JOURNAL OF NEUROTRAUMA

Volume 24, Supplement 1, 2007

© Brain Trauma Foundation
Pp. S-87–S-90
DOI: 10.1089/neu.2007.9982

XIV. Hyperventilation
SUSAN L. BRATTON,1 RANDALL M. CHESTNUT,2 JAMSHID GHAJAR,3,4
FLORA F. MCCONNELL HAMMOND,5 ODETTE A. HARRIS,6 ROGER HARTL,3
GEOFFREY T. MANLEY,7 ANDREW NEMECEK,8 DAVID W. NEWELL,9 GUY ROSENTHAL,7
JOOST SCHOUTEN,10 LORI SHUTTER,11 SHELLY D. TIMMONS,12 JAMIE S. ULLMAN,13,14
WALTER VIDETTA,15 JACK E. WILBERGER,16 and DAVID W. WRIGHT6

I. RECOMMENDATIONS II. OVERVIEW

A. Level I Aggressive hyperventilation (arterial PaCO2  25 mm

There are insufficient data to support a Level I rec-
ommendation for this topic.
B. Level II
Prophylactic hyperventilation (PaCO2 of 25 mm Hg
or less) is not recommended.
C. Level III
Hyperventilation is recommended as a temporizing
measure for the reduction of elevated intracranial pres-
sure (ICP).
Hyperventilation should be avoided during the first 24
hours after injury when cerebral blood flow (CBF) is of-
ten critically reduced.
If hyperventilation is used, jugular venous oxygen sat-
uration (SjO2) or brain tissue oxygen tension (PbrO2) mea-
surements are recommended to monitor oxygen delivery.
Hg) has been a cornerstone in the management of severe
traumatic brain injury (TBI) for more than 20 years because
it can cause a rapid reduction of ICP. Brain swelling and
elevated ICP develop in 40% of patients with severe TBI,15
and high or uncontrolled ICP is one of the most common
causes of death and neurologic disability after TBI.1,13,18
Therefore, the assumption has been made that hyperventi-
lation benefits all patients with severe TBI. As recent as
1995, a survey found that hyperventilation was being used
by 83% of U.S. trauma centers.6
However, hyperventilation reduces ICP by causing cere-
bral vasoconstriction and a subsequent reduction in CBF.20
Research conducted over the past 20 years clearly demon-
strates that CBF during the first day after injury is less than
half that of normal individuals,2,3,5,11,12,16,21,23,24 and that
there is a risk of causing cerebral ischemia with aggressive
hyperventilation. Histologic evidence of cerebral ischemia
has been found in most victims of severe TBI who die.7,8,22
A randomized study found significantly poorer outcomes

1Department of Pediatrics, University of Utah, Salt Lake City, Utah.

2Department of Neurological Surgery, University of Washington, Seattle, Washington.
3Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
4Brain Trauma Foundation, New York, New York.
5Carolinas Rehabilitation, Charlotte, North Carolina.
6Department of Neurosurgery, Emory University, Atlanta, Georgia.
7Department of Neurosurgery, San Francisco General Hospital, San Francisco, California.
8Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon.
9Seattle Neuroscience Institute, Seattle, Washington.
10Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands.
11Department of Neurology, University of Cincinnati, Cincinnati, Ohio.
12Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee.
13Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York.
14Deparment of Neurosurgery, Elmhurst Hospital Center, Flushing, New York.
15Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina.
16Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania.

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 XIV. HYPERVENTILATION
at 3 and 6 months when prophylactic hyperventilation was
used, as compared to when it was not.17 Thus, limiting the
use of hyperventilation following severe TBI may help im-
prove neurologic recovery following injury, or at least avoid
iatrogenic cerebral ischemia.
III. PROCESS
For this update, Medline was searched from 1996
through April of 2006 (see Appendix B for search strat-
egy), and results were supplemented with literature rec-
ommended by peers or identified from reference lists. Of
23 potentially relevant studies, 2 were added to the ex-
isting tables and used as evidence for this question (Ev-
idence Tables I, II, and III).
IV. SCIENTIFIC FOUNDATION
CBF Following TBI
Three studies provide Class III evidence that CBF can
be dangerously low soon after severe TBI (Evidence Table
I).2,12,26 Two measured CBF with xenon-CT/CBF method
during the first 5 days following severe TBI in a total of
67 patients. In one, CBF measurements obtained during the
first 24 h after injury were less than 18 mL/100 g/min in
31.4% of patients.2 In the second, the mean CBF during
the first few hours after injury was 27 mL/100g/min.12
The third study measured CBF with a thermodiffusion
blood flow probe, again during the first 5 days post-in-
jury, in 37 severe TBI patients.26 Twelve patients had a
CBF less than 18 mL/100g/min up to 48 h post-injury.
PaCO2/CBF Reactivity and Cerebral
Oxygen Utilization
Three Class III studies provide the evidence base for
this topic (Evidence Table II).10,19,25 Results associating
hyperventilation with SjO2 and PbrO2 values in a total of
102 patients are equivocal. One study showed no con-
sistent positive or negative change in SjO2 or PbrO2 val-
ues.10 A second study associated hyperventilation with a
reduction of PaCO2 and subsequent decrease in SjO2
from 73% to 67%, but the SjO2 values never dropped be-
low 55%.19 The third reported hyperventilation to be the
second most common identifiable cause of jugular ve-
nous oxygen desaturation in a sample of 33 patients.25
Studies on regional CBF show significant variation in
reduction in CBF following TBI. Two studies indicated
lowest flows in brain tissue surrounding contusions or
underlying subdural hematomas, and in patients with se-
vere diffuse injuries.12,23 Similarly, a third found that
CO2 vasoresponsivity was most abnormal in contusions
and subdural hematomas.14 Considering that CO2 va-
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soresponsivity could range from almost absent to three
times normal in these patients, there could be a danger-
ous reduction in CBF to brain tissue surrounding contu-
sions or underlying subdural clots following hyperventi-
lation. (Note only one of these three studies12 had
adequate design and sample to be included as evidence.)
Two studies, not included in the evidence base for this
topic, associated hyperventilation-induced reduction in
CBF with a significant increase in oxygen extraction frac-
tion (OEF), but they did not find a significant relation-
ship between hyperventilation and change in the cerebral
metabolic rate of oxygen (CMRO2).4,9
Effect of Hyperventilation on Outcome
One Class II randomized controlled trial (RCT) of 113
patients (Evidence Table III) used a stratified, random-
ized design to compare outcomes of severe TBI patients
provided normal ventilation (PaCO2 35  2 mm Hg; n 
41; control group), hyperventilation (PaCO2 25  2 mm
Hg; n  36), or hyperventilation with tromethamine
(THAM; n  36).17 One benefit of hyperventilation is
considered to be minimization of cerebrospinal fluid
(CSF) acidosis. However, the effect on CSF pH may not
be sustained due to a loss of HCO3 buffer. THAM treat-
ment was introduced to test the hypothesis that it would
reverse the effects of the loss of buffer.
Patients were stratified based on the motor component
of the Glasgow Coma Scale (GCS) score (1–3 and 4–5).
The Glasgow Outcome Scale (GOS) score was used to
assess patient outcomes at 3, 6, and 12 months. For pa-
tients with a motor GCS of 4–5, the 3- and 6-month GOS
scores were significantly lower in the hyperventilated pa-
tients than in the control or THAM groups. However, the
effect was not sustained at 12 months. Also, the effect was
not observed in patients with the lower motor GCS, min-
imizing the sample size for the control, hyperventilation,
and THAM groups to 21, 17, and 21, respectively. The
absence of a power analysis renders uncertainty about the
adequacy of the sample size. For these reasons, the rec-
ommendation that hyperventilation be avoided is Level II.
V. SUMMARY
In the absence of trials that evaluate the direct effect
of hyperventilation on patient outcomes, we have con-
structed a causal pathway to link hyperventilation with
intermediate endpoints known to be associated with out-
come. Independent of hyperventilation, CBF can drop
dangerously low in the first hours following severe TBI.
The introduction of hyperventilation could further de-
crease CBF, contributing to the likelihood of ischemia.
The relationship between hyperventilation and metabo-
lism, as well as cerebral oxygen extraction, is less clear.
The one study that evaluated patient outcomes strongly
suggests that hyperventilation be avoided for certain pa-
tient subgroups.
VI. KEY ISSUES FOR FUTURE
INVESTIGATION
The causal link between hyperventilation and inter-
mediate endpoints, and the subsequent relationship be-
VII. EVIDENCE TABLES
EVIDENCE TABLE I. CBF EARLY
Reference Study description
Bouma et al., Measurement of CBF with
19922 xenon-CT/CBF method during
first 5 days after severe TBI in
35 adults.
Marion et al., Measurement of CBF with
199112 xenon-CT/CBF method during
first 5 days after severe TBI in
32 adults.
Sioutos et al., Measurement of CBF with
199526 thermodiffusion blood flow
probe during first 5 days after
severe TBI in 37 adults.
EVIDENCE TABLE II. EFFECT OF HYPERVENTILATION
Reference Study description
Sheinberg et Results of SjO2 monitoring of
al., 199225 33 adults with severe TBI
during first 5 days after injury
New Studies
Imberti et al., Study of the effect of
200210 hyperventilation of SjO2 and
PbrO2 values in 36 adults with
severe TBI.
Oertel et al., Study of the effect of
200219 hyperventilation of SjO2
values in 33 adults with severe
TBI.
tween those endpoints and patient outcomes, needs to be
clearly specified. Further RCTs need to be conducted in
the following areas:
• How does short-term hyperventilation affect out-
come?
• The effect of moderate hyperventilation in specific
subgroups of patients.
• Critical levels of PaCO2/CBF and outcome.
AFTER SEVERE TBI
Data
class Conclusion
III CBF measurements
obtained during the first
24 h after injury were
less than 18 mL/100 g/min
in 31.4% of patients.
III The mean CBF during the
first few hours after injury
was 27 mL/100 g/min; CBF
always lowest during the
first 12–24 h after injury.
III 33% of patients had a
CBF less than 18
mL/100 g/min during the
first 24–48 h after injury.
ON CEREBRAL OXYGEN EXTRACTION
Data
class Conclusion
III Hyperventilation was the
second most common
identifiable cause for
jugular venous oxygen
desaturations.
III Hyperventilation (paCO2
from 36 to 29 mm Hg) for
20 min did not result
in consistent positive or
negative changes in the
SjO2 or PbrO2 values.
III A reduction of the paCO2
from 35 to 27 mm Hg led
to a decrease in the SjO2
from 73% to 67%; in no
case did it result in an
SjO2 of less than 55%.
 XIV. HYPERVENTILATION
EVIDENCE TABLE III. EFFECT OF
Reference Study description
Muizelaar et Sub-analysis of an RCT of THAM
al., 199117 in which 77 adults and children
with severe TBI were enrolled.
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HYPERVENTILATION ON OUTCOME
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