Neurocrit Care (2012) 17:4957

DOI 10.1007/s12028-012-9708-y

ORIGINAL ARTICLE

Early Cerebral Metabolic Crisis After TBI Influences Outcome

Despite Adequate Hemodynamic Resuscitation
Nathan R. Stein David L. McArthur
Maria Etchepare Paul M. Vespa

Published online: 24 April 2012

Springer Science+Business Media, LLC 2012

Abstract
Background Optimal resuscitation after traumatic brain
injury (TBI) remains uncertain. We hypothesize that
cerebral metabolic crisis is frequent despite adequate
resuscitation of the TBI patient and that metabolic crisis
negatively influences outcome.
Methods We assessed the effectiveness of a standardized
trauma resuscitation protocol in 89 patients with moderate
to severe TBI, and determined the frequency of adequate
resuscitation. Prospective hourly values of heart rate, blood
pressure, pulse oximetry, intracranial pressure (ICP),
respiratory rate, jugular venous oximetry, and brain extracellular values of glucose, lactate, pyruvate, glycerol, and
glutamate were obtained. The incidence during the initial
72 h after injury of low brain glucose <0.8 mmol/L, elevated lactate/pyruvate ratio (LPR) >25, and metabolic
crisis, defined as the simultaneous occurrence of both low
glucose and high LPR, were determined for the group.
Results 5 patients were inadequately resuscitated and
eight patients had intractable ICP. In patients with successful resuscitation and controlled ICP (n = 76), within
72 h of trauma, 76 % had low glucose, 93 % had elevated

Electronic supplementary material The online version of this

article (doi:10.1007/s12028-012-9708-y) contains supplementary
material, which is available to authorized users.
N. R. Stein
D. L. McArthur
M. Etchepare
P. M. Vespa (&)
Department of Neurosurgery, David Geffen School of Medicine
at UCLA, 757 Westwood Blvd, RR 6236A, Los Angeles,
CA 90095, USA
e-mail: pvespa@mednet.ucla.edu
P. M. Vespa
Department of Neurology, David Geffen School of Medicine at
UCLA, 757 Westwood Blvd, RR 6236A, Los Angeles,
CA 90095, USA

LPR, and 74 % were in metabolic crisis. The duration of

metabolic crisis was longer in those patients with unfavorable (GOSe B 6) versus favorable (GOSe C 7)
outcome at 6 months (P = 0.011). In four multivariate
models the burden of metabolic crisis was a powerful
independent predictor of poor outcome.
Conclusions Metabolic crisis occurs frequently after TBI
despite adequate resuscitation and controlled ICP, and is a
strong independent predictor of poor outcome at 6 months.
Keywords Brain trauma
Glucose
Lactate

Lactate/pyruvate ratio
Microdialysis
Resuscitation

Introduction
Traumatic Brain Injury (TBI) is a major cause of death and
disability. In the United States, there are 52,000 deaths
annually due to TBI, accounting for nearly 1/3 of all
trauma-related deaths [1]. The initial treatment of TBI has
improved through the formalization of trauma triage protocols and treatment guidelines [2], with a resultant
reduction in mortality from 39 % in 1987 to 27 % in 1996.
Resuscitation is particularly important in patients with TBI
since early physiological compromise such as hypoxemia,
hypotension, and elevated intracranial pressure can result
in secondary insults that markedly worsen neurological
outcome [3, 4]. Resuscitation after TBI is designed to avoid
profound secondary ischemic injury and is often focused on
hemodynamic endpoints that are readily measured such as
blood pressure, oxygenation, and ICP [5, 6]. However, the
effects of standard trauma resuscitation on brain metabolism and long term outcomes have not been well studied.
Many questions remain about what physiological endpoints
are ideal for the injured brain.

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In recent years, metabolic monitoring of the injured

brain has revealed the frequency, duration, and adverse
effects of widespread metabolic dysfunction in the brain
after TBI. Widespread brain regions suffer metabolic
dysfunction or crisis and are at risk for long term secondary
damage and cell loss [7, 8]. Metabolic crisis has been
characterized as a reduction in oxidative metabolism
(CMRO2), increased glucose consumption, and a resultant
imbalance in the redox state of the tissue. Metabolic crisis
can only be captured on a real-time basis by continuous
cerebral microdialysis. Positron Emission Tomography
(PET) scans can provide a snapshot of cerebral metabolism, but are difficult to acquire during acute
hospitalizations, and even if acquired, lack the ability to
diagnose the duration and trends of metabolic crisis.
Metabolic crisis has been defined as a low glucose
concentration and/or elevation in the lactate/pyruvate ratio
(LPR) [812]. For this research, we define metabolic crisis
as a simultaneous low glucose <0.8 mmol/L and elevated
LPR > 25 [9, 12]. Metabolic crisis can occur in the
presence or absence of cerebral ischemia, and prolonged
metabolic crisis is associated with adverse neurological
outcomes and tissue loss in a series of preliminary studies
[7, 10, 11, 13, 14].
The purpose of the present study was to determine the
frequency of metabolic crisis in the first 72 h post TBI, and
to determine if the occurrence of metabolic crisis was
associated with inadequate hemodynamic and intracerebral
resuscitation. Our hypothesis was that metabolic crisis can
occur despite adequate resuscitation as measured by
objective physiological endpoints. Our secondary hypothesis was that cumulative metabolic crisis is associated with
worsened long term neurological outcome.

Materials & Methods

Patient Data
This study was conducted as part of the UCLA Brain Injury
Research Center (BIRC) during a 12-year period in patients
with acute TBI. The main inclusion criterion was an
admission Glasgow Coma Scale (GCS) score of B8 or an
admission GCS of 912 with computerized tomography
brain scans demonstrating intracranial bleeding. The main
exclusion criteria were GCS > 12 with a nonsignificant
head CT, history of neurologic disease or TBI, brain death,
family was not found within 96 h, or the patient was
>96 h post injury upon admission to UCLA. Surrogate
informed consent was obtained. From 08/1998 to 02/2011
there were 130 patients who met these criteria and received
microdialysis monitoring. Of these, 37 patients were not

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Neurocrit Care (2012) 17:4957

included in this analysis because they did not receive

microdialysis monitoring within 72 h post injury and could
therefore not be used to look for early metabolic crisis. 4
patients were excluded because on CT the catheter was
found to be pericontusional (n = 3) or in a ventricle
(n = 1). The remaining 89 patients were included in this
analysis. Six-month functional outcomes were evaluated
using the Extended Glasgow Outcome Scale (GOSe) at
outpatient follow-up clinical appointments or off-site
appointments at the patients residence. Outcomes were
dichotomized as unfavorable (GOSe B 6, dead to upper
moderate disability) or favorable (GOSe C 7, lower to
upper good recovery). The study was approved by the
UCLA institutional review board.

General TBI Management Protocol

All patients were seen by level 1 trauma surgeons and
physicians in the emergency department, and underwent
primary and secondary survey evaluation and hemodynamic resuscitation (as outlined below). All patients were
admitted to the neurointensive care unit after initial stabilization in the emergency room or after surgery. Patients
requiring an initial emergency operation for a mass lesion
were taken to the operating room within 1 h of admission.
ICP monitoring was performed by a ventriculostomy in the
emergency room. As per protocol, ICP was kept below
20 mmHg by a stepwise management strategy (i.e., cerebrospinal fluid drainage, hyperventilation to PCO2 of
3035 mmHg, and hypertonic saline). Ventriculostomy
drainage was used for persistent elevation of the
ICP > 20 mmHg for >5 min. CSF was drained for
10 min and then the ventriculostomy was set to monitor.
Refractory intracranial pressure was managed by pentobarbital-induced burst suppression coma. Cerebral
perfusion pressure (CPP) was kept equal to or greater than
60 mmHg using norepinephrine when required. Jugular
venous oximetry (SjvO2) was performed to monitor for
jugular venous desaturation and for hyperemia. Blood
pressure was adjusted to keep the SjvO2 between 60 and
70 %. Core temperature from the jugular vein was used and
kept between 36.5 and 37.5 C through the use of medications (acetaminophen) and surface-cooling devices.
Systemic glucose was controlled using subcutaneous insulin to achieve serum glucose between 80 and 140 mg/dL.
All patients received a loading dose of phenytoin (18 mg/kg)
in the emergency room and were continued on phenytoin
300 mg/day for 7 days. Continuous electroencephalographic (EEG) monitoring was performed on all subjects
to assess the presence of seizure activity and/or to monitor the barbiturates effect when burst-suppression was
induced.

Neurocrit Care (2012) 17:4957

Resuscitation
In this study, a formalized standardized approach to hemodynamic resuscitation was used that begun in the emergency
room and consisted of intravenous crystalloid infusion of
24 L of normal saline, half-normal saline, or D5W over 2 h
to achieve mean arterial pressure >80 mmHg, heart rate
<100 bpm, and urine output >0.5 cc/kg/h. Fluids were
infused through large bore trauma venous catheters inserted
in the femoral vein and subclavian central venous catheters.
Thereafter, normal saline was infused at 100 cc/h as maintenance fluids, with additional boluses of normal saline
infused to achieve desired hemodynamic goals. Mechanical
ventilation was used in all patients, with oxygenation and
end-tidal carbon dioxide monitoring used to achieve goals of
PaO2 > 100 mmHg, and ETCO2 3035 mmHg. After
insertion of the subclavian central venous catheters and
radial arterial lines, additional hemodynamic resuscitation
was employed to achieve these goals: CVP > 6 mmHg,
MAP > 80 mmHg and CPP 5070 mmHg. In addition
to intravenous crystalloids, norepinephrine was used to
support blood pressure. Blood transfusions of PRBCs,
platelets, FFPs, and cryoprecipitate were used liberally
to keep hemoglobin >8 g/dl, INR <1.5 s, and platelet
count >90,000. Serum sodium values were checked every
6 h, and 3 % NaCl infusions at 2550 cc/h were used to
maintain serum sodium > 140 mEq/L. Written guidelines
for nurse monitoring of the hemodynamic endpoints were
employed, with physician notification triggers. The neurointensive care and trauma surgery attending physicians made
twice daily rounds to assess the adequacy of hemodynamic
resuscitation.
In order to classify which of the research patients were
adequately resuscitated, we first retrospectively appraised
the neurocritical care attending notes on the patient the first
few days to see if the overall clinical impression was that
the patient was or was not adequately resuscitated. All
patients were treated by the same single attending physician over the entire period.
Second, to more objectively classify the clinical
impression of resuscitation, we created a resuscitation
scoring system (RSS) based on six parameters: fluid balance (I/O), systolic blood pressure (SBP), heart rate (HR),
partial pressure of oxygen (pO2), hematocrit (HCT), and
hemoglobin (HGB). Using published literature on optimal
or ideal values for each of these parameters in the trauma
patient [2, 5, 6, 1518], we determined cut-off points to
characterize resuscitation success in the first 24 h post
injury. If the patient was below the desired value for all
24 h, 1223 h, or 011 h then they were assigned 2, 1, or 0
points, respectively. For example, if the patient had a
hematocrit <28 for all 24/24 h they were given 2 points, if
they had a hematocrit <28 for 15/24 h they were given 1

51

point, and if they had a hematocrit <28 for less than 11 h,

or not at all, then they were not given any points. This was
done for each of the six parameters and the total points
were summed. Those patients who were assigned 3 or more
points were determined to have inadequate resuscitation.
This criterion is summarized in Appendix 1 in Supplementary material. As an internal control to assess the
validity of the RSS we used the Modified Early Warning
Score (MEWS) as a comparison scale. The MEWS is a
validated scale [19] that factors in SBP, HR, RR, Temp,
and AVPU/GCS of patients in the emergency department,
with high scores associated with increased risk of death. Of
5 patients that failed resuscitation according to the RSS,
four had a high MEWS (independent of GCS). The other 1
patient had a MEWS score of 0 but failed the RSS because
of a low hematocrit and negative fluid balance (two
parameters MEWS does not take into account). No patients
deemed successfully resuscitated by the RSS had a high
MEWS.
Third, we looked at the jugular venous oximetry to
determine whether the systemic fluid resuscitation had
succeeded and resulted in adequate blood flow and oxygenation to the brain, and that the TBI patient was therefore
cerebrally resuscitated. Patients who were resuscitated
according to each of these three converging lines of evidence (clinical impression, RSS, and SjvO2) were labeled
successfully resuscitated.
Cerebral Microdialysis and Monitoring
A CMA70 probe (10-cm flexible shaft, 10-mm membrane
length), CMA 106 perfusion pump, and CMA 600 microdialysis analyzer were used. The microdialysis probes were
located in normal appearing white matter, almost exclusively in the dorsolateral frontal white matter ipsilateral to
the ventricular catheter. A post-insertion CT scan was
performed and any catheters that appeared to be pericontusional or in CSF were either adjusted to proper placement
or else excluded from this analysis. A standard flow rate of
0.3 lL/min was used and vials were sampled every 1 h and
analyzed bedside on the CMA600 (CMA Microdialysis
AB). Glucose, lactate and pyruvate were measured in all 89
patients, glycerol in 58 patients, and glutamate in 73
patients. A total of 9,105 samples were analyzed in this
study. Microdialysis monitoring was performed for the
initial 10 days starting at 23.5 10 h post injury. The
microdialysis data were available in real-time for use as a
diagnostic tool over the course of treatment. ICP, HR,
MAP, and SPO2 were recorded hourly in the ICU by
automatic monitoring and manual input by nurses, and the
data were electronically transferred in real-time to the
UCLA Brain Injury Research Center (BIRC) database for
analyses.

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Data Analysis
Statistical analyses were performed by the program R
version 2.13.2 (R Foundation for Statistical Computing,
Vienna, Austria; http://www.R-project.org; R Development
Core Team, 2011). Microdialysis data were analyzed on a
per-patient basis as was done in the largest microdialysis
study to date [12] (i.e., one data-point per patient, the
average for the period and parameter being evaluated) for
calculating medians, means, ranges, differences between
outcome groups, and predictors of outcome (logistic
model). We did not pool hourly data from multiple
patients. Intergroup statistical analysis was performed with
a simple non-parametric test (MannWhitney U-test) and
logistic regression. We did not adjust for multiple comparisons. Regression analyses were performed to determine
if metabolic crisis independently predicted outcome in this
population. Favorable outcome (GOSe C 7) was coded as
0 and unfavorable (GOSe B 6) coded as 1 in these models,
with predictors being age, incoming GCS, number of
pupils reactive on admission, and metabolic crisis. Metabolic crisis was entered into the model as % time spent in
crisis in the first 72 h, and then calculated for each 12-h
increment (half the standard deviation) spent in crisis to
facilitate interpretation of the odds ratio. We performed
additional robust regression analyses because the data
were not normally distributed. By means of R code provided by Wilcox [20] we computed a (1) bounded M
regression using Huber Psi and Schweppe weights and an
(2) adjusted M-estimator using Huber Psi and Schweppe
weights with regression outliers getting a weight of zero
[21]. In addition, we fit linear models via weighted likelihood which is robust against the presence of bad
leverage points [22].

Neurocrit Care (2012) 17:4957

The most frequent hemodynamic phenotype after TBI

was tachycardic, controlled blood pressure, and adequately
oxygenated state. In the first 48 h post injury, 55.9 % of
patients were tachycardic, 11.9 % were bradycardic, 9.1 %
were hypotensive, and 19.5 % were hypertensive. Adequate oxygen saturation occurred in 100 % of patients in
the first 48 h. Elevated ICP occurred in 19.48 % of patients
in the first 48 h. Intractable ICP, defined as
ICP > 20 mmHg for >24 h occurred in 8.9 % of patients
(n = 8). Hyperemia, defined as persistent SjvO2 > 75 %
for >12 h during the initial 72 h period occurred in
38.2 % of patients (n = 34).
Resuscitation and Intracranial Pressure
To assure for this study that metabolic crisis was not
caused by inadequate systemic blood flow due to failed
fluid resuscitation, and/or induced by uncontrolled intracranial pressure, we excluded all patients who were not
properly resuscitated (n = 5) and/or had intractable ICP
(n = 8). Resuscitation was determined by clinical
impression, resuscitation scoring system (RSS), and SjvO2.
Upon chart review, clinical impression was that 3 patients
were not adequately resuscitated, which was verified with
the RSS (Appendix 1 in Supplementary material). An
additional 2 patients were resuscitated by clinical impression but failed resuscitation by the RSS and were excluded.
2 patients had SjvO2 < 60 % but also failed RSS and
were already excluded. 8 patients had intractable ICP and
were excluded from further analysis. In total, 13 patients
were excluded and the remaining 76 were analyzed for the
occurrence of metabolic crisis (Table 1) and included
in the univariate (Table 2) and multivariate analysis
(Table 3).

Results

Microdialysis and Metabolic Crisis Results

A total of 89 subjects were enrolled, 74 male and 15

female, with a mean age of 46.43 16.42 years. The
mechanisms of injury were (1) falls (n = 28), (2) motor
vehicle accidents (n = 22), (3) motorcycle accidents
(n = 14), (4) pedestrians versus automobile (n = 12), (5)
blunt traumas (n = 7), (6) bicycle accidents (n = 3), and
(7) gunshot wounds (n = 3). The incoming GCS was 38
in 55 (62 %) patients, and 912 in 34 (38 %) patients, with
a median GCS of 6.5. All the patients were victims of a
major trauma; the median Injury Severity Score (ISS) of
the population was 26 (range 1751).
The median GOSe at 6 months was 4. There was a
23.7 % mortality rate in the patient population. An additional 61.8 % had a poor outcome GOSe B 6, and 14.5 %
had a good outcome GOSe C 7.

The time course of each microdialysis analyte is shown in

Fig. 1. Microdialysis levels of glucose, lactate, and pyruvate were analyzed in all patients. The frequency of
metabolic crisis was then determined on a per-patient basis,
excluding patients who were not adequately resuscitated
(n = 5) and/or had intractable ICP (n = 8). These patients

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Table 1 Incidence and duration of metabolic crisis in the first 72 h

post injury
Parameter

% Patients (n)

Mean duration (h)

Glucose < 0.8 mmol/L

76.3 (58/76)

38.0 21.5

LPR > 25

93.4 (71/76)

44.9 23.8

Metabolic crisis

73.7 (56/76)

33.5 22.8

Neurocrit Care (2012) 17:4957

Table 2 Data split by outcome
group shown as median
(interquartile range) and
statistical intergroup
comparison

53

Parameter

6 month outcome
Favorable (GOSe C 7)

P value
Unfavorable (GOSe B 6)

Admission characteristics
Age

32.5 (26.345.0)

50.5 (38.362.0)

0.008

GCS

9.0 (7.312.5)

6.0 (3.010.8)

0.131

Hypoxia (% of patients)

18.50

0.146

Hypotension (% of patients)

9.10

26.20

0.284

Pupils unreactive (% of patients)

20

25

0.243

Metabolic crisis (hours)

1.4 (0.014.2)

25.2 (6.550.4)

0.011

Lactate/pyruvate ratio

25.4 (18.930.7)

32.8 (24.741.6)

0.011

Lactate/pyruvate ratio > 25 (%)

46.8 (8.654.5)

66.0 (33.597.0)

0.074

Glucose (mmol/L)
Glucose < 0.8 mmol/L (% time)

1.3 (0.93.1)
9.1 (0.040.7)

0.9 (0.61.5)
47.3 (18.381.6)

0.061
0.021

Lactate (mmol/L)

1.8 (1.53.0)

2.7 (1.54.3)

0.132

Pyruvate (lmol/L)

78.7 (51.3117.5)

77.9 (49.9121.8)

0.978

Glycerol (lmol/L)

65.5 (49.196.9)

63.7 (42.3-124.6)

0.998

Monitoring parameters

Significant differences
(P < 0.05) in bold type
(MannWhitney U test)

Glutamate (lmol/L)

3.8 (3.36.4)

8.8 (5.815.7)

0.027

Jugular venous oximetry (%)

75.7 (73.479.7)

74.1 (69.375.2)

0.237

Intracranial pressure (mmHg)

14.5 (13.015.8)

14.1 (10.417.2)

0.703

Table 3 Multivariate analyses showing age, GCS, pupil reactivity, and metabolic crisis as predictors of poor 6 month outcome with P-value for
four different statistical iterations of the model
Predictor

B (standard
error)

OR

95 % CI

P value
1. Logistic
regression

2. M-regression

3. M-estimator

4. Weighted
likelihood

Age (years)

0.09 (0.03)

1.09

1.021.17

0.011

0.010

0.013

0.003

GCS (315)

-0.25 (0.11)

0.78

0.620.98

0.031

0.150

0.127

0.017

Pupils (# reactive)

0.28 (0.58)

1.32

0.434.08

0.629

0.965

0.938

0.678

Metabolic Crisis (each 12 h)

0.77 (0.37)

2.16

1.054.45

0.036

<0.001

<0.001

0.012

-1.52 (1.66)

0.22

Constant
2

Model summary: x = 22.2, P < 0.0001, R = 0.481 (Nagelkerke), Brier Score = 0.094
Significant differences (P < 0.05) in bold type

were excluded so we could determine if in patients whose

physiological parameters were deemed sufficiently controlled according to current treatment standards, there still
persisted a metabolic crisis in the brain as marked by
microdialysis that was otherwise unnoticed and untreated.
In the first 72 h post injury, 76 % of patients had low
glucose for a mean duration of 38 h. 93 % of patients had
elevated LPR for a mean duration of 45 h. In aggregate,
74 % of patients were in metabolic crisis, with a mean
duration of 33.5 h. The findings are summarized in
Table 1. Patients who were in metabolic crisis at 72 h post
injury saw the correction of their crisis occur (glucose
increased above 0.8 mmol/L and LPR reduced below 25)
over the following: 48 h (22 %), 96 h (24 %), 144 h
(26 %), >144 h (11 %) of patients. In total the metabolic

crisis resolved in 83 % of patients, but persisted throughout

monitoring in 17 % of patients.
We divided the patient population into favorable and
unfavorable outcome groups and performed a univariate
analysis to determine what physiologic and microdialysis
parameters differed (Table 2). There were statistically
significant differences in age, hours of metabolic crisis,
LPR, time spent with glucose <0.8 mmol/L, and glutamate between the two groups. The duration of metabolic
crisis in those with a favorable outcome was significantly
less (median 1.4 h) than those with an unfavorable outcome (median 25.2 h) (P = 0.011).
We then performed a multivariate analysis (n = 76) to
determine if metabolic crisis independently predicted
favorable vs. unfavorable outcome after factoring in other

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Neurocrit Care (2012) 17:4957

Glucose

100

L/P Ratio

90
80

Lactate / Pyruvate

Glucose (mmol/L)

70
60
50
40
30
20

10
0

0
24

48

72

24

48

Hours Post Injury

10

72

Hours Post Injury

Lactate

300

Pyruvate

250

Pyruvate (mol/L)

Lactate (mmol/L)

200

150

100

50

0
24

48

72

24

48

Hours Post Injury

300

Glycerol

50

Glutamate

40

Glutamate (mol/L)

Glycerol (mol/L)

250
200
150
100

30

20

10

50

0
24

48

72

Hours Post Injury

Fig. 1 Microdialysis time course from 24 to 72 h post injury. Shown

is the mean value standard deviation. a Mean glucose over the time
course was 1.4 1.1 mmol/L, the dashed line shows the cutoff for
what was considered low glucose (<0.8). b Mean lactate was

123

72

Hours Post Injury

24

48

72

Hours Post Injury

3.5 2.0 mmol/L. c Mean pyruvate was 111.2 59.6 lmol/L.

d Mean LPR was 37.7 25.9, the dashed line shows the cutoff for
what was considered elevated LPR (>25). e Mean glycerol was
96.6 85.3 lmol/L. f Mean glutamate was 16.5 36.0 lmol/L

Neurocrit Care (2012) 17:4957

known predictors, specifically age, GCS, and pupil reactivity (Table 3). We created four different models. The first
was a non-robust logistic regression with unfavorable
outcome as the dependent variable. Age was a strong
positive predictor of poor outcome (OR 1.09, CI 1.021.17,
P = 0.011). GCS was a strong negative predictor of poor
outcome (OR 0.78, CI 0.620.98, P = 0.031) meaning that
a high GCS on admission reduced the likelihood of having
a poor outcome. Metabolic crisis was a strong positive
predictor of poor outcome (OR 2.16, CI 1.054.45,
P = 0.036), meaning that for each 12 h spent in metabolic
crisis the odds of having a poor outcome more than
doubled.
The data were not normally distributed and logistic
regression is well-known to be sensitive to violations of
normality, so we also performed three robust regression
analyses. Age and metabolic crisis were significant predictors in all three robust models, and GCS in only the
weighted likelihood model. Number of pupils reactive on
admission was not a significant predictor in either the
logistic or robust regressions.

Discussion
The main findings in this study were: (1) Most patients
with TBI received adequate hemodynamic resuscitation
within 24 h after TBI. (2) The majority of patients demonstrated persistent metabolic crisis as measured by
cerebral microdialysis despite adequate resuscitation and
control of ICP. (3) The persistence of metabolic crisis
during the initial 72 h after TBI is a strong independent
predictor of neurological outcome, after controlling for
classical predictors.
The initial triage and resuscitation of TBI is focused on
accurate diagnosis, stabilization, and life saving treatments.
The goals of resuscitation after TBI are cardiopulmonary
endpoints such as heart rate, blood pressure, and oxygen
saturation, and later intracranial pressure [2, 5, 16]. While
these endpoints are well accepted, they may not best reflect
the state of cerebral resuscitation. In the present results,
most patients were hemodynamically resuscitated yet had
cerebral metabolic crisis, as reflected by low extracellular
glucose and elevated LPR. This finding suggests that direct
monitoring of the brain rather than systemic monitoring
alone is required to determine the clinical treatment endpoints for resuscitation. One could envision the use of
cerebral microdialysis or some other less invasive cerebral
monitor against which resuscitation could be better gauged,
while retaining the use of systemic hemodynamics for
evaluation of other organ systems. A fundamental message
from these data is that the brain compartment appears to be
distinct from that of the systemic circulation. Future

55

treatment trials of therapeutic interventions could be

enhanced by cerebral metabolic monitoring rather than
systemic monitoring alone.
Metabolic crisis is a state of energetic compromise after
TBI which may occur due to cerebral ischemia or nonischemic alterations in brain metabolism. Metabolic crisis
has been documented in many TBI cohorts [7, 8, 1012,
14]. However, most studies have performed only univariate
analyses, or only performed multivariate analyses that
correlate microdialysis values with acute mortality [12] and
fail to show metabolic crisis as an independent predictor of
overall outcome. Our results show four different interpretations of the regression model in which early metabolic
crisis always emerges as a strong independent predictor of
overall outcome. Our cohort included more patients with
moderate TBI (GCS 912) than other similar studies [12],
but it should be noted that GCS may not reflect the true
nature of the injury, and it has been suggested that there is a
need for better indicators of severity of injury in TBI [23].
Our patient population had a similar mortality rate to other
groups, but more poor outcomes [12]. This is in part
because we used the extended GOS (GOSe) for our analysis as opposed to the standard GOS which most other
groups have used. The GOSe has been shown to be more
sensitive to changes in moderate TBI [24]. In addition,
because of our location in Los Angeles and the patients that
we receive, this population contained more elderly patients
than many other trials.
Metabolic crisis appears to last for several days after
TBI, and can be elicited by increased energy demand or an
elevation in intracranial pressure. The cumulative duration
of metabolic crisis independently predicts poor long term
outcome and tissue loss after TBI [11]. Patients with more
prolonged elevation in LPR have more long term brain
tissue atrophy and worsened outcomes. We have shown
that the burden of metabolic crisis over the 72 h following
trauma is a stronger predictor of outcome than admission
GCS and pupil reactivity. Hence, metabolic crisis appears
to be an important early biomarker of ongoing injury and is
potentially a therapeutic target.
It is presently unclear why metabolic crisis persists
despite adequate hemodynamic resuscitation. On the surface, these data imply that the metabolic crisis is coming
from injury-induced mechanisms that are not responsive to
improvements in systemic hemodynamics, such as seizures, electrical instability, or inflammation. We have
documented seizures as a frequent event after TBI [25, 26],
but the current cohorts microdialysis results could not be
easily explained by seizures. Another possible explanation
is that the state of autoregulation is so disturbed during the
period of study that normal systemic blood pressure
resulted in excessive blood flow or hyperemia. The combined use of jugular venous oximetry, which showed mild

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hyperemia, is consistent with this, but we did not observe

persistent hyperemia with elevated ICP in this group of
patients. Indeed, ICP was well controlled for most patients.
A third explanation is that patients could have had an
oxygen diffusion deficit or local ischemia that was not
detectable by jugular venous oximetry, thus resulting in
metabolic crisis. We cannot exclude this possibility, since
we did not routinely employ brain tissue oxygen monitoring, but the global data from the jugular venous oximetry
and normal systemic oxygenation would speak somewhat
against this possibility. 38 % of patients were in fact
hyperemic in the first 72 h, while no patients demonstrated
global ischemia. A fourth potential mechanism would be
acutely dying cells as a result of the primary injury, leading
to cerebral microdialysis findings of metabolic distress.
The latter mechanism is possible, but our cumulative
experience with cerebral microdialysis and brain imaging
suggests that cell death occurs at a later time point and that
acute changes in microdialysis reflect reversible cellular
injury rather than dying cells.
In this study, we extend our understanding of the origins
and significance of metabolic crisis after TBI. The data
suggest that metabolic crisis persists despite aggressive
attempts to resuscitate the patient, and despite reasonable
critical care to avoid ischemic secondary insults. Said
another way, it appears that standard of care fluid and
hemodynamic resuscitation is inadequate to reverse posttraumatic metabolic crisis. Hence, these findings call into
question whether commonly used physiologic endpoints
are appropriate for the TBI patient, and raise the possibility
that direct biomarkers of brain metabolism should be
identified that might be preferentially used to judge the
adequacy of resuscitation.
In contrast to the prevailing sentiment that ischemia
plays the predominant role in secondary injury and that by
association resuscitation should focus on enhanced delivery
of cerebral blood flow and oxygen, these data along with
our previous studies [7, 10, 11, 13] suggest that metabolic
crisis is often non-ischemic. If we assert that no gross
deficit in brain oxygenation occurred, which is supported
by our previous studies, then metabolic crisis is unlikely to
be resolved by resuscitative efforts alone designed to normalize systemic and cerebral hemodynamics.

Limitations
The study is based on an observational dataset and therefore can only show relationships and correlations, without
definitive evidence that chemistry directly influences outcome. The data were collected over more than a decade
which could introduce bias due to gradually changing
monitoring and clinical practices. Most patients did not

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Neurocrit Care (2012) 17:4957

have brain tissue oxygen monitoring. Thus, brain ischemia

could have been missed by the lack of sensitivity of the
jugular venous oximetry method. In previous studies, we
have found a paucity of cerebral ischemia by formal metabolic criteria [7, 10, 11, 13]. However, a deficit of oxygen
diffusion into the brain tissue could explain the ongoing
metabolic distress [27]. In addition, the nature of microdialysis as a focal monitoring tool may limit the
generalization of the finding.

Summary
After TBI, resuscitation in the ER bay and neuro ICU was
successful in nearly all patients: 13 of 89 (14.6 %) patients
failed resuscitation and/or had intractable ICP. Nevertheless, metabolic crisis occurred in the first 72 h post injury
in 74 % of patients despite successful resuscitation and
controlled ICP. The duration of metabolic crisis was substantially longer for those patients with an unfavorable
outcome at 6 months. In four iterations of multivariate
models including age, GCS, pupil reactivity, and metabolic
crisis in the first 72 h, metabolic crisis was the strongest
predictor of unfavorable outcome. This research provides
further support for the utility of microdialysis to predict
outcome in TBI patients, and calls for further research in
controlled studies to determine whether specific treatment
interventions can influence early cerebral biochemistry and
thereby improve outcome.
Acknowledgments
by NS-058489.

UCLA Brain Injury Research Center, supported

Conflict of interest
report.

No commercial company conflicts of interest to

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