Simultaneous Cerebrovascular and Cardiovascular Responses During Presyncope
Background and Purpose Presyncope, characterized by symptoms and signs indicative of imminent syncope, can be aborted in many situations before loss of consciousness occurs. The plasticity of cerebral autoregulation in healthy humans and its behavior during this syncopal prodrome are unclear, although systemic hemodynamic instability has been suggested as a key factor in the precipitation of syncope. Using lower body negative pressure (LBNP) to simulate central hypovolemia, we previously observed falling mean flow velocities (MFVs) with maintained mean arterial blood pressure (MABP). These findings, and recent reports suggesting increased vascular tone within the cerebral vasculature at presyncope, cannot be explained by the classic static cerebral autoregulation curve; neither can they be totally explained by a recent suggestion of a rightward shift in this curve.
Methods Four male and five female healthy volunteers were exposed to presyncopal LBNP to evaluate their cerebrovascular and cardiovascular responses by use of continuous acquisition of MFV from the right middle cerebral artery with transcranial Doppler sonography, MABP (Finapres), and heart rate (ECG).
Results At presyncope, MFV dropped on average by 27.3±14% of its baseline value (P<.05), while MABP remained at 2.0±27% above its baseline level. Estimated cerebrovascular resistance increased during LBNP. The percentage change from baseline to presyncope in MFV and MABP revealed consistent decreases in MFV before MABP.
Conclusions Increased estimated cerebrovascular resistance, falling MFV, and constant MABP are evidence of an increase in cerebral vascular tone with falling flow, suggesting a downward shift in the cerebral autoregulation curve. Cerebral vessels may have a differential sensitivity to sympathetic drive or more than one type of sympathetic innervation. Future work to induce dynamic changes in MABP during LBNP may help in assessing the plasticity of the cerebral autoregulation mechanism.
The regulation of cerebral blood flow ensures that fluctuations of BP and flow are changed to a relatively constant level of perfusion and flow within the cerebral capillaries,1 through as yet unclarified mechanisms such as myogenic,2 metabolic,3 4 5 6 7 or neurogenic pathways.8 Orthostatic stress, such as that induced by LBNP, provides a challenge that allows the assessment of the cerebral autoregulatory response. In a previous study of simulated central hypovolemia induced by LBNP, we observed that MCA MFVs fell while MABP remained constant.9 Subsequently, in a study that was not intended to be of presyncope but in which some subjects became presyncopal, other researchers documented increased CVR with falling MFV during LBNP.10 This had also been noted during a tilt-bed protocol,11 suggesting that vasoconstriction rather than vasodilation occurs at presyncope. It was postulated that the increased sympathetic stimulation of cerebral vessels and subsequent vasoconstriction could override compensatory vasodilation and could shift the cerebral autoregulation curve to the right to account for falling MFV. Although a rightward shift in the curve could cause the lower limit of autoregulation to be reached at higher-than-expected levels of MABP, drops in MFV would still occur only in response to falling levels of MABP.
The objective of this study was to induce presyncope in healthy human subjects, both to confirm the results of previous studies and to help clarify the mechanism of the observed responses. We hypothesized that falling MFV would be observed consistently during LBNP, even in the absence of falling MABP, and that CVR would increase toward presyncope. We further postulated that this response may be due to a downward shift of the cerebral autoregulation curve. Expanding on previous studies with TCD, we used time-locked data to review the relationship between MFV and MABP in presyncope induced by simulated central hypovolemia, created by offloading both arterial baroreceptors and extra-arterial cardiopulmonary mechanoreceptors during high levels of LBNP. These data permitted us to observe changes in the pressure-flow relationship that may have resulted from a shift in the classic cerebral autoregulation curve.
Materials and Methods
Nine healthy volunteers, four men and five women aged 18 to 47 years, gave informed consent to undergo the Institutional Review Board–approved protocol for a presyncopal LBNP test in the supine position. Female subjects were not taking oral contraceptives, and pregnancy testing done before the study was negative in all five subjects. Initial instrumentation after the supine position was attained preceded 10 minutes of rest before baseline data were acquired. MFVs in the MCA were obtained with a 2-MHz pulsed flat TCD probe (Medasonics) through ultrasonic gel over the right temporal bone. The signal was range-gated to a depth that was consistent in each subject (45 to 55 mm). After the optimum signal was achieved, a plastic foam-lined headband with the attached probe was secured for the remainder of the test. Arterial BPs were obtained once per minute by standard sphygmomanometer on the right arm and continuously by a finger cuff on the left middle finger (Finapres, Ohmeda), which was maintained at heart level. A standard four-lead ECG provided HR data, and a pressure transducer registered LBNP box pressure. All data except manual arterial BP were recorded onto digital tape (TEAC) continuously and simultaneously for off-line analysis.
Baseline data were obtained during the last 5 minutes of the 15 minutes of rest in the control period, after which the LBNP box pressure was lowered to provide a 3-minute level of −20 mm Hg. At the end of this 3-minute period, the box pressure was lowered to −40 mm Hg for 3 minutes. This procedure continued, with lowering of the pressure in increments of 10 mm Hg at 3-minute intervals thereafter, until the test was aborted because of objective signs or subjective symptoms of presyncope. Syncope is the relatively abrupt episodic loss of consciousness and postural tone that is due to a diminished flow of blood to the brain, whereas presyncope, the state preceding syncope, is characterized by a variety of clinical manifestations with a variable duration of signs and symptoms.12 Given the variability in signs and symptoms between subjects and because signs and symptoms of presyncope during LBNP can progress rapidly to cardiac sinus arrest,13 the following criteria were adopted as end points to the presyncopal test: a decrease in HR of more than 15 beats per minute, a decrease in systolic BP of more than 25 mm Hg/min or a decrease in diastolic BP of more than 15 mm Hg/min, lightheadedness, or nausea. The tests also could be aborted upon subject request.
Off-line data analysis was performed on computer workstations with customized data analysis software.14 The peak velocity envelope of the TCD waveform was used to represent the instantaneous blood flow velocity in the MCA.15 All signals were displayed simultaneously, beat by beat, for examination of the relationship between changes in BP and flow velocity. Any artifacts appearing in the data (eg, those due to subject stimulation or movement or to equipment calibration) were removed to avoid contamination of statistical results.
The true mean values of the velocity and arterial BP waveforms were determined on a cardiac cycle–by–cardiac cycle basis, and instantaneous HR was derived from the RR interval of the ECG signal. Regional CVR in the distribution of the MCA was estimated as CVRest=MABP÷MFV. Although CVR is normally defined as the ratio of CPP to CBF, where CPP=MABP−ICP and CBF=MFV×MCAcs, this estimate should reflect the changes in the true regional CVR,16 because the changes in ICP and MCA vessel caliber are expected to be small during LBNP.10
After the beat-to-beat data were examined, each subject’s static response was summarized by averaging of MFV, MABP, HR, and CVRest over the last five beats at each box pressure level and at baseline. Segments immediately preceding the change in box pressure were chosen to allow the maximum time for the subjects’ responses to stabilize after the box pressure transition. The brief averaging period allowed us to smooth out transient beat-to-beat variations in the responses while maintaining adequate time resolution to follow the brief and sudden changes that appeared at the onset of presyncope. The averages were expressed as percentage changes from baseline to facilitate subject-to-subject comparisons and grouped by LBNP box pressure levels relative to each subject’s final box pressure. Groups comprised data from the final box pressure (presyncopal) and from box pressures 10, 20, and 30 mm Hg before the final box pressure level. Data were not grouped according to absolute box pressures because our objective was to compare the physiological responses at the presyncopal end point from subject to subject rather than to assess the maximal level of LBNP tolerated.
Statistical analysis consisted of a repeated-measures ANOVA with a Student-Newman-Keuls test for multiple comparisons. Data that did not satisfy the criteria of normality and equal variance (percentage change in MABP and HR) were tested with a Friedman repeated-measures ANOVA on ranks. Tests were performed separately on HR, MABP, and MFV measurements. Data are presented as mean±SD and levels of P<.05 are considered significant.
All nine subjects satisfied the criteria for presyncope as defined in our protocol. Presyncopal box pressure levels ranged from −50 to −130 mm Hg. Figs 1⇓ and 2⇓ present typical examples of the beat-to-beat data obtained during a complete LBNP test. In both subjects whose data are shown, HR remained near baseline levels in the early part of the test and then increased steadily until presyncope, with a sudden drop in HR occurring immediately before box pressure release. Although this gradual rise in HR was observed in all subjects during LBNP, the drop in HR at presyncope was seen in only seven subjects.
For the subject whose data are shown in Fig 1⇑, MABP remained reasonably constant until presyncope, at which point it began to fall. Fig 2⇑, however, shows MABP in another subject increasing gradually during LBNP, with no sudden drop in BP at the end of the test. Overall, four subjects had rising MABPs with increasing LBNPs, whereas the remaining five subjects had MABPs that remained reasonably constant until presyncope. These trends were also confirmed by the manual BP readings. At presyncope, six subjects experienced a sudden drop in BP from pre-presyncopal levels that was similar to that seen in Fig 1⇑. MABP did not always drop to below baseline levels, however, because in many cases MABP fell from an already elevated state. MABP remained above baseline levels at presyncope in four of the nine subjects.
MFV showed a consistent decreasing trend in all subjects, particularly at greater levels of LBNP. At presyncope, MFV was always below baseline levels. Regional CVRest always increased at higher levels of negative pressure.
Percentage change data averaged at box pressures relative to presyncope are illustrated in Fig 3⇓, and the corresponding numerical values are presented in the Table⇓ (all BP values are derived from the Finapres readings). The trends in the data are similar to those in Figs 1⇑ and 2⇑, with HR increasing, MABP remaining above baseline (on average), and MFV decreasing as box pressure was lowered. At presyncope, MFV had dropped by 27.3±14% of its baseline level, MABP had increased by 2.0±27%, and regional CVRest had increased by 36.4±12% over baseline values. Although most subjects experienced a drop in HR from its peak value at presyncope, we observed an average increase at presyncope of 74.9±50% over baseline levels.
Statistical analysis indicated that MFV was significantly lower than baseline at box pressures 10 and 20 mm Hg before presyncope and at presyncope (P<.05), even though MABP did not change significantly from baseline at any box pressure level. Standard deviations for MFV were smaller than for MABP, indicating that MFV had a more consistent response than MABP as presyncope was approached. Regional CVRest was significantly higher than baseline at 10, 20, and 30 mm Hg before presyncope and at presyncope. HRs were significantly higher than baseline at box pressures 10 and 20 mm Hg before presyncope, as well as at presyncope.
LBNP is used to simulate a central hypovolemic state in which the response of arterial baroreceptor and extra-arterial cardiopulmonary mechanoreceptor reflexes can be studied. The arterial baroreceptors are deactivated at larger LBNP pressures, whereas extra-arterial, or cardiopulmonary, mechanoreceptors mediate reflex changes by reduced afferent activity at both low and high negative pressures.17 18 For example, at low LBNP pressures (less than −20 mm Hg), HR and BP do not change significantly even in the presence of a decrease in central venous pressure17 19 and left atrial diameter.20 At LBNP pressures more negative than −20 mm Hg, however, HR increases and arterial pressure decreases in response to further lowering of central blood volume.13 21 Individual HR responses depend on the amount of the negative pressure used, and not the duration, for exposures of more than 1 or 2 minutes.22 The present study was designed to use LBNP to simulate a large enough decrease in central blood volume to unload both arterial and extra-arterial receptors to provide variations in HR and BP in order to evaluate the cerebral autoregulatory response.
Pooling of blood during LBNP of −30 to −50 mm Hg has been estimated at between 0.5 to 1.0 L throughout all areas of the lower body under LBNP stress.18 This reduction in effective blood volume through pooling decreases venous return with low end-diastolic volume and heart size.23 The compensatory rise in HR and peripheral resistance to maintain cardiac output eventually are ineffective as a critical level of venous pooling is reached. Tension receptors in the left ventricular wall fire to trigger a vasodepressor response.
Because of caliber changes in cerebral resistance vessels, the traditional cerebral autoregulation curve does not follow a linear pressure-flow relationship throughout the entire pressure range. Instead, the cerebral autoregulation mechanism normally maintains a fairly constant level of CBF within a range of BPs of approximately 50 to 140 mm Hg.1 24 This regulation can shift, however, in pathological states such as untreated hypertension, with an individual tolerating higher BPs but not lower BPs.4 The lower limit also can be reduced in patients with failure of the autonomic nervous system,5 whereas sympathetic overactivity in acute hemorrhage increases this lower limit.8 Shifting the limits of the cerebral autoregulation plateau to the right, as in hypertension, or to the left, as in autonomic failure, reflects flexibility and plasticity in this physiological system.
Importance of Time-Locked Data
The relationship between CBF and systemic pressure is critical to any study of the behavior of the cerebral autoregulation mechanism, but there are inherent limitations in the methods of data acquisition commonly used. Noninvasive BP measurements are traditionally performed with a standard sphygmomanometer or servo-controlled arm-cuff system. Data obtained in this manner are not continuous, because each measurement is taken over a number of cardiac cycles. In addition, early TCD monitors displayed flow velocities averaged over several cardiac cycles. It is impossible to relate individual BP and blood flow measurements to one another when these methods are used, because they are not based on the same set of cardiac cycles. The use of continuous, time-locked data collection and analysis, however, enabled us to relate simultaneous BP and blood flow measurements on a beat-by-beat basis. In addition, continuous collection of all waveforms throughout the duration of the test ensured that no important data points were lost. Averaging periods for steady state analysis could be chosen during the analysis stage, with a priori knowledge of the data trends, thus providing a greater appreciation of the implications in interpreting the averaged data. Even when the data were averaged, we were able to examine the pressure-flow relationship with confidence, because the averages of MABP and MFV were based on precisely the same set of cardiac cycles. This type of continuous, time-locked data collection will be required for an accurate study of cerebral autoregulatory dynamics.
Limitations of Averaged Data
The static responses of the subjects were based on data averaged over the last five cardiac cycles of each test segment. Because the tests were aborted at the first sign or symptom of presyncope, the averaging period was kept short to avoid masking of the few beats comprising the presyncopal response among the comparatively large number of cardiac cycles recorded before presyncope. Slow, oscillatory fluctuations known to be synchronous with B waves of intracranial pressure25 26 were observed in the continuous recordings of both MABP and MFV. Because the period of these oscillations was greater than five beats, the subject-to-subject variations may be exaggerated, since a given data point may have been taken during an oscillatory peak in some subjects and an oscillatory trough in others. This may have resulted in larger standard deviations when the data were grouped across all subjects. We believe, however, that the trends in the averaged data presented accurately reflect the overall response of the subjects to LBNP.
Validity of the TCD Method
TCD ultrasound noninvasively measures the velocity of blood flowing in the vessel under insonation. In studies of cerebral autoregulation, it is the level of blood flow, not the velocity, that is of interest. Because blood flow is the product of blood velocity and the cross-sectional area of the vessel, the validity of inferring changes in flow from changes in velocity depends on the likelihood of changes occurring in the caliber of the insonated vessel during testing. An increase in the diameter of the insonated vessel would result in a decrease in velocity and a decrease in diameter would result in an increase in velocity, even if the actual level of CBF did not change. However, several investigators have compared the response of MCA velocities measured by TCD against invasive blood flow measurements during a variety of stimuli and have found a very strong correlation.15 Because in general the change in the MCA diameter is thought to be minimal (less than 4%),27 28 29 it seems reasonable to conclude that TCD should be an appropriate method of examining MCA flow changes during orthostatic stress.
In the present study, we observed decreasing MFV with LBNP. On the basis of the foregoing explanation, two possibilities could account for these findings: a decrease in CBF and/or an increase in MCA diameter. As stated previously by other investigators,10 it is very unlikely that subjects would have experienced an increase in MCA diameter in the face of reduced cardiac output and increased sympathetic activity during LBNP. The increase in sympathetic activity would, if anything, result in slight constriction of the MCA, causing an increase in the measured velocity and therefore an overestimation of flow. Even if such an error had occurred in our study, its only effect would have been to lead to underestimation of the magnitude of the decrease in blood flow seen in response to LBNP. The onset of presyncopal symptoms at the end of the test provides further evidence of a decreased CBF relative to baseline levels. We are therefore of the opinion that the observed trend of decreased MFV does in fact indicate a drop in CBF, the magnitude of which may actually be underestimated by the use of TCD.
Pressure-Flow Relationship During LBNP
The physiology of presyncope and syncope in response to an orthostatic stress is individual and largely unknown, varying with the clinical state and predisposing hemodynamic conditions, including the dynamic potential of the cerebral autoregulation system. Somatosensory-evoked potentials, for example, do not indicate a decrease in global cerebral function during presyncopal LBNP.30 Characteristics of vasovagal syncope previously have been described in two phases during tilt and LBNP studies, with a gradual fall in MABP at the onset of phase I and an abrupt fall in HR and arterial BP in phase II,23 although the changes in HR are inconsistent. The length of phase I is quite variable and may have been very short in our subjects who underwent a more prolonged LBNP protocol. It is clear that there is great variability in individual responses to LBNP, presyncope, and syncope. Within the clinical definition of presyncope, we assume that syncope would follow if the cause of the presyncopal state, LBNP, continued to loss of consciousness. In an attempt to avoid syncope during LBNP-induced central hypovolemia at presyncopal levels in our study, we permitted subjects with symptoms of nausea and lightheadedness or a rapid decrease in HR to abort the LBNP run. Three subjects did not achieve falling BPs before the test was aborted but did exhibit other signs or symptoms of presyncope as defined in our protocol. In our subjects, noninvasive measurements of arterial BP may not have recorded instantaneous interarterial BP drops that have been recorded invasively in other studies,10 23 thereby being less sensitive to rapid decline in MABP readings. Although absolute measurements of Finapres BP have a poor correlation with invasive arterial BP readings, beat-to-beat information on arterial pressure trends by Finapres followed changes in invasive pressures in 83% of comparisons made in a recent study.31
During a previous study of graded orthostatic stress in high-level but nonpresyncopal LBNP,10 falling MFV and increased pulsatility were of a magnitude less than both calculated systemic and forearm resistances. Also, hyperventilation did not precipitate syncope but caused changes in MFV. Thus, cerebral vasoconstriction is thought to induce lower CBF in the presence of hypotension and hemodynamic instability rather than to itself cause syncope during orthostatic stress. Research on experimental animals has strongly suggested that cerebrovascular sympathetic nerves are involved in the autoregulation of CBF. A constant CBF is maintained at a lower MABP in animals after acute sympathectomy with the autoregulation curve shifting to the left,32 while activation of intracranial sympathetic nerves during systemic arterial hypertension keeps CBF closer to normal, with a shift of the upper limit of autoregulation to the right.33 More sympathetic activity may be necessary to constrict cerebral arterioles than their systemic counterparts,10 or there may be differences in the sensitivity of cerebral vessels to sympathetic stimulation.34 35 In our study, LBNP was increased stepwise until presyncope occurred, in subjects with or without falling MABP. The subjects responded to LBNP by increasing HR and maintaining or increasing MABP while MFV simultaneously decreased, concurrent with an increase in CVRest. This confirms the finding of vasoconstriction during presyncope,10 11 but suggests that the state of presyncope can be reached by lowering MFV while MABP is not falling.
The autoregulation mechanism that operates through metabolic vasodilatation cannot be explained in LBNP-induced simulation of central hypovolemia. If one accepts that the observed decreases in MFV reflect decreases in CBF, one would expect that, in normal autoregulation, falling MABP would be accompanied by decreasing CVR and a maintained MFV, not increasing CVR and a continued fall in MFV. Given the traditional static cerebral autoregulation curve, MABP would be falling as presyncope is approached, while MFV begins to drop close to presyncope and continues to fall at presyncope. The presence of maintained arterial BP, falling MFV, and rising CVRest at moderate levels of simulated central hypovolemia indicate that sympathetic drive affects blood flow in the MCA, with constriction of downstream arterioles. A critical reduction in blood volume may activate a sympathetic nervous system–dependent vasoconstriction that defeats normal autoregulatory metabolic vasodilatation. Our findings are in agreement with the previous suggestion10 that sympathetic drive in response to a severe reduction in central blood volume may overcome metabolism-dependent cerebral autoregulation and cause cerebral blood flow to fall.
In the present study, HR increased steadily at pressures more negative than −20 mm Hg, while MABP either remained constant or increased slightly. Despite nondecreasing BPs, MFV fell, relative to baseline levels, in all subjects. Although the decline in MFV began earlier in some subjects than in others, the drop in MFV always preceded any drop in MABP. Previous investigators have suggested that this response may be due to a rightward shift in the cerebral autoregulation curve (Fig 4a⇓) resulting from increased sympathetic activity during LBNP.10 This would cause the lower limit of autoregulation to be reached at higher-than-expected BPs, resulting in the development of a linear pressure-flow relationship. Even in this situation, a falling MABP would still be required to induce further changes in MFV.
An alternative explanation for the falling MFV in the face of constant or increasing MABP may be a downward shift of the cerebral autoregulatory set point level (Fig 4b⇑). This set point is known to change in response to changes in Pco2,36 and perhaps a similar vertical shift could be induced by other stimuli through as yet unknown pathways. For instance, LBNP may alter the mechanism that determines the autoregulatory set point so that changes in the level of CBF appear similar to those observed in a hypocapnic state. Although CO2 data were not collected in this study, the subjects were not observed to be hyperventilating to an extent that would induce changes in MFV of the magnitude seen here. Clearly, a downward shift in set point such as that depicted in Fig 4b⇑ would cause blood flow to decrease even if no change occurred in perfusion pressure; continued downward shifts may cause CBF to fall below the critical level required to maintain consciousness, resulting in presyncope.
In conclusion, the present study confirms the previous findings that significant drops in MFV can be seen during LBNP, even in the absence of similar drops in MABP, and that CVRest increases as presyncope is approached. MABP remained at or above baseline levels in four of nine subjects who satisfied the criteria for presyncope. We acknowledge that in any TCD study the ability to infer changes in blood flow and autoregulation from changes in velocity measurements relies on the assumption of minimal changes in the diameter of the insonated vessel. Although a decrease in MFV similar to that observed in the present study could have resulted from an increase in MCA diameter, even in the absence of any decrease in CBF, we have stated that dilatation of the MCA would have been unlikely in the face of the reduced cardiac output and increased sympathetic activity produced by LBNP. We therefore reasoned that the observed decrease in MFV corresponded to a decrease in CBF, and hypothesized that this response may be due to a downward change in the autoregulatory set point, possibly resulting from increased sympathetic activity. However, the possibility of a rightward shift in the curve, either on its own or in addition to a downward shift, cannot be ruled out, and further study is necessary to distinguish between these phenomena. Introduction of a step change in the BP at several stages throughout the LBNP test by use of, for example, the thigh cuff inflation/deflation method of Aaslid et al,37 would enable study of the dynamic autoregulatory response at various levels of MFV. The presence of a dynamic MFV recovery after a step change in BP would indicate an intact autoregulation mechanism and support the hypothesis of a downward-shifting set point. Conversely, a linear relationship between the MFV and MABP in response to a step change would suggest an operating point on the left side of the cerebral autoregulation curve, indicating the occurrence of a rightward shift in the curve. Clarification of the physiology of presyncope during LBNP will enhance our understanding of the pressure-flow relationship in the brain during presyncope and of the potential of plasticity of the cerebral autoregulation phenomena.
Selected Abbreviations and Acronyms
|CBF||=||cerebral blood flow|
|CPP||=||cerebral perfusion pressure|
|LBNP||=||lower body negative pressure|
|MABP||=||mean arterial blood pressure|
|MCA||=||middle cerebral artery|
|MCAcs||=||cross-sectional area of the insonated MCA|
|MFV||=||mean flow velocity|
|TCD||=||transcranial Doppler sonography|
The authors gratefully acknowledge the Centre for Advanced Technology Education at Ryerson Polytechnic University, Toronto, for administrative support, as well as Dr Andrew P. Blaber and Peyman Moradshahi for their assistance. This research was supported by the following: NSERC Industry/University Partnership grant 669-008-93 (Dr Bondar), NASA RTOP grant 199-14-11-13 (Dr Fortney), and NASA NAG grant 9-401 (Dr Riedesel).
Reprint requests to P.T. Dunphy, Centre for Advanced Technology Education (CATE), Ryerson Polytechnic University, 350 Victoria St, Toronto, Ontario, Canada M5B 2K3. E-mail firstname.lastname@example.org.
- Received February 7, 1995.
- Revision received June 28, 1995.
- Accepted July 6, 1995.
- Copyright © 1995 by American Heart Association
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