Influence of noninvasive peripheral arterial blood pressure measurements on assessment of dynamic cerebral autoregulation.

Assessment of dynamic cerebral autoregulation (CA) requires continuous recording of arterial blood pressure (ABP). In humans, noninvasive ABP recordings with the Finapres device have often been used for this purpose. We compared estimates of dynamic CA derived from Finapres with those from invasive recordings in the aorta. Measurements of finger noninvasive ABP (Finapres), intra-aortic ABP (Millar catheter), surface ECG, transcutaneous CO2, and bilateral cerebral blood flow velocity (CBFV) in the middle cerebral arteries were simultaneously and continuously recorded in 27 patients scheduled for percutaneous coronary interventions. Phase, gain, coherence, and CBFV step response from both the Finapres and intra-arterial catheter were estimated by transfer function analysis. A dynamic autoregulation index (ARI) was also calculated. For both hemispheres, the ARI index and the CBFV step response recovery at 4 s were significantly greater for the Finapres-derived estimates than for the values obtained from aortic pressure. The transfer function gain for frequencies <0.1 Hz was significantly smaller for the Finapres estimates. The phase frequency response was significantly greater for the Finapres estimates at frequencies >0.1 Hz, but not at lower frequencies. The Finapres gives higher values for the efficiency of dynamic CA compared with values derived from aortic pressure measurements, as indicated by biases in the ARI index, CBFV step response, gain, and phase. Despite the significance of these biases, their relatively small amplitude indicates a good level of agreement between indexes of CA derived from the Finapres compared with corresponding estimates obtained from invasive measurements of aortic ABP.     

Assessment of cerebral autoregulation: the quandary of quantification

We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal Pco(2) (Pet(CO(2))) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in Pet(CO(2)) were positively related to coherence [LF: β = 0.0065 arbitrary units (AU)/mmHg and VLF: β = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: β = -0.026 rad/mmHg and VLF: β = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: β = -0.042%/mmHg(2) and VLF: β = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: β = 0.0070 cm·s(-1)·mmHg(-2), P < 0.05; and VLF: β = 0.014 cm·s(-1)·mmHg(-2), P < 0.01). Thus, during changes in Pet(CO(2)), LF phase was inversely related to LF gain (β = -0.29 cm·s(-1)·mmHg(-1)·rad(-1), P < 0.01) but positively related to LF normalized gain (β = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.     

Cerebral vasoreactivity during hypercapnia is reset by augmented sympathetic influence

Sympathetic nerve activity influences cerebral blood flow, but it is unknown whether augmented sympathetic nerve activity resets cerebral vasoreactivity to hypercapnia. This study tested the hypothesis that cerebral vasodilation during hypercapnia is restrained by lower-body negative pressure (LBNP)-stimulated sympathoexcitation. Cerebral hemodynamic responses were assessed in nine healthy volunteers [age 25 yr (SD 3)] during rebreathing-induced increases in partial pressure of end-tidal CO(2) (Pet(CO(2))) at rest and during LBNP. Cerebral hemodynamic responses were determined by changes in flow velocity of middle cerebral artery (MCAV) using transcranial Doppler sonography and in regional cerebral tissue oxygenation (ScO(2)) using near-infrared spectroscopy. Pet(CO(2)) values during rebreathing were similarly increased from 41.9 to 56.5 mmHg at rest and from 40.7 to 56.0 mmHg during LBNP of -15 Torr. However, the rates of increases in MCAV and in ScO(2) per unit increase in Pet(CO(2)) (i.e., the slopes of MCAV/Pet(CO(2)) and ScO(2)/Pet(CO(2))) were significantly (P ≤0.05) decreased from 2.62 ± 0.16 cm·s(-1)·mmHg(-1) and 0.89 ± 0.10%/mmHg at rest to 1.68 ± 0.18 cm·s(-1)·mmHg(-1) and 0.63 ± 0.07%/mmHg during LBNP. In conclusion, the sensitivity of cerebral vasoreactivity to hypercapnia, in terms of the rate of increases in MCAV and in ScO(2), is diminished by LBNP-stimulated sympathoexcitation.     

Cerebral blood flow velocity response to induced and spontaneous sudden changes in arterial blood pressure

The influence of different types of maneuvers that can induce sudden changes of arterial blood pressure (ABP) on the cerebral blood flow velocity (CBFV) response was studied in 56 normal subjects (mean age 62 yr, range 23-80). ABP was recorded in the finger with a Finapres device, and bilateral recordings of CBFV were performed with Doppler ultrasound of the middle cerebral arteries. Recordings were performed at rest (baseline) and during the thigh cuff test, lower body negative pressure, cold pressor test, hand grip, and Valsalva maneuver. From baseline recordings, positive and negative spontaneous transients were also selected. Stability of PCO2 was monitored with transcutaneous measurements. Dynamic autoregulatory index (ARI), impulse, and step responses were obtained for 1-min segments of data for the eight conditions by fitting a mathematical model to the ABP-CBFV baseline and transient data (Aaslid's model) and by the Wiener-Laguerre moving-average method. Impulse responses were similar for the right- and left-side recordings, and their temporal pattern was not influenced by type of maneuver. Step responses showed a sudden rise at time 0 and then started to fall back to their original level, indicating an active autoregulation. ARI was also independent of the type of maneuver, giving an overall mean of 4.7 +/- 2.9 (n = 602 recordings). Amplitudes of the impulse and step responses, however, were significantly influenced by type of maneuver and were highly correlated with the resistance-area product before the sudden change in ABP (r = -0.93, P < 0.0004). These results suggest that amplitude of the CBFV step response is sensitive to the point of operation of the instantaneous ABP-CBFV relationship, which can be shifted by different maneuvers. Various degrees of sympathetic nervous system activation resulting from different ABP-stimulating maneuvers were not reflected by CBFV dynamic autoregulatory responses within the physiological range of ABP.     

Two-breath CO(2) test detects altered dynamic cerebrovascular autoregulation and CO(2) responsiveness with changes in arterial P(CO(2))

The new two-breath CO(2) method was employed to test the hypotheses that small alterations in arterial P(CO(2)) had an impact on the magnitude and dynamic response time of the CO(2) effect on cerebrovascular resistance (CVRi) and the dynamic autoregulatory response to fluctuations in arterial pressure. During a 10-min protocol, eight subjects inspired two breaths from a bag with elevated P(CO(2)), four different times, while end-tidal P(CO(2)) was maintained at three levels: hypocapnia (LoCO(2), 8 mmHg below resting values), normocapnia, and hypercapnia (HiCO(2), 8 mmHg above resting values). Continuous measurements were made of mean blood pressure corrected to the level of the middle cerebral artery (BP(MCA)), P(CO(2)) (estimated from expired CO(2)), and mean flow velocity (MFV, of the middle cerebral artery by Doppler ultrasound), with CVRi = BP(MCA)/MFV. Data were processed by a system identification technique (autoregressive moving average analysis) with gain and dynamic response time of adaptation estimated from the theoretical step responses. Consistent with our hypotheses, the magnitude of the P(CO(2))-CVRi response was reduced from LoCO(2) to HiCO(2) [from -0.04 (SD 0.02) to -0.01 (SD 0.01) (mmHg x cm(-1) x s) x mmHg Pco(2)(-1)] and the time to reach 95% of the step plateau increased from 12.0 +/- 4.9 to 20.5 +/- 10.6 s. Dynamic autoregulation was impaired with elevated P(CO(2)), as indicated by a reduction in gain from LoCO(2) to HiCO(2) [from 0.021 +/- 0.012 to 0.007 +/- 0.004 (mmHg x cm(-1) x s) x mmHg BP(MCA)(-1)], and time to reach 95% increased from 3.7 +/- 2.8 to 20.0 +/- 9.6 s. The two-breath technique detected dependence of the cerebrovascular CO(2) response on P(CO(2)) and changes in dynamic autoregulation with only small deviations in estimated arterial P(CO(2)).     

A new two-breath technique for extracting the cerebrovascular response to arterial carbon dioxide

Cerebrovascular autoregulation is evaluated from spontaneous fluctuations in mean flow velocity (MFV) by transcranial Doppler ultrasound of the middle cerebral artery (MCA) with respect to changes in arterial blood pressure (BP(MCA)), but the effects of spontaneous fluctuations in arterial Pco(2) on MFV have been largely ignored. Autoregressive moving average analysis (ARMA), a closed-loop system identification technique, was applied to data from nine healthy subjects during spontaneous breathing, during inspiration of 10% CO(2) for two breaths once per minute for 4 min, and during sustained breathing of 7% CO(2). Cerebrovascular resistance index (CVRi) was calculated (CVRi = BP(MCA)/MFV). Reliable estimates of gain for BP(MCA) --> MFV were obtained for spontaneous breathing and the two-breath method. In contrast, reliable gain estimates for Pco(2) --> MFV or Pco(2) --> CVRi were achieved only under the two-breath method. Pco(2) --> MFV gain was smaller with the two-breath method than during sustained 7% CO(2) (P < 0.05). BP(MCA) was elevated by 7% CO(2) but not by the two-breath method. The closed-loop model provides insight into interactions between BP(MCA) and Pco(2) on cerebrovascular control, but reliable solutions for Pco(2) effects with ARMA analysis require perturbation by the two-breath method.     

Regulation of middle cerebral artery blood velocity during dynamic exercise in humans: influence of aging.

Although cerebral autoregulation (CA) appears well maintained during mild to moderate intensity dynamic exercise in young subjects, it is presently unclear how aging influences the regulation of cerebral blood flow during physical activity. Therefore, to address this question, middle cerebral artery blood velocity (MCAV), mean arterial pressure (MAP), and the partial pressure of arterial carbon dioxide (Pa(CO(2))) were assessed at rest and during steady-state cycling at 30% and 50% heart rate reserve (HRR) in 9 young (24 +/- 3 yr; mean +/- SD) and 10 older middle-aged (57 +/- 7 yr) subjects. Transfer function analysis between changes in MAP and mean MCAV (MCAV(mean)) in the low-frequency (LF) range were used to assess dynamic CA. No age-group differences were found in Pa(CO(2)) at rest or during cycling. Exercise-induced increases in MAP were greater in older subjects, while changes in MCAV(mean) were similar between groups. The cerebral vascular conductance index (MCAV(mean)/MAP) was not different at rest (young 0.66 +/- 0.04 cm x s(-1) x mmHg(-1) vs. older 0.67 +/- 0.03 cm x s(-1) x mmHg(-1); mean +/- SE) or during 30% HRR cycling between groups but was reduced in older subjects during 50% HRR cycling (young 0.67 +/- 0.03 cm x s(-1) x mmHg(-1) vs. older 0.56 +/- 0.02 cm x s(-1) x mmHg(-1); P < 0.05). LF transfer function gain and phase between MAP and MCAV(mean) was not different between groups at rest (LF gain: young 0.95 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.88 +/- 0.06 cm x s(-1) x mmHg(-1); P > 0.05) or during exercise (LF gain: young 0.80 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.72 +/- 0.07 cm x s(-1) x mmHg(-1) at 50% HRR; P > 0.05). We conclude that despite greater increases in MAP, the regulation of MCAV(mean) is well maintained during dynamic exercise in healthy older middle-aged subjects.     

Effects of age and exercise on physiological dead space during simulated dives at 2.8 ATA.

Physiological dead space (Vds), end-tidal CO(2) (Pet(CO(2))), and arterial CO(2) (Pa(CO(2))) were measured at 1 and 2.8 ATA in a dry hyperbaric chamber in 10 older (58-74 yr) and 10 younger (19-39 yr) air-breathing subjects during rest and two levels of upright exercise on a cycle ergometer. At pressure, Vd (liters btps) increased from 0.34 +/- 0.09 (mean +/- SD of all subjects for normally distributed data, median +/- interquartile range otherwise) to 0.40 +/- 0.09 (P = 0.0060) at rest, 0.35 +/- 0.13 to 0.45 +/- 0.11 (P = 0.0003) during light exercise, and 0.38 +/- 0.17 to 0.45 +/- 0.13 (P = 0.0497) during heavier exercise. During these conditions, Pa(CO(2)) (Torr) increased from 33.8 +/- 4.2 to 35.7 +/- 4.4 (P = 0.0059), 35.3 +/- 3.2 to 39.4 +/- 3.1 (P < 0.0001), and 29.6 +/- 5.6 to 37.4 +/- 6.5 (P < 0.0001), respectively. During exercise, Pet(CO(2)) overestimated Pa(CO(2)), although the absolute difference was less at pressure. Capnography poorly estimated Pa(CO(2)) during exercise at 1 and 2.8 ATA because of wide variability. Older subjects had higher Vd at 1 ATA but similar changes in Vd, Pa(CO(2)), and Pet(CO(2)) at pressure. These results are consistent with an effect of increased gas density.     

Cerebrovascular responsiveness to steady-state changes in end-tidal CO2 during passive heat stress.

This study tested the hypothesis that passive heat stress alters cerebrovascular responsiveness to steady-state changes in end-tidal CO(2) (Pet(CO(2))). Nine healthy subjects (4 men and 5 women), each dressed in a water-perfused suit, underwent normoxic hypocapnic hyperventilation (decrease Pet(CO(2)) approximately 20 Torr) and normoxic hypercapnic (increase in Pet(CO(2)) approximately 9 Torr) challenges under normothermic and passive heat stress conditions. The slope of the relationship between calculated cerebrovascular conductance (CBVC; middle cerebral artery blood velocity/mean arterial blood pressure) and Pet(CO(2)) was used to evaluate cerebrovascular CO(2) responsiveness. Passive heat stress increased core temperature (1.1 +/- 0.2 degrees C, P < 0.001) and reduced middle cerebral artery blood velocity by 8 +/- 8 cm/s (P = 0.01), reduced CBVC by 0.09 +/- 0.09 CBVC units (P = 0.02), and decreased Pet(CO(2)) by 3 +/- 4 Torr (P = 0.07), while mean arterial blood pressure was well maintained (P = 0.36). The slope of the CBVC-Pet(CO(2)) relationship to the hypocapnic challenge was not different between normothermia and heat stress conditions (0.009 +/- 0.006 vs. 0.009 +/- 0.004 CBVC units/Torr, P = 0.63). Similarly, in response to the hypercapnic challenge, the slope of the CBVC-Pet(CO(2)) relationship was not different between normothermia and heat stress conditions (0.028 +/- 0.020 vs. 0.023 +/- 0.008 CBVC units/Torr, P = 0.31). These results indicate that cerebrovascular CO(2) responsiveness, to the prescribed steady-state changes in Pet(CO(2)), is unchanged during passive heat stress.     

Sympathetic regulation of the human cerebrovascular response to carbon dioxide

Although the cerebrovasculature is known to be exquisitely sensitive to CO(2), there is no consensus on whether the sympathetic nervous system plays a role in regulating cerebrovascular responses to changes in arterial CO(2). To address this question, we investigated human cerebrovascular CO(2) reactivity in healthy participants randomly assigned to the α(1)-adrenoreceptor blockade group (9 participants; oral prazosin, 0.05 mg/kg) or the placebo control (9 participants) group. We recorded mean arterial blood pressure (MAP), heart rate (HR), mean middle cerebral artery flow velocity (MCA(V mean)), and partial pressure of end-tidal CO(2) (Pet(CO(2))) during 5% CO(2) inhalation and voluntary hyperventilation. CO(2) reactivity was quantified as the slope of the linear relationship between breath-to-breath Pet(CO(2)) and the average MCAv(mean) within successive breathes after accounting for MAP as a covariate. Prazosin did not alter resting HR, Pet(CO(2)), MAP, or MCA(V mean). The reduction in hypocapnic CO(2) reactivity following prazosin (-0.48 ± 0.093 cm·s(-1)·mmHg(-1)) was greater compared with placebo (-0.19 ± 0.087 cm·s(-1)·mmHg(-1); P < 0.05 for interaction). In contrast, the change in hypercapnic CO(2) reactivity following prazosin (-0.23 cm·s(-1)·mmHg(-1)) was similar to placebo (-0.31 cm·s(-1)·mmHg(-1); P = 0.50 for interaction). These data indicate that the sympathetic nervous system contributes to CO(2) reactivity via α(1)-adrenoreceptors; blocking this pathway with prazosin reduces CO(2) reactivity to hypocapnia but not hypercapnia.     

Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise

Dynamic cerebral autoregulation (CA) is challenged by exercise and may become less effective when exercise is exhaustive. Exercise may increase arterial glucose concentration, and we evaluated whether the cerebrovascular response to exercise is affected by hyperglycemia. The effects of a hyperinsulinemic euglycemic clamp (EU) and hyperglycemic clamp (HY) on the cerebrovascular (CVRI) and systemic vascular resistance index (SVRI) responses were evaluated in seven healthy subjects at rest and during rhythmic handgrip exercise. Transfer function analysis of the dynamic relationship between beat-to-beat changes in mean arterial pressure and middle cerebral artery (MCA) mean blood flow velocity (V(mean)) was used to assess dynamic CA. At rest, SVRI decreased with HY and EU (P < 0.01). CVRI was maintained with EU but became reduced with HY [11% (SD 3); P < 0.01], and MCA V(mean) increased (P < 0.05), whereas brain catecholamine uptake and arterial Pco(2) did not change significantly. HY did not affect the normalized low-frequency gain between mean arterial pressure and MCA V(mean) or the phase shift, indicating maintained dynamic CA. With HY, the increase in CVRI associated with exercise was enhanced (19 +/- 7% vs. 9 +/- 7%; P < 0.05), concomitant with a larger increase in heart rate and cardiac output and a larger reduction in SVRI (22 +/- 4% vs. 14 +/- 2%; P < 0.05). Thus hyperglycemia lowered cerebral vascular tone independently of CA capacity at rest, whereas dynamic CA remained able to modulate cerebral blood flow around the exercise-induced increase in MCA V(mean). These findings suggest that elevated blood glucose does not explain that dynamic CA is affected during intense exercise.     

Middle cerebral artery flow velocity and pulse pressure during dynamic exercise in humans

Exercise challenges cerebral autoregulation (CA) by a large increase in pulse pressure (PP) that may make systolic pressure exceed what is normally considered the upper range of CA. This study examined the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) and systolic (V(s)), diastolic (V(d)). and mean (V(m)) middle cerebral artery (MCA) blood flow velocity during mild, moderate, and heavy cycling exercise. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated using transfer function analysis. PP increased by 37% and 57% during moderate and heavy exercise, respectively (P < 0.05), and the pulsatility of MCA V increased markedly. Thus exercise increased MCA V(m) and V(s) (P < 0.05) but tended to decrease MCA V(d) (P = 0.06). However, the normalized low-frequency transfer function gain between MAP and MCA V(m) and between SBP and MCA V(s) remained unchanged from rest to exercise, whereas that between DBP and MCA V(d) increased from rest to heavy exercise (P < 0.05). These findings suggest that during exercise, CA is challenged by a rapid decrease rather than by a rapid increase in blood pressure. However, dynamic CA remains able to modulate blood flow around the exercise-induced increase in MCA V(m), even during high-intensity exercise.     

Dynamic cerebral autoregulation during brain activation paradigms

Dynamic cerebral autoregulation (CA) describes the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (ABP). We tested the hypothesis that the efficiency of dynamic CA is increased by brain activation paradigms designed to induce hemispheric lateralization. CBF velocity [CBFV; bilateral, middle cerebral artery (MCA)], ABP, ECG, and end-tidal Pco(2) were continuously recorded in 14 right-handed healthy subjects (21-43 yr of age), in the seated position, at rest and during 10 repeated presentations (30 s on-off) of a word generation test and a constructional puzzle. Nonstationarities were not found during rest or activation. Transfer function analysis of the ABP-CBFV (i.e., input-output) relation was performed for the 10 separate 51.2-s segments of data during activation and compared with baseline data. During activation, the coherence function below 0.05 Hz was significantly increased for the right MCA recordings for the puzzle tasks compared with baseline values (0.36 +/- 0.16 vs. 0.26 +/- 0.13, P < 0.05) and for the left MCA recordings for the word paradigm (0.48 +/- 0.23 vs. 0.29 +/- 0.16, P < 0.05). In the same frequency range, significant increases in gain were observed during the puzzle paradigm for the right (0.69 +/- 0.37 vs. 0.46 +/- 0.32 cm.s(-1).mmHg(-1), P < 0.05) and left (0.61 +/- 0.29 vs. 0.45 +/- 0.24 cm.s(-1).mmHg(-1), P < 0.05) hemispheres and during the word tasks for the left hemisphere (0.66 +/- 0.31 vs. 0.39 +/- 0.15 cm.s(-1).mmHg(-1), P < 0.01). Significant reductions in phase were observed during activation with the puzzle task for the right (-0.04 +/- 1.01 vs. 0.80 +/- 0.86 rad, P < 0.01) and left (0.11 +/- 0.81 vs. 0.57 +/- 0.51 rad, P < 0.05) hemispheres and with the word paradigm for the right hemisphere (0.05 +/- 0.87 vs. 0.64 +/- 0.59 rad, P < 0.05). Brain activation also led to changes in the temporal pattern of the CBFV step response. We conclude that transfer function analysis suggests important changes in dynamic CA during mental activation tasks.     

Impaired cerebral autoregulation in obstructive sleep apnea

Obstructive sleep apnea (OSA) increases the risk of stroke independent of known vascular and metabolic risk factors. Although patients with OSA have higher prevalence of hypertension and evidence of hypercoagulability, the mechanism of this increased risk is unknown. Obstructive apnea events are associated with surges in blood pressure, hypercapnia, and fluctuations in cerebral blood flow. These perturbations can adversely affect the cerebral circulation. We hypothesized that patients with OSA have impaired cerebral autoregulation, which may contribute to the increased risk of cerebral ischemia and stroke. We examined cerebral autoregulation in patients with and without OSA by measuring cerebral artery blood flow velocity (CBFV) by using transcranial Doppler ultrasound and arterial blood pressure using finger pulse photoplethysmography during orthostatic hypotension and recovery as well as during 5% CO(2) inhalation. Cerebral vascular conductance and reactivity were determined. Forty-eight subjects, 26 controls (age 41.0+/-2.3 yr) and 22 OSA (age 46.8+/-2.3 yr) free of cerebrovascular and active coronary artery disease participated in this study. OSA patients had a mean apnea-hypopnea index of 78.4+/-7.1 vs. 1.8+/-0.3 events/h in controls. The oxygen saturation during sleep was significantly lower in the OSA group (78+/-2%) vs. 91+/-1% in controls. The dynamic vascular analysis showed mean CBFV was significantly lower in OSA patients compared with controls (48+/-3 vs. 55+/-2 cm/s; P <0.05, respectively). The OSA group had a lower rate of recovery of cerebrovascular conductance for a given drop in blood pressure compared with controls (0.06+/-0.02 vs. 0.20+/-0.06 cm.s(-2).mmHg(-1); P <0.05). There was no difference in cerebrovascular vasodilatation in response to CO(2). The findings showed that patients with OSA have decreased CBFV at baseline and delayed cerebrovascular compensatory response to changes in blood pressure but not to CO(2). These perturbations may increase the risk of cerebral ischemia during obstructive apnea.     

Impaired cerebrovascular autoregulation and reduced CO₂ reactivity after long duration spaceflight

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO(2). Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BP(MCA)) and expired CO(2) were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BP(MCA)/CBFV). Cerebrovascular autoregulation and CO(2) reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO(2) were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BP(MCA) (P = 0.017). The postflight responses to CO(2) were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO(2) reactivity.     

Dynamic Cerebral Autoregulation Changes during Sub-Maximal Handgrip Maneuver

Purpose

We investigated the effect of handgrip (HG) maneuver on time-varying estimates of dynamic cerebral autoregulation (CA) using the autoregressive moving average technique.

Methods

Twelve healthy subjects were recruited to perform HG maneuver during 3 minutes with 30% of maximum contraction force. Cerebral blood flow velocity, end-tidal CO₂ pressure (PETCO₂), and noninvasive arterial blood pressure (ABP) were continuously recorded during baseline, HG and recovery. Critical closing pressure (CrCP), resistance area-product (RAP), and time-varying autoregulation index (ARI) were obtained.

Results

PETCO₂ did not show significant changes during HG maneuver. Whilst ABP increased continuously during the maneuver, to 27% above its baseline value, CBFV raised to a plateau approximately 15% above baseline. This was sustained by a parallel increase in RAP, suggestive of myogenic vasoconstriction, and a reduction in CrCP that could be associated with metabolic vasodilation. The time-varying ARI index dropped at the beginning and end of the maneuver (p<0.005), which could be related to corresponding alert reactions or to different time constants of the myogenic, metabolic and/or neurogenic mechanisms.

Conclusion

Changes in dynamic CA during HG suggest a complex interplay of regulatory mechanisms during static exercise that should be considered when assessing the determinants of cerebral blood flow and metabolism.     

Cerebral and systemic hemodynamic changes during cognitive and motor activation paradigms

Cognitive and/or sensorimotor stimulations of the brain induce increases in cerebral blood flow that are usually associated with increased metabolic demand. We tested the hypothesis that changes in arterial blood pressure (ABP) and arterial Pco(2) also take place during brain activation protocols designed to induce hemispheric lateralization, leading to a pressure-autoregulatory response in addition to the metabolic-driven changes usually assumed by brain stimulation paradigms. Continuous recordings of cerebral blood flow velocity [CBFV; bilateral, middle cerebral artery (MCA)], ABP, ECG, and end-tidal Pco(2) (Pet(CO(2))) were performed in 15 right-handed healthy subjects (aged 21-43 yr), in the seated position, at rest and during 10 repeated presentations of a word generation and a constructional puzzle paradigm that are known to induce differential cortical activation. Derived variables included heart rate, cerebrovascular resistance, critical closing pressure, resistance area product, and the difference between the right and left MCA recordings (CBFV(R-L)). No adaptation of the CBFV(R-L) difference was detected for the repeated presentation of 10 activation tasks, for either paradigm. During activation with the word generation tasks, CBFV changed by (mean +/- SD) 9.0 +/- 3.7% (right MCA, P = 0.0007) and by 12.3 +/- 7.6% (left MCA, P = 0.0007), ABP by 7.7 +/- 6.0 mmHg (P = 0.0007), heart rate by 7.1 +/- 5.3 beats/min (P = 0.0008), and Pet(CO(2)) by -2.32 +/- 2.23 Torr (P = 0.002). For the puzzle paradigm, CBFV changed by 13.9 +/- 6.6% (right MCA, P = 0.0007) and by 11.5 +/- 6.2% (left MCA, P = 0.0007), ABP by 7.1 +/- 8.4 mmHg (P = 0.0054), heart rate by 7.9 +/- 4.6 beats/min (P = 0.0008), and Pet(CO(2)) by -2.42 +/- 2.59 Torr (P = 0.001). The word paradigm led to greater left hemispheric dominance than the right hemispheric dominance observed with the puzzle paradigm (P = 0.004). We concluded that significant changes in ABP and Pet(CO(2)) levels occur during brain activation protocols, and these contribute to the evoked change in CBFV. A pressure-autoregulatory response can be observed in addition to the hemodynamic changes induced by increases in metabolic demand. Simultaneous changes in Pco(2) and heart rate add to the complexity of the response, indicating the need for more detailed modeling and better understanding of brain activation paradigms.     

Contribution of arterial Windkessel in low-frequency cerebral hemodynamics during transient changes in blood pressure

The Windkessel properties of the vasculature are known to play a significant role in buffering arterial pulsations, but their potential importance in dampening low-frequency fluctuations in cerebral blood flow has not been clearly examined. In this study, we quantitatively assessed the contribution of arterial Windkessel (peripheral compliance and resistance) in the dynamic cerebral blood flow response to relatively large and acute changes in blood pressure. Middle cerebral artery flow velocity (MCA(V); transcranial Doppler) and arterial blood pressure were recorded from 14 healthy subjects. Low-pass-filtered pressure-flow responses (<0.15 Hz) during transient hypertension (intravenous phenylephrine) and hypotension (intravenous sodium nitroprusside) were fitted to a two-element Windkessel model. The Windkessel model was found to provide a superior goodness of fit to the MCA(V) responses during both hypertension and hypotension (R2 = 0.89 ± 0.03 and 0.85 ± 0.05, respectively), with a significant improvement in adjusted coefficients of determination (P < 0.005) compared with the single-resistance model (R2 = 0.62 ± 0.06 and 0.61 ± 0.08, respectively). No differences were found between the two interventions in the Windkessel capacitive and resistive gains, suggesting similar vascular properties during pressure rise and fall episodes. The results highlight that low-frequency cerebral hemodynamic responses to transient hypertension and hypotension may include a significant contribution from the mechanical properties of vasculature and, thus, cannot solely be attributed to the active control of vascular tone by cerebral autoregulation. The arterial Windkessel should be regarded as an important element of dynamic cerebral blood flow modulation during large and acute blood pressure perturbation.     

Cerebral hemodynamics during orthostatic stress assessed by nonlinear modeling.

The effects of orthostatic stress, induced by lower body negative pressure (LBNP), on cerebral hemodynamics were examined in a nonlinear context. Spontaneous fluctuations of beat-to-beat mean arterial blood pressure (MABP) in the finger, mean cerebral blood flow velocity (MCBFV) in the middle cerebral artery, as well as breath-by-breath end-tidal CO2 concentration (P(ET(CO2))) were measured continuously in 10 healthy subjects under resting conditions and during graded LBNP to presyncope. A two-input nonlinear Laguerre-Volterra network model was employed to study the dynamic effects of MABP and P(ET(CO2)) changes, as well as their nonlinear interactions, on MCBFV variations in the very low (VLF; below 0.04 Hz), low (LF; 0.04-0.15 Hz), and high frequency (HF; 0.15-0.30 Hz) ranges. Dynamic cerebral autoregulation was described by the model terms corresponding to MABP, whereas cerebral vasomotor reactivity was described by the model P(ET(CO2)) terms. The nonlinear model terms reduced the output prediction normalized mean square error substantially (by 15-20%) and had a prominent effect in the VLF range, both under resting conditions and during LBNP. Whereas MABP fluctuations dominated in the HF range and played a significant role in the VLF and LF ranges, changes in P(ET(CO2)) accounted for a considerable fraction of the VLF and LF MCBFV variations, especially at high LBNP levels. The magnitude of the linear and nonlinear MABP-MCBFV Volterra kernels increased substantially above -30 mmHg LBNP in the VLF range, implying impaired dynamic autoregulation. In contrast, the magnitude of the P(ET(CO2))-MCBFV kernels reduced during LBNP at all frequencies, suggesting attenuated cerebral vasomotor reactivity under dynamic conditions. We speculate that these changes may reflect a progressively reduced cerebrovascular reserve to compensate for the increasingly unstable systemic circulation during orthostatic stress that could ultimately lead to cerebral hypoperfusion and syncope.     

Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans

In humans, cerebrovascular responses to alterations in arterial Pco(2) and Po(2) are well documented. However, few studies have investigated human coronary vascular responses to alterations in blood gases. This study investigated the extent to which the cerebral and coronary vasculatures differ in their responses to euoxic hypercapnia and isocapnic hypoxia in healthy volunteers. Participants (n = 15) were tested at rest on two occasions. On the first visit, middle cerebral artery blood velocity (V(P)) was assessed using transcranial Doppler ultrasound. On the second visit, coronary sinus blood flow (CSBF) was measured using cardiac MRI. For comparison with V(P), CSBF was normalized to the rate pressure product [an index of myocardial oxygen consumption; normalized (n)CSBF]. Both testing sessions began with 5 min of euoxic [end-tidal Po(2) (Pet(O(2))) = 88 Torr] isocapnia [end-tidal Pco(2) (Pet(CO(2))) = +1 Torr above resting values]. Pet(O(2)) was next held at 88 Torr, and Pet(CO(2)) was increased to 40 and 45 Torr in 5-min increments. Participants were then returned to euoxic isocapnia for 5 min, after which Pet(O(2)) was decreased from 88 to 60, 52 and 45 Torr in 5-min decrements. Changes in V(P) and nCSBF were normalized to isocapnic euoxic conditions and indexed against Pet(CO(2)) and arterial oxyhemoglobin saturation. The V(P) gain for euoxic hypercapnia (%/Torr) was significantly higher than nCSBF (P = 0.030). Conversely, the V(P) gain for isocapnic hypoxia (%/%desaturation) was not different from nCSBF (P = 0.518). These findings demonstrate, compared with coronary circulation, that the cerebral circulation is more sensitive to hypercapnia but similarly sensitive to hypoxia.