The influence of carbon dioxide on cerebral metabolism and oxygen consumption: combining multimodal monitoring with dynamic systems modelling.

Hypercapnia increases cerebral blood flow. The effects on cerebral metabolism remain incompletely understood although studies show an oxidation of cytochrome c oxidase, Complex IV of the mitochondrial respiratory chain. Systems modelling was combined with previously published non-invasive measurements of cerebral tissue oxygenation, cerebral blood flow, and cytochrome c oxidase redox state to evaluate any metabolic effects of hypercapnia. Cerebral tissue oxygen saturation and cytochrome oxidase redox state were measured with broadband near infrared spectroscopy and cerebral blood flow velocity with transcranial Doppler ultrasound. Data collected during 5-min hypercapnia in awake human volunteers were analysed using a Fick model to determine changes in brain oxygen consumption and a mathematical model of cerebral hemodynamics and metabolism (BrainSignals) to inform on mechanisms. Either a decrease in metabolic substrate supply or an increase in metabolic demand modelled the cytochrome oxidation in hypercapnia. However, only the decrease in substrate supply explained both the enzyme redox state changes and the Fick-calculated drop in brain oxygen consumption. These modelled outputs are consistent with previous reports of CO2 inhibition of mitochondrial succinate dehydrogenase and isocitrate dehydrogenase. Hypercapnia may have physiologically significant effects suppressing oxidative metabolism in humans and perturbing mitochondrial signalling pathways in health and disease.

Special Section Guest Editorial: Thirty Years of Functional Near-Infrared Spectroscopy.

Functional Near-Infrared Spectroscopy (fNIRS) is a non-invasive optical technique that measures cerebral hemodynamics across multiple regions of interest, and thereby characterises brain functional activation. Since its first description in 1993, fNIRS has undergone substantial developments in hardware, analysis techniques, and applications. Thirty years later, this technique is significantly enchancing our understanding in diverse areas of neuroscience research such as neurodevelopment, cognitive neuroscience, psychiatric disorders, neurodegenerative conditions, and brain injury management in intensive care settings. This special issue outlines the latest progress in instrumentation and analysis techniques and showcases some applications within the expanding field of fNIRS over the past decade.

Advances in Neuroimaging and Monitoring to Defend Cerebral Perfusion in Noncardiac Surgery.

Noncardiac surgery conveys a substantial risk of secondary organ dysfunction and injury. Neurocognitive dysfunction and covert stroke are emerging as major forms of perioperative organ dysfunction, but a better understanding of perioperative neurobiology is required to identify effective treatment strategies. The likelihood and severity of perioperative brain injury may be increased by intraoperative hemodynamic dysfunction, tissue hypoperfusion, and a failure to recognize complications early in their development. Advances in neuroimaging and monitoring techniques, including optical, sonographic, and magnetic resonance, have progressed beyond structural imaging and now enable noninvasive assessment of cerebral perfusion, vascular reserve, metabolism, and neurologic function at the bedside. Translation of these imaging methods into the perioperative setting has highlighted several potential avenues to optimize tissue perfusion and deliver neuroprotection. This review introduces the methods, metrics, and evidence underlying emerging optical and magnetic resonance neuroimaging methods and discusses their potential experimental and clinical utility in the setting of noncardiac surgery.

Neurological Manifestations of Coronavirus Disease 2019: A Comprehensive Review and Meta-Analysis of the First 6 Months of Pandemic Reporting.

Background: There is growing evidence that SARS-Cov-2 infection is associated with severe neurological complications. Understanding the nature and prevalence of these neurologic manifestations is essential for identifying higher-risk patients and projecting demand for ongoing resource utilisation. This review and meta-analysis report the neurologic manifestations identified in hospitalised COVID-19 patients and provide a preliminary estimate of disease prevalence. Methods: MEDLINE, Embase and Scopus were searched for studies reporting the occurrence of neurological complications in hospitalised COVID-19 patients. Results: A total of 2,207 unique entries were identified and screened, among which 14 cohort studies and 53 case reports were included, reporting on a total of 8,577 patients. Central nervous system manifestations included ischemic stroke (n = 226), delirium (n = 79), intracranial haemorrhage (ICH, n = 57), meningoencephalitis (n = 13), seizures (n = 3), and acute demyelinating encephalitis (n = 2). Peripheral nervous system manifestations included Guillain-Barrè Syndrome (n = 21) and other peripheral neuropathies (n = 3). The pooled period prevalence of ischemic stroke from identified studies was 1.3% [95%CI: 0.9-1.8%, 102/7,715] in all hospitalised COVID-19 patients, and 2.8% [95%CI: 1.0-4.6%, 9/318] among COVID-19 patients admitted to ICU. The pooled prevalence of ICH was estimated at 0.4% [95%CI: 0-0.8%, 6/1,006]. Conclusions: The COVID-19 pandemic exerts a substantial neurologic burden which may have residual effects on patients and healthcare systems for years. Low quality evidence impedes the ability to accurately predict the magnitude of this burden. Robust studies with standardised screening and case definitions are required to improve understanding of this disease and optimise treatment of individuals at higher risk for neurologic sequelae.

Neuroanesthesia Practice During the COVID-19 Pandemic: Recommendations From Society for Neuroscience in Anesthesiology and Critical Care (SNACC).

The pandemic of coronavirus disease 2019 (COVID-19) has several implications relevant to neuroanesthesiologists, including neurological manifestations of the disease, impact of anesthesia provision for specific neurosurgical procedures and electroconvulsive therapy, and health care provider wellness. The Society for Neuroscience in Anesthesiology and Critical Care appointed a task force to provide timely, consensus-based expert guidance for neuroanesthesiologists during the COVID-19 pandemic. The aim of this document is to provide a focused overview of COVID-19 disease relevant to neuroanesthesia practice. This consensus statement provides information on the neurological manifestations of COVID-19, advice for neuroanesthesia clinical practice during emergent neurosurgery, interventional radiology (excluding endovascular treatment of acute ischemic stroke), transnasal neurosurgery, awake craniotomy and electroconvulsive therapy, as well as information about health care provider wellness. Institutions and health care providers are encouraged to adapt these recommendations to best suit local needs, considering existing practice standards and resource availability to ensure safety of patients and providers.

Management of the patient presenting with anaemia in the preoperative setting.

Preoperative anaemia is common, seen in a third of patients before major surgery. Both preoperative anaemia and blood transfusion are associated with increased patient risk and adverse outcome. Patient Blood Management (PBM) is the multidisciplinary, multimodal approach to optimising the care of patients who may require blood transfusion. Guidelines exist with many recommendations throughout the perioperative pathway. However, the efficacy of individual recommendations as an intervention in terms of clinical outcome can be confusing. In the UK the first national audit of PBM in surgery was carried out in 2015. This reviewed the use and impact of PBM recommendations in hospitals throughout the UK where major surgery was undertaken. The current evidence base for these PBM recommendations was reviewed and the patient outcome in terms of blood transfusion use and length of hospital stay assessed in those where PBM interventions were followed. For the patient who presents with preoperative anaemia, 'quick wins' were identified that reduced blood transfusion use and reduced length of stay in hospital; preoperative discontinuation of anticoagulation or antiplatelet therapy, and intraoperative use of tranexamic acid and cell salvage.

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury.

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (1H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA ( r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score ( p = 0.04), thalamic Lac/NAA ( p = 0.04) and neurodevelopmental outcome at one year ( p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.

Impact of postoperative intravenous fluid administration on complications following elective hepato-pancreato-biliary surgery.

BACKGROUND: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary (HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit (ICU), in this subgroup of patients. METHODS: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. RESULTS: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input (4790 vs. 4300 mL), higher colloid volume (2000 vs. 1500 mL), lower urine output (1595 vs. 1900 mL) and greater overall fluid balance (+3040 vs.+2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered (r = 0.278, P < 0.001), intravenous colloid input (r = 0.278, P < 0.001), urine output (r = -0.295, P < 0.001), positive fluid balance (r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors (OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). CONCLUSIONS: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear.

Image reconstruction of oxidized cerebral cytochrome C oxidase changes from broadband near-infrared spectroscopy data.

In diffuse optical tomography (DOT), overlapping and multidistance measurements are required to reconstruct depth-resolved images of oxy- ([Formula: see text]) and deoxy- (HHb) hemoglobin concentration changes occurring in the brain. These can be considered an indirect measure of brain activity, under the assumption of intact neurovascular coupling. Broadband systems also allow changes in the redox state of cytochrome c oxidase (oxCCO) to be measured, which can be an important biomarker when neurovascular coupling is impaired. We used DOT to reconstruct images of [Formula: see text], [Formula: see text], and [Formula: see text] from data acquired with a broadband system. Four healthy volunteers were measured while performing a visual stimulation task (4-Hz inverting checkerboard). The broadband system was configured to allow multidistance and overlapping measurements of the participants' visual cortex with 32 channels. A multispectral approach was employed to reconstruct changes in concentration of the three chromophores during the visual stimulation. A clear and focused activation was reconstructed in the left occipital cortex of all participants. The difference between the residuals of the three-chromophore model and of the two-chromophore model (recovering only [Formula: see text] and [Formula: see text]) exhibits a spectrum similar to that of oxCCO. These results form a basis for further studies aimed to further optimize image reconstruction of [Formula: see text].

Hyperoxia results in increased aerobic metabolism following acute brain injury.

Acute brain injury is associated with depressed aerobic metabolism. Below a critical mitochondrial pO2 cytochrome c oxidase, the terminal electron acceptor in the mitochondrial respiratory chain, fails to sustain oxidative phosphorylation. After acute brain injury, this ischaemic threshold might be shifted into apparently normal levels of tissue oxygenation. We investigated the oxygen dependency of aerobic metabolism in 16 acutely brain-injured patients using a 120-min normobaric hyperoxia challenge in the acute phase (24-72 h) post-injury and multimodal neuromonitoring, including transcranial Doppler ultrasound-measured cerebral blood flow velocity, cerebral microdialysis-derived lactate-pyruvate ratio (LPR), brain tissue pO2 (pbrO2), and tissue oxygenation index and cytochrome c oxidase oxidation state (oxCCO) measured using broadband spectroscopy. Increased inspired oxygen resulted in increased pbrO2 [ΔpbrO2 30.9 mmHg p < 0.001], reduced LPR [ΔLPR -3.07 p = 0.015], and increased cytochrome c oxidase (CCO) oxidation (Δ[oxCCO] + 0.32 µM p < 0.001) which persisted on return-to-baseline (Δ[oxCCO] + 0.22 µM, p < 0.01), accompanied by a 7.5% increase in estimated cerebral metabolic rate for oxygen ( p = 0.038). Our results are consistent with an improvement in cellular redox state, suggesting oxygen-limited metabolism above recognised ischaemic pbrO2 thresholds. Diffusion limitation or mitochondrial inhibition might explain these findings. Further investigation is warranted to establish optimal oxygenation to sustain aerobic metabolism after acute brain injury.

Multi-channel multi-distance broadband near-infrared spectroscopy system to measure the spatial response of cellular oxygen metabolism and tissue oxygenation.

We present a multi-channel, multi-distance broadband near-infrared spectroscopy (NIRS) system with the capability of measuring changes in haemoglobin concentrations (Δ[HbO2], Δ[HHb]), oxidation state of cytochrome-c-oxidase (Δ[oxCCO]) and tissue oxygen saturation (TOI) in the adult human brain. The main components of the instrument are two customized spectrographs and two light sources. Each spectrograph is lens-based to improve light throughput, has a grating enhanced to optimise reflection in the near-infrared (NIR) spectral region and uses a front illuminated cooled CCD camera (-70° C) with a square chip dimension of 12.3 x 12.3 mm (512 x 512 pixels). Each light source uses a 50W halogen bulb with a gold plated mirror to increase the intensity of the NIR light. Each light source was connected to a custom-built bifurcated fibre bundle to create two source fibre bundles (3.2 mm diameter each). Each spectrograph received light input from another custom-built fibre bundle comprised of six individual bundles (one with 0.6 mm diameter and the other five with 1.5 mm diameter). All fibre bundles were fixed on a 3D printed optode holder (two light sources x two fibre bundles each = four probes; and two spectrographs x six fibre bundles each = 12 probes) that allowed 24 multi-distance channels across the forehead (six channels at 20 mm, three channels at 30 mm and 15 channels at 35 mm) and six TOI measurements. We demonstrated the use of the system in a cohort of nine healthy adult volunteers during prefrontal cortex functional activation using the Stroop task. We have observed functional responses identified as significant increase in Δ[HbO2], decrease in Δ[HHb] and increase in Δ[oxCCO] in five channels (out of 12), that overlay the left and right dorsolateral prefrontal cortices. There was no observable TOI functional response and we have shown small variations in TOI across different sites within the same subject and within the same site across subjects.

Functional imaging of the human brain using a modular, fibre-less, high-density diffuse optical tomography system.

We present the first three-dimensional, functional images of the human brain to be obtained using a fibre-less, high-density diffuse optical tomography system. Our technology consists of independent, miniaturized, silicone-encapsulated DOT modules that can be placed directly on the scalp. Four of these modules were arranged to provide up to 128, dual-wavelength measurement channels over a scalp area of approximately 60 × 65 mm2. Using a series of motor-cortex stimulation experiments, we demonstrate that this system can obtain high-quality, continuous-wave measurements at source-detector separations ranging from 14 to 55 mm in adults, in the presence of hair. We identify robust haemodynamic response functions in 5 out of 5 subjects, and present diffuse optical tomography images that depict functional haemodynamic responses that are well-localized in all three dimensions at both the individual and group levels. This prototype modular system paves the way for a new generation of wearable, wireless, high-density optical neuroimaging technologies.

Towards a wearable near infrared spectroscopic probe for monitoring concentrations of multiple chromophores in biological tissue in vivo.

The first wearable multi-wavelength technology for functional near-infrared spectroscopy has been developed, based on a custom-built 8-wavelength light emitting diode (LED) source. A lightweight fibreless probe is designed to monitor changes in the concentrations of multiple absorbers (chromophores) in biological tissue, the most dominant of which at near-infrared wavelengths are oxyhemoglobin and deoxyhemoglobin. The use of multiple wavelengths enables signals due to the less dominant chromophores to be more easily distinguished from those due to hemoglobin and thus provides more complete and accurate information about tissue oxygenation, hemodynamics, and metabolism. The spectroscopic probe employs four photodiode detectors coupled to a four-channel charge-to-digital converter which includes a charge integration amplifier and an analogue-to-digital converter (ADC). Use of two parallel charge integrators per detector enables one to accumulate charge while the other is being read out by the ADC, thus facilitating continuous operation without dead time. The detector system has a dynamic range of about 80 dB. The customized source consists of eight LED dies attached to a 2 mm × 2 mm substrate and encapsulated in UV-cured epoxy resin. Switching between dies is performed every 20 ms, synchronized to the detector integration period to within 100 ns. The spectroscopic probe has been designed to be fully compatible with simultaneous electroencephalography measurements. Results are presented from measurements on a phantom and a functional brain activation study on an adult volunteer, and the performance of the spectroscopic probe is shown to be very similar to that of a benchtop broadband spectroscopy system. The multi-wavelength capabilities and portability of this spectroscopic probe will create significant opportunities for in vivo studies in a range of clinical and life science applications.

Care of elderly patients: a prospective audit of the prevalence of hypotension and the use of BIS intraoperatively in 25 hospitals in London.

BACKGROUND: Anaesthesia is frequently complicated by intraoperative hypotension (IOH) in the elderly, and this is associated with adverse outcome. The definition of IOH is controversial, and although management guidelines for IOH in the elderly exist, the frequency of IOH and typical clinically applied treatment thresholds are largely unknown in the UK. METHODS: We audited frequency of intraoperative blood pressure against national guidelines in elderly patients undergoing surgery. Depth of anaesthesia (DOA) monitoring was also audited due to the association between low DOA values and IOH with increased mortality (as part of "double" and "triple low" phenomena) and because it is a suggested management strategy to reduce IOH. RESULTS: Twenty-five hospitals submitted data on 481 patients. Hypotension varied depending on the definition, but affected 400 patients (83.3 %) using the AAGBI standard. Furthermore, 2.9, 13.5, and 24.6 % had mean arterial blood pressures <50, <60, and <70 mmHg for 20 min, respectively, and 136 (28.4 %) had systolic blood pressure decrease by 20 % for 20 min. DOA monitors were used for 45 (9.4 %) patients. CONCLUSIONS: IOH is common and use of DOA monitors is less than implied by guidelines. Improved management of IOH may be a simple intervention with real potential to reduce morbidity in this vulnerable group.

Near Infrared Light Scattering Changes Following Acute Brain Injury.

Acute brain injury (ABI) is associated with changes in near infrared light absorption reflecting haemodynamic and metabolic status via changes in cerebral oxygenation (haemoglobin oxygenation and cytochrome-c-oxidase oxidation). Light scattering has not been comprehensively investigated following ABI and may be an important confounding factor in the assessment of chromophore concentration changes, and/or a novel non-invasive optical marker of brain tissue morphology, cytostructure, hence metabolic status. The aim of this study is to characterize light scattering following adult ABI. Time resolved spectroscopy was performed as a component of multimodal neuromonitoring in critically ill brain injured patients. The scattering coefficient (µ's), absorption coefficient and cerebral haemoglobin oxygen saturation (SO2) were derived by fitting the time resolved data. Cerebral infarction was subsequently defined on routine clinical imaging. In total, 21 patients with ABI were studied. Ten patients suffered a unilateral frontal infarction, and mean µ' s was lower over infarcted compared to non-infarcted cortex (injured 6.9/cm, non-injured 8.2/cm p=0.002). SO2 did not differ significantly between the two sides (injured 69.3%, non-injured 69.0% p=0.7). Cerebral infarction is associated with changes in µ' s which might be a novel marker of cerebral injury and will interfere with quantification of haemoglobin/cytochrome c oxidase concentration. Although further work combining optical and physiological analysis is required to elucidate the significance of these results, µ' s may be uniquely placed as a non-invasive biomarker of cerebral energy failure as well as gross tissue changes.

Validation of a Hybrid Microwave-Optical Monitor to Investigate Thermal Provocation in the Microvasculature.

We have previously developed a hybrid microwave-optical system to monitor microvascular changes in response to thermal provocation in muscle. The hybrid probe is capable of inducing deep heat from the skin surface using mild microwaves (1-3 W) and raises the tissue temperature by a few degrees Celsius. This causes vasodilation and the subsequent increase in blood volume is detected by the hybrid probe using near infrared spectroscopy. The hybrid probe is also equipped with a skin cooling system which lowers the skin temperature while allowing microwaves to warm up deeper tissues. The hybrid system can be used to assess the condition of the vasculature in response to thermal stimulation. In this validation study, thermal imaging has been used to assess the temperature distribution on the surface of phantoms and human calf, following microwave warming. The results show that the hybrid system is capable of changing the skin temperature with a combination of microwave warming and skin cooling. It can also detect thermal responses in terms of changes of oxy/deoxy-hemoglobin concentrations.

BrainSignals Revisited: Simplifying a Computational Model of Cerebral Physiology.

Multimodal monitoring of brain state is important both for the investigation of healthy cerebral physiology and to inform clinical decision making in conditions of injury and disease. Near-infrared spectroscopy is an instrument modality that allows non-invasive measurement of several physiological variables of clinical interest, notably haemoglobin oxygenation and the redox state of the metabolic enzyme cytochrome c oxidase. Interpreting such measurements requires the integration of multiple signals from different sources to try to understand the physiological states giving rise to them. We have previously published several computational models to assist with such interpretation. Like many models in the realm of Systems Biology, these are complex and dependent on many parameters that can be difficult or impossible to measure precisely. Taking one such model, BrainSignals, as a starting point, we have developed several variant models in which specific regions of complexity are substituted with much simpler linear approximations. We demonstrate that model behaviour can be maintained whilst achieving a significant reduction in complexity, provided that the linearity assumptions hold. The simplified models have been tested for applicability with simulated data and experimental data from healthy adults undergoing a hypercapnia challenge, but relevance to different physiological and pathophysiological conditions will require specific testing. In conditions where the simplified models are applicable, their greater efficiency has potential to allow their use at the bedside to help interpret clinical data in near real-time.

Monitoring cerebral autoregulation after brain injury: multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy.

BACKGROUND: Continuous monitoring of cerebral autoregulation might provide novel treatment targets and identify therapeutic windows after acute brain injury. Slow oscillations of cerebral hemodynamics (0.05-0.003 Hz) are visible in multimodal neuromonitoring and may be analyzed to provide novel, surrogate measures of autoregulation. Near-infrared spectroscopy (NIRS) is an optical neuromonitoring technique, which shows promise for widespread clinical applicability because it is noninvasive and easily delivered across a wide range of clinical scenarios. The aim of this study is to identify the relationship between NIRS signal oscillations and multimodal neuromonitoring, examining the utility of near infrared derived indices of cerebrovascular reactivity. METHODS: Twenty-seven sedated, ventilated, brain-injured patients were included in this observational study. Intracranial pressure, transcranial Doppler-derived flow velocity in the middle cerebral artery, and ipsilateral cerebral NIRS variables were continuously monitored. Signals were compared using wavelet measures of phase and coherence to examine the spectral features involved in reactivity index calculations. Established indices of autoregulatory reserve such as the pressure reactivity index (PRx) and mean velocity index (Mx) and the NIRS indices such as total hemoglobin reactivity index (THx) and tissue oxygen reactivity index (TOx) were compared using correlation and Bland-Altman analysis. RESULTS: NIRS indices correlated significantly between PRx and THx (rs = 0.63, P < 0.001), PRx and TOx (r = 0.40, P = 0.04), and Mx and TOx (r = 0.61, P = 0.004) but not between Mx and THx (rs = 0.26, P = 0.28) and demonstrated wide limits between these variables: PRx and THx (bias, -0.06; 95% limits, -0.44 to 0.32) and Mx and TOx (bias, +0.15; 95% limits, -0.34 to 0.64). Analysis of slow-wave activity throughout the intracranial pressure, transcranial Doppler, and NIRS recordings revealed statistically significant interrelationships, which varied dynamically and were nonsignificant at frequencies <0.008 Hz. CONCLUSIONS: Although slow-wave activity in intracranial pressure, transcranial Doppler, and NIRS is significantly similar, it varies dynamically in both time and frequency, and this manifests as incomplete agreement between reactivity indices. Analysis informed by a priori knowledge of physiology underpinning NIRS variables combined with sophisticated analysis techniques has the potential to deliver noninvasive surrogate measures of autoregulation, guiding therapy.