ORIGINAL ARTICLE

Reduced Brain Tissue Oxygen in Traumatic Brain Injury: Are Most

Commonly Used Interventions Successful?
Jose L. Pascual, MD, PhD, FRCPS(C), Patrick Georgoff, BS, Eileen Maloney-Wilensky, CRNP,
Carrie Sims, MD, MS, FACS, Babak Sarani, MD, FACS, Michael F. Stiefel, MD, PhD,
Peter D. LeRoux, MD, FACS, and C. William Schwab, MD, FACS

Background: Brain tissue oxygenation (PbtO2)-guided management facilitates treatment of reduced PbtO2 episodes potentially conferring survival and
outcome advantages in severe traumatic brain injury (TBI). To date, the
nature and effectiveness of commonly used interventions in correcting
compromised PbtO2 in TBI remains unclear. We sought to identify the most
common interventions used in episodes of compromised PbtO2 and to
analyze which were effective.
Methods: A retrospective 7-year review of consecutive severe TBI patients
with a PbtO2 monitor was conducted in a Level I trauma centers intensive
care unit or neurosurgical registry. Episodes of compromised PbtO2 (defined
as 20 mm Hg for 0.25 4 hours) were identified, and clinical interventions
conducted during these episodes were analyzed. Response to treatment was
gauged on how rapidly (T) PbtO2 normalized (20 mm Hg) and how great
the PbtO2 increase was (PbtO2). Intracranial pressure (ICP) and cerebral
perfusion pressure (CPP) also were examined for these episodes.
Results: Six hundred twenty-five episodes of reduced PbtO2 were identified
in 92 patients. Patient characteristics were: age 41.2 years, 77.2% men, and
Injury Severity Score and head or neck Abbreviated Injury Scale score of
34.0 9.2 and 4.9 0.4, respectively. Five interventions: narcotics or
sedation, pressors, repositioning, FIO2/PEEP increases, and combined sedation or narcotics pressors were the most commonly used strategies.
Increasing the number of interventions resulted in worsening the time to
PbtO2 correction. Triple combinations resulted in the lowest ICP and dual
combinations in the highest CPP (p 0.05).
Conclusion: Clinicians use a limited number of interventions when correcting compromised PbtO2. Using strategies employing many interventions
administered closely together may be less effective in correcting PbO2, ICP,
and CPP deficits. Some PbtO2 deficits may be self-limited.
Key Words: Brain tissue oxygenation, Traumatic brain injury, Treatment
interventions, PbtO2-guided management, Clinical practice guidelines.
(J Trauma. 2011;70: 535546)

Submitted for publication September 20, 2010.

Accepted for publication December 13, 2010.
Copyright 2011 by Lippincott Williams & Wilkins
From the Division of Traumatology, Surgical Critical Care & Emergency Surgery
(J.L.P., P.G., C.S., B.S., C.W.S.); and Department of Neurosurgery (E.M.-W.,
M.F.S., P.D.L.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Supported, in part, by research grants from the Integra Foundation, Integra
Neurosciences, and the Mary Elisabeth Groff Surgical and Medical Research
Trust (to P.D.L.). P.D.L. is a member of the Integra Speakers Bureau.
Presented at the 69th Annual Meeting of the American Association for the Surgery
of Trauma, September 2225, 2010, Boston, Massachusetts.
Address for reprints: Jose L. Pascual, MD, PhD, FRCPS(C), Division of Traumatology, Surgical Critical Care and Emergency Surgery, Department of Surgery, 3400
Spruce Street, Philadelphia, PA 19104; email: jose.pascual@uphs.upenn.edu.
DOI: 10.1097/TA.0b013e31820b59de

raumatic brain injury (TBI) remains a major cause of

mortality and morbidity in young people worldwide and
has a significant long-term socioeconomic impact. In particular, severe TBI (Glasgow Comas Scale [GCS] 8) is associated with 30% mortality and significant disability among
survivors.1 To date, there is no effective drug treatment for
TBI. Instead, management is centered on identifying and
managing the secondary brain injury that evolves in the hours
and days after TBI. Secondary injury is known to occur with
cerebral underperfusion but also may occur with dysfunctional cerebral metabolism, tissue hypoxia, and inflammation
and contributes to further tissue destruction.2 4
Although there is no Level I evidence to suggest that
management of intracranial pressure (ICP) is associated with
better outcome, the use of an ICP monitor is endorsed by major
medical societies (The Brain Trauma Foundation [BTF], The
European Brain Injury Consortium, The American Association
of Neurologic Surgeons, and The Congress of Neurologic Surgeons Joint Section on Neurotrauma and Critical Care).5,6
Several lines of evidence suggest that reduced brain
oxygen is not a benign event and that compromised brain
oxygen (20 mm Hg) or brain hypoxia (variably defined as
15 or 10 mm Hg) is associated with increased mortality and
unfavorable outcome.710 Consistent with this, nonrandomized
clinical studies indicate that therapy based on both an ICP and
brain oxygenation (PbtO2) monitor is associated with better
outcome than management with only an ICP monitor.1116
There are, however, several unanswered questions about
PbtO2-based care including what are available treatments to
improve brain oxygenation, how effective are they, and how do
they affect traditional management parameters such as ICP and
cerebral perfusion pressure (CPP)? This retrospective study was
conducted to (1) identify the most common interventions administered by neurosurgeons and intensivists during short (4
hours) episodes of low PbtO2 and (2) whether these interventions (alone or in combination) resulted in significant benefits in
rapidly correcting PbtO2 deficits and improving ICP and CPP.

METHODS
Patient Population
All blunt TBI patients admitted to the intensive care unit
(ICU) of an academic Level I trauma center who had a parenchymal intracranial monitor able to measure partial brain tissue
oxygen tension (PbtO2) between October 2001 and September

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Pascual et al.

The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011

2008 were considered for study. Patients were retrospectively

identified from a prospective observational database, the Brain
Oxygen Monitoring Outcomes (BOMO) registry, which has
Institutional Review Board approval. Patients with gunshot
wounds or other penetrating cranial injuries, ongoing blood
loss, or whose postresuscitation systolic blood pressure was
90 mm Hg and arterial oxygen saturation (SaO2) 93%
were excluded from analysis. Patients in whom pupils were
bilaterally fixed and dilated or were brain dead or imminently
dead on admission also were excluded.

Brain Intraparenchymal Monitors

ICP, brain temperature, and brain tissue oxygen
(PbtO2) were continuously monitored using a commercially
available intracranial device (LICOX; Integra LifeSciences,
Plainsboro, NJ). All three intracranial monitors were inserted
at the bedside through the same burr-hole into the frontal lobe
and secured with a triple-lumen bolt. The PbtO2 monitor was
placed into white matter that appeared normal on the admission head CT and on the side of maximal pathology. Brain
tissue oxygenation data were acquired after a stabilization
period of 2 hours after probe insertion. Probe function and
location were confirmed by an appropriate increase in PbtO2
after an hyperoxic FIO2 challenge (FIO2 100%)17 and a
head CT scan to verify correct placement of the various
monitors, e.g., not in a contusion or infarct. CPP was calculated from measured parameters (CPP mean arterial pressure [MAP] ICP). All intracranial monitors were removed
when ICP was normal for 24 hours without specific treatment
other than sedation for ventilation, when the patient was able
to follow commands or when the patient was brain dead.

Physiologic Monitors
Heart rate, arterial line blood pressures, and arterial oxygen saturations (SaO2) were monitored continuously (Component Monitoring System M1046-9090C: Hewlett Packard,
Andover, MA). The MAP was derived from arterial lines with
transducers leveled at the phlebostatic axis. Central venous
pressures and pulmonary artery pressures were followed in patients
with intravascular depletion or cardiopulmonary compromise.

General Clinical Management of TBI

Trauma surgeons resuscitated all patients according to
Advanced Trauma Life Support (ATLS) protocols (American
College of Surgeons Committee on Trauma: Advanced
Trauma Life Support Course for Doctors. Chicago: American
College of Surgeons, 1997). Patients then were managed
according to a local algorithm based on the BTF Guidelines
for Severe TBI5 in the Neurosurgical Intensive Care Unit
or the Surgical and Trauma Intensive Care Unit. This
included (1) early identification and evacuation of traumatic
space-occupying intracranial hematomas, (2) intubation and
ventilation with low-volume pressure-limited ventilation to
maintain PaCO2 between 30 and 40 mm Hg and SaO2 93%, (3)
sedation using propofol during the first 24 hours followed by
sedation and analgesia using lorazepam, morphine, or fentanyl, (4) bedrest with head elevation of 30 degrees, (5)
normothermia 35C to 37C, (6) euvolemia using a baseline crystalloid infusion (0.9% normal saline, 20 mEq/L KCl;
536

80 100 mL/h), (7) anticonvulsant prophylaxis with phenytoin for 1 week or longer if seizures occurred, and (8) packed
red blood cell transfusion if their Hgb was 7.

Management of Intracranial Hypertension

If ICP remained persistently elevated (20 mm Hg
10 min) despite baseline initial measures, osmotherapy was
administered using repeated boluses of mannitol (1 gm/kg,
25% solution) provided that serum osmolar gap 20. Second
tier therapies for refractory intracranial hypertension (20
mm Hg 15 minutes in a 1-hour period despite therapy)
included optimized hyperventilation (PaCO2 30 35 mm Hg),
decompressive craniectomy, or pharmacological coma (with
propofol or pentobarbital). Induced hypothermia and hypertonic saline for ICP control were used to manage ICP in the
patients included during the last 2.5 years of this study.

Evaluation of Brain Oxygen Treatment

During the study period patients received cause directed
therapy at the intensivists discretion to maintain PbtO2 20
mm Hg according to our local protocol (Fig. 1). The BOMO
registry records and codes every event noted by a bedside nurse
in the chart and also records hemodynamics, cerebral parameters, and other nursing entries every 10 minutes to 20 minutes.
There was 8000 hours of PbtO2 monitoring in eligible patients
available for review. Episodes where PbtO2 was 20 mm Hg
for 15 minutes but 4 hours were abstracted. There have been
several important described thresholds for PbtO2 that identify
when cell death or ischemia may be evident and at what level to
treat. We chose a PbtO2 threshold of 20 mm Hg because this
corresponds to the minimal necessary oxygen tension for mitochondria, where the majority of cellular oxygen metabolism
occurs to maintain aerobic metabolism.18 In addition, it is the
threshold being used in a current NIH-funded trial to prospectively examine PbtO2 in TBI. We chose a 15-minute minimum
time window to eliminate incidental, self-limited episodes of
compromised PbtO2 and to allow time for a 2-minute oxygen
challenge as required by protocol to test monitor function. Thus,
this brief FIO2 challenge was not considered therapeutic and so
was excluded from analysis. We chose a 4-hour maximum to
avoid inclusion of patients who no longer were receiving active
treatment for PbtO2 deficits by bedside clinicians. Also this was
done to avoid the inclusion of episodes where clinicians were
aggressively using all possible interventions in the setting of a
resistant compromised PbtO2.
We consulted seasoned intensivists, neurologists, trauma
surgeons, and neurosurgeons who cared for brain injured patients to achieve a consensus of what therapies were considered
useful to correct PbtO2 deficits. Eleven interventions were selected by the panel and thereafter identified from the coded
treatments in the BOMO registry. They are presented in Table 1.
During each episode of PbtO2 compromise, various registry parameters were recorded before the decrease and on
correction of the PbtO2 deficit (20 mm Hg). Collected parameters included patient hemodynamics (systolic blood pressure,
MAP, and heart rate [HR]), ventilation parameters (positive end
expiratory pressure [PEEP], PaO2 or PaCO2, SaO2, and FIO2), and
cerebral parameters (ICP, CPP, and PbtO2). All coded interventions thought to potentially affect PbtO2 (Table 1) that were
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Interventions for PbtO2-Guided TBI Management

Figure 1. Institutional algorithm for severe TBI management. ET tube, endotracheal tube; ABG, arterial blood gas; SjvO2, jugular venous bulb oxygenation; Hgb, hemoglobin; PaCO2, partial carbon dioxide tension of blood.

administered during this time period were collected. Basic demographics (age, sex, and race) and illness scores (Injury Severity Score, Acute Physiology and Chronic Health Evaluation,
Abbreviated Injury Scale, and Glasgow Coma Score [GCS])
were collected for each patient.

Outcome Assessment
Discharge disposition was recorded for all patients. In
patients who survived past discharge, a functional outpatient
evaluation interview 3- to 6-month postdischarge was obtained
using the Glasgow Outcome Score-extended (GOS-e)19 and
modified Rankin Scale (mRS)20 scores. These data are acquired
2011 Lippincott Williams & Wilkins

routinely and entered into the BOMO registry by an outpatient

nurse.

Analysis and Statistics

Comparison between treatments, combination of treatments, or no treatment was evaluated with analysis of variance
and post hoc analysis (Tukey) to examine their effect on time to
normalization of PbtO2 (T), the magnitude of PbtO2 change
(PbtO2) as well as on ICP and CPP. To analyze which
treatment or combination of treatments, if any, was superior
linear regression analysis was used. SPSS software (SPSS,
Chicago, IL) was used for analysis. Continuous data are pre537

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Pascual et al.

TABLE 1.

Description of Interventions

Intervention
Paralytics
Cooling
Pressors
FIO2/PEEP increases
Narcotics/sedation
Repositioning
Fluids
Osmotherapy
PRBCs
Ionotropes
FFP

BOMO-Coded Treatments
Any addition/increase in dose of neuromuscular
blocking agents
Any event where body temperature was
purposefully reduced below normothermia
Any addition/increase in dose of norepinephrine,
phenylephrine, epinephrine, or vasopressin
Any net increase of inspired oxygen or positive
end expiratory pressure
Any addition/increase in dose of opiods,
benzodiazepines, or propofol
Any turn to right, left, head-of-bed elevation,
lowering
Any bolus of crystalloids or colloids (excluding
transfusion therapy)
Any boluses of mannitol or hypertonic saline
Any transfusion of packed red blood cells
Any addition/increase in dose of milrinone,
dopamine, or dobutamine
Any transfusion of fresh frozen plasma

PRBC, packed red blood cells; FFP, fresh frozen plasma; PEEP, positive end
expiratory pressure.

sented as mean SD unless otherwise specified and a twotailed p value of 0.05 was considered statistically significant.

RESULTS
Study Population
Four hundred sixty-two (462) patients who had 1,601
episodes of compromised PbtO2 (20 mm Hg) were identi-

fied in the BOMO registry from September 30, 2001, to

October 1, 2008 (Fig. 2). From these, 92 patients who had
625 episodes of compromised PbtO2 (between 15 minutes
and 4 hours) were selected once non-TBI patients and entries
with insufficient data were removed. Two hundred eighty
(280) compromised PbtO2 episodes received no intervention
and normalized within 4 hours, whereas 345 episodes were
identified in patients that received some form of intervention
before normalization of PbtO2. The age and ethnic breakdown of the patients included in this study are illustrated in
Figures 3 and 4. Each patient had an admission head CT scan,
and the findings are illustrated in Figure 5. Table 2 describes the demographic and clinical characteristics of
treated patients.

Clinical Course and Outcome

Of the 92 patient cohort, 26% had more than one ICP
monitor placed, 9% had placement of a jugular venous bulb
monitor and 34% underwent an operative neurosurgical procedure (evacuation of hematoma, decompressive craniectomy). Median hospital length of stay for all cohort patients
was 25 (0 146) days and in hospital mortality was 27.2%.
The mean number of episodes of compromised PbtO2 in
patients who survived to discharge was 8 7 compared with
5 5 in those who died in hospital, although those who died
generally had a shorter hospital stay and duration of PbtO2
monitoring. Advanced age, especially 70 years old was
associated with unfavorable outcome using both the GOS-e
(p 0.03) and mRS (p 0.03). In addition, female sex was
associated with better outcome (GOS-e, p 0.02; mRS, p
0.01).

Figure 2. Abstraction of study patients and low PbtO2 episodes.

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TABLE 2.

Interventions for PbtO2-Guided TBI Management

Demographics and Patient Characteristics

Mean SD (%) (Range)

Characteristic

Figure 3. Age distribution.

Sex (male/female)
Age
ISS
Head AIS
ED arrival GCS
Patients receiving 1 ICP monitor
Patients receiving and SjO2 monitor
Patients with craniotomy/craniectomy
Hospital LOS (days)
Hospital mortality
Post discharge GOS-e
Post discharge mRS

72/20 (78.2/21.8%)
41 19
34 12
4.88 0.42
64
24 (26%)
8 (9.1%)
31 (34%)
24.6 (0146)
25 (27.2%)
33
42

AIS, Abbreviated Injury Scale; ED, emergency department; ISS, Injury Severity
Score; SjO2, jugular bulb venous oxygen; LOS, length of stay; GOS-e, Glasgow
Outcome Score-extended; mRS, modified Rankin Scale.

TABLE 3.

Attributes of Reduced PbtO2 Episodes

No treatment
Any treatment
p

Figure 4. Racial distribution.

T (h)

PbtO2 (mm Hg)

280
345

0.84 0.63
1.15 0.85
0.05

9.12 9.14
9.77 10.43
1.0

T (h), duration of hypoxic episode (PbtO2 20 mm Hg) in hours; PbtO2 (mm

Hg), difference in mm Hg between first 20 mm Hg PbO2 recording and first
subsequent 20 mm Hg PbtO2 recording.

TABLE 4. Comparison of Interventions Number on Time to

PbtO2 Normalization
Episode Duration (T)
Interventions

Figure 5. TBI diagnoses by CT and clinical evaluation. SAH,

subarachnoid hemorrhage; SDH, subdural hemorrhage; NOS,
not otherwise specified; EDH, epidural hemorrhage; DAI, diffuse axonal injury; IPH, intraparenchymal hemorrhage.

No intervention
Any 1 intervention
Any 2 interventions
Any 3 interventions
Any 4 interventions
Any 5 interventions

Percentage
of Treated

Mean (h)*

Range

SD

280
187
101
41
11
3

54.2
30.0
11.9
3.2
0.8

0.84
1.03
1.13
1.49
1.74
2.42

0.253.58
0.253.97
0.253.83
0.253.50
0.333.75
0.583.83

0.63
0.79
0.82
0.86
1.26
1.66

* ANOVA, analysis of variance: p 0.0002 comparison among groups.

Brain Oxygen Treatment

We examined 92 patients who had 625 episodes of
compromised PbtO2 (280 episodes normalized without receiving an intervention and 345 received some form of
intervention). Among episodes of compromised PbtO2 that
received one or more interventions, mean time to PbtO2
normalization (T) was greater (p 0.05) but of similar
magnitude (PbtO2) to that observed in episodes that corrected without treatment (Table 3). One hundred eighty-seven
(54% of treated episodes) episodes of compromised PbtO2
were treated successfully with a single intervention and 101
(30% of treated episodes) with 2 interventions (Table 4; Fig.
6). No episode of compromised PbtO2 required more than
five interventions for PbtO2 correction. The time to PbtO2
correction (T) became longer (p 0.0002) as the number of
2011 Lippincott Williams & Wilkins

Figure 6. Number of interventions used in treated patients.

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Pascual et al.

interventions increased. The number of patients treated with

more than two interventions was small; however, T was
greater in patients that had more than two interventions than
those with one or two interventions (p 0.05; Table 5). The

magnitude of PbtO2 (PbtO2) increase averaged 9.5 mm

Hg 9.9 mm Hg and was not associated with number of
interventions used (p 0.53). The average (SD) T when no
intervention was administered was 0.84 hours 0.63 hours.

TABLE 5. Comparison Between Number of Interventions as

Described in Table 4

What Interventions Were Used to Correct

Compromised PbtO2?

No. of Intervention(s)

Only one or two interventions were used to correct

compromised PbtO2 in the majority of episodes and so
subsequent analyses were limited to these groups. The commonest strategies used to treat compromised PbtO2 are summarized in Table 6. The most common single interventions
were sedation or analgesia (N 60), pressors (N 51),
increase in FIO2/PEEP (N 24), and patient repositioning
(N 27; Table 7). Of these, pressors were associated with
the lowest T (fastest correction). Single interventions associated with the greatest PbtO2 were osmotherapy (14 mm
Hg 11 mm Hg) and red cell transfusion (27 mm Hg) but the
frequency of these interventions was low. No one intervention appeared superior using simple linear regression analysis
(R2 0.2; p 0.05). One hundred one episodes were treated
with two interventions; the most common was sedation or

1
1
1
2
2
2
5
5
2
4

vs.
vs.
vs.
vs.
vs.
vs.
vs.
vs.
vs.
vs.

3
4
5
5
4
3
3
4
1
3

0.00
0.01
0.01
0.01
0.03
0.03
0.07
0.24
0.33
0.38

Tukey posthoc analysis comparing the number of interventions used on time to

PbtO2 correction (T). One or two interventions always correct PbtO2 significantly
faster than 3, 4, or 5 interventions. There is no significance difference when using 1 or
2 interventions to correct PbtO2.

TABLE 6.

Most Popular Combinations of Interventions for Reduced PbtO2 Deficits

Intervention 1

Intervention 2

Narcotics/sedation
Pressors
Repositioning
FIO2/PEEP increases
Sedation/narcotics
Fluids
Sedation/narcotics
Sedation/narcotics
Sedation/narcotics
Pressors
Sedation/narcotics

Pressors
FIO2/PEEP increases
Reposition
Fluids
Fluids
Osmotherapy

Episode Duration T (h)

Magnitude PbO2 (mm Hg)

60
51
27
24
19
9
9
9
8
7
5

1.02 0.77
0.94 0.87
1.11 0.67
0.99 0.51
1.11 0.86
1.22 0.89
1.71 1.18
1.11 0.86
0.98 0.35
1.25 0.81
0.25 0.53

10.6 12.1
7.9 8.4
9.1 11.8
9.5 8.8
9.5 7.9
11.9 12.7
9 5.3
10.1 9.8
7.2 4.8
7.6 6.9
16.9 14.5

PEEP, positive end expiratory pressure.

TABLE 7.

Single Treatment Combinations on T and PbtO2

Episode Duration (T)

Intervention
Paralytics
Cooling
Pressors
FIO2/PEEP increases
Narcotics/sedation
Repositioning
Fluids
Osmotherapy
PRBCs
Ionotropes
FFP
Any single treatment

Magnitude of Change (PbtO2)

Mean (h)

Range

SD

Mean (mm Hg)

Range

SD

4
4
51
24
60
27
9
7
1
0
0
187

0.4
0.91
0.94
0.99
1.02
1.11
1.22
1.33
3.65
N/A
N/A
1.03

0.250.5
0.471.5
0.253.97
0.272.5
0.253.0
0.253.0
0.253.2
0.333.7
3.653.65
N/A
N/A
0.254.0

0.12
0.51
0.88
0.52
0.77
0.67
0.89
1.07
0
N/A
N/A
0.68

8.4
6.7
7.9
9.5
10.6
9.1
11.9
14.4
27.5
N/A
N/A
11.8

5.714
1.718
1.346.6
0.340
6.8 to 62.7
0.457
1.140
3.250
2828
N/A
N/A
6.863

4.01
7.8
8.35
8.83
12.16
11.81
12.68
16.85
0
N/A
N/A
10.31

PEEP, positive end expiratory pressure; PRBC, packed red blood cells; FFP, fresh frozen plasma.

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TABLE 8.

Interventions for PbtO2-Guided TBI Management

Double Treatment Combinations on T and PbtO2

Magnitude of Change
(PbtO2)

Event Duration (T)

Interventions
Cooling
Paralytics
Osmotherapy
Paralytics
Paralytics
Sedation/narcotics
Pressors
Reposition
Reposition
PRBCs
Cooling
Sedation/narcotics
Osmotherapy
Sedation/narcotics
Pressors
FFP
Pressors
Sedation/narcotics
Fluids
Sedation/narcotics
Cooling
FIO2/PEEP 1
FIO2/PEEP 1 Reposition
Cooling
Pressors
FIO2/PEEP 1 Pressors
Reposition
Sedation/narcotics
FIO2/PEEP 1 Osmotherapy
Fluids
Pressors
FIO2/PEEP 1 Fluids
FIO2/PEEP 1 Sedation/narcotics
Cooling
Reposition
Fluids
Osmotherapy
FIO2/PEEP 1 PRBCs
Osmotherapy
Pressors
Osmotherapy
Reposition
Any two treatments

Mean (h) (Range)

SD

Mean (mm Hg) (Range)

SD

1
2
3
4
4
5
5
2
19
8
1
4
1
6
9
2
7
3
9
1
2
1
1
1
101

0.33 (0.330.33)
0.54 (0.420.7)
0.63 (0.50.75)
0.67 (0.421.0)
0.67 (0.421.0)
0.78 (0.251.2)
0.82 (0.251.5)
0.94 (0.881.0)
0.99 (0.253.2)
0.99 (0.501.5)
1.00 (11)
1.01 (0.571.7)
1.03 (1.031.03)
1.06 (0.333.5)
1.11 (0.372.9)
1.13 (0.51.8)
1.25 (0.252.8)
1.31 (0.52.6)
1.74 (0.333.8)
2.00 (22)
2.08 (1.23.0)
2.58 (2.62.6)
3.00 (33)
3.00 (33)
1.28 (0.253.8)

N/A
0.18
0.13
0.26
0.26
0.46
0.53
0.08
0.83
0.35
N/A
0.48
N/A
1.22
0.86
0.88
0.81
1.1
1.26
N/A
1.3
N/A
N/A
N/A
0.65

11.9 (11.911.9)
6.8 (3.210.4)
5.3 (1.89.7)
11.0 (1.232)
11.0 (1.232)
11.4 (0.637.4)
16.9 (4.837)
10.0 (6.2138)
8.4 (1.617.5)
7.3 (3.117.5)
14.1 (14.114.1)
4.9 (3.26.6)
1.4 (1.41.4)
9.6 (1.817.8)
10.1 (2.2 to 33.6)
42.4 (5.879.0)
7.6 (1.721.3)
6.0 (4.78.0)
8.2 (2.214.6)
4.4 (4.44.4)
3.9 (2.65.2)
13.2 (13.213.2)
2.8 (2.82.8)
2.8 (2.82.8)
9.6 (2.2 to 79)

N/A
5.09
4.03
14.27
14.27
15.27
14.48
5.37
4.92
4.84
N/A
1.63
N/A
5.92
9.75
51.76
6.94
1.74
4.88
N/A
1.84
N/A
N/A
N/A
9.82

PEEP, positive end expiratory pressure; PRBC, packed red blood cells; FFP, fresh frozen plasma.

analgesia pressors (N 19; Table 8). Cooling paralytics

(n 1 episodes) was associated with the lowest T, and
osmotherapy FIO2/PEEP increase (n 2 episodes) with
the greatest PbtO2. An osmotherapy sedation or narcotics
combination appeared to demonstrate an optimal PbtO2/T
combination (16.9 mm Hg 14.5 mm Hg/0.82 hours 0.5
hours) but was only used in five episodes. When controlling
for age, sex, Injury Severity Score, and arrival GCS no
intervention or combination of interventions appeared to be
better than others in correction of compromised PbtO2.

PbtO2 Treatment and the Effect on ICP and

CPP
We next examined how PbtO2-related treatment influenced ICP and CPP during the same analyzed episodes (Table
9). As with T and PbtO2, use of osmotherapy sedation
or narcotics seemed to best manage ICP but did not translate
into an important CPP increase. Pressors, fluids and repositioning were associated with the greatest increases on CPP.
When evaluating the number of interventions on ICP, any
three-intervention regimen (6.40 mm Hg 2.5 mm Hg)
had greater ICP reduction than no intervention (1.19 mm
Hg 0.47 mm Hg, p 0.009), or one intervention (1.62
mm Hg 0.61 mm Hg, p 0.03). CPP was most increased
with combinations of two interventions (11.1 mm Hg 2.4
2011 Lippincott Williams & Wilkins

TABLE 9.
and CPP
N

Most Popular Intervention Combinations on ICP

Intervention 1

Narcotics/sedation
Pressors
Repositioning
FIO2/PEEP
increases
19 Sedation/narcotics
9 Fluids
9 Sedation/narcotics
9 Sedation/narcotics
8 Sedation/narcotics
7 Pressors
5 Sedation/narcotics

Intervention 2

60
51
27
24

ICP

CPP

2.6 11.2
1.4 7.5
0.8 7.8
0.1 4.8

4.0 16.6
8.3 18.9
10.2 12.8
5.3 15.4

1.2 6.8
0.8 2.8
2.1 5.3
FIO2/PEEP increases
Reposition
0.5 4.4
Fluids
2.0 4.2
Fluids
0.3 2.5
Osmotherapy
7.8 7.9
Pressors

9.6 22.7
6.8 16.9
7.1 10.2
20 35.2
4.7 7.7
13.9 26.2
1.5 12.3

mm Hg), which was significantly greater than that with no

intervention (3.8 mm Hg 1.2 mm Hg, p 0.02). We also
evaluated all compromised PbtO2 episodes that underwent
one or more interventions and found a mean decrease of ICP
of 1.25 mm Hg 5.9 mm Hg and CPP increase of 7.02
17.7 in the interval evaluated.
541

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Pascual et al.

DISCUSSION
In this study, we examined 92 severe TBI patients with
625 episodes of compromised PbtO2 (20 mm Hg for
0.25 4 hours) and how these episodes were treated. We
observed the following: (1) 44% of episodes were corrected
without specific treatment; (2) most episodes of compromised
PbtO2 could be successfully treated with one or two interventions and none required more than five interventions; (3)
no single intervention or combination of interventions appeared better than any other to reduce time to PbtO2 correction or to increase magnitude of PbtO2 change; (4) use of
more interventions was associated with a greater time to
PbtO2 normalization; (5) many episodes underwent PbtO2
normalization without interventions, and (6) an increasing the
number of interventions to a maximum of three only had a
favorable effect on ICP or CPP. These data may be used to
guide therapy of compromised PbtO2 and suggest what effect
can be expected.

Methodological Limitations
This study has several potential limitations. First, it is a
retrospective analysis of interventions recorded in a prospective observational database. Second, the sample size of 92
patients is relatively small. However, we examined 600
episodes of compromised PbtO2. Third, this is a single
institution series. Our results, therefore, may lack external
validity and should be considered preliminary. Fourth, we
defined an episode of compromised PbtO2 as 15 minutes to
240 minutes in duration. The lower time limit was arbitrarily
chosen to prevent transient self-limited changes in PbtO2, i.e.,
episodes of coughing, straining, or moving that bedside
clinicians do not routinely treat. Our upper time limit also
was arbitrarily chosen. However, we felt it reasonable to
conclude that if no treatment was initiated within 4 hours, that
care had been deliberately withheld. Fifth, although all specific treatments were prospectively coded in our BOMO
registry, we chose, for the purposes of this study, to examine
treatment classes or interventions (see Methods), thus, any
effects of the specific drug or fluid administered are beyond
the scope of this study. Sixth, we did not control for the
number of times a specific intervention was used to correct a
single episode of compromised PbtO2 or in which order
therapies were given. It was not our goal to describe a precise
recipe to treat compromised PbtO2 because such a recipe is
unlikely to exist. Seventh, the intention behind the clinicians
use of a given intervention was not examined and the use of
a given intervention could have occurred for reasons other
than to correct PbtO2 deficits. Finally, use of T as a primary
outcome may have lead to intrinsic bias because the greater
duration of compromised PbtO2 would inherently allow clinicians more time to administer more interventions. In addition, defining the episode endpoint as normalized PbtO2 (20
mm Hg) may have underestimated any interventions maximal effect on PbtO2. Despite these limitations, the results of
this study from an institution with several years experience
using and studying PbtO2 monitoring by a group of interdisciplinary clinicians provide an in-depth description of what
542

interventions are usually administered to patients with compromised PbtO2 and what results can be expected.

Significance of Reduced PbtO2

Increased ICP and reduced CPP are associated with
mortality and poor outcome in TBI.2124 Consequently, an
ICP monitor is recommended in current severe TBI guidelines in part to also maintain CPP.5,6 Although it may appear
physiologically plausible, there is no Level I evidence to
support the role of an ICP monitor (or any monitor) in TBI
care. However, some recent observational cohort studies
continue to question the use of ICP monitors,25,26 and a recent
meta-analysis of the literature suggests that use of an ICP
monitor is associated with better outcome.27
In a separate set of recent studies, the concept that
cellular hypoxia or dysfunction may occur when ICP and
CPP are normal has emerged.8,28 30 In particular, positron
emission tomography (PET) and microdialysis studies have
found that after TBI, cellular hypoxia or anerobic metabolism
often is associated with defects in oxygen diffusion and may
be independent of perfusion,2,3,28,31,32 and therefore not coupled with ICP variations. Consistent with this, several observational clinical studies found that mortality and poor
outcome can be associated with brain hypoxia particularly
of greater duration,10,1315,33,34 magnitude (15 mm
Hg),10,1315,33,34 or frequency.1315 Consequently, the most
recent edition of the BTF Guidelines recommended the use
of a brain tissue oxygen monitor.35

PbtO2-Based Care of Severe TBI

Several groups have described the use of a PbtO2
monitor and PbtO2-based care to supplement ICP and CPPbased care of severe TBI.1115 Management strategies include
protocols to correct CPP when reduced PbtO2 is observed12 or
tiered approaches based on physiologic targets although the
specific individual interventions often are not well detailed.13
Our usual protocol is illustrated in Figure 1 and described in
previous publications.14 There are seven published reports, all
nonrandomized, that compare PbtO2 and ICP or CPP-guided
TBI management strategies.1116,36 Six of the studies suggest
a potential benefit to PbtO2-based care and a pooled analysis
indicates that PbtO2-based care is associated with a twofold
increase chance of favorable outcome.37 However, Martini
et al.11 observed increased hospital mortality associated with
PbtO2-based care although this was no longer a significant
relationship when adjusted for variables such as age, head
Abbreviated Injury Scale, Marshall CT classification, and
GCS. In addition, these authors found that PbtO2-guided care
was associated with more use of osmotherapy, vasopressors,
and prolonged sedation. However, we have found that among
patients treated with PbtO2-based care that mortality is associated with longer periods of compromised PbtO2 deficits
(T), and with compromised PbtO2 that is less responsive to
treatment.14 This balance between effective treatment and
overtreatment is crucial because every therapy has potential
side-effects and although brain physiology may be improved,
this result may not always translate into better outcome if
other organ systems are harmed.38
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The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011

Therapeutic Interventions for Compromised

PbtO2

Interventions for PbtO2-Guided TBI Management

Specific Interventions for Compromised

PbtO2Alone or in Combination?

available oxygen through increases in FIO2, PEEP, or pulmonary dynamics (prostacyclin in other studies) were the
fourth most common intervention in our study.45 49 The
definitive benefits and, more importantly, risks (oxygen
toxicity) of hyperoxic treatment in TBI, however, remain
unknown.
Combined use of sedation or narcotics osmotherapy
resulted in the most rapid correction of compromised PbtO2
(about 15 minutes) and also appeared to increase PbtO2
and reduce ICP by the greatest margins. It must be noted,
however, that the occurrence of this combination was
exceeding low and therefore no durable conclusion can be
made. Both mannitol and hypertonic saline were included in
the osmotherapy intervention class and are well known to
reduce ICP.50,51 Hypertonic saline in particular has been
shown to improve PbtO2 in TBI patients52 refractive to
mannitol therapy. Efforts to enhance oxygen delivery (DO2)
through transfusion of red blood cells is commonly used
though an improvement in PbtO2 is not always present.53,54 In
addition, there remains controversy on what is the optimal
hemoglobin level for TBI patients.7,55 There is limited data on
how other blood products (e.g., plasma) affect PbtO2.56 A
combination of pressors and fluid boluses may also improve
DO2 although studies in subarachnoid hemorrhage suggest
only induced hypertension has a positive effect on PbtO2.57 In
our study, combined pressors and fluids was associated with
the greatest increase of CPP (14 mm Hg). Although infusions of crystalloids or colloids are commonplace in the ICU
and thought to benefit TBI patients by raising MAP and CPP,
their effect on PbtO2 remains intuitive with limited scientific
evaluation.58 Indeed, some studies suggests PbtO2 monitoring
may lead to overuse of fluids.59 Therapies such as induced
hypothermia and cerebral spinal fluid (CSF) drainage were
used infrequently in our patient cohort and so we cannot
make specific conclusions about their use.

The use of a single intervention for compromised PbtO2

was the most frequent strategy, and among these, narcotic
analgesics or sedatives, often used in TBI to control ICP,39 42
was most common (Table 4). Pressors were the next most
frequent therapy. These agents are also frequently used in
TBI care, but which specific agent (phenylephrine, dopamine,
norepinephrine) is preferable is not well defined.43,44 In addition, overuse of pressors may exacerbate lung function.5 Of
interest, we observed that, among the most popular treatments, pressors appeared to be associated with the shortest
time interval for PbtO2 correction (T). However, this may
mean pressors were only used late or after other interventions
failed. Patient repositioning was the third most common
intervention we observed and often increased PbtO2 by 10
mm Hg or more. Head and neck repositioning, elevating the
head of the bed, turning a patient or loosening a cervical
collar are common practice in TBI patients, but the direct
effects and durability of these interventions may be more
opinion than fact. These maneuvers, however, are recommended as good clinical care and are likely to benefit the
patient without significant risk. It is conceivable that we
underestimated their use and effect because they most likely
were applied as part of general care rather than when a
specific monitored abnormality occurred. Efforts to increase

Accumulating evidence suggests that PbtO2-directed

therapy may provide an advantage over ICP or CPP only
guided management. However, there is little data on what
interventions should be included in such a PbtO2 treatment
bundle. Bundled treatments have improved the care of
critically ill patients in other fields such as sepsis.60 However,
the individual components may not demonstrate this advantage in the absence of the remaining components and the
environment where they are administered. This study does
not provide a recipe for the best ICU intervention or combination of interventions to treat compromised PbtO2 in TBI
patients. However, we have learnt several important points.
First, clinicians tend to use a small number of treatments and
prefer to use combinations of at most one or two to correct
compromised PbtO2. Second, the most common interventions
may improve ICP or CPP but may not always increase PbtO2.
Third, use of more treatments does not mean more rapid
correction of compromised PbtO2. This is particularly
important because some interventions to correct intracranial abnormalities are known to exacerbate injury in other
organ systems of critically ill patients. Finally, some PbtO2

Although clinical series suggest that there may be a

benefit to PbtO2-based care, it remains unclear what constitutes this care as the specific therapies for compromised
PbtO2 are only beginning to be defined. In this study, we
describe what interventions may be used and their expected
efficacy when PbtO2 is compromised. Our registry (BOMO)
codes 80 clinician interventions in the ICU. This includes
specific items such as mouthcare, proning, abdominal
operation, or patient reposition that are recorded in the
nursing record at time intervals as short as 10 minutes to 20
minutes. We conducted a detailed evaluation of these coded
treatments and, with expert consensus, grouped them in 11
classes of interventions (Table 6). Although many of these
interventions are used by clinicians caring for TBI patients
worldwide and often in the setting of reduced ICP or MAP,
there is limited study of how these interventions affect compromised PbtO2. We thus sought to first delineate what
interventions were used most frequently in TBI patients with
compromised PbtO2. Greater than one third of such episodes
PbtO2 resolved without any apparent intervention. These
episodes may simply have been self-limited and thus raise the
question on how to identify reductions in PbtO2 that do not
require treatment. However, they also may represent an
episode where some other trigger (e.g., low ICP, high CPP)
resulted in treatment initiation before the identified decrease
in PbtO2 and the effect of these intervention(s) eventually
also normalized PbtO2. Yet, when evaluating the effect of any
intervention or combination of interventions on ICP and CPP
effects were at most modest.

2011 Lippincott Williams & Wilkins

CONCLUSIONS

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The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011

Pascual et al.

compromises may correct on their own and how to identify

such self-resolving deficits remains unclear. In summary, this
study provides an insight in what interventions are most used
in a center familiar with PbtO2-directed TBI care. The effects
of these popular interventions will need further evaluation
and comparisons to establish their efficacy, safety, timing,
and sequencing for future severe TBI management.
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DISCUSSION
Dr. William C. Chiu (Baltimore, Maryland): Dr. Pascual and his coauthors from the University of Pennsylvania
have presented another study investigating the utility of brain
tissue oxygen-directed management of traumatic brain injury.
Secondary brain injury is associated with episodes of
cerebral ischemia and hypoxia. Most current algorithms for
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Interventions for PbtO2-Guided TBI Management

neurologic monitoring use intracranial and cerebral perfusion

pressure monitoring-based therapy.
Previous work from this group has suggested that brain
tissue oxygen monitoring is safe and that low brain tissue
oxygen can be corrected, and may be associated with reduced
mortality.
This study has confirmed their previous findings that
common interventions employed for TBI management successfully improve episodes of low brain tissue oxygen and
that just one or two interventions normalize brain tissue
oxygen in the majority of patients.
There are two particular study results that I found most
intriguing: one, the combination of sedation and osmotherapy
resulted in the most rapid correction of compromised brain
tissue oxygen and reduction of ICP.
Change in CPP with this combination was not so
impressive. Instead, the combination of pressors and fluids
resulted in the greatest increase in CPP but the change in
brain tissue oxygen and ICP were only mild.
These findings suggest that interventions that reduce
ICP also improve brain tissue oxygen but not CPP. It also
reminds us that interventions that improve CPP may simply
improve mean arterial pressure without improving ICP.
Two, the proportion of reduced brain tissue oxygen
that normalized without treatment was 45 percent. Furthermore, normalization of brain tissue oxygen was more rapid
in those patients without intervention compared to those
with intervention.
Patients requiring an incremental increase in number
of interventions required an associated increased time for
normalization of brain tissue oxygen. This finding reminds
us of the difficulty in establishing causality in retrospective
research.
Patients requiring five interventions to normalize brain
tissue oxygen may have had more resistant hypoxia. Therefore, it is probably unfair to conclude that increasing the
number of interventions resulted in worsening the time to
brain tissue oxygen correction.
I just have two questions for Dr. Pascual, one, in the
group of 280 instances of low brain tissue oxygen with no
intervention the time to normalization was a mean of 50
minutes. Please speculate on the justification for no interventions during 50 minutes of brain tissue hypoxia.
And, two, based upon your institutions experience,
which patients, then, do you recommend should have brain
tissue oxygen-directed management?
Dr. Jose L. Pascual (Philadelphia, Pennsylvania):
Thank you, Dr. Chiu for your insightful comments.
I have to say that while interesting, the sedation/narcotics
plus osmotherapy combination is difficult to interpret in the
setting of such few occurrences in the whole sample size.
To address the specific questions, we also were wondering two questions: how is it that no intervention for a mean
time of 50 minutes results still in correction of brain tissue
oxygen?
We speculated a few answers. One, that brain tissue
oxygen in some cases does correct on its own without any
intervention.
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The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011

Another is that maybe some interventions occurred

before the drop in brain tissue oxygen because ICP or CPP
took a poor turn. ICP was increased; CPP was decreased
and interventions were performed just before the drop in
brain tissue oxygen and then affected brain oxygen.
Also, perhaps we didnt capture interventions such as a
bedside nurse repositioning the patient and not recording it in
the record.
Why would people not treat a patient with 50 minutes of
brain tissue decreases in oxygenation? Perhaps because they

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were being moved or the thought was that this would resolve on
its own and interventions had occurred that were not recorded by
the bedside nurse they waited for the effect to occur.
Who should we monitor brain tissue oxygen on remains
a difficult question. If greater than a third of patients correct
their brain tissue oxygenation on their own, this may be
something very important in the decision tree of what type of
intracranial monitor to insert.
Id like to thank the association, Dr. Jurkovich and Dr.
Cioffi. Thank you.

2011 Lippincott Williams & Wilkins