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J Physiol (2003), 549.1, pp. 299-311
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.036715
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ABSTRACT |
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To study cardiovascular control in the period leading to vasovagal syncope we monitored beat-to-beat blood pressure, heart rate (HR) and forearm blood flow in 14 patients with posturally related syncope, from supine through to tilt-induced pre-syncope. Signals of arterial blood pressure (BP) from a Finapres photoplethysmograph and an electrocardiograph (ECG) were fed into a NeuroScope system for continuous analysis. Non-invasive indices of cardiac vagal tone (CVT) and cardiac sensitivity to baroreflex (CSB) were derived on a beat-to-beat basis from these data. Brachial vascular resistance (VR) was assessed intermittently from brachial blood flow velocity (Doppler ultrasound) divided by mean arterial pressure (MAP). Patients underwent a progressive orthostatic stress test, which continued to pre-syncope and consisted of 20 min head-up tilt (HUT) at 60 deg, 10 min combined HUT and lower body suction (LBNP) at -20 mmHg followed by LBNP at -40 mmHg. Pre-syncope was defined as a fall in BP to below 80 mmHg systolic accompanied by symptoms. Baseline supine values were: MAP (means ± S.E.M.) 84.9 ± 3.2 mmHg; HR, 63.9 ± 3.2 beats min-1; CVT, 10.8 ± 2.6 (arbitrary units) and CSB, 8.2 ± 1.6 ms mmHg-1. HUT alone provoked pre-syncope in 30 % of the patients whilst the remaining 70 % required LBNP. The cardiovascular responses leading to pre-syncope can be described in four phases. Phase 1, full compensation: where VR increased by 70.9 ± 0.9 %, MAP was 89.2 ± 3.8 mmHg and HR was 74.8 ± 3.2 beats min-1 but CVT decreased to 3.5 ± 0.5 units and CSB to 2.7 ± 0.4 ms mmHg-1. Phase 2, tachycardia: a progressive increase in heart rate peaking at 104.2 ± 5.1 beats min-1. Phase 3, instability: characterised by oscillations in BP and also often in HR; CVT and CSB also decreased to their lowest levels. Phase 4, pre-syncope: characterised by sudden decreases in arterial blood pressure and heart rate associated with intensification of the symptoms of pre-syncope. This study has given a clearer picture of the cardiovascular events leading up to pre-syncope. However, the mechanisms behind what causes a fully compensated system suddenly to become unstable remain unknown.
(Received 2 December 2002; accepted after revision 11 March 2003; first published online 4 April 2003)
Corresponding author P. O. O. Julu: Peripheral Nerve and Autonomic Unit, Imperial College of Science, Technology and Medicine, Central Middlesex Hospital, Park Royal, Acton Lane, London, NW10 7NS, UK. Email: julu{at}udcf.gla.ac.uk
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INTRODUCTION |
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Vasovagal syncope, so named by Sir Thomas Lewis (1932) because of the combination of vasodilatation and bradycardia, is a common clinical problem, which has undergone extensive research in recent years. Despite this, the exact mechanisms by which the vasovagal reaction is initiated and a stable cardiovascular state becomes decompensated with a rapid drop in blood pressure remain uncertain. Clearly, there must be some alteration in the control of the circulation by reflex inputs and central nervous system processing, but details of this are lacking.
It is difficult to quantify the cardiovascular events leading to vasovagal syncope since they tend to be rapid and dramatic and most of the currently available methods require steady states and a pre-set number of cardiac cycle intervals to obtain a single reading. In order to quantify the events fully, continuous monitoring of cardiovascular parameters is required. The NeuroScope (MediFit Diagnostics Ltd, London) is a device, which has been shown to be able to derive a continuous non-invasive index of cardiac vagal tone (CVT) (Little et al. 1999). It also provides a continuous method of monitoring and quantifying the cardiac component of the baroreflex gain in real-time in humans (Julu et al. 1996). The validity of this method has been confirmed recently during cardiovascular surgery in human subjects (Sigaudo-Roussel et al. 2001). Therefore we now have the means for continuous monitoring of indices of cardiac baroreflex sensitivity and cardiac vagal tone. The aim of the present study was to use this technique to monitor and quantify beat-to-beat cardiovascular regulation in the period leading up to and during vasovagal syncope in human subjects provoked by the combination of head-up tilt and lower body suction.
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METHODS |
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Subjects
Ten men aged 30-55 years (mean ± S.E.M., 35 ± 8 years) and four women aged 35-50 years (40 ± 5 years) took part in the study. All subjects were being investigated because of a history suggestive of posturally related syncope. Subjects did not have any known cardiovascular or neurological disorders and were not taking any medications. All studies took place in the mornings in a temperature-controlled laboratory. Subjects were instructed to have only a light breakfast and not to have any caffeine-containing drinks from midnight before their test. Written informed consent was obtained and the Leeds Teaching Hospitals NHS trust Research Ethics Committee approved the study. The study was in accordance with the Declaration of Helsinki.
Measurement of arterial blood pressure
Digital arterial pressure was measured in the right hand using a photoplethysmographic device (Finapres, Ohmeda WI, USA). The appropriate size finger cuff was placed on the middle digit taking care to position the cuff correctly. Finapres values were calibrated by comparison with those from an automatic sphygmomanometer (Hewlett Packard, 78325C, Boeblingen, Germany). The right arm was supported at heart level by an armrest. The calibrated analog output of the blood pressure waveform (Fig. 1) was fed from the Finapres to the NeuroScope system (MediFit Diagnostics Ltd, London). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial pressures were calculated using VaguSoft software as follows. The software carefully tracked the blood pressure waveform to obtain first the DBP at the start of the pressure rise (Fig. 1), then the SBP at the peak of the pressure waveform. The MAP was calculated as the true arithmetic mean of pressures throughout one cardiac cycle by adding up the sampled pressures and dividing this total by the number of samples (sampling rate 200 Hz).
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Figure 1. Analog signal input into the NeuroScope for calculation of cardiovascular variables Continuous analog signals of blood pressure waveforms from a digital artery obtained by photoplethysmography (upper trace) and electrocardiogram (ECG, lower trace) fed into the NeuroScope system for measurement of arterial BP, the ECG R-R intervals (RR1 and RR2) representing pulse intervals and cardiac sensitivity to baroreflex (CSB). The point of inflexion in the arterial BP trace at DP represents the diastolic pressure and the point of inflexion at SP represents the systolic pressure in the same cardiac cycle. The mean arterial pressure of this cardiac cycle is the arithmetic mean of all pressures starting from DP, through SP and ending at DP1, sampled at 200 Hz. The CSB is the change in pulse intervals per unit change in systolic pressures and is represented by a 10-s-wide moving average of the quantity: (RR2 - RR1)/(SP2 - SP1) measured in ms mmHg-1 (see text for more details). | ||
Measurement of peripheral vascular resistance
Blood flow velocity in the right brachial artery was measured intermittently every 2 min using Doppler ultrasound (Doptek Ltd, UK). An 8 MHz probe was clamped in position over the brachial artery to the armrest and care was taken to ensure that the angle of the probe did not change throughout the test. An index of vascular resistance was calculated by dividing MAP (Finapres) by blood flow velocity. Responses were then calculated as percentage changes from the baseline supine values.
Measurement of the cardiac sensitivity to baroreflex (CSB)
The non-invasive index of cardiac sensitivity to baroreflex (CSB) was measured using a combination of the NeuroScope and MedullaLab (MediFit Diagnostics Ltd, London) as previously described (Julu et al. 1996, 2001a). Briefly, the index is defined as the increase in pulse interval per unit increase in systolic pressure. The NeuroScope samples the ECG signal at 1250 Hz for high precision measurement of R-R intervals. The CSB is calculated according to the formula given in Fig. 1. Whenever consecutive increases in either R-R intervals or SBP were not detected, the value of CSB was decreased from the current value towards zero using a decay time-constant suggested by Sleight et al. (1995) until successive increases resumed. The least value of CSB in this method is zero. The method allows detection of rapid changes in CSB within a continuous measurement.
Measurement of cardiac vagal tone (CVT)
The non-invasive index of cardiac vagal tone (CVT) was measured on a continuous beat-to-beat basis using the NeuroScope as described previously (Little et al. 1999). Briefly, the index is defined as 'pulse-synchronised phase shifts in consecutive cardiac cycles'. It is essentially a form of pulse interval variability that is quantified continuously from the ECG using a circuit of electronic integrators to convert the pulse intervals into voltages, and a set of voltage-controlled oscillators to prepare these voltages for the recognition of their rising and falling phases. A phase detector then quantifies only the appropriate phase shifts representing CVT (Little et al. 1999), which is measured in arbitrary units of a linear vagal scale (LVS) (Julu, 1992). The least value in this scale is zero, equivalent to full atropinisation of human subjects (Julu, 1992).
Experimental protocol
Subjects underwent a progressive orthostatic stress test of combined head-up tilt and lower body negative pressure (LBNP). This test has been described previously (El-Bedawi & Hainsworth, 1994). Briefly, subjects lay on the tilt table and were positioned, by way of an adjustable footboard, so that the iliac crest was level with the central pivot of the table. Subjects were fitted with a standard three-lead ECG and the Finapres as described above. An automatic sphygmomanometer cuff was fitted round the left upper arm. The LBNP chamber was fitted to the table and sealed around the level of the iliac crest with a suitable size neoprene-edged plate. Subjects then underwent 20 min supine rest during which baseline cardiovascular variables were measured, followed by a progressive orthostatic stress, which was terminated at the onset of pre-syncope. The test comprised 20 min head-up tilt at 60 deg, while the subject was still tilted then LBNP was applied at two levels, -20 mmHg and -40 mmHg for 10 min of each. The test was terminated and the subject returned to the supine position when systolic pressure dropped below 80 mmHg, associated with symptoms of impending syncope. The time in minutes from the start of head-up tilt to termination of the test was taken as the subjects' orthostatic tolerance.
Data analysis
Identification and measurements of data segments. The continuous real-time records from each subject had twelve clearly identifiable cardiovascular events (Table 1) and these were used as reference markers for the measurements of heart rate (HR), SBP, DBP, pulse pressure (PP), CSB, and CVT. The twelve cardiovascular events were used to describe four consistent response phases (see Results for description of response phases). Baseline values of the various variables were taken after the subject had remained supine for 20 min. The values were determined from 100 cardiac cycles. During the orthostatic stress, shorter periods were analysed after recognising the different response phases (see Results). During steady states 20 cardiac cycles were analysed and during the analysis of oscillations, values were taken as the means of three complete oscillatory cycles (Fig. 5).
Statistical analysis. Unless otherwise stated values are given as means ± S.E.M. Comparisons between phases and baseline were done using Student's paired t test or Wilcoxon's matched-pairs signed-ranks test as appropriate.
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RESULTS |
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Following 20 min of recumbent rest, the average baseline value of SBP was 124 ± 3.5 mmHg (range (111- 159 mmHg); DBP, 65.2 ± 3.5 mmHg (45-102 mmHg); MAP, 84.9 ± 3.2 mmHg (74-121 mmHg) and pulse pressure (PP, SBP-DBP) 59.4 ± 3.1 mmHg (45-87 mmHg). Resting HR was 63.9 ± 3.2 beats min-1 (44-86 beats min-1). The derived data obtained from subjects when they were in supine position were: CVT, 10.8 ± 2.6 units (4.2-23.9 units) in the LVS; CSB, 8.2 ± 1.6 ms mmHg-1 (2.1-23.2 ms mmHg-1).
Following head-up tilt and, if applied, graded lower body suction, mean blood pressure was initially well maintained but, in all subjects, pressure eventually fell, associated with symptoms of pre-syncope, and the test was terminated. The time from head-up tilt to pre-syncope ranged from 3 to 33 min (mean, 22.9 ± 2.8 min). Five (36 %) of the subjects reached pre-syncope during the tilt phase; the remainder required LBNP.
Figure 2 shows blood pressures during the entire procedure from one subject who reached pre-syncope early (Fig. 2A), that is, during the head-up tilt phase, and another who required the higher level of LBNP to induce pre-syncope (Fig. 2B). These two subjects had very different levels of orthostatic tolerance. However, in both of them, and in all other subjects in the series, it was possible to identify four phases, through which blood pressure and HR passed, from the start of head-up tilt to the point of pre-syncope. There were large differences in the durations and the magnitudes of the changes during the phases, but nevertheless, all phases could be seen in all subjects. The timings of the various phases are indicated on Fig. 2. The cardiovascular events are described below and are summarised in Table 1.
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Figure 2. Continuous record of cardiovascular variables during the entire orthostatic stress test in two subjects (A and B) with very different orthostatic tolerances (OT) showing the four response phases (1, 2, 3, and 4) leading to pre-syncope The start of the tilt is indicated by the vertical dotted line (T). Arterial blood pressure (BP) shows the systolic (upper trace) and diastolic (lower trace) values both displaying clear borders between response phases 3 and 4. Note the elevation of BP just before the start of phase 3 in both subjects; this was characteristic in all subjects studied. Heart rate (HR) responses show clear borders between response phases 1 and 2. Two derived indices, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of a linear vagal scale (LVS) are also shown. Note that the elevation of BP just before the beginning of response phase 3 coincides with further drops in both CSB and CVT levels to their lowest values during the entire experiment in both subjects, and this occurred in all subjects studied. During phase 1 HR increased, BP was stable, but there were large decreases in CSB and CVT. During phases 2 and 3 CSB and CVT decreased further but phase 4 was associated with sharp increases in these two variables. The subject in A had OT of only 3 min starting from the head-up tilt at T. The subject in B had a good OT of 32 min. This latter subject required lower body negative pressure of -20 mmHg at S1 and -40 mmHg at S2 to overcome the OT. | ||
Phase 1: full compensation
Immediately after head-up tilt in 10 (71 %) of the subjects there was a transient decrease in blood pressure (Fig. 3). The remainder had no initial dip. Within 30 s mean blood pressure had returned to become equal to or greater than the supine value. Systolic pressure was not significantly different but diastolic pressure was higher than baseline (+9.6 ± 2.0 %, P < 0.001). HR was 74.8 ± 3.2 beats min-1 and this was 21.3 ± 4.5 % higher than at baseline (P < 0.001). Forearm vascular resistance increased by 70.4 ± 9.1 % of the baseline value. The average duration of this phase was 15.8 min (range 1-26 min).
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Figure 3. Continuous record of cardiovascular responses to head-up tilt (at T) during full compensation in the response phase 1 recorded in real-time in a representative subject The important event in this response phase to orthostatic stress is a stable cardiovascular compensation (grey arrow; see Table 1 for a list of all important cardiovascular events in this experiment). There was an initial dip in arterial blood pressure (BP) that recovered within 30 s to values higher than the pre-tilt period. The upper BP trace is systolic and the lower trace is diastolic pressure. Note that following head-up tilt, both systolic and diastolic pressures were well compensated and remained stable. The heart rate (HR) increased steeply then varied about a mid value close to 80 beats min-1; the pre-tilt mid value was 71 beat min-1. Two derived variables, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of a linear vagal scale (LVS), both decreased steeply and then varied about mid values that were about 30 % of the pre-tilt period. Time was measured from the beginning of the experiment. | ||
During this phase CVT decreased to 3.5 ± 0.5 units in the LVS (P < 0.0005) and CBS decreased to 2.7 ± 0.4 ms mmHg-1 (P < 0.05). A continuous recording of the changes during this phase in one subject is shown in Fig. 3.
Phase 2: tachycardia
After a period of HR stability during phase 1, there was a progressive increase in HR, which either continued to increase up to the time when pressure and HR became unstable, or reached a peak which then remained relatively constant for the remainder of the phase (Fig. 4). The average duration of this phase was 4 min (range, 0.5-12 min). During this phase, HR increased to a peak of 104.2 ± 5.1 beats min-1, which represented a 33.4 ± 5.6 % increase (P < 0.001) above the level at the start of the phase and a 67.7 ± 1.2 % (P < 0.001) increase from the baseline level. There was a 15.0 ± 3.6 % decrease in SBP but no significant change in DBP. There was no further significant change in forearm vascular resistance during this phase.
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Figure 4. Segment of a continuous record of cardiovascular variables acquired in real-time during response phase 2 at a progressive orthostatic stress in a representative subject The important events in this phase are a sudden start of tachycardia (vertical dotted line) and a ramp increase of heart rate (HR) to a peak at P (see Table 1 for a list of all important cardiovascular events in this experiment). The arterial blood pressure (BP) trace shows the systolic (upper trace) and diastolic (lower trace) pressures. The abrupt and progressive increase in HR marks the beginning of response phase 2 during orthostatic stress. The amplitude of BP variation increased during this phase and there was a degree of overlap between phases 2 and 3 (see Fig. 5 for definition of response phase 3). The sudden decrease in pulse pressure (measured as the difference between systolic and diastolic pressures) towards the end was seen in all subjects studied. The two derived variables, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of a linear vagal scale (LVS) gradually decreased towards zero in steps. Time was measured from the beginning of the experiment. | ||
The CVT decreased during this phase to 2.2 ± 0.5 units in the LVS, which was not significantly different from the previous phase but significantly lower than the baseline value (P < 0.01). The CSB was 1.2 ± 0.4 ms mmHg-1 and also significantly below the baseline value (P < 0.01) (see also Table 1). An example of recordings obtained during this phase is given in Fig. 4.
Phase 3: instability
This phase was characterised by oscillations of arterial blood pressure and often also HR (Fig. 5). During this phase subjects began to experience the initial symptoms of pre-syncope. The average duration of this phase was 2.1 min (range 0.5-6 min). The average amplitude of the oscillations of SBP was 27.0 ± 3.1 mmHg. The average period of oscillations was 10.6±0.3 s (9-12 s), (0.094 Hz). The average value of SBP during these oscillations actually increased from that during the previous phase. HR was significantly less (P < 0.001) than during the previous phase although, at 97.8 ± 4.2 beats min-1, it was significantly higher than the supine value (P < 0.001).
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Figure 5. Segment of a continuous record of cardiovascular variables acquired in real-time during response phase 3 at a progressive orthostatic stress in a representative subject This is a phase of cardiovascular instability; the important event here is the rhythmic oscillations of vascular pressure (see Table 1 for a list of all important cardiovascular events in this experiment). The arterial blood pressure (BP) trace shows the oscillations of systolic (SBP, upper trace) and diastolic (lower trace) pressures. These were associated with erratic and large variation in heart rate (HR) demonstrating the instability during this phase. The two derived variables, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of a linear vagal scale (LVS) both dropped to levels lower than the previous phase, but continued to vary up and down. It is notable here that elevations in CSB are associated with reduced amplitudes of oscillations in both BP and HR. The amplitude and period of the oscillations of blood pressure were calculated as the mean of the three maximal fluctuations: amplitude, in mmHg, 1/6[(b - a) + (b - c) + (d - c) + (d - e) + (f - e) + (f - g)]; period, measured in seconds: 1/3 (g - a), where (g - a) is the time difference between points g and a. Time was measured from the beginning of the experiment. | ||
The average value of CVT during this phase was 2.1 ± 0.4 units. This was not different from the previous phase, but still less than the baseline value (P < 0.01). The value of CSB was 1.3 ± 0.3 ms mmHg-1 and this was not significantly different from the previous phase although it was lower than the baseline (-72.1 ± 10.8 %; P < 0.01). Figure 5 shows some of the cardiovascular variables recorded in real-time during this phase in one representative subject.
Phase 4: pre-syncope and recovery
This phase was characterised by sudden decreases in arterial blood pressure and HR and associated with intensification of the symptoms of pre-syncope. In 10 subjects (71 %) the decrease in blood pressure preceded bradycardia (Fig. 6) by an average of 23.1 ± 7 s (range, 2-53). In two subjects (14 %) cardiac and blood pressure changes occurred simultaneously (Fig. 7) and in the other two, bradycardia was the first event. The MAP decreased to an average of 51.4 ± 4.9 mmHg within an average time of 37.0 ± 0.5 s (range 19-45 s). In 10 subjects (71 %), there was an increase in forearm blood flow coinciding with the drop in pressure. Ending the procedure and restoring the subject to a supine position limited the duration and the minimum arterial pressure reached during this phase.
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Figure 6. Segment of a continuous record of cardiovascular variables acquired in real-time during response phase 4 (pre-syncope) at a progressive orthostatic stress in a subject who showed a gradual stepwise regulation of the baroreflex response This is a phase of cardiovascular decompensation and the important events are a sudden start of progressive decrease in arterial blood pressure (BP, vertical broken line) ending in troughs (P1 and P2), and a sudden start of a progressive decrease in heart rate (HR) at (C1) ending in a trough (C2). The two derived variables, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of a linear vagal scale (LVS), represent brainstem regulation of baroreceptor function. The CSB increased gradually in steps starting from a very low value (B1) to a peak (B2) and CVT also increased gradually starting from a very low value (V1) to a peak (V2), but V1 preceded B1 by 3 s (see Table 1 for a list of all important cardiovascular events in this experiment). In this subject BP decreased over the course of 1 min, following which the orthostatic stress was terminated. During the fall in pressure, HR remained high and CSB and CVT remained low. Following the return to a supine position there was a marked decrease in HR and increases in CSB and CVT. Note that at the beginning of vascular decompensation, the levels of both CVT and CSB were close to or at zero and did not begin to rise until the BP was at its trough. Time was measured from the beginning of the experiment. | ||
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Figure 7. Segment of a continuous record of cardiovascular variables acquired in real-time during response phase 4 (pre-syncope) at a progressive orthostatic stress in a subject who showed abrupt baroreflex reaction leading to asystole The pre-syncope started with simultaneous decreases in arterial blood pressure (BP) and heart rate (HR). The BP traces are systolic (upper) and diastolic (lower) pressures. The asystole at C2 lasted for 3.1 s followed later on by a brief period of second-degree heart blocks at C3. The two derived variables, cardiac sensitivity to baroreflex (CSB) and cardiac vagal tone (CVT) measured in arbitrary units of linear vagal scale (LVS), represent brainstem regulation of baroreceptor function. The CVT increased abruptly from a value close to zero at V1 to about 120 units at V2 preceding and leading directly to asystole. The brief period of heart blocks was also associated with large increases in CVT. The CSB also rose abruptly in large steps from a very low value at B1 to a peak at B2, but V1 preceded B1 by 30 s. The asystole and second-degree heart blocks did not impede recovery from the pre-syncope. It is notable that the level of CVT preceding the asystole was considerably higher than the average supine level of 8.4 units in this subject, or the average of 10.8 ± 2.6 units in all the subjects studied. | ||
Comparisons of the changes in the derived variables with the changes in blood pressure revealed that during the initial part of the hypotensive phase CVT and CSB remained very low (average values: 2.3 ± 0.4 units in the LVS and 1.4 ± 0.3 ms mmHg-1, respectively). However, usually after stopping the test, both increased (Fig. 6 and Fig. 7). The increase could be gradual (Fig. 6) or the increase in CVT could be abrupt and very large (Fig. 7). Abrupt and large increases in CVT were associated with asystole that lasted 2.7 and 3.1 s respectively in two subjects. The increase in CVT preceded the increase in CSB in seven (50 %) subjects by 11.3 ± 5.0 s (1-32 s). The increase in CSB occurred first in the other seven subjects preceding the increase in CVT by 11.0 ± 4.7 s (1-30 s). The average peak value of CVT during this phase was 16.7 ± 2.8 units (7-43 units) in the LVS (excluding the period leading to asystole in two subjects), 106.1 ± 40.3 % of the supine value. The average peak value of CSB in this phase was 6.2 ± 1.2 ms mmHg-1 (1-19 ms mmHg-1), which was not significantly different from the supine value although much higher than in the preceding phase. The various events during this phase are listed in Table 1 and this indicates the associations between the changes in HR and blood pressure with the changes in CSB and CVT.
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DISCUSSION |
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The aim of this study was to describe the principal cardiovascular events occurring during a progressive orthostatic stress and to interpret them, using non-invasive methods of assessing cardiac vagal activity and cardiac baroreflex sensitivity. The results have indicated that, despite very different tolerances to orthostatic stress between subjects, all showed a very similar sequence of events leading up to termination of the procedure at pre-syncope. We have for the first time in the study of vasovagal syncope classified these events into four response phases.
Suitability of methods used in this investigation
Cardiovascular variables. All techniques have been validated and used in several previous investigations. Finapres photoplethysmography is very widely used and is a reliable method of assessing changes in arterial blood pressure (Imholz et al. 1990). Because it is less accurate for assessing absolute pressure we compared it every 2 min with a sphygmomanometric method. Forearm vascular resistance was assessed as mean blood pressure divided by mean brachial artery blood flow velocity (Brown & Hainsworth, 2000). This does not provide a measure of absolute vascular resistance but does quantify the changes.
Orthostatic tolerance. We used the combination of head-up tilt and lower body suction (El-Bedawi & Hainsworth, 1994) as it is able to induce pre-syncope in all subjects and applies a graded stress which can be seen as a progressive decrease in cardiac output up to the point when compensation fails (El-Bedawi & Hainsworth, 1994). We have shown this technique to be sensitive, reproducible and able to discriminate between results of patients with frequent attacks of syncope and asymptomatic controls (El-Bedawi & Hainsworth, 1994).
Cardiac vagal tone (CVT). It is established that the amount of efferent vagal activity to the heart (cardiac vagal tone) is largely dependent on the degree of stimulation to arterial baroreceptors (Keele et al. 1982; Jordan, 1995; Guyenet et al. 1996). At MAP above 45 mmHg, ejection pressures of the heart are sufficient to stimulate the arterial baroreceptors at every heartbeat (Rushmer, 1972). Because of the very short latency of this baroreflex (Eckberg, 1976), changes in arterial pressure induce changes in cardiac cycle intervals on a beat-to-beat basis. It is this baroreceptor-induced variability in cardiac cycle intervals that is used as a measure of cardiac vagal tone. The NeuroScope quantifies this variability using an atropine-derived linear vagal scale (Julu, 1992). During this process, the recommended repetitive stimulation with averaging of the outputs for baroreceptor-related measurements (Eckberg & Sleight, 1992) is achieved by electronic integration using a long time constant of 2 s, equivalent to an oscillation period of 10 s (Little et al. 1999). The dose-response curve of the outputs from the NeuroScope to atropine has been established in dogs (Little et al. 1999) and in humans (Delamont et al. 1998). The dose-response curve in humans (Delamont et al. 1998) shows clearly the paradoxical central excitation of CVT by a small dose of atropine and a complete blockade at a dose at which no vagal activity can be observed in humans (Chamberlain et al. 1967). This device was also shown to be able to quantify changes in vagal activity (in arbitrary units) by determining its responses to direct vagal stimulation (Julu et al. 2001b,d) and mechanical stretching of the wall of the carotid sinus during surgery (Sigaudo-Roussel et al. 2001). The shortcomings in the NeuroScope's CVT has already been previously discussed in detail (Little et al. 1999).
Cardiac sensitivity to baroreflex (CSB). We measured CSB from the relationship between changes in cardiac cycle length and the preceding changes in systolic pressure. This method has the advantage over methods involving spectral or cross-spectral analysis in that it provides a continuous assessment of CSB whereas spectral methods require steady states lasting at least 240 cardiac cycles. Baroreflex interactions in conscious human subjects is complex, demanding critical methods of investigation (Eckberg & Sleight, 1992). Physiological stimulus, well-defined stimulus-response relations, brief interventions during stimulation and repetitive stimulation with averaging of outputs are among the requirements fulfilled by our method. The 'stimulus' during measurement of CSB comes during the ejection period similar to that for CVT. The magnitude of this stimulus is the difference between consecutive values of SBP. When there are no differences or the difference is negative, the stimuli are taken as zero. The 'response' during measurement of CSB is the difference between consecutive R-R intervals; 'no response' includes negative differences as explained above. This therefore means that CSB only quantifies the beat-to-beat negative feedback control of the cardiovascular system during times when increases in SBP are followed by increases in the R-R interval. This type of cardiovascular regulation is tonically regulated at the level of nucleus tractus solitarii in the brainstem (Kasparov & Paton, 1999). The recommended repetitive stimulation with averaging of the outputs is achieved through a 10 s period as explained in Methods.
Assessment of both CVT and CSB has been made in earlier studies during the Valsalva's manoeuvre (Engerström et al. 2001; Al-Rawas et al. 2001b), breath holding manoeuvres (Al-Rawas et al. 2001a) and administration of vasoactive drugs (Mackenzie et al. 2001; Julu et al. 2001a). Responses to these provocations have, at least qualitatively, been similar to those seen using other methods of assessment. Clinical utilities of CVT and CSB include the diagnosis of a rare congenital defect of blood pressure buffering causing frequent unexplained syncope (Julu et al. 1997c) and evaluation of the developmental immaturity of the brainstem in Rett syndrome (Julu et al. 1997a,b, 2001c). Measurement of CVT and CSB is a key investigation in the clinical management of Rett syndrome (Julu, 2001).
The four response phases during progressive orthostatic stress
It was most interesting that we observed four response phases in all our subjects despite their vastly different orthostatic tolerances ranging from as short as 3 min to as long as 33 min. Following the movement from supine to upright position, there was sometimes a transient decrease in blood pressure, but in all subjects blood pressure had become stable within about 30 s. Diastolic pressure at heart level was consistently higher and systolic pressure, more variable, but usually little changed. These responses, in subjects with apparently normal autonomic function, differ from those in patients with autonomic deficiency in whom blood pressure does not become stable but gradually decreases during head-up tilt. The period of pressure stability is associated with a moderate tachycardia and a marked vasoconstriction. These changes are accompanied by decreases in CVT and CSB. We have recently reported the effects of orthostasis on baroreflex sensitivity, measured by the responses of cardiac cycle intervals to neck suction or pressure, and showed that orthostasis had no consistent effect (Cooper & Hainsworth, 2001, 2002). We did show, however, that the response of vascular resistance to the same stimulus was increased in subjects with good orthostatic tolerance and not in those with poor tolerance. The present study examined continuously only the cardiac component and unlike in the previous study, the sensitivity of this limb of the reflex decreased in all subjects. The reasons for the differing effects reported seem to be related to the method used to assess baroreceptor sensitivity. Methods, such as those in the present study, which involve determining the effects of changes in blood pressure usually indicate that upright tilting or LBNP causes a decrease in cardiac baroreceptor sensitivity (Cooke et al. 1999; Gulli et al. 2001; Youde et al. 2002). Responses to more discrete stimulation of carotid receptors are, however, much less consistent (Harrison et al. 1986; Thompson et al. 1990). The measure of cardiac parasympathetic activity, CVT, also decreased during the initial phase of orthostasis.
The second phase of the response was characterised by a progressive tachycardia with a decrease in pulse pressure and little change in diastolic pressure. Forearm vascular resistance remained relatively stable during this phase remaining near the increased level achieved soon after the start of the orthostatic stress. This early peaking of vascular resistance has been reported previously (Mohanty et al. 1988; Baily et al. 1990; Joyner et al. 1990). During this phase, the indices of parasympathetic activity, CSB and CVT, responsible for cardiovascular buffering decreased further.
Following the increase in HR, the third phase is characterised by rhythmic oscillations of arterial blood pressure and, to a smaller extent, of HR. The frequency of these oscillations was about 0.1 Hz, which is believed to represent the resonant frequency of the cardiovascular system (Deboer et al. 1987). The CSB remained at very low levels during this phase and the almost complete absence of buffering is likely to explain the blood pressure instability. Similar oscillations have previously been reported in situations where baroreceptor buffering is absent (Julu et al. 1997c). These are the conditions where the classical Meyer waves are most prominent.
The phase of pre-syncope is characterised by a sudden decrease in systolic pressure, initially with little change in diastolic pressure so that pulse pressure decreases. It follows the period of instability often with the pressure decreases becoming larger until they form a continuous fall. Usually following the decline in pressure, although sometimes preceding it, there is a slowing of HR. This is associated with an increase in CVT. The CSB also increases at this time and, in some subjects, this may be associated with a profound bradycardia or even asystole. The hypotension is frequently associated with a decrease in forearm vascular resistance. This indicates a decrease in sympathetic activity, which has been seen by others at that stage using microneurographic techniques (Sanders & Ferguson, 1989).
The increases in CSB and CVT at this stage are of interest as it is at this stage, often after stopping the orthostatic stress and returning the subject to a supine position, that the pronounced bradycardia or even asystole may occur. Furthermore, there is evidence that baroreceptors may 'reset' after as little as 20 min of being adjusted to low blood pressures (McMahon et al. 1998), so this and the restoration of CSB may at least contribute to the initiation of vasovagal syncope proper.
Physiological implications of our results
The main importance of these results is the insight that they provide into the events occurring during orthostatic stress and in particular on the changes in autonomic activity in the period leading up to syncope. Immediately after the onset of the stress and for a variable and often long period thereafter, there is full compensation of arterial pressure. The HR had a minor role in this early phase of compensation with a tachycardia of only about 20 % of the baseline rate. The major parasympathetic and sympathetic activities during this cardiovascular compensation were the low levels of CVT and CSB, reduced to only about one-third of supine values, and evidence of increased sympathetic activity to resistance vessels causing vascular resistance to increase by as much as 70 %. The withdrawal of CVT and CSB matched the increase in forearm vascular resistance (FVR) negating the role of the HR in this compensation process. It is unlikely that changes in HR would make a significant contribution to the maintenance of blood pressure. This is partly because the actual change in HR is relatively small, but also because during conditions of reduced venous return, change in HR would have little effect on cardiac output (Hainsworth, 2000). This was evident in our study here where the tachycardia phase only aggravated the reduction of the arterial pulse pressure as seen in Table 1. The low value of CSB during the first response phase is also of interest, as it seems to be associated with high levels of peripheral vascular resistance. This is the situation that is also seen in systemic hypertension (Guo & Thames, 1983; Mancia et al. 1986; Victor & Morgan, 1990).
The second phase of the responses, that of the developing tachycardia, represents the beginning of the failure of compensation. Despite the tachycardia, associated with very low levels of CVT and CSB, blood pressure starts to decrease and the pulse pressure gets even smaller. However, FVR has already peaked and does not increase further. The inability to fully compensate for the blood pressure decline, and probably also the very low baroreceptor sensitivity, leads to the instability of the system whereby blood pressure and HR show large oscillations. The oscillations are likely to be due to variation in sympathetic activity occurring when parasympathetic activity is so low that it is unable to buffer the oscillations.
Sooner or later, the period of instability gives way to phase 4, decompensation and pre-syncope. The events here are very complex as seen from Table 1. They are to some extent variable in that either the fall in blood pressure or the fall in HR may be the first event. The large increases in both CVT and CSB may at least partly explain the paradoxical response later at syncope, but they are not the trigger of the sudden fall in either HR or blood pressure at pre-syncope. This large increase in parasympathetic activity at pre-syncope can start as a sudden rise in either CVT or CSB without preference. What is still unclear, however, is the trigger that induces the sudden decompensation associated with reduced sympathetic activity at pre-syncope. There is considerable evidence now that it is not due to stimulation of ventricular receptors as previously was thought (Hainsworth, 2003).
Conclusion
Progressive orthostatic stress triggers a succession of blood pressure and heart rate reactions that are independent of the subject's tolerance. These reactions can be categorised into four response phases although there may be overlap of some phases. The mechanism responsible for initiating the vasovagal reaction during the last response phase is still unknown but this research raises the possibility that it may result from an increase in sensitivity and resetting of the arterial baroreceptors functions. However, further work is needed to explore this idea.
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