Cerebrovascular and Cardiovascular Responses to Graded Tilt in Patients With Autonomic Failure
Background and Purpose Patients with autonomic nervous system failure often experience symptoms of orthostatic intolerance while standing. It is not known whether these episodes are caused primarily by a reduced ability to regulate arterial blood pressure or whether changes in cerebral autoregulation may also be implicated.
Methods Eleven patients and eight healthy age- and sex-matched control subjects were studied during a graded-tilt protocol. Changes in their steady state middle cerebral artery mean flow velocities (MFV), measured by transcranial Doppler, brain-level mean arterial blood pressures (MABPbrain), and the relationship between the two were assessed.
Results Significant differences between patients and control subjects (P<.05) were found in both their MFV and MABPbrain responses to tilt. Patients’ MFV dropped from 60±10.2 cm/s in the supine position to 44±14.0 cm/s at 60° head-up tilt, whereas MABPbrain fell from 109±11.7 to 42±16.9 mm Hg. By comparison, controls’ MFV dropped from 54±7.8 cm/s supine to 51±8.8 cm/s at 60°, whereas MABPbrain went from 90±11.2 to 67±8.2 mm Hg. Linear regression showed no significant difference in the MFV-MABPbrain relationship between patients and control subjects, with slopes of 0.228±0.09 cm · s–1 · mm Hg–1 for patients and 0.136±0.16 cm · s–1 · mm Hg–1 for control subjects.
Conclusions The present study found significant differences between patients and control subjects in their MFV and MABPbrain responses to tilt but no difference in the autoregulatory MFV-MABPbrain relationship. These results suggest that patients’ decreased orthostatic tolerance may primarily be the result of impaired blood pressure regulation rather than a deficiency in cerebral autoregulation.
Patients with ANS failure often are unable to maintain an upright posture without developing symptoms of orthostatic intolerance. Since these symptoms are the result of insufficient CBF, they may reflect intracranial involvement of the ANS that could cause a deficiency in cerebral autoregulation. Alternatively, since arterial blood pressure regulation is known to be compromised in ANS failure, and cerebral autoregulation functions only within certain limits of CPP (typically 60 to 140 mm Hg in healthy humans),1 it may simply be that patients’ CPPs fall to a level below that in which cerebral autoregulation is able to function, resulting in a decrease in CBF that leads to symptoms of orthostatic intolerance.
Little is known about the behavior of cerebral autoregulation in ANS failure patients, and most studies to date have been performed using nonsimultaneous measurements of CBF and blood pressure, making it difficult to establish a precise relationship between the two. These studies have produced conflicting evidence as to whether ANS failure patients autoregulate2 3 4 5 6 or do not.7 8 9 In addition, one study2 suggested that the lower limit of perfusion pressure, below which cerebral autoregulation no longer functions, may be lower in ANS failure patients than in healthy individuals, enabling them to better tolerate the low blood pressures commonly experienced by patients in the upright posture. The existence of this shift has not been proven, however, and its magnitude, if present, is not known. It is also not known whether ANS failure may result in changes in the cerebral autoregulatory response within the “plateau region” of the cerebral autoregulation curve.
In addition to possible changes in the limits of pressure in which cerebral autoregulation functions in ANS failure patients, there may be changes in the pressure-flow relationship even within the limits of autoregulation. Most studies to date have used only a single stimulus, such as HUT to a single angle,2 or rapid thigh-cuff deflation.9 These tests allow the pressure-flow relationship to be examined at only one or two “points” (eg, before and after the stimulus). Tests that allow the pressure-flow relationship to be assessed at multiple points, within and outside of the limits of cerebral autoregulation, are needed to fully establish which changes, if any, in autoregulatory response are present in ANS failure patients. Such information may help us understand the reasons for presyncopal symptoms in patients and allow us to prescribe effective countermeasures.
In the present study, patients who had been previously diagnosed with autonomic failure underwent a graded-tilt protocol at multiple tilt angles. This protocol allowed the assessment of patients at multiple levels of orthostatic stress, providing several points at which to determine their pressure-flow relationship. In addition, since patients often are unable to perform a tilt or stand test because of the onset of presyncopal symptoms, a graded tilt provides a gentler alternative that may allow testing of individuals without immediately exceeding their limit of orthostatic tolerance. Continuous, time-locked measurements of MFV in the MCA were recorded by TCD ultrasonograpy, along with MABP and end-tidal CO2. In this article, patients’ steady state responses are compared with those of an age- and sex-matched healthy control group; a comparison of these subjects’ response dynamics and their relationship to cerebral autoregulation is presented in a separate article.10 Our objective in the present study was to determine whether there are significant changes in the steady state MFV-MABP relationship in ANS failure patients, compared with the control group, that may reflect an altered cerebral autoregulatory response and contribute to symptoms of orthostatic intolerance or presyncope in the upright posture. Although we did not examine the mechanisms of cerebral autoregulation itself, our results will help determine whether or not the autoregulatory response of ANS failure patients is different from that of healthy individuals even while operating within the plateau region of the cerebral autoregulation curve.
Subjects and Methods
Eleven patients (5 men and 6 women) and 10 age- and sex-matched control subjects gave informed consent to undergo an Institutional Review Board–approved (Beth Israel Deaconess Medical Center, Boston, Mass) protocol. Subjects ranged in age from 42 to 82 years, with a mean (±SD) age of 60±10 years. Patient characteristics and medications have been previously described,11 and are summarized in Table 1⇓. Patients who were taking medication discontinued their medication at least 24 hours before testing.
Heart rate was obtained continuously from a standard 4-lead electrocardiograph (Hewlett-Packard 782036). A noninvasive finger-cuff method (Finapres 2300, Ohmeda) was used to provide beat-to-beat estimates of arterial blood pressure; this method has been shown to reliably track beat-by-beat changes in arterial pressure as used in this study.12 During the data collection period, the arm of the subject was supported at the level of the left ventricle by an armrest attached to the tilt bed, and the Finapres servo reset mechanism was turned off to permit uninterrupted observations.
During the test, MFV in the MCA was monitored continuously using TCD ultrasonography (Transpect-Medasonics). A 2-MHz pulsed Doppler probe, range-gated to a depth of 50 to 55 mm, was held in place using a lightweight Velcro headband. The signal was continually monitored to ensure optimal probe placement. The vertical distance between the blood pressure finger cuff and the TCD probe was measured to allow MABPbrain to be estimated from the Finapres measurements. Distances were measured each time the subject was tilted to a new position to correct for any slight movements of the hand or head during the tilt.
End-tidal CO2 was measured by sampling exhaled CO2 using a nasal adapter (Datex Normocap 200). Subjects were instructed to breathe through their noses whenever possible during the test, to minimize speaking except when prompted by the investigators, and to report discomfort or symptoms of presyncope.
The analog signals from these devices, along with a tilt-bed angle signal, were recorded simultaneously at 12 kHz per channel using an 8-channel digital tape recorder (TEAC RD-111T).
A motorized tilt bed was used (Ratiotrol 3530-VS, Laberne Mfg Co). The tilt bed was fitted with a footplate but not a saddle support. Subjects were instrumented in the supine position over a period of approximately 10 minutes. Immediately after instrumentation, 5 minutes of baseline data were collected in the supine position. This was followed by 5 minutes in each of the following positions: −10°, 10°, 30°, and 60°. (Data were also collected for a final tilt of −10° and a supine recovery period, but those results are not reported in this article. This article focuses on the steady state changes in cerebral autoregulation during upright tilt; the recovery phases are analyzed in our article on the response dynamics of these subjects.10 ) Subjects who became presyncopal during the protocol were returned immediately to the −10° position for 5 minutes, followed by a 5-minute supine recovery period. Blood was drawn after testing to obtain hematocrit measurements.
Data were analyzed off-line using specialized custom software on a UNIX-based workstation (SUN SPARC 2; Sun Microsystems). Fast Fourier transform methods were used to generate the peak envelope of the MCA blood flow velocity from the stored TCD audio signal.13 The peaks of the QRS complexes (R waves) in the electrocardiographic data were used to produce RR interval and its inverse, HR. The systolic blood pressures were determined from the maximum blood pressure that occurred during an RR interval. The hydrostatic pressure gradient was calculated for each tilt angle and subtracted from the blood pressure data to reference the measurements to brain level for comparison with TCD. MFV, MABPbrain, and HR were calculated on a beat-to-beat basis, and changes in downstream cerebrovascular resistance (ie, resistance vessels) were estimated as CVRest equals MABPbrain divided by MFV. Since changes in MFV track changes in CBF when MCA diameter remains constant, and changes in MABPbrain follow changes in CPP when ICP is unchanged, the changes indicated by CVRest are valid as long as changes in MCA diameter and ICP are small. End-tidal CO2 was calculated on a breath-by-breath basis.
The primary focus of our analysis was to explore the possibility of differences in the MFV-MABPbrain relationship between patients and control subjects that may lead to symptoms of orthostatic intolerance or presyncope. The slope of this relationship was therefore examined for each subject using linear regression analysis. Linear regressions were performed individually on each subject’s MFV versus MABPbrain data, using values averaged over the final 30 beats in each tilt position. Slopes were determined both over the entire range of blood pressure responses and over a range that was limited to the blood pressures experienced by the control subjects (65 to 95 mm Hg). The latter allowed the MFV-MABPbrain relationships to be compared at blood pressure levels that were experienced by both the patient and control groups, rather than comparing the relatively narrow range of control subjects’ blood pressures with the patients who, because of ANS failure, experienced a much wider range of blood pressure values in response to tilt (Fig 1⇓). A steeper slope with this method of analysis would imply a greater change in MFV for a given change in MABPbrain and suggest a less effective, or impaired, cerebral autoregulation. In contrast, a flatter slope would suggest a reduced influence of changes in MABPbrain on MFV and therefore more effective autoregulation. Thus, a comparison of regression slopes between patients and control subjects would indicate whether or not there were differences in the pressure-flow relationship between the two groups.
For the final 2 minutes of each tilt position, spontaneous baroreflex response was determined from beat-to-beat changes in RR interval and systolic arterial pressure as described by Blaber et al.14 15 With this method, specific selection criteria14 are used to observe sequences of three or more beats in which systolic arterial blood pressure and the RR interval changed in the same direction (either increasing or decreasing). In previous studies14 15 it was demonstrated that the spontaneous baroreflex response represented physiological rather than chance events and that this relationship remained intact when the RR interval was changed by lower body negative pressure.
Data were grouped by averaging each variable over the final 30 beats in each tilt position (except for the spontaneous baroreflex, which spanned the final 2 minutes of each position as described above). All statistical analyses were performed using the statistical package SigmaStat (Jandel Scientific). Statistical analysis of variables across the tilt levels (baseline, −10°, 10°, 30°, and 60°), comparing patients with age-matched healthy control subjects, was performed using a two-way repeated measures ANOVA. In all tests, if main effects (P<.05) were detected, subsequent post hoc analysis using a Student-Newman-Keuls test was performed. Slope data were compared using Student’s t test or an equivalent nonparametric test (Mann-Whitney). Comparison of hematocrit values between the patient and control groups was performed using a t test. All data are quoted as mean±SD.
All of the control subjects and 9 of 11 patients completed the test without becoming presyncopal. The remaining 2 patients (patients 10 and 11) became presyncopal during the 30° and 60° HUT segments, respectively. Two control subjects were excluded from the analysis because their blood pressure measurements were of poor quality.
A summary of MFV, MABPbrain, CVRest, end-tidal CO2, and HR results from one typical control subject, a typical non–presyncopal patient, and the two presyncopal patients is presented in Fig 2⇓. Baseline MABPbrain was significantly higher in the patients (108.7±12 mm Hg) than the control subjects (90.0±11 mm Hg), but baseline HR (68.9±8 versus 69.9±11 beats/min), MFV (54.2±8 versus 60.0±10 cm/s), CVRest (1.75±0.5 versus 1.88±0.5 mm Hg · cm–1 · s), and end-tidal CO2 (6.09±0.4% versus 6.04±0.6%) values were not significantly different between control subjects and patients, respectively. As predicted, however, there were significant differences between responses to tilt from control subjects and patients (Fig 3⇓).
Of all the variables measured, only the HR response (Fig 3⇑) was the same between the two groups throughout the test. There was a significant increase in HR with tilt in both control subjects and patients (P<.001), with the HR at 60° significantly greater than baseline. The response of MABPbrain to tilt was significantly different between the control subjects and patients (P<.04); post hoc analysis showed that control subjects’ MABPbrain was not significantly affected by tilt until the 30° HUT position; however, there was a significant decrease in MABPbrain in patients beginning at 10° HUT (Fig 3⇑). In the −10° position, patients’ MABPbrain was significantly greater than that of the control subjects, and at the greatest HUT position (60°) the MABPbrain was significantly less than in the control subjects (Fig 3⇑).
MFV in the control subjects was not significantly affected by tilt, and changes in CVRest followed those in MABPbrain. In the patients, however, a downward trend was observed in MFV with increasing tilt angles, and changes in CVRest were more pronounced than those in the control subjects (Fig 3⇑). Patients had a significant decrease in CVRest in the 10°, 30°, and 60° HUT positions (P<.05), whereas control subjects showed a significant decrease from baseline only at 60° HUT. Patients’ CVRest was significantly lower than control subjects’ CVRest in the 60° HUT position.
The spontaneous baroreflex response showed a trend (P=.08) toward being reduced in the patients (4.15±4.4 ms/mm Hg) compared with that in the control subjects (6.65±3.0 ms/mm Hg) when averaged over all of the tilt positions (Fig 4⇓), and both decreased significantly from supine to 60° HUT (P<.001). As can be seen from Fig 4⇓, the presyncopal patients had a lower spontaneous baroreflex than either the control subjects or the patient group as a whole.
The responses of the two presyncopal patients were different from one another. Patient No. 11, who was presyncopal in the 60° position, had MABPbrain values that were within 1 SD of the non-presyncopal patients’ values at each tilt position. Although MFV and CO2 were both below average at each position, including baseline, they were maintained at a reasonably constant level until presyncope, when both dropped. Patient No. 10, on the other hand, who was presyncopal during the 30° tilt, had consistently falling MABPbrain, MFV, and CO2 responses with increasing tilt angles. In both cases, rapid drops in MFV occurred just before presyncope, beginning at MABPbrain levels between 50 and 60 mm Hg (often, the corresponding fall in MABPbrain was so rapid that no intermediate values within this range were obtained, even on a beat-to-beat basis).
Results of the linear regression analysis of the relationship between MFV and MABPbrain in patients and control subjects are presented in Table 2⇓. Each “point” on the regression line represented the average of the final 30 seconds of data in each tilt position. The overall slope of the patients (0.228±0.09 cm · s–1 · mm Hg–1) was not different from that of the control subjects (0.136±0.16 cm · s–1 · mm Hg–1). Slopes within the MABPbrain range of 65 to 95 mm Hg showed the same trend (0.273±0.21 cm · s–1 · mm Hg–1 for patients versus 0.176±0.20 cm · s–1 · mm Hg–1 for control subjects), and were not significantly different from the slopes obtained when all of the data points were used. In many cases, these slopes were based on a smaller number of points than the overall slopes were, even for the control subjects, since blood pressures were either above 95 mm Hg at baseline or below 65 mm Hg at 60° HUT.
End-tidal CO2 levels were not significantly different between patients and control subjects at any tilt level; however, patients’ end-tidal CO2 decreased significantly from baseline at 60° HUT (P<.05). Respiratory rate also was not different between patients and control subjects, and did not change with tilt angle in either group (Fig 5⇓). Hematocrit levels were not different between the two groups (0.41±0.03 for control subjects versus 0.40±0.04 for patients).
Autonomic failure is caused by dysfunction of the peripheral and/or central ANS. The most striking clinical manifestations are orthostatic hypotension and loss of normal autonomic reflexes. In the present study, although only two patients became presyncopal during the test, differences were seen even in the responses of the non-presyncopal patients compared with the control subjects.
Control Subjects Versus ANS Failure Patients
We have previously shown an impaired ability to regulate MABPbrain in these patients,11 which is consistent with the reduced spontaneous baroreflex values seen here. The present study revealed marked differences between the MABPbrain responses of patients and control subjects. Compared with control subjects, the patients had a much wider blood pressure variation from baseline, with pressures significantly below baseline level at each of the HUT positions. These data confirm the expected findings of impaired blood pressure regulation with ANS failure. It is also interesting that despite the large differences in MABPbrain, HR responded similarly in both the patients and control subjects. Clearly, this response was inappropriate for the patients, whose larger drops in blood pressure during HUT would be expected to evoke a greater HR response. The reduced spontaneous baroreflex response we observed in the patients is consistent with previous suggestions of an impaired baroreflex response in ANS failure,16 and may in part explain the HR and MABPbrain trends we observed.
In addition to these findings, the MFV data also showed significant differences between the patient and control groups, despite the fact that end-tidal CO2 responses, which are known to influence MFV,1 were similar. For the control subjects, MFV remained nearly constant across all tilt angles. This is reflected in the CVRest plot (Fig 3⇑), which shows decreasing CVRest with increasing tilt angles corresponding to decreases in MABPbrain. This behavior agrees with the classic theory of cerebral autoregulation, which predicts dilatation of the downstream resistance vessels, and therefore decreased resistance, in response to a decreasing perfusion pressure. In patients, MFV and MABPbrain both declined steadily with increasing tilt angles; however, CVRest, which is defined as MABPbrain divided by MFV, again decreased, indicating that MFV was still dropping relatively less than MABPbrain. As with the control subjects, this response is consistent with a functioning autoregulation mechanism. The greater decrease in patients’ CVRest compared with that in control subjects at 60° HUT suggests that, as expected, cerebral autoregulation is responding to the larger decrease in perfusion pressure in these subjects by lowering the resistance of the cerebral vessels by a greater amount. Despite this, autoregulation is unable to maintain the MFV at a constant level. These results indicate clear differences between the patients’ and control subjects’ MFV responses to tilt; the question that must now be addressed is whether these differences are caused solely by the differences in MABPbrain experienced by these subjects, or whether a change in cerebral autoregulation may also be implicated.
Linear regression analysis was performed on the data from each subject to attempt to answer this question, comparing the slopes of the MFV-MABP relationships of patients against those of the control subjects. One would expect that with a functioning cerebral autoregulation mechanism, changes in the steady state level of MFV would be minimal in response to changes in MABPbrain, resulting in a relatively low regression slope. Therefore, an increase in slope may indicate a reduced capacity to regulate CBF in the face of pressure changes. Although the present study revealed a trend toward increased slopes in patients relative to control subjects, the difference was not significant in our study. In fact, there was variability in slope values even within each group (Table 2⇑).
A variety of factors may help explain this variability. For example, we know that there were changes in end-tidal CO2 in some subjects during tilt. Arterial Pco2 is a potent vasodilator that can cause changes in CBF that are independent of perfusion pressure. For example, a decrease in Pco2 results in vasoconstriction of the resistance vessels, and hence a lowering of the level of CBF (ie, the autoregulatory set point) for a given level of CPP. Although methods of correcting MFV to a fixed level of CO2 have been proposed, they are not reliable under conditions of low perfusion pressure such as those in the present study.17 Even though changes in CO2 may help explain some of the subject-to-subject variability, it is important to be mindful that the overall CO2 response to tilt was similar between patients and control subjects and therefore should not affect the comparison between the two groups.
The existence of very low or negative slope values (control subject Nos. 1, 8, and 9) seems unusual; however, this occurred only when variations in MFV were very small (less than 5 cm/s). Changes of this magnitude may be the result of low-frequency oscillations that are known to occur in MFV, such as those caused by B-waves or respiratory related changes,18 not autoregulation. It is difficult, therefore, to interpret the slopes resulting from such small MFV changes in the context of cerebral autoregulation.
One potential problem with performing a linear regression analysis on the patients’ data is that in many cases the patients experienced large drops in perfusion pressure suddenly when tilting from one position to another, creating large gaps on the blood pressure axis between points. Furthermore, it is possible, particularly at larger angles of HUT, that perfusion pressure may actually be below the lower limit of cerebral autoregulation in these subjects. If these points are included in the calculation of the regression slope, it would corrupt the comparison between patients and control subjects, since we are comparing the results of the patients to those of the control subjects, whose blood pressure values remained within the limits of cerebral autoregulation at all times. Therefore, to verify our results, we performed a second set of linear regressions, using only the data points for which blood pressures were similar between both the patients and the control subjects. This ensured that both patients and control subjects were within the limits of cerebral autoregulation for this part of the analysis. Slopes obtained in this manner were very similar to the slopes we had calculated when all of the data points were used (Table 2⇑), suggesting no significant differences in the plateau region of cerebral autoregulation between patients and control subjects.
The impaired regulation of MABPbrain observed in the non-presyncopal patients was even more evident in the patients who became presyncopal during HUT. Although their baseline MABPbrain levels (116 and 112 mm Hg) were almost the same as the non-presyncopal patients’ average baseline MABPbrain (108±13 mm Hg), the presyncopal patients’ pressures were below the overall patients’ averages in each of the HUT positions (Fig 3⇑). Both MABPbrain and MFV dropped noticeably immediately before presyncope.
Classic cerebral autoregulation theory suggests that cerebrovascular resistance must decrease to maintain adequate flow in the face of the drop in MABPbrain induced by HUT. As with all of our other subjects, both presyncopal patients showed this decreasing trend in CVRest, suggesting the presence of a functioning cerebral autoregulation mechanism in these patients. Clearly, however, the change in resistance was not adequate to allow CBF to be maintained above presyncopal levels. It is possible that the resistance vessels in these subjects reached their maximum dilatation at, or just before, presyncope, as is the case on the left-hand side of the autoregulation curve.
In both presyncopal subjects, MABPbrain was well below 60 mm Hg, the level normally associated with CPP at the lower limit of cerebral autoregulation,1 when the test was stopped because of impending syncope. However, sudden, simultaneous drops in MFV and MABPbrain began occurring at MABPbrain levels between 50 and 60 mm Hg. These results may suggest a slightly lower-than-normal lower limit of autoregulation in the patients, consistent with a previous ANS failure study2 ; however, our data do not provide sufficient evidence to definitely conclude whether or not this is the case. It is also important to remember that the measurements of MABPbrain were derived from Finapres readings that, although following pressure trends reliably, do not always provide accurate absolute measurements when compared with intra-arterial lines.19
The present study used TCD ultrasonography, a noninvasive ultrasound method of estimating changes in CBF in the territory of the insonated vessel. However, this method does not measure flow directly but instead measures flow velocity. The relationship between the velocity changes measured and changes in actual CBF depends on the diameter of the insonated vessel. A decrease in diameter will result in an increase in the velocity measured; whereas an increase in diameter will have the opposite effect, assuming that the actual flow level remains unchanged. Changes in velocity can only be equated to changes in flow, then, if changes in the diameter of the insonated vessel, in this case the MCA, are minimal. This is not to be confused with the fact that downstream peripheral resistance vessels may change diameter, for example with autoregulation, which will in turn affect flow—and hence flow velocity—in the insonated vessel. Such changes do not result in erroneous flow velocity readings, since they reflect actual changes in flow.
Changes in MCA diameter were not measured in the present study because no reliable noninvasive technique existed for doing this at the time this study was done. However, previous studies in which invasive techniques were used have shown minimal changes in MCA diameter under a variety of conditions known to affect cerebral perfusion,20 21 22 23 and have validated the use of TCD ultrasonography to estimate changes in MCA flow.20 21 22 This study presents a situation similar to that in a previous study in our laboratory based on lower body negative pressure24 ; since a decrease in MFV was observed with HUT, this could only be explained in two ways: Either blood flow in the territory of the MCA decreased or the diameter of the MCA increased. Previous studies have found an increase in sympathetic activity with HUT,25 which if anything may cause some vasoconstriction, not dilatation, of the large cerebral conductance vessels.26 Although this increase in sympathetic activity may have been reduced or even absent in patients, they would most likely also have experienced a drop in MCA blood flow, given the severe drop in arterial perfusion pressure observed during HUT. The presyncopal episodes experienced by two of our patients further support the concept of a reduced MCA flow. We believe therefore that changes in MCA caliber are likely to be minimal but that even if such changes did take place they would not have adversely affected our interpretation of the fall in MFV as a fall in actual MCA blood flow during HUT.
The other methodological consideration deals with the use of changes in MABPbrain to represent changes in CPP. Since CPP equals MABPbrain minus ICP, our method of using changes in MABPbrain to examine changes in CPP is valid only if changes in ICP are minimal. (Indeed, drops in ICP of approximately the same magnitude as those in MABPbrain would indicate that there was in fact little or no change in actual CPP.) Although changes in ICP cannot be measured noninvasively, and therefore were not measured in the present study, the validity of assuming minimal ICP changes during HUT has been demonstrated by Rosner and Coley,27 who showed a drop in ICP of only 1 mm Hg for every 10° of HUT. This drop is much less than the MABPbrain changes we observed, and its effect on CPP would be quite small. Therefore, although the actual changes in CPP may be slightly smaller than the changes we report in MABPbrain during tilt, the difference between them is minimal. More importantly, since ICP changes during HUT are thought not to be mediated by the ANS,27 any changes in ICP should have had the same effect on both the patient and control groups, and hence our comparison of the two groups would be valid.
In conclusion, as expected the present study found significant differences between our ANS failure patients and the age- and sex-matched control subjects in their steady state MFV and MABPbrain responses to tilt. However, our study did not indicate any significant differences in the relationship between MFV and MABPbrain for the patients, either presyncopal or non-presyncopal, compared with the control subjects. The slope and CVRest results both suggested that cerebral autoregulation was functioning in patients and control subjects and that their behavior in the “plateau” region of the curve was similar. Therefore, our results agree with previous studies that found that cerebral autoregulation continues to function in ANS failure patients,2 3 4 5 6 rather than those that found an absence of cerebral autoregulation.7 8 9 However, differences in the MABPbrain responses of patients and control subjects make it difficult to determine whether or not patients’ autoregulation was entirely “normal.” Differences in the MFV response of patients, compared with control subjects, were most likely because of the patients’ greater MABPbrain decrease with tilt rather than a change in the behavior of cerebral autoregulation.
This study provided evidence that suggests that the patients who were presyncopal may have been operating on the left-hand side of the cerebral autoregulation curve, at pressures below the lower limit of autoregulation, when they became presyncopal. Thus, their presyncopal episodes may have been caused primarily by poor MABP regulation rather than inadequate cerebral autoregulation. Although it is possible that the limits of autoregulation may have shifted in the patient group, the present study was not able to provide any conclusive evidence that a lowering of the lower limit of cerebral autoregulation had occurred in patients. Although we cannot rule out the possibility that some changes in cerebral autoregulation may also have taken place, it appears that a primary goal in the treatment of ANS failure patients should be to find ways to limit the fall in CPP in the upright position.
Selected Abbreviations and Acronyms
|ANS||=||autonomic nervous system|
|CBF||=||cerebral blood flow|
|CPP||=||cerebral perfusion pressure|
|CVRest||=||estimated cerebrovascular resistance|
|MABP||=||mean arterial blood pressure|
|MABPbrain||=||brain-level mean arterial blood pressures|
|MCA||=||middle cerebral artery|
|MFV||=||mean flow velocities|
|TCD||=||transcranial Doppler ultrasonography|
This research was supported by a joint Natural Sciences and Engineering Research Council of Canada, Medical Research Council, Canadian Space Agency grant under NSERC file #669-008-93 (R.L.B.) and by grant FD-R-000393 from the Public Health Service (R.F.).
Reprint requests to Dr Roy Freeman, The Autonomic and Peripheral Nerve Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center—West Campus, 110 Francis St, Boston, MA 02215.
- Received February 11, 1997.
- Revision received May 8, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
Skinhoj E, Olesen J, Strandgaard S. Brain and Blood Flow. London, UK: Pitman; 1971:351-353.
Caronna JJ, Plum F. Cerebrovascular regulation in preganglionic and postganglionic autonomic insufficiency. Stroke. 1973;4:12-19.
Brooks DJ, Redmond S, Mathias CJ, Bannister R, Symon L. The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure, with observations on the action of ephedrine. J Neurol Neurosurg Psychiatry. 1989;52:962-966.
Meyer JS, Shimazu K, Fukuuchi Y, Ohuchi T, Okamoto S, Koto A, Ericsson AD. Cerebral dysautoregulation in central neurogenic orthostatic hypotension (Shy-Drager syndrome). Neurology. 1973;23:262-273.
Shinohara Y, Gotoh F, Takagi S. Cerebral hemodynamics in Shy-Drager syndrome: variability of cerebral blood flow dysautoregulation and the compensatory role of chemical control in dysautoregulation. Stroke. 1978;9:504-508.
Lagi A, Bacalli S, Cencetti S, Paggetti C, Colzi L. Cerebral autoregulation in orthostatic hypotension: a transcranial Doppler study. Stroke. 1994;25:1771-1775.
Blaber AP, Bondar RL, Stein F, Dunphy PT, Moradshahi P, Kassam MS, Freeman R. Transfer function analysis of cerebral autoregulation dynamics in autonomic failure patients. Stroke. 1997;28:1686-1692.
Blaber AP, Bondar RL, Freeman R. Coarse graining spectral analysis of heart rate and blood pressure variability in patients with autonomic failure. Am J Physiol. 1996;271:H1555-H1564.
Omboni S, Parati G, Frattola A, Mutti E, Dirienzo M, Castiglioni P, Mancia G. Spectral and sequence analysis of finger blood pressure variability: comparison with analysis of intra-arterial recordings. Hypertension. 1993;22:26-33.
Kassam M, Bondar RL, Johnston KW, Cobbold RSC, Vaitkus PJ, Stein F, Dunphy PT. Transcranial Doppler ultrasound studies of cerebral blood-flow in microgravity: technical issues, analysis and results. In: Proceedings of the Second Workshop on Microgravity Experimentation, Canadian Space Agency; Ottawa. 1990:131-138.
Blaber AP, Yamamoto Y, Hughson RL. Methodology of spontaneous baroreflex relationship assessed by surrogate data analysis. Am J Physiol. 1995;268:H1682-H1687.
Blaber AP, Yamamoto Y, Hughson RL. Change in phase relationship between SBP and R-R interval during lower body negative pressure. Am J Physiol. 1995;268:H1688-H1693.
Stokes DN, Clutton-Brock T, Patil C, Thomson JM, Hutton P. Comparison of invasive and non-invasive measurement of continuous arterial pressure using the Finapres. Br J Anaesth. 1991;67:26-35.
Newell DW, Aaslid R, Lam A, Mayberg TS, Winn HR. Comparison of flow and velocity during dynamic autoregulation testing in humans. Stroke. 1994;25:793-797.
Lindegaard K, Lundar T, Wiberg J, Sjoberg D, Aaslid R, Nornes H. Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements. Stroke. 1987;18:1025-1030.
Bondar RL, Kassam MS, Stein F, Dunphy PT, Fortney S, Riedesel ML. Simultaneous cerebrovascular and cardiovascular responses during presyncope. Stroke. 1995;26:1794-1800.
Baumbach GL, Heistad DD. Effects of sympathetic stimulation and changes in arterial pressure on segmental resistance of cerebral vessels in rabbits and cats. Circ Res. 1983;52:527-533.