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1Department of Zoology, Latrobe University, Melbourne, Australia; and 2Department of Physiology, University of Otago, Dunedin, New Zealand
Submitted 18 December 2006 ; accepted in final form 15 February 2007
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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E)] responsiveness and a reduction in cerebral oxygenation. In 20 healthy male individuals with no sleep-related disorders, continuous recordings of blood velocity in the middle cerebral artery, arterial blood pressure, E, end-tidal gases, and frontal cortical oxygenation using near infrared spectroscopy were monitored during hypercapnia (inspired CO2, 5%), hypoxia [arterial O2 saturation (SaO2) 
84%], and during a 20-s breath hold to investigate the related responses to hypercapnia, hypoxia, and apnea, respectively. Measurements were conducted in the evening (6–8 PM) and in the early morning (6–8 AM). From evening to morning, the cerebrovascular reactivity to hypercapnia was reduced (5.3 ± 0.6 vs. 4.6 ± 1.1%/Torr; P < 0.05) and was associated with a reduced increase in cerebral oxygenation (r = 0.39; P < 0.05) and an elevated morning hypercapnic E response (r = 0.54; P < 0.05). While there were no overnight changes in cerebrovascular reactivity or E response to hypoxia, there was greater cerebral desaturation for a given SaO2 in the morning (AM, –0.45 ± 0.14 vs. PM, –0.35 ± 0.14%/SaO2; P < 0.05). Following the 20-s breath hold, in the morning, there was a smaller surge middle cerebral artery velocity and cerebral oxygenation (P < 0.05 vs. PM). These data indicate that normal diurnal changes in the cerebrovascular response to CO2 influence the hypercapnic ventilatory response as well as the level of cerebral oxygenation during changes in arterial PCO2; this may be a contributing factor for diurnal changes in breathing stability and the high incidence of stroke in the morning. early morning; cerebrovascular reactivity; ventilatory control
Accordingly, we tested two hypotheses: first, that a morning reduction in cerebrovascular CO2 reactivity would be reflected in an elevation in the ventilatory response to CO2; second, due to a morning reduction in cerebrovascular CO2 reactivity, that the relative level of cerebral oxygenation with elevated inspired CO2, mild hypoxia, or during a breath hold is reduced in the morning compared with evening. To test these hypotheses, we combined transcranial Doppler to assess middle cerebral artery blood velocity (MCAV) and near infrared spectroscopy (NIRS) for the monitoring of local cerebral oxygenation. Transcranial Doppler provides a direct measure of blood flow velocity, whereas NIRS provides activation-dependent information; therefore, the combination of both NIRS and MCAV provides complementary information for the evaluation of cerebral hemodynamics. Although there are some reports using combined measurements of NIRS and MCAV during vasomotor reactivity tests (4, 40), no studies have examined the overnight changes in the simultaneous assessment of cerebrovascular reactivity using NIRS and transcranial Doppler measurements of MCAV.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Twenty healthy male individuals [aged 25 ± 4 (mean ± SD), body mass index 24 ± 4 kg/m2] volunteered for this study, which was approved by the Lower South Regional Ethics committee and conformed to the standards set by the Declaration of Helsinki. Subjects were informed of the experimental procedures and possible risks involved in the study, and written, informed consent was obtained. Subjects were not taking any medication, all were nonsmokers, and none had any history of cardiovascular, cerebrovascular, or respiratory disease.
Experimental Design
Subjects were instructed to abstain from exercise and alcohol 24 h before and not to eat a heavy meal or consume caffeine 4 h before experimental testing. Each subject then visited the laboratory on three occasions. The first visit served to fully familiarize each subject with all of the experimental procedures (between 6 and 8 PM) and to enable a comparison with the main testing session at the same time of day (>2 days apart). During this initial visit, all of the main tests, with the exceptions of the overnight polysomnography sleep study, were performed on each participant. On the second and third visit, experimental testing was carried out in the evening (between 6 and 8 PM) and the following morning (between 6 and 8 AM), respectively. Following the evening tests of the second visit only, subjects underwent an overnight domiciliary sleep study to ensure adequate sleep quality and exclude obstructive sleep apnea or other sleep pathology. Subjects were awakened at 5:30 AM, and morning experiments were conducted 30 min after awakening at 6 AM. All subjects resided close to the university (within a 10-min drive) and were transported via car the short distance to the laboratory. Following a 30-min period of rest, the combined cardiorespiratory and cerebrovascular responses to hypercapnia, hypoxia, and apnea were determined, as detailed below. Recovery was allowed in between each test to ensure that baseline cardiorespiratory and cerebrovascular responses were obtained (i.e., baseline in the last 5 min of rest before any intervention). All variables were recorded continuously into a computer for off-line analysis.
Measurements of cerebral blood flow velocity, arterial blood pressure, and cortical oxygenation. Cerebral blood flow (CBF) MCAV was measured using a 2-MHz pulsed Doppler ultrasound system (DWL Doppler, Sterling, VA) using search techniques described elsewhere (1). Beat-to-beat arterial blood pressure (BP) was monitored using finger photoplethysmography (Finometer, TPD Biomedical Instrumentation). Although photoplethysmographic measurements correlate well with intra-arterial measurements during experimental manipulations of arterial pressure (26), the absolute values can sometimes be inaccurate; therefore, all BP data are normalized to the 5-min baseline proceeding any intervention and expressed as percent change from this baseline. Likewise, as used in other studies, MCAV was also expressed at the percent change from this baseline to enable the same relative comparison to the changes in BP and to reduce interindividual variability that is unrelated to the experimental manipulation (2, 3, 27). Frontal cortical oxyhemoglobin (oxy-Hb) concentrations were monitored noninvasively using NIRS (NIRO-200; Hamamatsu Photonics KK, Hamamatsu, Japan). A probe holder containing an emission probe and detection probe was attached at the right side of forehead with a distance of 5 cm between the probes. The methodology of this system has been described previously (24). NIRO-200 measures the concentration changes of oxy-Hb, deoxyhemoglobin (deoxy-Hb), and total hemoglobin (t-Hb) using a modified Beer-Lambert law (5). It gives an absolute unit (micromoles per liter) for the changes in oxy- and deoxy-Hb by incorporating an optical path length. In the brain, t-Hb, oxy-Hb, and deoxy-Hb were measured simultaneously every 1 s throughout the experiment and expressed as the magnitude of the change from the initial value. Total oxygenation index (TOI% = oxyHb/t-Hb x 100) was calculated by the NIRS system from the light attenuation slope along the distance from the emitting point as detected by the sensors in the receiving optode. All data, including measurements of respiratory gas exchange, were acquired continuously at 200 Hz using an analog-to-digital converter (Powerlab/16SP ML795; ADInstruments, Colorado Springs, CO) interfaced with a computer. Data were sampled at 200 Hz and stored for subsequent analysis using commercially available software (Chart version 5.02, ADInstruments).
Measurements of respiratory gas exchange. Subjects breathed through a leak-free respiratory mask (Hans-Rudolph 8980, Kansas City, MO) attached to a one-way non-rebreathing valve (Hans-Rudolph 2700). Expiratory flow was measured using a heated pneumotach (Hans-Rudolph HR800). Arterial O2 saturation (SaO2) was measured using pulse oximetry at the finger (model ML320). End-tidal PCO2 (PETCO2) and PO2 (PETO2) were sampled from a leak-free mask and measured by a gas analyzer (model CD-3A, AEI Technologies, Pittsburgh, PA). Ventilatory and gas values (flow, tidal volume, frequency) were displayed in real time during testing (PowerLab, ADI Instruments, Colorado Springs, CO). Expiratory volume was calculated using the integrated flow signal and the frequency of breathing.
Hypercapnic challenge.
Following an 8-min baseline, 5% CO2 with 21% O2 and a balance of nitrogen were added to the breathing circuit for 3 min. The last minute of the exposure was used for data analysis. The cerebrovascular reactivity to hypercapnia was characterized as the slope of the linear regression fitted to the percent change in MCAV from baseline per Torr increase in PETCO2. Likewise, for the NIRS recordings, hypercapnic reactivity was considered as the relative change from baseline in the values of oxy-Hb, deoxy-Hb, t-Hb, and cerebral TOI per Torr increase in PETCO2. The slope of the ventilatory and mean arterial BP (MAP) response to hypercapnia was characterized in the same way, i.e., the change in ventilation (E) or MAP per Torr increase in PETCO2.
Poikilocapnic hypoxic challenge.
Following an 8-min baseline, hypoxemia (average SaO2 82–86%) was induced with 12% O2 and a balance of nitrogen, added to the breathing circuit for 3 min. This level of inspired O2 was chosen to induce a mild desaturation, in the range of that observed with Cheyne-Stokes breathing in patients with congestive heart failure (6). Exposure to acute poikilocapnic hypoxia was selected to examine the interactive effects of hypocapnia and hypoxia on CBF. The last minute of the exposure was used for data analysis. The hypoxic cerebrovascular reactivity was characterized as the slope of the linear regression between the percent changes in MCAV from baseline with SaO2. For the NIRS recordings, hypoxic reactivity was considered as the relative change from baseline in the values of oxy-Hb, deoxy-Hb, t-Hb, and cerebral TOI per percent decrease in SaO2. The slope of the ventilatory and MAP response to hypoxia was characterized in the same way, i.e., the change in E or MAP per percent decrease in SaO2.
Breath hold. Starting at functional residual capacity, subjects refrained from breathing for 20 s, followed by exhaling for the determination of PETCO2. Three to four breath-hold trials were repeated in each individual. The changes in MAP, CBF velocity, and cerebral oxygenation, as well as to the subsequent nadir of SaO2 after the breath hold, were compared with the baseline.
Sleep studies. All sleep studies were carried out with a Compumedics portable system (PS2; Melbourne, Australia). The portable sleep system allowed the collection of 13 channels of data, very similar in scope to that available in the sleep laboratory: one channel of ECG; two channels of EEG; two channels of electrooculogram; one channel of submental electromyogram; one channel of leg movement; one channel of body position; two channels of respiratory displacement (thoracic and abdominal displacement by inductance plethysmography); one channel for a microphone to record snoring; one channel of nasal flow signal via nasal cannula; and one channel of saturation by digital pulse oximetry (saturation accuracy ±2% between 70 and 100% with finger probe). The subjects were set up for the polysomnogram and manually scored according to standard format (29).
Statistical analysis.
All data were analyzed using the SPSS social statistics package (Version 9, Surrey, UK). A Shapiro-Wilks test was applied to each dependent variable to mathematically assess distribution normality. Statistical comparisons between evening and morning measurement were performed using a Student's paired sample t-test. Correlational analyses were used to determine the reproducibility of the dependent variables between repeat trials by comparing the two data sets, which were both collected between 6 and 8 PM using correlational analyses. Significance for all two-tailed tests were established at an 
-level of P < 0.05, and data are expressed as means ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All subjects were observed to have normal sleep architecture, good sleep efficiency (81 ± 5%), did not snore, and had no sleep-disordered breathing. The mean values for steady-state cerebrovascular and cardiorespiratory variables in the evening and morning are shown in Table 1. There were no significant differences in any of the cerebrovascular or cardiorespiratory variables.
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From evening to morning, there was a significant decrease in both hypercapnic cerebrovascular reactivity (PM, 5.1 ± 1.1 vs. AM, 4.6 ± 1.1%/Torr PETCO2; P < 0.05; Fig. 1) and cerebral oxygenation (PM, 1.5 ± 0.7 vs. AM, 1.1 ± 0.5%/Torr PETCO2; P < 0.05; Fig. 1), while the hypercapnic ventilatory response was elevated (PM, 1.24 ± 0.91 vs. AM, 1.59 ± 1.0 l·min–1·Torr–1 PETCO2; P < 0.05; Fig. 1). The reduced cerebrovascular reactivity to hypercapnia in the morning was associated with the increased hypercapnic ventilatory response (r = 0.54; P < 0.05; Fig. 2A) and to the smaller increase in cerebral oxygenation (r = 0.39; P < 0.05; Fig. 2B), compared with the evening measurements. The relative decrease in cerebral oxygenation during hypercapnia in the morning was attributable mainly to a smaller increase in oxy-Hb (PM, 4.1 ± 0.7 vs. AM, 3.81 ± 0.5 µmol·l–1·Torr–1 PETCO2; P < 0.05). There were no overnight differences in the hypercapnic response of either t-Hb (PM, –0.9 ± 0.3 vs. AM, –1.0 ± 0.5 µmol·l–1·Torr–1 PETCO2; P > 0.05) or MAP (PM, 0.35 ± 0.21 vs. AM, 0.38 ± 0.25 mmHg/Torr PETCO2; P > 0.05).
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In the last minute of hypoxia, the mild decrease in MCAV was not significantly different from the baseline value in either the evening or morning (sensitivity: PM, 0.71 ± 0.42%/SaO2; AM, 0.60 ± 0.56%/SaO2; Fig. 3). There were no overnight differences in the level of hypoxemia between morning and evening (SaO2: PM, 84.4 ± 1.9%; AM, 84.0 ± 2.1%) or hypocapnia (PETCO2: PM, –2.9 ± 1.3 Torr; AM, –2.7 ± 1.9 Torr). Despite this same stimulus, during the last minute, there was a greater cerebral desaturation during hypoxia in the morning compared with evening (PM, –0.35 ± 0.14 vs. AM, –0.45 ± 0.14% TOI/SaO2; P < 0.05; Fig. 3), owing to a greater decrease in oxy-Hb (PM, –2.1 ± 0.7 vs. AM, –2.9 ± 0.5 µmol/l SaO2; P < 0.05), with no changes in t-Hb (PM, –0.4 ± 0.4 vs. AM, –0.6 ± 0.5 µmol/l SaO2). There were no overnight differences in the response of MAP to changing SaO2 (PM: 0.18 ± 0.12 vs. 0.16 ± 0.09 mmHg/SaO2; P > 0.05).
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As illustrated in Fig. 4, after a 20-s breath hold, there was a smaller surge in both MCAV (AM, 29 ± 5 vs. PM, 35 ± 7% of baseline, P < 0.05) and in cerebral oxygenation (AM, 5.6 ± 2.7 vs. PM, 7.2 ± 2.3% of baseline, P < 0.05) in the early morning compared with the early evening. Similar to the cerebral oxygenation changes during hypercapnia, the reduction in cerebral oxygenation during the breath hold was predominantly due to a reduction in oxy-Hb, since t-Hb was unchanged between the evening and morning testing sessions. There were no overnight differences in SaO2, BP, or PETCO2 during or following the 20-s breath hold.
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Reproducibility of the two evening measurements was compared with that of the evening and morning measurements. If more variability exists between the evening and morning (i.e., reflected in a lower correlation) compared with the variability between the two evening tests, it suggests an altered physiological response between evening and early morning. The correlation coefficients (r value) for the slopes of the MCAV cerebral oxygenation and ventilatory responses to hypercapnia, between the two evening experiments, were 0.81, 0.79, and 0.62, respectively (P < 0.05). Conversely, there were lower correlations between the evening and morning values (r = 0.36; 0.42, 0.31, respectively; P < 0.05 vs. PM). The two evening correlation coefficients for the slopes of the MCAV and ventilatory responses to hypoxia were not different from the correlations between the evening and morning slopes. Conversely, the correlation between the slopes of the cerebral oxygenation to hypoxia for the two evening tests (r = 0.65; P < 0.05) was higher than the correlations between evening and morning slope (r = 0.42; not significant). These results indicate selective overnight alterations in cerebrovascular, oxygenation, and ventilatory response to hypercapnia and hypoxic-induced cerebral deoxygenation, but not in the cerebrovascular or ventilatory responses to poikilocapnic hypoxia.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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E, or PETCO2 during the last minute of hypoxia, there was a greater decrease in cerebral oxygenation with hypoxemia in the morning than in the evening. Third, after a 20-s breath hold, we observed a marked increase in both cerebral oxygenation and MCAV, but both increases were of lesser magnitude in the morning compared with evening. Therefore, the increased ventilatory response to hypercapnia observed in our study is likely a result of the reduced cerebrovascular reactivity to CO2, especially given recent findings showing a direct effect of manipulating the cerebrovascular reactivity, via the use of indomethacin administration, on the hypercapnic response (45). Furthermore, our results suggest that morning cerebral tissue oxygenation might be reduced as a result of a decreased cerebrovascular responsiveness to CO2 or other factors, leading to a higher level of desaturation. Methodological Considerations
Although not a direct measure of flow, the majority of research suggests that there is little or no change in the cross-sectional area of the MCA during either hypercapnia or hypoxia, suggesting that MCAV is a reliable index of CBF (13, 33, 39). Cerebral NIRS has been shown to track changes in jugular venous bulb saturation in healthy volunteers under conditions of isocapnic hypoxia (19) and has also been validated compared with PET scanning (30), with 133Xe washout methods (34) and with internal carotid artery stump pressures (42). Since there were no overnight changes in total-Hb (as an index of cerebral blood volume), the changes in cerebral oxygenation are unlikely to be related primarily to differential volume shifts between the proportions of blood in the arterial or venous part of the cerebrovascular bed. It should be acknowledged that NIRS measures only local (i.e., to one depth) oxygenation and that discreet regions of the brain may respond differently during conditions of hypoxia. Although we only used one steady-state step of CO2 and O2 for our reactivity calculations, our cardiorespiratory and cerebrovascular reactivity values are comparable with previous studies using three increments in inspired CO2 (45), seven increments in PETCO2 (16), or seven decrements in poikilocapnic PETO2 (3).
Polysomnographic-monitored sleep was used to confirm adequate sleep quality and to rule out the possibility of any sleep-related pathology. This was important since both inadequate sleep and/or sleep apnea can independently impair cerebrovascular function (17, 18) and/or the hypercapnic or hypoxic ventilatory response (10, 41). Likewise, the larger variability between the evening and the morning test, compared with the variability between the two evening tests (one of which served as a full familiarization), suggests a selective change in the cerebrovascular and ventilatory response to CO2 from evening to morning.
Diurnal Rhythm in Ventilatory and Cerebrovascular Reactivity
Circadian rhythm has been shown to influence the chemical control of breathing in both animals (27, 32), as well as humans (36, 38). We found no significant differences in any cardiorespiratory or cerebrovascular parameters at rest between the evening and early morning, consistent with other reports (22, 31). Although hypoventilation leading to a 3- to 7-Torr increase in arterial PCO2 can occur during sleep (28), in normal, awake humans, it has been demonstrated that arterial PCO2 remains unchanged from morning and evening (8). This has been confirmed in other studies where subjects remain awake in constant light and bed rest (constant routine conditions), where it has been demonstrated that the changes in metabolic rate and E observed during sleep are reduced considerably or eliminated, leading to only small changes (within 1–2 Torr) in PETCO2throughout a 24-h period (37, 38). Together, these observations indicate that the small circadian changes in E are mediated almost exclusively by the changes in the state of arousal (23).
Consistent with these observations and others (22, 31), our data show no significant differences in PETCO2 or E at rest between the evening and early morning. PETCO2 is a good reflection of arterial PCO2 at rest, and data from our laboratory indicate that the change in PETCO2 is closely related to the change in arterial PCO2 during hypercapnia (R2 = 0.79, P < 0.05; mean bias, –0.08; n = 12; Ainslie PN, et al., unpublished observations). That being said, we cannot rule out the possibility that an enhanced ventilatory response to hypercapnia in the morning, subsequently leading to a difference in arterial PCO2/pH, results in the attenuated cerebrovascular response to CO2 in the morning that we observed in our study.
Previous studies have shown that MCAV is reduced during sleep (2, 14) and that there is a marked reduction (70%) in sleep-related cerebrovascular response to CO2 in otherwise healthy humans (21). A postsleep reduction in blood flow velocity has been confirmed in normal volunteers in some studies using TCD ultrasound (20) and with H215O positron emission tomography (7), but not all studies (22). These findings provide evidence of some form of "sleep inertia" or "carryover" of sleep-related processes into waking. Conversely, there is also one report describing an endogenous circadian rhythm in MCAV (9), providing preliminary evidence that the decline in MCAV is present during wakefulness in the nighttime hours and therefore may not be attributed solely to sleep and associated changes that normally influence MCAV (including factors such as the shift to recumbency, and reduced activity, metabolic rate, and respiratory rate); however, it is unknown if there is a similar endogenous circadian rhythm in cerebrovascular reactivity independent of sleep.
Collectively, the extent to which the morning reduction in the "awake" cerebrovascular response to CO2 can be attributed to a "carryover" effect from sleep or to an endogenous circadian rhythm in cerebrovascular reactivity, independent of sleep, remains to be examined.
Cerebrovascular Reactivity to CO2 and the Implications for Breathing Stability
Our data indicate that the cerebrovascular reactivity to CO2 in healthy subjects is significantly reduced in the morning and is strongly associated with an augmented ventilatory response to CO2. It is likely that this reduction in MCAV CO2 reactivity, by reducing blood flow through medullary respiratory control centers, increases both the arterial-brain tissue PCO2 difference and the H+ concentration presented to the central chemoreceptor(s) (11, 44). In effect, it appears the brain tissue is more susceptible in the morning to changes in arterial PCO2, which could increase the likelihood of ventilatory overshoots and undershoots. However, changes in cerebral responsiveness to CO2 may not be sufficient to destabilize breathing, as the carotid bodies play a significant role in the rapid ventilatory response to CO2 challenge (35). In addition, the carotid bodies are an important determinant in breathing stability at rest through tonic inputs and by possibly compensating for a reduced central CO2 sensitivity (12, 15, 25, 35). However, it is tempting to speculate that this decrease in the morning responsiveness of the cerebral circulation to CO2, by increasing the central contribution to loop gain, might also increase the risk for unstable breathing during the morning hours, especially when occurring in a background of other risk factors, such as heart failure.
Cerebrovascular Oxygenation During Hypoxia
From evening to morning, there was no change in MCAV sensitivity to poikilocapnic hypoxia. Although levels of hypoxia-induced hypocapnia were statistically identical from evening to morning, it remains possible that a difference in the hypoxic sensitivity from evening to morning was counteracted by a difference in the cerebrovascular response to the ensuing mild hypocapnia. As we did not compare cerebrovascular responses to hypocapnia alone, it is not possible for us to determine whether this is the case. However, our finding is in agreement with data from Meadows and colleagues (22), who found no changes in the CBF responses to isocapnic hypoxia, and hypothesized that the maintenance of the cerebrovasculature response to hypoxia in the early morning may be a protective mechanism against cerebral ischemia and stroke (22).
Interestingly though, despite an unchanged MCAV responsiveness to hypoxia from evening to morning, there was a smaller increase in cerebral oxygenation compared with the evening. This indicates that, despite there being no differences in the cerebrovascular response to poikilocapnic hypoxia, the cerebral tissue is more prone to desaturation in the morning. This could partially explain the increased risk for morning cerebral ischemia and stroke, especially when occurring in a background of other risk factors.
The Effect of Breath Hold on MCAV and Cerebral Oxygenation
Similarly to Xie et al. (45), we used a breath-hold protocol to mimic apnea and initiate endogenous changes in arterial blood gases. From evening to morning, equivalent changes occurred in SaO2, BP, and PETCO2 during the breath hold. However, as was the case with the hypercapnic challenge, subjects holding their breath in the morning experienced a significantly blunted increase in MCAV compared with evening, likely a result of a reduced cerebrovascular responsiveness to CO2. Although there appears to be no difference in the cerebrovascular response to hypoxemia from evening to morning, the lower increase in cerebral oxygenation in the morning after a breath hold could be from either a reduced cerebrovascular responsiveness to CO2 or to additional, yet-to-be identified factors.
In conclusion, our results suggest that early morning reductions in cerebrovascular CO2 reactivity strongly influence the magnitude of the ventilatory response to CO2. This may have significant implications for breathing stability, increasing the chances of periodic breathing in the morning in patients with additional risk factors. The early morning reduction in cerebral oxygenation with hypercapnic challenge, mild hypoxemia, or during apnea may be a contributing factor in the high prevalence of early morning stroke. Whether differences in the responses of CBF, oxygenation, or E to CO2 challenge are associated with other risk factors for stroke, such as gender or age, remains to be elucidated.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* K. J. Cummings and M. Swart contributed equally to this work. 
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and morning (AM: 
). After the breath hold in the early morning, there was a smaller increase in cerebral blood flow velocity, reflected in a greater decrease in cerebral oxygenation compared with evening measurements (*P < 0.05 compared with PM). There were no differences in SaO2, blood pressure, or end-tidal PCO2 (data not shown).