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 facili-
tates 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 seda-
tion 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 correct-
ing 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, Philadel-
phia, 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 Traumatol-
ogy, 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
The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011
T 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 partic-
ular, severe TBI (Glasgow Comas Scale [GCS] 8) is asso-
ciated 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 dysfunc-
tional 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 Sur-
geons 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 ad-
ministered by neurosurgeons and intensivists during short (4
hours) episodes of low PbtO2 and (2) whether these interven-
tions (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 paren-
chymal 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 admis-
sion 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 calcu-
lated from measured parameters (CPP mean arterial pres-
sure [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 oxy-
gen saturations (SaO2) were monitored continuously (Compo-
nent 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 fenta-
nyl, (4) bedrest with head elevation of 30 degrees, (5)
normothermia 35C to 37C, (6) euvolemia using a base-
line crystalloid infusion (0.9% normal saline, 20 mEq/L KCl;
536
80 100 mL/h), (7) anticonvulsant prophylaxis with phenyt-
oin 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 hyper-
tonic 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 parame-
ters, 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 mito-
chondria, 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 prospec-
tively 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 pa-
tients to achieve a consensus of what therapies were considered
useful to correct PbtO2 deficits. Eleven interventions were se-
lected 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 reg-
istry parameters were recorded before the decrease and on
correction of the PbtO2 deficit (20 mm Hg). Collected param-
eters 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 interven-
tions thought to potentially affect PbtO2 (Table 1) that were
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The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011 Interventions for PbtO2-Guided TBI Management

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

administered during this time period were collected. Basic de-
mographics (age, sex, and race) and illness scores (Injury Se-
verity 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
routinely and entered into the BOMO registry by an outpatient
nurse.
Analysis and Statistics
Comparison between treatments, combination of treat-
ments, 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 pre-

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

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

TABLE 1. Description of Interventions
October 1, 2008 (Fig. 2). From these, 92 patients who had
Intervention BOMO-Coded Treatments 625 episodes of compromised PbtO2 (between 15 minutes
Paralytics Any addition/increase in dose of neuromuscular and 4 hours) were selected once non-TBI patients and entries
blocking agents with insufficient data were removed. Two hundred eighty
Cooling Any event where body temperature was (280) compromised PbtO2 episodes received no intervention
purposefully reduced below normothermia and normalized within 4 hours, whereas 345 episodes were
Pressors Any addition/increase in dose of norepinephrine, identified in patients that received some form of intervention
phenylephrine, epinephrine, or vasopressin
before normalization of PbtO2. The age and ethnic break-
FIO2/PEEP increases Any net increase of inspired oxygen or positive
end expiratory pressure down of the patients included in this study are illustrated in
Narcotics/sedation Any addition/increase in dose of opiods, Figures 3 and 4. Each patient had an admission head CT scan,
benzodiazepines, or propofol and the findings are illustrated in Figure 5. Table 2 de-
Repositioning Any turn to right, left, head-of-bed elevation, scribes the demographic and clinical characteristics of
lowering treated patients.
Fluids Any bolus of crystalloids or colloids (excluding
transfusion therapy)
Osmotherapy Any boluses of mannitol or hypertonic saline Clinical Course and Outcome
PRBCs Any transfusion of packed red blood cells Of the 92 patient cohort, 26% had more than one ICP
Ionotropes Any addition/increase in dose of milrinone, monitor placed, 9% had placement of a jugular venous bulb
dopamine, or dobutamine monitor and 34% underwent an operative neurosurgical pro-
FFP Any transfusion of fresh frozen plasma cedure (evacuation of hematoma, decompressive craniec-
PRBC, packed red blood cells; FFP, fresh frozen plasma; PEEP, positive end tomy). Median hospital length of stay for all cohort patients
expiratory pressure. was 25 (0 146) days and in hospital mortality was 27.2%.
The mean number of episodes of compromised PbtO2 in
sented as mean SD unless otherwise specified and a two- patients who survived to discharge was 8 7 compared with
tailed p value of 0.05 was considered statistically significant. 5 5 in those who died in hospital, although those who died
generally had a shorter hospital stay and duration of PbtO2
RESULTS monitoring. Advanced age, especially 70 years old was
associated with unfavorable outcome using both the GOS-e
Study Population (p 0.03) and mRS (p 0.03). In addition, female sex was
Four hundred sixty-two (462) patients who had 1,601 associated with better outcome (GOS-e, p 0.02; mRS, p
episodes of compromised PbtO2 (20 mm Hg) were identi- 0.01).

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

538 2011 Lippincott Williams & Wilkins

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TABLE 2. Demographics and Patient Characteristics

Characteristic Mean SD (%) (Range)
Sex (male/female) 72/20 (78.2/21.8%)
Age 41 19
ISS 34 12
Head AIS 4.88 0.42
ED arrival GCS 64
Patients receiving 1 ICP monitor 24 (26%)
Patients receiving and SjO2 monitor 8 (9.1%)
Patients with craniotomy/craniectomy 31 (34%)
Hospital LOS (days) 24.6 (0146)
Figure 3. Age distribution. Hospital mortality 25 (27.2%)
Post discharge GOS-e 33
Post discharge mRS 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

N T (h) PbtO2 (mm Hg)
No treatment 280 0.84 0.63 9.12 9.14
Any treatment 345 1.15 0.85 9.77 10.43
p 0.05 1.0
T (h), duration of hypoxic episode (PbtO2 20 mm Hg) in hours; PbtO2 (mm
Figure 4. Racial distribution. 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)
Percentage
Interventions N of Treated Mean (h)* Range SD
No intervention 280 0.84 0.253.58 0.63
Any 1 intervention 187 54.2 1.03 0.253.97 0.79
Any 2 interventions 101 30.0 1.13 0.253.83 0.82
Figure 5. TBI diagnoses by CT and clinical evaluation. SAH,
Any 3 interventions 41 11.9 1.49 0.253.50 0.86
subarachnoid hemorrhage; SDH, subdural hemorrhage; NOS,
not otherwise specified; EDH, epidural hemorrhage; DAI, dif- Any 4 interventions 11 3.2 1.74 0.333.75 1.26
fuse axonal injury; IPH, intraparenchymal hemorrhage. Any 5 interventions 3 0.8 2.42 0.583.83 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 re-
ceiving 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 cor-
rected 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 Figure 6. Number of interventions used in treated patients.

2011 Lippincott Williams & Wilkins 539

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

interventions increased. The number of patients treated with magnitude of PbtO2 (PbtO2) increase averaged 9.5 mm
more than two interventions was small; however, T was Hg 9.9 mm Hg and was not associated with number of
greater in patients that had more than two interventions than interventions used (p 0.53). The average (SD) T when no
those with one or two interventions (p 0.05; Table 5). The intervention was administered was 0.84 hours 0.63 hours.

TABLE 5. Comparison Between Number of Interventions as What Interventions Were Used to Correct
Described in Table 4 Compromised PbtO2?
No. of Intervention(s) p Only one or two interventions were used to correct
1 vs. 3 0.00
compromised PbtO2 in the majority of episodes and so
1 vs. 4 0.01
subsequent analyses were limited to these groups. The com-
1 vs. 5 0.01
monest strategies used to treat compromised PbtO2 are sum-
2 vs. 5 0.01
marized in Table 6. The most common single interventions
2 vs. 4 0.03
were sedation or analgesia (N 60), pressors (N 51),
2 vs. 3 0.03
increase in FIO2/PEEP (N 24), and patient repositioning
5 vs. 3 0.07
(N 27; Table 7). Of these, pressors were associated with
5 vs. 4 0.24
the lowest T (fastest correction). Single interventions asso-
2 vs. 1 0.33
ciated with the greatest PbtO2 were osmotherapy (14 mm
4 vs. 3 0.38
Hg 11 mm Hg) and red cell transfusion (27 mm Hg) but the
frequency of these interventions was low. No one interven-
Tukey posthoc analysis comparing the number of interventions used on time to tion appeared superior using simple linear regression analysis
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 (R2 0.2; p 0.05). One hundred one episodes were treated
2 interventions to correct PbtO2. with two interventions; the most common was sedation or

TABLE 6. Most Popular Combinations of Interventions for Reduced PbtO2 Deficits

Intervention 1 Intervention 2 N Episode Duration T (h) Magnitude PbO2 (mm Hg)
Narcotics/sedation 60 1.02 0.77 10.6 12.1
Pressors 51 0.94 0.87 7.9 8.4
Repositioning 27 1.11 0.67 9.1 11.8
FIO2/PEEP increases 24 0.99 0.51 9.5 8.8
Sedation/narcotics Pressors 19 1.11 0.86 9.5 7.9
Fluids 9 1.22 0.89 11.9 12.7
Sedation/narcotics FIO2/PEEP increases 9 1.71 1.18 9 5.3
Sedation/narcotics Reposition 9 1.11 0.86 10.1 9.8
Sedation/narcotics Fluids 8 0.98 0.35 7.2 4.8
Pressors Fluids 7 1.25 0.81 7.6 6.9
Sedation/narcotics Osmotherapy 5 0.25 0.53 16.9 14.5
PEEP, positive end expiratory pressure.

TABLE 7. Single Treatment Combinations on T and PbtO2

Episode Duration (T) Magnitude of Change (PbtO2)
Intervention N Mean (h) Range SD Mean (mm Hg) Range SD
Paralytics 4 0.4 0.250.5 0.12 8.4 5.714 4.01
Cooling 4 0.91 0.471.5 0.51 6.7 1.718 7.8
Pressors 51 0.94 0.253.97 0.88 7.9 1.346.6 8.35
FIO2/PEEP increases 24 0.99 0.272.5 0.52 9.5 0.340 8.83
Narcotics/sedation 60 1.02 0.253.0 0.77 10.6 6.8 to 62.7 12.16
Repositioning 27 1.11 0.253.0 0.67 9.1 0.457 11.81
Fluids 9 1.22 0.253.2 0.89 11.9 1.140 12.68
Osmotherapy 7 1.33 0.333.7 1.07 14.4 3.250 16.85
PRBCs 1 3.65 3.653.65 0 27.5 2828 0
Ionotropes 0 N/A N/A N/A N/A N/A N/A
FFP 0 N/A N/A N/A N/A N/A N/A
Any single treatment 187 1.03 0.254.0 0.68 11.8 6.863 10.31
PEEP, positive end expiratory pressure; PRBC, packed red blood cells; FFP, fresh frozen plasma.

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TABLE 8. Double Treatment Combinations on T and PbtO2

Magnitude of Change
Event Duration (T) (PbtO2)
Interventions N Mean (h) (Range) SD Mean (mm Hg) (Range) SD
Cooling Paralytics 1 0.33 (0.330.33) N/A 11.9 (11.911.9) N/A
Osmotherapy Paralytics 2 0.54 (0.420.7) 0.18 6.8 (3.210.4) 5.09
Paralytics Sedation/narcotics 3 0.63 (0.50.75) 0.13 5.3 (1.89.7) 4.03
Pressors Reposition 4 0.67 (0.421.0) 0.26 11.0 (1.232) 14.27
Reposition PRBCs 4 0.67 (0.421.0) 0.26 11.0 (1.232) 14.27
Cooling Sedation/narcotics 5 0.78 (0.251.2) 0.46 11.4 (0.637.4) 15.27
Osmotherapy Sedation/narcotics 5 0.82 (0.251.5) 0.53 16.9 (4.837) 14.48
Pressors FFP 2 0.94 (0.881.0) 0.08 10.0 (6.2138) 5.37
Pressors Sedation/narcotics 19 0.99 (0.253.2) 0.83 8.4 (1.617.5) 4.92
Fluids Sedation/narcotics 8 0.99 (0.501.5) 0.35 7.3 (3.117.5) 4.84
Cooling FIO2/PEEP 1 1 1.00 (11) N/A 14.1 (14.114.1) N/A
FIO2/PEEP 1 Reposition 4 1.01 (0.571.7) 0.48 4.9 (3.26.6) 1.63
Cooling Pressors 1 1.03 (1.031.03) N/A 1.4 (1.41.4) N/A
FIO2/PEEP 1 Pressors 6 1.06 (0.333.5) 1.22 9.6 (1.817.8) 5.92
Reposition Sedation/narcotics 9 1.11 (0.372.9) 0.86 10.1 (2.2 to 33.6) 9.75
FIO2/PEEP 1 Osmotherapy 2 1.13 (0.51.8) 0.88 42.4 (5.879.0) 51.76
Fluids Pressors 7 1.25 (0.252.8) 0.81 7.6 (1.721.3) 6.94
FIO2/PEEP 1 Fluids 3 1.31 (0.52.6) 1.1 6.0 (4.78.0) 1.74
FIO2/PEEP 1 Sedation/narcotics 9 1.74 (0.333.8) 1.26 8.2 (2.214.6) 4.88
Cooling Reposition 1 2.00 (22) N/A 4.4 (4.44.4) N/A
Fluids Osmotherapy 2 2.08 (1.23.0) 1.3 3.9 (2.65.2) 1.84
FIO2/PEEP 1 PRBCs 1 2.58 (2.62.6) N/A 13.2 (13.213.2) N/A
Osmotherapy Pressors 1 3.00 (33) N/A 2.8 (2.82.8) N/A
Osmotherapy Reposition 1 3.00 (33) N/A 2.8 (2.82.8) N/A
Any two treatments 101 1.28 (0.253.8) 0.65 9.6 (2.2 to 79) 9.82
PEEP, positive end expiratory pressure; PRBC, packed red blood cells; FFP, fresh frozen plasma.

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

TABLE 9. Most Popular Intervention Combinations on ICP
(n 1 episodes) was associated with the lowest T, and
and CPP
osmotherapy FIO2/PEEP increase (n 2 episodes) with
the greatest PbtO2. An osmotherapy sedation or narcotics N Intervention 1 Intervention 2 ICP CPP
combination appeared to demonstrate an optimal PbtO2/T 60 Narcotics/sedation 2.6 11.2 4.0 16.6
combination (16.9 mm Hg 14.5 mm Hg/0.82 hours 0.5 51 Pressors 1.4 7.5 8.3 18.9
hours) but was only used in five episodes. When controlling 27 Repositioning 0.8 7.8 10.2 12.8
for age, sex, Injury Severity Score, and arrival GCS no 24 FIO2/PEEP 0.1 4.8 5.3 15.4
intervention or combination of interventions appeared to be increases
better than others in correction of compromised PbtO2. 19 Sedation/narcotics Pressors 1.2 6.8 9.6 22.7
9 Fluids 0.8 2.8 6.8 16.9
PbtO2 Treatment and the Effect on ICP and 9 Sedation/narcotics FIO2/PEEP increases 2.1 5.3 7.1 10.2
CPP 9 Sedation/narcotics Reposition 0.5 4.4 20 35.2
We next examined how PbtO2-related treatment influ- 8 Sedation/narcotics Fluids 2.0 4.2 4.7 7.7
enced ICP and CPP during the same analyzed episodes (Table 7 Pressors Fluids 0.3 2.5 13.9 26.2
9). As with T and PbtO2, use of osmotherapy sedation 5 Sedation/narcotics Osmotherapy 7.8 7.9 1.5 12.3
or narcotics seemed to best manage ICP but did not translate
into an important CPP increase. Pressors, fluids and reposi-
tioning were associated with the greatest increases on CPP.
When evaluating the number of interventions on ICP, any mm Hg), which was significantly greater than that with no
three-intervention regimen (6.40 mm Hg 2.5 mm Hg) intervention (3.8 mm Hg 1.2 mm Hg, p 0.02). We also
had greater ICP reduction than no intervention (1.19 mm evaluated all compromised PbtO2 episodes that underwent
Hg 0.47 mm Hg, p 0.009), or one intervention (1.62 one or more interventions and found a mean decrease of ICP
mm Hg 0.61 mm Hg, p 0.03). CPP was most increased of 1.25 mm Hg 5.9 mm Hg and CPP increase of 7.02
with combinations of two interventions (11.1 mm Hg 2.4 17.7 in the interval evaluated.

2011 Lippincott Williams & Wilkins 541

Pascual et al. The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011
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 inter-
ventions and none required more than five interventions; (3)
no single intervention or combination of interventions ap-
peared better than any other to reduce time to PbtO2 correc-
tion 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 prospec-
tive 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 spe-
cific 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 cli-
nicians more time to administer more interventions. In addi-
tion, defining the episode endpoint as normalized PbtO2 (20
mm Hg) may have underestimated any interventions maxi-
mal 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 interdis-
ciplinary clinicians provide an in-depth description of what
542
interventions are usually administered to patients with com-
promised 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 guide-
lines 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 cou-
pled with ICP variations. Consistent with this, several obser-
vational 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 CPP-
based 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 asso-
ciated 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
Although clinical series suggest that there may be a
benefit to PbtO2-based care, it remains unclear what consti-
tutes 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 com-
promised 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.
Specific Interventions for Compromised
PbtO2Alone or in Combination?
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 ad-
dition, overuse of pressors may exacerbate lung function.5 Of
interest, we observed that, among the most popular treat-
ments, 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 recom-
mended 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
2011 Lippincott Williams & Wilkins
Interventions for PbtO2-Guided TBI Management
available oxygen through increases in FIO2, PEEP, or pul-
monary 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 infu-
sions 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.
CONCLUSIONS
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 advan-
tage 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 combi-
nation 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 intracra-
nial abnormalities are known to exacerbate injury in other
organ systems of critically ill patients. Finally, some PbtO2
543
Pascual et al. The Journal of TRAUMA Injury, Infection, and Critical Care Volume 70, Number 3, March 2011
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. Pas-
cual 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
2011 Lippincott Williams & Wilkins
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 suc-
cessfully 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. Further-
more, 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. There-
fore, 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 interven-
tions 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 won-
dering 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.
545
Pascual et al. 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