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366
C. Batson et al.
failure, and activation of cell death pathways [8–10]. Without
intervention, secondary brain injury leads to substantial loss
of neurological tissue and potentiates the morbidity and mortality seen in moderate and severe TBI [8–10].
Early and rapid intervention is critical to mitigate secondary brain injury. To facilitate rapid and pointed intervention
directed at these secondary brain injury mechanisms, we
have seen the development of guideline-based therapeutic
approaches, such as those supported by the Brain Trauma
Foundation (BTF) [11, 12]. Therapeutic intervention is further supported by continuous multi-modal assessments of
various aspects of cerebral physiology at the bedside. Such
advanced monitoring allows for early rapid detection of secondary brain insult, with continuous feedback regarding the
therapeutic efcacy of interventions [11, 12]. This monitoring has advanced TBI care in recent years from guideline
physiologic therapies to personalized medicine approaches
in the intensive care unit (ICU) [3, 13, 14].
Acute-Phase Stabilization inModerate/
Severe TBI Care
Advanced Trauma Life Support (ATLS)—The Basics
Despite the presence of advanced monitoring techniques and
interventions for moderate/severe TBI, the principles of
acute-phase stabilization of the trauma patient still apply and
take precedence at the beginning of care implementation.
Advanced trauma life support (ATLS), common knowledge
to most trauma care providers, comprises a set of guidelines
via a primary and secondary survey in order to assess and
manage patients who have suffered a traumatic injury [6,
15]. The basic premise of the primary survey is the ABCDE
(Airway, Breathing, Circulation, Disability and Exposure/
Environmental Control) of ATLS [15]. Routinely, most
trauma patients have their vitals taken and are placed on a
cardiac monitor, blood pressure monitor, and pulse oximeter
in order to gather baseline information for management [15].
With sequentially addressing airway, breathing, and circulation during the primary survey, major contributors to secondary brain injury in the TBI patient, hypotension and hypoxia,
are addressed. An additional and very important aspect of
management in the eld before arriving to the hospital is to
ensure adequate immobilization of the head and neck in
order to maintain cervical-spine alignment and to decrease
the chance of any spinal cord injury secondary to any vertebral instability [6, 15]. This immobilization must be main-
tained throughout management where vertebral motion may
arise, e.g., logrolls [15].
The disability section of the primary survey deals with the
neurological status of a trauma patient [15]. Neurological
status is assessed using various parameters like the Glasgow
Coma Scale (GCS), pupillary status, blood glucose levels,
and toxic substances levels [6, 15]. Neurological injuries are
usually associated with decreased sensation, syncope, motor
decits, headache, aphasia, vital sign derangement, etc.
Spinal cord injury can cause derangement in cardiovascular
status, be refractory to uid resuscitation, and can cause neurogenic shock [6, 8, 15]. Some patients may or may not
require a CT scan of the head. The Canadian CT Head Injury/
Trauma Rule assesses head injury status without imaging
and identies patients who do not require neurosurgical
intervention. CT scan of the head and neck is warranted in a
patient with neurological decits providing they are stable
enough to undergo this study. Based on the severity of trauma
and ndings, a patient may require transfer to a higher-level
trauma center for more specialist care if the current facility is
not able to provide the same [6, 15].
Advanced TBI Guideline-Based Care
Brain Trauma Foundation (BTF) guidelines are widely used
in practice and aid in reduced mortality from moderate and
severe traumatic brain injury (sTBI) [16]. It states that “in
general a TBI patient with a poor neurological exam, abnormal CT of the brain and risk factors for secondary injury
should be monitored” [17]. Invasive intracranial pressure
(ICP) monitoring is done for TBI patients within the ICU;
prolonged elevations are associated with poor patient outcomes [17]. The threshold for ICP treatment is 22mmHg,
with sustained periods of time spent above this threshold
associated with poor global outcomes [17]. More recently,
the Seattle International Severe Traumatic Brain Injury
Consensus Conference (SIBICC) guidelines comprise tier
zero to tier three management algorithms for sTBI [16]. Tier
zero comprises basic care for an sTBI patient admitted to the
ICU with an ICP monitor in place [16]. The aim is to stabilize the patient neurologically, e.g., manage intracranial
hypertension, as the minimal cerebral perfusion pressure
(CPP) threshold is 60mmHg and the initial ICP threshold is
22mmHg [16]. Tier 1–3 steps up management based on the
severity of the situation [16]. We refer the interested reader to
the BTF and SIBICC guidelines for more details surrounding the tiered management approaches for secondary brain
injury mitigation [12, 16–18].
43 Advanced Neuromonitoring forModerate andSevere Traumatic Brain Injury
367
Acute Neuromonitoring Techniques
inModerate/Severe TBI
ICP andCPP—Invasive Monitoring
andtheBasics
The cornerstone of acute monitoring in moderate/severe TBI
is ICP and CPP, as previously mentioned. ICP is the pressure
exerted by the contents of an intact calvarium, i.e., brain tissue volume, blood, CSF, and any space-occupying lesion.
ICP can be monitored invasively and noninvasively, with
invasive techniques and external ventricular drains (EVDs)
considered the “gold standard.” The zero reference point for
ICP is considered the foramen of Monro. The origins of ICP
monitoring trace back to times when CT and MRI were
unavailable. It aided with the detection of hematomas in
postoperative patients, and the potential need for intervention could be signaled by increased values in postop recovery
[17, 19]. Since then, ICP monitoring has been adopted for
continuous bedside assessment in TBI care within the ICU,
with the majority of current guideline targets and therapies
based on ICP values, or derived measures such as CPP.BTF
guidelines recommend ICP monitoring of patients admitted
to the ICU with TBI and state that an ICP of ≥22mmHg
requires management [16, 17], as extensive literature documented the association between time spent above this ICP
value and poor outcome at 6-months post-injury [17, 20].
Invasive methods for ICP monitoring include parenchymal devices (strain gauge monitors and ber-optic-based
pressure sensors) which can in theory be inserted anyplace in
the cranial cavity (typically right frontal lobe), and external
ventricular drains (EVD) inserted in the ventricular system,
all used to assess liquid or tissue pressure within the cranium
[17, 21]. Such techniques are considered the standard for
ICP monitoring in TBI care. Table43.1 provides an outline
for each invasive and noninvasive monitoring technique,
with advantages and disadvantages.
Aside from targeting ICP thresholds, we are also interested in maintaining cerebral blood ow (CBF) in
TBI.Currently, we lack effective continuous bedside methods for objective CBF measurement. As such, we rely on
potential surrogate metrics for CBF, with one such measure
being CPP.CPP is thought to be the pressure within the brain
that maintains CBF.In its simplistic form, CPP is dened as
the difference between mean arterial pressure (MAP) and
ICP.It is believed that low CPP causes low CBF which can
cause harmful effects (ischemia and/or infarction) of the
brain parenchyma as less oxygen and nutrients will reach the
tissues [17]. Similarly, persistently high CPP is believed to
be associated with cerebral hyperemia, break down of the
blood-brain barrier, and potentially intracerebral hemor-
rhage. The gold standard for CPP measurement requires both
invasive arterial blood pressure (ABP) and ICP measures
[17, 20]. BTF guidelines recommend that CPP should be
maintained between 60 mmHg and 70 mmHg, but some
research works suggest a threshold of 70mmHg and report
unfavorable outcomes noted in patients with values below
this number over time [17, 22]. Some controversy exists surrounding maintaining CPP above 70mmHg, as historically
the literature has linked this to unfavorable outcomes as a
result of increased precapillary arteriolar pressure, capillary
bed ltration pressures, cerebral edema, and even acute
respiratory distress syndrome (ARDS) [17, 23]. However,
recent literature suggests with advances in general cardiopulmonary care in the ICU, systemic complications of elevated
CPP targets may not remain a substantial concern [23].
Noninvasive ICP/CPP Determination Methods
However, recent advances in transcranial ultrasonic techniques have led to the development of noninvasive methods
including optic nerve sheath diameter (ONSD) ultrasound
and transcranial Doppler (TCD) ICP estimations. First, for
ONSD, it is thought that the subarachnoid space enclosing
the optic nerve is continuous with the intracranial subarachnoid space, with pressure changes in the cranium causing
similar changes in the optic nerve diameter due to stretching
of the dural-based sheath [17]. The measured diameter is
believed to approximate ICP [17]. Most studies have not
clearly outlined what normal readings are, they suggest a
cutoff of approximately 5 mm or less with readings exceeding that considered pathologic [17].
TCD was developed as a method of interrogating CBF
through the basal cerebral arteries noninvasively [24]. By
measuring cerebral blood ow velocity (CBFV) through
these vessels, using the Doppler effect, CBF can be inferred
so long as vessel caliber remains relatively constant. Shortly
after its development, invasive studies in a non-TBI population found relatively good concordance with invasive CPP
and those estimated by TCD [25]. This led to interest in
developing TCD-based estimates of ICP and CPP in TBI
patients [26–30]. Ultimately their conclusions were all similar. TCD was somewhat effective at identifying episodes of
low CPP and high ICP but, regardless of the methodology
used, estimates of ICP and CPP had too large a margin of
error to effectively eliminate the need for invasive monitoring [29, 30]. TCD then, like ONSD, may have a place in
guiding the management of TBI patients prior to the availability of invasive monitoring, such as in the pre-hospital setting [31].
368
Table 43.1 Summary of invasive and noninvasive ICP monitoring techniques
ICP monitoring techniques Summary
Invasive
Strain gauge Location: Parenchyma, CSF compartments, or subdural space [17]
Functioning: ICP changes cause sensors to bend. Helps approximate ICP
Advantages: Easily inserted and easily manipulated
Disadvantages: Risk of hemorrhage and infection, signicant zero drift, and cannot re-zero
once inserted [17]
Fiber optic Location: Parenchyma
Function: “Light is continuously transmitted through ber optics to the probe tip. ICP
changes lead to the deection of a mirror in the tip, leading to varying light intensity
reected” [17]. Helps approximate ICP
Advantages: Easily inserted compared to an EVD
Disadvantages: Risk of hemorrhage and infection, signicant zero drift and cannot re-zero
once inserted [17]. Also, can be easily damaged by twisting/knotting
External ventricular drain (EVD) Location: Ventricular CSF compartment
Function: Manometer assesses uid pressure. The foramen of Monro is considered the zero
point [17]
Advantages: “Gold standard” for ICP monitoring, can be re-zeroed at any time, used for
CSF sampling, and can be used therapeutically
Disadvantages: Insertion can be challenging and there is risk of infection and hemorrhage
Noninvasive
Optic nerve sheath diameter (ONSD) ultrasound Location: External
Function: Optic nerve is covered with dura mater and therefore changes in ICP can be
assessed via this method as it can cause stretching in optic nerve sheath. A cutoff of
approximately 5mm or less is considered normal ONSD; higher values are deemed
abnormal
Advantages: Noninvasive
Disadvantages: Baseline normal non-pathologic ONSD varies from person to person,
operator dependent, and may require invasive ICP monitoring [17]
TCD-based methods Location: External
Function: Mainly used to assess MCA ow velocity, and (in theory) can estimate ICP and
CPP
Advantages: Noninvasive
Disadvantages: Lesions can interfere with recording, probe has to be repositioned every so
often, and there is interoperator variability and low accuracy
CPP cerebral perfusion pressure, CSF cerebrospinal uid, EVD external ventricular drain, ICP intracranial pressure, MCA middle cerebral artery,
ONSD optic nerve sheath diameter, TCD transcranial Doppler
C. Batson et al.
Advanced Invasive Techniques forEarly
Multi-modal Monitoring ofCerebral
Physiology
In the following subsections, we will briey overview common advanced invasive cerebral physiologic monitoring
devices employed in TBI care within the acute phase. Such
devices overviewed include brain tissue oxygen monitoring
(PbtO2), thermal diffusion CBF monitoring, and extracellular uid chemistry through cerebral microdialysis. As these
sub-sections only briey introduce the techniques, we refer
the interested reader to the referenced literature for more
information if desired. Table43.2 highlights the main points
on these invasive techniques.
Brain Tissue Oxygen Monitoring (PbtO2)
Parenchymal brain tissue oxygen (PbtO2) was introduced as
a means to potentially provide information regarding end-
organ oxygen delivery in the brain. It is assessed by inserting
an invasive parenchymal PbtO2 probe, which analyzes the
extracellular partial pressure of oxygen using a Clark electrode [17, 32]. This device provides continuous bedside
extracellular oxygen values, updated every minute [32].
Normal threshold for intervention in TBI is considered
20mmHg [17]. Recent literature supports a strong association between time spent below PbtO2 of 20mmHg and poor
outcome at 6-month post-TBI [32]. Similarly, high PbtO2 has
been associated with poor outcomes in patients where mitochondrial failure is suspected, through cerebral microdialysis analysis, where high PbtO2 with corresponding elevations
in extracellular lactate:pyruvate ratios suggests failure of
oxidative metabolism [17, 33]. This strong association with
outcome in TBI has triggered phase II randomized control
trial assessments of ICP versus ICP+PbtO2-directed therapies in moderate/severe TBI patients [18, 32]. Such work has
demonstrated the feasibility of implementing such combined
therapeutic approaches and provides early support for ICP
and PbtO2 therapies leading to superior long-term outcomes
over standard ICP-directed therapy alone [18, 32]. As such,
43 Advanced Neuromonitoring forModerate andSevere Traumatic Brain Injury
Table 43.2 Summary of invasive/noninvasive monitoring technique and role in TBI
Early multi-modal monitoring technique/
device Summary Role in TBI
Invasive techniques
Brain tissue oxygen monitoring (Licox) Assesses the extracellular partial pressure of
oxygen within the brain parenchyma [39].
Normal threshold is 20mmHg, values above
or below 20mmHg are linked to poor
outcomes [17]
Continuous CBF monitoring (Hemedex/
thermal diffusion probes)
Brain chemistry monitoring (cerebral
microdialysis)
Non-invasive techniques
Transcranial Doppler (TCD) Assesses the blood ow velocity through the
Near-infrared spectroscopy (NIRS) Involves the use of light between wavelengths
Electroencephalogram (EEG) Assesses the electrical activity of the brain in
CBF cerebral blood ow, CBV cerebral blood volume, CPP cerebral perfusion pressure, EEG electroencephalogram, ICP intracranial pressure,
MCA middle cerebral artery, mmHg millimeters of Mercury, NIRS near-infrared spectroscopy, nm nanometers, TBI traumatic brain injury, TDF
thermal diffusion owmetry
Assesses power required to maintain a
temperature difference between a proximal
and distal TDF probe which is synonymous
with CBF [58]. Levels thought to be normal
are between 20–40mL/100g/min and
70–100mL/100g/min, values constantly
below 20mL/100g/min and above
80–100mL/100g/min have been linked to
poor outcome
Assesses the following metabolites in the
extracellular space: Glucose, lactate, pyruvate,
glutamate, glycerol, sodium, and potassium
[40]. Decreased levels of brain glucose and
increased lactate:Pyruvate ratio have been
linked to poor patient outcomes [40]
cerebral vessels, with the MCA being the
most commonly insonated vessel in TBI
of 700 and 1000nm to monitor oxygenated
hemoglobin, deoxygenated hemoglobin, and
other derived regional brain oxygenation
parameters [41]
TBI patients to detect secondary brain injury
Monitors parenchymal partial pressure of
oxygen
Monitors CBF
Monitors extracellular metabolites
Monitors MCA blood ow
In theory can approximate ICP and CPP
Monitors frontal cerebral oxygen hemoglobin
concentration
Surrogate CBV marker
Monitors brain electrical activity
Auxiliary measure to assess brain death
369
phase III trials on ICP+PbtO2-directed therapy are ongoing.
Of note, SIBICC has also developed a management algorithm for patients with ICP and brain oxygen monitoring in
situ. It comprises four types (A to D) where type A involves
normal monitored values and types B to D involve abnormal
values and their management [18].
Thermal Diusion Cerebral Blood Flow
Monitoring
In an attempt to avoid proxy measures of CBF, thermal diffusion owmetry (TDF) probes have been developed to facilitate continuous bedside assessments of CBF.Such monitoring
provides absolute measurements with a high temporal resolution, which can aid in the detection and prevention of secondary injury [34]. By this method, evidence suggests that
continual high or low measures are linked to poor outcomes
[34]. Commonly used TDF probes (Bowman Perfusion
Monitor and Saber) function by evaluating the power needed
to sustain a temperature difference between thermistors,
which correlates to brain tissue blood ow [34, 35]. Probe
placement can be on the cortical surface of interest (Saber) or
placed in the brain tissue (Bowman Perfusion Monitor), typically the right frontal lobe concurrent with ICP monitor
placement [34].
Although this method has been used for years in experimental models, and there is potential for it to be included in
a multimodal monitoring regimen, there is no threshold
agreed upon for this technique or an understanding of how to
utilize this device for monitoring TBI patients [36]. Further,
the consensus summary by the International Multidisciplinary
Consensus Conference on Multimodality Monitoring provides little additional guidance regarding this matter [36].
Furthermore, some of the commercially available TDF
probes are thought to assess blood ow “continuously,” but
in fact they require regular recalibration periods every 30min
to 2h which takes about 2–5min to complete and interrupts
the recordings. CBF ranges considered normal by the TDF
method range from 20–40mL/100g/min (lower threshold)
370
C. Batson et al.
to 70–100mL/100g/min (upper threshold), depending on if
the TDF measurement was cortical or parenchymal [34, 37].
In theory, increasing CBF could be achieved by expanding plasma volume, inotropic support, and osmotic agents
and lowering CBF achieved by hyperventilation and barbiturate coma [37]. Based on several small studies in adult TBI
cohorts, it was noted that CBF continuously below
20mL/100g/min and above 80–100mL/100g/min (hyperemia) was linked to poor outcomes. Some probe-related
complications that arose in some studies were CSF leak
around the probe, meningitis, intracerebral abscess, and
supercial soft tissue infection [37, 38]. Of note, the literature supports a positive correlation between changes in
regional cerebral blood ow (rCBF) and PbtO2, which is
consistent with Xenon CT (Xe-CT) ndings showing a positive correlation between brain tissue oxygen and regional
blood ow [39]. Despite these promising ndings, widespread adoption of this monitoring modality remains limited
to leading academic neurotrauma centers globally.
Extracellular Brain Chemistry—Cerebral Microdialysis
Cerebral microdialysis done at the bedside serves as a means
of invasively monitoring metabolites in the extracellular
space via a semi-permeable intraparenchymal catheter which
aids in avoiding metabolic derangements in TBI patients [40,
41]. Extracellular dialysate uid is captured in microvials
and processed typically by hour at the bedside for a panel of
common analytes. This technique has mainly been described
within the TBI population, and the information gained can be
useful in guiding clinical therapy [10]. Main analytes processed at the bedside include glucose, lactate, pyruvate, glutamate, and glycerol. Decreased levels of brain glucose and
increased lactate:pyruvate ratio can provide information on
aerobic/anaerobic metabolism and oxidative mitochondrial
function, with derangements in adult TBI patients linked to
poor patient outcomes [10, 40, 42–44]. Glutamate, an excitatory neurotransmitter, provides information regarding
potential excitotoxicity post-injury [9], whereas glycerol
provides information regarding the degree of neural injury
[10]. Given the cost and complexity of interpretation, cerebral microdialysis is another monitored modality in TBI relegated to leading academic neurotrauma units. However,
with improvements in microuidic chips, self-contained
bedside microanalyzers are on the horizon, set to improve
accessibility and cost associated with the technique.
Advanced Noninvasive Techniques forEarly
Multi-modal Monitoring ofCerebral
Physiology
In the following subsections, we will briey overview common advanced noninvasive cerebral physiologic monitoring
devices employed in TBI care within the acute phase. Three
such devices will be highlighted: TCD, near-infrared spectroscopy (NIRS), and continuous electroencephalogram
(cEEG). As these subsections only briey introduce the techniques, we refer the interested reader to the referenced literature for more information if desired. Table 43.2 provides
highlights on these noninvasive techniques. Figure43.1 provides an example of multi-modal cerebral physiologic monitoring using both invasive and noninvasive methods
simultaneously.
Transcranial Doppler
As mentioned previously, TCD is a method of noninvasively
measuring CBFV in the basal cerebral arteries [24]. In recent
years, its adoption into neurointensive care units (NICU) has
increased dramatically with one recent European study nd-
Fig. 43.1 Example of
high-frequency multi-modal
cerebral physiologic
monitoring. CPP cerebral
perfusion pressure, ICP
intracranial pressure, MAP
mean arterial pressure, mmHg
millimeters of Mercury, rSO2
regional cerebral oxygen
saturations (Right Frontal
Lobe), % percentage
43 Advanced Neuromonitoring forModerate andSevere Traumatic Brain Injury
371
ing it to be the second most common form of bedside intracranial monitoring behind only ICP monitoring [45]. Direct
parameters measured by TCD include CBFV and the pulsatility index (PI) and have been found to be associated with
global outcomes following TBI [46–50]. There has also been
evidence linking episodes of reduced CBFV as measured
with TCD and reduced PbtO2 as measured by invasive monitors [51]. TCD has also been used as a robust method of
identifying post-traumatic vasospasm at the bedside, which
has independently been linked to poor outcomes [52].
Ultimately, TCD is limited by its need for expertise in order
to both acquire consistent signals and interpret the data
obtained.
Near-Infrared Spectroscopy
Near-infrared spectroscopy (NIRS) is a noninvasive technique utilized to monitor frontal cerebral oxygen hemoglobin concentration in TBI patients as a way of identifying
brain tissue at risk for potential secondary injury [41]. It is
used as a marker for pulsatile cerebral blood volume (CBV)
[21]. Near-infrared (NIR) involves the use of wavelengths
between 700 and 1000nm on the electromagnetic spectrum,
a range that allows signal penetration through tissues [41]. In
neurocritical care, these spectrometers are usually used to
measure the concentration of oxygenated hemoglobin (HbO)
and deoxygenated hemoglobin (HHb) within the target tissue, to gain information on blood and oxygen supply [53].
Simpler NIRS equipment utilizes constant wave technology
while newer versions utilize multi-distance techniques. They
assess cerebral oxygenation status and newer versions are
able to rene hemoglobin signals by removing interferences
and thus purer results like total oxygen index (TOI) and total
hemoglobin index (THI) are gained [53]. As opposed to
other noninvasive neuromonitoring techniques, e.g.,
TCD- based methods, NIRS is not signicantly impacted by
interoperator variability [54] and can provide continuous
multi-channel (typically bifrontal) assessments of regional
cerebral oxygen saturations and oxy−/deoxyhemoglobin
concentrations in the TBI patient. NIRS use in the TBI population can be challenged by signal issues related to injured
extracranial tissue and intracranial lesions, but there has been
improvement in the signal-to-noise ratio with newer multidistance methods [41]. This technology is reasonably expensive but can provide long durations of uninterrupted
intracranial oxygenated/deoxygenated cerebral blood ow
volume (CBFV) surrogate measures, which can be used in
concert with noninvasive arterial blood pressure (nABP)
devices like the Finapres [21], to derive entirely noninvasive
metrics of cerebrovascular reactivity (CVR). However, it
must be acknowledged that arterial, venous, and capillary
blood are assessed by NIRS in a portion of the cortex (typi-
cally frontal lobes), and recordings are affected by the degree
of oxygen extraction [21].
Adult TBI literature for NIRS-based regional oxygen saturation supports an association between low regional saturations in the frontal lobes and poor functional outcomes after
TBI [55]. Similarly, preliminary work with NIRS-based
CVR metrics supports an association between impaired
NIRS-derived CVR and poor outcomes in moderate/severe
TBI [53]. Similarly, in theory, the device could be used for
long-term follow-up, providing information on persistent
cerebral physiologic dysfunction and long-term functional
outcomes in TBI.Upcoming multi-center prospective trials
on NIRS application in moderate/severe TBI are planned. It
is expected that NIRS monitoring will become more standard in TBI bedside monitoring in the near future.
Continuous Electroencephalography (cEEG)
Continuous electroencephalography (cEEG) is a noninvasive
means of monitoring the brain’s electrical activity via supercial scalp electrodes. However, it must be acknowledged
that the practice of placing the electrodes internally exists,
where subdural paddles or parenchymal depth monitors can
be inserted. Such invasive cEEG methods will not be discussed here, as they are primarily utilized for epilepsy monitoring and surgical intervention, not for TBI care [17]. Two
types of cEEG existing for use with TBI patients in the neurointensive care unit (NICU) are the standard multi-channel
and focal reduced channel [17]. In cases where regular epileptic specialists are unable to interpret the results, there are
automatic signal detection algorithms accessible [56]. cEEG
has been used in seizure detection, prognostication post-TBI,
detection of ischemia, detection of spreading cortical depolarizations, and vasospasm post-aneurysmal subarachnoid
hemorrhage [17]. Seizures after TBI are common, and early
detection and treatment can prevent secondary brain injury
[6]. This method has been used as an auxiliary test to assess
brain death as it provides a comprehensive analysis of
regional and global electrical activity [17, 57].
Derived Metrics forContinuous Physiologic
Assessment
Aside from the raw physiologic measures provided by the
above-mentioned core and advanced monitoring devices,
much more can be obtained from the signal information provided. Advances in bedside data acquisition platforms and
real-time signal processing have allowed us to derive additional, continuously updating, cerebral physiologic metrics
in moderate/severe TBI care. In the subsections below, we
will outline some of the main derived metrics that have dem-
372
C. Batson et al.
onstrated a strong association with outcomes in TBI, including cerebrovascular reactivity monitoring and cerebral
compensatory reserve measures.
Cerebrovascular Reactivity Monitoring
Aside from derangements in ICP and CPP, recent work in
bedside signal processing has afforded treating clinicians the
ability to continuously measure aspects of cerebral autoregulation. Cerebral autoregulation is dened as the innate ability
of the cerebral vessels to maintain constant CBF over a wide
range of MAP or CPP, ensuring a steady state of oxygen and
nutrient delivery to the brain [59]. In the injured state, cerebral autoregulation is known to be disrupted, leading to
impaired or even absent autoregulation of CBF altogether.
By evaluating the relationship between slow-wave uctuations in ICP (a surrogate for pulsatile CBV) and MAP (a
driver for blood ow), one can provide some information
regarding cerebrovascular responsiveness or reactivity [60].
This concept has led to the derivation of the pressure reactivity index (PRx) from the Pearson correlation between slowwave vasogenic uctuations in ICP and MAP [61]. This
index is then updated every minute, providing real-time
information regarding cerebrovascular reactivity, and potentially cerebral autoregulation. PRx has received validation as
a measure of the autoregulatory curve in experimental animal models of intracranial hypertension and systemic arterial hypotension [62–64]. In its most simplistic interpretation,
positive values of PRx indicate impaired autoregulation,
while negative values denote intact autoregulation [65].
In the adult TBI literature, there exists numerous retrospective and prospective studies linking derangements in
PRx and increased mortality and morbidity post-TBI [61,
65–68]. Thresholds for morbidity and mortality have been
dened in multiple TBI populations [65, 67]. In addition,
recent literature supports an association between impaired
cerebrovascular reactivity and computed tomography (CT)-
based contusion progression in the acute phase after TBI
[69]. Further, evaluating the burden of physiologic derangements in TBI, recent work suggests that in the era of current
guideline-based therapeutics, the majority of the acute phase
physiology in moderate/severe TBI is dominated by impaired
autoregulation, and not ICP, CPP, or PbtO2 issues [70, 71].
These ndings suggest that cerebrovascular reactivity monitoring may play a crucial future role in the monitoring and
therapeutic intervention of the TBI patient.
Cerebral Compensatory Reserve
ICP alone provides only a small amount of information
regarding the intracranial pressure dynamics after TBI.In an
attempt to improve our ability to estimate how “tight” or
“relaxed” the brain might be after injury, cerebral compensatory reserve metrics have been developed. By assessing the
correlation between slow-wave vasogenic uctuations in
ICP and pulse amplitude of ICP (derived through Fourier
decomposition of the ICP waveform), one in theory can produce an index of compliance or compensatory reserve [72].
The RAP (R—correlation, A—pulse amplitude of ICP,
P—intracranial pressure) is derived through the moving
Pearson correlation between slow-waves of ICP and pulse
amplitude of ICP, updated every minute [19, 72–74]. This
RAP measure varies from −1 to +1 and provides a continuous bedside assessment of cerebral compensatory reserve.
Though its use is not widespread, preliminary work supports its association with patient outcomes in TBI, with
impaired compensatory reserve associated with increased
mortality [19, 72, 74]. Similarly, impaired RAP values have
been linked to diffuse intracranial injury patterns present on
admission CT scans of the brain [72]. However, despite from
initial promising results, much further work is required on
RAP, with studies validating it as a true measure of compliance on the horizon (Fig.43.2).
30
(mmHg)
(mmHg)
11/12 18:45 11/12 19:00 11/12 19:1511/12 19:30 11/12 19:45 11/12 20:00 11/12 20:1511/12 20:30
43 Advanced Neuromonitoring forModerate andSevere Traumatic Brain Injury
ICP
20
10
80
CPP
60
0.5
PRx
(a.u.)
0
-0.5
1
RAP
0.9
(a.u.)
0.8
0.7
74
rSO2
72
(%)
70
68
COx
0
(a.u.)
-0.5
373
Fig. 43.2 Example of high-frequency multi-modal cerebral physiologic monitoring with advanced derived metrics—cerebrovascular
reactivity and cerebral compensatory reserve. a.u. arbitrary units, COx
cerebrovascular reactivity index using rSO2 (correlation between slowwaves of rSO2 and CPP), CPP cerebral perfusion pressure, ICP intracranial pressure, MAP mean arterial pressure, mmHg millimeters of
Future Directions ofEarly Monitoring
inSevere TBI
As outlined in the sections above, it is clear that there has
been a massive expansion of advanced acute-phase monitoring for TBI patients. This has ushered in the era of multimodal monitoring (MMM) for the moderate/severe TBI
patient, where numerous different/complimentary aspects of
cerebral physiology are monitored and captured in real time
at the bedside. This wealth of information has led to MMM
consensus statements from major international critical care
bodies and is slowly shifting the focus of acute TBI care
from guideline-based approaches to individual personalized
physiologic targets based on MMM information. In this nal
section, we will outline some of the main personalized physiologic approaches emerging in acute TBI care.
Optimal CPP (CPPopt) andPersonalized CPP
Targets
Recent multimodal monitoring (MMM) consensus statements
have supported assessing cerebrovascular reactivity in severely
ill TBI patients [75]. Given the strong association between
cerebrovascular reactivity metrics, such as PRx, and patient
outcome [61, 65–68, 76], there has been extensive exploration
into how these metrics can be exploited to improve patient
Mercury, PRx pressure reactivity index (correlation between slow-wave
vasogenic uctuations in ICP and MAP), RAP cerebral compensatory
reserve index (correlation (R) between slow-wave of pulse amplitude of
ICP (A) and ICP (P)) rSO2 regional cerebral oxygen saturations (Right
Frontal Lobe), % percentage
care and outcomes. Unfortunately, at this time, we do not have
directed therapeutics at cerebrovascular reactivity, with recent
multi-center data suggesting that current guideline-based
treatments do not impact recorded PRx values [77, 78].
However, exploration of the relationship between PRx
and CPP has demonstrated a reproducible parabolic relationship, where the minimum in this “U-shaped” curve represents the CPP value where PRx is the least deranged. This
concept is referred to as the optimal CPP (CPPopt) [79, 80].
This CPPopt value can be derived from various windows of
PRx and CPP data [14] and updated continuously at the bedside. Furthermore, CPPopt values vary from patient to
patient, suggesting that the optimal CPP target is not the
same between individuals. Finally, CPPopt values also vary
over time within an individual patient, given changes in
physiology and injury response mechanisms that occur during the acute phase after TBI [17]. Thus, the concept of
CPPopt has ushered in the personalized physiologic target
era for acute bedside care in TBI.Figure43.3 provides an
example of a CPPopt curve derived from PRx and CPP data.
Numerous retrospective single-center, [81] and recent
prospective multi-center [82] data sets have conrmed that
the time spent away from CPPopt during the acute phase of
TBI care is directly associated with poor outcome at 6-month
post-TBI. Furthermore, time spent away from CPPopt
appears to be a stronger predictor of outcome, compared to
time spent away from BTF guideline-based CPP targets.
374
PRx (a.u.)
CPP (mmHg)
20
0.75
0.7
0.65
0.6
0.55
0.5
0.45
0.4
<4042.50 52.50
C. Batson et al.
62.50 72.50 82.50 92.50 102.50 112.50 >=1
Fig. 43.3 Example of CPP optimum curve—4-hour window of data.
a.u. arbitrary units, CPP cerebral perfusion pressure, ICP intracranial
pressure, MAP mean arterial pressure, mmHg millimeters of Mercury,
PRx pressure reactivity index (correlation between slow-wave vasogenic uctuations in ICP and MAP). Figure depicts 4h of data, with
error-bar plotting of PRx vs. CPP.Error bars are generated for bins of
These critical ndings have sparked a phase II randomized
trial comparing BTF guideline-based CPP targets to CPPopt
targets [14]. Phase III trials are already in the planning stage.
Individualized ICP Thresholds (iICP)
In line with individualized CPP targets, work has been conducted to explore the potential for personalized ICP thresholds
in TBI.Again, given the literature supporting the importance
of cerebrovascular reactivity and patient outcome in TBI, preliminary work into the relationship between ICP and PRx has
been conducted [12, 83]. With the understanding that the PRx
levels above +0.20 are considered grossly impaired cerebrovascular reactivity in TBI [65], evaluating the relationship
between ICP and this PRx threshold of +0.20 has led to the
possibility of generating individual ICP targets. The concept
focuses on the ICP value, above which, PRx remains grossly
impaired (i.e., above +0.20). This ICP value, in theory, would
represent a patient’s individual ICP (iICP) threshold. To date,
only two studies have explored this concept, providing complimentary support for its potential [12, 83]. Approximately
two-thirds of TBI patients displayed the ability to derive this
iICP threshold, with iICP values often quite different from the
suggested BTF guideline ICP threshold of 22 mmHg [12].
Both studies conrm that the time spent above iICP has a
stronger association with mortality, compared to time spent
above BTF guideline ICP thresholds [12]. However, one must
be cautioned, as these results are still considered exploratory
and very preliminary with much further work on the horizon
required for both validation and improving the ability to continuously derive iICP targets at the bedside.
CPP values (i.e., 5mmHg bins of CPP). Then a parabolic curve is t to
the error-bar plot, with the minimum of the parabola demonstrating the
CPP value with the most intact PRx (i.e., lowest PRx). This CPP value
is the optimal CPP (i.e., CPPopt) for this individual patient, based on
the prior 4h of data. Note: the CPPopt here is outside of the guidelinedened CPP targets for acute TBI care
Integrating “Omics” into Acute Phase TBI Care—The Future
This chapter has mainly focused on advanced physiologic
information and its value in the acute management of moderate/severe TBI patients. It is clear from the above sections
that the “physiome” in acute TBI care is of critical importance in management. As we look into the future of acute
TBI monitoring and care, it is expected that the physiome
will be integrated with additional aspects of “omics” data at
the bedside, facilitating ongoing transition into personalized
therapeutic approaches [3, 8, 13, 84–88]. Such omics data is
expected to take the form of integrated proteomic, genomic,
and epigenomic information. Proteome data can be gleaned
from serial serum CSF and microdialysis sampling. With the
advances seen in multiplex immune-assays, numerous biomarkers can be readily obtained, including those pertaining
to neural injury, [86] vascular/endothelial function and integrity [89], pro-inammatory cytokine responses [8, 90, 91]
and metabolic byproducts [9, 33, 92, 93]. Genomic information is expected to be rapidly provided through genome-wide
association chips, allowing for simultaneous assessment of
one million+ single nucleotide polymorphisms [3, 13, 85].
Similarly, advances in epigenetic techniques will lead to
admission quantication of biological age based on methylation and histone methylation proling.
This omics information provides the opportunity to
improve both prognostication modeling in moderate/severe
TBI care (physiome, proteome, genome, epigenome) and our
ability to monitor treatment response (physiome and proteome), predict/sub-classify treatment responders (physiome, proteome, genome, epigenome), and uncover
43 Advanced Neuromonitoring forModerate andSevere Traumatic Brain Injury
375
therapeutic pathways (physiome, proteome, and genome)
[94, 95]. Such a wealth of information will require multidisciplinary teams of clinicians, epidemiologists, data scientists, statisticians, and biomedical engineers. It will also
necessitate the utilization of complex machine learning and
articial intelligence techniques to aid in the interpretation
of such large and continuously updating data sets. Preliminary
advances in this eld are being made by various multidisciplinary international collaborative efforts in Canada,
[88] the USA, [96] and Europe [22, 76, 87, 97].
Conclusions
The acute-phase care of the moderate/severe TBI patient is
complex, with increasing advances being made in cerebral
physiologic monitoring. Current monitoring modalities
allow for continuous bedside assessments of pressure-ow
dynamics, oxygen delivery, metabolism, and electrophysiologic activity. Recent advances in cerebrovascular reactivity
monitoring have led to the development of individual physiologic targets in acute TBI monitoring and care, ushering in
the era of personalized medicine for TBI care. The future for
acute TBI care will see further adoption of “omics” information for integrated real-time bedside updates on physiologic response to therapeutic measures, as well as the
development of novel personalized treatments.
Key Points
• Recovery post-moderate/severe traumatic brain
injury (TBI) is dependent on adherence to basic
tenets of secondary neural injury detection and
mitigation.
• Secondary neural injury after TBI takes multiple
forms, including edema, neuroinammation,
impaired cerebral blood ow regulation, bloodbrain barrier breakdown, metabolic dysfunction,
and free radicle formation.
• Advanced cerebral physiologic monitoring of cerebral pressure ow, oxygen, and nutrient delivery
during the acute phase of TBI care can be leveraged
for early detection of secondary injury and subsequent intervention.
• Invasive and noninvasive multi-modal physiologic
monitoring devices exist, providing both raw and
derived metrics of cerebral physiology.
• Future care pathways for moderate/severe TBI will
leverage such monitoring for the derivation of personalized cerebral physiologic targets, with the goal
of neural tissue preservation.
Acknowledgments FAZ receives research support from the Manitoba
Public Insurance (MPI) Neuroscience/TBI Research Endowment, the
Health Sciences Centre Foundation Winnipeg, the United States
National Institutes of Health (NIH) through the National Institute of
Neurological Disorders and Stroke (NINDS) (Grant #:
R03NS114335- 01), the Canadian Institutes of Health Research (CIHR)
(Grant #: 432061), the Canada Foundation for Innovation (CFI) (Project
#: 38583), Research Manitoba (Grant #: 3906), the University of
Manitoba VPRI Research Investment Fund (RIF), the University of
Manitoba Centre on Aging, and the University of Manitoba Rudy Falk
Clinician-Scientist Professorship.
LF is supported through the University of Manitoba (Department of
Surgery GFT Research Grant) and the University of Manitoba Ofce of
Research Services (ORS) (University Research Grant Program
(URGP)).
CB is supported through the Centre on Aging Fellowship at the
University of Manitoba.
AG is supported through the University of Manitoba Clinician
Investigator Program.
Disclosures The authors have nothing to disclose.
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