentiated by visual inspection of a tracing recorded from C3-C4 (Fig. 1). Stage 1 consisted of fast, low voltage (20-50 pV) activity. Stage 2 included some higher amplitude (75-100 pV) waves on a background of fast low voltage activity. Stage 3 consisted of high amplitude (100-150 pV) slow waves. Stage 4 contained bursts of high amplitude (150-200 pV) waves separated by intervals of very low voltage activity (trach alternant). These patterns were found to correspond closely to those described by Dreyfus Brisac [7] . It was not possible to make consistent distinctions on behavioral grounds between stage 3 and stage 4, and the two patterns would sometimes alternate over a period of about one minute. Three sleep states were therefore defined. Active sleep consisted of rapid eye movements, frequent small body movements and a stage 1 EEG. Intermediate sleep was associated with infrequent body movements, a stage 2 EEG and, sometimes, with slow eye movements. Quiet sleep was defined when there were no eye movements, no body movements apart from an occasional startle or sigh, and a stage 3 or stage 4 EEG.
‘“;;t
10set I
I
stage 1 lcovvIr+crrrrLuurh
stage
4
Fig. 1. Single channel biparietal (C,-C,) EEG, taken from a 3.day-old illustrating the 4 patterns described in the text.
MATERIALS
full-term
infant,
AND METHODS
The study group consisted of 12 normal full-term infants (6 male, 6 female) born at the London Hospital. The study was approved by the ethical com-
323
mittee of the London Hospital, and informed consent was obtained from one or both parents. The mother was always present at some time during the study on her infant. The mean age of the infants at the time of the study was 3.4 days, and their mean weight was 3.36 kg. No study commenced sooner than 50 minutes after the end of the preceding feed (mean start time 78 minutes). Eleven infants were breast fed and one was formula fed. A single channel EEG was recorded from C3-C4 using Beckman electrodes and a Hewlett-Packard Bioelectric amplifier 8811A, using a time constant of 0.3 seconds and an upper frequency cut-off at 30 Hz. A three-lead ECG was recorded using another Bioelectric amplifier. A mercury in Silastic* strain gauge [6] (length 60 cm, I.D. 0.76 mm, E.D. 1.65 mm) arranged in four 15cm strands was positioned around the occipitofrontal circumference of the infant’s head, and adjusted to a predetermined tension. A consistent gauge tension was ensured for each infant by first balancing the Wheatstone bridge circuit for zero output when the gauge was loaded with 150 g on the bench. The gauge tension was then adjusted on the infant’s head until balance was again achieved. Calibration was effected on the infant’s head by means of a pneumatically operated calibrating block with a fixed movement of 1 mm. The output from the Wheatstone bridge circuit was amplified using a Hewlett-Packard low level amplifier (88038). Eye movements and body movements were noted by the observers and recorded on the chart. Sleep state was defined as described above. The infant was allowed to settle in a supine position on the assistant’s lap, the gauge was calibrated and the first series of about 10 jugular compressions was performed. If the infant was not in quiet sleep at this time, no further compressions were performed until the criteria for quiet sleep were met, as it was felt that repeated tactile stimuli might disrupt the sleep cycle. Subsequent experience has shown that this does not usually occur. When quiet sleep was established a series of compressions was performed every 5-10 minutes until the infant again entered an epoch of active sleep, when one or more further series of measurements were made. It was hoped in this way to obtain measurements on either side of the quiet to active transition which were relatively close together, as the transition in this direction is usually more abrupt than the gradual change from active to quiet sleep. The rate of skull circumference increase was calculated from the slope of a straight line drawn through the diastolic nadirs (pulse minima) of the first pulsation following jugular occlusion (points 0 and 1 in Fig. 2). The results presented here are the means of about 10 consecutive compression waveforms. The occipitofrontal circumference was measured, and the rate of volume increase computed using the formula V = C3/89, where V is volume and C head circumference [6] . Brain weight was calculated from head circumference [4] , and the rate of skull volume increase expressed as an index of cerebral blood flow in nominal units of ml/min/lOO g brain. Heart rate was counted for 10 second periods from the ECG recording. *Dow
Corning
silicone
rubber
tubing.
324
Fig. 2. Recording from the strain gauge during internal jugular occlusion, showing the increase in head circumference (vertical scale) with time (horizontal scale). Jugular compression was applied at time 0 and released at 4.95 sec. The straight line described in the text passes through the pulse minima at points 0 and 1.
RESULTS
Measurements were obtained from all 12 infants in active and quiet sleep and from 7 in intermediate sleep. The cerebral blood flow index was consistently higher in active sleep (mean 37, SD 4.3) than in quiet sleep (mean 30, SD 4.1). The differences were significant (P < 0.001 on paired t-test) (Fig. 3).
40
5 D
40
35
35
::
z 2
:
%
U
U
30
303
25
25. ACTIVE
ACTIVE
QUIET
Fig. 3. CBF index in active active sleep in all 12 infants.
and quiet
Fig. 4. CBF index vs. sleep between the 3 sleep states.
state
sleep.
in 7 infants.
A consistently
There
higher
is a consistent
INTERMEDIATE
QUIET
value is obtained
gradation
in
of CBF
325
There were smaller but consistent differences between active sleep and intermediate sleep (mean 33, SD 3.8, P < O.OOl), and between intermediate and quiet sleep (P < 0.02) (Fig. 4). Differences did not vary significantly with direction of sleep state change, but sequential measurements in active sleep were found to vary more than those in quiet sleep. The mean coefficient of variation for all infants was 9.0% in active sleep, 7.9% in intermediate sleep, and 6.5% in quiet sleep. There was a significant difference between the variation in quiet sleep and the variation in active and intermediate sleep (P < 0.001 by paired t-test). The values obtained within infants during the same sleep state in the subsequent sleep cycle were within 10% of the first measurement (mean 4.3, SEM 0.64). Measurements in two infants who were awake yielded values similar to and slightly lower than those obtained in active sleep. Heart rate was consistently higher and more variable in active sleep (mean 118 beats/min) than in quiet sleep (mean 106 beats/min). The difference was significant (P < 0.001 on paired t-test). There was no significant difference in heart rate between intermediate and quiet sleep.
Defence
of method
of analysis
It has been pointed out that the method of measurement described only estimates jugular venous blood flow [6], and that, if total intracranial flow is to be obtained, a more sophisticated method of analysis must be used. Essentially, this involves the fitting of exponential curves to the inflow and outflow portions of the compression waveform so that allowance may be made for the progressive steal of blood through the vertebral veins. In order to obtain an adequate number of points for a satisfactory curve fit, a compression lasting about 10 cardiac cycles is needed (Fig. 2). In the present study the mean length of compression was 4 cardiac cycles, which precludes any
IO
IV
10
Fig. from and sion
50 STRAIGHT
I
I
I
30 CBF INDEX
70 LINE
5. The relationship between results from a curve-fitting analysis (ordinate) and those a straight line construction (abscissa). Jugular flow is represented by closed circles the regression line ‘j’. Total intracranial flow is shown as open circles and the regresline ‘c’. ‘i’ is the line of identity.
326
but a straight line analysis. Agreement between results obtained using the two methods are, however, close, and differences will be obtained only in magnitude, and not direction of change, especially if comparisons are made only between changes within infants. Figure 5 illustrates the relationship between the results obtained by the different methods of analysis on 279 waveforms from 33 experiments on normal term newborn infants. The regression equation for jugular blood flow [6] is y = 0.93&+0.857, I”= 0.892 , and for total intracranial flow [6] it is y = 1.21&-1.259, r = 0.867. Thus, the mean values for total intracranial flow in the present study would be 44 ml/min/lOO g brain for active sleep, 39 for intermediate sleep, and 35 for quiet sleep. The proportionate difference between active and quiet sleep is little changed at 24%.
DISCUSSION
The finding of a higher cerebral blood flow index in active sleep than in quiet sleep is in accordance with other published work on sleep and cerebral blood flow. Direct comparison of results is not possible because each author has used different methods, and the criteria for sleep state definition do not always coincide. Cerebral blood flow measured by a thermal technique was found to be from 30 to 50% higher in desynchronized (REM) sleep in unanesthetized unrestrained cats [9]. Reivich et al. [19] used an autoradiographic technique to measure regional CBF in cats, and found an increase of 62-173s in flow compared with the waking state. They also found small increases in some regions in slow wave sleep. Cerebral impedance pulsations were reported to resemble those of awake cats when the animals were in paradoxical (REM) sleep (21. Invasive techniques have largely confined measurement in man to individuals with an already compromised cerebral circulation, Normal healthy adult males have been studied by the nitrous oxide technique [ 161 and the inhaled 133Xe method [24]. The former group found an increase in blood flow during sleep of about 10% compared with the waking state. Townsend et al. [24] found a 3-12s increase in REM sleep and a 6-14s decrease during slow wave sleep compared with waking levels. The changes could not be accounted for by alterations in blood gas tensions or arterial blood pressure. The increased CBF index found in active sleep in the present study could be secondary to changes in cardiorespiratory status, or could be a response to increased cerebral metabolism. Arterial blood gases are not available for this study group, but other authors have reported a slight fall in both PaO, and PaCOz during active sleep [17,20]. The CBF response of the neonate to changes in arterial blood gas tensions [14] (Milligan, unpublished data and P.M. Rahilly, personal communication) is similar to that seen in adults [ll]. Arterial blood pressure is higher and less stable in active sleep than in slow wave sleep in adults [ 12,221, and is accompanied by an increase in cardiac
327
output, which is probably secondary to an increased heart rate as stroke volume remains unchanged [12]. The change in heart rate, and thus cardiac output, between active and quiet sleep in this study was about half of the observed change in CBF index, although there was not the same parallel trend between intermediate and quiet sleep. Few measurements of blood pressure in infants have been related to sleep state, but in one study [8] the blood pressure fell in infants, “who became quietly asleep”. In order to accept a rise in arterial blood pressure or an increase in cardiac output as an explanation for the increase in flow index found, it would be necessary to postulate a loss of autoregulation such as has been described in sick infants [ 151. There is some evidence that this may occur in the cat [9], but this has not been confirmed, and the usual pattern in the cat is for CBF to rise and blood pressure to fall. To avoid disturbance of the infant, blood pressure was not measured in this present study. Indirect evidence for increased metabolic rate in active sleep has been obtained in rabbits [lo] and cats [21] using measurements of brain temperature. Similar studies have not been reported in man, but total oxidative metabolism increases by from 4 to 10% in adults [3] and newborn infants [23] during REM sleep, and a major proportion of this increase is probably accounted for by the brain. The estimate of the difference found in this study is likely to be a conservative one for two reasons. Central venous pressure usually falls slightly in quiet sleep [ 121. This would have the effect of allowing the head to collapse more in diastole and placing it lower on its compliance curve, so that the first pulsatile increase with jugular occlusion will be steeper and the measured CBF index higher. Conversely, in active sleep the measurement is likely to underestimate the flow, as the concomitant rise in CSF pressure which probably occurs will mean that head expansion starts from a less compliant baseline. Further investigation is needed into the relationship between cerebral blood flow, intracranial pressure and arterial blood pressure. The possibility of a partial loss of autoregulation in a system where the expansile skull damps alterations in the transmural pressure of cerebral vessels is not inconceivable, and is most likely to occur in active sleep, when homeostasis is known to be compromised.
ACKNOWLEDGEMENTS
I would like to thank Professor K.W. Cross for his support, Ms. Norma Cullen for technical assistance and Dr. Nestor Muller for translating reference no. 9. REFERENCES 1
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