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How continuous cerebral autoregulation (CCA) knowledge should be optimally gained and interpreted is still an active area of research and refinement. We now experience a unique situation of having indices clinically available before definitive evidence of benefit or practice guidelines, in a moment when high rates of institutional variability exist both in the application of monitoring as well as in monitoring-guided treatments. Responses from 47 international clinicians, experts in this field, were collected with polling and discussion of the results. The clinical use of CCA in critical illness was not universal among experts, with 34% not using it. Of those who use a CCA index in clinical practice, 64% use intracranial pressure–based Pressure Reactivity index (PRx). There seems to exist a considerable trust in the physiologic plausibility of CCA to guide individual arterial blood pressure and cerebral perfusion pressure therapy and provide benefit, regardless of the difficulty of proving this. A total of 59% feel the need for phase II and III prospective studies but would continue to use CCA information in their practice even if randomized controlled trials (RCTs) did not show clear clinical benefit. There was nearly universal interest to participate in an RCT, with agreement that the research community must together determine end points and interventions to reduce wasted effort and time, and that investigations should include the following: the most appropriate way of inclusion of CCA into the clinical workflow; whether CCA-guided interventions should be prophylactic, proactive; or reactive; and whether a CCA-centric (unimodal) or a multimodal monitoring-integrated tiered therapy approach should be adopted. Pediatric and neonatal populations were highlighted as having urgent need and even more plausibility than adults. On the whole, the initiative was enthusiastically embraced by the experts, with the general feeling that a strong push should be now made by the community to convert the plausible benefits of CCA monitoring, already implemented in some centers, into a more standardized and RCT-validated clinical reality. [ABSTRACT FROM AUTHOR]

Background: Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity. Methods: A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx). Results: A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact. Conclusions: In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF. [ABSTRACT FROM AUTHOR]

Impaired cerebral autoregulation (CA) in moderate/severe traumatic brain injury (TBI) has been identified as a strong associate with poor long-term outcomes, with recent data highlighting its dominance over cerebral physiological dysfunction seen in the acute phase post-injury. With advances in bedside continuous cerebral physiological signal processing, continuously derived metrics of CA capacity have been described over the past two decades, leading to improvements in cerebral physiological insult detection and development of novel personalized approaches to TBI care in the intensive care unit (ICU). This narrative review focuses on highlighting the concept of continuous CA monitoring and consequences of impairment in moderate/severe TBI. Further, we provide a comprehensive description and overview of the main personalized cerebral physiological targets, based on CA monitoring, that are emerging as strong associates with patient outcomes. The CA-based personalized targets, such as optimal cerebral perfusion pressure (CPPopt), lower/upper limit of regulation (LLR/ULR), and individualized intracranial pressure (iICP) are positioned to change the way we care for patients with TBI in the ICU, moving away from the "one treatment fits all" paradigm of current guideline-based therapeutic approaches toward a true personalized medicine approach tailored to the individual patient. Future perspectives regarding research needs in this field are also discussed. [ABSTRACT FROM AUTHOR]

The cerebral pressure reactivity index (PRx), through intracranial pressure (ICP) measurements, informs clinicians about the cerebral autoregulation (CA) status in adult-sedated patients with traumatic brain injury (TBI). Using PRx in clinical practice is currently limited by variability over shorter monitoring periods. We applied an innovative method to reduce the PRx variability by ventilator-induced slow (1/min) positive end-expiratory pressure (PEEP) oscillations. We hypothesized that, as seen in a previous animal model, the PRx variability would be reduced by inducing slow arterial blood pressure (ABP) and ICP oscillations without other clinically relevant physiological changes. Patients with TBI were ventilated with a static PEEP for 30 min (PRx period) followed by a 30-min period of slow [1/min (0.0167 Hz)] + 5 cmH2O PEEP oscillations (induced (iPRx period). Ten patients with TBI were included. No clinical monitoring was discontinued and no additional interventions were required during the iPRx period. The PRx variability [measured as the standard deviation (SD) of PRx] decreased significantly during the iPRx period from 0.25 (0.22-0.30) to 0.14 (0.09-0.17) (P = 0.006). There was a power increase around the induced frequency (1/min) for both ABP and ICP (P = 0.002). In conclusion, 1/min PEEP-induced oscillations reduced the PRx variability in patients with TBI with ICP levels <22 mmHg. No other clinically relevant physiological changes were observed. Reduced PRx variability might improve CA-guided perfusion management by reducing the time to find "optimal" perfusion pressure targets. Larger studies with prolonged periods of PEEP-induced oscillations are required to take it to routine use. NEW & NOTEWORTHY Cerebral autoregulation assessment requires sufficient slow arterial blood pressure (ABP) waves. However, spontaneous ABP waves may be insufficient for reliable cerebral autoregulation estimations. Therefore, we applied a ventilator "sigh-function" to generate positive end-expiratory pressure oscillations that induce slow ABP waves. This method demonstrated a reduced variability of the pressure reactivity index, commonly used as continuous cerebral autoregulation measure in a traumatic brain injury population. [ABSTRACT FROM AUTHOR]

Impairments in cerebral autoregulation (CA) are related to poor clinical outcome. Near infrared spectroscopy (NIRS) is a non-invasive technique applied to estimate CA. Our general purpose was to study the clinical feasibility of a previously published 'NIRS-only' CA methodology in a critically ill intensive care unit (ICU) population and determine its relationship with clinical outcome. Bilateral NIRS measurements were performed for 1–2 h. Data segments of ten-minutes were used to calculate transfer function analyses (TFA) CA estimates between high frequency oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb) signals. The phase shift was corrected for serial time shifts. Criteria were defined to select TFA phase plot segments (segments) with 'high-pass filter' characteristics. In 54 patients, 490 out of 729 segments were automatically selected (67%). In 34 primary neurology patients the median (q1–q3) low frequency (LF) phase shift was higher in 19 survivors compared to 15 non-survivors (13° (6.3–35) versus 0.83° (−2.8–13), p = 0.0167). CA estimation using the NIRS-only methodology seems feasible in an ICU population using segment selection for more robust and consistent CA estimations. The 'NIRS-only' methodology needs further validation, but has the advantage of being non-invasive without the need for arterial blood pressure monitoring. [ABSTRACT FROM AUTHOR]

Cerebral perfusion may be altered in sepsis patients. However, there are conflicting findings on cerebral autoregulation (CA) in healthy participants undergoing the experimental endotoxemia protocol, a proxy for systemic inflammation in sepsis. In the current study, a newly developed near-infrared spectroscopy (NIRS)-based CA index is investigated in an endotoxemia study population, together with an index of focal cerebral oxygenation. Methods: Continuous-wave NIRS data were obtained from 11 healthy participants receiving a continuous infusion of bacterial endotoxin for 3 h (ClinicalTrials.gov NCT02922673) under extensive physiological monitoring. Oxygenated–deoxygenated hemoglobin phase differences in the (very)low frequency (VLF/LF) bands and the Tissue Saturation Index (TSI) were calculated at baseline, during systemic inflammation, and at the end of the experiment 7 h after the initiation of endotoxin administration. Results: The median (inter-quartile range) LF phase difference was 16.2° (3.0–52.6°) at baseline and decreased to 3.9° (2.0–8.8°) at systemic inflammation (p = 0.03). The LF phase difference increased from systemic inflammation to 27.6° (12.7–67.5°) at the end of the experiment (p = 0.005). No significant changes in VLF phase difference were observed. The TSI (mean ± SD) increased from 63.7 ± 3.4% at baseline to 66.5 ± 2.8% during systemic inflammation (p = 0.03) and remained higher at the end of the experiment (67.1 ± 4.2%, p = 0.04). Further analysis did not reveal a major influence of changes in several covariates such as blood pressure, heart rate, PaCO2, and temperature, although some degree of interaction could not be excluded. Discussion: A reversible decrease in NIRS-derived cerebral autoregulation phase difference was seen after endotoxin infusion, with a small, sustained increase in TSI. These findings suggest that endotoxin administration in healthy participants reversibly impairs CA, accompanied by sustained microvascular vasodilation. [ABSTRACT FROM AUTHOR]

We tested the influence of blood pressure variability on the reproducibility of dynamic cerebral autoregulation (DCA) estimates. Data were analyzed from the 2nd CARNet bootstrap initiative, where mean arterial blood pressure (MABP), cerebral blood flow velocity (CBFV) and end tidal CO2 were measured twice in 75 healthy subjects. DCA was analyzed by 14 different centers with a variety of different analysis methods. Intraclass Correlation (ICC) values increased significantly when subjects with low power spectral density MABP (PSD-MABP) values were removed from the analysis for all gain, phase and autoregulation index (ARI) parameters. Gain in the low frequency band (LF) had the highest ICC, followed by phase LF and gain in the very low frequency band. No significant differences were found between analysis methods for gain parameters, but for phase and ARI parameters, significant differences between the analysis methods were found. Alternatively, the Spearman-Brown prediction formula indicated that prolongation of the measurement duration up to 35 minutes may be needed to achieve good reproducibility for some DCA parameters. We conclude that poor DCA reproducibility (ICC<0.4) can improve to good (ICC > 0.6) values when cases with low PSD-MABP are removed, and probably also when measurement duration is increased. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend maintaining cerebral perfusion pressure (CPP) between 60 and 70 mmHg in patients with severe traumatic brain injury (TBI), but acknowledge that optimal CPP may vary depending on cerebral blood flow autoregulation. Previous retrospective studies suggest that targeting CPP where the pressure reactivity index (PRx) is optimized (CPPopt) may be associated with improved recovery.Methods: We performed a retrospective cohort study involving TBI patients who underwent PRx monitoring to assess issues of feasibility relevant to future interventional studies: (1) the proportion of time that CPPopt could be detected; (2) inter-observer variability in CPPopt determination; and (3) agreement between manual and automated CPPopt estimates. CPPopt was determined for consecutive 6-h epochs during the first week following TBI. Sixty PRx-CPP tracings were randomly selected and independently reviewed by six critical care professionals. We also assessed whether greater deviation between actual CPP and CPPopt (ΔCPP) was associated with poor outcomes using multivariable models.Results: In 71 patients, CPPopt could be manually determined in 985 of 1173 (84%) epochs. Inter-observer agreement for detectability was moderate (kappa 0.46, 0.23-0.68). In cases where there was consensus that it could be determined, agreement for the specific CPPopt value was excellent (weighted kappa 0.96, 0.91-1.00). Automated CPPopt was within 5 mmHg of manually determined CPPopt in 93% of epochs. Lower PRx was predictive of better recovery, but there was no association between ΔCPP and outcome. Percentage time spent below CPPopt increased over time among patients with poor outcomes (p = 0.03). This effect was magnified in patients with impaired autoregulation (defined as PRx > 0.2; p = 0.003).Conclusion: Prospective interventional clinical trials with regular determination of CPPopt and corresponding adjustment of CPP goals are feasible, but measures to maximize consistency in CPPopt determination are necessary. Although we could not confirm a clear association between ΔCPP and outcome, time spent below CPPopt may be particularly harmful, especially when autoregulation is impaired. [ABSTRACT FROM AUTHOR]

Methods to identify an autoregulation guided 'optimal' cerebral perfusion pressure (CPPopt) for traumatic brain injury patients (TBI) have been reported through several studies. An important drawback of existing methodology is that CPPopt can be calculated only in ∼50-60% of the monitoring time. In this study, we hypothesized that the CPPopt yield and the continuity can be improved significantly through application of a multi-window and weighting calculation algorithm, without adversely affecting preservation of its prognostic value. Data of 526 severe TBI patients admitted between 2003 and 2015 were studied. The multi-window CPPopt calculation was based on automated curve fitting in pressure reactivity index (PRx)-CPP plots using data from 36 increasing length time windows (2-8 h). The resulting matrix of CPPopts was then averaged in a weighted manner. The yield, continuity, and stability of CPPopt were studied. The difference between patients' actual CPP and CPPopt (ΔCPP) was calculated and the association with outcome was analyzed. Overall, the multi-window method demonstrated more continuous and stable presentation of CPPopt in this cohort. The new method resulted in a mean (±SE) CPPopt yield of 94% ± 2.1%, as opposed to the previous single-window-based CPPopt yield of 51% ± 0.94%. The stability of CPPopt across the whole monitoring period was significantly improved by using the new algorithm ( p < 0.001). The relationship between ΔCPP according to the multi-window algorithm and outcome was similar to that for CPPopt calculated on the basis of a single window. In conclusion, this study validates the use of a new multi-window and weighting algorithm for significant improvement of CPPopt yield in TBI patients. This methodological improvement is essential for its clinical application in future CPPopt trials. [ABSTRACT FROM AUTHOR]

Managing traumatic brain injury (TBI) patients with a cerebral perfusion pressure (CPP) near to the cerebral autoregulation (CA)-guided "optimal" CPP (CPPopt) value is associated with improved outcome and might be useful to individualize care, but has never been prospectively evaluated. This study evaluated the feasibility and safety of CA-guided CPP management in TBI patients requiring intracranial pressure monitoring and therapy (TBIicp patients). The CPPopt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) parallel two-arm feasibility trial took place in four tertiary centers. TBIicp patients were randomized to either the Brain Trauma Foundation (BTF) guideline CPP target range (control group) or to the individualized CA-guided CPP targets (intervention group). CPP targets were guided by six times daily software-based alerts for up to 5 days. The primary feasibility end-point was the percentage of time with CPP concordant (±5 mm Hg) with the set CPP targets. The main secondary safety end-point was an increase in therapeutic intensity level (TIL) between the control and intervention group. Twenty-eight patients were randomized to the control and 32 patients to the intervention group. CPP in the intervention group was in the target range for 46.5% (interquartile range, 41.2–58) of the monitored time, significantly higher than the feasibility target specified in the published protocol (36%; p < 0.001). There were no significant differences between groups for TIL or for other safety end-points. Conclusively, targeting an individual and dynamic CA-guided CPP is feasible and safe in TBIicp patients. This encourages a prospective trial powered for clinical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed “optimal cerebral perfusion pressure.” Design: Retrospective analysis of prospectively collected data. Setting: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. Patients: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. Interventions: None. Measurements and Main Results: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70 mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70 mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/ optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. Conclusions: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment. [ABSTRACT FROM AUTHOR]

Aim Of the Study: Estimation of cerebral anaerobic metabolism in survivors and non-survivors after cardiac arrest.Methods: We performed an observational study in twenty comatose patients after cardiac arrest and 19 healthy control subjects. We measured mean flow velocity in the middle cerebral artery (MFVMCA) by transcranial Doppler. Arterial and jugular blood samples were used for calculation of the jugular venous-to-arterial CO2/arterial to-jugular venous O2 content difference ratio.Results: After cardiac arrest, MFVMCA increased from 26.0[18.6-40.4]cm/sec on admission to 63.9[48.3-73.1]cm/sec after 72h (p<0.0001), with no significant differences between survivors and non-survivors (p=0.4853). The MFVMCA in controls was 59.1[52.8-69.0]cm/sec. The oxygen extraction fraction (O2EF) was 38.9[24.4-47.7]% on admission and decreased significantly to 17.3[12.1-26.2]% at 72h (p<0.0001). The decrease in O2EF was more pronounced in non-survivors (p=0.0173). O2EF in the control group was 35.4[32.4-38.7]%. The jugular bulb-arterial CO2 to arterial-jugular bulb O2 content difference ratio was >1 at all time points after cardiac arrest and did not change during admission, with no differences between survivors and non-survivors. Values in cardiac arrest patients were similar to those in normal subjects.Conclusions: In this study, low CBF after cardiac arrest is not associated with anaerobic metabolism. Hypoperfusion appears to be the consequence of a decrease of neuronal functioning and metabolic needs. Alternatively, hypoperfusion may decrease cerebral metabolism. Subsequently, metabolism increases in survivors, consistent with resumption of neuronal activity, whereas in non-survivors lasting low metabolism reflects irreversible neuronal damage. [ABSTRACT FROM AUTHOR]

Objectives: In severe traumatic brain injury, cerebral perfusion pressure management based on cerebrovascular pressure reactivity index has the potential to provide a personalized treatment target to improve patient outcomes. So far, the methods have focused on identifying "one" autoregulation-guided cerebral perfusion pressure target-called "cerebral perfusion pressure optimal". We investigated whether a cerebral perfusion pressure autoregulation range-which uses a continuous estimation of the "lower" and "upper" cerebral perfusion pressure limits of cerebrovascular pressure autoregulation (assessed with pressure reactivity index)-has prognostic value.Design: Single-center retrospective analysis of prospectively collected data.Setting: The neurocritical care unit at a tertiary academic medical center.Patients: Data from 729 severe traumatic brain injury patients admitted between 1996 and 2016 were used. Treatment was guided by controlling intracranial pressure and cerebral perfusion pressure according to a local protocol.Interventions: None.Methods and Main Results: Cerebral perfusion pressure-pressure reactivity index curves were fitted automatically using a previously published curve-fitting heuristic from the relationship between pressure reactivity index and cerebral perfusion pressure. The cerebral perfusion pressure values at which this "U-shaped curve" crossed the fixed threshold from intact to impaired pressure reactivity (pressure reactivity index = 0.3) were denoted automatically the "lower" and "upper" cerebral perfusion pressure limits of reactivity, respectively. The percentage of time with cerebral perfusion pressure below (%cerebral perfusion pressure < lower limit of reactivity), above (%cerebral perfusion pressure > upper limit of reactivity), or within these reactivity limits (%cerebral perfusion pressure within limits of reactivity) was calculated for each patient and compared across dichotomized Glasgow Outcome Scores. After adjusting for age, initial Glasgow Coma Scale, and mean intracranial pressure, percentage of time with cerebral perfusion pressure less than lower limit of reactivity was associated with unfavorable outcome (odds ratio %cerebral perfusion pressure < lower limit of reactivity, 1.04; 95% CI, 1.02-1.06; p < 0.001) and mortality (odds ratio, 1.06; 95% CI, 1.04-1.08; p < 0.001).Conclusions: Individualized autoregulation-guided cerebral perfusion pressure management may be a plausible alternative to fixed cerebral perfusion pressure threshold management in severe traumatic brain injury patients. Prospective randomized research will help define which autoregulation-guided method is beneficial, safe, and most practical. [ABSTRACT FROM AUTHOR]