Cucciolini et al.

J Anesth Analg Crit Care (2023) 3:31 Journal of Anesthesia,

https://doi.org/10.1186/s44158-023-00115-5
Analgesia and Critical Care

REVIEW Open Access

Intracranial pressure for clinicians: it

is not just a number
Giada Cucciolini1,2*† , Virginia Motroni1,2† and Marek Czosnyka2,3

Abstract
Background Invasive intracranial pressure (ICP) monitoring is a standard practice in severe brain injury cases,
where it allows to derive cerebral perfusion pressure (CPP); ICP-tracing can also provide additional information
about intracranial dynamics, forecast episodes of intracranial hypertension and set targets for a tailored therapy
to prevent secondary brain injury. Nevertheless, controversies about the advantages of an ICP clinical management
are still debated.
Findings This article reviews recent research on ICP to improve the understanding of the topic and uncover the hid-
den information in this signal that may be useful in clinical practice. Parameters derived from time-domain as well
as frequency domain analysis include compensatory reserve, autoregulation estimation, pulse waveform analysis,
and behavior of ICP in time. The possibility to predict the outcome and apply a tailored therapy using a personalised
perfusion pressure target is also described.
Conclusions ICP is a crucial signal to monitor in severely brain injured patients; a bedside computer can empower
standard monitoring giving new metrics that may aid in clinical management, establish a personalized therapy,
and help to predict the outcome. Continuous collaboration between engineers and clinicians and application of new
technologies to healthcare, is vital to improve the accuracy of current metrics and progress towards better care
with individualized dynamic targets.
Keywords Intracranial pressure, Multimodality monitoring, Traumatic brain injury, Spectral analysis, Optimal CPP

Background and provides achievable targets for therapy, in order

Invasive intracranial pressure (ICP) monitoring is now- to avoid secondary brain injuries. Generally, in brain-
adays a standard of care in severe brain injury cases, as injured adults ICP greater than 20–22 mmHg is defined
indicated by most recent guidelines [1]. Monitoring of as “high ICP” and demands active management [1].
ICP allows to derive cerebral perfusion pressure (CPP) Even if the single value of ICP remains important, a
defined threshold of ICP is still object of debate, and the
ICP signal carries many additional information about
†
Giada Cucciolini and Virginia Motroni contributed equally to this work. intracranial dynamics, retrievable either visually at the
*Correspondence:
bedside or applying different computational techniques
Giada Cucciolini [2]. ICP trace can be used to (Table 1):
[email protected]
1
Department of Surgical, Medical, Molecular Pathology and Critical Care
Medicine, University of Pisa, Pisa, Italy
• Better comprehend pathophysiology of the injury and
2
Department of Clinical Neurosciences, Division of Neurosurgery, Brain suggest targeted treatments (e.g., response to mean
Physics Laboratory, University of Cambridge, Cambridge, UK
3
arterial pressure changes as suggested by the most
Institute of Electronic Systems, Warsaw University of Technology,
Warsaw, Poland
recent Brain Trauma Foundation guidelines) [3, 4].

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Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 2 of 13

Table 1 Utility of ICP monitoring in clinical practice

Comprehension Forecasts and predictions Tailored therapy

Comprehend better pathophysiology of the injury Forecast episodes of intracranial hypertension. Provide information about cerebrovascular
and suggest different treatments. Predict response to certain therapies. reactivity and optimal cerebral perfusion
Prediction of outcome. pressure

• Predict response to therapies [2]. Each intracranial component can modify its volume in
• Forecast episodes of intracranial hypertension, using different ways and with a different time lag. Brain paren-
artificial intelligence algorithms, waveform morphol- chyma is nearly incompressible; therefore, it is considered
ogy, or behavior of ICP in time [5–7]. a static component, while blood and CSF are considered
• Predict the outcome throughout derived parameters as “dynamic” as they can rapidly augment or reduce their
(i.e., “ICP-dose” and “pressure-reactivity index”) [8–10]. volume [14].
• Provide information about cerebrovascular reactivity
and optimal CPP (tailored therapy) [8, 11]. Arterial compartment
The arterial compartment can regulate cerebral blood volume
ICP signal has been extensively explored during the last (CBV) modifying vessels’ diameter (e.g., modulating cerebral
50 years; techniques of signal analysis and artificial intel- blood flow, CBF). The amount of arterial blood in the skull
ligence have been applied to ICP waveform and its trend. can vary from 15 to 68 ml [15]. Regulation of CBF can act in
The published work includes animal and human experi- seconds, with a mean time of reaction of 3–10’’ [16].
mental studies, mathematical modelling of intracranial
components, as well as observational studies. Venous compartment
Many papers come from basic research and may pass Blood outflow has been less studied but plays a crucial role
unnoticed by clinicians. Thus, the aim of this narrative in determination of ICP. Nearly 70% of the total amount of
review is to summarize the recent research on invasive blood in the skull is venous, and ICP is directly related to
ICP monitoring to provide insights concerning (1) com- central venous pressure (CVP) [14]. Behavior of the venous
prehension of intracranial pathophysiology, (2) outcome circulation is thought to be a passive reflection of arterial
prediction, and (3) perspectives about tailored therapies inflow because the eventually increased arterial inflow
and individualized thresholds of CPP and ICP. increases venous outflow. However, an imbalance between
inflow and outflow may provoke a rise in ICP; in fact, pres-
sure in the sagittal sinus regulates CSF reabsorption and
Comprehension of intracranial pathophysiology is a major determinant of ICP [17]. Pressure in the venous
The Monro‑Kelly doctrine and components of ICP: system is influenced by downstream pressure, even if it is
past and new insights not passively transmitted: bridging veins within the skull
The balance between fundamental contents within the act as a Starling resistor [18], preventing the retrograde
skull was first described in 1783 by Monro and is still transmission from CVP to ICP [14]. Research into the
considered valid. Assuming that the skull is a rigid and behavior of the venous compartment and the time lag of its
non-expandable box, Monro stated that the blood con- compensatory mechanisms is highly awaited.
tent within the skull should have been constant, so the
amount of inflow should have equalized the outflow Brain parenchyma
[12]. Kellie, gave a further contribution in understand- Brain parenchyma represents ~80% of the intracranial vol-
ing intracranial dynamic, including cerebrospinal fluid ume (1200–1600 ml); this compartment has a less static
(CSF); he stated that any fluid contained in the cranium behavior than previously thought [19]. Some authors,
cannot be displaced without being replaced by another proved that both neurons and glia may shrink, adjusting
component, and that the same is valid if you introduce cell volume in response to different environmental stress-
a new component into the skull [13]. When a displace- ors like pressure or osmotic changes. An experimental
ment is not possible, any factor that provokes an increase study by Kalisvaart et al. tested various models of intrac-
in intra-cranial volume results in increased ICP. ranial damage in adult rats, to elucidate timing and extent
Vbrain + Vblood + VCSF = K of tissue modifications. After ischemic and hemorrhagic
insults there was an increase in neuronal packing density
Where ­Vbrain = brain volume, V ­ blood = blood volume, and a reduction in cell volume diffused to many brain areas
­VCSF = cerebrospinal fluid volume, K = constant (even contralateral to the lesion), involving neurons and
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 3 of 13

astrocytes [20]. The sum of apoptotic and pre-apoptotic the lumbar sac, which has a relative capability of expan-
shrinking in injured and non-injured neurons and glia, may sion in case of increased CSF pressure. In addition, other
alter the whole brain tissue volume and compliance, which mechanisms of CSF reabsorption and displacement have
changes dynamically over hours and days [21]; unfortu- been observed, such as filtration of CSF through nerve
nately, evaluation of the sole brain compliance remains roots holes, and direct infiltration of CSF in the peri-ven-
nowadays a challenge. tricular brain tissue; this latter mechanism achieves CSF
reabsorption by mixing CSF with extracellular fluid, that
Cerebrospinal fluid is directly reabsorbed into capillaries. This reabsorption
CSF has a volume of 1/10 of the brain (~150 ml), and reg- mechanism has been called glymphatic circulation [27].
ulation of its production and reabsorption is described by
the Davson equation [22]: Conclusions and panoramic overview about raised ICP
Each compartment has its own dynamic behavior and
ICP = P CSF = Pss + RCSF × If
co-participate to compensate an eventual rise in ICP.
Where ICP = intracranial pressure, ­ PCSF = pressure Every compartment has a different time of adaptation to
of cerebrospinal fluid, ­ PSS = sagittal sinus pressure, changes, and different chemical and physical ways to do
­RCSF = resistance to CSF outflow, ­If = liquor formation. it. ICP represents the picture of elasticity and compliance
In 1973, Marmarou expanded Davson’s work with a of the whole system.
mathematical model explaining CSF formation, circula- A panoramic overview of the main causes of raised ICP
tion and reabsorption [23, 24]. The model is based on the and their associated treatments is illustrated in Table 2 [28].
concept of capacitance and resistance, where capacitance
is offered by the ventricles and resistance by the stric- Estimation of compensatory reserve with ICP
tures in the CSF circulation. Cerebrospinal compensatory reserve is a general concept
The main determinant of CSF pressure is the sagittal related to the contents of the skull and expresses the rela-
sinus pressure, and CSF flow has a static and dynamic tionship between any increase in volume to an increase in
component (e.g., continuous and pulsatile flow, similarly pressure (Fig. 1) [29]. During the years researchers have
to blood flow in arteries). One of the main roles of CSF is been trying to plot the pressure-volume curve of the
to distribute and equalize ICP; CSF compensatory reserve intracranial content, starting from the ICP signal. The
(e.g., the ability of CSF to absorb changes in volume with- relationship between pressure and volume defines the
out an increase in ICP) can be measured with infusion or compliance of the system, and its inverse index, elastance.
withdrawal of fluid from the ventricles (see “Estimation of Compliance is the increase in volume provoked by an
compensatory reserve with ICP” section for details) [25, increase in pressure, while elastance is the change in pres-
26]. Part of the CSF compliance has to be addressed to sure per unit change in volume (ΔP/ΔV) [30].

Table 2 Possible mechanisms of raised ICP that involve increase in one or more of the contents of the skull: blood (arterial or venous),
CSF (hydrocephalus), or brain parenchyma (interstitial edema or tumor). ARDS: acute respiratory distress syndrome; SDH: subdural
hemorrhage
Compartment Cause of raised ICP Possible adequate treatment
involved in raised
ICP

CSF Increased production (rare) or reduced absorption CSF drainage

Blood Obstructed venous outflow (i.e. head positioning, sinuses thrombosis Repositioning of the head
or compression, ARDS, prone positioning, abdominal compartment Adjust ventilation
syndrome) Neuromuscular blockage
Venous thrombectomy or stent
Anticoagulants
Abdominal surgery
Arterial vasodilation (impaired autoregulation) Brief hyperventilation
Vasoconstrictor drugs increase
Bleeding Appropriate treatment based on the source (i.e. coiling/
clipping of aneurysms, evacuation and hemostasis
for SDH)
Parenchyma Interstitial edema Mannitol, hypertonic saline, decompressive craniectomy
Tumor/other mass lesions Steroids
Surgical excision
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 4 of 13

Fig. 1 Hypothetical shape of cerebrospinal pressure-volume curve. For small increases in volumes (left part of the graph), pressure responds slowly
and proportionally. This is a zone of good compensatory reserve: changes in volume produce low-pressure response. After the first breakpoint,
ICP responds exponentially to a volume increase. This is an area of compromised compensatory reserve. Above a certain critical threshold of ICP
(sources say that this threshold may vary between patients from 25 to 55 mmHg) the arterial bed starts to collapse and the curve tends to flatten,
indicating exaustion of compensatory reserve along with decreasing CBF. RAP: correlation between amplitude and mean value of ICP (see text
for details)

Quantifying elastance is clinically attractive as it should 31]. He developed a mathematical model and introduced
be predictive of impending exhaustion of the compen- the pressure-volume index (PVI) defined as the notional
satory reserve. The volume-pressure curve of the brain volume (millimeters), which when added to cerebrospinal
describes a non-linear relationship with three distinct space, causes a 10-fold raise in ICP. PVI was calculated by
parts and slopes: measuring ICP changes in response to rapid injections or
withdrawals of liquid from subarachnoid space. This metric
• At physiological volumes and low ICP, there is a lin- has been used clinically [32]; however, due to the difficulty
ear rise in ICP with increasing intracranial volume. in standardizing the rate of volume change and the elevated
For small increases in volume, the ICP remains quite risk of infection (needs to manipulate a ventricular catheter
low, and the patient has a high compensatory reserve; multiple times) this metric fell into disuse [33, 34].
small increases in volume can be compensated by a Subsequently, a continuous index indicating the rela-
reduction in CBV or CSF displacement. tionship between pulsatile CBV and ICP has been devel-
• Once the reserve is exhausted, a breakpoint is oped: the RAP index (R-symbol of correlation between
reached, and any subsequent increase in volume, A-amplitude of fundamental component of ICP and
increases the ICP exponentially. P-mean pressure) [35]. RAP is an index of compensatory
• At high volumes, there is a change in pendency so reserve ranging from +1 to −1. When RAP is close to +1,
the changes in volume are no more transmitted to there is synchronisation between the rise in mean ICP and
changes in pressure, as this is already near the value its mean pulse amplitude (AMP), so a small rise in intrac-
above which a collapse in brain arterioles may occur. ranial volume results in a high rise of ICP. A RAP value
At this point, the patient has intracranial refractory close to 0 indicates a lack of relationship between the
hypertension and will go towards brain herniation if changes in AMP and mean ICP. When RAP is −1 AMP
no intervention is performed. has an inverse relationship with ICP (AMP decreases as
the ICP continues to rise): at this stage, the compensatory
Estimation of dynamic compensatory reserve in research reserve is exhausted and CBF falls (Fig. 1) [29, 36].
and at the bedside
Several approaches have been proposed to quantify the Autoregulation estimation with pressure reactivity index
intracranial elastance at the bedside either intermittently or An estimation of autoregulation is possible through-
continuously. The first description of intracranial volume- out the ICP signal [37]. Autoregulation is an impor-
pressure relationship was published by Marmarou et al. [6, tant autoprotective mechanism by which arterioles in
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 5 of 13

cerebral vasculature dilate or constrict in order to main- Time domain analysis

tain a constant CBF to the brain over a wide range of CPP Time domain looks at the ICP waveform as it comes out
(50–150 mmHg). After brain injuries autoregulation can from bedside monitors. Each ICP pulse waveform is gen-
be impaired, and continuous assessment of vessels reac- erally composed of three peaks, strictly related to pulsa-
tivity might assist neurocritical care management [38, tion of ABP [2, 26, 44]:
39]. The pressure reactivity index (PRx) is a simple cor-
relation coefficient between 10 s averaged ICP and ABP • P1 (percussion wave): caused by the distension of the
that measures cerebrovascular reactivity by observing walls of cerebral arteries transmitted from the aorta
the ICP response to spontaneous oscillations of ABP [8]. (synchronous and related to the systolic peak in
PRx measures the ability of arterial smooth muscles to ABP).
respond to changes in transmural pressure [37]. A posi- • P2 (tidal wave): related to the increase in cerebral
tive PRx means a positive correlation between ABP and blood volume. As cerebral arteries are compliant, the
ICP thus, passive behavior of CBV with a non-reactive eventually increased CBV is mirrored by a delayed P2
vascular bed. A negative value of PRx reflects a nor- in comparison to P1. P2 is more represented when
mally reactive vascular bed (the ABP increase produces brain compliance decreases.
an inverse change in CBV and ICP). It has been demon- • P3 (dicrotic wave): it may represent aortic valve clo-
strated a tight and positive correlation between averaged sure (synchronous with venous blood outflow) or a
PRx and the clinical outcome [40]; as PRx offers the pos- second peak of CBV.
sibility to calculate an optimal CPP, is possible to infer
that targeting an optimal CPP in the context of a tailored Generally, P1 is related to cardiac ejection, while an
treatment strategy might be possible in TBI patients. increase in the arterial blood volume and its transporta-
Nevertheless, PRx suffers from some weaknesses which tion is probably related to P2 and P3. Not all these peaks
should be kept in mind when interpreting this index. In are always visible; nevertheless, P1 is normally dominant,
some circumstances, it can be not reliable because it is followed by P2 and P3.
based on the assumption that the only determinant of
ICP variability is represented by an extracranial source, Normal and pathologic patterns
the ABP. On the contrary, brain’s arterial vasomotor tone Peaks in ICP may change their proportions depending on
can be influenced by other mechanisms of regulation cerebrospinal compliance, and there is a stepwise modifi-
of CBF, such as internal neurovascular adjustment and cation of the waveform with increasing ICP, as described
endothelial biochemical signalling. In addition, PRx by Kazimierska et al. [45].
may be unreliable in case of decompressive craniectomy When brain compliance decreases, P2 increases
(extremely high brain compliance), or during the applica- and becomes predominant over P1 (type B waveform,
tion of external devices affecting simultaneously ABP and Fig. 2). If the intracranial compliance is further reduced,
ICP (mimicking non-functioning autoregulation) [41]. then P1 becomes less visible and P3 approaches P2 (type
Still, this index is extensively validated in many condi- C waveform, Fig. 2). The final stage is a “triangular-like”
tions, and it is the most widely used in clinical practice shape where the peaks are not anymore distinguishable
for continuous autoregulation estimation; improvement (type D, Fig. 2).
on its calculation, exploration of its pitfalls and a consen- Many metrics have been proposed to estimate brain
sus on its use is awaited [42, 43]. compliance with waveform analysis. A well-known
parameter is the P1/P2 ratio, that normally is > 1, and
Pulse waveform analysis in time and frequency domain reaches values of 1 or < 1 in pathologic conditions [26].
The ICP pulse waveform can be analyzed in the time Many research groups are working with algorithms
domain and the frequency domain. Each method is valuable that try to extrapolate an averaged pulse waveform from
and can give different information about ICP. Time domain multiple series; once the mean shape of ICP is extracted,
is the most known by clinicians and available at the bedside, it is possible to calculate different metrics about cerebro-
while frequency domain analysis requires techniques of spinal compliance. One example of this research projects
spectral analysis (Fourier transform) and expertise, which is the MOCAIP (morphological clustering and analysis
may not be available in all centers. Nevertheless, frequency of intracranial pressure), a study in which 700 h of ICP
analysis is becoming popular for its capacity of adding use- recordings were analyzed with a proposed algorithm able
ful information in real-time and a simple laptop at the bed- to recognise non-artefactual signals and automatically

analysis (i.e., I­ CMplus®, Cambridge Enterprise Ltd., UK).

side provided with proper software can easily perform such distinguish the three ICP peaks, allowing further wave-
form analysis process [7, 46].
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 6 of 13

Fig. 2 Pulse waveform analysis of ICP. Type A indicates normal ICP; there is a stepwise modification towards type D as intracranial compliance
decreases. P1: percussion wave; P2: tidal wave; P3: dicrotic wave. See text for description

Frequency domain analysis (Fig. 3). RR is usually around 8–20 cycles/min, thus 0.13–
The process of decomposing a signal into its different frequen- 0.33 Hz. In the slow frequency range, some waves that
cies is called spectral analysis and generates a power spectrum have a period of 20 s–3 min are represented; they are
of that signal by applying the fast Fourier transform (FFT). thought to represent cerebrovascular cyclic dilation and
By decomposing the ICP signal, three main com- constriction in response to systemic haemodynamic vari-
ponents can be identified: the heart rate (HR), the ations or brain metabolism [47, 48].
respiratory rate (RR), and other slow waves. HR is gen-
erally between 60 and 130 bpm, which translates into Behavior of ICP in time: during minutes (waves)
1–2.16Hz, and is usually the most represented compo- and during hours (patterns)
nent, also called the fundamental harmonic of ICP. Res- During prolonged ICP monitoring, many types of waves
piratory waves are also well represented, and in patients have been observed. Based on the authors, different types
sedated and ventilated the peak is usually very sharp of waves were described with different terms, and this
and defined, as the respiratory rate is extremely regular contributed to generate confusion.

Fig. 3 ICP in time domain (A), and frequency domain (B). Numbers represent: slow waves (1), respiratory waves (2), heart rate frequency (3). 2b
is the second harmonic of the respiratory waves, and 3b the second harmonic of the heart rate
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 7 of 13

Overall, waves can be described by their frequency long-lasting waves (from 20 s to 3 min), regular and
(period), amplitude (intensity), regularity, duration in repetitive, associated with changes in CBF, and they are
time, and relationship with other waves. Among ICP probably associated with brain metabolism (Fig. 4). How-
waves we can recognize mainly: A-waves, B-waves, ever, the term B-waves includes a lot of different subcat-
C-waves, and respiratory waves (Table 3) [2, 47, 49]. egories based on symmetry/asymmetry, the presence of
included plateau waves, and frequency; several authors
refer to B-waves with different terminologies as slow
Low frequency range waves B waves, or vasogenic waves [51].
Slow waves of ICP have been extensively described.
Slow waves represent ICP oscillations that have a dura- During these kinds of waves the increase of CBF veloc-
tion of at least 20 s, up to several minutes (frequency of ity and ICP is synchronised. The average magnitude of
0.005–0.05 Hz) [16]. These waves are generally repetitive B waves after TBI is associated with the outcome: the
but not regular, with variable amplitude. Because of their grater the amplitude, the better is the outcome [29]. In
frequency, they occupy the left part of the ICP spectrum addition, in awake patients with hydrocephalus, B waves
(Fig. 3), and they are thought to be the expression of vas- alternate periods of silence and periods of regular waves.
odilation and constriction peculiar of the brain vessels. Usually, these waves appear when patients are in the
REM phase of sleep, but they have been described in
B waves or hyperemic waves B waves were first association with sleep breathing disorders outside of the
described by Lundberg in the late ‘50 s [50]. They are REM phase [52].

Table 3 Resume of the nomenclature and characteristics of the waves observable in ICP. A-B-C waves were first observed by
Lundberg in the late 1950s and early 1960s. Subsequently, more studies involving continuous recording of ICP were published, and
other nomenclatures appear
Frequency range Alphabetical Name Alternative names Description

Episodic, no frequency defined A-waves Plateau waves Characteristically shaped waves in ICP with three
phases: ascending, plateau, descending.
Slow waves, 0.005–0.05 Hz B-waves Hyperaemic waves, vasogenic waves, Very heterogeneous category, composed of slow
waves with different morphologies: symmetric/
asymmetric, with/without plateau waves superim-
posed, with/without ramps. Associated with increase
in CBF and probably brain metabolism.
0.1–0.15 Hz C-waves Mayer waves or M-waves, Traube- Sympathetic waves originating in the systemic circu-
Hering-Mayer waves lation and transmitted to ICP.
0.16–0.3 Hz R-waves Respiratory waves Waves synchronous with breathing.

Fig. 4 B waves in ICP. abp: arterial blood pressure, icp: intracranial pressure; ecg: electrocardiogram. It is possible to see that icp shows fluctuations
(B-waves) while abp and ecg show not. In abp it is possible to se an artifact related to the flush of the arterial line
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 8 of 13

A waves or plateau waves by using any vasoconstrictor stimulus such as a brief

A waves, also called plateau waves, are represented by a period of hyperventilation or vasoconstrictor drugs [1].
sustained elevation of ICP that lasts for 5–30’ associated Plateau waves lasting more than 30 min are in fact associ-
with a reduction in CPP and CBF. These waves are con- ated with worst outcomes in terms of mortality [29, 53].
stituted by three phases: rise of ICP, plateau phase, and
decrease of ICP (Fig. 5). These waves of ICP increase are Respiratory waves
caused by vessels’ dilation associated with impaired cer- Respiratory waves are synchronous with breathing, so
ebrovascular pressure reactivity; cerebrospinal compen- they have a frequency of 10–25 cycles/min (Fig. 6) [29].
satory reserve is usually low. After the plateau phase, ICP Even if patients always breathe, these waves are not
usually drops below the baseline level and cerebrospinal always visible in ICP. This kind of waves have been asso-
compensatory reserve improves [29]. ciated with increased resistance to CSF circulation in
These kinds of waves are relatively common, and they patients with hydrocephalus [55], and their amplitude is
occur in approximately 40% of TBI patients. Plateau correlated with intracranial compliance in patients with
waves are significantly more frequent in young patients, hydrocephalus [56].
in patients with low midline-shift, low volume of contu-
sion on CT scan, absence of skull fractures and low brain C waves o Mayer waves
tissue concentration of carbon dioxide [53]. A waves may Traube-Hearing-Mayer waves have a frequency of 0.1–
be observed as one-time transients or as a cyclic phe- 0.15 Hz and are potentially associated with sympathetic
nomenon; the mechanism of the plateau waves involves nervous activity; they are thought to be linked to oscil-
a “vicious cycle” which begins with cerebral vasodilation lations in baroceptors and chemoreceptors reflex control
(i.e. as a consequence of a drop in ABP), resulting in an system. These waves originate in the systemic circula-
increase in CBV and ICP; the decrease in CPP provoked tion and are transmitted with the modulation of cerebral
by increased ICP produces further cerebral vasodilation autoregulation to intracranial vessels. Their amplitude
(vasodilatory cascade) which increases CBV and ICP [2, has been proposed as a measure of sympathetic activity
54]. This occurs especially when autoregulation is working. as it is determined by baroreflex gain and strength of the
Even though vascular resistance decreases, trying to aug- triggering [57].
ment CBF, this is not enough to outweigh the fall in CPP;
thus, plateau waves represent a temporary brain hypop- Patterns of ICP behavior in patients with acute brain injury
erfusion. Plateau waves usually terminate spontaneously Different waves and a baseline ICP can be combined in
after a few minutes, but this is not always the case [2]. It is different ways in each patient, offering some distinguish-
recommended to terminate a plateau wave in 10–15 min able patterns:

Fig. 5 Plateau wave in a TBI patient. abp: arterial blood pressure; icp: intracranial pressure; rso2_l: brain oxygen saturation collected
with near infrared spectroscopy, left side; rso2_r: brain oxygen saturation, right side; fvl: flow velocity left acquired with transcranial doppler; fvr: flow
velocity right. On the left (A) raw signals collected during multimodal monitoring in ICU. On the right side, the same raw signals are represented
as means over 10 s. While ICP increases, it is possible to see that flow velocity decreases in both sides, as well as the brain regional oxygen saturation
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 9 of 13

Fig. 6 Respiratory waves present in arterial blood pressure (abp) and transmitted to intracranial pressure (icp) and blood flow in the right MCA (fvr).
In A, the signals are shown in the time domain, while in B, there is icp and fvr represented in the frequency domain. Frequency of these respiratory
waves is ~0.22 Hz, corresponding to about 13breaths/min. ^ represent the slow waves peak; * represents the respiratory waves peak. # represents
the heartbeat peak

• Low and stable ICP (lower than 20 mmHg); ICP dose capacity of prediction has been demonstrated
• Low baseline ICP with plateau waves; in TBI as well as in subarachnoid hemorrhage [61, 62].

using continuous monitoring software such as ICM ­plus®

• High stable ICP (higher than 20 mmHg): could be the The overall ICP burden can be evaluated at the bedside
initial pattern after TBI;
• High unstable ICP (high ICP and plateau waves); (Cambridge, Cambridge Enterprise Ltd., UK), and might
• Refractory intracranial hypertension: defined as a give useful information about therapy strategies.
recurrent increase of ICP above 22 mmHg for a sus- In addition, recent studies have investigated not only
tained period (10–15 min) despite conventional ther- the ICP burden but also the CPP insults, demonstrating
apies [58]. The dramatic increase in ICP may cause that CPP insults intensity and duration is related to out-
brainstem ischemia and result in the Cushing reflex come, and that the tolerance to CPP insults is different
(or vasopressor response). In the first stage of the for different state of autoregulation and for the absolute
Cushing reflex, a sympathetic activation is triggered mean ICP (threshold 25 mmHg). In a study by Guiza
by the increase in ICP; ABP and heart rate (HR) rise et al. [10], the low and high CPP insults were evalu-
trying to maintain an adequate CPP. In the second ated for intensity and duration and were plotted against
stage, the patient becomes bradycardic due to activa- the Glasgow Outcome Scale (GOS) using a color-coded
tion of baroceptors in the aortic arch consequent to scale. Interestingly, the tolerance to low and elevated CPP
the increased ABP. In the final stage, compression of was higher if the duration of the insult was low. Episodes
the brainstem results in respiratory centers malfunc- with ICP > 25 mmHg were associated with poor out-
tioning. This may be a preterminal pattern [59]. The comes regardless of CPP. Patients with intact autoregula-
pulse amplitude of ICP (AMP) starts to disappear tion better tolerated both higher and lower CPP insults.
before the terminal event [29]. The possibility to visualize ICP and CPP thresholds and
duration and extension of the insult opens new perspec-
Outcome prediction tives about the identification of a personalized ICP and
ICP dose and CPP insults CPP threshold, and challenges the canonical concept of a
The concept of ICP dose expresses the area under the universal and fixed ICP number that fits all [62].
curve for which ICP stays over a defined threshold and
is expressed in mmHg/h. This method accounts for Prx and outcome
intensity and duration of intracranial hypertension and Many studies confirm the association between continu-
is thought to be an estimator of secondary brain injury. ously measured PRx and global outcome in brain-injured
The ICP dose was demonstrated to correlate with mortal- patients [8, 39, 63]. Abnormal values of PRx indicate
ity and functional outcome, and it is more sensitive when poor autoregulation and are associated with high ICP,
high-resolution data are used [9, 60]. low CPP, low GCS on admission and poor outcome at
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 10 of 13

6 months [37, 64]. Averaged PRx is an independent pre- when actual CPP is higher than ­ CPPopt there is an
dictor of outcome after TBI; the critical value associ- increased disability [2, 37, 64].
ated with increased mortality is approximately +0.25 The concept of PRx-guided CPP therapy is also sup-
[2, 40]. PRx well correlates with indices of autoregula- ported by the fact that brain tissue oxygenation increases
tion based on transcranial doppler and ultrasonography with increasing CPP but only until the level of C ­ PPopt;
[2, 29]. When the lower limit of cerebral autoregula- further increase in CPP does not improve oxygenation
tion is reached, PRx is strongly dependent on CPP and [67]. In addition, retrospective analysis showed that
it increases with decreasing CPP. PRx has been used to ­CPPopt may vary individually, from 60 to 100 mmHg, so
calculate “optimal CPP” and guide therapies for patients can differ dramatically from the guideline’s fixed thresh-
with TBI; this could have a significant impact on mortal- olds (60-70mmHg) [4].
ity and outcomes in the next few years [64]. The CPPopt can be clinically estimated in real time
by plotting and analyzing PRx-CPP curves in sequential
Tailored therapy 4-h time windows, to have a constant updated value for
Optimal CPP and ICP the ­CPPopt. Recent studies have updated the algorithm
Some authors demonstrated that in some patients the for ­CPPopt calculation, using a multi-window weighted
relationship between PRx and CPP might show a char- approach, to improve reliability and stability of C ­ PPopt
acteristic U-shaped curve [64]; this curve is obtained calculation [68]. The ­CPPopt Guided Therapy Assessment
plotting CPP on the x-axis and PRx on the y-axis (Fig. 7). of Target Effectiveness (COGiTATE) study demonstrated
The U-shaped curve, if obtained, suggests that there is a the safety and feasibility of targeting the ­CPPopt in TBI
value of CPP at which PRx is the lowest, so potentially patients with ICP monitoring [11]. Nevertheless, PRx is
a “best” CPP in which autoregulation status is the best under evaluation for its reliability and pitfalls, and new
for the patient. In this context, PRx can be used for the insights about its limitations and automatic recognition
assessment of patient’s optimal CPP ­(CPPopt), which has of unreliable raw data are awaited [43, 69].
been defined as the CPP at which PRx is most negative
[65, 66]. Controversies about ICP monitoring
Too low or too high CPP levels might be detrimen- ICP monitoring is considered a standard of care for
tal to the brain, potentially leading to ischemia or brain brain-injured patients in many centres worldwide, even if
oedema. The greater the distance between the current an advantage of monitoring was never demonstrated. As
and the C ­ PPopt, the worse the outcome: when actual CPP indications for placing invasive monitoring of ICP are not
is lower than ­CPPopt there is an increase in mortality, clear, clinical practice between centres can be extremely

Fig. 7 U-shaped curve for optimal cerebral perfusion pressure. CPP: cerebral perfusion pressure. PRx: pressure reactivity index. In the first time series
is illustrated the mean CPP averaged every minute. PRx is shown as a risk bar chart, where green zones are indicating good autoregulation (PRx < 0),
red zones are representing bad autoregulation (PRx > 0.3) and yellow areas are transition zones. When CPP is plotted against PRx, it is possible
to evidence a ­CPPopt, that is the lowest point of the U-shaped curve, where PRx is the most negative. Crossing of the U-shaped curve with the x
axis (PRx = 0) might represent the lower and upper limit of autoregulation. The graph at the bottom represents the distribution of the values of CPP
for the period analyzed
Cucciolini et al. J Anesth Analg Crit Care (2023) 3:31 Page 11 of 13

heterogeneous [70]. Recent randomised controlled trials CBV Cerebral blood volume
FFT Fast Fourier transform
(RCT) have further ignited the debate; a multicentre RCT PRx Pressure reactivity index
by Chestnut et al. conducted on 324 Bolivian and Ecua- PVI Pressure-volume index
dorean patients investigated the efficacy of treatment RCT​ Randomised controlled trials
RR Respiratory rate
based on monitoring of ICP vs standard treatment where RAP Index of compensatory reserve
ICP was not monitored [71, 72]. The authors showed no
difference in the primary outcome (composite measure- Acknowledgements
Not applicable.
ment of survival, impaired consciousness, functional and
neuropsychological status at 6 months). Other observa- Authors’ contributions
tional studies comparing outcomes of patients in centres MC, GC, and VM contributed to the conception and design of the paper. GC
and VM drafted the article. MC supervised the work. All the authors revised
that use ICP monitoring have controversial results, with the article, contributed for its intellectual content, read and approved the final
some authors reporting a better outcome, and others version of the article.
showing no differences [73]. In addition, as ICP moni-
Funding
toring implies intervention for targeting low ICP and an The authors received no fundings for the article.
adequate CPP, a study by Cremer et al. showed increased
levels of interventions, without an improvement in out- Availability of data and materials
Not applicable.
come [74].
Many confounding factors can influence results of
these observational studies, as differences in treatment Declarations
between centres and bias of selection, with exclusion Ethics approval and consent to participate
of either the most or less severely injured. For this rea- Not applicable.
son, while more RCT are awaited to clarify the role of Consent for publication
ICP monitoring, the current brain trauma fundation All the authors approved the final content of the manuscript for publication.
guidelines still recommends to monitor ICP in all severe
Competing interests
trauma with a level of evidence IIb, in order to reduce in MC receive part of the licensing fees for ICM+ software, licensed by Cam-
hospital and 2 weeks post injury mortality [4]. bridge Enterprise Ltd, University of Cambridge, Cambridge. The rest of the
authors declare that they have no competing interests.
Conclusions
ICP monitoring guides the management of acute brain- Received: 29 June 2023 Accepted: 16 August 2023
injured patients in many centers worldwide, even
though some controversies about its use are still ongo-
ing. While a well-defined threshold for interventions has
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