Multimodality monitoring during passive tilt and Valsalva maneuver under hypercapnia.

In occlusive cerebrovascular disease cerebral blood flow (CBF) autoregulation can be impaired and constant CBF during fluctuations in blood pressure (BP) cannot be guaranteed. Therefore, an assessment of cerebral autoregulation should consider not only responsiveness to CO2 or Diamox. Passive tilting (PT) and Valsalva maneuver (VM) are established tests for cardiovascular autoregulatory function by provoking BP changes. To develop a comprehensive test for vasomotor reactivity with a potential increase of sensitivity and specificity, the authors combined these maneuvers. Blood pressure, corrected to represent arterial pressure at the level of the circle of Willis, middle cerebral artery Doppler frequencies (DF), heart rate (HR) and endtidal partial pressure of CO2 (PtCO2) were measured continuously and noninvasively in 81 healthy subjects (19-74 years). Passive tilt and Valsalva maneuver were performed under normocapnia (mean, 39 + 4 mmHg CO2) and under hypercapnia (mean, 51 + 5 mm Hg CO2). Resting BP, HR, and DF increased significantly under hypercapnia. Under normocapnia and hypercapnia, PT induced only minor, nonsignificant changes in mean BP at the level of the circle of Willis compared to baseline (normocapnia: + 2 + 15 mm Hg; hypercapnia: -3 +/- 13 mm Hg). This corresponded with a nonsignificant decrease of the mean of DF (normocapnia: -4 +/- 11%; hypercapnia -6 +/- 12%). Orthostasis reduced pulsatility of BP by a predominantly diastolic increase of BP without significant changes in pulsatility of DF. Valsalva maneuver, with its characteristic rapid changes of BP due to elevated intrathoracic pressure, showed no significant BP differences in changes to baseline between normocapnic and hypercapnic conditions. Under both conditions the decrease in BP in phase II was accompanied by significantly increased pulsatility index ratio (PIDF/PIBP). Valsalva maneuver and PT as established tests in autonomic control of circulation provoked not only changes in time-mean of BP but also in pulsatility of BP. The significant increase in pulsatility ratio and decrease of the DF/BP ratio during normocapnia and hypercapnia indicated preserved CBF autoregulation within a wide range of CO2 partial pressures. Hypercapnia did not significantly influence the autoregulatory indices during VM and PT. Physiologically submaximally dilated cerebral arterioles can guarantee unchanged dynamics of cerebral autoregulation. Combined BP and MCA-DF assessment under hypercapnia enables investigating the effect of rapid changes of blood pressure on CO2-induced predilated cerebral arterioles. Assuming no interference of hypercapnia-induced vasodilation, VM, with its rapid, distinct changes in BP, seems especially to be adequate provocation for CBF autoregulation. This combined vasomotor reactivity might provide a more sensitive diagnostic tool to detect impaired cerebral autoregulation very early.     

Effect of 2-chloroadenosine on cerebrovascular reactivity to hypercapnia in newborn pig.

The effect of local administration of vasodilative concentrations of the adenosine receptor agonist 2-chloroadenosine (2-CADO) on the hyperemic responses of the pial and parenchymal microcirculations to graded hypercapnia was determined. The cranial window and brain microdialysis-hydrogen clearance techniques were utilized in two groups of isoflurane-anesthetized newborn pigs to measure changes in pial diameters and local CBF, respectively, in response to graded hypercapnia in the absence and presence of 2-CADO. Progressive size-dependent dilations of pial arterioles [small = 41 +/- 7 microns (mean +/- SD), intermediate = 78 +/- 13 microns, and large = 176 +/- 57 microns in diameter] occurred in response to graded hypercapnia alone (PaCO2 = 58 and 98 mm Hg) and to superfusions of 2-CADO (10(-5) M) during normocapnia; the magnitude of the dilative response to each of these stimuli was inversely proportional to vessel size. When hypercapnia was induced concomitantly with 2-CADO superfusion, the dilative effects of each stimulus were directly additive. Similarly, local microdialysis infusion of 10(-5) M 2-CADO, which doubled CBF during normocapnia, did not affect the hyperemic response of the parenchymal circulation to graded hypercapnia (PaCO2 = 69 and 101 mm Hg). Our findings are consistent with the participation of adenosine in the mediation of cerebral hypercapnic hyperemia. If, however, adenosine is not involved in this dilative response, our results indicate that concomitant vascular and neuromodulatory actions induced by adenosine receptor stimulation do not affect the mechanism responsible for the hypercapnic hyperemic response.     

Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension.

The importance of nitric oxide (NO) for CBF variations associated with arterial carbon dioxide changes was investigated in halothane-anesthetized rats by using an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (NOLAG). CBF was measured by intracarotid injection of 133Xe. In normocapnia, intracarotid infusion of 1.5, or 7.5, or 30 mg/kg NOLAG induced a dose-dependent increase of arterial blood pressure and a decrease of normocapnic CBF from 85 +/- 10 to 78 +/- 6, 64 +/- 5, and 52 +/- 5 ml 100 g-1 min-1, respectively. This effect lasted for at least 2 h. Raising PaCO2 from a control level of 40 to 68 mm Hg increased CBF to 230 +/- 27 ml 100 g-1 min-1, corresponding to a percentage CBF response (CO2 reactivity) of 3.7 +/- 0.6%/mm Hg PaCO2 in saline-treated rats. NOLAG attenuated this reactivity by 32, 49, and 51% at the three-dose levels. Hypercapnia combined with angiotensin to raise blood pressure to the same level as the highest dose of NOLAG did not affect the CBF response to hypercapnia. L-Arginine significantly prevented the effect of NOLAG on normocapnic CBF as well as blood pressure and also abolished its inhibitory effect on hypercapnic CBF. D-Arginine had no such effect. Decreasing PaCO2 to 20 mm Hg reduced control CBF to 46 +/- 3 ml 100 g-1 min-1 with no further reduction after NOLAG. Furthermore, NOLAG did not change the percentage CBF response to an extracellular acidosis induced by acetazolamide (50 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of caffeine on dilated cerebral circulation and on diagnostic CO2 reactivity testing.

Reduction of cerebral blood flow by caffeine has been shown in multiple studies. However, the effect of this substance on pathologically dilated cerebral vessels is not clearly defined. The aim of this study was to investigate the effect of caffeine on an already dilated cerebral circulation and specify if these vessels are still able to constrict as a consequence of caffeine stimulation. A second aim of this study was to compare results of cerebral vasomotor CO(2) reactivity testing with and without caffeine ingestion. Seventeen healthy adult volunteers had vasomotor reactivity tested before and thirty minutes after ingestion of 300 mg of caffeine. Each vasomotor reactivity test consisted of velocity measurements from both middle cerebral arteries using transcranial Doppler ultrasound during normocapnia, hypercapnia, and hypocapnia. Hemodynamic data and end-tidal CO(2) (etCO(2)) concentration were also recorded. The vasomotor reactivity (VMR) and CO(2) reactivity were calculated from a measured data pool. At a level of etCO(2)=40 mmHg the resting velocity in the middle cerebral artery (V(MCA)) dropped from 70.7+/-22.8 cm/sec to 60.7 +/- 15.4 cm/sec 30 minutes after caffeine stimulation (14.1% decrease, p<0.001). During hypercapnia of etCO(2)=50 mmHg there was also a significant decline of V(MCA) from 103.1+/-25.4 to 91.4+/-21.8 cm/sec (11.3%, p<0.001). There was not a statistically significant reduction of V(MCA) during hypocapnia. Calculated VMR and CO(2) reactivity before and after caffeine intake were not statistically significant. The presented data demonstrate a significant decrease in cerebral blood flow velocities after caffeine ingestion both in a normal cerebrovascular bed and under conditions of peripheral cerebrovascular vasodilatation. These findings support the important role of caffeine in regulation of CBF under different pathological conditions. Despite significant reactive vasodilatation in the brain microcirculation, caffeine is still able to act as a competitive antagonist of CO(2) on cerebral microvessels. The fact that caffeine may decrease CBF despite significant pathological vasodilatation offers the possibility of therapeutic manipulation in patients with traumatic vasoparalysis. For routine clinical testing of CO(2) reactivity it is not necessary to insist on pre-test dietary restrictions.     

Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography.

Hypercapnia induces cerebral vasodilation and increases cerebral blood flow (CBF), and hypocapnia induces cerebral vasoconstriction and decreases CBF. The relation between changes in CBF and cerebral blood volume (CBV) during hypercapnia and hypocapnia in humans, however, is not clear. Both CBF and CBV were measured at rest and during hypercapnia and hypocapnia in nine healthy subjects by positron emission tomography. The vascular responses to hypercapnia in terms of CBF and CBV were 6.0 +/- 2.6%/mm Hg and 1.8 +/- 1.3%/mm Hg, respectively, and those to hypocapnia were -3.5 +/- 0.6%/mm Hg and -1.3 +/- 1.0%/mm Hg, respectively. The relation between CBF and CBV was CBV = 1.09 CBF0.29. The increase in CBF was greater than that in CBV during hypercapnia, indicating an increase in vascular blood velocity. The degree of decrease in CBF during hypocapnia was greater than that in CBV, indicating a decrease in vascular blood velocity. The relation between changes in CBF and CBV during hypercapnia was similar to that during neural activation; however, the relation during hypocapnia was different from that during neural deactivation observed in crossed cerebellar diaschisis. This suggests that augmentation of CBF and CBV might be governed by a similar microcirculatory mechanism between neural activation and hypercapnia, but diminution of CBF and CBV might be governed by a different mechanism between neural deactivation and hypocapnia.     

Bell-shaped relationship between central blood volume and spontaneous baroreflex function

Spontaneous baroreflex function can be altered by acute changes in central blood volume. Both a reduction in spontaneous baroreflex function at central hypovolemia and augmentation at hypervolemia suggest a dose-effect relationship between central blood volume and spontaneous baroreflex function. However, this relationship has not been quantified over stepwise widespread changes in central blood volume. Twelve individuals underwent central hypovolemia at two levels of lower body negative pressure (LBNP) (-15 mm Hg, LBNP15; -30 mm Hg, LBNP30) and hypervolemia with two discrete infusions of normal saline (NS) (15 ml kg(-1), NS15; total 30 ml kg(-1), NS30). Spontaneous baroreflex function was assessed using transfer function analysis and the sequence method between blood pressure and R-R interval. Both central venous pressure (-0.6-7.9 mm Hg) and left ventricular end-diastolic volume (72.4-133.1 ml) decreased during LBNP and increased after saline infusion. Both spontaneous baroreflex indices of high-frequency transfer function gain (LBNP30, 17.4+/-3.2; LBNP15, 22.3+/-3.8; baseline, 25.6+/-4.1; NS15, 28.5+/-4.2 ms mm Hg(-1), ANOVA P=0.001) and of the sequence slope (LBNP30, 14.4+/-2.2; LBNP15, 17.2+/-2.5; baseline, 20.5+/-2.8; NS15, 24.5+/-3.1 ms mm Hg(-1), ANOVA P=0.001) increased stepwise from hypovolemia of LBNP30 to hypervolemia of NS15. However, these indices were lower at NS30 (high-frequency transfer function gain, 22.0+/-2.2 ms mm Hg(-1), post-hoc P=0.071; sequence slope, 17.7+/-1.7 ms mm Hg(-1), post-hoc P<0.05) than NS15 during hypervolemia. These results indicated that the relationship between central blood volume and spontaneous baroreflex function is apparently bell-shaped, with maximal augmentation at moderate hypervolemia.     

Head position modifies cerebrovascular response to orthostatic stress

Previous experiments have shown that the vestibular system participates in cardiovascular control. However, the effects of vestibular activation on cerebrovascular regulation are not known. Therefore, the present experiment tested the hypothesis that specific vestibular activations may be beneficial to cerebral circulation during simulated orthostatic stress. Middle cerebral artery blood flow velocity (CBV; Doppler ultrasound) was measured to examine the effects of head-down neck flexion (HDNF) compared to head-down neck extension (HDNE) with and without lower body negative pressure (LBNP; -40 mmHg) (n=9). The change in CBV (DeltaCBV) during HDNF and HDNE were not different during baseline conditions, however, during LBNP, DeltaCBV was greater in HDNE compared to HDNF (-5.5+/-3.2 cm/s, -11+/-4.6%) vs. (-0.7+/-1.0 cm/s, -1.9+/-1.9%), respectively (P<0.05). Concomitantly, the change in cerebrovascular resistance (DeltaCVR) between rest and LBNP was also greater during HDNE (0.48+/-0.08 mmHg/cm per s, 42.8+/-10.8%) compared with HDNF (0.26+/-0.05 mmHg/cm per s, 22+/-4.1%) (P<0.05). P(ET)CO(2) was greater in HDNE (45+/-2 mmHg) compared to HDNF (42+/-2 mmHg; P<0.05) during LBNP. These results suggest that the vestibular system may affect cerebrovascular tone during simulated postural stress by either constriction or dilation, depending on the vestibular stimulus.     

Influence of the endothelial glycocalyx on cerebral blood flow in mice.

The endothelial surface layer (glycocalyx) of cerebral capillaries may increase resistance to blood flow. This hypothesis was investigated in mice by intravenous administration of heparinase (2500 IU/kg body weight in saline), which cleaves proteoglycan junctions of the glycocalyx. Morphology was investigated by transmission electron microscopy. Cerebral perfusion velocity was recorded before and during heparinase or saline treatment using laser-Doppler flowmetry. In addition, cerebral blood flow (CBF) was measured 10 minutes after heparinase or saline treatment using the iodo[14C]antipyrine method. Laser-Doppler flowmetry and CBF measurements were performed during normocapnia and severe hypercapnia (PCO2: 120 mm Hg). After heparinase, morphology showed a reduced thickness of the glycocalyx in cortical microvessels by 43% (P < 0.05) compared with saline-treated controls. Under normocapnic conditions, a 15% (P < 0.05) transient increase of cerebral flow velocity occurred 2.5 to 5 minutes after heparinase injection. Laser-Doppler flow and CBF returned to control values ten minutes after the injection. However, during severe hypercapnia, heparinase treatment resulted in a persisting increase in laser-Doppler flow (6%, P < 0.05) and CBF (30%, P < 0.05). These observations indicate the existence of a flow resistance in cerebral capillaries exerted by the glycocalyx. The transient nature of the CBF increase during normocapnia may be explained by a vascular compensation that is exhausted during severe hypercapnia.     

Pial artery pressure after one hour of global ischemia

Pial artery pressure was measured in anesthetized control cats and in animals subjected to 1 h of global ischemia and 6 h of recirculation. Cerebral blood flow (CBF) was measured with the intraarterial 133Xe technique before and after ischemia, and lumped segmental resistances upstream and downstream to the pial artery were calculated. In the control brain, upstream resistance was 1.30 +/- 0.28 and downstream resistance 0.94 +/- 0.1 mm Hg ml-1 100 g min. During the postischemic hypoperfusion period, both resistances significantly increased, indicating that hypoperfusion constitutes a dysregulation of both large extracerebral and small intracerebral vessels. Hypercapnia induced an increase of CBF in the control brain and was accompanied by a fall in downstream resistance, demonstrating intracortical vasodilation. By contrast, hypercapnia did not provoke changes in either CBF or segmental resistances in the hypoperfusion period. In conclusion, during the postischemic hypoperfusion period, both extra- and intracortical resistances are increased and vascular reactivity to CO2 is abolished.     

Assessment of cerebrovascular and cardiovascular responses to lower body negative pressure as a test of cerebral autoregulation

The aim of this study was to determine whether lower body negative pressure (LBNP), combined with noninvasive methods of assessing changes in systemic and cerebral vascular resistance, is suitable as a method for assessing cerebral autoregulation.In 13 subjects we continuously assessed heart rate, blood pressure, cerebral blood flow velocity (CBFV) and cardiac output during graded levels of LBNP from 0 to -50 mm Hg. With increasing levels of LBNP, cardiac output declined significantly (to 55.8+/-4.5% of baseline value) but there was no overall change in mean arterial pressure. CBFV also fell at higher levels of LBNP (to 81.4+/-3.2% of baseline) but the percentage CBFV change was significantly less than that in cardiac output (P<0.01). The maximum increase in cerebrovascular resistance (pulsatility ratio) was significantly less than that in total peripheral resistance (17+/-6% vs. 105+/-16%, P<0.01). Spectral analysis showed that the power of low-frequency oscillations in mean arterial pressure, but not CBFV, increased significantly at the -50 mm Hg level of LBNP.These results show that, even during high levels of orthostatic stress, cerebral autoregulation is preserved and continues to protect the cerebral circulation from changes in the systemic circulation. Furthermore, assessment of cardiovascular and cerebrovascular parameters during LBNP may provide a useful clinical test of cerebral autoregulation.     

Comparison between pial and intraparenchymal vascular responses to sympathetic stimulation under hypercapnic conditions. With special reference to the mechanism for escape phenomenon

We have shown that secondary vasodilation ('escape' phenomenon) during sympathetic nerve stimulation occurs in the intraparenchymal vessels but not remarkable in the pial vessels. To test a possible role of CO2 accumulation in the brain tissue in this phenomenon, the responses of pial and intraparenchymal vessels to sympathetic nerve stimulation were investigated during hypercapnia in 9 cats by using a video camera photoelectric system. The ipsilateral superior cervical ganglion was electrically stimulated for 5 min during hypercapnia (PaCO2 = 50 +/- 2 mm Hg). The intraparenchymal vessels as well as pial vessels remained constricted throughout the stimulation. Secondary dilation of the intraparenchymal vessels as seen at the later stage of sympathetic stimulation during normocapnia was not observed under the hypercapnic conditions. We assume that the arterial CO2 tension was so high that the constriction of inflow vessels could not result in accumulation of CO2 in the brain parenchyma. The accumulation of chemical metabolites as represented by CO2 is therefore considered to be the most probable mechanism underlying the escape phenomenon of the intraparenchymal vessels.     

Regional cerebral blood flow after cortical impact injury complicated by a secondary insult in rats

BACKGROUND AND PURPOSE: Traumatic injury makes the brain susceptible to secondary insults. An uncomplicated mild lateral cortical impact injury (3 m/s, 2.5-mm deformation) that causes little or no permanent sequelae results in a large contusion at the impact site when the traumatic injury is complicated by a secondary insult, such as 40 minutes of bilateral carotid occlusion. METHODS: To determine whether the increased sensitivity to secondary insults in this model is caused by a vascular mechanism, cerebral blood flow (CBF) was measured with (14)C-isopropyliodoamphetamine quantitative autoradiography, and brain tissue PO(2) (PbtO(2)) was measured at the impact site and in the contralateral parietal cortex. RESULTS: In animals that underwent bilateral carotid occlusion 1 hour after the impact injury, CBF and PbtO(2) were lower at the impact site than they were in animals that had either the impact injury or the carotid occlusion alone. In the immediate area of the impact, CBF was 14+/-6 mL. 100 g(-1). min(-1) in the animals with the impact injury followed by carotid occlusion compared with 53+/-24 mL. 100 g(-1). min(-1) in the animals with the impact injury alone and 74+/-14 mL. 100 g(-1). min(-1) in the animals with the carotid occlusion alone (P<0.001). At the time of this very low CBF value in the animals with the carotid occlusion after the impact injury, PbtO(2) at the impact site averaged 1.3+/-1.6 mm Hg and was <3 mm Hg in 5 of the 6 animals. In contrast, PbtO(2) in the animals with the impact injury alone averaged 9.3+/-2.9 mm Hg, and none of the animals had a PbtO(2) of <3 mm Hg (P=0.008). CONCLUSIONS: The CBF and PbtO(2) findings in this model suggest that the reduced CBF after traumatic injury predisposes the brain to secondary insults and results in ischemia when confronted with a reduction in cerebral perfusion pressure.     

Quantitative measurement of blood flow velocity in feline pial arteries during hemorrhagic hypotension and hypercapnia

Due to methodologic difficulties, few investigations have been made on the blood flow velocity in the cerebral microcirculation. Using a newly developed video camera method, we simultaneously measured the blood flow velocity and diameter of pial arteries during hemorrhagic hypotension, after blood pressure recovery, and during CO2 inhalation in cats. When the mean arterial blood pressure was lowered from 129.7 +/- 6.6 to 71.5 +/- 4.1 mm Hg, the blood flow velocity inevitably decreased from 36.6 +/- 5.3 to 27.0 +/- 3.9 mm/sec (p less than 0.001). The calculated blood flow rate [pi X (diameter/2)2 X flow velocity] was preserved in cases with concomitant vasodilation. Conversely, the blood flow velocity increased from 25.3 +/- 5.1 to 31.0 +/- 5.4 mm/sec (p less than 0.001) after mean arterial blood pressure recovery from 67.1 +/- 3.7 to 129.8 +/- 5.8 mm Hg. The blood flow rate was again preserved in vessels with a vasoconstrictive response. Each pial artery apparently dilated or constricted in proportion to the decrease or increase in flow velocity during blood pressure changes, maintaining a constant cerebral blood flow. This indicated the importance of the pial arteries in the mechanisms of cerebral blood flow autoregulation. During 5% CO2 inhalation, the blood flow velocity increased markedly from 25.4 +/- 4.6 to 37.2 +/- 10.0 mm/sec (p less than 0.05), while the pial artery diameter (85.0 +/- 13.7 microns) increased by 9.6 +/- 1.5% (p less than 0.01). The increased flow velocity might be attributable to preferential dilatation of small arterioles or intraparenchymal vessels during hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cortical spreading depression causes a long-lasting decrease in cerebral blood flow and induces tolerance to permanent focal ischemia in rat brain.

Cortical spreading depression (CSD) has previously been shown to induce tolerance to a subsequent episode of transient cerebral ischemia. The objective of the present study was to determine whether CSD also induces tolerance to permanent focal ischemia and, if so, whether tolerance may be mediated by alterations in cerebral blood flow (CBF). Sprague-Dawley rats were preconditioned by applying potassium chloride to one hemisphere for 2 hours, evoking 19 +/- 5 episodes of CSD (mean +/- SD, n = 19). Three days later, the middle cerebral artery (MCA) was permanently occluded using an intraluminal suture. In a subset of animals, laser Doppler blood flow (LDF) was monitored over the parietal cortex before and during the first 2 hours of MCA occlusion. Preconditioning with CSD reduced the hemispheric volume of infarction from 248 +/- 115 mm3 (n = 18) in sham-conditioned animals to 161 +/- 81 mm3 (n = 19, P< 0.02). Similarly, CSD reduced the neocortical volume of infarction from 126 +/- 82 mm3 to 60 +/- 61 mm3 (P < 0.01). Moreover, preconditioning with CSD significantly improved LDF during MCA occlusion from 21% +/- 7% (n = 9) of preischemic baseline in sham-conditioned animals to 29% +/- 9% (n = 7, P< 0.02). Preconditioning with CSD therefore preserved relative levels of CBF during focal ischemia and reduced the extent of infarction resulting from permanent MCA occlusion. To determine whether CSD may have altered preischemic baseline CBF, [14 C]iodoantipyrine was used in additional animals to measure CBF 3 days after CSD conditioning or sham conditioning. CSD, but not sham conditioning, significantly reduced baseline CBF in the ipsilateral neocortex to values 67% to 75% of those in the contralateral cortex. Therefore, CSD causes a long-lasting decrease in baseline CBF that is most likely related to a reduction in metabolic rate. A reduction in the rate of metabolism may contribute to the induction of tolerance to ischemia after preconditioning with CSD.     

Middle Cerebral Artery Flow Velocity Correlates With Common Carotid Artery Volume Flow Rate After CO2 Inhalation

Cerebral vasoreactivity can be studied with transcranial Doppler (TCD) by monitoring CO2-induced middle cerebral artery (MCA) velocity changes. Expected MCA mean velocity (Vm) changes due to changes in end-expiratory CO2 (EE-CO2) are established, but reactivity of common carotid artery (CCA) volume flow rate (VFR) has not been extensively reported. The authors assess the relationship between MCA Vm, CCA VFR, and EE-CO2. Ten normal individuals without cerebrovascular disease and with CCA diameters of more than 3.0 mm were studied. CCA VFR was obtained by Color Velocity Imaging Quantification and Ipsilateral MCA Vm by standard TCD methods. Each side was studied before, during, and after inhalation of 5% CO2. EE-CO2, blood pressure, and pulse rate were monitored. Four women and 6 men with mean age of 36 years were included. Significant correlations between MCA Vm and EE-CO2, CCA VFR and EE-CO2, and MCA Vm and CCA VFR were found. MCA Vm and CCA VFR increased 5.2% and 4.3% per mm Hg increase in EE-CO2, respectively. MCA Vm increased 0.3 cm/s for each ml/min increase in CCA VFR. In normal individuals, there is a direct correlation between MCA Vm, CCA VFR, and EE-CO2. Measurement of CCA VFR changes during CO2 inhalation may be an alternative method to estimate cerebral vasoreactivity when the MCA velocity cannot be obtained because of inadequate acoustic temporal windows.     

Acute exposure to normobaric mild hypoxia alters dynamic relationships between blood pressure and cerebral blood flow at very low frequency.

Acute hypoxia directly causes cerebral arteriole vasodilation and also stimulates peripheral chemoreceptors to change autonomic neural activity. These changes may alter cerebral vascular modulation. We therefore hypothesized that dynamic cerebral autoregulation would be altered during acute exposure to hypoxia. Fifteen healthy men were examined under normoxic (21%) and hypoxic conditions. Oxygen concentrations were decreased in stepwise fashion to 19%, 17%, and 15%, for 10 mins at each level. Mean blood pressure (MBP) in the radial artery was measured via tonometry, and cerebral blood flow velocity (CBFV) in the middle cerebral artery was measured by transcranial Doppler ultrasonography. Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis of beat-by-beat changes in MBP and CBFV. Arterial oxygen saturation decreased significantly during hypoxia, while end-tidal CO2 and respiratory rate were unchanged, as was steady-state CBFV. With 15% O2, very-low-frequency power of MBP and CBFV variability increased significantly by 185% and 282%, respectively. Moreover, transfer function coherence (21% O2, 0.46+/-0.04; 15% O2, 0.64+/-0.04; P=0.028) and gain (21% O2, 0.61+/-0.05 cm/secs/mm Hg; 15% O2, 0.86+/-0.08 cm/secs/mm Hg; P=0.035) in the very-low-frequency range increased significantly by 53% and 48% with 15% O2, respectively. However, these indices were unchanged in low- and high-frequency ranges. Acute hypoxia thus increases arterial pressure oscillations and dependence of cerebral blood flow (CBF) fluctuations on blood pressure oscillations, resulting in apparent increases in CBF fluctuations in the very-low-frequency range. Hypoxia may thus impair dynamic cerebral autoregulation in this range. However, these changes were significant only with hypoxia at 15% O2, suggesting a possible threshold for such changes.     

Neuroprotective effect of sumatriptan, a 5-HT(1D) receptor agonist, in focal cerebral ischemia of rat brain.

The effect of the 5-HT(1D) receptor agonist sumatriptan on the volume of ischemic injury was studied in rats subjected to permanent middle cerebral artery (MCA) occlusion. Sumatriptan (2 mg/kg) was administered intravenously 5 minutes after MCA occlusion and the ischemic injury volume was determined 3 hours after MCA occlusion using regional adenosine-5'-triphosphate imaging. In addition, electroencephalographic activity, direct current (DC) potential and cortical blood flow (CBF) was monitored throughout the experiment. In untreated animals, MCA occlusion resulted in a decline in penumbral CBF to 43.3%+/-7.6% of control, 21 spreadsing depression (SD)-like DC shifts with an average integrated depolarization negativity of 320.2+/-297.4 (mVxmin) and an ATP depletion volume of 61.8+/-22.9 mm(3) (mean+/-SD). Three hours after MCA occlusion in sumatriptan-treated animals, penumbral CBF recovered to 63.5%+/-12.6% of control (P<.05), only 13 SD-like shifts were detected (P<.05) with a significantly reduced integrated depolarization negativity of 104.7+/-98.4 (mVxmin) (P<.05), and the volume of ATP depletion decreased to 16.6+/-12.3 mm(3) (P<.01). However, no significant neuroprotective effect was observed for the caudate nucleus (untreated, 19.7+/-16.5 mm(3); treated, 7.9+/-8.5 mm(3)). The reduction in the volume of ischemic injury in sumatriptantreated animals is explained by both the improvement of blood flow and the inhibition of SD-like shifts leading to an amelioration of the misrelationship between the depolarization-related energy demand and flow-dependent substrate delivery.     

The effects of graded hypercapnia on the activation flow coupling response due to forepaw stimulation in alpha-chloralose anesthetized rats

Activation flow coupling (AFC), changes in cerebral blood flow (CBF) due to changes in neural activity with functional stimulation, provides the physiological basis of many neuroimaging techniques. Hypercapnia leads to an increase in CBF while neural activity remains unaffected. Laser Doppler (LD) flowmetry was used to measure CBF changes (LD(CBF)) in the somatosensory cortex due to periodic electrical forepaw stimulation (4 s in duration) before and during graded hypercapnia (3% CO(2), 5% CO(2) and 10% CO(2)). With increasing CO(2) concentrations, the baseline LD(CBF) progressively increased. The peak height (PH) of the LD(CBF) response, expressed as a percent change from the observed baseline for each hypercapnic state, significantly decreased (P<0.05) with increasing CO(2) concentrations. However, the absolute magnitude of the LD(CBF) change was independent of CO(2) concentration. The temporal dynamics of the LD(CBF) response during hypercapnia were significantly prolonged compared to baseline conditions (P<0.05).     

Cerebral blood flow reactivity to changes in carbon dioxide calculated using end-tidal versus arterial tensions

We retrospectively examined arerial and end-tidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients. CBF was measured using the intravenous 133Xe technique at mean +/- SD PaCO2 values of 28.2 +/- 5.2 and 38.8 +/- 4.8 mm Hg. The correlation between all PaCO2 and end-tidal PCO2 (PetCO2) values was y = 0.85x - 0.49 (r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between PaCO2 and PetCO2 (y = 0.11x + 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g-1 min-1 mm Hg-1) was similar (p = 0.358) when calculated by using either PaCO2 (1.9 +/- 0.8) or PetCO2 (1.8 +/- 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.91, p = 0.0001). The CBF response to changes in CO2 tension can be reliably estimated from noninvasive measurement of PetCO2.     

Stroke volume and sympathetic responses to lower-body negative pressure reveal new insight into circulatory shock in humans

We measured various hemodynamic responses and muscle sympathetic nerve activity (MSNA) in human subjects during a graded lower-body negative pressure (LBNP) protocol to test the hypotheses that: (1) reduced stroke volume (SV) is linearly related to increased MSNA; and (2) the onset of symptoms of impending cardiovascular collapse is associated with hypoadrenergic responses to central hypovolemia. We measured heart rates, arterial blood pressures, sympathetic neural activity (MSNA; peroneal nerve microneurography), and relative changes (% Delta) in SV (thoracic electrical bioimpedance) in 13 men during exposure to graded levels of LBNP. After a 12-min baseline data collection period, LBNP was initiated at -15 mm Hg for 12 min followed by continuous stepwise increments to -30, -45, and -60 mm Hg for 12 min each. Eight subjects completed the LBNP protocol (finishers), while the protocol was terminated prematurely during -60 mm Hg in five subjects due to onset of symptoms of cardiovascular collapse (nonfinishers). Of these subjects, we were able to record MSNA successfully throughout the LBNP protocol in four finishers and two nonfinishers. The relationship between average change in stroke volume and average change in MSNA was linear (% DeltaMSNA=464-3.6 [% DeltaSV], r2=0.98). On average, MSNA was greater in the nonfinishers at each level of LBNP compared to finishers, but peripheral resistance was lower. Our results support the hypothesis that MSNA activation is inversely related and linear to stroke volume reductions during central hypovolemia. Sympathetic withdrawal rather than hypoadrenergic function may represent a fundamental mechanism for the development of circulatory shock.