Do abnormalities in dynamic cerebral auto-regulation underlie the pathophysiological processes

409 Pages·2015·6.2 MB·English

Do abnormalities in dynamic
cerebral auto-regulation
underlie the
pathophysiological processes
behind syncope in older

people?
Alice C. L. Ong
Faculty of Medicine & Health Sciences
PhD Thesis 2014
This copy of the thesis has been supplied on condition that anyone who consults it is
understood to recognize that its copyright rests with the author and that use of any
information derived there from must be in accordance with current UK Copyright Law. In
addition, any quotation or extract must include full attribution.
Abstract
Do abnormalities in dynamic cerebral auto-regulation underlie the
pathophysiological processes behind syncope in older people?
Introduction: The aim of this thesis was to investigate whether abnormalities in
dynamic cerebral auto-regulation (dCA) explain the symptoms associated with
orthostatic (OH) and post-prandial hypotension (PPH).
Methods: Based on clinical symptoms and signs for the OH study: 4 Groups:
Asymptomatic No OH (control), Symptomatic No OH, Asymptomatic OH, and
Symptomatic OH. PPH study: double-blind placebo controlled cross-over study of
glucose (50g) drink. 2 Groups: No PPH (control) and PPH. Baseline and head-up-tilt
(HUT, for OH maximum 30 minutes study or to symptoms; PPH study maximum 60
minutes per visit). All had Transcranial Doppler ultrasound, beat-to-beat BP, ECG and
CO monitoring. Baseline autonomic function, arterial stiffness, cardiac baroreceptor
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sensitivity (BRS) were calculated and dynamic cerebral auto-regulation (as the auto-
regulatory index ARI) assessed before and during tilt.
Results: OH: n=85, mean age 73.9±7.1 years; PPH: n= 40, mean age 73.4±7.3 years
Baseline: No significant differences were found between groups for cardiac BRS,
arterial stiffness, cerebral blood flow velocity (CBFV) or dCA in either study. HUT
both studies: falls in BP, CO and CBFV, increases in HR, and fall in ARI amongst
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symptomatic subjects prior to the end of HUT (maximum duration or symptom onset)
compared to pre-HUT values. PPH study: fall in ARI with HUT irrespective of
whether glucose or placebo phase.
Conclusions: The development of symptoms during tilt in both studies was related to a
fall in CBFV and impaired cerebral auto-regulation. Abnormalities in cerebral auto-
regulation may explain the symptoms of OH and PPH although these changes can only
be detected during head-up-tilt.

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Contents

1 Introduction ......................................................................................................................... 1
2 Background ......................................................................................................................... 3
2.1 Orthostatic Hypotension and Post-Prandial Hypotension in the context of Syncope . 3
2.2 Orthostatic Hypotension (OH) .................................................................................... 5
2.2.1 Definition ............................................................................................................ 5
2.2.2 Epidemiology ...................................................................................................... 7
2.2.3 Morbidity and Mortality .................................................................................... 11
2.2.4 Clinical Presentation ......................................................................................... 12
2.3 Post-prandial Hypotension (PPH) ............................................................................. 14
2.3.1 Definition .......................................................................................................... 14
2.3.2 Epidemiology .................................................................................................... 14
2.3.3 Morbidity & Mortality ...................................................................................... 15
2.3.4 Clinical Presentation ......................................................................................... 16
2.4 The relationship between the pathophysiology of OH, PPH and symptoms ............ 17
2.4.1 The case of OH ................................................................................................. 17
2.4.2 The case of PPH ................................................................................................ 19
2.5 The physiological processes...................................................................................... 20
2.6 Cerebral auto-regulation ........................................................................................... 21
2.6.1 Physiology ......................................................................................................... 21
2.7 The physiological response to standing .................................................................... 27
2.7.1 Systemic BP and standing ................................................................................. 27
2.8 The baroreceptor reflex arc ....................................................................................... 32
2.8.1 About baroreceptor sensitivity .......................................................................... 33
2.9 Active versus passive upright posture ....................................................................... 36
2.9.1 Younger adults .................................................................................................. 36
2.9.2 Older adults ....................................................................................................... 37
2.9.3 The Haemodynamic response to tilt .................................................................. 38
2.9.4 Cerebral blood flow and postural change .......................................................... 39
2.10 The physiological response to eating ........................................................................ 40
2.11 Changes in Cardiac BRS with age and disease ......................................................... 42
2.12 Pulse Wave Velocity, Augmentation Index and Arterial Stiffness ........................... 44
2.12.1 Arterial stiffness and disease ............................................................................. 44
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2.13 Cerebral auto-regulation and ageing ......................................................................... 45
2.14 Dynamic cerebral auto-regulation and arterial baroreceptor sensitivity ................... 46
2.15 Cerebral auto-regulation and symptoms in subjects with OH and PPH ................... 46
2.16 Summary of the issues .............................................................................................. 50
3 A systematic review of the pharmacological management of orthostatic hypotension .... 52
3.1 Introduction ............................................................................................................... 52
3.2 Methods..................................................................................................................... 54
3.2.1 Study selection .................................................................................................. 54
3.2.2 Data extraction and synthesis ............................................................................ 55
3.3 Results ....................................................................................................................... 62
3.3.1 Systematic review of ‘Repeated doses’ drug interventions .............................. 62
3.3.2 Systematic review of ‘Single dose’ drug intervention ...................................... 66
3.3.3 Bias ................................................................................................................... 71
3.4 Discussion ................................................................................................................. 72
3.5 Conclusions ............................................................................................................... 78
4 Pharmacological Treatment of Post-prandial Reductions in Blood Pressure: A Systematic
Review ...................................................................................................................................... 79
4.1 Introduction ............................................................................................................... 79
4.2 Methods..................................................................................................................... 81
4.2.1 Eligibility Criteria ............................................................................................. 81
4.2.2 Information Sources .......................................................................................... 81
4.2.3 Search Terms .................................................................................................... 82
4.2.4 Data Collection ................................................................................................. 82
4.2.5 Data Items ......................................................................................................... 83
4.2.6 Risk of Bias in Individual Studies ..................................................................... 83
4.2.7 Summary Measures ........................................................................................... 83
4.3 Results ....................................................................................................................... 84
4.3.1 Single dose Studies ........................................................................................... 90
4.3.2 Repeated doses Studies ..................................................................................... 94
4.3.3 Results Summary .............................................................................................. 94
4.4 Discussion ................................................................................................................. 97
4.5 Conclusion .............................................................................................................. 101
5 Methodology ................................................................................................................... 102
5.1 Introduction ............................................................................................................. 102
5.2 Assessing autonomic function ................................................................................ 103
5.3 Assessing Arterial Stiffness .................................................................................... 104
5.4 Measuring Blood Pressure ...................................................................................... 106
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5.5 Measuring carbon dioxide ....................................................................................... 111
5.6 Measuring spontaneous cardiac BRS ...................................................................... 112
5.7 Estimating cerebral auto-regulation ........................................................................ 118
5.7.1 Transcranial Doppler Ultrasound .................................................................... 118
5.7.2 Static CA ......................................................................................................... 121
5.7.3 Dynamic CA ................................................................................................... 123
5.7.4 Limitations ...................................................................................................... 132
6 General Methods ............................................................................................................. 133
6.1 Recruitment ............................................................................................................. 133
6.2 Sample size ............................................................................................................. 134
6.3 Inclusion criteria ..................................................................................................... 135
6.4 Exclusion criteria .................................................................................................... 135
6.5 Consent ................................................................................................................... 135
6.6 Ethics....................................................................................................................... 136
6.7 Measurements ......................................................................................................... 136
6.7.1 Clinical Data ................................................................................................... 136
6.7.2 Autonomic Function Tests .............................................................................. 137
6.7.3 Laboratory Data .............................................................................................. 142
6.7.4 Transcranial Doppler Measurements Generic Procedure................................ 142
6.7.5 Baroreflex sensitivity ...................................................................................... 149
6.7.6 Pulse Wave Velocity and Augmentation Index .............................................. 149
6.7.7 Data analysis ................................................................................................... 153
7 Methods - Orthostatic Hypotension Study ...................................................................... 157
7.1 Aims ........................................................................................................................ 157
7.2 Methods................................................................................................................... 157
7.2.1 Recruitment ..................................................................................................... 157
7.2.2 Study Groups .................................................................................................. 157
7.2.3 Data collection ................................................................................................ 158
7.2.4 Data analysis ................................................................................................... 158
8 Results – Orthostatic Hypotension Study - Baseline ...................................................... 159
8.1 Baseline data ........................................................................................................... 159
8.2 Population summary ............................................................................................... 161
8.3 Baroreceptor Sensitivity .......................................................................................... 162
8.4 Arterial Stiffness ..................................................................................................... 162
8.5 Baseline Supine Cerebral Haemodynamic Measurements ..................................... 166
8.5.1 Supine Measurements ..................................................................................... 166
8.5.2 Estimates of supine Dynamic Cerebral Auto-regulation (Tiecks model) ....... 166
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8.5.3 Baseline ARI and ARMA ARI estimates of Dynamic Cerebral Auto-regulation
167
8.6 Orthostatic Hypotension Study – Summary of Baseline Data Results ................... 171
9 Orthostatic Hypotension Study – Discussion of Baseline Data ...................................... 172
10 Orthostatic Hypotension Study – Effects of Head-Up-Tilt ......................................... 176
10.1 Cerebral Blood Flow Velocities and Blood Pressure .............................................. 176
10.1.1 Group Measurements ...................................................................................... 176
10.1.2 Blood Pressure and Heart Rate with HUT ...................................................... 178
10.1.3 Cerebral Haemodynamic measurements with HUT........................................ 180
10.1.4 Group Changes during HUT ........................................................................... 183
10.1.5 Time varying estimates of ARI ....................................................................... 191
10.1.6 The changes in Time varying estimates of ARI .............................................. 198
10.2 Sub-Group Analysis of Original Groups with HUT ............................................... 203
10.2.1 Comparing symptomatic versus asymptomatic HUT within original groups . 203
10.2.2 Comparing symptomatic versus asymptomatic HUT – All groups combined 207
10.3 Orthostatic Hypotension Study – Effects of HUT Results Summary ..................... 212
11 Orthostatic Hypotension Study – Discussion of Effects of HUT................................ 214
12 Closing Remarks on the Orthostatic Hypotension Study ............................................ 219
12.1 Orthostatic Hypotension Study Results Summary .................................................. 219
12.2 Discussion of the Orthostatic Hypotension Study .................................................. 220
12.3 Future work in the Orthostatic Hypotension Study ................................................. 223
12.4 Conclusion of the Orthostatic Hypotension Study .................................................. 223
13 Post-Prandial Hypotension Study ............................................................................... 224
13.1 Aims ........................................................................................................................ 224
13.2 Methods................................................................................................................... 224
13.2.1 Participants ...................................................................................................... 224
13.2.2 Randomisation ................................................................................................ 225
13.2.3 Data Analysis .................................................................................................. 226
14 Results - Post-Prandial Hypotension Study - Baseline ............................................... 227
14.1 Post-Prandial Hypotension Study Recruitment ....................................................... 227
14.2 Baseline data for the PPH Study ............................................................................. 229
14.2.1 Population summary ....................................................................................... 229
14.2.2 Cardiac Baroreceptor Sensitivity .................................................................... 229
14.2.3 Arterial Stiffness ............................................................................................. 230
14.3 Baseline Supine Cerebral Haemodynamic values of PPH study participants ......... 234
14.3.1 Cerebral Haemodynamic Supine Measurements ............................................ 234
14.3.2 Estimates of supine ARI (Tiecks model) ........................................................ 234
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14.3.3 ARI and ARMA ARI estimates ...................................................................... 234
14.4 Post-Prandial Hypotension Study – Summary of Baseline Data Results ................ 238
15 Post-Prandial Hypotension Study – Discussion of Baseline Data .............................. 239
16 Post-Prandial Hypotension Study – Effects of HUT ................................................... 241
16.1 Duration of HUT ..................................................................................................... 241
16.2 Capillary blood glucose .......................................................................................... 242
16.3 Cerebral Blood Flow Velocity and Blood Pressure changes .................................. 244
16.3.1 Blood Pressure and Heart Rate with HUT ...................................................... 244
16.3.2 Cerebral Haemodynamic responses to HUT ................................................... 247
16.4 Group Changes during HUT ................................................................................... 249
16.4.1 Changes in Blood Pressure and Heart Rate ..................................................... 249
16.4.2 Changes in Cerebral Haemodynamic values ................................................... 251
16.5 Time varying estimates of ARI ............................................................................... 253
16.5.1 The “UP” component: Pre-HUT ..................................................................... 253
16.5.2 The “UP” component: HUT 1 minute ............................................................. 254
16.5.3 The “UP” component: HUT 2 minutes ........................................................... 254
16.5.4 Group Changes during HUT ........................................................................... 258
16.6 Sub-group analysis .................................................................................................. 261
16.6.1 Post-prandial fall in BP ................................................................................... 261
16.6.2 No post-prandial fall in BP ............................................................................. 264
16.6.3 BP fall versus No BP fall comparison............................................................. 267
16.6.4 Symptomatic versus Asymptomatic combined groups ................................... 268
16.7 Post-Prandial Hypotension Study – Effects of HUT Results Summary ................. 270
16.8 Post-Prandial Hypotension Study – Discussion of Effects of HUT ........................ 272
17 Summary of Results: Post-Prandial Hypotension Study ............................................. 274
18 Summary of Discussion: Post-Prandial Hypotension Study ....................................... 276
19 Thesis Discussion ........................................................................................................ 281
20 Future Work ................................................................................................................ 290
21 Appendix ..................................................................................................................... 291
22 References ................................................................................................................... 366

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List of Figures
Figure 1 Reduced probability of survival with syncope of differing aetiology over a 25 year
period (Adapted from Figure 2 in Soteriades et al, 2002)[The Kaplan Meier survival curves
demonstrate that those with cardiac syncope have a lower survival than those without syncope]
.................................................................................................................................................... 2
Figure 2 Cerebral Auto-regulation Curve under stable conditions ........................................... 24
Figure 3 The Auto-regulatory Index (ARI), adapted from Tiecks et al. (2005) ....................... 26
Figure 4 Normal control of BP ................................................................................................. 29
Figure 5 Brainstem control of BP [Key: AH=anterior hypothalamus, CVM=caudal
ventrolateral medulla, DVN=dorsal vagal motonucleus, NA=nucleus ambigus, NTS=nucleus
tractus solitarius, RVM=rostral ventrolateral medulla] ........................................................... 31
Figure 6 Baroreceptor discharge and mean arterial pressure (MAP) (adapted from Berdeaux
and Giudicelli, 1987) ................................................................................................................ 32
Figure 7 Normal BRS. SBP (solid line) and corresponding RR interval (dotted line) for
consecutive beats. ..................................................................................................................... 34
Figure 8 Normal BRS. Correlation of regression line between SBP and RR interval. ........ 34
Figure 9 Abnormal BRS. SBP (solid line) and corresponding RR interval (dotted line) for
consecutive beats. ..................................................................................................................... 35
Figure 10 Abnormal BRS. Correlation of regression line between SBP and RR interval. .. 35
Figure 11 Flow diagram of Orthostatic Hypotension Treatment Systematic Review .............. 57
Figure 12 Flow diagram of post-prandial BP reductions systematic review of drug treatment 85
Figure 13 Augmentation Index (AIx) calculation (adapted from Wilkinson et al., 1998a) .... 106
Figure 14 Time and Frequency Domain of a BP signal .......................................................... 108
Figure 15 SBP (A) and R-R interval (B) with Time, Power Density Spectrum of SBP (C) and
R-R interval (D), Coherence between SBP and R-R interval (E), Modulus or Gain (F) ........ 116
Figure 16 Auto-regulatory indices, Tiecks et al. (2005) ......................................................... 126
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Figure 17 Principles of Transfer Function Analysis. [The diagram shows two sinuoidal
waveforms and within the period (T), the phase shift illustrates a delay between solid wave and
dotted wave, and an alteration in gain] ................................................................................... 129
Figure 18 Taskforce Monitor Screen showing ECG, beat-to-beat BP and oscillometric BP . 138
Figure 19 Taskforce connections ............................................................................................ 138
Figure 20 Taskforce beat-to-beat BP measurements .............................................................. 139
Figure 21 Handgrip using Greenlight 300 blood pressure cuff............................................... 141
Figure 22 Transcutaneous carbon dioxide sensor (TINA) ...................................................... 144
Figure 23 Finapres BP finger cuff........................................................................................... 144
Figure 24 Finapres BP monitor ............................................................................................... 145
Figure 25 ECG signal .............................................................................................................. 145
Figure 26 Doppler signal showing CBFV from Left MCA (A) and Right MCA (B). Doppler
signal (C) towards probe (red) and signal away from probe (blue). Left and right CBFV
superimposed on each other in real time recording (D). ......................................................... 146
Figure 27 Physidas screen ....................................................................................................... 147
Figure 28 Headband holding transducers (as demonstrated by a colleague) .......................... 150
Figure 29 Neck cuff of Vicorder ............................................................................................. 151
Figure 30 Thigh cuff of Vicorder ............................................................................................ 151
Figure 31 Vicorder Unit .......................................................................................................... 152
Figure 32 Vicorder screen showing adequate tracings for carotid and femoral pulses ........... 152
Figure 33 Flowchart for the Orthostatic Hypotension Study .................................................. 160
Figure 34 The effect of HUT on SBP (…. = varying time scale) ........................................... 178
Figure 35 The effect of HUT on DBP (…. = varying time scale) .......................................... 179
Figure 36 The effect of MAP with HUT (…. = varying time scale) ...................................... 179
Figure 37 The effect of HUT on HR (…. = varying time scale) ............................................. 180
Figure 38 The effect of HUT on mean CBFV ........................................................................ 181
Figure 39 The effect of HUT on tCO .................................................................................... 181
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Figure 40 The mean group change in SBP during HUT ......................................................... 184
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Figure 41 The mean group change in DBP during HUT (The change from pre-HUT to HUT at
1 and 3 minutes, and in the minute prior to the end of HUT) ................................................. 184
Figure 42 The mean group change in HR during HUT (The change from pre-HUT to HUT at 1
and 3 minutes, and in the minute prior to the end of HUT) .................................................... 185
Figure 43 The mean group change in CBFV (combined mean of left and right CBFV) during
HUT (The change from pre-HUT to HUT at 1 and 3 minutes, and in the minute prior to the
end of HUT) ............................................................................................................................ 186
Figure 44 The mean group change in systolic CBFV (combined mean of left and right CBFV)
during HUT (The change from pre-HUT to HUT at 1 and 3 minutes, and in the minute prior to
the end of HUT) ...................................................................................................................... 186
Figure 45 The mean group change in diastolic CBFV (combined mean of left and right CBFV)
during HUT (The change from pre-HUT to HUT at 1 and 3 minutes, and in the minute prior to
the end of HUT) ...................................................................................................................... 187
Figure 46 Changes in BP and CBFV during HUT - Asymptomatic No OH (control) group . 187
Figure 47 Changes in BP and CBFV during HUT - Symptomatic No OH group .................. 188
Figure 48 Changes in BP and CBFV during HUT - Asymptomatic OH group ...................... 188
Figure 49 Changes in BP and CBFV during HUT - Symptomatic OH group ........................ 189
Figure 50 The mean group change in tCO during HUT (The change from pre-HUT to HUT at
2
1 and 3 minutes, and in the minute prior to the end of HUT) ................................................. 189
Figure 51 Time varying estimate of the mean ARI (combined left and right) during HUT(Data
calculated from time-varying estimates, Pre-HUT value is not always equal to the baseline
value) ...................................................................................................................................... 192
Figure 52 Time varying ARI of Right MCA during HUT (Data calculated from time-varying
estimates, Pre-HUT value is not always equal to the baseline value) .................................... 193
Figure 53 Time varying ARI of Left MCA during HUT (Data calculated from time-varying
estimates, Pre-HUT value is not always equal to the baseline value) .................................... 194
Figure 54 Percentage change in MAP from pre-HUT during HUT ........................................ 198
Figure 55 Percentage change in HR from pre-HUT during HUT ........................................... 199
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