Hyperventilation in head injury - A review

Abstract

The aim of this review was to consider the effects of induced hypocapnia both on systemic physiology and on the physiology of the intracranial system. Hyperventilation lowers intracranial pressure (ICP) by the induction of cerebral vasoconstriction with a subsequent decrease in cerebral blood volume. The downside of hyperventilation, however, is that cerebral vasoconstriction may decrease cerebral blood flow to ischemic levels. Considering the risk-benefit relation, it would appear to be clear that hyperventilation should only be considered in patients with raised ICP, in a tailored way and under specific monitoring. Controversy exists, for instance, on specific indications, timing, depth of hypocapnia, and duration. This review has specific reference to traumatic brain injury, and is based on an extensive evaluation of the literature and on expert opinion.

Full text

Hyperventilation in Head Injury*
A Review
Nino Stocchetti, MD; Andrew I.R. Maas, MD, PhD; Arturo Chieregato, MD; and
Anton A. van der Plas, MD
The aim of this review was to consider the effects of induced hypocapnia both on systemic
physiology and on the physiology of the intracranial system. Hyperventilation lowers intracranial
pressure (ICP) by the induction of cerebral vasoconstriction with a subsequent decrease in
cerebral blood volume. The downside of hyperventilation, however, is that cerebral vasoconstric-
tion may decrease cerebral blood flow to ischemic levels. Considering the risk-benefit relation, it
would appear to be clear that hyperventilation should only be considered in patients with raised
ICP, in a tailored way and under specific monitoring. Controversy exists, for instance, on specific
indications, timing, depth of hypocapnia, and duration. This review has specific reference to
traumatic brain injury, and is based on an extensive evaluation of the literature and on expert
opinion. (CHEST 2005; 127:1812–1827)
Key words: cerebral ischemia; hyperventilation; intracranial pressure; traumatic brain injury
Abbreviations: AVDO
2
⫽ cerebral arteriovenous difference of oxygen content; CBF ⫽ cerebral blood flow;
CMRO
2
⫽ cerebral metabolic rate of oxygen; CPP ⫽ cerebral perfusion pressure; CSF ⫽ cerebrospinal fluid;
DPG ⫽ diphosphoglycerate; ICP ⫽ intracranial pressure; ITP ⫽ intrathoracic pressure; LV ⫽ left ventricle, ventricular;
NO ⫽ nitric oxide; Pbro
2
⫽ brain tissue oxygen tension; PET ⫽ positron emission tomography; RV ⫽ right ventricle,
ventricular; SjO
2
⫽ jugular bulb oxygen saturation; TBI ⫽ traumatic brain injury
M
odulation of Paco
2
has been used for ⬎ 40
years,
1
first in neuroanesthesia and subse-
quently also in neuro-intensive care. Preliminary
work has shown that the volume of the swollen brain
could be decreased by lowering Paco
2
. With the
realization that raised intracranial pressure (ICP) is a
significant, treatable problem in patients with trau-
matic brain injury (TBI), hyperventilation became a
cornerstone in the management of TBI and has
remained so for decades. Hyperventilation lowers
ICP by the induction of cerebral vasoconstriction
with a subsequent decrease in cerebral blood vol-
ume.
2
The downside of hyperventilation, however, is
that cerebral vasoconstriction may decrease cerebral
blood flow (CBF) to ischemic levels. Already in
1942, a slowing of the EEG was observed during
active hyperventilation and was interpreted as a sign
of cerebral ischemia, thus illustrating the potentially
harmful effects of hypocapnia.
3
Over the past de-
cade, relatively more attention has been paid to the
adverse effects of hyperventilation and concern
seems to exceed enthusiasm. This change in attitude
would appear more emotional than data-driven and
reflects the lack of conclusive data.
The aim of this review was to consider the effects
of induced hypocapnia both on systemic physiology
and on the physiology of the intracranial system, with
specific reference to TBI. We chose to focus this
review on TBI, as much of the research on hyper-
ventilation has been conducted in this field and less
information exists on other acute cerebral disorders,
such as aneurysmal subarachnoid hemorrhage or
*From the Neuroscience ICU (Drs. Stocchetti and Chieregato),
Ospedale Maggiore Policlinico, Milan University, IRCCS, Milan;
Department of Intensive Care Medicine (Dr. Chieregato), Os-
pedale Bufalini, Cesna, Italy; the Departments of Neurosurgery
(Dr. Maas) and Intensive Care Medicine (Dr. van der Plas),
Erasmus Medical Center, Rotterdam, the Netherlands.
Manuscript received September 23, 2004; revision accepted
November 25, 2004.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Nino Stocchetti, MD, Terapia Intensiva
Neuroscienze, Padiglione Beretta Neuro, Ospedale Maggiore
Policlinico, Via F. Sforza 35, 20122 Milan, Italy; e-mail stocchet@
policlinico.mi.it
reviews
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stroke. This review is based on an extensive evalua-
tion of the literature, and to this purpose we selected
relevant experimental and clinical articles on hyper-
ventilation from among ⬎ 5,000 citations found on
MEDLINE since 1966. We have indicated explicitly
in the text when expert opinion is being expressed
rather than available evidence being quoted.
Definition of Hyperventilation
A remarkable confusion exists on terminology.
What is usually referred to as hyperventilation is, in
fact, hypocapnia. Since a reduction of Paco
2
below
the normal level (40 mm Hg) is obtained by increas-
ing the alveolar ventilation, hyperventilation became
synonymous with hypocapnia. In this review, we will
use the less precise (but much more common) term
hyperventilation. Hyperventilation may be defined
as “the induction and/or maintenance of levels of
CO
2
tension in the arterial blood below the normal
range.” In this sense, normal levels of Paco
2
should
be corrected for barometric pressure at different
altitudes.
Pathophysiology
CBF Regulation and CO
2
Reactivity
The CNS, accounting for 2% of body weight
(average weight of the brain, 1,300 to 1,500 g), has a
high energy requirement. The cerebral oxygen con-
sumption is 3.5 mL per 100 g/min, which corre-
sponds to 20% of total body oxygen consumption.
Under normal conditions, CBF is maintained at a
constant flow rate of 50 to 60 mL per 100 g/min, with
50 mL of oxygen being extracted every minute from
700 to 800 mL of blood (Table 1). The extraction
rate for oxygen is high, and the mean arteriovenous
difference of O
2
for the CNS is 6.3 mL per 100 mL
of blood. CBF depends on the differential pressure
between the arterial and the venous side of the
cerebral circulation, and is inversely proportional to
cerebral vascular resistance. Pressure on the venous
side of the capillary bed cannot be measured, and
ICP, which is extremely close to venous pressure, is
used for estimating the cerebral perfusion pressure
(CPP). CPP is calculated as the difference between
mean arterial pressure and ICP.
Normal ICP values in adults are ⬍ 10 mm Hg, and
a threshold of 20 mm Hg is usually accepted for
starting active treatment. A CPP of 60 mm Hg is
commonly accepted as the minimum value necessary
for adequate cerebral perfusion.
4
Two important
concepts are:
1. the Monro-Kellie doctrine; and
2. the volume-pressure curve.
The Monro-Kellie doctrine states that the total
volume of the intracranial contents (ie, brain tissue,
blood, and cerebrospinal fluid [CSF]) remains con-
stant as these are contained within a rigid compart-
ment (the skull), as follows:
V
C
⫽ V
brain
⫹ V
blood
⫹ V
CSF
.
An increase in the volume of one of these com-
partments can initially be compensated for by the
displacement of parts of the other components.
Cerebral veins can be compressed, resulting in de-
creased cerebral blood volume, and the volume of
the CSF compartment can decrease due to a com-
bination of increased resorption and the displace-
ment of CSF toward the spinal compartment. As
volume increases, compensatory mechanisms are
exhausted, and a further increase in volume results
in a sharp rise of ICP, leading to the volume-
pressure curve depicted in Figure 1.
The high metabolic demands of the brain in
combination with the limited storage of substrates
necessitate maintaining CBF levels within normal
ranges. In physiologic circumstances, this is effected
through a number of mechanisms, which are com-
monly referred to as autoregulation. CBF increases
with vasodilatation and decreases with the constric-
tion of cerebral arteriolae, termed cerebral resistance
vessels. These vessels respond to changes in systemic
BP (pressure autoregulation), blood viscosity (viscos-
ity autoregulation), and metabolic demand, main-
taining CBF levels within limits that are appropriate
to meet metabolic demands. Pressure autoregulation
is shown in Figure 2.
CBF is functionally coupled to the regional cere-
bral metabolism as expressed in the Fick equation
CMRO
2
⫽ CBF ⫻ AVDO
2
, in which CMRO
2
is the
cerebral metabolic rate of oxygen and AVDO
2
is the
Table 1—Normal Values and Ischemia Thresholds for
the Main Cerebral Variables*
Variables Normal Value
Threshold for
Ischemia
Brain weight, g 1,300–1,500
CBF 50–60 mL/100 g/min
brain tissue
⬍ 18 mL/100 g
OEF 30%
AVDO
2
6.3 mL O
2
/100 mL
blood
⬎ 9mLO
2
/100 ml
blood
SjO
2
,% 55–75 ⬍ 50
Pbro
2
,mmHg ⬎ 20 15
ICP, mm Hg ⱕ 10
CPP, mm Hg 60 ⬍ 55–60
*OEF ⫽ oxygen extraction fraction.
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cerebral arteriovenous difference of oxygen content.
CO
2
reactivity refers to the response of cerebral
vessels and, consequently, of CBF to changes
in Paco
2
. An increasing CO
2
tension relaxes cere-
bral arteries in vitro.
5
In vivo, very localized peri-
vascular changes of Paco
2
or pH can change
the vascular diameter, indicating that elements of the
vascular wall are responsible for effecting changes in
the diameter of vessels. Both vascular cells (ie, the
endothelium and smooth muscle) and extravascular
cells (ie, the perivascular nerve cells, neurons, and
glia) may be involved. In the clinical situation, CBF
changes approximately by 3% for each millimeter of
mercury change in Paco
2
over the clinically impor-
tant range of 20 to 60 mm Hg in patients with TBI.
6,7
Hypoventilation resulting in hypercarbia causes va-
sodilatation and increased CBF, while hyperventila-
tion results in vasoconstriction and decreased CBF.
The mechanisms underlying the three forms of
autoregulation (ie, pressure, viscosity, and metabolic)
have not been precisely unraveled to date, but,
compared to mechanisms underlying CO
2
reactivity,
the differences are recognized. Whereas pressure
autoregulation seems to be located in the pial arter-
ies, with a diameter ⬎ 50 ␮m, CO
2
reactivity in-
volves smaller pial arteriolae.
8
Different data have
been obtained from in vitro and in vivo experiments.
In vitro, the middle cerebral artery constricts when it
is exposed to raised extracellular pH. In contrast, in
vivo, large intracranial vessels are not significantly
affected by changes in Paco
2
.
9
Further, in autoreg-
ulation the vascular endothelium-derived nitric oxide
(NO) or endothelium-derived relaxing factors are
important, but some debate exists about whether
these factors are involved in the maintenance of
basal CBF or actually couple regional CBF to me-
tabolism. An astrocyte-mediated coupling of synaptic
activity to local vasodilation has been proposed and
will need further evaluation.
10
Vessel caliber follows changes in arterial CO
2
by
responding to the pH in the perivascular space
without molecular CO
2
and bicarbonate ions acting
independently on cerebral vessels.
11,12
Nevertheless,
changes in pH may exert their effect on smooth
muscle tone through second messenger systems or
by altering the calcium concentration in vascular
smooth muscles directly. Various agents have been
identified as potential second messengers, including
prostanoids, NO, cyclic nucleotides, potassium, and
calcium.
Prostanoids are potent vasodilators, activating ad-
enylate cyclase and increasing cyclic adenosine
monophosphate, and are considered to be important
regulators of the cerebral circulation in neonates but
seem less important in adults. NO, which is pro-
duced by a family of NO synthase enzymes in brain
vascular endothelial cells, in perivascular nerves, as
well as in neurons and glia, increases the intracellular
concentration of cyclic guanosine monophosphate,
causing vasodilation. Although NO has been shown
to act as a vasodilator in response to hypercapnia and
acidosis, it cannot account for total vasodilation, as a
significant portion (10 to 70%) still occurs when NO
synthase is inhibited. The role of NO appears to be
complex. It has been hypothesized that a vasodilatory
signal is constantly produced by the brain through
the synthesis of NO and that an additional signal
such as hypercapnia may act on the baseline regula-
tion of the vascular tone. Cyclic nucleotides, such
Figure 1. Volume-pressure curve, illustrating the exponential
increase of ICP following an increase in the volume of the
intracranial compartment.
Figure 2. The normal autoregulatory curve of CBF vs CPP. CPP
is calculated as the mean arterial pressure (arterial BP
[ABP]) ⫺ ICP. With rising ICP, CBF is maintained at a lower
CPP than with declining ABP. Adapted from Miller et al.
148
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as cyclic adenosine monophosphate and cyclic
guanosine monophosphate, reduce the entry of cal-
cium into vascular smooth muscle, and exert vasodi-
latory effects either directly or in a permissive role,
allowing hypercapnia to exert its vasodilatory effects.
The opening of potassium channels indirectly re-
duces the influx of extracellular calcium into the cell,
reducing vascular smooth muscle tone. In contrast,
the disturbance of the calcium homeostasis will lead
to increased intracellular calcium concentrations,
resulting in vasoconstriction. This constitutes one of
the reasons underpinning investigations on the effi-
cacy of calcium channel blockers in patients with
TBI.
Systemic Effects of Hyperventilation
The importance of the systemic effects of hyper-
ventilation is often underrecognized. In some re-
views,
13
guidelines,
14
editorial comments,
15,16
re-
search syntheses,
17
or systematic reviews
18
little or
no attention has been directed to the systemic effects
of hyperventilation. Systemic effects are multifacto-
rial and interrelated, affecting multiple sites of the
body. Substantial differences exist between active
hyperventilation (when the subject voluntarily in-
creases his ventilation) and passive hyperventilation
(by means of artificial ventilation). In the former,
autonomic flow is markedly affected, while in the
latter the effects of CO
2
are combined with those of
the complex interaction between artificial ventilation
and hemodynamics. Additionally, when hyperventi-
lation is applied for reducing ICP, it is usually
combined with a number of concurrent interventions
such as sedation, paralysis, and increased fluid input.
Ventilatory and Hemodynamic Effects
Positive-pressure ventilation increases lung vol-
ume and intrathoracic pressure (ITP), even when a
normal level of arterial Pco
2
is maintained, affecting
systemic hemodynamics and lung physiology. It is
likely that the induction of hyperventilation en-
hances this effect, as an increase in alveolar ventila-
tion is necessary for inducing hypocapnia.
This may be achieved by increasing the tidal
volume and/or the respiratory rate, or by decreasing
the dead space. The most appropriate way for induc-
ing hypocapnia has not been determined, but it is
usually effected by increasing tidal volume. In stable
patients, this has little effect on ITP, but sudden
profound hyperventilation may cause marked hemo-
dynamic perturbations,
19
particularly in patients with
relative hypovolaemia. An increase in ITP has the
following four effects:
1. A reduction of the venous return to the right
side of the heart;
2. An increase in right ventricular (RV) afterload
(because of the compression of the pulmonary
capillaries);
3. A decrease in the size, volume, and compliance
of the left ventricle (LV) [the increased RV
end-systolic volume causes the interventricular
septum to bulge into the left ventricle]; and
4. A decrease of transmural LV pressure output.
The overall effect is that venous return is im-
paired. This adverse effect can in part be compen-
sated for by an increase in abdominal pressure and
intraabdominal vascular pressure due to a more
pronounced descent of the diaphragm following an
increase in lung volume.
20
Increased abdominal
pressure, however, may have an adverse effect on
ICP.
21
In the clinical setting, a reduced lung com-
pliance (resulting frequently from the concomitant
occurrence of pneumonia, pulmonary contusions, or
ARDS) will limit the increase in ITP even if alveolar
pressure increases.
The effect of positive-pressure ventilation on RV
performance depends on the degree to which venous
return (preload) is compromised and pulmonary
vascular resistance (afterload) is affected. If compen-
satory mechanisms are inadequate or if a dysfunction
of the RV was already present,
22
the most common
and important hemodynamic effect of an increase in
ventilation is a decrease in cardiac output due to a
decrease in the pressure gradient for systemic ve-
nous return.
The effects of positive-pressure ventilation on LV
function are less important but may also lead to a
reduction of cardiac output. This is primarily caused
by a reduced venous return as a consequence of
decreased LV end-diastolic volume, but also by a
reduction of LV diastolic compliance. This may
result from a septal shift (ie, ventricular interdepen-
dence) due to RV dilatation,
23
by pericardial volume
limitations
24
or by an increase in lung volume result-
ing in a direct mechanical compressive effect of the
expanding lung on the cardiac fossa.
25,26
These con-
siderations emphasize the importance of maintaining
normovolemia in patients with TBI in general and
particularly when artificial ventilation is employed.
A beneficial effect of artificial ventilation is the
reduction of LV afterload. In fact, LV systolic pres-
sure load is represented more accurately by LV
pressure relative to ITP, and an increase in ITP,
reducing the transmural LV pressure, decreases the
LV afterload. This mechanism may compensate for
the reduction in preload and the worsening of LV
compliance, thus maintaining a stable cardiac out-
put
27
and may even improve cardiac output when LV
end-diastolic volume is preserved.
28
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Respiratory Alkalosis and Electrolyte Disturbances
A fall of Paco
2
is associated with a primary
decrease in extracellular H
⫹
concentration.
29
The
cellular membranes, particularly the blood-brain
barrier, are relatively impermeable to hydrogen ions,
but permit a rapid diffusion of CO
2
. Therefore, the
intracellular hydrogen ion concentration is scarcely
influenced by changes in extracellular pH but can be
altered by changes in Paco
2
. The CO
2
passes
through the membrane, and, once inside the cell, is
able to hydrate and ionize, thus producing hydrogen
ions.
30
Following the onset of hyperventilation, a
rapid efflux of H
⫹
occurs within 10 min. In the
extracellular fluid, H
⫹
combines to HCO
3
⫺
to pro-
duce CO
2
. The extent of this compensatory reaction
is, however, not very efficient and, if hypocapnia is
prolonged, alkalosis develops.
29
A more efficient compensatory mechanism is ef-
fected by the kidney. A reduction in cellular Paco
2
in
tubular cells induces an increase in intracellular pH,
a reduction of H
⫹
secretion, and a loss of bicarbon-
ate, together with a decreased excretion of ammo-
nium (NH
4⫹
).
29
This response begins within2hbut
is fully effective for 2 to 3 days.
31
In the mammalian
nervous system, intracellular pH is one of the most
tightly regulated parameters. The maximum change
in H
⫹
concentration that can be tolerated is approx-
imately 0.0005 mmol.
32
One of the effects of intracellular alkalosis is the
activation of glycolysis, which occurs as a conse-
quence of the modulation of the rate-limiting en-
zyme phosphofructokinase.
33,34
The effect on pH of
lactic acid production provides a homeostatic mech-
anism for generating H
⫹
ions to rapidly counteract a
state of intracellular alkalosis.
32,35,36
The increase of
lactate levels during hypocapnia, which develops in
the absence of any failure of oxidative metabolism,
furnishes H
⫹
to compensate for the extracellular
reduction of H
⫹
. As a consequence of the shift of H
⫹
from the cellular to the extracellular compartment,
an opposite movement of K
⫹
(and Na
⫹
) from extra-
cellular fluid to the cell occurs. The resulting hypo-
kalemia is, however, typically mild.
29
The increase in
cellular phosphorylation causes a rapid shift of phos-
phate from the extracellular fluid into the cell, with
an associated reduction in plasma phosphate concen-
tration.
37
In patients with severe alkalosis, albumin
releases H
⫹
, and the binding of Ca
2⫹
is increased,
resulting in a reduction of the ionized fraction of
calcium,
38
,
37
which may result in clinical symptoms
including bradycardia and heart block, or even heart
failure and cardiac arrest. Such serious complications
are rare unless the concentration of ionized calcium
falls to ⬍ 0.8 mmol (3.2 mg/dL).
39
It may be sup-
posed that similar effects also pertaining to Mg
homeostasis are likely, and in this regard we note
that low Mg levels occur frequently following TBI.
40
In our opinion, particular attention should, there-
fore, be focused on electrolyte concentrations in
general following TBI, and in particular if hyperven-
tilation is employed.
Effects on Hemoglobin Dissociation Curve and
Drug Metabolism
Alkalosis increases the affinity of hemoglobin for
O
2
and displaces the dissociation curve to the left.
The following two compensatory mechanisms coun-
teract this leftward shift: a rapid increase in lactate
production
41
; and the induction of enzymatic activ-
ity. The increased intracellular pH activates glycoly-
sis, increases the activity of 2,3-diphosphoglycerate
(DPG) mutase and reduces the activity of DPG
phosphatase.
30
These enzymatic adjustments lead to
an increased concentration of 2,3-DPG, which over a
period of several hours may normalize the dissocia-
tion curve. The influence of the Bohr effect on O
2
affinity varies inversely with the degree of hemoglo-
bin saturation. Shifts of the dissociation curve are
therefore more relevant to the venous side of the
circulation. The importance of the Bohr effect on
changes in venous cerebral Po
2
has been studied by
various authors. Gotoh et al
42
found a decrease of
jugular Po
2
due to the Bohr effect of approximately
2.4 mm Hg. Cruz et al
43
reported a moderately
disproportional increase in jugular bulb oxygen sat-
uration (SjO
2
) relative to jugular bulb Po
2
when pH
increased to ⬎ 7.6.
Hypocapnia and respiratory alkalosis may also
affect the pharmacokinetic metabolism of drugs in
many of the following ways: changes in distribution
due to variations of the perfusion of organs; changes
of ionization of the drug due to a change in blood
pH; changes in solubility and transmembrane diffu-
sion; and changes in protein binding. Finally, the
urinary excretion of some drugs also may be altered
by changes in urinary pH.
Effects on Organ Systems
Hypocapnia decreases perfusion in most of the
body organ systems, including the heart,
44
the liver,
the gut,
45,46
skeletal muscle,
47
and skin.
48
A reduc-
tion in coronary perfusion due to hypocapnia may
cause increased risk for cardiac ischemia in patients
with preexisting coronary artery disease. Kazmaier et
al
44
found a mild increase in systemic vascular
resistance and a mild reduction in cardiac index
when passive mild hyperventilation was employed in
patients with coronary artery disease. Despite the
absence of significant changes in coronary perfusion
pressure and myocardial blood flow, a reduction in
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coronary sinus Po
2
and oxygen saturation have been
reported. The risk of coronary spasm is increased
during hypocapnia, and in fact active hyperventila-
tion has been used for the noninvasive diagnosis of
coronary spasm.
49
The kidney is the main organ
involved in the compensatory control of pH during
chronic hyperventilation.
50,51
Urinary electrolyte
changes (ie, an increase in Na
⫹
or a decrease in K
⫹
)
together with a pH increase are part of the compen-
satory mechanisms in cases of alkalosis.
In the lung, respiratory alkalosis induces vasodila-
tation of pulmonary vessels
52
and bronchoconstric-
tion.
53,54
The cumulative resulting effect is a reduc-
tion in Pao
2
due to a ventilation/perfusion
mismatch.
55
In patients with severe head injury,
Turner et al
56
found a decrease in Pao
2
from 115 to
99.5 mm Hg after1hofhyperventilation. Other
clinical research has suggested further adverse pul-
monary effects, including increased airway perme-
ability,
57
dysfunctional surfactant levels,
58
and re-
duced lung compliance.
59
Further, Laffey et al
60
showed in an experimental study that hypocap-
nic alkalosis may potentiate ischemia-reperfusion-
induced lung injury. Ventilation strategies that are
commonly employed in patients with TBI include
high tidal volume and low positive end-expiratory
pressure, and these may increase the risk of worsen-
ing acute lung injury,
61–63
both as a consequence of
an increase of lung stretch and the reversal of a
“protective effect” of hypercapnia. These potentially
adverse effects of hyperventilation on pulmonary
function are particularly relevant to the treatment of
TBI as approximately 20% of patients experience
concomitant acute lung injury
64
and the incidence of
pneumonia has been reported to be as high 40 to
50%.
65
Cerebral Effects of Hyperventilation
Hyperventilation and ICP
Hyperventilation has been used in the manage-
ment of severe TBI for ⬎ 40 years since Lundberg et
al
66
reported its use to lower elevated ICP in 1959.
Hyperventilation reduces ICP by causing cerebral
vasoconstriction and a subsequent reduction in ce-
rebral blood volume.
2
Fortune et al
67
showed that
decreasing arterial Pco
2
to 26 mm Hg in eight
healthy individuals decreased cerebral blood volume
by 7.2% and further decreased CBF by 30.7%.
Obrist et al
68
showed a beneficial effect of hyperven-
tilation on ICP in 15 of 31 patients with severe TBI
but at the same time demonstrated a reduction in
CBF in 29 of 31 patients. Several investigators have
reported
69,70
that the relationship between Paco
2
and ICP is not linear, and that the greatest effect is
between Paco
2
values of 30 and 50 mm Hg in
humans. In experimental studies over wide ranges of
Paco
2
, a sigmoid relation between ICP and Paco
2
has been found.
71
In a clinical study of 94 patients with severe head
injury, Yoshihara et al
72
found that a blood volume
change of only 0.5 mL was necessary to produce an
ICP change of 1 mm Hg. Consistent with the
concept of the pressure-volume curve (Fig 1), a
lower blood volume was necessary to produce a
significant ICP change in patients with reduced
compliance. Further, it was shown that the effects on
ICP were greater during hypercapnia than during
hypocapnia. Similar results have also been reported
by Stocchetti et al,
73
who calculated a mean (⫾ SD)
blood volume change of 0.72 ⫾ 0.42 mL for each
millimeter of mercury of change in Paco
2
. Surpris-
ingly, only a few studies have addressed the impor-
tant question of whether beneficial effects on ICP
remain present during prolonged hyperventilation.
Muizelaar et al
12
have stressed that the vasoconstric-
tive effect will be diminished in prolonged hyperven-
tilation as the pH of the perivascular spaces normal-
izes after 24 h. They further demonstrated in
experimental studies that a rebound vasodilation may
occur along with a risk of increasing ICP following
the discontinuation of hyperventilation.
Hyperventilation and CBF
A major concern in treating raised ICP by hyper-
ventilation is the risk of inducing cerebral ischemia,
either globally or regionally. As in stroke, the risk of
ischemic damage is dependent on the extent and
duration of low-flow states (Fig 3). In the early
posttraumatic phase, both global and regional CBF
are markedly decreased,
74,75
and the presence of low
Figure 3. Graph illustrating the relations among decreased
CBF, reversible ischemia, and infarction. Adapted from Jones et
al.
149
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CBF early following TBI is significantly associated
with early mortality and poorer outcome.
76,77
CBF
can be measured, directly or indirectly, by a number
of methods, none of which, however, are easily
available at the bedside in the ICU environment.
CBF measurements with radioactive
131
Xe were
introduced for clinical use in the 1970s, but this
technique was later banned from clinical use because
of radiation dangers. Following the introduction of
faster multislice CT scanners, Xe-CT scans became a
standard technique for measuring CBF with the use
of stable, nonradioactive Xe during CT scans of the
brain. Inhaled Xe, which is freely diffusable from the
lungs to the blood, and from the cerebral vasculature
to the brain tissue, can be detected in the brain via
CT scan because it increases the attenuation of
x-rays.
78
Direct measurements of CBF can further
be performed with positron emission tomography
(PET) scanners, which offer the additional benefit of
assessing metabolic parameters. PET scanning is,
however, available in only a few research centers;
provides, as is also the case in stable Xe-CT scanning,
only momentary information; and involves transport
from the ICU environment for longer periods of
time. Indirect measurements of CBF can be per-
formed with transcranial Doppler ultrasonography
techniques, which permit measurements of blood
flow velocity through the basal intracranial arteries.
Blood flow velocity, however, does not directly cor-
respond to CBF, as no information is available on the
diameter of the cerebral arteries.
Using Xe-CT scanning to quantify regional CBF,
Bouma et al
77
found CBF values below ischemic
thresholds of 18 mL per 100 g of tissue per minute
in 31% of TBI patients. In a retrospective analysis of
TBI patients with subdural hematomas, Marion et
al
13
observed the lowest CBF within the first 24 h
following injury ipsilateral to the hematoma. Studies
with transcranial Doppler ultrasonography have also
shown a low-flow velocity state in the early phase
after injury, occurring in 63% of patients.
79
As low CBF is common in the first 24 h after a
TBI, there is particular concern for aggravating the
risk of ischemia by the institution of hyperventila-
tion.
13
In healthy volunteers, Raichle et al
80
de-
scribed a 40% decrease in CBF 30 min after decreas-
ing Paco
2
by 15 to 20 mm Hg. The response,
however, was transitory, and after 4 h, CBF was
restored to 90% of baseline values. Clinical studies in
patients with TBI have shown a 3% change in CBF
per millimeter of mercury change in Paco
2
, but the
response was lower in patients with lower CBF
levels.
81
Various clinical studies
68,82–85
have confirmed an
adverse effect of hyperventilation on CBF levels in
patients with TBI. McLaughlin and Marion
86
further
showed increased CO
2
vasoresponsivity in contu-
sions and the surrounding penumbra, and they hy-
pothesized that this possible hypersensitivity in com-
bination with relative hypoperfusion may render
such lesions particularly vulnerable to secondary
ischemic injury, which may be aggravated by hyper-
ventilation. The ultimate question, however, is
whether the observed reduction in CBF following
hyperventilation indeed leads to clinically significant
ischemia, as evidenced by metabolic studies. Dir-
inger et al,
87
for instance, showed that brief moder-
ate hyperventilation did not impair global cerebral
metabolism and oxygen extraction in patients with
severe TBIs, despite a clear decrease in global CBF
level. Cruz
88
has argued that the decrease in CBF
level following hyperventilation is acceptable as long
as the metabolic parameters are not deranged.
Hyperventilation and Cerebral Oxygenation
The monitoring of cerebral oxygenation has re-
ceived considerable attention in view of the signifi-
cant risk of hyperventilation to decrease CBF levels
and possibly to induce/aggravate ischemia. Clinical
studies have focused on jugular bulb oximetry and
the monitoring of brain tissue oxygen tension
(Pbro
2
).
In jugular bulb oximetry, SjO
2
is monitored either
continuously with fiber optic techniques or intermit-
tently from blood sampling. It is therefore a global
technique providing information on the oxygen ex-
traction from the cerebral venous blood draining via
that particular vein. However, this does not neces-
sarily reflect hemispheric values as cross-flow may
exist, with one jugular vein being more dominant.
89
It is generally preferred to measure/sample in the
dominant vein.
Under normal circumstances (eg, awake or under
normal hemoglobin concentration) the SjO
2
ranges
from 55 to 70%. Values below 50 to 55% are
generally regarded to represent global cerebral hy-
poperfusion with an increase in cerebral oxygen
extraction.
90
Additional information can be obtained
by calculating AVDO
2
or by determining the oxygen
extraction fraction. Some studies
91,92
have shown
that forced hyperventilation, although normalizing
ICP, can lead to significantly reduced cerebral oxy-
genation. Other studies,
93,94
however, have de-
scribed SjO
2
values of ⬎ 55% with a concomitant
reduction in ICP. In the experimental situation,
Sutton et al
95
found a significant drop in venous
oxygen content following hyperventilation in two of
six animals studied, accompanied by a decrease in
phosphocreatine level, which was rapidly reversible
after reestablishing normocapnia.
Cruz and colleagues
88,96–98
investigated the so-
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called flow-metabolism coupling and showed that in
approximately 20% of patients with elevated ICP
blood flow outstrips cerebral metabolic demands.
Hyperventilation in this subgroup may lower CBF
and improve ICP without reducing cerebral oxygen-
ation. Cruz and colleagues
88,96–98
have proposed the
concept of optimizing hyperventilation on the basis
of SjO
2
-derived parameters, aiming to both normal-
ize ICP and decrease the cerebral extraction of
oxygen by manipulating hyperventilation, to Paco
2
values ranging from18 to 30 mm Hg. Cruz et al
88
have claimed that this approach yielded better pa-
tient outcomes compared to CPP-directed therapy.
However, others
94
have argued that, even with care-
ful SjO
2
monitoring, the risk of inducing iatrogenic
ischemia with hyperventilation to Paco
2
levels ⬍ 30
mm Hg is too large, and therefore the physician
should adhere to CPP-based therapy by maintaining
Paco
2
levels at ⬎ 30 mm Hg.
In contrast to SjO
2
monitoring, Pbro
2
monitoring
is a regional technique. Most studies on monitoring
Pbro
2
also have shown a deleterious effect of hyper-
ventilation on cerebral oxygenation. Continuous
Pbro
2
monitoring became possible when miniatur-
ized probes, which can be inserted into the cerebral
cortex, were manufactured. The first probe was a
polarographic, Clark-type sensor, in which a cathode
and an anode were contained in a membrane that
was only permeable to oxygen. When oxygen diffuses
from the tissue into the probe, it generates an
electric current between the cathode and anode that
is proportional to the oxygen tension. Subsequently,
additional technologies for Pbro
2
monitoring (ie,
colorimetric systems) became available.
99
All systems
display numeric values, expressing the oxygen ten-
sion in millimeters of mercury. Normal values in the
brains of various species, including humans, are ⬎ 20
mm Hg. Prolonged and profound reductions below
this value have proven to be an independent predic-
tor of unfavorable outcome and death.
100
Hemphill et al
101
showed a linear relation between
Pbro
2
and CBF with changes in end-tidal CO
2
and
further confirmed a linear relation between Pbro
2
and end-tidal CO
2
levels over ranges between 20 and
60 mm Hg. Various other experimental studies
102–104
have shown a decrease in Pbro
2
following hyperven-
tilation. In a study on 16 swine, Manley et al
103
showed a 40% decrease in mean ( ⫾ SD) Pbro
2
level
from 36 ⫾ 11 to 20 ⫾ 9 mm Hg after hyperventila-
tion. The deleterious effect of hyperventilation on
Pbro
2
has been confirmed in many clinical stud-
ies.
91,105–111
In two studies,
112,113
however, the de-
crease in Pbro
2
was not significant, and some stud-
ies
108,110,111
have even reported an increase in Pbro
2
in some cases. These seemingly conflicting results
may be explained by differences in pathophysiology
between individual patients and would seem to favor
the optimized hyperventilation approach advocated
by Cruz et al.
98
In patients with raised ICP that is
due mainly to cerebral vasodilation (hyperemia),
hyperventilation may restore blood flow within dam-
aged regions. This is also illustrated by different
responses on SjO
2
monitoring compared to brain
tissue oxygenation when Pbro
2
catheters are placed
near the penumbra of focal lesions.
113
The effect of hyperventilation on Pbro
2
seems to
be time-dependent. Initially, van Santbrink et al
105
showed in 1996 that the tissue oxygen response to
changes in Paco
2
was most marked on day 5 after
trauma. In a follow-up study in 2000, Carmona
Suazo et al
109
showed increasing tissue oxygen re-
sponse to hyperventilation over time, and found a
significant relation between increased tissue oxygen
response on day 5 and poorer outcome. Similar
observations have been reported by others.
107,114
The observation that the deleterious effect of hyper-
ventilation on Pbro
2
increases over time is intrigu-
ing. Until now, the greatest clinical concern for the
risk of ischemia following hyperventilation has been
within the first 24 h after injury as low CBF fre-
quently occurs in this time period. It may, however,
be argued that within this time frame of 24 h a
general state of vascular narrowing exists and that
further effects of hyperventilation may not have
serious adverse consequences. The increasing tissue
oxygen response over time may indicate an increased
risk of ischemia, particularly at later time points.
However, further research is necessary to confirm
these results.
Hyperventilation, Neurochemical
Monitoring, and Metabolism
Information on the metabolic status of the brain
can be obtained from chemical monitoring in the
jugular venous blood, from microdialysis studies,
from PET scan studies, or from MRI spectroscopy.
After severe head injury, elevated levels of lactate in
the CSF have been frequently shown.
115–119
Based on the results of lactate determinations in
jugular venous blood, various authors
116,120,121
have
shown the increased cerebral formation of lactate. In
the study by Robertson et al,
120
lactate levels in-
creased in proportion to the severity of cerebral
trauma experienced during the first 2 days after
injury. Murr et al,
122
in a study of 21 patients with
severe TBI, showed that in patients with intracranial
hypertension the cerebral lactate level difference
remained significantly increased from the first to the
fifth day after injury, but normalized over this period
in the group with normal or minimally elevated ICP
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values. Averaged over the short-term course, pa-
tients with increased ICP had significantly higher
mean lactate level differences, and a significant
correlation of increased mean cerebral lactate differ-
ence to poor outcome was noted.
Cerebral microdialysis is a relatively new tech-
nique for measuring metabolic parameters in the
extracellular fluid and is being increasingly used in
the monitoring of TBI patients, particularly in the
research setting. Artificial CSF is injected into, and
recovered from, a probe inserted in the cerebral
cortex. The fluid equilibrates with the extracellular
concentration of various metabolites, depending on
the permeability of the microdialysis membrane, the
length of the probe, and the velocity of injection.
Microdialysis allows the long-term measurement of
extracellular fluid energy-related metabolites (eg,
glucose, lactate, and pyruvate) and amino acids in the
cerebral cortex.
123
Goodman et al
45
measured lactate
and glucose levels in 126 patients with head injuries.
They found an initial increase in lactate level, per-
haps indicating the presence of compensated hyper-
glycolysis, which gradually decreased during the first
24 to 48 h. Correlations have been demonstrated
between low brain tissue oxygen levels and increased
lactate levels.
124,125
Reinert et al
126
further demon-
strated that increases in potassium levels were cor-
related with lactate accumulation, and were associ-
ated with increased ICP and poorer outcome. In
contrast to other studies,
126
however, some episodes
of high lactate levels were not associated with low
brain tissue oxygen levels. The specific effect of
hyperventilation on extracellular concentrations of
glutamate, lactate, pyruvate, and local CBF in pa-
tients with TBIs were reported by Marion et al.
127
Hyperventilation studies, lowering arterial Pco
2
by 8
to 12 mm Hg, were conducted 24 to 36 h after injury
and again at 3 to 4 days after injury. At 24 to 36 h
after TBI, hyperventilation led to a significant in-
crease in lactate levels and in the lactate/pyruvate
ratio. At 3 to 4 days after TBI, hyperventilation also
led to a significant increase in lactate levels, but the
differences in the lactate/pyruvate ratio were not
significant. The authors concluded that hyperventi-
lation-induced changes are more pronounced during
the first 24 to 36 h after TBI than at 3 to 4 days after
TBI.
The distribution and intensity of the uptake of
positron-emitting radiotracers in the tissue is an
indicator of metabolism. PET scanning is a tech-
nique that allows the precise measurement of bio-
molecules such as glucose or oxygen in a living organ,
such as the brain. A short-lived radioisotope is
synthetically bound to the molecule of interest to
form a positron-emitting radiotracer, which can be
detected and quantitatively measured by PET scan-
ning.
128
The effect of hyperventilation on the cerebral
oxygen metabolism has been studied by Diringer et
al
129
with PET scan studies. Nine patients with
severe TBIs were moderately hyperventilated, and
four more patients were intensely hyperventilated to
a mean Paco
2
of 25 ⫾ 2 mm Hg. Although this study
demonstrated a significant decrease in CBF and an
increase in oxygen extraction fraction following hy-
perventilation, CMRO
2
remained unchanged. It was
concluded that brief hyperventilation may produce
large reductions in CBF but does not lead to energy
failure, and the authors considered that the observed
reductions in CBF are therefore unlikely to cause
further brain injury. Some serious limitations of this
study were that only a few patients were studied, and
that the duration of hyperventilation was relatively
short and was maintained only for the duration of the
actual PET scan study.
Coles et al
94
have shown in studies by conducted
by PET scanning (see next section) that hyperventi-
lation increases the volume of severely hypoperfused
tissue within the injured brain, despite improve-
ments in CPP and ICP. The same group has sug-
gested more recently
130
that the injured brain may
be less capable of increasing oxygen extraction in
response to hypoperfusion, so that shortly after
injury the brain could be more vulnerable to the
CBF reduction induced by hyperventilation.
Hyperventilation and Clinical Outcome
Despite the wide use of hyperventilation in the
treatment of raised ICP after TBI and the large body
of evidence indicating the possible deleterious ef-
fects of hyperventilation on CBF levels, oxygenation,
and metabolism, only one prospective randomized
clinical trial has been reported concerning the effect
of hyperventilation on clinical outcome. Muizelaar et
al
131
compared the outcomes of patients who were
hyperventilated to a Paco
2
of 25 mm Hg for 5 days
to patients in whom the Paco
2
was kept at 35 mm
Hg. At both 3 and 6 months after injury, patients
with an initial Glasgow coma scale motor score of 4
or 5 had a significantly better outcome when they
were not hyperventilated. This study formed the
basis for the recommendation at the level of a
standard (class I evidence) in the guidelines for the
management of TBI stating the following: “. . . in the
absence of increased ICP, prolonged hyperventila-
tion therapy (Paco
2
ⱕ 25 mm Hg) should be
avoided.” In addition, the guidelines state that “the
use of prophylactic hyperventilation (Paco
2
⬍ 35
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mm Hg) should be avoided during the first 24 h after
severe TBI because it can compromise cerebral
perfusion during a time when CBF is reduced.”
However, at the level of an option, it is recognized
that hyperventilation therapy may be necessary for
brief periods when there has been acute neurologic
deterioration or for longer periods if intracranial
hypertension is refractory to other therapy.
We consider the class I evidence underlying the
standard of these guidelines debatable and open to
criticism. First, the control group was in fact mildly
hyperventilated with a Paco
2
of 31 to 32 mm Hg.
Second, the subgroup of patients with a Glasgow
coma score motor score of 4 to 5 was not prespeci-
fied, and numbers were small (control group, 21
patients; hyperventilation group, 17 patients). Third,
the study was confined to patients without raised
ICP. Fourth, the best outcome was achieved by a
third group of TBI patients, included in the study
but neglected in further discussions, who had been
hyperventilated and had received tromethamine
(TRAM).
Synthesis and Conclusions
The use of hyperventilation in the treatment of
patients with TBI remains controversial. Studies
reporting beneficial and potentially adverse effects of
hyperventilation on cerebral parameters are summa-
rized in Table 2. The controversy has been illustrated
by various editorials and comments in the litera-
ture.
111,132–135
The proponents of hyperventilation
claim that it is effective in reducing ICP and that,
despite a concomitant reduction in CBF levels, there
is no evidence that this results in further metabolic
derangement, and from this they conclude that the
risk of ischemia is a nonissue. Adversaries of hyper-
ventilation focus on the deleterious effects on CBF
level, cerebral oxygenation, and neurochemical pa-
rameters obtained in microdialysis studies. Further,
the lack of evidence of a beneficial effect on clinical
outcome has been emphasized.
136
How can these two widely different points of view
and approaches be reconciled? The answer to this
question touches on the general discussion on stan-
dardized management vs more individually targeted
approach. As Chesnut
132
summarizes in the follow-
ing way: “It is unclear why the various treatment
modalities are felt to be mutually exclusive and all
encompassing in the area of neurotrauma manage-
ment.” Even the greatest proponent of hyperventi-
lation
88
has emphasized the need for “optimized
hyperventilation” aiming at correcting the mismatch
between flow and oxygen metabolism, to which
purpose multimodality monitoring including jugular
oximetry is required. The adversaries of hyperventi-
lation, who usually belong to the school advocating
CPP therapy, will have to admit that the inadvertent
use of therapy with vasopressors and hypervolemia
also carries risks concerning a prolonged course of
raised ICP, fluid overload, and an increased risk of
ARDS.
137
We submit that both approaches may
be appropriate under specifically defined circum-
stances, targeting the therapy to the individual
requirements of patients. The standard, as contained
in the international guidelines
14
on hyperventilation,
stating that prolonged hyperventilation in TBI pa-
tients without raised ICP should be avoided, must be
put into the appropriate perspective. It may be
argued that in patients without raised ICP there is no
indication for hyperventilation. To date, there is no
evidence in the literature unequivocally demonstrat-
ing that hyperventilation for the treatment of raised
ICP in patients with TBI is related to poorer out-
come, and there is also no evidence showing bene-
ficial effects on overall outcome. When considering a
therapy without proven clinical efficacy, a careful
analysis of risks and benefits is required, considering
the indication for and the duration of treatment.
Risks concern systemic and cerebral complications.
Systemic risks would appear to be greater, particu-
larly in patients with preexistent cardiac disease and
in patients with absolute or relative hypovolemia. In
this regard, it should be noted that inadvertent
hyperventilation is frequent in the prehospital set-
ting at a time when optimal volume resuscitation has
not yet been accomplished. Thomas et al
138
reported
an incidence of low end-tidal CO
2
in 70% of patients
with TBI who were undergoing helicopter transport
to an urban level 1 trauma center.
Cerebral complications particularly relate to the
risk of ischemia. Considering the risk-benefit rela-
tion, it would appear to be clear that the possibility of
instituting hyperventilation therapy should be con-
sidered only in patients with raised ICP. No benefit
may be expected in the absence of raised ICP.
Theoretically, the benefit of hyperventilation may be
more particularly expected in patients in whom
raised ICP is considered mainly due to increased
cerebral blood volume due to vasodilation. In the
opinion of the authors, this would preferentially be
the pediatric and young adult population. In clinical
practice, however, it may be very difficult, if not
impossible, to differentiate between the contribution
of edema and cerebral blood volume to traumatic
brain swelling following TBI, without facilities for
PET scanning or MRI diffusion-weighted imaging.
Marmarou et al
139
showed in a study of 31 patients
with TBI that brain swelling due to cerebral blood
volume averaged 2.94% compared with an average of
9.1% for brain swelling due to edema. In this group
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Table 2—Effect of Hyperventilation on Cerebral Parameters*
Study/Year
No.
Patients
Duration of
hyperventilation ICP CBF TCD SJO
2
PbrO
2
Comments and Remarks
Ausina et al
142
/1998 33 4 h ss Maximum effect at 30 min; mild tendency to
return at 2 h; on average, no change in
AVDO
2
, but dangerous increase in 1
patient
Berre´etal
143
/1998 36 20 min ss s s CMRO
2
: no change
Carmona Suazo et al
109
/
2000
90 15 min s Absent or low effect on day 1, increasing to
day 5
Cold et al
81
/1989 27 10 min ss Increase of regional oligemia of 5–16%
Coles et al
94
/2002 33 10 min ss PET studies shows an increase in the
volume of critically perfused brain tissue
at Paco
2
values ⬍ 34 mm Hg
Dings et al
114
/1996 17 10 min ssAbsent or low CO
2
reactivity on day 1;
highest reactivity on day 5
Diringer et al
129
/2002 9 30 min s CMRO
2
, no change; OEF, a;Cvo
2
, s;
CBV s
Fandino et al
107
/1999 9 10 min ss sHigher CO
2
reactivity day 5–7
Fortune et al
67
/1995 22 20 min ss
Gupta et al
113
/1999 13 15 min ssDecrease in Pbro
2
most marked in areas of
focal pathology.
Local changes not detected bo SJO
2
Imberti et al
111
/2002 36 20 min sssCritical decrease of PbrO
2
or increase of
Sjo
2
in 7 patients
Lee et al
144
/2001 20 10 min s Mean CO
2
reactivity, 3.3 ⫾ 1.6% Vmca/mm
Hg; tendency to higher values on days
5–13
Marion and Bouma
145
/
1991
17 20 min s CO
2
responsivity ranges from 1.3–8.5%/mm
Hg Pco
2
; regional differences of ⱖ 50%
compared to global values in 16 patients
Marion et al
127
/2002 20 30 min s Decrease in pericontusional CBF more
pronounced 24–36 h after trauma;
microdialysis studies demonstrate increase
in glutamate and lactate following
hyperventilation
McLaughin and Marion
86
/
1996
10 20 min s Large variations in vasoresponsitivity to
hyperventilation in and around contusions
Minassian et al
150
/1998 12 10–15 min ss AVDO
2
; higher reactivity on days 4–6 is
related to better outcome
Newell et al
152
/1996 10 10 min ss Mild hyperventilation may improve vascular
tone and autoregulation
Obrist et al
68
/1984 31 Short duration ss Higher reactivity in patients with hyperaemia
Oertel et al
146
/2002 33 15 min sss Greater effect at higher baseline Paco
2
Oertel et al
147
/2002 20 ? ? Normal ICP, hyperventilation increases
pulsatility index
ICP, ⬎ 30: hyperventilation decreases
pulsatility index
The authors suggested that hyperventilation
may improve cerebral microcirculation in
the setting of raised ICP
Schneider et al
112
/1998 15 10 min ssHyperventilation challenge stopped in 1
patient because of a critical decrease in
Pbro
2
Skippen et al
83
/1997 23 15 min s Pediatric population; mean CO
2
reactivity
2.7%/mm Hg (range, 7.1–2.3%/mm Hg)
Thiagarajan et al
151
/1998 18 30 min s Decrease in SjO
2
following hyperventilation
may be offset by increasing PAo
2
Vigue et al
141
/2000 20 20 min ss s sChanges in ICP and Vmca following
hypothermia can be explained by changes
in temperature-corrected Paco
2
*s ⫽ decrease; a ⫽ increase; Cvo
2
⫽ venous oxygen content; Vmca ⫽ velocity in the middle cerebral artery change for every mm Hg;
? ⫽ unknown.
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of patients, cerebral blood volume was increased in
only five patients compared to the levels obtained in
seven volunteers. However, no mention was made on
the time period within which these studies were
performed.
It has been argued that the main risk of ischemia
due to hyperventilation will be present within the
first 24 h after injury, as this is the period in which
low CBF levels occur. We think that this generally
accepted opinion may be challenged. If indeed this
acute phase is characterized by a generalized state of
vascular narrowing, the additional effect of hyper-
ventilation may be expected to be low, and this has
indeed been demonstrated in various studies.
109
Therefore, it may be tentatively concluded that the
institution of hyperventilation therapy may be more
appropriate during the relative hyperemic phases of
days 2 and 3 after TBI. Nevertheless, the risk of
ischemic complications cannot be excluded, and the
careful monitoring of cerebral oxygenation is re-
quired.
Current evidence would favor a relatively short
duration of hyperventilation therapy. The general
consensus is not to hyperventilate TBI patients
below a Paco
2
of 30 mm Hg. In exceptional circum-
stances, more intense hyperventilation may, how-
ever, be considered under careful monitoring.
Jugular oximetry permits the monitoring of global
cerebral oxygen extraction, and local brain tissue Po
2
monitoring may yield additional information in the
penumbra around contusions. McLaughlin and
Marion
86
have reported increased vasoreactivity in
the penumbra zones around the contusions up to
nearly three times normal, suggesting the hypersen-
sitivity of this region to hyperventilation therapy.
Metabolic studies with MRI spectroscopy or PET
scanning may be required before the possibility of
local adverse effects of hyperventilation can be fully
evaluated.
When considering the appropriate depth of hyper-
ventilation, two specific circumstances need to be
recognized. First, at higher altitudes normal Paco
2
levels may be well below the generally accepted
levels of 35 to 45 mm Hg that were determined at
sea level. A correction for the influence of altitude is
therefore required. Second, the influence of temper-
ature, particularly when hypothermia therapy is
used, should be considered. In the laboratory, blood
gas measurements are generally performed at 37°C,
and the results are not corrected for body core
temperature. The validity for performing tempera-
ture corrections has been argued.
140
In a more
recent article, Vigue et al
141
showed that the institu-
tion of hypothermia leads to a decrease in end-tidal
CO
2
and Paco
2
due to a systemic and cerebral
reduction of metabolism. In fact, these authors
argued that the reduction of ICP following hypother-
mia may be fully explained by the concomitant
decrease of Paco
2
.
In conclusion, controversy exists, as exemplified in
Table 2, and conflicting data may support a range of
therapeutic options, from the enthusiastic overuse of
hyperventilation to the avoidance of hyperventila-
tion. It is our opinion that the careful use of hypo-
capnia for the short-term control of raised ICP
remains a useful therapeutic tool. Multimodality
monitoring is required in order to safely target
hyperventilation therapy to specific patients who
may benefit from it.
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