P a t h o p h y s i o l o g y an d

Management of
I n t r a c r a n i a l H y p e r t e n s i o n an d
T i s s u l a r Br a i n H y p o x i a A f t e r
S e v e re Tr a u m a t i c B r a i n In j u r y
An Integrative Approach
Daniel Agustín Godoy, MDa,b,*, Santiago Lubillo, MDc,
Alejandro A. Rabinstein, MDd

KEYWORDS

Intracranial pressure
Intracranial hypertension
Acute brain injury
Cerebral perfusion pressure

Cerebral oxygenation
Brain hypoxia
Multimodal monitoring
Traumatic brain injury

KEY POINTS

Intracranial hypertension (IHT) is a major mechanism of damage after acute brain injury.

IHT and brain hypoxia (BH) are potentially life-threatening secondary brain insults and they are
closely interconnected.

Invasive monitoring of intracranial pressure is the gold standard to obtain reliable values and is the
cornerstone to guide treatment, whereas brain oxygenation may be monitored globally through
saturation of jugular bulb (SjO2) or locally through determination of oxygen tissular pressure (ptiO2).

There are multiple causes of IHT and BH, and a pathophysiological assessment is fundamental to
adopt appropriate therapy.

Achieving homeostasis of basic physiologic variables (physiologic neuroprotection) and avoiding
secondary insults are crucial steps to control IHT and prevent BH.

INTRODUCTION and degrees of cerebral displacement and herni-

ation. Vascular effects result from lowering cere-
Increased intracranial pressure (ICP) can be a bral perfusion pressure (CPP), which is defined
medical or surgical emergency.1 Both intracra- as mean arterial pressure (MAP) minus ICP.
nial and systemic events contribute to increased The CPP is the driving force of cerebral blood
ICP after traumatic brain injury (TBI).1,2 Intracra- flow (CBF). As the CPP decreases, CBF may
nial hypertension (IHT) can be life-threatening become insufficient for adequate brain tissue
by mechanical or vascular effects. Mechanical perfusion and oxygenation.3,4 The adequate
effects are mediated through different types levels of CBF and CPP vary among patients,
neurosurgery.theclinics.com

The authors declare no conflict of interest.

a
Intensive Care Unit, San Juan Bautista Hospital, Catamarca, Argentina; b Neurointensive Care Unit, Sanatorio
Pasteur, Catamarca, Argentina; c Intensive Care Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain;
d
Neuroscience Critical Care Unit, Mayo Clinic, Rochester, MN, USA
* Corresponding author. Neurointensive Care Unit, Sanatorio Pasteur, Chacabuco 675, Catamarca 4700,
Argentina.
E-mail address: [email protected]

Neurosurg Clin N Am 29 (2018) 195–212

https://doi.org/10.1016/j.nec.2017.12.001
1042-3680/18/Ó 2018 Elsevier Inc. All rights reserved.
196 Godoy et al

and the optimal CPP value changes over time index evaluates the autoregulatory capacity
and is normally regulated by cerebral autoregula- of the cerebral vasculature by analyzing the
tion. Increased ICP and low CPP are associated changes of ICP in relation to changes in MAP,
with mortality and poor long-term outcome.5–9 and this dynamic correlation may be used to
Ischemic lesions are highly prevalent in autopsy individualize the CPP target and consequently
specimens of individuals who die after severe the ICP threshold for treatment.29 Measurements
TBI. Therefore, preventing brain hypoxia (BH) of cerebral perfusion also may be used to indi-
and ischemia by maintaining adequate supplies vidualize ICP therapy.30
of oxygen and glucose represent major priorities
in the management of any form of severe acute INTRACRANIAL PRESSURE MONITORING
brain injury.10–13 Recently, monitoring of cerebral
tissue oxygenation has become increasingly Invasive ICP measurement (intraparenchymal,
used.14–16 The causes of brain tissue hypoxia intraventricular) is the ‘’gold standard’’ for moni-
are multiple and may even occur in the absence toring.1,2 ICP waves are the result of pulse trans-
of ICP increase or CPP decrease; thus, an mission of arterial pressure via the choroid
exhaustive analysis of oxygen supply and utiliza- plexus to the cerebrospinal fluid (CSF) and brain
tion is necessary to optimize care and improve parenchyma.31 Intracranial compliance can be
outcomes in TBI.16–20 assessed by ICP waveform analysis and the corre-
lation coefficient between the ICP waveform
amplitude and the mean ICP.31–34 The relationship
WHEN TO START THERAPY FOR between ICP and MAP fluctuations can provide
INTRACRANIAL HYPERTENSION? vital information pertaining to the underlying
Normal ICP varies with age, body position, and status of the cerebrovascular reactivity and
clinical condition.1,21 In healthy individuals in su- autoregulation.35,36
pine position, it ranges between 7 and 15 mm Hg. Attempts have been made to identify loss
Meanwhile, it becomes negative on standing intracranial compliance through ICP waveform
(average 10 mm Hg).1,2,21 In term infants, 1.5 analysis. The normal ICP waveform has 3 com-
to 6.0 mm Hg is considered normal, whereas ponents of progressively decreasing amplitude
in children, these values range between 3 and (P1 > P2 > P3), but as intracranial compliance
7 mm Hg.22 ICP can be increased transiently in gets exhausted, the P2 component becomes
physiologic situations, such as coughing or sneez- higher than P1, thus adopting a pyramidal
ing. In critically ill patients, occasional elevations form (Fig. 1).32,33,37 Oftentimes the ICP wave-
can be observed with changes in position, aspira- form changes before any major rise in ICP
tion of secretions, asynchrony with mechanical can be detected. Thus, the analysis of the ICP
ventilation, and physical therapy.1,2,5 wave is a useful tool to gauge the intracranial
IHT is traditionally defined as ICP greater than compliance.31–33,37,38 When ICP becomes
20 mm Hg for more than 5 to 10 minutes.23,24 elevated, abnormal waves begin to appear.
Treatment is generally considered indicated These pathologic waves, known as “Lundberg
above this threshold. In other situations, such waves,” reflect poor compliance. A waves,
as after decompressive craniectomy or when also known as plateau waves, represent
there are contusions close to the midbrain (tem- sustained, pronounced elevations of ICP and de-
poral lobes, basal region of frontal lobes), it may mand emergency treatment. B waves are briefer
be advisable to use a threshold of 15 mm Hg to and less severe raises in ICP that uncover
start therapy.25 Yet, the ICP threshold and the decreased intracranial compliance but do not
optimal time to initiate or intensify ICP treatment always necessitate emergent interventions
are subjects of debate because available evi- (see Fig. 1).37–39
dence has limitations.5,6,24–28 The cutoff of
20 mm Hg was established from retrospective PATHOPHYSIOLOGY OF INCREASED
analysis of data from the Traumatic Coma Data INTRACRANIAL PRESSURE
Bank.5 This threshold fails to take into account For a correct therapeutic approach, it is essential
the age of the patient or the lesional type. to take into account the following premises
Furthermore, the cutoff of 20 mm Hg is taken (Table 1):
as a static parameter, when in truth is highly dy-
namic and dependent on the situation. The last 1. Any increase in an intracranial component
version of the Brain Trauma Foundation guide- (brain tissue, arterial or venous blood, or
lines suggests initiating treatment when ICP is CSF) comes at the expense of another compo-
greater than 22 mm Hg.28 The pressure reactivity nent (Monroe-Kellie principle). The addition of
 IHT and Tissular BH After Severe TBI 197

Fig. 1. ICP waves registered at 25 mm per second showing the 3 components (P1, P2, and P3). (A) Normal wave-
form. (B) Pattern of reduced compliance. (C) A and B waves in a patient with IHT.

a brain mass will therefore result in reduction 2. Extracranial events may cause IHT by
of CSF and venous blood volumes first, increasing transmitted pressures. For example,
and then reductions in arterial blood and herni- markedly increased intra-abdominal or intra-
ation of brain tissue through existing cranial thoracic pressures may elevate ICP by compro-
openings.1,2,40 mising venous or CSF drainage.41–48

Table 1
Causes of intracranial hypertension

Localization Pathophysiology Etiology

1. Intracranial
a. Brain Occupying mass lesions Hematoma, contusions, tumors
parenchyma Water content increase Cellular (ischemia), vasogenic (increased BBB
permeability), or osmotic edema (hyponatremia).
Hydrocephalus
b. Vascular
I. Arterial Vasodilatation Hypoxemia, hypercapnia, hyperthermia, seizures,
drugs (nitroglycerine)
Increased cerebral blood Hyperemia, SIRS, sepsis, severe arterial hypertension
flow (loss of autoregulation)
II. Venous Drainage obstruction Jugular compression or thrombosis (eg, inadequate
head position)
c. Cerebrospinal Increased production Choroid plexus tumor
fluid Decreased absorption Communicating hydrocephalus (SAH, meningitis)
Obstruction of Obstructive hydrocephalus (mass lesions,
circulation intraventricular blood)
2. Extracranial
a. Increased Reduced cerebral venous Airway obstruction, pneumothorax, hemothorax,
intrathoracic drainage ventilation asynchrony, excessive PEEP, ARDS, lung
pressure hyperinflation
b. Increased Reduced cerebral venous Abdominal compartment syndrome,
intra-abdominal drainage pneumoperitoneum, hemoperitoneum, ascites,
pressure ileus

Abbreviations: ARDS, acute respiratory distress syndrome; BBB, brain blood barrier; CSF, cerebrospinal fluid; ICP, intracra-
nial pressure; PEEP, positive end expiratory pressure; SAH, subarachnoid hemorrhage; SIRS, systemic inflammatory
response syndrome.
198 Godoy et al

MANAGEMENT OF INTRACRANIAL scientific evidence, there is broad empirical proof

HYPERTENSION of their usefulness.49–51
General Measures for Physiologic IHT management requires order and systemati-
Neuroprotection zation. Measures should be implemented in a
sequential and stepwise manner, from the least

Neutral head positioning
to the most aggressive in terms of their potential

Avoidance/treatment of fever
to generate undesirable effects.1,23,25

Avoidance/correction of hypoxemia
The measures must be “additive,” meaning that

Avoidance/correction of hypercapnia or
when we decide to implement one, we do not
hypocapnia
abandon the previous one. It is also important to

Avoidance of hyponatremia
take some time, usually 20 to 30 minutes, to eval-

Recognition and treatment of shivering
uate the effectiveness of each measure before

Recognition and treatment of seizures
proceeding to the next step1,23,25 (Fig. 3). In

Avoidance of iatrogenic complications (eg,
most cases, the goals are to achieve a CPP be-
acute kidney injury from osmotic therapy
tween 60 and 70 mm Hg and to maintain an ICP
and intravascular volume contraction, acute
22 mm Hg.
lung injury from transfusions)
Determining the cause of the IHT should be the

Recognition and treatment of systemic infec-
first priority. Emergency evacuation of mass lesions
tions (eg, ventilator-associated pneumonia,
and CSF drainage in cases of hydrocephalus are the
urinary infection, bacteriemia)
most effective strategies and should therefore be

Prevention and treatment of other systemic
considered first. First-level measures also should
complications (eg, venous thromboembolism,
include placing the head in neutral position (neither
pressure ulcers)
flexed nor extended), aligned with the rest of the

In Fig. 2 we depicted the target of variables to
body, and raised to 30 from the horizontal.1,2,23,25
achieve and maintain during physiological
Check the position of orotracheal tube restraints
neuroprotection.
and cervical collars to ensure that they do not
compress jugular veins. In addition to facilitating
venous drainage from the intracranial compartment,
Specific Therapy for Raised Intracranial
this position helps prevent microaspiration of gastric
Pressure
content, which may reduce the risk of pneumonia.25
Although the therapeutic measures typically used Optimization of intracranial venous drainage
to control raised ICP lack solid supporting also requires ensuring that there are no

Central
Temperature
<37.5°C

Na+ 135 –145

Euvolemia
mmol/L

Physiological
Neuroprotecon
SaO2>92% Hemoglobin
paO2>90
7–10 g/dL
mmHg

paCO2 Glycemia
35– 40 110 –150
mmHg mg/dL

Fig. 2. Physiologic neuroprotection.

 IHT and Tissular BH After Severe TBI 199

Fig. 3. Escalating approach to specific IHT management.

physiologic derangements in the chest (pneumo- Benzodiazepines reduce CBF and metabolic
thorax or hemothorax, hyperinflation, excessive rate for oxygen in a coupled manner, without
positive end expiratory pressure [PEEP]) or affecting ICP. Prolonged infusion of benzodiaze-
abdomen (ileus, gastroparesis, hemoperito- pines may significantly delay arousal because of
neum) compromising venous outflow.41–48 reduced clearance, especially in the elderly.54–56
Cerebral causes of ICP increase should be If a benzodiazepine needs to be used, we prefer
excluded.52,53 Agitation, anxiety, and pain can midazolam (2–15 mg/h) because of its short half-
significantly increase blood pressure and ICP. life.54–56 Benzodiazepines also can be useful in pa-
Asynchrony with the ventilator is another possible tients with suspected or documented seizures.
cause of ICP surges. Therefore, adequate anal- Dexmetomidine, a central a2 receptor agonist,
gesia and sedation are essential to control can be used as an alternative to traditional seda-
IHT.23,25,54–56 We prefer short-acting agents that tives. It has a short half-life (2 hours), allows a
allow brief interruptions to perform neurologic quick and comfortable arousal, and does not
examinations. compromise ventilation.57,58 It attenuates sympa-
Propofol can help reduce ICP by diminishing thetic activity and may lead to bradycardia, hypo-
cerebral metabolism and cerebral blood volume. tension, and decrease in CPP, especially in the
It has a short half-life (2–4 minutes) but can presence of hypovolemia. It does not affect ICP.
accumulate in the adipose tissue. It does not Usual doses are 0.2 to 0.7 mg/kg per hour.57,58
have an analgesic effect, and should therefore Ketamine (1–5 mg/kg per hour) can be used
be combined with opioids. Long-term adminis- as an adjunct to standard sedatives to reinforce
tration of high doses may lead to propofol their effects and limit excessive drug require-
infusion syndrome, which is characterized ment. Ketamine is less prone to cause arterial
by rhabdomyolysis, metabolic acidosis, hypotension.57,58
hypertriglyceridemia, and cardiac toxicity (malig- For analgesia, morphine (3–5 mg/h) is a reason-
nant ventricular arrhythmias); therefore, it is able option unless the patient has cardiac disease
recommended not to exceed 80 to 100 mg/kg or severe hemodynamic compromise, in which
per minute and avoiding as much as possible case fentanyl is preferred (25–200 mg/h).54–56 Fen-
its continuous infusion over multiple days tanyl has more potent analgesic activity than
if high doses are required.54–56 Propofol has morphine. It accumulates in the fatty tissue and
antiepileptic effects and therefore it is par- its redistribution can cause a rebound effect and
ticularly useful in patients with concomitant respiratory depression after the infusion is discon-
seizures. tinued.54–56 Sufentanil is more potent than fentanyl
200 Godoy et al

and its half-life is much shorter, averaging 60 mi- ICP falls immediately after CSF drainage, this effect
nutes. It has a sedative effect.54–56 Remifentanil is often transient.31 Obstruction, bleeding, and
has favorable pharmacokinetic properties that infection are relatively common complications,
bring it closer to the ideal drug. Its volume of distri- although their rates of occurrence vary markedly
bution is lower and its half-life is very short (6– across centers.23,25 Overdrainage may cause sub-
15 minutes). It undergoes plasma metabolism dural hemorrhages and brain sagging, although
through stearases, which allows for its rapid elim- these complications are very unlikely in patients
ination. ICP may decrease without substantial with increased ICP.23,25 Ventricular catheters may
changes of the CPP, but the exact effect on cere- be difficult to place when there is compression or
bral hemodynamics remains to be elucidated.54–56 shift of the ventricles. When the catheter is mis-
The approach to sedation should consider the placed, the ICP waveform may appear dampened,
severity of the injury and the cerebral physiologic and the ICP values will be inaccurate.23,25
state, especially ICP. Attention should be given
to adequately control pain and agitation and pro- Osmotherapy
mote ventilator synchrony. The implementation of For more than 30 years, osmotic therapy has been
protocols may limit excessive sedation.56–59 In the cornerstone for the control of IHT.1,2,25,64 Os-
deeply sedated patients and in those treated motic agents work by creating pressure gradients
with neuromuscular blocking agents, the role of that cause fluid mobilization from the interstitium
electroencephalogram (EEG) to monitor sedation to the intravascular space.25,64 Also, by improving
has been a topic of clinical investigation. Simplified the rheological properties of the blood, they in-
EEG tools providing quantitative bispectral index crease CBF, in turn causing vasoconstriction,
have shown good correlation with the Richmond reduction in cerebral blood volume, and lowering
Agitation Sedation Scale and Sedation-Agitation of ICP. The most commonly used agents are
Scale scores.59 The Nociception Coma Scale has mannitol and hypertonic saline solutions (HSS).
recently emerged as a valid tool to assess pain in Both share pharmacologic properties: low molec-
patients with disorders of consciousness.59 In ular weight, same distribution in the extracellular
practice, the determination of the adequacy of space, and similar half-life.23,25,64
analgesia still relies on the observation of indirect Mannitol is a mannose-derived sugar that is not
signs of pain, such as tachycardia, systemic hy- metabolized by the body and is eliminated by the
pertension, and ICP elevation with potentially kidneys without reabsorption. Maximum effects
noxious stimulation.56–59 are reached after 30 to 40 minutes, and its duration
Neuromuscular paralysis is not routinely indicated of action varies between 2 and 12 hours. The
for ICP control except for specific situations, such optimal dose and regimen of administration of
as intubation, shivering (hypothermia, controlled mannitol (continuous or bolus) remain uncertain.
normothermia), and difficult ventilation (eg, refrac- It is typically used in boluses of 0.25 to 1 g/kg
tory hypoxemia from severe acute respiratory with a concentration of 20% in the solution.1,23,25,64
distress syndrome [ARDS]). Additionally, neuro- The use of mannitol as well as HSS requires
muscular blockers (NMBs) can be used during a monitoring of serum osmolality and intravascular
dangerous increase of ICP; for example, due to se- volume. Mannitol provokes intense diuresis and it
vere agitation.23,25,54–63 On the other hand, NMBs is very important to replace fluids to maintain nor-
prevent neurologic examination, mask seizures, movolemia.2,23,25,64 It can trigger hydroelectrolytic
and predispose to infections, deep venous throm- disorders, particularly of sodium and potassium. It
bosis, and decubitus ulcers.23,25,54–63 NMBs are has been arbitrarily established that 320 mOsm/L
linked to prolonged mechanical ventilation and, if is the maximum tolerable serum osmo-
used in conjunction with aminoglycosides, cortico- lality,2,23,25,64 although this cutoff is strictly a safety
steroids, or in septic patients, they can predispose measure; mannitol can continue to be effective in
to critical illness myoneuropathy.23,25,54–63 If NMBs reducing ICP at much higher osmolalities as long
must be used, short-acting agents that do not cause as the osmolar gap is not markedly increased.
histamine release, such as vecuronium or cisatracu- The main risk of mannitol is renal toxicity by
rium, are preferred.23,25,54–63 precipitating in renal tubules.2,23,64 This complica-
tion can be minimized by avoiding intravascular
Cerebrospinal fluid drainage volume contraction. Mannitol works best in situa-
The intraventricular catheter is the “gold standard” tions of low CPP with preserved autoregulation
for ICP monitoring.23 External ventricular drainage and intact blood brain barrier. If there is increased
drains also allow treatment of raised ICP by CSF permeability of the blood brain barrier, mannitol
drainage, although monitoring and drainage may accumulate in the interstitium with the theo-
cannot be performed at the same time. Although retic risk of causing rebound elevation of ICP.
 IHT and Tissular BH After Severe TBI 201

HSSs were introduced into clinical practice larger caliber than at baseline, which can cause
more than 20 years ago for the treatment of trau- increased CBV and ICP (rebound hyperemia).87,89
matic shock.65–74 They are used in different con- When hypocapnia is induced and maintained for
centrations and dosages. They generate greater several hours, it should be reversed slowly to mini-
osmolality than mannitol; thus, it is necessary to mize this risk.23,25,87–89
infuse less volume of HSS to achieve the same ef- Hyperventilation can be easily induced by
fect as mannitol.75–84 HSSs rapidly expand the increasing tidal volume or respiratory rate, the
intravascular space and can be effective even latter being preferred because it is less likely to
when autoregulation is compromised.65–74 In com- induce alveolar injury. The usual PaCO2 target is
parison with mannitol, they appear to have a more 30 to 35 mm Hg.2,25,87 For hyperventilation to
pronounced and lasting effect (18–24 hours). In work, it is necessary that the reactivity to CO2 be
addition, it has been postulated that HSSs have preserved. Hyperventilation should not be used
inotropic, anti-inflammatory, and immunomodula- prophylactically or for prolonged periods. Instead,
tory properties, and might improve hepatic and its use should be restricted to emergency man-
splanchnic blood flow.65–74 They can be used in agement of life-threatening IHT, such as herniation
continuous infusion or in boluses. Concentrations syndromes or to abort plateau waves. Normocap-
range from 3.5% to 23.4%. Our usual practice nia should be the standard of care for brain injured
is to use boluses at 7.5% at 1.5 to 3.0 mL/kg. patients.28 During hyperventilation, continuous
Monitoring of serum sodium is necessary, and monitoring of expired CO2 (end tidal CO2) and
it is advisable to avoid levels higher than 160 measures of regional or global cerebral oxygena-
mEq/L.65–74 Undesirable effects include phlebitis tion often is recommended.2,25,87–89
(which requires that HSS be administered through
a central venous catheter, unlike mannitol), pulmo- Cerebral Perfusion Pressure
nary edema, coagulopathy, hyperosmolar states,
Maintaining adequate CPP is as vital as controlling
and, exceptionally, pontine myelinolysis.65–74
ICP.10,28 Regardless of the type of injury, arterial
Hypertonic lactate has emerged as an alterna-
hypotension should be avoided.90,91 Maintaining
tive osmotic agent.85,86 From the point of view
systolic blood pressure 100 mm Hg for patients
of its mechanism of action and the osmolality
between 50 and 69 years old and 110 mm Hg
achieved after its infusion, it resembles HSSs at
for patients 15 to 49 or older than 70 years may
3%.85,86 Hypertonic lactate also exerts sufficient
be considered to decrease mortality and improve
expansion of the intravascular space to improve
outcomes according to current TBI management
systemic hemodynamics with less volume than
guidelines.28 The first step is ensuring normal
the usual crystalloids. Its effects may be longer
intravascular volume with either isotonic or hyper-
than equimolar mannitol or hypertonic saline.85,86
tonic fluids. If the desired MAP is not achieved, va-
Two additional properties of this solution make
sopressors and/or inotropes should be used
it extremely attractive. First, hypertonic lactate so-
according to hemodynamic monitoring, and the
lution does not have chloride, and, therefore, it
pathophysiology of the individual situation. In se-
does not generate hyperchloremic metabolic
vere TBI, a CPP between 60 and 70 mm Hg is
acidosis. Second, the lactate can help mitigate
generally recommended, but the optimal CPP
the increased energetic demands caused by
may vary depending on the autoregulatory status
the injury, as it can be used as fuel by astrocytes
of each patient.
and neurons.85,86
Refractory Intracranial Hypertension
Hyperventilation
Hyperventilation decreases arterial carbon dioxide IHT is categorized as refractory when first-level
pressure (PaCO2), which can induce vasoconstric- and second-level therapeutic measures fail to
tion by alkalinizing CSF. The resulting reduction normalize the ICP, a situation that occurs in
in cerebral blood volume (CBV) decreases approximately 10% to 15% of cases.21,25,28 Re-
ICP.87–89 Hyperventilation has limited use in the fractory IHT is associated with a high mortality
management of IHT because the effect on ICP is rate in TBI. The rescue measures (third-level ther-
relatively brief and excessive vasoconstriction apeutic measures) used in these instances are all
can cause cerebral ischemia, particularly with pro- hazardous and not always effective.21,25,28
longed use.87–89 The brief duration of the hyper- Barbiturates at high doses are an option to treat
ventilation effect on ICP is because the pH of the refractory IHT.23,25,28 The most commonly used
CSF rapidly equilibrates to the new PaCO2 agents are thiopental and pentobarbital. Barbitu-
level. As the CSF pH equilibrates, the cerebral ar- rates decrease cerebral metabolism, causing
terioles increase in diameter, possibly reaching a vasoconstriction and decreased CBF.92,93 They
202 Godoy et al

purportedly have neuroprotective properties Tromethamine

acting as a scavenger of free oxygen radicals, Cerebral acidosis in the setting of brain injury is a
attenuating the release of fatty acids and prevent- known predictor of poor outcome. Acidosis leads
ing calcium entry into the cells.92,93 Thiopental has to excitotoxicity and mitochondrial dysfunction.
a half-life of 9 to 27 hours, and is administered in a Furthermore, cerebral acidosis leads to glial
loading dose of 300 to 500 mg, which can be swelling, through modulation of aquaporin chan-
repeated every 30 minutes until the desired effect nels, contributing to ICP increase.80–82 Thus, the
is achieved, followed by continuous infusion at the attenuation of acidosis provides a potential mech-
rate of 1 to 6 mg/kg per hour. Pentobarbital re- anism for edema reduction and improved cell
quires an initial bolus of 5 to 10 mg/kg, which viability.80–82
can be repeated every 15 to 20 minutes. Usual Tromethamine (THAM) is a buffer solution that
doses for continuous infusion are between 1 and causes CSF alkalosis.80–82 THAM should be
8 mg/kg per hour. infused only by central venous access. If the initial
Barbiturate infusion requires strict hemodynamic bolus of 1 mmol/kg is effective in decreasing ICP, it
monitoring, as it causes arterial hypotension, can then be administered continuously, titrating
myocardial depression, and potentially severe re- the infusion to achieve blood pH between 7.5 and
ductions of CPP. In addition, barbiturates have 7.55.80–82 THAM can induce arterial hypotension.
immunosuppressant properties, thus increasing Controlled lumbar drainage may reduce ICP by
the susceptibility to infections, especially respira- decreasing CSF volume, and reduce craniocaudally
tory. During barbiturate infusion, continuous EEG resistance to CSF flow. It also may improve cerebral
monitoring is recommended.23,25,28 The target to venous outflow. Lumbar drainage is, however,
achieve is ICP control and not burst suppression contraindicated when there are space-occupying
pattern in EEG. lesions, midline shift greater than 10 mm, or efface-
Indomethacin is a nonsteroidal anti-inflammatory ment of the basal cisterns.83,84,96–98
drug, unique for its vasoactive properties at the level Hypothermia has been shown to be an excellent
of resistance vessels, that causes vasoconstriction, measure of neuroprotection in experimental
and consequently decreased CBV and ICP.75,94 studies. It reduces metabolic demands, protein
After indomethacin bolus, CBF decreases on degradation, oxidation, lactate accumulation, and
average approximately 30%. In theory, this effect calcium toxicity, and it stabilizes cell membranes.
can induce cerebral ischemia, but this effect has It also inhibits cortical spreading depolarizations,
never been demonstrated, possibly because the and reduces apoptosis and inflammation.99–102
cerebral metabolic rate of oxygen decreases in a All these effects may contribute to lower ICP and
coupled manner with CBF.75,76,94,95 The mecha- reduce cerebral edema formation; however, large
nism of action is still unclear, although it has clinical trials, especially in severe TBI, have not
been postulated to be related to modulation of pros- shown favorable results.99–102 Its implementation
taglandin levels. Other beneficial actions of indo- requires a dedicated multidisciplinary team.
methacin include decrease of CSF production, The optimal cooling method, target temperature,
improvement in cerebrovascular autoregulation, duration of hypothermia, and pace of rewarming
edema reduction, and antipyretic effect.75–79,94,95 remain unknown.
A recent review examined studies that Decompressive craniectomy consists of
used indomethacin for control of raised ICP.79 removing part of the skull and opening of the
Some important points were identified. First, dura mater to increase the capacity of the cranial
indomethacin seems to reduce ICP in a signifi- cavity to tolerate increases in cerebral volume.
cant manner in almost all patients (Oxford 2b, Its effectiveness is directly proportional to its
GRADE C). Second, the ICP reduction occurred size.103–106 It can be performed preemptively
with boluses ranging between 15 and 50 mg (eg, during the evacuation of an acute subdural
and infusion rates from 0.3 to 0.8 mg/kg hematoma associated with brain swelling) or as
per hour. Third, the ICP effect seemed to be a rescue measure when traditional measures
sustained for the duration of the infusion. No for the control of IHT have failed. The decom-
serious complications related to indomethacin pressive craniectomy can be bifrontal or fronto-
were identified.79 temporo-parieto-occipital, and unilateral or bilat-
Apart from the theoretic concern of inducing ce- eral. It can decrease ICP, and increase CPP,
rebral ischemia, the potential side effects of indo- CBF, and cerebral oxygenation. It also allows
methacin are renal failure, bleeding disorders, and deescalating the intensity of other interventions
gastroduodenal ulcers.75,94 Abrupt discontinua- for ICP control. Two large trials were recently
tion is not recommended because ICP can in- published. The DECRA trial showed no benefit
crease suddenly (rebound effect).78,79 from the surgery,107 but the RESCUE ICP trial
 IHT and Tissular BH After Severe TBI 203

demonstrated reduction in mortality in the sur- where DO2 is brain oxygen delivery, CaO2 is
gery group, as well as a trend toward better arterial content of O2, and CBF is cerebral blood
functional outcomes.108 flow.
Oxygen movement in the body follows a concen-
tration gradient. The atmospheric air is a gaseous
PATHOPHYSIOLOGY OF TISSULAR BRAIN mixture that has a pressure at sea level of 760
HYPOXIA mm Hg, of which 21% corresponds to oxygen
Cerebral metabolism is essentially aerobic.13 (fraction of inspired oxygen 5 FiO2); thus, the
Despite being a relatively small organ (2% of inspired oxygen pressure is 159 mm Hg.13,15,17
body weight), it receives 15% of the total cardiac When passing through the upper airway and
output and consumes 20% and 25% of the total during alveolar ventilation, the gas mixture is hu-
oxygen and glucose consumed by the body midified, thereby water vapor pressure increases
because of its very high metabolic activity.13 (47 mm Hg) at the expense of decrease of oxygen
pressure. In this manner, the oxygen available for
More than 90% of the oxygen consumed is used
to generate ATP.13 To ensure cell survival, the gas exchange in the alveolus has a pressure of
brain needs a continuous supply of oxygen and approximately 110 mm Hg (alveolar pressure of ox-
ygen). If the process of gaseous exchange is
glucose, its essential energy sources, and after
an acute injury these demands increase markedly. carried out without difficulty, the oxygen reaches
Oxygen delivery to the brain depends on the the bloodstream to bind in large proportion
following equation: (97%) with hemoglobin (Hgb), whereas the remain-
ing 3% travels dissolved with a pressure of
DO2 5 CaO2  CBF, 98 mm Hg (PaO2)13,15 (Fig. 4A).

Fig. 4. (A) Oxygen transport system. pvO2, venous oxygen pressure. (B) Oxygen/hemoglobin dissociation curve.
(C) Oxygen levels at the microcirculation (px), brain interstitial tissue (ptiO2), and into the mitochondria. See
text for more details.
204 Godoy et al

In turn, CaO2 is determined by the sum of What Is the Meaning of Cerebral Tissue
the oxygen dissolved in the plasma (paO2) Hypoxia?
and the oxygen that bound to Hgb. Each gram
Brain tissue hypoxia is a state in which the tissues
of hemoglobin is capable of transporting
and cells do not receive the adequate supply of
1.34 mL of oxygen.13,15 CaO2 can be calculated
oxygen (according to their needs) or receive it in
as follows:
sufficient quantities but cannot use it. When
hypoxic, the brain cannot meet its metabolic-
CaO2 5 (Hgb  1.34  SaO2) 1 (PaO2  0.003),
energetic demands, which leads to cellular
where CaO2 is the arterial content of O2, Hgb is the dysfunction and eventually cell death.
hemoglobin concentration (gr/dL), SaO2 is the ox- All available methods to monitor brain oxygen-
ygen arterial saturation (%), and PaO2 is the arterial ation measure the balance between availability
oxygen partial pressure (mm Hg). and consumption of oxygen.13–17 If we monitor
The affinity of oxygen for Hgb is expressed bet- cerebral oxygenation by means of a catheter
ter and clearer when analyzing the oxygen-Hgb placed in the bulb of the internal jugular vein
dissociation curve13,16,17 (Fig. 4B). P50 is the par- (SajO2), we will obtain global values of oxygena-
tial pressure of O2 in which Hgb is saturated at tion; whereas if we monitor brain tissue oxygen
50% (normally 27 mm Hg). A shift of the dissoci- pressure (ptiO2), we will be evaluating local values
ation curve to the right indicates lower Hgb affin- in a very small area.13–17 SajO2 less than 50% or
ity for oxygen and facilitates oxygen delivery to ptiO2 less than 20 mm Hg are considered indica-
the tissues. This shift to the right can be caused tive of BH. Both methods of monitoring are not
by increased body temperature, 2,3 DPG mutually exclusive and can actually be comple-
(diphosphoglycerate), acidosis, and local CO2 in- mentary, although their use to guide management
crease.13,17 Conversely, a shift of the dissociation has not be proven to improve functional out-
curve to the left indicates higher Hgb affinity for comes. From the SajO2, we can also derive the
oxygen and diminishes oxygen delivery to the tis- arterio-jugular oxygen difference (AVDO2), which
sues. Factors that can shift the dissociation curve increases when the brain needs to extract more
to the left include hypothermia, alkalosis, hypo- oxygen.
capnia, and decrease of 2, 3 DPG.13,17
Normally CBF is heterogeneous; it varies ac- Causes and Management of Cerebral Tissue
cording to metabolic activity (between 45 and Hypoxia
60 mL/100 g per minute) and is consistently
greater in areas with higher metabolic demand There are different types of tissue hypoxia and
(such as the cerebral cortex). The metabolic rate each requires a specific therapy (Fig. 5).
for oxygen (CMRO2) ranges between 1.3 and
a. Hypoxemic hypoxia occurs because of abnormal
1.8 mmol/g per minute. Normally, changes in CBF
gas exchange. Its marker is hypoxemia
and CMRO2 are coupled.1,2,13–16 The brain does
(decreased PaO2 and SaO2).15–18 In severe TBI,
not use all the oxygen provided by the circulation.
this occurs mainly due to ventilation-perfusion
The oxygen extraction fraction is on average 33%,
mismatch or increased intrapulmonary shunting.
under usual circumstances.1,2,13
Atelectasis, pulmonary contusions, pneumonia,
CBF depends mainly on 2 variables: CPP and
injury associated with mechanical ventilation,
vessel diameter, as follows:
and ARDS are among the most common
causes.15–18 Therapy includes using lung-
CPPðMAP  ICPÞ  r4
CBF 5 protective ventilation bundles, increase FiO2,
8nl appropriate levels of PEEP, recruitment maneu-
Circulating arterial oxygen (at 98 mm Hg) rea- vers, antibiotics, respiratory therapy, bronchodi-
ches the microcirculation where the oxygen lators, and aspiration of secretions.15–18
pressure at the capillary level (px) is on average b. Anemic hypoxia occurs when the amount of
32 mm Hg.17 It then diffuses into the cell after Hgb is insufficient. It is treated with transfusion
passing through the interstitial space in which of fresh red blood cells. Blood stored for a pro-
the oxygen pressure oscillates between 20 and longed time may lack adequate levels of 2,3
40 mm Hg.13,17 The distance that oxygen must DFG, and this deficiency increases the affinity
travel on its way to the cell varies between of Hgb for O2 (hypoxia due to high affinity).109
20 and 60 mm.13 Within the cell, the oxygen The optimum level of Hgb in severe TBI has
pressure is only 1.5 mm Hg, enough to ensure not been fully established. Some centers
the optimal functioning of the mitochondria13 favor transfusion to maintain Hgb greater than
(Fig. 4C). 10 g/dL, whereas others endorse a conservative
 IHT and Tissular BH After Severe TBI 205

Insertion of pO2 catheter

Running me (2 hs) Confirm localizaon

Confirm good funcon CT scan Exclude complicaons
with hyperoxia test
pO2 <20 mm Hg

Connue
YES NO monitoring

Increase FiO2
Titrate PEEP
paO2 >80 mm Hg Hypoxemic Recruitment maneuvers
SaO2 >92% NO Hypoxia Respiratory therapy
Broncodilators
Anbiocs

YES

paCO2 35–45 mm Hg
High Affinity Correct specific
Temp 36–37ºC NO derangement
pH 7.35–7.45 Hypoxia
p50<27 mm Hg

YES

Transfuse
Hgb>7 gr/dL NO Anemic Hypoxia fresh red blood cells

YES Fluids
MAP<70 –80 Vasopressors
mm Hg Inotropics

Ischemic
CPP>50– 60 NO
Hypoxia
mm Hg

Follow ICP
ICP>20 –22 reducon protocol
Check PaCO2 mm Hg
YES TCD (vasospasm)
CT perfusion
CTA (dissecon)

Fever/Sepsis Control fever

Hypermetabolic Anconvulsants
Seizures YES Hypoxia Sedaon-Analgesia
PSH Anbiocs
PSH control

Cytotoxic
NO Hypoxia

Fig. 5. Algorithm for diagnosis and management of cerebral hypoxia. CT, computed tomography; hs, hours; PSH,
paroxysmal symphatetic hyperactivity; TCD, transcranial Doppler; Temp, central temperature.

strategy (Hgb >7 g/dL).110–113 A randomized clinical outcomes, and keeping the Hgb above
controlled trial evaluating erythropoietin admin- 10 g/dL not only failed to improve neurologic
istration and these 2 Hgb transfusion thresholds outcomes but also was associated with a higher
concluded that erythropoietin did not improve incidence of adverse events.114
206 Godoy et al

c. High-affinity hypoxia occurs when there is h. Cytotoxic hypoxia is produced by O2/ATP un-
an increase in the affinity of Hgb for oxygen coupling as a consequence of mitochondrial
(ie, a shift in the dissociation curve to the dysfunction from neurotoxic cascades trig-
left). It can be caused by hypothermia, any gered by the trauma itself, repeated metabolic
form of alkalosis, hypocapnia (hyperventila- crises due to insufficient supply of glucose, or
tion), and transfusion of blood stored for a sepsis.15–18 It is both difficult to diagnose and
long time (with low levels of 2,3 DPG).15–18 difficult to treat.
Its treatment relies on the correction or
removal of the factor responsible for the Clinical Evidence
disorder.
Multiple observational studies have shown that ce-
d. Ischemic hypoxia occurs when CBF is insuffi-
rebral tissue hypoxia is a common phenomenon
cient. It is one of the main causes of cerebral
after severe TBI, with an incidence that may
hypoxia after severe TBI. Because CBF is
reach 70%, especially in the first days after
determined by CPP and arterial diameter,
trauma.117–119 Cerebral hypoxia may be observed
the main causes of ischemic hypoxia are
even in the absence of IHT or decreased
decreased CPP and vasoconstriction or flow
CPP.117–119 Also, it has been well documented
obstruction.15–18 CPP decreases as a conse-
that cerebral hypoxia is associated with poor
quence of arterial hypotension or IHT. In turn,
outcome.118,120–122 Observational studies suggest
arterial hypotension may be caused by
that incorporating ptiO2 monitoring and following a
decreased cardiac output or peripheral vasodi-
therapeutic strategy that takes ptiO2 into account
latation. Depressed cardiac output can obey to
in addition to ICP and CPP may be associated
a decrease in preload (hypovolemia), dimin-
with better outcomes.123–125
ished cardiac contractility, or increase in after-
A phase II, prospective, controlled, randomized,
load (increase in systemic vascular resistance
multicentric trial (BOOST-II) comparing a thera-
or decrease in transmural pressure of the left
peutic strategy guided by ICP monitoring versus
ventricle secondary to inadequate levels of
another strategy guided by integration of ICP and
PEEP, hemothorax, pneumothorax). Arterial
ptiO2 values showed that the latter was associated
diameter may be reduced by vasoconstriction
with a trend toward lower mortality and better
(hyperventilation, drugs), vasospasm, arterial
functional outcome at 6 months.20 However, these
dissection, or obstruction due to thrombosis
results must be confirmed by a phase III trial
or endothelial edema. Therapy depends on
before they can be considered conclusive.
the mechanism responsible for the reduction
in CBF. Options include optimizing MAP with
Integrative Approach
fluids or vasopressor/inotropic drugs, lowering
ICP, correcting hyperventilation, and treating During the past 30 years, management of raised
vasospasm or vessel occlusion with endovas- ICP has evolved toward standardized strategies
cular therapy. that use a pathway of escalating treatment inten-
e. Hypoxemia caused by the opening of extrapul- sity.1,2,23,25,28 The fundamental limitation of this
monary shunts, such as arteriovenous fistulas approach is that it does not take into account the
and hyperdynamic syndromes, such as severe need to individualize therapy based on patient-
sepsis. specific considerations.
f. Diffusion hypoxia occurs when cerebral edema TBI is a heterogeneous condition with multiple
increases the distance that oxygen must travel and evolutive injury patterns. A wide range of path-
from the capillary to the cell.115,116 Treatment ophysiological mechanisms of secondary brain
consists of reducing the cerebral edema with injury can occur, and they may not be detectable
measures such as osmotic therapy. solely with ICP monitoring.19,28,90,126–128 In this
g. Hypermetabolic hypoxia occurs as a conse- scenario, multimodal monitoring (MMM) can add
quence of increase in metabolic demands, valuable information to inform management deci-
such as seen with fever, seizures, paroxysmal sions.118,122 Integrating multiple monitoring mo-
sympathetic hyperactivity, or sepsis.15–18,117 dalities, such as ICP, CPP, transcranial Doppler,
Therapy should focus on temperature ma- structural brain imaging, perfusion scans, ptiO2,
nagement, seizure control, antibiotics when SjO2, and continuous EEG, may allow a more
pertinent, adequate nutrition, deepening se- meticulous and pathophysiologically oriented
doanalgesia, and control of paroxysmal assessment, recognize otherwise occult second-
sympathetic hyperactivity with morphine as ary insults, and confirm derangements by multiple
abortive therapy and beta blockers and gaba- parameters (Fig. 6).19,59,126–129 That said, when to
pentin to prevent further episodes. use and how best to integrate these multiple
 IHT and Tissular BH After Severe TBI 207

Fig. 6. Targeted therapy based in multimodal monitoring. CT, computed tomography; TCD, transcranial Doppler.

sources of information, all of which have particular expensive and available in only a few select
limitations, remain unanswered questions. centers.
Knowing the value and limitations of each In summary, an individually targeted therapy
modality is essential to optimize their use. For seems to be a more rational approach to severe
instance, in addition to providing data on the acute brain injury after the initial general measures
oxygenation of the brain parenchyma, ptiO2 deter- have been implemented.19,126–129 Targeted ther-
mination may allow us to optimize the CPP in the apy guided by the use of an MMM platform has
autoregulatory range through the determination been recently recommended on a consensus
of the “oxygen reactivity index.”19,126–129 How- statement on neuromonitoring.59 The principle is
ever, this modality only offers local information to administer individualized therapies for the spe-
on the oxygen status of the very small area of brain cific pathophysiological processes at play. Exam-
that is immediately adjacent to the tip of the cath- ples are the use of hyperventilation in the presence
eter. Meanwhile, transcranial Doppler provides of hyperemia, hypertonic saline or mannitol for ce-
information about flow resistance (pulsatility in- rebral edema when autoregulation is preserved, or
dex), can diagnose high flow states (vasospasm, the use of blood pressure elevation in the pres-
hyperemia), allows testing of autoregulation, and ence of B waves and suboptimal CPP.59,129
can monitor response to therapy (hyperventilation, Although this approach is intellectually appealing,
vasopressors), but the technique is highly it is hindered by the fact that the underlying
operator-dependent. Energetic dysfunction can pathophysiological derangements are usually
be monitored with microdialysis, which allows us complex and mixed, and global monitors of brain
to obtain data about lactate, pyruvate, and their physiology may miss critical focal abnormalities,
mutual relationship (lactate/pyruvate ratio), and and focal monitors may miss areas of ongoing
PET, which also provides information on the meta- damage.
bolic rates for glucose and oxygen and the oxygen
extraction fraction.85,126,129–132 With these tech-
How and When to Stop ICP and Brain
niques, it is possible to determine the presence
Oxygenation Monitoring?
of “metabolic crises” (manifested by increased
lactate/pyruvate ratio), which in general are related There are no widely validated guidelines to answer
to substrate deficit (oxygen, glucose) or perfusion this question. Based on clinical experience, moni-
deficit (ischemia). Yet, microdialysis is spatially toring can be stopped when the causes of the IHT
limited (measures only local metabolism around or BH have resolved, the patient has been clinically
the tip of the catheter) and measurement results and radiologically stable for at least 2 days, and
are delayed by the processing time. PET offers there has been no evidence of worsening physio-
global information, but limited to the time of scan- logic markers during gradual tapering of ICP
ning. Furthermore, both microdialysis and PET are reduction therapies. Prolonged use of ventricular