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Clinical Science (1992) 83, 149-155 (Printed in Great Britain) I49 Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis W. WIELING, D. P. VEERMAN, J. H. A. DAMBRINK and B. P. M. IMHOLZ Department of Internal Medicine, University of Amsterdam, Academic Medical Centre. Amsterdam, The Netherlands (Received 28 October 1991/3 February 1992; accepted 10 March 1992) 1. The circulatory adjustment to standing was investigated in two age groups. Young subjects consisted of 20 healthy 10-14-year-old girls and boys. Elderly subjects consisted of 40 70-86-year-old healthy and active females and males. Continuous responses of blood pressure and heart rate were recorded by Finapres. A pulse contour algorithm applied to the finger arterial pressure waveform was used to assess stroke volume responses. 2. During the first 30s (initial phase), an almost identical drop in mean blood pressure was found in both age groups (young, 16+10mmHg; old, 17f lOmmHg), but the initial heart rate increase was attenuated in the elderly subjects (young, 29 f 7 beats/min; old, 17 7 beats/min). 3. During the period from 30 s to 10min of standing, mean blood pressure increased from 96 f 12 to 106f 12mmHg in the elderly subjects compared with almost no change in the young subjects (from 8 2 f 8 to 84 f 7mmHg). In the elderly subjects a progressive increase in total peripheral resistance (from 114f 14% to 146f29%) was found, compared with an initial rapid increase in total peripheral resistance (126+18% after 30s) with no further change during prolonged standing (124f17% after 10min) in the young subjects. In this age group the decrease in stroke volume and the increase in heart rate after 10min of standing were large (young, -37+11% and 27 f 11beats/min; old, - 31f 9% and 7 f 6 beats/ min, respectively). 4. In conclusion, young subjects adjust to orthostatic stress mainly by a marked increase in heart rate. In healthy elderly subjects an attenuation of the heart rate response during orthostatic stress is compensated by a pronounced increase in total peripheral resistance resulting in an increase in blood pressure. + INTRODUCTION In earlier studies we reported the magnitude and time course of blood pressure (BP) and heart rate (HR) responses induced by standing in healthy 10- 14-year-old children [11 and healthy 70-86-year-old subjects [2], using continuous monitoring of finger arterial BP [3, 41. In the present study we extended these observations by analysing the differences in circulatory adjustment to standing between young and elderly subjects in detail. We compared not only BP and HR responses, but also changes in stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) by applying a pulse contour algorithm to the finger arterial BP waveform [5, 61. Three specific questions raised in our previous studies [l, 21 were addressed: (1) Why do young and elderly subjects have a comparable initial BP drop upon standing notwithstanding the attenuation of the initial HR response in old age [l, 2]? (2) Is the progressive rise in BP in the elderly during prolonged standing accompanied by a progressive increase in TPR [2]? (3) Is the large HR increase present in young subjects during prolonged standing accompanied by an equally large fall in SV [l]? METHODS Subjects The responses of 10 girls and 10 boys aged 10-14 years and of 20 healthy females and 20 healthy males aged 70-86 years were investigated. A detailed description of the setting of the study, the selection procedure and the anthropometric data of the subjects has been given previously [l, 21. Measurements Continuous non-invasive finger arterial BP was recorded by means of a TNO Finapres model 5 [3]. It has been demonstrated previously that, in steadystate conditions, finger mean arterial BP is 510mmHg below brachial arterial BP owing to the pressure gradient between the brachial and the Key words: ageing, cardiac output, heart rate, non-invasive continuous blood pressure, orthostatic hypotension, postural changes, stroke volume, total peripheral resistance. Abbreviations: BP, blood pressure; CO, cardiac output; HR, heart rate; SV, stroke volume; TPR, total peripheral resistance. Correspondence: Dr W. Wieling, Department of Internal Medicine, F4-222, Academic Medical Centre, Meibergdreef 9, I105 AZ Amsterdam, The Netherlands. I50 W. Wieling et al. finger artery [4, 71. Changes in arterial BP during laboratory tests, including orthostatic manoeuvres, are followed reliably by Finapres [3, 4, 7, 81. Subjects were instructed to keep the measuring finger cuff at heart level to avoid interference of hydrostatic pressure differences. For direct inspection during the measurement from each subject, a single-lead ECG was recorded and was input to a cardiotachometer to obtain instantaneous HR responses. Together with BP, HR and an event marker, this was recorded on a strip chart (7402-A, Hewlett-Packard, Los Angeles, CA, U.S.A.). For offline analysis, the ECG, the BP signal and the event marker were recorded on tape using a cassette data recorder (TEAC R-61; TEAC Corp, Tokyo, Japan). The standing-up manoeuvre was performed after 5 min of supine rest and subjects remained standing for 10min. The duration of the time from the onset of the manoeuvre to stable stand was marked. In some elderly subjects, an assisting hand was needed to ensure a quick change of posture. Data analysis Upon playback, a 30s control period before and 10min after the onset of standing were selected for further analysis. First, the Finapres BP and the event-marker signals were analog-to-digital converted at a sampling rate of 200Hz and were input into a PDP-11/44 computer system [l, 21. By means of the signal analysis program BEATFAST [9], the beat-to-beat integrated mean BP and the instantaneous HR values were determined. In addition, this program calculates the beat-to-beat values of left ventricular SV, CO and TPR using the pulse contour algorithm of Wesseling et al. [5]. In short, SV is calculated as the integral of the pressure pulse over the arterial systolic period divided by the aortic characteristic impedance [ 5 , 61. Smith et al. [lo], using radial and brachial artery waveforms, found pulse contour CO in good agreement with dye-dilution measurements, while varying BP, HR and CO over a wide range by pharmacological intervention. Wesseling et al. [l 11, on estimating the transfer function between aortic and brachial waveforms, found a constant (15%) overestimation of SV from the brachial pulse contour data. We have shown previously that when intrabrachial measurements upon standing are repeated within a short time period, almost identical responses are obtained both for the arterial BP measurements and for the pulse contour computations [12]. To obtain absolute SV values, calibration with a standard method such as thermodilution is needed [5, 12, 131, but without such calibration one can use the relative changes in SV [ 5 , 61. The reliability of the use of the pulse contour algorithm in BEATFAST on indirect finger arterial BP waveforms has not yet been evaluated. We, therefore, compared pulse contour data from simul- taneously measured intrabrachial and finger BP tracings recorded during standing up in a previous study [4]. The results of this evaluation are given separately in the Results section. Calculations After the calculation of beat-to-beat values, corrections were made for occasional ectopic beats by means of linear interpolation. In three of the 40 elderly subjects, the extent of ectopic beats during one of the stages of prolonged standing was too large and made the interpolation unreliable. Individual responses of the remaining 37 elderly and the 20 young subjects were averaged to obtain group responses. The onset of standing up was taken as t=O. Average BP and HR values of a 30s period before standing were taken as controls. The circulatory adjustment to standing was divided into three phases as described previously [l, 23: an initial phase (first 30 s) with characteristic changes in BP and HR, an early steady-state phase (1-2 min standing) and a phase of prolonged standing (5-10min upright). The circulatory responses in the three time periods were quantified as follows. (1) Initial response (first 30s). The changes in BP and HR from control and the percentage changes in SV, CO and TPR were determined each 0.5s. In contrast to earlier studies [l, 2, 61, we did not sample at characteristic peaks and troughs, since these points could not always be identified clearly for all variables in the elderly subjects. (2) Early steady-state response (1-2 min of standing). The changes in BP and HR from control and the percentage changes in SV, CO and TPR during a 10s period centred at 1 and 2min of standing were calculated [l, 21. (3) Prolonged standing (5-10min of standing). The changes in BP and HR from control and the percentage changes in SV, CO and TPR during a 10 s period centred at 5 and 10min of standing were calculated [l, 21. Influence of the level of supine BP on circulatory responses upon standing up In our previous study in elderly subjects [2] it was found that the level of supine BP affected the changes in BP during prolonged standing. We therefore analysed the circulatory responses after 2, 5 and 10min standing of ten elderly subjects with the lowest supine mean BP values (lower BP quartile) and the ten elderly subjects with the highest supine mean BP values (upper BP quartile). Statistics Two-way analysis of variance was used to compare the data of the two age groups and the Orthostatic circulatory adjustment: young compared with elderly 151 different instants of measurements. Student’s t-test for unpaired observations was used to perform comparisons between the two age groups. A P value of <0.05 was considered significant. Results are expressed as means SD. + RESULTS SOJ Comparison of the pulse contour analysis applied to simultaneously recorded intrabrachial and finger arterial waveforms : lsol This comparison was based on BP tracings recorded in 11 healthy subjects aged 18-40 years during standing up [4]. Group average brachial and finger mean arterial BP and HR responses during orthostatic stress are given in the upper two panels of Fig. 1. The lower three panels show the group average percentage changes in SV, CO and TPR calculated from both signals. The mean Finapres arterial BP upon standing was somewhat lower than the intrabrachial arterial BP. The changes in SV, CO and TPR in a period up to 2min standing of Finapres and intrabrachial arterial BP are almost identical. 50’ I 50-] Control period Supine BP was substantially higher in the elderly subjects; supine HR did not differ (Table 1). Initial response (first 30s) In the young subjects (Fig. 2) the standing up manoeuvre was performed in 3 f1s. It was accompanied by an 8+8mmHg rise in mean arterial BP at 2.5s and an instantaneous large increase in HR. This immediate BP increase was followed by a pronounced drop in pressure to a minimum of 16f10mmHg below the control level at 9 s after the start of standing up. The increase in HR reached a maximum of 29+7beats/min after 12s. Upon standing, SV remained unchanged for 7s. The combination of an increase in HR and a stable SV in this phase resulted in a rise in CO, with a maximum of 143& 23% after 6 s. A drop in BP despite a rise in CO can only be explained by a reduction in TPR a minimum of 60f8% was reached at 9 s after the start of the manoeuvre. After 9s, at the moment when CO was still elevated, TPR started to increase. BP recovered and even showed a slight overshoot. HR showed a subsequent rapid decrease around 21s. At the end of the initial phase SV had decreased to 68+ 12% and CO to 86f 14%. Meanwhile, TPR had increased to a value of 126+18% and BP had increased by 4+7mmHg. In the elderly subjects (Fig. 2), the standing up manoeuvre took significantly longer (6 f 1 s, P<O.OOl compared with young subjects) and the immediate increase in BP upon standing was significantly more pronounced (17 f 10mmHg, P <0.001 sE I- 1 0 ~ . . . ....................................... 100 501 -I5 5 \ 0 I I 30 I I I 60 Time (s) 90 , 1 I20 Fig. I. Average mean intrabrachial and finger BP (MAP) and HR responses during a period up to Zmin of standing in II adult subjects [4]. Average relative SV, CO and TPR responses calculated from the direct brachial artery BP waveform are indicated by the solid line, and data from the simultaneously recorded indirect finger BP waveform as a broken line. compared with young subjects). This increase was accompanied by a large drop in SV to a minimum of 58 19% at 2 s after the onset of standing, a drop in CO to 63+20% and a concomitant increase in TPR of 170+47%. At 9.5s, the immediate increase in BP was followed by a fall of 17 10mmHg from the control value, similar to that in the young subjects. The maximal increase in HR, occurring at 14 s, was smaller in the elderly subjects (17 7 beats/ min, P<O.Ol compared with young subjects). The + + + I52 W. Wieling et al. Table I. Orthostatic responses in young and elderly subjects. Values are means SD. Statistical significance: *P <0.05, **P <0.01, ***P <0.00 I + compared with young subjects. Abbreviation: MAP, finger mean arterial BP. Young subjects (IC-I5 years) (n =20) Supine MAP(mmHg) HR (beatslrnin) sv (%) co (%I TPR (%) Upright I min MAP(mmHg) HR (beatslmin) sv (%I co (%I TPR (%) 2min MAP(mmHg) HR (beatslmin) sv (%) co (%I TPR (%) 5min MAP(mmHg) HR (beatslmin) sv 6) co (%I TPR (%) IOmin MAP(mmHg) HR (beatslmin) sv (%I co (%I TPR (%) Elderly subjects (>70 years) (n = 37) 76+6 63+9 100 I00 100 96 f lo*** 59+8 I00 I00 I00 7+6 20+ 10 -34+9 - 12+ 10 25+ 10 I +9** 9 7*** -24+ lo*** -13+12 17+24 7+6 22+11 -36+ I I - 12+ 10 28, I 6 6+8 7 6*** -28+11* - l8+ I3 34 & 27 9+5 23+ 10 -36+ I I - I 2 + I I* 28+ I6 7-1: 10 6 6*** -29+11* -19+11* 38 29 7+7 27+11 -37+ I I - l o + I3 14+ 17 10+9 7 f6*** -31 +9* -21 f 14** 46 29** + + + + + fall in BP at 9.5s was again accompanied by a transient rise in CO, but the magnitude of this rise was smaller than in the young subjects (127 +20%, P ~ 0 . 0 5 ) The . magnitude of the drop in TPR with a minimum of 69 _+ 13% near 11 s after the onset of standing up was also less in the elderly subjects ( P <0.01 compared with young subjects). After 9.5 s, BP increased, but an overshoot was not observed. After 30s of standing, orthostatic falls in SV to 77+12% and in CO to 87f13% were observed (P<O.Ol and P>0.05 compared with young subjects, respectively) with no change in BP. TPR had increased to 114 14% ( P >0.05 compared with young subjects). + Early steady state (I-2min of standing) and prolonged standing (5-l0min of standing) After lmin of standing, mean BP had increased in the young subjects, but not in the elderly subjects. After 2min, a comparable increase in BP was present in both groups. The increase in HR and the decrease in SV remained greater in the young subjects in this phase (Table 1). During the period from 1 to 10min after the onset of standing, BP increased from 96+12 to 106f 12mmHg in the elderly subjects, ( P <0.01), whereas HR hardly changed. In the young subjects there were almost no further changes in BP; HR increased, but not significantly (Fig. 2, Table 1). At 5 and 10min of standing the increase in HR and the decrease in SV were still greater in the young subjects. At the end of the 10min standing period CO had decreased and TPR had increased by significantly more in the elderly subjects, but the BP responses did not differ. Influence of the level of supine BP on circulatory responses upon standing up Upon standing, mean arterial BP increased more in the lower BP quartile than in the upper BP quartile (Table 2). In the lower BP quartile the decrease in CO was 5-10% less than in the upper BP quartile, but this difference was not significant. DISCUSS10N Since the subjects were instructed to keep their hand at heart level (i.e. just a few centimetres above the hydrostatic indifference point) when moving from recumbency to the upright posture, alterations in finger haemodynamics are consequences of circulatory adjustment to standing [14]. Variations at the hydrostatic indifference point should not be extrapolated to other vascular beds. Arterial and venous pressures taken in the lower part of the body should be corrected by subtracting the pressure equivalent of the vertical distance of the hydrostatic column of blood below the heart, and pressures in the upper part by adding the distance above the heart [14]. In the adult validation group, excellent agreement of the pulse contour data for the simultaneously measured intrabrachial and finger BP recordings in a period up to 2min of standing was found (Fig. 1). Thus, we feel confident that the use of this pulse contour method on distal peripheral pressure waves such as those obtained with a Finapres device is appropriate for the comparison of percentage changes in SV, CO and TPR in this study. Initial circulatory response In the young subjects the initial cardiovascular responses follow the same time course as reported for adult subjects [6]. The magnitude of the responses appears to be even more pronounced (Figs. 1 and 2). The explanation of the characteristic initial response on standing has been described recently [6]. Orthostatic circulatory adjustment: young compared with elderly IS01 I53 I ;++ 50 8 .......................................... +l- 50 50i 200 1 - -ll- * i l - -8- ++ .8 I I : - i ++-I++ .Iti l - .e i= 100 50 -15 0 15 30 ' 60 I20 300 600 Time (I) -IS 0 15 30 60 I20 300 600 Time (s) Fig. 2 Group mean finger arterial BP (MAP) and HR responses and relative changes in SV, CO and TPR during the initial response upon standing. Average responses of 20 young subjects (left panel) and 37 elderly subjects (right panel) are shown. Briefly, the muscular effort of standing up compresses vessels in the legs and abdomen, causing an immediate translocation of blood towards the heart and increasing right atrial pressure. Left ventricular SV remains stable for the first 5s, most probably owing to the combination of the blood translocated towards the heart by the muscular effort of standing up and the buffering effect of the pulmonary blood volume [14, 151. The combination of an instantaneous HR increase and a stable SV results in a pronounced increase in CO, with a maximum around 7 s after the onset of standing. Simultaneously, a drop in mean arterial BP of about 20mmHg (Figs. 1 and 2) is found. The two phenomena taken together reflect a pronounced drop in TPR. It is our view that the immediate increase in right atrial pressure upon standing activates lowpressure receptors, resulting in a reflex release of vasoconstrictor tone [6]. In contrast, with a passive head-up tilt, an immediate fall in right atrial pressure has been reported [16] and the transient dip in arterial pressure is usually not observed [l, 2, 4, 61. Vasodilatation in the working leg and abdominal muscles is possibly an additional factor in the drop in systemic vasoconstrictor tone upon standing, but the relative contribution of reflex vasodilatation due to an increase in right atrial pressure and local vasodilatation in working muscles is unknown [l5]. In the elderly subjects (Fig. 2) standing up evoked a different cardiovascular response: the immediate temporary increase in BP during the act of standing (6s duration) was larger than in the young subjects. Meanwhile, an abrupt decrease in SV and an increase in TPR were now observed. These immediate changes resemble the response induced by the Valsalva manoeuvre [17] and are most probably due to the straining that accompanied the considerable physical activity needed for this age group to stand up quickly. From about 7 s after the onset of standing up the cardiovascular responses in the elderly subjects appeared similar to those in the young subjects. The magnitude of the initial drop in BP did not differ between the two age groups (Fig. 2). Pulse contour analysis showed that the almost identical values of the initial drop in BP could be traced back to a smaller transient rise in CO combined with a less pronounced drop in TPR in the elderly subjects. The reduction in the transient increase in CO in the elderly subjects is caused by an attenuation of the initial HR response, since SV in both groups was comparable around 7 s after the onset of 154 W . Wieling et al. Table 2. Orthostatic responses in elderly subjects subdivided into upper and lower BP quartiles during prolonged standing. Values are means SD. Statistical significance: *P <0.05, **P <O.W I compared with + u m r BP auartile. Abbreviation: MAP, finner mean arterial BP. Supine MAP(mmHg) HR (beatslmin) sv 6) co (%I TPR (%) Upright 2min MAP(mmHg) HR (beatslmin) sv (%I co ("6) TPR (%) Upper BP quartile Lower BP quartile (n=IO) (n=IO) 108+9 60+7 I00 84 f4** 54+9 I00 I00 I00 100 I00 42+40 12+8* 6+5 -22* 10 --13+8 32+ I9 3+6 7+6 -32+13 -23+ 14 38 33 14+ 12* s,6 -25+12 -17+9 43 + 32 5+4 7+6 -29+ 12 13+9* 8+5 -29+ I I - l9+ 10 46 29 3+7 7+5 -32+12 -23+ 15 5 min MAP (mmHg) HR (beatslmin) sv (%I co (%I TPR (%) IOmin MAP(mmHg) HR (beatslmin) sv (%I co !%) TPR (%) + -25+ll 44+32 standing up (Fig. 2). Attenuation of the initial HR response on standing in the elderly is a sign of diminished vagal HR responsiveness; it is attributed to age-related functional changes in the parasympathetic limb of the arterial baroreflex arc, yet the site is still debated [18-211. The less pronounced drop in TPR upon standing in the elderly subjects might be related to an agerelated reduction in vasodilator capacity. Changes in end-organ responsiveness or in the capacity involved in reflex release of vasoconstrictor tone should be taken into consideration [22-271. It must be realized, however, that the stimulus inducing cardiovascular reflex responses must have been different for the two age groups: in the elderly standing up was accompanied by a pronounced and prolonged increase in BP (Fig. 2). Early steady state and prolonged standing In the elderly subjects mean BP increased gradually by 10mmHg in the period from 30s to 10min of standing, whereas in the young subjects BP was more elevated initially, but hardly changed after 30s of standing. The increase in BP in the elderly subjects is accompanied by a progressive increase in TPR during prolonged standing; TPR increased from 114% to 146% in the period from 30s to 10min of standing (Fig. 2, Table 1). Although there is no unanimity on the vasoconstrictor response to circulatory stresses in old age, a tendency towards an augmented response during prolonged stresses has been reported in some [26, 271 but not all [28] studies. The timing of the measurement [l, 2, 151 and the use of invasive versus non-invasive measurements [7, 291 are important considerations when explaining the discrepancies between studies. In the young subjects an initial rapid increase in TPR to 125% was found, with no further change after 30s of standing. Thus the major difference between the young and old subjects investigated is the progressive increase in TPR in the elderly subjects, resulting in a larger increase in TPR after 2min of standing in the latter (Fig. 2, Tables 1 and 2). A large difference in the increase in TPR in response to orthostasis has been reported in the literature when adult normotensive subjects and hypertensive patients were compared: in the hypertensive patients the increase in TPR was greater [27]. In the present study, in the (mainly normotensive) elderly subjects the level of BP was not an influence on the TPR responses. The larger increase in mean BP during prolonged standing in the elderly subjects with the lower supine BP can be explained by a less pronounced decrease in CO upon standing in this group (Table 2). The increase in HR after 10min of standing in the young subjects is almost four times as large as in the elderly subjects (27 versus 7 beats/min). This large postural increase in HR could be considered as compensation for the more pronounced decrease in SV that we found in these subjects (Fig. 2, Table 1). We attribute this to a more pronounced gravitational pooling of blood [30-321 and the consequent reduction in heart size on standing [33, 341. Smith and co-workers [26, 351 have, indeed, shown that during lower body negative pressure and the Valsalva manoeuvre, caudal displacement of blood is more pronounced in young adult subjects. However, during head-up tilt in adult and elderly male subjects, there were no significant differences in thoracic blood volume responses [28]. The postulated increase in peripheral pooling of blood in the young subjects during orthostatic stress could be related to the function and/or structure of the lower limb veins and the surrounding skeletal muscle [14]. Initial increases in venous volume due to a shift of blood to the lower part of the body during orthostasis should be considered, enhanced by venous stress-relaxation and additional transcapillary fluid movement to the interstitial spaces [14]. The effect of age on these responses is largely unknown; evidence of disordered venous innervation has been reported in adult patients with postural tachycardia and venous distensibility has been reported to decrease with ageing [30, 36, 371. Orthostatic circulatory adjustment: young compared with elderly CONCLUSIONS Non-invasive continuous finger BP recording and pulse contour analysis of the finger arterial waveform enabled us to disclose different haemodynamic mechanisms underlying cardiovascular adjustment to orthostatic stress in healthy young and elderly subjects; it showed that in these age groups postural stress appears to evoke differential cardiovascular responses. In the active elderly subjects orthostatic BP control appears adequate, despite a blunted HR response on standing. Our data suggest that in healthy elderly subjects orthostatic stress evokes a reduced vasodilatation in the initial phase of standing. 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