Abstract

Neuromonitoring plays an important role in the management of traumatic brain injury. Simultaneous assessment of cerebral hemodynamics, oxygenation, and metabolism allows an individualized approach to patient management in which therapeutic interventions intended to prevent or minimize secondary brain injury are guided by monitored changes in physiologic variables rather than generic thresholds. This narrative review describes various neuromonitoring techniques that can be used to guide the management of patients with traumatic brain injury and examines the latest evidence and expert consensus guidelines for neuromonitoring.

TRAUMATIC brain injury (TBI) is a leading cause of death and disability worldwide. Clinical outcomes are determined not only by the severity of the initial injury but also by biochemical, excitotoxic, and inflammatory responses that lead to further (secondary) brain injury.1  The management of TBI is based on the central concept that prevention of secondary brain injury is associated with improved outcomes. Neuromonitoring plays an important role in the management of TBI because it is able to assess multiple aspects of cerebral physiology and guide therapeutic interventions intended to prevent or minimize secondary injury.2–4  No single neuromonitor is able to identify comprehensively the spectrum of pathophysiologic changes after TBI, and multimodality monitoring—the measurement of several variables simultaneously—provides a more comprehensive picture of the (patho)physiology of the injured brain and its response to treatment.5  Assessment of cerebral hemodynamics, oxygenation, and metabolic status allow an individually tailored approach to patient management in which treatment decisions can be guided by monitored changes in physiologic variables rather than by predefined, generic thresholds.4  Several monitoring techniques are available for clinical use (table 1). Normal ranges and treatment thresholds for many monitored variables are derived from observational data studying a variety of correlates of tissue injury rather than clinical outcomes. Furthermore, there is uncertainty about which physiologic variables are the most clinically relevant, how and when they should be monitored, and whether monitoring is cost-effective and impacts outcome.2  Expert consensus guidelines on multimodality neuromonitoring have been published by the Neurocritical Care Society and the European Society of Intensive Care Medicine after comprehensive review of the literature.6 

Table 1.

Multimodal Neuromonitoring in Traumatic Brain Injury

Multimodal Neuromonitoring in Traumatic Brain Injury
Multimodal Neuromonitoring in Traumatic Brain Injury

Clinical Monitoring

Clinical assessment using objective scales to assess consciousness and motor power is a key component of neuromonitoring.7  The Glasgow coma scale was the first attempt to standardize assessment of neurologic state after TBI by recording best eye opening and verbal and motor responses to standardized verbal and physical stimuli.8  The Glasgow coma score is used to classify the severity of TBI, identify changes in neurologic state by means of serial recording, and assist in prognostication, although it does have some limitations. Verbal responses cannot be assessed in intubated patients, brainstem function is not tested, and a Glasgow coma score of 3 may cover a spectrum of brain injury severity. Alternative clinical assessment methods such as the Full Outline of UnResponsiveness (FOUR) score that assesses four components of neurologic function—eye, motor, brainstem, and respiratory functions—have been developed to overcome some of these limitations.9  However, newer scoring systems have not been widely adopted, and the Glasgow coma score remains the most popular clinical assessment scale of neurologic status more than 40 yr since its first description. In addition to assessment of consciousness, it is also important to identify and document focal limb deficits using the validated Medical Research Council scale and pupil responses.10  Infrared pupillometry provides an objective assessment of pupillary reactivity and may be superior to its clinical assessment.11 

Deep sedation and the use of muscle relaxants prevent informative clinical assessment, and sedation holds to allow neurologic examination are not recommended in patients with raised intracranial pressure (ICP).10  Furthermore, clinical examination may not reliably detect subtle changes in intracranial physiology, and alterations in neurologic state can occasionally occur late. Clinical assessment should therefore be seen as a compliment to neuromonitoring and vice versa.

Intracranial Pressure and Derived Indices

The monitoring and management of ICP is the cornerstone of neuromonitoring after TBI, although the indications for monitoring continue to generate debate. In addition to absolute ICP measurement, ICP monitoring allows calculation of cerebral perfusion pressure (CPP) and waveform analysis assessment of cerebrovascular reactivity and autoregulatory status.12 

Intracranial Pressure

Two methods of monitoring ICP are commonly used in clinical practice: ventricular catheters and microtransducer devices (strain gauge or fiberoptic types).13  Ventricular catheters measure global ICP and have the advantage of allowing therapeutic drainage of cerebrospinal fluid to treat intracranial hypertension. However, they are associated with higher complication rates, including infection, compared to microtransducer systems. The latter are sited in brain parenchyma or subdural space and measure localized ICP, although this correlates with ventricular pressure in most circumstances.14  Several noninvasive ICP monitoring techniques have been described including transcranial Doppler flow velocity waveform morphology or derived pulsatility index15  and ultrasound or computed tomography measurement of optic nerve sheath diameter.16  However, many noninvasive techniques are unable to monitor intracranial dynamics continuously, and most are insufficiently accurate for routine clinical use.17 

Despite absence of high-quality evidence, the fourth edition of the Brain Trauma Foundation guidelines (2016) recommends ICP monitoring in all salvageable patients with severe TBI and an abnormal computed tomography scan (presence of hematomas, contusions, swelling, herniation, or compressed basal cisterns) and also in those with a normal scan and two of three high-risk characteristics (age more than 40 yr, motor posturing, and systolic blood pressure less than 90 mmHg).18  Alternative guidelines (the Milan consensus) from a group of mainly European clinical experts provide pragmatic and specific recommendations for ICP monitoring for different TBI scenarios and cranial computed tomography findings.19  Although there is much consistency between the two, in contrast to those from the Brain Trauma Foundation, the Milan consensus statement does not recommend routine ICP monitoring in comatose TBI patients with a normal computed tomography scan but advises a second scan and institution of monitoring only if there is radiologic worsening (table 2). All clinical guidelines advocate early treatment of raised ICP after TBI, although recommended treatment thresholds may vary. The Brain Trauma Foundation recommends treatment of ICP of greater than or equal to 22 mmHg based on evidence that ICP–guided management of severe TBI may reduce in-hospital and 2-week postinjury mortality.18 

Table 2.

Indications for Intracranial Pressure Monitoring in Traumatic Brain Injury

Indications for Intracranial Pressure Monitoring in Traumatic Brain Injury
Indications for Intracranial Pressure Monitoring in Traumatic Brain Injury

Raised ICP is a long-established and important cause of TBI-related secondary brain injury and has been associated with higher mortality and poor long-term functional outcomes in many studies.20,21  In contrast, a secondary analysis of data from a randomized trial of severe TBI found that average ICP was not independently associated with worse neuropsychologic function in survivors at 6 months after injury.22  It is the overall burden (or “dose”) of intracranial hypertension—its duration as well as severity—that is the prognostic factor,23,24  particularly if elevated ICP is refractory to treatment.25  Despite evidence of potential mortality benefits from ICP monitoring–guided therapy, several studies report monitoring rates less than 50% in patients eligible for monitoring according to standard guidelines.26–28  In a multicenter study, ICP monitoring was associated with an 8.3-percentage point reduction in risk-adjusted mortality rate but undertaken in only 46% of 844 eligible patients.26  On the other hand, a single-center study found that patients eligible for ICP monitoring who did not have a monitor placed were 1.21 times more likely to survive compared to those who underwent monitoring.29  The largest, multicenter observational study of ICP monitoring to date confirmed that monitoring is associated with lower in-hospital mortality after TBI, although the observed interinstitution variability in ICP monitoring rates in this study contributed only modestly to the substantial variability in mortality.30  This emphasizes that it is the impact of monitor-guided therapeutic interventions, rather than monitoring per se, that are the critical determinants of outcome.

Based on historic, observational data, the thresholds for initiation and escalation of treatment of intracranial hypertension have traditionally been set at between 20 and 25 mmHg,31  despite reports that lower and higher ICP thresholds are associated with poor outcome20  and in the absence of direct evidence of benefit from this approach.32  The only randomized clinical trial evaluating the utility of ICP monitoring in TBI—the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial—found similar 3- and 6-month outcomes in patients in whom treatment was guided by ICP monitoring compared to treatment guided by imaging and clinical examination in the absence of ICP monitoring.33  Because both treatment approaches provided satisfactory outcomes despite the absence of ICP monitoring in one, the results of this study challenge the established practice of maintaining ICP below universal and arbitrary thresholds.34  Reliance on absolute ICP thresholds as recommended by some clinical guidelines ignores the variability of brain injury after TBI, different host characteristics and responses, and temporal changes in pathophysiology. It is now recognized that treatment interventions can be better optimized by individualized interpretation of ICP values in association with other neuromonitoring variables (described in subsequent sections), patient characteristics, and after assessment of the potential benefits and risks of treatment.35 

The possibility of using ICP data to provide early warning of deterioration and more accurate prognostication is an area of recent interest. In a retrospective analysis of 817 TBI patients, an automated computer algorithm was able to predict ICP crises with 30 min advance warning from previous ICP measurements and time since last episode of elevated ICP.36  Another model using ICP and mean arterial blood pressure as inputs also robustly predicted future increased ICP events 30 min in advance of their occurrence.37  Although these computerized analyses in many ways simply confirm everyday clinical experience that patients with episodes of intracranial hypertension are at high risk of further ICP crises, they do also highlight potential for the development of widely applicable early warning systems of worsening brain state that could provide clinicians with time to intervene before irreversible secondary brain injury has occurred. Güiza et al.38  used a novel approach to display the complexity and dynamic aspects of secondary insults of intracranial hypertension by displaying color-coded plots to summarize the relationship between ICP insults (defined by intensity and duration) with 6-month Glasgow Outcome Scale after TBI. Episodes of higher ICP were tolerated for shorter durations than more modestly elevated ICP, and impaired cerebrovascular autoregulation or reduced CPP reduced the ability of the brain to tolerate increases in ICP. These data support the dose of intracranial hypertension concept and highlight the importance of early intervention to reduce raised ICP, particularly if autoregulatory responses, as described in a subsequent section, are attenuated.

Cerebral Perfusion Pressure

CPP is calculated as the difference between mean arterial pressure and ICP and modifiable through manipulation of these variables.35  Its accurate calculation requires the same zero reference point for both arterial pressure and ICP, i.e., at the level of the brain using the tragus of the ear as the external landmark.39  Head elevation is routinely used to optimize ICP after TBI, but hydrostatic effects mean that cerebral arterial blood pressure is reduced by a magnitude dependent on the degree of head elevation and distance between heart and brain reference points. In a patient with 30° head elevation, actual CPP may be up to 11 mmHg lower than calculated CPP if ICP is referenced to the level of brain and mean arterial pressure to the level of the heart.40  Despite the crucial importance of the accurate assessment of CPP, a recent narrative review was unable to determine how mean arterial pressure was measured in the calculation of CPP in 50% of 32 widely cited studies of CPP–guided management.41 

Consensus guidelines recommend that CPP should be maintained between 60 and 70 mmHg after TBI,18  with evidence of adverse outcomes if CPP is lower or higher.20  It is likely that the CPP threshold resulting in cerebral hypoperfusion and ischemia exists on an individual basis, and the concept of targeting an individualized “optimal” CPP range is gaining traction.42 

Cerebral Autoregulation

In the healthy brain, cerebral autoregulation acts to maintain cerebral blood flow constant over a wide range of arterial blood pressure. Autoregulatory responses may be impaired after TBI and result in derangements in the relationships between regional cerebral blood flow and metabolic demand, thereby rendering the brain more susceptible to secondary ischemic insults. Although some degree of autoregulatory response is often maintained after TBI, it exists over a narrowed mean arterial pressure/CPP range, which can be identified by real-time measurement of cerebrovascular state.43 

The pressure reactivity index is one of the most established methods to assess cerebral autoregulation continuously. It is calculated as the moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of ICP and arterial blood pressure over a 4-min period and varies between −1 and +1.42  An inverse correlation between arterial pressure and ICP, indicated by a negative value for pressure reactivity index, represents normal cerebrovascular reactivity, whereas an increasingly positive pressure reactivity index defines a continuum of increasingly nonreactive cerebrovascular responses when changes in arterial blood pressure and ICP are in phase. Plotting pressure reactivity index against CPP results in a U-shaped curve in many patients, and the point where the pressure reactivity index is most negative represents optimal CPP, that is, the CPP range in which autoregulatory capacity is most preserved in that injured brain (fig. 1).44  Targeting optimal CPP rather a generic CPP threshold avoids the risks of low CPP on the one hand and excessive CPP on the other and has been associated with improved outcomes in uncontrolled case series.42,44  Abnormal autoregulation defined by pressure reactivity index monitoring is also a strong predictor of mortality and functional outcome after TBI.45  In addition to allowing optimization of CPP, knowledge of the status of cerebrovascular reactivity also facilitates interpretation of the relationships between cerebral blood flow, oxygen delivery/demand, and cellular metabolism, and guides interventions targeted toward optimization of cerebral oxygenation and metabolic state.46  Cerebrovascular reactivity can also be assessed using an oxygen reactivity index calculated as the moving correlation between brain tissue Po2 and arterial blood pressure47  and noninvasively using the correlation between arterial pressure and transcranial Doppler-derived mean blood flow velocity48  or arterial pressure and several near infrared spectroscopy-derived variables.49 

Fig. 1.

Monitoring cerebrovascular reactivity to identify optimal cerebral perfusion pressure. This figure shows 4-h trend charts. (A) Cerebral perfusion pressure (CPP). (B) Pressure reactivity index (PRx). (C) PRx/CPP for evaluation of optimal CPP. Note the U-shaped relationship between CPP and PRx. The point where the PRx is most negative represents optimal CPP, the perfusion pressure range in which autoregulatory capacity is most preserved. Modified from figure by Dias et al.44  with permission from Springer.

Fig. 1.

Monitoring cerebrovascular reactivity to identify optimal cerebral perfusion pressure. This figure shows 4-h trend charts. (A) Cerebral perfusion pressure (CPP). (B) Pressure reactivity index (PRx). (C) PRx/CPP for evaluation of optimal CPP. Note the U-shaped relationship between CPP and PRx. The point where the PRx is most negative represents optimal CPP, the perfusion pressure range in which autoregulatory capacity is most preserved. Modified from figure by Dias et al.44  with permission from Springer.

Standard methods of calculating the pressure reactivity index and other indices of autoregulatory reserve require high-frequency signal processing and automated analysis, which can be time consuming, costly, and not widely available. A recent study demonstrated that routine, minute-by-minute assessment of ICP and arterial blood pressure data contains relevant information for autoregulation monitoring.50  In this study, a low-frequency autoregulation index, defined as the moving 1-min correlation of ICP and arterial blood pressure calculated over time intervals varying from 3 to 120 min, was able to identify optimal CPP recommendations that did not differ from those obtained using standard pressure reactivity index methodology. Further, because there is no requirement for high fidelity data collection and analysis with this methodology, there is less data “loss” and therefore identification of optimal CPP during a higher proportion of monitoring time.

Another challenge in the search for reliable and accessible indices of cerebrovascular reactivity is the identification of appropriate analysis techniques that take account of the dynamic nonstationary, nonlinear nature of the measured signals that relate to autoregulation. Novel approaches such as wavelet analysis of slow wave oscillations in arterial blood pressure and near infrared spectroscopy-derived cerebral hemodynamic variables may overcome this issue.51  Despite the intuitive good sense of targeting optimal CPP after TBI, there are currently insufficient high-quality data to recommend its routine clinical application.52 

Cerebral Blood Flow

Alterations in cerebral blood flow in association with impairment of autoregulatory reserve may cause or worsen secondary ischemic brain injury after TBI. Cerebral blood flow may be determined directly or indirectly, although direct measurement at the bedside has proved challenging until recently.53  Modern imaging techniques such as positron emission tomography and computed tomography perfusion provide detailed information about cerebral hemodynamics (and metabolism) over multiple regions of interest.54  Although widely used as diagnostic and clinical research tools, imaging modalities are unable to provide continuous data for clinical monitoring that primarily relies on two methods for the continuous assessment of cerebral blood flow at the bedside.53 

Transcranial Doppler Ultrasonography

Introduced in 1982, transcranial Doppler is a noninvasive technique that uses ultrasound waves to monitor blood flow velocity in large cerebral vessels by examining the Doppler shift caused by red blood cells moving through the field of view.55  Transcranial Doppler measures relative rather than absolute flow, but there is a linear relationship between cerebral blood flow and flow velocity if vessel cross-sectional area and angle of insonation remain constant during the period of measurement. The transcranial Doppler waveform resembles an arterial pulse wave, which can be quantified by peak systolic, end diastolic and mean flow velocities, and the pulsatility index, which provides an assessment of distal cerebrovascular resistance. Although primarily used to detect and monitor cerebral vasospasm after aneurysmal subarachnoid hemorrhage, transcranial Doppler can detect inadequate cerebral blood flow, assess pressure autoregulation and CO2 reactivity, determine response to therapeutic interventions, and offer prognostic information after TBI.56  In a prospective, observational, multicenter study, early abnormalities in transcranial Doppler-derived pulsatility index and diastolic flow velocity had 80% sensitivity and 79% specificity for the prediction of subsequent neurologic deterioration in patients with mild and moderate TBI, with negative and positive predictive values of 98 and 18%, respectively.57  As noted earlier, transcranial Doppler can also provide a noninvasive assessment of ICP, although the absolute accuracy of this technique is only ±15 mmHg, making it unsuitable for routine clinical use.58 

The advantages of transcranial Doppler include its noninvasiveness and ability to provide real-time and continuous assessment of cerebral hemodynamics. Although it requires a degree of technical skill, there is reasonable interobserver agreement between transcranial Doppler measurements.59 

Thermal Diffusion Flowmetry

Thermal diffusion flowmetry is an invasive, continuous, and quantitative monitor of regional cerebral blood flow.60  The thermal diffusion flowmetry catheter consists of a thermistor heated to a few degrees above tissue temperature and a second, more proximal, temperature probe. The temperature difference between the two is a reflection of heat transfer that is converted into an absolute measurement of blood flow in ml · 100 g−1 · min−1. The thermal diffusion flowmetry probe is sited in white matter, usually in an “at-risk” brain region where quantitative knowledge of perfusion is desirable. Thermal diffusion flowmetry can be used to detect changes in cerebral blood flow in real time, detect vasospasm in comatose patients, and assess autoregulation,61  although there are limited clinical data using this technology and concerns over its reliability. It has been reported that thermal diffusion flowmetry provides useful data for only 30 to 40% of monitoring time because of monitor dysfunction secondary to placement errors and missing data during recalibrations.53 

Cerebral Oxygenation

Although ICP and CPP are crucially important and routinely monitored variables after TBI, they provide limited assessment of the adequacy of cerebral perfusion. Cerebral ischemia is widely reported to occur despite ICP and CPP values that lie within accepted thresholds for normality.62,63  Cerebral oxygenation monitoring provides information about the balance between cerebral oxygen delivery and utilization and therefore the adequacy of cerebral perfusion.64 

Jugular Venous Oxygen Saturation

Jugular venous oxygen saturation can be measured by intermittent sampling from a catheter sited in the jugular bulb or continuously using a fiberoptic catheter. Jugular saturation monitoring is based on the simple principle that oxygen delivery and supply mismatch results in changes in oxygen extraction and therefore in jugular venous saturation (table 3).65  The normal range of jugular venous oxygen saturation is 55 to 75%. Jugular desaturation is associated with worse outcome after TBI in a dose-dependent manner,66  and guidelines recommend maintaining jugular saturation more than 50%, despite absence of evidence of benefit from jugular venous oxygen saturation–directed therapy.18  On the other hand, elevated jugular venous oxygen saturation can be falsely reassuring because it may relate to scenarios associated with arteriovenous shunting or brain death when tissues are not metabolically active. In an early study, jugular venous oxygen saturation more than 75% occurred in almost 20% of 450 patients with severe TBI and was associated with worse outcomes compared to patients in whom jugular saturation was normal despite not being consistently related to either cerebral blood flow or CPP.67 

Table 3.

Interpretation of Changes in Jugular Venous Oxygen Saturation

Interpretation of Changes in Jugular Venous Oxygen Saturation
Interpretation of Changes in Jugular Venous Oxygen Saturation

Jugular venous oxygen saturation monitoring is dependent on technical aspects such as correct catheter placement to exclude the extracranial circulation. Sampling from the internal jugular vein with the dominant drainage, usually the right, is also recommended because oxygen saturation in the two jugular veins may be different.68  Importantly, jugular venous oxygen saturation is a global, flow-weighted measure that may miss critical regional ischemia.65  After early enthusiasm, its clinical use has decreased in favor of other methods of monitoring brain tissue oxygenation.68 

Brain Tissue Oxygen Partial Pressure

Brain tissue Po2 monitoring has the most robust evidence base of all bedside cerebral oxygenation monitoring techniques.64  It is a focal measure so the utility of the technique is dependent on correct brain tissue Po2 probe placement and knowledge of the location of the probe tip. Placement in at risk but viable subcortical white matter, such as perihematoma placement after TBI, is considered optimal,69  although such precise placement can be technically challenging or impossible and risks inadvertent intralesional placement, which yields useless information.64  There is therefore an argument for routine probe placement in normal-appearing brain, typically in the nondominant frontal lobe, where it provides a reflection of global brain oxygenation.69  Brain tissue Po2 is a complex variable influenced by global determinants of oxygen delivery such as PaO2, PaCO2, FiO2, arterial blood pressure, cardiac output, hemoglobin, and cardiorespiratory function, as well as by cerebral variables including ICP, CPP, autoregulation, metabolism, seizures, and cerebral tissue oxygen gradients (which are often increased in the injured brain).64  Normal brain tissue Po2 values range from 20 to 40 mmHg. In the clinical setting, values less than 15 to 20 mmHg are considered indicative of brain ischemia and below 10 mmHg of severe ischemia, although brain tissue Po2 is best interpreted in the context of duration as well as depth of ischemia.70 

Multiple studies have demonstrated an association between low brain tissue Po2 and poor outcomes after TBI71–73  independently of ICP and CPP.63  Observational studies using historic controls suggest outcome benefits of supplementing ICP/CPP–guided management with brain tissue Po2–directed therapy to maintain brain tissue Po2 more than 20 mmHg.72,73  A systematic review of four studies incorporating 491 patients confirmed that brain tissue Po2 and ICP/CPP–directed therapy combined is associated with superior outcomes compared to ICP/CPP–guided therapy alone, but all studies in this review were nonrandomized, and only two (with small sample sizes) were truly prospective.74  Preliminary results have been released from a prospective, phase II randomized controlled trial (the brain tissue oxygen monitoring in traumatic brain injury–2 study) in which 110 patients with severe TBI were randomized to receive treatment guided by ICP monitoring alone or by brain tissue Po2 and ICP monitoring according a prespecified protocol to maintain brain tissue Po2 more than 20 mmHg and ICP less than 20 mmHg.75  Compared to ICP–guided therapy, the combination of ICP and brain tissue Po2–directed therapy resulted in reduced time with brain tissue Po2 less than 20 mmHg and was associated with a nonsignificant trend toward lower overall mortality and poor outcomes (although the study was not powered for outcome). In a more recent prospective multicenter study of 50 patients with moderate and severe TBI, brain tissue Po2/ICP–guided therapy was associated with a significant reduction in mortality at 3 and 6 months after injury compared to ICP–guided therapy alone.71  Although there was no absolute difference in functional outcomes between the two groups in this study, patients in the brain tissue Po2-guided group had a 1.8 to 2.9 times higher rate of more favorable outcome between 1 and 6 months postinjury compared to those in the ICP–guided group. Further adequately powered, prospective studies are required to identify the effects of brain tissue Po2 monitoring–guided therapy on TBI outcomes.

Recent guidelines recommend interventions to maintain brain tissue Po2 more than 20 mmHg after TBI.76  Brain hypoxia can be reversed by several factors including optimization of mean arterial pressure, CPP, PaO2, PaCO2, and hemoglobin concentration,77  but which intervention or combination of interventions should be used to reverse reduced brain tissue Po2 is undefined. The responsiveness of brain tissue hypoxia to a given intervention, rather than the nature of the intervention, appears to be the prognostic factor with reversal of hypoxia being associated with reduced mortality.78  Although brain tissue Po2 can be normalized by incremental increases in FiO2, reliance on this intervention is unlikely to be the solution because hyperoxia can lead to increased cerebral excitotoxicity and potentially aggravate secondary brain damage independent of brain tissue Po2.79 

Near Infrared Spectroscopy

Near infrared spectroscopy is a noninvasive technique based on the transmission and absorption of near infrared light (700 to 950 nm) as it passes through tissue. Oxygenated and deoxygenated hemoglobin have characteristic and different absorption spectra in the near infrared, and their relative concentrations in tissue can be determined by their absorption of light in this wavelength range.80  Near infrared spectroscopy-based cerebral oximeters derive a scaled absolute hemoglobin concentration (the relative proportions of oxy- and deoxyhemoglobin in the field of view) from which regional cerebral tissue oxygen saturation is calculated. This is largely, but not exclusively, sensitive to oxygen extraction and therefore provides regional assessment of critical oxygen supply/demand mismatch. The “normal” range of regional cerebral oxygen saturation is reported to lie between 60 and 75%, but there is substantial intra- and interindividual variability in near infrared spectroscopy–derived cerebral saturation and no validated regional cerebral saturation-defined ischemic thresholds to guide therapeutic interventions.81  Low regional cerebral oxygen saturation values have been associated with poor outcome in small case series,82  and near infrared spectroscopy has been used to determine optimal CPP noninvasively.83  However, there are limited high-quality data on the application of near infrared spectroscopy for monitoring after TBI, and no outcome studies investigating near infrared spectroscopy-guided management.49  In the research setting, near infrared spectroscopy-monitored changes in the oxidation state of oxidized cytochrome c oxidase, the final electron acceptor in the mitochondrial electron transport chain responsible for more than 95% of oxygen metabolism, provides additional information about cellular energy status and may aid in the determination of near infrared spectroscopy-defined ischemic thresholds.84 

The near infrared spectroscopy technique has several confounders including potential signal contamination from extracranial tissue.80  The presence of intracranial hematoma, cerebral edema, or traumatic subarachnoid hemorrhage might also invalidate some of the assumptions upon which near infrared spectroscopy algorithms are based, but this has been used to advantage in the development of a handheld device to screen for traumatic intracranial haematomas in prehospital environments.85  Technologic advances, including the development of frequency (or domain) and time-resolved spectroscopy systems, have allowed measurement of absolute chromophore concentration with obvious advantages for clinical applications.81  Diffuse correlation spectroscopy provides noninvasive measures of cerebral blood flow in addition to cerebral tissue oxygen saturation and the potential to derive cerebral metabolic rate.86  Although the future holds promise for the development of a single near infrared spectroscopy device with capability to noninvasively measure cerebral hemodynamics, oxygenation, and metabolism over multiple regions of interest,87  routine near infrared spectroscopy monitoring is currently not recommended in adult TBI patients.49 

Brain Metabolism and Biochemistry

Cerebral microdialysis is a well established laboratory technique that was introduced into clinical practice during the 1990s to monitor brain tissue chemistry. The tip of a microdialysis catheter incorporates a semipermeable dialysis membrane, and diffusion drives the passage of molecules across the membrane along their concentration gradient from the brain extracellular fluid into the isotonic dialysis fluid (fig. 2).88  The concentrations of clinically relevant compounds that accumulate in the dialysate are measured in a semiautomated calorimetric bedside analyzer, usually at hourly intervals.89  Clinical microdialysis catheters have a molecular weight cutoff of 20 kDa and are suitable for recovery of small molecules including glucose, lactate, pyruvate, glycerol, and glutamate.90  Each of these, and the lactate:pyruvate ratio, is a marker of a particular cellular process associated with glucose metabolism, hypoxia/ischemia, and cellular energy failure (fig. 2). The microdialysis catheter is placed in at-risk brain tissue so that biochemical changes in the area of brain most vulnerable to secondary insults can be monitored.90 

Fig. 2.

Principle of cerebral microdialysis (MD) monitoring. (A) The MD catheter is located in at-risk brain tissue. Isotonic fluid is pumped through the MD catheter at a rate of 0.3 μl/min. Molecules at high concentration in the brain extracellular fluid (ECF) equilibrate across the semipermeable MD membrane into the microdialysate, which is collected for subsequent analysis. (B) The effects of decreased brain glucose and oxygen supply and cellular energy failure can be monitored by the bedside measurement of biomarkers of bioenergetics, cellular degeneration, and excitotoxicty. Additional, novel biomarkers can be measured in the research setting. BC = blood capillary; LPR = lactate:pyruvate ratio. Modified from figure by Kirkman and Smith88  with permission from Elsevier.

Fig. 2.

Principle of cerebral microdialysis (MD) monitoring. (A) The MD catheter is located in at-risk brain tissue. Isotonic fluid is pumped through the MD catheter at a rate of 0.3 μl/min. Molecules at high concentration in the brain extracellular fluid (ECF) equilibrate across the semipermeable MD membrane into the microdialysate, which is collected for subsequent analysis. (B) The effects of decreased brain glucose and oxygen supply and cellular energy failure can be monitored by the bedside measurement of biomarkers of bioenergetics, cellular degeneration, and excitotoxicty. Additional, novel biomarkers can be measured in the research setting. BC = blood capillary; LPR = lactate:pyruvate ratio. Modified from figure by Kirkman and Smith88  with permission from Elsevier.

Energy dysfunction is increasingly recognized as a key factor in the pathophysiology of TBI.91  Imbalance in the supply and demand for glucose can trigger a cerebral metabolic crisis from ischemic and nonischemic causes, and cerebral microdialysis is unique among bedside neuromonitoring techniques in that it is able to identify both.92  Increased lactate:pyruvate ratio in the presence of low pyruvate indicates a profound reduction in energy substrate supply and classic ischemia, whereas elevated lactate:pyruvate ratio in the presence of normal or high pyruvate indicates a nonischemic cause related to mitochondrial dysfunction with or without increased metabolic demand.93  Cerebral microdialysis-monitored glutamate is a marker of hypoxia/ischemia and excitotoxicity,94  and glycerol is a (nonspecific) marker of hypoxia/ischemia-related cell membrane breakdown.95  Because microdialysis measures changes at the cellular level, it has the potential to identify cerebral compromise before changes in other monitored variables.96 

Expert consensus recommendations for the clinical application of cerebral microdialysis have recently been published, although there is no evidence that microdialysis-guided therapy improves outcomes.90  Periods of low brain glucose concentration (less than 0.7 to 1 mM) combined with elevated lactate:pyruvate ratio (more than 40) suggest severe hypoxia/ischemia and correlate with poor outcome.97  After TBI, the normal relationship between serum glucose concentration, glycemic control, and brain glucose may be lost, and brain glucose may fall to levels that are insufficient to meet metabolic demand even when serum glucose concentration is within a normal range.98  This phenomenon is referred to as neuroglycopenia and is the origin of a nonhypoxic metabolic crisis. If brain extracellular fluid glucose concentration is very low (0.2 mM), a trial of increasing serum glucose concentration (even if within normal limits) has been recommended to minimize the burden of neuroglypenia.90  The lactate:pyruvate ratio has been used to guide CPP management,99  although some studies have found that elevated lactate:pyruvate ratio can occur despite CPP values that are customarily considered to be adequate.100  This is unsurprising given the nonischemic causes of elevated lactate:pyruvate ratio, and further highlights the importance of using multimodality physiologic data to inform individualized treatment strategies.

The dialysate provides a facsimile of brain extracellular fluid because it contains all molecules small enough to pass through the microdialysis membrane. Macromolecules can be sampled for research purposes using high-molecular-weight cutoff (100 kDa) dialysis membranes. Several novel biomarkers, including S100B,101  nitric-oxide metabolites,102  and N-acetylaspartate,103  have been investigated, as have TBI-related inflammatory processes via the temporal profile of multiple cytokines.104  Metabolic distress after TBI is associated with a differential proteome indicating cellular destruction,105  and incorporation of proteomics into the microdialysis technique has potential to provide new insights into the pathophysiology of brain injury. Cerebral microdialysis can also provide unique information during neuroprotective drug trials, establishing whether systemically administered agents cross the blood–brain barrier to their site of action and monitoring the downstream effects of drug actions directly.89 

The only commercially available clinical microdialysis system has limited temporal resolution,89  and this may miss short-lived but important changes in brain tissue chemistry, including those induced by electrophysiologic abnormalities such as cortical spreading depolarizations.106  A continuous rapid-sampling cerebral microdialysis technique that allows online measurement of potassium, glucose, and lactate but not pyruvate has been described for research use.107 

Despite evidence from large numbers of studies confirming that abnormal brain chemistry relates to poor outcomes after TBI, the clinical utility of cerebral microdialysis-guided therapy is still debated.90  Further studies are required to determine the effectiveness of microdialysis-guided clinical decision-making as part of multimodality monitoring paradigms.

Electroencephalography

Seizures occur in 20 to 40% of TBI patients, and early detection and treatment are crucial to minimize the burden of seizure-related secondary injury. Intermittent electroencephalography (EEG) has historically been used for the diagnosis of seizures and status epilepticus, but continuous EEG monitoring is now recommended for the detection of posttraumatic seizures and to guide anticonvulsant therapy because of the high incidence of nonconvulsive seizures after TBI.6,108  Integration of continuous EEG into multimodal neuromonitoring strategies identifies associations between seizures, intracranial hypertension, and cerebral metabolic derangements109  and offers prognostic information.75  Continuous EEG monitoring is a resource-intense technology requiring specialized technicians for application and maintenance of electrodes and neurophysiologists for interpretation of EEG recordings.110  Telemedicine allows interpretation away from the bedside and may facilitate the adoption of continuous EEG, as might the development of automated seizure detection software.75 

Invasive EEG monitoring using subdural strip or intracortical depth electrodes allows detection of seizures that are not visible on standard (scalp) EEG monitoring.111  In a small prospective multicenter study, more than 40% of EEG-defined seizures or periodic discharges were detected only by intracortical depth electrodes.106  Cortical spreading depolarizations, an important cause of secondary brain injury, have been identified in more than half of TBI patients using invasive continuous EEG monitoring.112  They are associated with unfavorable outcomes, but a definite causal relationship between spreading depolarizations and outcome has yet to be established. Further research is required to determine whether therapies to prevent or treat these electrophysiologic abnormalities limit brain injury progression and improve outcomes. Spreading depolarizations can currently only be detected by invasive EEG monitoring, but developments in scalp EEG and noninvasive technologies that measure surrogates of regional cerebral blood flow (such as near infrared spectroscopy) are likely to lead to the introduction of noninvasive methods for their detection.

Integrating Multimodality Neuromonitoring Data

Despite the many benefits of multimodality neuromonitoring after TBI, including insights into the mechanisms of secondary brain injury, identification of deterioration in brain state, and guidance of individualized therapeutic interventions, the adoption of monitoring strategies is highly variable between centers.6  Simple approaches are most likely to gain traction in the clinical setting, and the simultaneous measurement of ICP and brain tissue Po2 is a logical approach aided by the availability of a single probe capable of monitoring both.113 

Because of the number and complexity of monitored physiologic variables and the interplay between them, computational analysis and integration of data are essential prerequisites for the presentation of user-friendly and clinically relevant information at the bedside.114  Commercial systems are available to process and display multiple data streams, although many systems in clinical use have been designed around the needs of individual institutions or researchers.115  Several challenges hinder data integration and interpretation, including situations where one or more variables remain normal in the face of derangements in another. One area of particular uncertainty is what, if any, action should be taken in response to increases in ICP in the context of normal brain tissue oxygenation or metabolism.35  Advanced mathematical tools can be applied to large volumes of clinical physiologic data with the goals of artifact removal and identification of more specific markers of secondary brain injury.114  An alternative approach incorporates computational model interpretation of complex multimodal data sets to provide summary outputs of patient-specific simulations of brain state that can guide individualized clinical decision making and also generate clinically important but currently unmeasured variables such as cerebral metabolism.116 

Future Directions

Although there is substantial evidence that multimodality neuromonitoring-guided therapy results in improvements in cerebral physiology, high-quality evidence that this translates into beneficial effects on clinical outcomes remains elusive. Neuromonitoring can only modulate patient outcome if a monitor-detected change in physiology prompts timely and appropriate therapeutic intervention to reverse an abnormality that is itself an integral determinant of outcome.117  It has been suggested that interventions that result in transition from an abnormal to normal brain state are more likely to be efficacious than those focusing on response to individual thresholds.118  Furthermore, thresholds for intervention and optimal therapeutic interventions in response to changes in monitored variables remain undefined in many circumstances. It is also unclear whether all TBI patients can benefit from neuromonitoring, although it seems plausible that those with certain injuries or physiologic phenotypes might have the most to gain from neuromonitor-guided interventions. Incorporating patient demographics and brain imaging with multimodality neuromonitoring strategies might better optimize individualized treatment decisions. A pragmatic approach to identify those who might benefit from ICP monitoring, combining clinical and cranial computed tomography scan findings, has been suggested.19 

There are substantial challenges in the conduct of robust prospective outcome studies to establish whether adoption of a multimodal neuromonitoring strategy is beneficial, and multiple examples in TBI research of promising results from single-center studies failing to translate into evidence of benefit in subsequent multicenter trials.119  Study design and conduct are clearly of crucial importance in this regard. The ideal neuromonitoring study would be one in which all participants underwent the monitoring modality under investigation with some randomized to receive monitor-guided therapy and others to standard care, with standardization of treatments across centers. However, ensuring such homogeneity between centers, not only in monitor-defined therapeutic thresholds but also in all applied treatments, is a major challenge. Even well conducted studies with clearly defined treatment protocols have reported treatment variations between centers, which may have influenced the results.120  Other key limitations in demonstrating the efficacy of neuromonitoring are the heterogeneity of pathophysiologic changes after TBI and the need for complex and multiple therapeutic interventions in the absence of a single intervention that is unequivocally associated with improved outcomes.121  Which monitored variables are modifiable targets for treatment and which are simply markers of injury severity also remain unclear. Furthermore, TBI does not represent a single pathophysiologic entity but a complicated and heterogeneous set of disease processes with substantial temporal and regional heterogeneity. It is also not clear whether different forms of TBI, such as traumatic hematoma and diffuse axonal injury, should be treated differently. Finally, it can be argued that there is no longer clinical equipoise to conduct randomized studies in which some patients may not receive low-risk, potentially high-yield monitor-guided interventions that are now considered standards of care by many.

The failure of recent high-profile therapeutic clinical trials has raised questions as to whether randomized controlled trials are appropriate instruments to assess a condition as heterogeneous as TBI, and it has been suggested that there should be a paradigm shift in TBI research to incorporate concepts such as precision medicine and comparative effectiveness research.122  The International Initiative for Traumatic Brain Injury Research is a global collaboration that aims to revolutionize the study of TBI by international collaboration, coordination of standardized date collection, and big-data sharing.123  It remains to be seen whether this approach will resolve the outstanding questions about the roles and indications for neuromonitoring after TBI and demonstrate unequivocally whether monitor-guided interventions lead to improved outcomes for patients.

Competing Interests

The author declares no competing interests.

References

References
1.
Bramlett
HM
,
Dietrich
WD
:
Long-term consequences of traumatic brain injury: Current status of potential mechanisms of injury and neurological outcomes.
J Neurotrauma
2015
;
32
:
1834
48
2.
Citerio
G
,
Oddo
M
,
Taccone
FS
:
Recommendations for the use of multimodal monitoring in the neurointensive care unit.
Curr Opin Crit Care
2015
;
21
:
113
9
3.
Kirkman
MA
,
Smith
M
:
Multimodality neuromonitoring.
Anesthesiol Clin
2016
;
34
:
511
23
4.
Makarenko
S
,
Griesdale
DE
,
Gooderham
P
,
Sekhon
MS
:
Multimodal neuromonitoring for traumatic brain injury: A shift towards individualized therapy.
J Clin Neurosci
2016
;
26
:
8
13
5.
Bouzat
P
,
Marques-Vidal
P
,
Zerlauth
JB
,
Sala
N
,
Suys
T
,
Schoettker
P
,
Bloch
J
,
Daniel
RT
,
Levivier
M
,
Meuli
R
,
Oddo
M
:
Accuracy of brain multimodal monitoring to detect cerebral hypoperfusion after traumatic brain injury.
Crit Care Med
2015
;
43
:
445
52
6.
Le Roux
P
,
Menon
DK
,
Citerio
G
,
Vespa
P
,
Bader
MK
,
Brophy
GM
,
Diringer
MN
,
Stocchetti
N
,
Videtta
W
,
Armonda
R
,
Badjatia
N
,
Boesel
J
,
Chesnut
R
,
Chou
S
,
Claassen
J
,
Czosnyka
M
,
De
GM
,
Figaji
A
,
Fugate
J
,
Helbok
R
,
Horowitz
D
,
Hutchinson
P
,
Kumar
M
,
McNett
M
,
Miller
C
,
Naidech
A
,
Oddo
M
,
Olson
D
,
O’Phelan
K
,
Provencio
JJ
,
Puppo
C
,
Riker
R
,
Robertson
C
,
Schmidt
M
,
Taccone
F
:
Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine.
Intensive Care Med
2014
;
40
:
1189
209
7.
Riker
RR
,
Fugate
JE
;
Participants in the International Multi-disciplinary Consensus Conference on Multimodality Monitoring
:
Clinical monitoring scales in acute brain injury: Assessment of coma, pain, agitation, and delirium.
Neurocrit Care
2014
;
21
(
suppl 2
):
S27
37
8.
Teasdale
G
,
Maas
A
,
Lecky
F
,
Manley
G
,
Stocchetti
N
,
Murray
G
:
The Glasgow Coma Scale at 40 years: Standing the test of time.
Lancet Neurol
2014
;
13
:
844
54
9.
Wijdicks
EF
,
Bamlet
WR
,
Maramattom
BV
,
Manno
EM
,
McClelland
RL
:
Validation of a new coma scale: The FOUR score.
Ann Neurol
2005
;
58
:
585
93
10.
Sharshar
T
,
Citerio
G
,
Andrews
PJ
,
Chieregato
A
,
Latronico
N
,
Menon
DK
,
Puybasset
L
,
Sandroni
C
,
Stevens
RD
:
Neurological examination of critically ill patients: A pragmatic approach: Report of an ESICM expert panel.
Intensive Care Med
2014
;
40
:
484
95
11.
Suys
T
,
Bouzat
P
,
Marques-Vidal
P
,
Sala
N
,
Payen
JF
,
Rossetti
AO
,
Oddo
M
:
Automated quantitative pupillometry for the prognostication of coma after cardiac arrest.
Neurocrit Care
2014
;
21
:
300
8
12.
Czosnyka
M
,
Pickard
JD
,
Steiner
LA
:
Principles of intracranial pressure monitoring and treatment.
Handb Clin Neurol
2017
;
140
:
67
89
13.
Smith
M
:
Monitoring intracranial pressure in traumatic brain injury.
Anesth Analg
2008
;
106
:
240
8
14.
Zacchetti
L
,
Magnoni
S
,
Di Corte
F
,
Zanier
ER
,
Stocchetti
N
:
Accuracy of intracranial pressure monitoring: Systematic review and meta-analysis.
Crit Care
2015
;
19
:
420
15.
Cardim
D
,
Robba
C
,
Bohdanowicz
M
,
Donnelly
J
,
Cabella
B
,
Liu
X
,
Cabeleira
M
,
Smielewski
P
,
Schmidt
B
,
Czosnyka
M
:
Non-invasive monitoring of intracranial pressure using transcranial doppler ultrasonography: Is it possible?
Neurocrit Care
2016
;
25
:
473
91
16.
Sekhon
MS
,
Griesdale
DE
,
Robba
C
,
McGlashan
N
,
Needham
E
,
Walland
K
,
Shook
AC
,
Smielewski
P
,
Czosnyka
M
,
Gupta
AK
,
Menon
DK
:
Optic nerve sheath diameter on computed tomography is correlated with simultaneously measured intracranial pressure in patients with severe traumatic brain injury.
Intensive Care Med
2014
;
40
:
1267
74
17.
Kristiansson
H
,
Nissborg
E
,
Bartek
J
Jr
,
Andresen
M
,
Reinstrup
P
,
Romner
B
:
Measuring elevated intracranial pressure through noninvasive methods: A review of the literature.
J Neurosurg Anesthesiol
2013
;
25
:
372
85
18.
Carney
N
,
Totten
AM
,
O’Reilly
C
,
Ullman
JS
,
Hawryluk
GW
,
Bell
MJ
,
Bratton
SL
,
Chesnut
R
,
Harris
OA
,
Kissoon
N
,
Rubiano
AM
,
Shutter
L
,
Tasker
RC
,
Vavilala
MS
,
Wilberger
J
,
Wright
DW
,
Ghajar
J
:
Guidelines for the management of severe traumatic brain injury, fourth edition.
Neurosurgery
2017
;
80
:
6
15
19.
Stocchetti
N
,
Picetti
E
,
Berardino
M
,
Buki
A
,
Chesnut
RM
,
Fountas
KN
,
Horn
P
,
Hutchinson
PJ
,
Iaccarino
C
,
Kolias
AG
,
Koskinen
LO
,
Latronico
N
,
Maas
AI
,
Payen
JF
,
Rosenthal
G
,
Sahuquillo
J
,
Signoretti
S
,
Soustiel
JF
,
Servadei
F
:
Clinical applications of intracranial pressure monitoring in traumatic brain injury: Report of the Milan consensus conference.
Acta Neurochir (Wien)
2014
;
156
:
1615
22
20.
Balestreri
M
,
Czosnyka
M
,
Hutchinson
P
,
Steiner
LA
,
Hiler
M
,
Smielewski
P
,
Pickard
JD
:
Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury.
Neurocrit Care
2006
;
4
:
8
13
21.
Farahvar
A
,
Gerber
LM
,
Chiu
YL
,
Härtl
R
,
Froelich
M
,
Carney
N
,
Ghajar
J
:
Response to intracranial hypertension treatment as a predictor of death in patients with severe traumatic brain injury.
J Neurosurg
2011
;
114
:
1471
8
22.
Badri
S
,
Chen
J
,
Barber
J
,
Temkin
NR
,
Dikmen
SS
,
Chesnut
RM
,
Deem
S
,
Yanez
ND
,
Treggiari
MM
:
Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury.
Intensive Care Med
2012
;
38
:
1800
9
23.
Kahraman
S
,
Dutton
RP
,
Hu
P
,
Xiao
Y
,
Aarabi
B
,
Stein
DM
,
Scalea
TM
:
Automated measurement of “pressure times time dose” of intracranial hypertension best predicts outcome after severe traumatic brain injury.
J Trauma
2010
;
69
:
110
8
24.
Vik
A
,
Nag
T
,
Fredriksli
OA
,
Skandsen
T
,
Moen
KG
,
Schirmer-Mikalsen
K
,
Manley
GT
:
Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury.
J Neurosurg
2008
;
109
:
678
84
25.
Treggiari
MM
,
Schutz
N
,
Yanez
ND
,
Romand
JA
:
Role of intracranial pressure values and patterns in predicting outcome in traumatic brain injury: A systematic review.
Neurocrit Care
2007
;
6
:
104
12
26.
Dawes
AJ
,
Sacks
GD
,
Cryer
HG
,
Gruen
JP
,
Preston
C
,
Gorospe
D
,
Cohen
M
,
McArthur
DL
,
Russell
MM
,
Maggard-Gibbons
M
,
Ko
CY
;
Los Angeles County Trauma Consortium
:
Intracranial pressure monitoring and inpatient mortality in severe traumatic brain injury: A propensity score-matched analysis.
J Trauma Acute Care Surg
2015
;
78
:
492
501
;
discussion 501–2
27.
MacLaughlin
BW
,
Plurad
DS
,
Sheppard
W
,
Bricker
S
,
Bongard
F
,
Neville
A
,
Smith
JA
,
Putnam
B
,
Kim
DY
:
The impact of intracranial pressure monitoring on mortality after severe traumatic brain injury.
Am J Surg
2015
;
210
:
1082
7
28.
Talving
P
,
Karamanos
E
,
Teixeira
PG
,
Skiada
D
,
Lam
L
,
Belzberg
H
,
Inaba
K
,
Demetriades
D
:
Intracranial pressure monitoring in severe head injury: Compliance with Brain Trauma Foundation guidelines and effect on outcomes: A prospective study.
J Neurosurg
2013
;
119
:
1248
54
29.
Tang
A
,
Pandit
V
,
Fennell
V
,
Jones
T
,
Joseph
B
,
O’Keeffe
T
,
Friese
RS
,
Rhee
P
:
Intracranial pressure monitor in patients with traumatic brain injury.
J Surg Res
2015
;
194
:
565
70
30.
Alali
AS
,
Fowler
RA
,
Mainprize
TG
,
Scales
DC
,
Kiss
A
,
de Mestral
C
,
Ray
JG
,
Nathens
AB
:
Intracranial pressure monitoring in severe traumatic brain injury: Results from the American College of Surgeons Trauma Quality Improvement Program.
J Neurotrauma
2013
;
30
:
1737
46
31.
Marmarou
A
,
Anderson
RL
,
Ward
JD
,
Choi
SC
,
Young
HF
,
Eisenberg
HM
,
Foulkes
MA
,
Marshall
LF
,
Jane
JA
:
Impact of ICP instability and hypotension on outcome in patients with severe head trauma.
J Neurosurg
1991
;
75
:
S59
66
32.
Yuan
Q
,
Wu
X
,
Sun
Y
,
Yu
J
,
Li
Z
,
Du
Z
,
Mao
Y
,
Zhou
L
,
Hu
J
:
Impact of intracranial pressure monitoring on mortality in patients with traumatic brain injury: A systematic review and meta-analysis.
J Neurosurg
2015
;
122
:
574
87
33.
Chesnut
RM
,
Temkin
N
,
Carney
N
,
Dikmen
S
,
Rondina
C
,
Videtta
W
,
Petroni
G
,
Lujan
S
,
Pridgeon
J
,
Barber
J
,
Machamer
J
,
Chaddock
K
,
Celix
JM
,
Cherner
M
,
Hendrix
T
;
Global Neurotrauma Research Group
:
A trial of intracranial-pressure monitoring in traumatic brain injury.
N Engl J Med
2012
;
367
:
2471
81
34.
Chesnut
RM
:
Intracranial pressure monitoring: Headstone or a new head start. The BEST TRIP trial in perspective.
Intensive Care Med
2013
;
39
:
771
4
35.
Kirkman
MA
,
Smith
M
:
Intracranial pressure monitoring, cerebral perfusion pressure estimation, and ICP/CPP–guided therapy: A standard of care or optional extra after brain injury?
Br J Anaesth
2014
;
112
:
35
46
36.
Myers
RB
,
Lazaridis
C
,
Jermaine
CM
,
Robertson
CS
,
Rusin
CG
:
Predicting intracranial pressure and brain tissue oxygen crises in patients with severe traumatic brain injury.
Crit Care Med
2016
;
44
:
1754
61
37.
Güiza
F
,
Depreitere
B
,
Piper
I
,
Citerio
G
,
Jorens
PG
,
Maas
A
,
Schuhmann
MU
,
Lo
TM
,
Donald
R
,
Jones
P
,
Maier
G
,
Van den Berghe
G
,
Meyfroidt
G
:
Early detection of increased intracranial pressure episodes in traumatic brain injury: External validation in an adult and in a pediatric cohort.
Crit Care Med
2017
;
45
:
e316
20
38.
Güiza
F
,
Depreitere
B
,
Piper
I
,
Citerio
G
,
Chambers
I
,
Jones
PA
,
Lo
TY
,
Enblad
P
,
Nillson
P
,
Feyen
B
,
Jorens
P
,
Maas
A
,
Schuhmann
MU
,
Donald
R
,
Moss
L
,
Van den Berghe
G
,
Meyfroidt
G
:
Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury.
Intensive Care Med
2015
;
41
:
1067
76
39.
Smith
M
:
Cerebral perfusion pressure.
Br J Anaesth
2015
;
115
:
488
90
40.
Rao
V
,
Klepstad
P
,
Losvik
OK
,
Solheim
O
:
Confusion with cerebral perfusion pressure in a literature review of current guidelines and survey of clinical practice.
Scand J Trauma Resusc Emerg Med
2013
;
21
:
78
41.
Kosty
JA
,
Leroux
PD
,
Levine
J
,
Park
S
,
Kumar
MA
,
Frangos
S
,
Maloney-Wilensky
E
,
Kofke
WA
:
Brief report: A comparison of clinical and research practices in measuring cerebral perfusion pressure: A literature review and practitioner survey.
Anesth Analg
2013
;
117
:
694
8
42.
Aries
MJ
,
Czosnyka
M
,
Budohoski
KP
,
Steiner
LA
,
Lavinio
A
,
Kolias
AG
,
Hutchinson
PJ
,
Brady
KM
,
Menon
DK
,
Pickard
JD
,
Smielewski
P
:
Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
Crit Care Med
2012
;
40
:
2456
63
43.
Czosnyka
M
,
Miller
C
:
Monitoring of cerebral autoregulation.
Neurocrit Care
2014
;
21
(
suppl 2
):
S95
102
44.
Dias
C
,
Silva
MJ
,
Pereira
E
,
Monteiro
E
,
Maia
I
,
Barbosa
S
,
Silva
S
,
Honrado
T
,
Cerejo
A
,
Aries
MJ
,
Smielewski
P
,
Paiva
JA
,
Czosnyka
M
:
Optimal cerebral perfusion pressure management at bedside: A single-center pilot study.
Neurocrit Care
2015
;
23
:
92
102
45.
Rivera-Lara
L
,
Zorrilla-Vaca
A
,
Geocadin
R
,
Ziai
W
,
Healy
R
,
Thompson
R
,
Smielewski
P
,
Czosnyka
M
,
Hogue
CW
:
Predictors of outcome with cerebral autoregulation monitoring: A systematic review and meta-analysis.
Crit Care Med
2017
;
45
:
695
704
46.
Lazaridis
C
,
Andrews
CM
:
Brain tissue oxygenation, lactate-pyruvate ratio, and cerebrovascular pressure reactivity monitoring in severe traumatic brain injury: Systematic review and viewpoint.
Neurocrit Care
2014
;
21
:
345
55
47.
Jaeger
M
,
Schuhmann
MU
,
Soehle
M
,
Meixensberger
J
:
Continuous assessment of cerebrovascular autoregulation after traumatic brain injury using brain tissue oxygen pressure reactivity.
Crit Care Med
2006
;
34
:
1783
8
48.
Sorrentino
E
,
Budohoski
KP
,
Kasprowicz
M
,
Smielewski
P
,
Matta
B
,
Pickard
JD
,
Czosnyka
M
:
Critical thresholds for transcranial Doppler indices of cerebral autoregulation in traumatic brain injury.
Neurocrit Care
2011
;
14
:
188
93
49.
Weigl
W
,
Milej
D
,
Janusek
D
,
Wojtkiewicz
S
,
Sawosz
P
,
Kacprzak
M
,
Gerega
A
,
Maniewski
R
,
Liebert
A
:
Application of optical methods in the monitoring of traumatic brain injury: A review.
J Cereb Blood Flow Metab
2016
;
36
:
1825
43
50.
Depreitere
B
,
Güiza
F
,
Van den Berghe
G
,
Schuhmann
MU
,
Maier
G
,
Piper
I
,
Meyfroidt
G
:
Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data.
J Neurosurg
2014
;
120
:
1451
7
51.
Highton
D
,
Ghosh
A
,
Tachtsidis
I
,
Panovska-Griffiths
J
,
Elwell
CE
,
Smith
M
:
Monitoring cerebral autoregulation after brain injury: Multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy.
Anesth Analg
2015
;
121
:
198
205
52.
Needham
E
,
McFadyen
C
,
Newcombe
V
,
Synnot
AJ
,
Czosnyka
M
,
Menon
D
:
Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: A systematic review.
J Neurotrauma
2017
;
34
:
963
70
53.
Akbik
OS
,
Carlson
AP
,
Krasberg
M
,
Yonas
H
:
The utility of cerebral blood flow assessment in TBI.
Curr Neurol Neurosci Rep
2016
;
16
:
72
54.
Rostami
E
,
Engquist
H
,
Enblad
P
:
Imaging of cerebral blood flow in patients with severe traumatic brain injury in the neurointensive care.
Front Neurol
2014
;
5
:
114
55.
Aaslid
R
,
Markwalder
TM
,
Nornes
H
:
Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries.
J Neurosurg
1982
;
57
:
769
74
56.
Bouzat
P
,
Oddo
M
,
Payen
JF
:
Transcranial Doppler after traumatic brain injury: Is there a role?
Curr Opin Crit Care
2014
;
20
:
153
60
57.
Bouzat
P
,
Almeras
L
,
Manhes
P
,
Sanders
L
,
Levrat
A
,
David
JS
,
Cinotti
R
,
Chabanne
R
,
Gloaguen
A
,
Bobbia
X
,
Thoret
S
,
Oujamaa
L
,
Bosson
JL
,
Payen
JF
,
Asehnoune
K
,
Pes
P
,
Lefrant
JY
,
Mirek
S
,
Albasini
F
,
Scrimgeour
C
,
Thouret
JM
,
Chartier
F
,
Ginet
M
;
TBI-TCD Study Investigators
:
Transcranial Doppler to predict neurologic outcome after mild to moderate traumatic brain injury.
Anesthesiology
2016
;
125
:
346
54
58.
Zweifel
C
,
Czosnyka
M
,
Carrera
E
,
de Riva
N
,
Pickard
JD
,
Smielewski
P
:
Reliability of the blood flow velocity pulsatility index for assessment of intracranial and cerebral perfusion pressures in head-injured patients.
Neurosurgery
2012
;
71
:
853
61
59.
Dupont
G
,
Burnol
L
,
Jospe
R
,
Raphael
T
,
Auboyer
C
,
Molliex
S
,
Gergelé
L
,
Morel
J
:
Transcranial color duplex ultrasound: A reliable tool for cerebral hemodynamic assessment in brain injuries.
J Neurosurg Anesthesiol
2016
;
28
:
159
63
60.
Vajkoczy
P
,
Roth
H
,
Horn
P
,
Lucke
T
,
Thomé
C
,
Hubner
U
,
Martin
GT
,
Zappletal
C
,
Klar
E
,
Schilling
L
,
Schmiedek
P
:
Continuous monitoring of regional cerebral blood flow: Experimental and clinical validation of a novel thermal diffusion microprobe.
J Neurosurg
2000
;
93
:
265
74
61.
Rosenthal
G
,
Sanchez-Mejia
RO
,
Phan
N
,
Hemphill
JC
3rd
,
Martin
C
,
Manley
GT
:
Incorporating a parenchymal thermal diffusion cerebral blood flow probe in bedside assessment of cerebral autoregulation and vasoreactivity in patients with severe traumatic brain injury.
J Neurosurg
2011
;
114
:
62
70
62.
Chang
JJ
,
Youn
TS
,
Benson
D
,
Mattick
H
,
Andrade
N
,
Harper
CR
,
Moore
CB
,
Madden
CJ
,
Diaz-Arrastia
RR
:
Physiologic and functional outcome correlates of brain tissue hypoxia in traumatic brain injury.
Crit Care Med
2009
;
37
:
283
90
63.
Oddo
M
,
Levine
JM
,
Mackenzie
L
,
Frangos
S
,
Feihl
F
,
Kasner
SE
,
Katsnelson
M
,
Pukenas
B
,
Macmurtrie
E
,
Maloney-Wilensky
E
,
Kofke
WA
,
LeRoux
PD
:
Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure.
Neurosurgery
2011
;
69
:
1037
45
64.
Kirkman
MA
,
Smith
M
:
Brain oxygenation monitoring.
Anesthesiol Clin
2016
;
34
:
537
56
65.
Schell
RM
,
Cole
DJ
:
Cerebral monitoring: Jugular venous oximetry.
Anesth Analg
2000
;
90
:
559
66
66.
Robertson
CS
,
Gopinath
SP
,
Goodman
JC
,
Contant
CF
,
Valadka
AB
,
Narayan
RK
:
SjvO2 monitoring in head-injured patients.
J Neurotrauma
1995
;
12
:
891
6
67.
Cormio
M
,
Valadka
AB
,
Robertson
CS
:
Elevated jugular venous oxygen saturation after severe head injury.
J Neurosurg
1999
;
90
:
9
15
68.
Stocchetti
N
,
Magnoni
S
,
Zanier
ER
:
My paper 20 years later: Cerebral venous oxygen saturation studied with bilateral samples in the internal jugular veins.
Intensive Care Med
2015
;
41
:
412
7
69.
Ponce
LL
,
Pillai
S
,
Cruz
J
,
Li
X
,
Julia
H
,
Gopinath
S
,
Robertson
CS
:
Position of probe determines prognostic information of brain tissue Po2 in severe traumatic brain injury.
Neurosurgery
2012
;
70
:
1492
502
;
discussion 1502–3
70.
van den Brink
WA
,
van Santbrink
H
,
Steyerberg
EW
,
Avezaat
CJ
,
Suazo
JA
,
Hogesteeger
C
,
Jansen
WJ
,
Kloos
LM
,
Vermeulen
J
,
Maas
AI
:
Brain oxygen tension in severe head injury.
Neurosurgery
2000
;
46
:
868
78
71.
Lin
CM
,
Lin
MC
,
Huang
SJ
,
Chang
CK
,
Chao
DP
,
Lui
TN
,
Ma
HI
,
Liu
MY
,
Chung
WY
,
Shih
YH
,
Tsai
SH
,
Chiou
HY
,
Lin
MR
,
Jen
SL
,
Wei
L
,
Wu
CC
,
Lin
EY
,
Liao
KH
,
Chiang
YH
,
Chiu
WT
,
Lin
JW
:
A prospective randomized study of brain tissue oxygen pressure-guided management in moderate and severe traumatic brain injury patients.
Biomed Res Int
2015
;
2015
:
529580
72.
Narotam
PK
,
Morrison
JF
,
Nathoo
N
:
Brain tissue oxygen monitoring in traumatic brain injury and major trauma: Outcome analysis of a brain tissue oxygen-directed therapy.
J Neurosurg
2009
;
111
:
672
82
73.
Spiotta
AM
,
Stiefel
MF
,
Gracias
VH
,
Garuffe
AM
,
Kofke
WA
,
Maloney-Wilensky
E
,
Troxel
AB
,
Levine
JM
,
Le Roux
PD
:
Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury.
J Neurosurg
2010
;
113
:
571
80
74.
Nangunoori
R
,
Maloney-Wilensky
E
,
Stiefel
M
,
Park
S
,
Andrew Kofke
W
,
Levine
JM
,
Yang
W
,
Le Roux
PD
:
Brain tissue oxygen-based therapy and outcome after severe traumatic brain injury: A systematic literature review.
Neurocrit Care
2012
;
17
:
131
8
75.
Korbakis
G
,
Vespa
PM
:
Multimodal neurologic monitoring.
Handb Clin Neurol
2017
;
140
:
91
105
76.
Oddo
M
,
Bosel
J
:
Monitoring of brain and systemic oxygenation in neurocritical care patients.
Neurocrit Care
2014
;
21
(
suppl 2
):
S103
20
77.
Bouzat
P
,
Sala
N
,
Payen
JF
,
Oddo
M
:
Beyond intracranial pressure: Optimization of cerebral blood flow, oxygen, and substrate delivery after traumatic brain injury.
Ann Intensive Care
2013
;
3
:
23
78.
Bohman
LE
,
Heuer
GG
,
Macyszyn
L
,
Maloney-Wilensky
E
,
Frangos
S
,
Le Roux
PD
,
Kofke
A
,
Levine
JM
,
Stiefel
MF
:
Medical management of compromised brain oxygen in patients with severe traumatic brain injury.
Neurocrit Care
2011
;
14
:
361
9
79.
Quintard
H
,
Patet
C
,
Suys
T
,
Marques-Vidal
P
,
Oddo
M
:
Normobaric hyperoxia is associated with increased cerebral excitotoxicity after severe traumatic brain injury.
Neurocrit Care
2015
;
22
:
243
50
80.
Ghosh
A
,
Elwell
C
,
Smith
M
:
Cerebral near-infrared spectroscopy in adults: A work in progress.
Anesth Analg
2012
;
115
:
1373
83
81.
Smith
M
:
Shedding light on the adult brain: A review of the clinical applications of near-infrared spectroscopy.
Philos Trans A Math Phys Eng Sci
2011
;
369
:
4452
69
82.
Dunham
CM
,
Ransom
KJ
,
Flowers
LL
,
Siegal
JD
,
Kohli
CM
:
Cerebral hypoxia in severely brain-injured patients is associated with admission Glasgow Coma Scale score, computed tomographic severity, cerebral perfusion pressure, and survival.
J Trauma
2004
;
56
:
482
91
83.
Zweifel
C
,
Castellani
G
,
Czosnyka
M
,
Helmy
A
,
Manktelow
A
,
Carrera
E
,
Brady
KM
,
Hutchinson
PJ
,
Menon
DK
,
Pickard
JD
,
Smielewski
P
:
Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients.
J Neurotrauma
2010
;
27
:
1951
8
84.
Bale
G
,
Elwell
CE
,
Tachtsidis
I
:
From Jöbsis to the present day: A review of clinical near-infrared spectroscopy measurements of cerebral cytochrome-c-oxidase.
J Biomed Opt
2016
;
21
:
091307
85.
Robertson
CS
,
Zager
EL
,
Narayan
RK
,
Handly
N
,
Sharma
A
,
Hanley
DF
,
Garza
H
,
Maloney-Wilensky
E
,
Plaum
JM
,
Koenig
CH
,
Johnson
A
,
Morgan
T
:
Clinical evaluation of a portable near-infrared device for detection of traumatic intracranial hematomas.
J Neurotrauma
2010
;
27
:
1597
604
86.
Verdecchia
K
,
Diop
M
,
Lee
TY
,
St Lawrence
K
:
Quantifying the cerebral metabolic rate of oxygen by combining diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy.
J Biomed Opt
2013
;
18
:
27007
87.
Elwell
CE
,
Cooper
CE
:
Making light work: Illuminating the future of biomedical optics.
Philos Trans A Math Phys Eng Sci
2011
;
369
:
4358
79
88.
Kirkman
MA
,
Smith
M
:
Multimodal intracranial monitoring: Implications for clinical practice.
Anesthesiol Clin
2012
;
30
:
269
87
89.
Carpenter
KL
,
Young
AM
,
Hutchinson
PJ
:
Advanced monitoring in traumatic brain injury: Microdialysis.
Curr Opin Crit Care
2017
;
23
:
103
9
90.
Hutchinson
PJ
,
Jalloh
I
,
Helmy
A
,
Carpenter
KL
,
Rostami
E
,
Bellander
BM
,
Boutelle
MG
,
Chen
JW
,
Claassen
J
,
Dahyot-Fizelier
C
,
Enblad
P
,
Gallagher
CN
,
Helbok
R
,
Hillered
L
,
Le Roux
PD
,
Magnoni
S
,
Mangat
HS
,
Menon
DK
,
Nordström
CH
,
O’Phelan
KH
,
Oddo
M
,
Perez Barcena
J
,
Robertson
C
,
Ronne-Engström
E
,
Sahuquillo
J
,
Smith
M
,
Stocchetti
N
,
Belli
A
,
Carpenter
TA
,
Coles
JP
,
Czosnyka
M
,
Dizdar
N
,
Goodman
JC
,
Gupta
AK
,
Nielsen
TH
,
Marklund
N
,
Montcriol
A
,
O’Connell
MT
,
Poca
MA
,
Sarrafzadeh
A
,
Shannon
RJ
,
Skjøth-Rasmussen
J
,
Smielewski
P
,
Stover
JF
,
Timofeev
I
,
Vespa
P
,
Zavala
E
,
Ungerstedt
U
:
Consensus statement from the 2014 International Microdialysis Forum.
Intensive Care Med
2015
;
41
:
1517
28
91.
Carre
E
,
Ogier
M
,
Boret
H
,
Montcriol
A
,
Bourdon
L
,
Jean-Jacques
R
:
Metabolic crisis in severely head-injured patients: Is ischemia just the tip of the iceberg?
Front Neurol
2013
;
4
:
146
92.
Vespa
P
,
Bergsneider
M
,
Hattori
N
,
Wu
HM
,
Huang
SC
,
Martin
NA
,
Glenn
TC
,
McArthur
DL
,
Hovda
DA
:
Metabolic crisis without brain ischemia is common after traumatic brain injury: A combined microdialysis and positron emission tomography study.
J Cereb Blood Flow Metab
2005
;
25
:
763
74
93.
Larach
DB
,
Kofke
WA
,
Le Roux
P
:
Potential non-hypoxic/ischemic causes of increased cerebral interstitial fluid lactate/pyruvate ratio: A review of available literature.
Neurocrit Care
2011
;
15
:
609
22
94.
Chamoun
R
,
Suki
D
,
Gopinath
SP
,
Goodman
JC
,
Robertson
C
:
Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury.
J Neurosurg
2010
;
113
:
564
70
95.
Clausen
T
,
Alves
OL
,
Reinert
M
,
Doppenberg
E
,
Zauner
A
,
Bullock
R
:
Association between elevated brain tissue glycerol levels and poor outcome following severe traumatic brain injury.
J Neurosurg
2005
;
103
:
233
8
96.
Belli
A
,
Sen
J
,
Petzold
A
,
Russo
S
,
Kitchen
N
,
Smith
M
:
Metabolic failure precedes intracranial pressure rises in traumatic brain injury: A microdialysis study.
Acta Neurochir (Wien)
2008
;
150
:
461
70
97.
Timofeev
I
,
Carpenter
KL
,
Nortje
J
,
Al-Rawi
PG
,
O’Connell
MT
,
Czosnyka
M
,
Smielewski
P
,
Pickard
JD
,
Menon
DK
,
Kirkpatrick
PJ
,
Gupta
AK
,
Hutchinson
PJ
:
Cerebral extracellular chemistry and outcome following traumatic brain injury: A microdialysis study of 223 patients.
Brain
2011
;
134
:
484
94
98.
Magnoni
S
,
Tedesco
C
,
Carbonara
M
,
Pluderi
M
,
Colombo
A
,
Stocchetti
N
:
Relationship between systemic glucose and cerebral glucose is preserved in patients with severe traumatic brain injury, but glucose delivery to the brain may become limited when oxidative metabolism is impaired: Implications for glycemic control.
Crit Care Med
2012
;
40
:
1785
91
99.
Nordström
CH
,
Reinstrup
P
,
Xu
W
,
Gärdenfors
A
,
Ungerstedt
U
:
Assessment of the lower limit for cerebral perfusion pressure in severe head injuries by bedside monitoring of regional energy metabolism.
Anesthesiology
2003
;
98
:
809
14
100.
Vespa
PM
,
O’Phelan
K
,
McArthur
D
,
Miller
C
,
Eliseo
M
,
Hirt
D
,
Glenn
T
,
Hovda
DA
:
Pericontusional brain tissue exhibits persistent elevation of lactate/pyruvate ratio independent of cerebral perfusion pressure.
Crit Care Med
2007
;
35
:
1153
60
101.
Afinowi
R
,
Tisdall
M
,
Keir
G
,
Smith
M
,
Kitchen
N
,
Petzold
A
:
Improving the recovery of S100B protein in cerebral microdialysis: Implications for multimodal monitoring in neurocritical care.
J Neurosci Methods
2009
;
181
:
95
9
102.
Carpenter
KL
,
Timofeev
I
,
Al-Rawi
PG
,
Menon
DK
,
Pickard
JD
,
Hutchinson
PJ
:
Nitric oxide in acute brain injury: A pilot study of NO(x) concentrations in human brain microdialysates and their relationship with energy metabolism.
Acta Neurochir Suppl
2008
;
102
:
207
13
103.
Belli
A
,
Sen
J
,
Petzold
A
,
Russo
S
,
Kitchen
N
,
Smith
M
,
Tavazzi
B
,
Vagnozzi
R
,
Signoretti
S
,
Amorini
AM
,
Bellia
F
,
Lazzarino
G
:
Extracellular N-acetylaspartate depletion in traumatic brain injury.
J Neurochem
2006
;
96
:
861
9
104.
Helmy
A
,
Carpenter
KL
,
Menon
DK
,
Pickard
JD
,
Hutchinson
PJ
:
The cytokine response to human traumatic brain injury: Temporal profiles and evidence for cerebral parenchymal production.
J Cereb Blood Flow Metab
2011
;
31
:
658
70
105.
Lakshmanan
R
,
Loo
JA
,
Drake
T
,
Leblanc
J
,
Ytterberg
AJ
,
McArthur
DL
,
Etchepare
M
,
Vespa
PM
:
Metabolic crisis after traumatic brain injury is associated with a novel microdialysis proteome.
Neurocrit Care
2010
;
12
:
324
36
106.
Vespa
P
,
Tubi
M
,
Claassen
J
,
Buitrago-Blanco
M
,
McArthur
D
,
Velazquez
AG
,
Tu
B
,
Prins
M
,
Nuwer
M
:
Metabolic crisis occurs with seizures and periodic discharges after brain trauma.
Ann Neurol
2016
;
79
:
579
90
107.
Rogers
ML
,
Leong
CL
,
Gowers
SA
,
Samper
IC
,
Jewell
SL
,
Khan
A
,
McCarthy
L
,
Pahl
C
,
Tolias
CM
,
Walsh
DC
,
Strong
AJ
,
Boutelle
MG
:
Simultaneous monitoring of potassium, glucose and lactate during spreading depolarization in the injured human brain: Proof of principle of a novel real-time neurochemical analysis system, continuous online microdialysis.
J Cereb Blood Flow Metab
2017
;
37
:
1883
95
108.
Claassen
J
,
Taccone
FS
,
Horn
P
,
Holtkamp
M
,
Stocchetti
N
,
Oddo
M
;
Neurointensive Care Section of the European Society of Intensive Care Medicine
:
Recommendations on the use of EEG monitoring in critically ill patients: Consensus statement from the neurointensive care section of the ESICM.
Intensive Care Med
2013
;
39
:
1337
51
109.
Vespa
PM
,
Miller
C
,
McArthur
D
,
Eliseo
M
,
Etchepare
M
,
Hirt
D
,
Glenn
TC
,
Martin
N
,
Hovda
D
:
Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis.
Crit Care Med
2007
;
35
:
2830
6
110.
Gavvala
J
,
Abend
N
,
LaRoche
S
,
Hahn
C
,
Herman
ST
,
Claassen
J
,
Macken
M
,
Schuele
S
,
Gerard
E
;
Critical Care EEG Monitoring Research Consortium (CCEMRC)
:
Continuous EEG monitoring: A survey of neurophysiologists and neurointensivists.
Epilepsia
2014
;
55
:
1864
71
111.
Claassen
J
,
Vespa
P
:
Electrophysiologic monitoring in acute brain injury.
Neurocrit Care
2014
;
21
(
suppl 2
):
S129
47
112.
Hartings
JA
,
Bullock
MR
,
Okonkwo
DO
,
Murray
LS
,
Murray
GD
,
Fabricius
M
,
Maas
AI
,
Woitzik
J
,
Sakowitz
O
,
Mathern
B
,
Roozenbeek
B
,
Lingsma
H
,
Dreier
JP
,
Puccio
AM
,
Shutter
LA
,
Pahl
C
,
Strong
AJ
;
Co-Operative Study on Brain Injury Depolarisations
:
Spreading depolarisations and outcome after traumatic brain injury: A prospective observational study.
Lancet Neurol
2011
;
10
:
1058
64
113.
Huschak
G
,
Hoell
T
,
Hohaus
C
,
Kern
C
,
Minkus
Y
,
Meisel
HJ
:
Clinical evaluation of a new multiparameter neuromonitoring device: Measurement of brain tissue oxygen, brain temperature, and intracranial pressure.
J Neurosurg Anesthesiol
2009
;
21
:
155
60
114.
Hemphill
JC
,
Andrews
P
,
De Georgia
M
:
Multimodal monitoring and neurocritical care bioinformatics.
Nat Rev Neurol
2011
;
7
:
451
60
115.
Sorani
MD
,
Hemphill
JC
3rd
,
Morabito
D
,
Rosenthal
G
,
Manley
GT
:
New approaches to physiological informatics in neurocritical care.
Neurocrit Care
2007
;
7
:
45
52
116.
Caldwell
M
,
Hapuarachchi
T
,
Highton
D
,
Elwell
C
,
Smith
M
,
Tachtsidis
I
:
BrainSignals revisited: Simplifying a computational model of cerebral physiology.
PLoS One
2015
;
10
:
e0126695
117.
Zygun
D
:
Can we demonstrate the efficacy of monitoring?
Eur J Anaesthesiol Suppl
2008
;
42
:
94
7
118.
Frontera
J
,
Ziai
W
,
O’Phelan
K
,
Leroux
PD
,
Kirkpatrick
PJ
,
Diringer
MN
,
Suarez
JI
;
Second Neurocritical Care Research Conference Investigators
:
Regional brain monitoring in the neurocritical care unit.
Neurocrit Care
2015
;
22
:
348
59
119.
Kofke
WA
:
Incrementally applied multifaceted therapeutic bundles in neuroprotection clinical trials: Time for change.
Neurocrit Care
2010
;
12
:
438
44
120.
Clifton
GL
,
Choi
SC
,
Miller
ER
,
Levin
HS
,
Smith
KR
Jr
,
Muizelaar
JP
,
Wagner
FC
Jr
,
Marion
DW
,
Luerssen
TG
:
Intercenter variance in clinical trials of head trauma–experience of the National Acute Brain Injury Study: Hypothermia.
J Neurosurg
2001
;
95
:
751
5
121.
Bragge
P
,
Synnot
A
,
Maas
AI
,
Menon
DK
,
Cooper
DJ
,
Rosenfeld
JV
,
Gruen
RL
:
A state-of-the-science overview of randomized controlled trials evaluating acute management of moderate-to-severe traumatic brain injury.
J Neurotrauma
2016
;
33
:
1461
78
122.
Menon
DK
,
Maas
AI
:
Traumatic brain injury in 2014: Progress, failures and new approaches for TBI research.
Nat Rev Neurol
2015
;
11
:
71
2
123.
Tosetti
P
,
Hicks
RR
,
Theriault
E
,
Phillips
A
,
Koroshetz
W
,
Draghia-Akli
R
;
Workshop Participants
:
Toward an international initiative for traumatic brain injury research.
J Neurotrauma
2013
;
30
:
1211
22