Autoregulation Index Research Articles

21: Cerebral autoregulation in eclampsia

Eclampsia is the occurrence of tonic-clonic seizures in pregnant or recently postpartum women with preeclampsia. The etiology of these convulsions is unknown. Cerebral autoregulation (CA) is a physiological process that maintains blood flow constant despite changes in blood pressure (BP). Impaired CA may cause overperfusion injury, edema formation and neurological symptoms. We tested the hypothesis that eclampsia is associated with impaired cerebral autoregulation. In a prospective cohort study of recent postpartum patients, we included eclamptic patients studied at < 48 hour after the insult (n=7), and compared them with a normotensive control group (n=10), matched for gestational age (EGA). Eclamptic patients received MgSO4 and anti-hypertensive therapy according to local protocol. Preterm delivery in the control group was due to spontaneous preterm birth or fetal distress. Cerebral blood flow velocity (CBFV) in the middle cerebral artery (transcranial Doppler ultrasound), BP (noninvasive arterial volume clamping), and end-tidal carbon dioxide (EtCO2) were recorded during a 7-minute period of rest. Autoregulation Index (ARI) was determined from the CBFV responses to spontaneous fluctuations in BP. ARI values of 0 and 9 indicate absent and perfect autoregulation, respectively. Cerebral perfusion pressure (CPP) was calculated as previously described. Statistics: student t-test, with P< 0.05 considered significant. Data are presented as mean±SD The groups had similar EGA at delivery (33.6±5.3 vs 34.1±4.4 weeks) and no patients had neurological symptoms at time of recording. ARI was significantly reduced in eclampsia (ARI 4.3±0.7) when compared to controls (7.4±0.5, P< 0.01), while CPP was higher (108±13 vs 82±19 mmHg, P< 0.01). EtCO2 was similar (34.8±1.4 vs 33.8±1.8 mmHg). Women with a recent eclamptic insult have severely impaired CA and increased CPP compared with gestational age-matched normotensive women. Further research should focus on possible modifiable factors to improve CA and on the association between CA and long-term neurological outcome after eclampsia.

BP Fluctuations and the Real-Time Dynamics of Renal Blood Flow Responses in Conscious Rats.

Renal autoregulation maintains stable renal function despite BP fluctuations and protects glomerular capillaries from hypertensive injury. However, real-time dynamics of renal autoregulation in conscious animals have not been characterized. To develop novel analytic methods for assessing renal autoregulation, we recorded concurrent BP and renal blood flow in conscious rats, comparing animals with renal autoregulation that was intact versus impaired (from 3/4 nephrectomy), before and after additional impairment (from the calcium channel blocker amlodipine). We calculated autoregulatory indices for adjacent short segments of increasing length (0.5, 1, 2.5, 5, 10, and 20 seconds) that exhibited a mean BP difference of at least 5 mm Hg. Autoregulatory restoration of renal blood flow to baseline after BP changes in conscious rats occurs rapidly, in 5-10 seconds. The response is significantly slower in states of impaired renal autoregulation, enhancing glomerular pressure exposure. However, in rats with severe renal autoregulation impairment (3/4 nephrectomy plus amlodipine), renal blood flow in conscious animals (but not anesthetized animals) was still restored to baseline, but took longer (15-20 seconds). Consequently, the ability to maintain overall renal blood flow stability is not compromised in conscious rats with impaired renal autoregulation. These novel findings show the feasibility of renal autoregulation assessment in conscious animals with spontaneous BP fluctuations and indicate that transient increases in glomerular pressure may play a greater role in the pathogenesis of hypertensive glomerulosclerosis than previously thought. These data also show that unidentified mechanosensitive mechanisms independent of known renal autoregulation mechanisms and voltage-gated calcium channels can maintain overall renal blood flow and GFR stability despite severely impaired renal autoregulation.

The upper frequency limit of dynamic cerebral autoregulation.

Dynamic cerebral autoregulation (CA) is expressed by the temporal pattern of cerebral blood flow (CBF) recovery following a sudden change in arterial blood pressure (BP). Transfer function analysis of BP as input and CBF velocity as output can express dynamic CA through its amplitude (or gain) and phase frequency responses. The upper frequency limit (FupLim ) at which dynamic CA can operate is of considerable physiological interest and can also provide additional information about worsening CA due to disease processes. In healthy subjects FupLim was strongly dependent on arterial changes induced by four different breathing manoeuvres. The considerable intersubject variability in FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in studies of dynamic CA. Dynamic cerebral autoregulation (CA) can be expressed in the frequency domain by the amplitude and phase frequency responses calculated by transfer function analysis of arterial blood pressure (BP) and cerebral blood flow velocity (CBFV). We studied the effects of arterial ( ) on the upper frequency limit (FupLim ) of these responses and its intersubject variability. Twenty-four healthy subjects (11 female, age 36.0±13.4years) were recruited. Recordings of CBFV (transcranial Doppler ultrasound), BP (Finometer) and end-tidal CO2 ( , capnography) were performed during 5min at rest (normocapnia) and during four breathing manoeuvres: 5% and 8% CO2 in air and hyperventilation targeting reductions of 5 and 10mmHg compared to normocapnia. FupLim was determined by the break point of the autoregulation index (ARI) curve as a function of frequency when the phase response was gradually set to zero. The five breathing conditions led to highly significant differences in (p<0.0001), CBFV (P<0.0001), ARI (p<0.0001) and FupLim (p<0.0001). FupLim ranged from 0.167±0.036Hz at the lowest values of hypocapnia (28.1±1.9mmHg) to 0.094±0.040Hz at the highest level of hypercapnia (41.7±5.4mmHg), showing a correlation of r=-0.53 (p<0.001) with . These findings reinforce the key role of in CBF regulation. The considerable intersubject variability of FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in dynamic CA studies, and that the higher frequency band (0.20-0.40Hz), in particular, does not contain relevant information about dynamic CA. Further investigations are needed to assess the information value of FupLim as a marker of dynamic CA efficiency in physiological and clinical studies.

Intra-aortic balloon pump does not influence cerebral hemodynamics and neurological outcomes in high-risk cardiac patients undergoing cardiac surgery: an analysis of the IABCS trial

BackgroundThe intra-aortic balloon pump (IABP) is often used in high-risk patients undergoing cardiac surgery to improve coronary perfusion and decrease afterload. The effects of the IABP on cerebral hemodynamics are unknown. We therefore assessed the effect of the IABP on cerebral hemodynamics and on neurological complications in patients undergoing cardiac surgery who were randomized to receive or not receive preoperative IABP in the ‘Intra-aortic Balloon Counterpulsation in Patients Undergoing Cardiac Surgery’ (IABCS) trial.MethodsThis is a prospectively planned analysis of the previously published IABCS trial. Patients undergoing elective coronary artery bypass surgery with ventricular ejection fraction ≤ 40% or EuroSCORE ≥ 6 received preoperative IABP (n = 90) or no IABP (n = 91). Cerebral blood flow velocity (CBFV) of the middle cerebral artery through transcranial Doppler and blood pressure through Finometer or intra-arterial line were recorded preoperatively (T1) and 24 h (T2) and 7 days after surgery (T3) in patients with preoperative IABP (n = 34) and without IABP (n = 33). Cerebral autoregulation was assessed by the autoregulation index that was estimated from the CBFV response to a step change in blood pressure derived by transfer function analysis. Delirium, stroke and cognitive decline 6 months after surgery were recorded.ResultsThere were no differences between the IABP and control patients in the autoregulation index (T1: 5.5 ± 1.9 vs. 5.7 ± 1.7; T2: 4.0 ± 1.9 vs. 4.1 ± 1.6; T3: 5.7 ± 2.0 vs. 5.7 ± 1.6, p = 0.97) or CBFV (T1: 57.3 ± 19.4 vs. 59.3 ± 11.8; T2: 74.0 ± 21.6 vs. 74.7 ± 17.5; T3: 71.1 ± 21.3 vs. 68.1 ± 15.1 cm/s; p = 0.952) at all time points. Groups were not different regarding postoperative rates of delirium (26.5% vs. 24.2%, p = 0.83), stroke (3.0% vs. 2.9%, p = 1.00) or cognitive decline through analysis of the Mini-Mental State Examination (16.7% vs. 40.7%; p = 0.07) and Montreal Cognitive Assessment (79.16% vs. 81.5%; p = 1.00).ConclusionsThe preoperative use of the IABP in high-risk patients undergoing cardiac surgery did not affect cerebral hemodynamics and was not associated with a higher incidence of neurological complications.Trial registrationhttp://www.clinicaltrials.gov (NCT02143544).

Dynamic Autoregulation is Impaired in Circulatory Shock.

Circulatory shock is a life-threatening disorder that is associated with high mortality, with a state of systemic and tissue hypoperfusion that can lead to organ failure, including the brain, where altered mental state is often observed. We hypothesized that cerebral autoregulation (CA) is impaired in patients with circulatory shock. Adult patients with circulatory shock and healthy controls were included. Cerebral blood flow velocity (CBFV, transcranial Doppler ultrasound) and arterial blood pressure (BP, Finometer or intra-arterial line) were continuously recorded during 5 min in both groups. Autoregulation Index (ARI) was estimated from the CBFV response to a step change in BP, derived by transfer function analysis; ARI ≤ 4 was considered impaired CA. The relationship between organ dysfunction, assessed with the Sequential Organ Failure Assessment (SOFA) score and the ARI, was assessed with linear regression. Twenty-five shock patients and 28 age-matched healthy volunteers were studied. The mean ± SD SOFA score was 10.8 ± 4.3. Shock patients compared with control subjects had lower ARI values (4.0 ± 2.1 vs. 5.9 ± 1.5, P = 0.001). Impaired CA was more common in shock patients (44.4% vs. 7.1%, P = 0.003). There was a significant inverse relationship between the ARI and the SOFA score (R = -0.63, P = 0.0008). These results suggest that circulatory shock is often associated with impaired CA and that the severity of CA alterations is correlated with the degree of multiple organ failure, reinforcing the need to monitor cerebral hemodynamics in patients with circulatory shock.

Can we assess dynamic cerebral autoregulation in stroke patients with high rates of cardiac ectopicity?

It is unclear whether physiological recordings containing high numbers of ectopic heartbeats can be used to measure the cerebral autoregulation (CA) of blood flow. This study evaluated the utility of such data for assessing dynamic CA capacity. Physiological recordings of cerebral blood flow velocity, heart rate, end-tidal CO2 and beat-to-beat blood pressure from acute ischaemic stroke (AIS) patients (n = 46) containing ectopic heartbeats of varying number (0.2 to 25 occurrences per minute) were analysed. Dynamic CA was determined using the autoregulation index (ARI) and the normalised mean square error (NMSE) was used to evaluate the fitting of the step response between BP and CBFV to Tiecks' model. We fitted linear mixed models on the CA variables incorporating ectopic burden, age, sex and hemisphere as predictor variables. Ectopic activity demonstrated an association with mean coherence (p = 0.006) but not with ARI (p = 0.162), impaired CA based on dichotomised ARI (p = 0.859) or NMSE (p = 0.671). Dynamic CA could be reliably assessed in AIS patients using physiological recordings with high rates of cardiac ectopic activity. This provides supportive data for future studies evaluating CA capability in AIS patients, with the potential to develop more individualised treatment strategies. Graphical Abstract.

Feasibility of improving cerebral autoregulation in acute intracerebral hemorrhage (BREATHE-ICH) study: Results from an experimental interventional study.

Cerebral autoregulation is impaired in a multitude of neurological conditions. Increasingly, clinical studies are correlating the nature of this impairment with prognostic markers. In acute intracerebral hemorrhage, impairment of cerebral autoregulation has been associated with worsening clinical outcomes including poorer Glasgow Coma Score and larger hematoma volume. Hypocapnia has been shown to improve cerebral autoregulation despite concerns over hypoperfusion and consequent ischemic risks, and it is therefore hypothesized that hypocapnia (via hyperventilation) in acute intracerebral hemorrhage may improve cerebral autoregulation and consequently clinical outcome. To assess the feasibility and acceptability of the first cerebral autoregulation-targeted intervention in acute intracerebral hemorrhage utilizing a simple bed-side hyperventilatory maneuver. Twelve patients with acute intracerebral hemorrhage within 48 h of onset were enrolled. The experimental setup measured cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), and end-tidal CO2 (EtCO2, capnography) at baseline, and in response to hypocapnia (-5 mmHg below baseline) achieved via a 90-s hyperventilatory maneuver. Cerebral autoregulation was evaluated with transfer function analysis and autoregulatory index calculations. We observed tolerance to the protocol in a cohort of mild (National Institutes of Health Scale 4) supratentorial intracerebral hemorrhage patients with small volume hematomas without intraventricular extension. Importantly, a significant difference was noted between ipsilateral autoregulatory index at baseline 4.8 (1.7) and autoregulatory index during hypocapnic intervention 7.0 (0.8) (p = 0.0004), reflecting improved cerebral autoregulation, though a dose-dependent effect of EtCO2 on autoregulatory index was not observed. In this small study, there was no observed effect on 14-day death and disability in recruited participants. This is the first report of improvement in cerebral autoregulation in acute intracerebral hemorrhage using a non-invasive interventional maneuver, through induction of hypocapnia via hyperventilation.ClinicalTrials.gov Identifier: NCT03324321URL: https://clinicaltrials.gov/ct2/show/NCT03324321.

Deviation From Personalized Blood Pressure Targets Is Associated With Worse Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Optimal blood pressure (BP) management during the early stages of aneurysmal subarachnoid hemorrhage remains uncertain. Observational studies have found worse outcomes in patients with increased hemodynamic variability, suggesting BP optimization as a potential neuroprotective strategy. In this study, we calculated personalized BP targets at which cerebral autoregulation was best preserved. We analyzed how deviation from these limits correlates with functional outcome. Methods- We prospectively enrolled 31 patients with aneurysmal subarachnoid hemorrhage. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy (NIRS)-derived tissue oxygenation-a surrogate for cerebral blood flow-as well as intracranial pressure (ICP) in response to changes in mean arterial pressure using time-correlation analysis. The resulting autoregulatory indices were used to identify the upper and lower limit of autoregulation. Percent time that mean arterial pressure exceeded limits of autoregulation was calculated for each patient. Functional outcome was assessed using the modified Rankin Scale at discharge and 90 days. Associations with outcome were analyzed using ordinal multivariate logistic regression. Results- Personalized limits of autoregulation were computed in all patients (age 57.5±13.4, 23F, mean World Federation of Neurological Surgeons 2±1, monitoring time 67.8±50.8 hours). Optimal BP and limits of autoregulation were calculated on average for 89.5±6.7% of the total monitoring period. ICP- and NIRS-derived optimal pressures strongly correlated with one another (P<0.0001). Percent time that mean arterial pressure deviated from limits of autoregulation significantly associated with worse functional outcome at discharge (NIRS, P=0.001; ICP, P=0.004) and 90 days (NIRS, P=0.002; ICP, P=0.003), adjusting separately for age, World Federation of Neurological Surgeons, vasospasm, and delayed cerebral ischemia. Conclusions- Both invasive (ICP) and noninvasive (NIRS) determination of personalized BP targets after aneurysmal subarachnoid hemorrhage is feasible, and these 2 approaches revealed significant collinearity. Furthermore, exceeding individualized limits of autoregulation was associated with poor functional outcomes.

Effects of Resistance Exercise and Nutritional Supplementation on Dynamic Cerebral Autoregulation in Head-Down Bed Rest.

Head-down bed rest (HDBR) is commonly considered as ground-based analog to spaceflight and simulates the headward fluid shift and cardiovascular deconditioning associated with spaceflight. We investigated in healthy volunteers whether HDBR, with or without countermeasures, affect cerebral autoregulation (CA). Twelve men (at selection: 34 ± 7 years; 176 ± 7 cm; 70 ± 7 kg) underwent three interventions of a 21-day HDBR: a control condition without countermeasure (CON), a condition with resistance vibration exercise (RVE) comprising of squats, single leg heel, and bilateral heel raises and a condition using also RVE associated with nutritional supplementation (NeX). Cerebral blood flow velocity was assessed using transcranial Doppler ultrasonography. CA was evaluated by transfer function analysis and by the autoregulatory index (Mxa) in order to determine the relationship between mean cerebral blood flow velocity and mean arterial blood pressure. In RVE condition, coherence was increased after HDBR. In CON condition, Mxa index was significantly reduced after HDBR. In contrast, in RVE and NeX conditions, Mxa were increased after HBDR. Our results indicate that HDBR without countermeasures may improve dynamic CA, but this adaptation may be dampened with RVE. Furthermore, nutritional supplementation did not enhance or worsen the negative effects of RVE. These findings should be carefully considered and could not be applied in spaceflight. Indeed, the subjects spent their time in supine position during bed rest, unlike the astronauts who perform normal daily activities.

Deviation from Dynamic and Personalized Optimal Blood Pressure Targets is Associated With Worse Functional Outcomes After Aneurysmal Subarachnoid Hemorrhage

Abstract INTRODUCTION Effective blood pressure (BP) management after aneurysmal subarachnoid hemorrhage (aSAH) is critical for maintaining optimal cerebral perfusion and protecting the brain from further injury. How to best manage BP during the early stages of aSAH remains uncertain. In this study, we calculated individualized BP thresholds at which cerebral autoregulation was best preserved. We analyzed how deviating from these limits correlates with functional outcome. METHODS We prospectively enrolled 31 patients with aSAH. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy (NIRS)-derived tissue oxygenation – a surrogate for cerebral blood flow – as well as intracranial pressure (ICP) in response to changes in mean arterial pressure (MAP) using time-correlation analysis. The resulting autoregulatory indices were used to trend BP ranges at which autoregulation was most preserved. The percent time that MAP exceeded limits of autoregulation (LA) was calculated for each patient. Functional outcome was assessed using the modified Rankin Scale (mRS) at discharge and 90 d. Associations with outcome were analyzed using ordinal multivariate logistic regression. RESULTS Personalized LA were computed in all patients (age 57.5, 23F, mean WFNS 2, monitoring time 67.8 h). Optimal BP and LA were calculated on average for 89.5% of the total monitoring period. ICP- and NIRS-derived optimal pressures and LA strongly correlated with one another (P &lt; .0001). Percent time that MAP deviated from LA significantly associated with worse functional outcome at discharge (NIRS P = .001, ICP P = .004) and 90 d (NIRS P = .002, ICP P = .003), adjusting separately for age, WFNS, vasospasm, or delayed cerebral ischemia. CONCLUSION Both invasive (ICP) and non-invasive (NIRS) determination of personalized BP thresholds for aSAH patients is feasible, and these 2 approaches revealed significant collinearity. Exceeding individualized autoregulatory thresholds may increase the risk of poor functional outcomes.

Cerebral Autoregulation Is Impaired During Deep Hypothermia-A Porcine Multimodal Neuromonitoring Study.

Effects of brain temperature modulation on cerebral hemodynamics are unclear. We aimed at investigating changes of dynamic cerebral autoregulation (AR) indices during induction of deep hypothermia (HT) in a porcine model mimicking the clinical scenario of accidental HT. Thirteen pigs were surface-cooled to a core temperature of 28°C. High-frequency monitoring included brain temperature, mean arterial blood pressure (MAP), intracranial pressure (ICP), brain tissue oxygen tension (PbtO2), and regional oxygen saturation (rSO2) assessed by near-infrared spectroscopy to calculate AR-indices (pressure reactivity index [PRx], oxygen reactivity index [ORx], and cerebral oximetry index [COx]). Brain temperature decreased from 39.3°C ± 0.8°C to 28.8°C ± 1.0°C within a median 160 minutes (interquartile range 146-191 minutes), reflecting a rapid induction of deep HT (-4°C/h). MAP and cerebral perfusion pressure (CPP) remained stable until a brain temperature of 35°C (69 ± 8 mmHg, 53 ± 7 mmHg) and decreased to 58 ± 17 mmHg and 40 ± 17 mmHg at 28°C (p = 0.031 and p = 0.015). Despite the decrease in MAP and CPP, brain oxygenation increased (PbtO2: +5 mmHg, p = 0.037; rSO2: +7.3%, p = 0.029). There was no change in ICP during HT induction. Baseline AR-indices reflected normal cerebral AR and did not change until a brain temperature of 34°C (ORx), 33°C (PRx), and 30°C (COx). At lower temperature, AR-indices increased (PRx: p < 0.001, ORx: p = 0.02, COx: p = 0.03), reflecting impaired cerebral AR. Cerebrovascular reactivity is impaired at lower brain temperature levels. Although these temperatures are usually not targeted in clinical routine, this should be kept in mind when treating patients with accidental deep HT.

Can we use short recordings for assessment of dynamic cerebral autoregulation? A sensitivity analysis study in acute ischaemic stroke and healthy subjects

Objective: It is unclear whether the duration of recordings influences estimates of dynamic cerebral autoregulation (dCA). Therefore, we performed a retrospective study of the effects of reducing recording durations on dCA estimates; with the potential to inform recording duration for reliable estimates in challenging clinical populations. Approach: Seventy-eight healthy control subjects and 79 acute ischaemic stroke (AIS) patients were included. Cerebral blood flow (CBF) velocity was recorded with transcranial Doppler (TCD) and continuous blood pressure (BP) with a Finapres device. The autoregulation index (ARI), derived with transfer function analysis (TFA), was calculated for recording durations at one-minute intervals between 1 and 5 min using the same starting point of each recording. Main results: Though recording duration did not affect the overall ARI value, when compared to control subjects, AIS patients had significantly lower ARI values for durations between 3 and 5 min (p < 0.0001), but not 1 and 2 min. The intraclass correlation coefficient of all participants, for reproducibility of the five recording durations, was 0.69. AIS patients classified as having impaired cerebral autoregulation (CA; ARI ⩽ 4) at 5 min, had a 7.1% rate of false negatives for both 4 and 3 min recordings, reaching 42.9% for 1 min recording. The percentage of false-positives also increased with reduced recording durations (from 0% at 5 to 16.2% at 1 min). Significance: Reducing recording durations from 5 to 3 min can still provide reliable estimates of ARI, and may facilitate CA studies in potentially medically unstable AIS patients, as well as in other patient groups.

Dynamic Cerebral Autoregulation Reproducibility Is Affected by Physiological Variability.

Parameters describing dynamic cerebral autoregulation (DCA) have limited reproducibility. In an international, multi-center study, we evaluated the influence of multiple analytical methods on the reproducibility of DCA. Fourteen participating centers analyzed repeated measurements from 75 healthy subjects, consisting of 5 min of spontaneous fluctuations in blood pressure and cerebral blood flow velocity signals, based on their usual methods of analysis. DCA methods were grouped into three broad categories, depending on output types: (1) transfer function analysis (TFA); (2) autoregulation index (ARI); and (3) correlation coefficient. Only TFA gain in the low frequency (LF) band showed good reproducibility in approximately half of the estimates of gain, defined as an intraclass correlation coefficient (ICC) of >0.6. None of the other DCA metrics had good reproducibility. For TFA-like and ARI-like methods, ICCs were lower than values obtained with surrogate data (p < 0.05). For TFA-like methods, ICCs were lower for the very LF band (gain 0.38 ± 0.057, phase 0.17 ± 0.13) than for LF band (gain 0.59 ± 0.078, phase 0.39 ± 0.11, p ≤ 0.001 for both gain and phase). For ARI-like methods, the mean ICC was 0.30 ± 0.12 and for the correlation methods 0.24 ± 0.23. Based on comparisons with ICC estimates obtained from surrogate data, we conclude that physiological variability or non-stationarity is likely to be the main reason for the poor reproducibility of DCA parameters.

Glasgow Coma Scale Score Fluctuations are Inversely Associated With a NIRS-based Index of Cerebral Autoregulation in Acutely Comatose Patients.

The Glasgow Coma Scale (GCS) is an essential coma scale in critical care for determining the neurological status of patients and for estimating their long-term prognosis. Similarly, cerebral autoregulation (CA) monitoring has shown to be an accurate technique for predicting clinical outcomes. However, little is known about the relationship between CA measurements and GCS scores among neurological critically ill patients. This study aimed to explore the association between noninvasive CA multimodal monitoring measurements and GCS scores. Acutely comatose patients with a variety of neurological injuries admitted to a neurocritical care unit were monitored using near-infrared spectroscopy-based multimodal monitoring for up to 72 hours. Regional cerebral oxygen saturation (rScO2), cerebral oximetry index (COx), GCS, and GCS motor data were measured hourly. COx was calculated as a Pearson correlation coefficient between low-frequency changes in rScO2 and mean arterial pressure. Mixed random effects models with random intercept was used to determine the relationship between hourly near-infrared spectroscopy-based measurements and GCS or GCS motor scores. A total of 871 observations (h) were analyzed from 57 patients with a variety of neurological conditions. Mean age was 58.7±14.2 years and the male to female ratio was 1:1.3. After adjusting for hemoglobin and partial pressure of carbon dioxide in arterial blood, COx was inversely associated with GCS (β=-1.12, 95% confidence interval [CI], -1.94 to -0.31, P=0.007) and GCS motor score (β=-1.06, 95% CI, -2.10 to -0.04, P=0.04). In contrast rScO2 was not associated with GCS (β=-0.002, 95% CI, -0.01 to 0.01, P=0.76) or GCS motor score (β=-0.001, 95% CI, -0.01 to 0.01, P=0.84). This study showed that fluctuations in GCS scores are inversely associated with fluctuations in COx; as COx increases (impaired autoregulation), more severe neurological impairment is observed. However, the difference in COx between high and low GCS is small and warrants further studies investigating this association. CA multimodal monitoring with COx may have the potential to be used as a surrogate of neurological status when the neurological examination is not reliable (ie, sedation and paralytic drug administration).

Alternative representation of neural activation in multivariate models of neurovascular coupling in humans.

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and , rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. The simultaneous effects of neural stimulation, BP, and on CBFV were expressed with a dynamic multivariate model, using BP, EtCO2, and stimulation [s(t)] as inputs. Two versions of s(t) were considered: a gate function [sG(t)] or an orthogonal decomposition [sO(t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO2 reactivity [vasomotor reactivity step response (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO(t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10-5) and was correlated with the CBFV change (r = 0.73, P = 0.0001). The sO(t) explained a greater fraction of CBFV variance (~50%) than sG(t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for sG(t), and 6.9 and 7.4 for sO(t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO2 in response to sensorimotor stimulation, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO2 reactivity, and NVC in humans.NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 () to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or . This new marker of NVC, together with the model-predicted outputs for the contributions of BP, and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions.

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9cms-1 (11.1), old 51.7 (12.9) vs. 37.8cms-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7mmHg (16.0), old 33.9 (13.5) vs. 39.3mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09mmHgcms-1 (11.07), old 1.16 (0.34) vs. 1.34mmHgcms-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Static Cerebral Autoregulation is Not Altered in Symptomatic Concussed Athletes During Acute Central Hypervolemia

Dynamic cerebral autoregulation is impaired in concussed individuals. However, less is known regarding static cerebral autoregulation in symptomatic concussed athletes during a central hypervolemic challenge that increases blood pressure. PURPOSE: We tested the hypothesis that static cerebral autoregulation during a central hypervolemic challenge is impaired in symptomatic concussed college athletes (CA) vs healthy controls (HC). METHODS: Seven CA (age: 19±2 y, 5 females) and ten HC (age: 21±2 y, 6 females) completed one study visit. After 5 min of resting baseline, 20 mmHg of lower body positive pressure (LBPP) was applied for 5 min using an airtight chamber. Beat to beat blood pressure (photoplethysmography) and middle cerebral artery blood velocity (MCAv; transcranial Doppler) were recorded continuously. Static cerebral autoregulation was calculated using Fourier transfer function analysis with 3 min segments at baseline and after mean arterial pressure (MAP) stabilized during LBPP. Cerebral vascular resistance (CVR) was calculated as MAP/MCAv. Pulsatility index (PI) was calculated as the difference of peak systolic MCAv and end diastolic MCAv, divided by mean MCAv. Values are reported as a change from baseline. RESULTS: MAP (CA: 90±6 vs HC: 92±11 mmHg; P=0.32), MCAv (CA: 58.7±19.4 vs HC: 62.6±11.1 cm/s; P=0.30), gain (CA: 0.7±0.2 vs HC: 0.8±0.2 cm/s/mmHg; P=0.17), coherence (CA: 0.5±0.1 vs HC: 0.5±0.1; P=0.21), CVR (CA: 1.7±0.6 vs HC: 1.5±0.3 mmHg/cm/s; P=0.21), and PI (CA: 0.9±0.1 vs HC: 0.9±0.2; P=0.31) were not different at baseline. The change in MAP was not different between CA (12±6 mmHg) and HC (8±6 mmHg; P=0.12). The change in MCAv was greater in CA (CA: 4.8±4.6 vs HC: -4.3±8.7 cm/s; P=0.01). There were no differences in the change from baseline for gain (CA: 0.1±0.2 vs HC: 0.1±0.5 cm/s/mmHg; P=0.49) or coherence (CA: -0.0±0.1 vs HC: -0.0±0.1; P=0.40). The increase in CVR was attenuated in CA (CA: 0.0±0.2 vs HC: 0.3±0.3 mmHg/cm/s; P=0.04). The decrease in PI was greater in CA (CA: -0.1±0.0 vs HC: 0.0±0.1; P=0.02). CONCLUSION: These data indicate that indices of static cerebral autoregulation are not different between CA and HC during an acute increase in MAP. The blunted increase in CVR and greater decrease in PI appears to allow for a rise in MCAv during an acute increase in MAP in CA.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia

Introduction: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. Methods: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. Results: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO₂), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. Conclusion: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO₂ and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

Author response: The systolic blood pressure sweet spot after intracerebral hemorrhage: 130 mm Hg?

We appreciated Dr. Munakomi's response to our viewpoint1 on the data from Buletko et al.2 that suggested systolic blood pressure (BP) of 130 mm Hg as an ideal lower limit in BP reduction after spontaneous intracerebral hemorrhage (ICH). We agree with the comment on the remaining role for caution in aggressive BP reduction. However, a pressure autoregulatory shift to the right is disparate, complex, dynamic, not omnipresent,3 and should not prevail over compelling data that lower is better in BP reduction.4 Similarly, oxygen extraction fraction (OEF) as a predicate for therapeutic decision-making has not been successful.5 The focus of the index study was the lower limit of the targeted range.2 Clinicians may reconcile with a 130–160 mm Hg target, if worried about low goals. Others can use 120–140, but it may now be deemed unsafe to linger below 120, in view of the risk of ischemic deterioration.2 We agree that best management may lie ultimately in individualized goal-directed therapy, using autoregulation indices and neuroimaging biomarkers of ischemic risk (e.g., OEF). However, substantial observations have refuted a preponderant presence of perihematomal or regional ischemic penumbra in ICH.6 Serial OEF assessments in the hyperacute phase of ICH are seductive, but not readily applicable. Coupled with renal injury biomarkers, trending of multimodal neuromonitoring physiologic values may yield a U curve for stewardship of hyperacute BP reduction.

Prevalence, Evolution, and Extent of Impaired Cerebral Autoregulation in Children Hospitalized With Complex Mild Traumatic Brain Injury.

To examine cerebral autoregulation in children with complex mild traumatic brain injury. Prospective observational convenience sample. PICU at a level I trauma center. Children with complex mild traumatic brain injury (trauma, admission Glasgow Coma Scale score 13-15 with either abnormal head CT, or history of loss of consciousness). Cerebral autoregulation was tested using transcranial Doppler ultrasound between admission day 1 and 8. The primary outcome was prevalence of impaired cerebral autoregulation (autoregulation index < 0.4),determined using transcranial Doppler ultrasonography and tilt testing. Secondary outcomes examined factors associated with and evolution and extent of impairment. Cerebral autoregulation testing occurred in 31 children 10 years (SD, 5.2 yr), mostly male (59%) with isolated traumatic brain injury (91%), median admission Glasgow Coma Scale 15, Injury Severity Scores 14.2 (SD, 7.7), traumatic brain injury due to fall (50%), preadmission loss of consciousness (48%), and abnormal head CT scan (97%). Thirty-one children underwent 56 autoregulation tests. Impaired cerebral autoregulation occurred in 15 children (48.4%) who underwent 19 tests; 68% and 32% of tests demonstrated unilateral and bilateral impairment, respectively. Compared with children on median day 6 of admission after traumatic brain injury, impaired autoregulation was most common in the first 5 days after traumatic brain injury (day 1: relative risk, 3.7; 95% CI, 1.9-7.3 vs day 2: relative risk, 2.7; 95% CI, 1.1-6.5 vs day 5: relative risk, 1.33; 95% CI, 0.7-2.3). Children with impaired autoregulation were older (12.3 yr [SD, 1.3 yr] vs 8.7 yr [SD, 1.1 yr]; p = 0.04) and tended to have subdural hematoma (64% vs 44%), epidural hematoma (29% vs 17%), and subarachnoid hemorrhage (36% vs 28%). Eight children (53%) were discharged home with ongoing impaired cerebral autoregulation. Impaired cerebral autoregulation is common in children with complex mild traumatic brain injury, despite reassuring admission Glasgow Coma Scale 13-15. Children with complex mild traumatic brain injury have abnormal cerebrovascular hemodynamics, mostly during the first 5 days. Impairment commonly extends to the contralateral hemisphere and discharge of children with ongoing impaired cerebral autoregulation is common.