Dynamic cerebral autoregulation is impaired during submaximal isometric handgrip in patients with heart failure.

The incidence of neurological complications, including stroke and cognitive dysfunction, is elevated in patients with heart failure (HF) with reduced ejection fraction. We hypothesized that the cerebrovascular response to isometric handgrip (iHG) is altered in patients with HF. Adults with HF and healthy volunteers were included. Cerebral blood velocity (CBV; transcranial Doppler, middle cerebral artery) and arterial blood pressure (BP; Finometer) were continuously recorded supine for 6 min, corresponding to 1 min of baseline and 3 min of iHG exercise, at 30% maximum voluntary contraction, followed by 2 min of recovery. The resistance-area product was calculated from the instantaneous BP-CBV relationship. Dynamic cerebral autoregulation (dCA) was assessed with the time-varying autoregulation index estimated from the CBV step response derived by an autoregressive moving-average time-domain model. Forty patients with HF and 23 BP-matched healthy volunteers were studied. Median left ventricular ejection fraction was 38.5% (interquartile range: 0.075%) in the HF group. Compared with control subjects, patients with HF exhibited lower time-varying autoregulation index during iHG, indicating impaired dCA ( P < 0.025). During iHG, there were steep rises in CBV, BP, and heart rate in control subjects but with different temporal patterns in HF, which, together with the temporal evolution of resistance-area product, confirmed the disturbance in dCA in HF. Patients with HF were more likely to have impaired dCA during iHG compared with age-matched control subjects. Our results also suggest an impairment of myogenic, neurogenic, and metabolic control mechanisms in HF. The relationship between impaired dCA and neurological complications in patients with HF during exercise deserves further investigation. NEW & NOTEWORTHY Our findings provide the first direct evidence that cerebral blood flow regulatory mechanisms can be affected in patients with heart failure during isometric handgrip exercise. As a consequence, eventual blood pressure modulations are buffered less efficiently and metabolic demands may not be met during common daily activities. These deficits in cerebral autoregulation are compounded by limitations of the systemic response to isometric exercise, suggesting that patients with heart failure may be at greater risk for cerebral events during exercise.

How many squat-stand manoeuvres to assess dynamic cerebral autoregulation?

PURPOSE: Squat-stand manoeuvres (SSMs) have been used to induce blood pressure (BP) changes for the reliable assessment of dynamic cerebral autoregulation. However, they are physically demanding and thus multiple manoeuvres can be challenging for older subjects. This study aimed to determine the minimum number of SSMs required to obtain satisfactory coherence, thus minimising the subjects' workload. METHOD: 20 subjects performed SSMs at a frequency of 0.05 Hz. End-tidal CO2, cerebral blood flow velocity, heart rate, continuous BP and the depth of the squat were measured. 11 subjects returned for a repeat visit. The time points at which subjects had performed 3, 6, 9, 12 and 15 SSMs were determined. Transfer function analysis was performed on files altered to the required length to obtain estimates of coherence and the autoregulation index (ARI). RESULTS: After three SSMs, coherence (0.05 Hz) was 0.93 ± 0.05, and peaked at 0.95 ± 0.02 after 12 manoeuvres. ARI decreased consecutively with more manoeuvres. ARI was comparable across the two visits (p = 0.92), but coherence was significantly enhanced during the second visit (p < 0.01). The intra-subject coefficients of variation (CoV) for ARI remained comparable as the number of manoeuvres varied. CONCLUSIONS: This analysis can aid those designing SSM protocols, especially where participants are unable to tolerate a standard 5-min protocol or when a shorter protocol is needed to accommodate additional tests. We emphasise that fewer manoeuvres should only be used in exceptional circumstances, and where possible a full set of manoeuvres should be performed. Furthermore, these results need replicating at 0.10 Hz to ensure their applicability to different protocols.

Cerebral blood flow autoregulation in ischemic heart failure.

Patients with ischemic heart failure (iHF) have a high risk of neurological complications such as cognitive impairment and stroke. We hypothesized that iHF patients have a higher incidence of impaired dynamic cerebral autoregulation (dCA). Adult patients with iHF and healthy volunteers were included. Cerebral blood flow velocity (CBFV, transcranial Doppler, middle cerebral artery), end-tidal CO2 (capnography), and arterial blood pressure (Finometer) were continuously recorded supine for 5 min at rest. Autoregulation index (ARI) was estimated from the CBFV step response derived by transfer function analysis using standard template curves. Fifty-two iHF patients and 54 age-, gender-, and BP-matched healthy volunteers were studied. Echocardiogram ejection fraction was 40 (20-45) % in iHF group. iHF patients compared with control subjects had reduced end-tidal CO2 (34.1 ± 3.7 vs. 38.3 ± 4.0 mmHg, P < 0.001) and lower ARI values (5.1 ± 1.6 vs. 5.9 ± 1.0, P = 0.012). ARI <4, suggestive of impaired CA, was more common in iHF patients (28.8 vs. 7.4%, P = 0.004). These results confirm that iHF patients are more likely to have impaired dCA compared with age-matched controls. The relationship between impaired dCA and neurological complications in iHF patients deserves further investigation.

Cerebral Hemodynamic Effects of Cheyne-Stokes Respiration in a Patient with Stroke.

INTRODUCTION: Cheyne-Stokes respiration (CSR) and central sleep apnea (CSA) are common in patients with heart failure and/or stroke. We aim to describe the cerebrovascular effects of CSR during the acute phase of stroke in a heart failure patient. CASE REPORT: A 74-year-old male with previous dilated cardiomyopathy had sudden onset of right hemiparesis and aphasia. A transcranial Doppler was performed with continuous measurement of blood pressure (BP) (Finometer) and end-tidal CO2 (nasal capnography). Offline analysis of hemodynamic data disclosed relatively large periodic oscillations of both cerebral blood flow velocity and BP related to the CSR breathing pattern. Derivate variables from the cerebrovascular resistance were calculated (critical closing pressure and resistance-area product), demonstrating that there may be a myogenic impairment of cerebral blood flow (CBF) control in the affected hemisphere of this subgroup of patient. CONCLUSION: There is an impairment of CBF regulation in the affected hemisphere of the patient with ischemic stroke and CSR, highlighting the role of cerebral hemodynamic monitoring in this scenario.

Cerebrovascular effects of the thigh cuff maneuver.

Arterial hypotension can be induced by sudden release of inflated thigh cuffs (THC), but its effects on the cerebral circulation have not been fully described. In nine healthy subjects [aged 59 (9) yr], bilateral cerebral blood flow velocity (CBFV) was recorded in the middle cerebral artery (MCA), noninvasive arterial blood pressure (BP) in the finger, and end-tidal CO2 (ETCO2) with nasal capnography. Three THC maneuvers were performed in each subject with cuff inflation 20 mmHg above systolic BP for 3 min before release. Beat-to-beat values were extracted for mean CBFV, BP, ETCO2 , critical closing pressure (CrCP), resistance-area product (RAP), and heart rate (HR). Time-varying estimates of the autoregulation index [ARI(t)] were also obtained using an autoregressive-moving average model. Coherent averages synchronized by the instant of cuff release showed significant drops in mean BP, CBFV, and RAP with rapid return of CBFV to baseline. HR, ETCO2 , and ARI(t) were transiently increased, but CrCP remained relatively constant. Mean values of ARI(t) for the 30 s following cuff release were not significantly different from the classical ARI [right MCA 5.9 (1.1) vs. 5.1 (1.6); left MCA 5.5 (1.4) vs. 4.9 (1.7)]. HR was strongly correlated with the ARI(t) peak after THC release (in 17/22 and 21/24 recordings), and ETCO2 was correlated with the subsequent drop in ARI(t) (19/22 and 20/24 recordings). These results suggest a complex cerebral autoregulatory response to the THC maneuver, dominated by myogenic mechanisms and influenced by concurrent changes in ETCO2 and possible involvement of the autonomic nervous system and baroreflex.

Dynamic cerebral autoregulation assessed by respiratory manoeuvres in non-insulin-treated Type 2 diabetes mellitus.

AIMS: This study investigated dynamic cerebral autoregulation in Type 2 diabetes, where dynamic cerebral autoregulation may be impaired as a consequence of microvascular changes and/or autonomic neuropathy. METHODS: Eleven healthy control subjects and 11 age- and sex-matched patients with Type 2 diabetes controlled with lifestyle modifications or oral anti-diabetes treatment were recruited. Dynamic cerebral autoregulation was calculated by the autoregressive moving average autoregulatory index from a continuous blood pressure and R-R interval (time between each ventricular systole) recording. End-tidal carbon dioxide was also monitored and changes in response to breath holding and hyperventilation as a metabolic stimulus were measured. RESULTS: No significant differences were seen in cerebral blood flow velocity at baseline, or in response to breath holding between people with diabetes and control subjects, although the cerebral blood flow velocity response associated with hyperventilation was significantly reduced in the diabetes group. No significant differences in dynamic cerebral autoregulation were seen at baseline or in response to respiratory manoeuvres between the groups. CONCLUSIONS: Dynamic cerebral autoregulation is not impaired in patients with Type 2 diabetes, although a small difference could not be excluded as the study was only powered to detect an autoregulatory index difference > 2 units. Further study in a larger population with a spectrum of disease severity may reveal clinically important differences.

INFOMATAS multi-center systematic review and meta-analysis individual patient data of dynamic cerebral autoregulation in ischemic stroke.

RATIONALE: Disturbances in dynamic cerebral autoregulation after ischemic stroke may have important implications for prognosis. Recent meta-analyses have been hampered by heterogeneity and small samples. AIM AND/OR HYPOTHESIS: The aim of study is to undertake an individual patient data meta-analysis (IPD-MA) of dynamic cerebral autoregulation changes post-ischemic stroke and to determine a predictive model for outcome in ischemic stroke using information combined from dynamic cerebral autoregulation, clinical history, and neuroimaging. SAMPLE SIZE ESTIMATES: To detect a change of 2% between categories in modified Rankin scale requires a sample size of ∼1500 patients with moderate to severe stroke, and a change of 1 in autoregulation index requires a sample size of 45 healthy individuals (powered at 80%, α = 0.05). Pooled estimates of mean and standard deviation derived from this study will be used to inform sample size calculations for adequately powered future dynamic cerebral autoregulation studies in ischemic stroke. METHODS AND DESIGN: This is an IPD-MA as part of an international, multi-center collaboration (INFOMATAS) with three phases. Firstly, univariate analyses will be constructed for primary (modified Rankin scale) and secondary outcomes, with key co-variates and dynamic cerebral autoregulation parameters. Participants clustering from within studies will be accounted for with random effects. Secondly, dynamic cerebral autoregulation variables will be validated for diagnostic and prognostic accuracy in ischemic stroke using summary receiver operating characteristic curve analysis. Finally, the prognostic accuracy will be determined for four different models combining clinical history, neuroimaging, and dynamic cerebral autoregulation parameters. STUDY OUTCOME(S): The outcomes for this study are to determine the relationship between clinical outcome, dynamic cerebral autoregulation changes, and baseline patient demographics, to determine the diagnostic and prognostic accuracy of dynamic cerebral autoregulation parameters, and to develop a prognostic model using dynamic cerebral autoregulation in ischemic stroke. DISCUSSION: This is the first international collaboration to use IPD-MA to determine prognostic models of dynamic cerebral autoregulation for patients with ischemic stroke.

Unconstrained parameter estimation for assessment of dynamic cerebral autoregulation.

Measurement of dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow (CBF) to changes in arterial blood pressure (ABP), has been performed with an index of autoregulation (ARI), related to the parameters of a second-order differential equation model, namely gain (K), damping factor (D) and time constant (T). Limitations of the ARI were addressed by increasing its numerical resolution and generalizing the parameter space. In 16 healthy subjects, recordings of ABP (Finapres) and CBF velocity (ultrasound Doppler) were performed at rest, before, during and after 5% CO(2) breathing, and for six repeated thigh cuff maneuvers. The unconstrained model produced lower predictive error (p < 0.001) than the original model. Unconstrained parameters (K'-D'-T') were significantly different from K-D-T but were still sensitive to different measurement conditions, such as the under-regulation induced by hypercapnia. The intra-subject variability of K' was significantly lower than that of the ARI and this parameter did not show the unexpected occurrences of zero values as observed with the ARI and the classical value of K. These results suggest that K' could be considered as a more stable and reliable index of dynamic autoregulation than ARI. Further studies are needed to validate this new index under different clinical conditions.

Continuous estimates of dynamic cerebral autoregulation: influence of non-invasive arterial blood pressure measurements.

Temporal variability of parameters which describe dynamic cerebral autoregulation (CA), usually quantified by the short-term relationship between arterial blood pressure (BP) and cerebral blood flow velocity (CBFV), could result from continuous adjustments in physiological regulatory mechanisms or could be the result of artefacts in methods of measurement, such as the use of non-invasive measurements of BP in the finger. In 27 subjects (61+/-11 years old) undergoing coronary artery angioplasty, BP was continuously recorded at rest with the Finapres device and in the ascending aorta (Millar catheter, BP(AO)), together with bilateral transcranial Doppler ultrasound in the middle cerebral artery, surface ECG and transcutaneous CO(2). Dynamic CA was expressed by the autoregulation index (ARI), ranging from 0 (absence of CA) to 9 (best CA). Time-varying, continuous estimates of ARI (ARI(t)) were obtained with an autoregressive moving-average (ARMA) model applied to a 60 s sliding data window. No significant differences were observed in the accuracy and precision of ARI(t) between estimates derived from the Finapres and BP(AO). Highly significant correlations were obtained between ARI(t) estimates from the right and left middle cerebral artery (MCA) (Finapres r=0.60+/-0.20; BP(AO) r=0.56+/-0.22) and also between the ARI(t) estimates from the Finapres and BP(AO) (right MCA r=0.70+/-0.22; left MCA r=0.74+/-0.22). Surrogate data showed that ARI(t) was highly sensitive to the presence of noise in the CBFV signal, with both the bias and dispersion of estimates increasing for lower values of ARI(t). This effect could explain the sudden drops of ARI(t) to zero as reported previously. Simulated sudden changes in ARI(t) can be detected by the Finapres, but the bias and variability of estimates also increase for lower values of ARI. In summary, the Finapres does not distort time-varying estimates of dynamic CA obtained with a sliding window combined with an ARMA model, but further research is needed to confirm these findings in healthy subjects and to assess the influence of different physiological manoeuvres.

Modelling the cerebral haemodynamic response in the physiological range of PaCO2.

OBJECTIVE: Arterial CO2 (PaCO2) has a strong effect on cerebral blood flow (CBF), but its influence on CBF regulatory mechanisms and circulatory systemic variables has not been fully described over the entire physiological range of PaCO2. APPROACH: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in 45 healthy volunteers (19 male, mean age 37.5 years, range 21-71) at baseline, and in response to hypo- (-5 mm Hg and -10 mm Hg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. MAIN RESULTS: CBFV, cerebral dynamic autoregulation index (ARI), heart rate (HR), arterial blood pressure (ABP), critical closing pressure (CrCP) and resistance-area product (RAP) changed significantly (all p < 0.0001) for hypo- and hyper-capnia. These parameters were shown to follow a logistic curve relationship representing a 'dose-response' curve for the effects of PaCO2 on the cerebral and systemic circulations. The four logistic model parameters describing each 'dose-response' curve were specific to each of the modelled variables (ANOVA p < 0.0001). SIGNIFICANCE: The ability to model the CBFV, ARI, HR, ABP, CrCP and RAP dependency of PaCO2 over its entire physiological range is a powerful tool for physiological and clinical studies, including the need to perform adjustments in disease populations with differing values of baseline PaCO2.

Sex differences in cerebral haemodynamics across the physiological range of PaCO2.

OBJECTIVE: Cerebral blood flow (CBF) is influenced by changes in arterial CO2 (PaCO2). Recently, cerebral haemodynamic parameters were demonstrated to follow a four parameter logistic curve offering simultaneous assessment of dCA and CO2 vasoreactivity. However, the effects of sex on cerebral haemodynamics have yet to be described over a wide range of PaCO2. APPROACH: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in healthy volunteers at baseline, and in response to hypo- (-5 mmHg and -10 mmHg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. MAIN RESULTS: Forty-five subjects (19 male, 26 female, mean age 37.5 years) showed significant differences between males and females in CBFV (50.9 ± 10.4 versus 61.5 ± 12.3 cm · s-1, p = 0.004), EtCO2 (39.2 ± 2.8 versus 36.9 ± 3.0 mmHg, p = 0.005), RAP (1.16 ± 0.23 versus 0.94 ± 0.40 mmHg cm · s-1, p = 0.005) and systolic BP (125.2 ± 8.0 versus 114.6 ± 12.4 mmHg, p = 0.0372), respectively. Significant differences between sexes were observed in the four logistic parameters: y min, y max, k (exponential coefficient) and x (EtCO2 level) across the haemodynamic variables. Significant differences included the CBFV-EtCO2 and ARI-EtCO2 relationship; ARImin (p = 0.036) and CBFVmax (p = 0.001), respectively. Furthermore, significant differences were observed for both CrCPmin (p = 0.045) and CrCPmax (p = 0.005) and RAPmin (p < 0.001) and RAPmax (p < 0.001). SIGNIFICANCE: This is the first study to examine sex individually within the context of a multi-level CO2 protocol. The demonstration that the logistic curve parameters are influenced by sex, highlights the need to take into account sex differences between participants in both physiological and clinical studies.

Inter-subject analysis of transfer function coherence in studies of dynamic cerebral autoregulation.

OBJECTIVE: The gain and phase of the arterial blood pressure (BP)-cerebral blood flow velocity (CBFV) relationship, assessed by transfer function analysis (TFA), are widely used dynamic cerebral autoregulation (CA) metrics, but their reliability depend on the statistical significance of the magnitude squared coherence (MSC) function. We tested a new approach, based on inter-subject data, to estimate the confidence limits of MSC. APPROACH: Five minute beat-to-beat time series of mean arterial BP (MAP, Finometer) and CBFV (transcranial Doppler) were used for intra-subject (MAP and CBFV from same subject) and inter-subject (BP and CBFV swapped between subjects) estimates of MSC. The 95% confidence limit of MSC was obtained by non-parametric methods for the cases of single frequency harmonics in the range (0.02-0.50 Hz), and also from the mean value of all possible frequency intervals in this range. MAIN RESULTS: Intra-subject estimates of MSC were obtained from 100 healthy subjects (48 female, age range: 21-82 years old) allowing calculation of 9900 inter-subject estimates, with 95% confidence limits in excellent agreement with classical values derived from surrogate random data. Confidence limits of MSC, derived from mean values, decreased asymptotically to around 0.16 with the increasing number of harmonics averaged. SIGNIFICANCE: Replacing estimates of MSC at a single frequency harmonic by the mean calculated over the range (0.02-0.30 Hz) could lead to more robust studies of dynamic CA with greater acceptance of recordings, an important consideration in clinical studies where measurements tend to be more susceptible to noise and artefacts.

Reproducibility of task activation using the Addenbrooke's cognitive examination in healthy controls: A functional Transcranial Doppler ultrasonography study.

INTRODUCTION: Cerebral blood flow velocity (CBFv) changes occurring with cognitive stimulation can be measured by Transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the reproducibility of CBFv changes to the Addenbrooke's cognitive examination (ACE-III). NEW METHOD: 13 volunteers underwent bilateral TCD (middle cerebral artery), continuous heart rate (HR, 3-lead ECG, Finometer), beat-to-beat mean arterial pressure (MAP, Finometer), and end-tidal CO2 (ETCO2, capnography). After 5min baseline, all ACE-III tasks were performed in 3 domains (A/B/C). Data presented are population CBFv peak normalised changes and area under the curve (AUC). Statistical analysis was by 2-way repeated measures (ANOVA), intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). RESULTS: 12 bilateral data sets were obtained (10 right hand dominant, 6 female). Baseline parameters (MAP, HR, ETCO2) did not differ between visits. All tasks increased CBFv. Only domain A on AUC analysis differed significantly on ANOVA, and one task on post hoc testing (p <0.05). ICC values were poor (<0.4) for most tasks, but 3 tasks produced more consistent results on AUC and peak CBFv analysis (range ICC: 0.15-0.73, peak CV: 16.2-56.1(%), AUC CV: 23.2-60.2(%), peak SEM: 2.5-6.0 (%), AUC SEM: 21.8-135.8 (%*s). COMPARISON WITH EXISTING METHODS: This is the first study to examine reproducibility of CBFv changes to a complete cognitive assessment tool. CONCLUSIONS: Reproducibility of CBFv measurements to the ACE-III was variable. AUC may provide more reliable estimates than peak CBFv responses. These data need validating in patient populations.

Transcranial Doppler ultrasonography in the assessment of neurovascular coupling responses to cognitive examination in healthy controls: A feasibility study.

BACKGROUND: We tested the hypothesis that paradigms from the Addenbrooke's Cognitive Examination (ACE-III), including those that had not been studied using TCD previously (novel) versus those which had been (established), would elicit changes in CBF velocity (CBFv). NEW METHOD: Healthy subjects were studied with bilateral transcranial Doppler (TCD), beat-to-beat blood pressure (Finapres), continuous electrocardiogram (ECG), and end-tidal CO2 (nasal capnography). After a 5-min baseline recording, cognitive tests of the ACE-III were presented to subjects, covering attention (SUB7, subtracting 7 from 100 sequentially), language (REP, repeating words and phrases), fluency (N-P, naming words), visuospatial (DRAW, clock-drawing), and memory (MEM, recalling name and address). An event marker noted question timing. RESULTS: Forty bilateral data sets were obtained (13 males, 37 right-hand dominant) with a median age of 31 years (IQR 22-52). Population normalized mean peak CBFv% in the dominant and non-dominant hemispheres, respectively, were: SUB7 (11.3±9.6%, 11.2±10.5%), N-P (12.7±11.7%, 11.5±12.0%), REP (12.9±11.7%, 11.6±11.6%), DRAW (13.3±11.7%, 13.2±15.4%) and MEM (13.2±10.3%, 12.0±10.1%). There was a significant difference between the dominant and non-dominant CBFv responses (p<0.008), but no difference between the amplitude of responses. COMPARISON WITH EXISTING METHODS: For established paradigms, our results are in excellent agreement to what has been found previously in the middle cerebral artery. CONCLUSIONS: Cognitive paradigms derived from the ACE-III led to significant lateralised changes in CBFv that were not distinct for novel paradigms. Further work is needed to assess the potential of paradigms to improve the interpretation of cognitive assessments in patients at risk of mild cognitive impairment.

Cerebral hemodynamics with intra-aortic balloon pump: business as usual?

OBJECTIVE: Intra-aortic balloon pump (IABP) is commonly used as mechanical support after cardiac surgery or cardiac shock. Although its benefits for cardiac function have been well documented, its effects on cerebral circulation are still controversial. We hypothesized that transfer function analysis (TFA) and continuous estimates of dynamic cerebral autoregulation (CA) provide consistent results in the assessment of cerebral autoregulation in patients with IABP. APPROACH: Continuous recordings of blood pressure (BP, intra-arterial line), end-tidal CO2, heart rate and cerebral blood flow velocity (CBFV, transcranial Doppler) were obtained (i) 5 min with IABP ratio 1:3, (ii) 5 min, starting 1 min with the IABP-ON, and continuing for another 4 min without pump assistance (IABP-OFF). Autoregulation index (ARI) was estimated from the CBFV response to a step change in BP derived by TFA and as a function of time using an autoregressive moving-average model during removal of the device (ARI t ). Critical closing pressure and resistance area-product were also obtained. MAIN RESULTS: ARI with IABP-ON (4.3 ± 1.2) were not different from corresponding values at IABP-OFF (4.7 ± 1.4, p = 0.42). Removal of the balloon had no effect on ARI t , CBFV, BP, cerebral critical closing pressure or resistance area-product. SIGNIFICANCE: IABP does not disturb cerebral hemodynamics. TFA and continuous estimates of dynamic CA can be used to assess cerebral hemodynamics in patients with IABP. These findings have important implications for the design of studies of critically ill patients requiring the use of different invasive support devices.

Objective selection of signals for assessment of cerebral blood flow autoregulation in neonates.

A number of different system identification techniques have been proposed to assess dynamic cerebral autoregulation in critically ill patients. From these methods, the response to a standard stepwise change in blood pressure can be estimated. Responses lacking physiological consistency are a common occurrence and could be the consequence of particular system identification procedures or, alternatively, caused by measurements with a poor signal-to-noise ratio. A multi-observer approach was adopted in this paper to classify cerebral blood flow velocity (CBFV) step responses to spontaneous changes in arterial blood pressure in a group of 43 neonates with a mean gestational age of 33.7 weeks (range 24-42 weeks) and a mean birthweight of 1,980 g (range 570-3,910 g). Three experienced observers independently analysed the estimated step responses in 191 recordings each lasting 100 s; for an autoregressive (ARX) model, 124 (65%) of the step responses were accepted by at least two of the three observers. Two other system identification methods, transfer function analysis and the moving average Wiener-Laguerre model, gave 90 (45%) and 98 (51%) acceptable responses, respectively. Only 54 epochs (28%) were accepted with all three methods. With 88 (46%) responses rejected by at least two methods, it can be concluded that signal quality was the main reason for nonphysiological step responses. To avoid the need for subjective visual selection, an automatic procedure for classifying step responses was implemented leading to sensitivities and specificities in the range 85-90%, with respect to the agreement with subjective evaluations. Objective selection of CBFV step responses is thus feasible and could also be adapted for other physiological measurement techniques relying on system identification methods.

Cerebral critical closing pressure estimation from Finapres and arterial blood pressure measurements in the aorta.

Estimates of cerebral critical closing pressure (CrCP) and resistance-area product (RAP) are often derived using noninvasive measurements of arterial blood pressure (ABP) in the finger, but the errors introduced by this approach, in relation to intra-vascular measurements of ABP, are not known. Continuous recordings of ABP (Finapres and solid-state catheter-tip transducer in the ascending aorta), cerebral blood flow velocity (CBFV, bilateral Doppler), ECG and transcutaneous CO(2) were performed following coronary catheterization. CrCP and RAP were calculated for each of 12,784 cardiac cycles from 27 subjects using the classical linear regression (LR) of the instantaneous CBFV-ABP relationship and also the first harmonic (H(1)) of the Fourier transform. There was a better agreement between LR and H(1) for the aortic measurements than for the Finapres (p < 0.000,01). For LR there were no significant differences for either CrCP or RAP due to the source of ABP measurement, but for H(1) the differences were highly significant (p < 0.000,03). The coherence functions between either CrCP or RAP values calculated with aortic pressure (input) or the Finapres (output) were significantly higher for H(1) than for LR for most harmonics below 0.2 Hz. When using the Finapres to estimate CrCP and RAP values, the LR method produces similar results to intra-arterial measurements of ABP for time-averaged values, but H(1) should be preferred in applications analysing beat-to-beat changes in these parameters.

Statistical criteria for estimation of the cerebral autoregulation index (ARI) at rest.

The autoregulation index (ARI) can reflect the effectiveness of cerebral blood flow (CBF) control in response to dynamic changes in arterial blood pressure (BP), but objective criteria for its validation have not been proposed. Monte Carlo simulations were performed by generating 5 min long random input/output signals that mimic the properties of mean beat-to-beat BP and CBF velocity (CBFV) as usually obtained by non-invasive measurements in the finger (Finometer) and middle cerebral artery (transcranial Doppler ultrasound), respectively. Transfer function analysis (TFA) was used to estimate values of ARI by optimal fitting of template curves to the output (or CBFV) response to a step change in input (or BP). Two-step criteria were adopted to accept estimates of ARI as valid. The 95% confidence limit of the mean coherence function (0.15-0.25 Hz) ([Formula: see text]) was estimated from 15 000 runs, resulting in [Formula: see text] = 0.190 when using five segments of data, each with 102.4 s (512 samples) duration (Welch's method). This threshold for acceptance was dependent on the TFA settings and increased when using segments with shorter duration (51.2 s). For signals with mean coherence above the critical value, the 5% confidence limit of the normalised mean square error (NMSEcrit) for fitting the step response to Tieck's model, was found to be approximately 0.30 and independent of the TFA settings. Application of these criteria to physiological and clinical sets of data showed their ability to identify conditions where ARI estimates should be rejected, for example due to CBFV step responses lacking physiological plausibility. A larger number of recordings were rejected from acute ischaemic stroke patients than for healthy volunteers. More work is needed to validate this procedure with different physiological conditions and/or patient groups. The influence of non-stationarity in BP and CBFV signals should also be investigated.