Revista Española de Anestesiología y Reanimación 68 (2021) 280---292

Revista Española de Anestesiología

y Reanimación
www.elsevier.es/redar

SPECIAL ARTICLE

Ten physiological commandments for severe head

injury夽
D.A. Godoy a,b,∗ , R. Badenes c,d,e , F. Murillo-Cabezas f

a
Unidad de Cuidados Neurointensivos, Sanatorio Pasteur, Catamarca, Argentina
b
Unidad de Terapia Intensiva, Hospital San Juan Bautista, Catamarca, Argentina
c
Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valencia, Valencia, Spain
d
Departamento de Cirugía, Universitat de València, Valencia, Spain
e
Instituto de Investigación Sanitaria de Valencia (INCLIVA), Valencia, Spain
f
Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain

Received 19 April 2020; accepted 7 September 2020

Available online 15 May 2021

KEYWORDS Abstract Advances in multiparametric brain monitoring have allowed us to deepen our knowl-
Severe head trauma; edge of the physiopathology of head injury and how it can be treated using the therapies
Physiopathology; available today. It is essential to understand and interpret a series of basic physiological and
Intracranial physiopathological principles that, on the one hand, provide an adequate metabolic environ-
hypertension; ment to prevent worsening of the primary brain injury and favour its recovery, and on the
Cerebral hypoxia; other hand, allow therapeutic resources to be individually adapted to the specific needs of the
Physiological patient.
neuroprotection Based on these notions, this article presents a decalogue of the physiological objectives to be
achieved in brain injury, together with a series of diagnostic and therapeutic recommendations
for achieving these goals. We emphasise the importance of considering and analysing the phys-
iological variables involved in the transport of oxygen to the brain, such as cardiac output and
arterial oxygen content, together with their conditioning factors and possible alterations. Spe-
cial attention is paid to the basic elements of physiological neuroprotection, and we describe
the multiple causes of cerebral hypoxia, how to approach them, and how to correct them. We
also examine the increase in intracranial pressure as a physiopathological element, focussing on
the significance of thoracic and abdominal pressure in the interpretation of intracranial pres-
sure. Treatment of intracranial pressure should be based on a step-wise model, the first stage
of which should be based on a physiopathological reflection combined with information on the
tomographic lesions rather than on rigid numerical values.
© 2020 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published
by Elsevier España, S.L.U. All rights reserved.

夽 Please cite this article as: Godoy DA, Badenes R, Murillo-Cabezas F. Diez mandamientos fisiológicos a lograr durante el traumatismo

craneoencefálico grave. Rev Esp Anestesiol Reanim. 2021;68:280---292.

∗ Corresponding author.

E-mail address: dagodoytorres@yahoo.com.ar (D.A. Godoy).

2341-1929/© 2020 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published by Elsevier España, S.L.U. All rights
reserved.
 Revista Española de Anestesiología y Reanimación 68 (2021) 280---292

PALABRAS CLAVE Diez mandamientos fisiológicos a lograr durante el traumatismo craneoencefálico

Traumatismo grave
craneoencefálico
Resumen Los avances en la monitorización cerebral multiparamétrica han permitido ahondar
grave;
en el conocimiento de la fisiopatología del traumatismo craneoencefálico, y en cómo la ter-
Fisiopatología;
apéutica disponible puede modularla. Para ello, se antoja imprescindible conocer e interpretar
Hipertensión
una serie de principios fisiológicos y fisiopatológicos básicos que propician, por un lado, un
intracraneal;
entorno metabólico cerebral adecuado para prevenir un incremento de la lesión cerebral pri-
Hipoxia cerebral;
maria y favorecer su recuperación, y por otro lado, permiten adaptar de forma individualizada
Neuroprotección
los recursos terapéuticos a la situación concreta del paciente.
fisiológica
En el presente artículo se exponen, en forma de decálogo, sustentados en dichas nociones,
los objetivos fisiológicos a conseguir, junto con una serie de recomendaciones diagnósticas y
terapéuticas que posibiliten su logro. Se hace énfasis en la consideración y análisis de las varia-
bles fisiológicas implicadas en el transporte de oxígeno al cerebro, como el gasto cardiaco y
el contenido arterial de oxígeno, junto con sus condicionantes y las posibles alteraciones de
cada uno de ellos. Cobran especial atención los elementos básicos que constituyen la neuro-
protección fisiológica. Asimismo, se razonan las múltiples causas que provocan hipoxia cerebral
y el modo de abordarlas y corregirlas. El aumento de la presión intracraneal, como elemento
fisiopatológico, se examina, subrayándose para interpretarla la interconexión e influencia de
la presión torácica y abdominal sobre la intracraneal. El tratamiento de la presión intracraneal
debe efectuarse sobre un modelo de acciones escalonadas, cuyo inicio debería cimentarse más
que en valores numéricos rígidos, en una reflexión fisiopatológica unida a la información de las
lesiones tomográficas.
© 2020 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Publicado
por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction Physiological principles

Traumatic brain injury (TBI) is a major concern because
it occurs predominantly among young adults at the height
of their productiveness, and is one of the main causes of
disability and death in this population.1 The pathophysiol-
ogy of TBI is complex, dynamic, changes over time,1 and
is categorised into primary, secondary, tertiary and qua-
ternary lesions.2 Treatment in intensive care units (ICU)
or in operating rooms in the perioperative period is usu-
ally aimed at avoiding and correcting both systemic and
intracranial secondary injuries; however, the latest strate-
gies take a comprehensive approach to all phases of
TBI.1 Advances in multimodal monitoring have contributed
notably to our understanding of the different aspects of TBI
pathophysiology, and now forms the basis for a detailed,
rational, and targeted analysis of the benefit of the differ-
ent therapeutic strategies available.1,3 Unfortunately, these
technological advances are not available in many middle-
income countries.4 Despite this situation and the availability
of resources, understanding and correctly interpreting cer-
tain basic physiological principles will be of great help
in making the right decisions. Below, we present a series
of pathophysiological principles encountered in the acute
phase of severe TBI, together with their respective recom-
mendations (Table 1).
1. Avoid arterial hypotension
Hypotension is one of the most widely studied secondary
lesions, and the one with the greatest negative impact on
clinical outcomes.5,6 Hypotension, regardless of its intensity
or duration, will always increase mortality in patients with
acute brain damage.5,6
On a physiological level, cerebral blood flow (CBF) is
linked to metabolic activity, in other words, the cerebral
metabolic rate of oxygen.1,7 The main determinants of CBF
are cerebral perfusion pressure (CPP) and resistance arteri-
ole diameter (<50␮).1,7 CPP is the difference between mean
arterial pressure (MAP) and cerebral venous pressure. As the
latter is difficult to measure, intracranial pressure (ICP) is
used as a proxy.1,7
CPP = MAP−ICP
CBF remains normal and homeostatic by the intrinsic
capacity of its resistance vessels to modify their diame-
ter by a mechanism that is not yet fully understood called
‘‘cerebral autoregulation’’, in which cardiovascular (MAP),
respiratory (PaO2 and PaCO2 ) and neuralolgical factors are
also involved.1,7

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 D.A. Godoy, R. Badenes and F. Murillo-Cabezas

Table 1 Summary of physiological principles and recommendations.

Physiological principle Recommendations References
1. Avoid arterial hypotension Maintain SAP > 100 mmHg 1,5---9
2. Identify cause of low blood pressure Perform a systematic investigation 10---13
3. Avoid extreme fluctuations in heart rate Investigate cause and treat 14---16
accordingly. HR target: 60---90 minute
4. Do not attempt to identify ‘‘normal’’ CSF Maintain CPP between 60 and 70 1,7,9,17---19
and CPP values mmHg
5. The brain does not exist in isolation, it ICP and CPP are influenced by 7,20---22
interacts intrathoracic and intra-abdominal
pressures
6. Avoid rigid ‘‘ICP threshold’’ thinking Adjust the value based on the clinical 1,7, 9, 27---34
context
SaO2 > 92%; PaO2 > 60 mmHg 7,10
PaCO2 : 35---40 mmHg
Natraemia: 135---145 mEq/L
7. Achieve physiological homeostasis Core Temp.: 36---37.5 ◦ C
Normovolaemia: CVP: 8---12 mmHg
Hb > 7 g/dL
Blood glucose: 110---180 mg/dL
Do not restrict fluids 7, 10, 35−40
8. Avoid hypovolaemia, fluid overload, Goal-directed fluid therapy
extreme hyposmolarity and hyperosmolarity. Do not administer hypotonic fluids
Avoid natraemia >160 mEq/L and/or
plasma osmolarity >320 mOsm/L
PaO2 > 60 mmHg 7. 41---46
SaO2 > 92% (ph: 7.35---7.45;
9. Ensure adequate oxygen delivery PaCO2 : 35---40 mmHg; C Temp.:
36---37.5 ◦ C)
CPP > 60 mmHg
Hb > 7 g/dL
10. Adequate pressure does not ensure Physiological reasoning. Follow the 7, 47
adequate flow and tissue oxygenation oxygen pathway from start to finish
CBF: cerebral blood flow; CPP: cerebral perfusion pressure; CVP: central venous pressure; Hb: haemoglobin; HR: heart rate; ICP: intracra-
nial pressure; PaCO2 : partial pressure of carbon dioxide; PaO2 : partial pressure of oxygen; SaO2 : arterial oxygen saturation; SAP: systolic
arterial pressure; Temp: temperature.

Cerebral autoregulation (CAR) is a natural, though lim-
ited, survival mechanism that is effective within a certain
range of CPP (50---150 mmHg), beyond which CBF passively
follows MAP1,7 (Fig. 1).
During injury, this mechanism is altered and the CPP
range is generally narrowed and shifts to the right.1,7 This
means that higher levels of CPP are needed to main-
tain stable CBF. Hypotension is deleterious when CAR is
altered or completely lost, even temporarily, since lower-
ing CBF can cause ischaemia with irreversible, catastrophic
consequences.1,7
CAR status can be estimated at the bedside using static
or dynamic indices. Dynamic indices include the transient
hyperemic response ratio first proposed by Giller, which
analyses changes in the mean systolic velocity of the middle
cerebral artery before and after compressing the internal
carotid artery for 3 s.8 The value is normal when the sys-
tolic velocity increases by at least 10% of baseline after
pressure is released. Also useful is the pressure-reactivity
index (PRx), which measures the moving correlation coeffi-
cient between ICP and spontaneous fluctuations in MAP over
different periods of time,8 and requires specific software
for data collection and interpretation. CAR is preserved
when these variables correlate negatively; a positive cor-
relation implies that ICP passively follows changes in MAP
due to the absence of vasoconstriction to compensate for
a MAP-induced increase in CBF.8 The simplest static index,
meanwhile, involves using transcranial Doppler to mea-
sure mean middle cerebral artery flow velocity at baseline
and after increasing MAP by 20% with the administra-
tion of phenylephrine or norepinephrine.8 CAR preservation
is manifested by minimal or no changes in flow velocity
after increasing MAP. Monitoring CAR has both a prognos-
tic and therapeutic benefit, since strategies to control ICP
(osmotherapy, barbiturates) will only be effective if this
physiological mechanism is preserved.8 Defining CAR status
can also help calculate optimal CPP values.8
Recommendations
a Regularly verify the status of CAR.8
b Perform invasive blood pressure monitoring.1,7
c Maintain systolic blood pressure >100---110 mmHg.9

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Figure 1 Brain autoregulation curve.
2. Systematically investigate the cause of arterial
hypotension: not always due to volume deficit
Brain injury does not in itself cause arterial hypotension,
and it should not always be attributed to hypovolaemia.
Several trauma-related circumstances must be investigated
systematically10 (Table 2).
First, sources of extra-cavity bleeding (haemothorax,
pneumothorax, abdomino-pelvic bleeding, vascular rup-
tures) and associated spinal trauma must be ruled out.11
Changes in haemodynamics caused by mechanical venti-
lation and intra-abdominal hypertension and the adverse
effects of blood products or drugs must also be taken into
account.7
Hypothalamic dysfunction and hypopituitarism can also
occur, although these are less frequent in the acute
phase.12 Finally, it is essential to evaluate cardiac activity
to rule out cardiac tamponade or ventricular dysfunc-
tion associated with stunned myocardium or stress-induced
cardiomyopathy.13
Recommendations
a Use systematic clinical evaluation protocols and imag-
ing tools to evaluate the injury (Advanced Trauma Life
Support).11
b Rule out active bleeding.7,10,11
c Bear in mind the pharmacokinetics and pharmacodynam-
ics of the drugs used.7
d Monitor transfusion reactions.10
e Perform an echocardiogram.10,11,13
f Determine the hypothalamic-pituitary hormonal profile.12
3. Avoid extreme fluctuations in heart rate
Adrenergic discharge is a key component of the
metabolic-hormonal response to injury that initially helps
maintain haemodynamic stability.14 However, persistent dis-
charge indicates that the triggering situation has not yet
resolved or another deleterious factor has been added.14
Tachycardia is an independent predictor of mortality in
critically ill patients.15 Given its multifactorial origin,15,16
283
multiple causes should be investigated: active bleed-
ing, fever, pain, agitation, delirium, severe anaemia,
systemic inflammatory response, sepsis, and sympathetic
hyperactivity.15,16
At the other extreme, bradycardia, which is less com-
mon, can affect haemodynamics when associated with
hypotension and low cardiac output.16 The causes of
bradycardia include: electrolyte disorders (hyperkalemia,
hypocalcemia, hypermagnesemia); hypothermia, adverse
effects of antiarrhythmic drugs, beta-blockers, or intracra-
nial hypertension (ICH).16
Recommendations
a Always investigate the cause.14---16
b Target therapy at the triggering event.14---16
c Consider using beta-blockers (sympathetic
hyperactivity).14,16
4. Do not attempt to identify ‘‘normal’’ CBF and CPP
values
The main target in monitoring CBF is to maintain a
constant supply of energy sources (O2 and glucose), since
the brain lacks reserves or deposits.17,18 Normal CBF is 50
mL/100 g tissue/min17,18 ; however, these values can vary,
depending mainly on metabolic coupling.17,18 The deter-
minants and regulatory mechanisms of CBF are discussed
above. During brain injury, CBF evolves through 3 distinct
phases: it decreases in the first 24 h (hypoperfusion), then
increases, exceeding metabolic needs (relative hyperemia),
a phase that lasts until approximately the fifth day, and then
enters the fluctuating vasospasm phase, which lasts until the
end of the second week.19
No solid evidence has yet been put forward to establish
‘‘normal’’ CBF and CPP values in the acute phase of severe
TBI, nor is there any evidence to show the optimal target
values adjusted for age, evolutionary stage, type of injury,
and presence or absence of preserved CAR.
Recommendations
 D.A. Godoy, R. Badenes and F. Murillo-Cabezas

Table 2 Causes of arterial hypotension to be investigated in severe traumatic brain injury.

Causes of arterial hypotension in the context of severe TBI
1. Active bleeding (traumatic and/or hemorrhagic shock: thoracic, abdominal, pelvic, vascular injuries).
2. Sedative-analgesic drugs (opioids, benzodiazepines, propofol) at incorrect dosage or in the presence of
hypovolaemia.
3. Allergic reaction to drugs.
4. Inadequate resuscitation.
5. Pneumothorax.
6. Myocardial dysfunction (stress cardiomyopathy).
7. Cardiac tamponade.
8. Hypothermia.
9. Inadequate PEEP-mechanical ventilation.
10. Intra-abdominal hypertension.
11. Transfusion reaction (blood, plasma, platelets).
12. Acute adrenal insufficiency.
13. Panhypopituitarism.
14. Neurogenic hypotension.
15. Associated spinal cord injury (spinal shock, neurogenic shock).
PEEP: positive end expiratory pressure.

a Avoid arterial hypotension.1,7,9
b Check CAR.8
c Maintain CPP levels between 60---70 mmHg (Level IIb. Brain
Trauma Foundation Guidelines), in conditions of normox-
aemia (PaO2 > 70 mmHg), normocapnia (PaCO2 35---40
mmHg)n, under deep conscious sedation in the acute
phase (RASS −3; −4).9
5. The brain does not exist in isolation
ICP is the result of intracranial pressures.20 According to
the Monro---Kellie doctrine, ICP is the sum total of the pres-
sures exerted by the parenchyma, cerebrospinal fluid (CSF)
and the blood contained in veins and arteries.20
ICP = parenchyma + CSF pressure + cerebral blood volume
(CBV) pressure.
The contributions of the different components are:
• Glía: 700---900 mL = 45.5%
• Neurons: 500---700 mL = 35.5%
• Blood: 100---150 mL = 7.5%
• CSF: 100---150 mL = 7.5%
• Extracellular fluid: 50---70 mL = 3.5%
The supratentorial space is responsible for 50% of ICP, the
infratentorial space for 30%, and the remaining 20% corre-
sponds to the spinal space.21
Normal values will vary with age, posture, and clinical
picture. In healthy individuals in a supine position it ranges
from 7 to 15 mmHg, and when standing it falls to around
−10 mmHg.7,21
The structures that make up the brain parenchyma (glia,
neurons) are static, only the extracellular fluid can inter-
vene dynamically when it is mobilised by pressure or osmotic
gradients to occupy different compartments, such as the
intravascular space or the CSF.7,21
Changes in CSF production or absorption have no major
effect on the absolute value of ICP.7,21 The arterial vascu-
lar compartment (25% of total CBV) can change ICP through
vasodilation or vasoconstriction.7,21
The CSF and blood contained in the cerebral veins (75%
of total blood volume) are the only components capable of
rapidly and effectively reducing ICP levels when moved to
the spinal compartment.22
The cerebral veins are not compressible (except in the
presence of ICH).22 They do not react in the same way or
respond to the same stimuli as the arterial bed; therefore,
intracranial dynamics are mainly determined by venous flow,
because from its origin to the right atrium the system is
continuous and free of valves.22
It is important to remember that the brain is compart-
mentalized by the folds of the dura mater, such as the
falx cerebri or the tentorium.7,23 Therefore, ICP is not uni-
form across the cranial cavity, especially in the presence of
pathology, where gradients can develop from one space to
another.7
Moreover, the brain is not isolated from the rest of the
body.7,22 The major vessels (carotid and vertebral arteries,
jugular veins) communicate with the thoracic cavity, which
in turn communicates with the abdomen.7,22 These 3 cav-
ities do not function independently; rather, they are in a
state of constant interaction, to the extent that a change in
intra-abdominal pressure affects systemic haemodynamics
and intrathoracic pressure, which in turn modifies cere-
bral venous return.7,22 This 3-compartment model is vitally
important in brain injury, since it shows that the origin of
the increase in ICP often lies outside the cranium7,22 (Fig. 2).
Recommendations
a Remember that ICP is dynamically influenced by intra-
abdominal and intrathoracic pressures.7,20---22
b Evaluate intracranial haemodynamics together with sys-
temic haemodynamics.10,20---22
6. Avoid rigid and static ÏCP thresholdättitudes to ther-
apeutic decision-making. There are no magic numbers!

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Figure 2 Causes of high ICP, according to our 3-compartment model.

ARDS: acute respiratory distress syndrome; CBV: cerebral blood volume; CPP: cerebral perfusion pressure; CSF: cerebrospinal fluid;
CSFP: cerebrospinal fluid pressure; ICP: intracranial pressure; MAP: mean arterial pressure; MV: mechanical ventilation; PEEP:
positive end-expiratory pressure; PTC: brain tissue pressure; VP: vascular pressure.

ICH is a multifactorial secondary complication that plays
a major role in the pathophysiology of traumatic brain
injury,1,10,14,24 but is no more than one of the factors in a
complex equation --- the tip of the iceberg. Controlling ICH,
though important, is just one of the steps towards the final
destination. ICH is an independent predictor of mortality,
and may be deleterious by inducing ischaemia, displac-
ing anatomical structures, or causing herniation.1,7,9,17 Its
definition, and the threshold value for starting therapy, is
controversial.24,25 Traditionally,ICH is defined as ICP > 20
mmHg over a given time, usually 20---30 min. The evidence,
however, is neither conclusive nor widely accepted. This
value has its origin in retrospective studies based on the
U.S. National Traumatic Coma Database, which was pub-
lished over 50 years ago.1,9,21 Recently, the Brain Trauma
Foundation changed the threshold to 22 mmHg, based on
a single-centre study to identify variables associated with
clinical outcomes.9 Several well justified doublts have been
raised about the aforementioned study, and it has therefore
been awarded a low level of evidence (IIb).26
In specific situations, such as after decompressive
craniectomy or in the presence of contusions close to the
brainstem (temporal, fronto-basal) that extend (oedema,
rebleeding) in that direction, the optimal threshold and
time to start or intensify treatment is still under debate;
however, a lower threshold of around 15 mmHg or less is
recommended.27---29
The problem has been further complicated by the
development of symptom- and image-guided protocols
to treat ICH without ICP monitoring and with no
specified thresholds.30 In short, given the scant infor-
mation and low-quality evidence available to date,
it is difficult to decide when to start treating ICH.
Specific studies on this topic are required to allow
us to make the quantum leap from heuristics to
certainty.31
It is particularly important to arrive at a general consen-
sus and validate the definition of ICH in terms of absolute
values and duration. The determination of ICP values raise
other issues related to age, timing of appearance, and
its association with different types of injury.7,27 Instead of
focussing on a single number, it is more important to iden-
tify the underlying cause of ICP and carefully evaluate its
changes over time.32---34

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 D.A. Godoy, R. Badenes and F. Murillo-Cabezas

a
Manejo de hipertensión Intracraneal
Remove Primer nivel terapéutico
SOL

Head 30º - neutral

– sedation and
analgesia –
MV Physiological
neuroprotection
PPC 55-70
mmHg
CSF drainage PIC < 22 mmHg
Transient
Limit 20 ml/h
30 min
Consider CT
Osmotherapy
HS – Manitol • Manitol: 0.05 – 1 gr/kg
Limit: Na+ 160 mEq/l • HS 7.5%: 1.4 ml/kg
Osm pl >320 mosm/l
No response > 2 boluses

Moderate hyperventilation
paCO2: 30 – 35 mmHg
Transient
Limit: SjvO2 < 55%
Pti02 < 20 mmHg

b
Intra-cranial hypertension

1st therapeutic step

No response

Refractory intra-cranial hypertension

2nd therapeutic step

Decompressive craniotomy
High-dose barbiturates
Hypothermia
Ketorolac
Indometacin
Controlled CSF drainage

Figure 3 Management of intra-cranial hypertension First therapeutic step. A) First line therapeutic measures to control intracra-
nial hypertension. B) Second line therapeutic measures to control intracranial hypertension.
CT: computed tomography; CPP: cerebral perfusion pressure; CSF: cerebrospinal fluid; HS: hypertonic saline; ICP: intracranial pres-
sure; MV: mechanical ventilation; PtiO2 : tissue pressure of oxygen; SOL: space occupying lesion; SjvO2 : jugular venous oxygen
saturation.

Order and system are essential for good management;
measures should be implemented in a sequential and (more
or less) stepwise manner, from the least to the most aggres-
sive in terms of their potential to generate undesirable
effects.1,7,9 An ‘‘additive’’ approach must be taken; in other
words, adding one measure does not imply that the preced-
ing measures should be discontinued. The minimum waiting
time needed to evaluate the effectiveness of the measures
taken should be 20−30 min. Consider performing neuroimag-
ing studies, if necessary (increase in ICP or therapeutic
escalation with insufficent justification), since it is essen-
tial to rule out the presence of space-occupying lesions that
require surgical intervention.1,7,9
‘‘Generally speaking, the targets to be achieved are: CPP
55−70 mmHg and ICP < 22 mmHg’’.
Fig. 3 outlines the first-level therapeutic options for the
control of ICH. Lack of response to these measures sig-
nals a refractory condition and the need to progress to a
higher, more aggressive and potentially risky therapeutic
step (Fig. 3b).

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8. Avoid hypovolaemia, fluid overload, extreme hypos-

Normal molarity and hyperosmolarity.
temperature The first therapeutic step in trauma resuscitation is
Rectal T < 37.5 fluid infusion, which should be aimed at ensuring ade-
quate blood volume and avoiding hypotension.7,10,35 The
Normal volume Normal sodium injured brain is extremely vulnerable to fluid and electrolyte
CVP 10-12 Na+135-145 imbalance.1,10 There is no exact definition of normovolaemia
cmH2P mEq/l or the monitoring variables that signal that balance been
achieved.36 In general, macro and microhaemodynamics are

6N not correlated, so both must be evaluated simultaneously

Normal blood
Normal blood sugar
oxygen 110-180 mg/dl
SaO2 > 92%
Normocapnia
paCO2 35-
40mmHg
Figure 4 «The 6 Ns».
CVP: central venous pressure; Na+ : serum sodium; PaCO2 :
partial pressure of carbon dioxide; SaO2 : arterial oxygen sat-
uration; T: temperature.
Recommendations
a Carefully evaluate the cause of ICH.1,7,9
b Do not focus on correcting a specific value (analyse curve
morphology and amplitude).7,27---29,32---34
c Evaluation the general systemic and intracranial
context.1,7,9
d Develop a protocol or algorithm to treat ICH.1,7,9
7. Establish ‘‘physiological homeostasis’’ as the primary
goal
Neuroprotection is defined as the therapeutic measures
designed to protect the brain from any injury, thereby
increasing tolerance to aggression and the patient’s chances
of survival.7
‘‘Physiological neuroprotection’’ is a group of measures
aimed at maintaining basic physiological parameters in bal-
ance in order to create an appropriate microenvironment
that prevents the primary injury from progressing and pro-
motes the repair of tissue damage.7,10 Alteration of these
parameters will have a negative impact on brain function.
From a practical point of view, physiological neuroprotec-
tion involves avoiding, controlling, and correcting secondary
systemic complications. This is achieved by following ‘‘The
6 Ns’’ ‘‘(normalities)7,10 (Fig. 4).
Recommendations
and in context.36,37 Preference is currently give to restric-
tive, staged replacement for balanced, goal-directed fluid
management.38 Vasopressors can be administered at an early
stage if they will help achieve fluid management goals.38
Regarding fluid quality, the first choice should be nor-
mal saline solution (slightly hypertonic with respect to
plasma).7,10,35
Osmotic therapy is one of the pillars of intracranial
hypertension management.1,7,9,21 Osmotic agents basically
work by creating concentration gradients that mobilise flu-
ids from the interstitium to the intravascular space.1,7,9,21
They increase CPP and CBF (improving blood rheology), and
their vasoconstricting action reduces ICP.1,9,10,14,29,30 Manni-
tol and hypertonic saline solutions are the most widely used
agents.1,7,9,21
Both share pharmacological properties1,7,9,21 : they are
low molecular weight crystalloids, have the same distribu-
tion in the extracellular space, and a similar half-life.
Mannitol is a metabolically inert sugar derived from
mannose that is eliminated via the kidneys without being
reabsorbed.1,7,9,21 Peak effects are reached 30---40 min after
being infused, and its duration of action ranges from 2 to
12 h. It is usually administered at a dose of between 0.25
to 1 g/kg,1,7,9,21 although the most effective regimen (con-
tinuous or bolus) has not been reliably determined. A peak
serum osmolality of 320 mOsm/L has been arbitrarily set as
the limit for mannitol indication.
Mannitol works best in low CPP situations, and also
depends on autoregulation and an intact blood-brain barrier
(BBB).1,7,9,21
Hypertonic saline solutions generate higher osmolarity
than mannitol, and can therefore be administered a lower
doses. They increase blood volume, act independently of
CPP and CAR status,1,7,9,21 and have a deeper and longer
lasting effect (18---24 h) than mannitol. They also exert an
inotropic, anti-inflammatory and immunomodulatory effect,
and improve liver and splanchnic blood flow.1,7,9,21 Dif-
ferent concentrations (3.5%, 7.5% and 20%) and regimens
(continuous, bolus) are currently used. Although none has
shown clear superiority, bolus administration of 7.5% saline
at a rate of 1.5---4 mL/kg is usually used. Therapeutic
effectiveness is monitored by measuring natraemia, and
administration is suspended when levels reach 160 mEq/L
or higher.1,7,9,21

a Maintain established targets over the course of the
injury.7,10
b It is preferable, especially in the acute phase, to cre-
ate a slightly ‘‘hyperosmolar’’ environment (plasma Na+
> 145 < 155 mEq/L and blood glucose between 110---180
mg/dL).7,10
Mannitol or hypertonic saline?
The debate is ongoing. The choice should be based on
pathophysiological reasoning, taking into account phar-
macokinetics, pharmacodynamics, underlying pathology,
associated comorbidities, renal function and, obviously, the

287
 D.A. Godoy, R. Badenes and F. Murillo-Cabezas
Figure 5 Oxygen pathway and causes of brain tissue hypoxia.
CaO2 : arterial oxygen content; CBF: cerebral blood flow; DCD: disseminated cortical depression; DO2 c: cerebral oxygen delivery; ICP:
intracranial pressure; MAP: mean arterial pressure; SaO2 : arterial oxygen saturation; SHAS: sympathetic hyperactivity syndrome;
V/Q: ventilation-perfusion ratio.
possibility of monitoring the infusion. Hypertonic solutions
are should be chosen in patients with symptomatic hypona-
traemia.
Meta-analyses comparing the effectiveness of equimolar
doses of mannitol and hypertonic solution to correct ICP
have concluded that hypertonic solutions are more effec-
tive (RR 1.16 CI 1.00---1.36).39 Nevertheless, due to the
methodological limitations of the studies included, larger
and better-designed trials are needed.39
0.5 M sodium lactate is an alternative osmotic agent.40
Its mechanism of action, properties and osmolarity are sim-
ilar to 3% hypertonic saline (1020 mOsm/L),40 and it has a
longer duration of action than equimolar hypertonic manni-
tol or saline.40 This solution has two additional advantages:
it does not contain chlorine, and therefore does not cause
hyperchloraemic metabolic acidosis; lactate is an astrocytic
energy substrate, and is particularly beneficial in situations
of high metabolic demands. Data from clinical trials are
encouraging.40
Recommendations
a Do not restrict fluids in the acute phase.7,10,35 Estab-
lish a management strategy. We recommend the «ROSE»
(Resuscitation. Optimization. Stabilization. Evacuation)
model.38
b Monitor systemic haemodynamic variables and tis-
sue perfusion (lactate, venous-to-arterial CO2 differ-
ence).7,10,35,36
c Do not administer hypotonic fluids (5% dextrose, lactated
ringer’s soltuion, 4% albumin).7,10,35
d Do not use osmotherapy empirically.35,39
288
e Establish an infusion and systematic monitoring protocol
for osmolar therapy.35,37,38
9. Ensure adequate brain oxygenenation
Oxygen and glucose are indispensable for brain cell
survival.18 During acute injury, the demand for these
increases. The brain has no energy deposits, so a continuous,
ample supply is needed to meet demand.17 Oxygen, which
passes through the cell membrane, is mobilized according
to concentration gradients (higher to lower), while glu-
cose requires specific transporters.18,41 Oxygen supply to the
brain depends on the proper functioning of the respiratory,
haematological and cardiovascular systems, controlled and
regulated by the extracellular fluid.18 O2 delivery depends
on two variables:
DO2 c = CaO2 ×CBF
where DO2 c is cerebral oxygen delivery; CaO2 : arterial O2
content, and CBF: cerebral blood flow.
CBF has been discussed above. CaO2 is the sum of the
oxygen dissolved in plasma (PaO2 ) plus the oxygen bound to
haemoglobin (Hb), which must obviously be of good quality
and abundant.18
CaO2 = (Hb×1.34×arterialO2 ) + (PaO2 ×0.003)
The quality of the extracellular fluid will determine the
facility with which oxyhaemoglobin (95% of the total) is
transferred to cells.18 Plotting the O2 /Hb dissociation curve
will show the value of p50,18 which is the oxygen ten-
sion when haemoglobin is 50% saturated with oxygen. Its
 Revista Española de Anestesiología y Reanimación 68 (2021) 280---292
Table 3 Physiological targets in multimodal monitoring of severe TBI.
Physiological variable Monitored parameter
ICP
Intracranial haemodynamics
CPP
VmMCA (TCD)
Cerebral blood flow
Laser Doppler flowmetry (regional)
Brain oxygenation SJvO2
PtiO2
Glucose
Lactate
Pyruvate
Brain metabolism (microdialysis)
Lactate/pyruvate
Glycerol
Glutamate
Neurophysiology EEG
CPP: cerebral perfusion pressure; EEG: electroencephalogram; ICP: intracranial pressure; MCAV (TCD): mean middle cerebral artery flow
velocity (transcranial Doppler); PtiO2 : tissue pressure of oxygen; SvJO2 : jugular venous oxygen saturation.
physiological value is 27 mmHg.18 Higher values indicate a
shift to the right, which facilitates O2 tissue perfusion.18
Contributing factors are an increase in temperature, 2,3-
biphosphoglycerate acid, acidosis, and local CO2 levels.18
If p50 is lower than normal, the dissociation curve of Hb
is shifted to the left, increasing the affinity of Hb for O2
and thus reducing oxygen unloading to tissue.18 Hypother-
mia, alkalosis, hypocapnia and low 2,3-biphosphoglycerate
values contribute to this condition.18
If the variables analysed interact harmoniously, O2 will
reach the microcirculation. If this is both functionally and
structurally normal, it will facilitate oxygen delivery to the
cells, oxygen uptake, if possible, and allow the oxygen to
reach its final goal, the mitochondrial respiratory chain (O2
kinetics)18 (Fig. 5).
Cerebral hypoxia means the lack of oxygen in brain tissue,
due either to the organism’s inability to deliver sufficient O2 ,
or to the cell’s inability to use the oxygen even when it is
correctly delivered.42---45
The alteration of any component of the O2 transport
system will compromise tissue oxygenation.42---45 Monitoring
tissue O2 pressure (PtiO2 ) only shows the balance between
O2 supply and tissue demand.44 This technology will only
detect alterations in the availability of O2 .44
Interrupting CBF leads to ischaemic tissue hypoxia.42---44
In terms of physiopathology, CBF may fall due to a decrease
in CPP, which in turn is either caused by low MAP or high
ICP.42---44 Low MAP may be due to low cardiac output or
low systemic vascular resistance (vasodilation). Low cardiac
output may be due to inadequate preload (hypovolaemia,
compromised venous return), myocardial hypocontractility,
or increased afterload (situations that prevent adequate
ventricular emptying).
ICP increases because the pressure of its determinants
increases. Parenchymal pressure may be due to a space-
occupying lesion or an increase in parenchymal volume
(oedema), while CSF causes an increase in ICP when it does
289
Targets
<22 mmHg
55---70 mmHg
40---60 cm/s
18---25 mL/100 g/min (white matter)
60---80 mL/100 g/min (grey matter)
55%---75%
>20 mmHg
1.2 ± 0.6 mmol/L
1.2 ± 0.6 mmol/L
70 ± 24 umol/L
22 ± 6
28 ± 16 umol/L
17 ± 12 umol/L
Slowed according to sedation level.
No epileptiform discharges.
Avoid burst suppression.
not circulate or is not adequately absorbed (hydrocephalus).
CBV contributes to high ICP when it increases either due to
vasodilation or compromised venous return.
Finally, CBF can decrease due to blood vessel constriction
(hypocapnia, drugs), vasospasm, or obstruction (thrombosis,
extrinsic compression, arterial dissection).
There are other causes of compromised brain oxygena-
tion. If it is a result of inadequate gas exchange, then it is
called hypoxaemic hypoxia.42---44 The marker of this condi-
tion is hypoxaemia (low PaO2 ). Atelectasis, pneumonia and
acute respiratory distress syndrome (ARDS) are among the
most common causes.
Anaemic hypoxia occurs when Hb levels are too low,
while high affinity hypoxia is triggered when oxygen affin-
ity for Hb increases.42---44 The marker of this condition is
p50 < 27 mmHg. It is caused by the previously described
situations and the transfusion of blood that lacks 2,3-
biphosphoglycerate and has been stored for a long time.42---44
Finally, the unloaded oxygen still has to cross the intersti-
tial space before reaching the cell membrane and hence the
mitochondria. When this pathway widens, for example as a
result of cerebral oedema, tissue hypoxia can be triggered
by disturbances in O2 diffusion.45,46
Recommendations
a Remember the physiology.18,42---46
b Consider the components of the oxygen pathway.18,42---44
c Normalize all previously described parameters.7,10,35,42---44
10. Adequate pressure does not ensure adequate flow
and tissue oxygenation
We have mentioned above that a ‘‘normal’’ CPP does
not ensure tissue oxygenation, since there are other factors
that can compromise oxygen delivery.42---47 It is important to
understand that in the brain, within autoregulatory limits,
arterial blood pressure correlates only poorly with microcir-
culatory flow.47
 D.A. Godoy, R. Badenes and F. Murillo-Cabezas
Microcirculatory perfusion is physiologically regulated by
changes in blood flow and not arterial blood pressure, which
in turn is determined by metabolic activity.47 This relation-
ship is finely regulated by the release of local vasoactive
substances produced by endothelial shear stress or as an
end product of metabolism (adenosine, potassium, nitric
oxide).18,47
Therefore, CPP and adequate tissue oxygenation do not
ensure adequate tissue perfusion or cell function.
Some factors that can cause microcirculatory and cellu-
lar hypoxia cannot be detected with the monitoring systems
available today, so it is important to take them into consid-
eration when other possible causes have been ruled out42---47
(Fig. 5):
a Shunt-induced hypoxia: this occurs when the rate of flow
between the capillary and venous system increases, leav-
ing insufficient time for oxygen unloading. This may be
caused by arteriovenous malformations, systemic inflam-
matory response syndromes (SIRS), or sepsis.
b Hypermetabolic hypoxia: caused by increased brain
metabolism. Fever, seizures, SIRS, or sepsis are the most
common causes.
c Cytotoxic hypoxia: caused by mitochondrial dysfunction
secondary to the activation of trauma-induced neurotoxic
cascades, metabolic crises triggered by insufficient supply
of energy substrate (glucose), or sepsis.
Another equally important factor to consider is the
absence of bedside markers of cerebral tissue hypoxia
or indicators of anaerobic metabolism. Unlike systemic
lactate, ‘‘normal’’ levels of cerebral lactate, which is pro-
duced as actively as it is consumed and is one of the
main sources of energy in brain injury, are unknown.48,49
Current evidence suggests that increased production of aer-
obic lactate, stimulated by the adrenergic pathway (stress
hyperlactacidemia), seems to be a protective, preserva-
tive mechanism, especially when cellular metabolic demand
increases.48,49
It is often impossible to find the exact origin of cere-
bral hypoxia using PtiO2 , and some authors have suggested
that this may be due to the presence of vascular shunt-
ing, increased diffusion space, or cytotoxicity.42---46 In these
situations, microdialysis could be of considerable benefit.50
An increased lactate/pyruvate ratio (>25) in interstitial
dialysate with normal ICP and CPP values on transcranial
Doppler can indicate that these ‘‘normal’’ values are inap-
propriate for that specific patient. On the other hand, it
can also suggest the presence of non-ischaemic cerebral
hypoxia caused by mitochondrial dysfunction or failure.50
Likewise, a lactate/pyruvate ratio (>25) with normal or ele-
vated pyruvate values in the presence of normal PtiO2 values
is indicative of metabolic crisis due to non-ischaemic mito-
chondrial dysfunction.50
Recommendations
a Pressure is not the same as flow.47
b There are no bedside markers of brain tissue hypoxia.42---46
c Consider all causes of tissue hypoxia when it persists after
oxygen transportation has been normalized.42,46
290
Conclusions
As there is no specific treatment for the primary lesion
in severe TBI, clinicians need to prevent, avoid and
treat secondary complications. In this article, we have
shown that achieving this goal involves: 1. Understand-
ing the physiological principles of normal brain function.
2. Basing therapeutic decisions on physiopathological rea-
soning, because the physiological principles are altered
during brain injury. 3. Taking into account the connec-
tion between the brain and other bodily systems when
determining the origin of the alteration and the treatment
required. Physiological neuroprotection measures are essen-
tial.
The ten physiological commandments combined with
multimodal monitoring will bring us nearer to precision
medicine. In the context of severe TBI, the information
obtained from modern monitoring systems can be amalga-
mated to give deeper insight into the patient’s situation
and minimise decision-making errors. It is important to
implement the measures needed to achieve the different
physiological targets, such as those shown in Table 3.
Finally, since there are no magic numbers or bed-
side monitoring methods that can reliably indicate the
pathophysiological mechanism in play and its reper-
cussion, clinicians must rely on comprehensive clinical
reasoning and constantly refer back to clinical recommen-
dations.
Conflict of interests
The authors have no conflict of interest to declare.
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