Fiona G. Brodie

Reliability of dynamic cerebral autoregulation measurement using spontaneous fluctuations in blood pressure

Spontaneous fluctuations in BP (blood pressure) and subsequent change in CBFV (cerebral blood flow velocity) in the MCA (middle cerebral artery) can be used to assess dynamic cerebral autoregulation using transfer function analysis; however, the reliability of this technique has not been assessed, in particular the contribution of intra-subject variability relative to inter-subject variability. Three bilateral CBFV, BP and RR interval recordings were performed in ten healthy volunteers on four separate occasions over a 2-week period. Data were analysed to provide the ARI (autoregulatory index), CBFV, RAP (resistance-area product) and CrCP (critical closing pressure). We also measured systolic and diastolic BP, and resting HR (heart rate). We calculated the SEM (standard error of measurement) and the ICC (intra-class correlation coefficient) and their 95% CIs (confidence intervals) for each parameter to assess their absolute (intra-subject) and relative (inter-subject) reliability. The CV (coefficient of variation) of SEM ranged from 1.7% (for CBFV) to 100.0% (for RAP), whereas the ICC was <0.5 for ARI, rising to >0.8 for CBFV and diastolic BP. These data demonstrate excellent absolute and relative reliability of CBFV, whereas ARI is of comparable reliability with the measurement of HR. Using these results it is possible to determine the sample size required to demonstrate a change in ARI, with a sample of 45 subjects in each group required to show a change in ARI of 1, whereas to detect a change in ARI >2 would require only 11 subjects per group. The results of the present study could be valuable to the future planning of cerebral autoregulation studies, but more work is needed to understand the determinants of intra-subject variability in autoregulatory parameters.

Continuous estimates of dynamic cerebral autoregulation during transient hypocapnia and hypercapnia.

Dynamic cerebral autoregulation (CA) is the transient response of cerebral blood flow (CBF) to rapid blood pressure changes: it improves in hypocapnia and becomes impaired during hypercapnia. Batch-processing techniques have mostly been used to measure CA, providing a single estimate for an entire recording. A new approach to increase the temporal resolution of dynamic CA parameters was applied to transient hypercapnia and hypocapnia to describe the time-varying properties of dynamic CA during these conditions. Thirty healthy subjects (mean +/- SD: 25 +/- 6 yr, 9 men) were recruited. CBF velocity was recorded in both middle cerebral arteries (MCAs) with transcranial Doppler ultrasound. Arterial blood pressure (Finapres), end-tidal CO(2) (ET(CO(2)); infrared capnograph), and a three-lead ECG were also measured at rest and during repeated breath hold and hyperventilation. A moving window autoregressive moving average model provided continuous values of the dynamic CA index [autoregulation index (ARI)] and unconstrained gain. Breath hold led to significant increase in ET(CO(2)) (+5.4 +/- 6.1 mmHg), with concomitant increase in CBF velocity in both MCAs. Continuous dynamic CA parameters showed highly significant changes (P < 0.001), with a temporal pattern reflecting a delayed dynamic response of CA to changes in arterial Pco(2) and a maximal reduction in ARI of -5.1 +/- 2.4 and -5.1 +/- 2.3 for the right and left MCA, respectively. Hyperventilation led to a marked decrease in ET(CO(2)) (-7.2 +/- 4.1 mmHg, P < 0.001). Unexpectedly, CA efficiency dropped significantly with the inception of the metronome-controlled hyperventilation, but, after approximately 30 s, the ARI increased gradually to show a maximum change of 5.7 +/- 2.9 and 5.3 +/- 3.0 for the right and left MCA, respectively (P < 0.001). These results confirm the potential of continuous estimates of dynamic CA to improve our understanding of human cerebrovascular physiology and represent a promising new approach to improve the sensitivity of clinical applications of dynamic CA modeling.

Spontaneous fluctuations in cerebral blood flow regulation: contribution of PaCO2.

To investigate the temporal variability of dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow to rapid changes in arterial blood pressure, a new approach was introduced to improve the temporal resolution of dynamic CA assessment. Continuous bilateral recordings of cerebral blood flow velocity (transcranial Doppler, middle cerebral artery), end-tidal Pco(2) (Pet(CO(2)), infrared capnograph), and blood pressure (Finapres) were obtained at rest and during breath hold in 30 young subjects (25 ± 6 yr old) and 30 older subjects (64 ± 4 yr old). Time-varying estimates of the autoregulation index [ARI(t)] were obtained with an autoregressive-moving average model with coefficients expanded by orthogonal decomposition. The temporal pattern of ARI(t) varied inversely with Pet(CO(2)), decreasing with hypercapnia. At rest, ARI(t) showed spontaneous fluctuations that were significantly different from noise and significantly correlated with spontaneous fluctuations in Pet(CO(2)) in the majority of recordings (young: 72% and old: 65%). No significant differences were found in ARI(t) due to aging. This new approach to improve the temporal resolution of dynamic CA parameters allows the identification of physiologically meaningful fluctuations in dynamic CA efficiency at rest and in response to changes in arterial CO(2).

Dynamic Cerebral Autoregulation Is Compromised Acutely following Mild Ischaemic Stroke but Not Transient Ischaemic Attack

Background: Dynamic cerebral autoregulation (dCA), the process by which the cerebral blood flow (CBF) is normally maintained relatively constant despite fluctuations in beat-to-beat blood pressure (BP), is impaired acutely following major ischaemic stroke. It is uncertain if dCA is impaired acutely after mild ischaemic stroke or transient ischaemic attack (TIA). We assessed dCA in patients acutely and sub-acutely following TIA or mild ischaemic stroke. Methods: Nineteen consecutive mild ischaemic stroke patients and 17 consecutive TIA patients underwent recordings of beat-to-beat BP, cerebral blood flow velocity (bilateral transcranial Doppler insonation of the middle cerebral artery) and heart rate a median of 36 h from onset and again a median of 96 h from onset. Dynamic autoregulatory indices (ARI) were then calculated from these data and the results compared to 22 age-, BP- and gender-matched controls. Results: ARI was significantly reduced in affected hemispheres of mild stroke patients at baseline compared to controls (4.0 ± 1.7 vs. 5.6 ± 1.1, p < 0.01) and remained so after adjustment for significant covariates. ARI was significantly reduced in both affected (4.0 ± 2.7 vs. 5.6 ± 1.1, p = 0.03) and unaffected hemispheres (4.2 ± 1.8 vs. 5.6 ± 1.1, p = 0.01) of mild stroke patients at follow-up compared to controls. However, after adjustment for significant covariates including ipsilateral carotid stenosis these results were not significant. No reduction in ARI was seen in TIA patients. Conclusions: The impairment of cerebrovascular haemodynamic control that was observed acutely following mild ischaemic stroke may have implications for the appropriate timing of anti-hypertensive therapy acutely following mild ischaemic stroke. No impairment of cerebrovascular haemodynamic control was seen following TIA.

Controlling hypertension and hypotension immediately post stroke (CHHIPS)--a randomised controlled trial.

OBJECTIVES To assess the effects of acute pressor and depressor blood pressure (BP) manipulation on 2-week death and dependency following acute stroke and investigate the safety and efficacy of such treatments. DESIGN A multicentre, prospective, randomised, double-blind, placebo-controlled titrated-dose trial. SETTING Five hospitals in England. PARTICIPANTS Patients over 18 years admitted to hospital with a clinical diagnosis of suspected stroke and either (1) symptom onset < 36 hours and hypertension, defined as systolic BP (SBP) < 160 mmHg (depressor arm), or (2) symptom onset < 12 hours and hypotension, defined as SBP < or = 140 mmHg (pressor arm). INTERVENTIONS Patients were allocated to either the pressor or the depressor arm depending on blood pressure at randomisation. The ratio of allocation to active intervention versus matched placebo was 2:1 for the depressor arm and 1:1 for the pressor arm. MAIN OUTCOME MEASURES The primary end point was death and dependency at 2 weeks, with dependency defined as a modified Rankin score < 3. Secondary end points were the safety of acute pressor (0-12 hours post stroke) and depressor (0-36 hours post stroke) BP manipulation in stroke patients; whether effects of BP reduction are influenced by stroke type (ischaemic versus haemorrhagic); whether alternative routes for administration of antihypertensive therapy (including sublingual and intravenous) are effective in dysphagic stroke patients; whether effects of BP manipulation are influenced by the time to treatment; and the short- and medium-term cost-effectiveness of such therapy in the acute post-stroke period on subsequent disability or death. RESULTS 180 patients were recruited over the 36-month trial period, 179 in the depressor arm and one in the pressor arm (who received placebo). No significant difference was found in death or dependency at 2 weeks between those receiving active depressor treatment with lisinopril or labetalol and those receiving placebo, although numbers recruited to the trial were lower than projected. Active treatment was not associated with an increase in early neurological deterioration despite significantly greater reductions in BP at 24 hours and 2 weeks with active therapy compared with placebo. Active treatment was generally well tolerated and treatment discontinuation rates were similar in active and placebo groups. Survival analysis showed that the active treatment group had a lower mortality at 3 months than the placebo group (p = 0.05). The pressor arm was closed early because of problems with recruitment, so no conclusions can be drawn regarding this therapy. CONCLUSIONS Oral and sublingual lisinopril and oral and intravenous labetalol are effective BP-lowering agents in acute cerebral infarction and haemorrhage and do not increase the likelihood of early neurological deterioration. The study was not sufficiently powered to detect a difference in disability or death at 2 weeks. However, the 3-month difference in mortality in favour of active treatment is of interest, although care must be taken in interpretation of the results. Further work is needed to confirm this and to assess whether there are differences in the effectiveness of labetalol compared with lisinopril in terms of reducing death or dependency after acute stroke, and whether the introduction of treatment post stroke earlier than was achieved here would be of greater benefit.

Long-term changes in dynamic cerebral autoregulation: a 10 years follow up study

This study takes a novel approach to describing time‐related changes in dynamic cerebral autoregulation (dCA). It is well‐recognized that dCA exhibits both intra‐ and inter‐ subject variability, and this study seeks to characterize the extent to which intra‐subject variability occurs after a significant period of time by studying the same subjects 10 years apart, thus eliminating inter‐subject variability as a source of error. Ten healthy subjects were identified in 1998 and followed up in 2008. On each visit they underwent simultaneous recordings of right middle cerebral artery cerebral blood flow velocity (RMCA CBFV), blood pressure and heart rate. Data were analysed in the frequency domain using transfer function analysis and in the time domain using CBFV step response, from which the autoregulatory index (ARI) was calculated. Ten subjects of mean age 35·5 (range 24–51) years in 1998 (seven male) were studied. There was a significant fall in ARI from 1998–2008 (ΔARI = 1·1, P = 0·021), along with a significant rise in coherence in 2008 (at 0·05 Hz, P = 0·018). Difference in mean step response between 1998 and 2008 was also significant (P = 0·045). This is the first study to assess dCA in the same subjects 10 years apart, providing a novel opportunity to assess intra‐subject variation in dCA after a long time period has elapsed. A fall in frequency and time domain parameters was observed. This is important, and needs to be considered in future studies assessing long‐term changes in dCA, particularly given the body evidence which suggests that dCA is unaffected by ageing.

The Leicester cerebral haemodynamics database: normative values and the influence of age and sex

Normative values of physiological parameters hold significance in modern day clinical decision-making. Lack of such normative values has been a major hurdle in the translation of research into clinical practice. A large database containing uniform recordings was constructed to allow more robust estimates of normative ranges and also assess the influence of age and sex. Doppler recordings were performed on healthy volunteers in the same laboratory, using similar protocols and equipment. Beat-to-beat blood pressure, heart-rate, electrocardiogram, and end-tidal CO2 were measured continuously. Bilateral insonation of the middle cerebral arteries (MCAs) was performed using TCD following a 15 min stabilisation, and a 5 min baseline recording. Good quality Doppler recordings for both MCAs were obtained in 129 participants (57 female) with a median age of 57 years (range 20-82). Age was found to influence baseline haemodynamic and transfer function analysis parameters. Cerebral blood flow velocity and critical closing pressure were the only sex-related differences found, which was significantly higher in females than males. Normative values for cerebral haemodynamic parameters have been defined in a large, healthy population. Such age/sex-defined normal values can be used to reduce the burden of collecting additional control data in future studies, as well as to identify disease-associated changes.

Effects of ageing on cerebral haemodynamics assessed during respiratory manoeuvres

BACKGROUND cerebral autoregulation (CA) is the ability to control cerebral blood flow during fluctuations in arterial blood pressure (ABP). It is impaired in a number of conditions including acute stroke, though studies so far have not found a decline in CA with age. CA is very sensitive to changes in pCO₂. OBJECTIVE this study investigates the effect of ageing on CA using a moving-window autoregressive moving average (MW-ARMA) to calculate CA as autoregulatory index (ARMA-ARI) during hypercapnia and hypocapnia, to ascertain whether this method would detect age-related differences in CA due to change in pCO₂. METHOD ECG was used to measure R-R interval, Finapres to measure ABP and capnography to measure end-tidal CO₂. Transcranial Doppler ultrasonography was used to measure left and right middle cerebral artery cerebral blood flow velocity (CBFV). Hypercapnia was induced by a breath-hold, hypocapnia by hyperventilation. RESULTS thirty volunteers of mean age 25 ± 6 years and 30 volunteers of mean age 64 ± 4 years were recruited. CBFV was higher and change in CBFV due to respiratory manoeuvre was significantly greater in the younger group compared with the older group. However, no difference in ARMA-ARI was found between the groups. CONCLUSION these findings suggest that CA is not affected by healthy ageing.

Signal-to-noise ratio of bilateral nonimaging transcranial Doppler recordings of the middle cerebral artery is not affected by age and sex.

Differences between transcranial Doppler ultrasonography (TCD) recordings of symmetrical vessels can show true physiologic differences, but can also be caused by measurement error and other sources of noise. The aim of this project was to assess the influence of noise on estimates of dynamic cerebral autoregulation (dCA), and of age, sex and breathing manoeuvres on the signal-to-noise ratio (SNR). Cerebral blood flow (CBF) was monitored in 30 young (<40 years) and 30 older volunteers (age >60 years) during baseline conditions, breath-holding and hyperventilation. Noise was defined as the difference between beat-to-beat values of the two mean CBF velocity (CBFV) signals. Magnitude squared coherence estimates of noise vs. ABP and ABP vs. CBFV were obtained and averaged. A similar approach was adopted for the CBFV step response. The effect of age and breathing manoeuvre on the SNR was assessed using a two-way analysis of variance (ANOVA), whilst the effect of sex was investigated using a Students t test. No significant differences were observed in SNR (baseline 6.07 ± 3.07 dB and 7.33 ± 3.84 dB, breath-hold: 13.53 ± 3.93 dB and 14.64 ± 4.52 dB, and hyperventilation: 14.69 ± 4.04 dB and 14.84 ± 4.05 dB) estimates between young and old groups, respectively. The use of breathing manoeuvres significantly improved the SNR (p < 10(-4)) without a significant difference between manoeuvres. Sex does not appear to have an effect on SNR (p = 0.365). Coherence estimates were not influenced by the SNR, but significant differences were found in the amplitude of the CBFV step response.

Cerebral Haemodynamics following Acute Ischaemic Stroke: Effects of Stroke Severity and Stroke Subtype.

Background: Acute ischaemic stroke (AIS) patients often show impaired cerebral autoregulation (CA). We tested the hypothesis that CA impairment and other alterations in cerebral haemodynamics are associated with stroke subtype and severity. Methods: AIS patients (n = 143) were amalgamated from similar studies. Data from baseline (< 48 h stroke onset) physiological recordings (beat-to-beat blood pressure [BP], cerebral blood flow velocity (CBFV) from bilateral insonation of the middle cerebral arteries) were calculated for mean values and autoregulation index (ARI). Differences were assessed between stroke subtype (Oxfordshire Community Stroke Project [OCSP] classification) and severity (National Institutes of Health Stroke Scale [NIHSS] score < 5 and 5–25). Correlation coefficients assessed associations between NIHSS and physiological measurements. Results: Thirty-two percent of AIS patients had impaired CA (ARI < 4) in affected hemisphere (AH) that was similar between stroke subtypes and severity. CBFV in AH was comparable between stroke subtype and severity. In unaffected hemisphere (UH), differences existed in mean CBFV between lacunar and total anterior circulation OCSP subtypes (42 vs. 56 cm•s–1, p < 0.01), and mild and moderate-to-severe stroke severity (45 vs. 51 cm•s–1, p = 0.04). NIHSS was associated with peripheral (diastolic and mean arterial BP) and cerebral haemodynamic parameters (CBFV and ARI) in the UH. Conclusions: AIS patients with different OCSP subtypes and severity have homogeneity in CA capability. Cerebral haemodynamic measurements in the UH were distinguishable between stroke subtype and severity, including the association between deteriorating ARI in UH with stroke severity. More studies are needed to determine their clinical significance and to understand the determinants of CA impairment in AIS patients.