The Impact of the Estimation Strategy of the Cerebral Critical Closing Pressure on the Autoregulation Index.

Background and Purpose: Hypercapnia leads to increased cerebral blood flow and impaired autoregulation by changing the cerebrovascular resistance (CVR). We studied the effect of hypercapnia on critical closing pressure (CCP) and resistance area product (RAP) which effectively reflects the role of vascular tone and resistance respectively in altering cerebrovascular resistance and maintaining cerebral autoregulation during transient hypotension. Methods: –26 healthy subjects had continuous cerebral blood flow velocity and arterial blood pressure recording. Transient hypotension was induced by sudden release of thigh cuff after suprasystolic inflation for 3 minutes. 3 trials of thigh cuff maneuver were performed with normal breathing, 3% CO 2 breathing and 5% CO 2 breathing. CO 2 inhalation was given for last 45 seconds of thigh cuff maneuver and continued for 90 seconds after release. Autoregulatory Index (ARI) was calculated for each trial with Tieck’s model. CCP and RAP were computed for 10 seconds’ window each at 1 minute after inflation (Baseline), immediately before release (Prerelease) and immediately after release (Release) of inflated thigh cuff. Results: –ARI values decreased significantly (p < 0.0001) from 5.46 ± 1.47 to 2.0 ± 1.35 and 1.63 ± 1.09 during 3% CO 2 and 5% CO 2 trial respectively. No significant changes were observed in CCP value during thigh cuff release with all three trials. RAP significantly dropped from prerelease value after thigh cuff release in all 3 trials. Drop in RAP attenuated during hypercapnia trial and had significant (p < 0.0001) difference between RAP Prerelease – Release ( d RAP) for Normal breathing (0.20 ± 0.12) and 3% and 5 % CO 2 trials (0.089 ± 0.090, 0.081 ± 0.093). d RAP was significantly correlated (Spearmen r = 0.42, p = 0.0004) with the ARI values where higher d RAP had better autoregulation. Conclusion: – Cerebral autoregulation during transient hypotension acts by changing vascular resistance i.e. RAP without any effect on vascular tone i.e. CCP and had been suggested to reflect myogenic component of autoregulation to blood pressure changes. We concluded that hypercapnia leads to impairment of myogenic component of autoregulation during transient arterial blood pressure changes as suggested by attenuated d RAP.

Septic shock, a life-threatening condition, can result in cerebral dysfunction and heightened mortality rates. In these patients, disturbances in cerebral hemodynamics, as reflected by impairment of myogenic cerebral autoregulation (CA), metabolic regulation, expressed by critical closing pressure (CrCP) and reductions in intracranial compliance (ICC), can adversely impact septic shock outcomes. The general recommendation is to maintain a target mean arterial pressure (MAP) of 65 mmHg but the effect of different MAP targets on cerebral hemodynamics in these patients is not clear and optimal targets might be dependent on the status of CA. This protocol aims to assess the cerebral hemodynamics profile at different pressure targets in septic shock patients. Prospective, non-randomized, single-center trial, which will study cerebral hemodynamics in patients with septic shock within 48 hours of its onset. Patients will be studied at their baseline MAP and at three MAP targets (T1: 65, T2: 75, T3: 85 mmHg). Cerebral hemodynamics will be assessed by transcranial Doppler (TCD) and a skull micro-deformation sensor (B4C). Dynamic CA will be expressed by the autoregulation index (ARI), calculated by transfer function analysis, using fluctuations of MAP as input and corresponding oscillations in cerebral blood velocity (CBv). The instantaneous relationship between arterial blood pressure and CBv will be used to estimate CrCP and resistance-area product (RAP) for each cardiac cycle using the first harmonic method. The B4C will access ICC by intracranial pressure waveforms (P2/P1). The primary aim is to assess cerebral hemodynamics (ARI, CrCP, RAP, and P2/P1) at different targets of MAP in septic shock patients. Our secondary objective is to assess cerebral hemodynamics at 65mmHg (target recommended by guidelines). In addition, we will assess the correlation between markers of organ dysfunction (such as lactate levels, vasoactive drugs usage, SOFA score, and delirium) and CA. The results of this study may help to understand the effect of the recommended MAP and variations in blood pressure in patients with septic shock and impaired CA and ICC. Furthermore, the results can assist large trials in establishing new hypotheses about neurological management in this group of patients. Approval was obtained from the local Ethics Committee (28134720.1.0000.0048). It is anticipated that the results of this study will be presented at national and international conferences and will be published in peer-reviewed journals in 2024 and 2025. Trial registration number: NCT05833607. https://clinicaltrials.gov/study/NCT05833607.

Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)-cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR). In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance-area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing. Transfer function analysis of the MAP-CBFV relationship can be extended to the MAP-RAP and MAP-CrCP relationships, to assess their contribution to the dynamic CA response. During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP-CBFV relationship. Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra-cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21-70years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end-tidal CO2 (capnography) and heart rate (ECG) were performed for 5min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance-area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P<0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70±1.58 (normocapnia) to 4.14±2.05 (hypercapnia; P<0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies.

The role of autonomic nervous system (ANS) in adapting cerebral blood flow (CBF) to arterial blood pressure (ABP) fluctuations [cerebral autoregulation (CA)] is still controversial. We aimed to study the repercussion of autonomic failure (AF) on dynamic CA during the Valsalva maneuver (VM). Eight AF subjects with familial amyloidotic polineuropahty (FAP) were compared with eight healthy controls. ABP and CBF velocity (CBFV) were measured continuously with Finapres and transcranial Doppler, respectively. Cerebrovascular response was evaluated by cerebrovascular resistance index (CVRi), critical closing pressure (CrCP), and resistance-area product (RAP) changes. Dynamic CA was derived from continuous estimates of autoregulatory index (ARI) [ARI(t)]. During phase II of VM, FAP subjects showed a more pronounced decrease in normalized CBFV (78 ± 19 and 111 ± 16%; P = 0.002), ABP (78 ± 19 and 124 ± 12%; P = 0.0003), and RAP (67 ± 17 and 89 ± 17%; P = 0.019) compared with controls. CrCP and CVRi increased similarly in both groups during strain. ARI(t) showed a biphasic variation in controls with initial increase followed by a decrease during phase II but in FAP this response was blunted (5.4 ± 3.0 and 2.0 ± 2.9; P = 0.033). Our data suggest that dynamic cerebral autoregulatory response is a time-varying phenomena during VM and that it is disturbed by autonomic dysfunction. This study also emphasizes the fact that RAP + CrCP model allowed additional insights into understanding of cerebral hemodynamics, showing a higher vasodilatory response expressed by RAP in AF and an equal CrCP response in both groups during the increased intracranial and intrathoracic pressure, while classical CVRi paradoxically suggests a cerebral vasoconstriction.

Impaired cerebral autoregulation, cerebral perfusion pressure, and intracranial pressure in eclampsia

Cerebral blood flow (CBF) can be altered by a change in partial pressure of arterial CO2 (Pco2), being reduced during hyperventilation (HPV). Critical closing pressure (CrCP) and resistance area product (RAP) are parameters that can be studied to understand this change, but their dynamic response has not been investigated during paced HPV (PHPV). Seventy-five participants had recordings at rest and during PHPV. Blood pressure (BP) (Finometer), bilateral CBF velocity (CBFV) (transcranial Doppler), end-tidal CO2 (capnography), and heart rate (HR) were recorded continuously. Subcomponent analysis (SCA) and time-varying CrCP, RAP, and dynamic cerebral autoregulation (autoregulation index, ARI) were estimated by comparing PHPV with poikilocapnia. PHPV caused a change in CBFV (P < 0.01), EtCO2, (P < 0.01), HR (P < 0.001), and RAP (P < 0.01). SCA demonstrated RAP was the main parameter explaining the changes in CBFV due to PHPV. The time-varying step responses for CBFV and RAP during PHPV demonstrated considerable nonstationarity compared with poikilocapnia (P < 0.00001). Although time-varying ARI was temporarily depressed, after 60 s of PHPV it was significantly higher (6.81 ± 1.88) (P < 0.0001) than in poikilocapnia (5.08 ± 1.86). The mean plateau of the RAP step response was -98.3 ± 58.8% 60 s after the onset of PHPV but -71.7 ± 45.0% for poikilocapnia (P = 0.0026), with no corresponding changes in CrCP (P = 0.6). Further work is needed to assess the role of sex and aging in our findings, and the potential for using RAP and CrCP to improve the sensitivity and specificity of CO2 reactivity studies in cerebrovascular conditions.NEW & NOTEWORTHY The dynamic response of critical closing pressure (CrCP) and resistance-area product (RAP) of the cerebral circulation to a step change in mean arterial pressure can shed light on the nonstationary changes induced by paced hyperventilation and the effects of hypocapnia on the autoregulation of cerebral blood flow. Contrary to hypercapnia, where the response is dominated by CrCP, hypocapnia shows an initial depression of cerebral autoregulation, followed by improvements controlled by changes in RAP.

Cerebral blood flow (CBF) is affected by posture changes, but there is a paucity of research examining the effect of posture on dynamic cerebral autoregulation (dCA). The step responses of critical closing pressure (CrCP) and resistance area product (RAP) obtained from the cerebral blood velocity (CBv) signal can reflect the changes in dCA, enabling exploration of dCA changes in supine, sitting and upright postures. In 22 participants (11 males, aged 30.2 ± 14.3years), two recordings were made for each posture, corresponding to supine, sitting, and standing. Blood pressure (BP, Finometer), MCAv and PCAv (transcranial Doppler ultrasound), end-tidal carbon dioxide (EtCO2, capnography) and heart rate (ECG) were continuously recorded. CrCP and RAP were obtained for each cardiac cycle, and the step responses of CBv (SRVMCA/PCA), CrCP (SRVCrCP), and RAP (SRVRAP), for both arteries, were calculated after subcomponent and transfer function analysis. Moving from supine to sitting, and then standing, led to reductions in mean MCAv (p < 0.001), PCAv (p = 0.037), BP (p < 0.001) and EtCO2 (p < 0.001), accompanied by changes in SRVMCA (p = 0.002), but not in SRVPCA (p = 0.78). For both arteries, SRVRAP and SRVCrCP reflected changes in posture (both p < 0.001). Posture changes can significantly affect the step responses of MCAv, CrCP, and RAP. The interaction between posture and EtCO2 from the perspective of the CrCP and RAP step responses needs further exploration in future studies.

Introduction: Cerebral autoregulation (CA) is impaired in acute ischemic stroke (AIS) and is associated with worse patient outcomes, but the underlying physiological cause is unclear. This study tests whether depressed CA in AIS can be linked to the dynamic responses of critical closing pressure (CrCP) and resistance area product (RAP). Methods: Continuous recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), arterial blood pressure (BP), end-tidal CO2 and electrocardiography allowed dynamic analysis of the instantaneous MCAv-BP relationship to obtain estimates of CrCP and RAP. The dynamic response of CrCP and RAP to a sudden change in mean BP was obtained by transfer function analysis. Comparisons were made between younger controls (≤50 years), older controls (>50 years), and AIS patients. Results: Data from 24 younger controls (36.4 ± 10.9 years, 9 male), 38 older controls (64.7 ± 8.2 years, 20 male), and 20 AIS patients (63.4 ± 13.8 years, 9 male) were included. Dynamic CA was impaired in AIS, with lower autoregulation index (affected hemisphere: 4.0 ± 2.3, unaffected: 4.5 ± 1.8) compared to younger (right: 5.8 ± 1.4, left: 5.8 ± 1.4) and older (right: 4.9 ± 1.6, left: 5.1 ± 1.5) controls. AIS patients also demonstrated an early (0–3 s) peak in CrCP dynamic response that was not influenced by age. Conclusion: These early transient differences in the CrCP dynamic response are a novel finding in stroke and occur too early to reflect underlying regulatory mechanisms. Instead, these may be caused by structural changes to cerebral vasculature.

The study of dynamic cerebral autoregulation (CA), which adapts cerebral blood flow to arterial blood pressure (ABP) fluctuations, has been limited in orthostatic intolerance syndromes, mainly due to its stationary prerequisites hardly to meet during maneuvers to provoke syncope itself. New techniques of continuous estimates of CA could overcome this pitfall. We aimed to evaluate CA during head-up tilt test in common conditions causing syncope. We compared three groups: eight controls; eight patients with autonomic failure due to familial amyloidotic polyneuropathy; eight patients with vasovagal syncope (VVS). ABP and cerebral blood flow velocity (CBFV) were measured with Finometer® and transcranial Doppler. We calculated cerebrovascular resistance index (CVRi), critical closing pressure (CrCP) and resistance area product (RAP), and derived CA continuously from autoregulation index [ARI(t)]. With HUTT, AF subjects showed a pronounced decrease in CBFV (-36±17 versus -7±6%, p<0.0001), ABP (-29±27 versus 7±12%, p<0.0001) and RAP (-17±23 versus 3±18%, p<0.0001) but not CVRi (p=0.110). VVS subjects showed progressive cerebral vasoconstriction prior to syncope, (reduced CBFV 19±15 versus 1±6, p<0.000; increased RAP 12±18 versus 2±3%, p=0.024 and CVRi 12±18 versus 2±3%, p=0.005). ARI(t) increased significantly in AF patients (5.7±1.2 versus 6.9±1.2, p=0.040) and VVS (5.8±1.2 versus 7.3±1.2, p=0.015) in response to ABP fall during syncope. Our data suggest that dynamic cerebral autoregulatory response to orthostatic challenge is neither affected by autonomic dysfunction nor in neutrally mediated syncope. This study also emphasizes that RAP+CrCP model is more informative than CVRi, mainly during cerebral vasodilatory response to orthostatic hypotension.

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.

Syncope from sustained orthostasis results from cerebral hypoperfusion associated with reductions in arterial pressure at the level of the brain (BPMCA) and reductions in arterial CO2 as reflected by end-tidal values (PetCO2). It was hypothesized that reductions in PetCO2 increase cerebrovascular tone before a drop in BPMCA that ultimately leads to syncope. Twelve men (21-42 yr of age) completed an orthostatic tolerance test consisting of head-up tilt and progressive lower body negative pressure to presyncope, before and after completing 5 days of continuous head-down bed rest (HDBR). Cerebral blood velocity (CBFV), BPMCA, and PetCO2 were continuously recorded throughout the test. Cerebrovascular indicators, cerebrovascular resistance, critical closing pressure (CrCP), and resistance area product (RAP), were calculated. Comparing from supine baseline to 6-10 min after the start of tilt, there were reductions in CBFV, PetCO2, BPMCA, and CrCP, an increase in RAP, and no change in cerebrovascular resistance index. Over the final 15 min before syncope in the pre-HDBR tests, CBFV and CrCP were significantly related to changes in PetCO2 (r = 0.69 ± 0.17 and r = 0.63 ± 0.20, respectively), and BPMCA, which was not reduced until the last minute of the test, was correlated with a reduction in RAP (r = 0.91 ± 0.09). Post-HDBR, tilt tolerance was markedly reduced, and changes in CBFV were dominated by a greater reduction in BPMCA with no relationships to PetCO2. Therefore, pre-HDBR, changes in PetCO2 with orthostasis contributed to increases in cerebrovascular tone and reductions in CBFV during the progression toward syncope, whereas, after 5 days of HDBR, orthostatic responses were dominated by changes in BPMCA.

Antihypertensives (AHD) can influence cerebral autoregulation (CA) and attenuate hypertrophic concentric remodelling of arterioles. The aim of this study was to examine the associations between AHD, CA and structural and functional properties of cerebral arteries. In this observational, cross-sectional study 115 volunteers were divided in group 1 (non-hypertensive) [n = 30]; group 2 (hypertensive with systolic blood pressure [SBP] < 140 and diastolic blood pressure [DBP] < 90 mmHg) [n = 54]; group 3 (hypertensive with SBP ≥ 140 or DBP ≥ 90 mmHg) [n = 31] and simultaneous measurements of systemic blood pressure (BP) and middle cerebral artery blood flow velocity (CBFV) were obtained from digital plethysmography and transcranial Doppler. Beat-to-beat, critical closing pressure (CrCP), resistance-area product (RAP) and autoregulation index (ARI) values were extracted by linear regression analysis of instantaneous BP and CBFV waveforms using computerised analysis. Pulsatility index (PI) was calculated and CO2 reactivity was assessed by the breath-holding test. Despite their higher RAP (1.7 [±0.7], p < 0.001) compared to groups 1 and 2, uncontrolled hypertensive using diuretics (p = 0.047) and α2-agonists (p = 0.009) had significantly lower PI. Impaired CO2 reactivity was common between the two hypertensive groups (p = 0.008), however ARI, CrCP and CBFV did not differ between them and non-hypertensive individuals and also did not correlate with any AHD used. Unlike the RAP, PI does not seem to reflect the real cerebrovascular resistence resulting from chronic arterial remodelling. Despite impaired CO2 reactivity, hypertensivehavearterial tonus and CA comparable to non-hypertensive. Experimental studies involving an untreated hypertensive control group are required to robustly make definitive conclusions about these questions.

PurposeWe investigated the effect of handgrip (HG) maneuver on time-varying estimates of dynamic cerebral autoregulation (CA) using the autoregressive moving average technique.MethodsTwelve healthy subjects were recruited to perform HG maneuver during 3 minutes with 30% of maximum contraction force. Cerebral blood flow velocity, end-tidal CO2 pressure (PETCO2), and noninvasive arterial blood pressure (ABP) were continuously recorded during baseline, HG and recovery. Critical closing pressure (CrCP), resistance area-product (RAP), and time-varying autoregulation index (ARI) were obtained.ResultsPETCO2 did not show significant changes during HG maneuver. Whilst ABP increased continuously during the maneuver, to 27% above its baseline value, CBFV raised to a plateau approximately 15% above baseline. This was sustained by a parallel increase in RAP, suggestive of myogenic vasoconstriction, and a reduction in CrCP that could be associated with metabolic vasodilation. The time-varying ARI index dropped at the beginning and end of the maneuver (p<0.005), which could be related to corresponding alert reactions or to different time constants of the myogenic, metabolic and/or neurogenic mechanisms.ConclusionChanges in dynamic CA during HG suggest a complex interplay of regulatory mechanisms during static exercise that should be considered when assessing the determinants of cerebral blood flow and metabolism.

The primary objective of this study was to estimate the effective cerebral perfusion pressure (CPPe), critical closing pressure (CrCP), and resistance-area product (RAP) of the intravascular common carotid artery using three different methods. These estimates were then compared to the reference method of linear regression (LR). In our previous study, we employed linear regression to evaluate the values of CrCP and RAP. To assess the consistency of results obtained from alternative assessment methods (CPPe, CrCP, and RAP) with the linear regression LR, we conducted a secondary analysis of the previously collected data. We estimated the CPPe, CrCP, and RAP of the intravascular common carotid artery using three different methods: Belford's method (mean/diastolic pressure), Czosnyka's method (systolic/diastolic pressure, CZO), and Schmidt's method (systolic/diastolic pressure, SCH), and compared these estimates with LR. CPPe is calculated as the difference between mean arterial pressure and CrCP. The primary outcome was the mean differences and biases between CPPe, CrCP, and RAP of intravascular common carotid artery, the secondary outcome was correlations and agreement among these various estimates of CPPe measurements. Nineteen patients were included in this analysis. The median age was 53.5 ± 11.6 years, with 73.7% being men. There were no significant differences in CPPe, RAP and CrCP between the right common carotid artery (RCCA) and the left common carotid artery (LCCA) by using three different methods. Compared to the LR, the mean differences in CPPe and CrCP values were no significant for LCCA according to SCH, CZO and BEL method. But for RAP, the three methods are different in terms of mean differences compared with the LR. CPPe and CrCP revealed a small mean bias compared CPPCZO with CPPLR. Comparing CPPLR measurements with CPPBEL, the mean bias was higher with wider LoA. BEL and CZO showed a strong correlation with LR in Pearson correlation coefficients. The CPPe, CrCP, and RAP values obtained using the CZO calculation methods are comparable to those measured using the reference method. These findings may provide valuable insights for patients undergoing digital subtraction brain angiography, aiding in the determination of the most suitable approach for individualized blood pressure management.

RationaleCerebrovascular resistance (CVR), calculated from mean cerebral blood flow (CBF) and mean arterial blood pressure (ABP), can be further characterized by two independent parameters: critical closing pressure (CrCP) and resistance area product (RAP). These parameters are believed to reflect differences in the metabolic and myogenic control of CVR, respectively. The objective of this study was to assess how CVR, CrCP and RAP interrelate in a healthy aging population and how they adapt to postural change.MethodsSixty‐three older adults (36 women, 74 ± 5 years) were categorized in tertiles according to CVR determined from bilateral internal carotid artery blood flow and mean ABP. Apparent CrCP and RAP were estimated from continuous middle cerebral artery blood flow velocity and ABP in supine, sitting and standing postures.ResultsIndividuals in the highest tertile for CVR had both higher ABP (P &lt; 0.001) and lower CBF (P &lt; 0.001) than the lowest tertile. Lying supine, CVR was directly related to CrCP (r = 0.43, P &lt; 0.001), but not RAP (P = 0.697). CrCP was reduced (P &lt; 0.001) and RAP was slightly increased (P = 0.010) in upright posture.ConclusionHigh CVR in aging was primarily related to CrCP which might reflect structural changes leading to lower CBF in these individuals. Reduced CrCP with upright posture protects the brain from hypoperfusion during sitting and standing. Funded by CIHR, HSF, NSERC