Article

Ichai C, Armando G, Orban JC, Berthier F, Rami L, Samat-Long C, Grimaud D, Leverve XSodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensive Care Med 35:471-479

Faculté de Médecine and CHU de Nice, Service de Réanimation, Hôpital Saint-Roch, Nice Cedex 1, France.
Intensive Care Medicine (Impact Factor: 7.21). 09/2008; 35(3):471-9. DOI: 10.1007/s00134-008-1283-5
Source: PubMed

ABSTRACT

Traumatic brain injury (TBI) is still a major cause of mortality and morbidity. Recent trials have failed to demonstrate a beneficial outcome from therapeutic treatments such as corticosteroids, hypothermia and hypertonic saline. We investigated the effect of a new hyperosmolar solution based on sodium lactate in controlling raised intracranial pressure (ICP).
Prospective open randomized study in an adult ICU.
Thirty-four patients with isolated severe TBI (Glasgow Coma Scale <or= 8) and intracranial hypertension were allocated to receive equally hyperosmolar and isovolumic therapy, consisting of either mannitol or sodium lactate. Rescue therapy by crossover to the alternative treatment was indicated when ICP could not be controlled. The primary endpoint was efficacy in lowering ICP after 4 h, with a secondary endpoint of the percentage of successfully treated episodes of intracranial hypertension. The analysis was performed with both intention-to-treat and actual treatments provided.
Compared to mannitol, the effect of the lactate solution on ICP was significantly more pronounced (7 vs. 4 mmHg, P = 0.016), more prolonged (fourth-hour-ICP decrease: -5.9 +/- 1 vs. -3.2 +/- 0.9 mmHg, P = 0.009) and more frequently successful (90.4 vs. 70.4%, P = 0.053).
Acute infusion of a sodium lactate-based hyperosmolar solution is effective in treating intracranial hypertension following traumatic brain injury. This effect is significantly more pronounced than that of an equivalent osmotic load of mannitol. Additionally, in this specific group of patients, long-term outcome was better in terms of GOS in those receiving as compared to mannitol. Larger trials are warranted to confirm our findings.

Full-text

Available from: Jean-Christophe Orban, Nov 26, 2014
Carole Ichai
Guy Armando
Jean-Christophe Orban
Frederic Berthier
Laurent Rami
Corine Samat-Long
Dominique Grimaud
Xavier Leverve
Sodium lactate versus mannitol in the
treatment of intracranial hypertensive episodes
in severe traumatic brain-injured patients
Received: 17 February 2008
Accepted: 19 August 2008
Published online: 20 September 2008
Ó Springer-Verlag 2008
Electronic supplementary material
The online version of this article
(doi:10.1007/s00134-008-1283-5) contains
supplementary material, which is available
to authorized users.
C. Ichai (
)
) G. Armando J.-C. Orban
L. Rami C. Samat-Long D. Grimaud
Service de Re
´
animation, Faculte
´
de
Me
´
decine and CHU de Nice,
Ho
ˆ
pital Saint-Roch, 5 Rue Pierre De
´
voluy,
06006 Nice Cedex 1, France
e-mail: ichai@unice.fr
Tel.: ?33-492-033627
Fax: ?33-492-033558
F. Berthier
De
´
partement d’Informatique Me
´
dicale,
CHU de Nice, Ho
ˆ
pital Cimiez,
Avenue Reine Victoria, 06000 Nice, France
X. Leverve
Inserm U884 and Universite
´
Joseph Fourier,
38041 Grenoble Cedex, France
Abstract Objectives: Traumatic
brain injury (TBI) is still a major
cause of mortality and morbidity.
Recent trials have failed to demon-
strate a beneficial outcome from
therapeutic treatments such as corti-
costeroids, hypothermia and
hypertonic saline. We investigated
the effect of a new hyperosmolar
solution based on sodium lactate in
controlling raised intracranial pres-
sure (ICP). Design and
setting: Prospective open random-
ized study in an adult ICU.
Patients: Thirty-four patients with
isolated severe TBI (Glasgow Coma
Scale B 8) and intracranial hyper-
tension were allocated to receive
equally hyperosmolar and isovolumic
therapy, consisting of either mannitol
or sodium lactate. Rescue therapy by
crossover to the alternative treatment
was indicated when ICP could not be
controlled. The primary endpoint was
efficacy in lowering ICP after 4 h,
with a secondary endpoint of the
percentage of successfully treated
episodes of intracranial hypertension.
The analysis was performed with both
intention-to-treat and actual treat-
ments provided. Measurements and
results: Compared to mannitol, the
effect of the lactate solution on ICP
was significantly more pronounced
(7 vs. 4 mmHg, P = 0.016), more
prolonged (fourth-hour-ICP decrease:
-5.9 ± 1 vs. -3.2 ± 0.9 mmHg,
P = 0.009) and more frequently suc-
cessful (90.4 vs. 70.4%, P = 0.053).
Conclusion: Acute infusion of a
sodium lactate-based hyperosmolar
solution is effective in treating intra-
cranial hypertension following
traumatic brain injury. This effect is
significantly more pronounced than
that of an equivalent osmotic load of
mannitol. Additionally, in this spe-
cific group of patients, long-term
outcome was better in terms of GOS
in those receiving as compared to
mannitol. Larger trials are warranted
to confirm our findings.
Keywords TBI Osmotherapy
Cerebral edema Plasma ions
Neurological outcome Disability
Introduction
Traumatic brain injury (TBI) remains a highly detri-
mental illness with fatal outcomes ranging from 20–50%
and severe neurological disability affecting 35–50%
[14]. Three recent multicenter trials investigating
the effect of prehospital management with hypertonic
sodium chloride [5], corticosteroids [6] or hypothermia
during the acute phase [7] all proved negative on
outcome. Several treatments including drainage of
cerebrospinal fluid [8], hypothermia [7, 9] may lower
intracranial pressure as does osmotherapy. Nevertheless,
the infusion of bolus(es) of mannitol represents the first
treatment currently recommended to decrease cerebral
Intensive Care Med (2009) 35:471–479
DOI 10.1007/s00134-008-1283-5
ORIGINAL
Page 1
edema, since its efficacy has been demonstrated over
many years [1012]. Only a few randomized controlled
trials have evaluated the effect of mannitol on intracra-
nial hypertension [10, 13]. None showed much
difference between treatments, and the effect of manni-
tol on neurological outcome is still open to debate [14].
Side effects such as dehydration, hypotension and renal
failure may limit its use [11], and its transitory action
may be accompanied by a rebound effect [15]. The
principal mechanism of mannitol is believed to be
osmotic, leading to brain dehydration and a decrease in
ICP, thus improving cerebral perfusion. Although this
mechanism of osmotic dehydration of the swollen brain
may occur, mannitol lowers ICP through several other
mechanisms, including increased CSF absorption, rhe-
ology (induction of blood dilution decreasing viscosity),
and perfusion pressure changes leading to vasoconstric-
tion and decreased cerebral blood volume [12, 16, 17].
In recent years, hypertonic sodium chloride has been
introduced in the treatment of brain edemas in animal
studies [18] and in humans [19, 20]. In a prospective
study in patients with TBI [21], saline/dextran mixture
was judged to be superior to mannitol in decreasing ICP;
however, contradictory results have recently been shown
[12].
Contrary to popular belief, lactate is now recognized
as a key inter-cellular or inter-organ metabolite between
glycolysis and oxidative phosphorylation that can be
both produced and utilized by the brain under patho-
logical conditions [22, 23]. Animal and human studies
show that lactate can prevent the neurological effect of
hypoglycemia [24, 25], indicating that systemic lactate
can be metabolized by the brain. Experimental data on
rat hippocampi submitted to an ischemia reperfusion
injury found that lactate was a better substrate than
glucose [26]. Hypertonic sodium lactate also produced a
significantly better cognitive function in rats 10–15 days
post-TBI when compared to a hypertonic sodium chlo-
ride solution [27, 28]. In a porcine model of TBI,
hyperosmolar sodium lactate was shown to decrease ICP
and to increase cerebral blood flow by arteriolar vaso-
dilation [29, 30].
We therefore hypothesized that hypertonic sodium
lactate may combine the advantages of lactate as a pre-
ferred fuel for the brain under the condition of ischemia-
reperfusion injury (as in the early phase of severe TBI),
together with arteriolar cerebral vasodilation and anti-
edematous effect. Consequently, we undertook a pro-
spective randomized controlled study of patients suffering
from severe TBI. The study endpoint was to compare the
effect of a bolus of an equally hyperosmolar, isovolumic
infusion of either sodium lactate or mannitol on the
evolution of ICP during episodes of intracranial hyper-
tension. We have also compared (1) the efficacy
(percentage of failure) of both treatments on intracranial
pressure (ICP), and (2) the effects of these two treatments
on 1-year neurological outcomes assessed by the Glasgow
Outcome Score.
Materials and methods
Patients
Approval was obtained from the Nice Hospital Ethical
Research Committee. All patients presenting with an
acute, isolated, severe head injury were eligible for
enrolment. Patients were included within the first 8 h after
injury if they had either an initial prehospital Glasgow
Coma Score of B8, or a rapid worsening in neurological
status before admission. Patients younger than 18 years,
older than 65 years and pregnant women were excluded,
as were patients requiring (1) a neurosurgical interven-
tion, (2) with polytrauma, (3) with bilateral fixed dilated
pupils, (4) with a prolonged prehospital episode of hyp-
oxemia or arterial hypotension, (6) with rhinorrhea, (7)
with initial hypernatremia ([155 mmol/L), (8) with
penetrating head injury, and (9) patients with prehospital
barbiturate, steroids or osmotherapy administration.
General head injury management is described in detail
in the electronic supplement material. Any increase in
ICP [ 25 mmHg which persisted for more than 5 min in
the absence of noxious stimulations was considered to be
an episode of intracranial hypertension requiring
osmotherapy.
Study protocol
Following approval from the next-of-kin, suitable patients
were randomly allocated to receive either treatment by
using sealed envelopes to a ratio of 5:5 in blocks of 10.
Sodium lactate solution (half-molar sodium lactate) was
specifically designed to have a similar osmolarity to 20%
mannitol, as assessed by D cryoscopic determination
(1,100 mosm/L for LAC and 1,160 mosm/L for MAN).
The lactate solution contained Na 504 mmol/L, K
4 mmol/L, Ca 1.36 mmol/L, Cl 6.74 mmol/L and lactate
504.1 mmol/L. Osmotic treatment consisted of an acute
infusion of 1.5 ml/kg of either mannitol (20%, i.e., 0.3 g/
kg) or lactate over 15 min. Fifteen minutes after the end
of infusion, treatment was considered to be successful if
ICP decreased by [5 mmHg or reached a value of
B20 mmHg. In case of failure, a second treatment was
immediately prescribed in a crossover fashion, i.e., lactate
after mannitol or vice versa. Hence, the raised ICP epi-
sode was treated with either (1) mannitol alone, (2) lactate
alone or (3) both mannitol and lactate, depending on the
efficacy of the first treatment. In the case of frequent
recurrent episodes in one patient, the study protocol
considered only the first three episodes which occurred
472
Page 2
during the first 48 h. Further episodes were treated by
standard osmotherapy, i.e., mannitol, in both groups.
Data collection
Neurological status was scored before inclusion in the
prehospital period using the Glasgow Coma Scale [31].
Brain damage was evaluated by CT scan performed
immediately after admission and stratified according to
the Marshall score [32]. Long-term outcome was assessed
12 months after trauma by physician-conducted blind
phone interviews. The questionnaire was based on the
five-category Glasgow Outcome Score (GOS): G = good
recovery, M = moderate disability, S = severe disability,
V = vegetative state, D = death [31].
Temperature, heart rate, mean arterial pressure, urine
output, ICP, CPP, SvJO
2
, laboratory values and doses of
selected medications were recorded during the entire
course of ICP monitoring. Osmotherapy was evaluated on
data collected before (baseline) and 15 min after the end
of infusion, i.e., 30 min after baseline measurements.
When rescue therapy was necessary, the baseline data
measured before the second treatment corresponded to
those obtained after the end of the previous infusion.
Arterial samples were collected at the same time for
assessing glucose, lactate, plasma osmolality, hemoglo-
bin, hematocrit, sodium, chloride and blood gases.
Simultaneously, venous blood samples were drawn to
measure glucose and lactate in order to calculate arte-
riojugular venous differences and SvJO
2
.
Study endpoints
The study endpoint was to evaluate the efficacy of both
acute osmotherapies (mannitol or lactate) on ICP at the
fourth hour following the commencement of infusion. In
addition, we also considered (1) the percentage of suc-
cessfully treated episodes between both acute osmotherapy
treatments, and (2) the 1-year neurological status.
Sample size determination and statistical analysis
The maximal effect of mannitol mainly occurs during the
first 2 h after administration (20% decrease of ICP); a
more prolonged action is not well established. Our aim
was to examine the longer-term effects of LAC in com-
parison to MAN at the fourth hour. This aim was based on
the literature as well as on our own data with mannitol;
we therefore hypothesized a 20 ± 14% ICP decrease at
the 4th hour with LAC, compared to 10 ± 14% with
mannitol [16]. Given this hypothesis, we calculated that a
total number of 64 episodes (i.e., 32 in each group) would
be required to reach a statistical power of 80% at a
significance level of 0.05. Assuming (1) that outcomes
(ICP decrease) of the different episodes are independent,
(2) an average number of 1.5 intracranial hypertensive
episodes per enrolled patient and (3) a probability of
failure of the mannitol therapy of 20% (a value hypoth-
esized to be identical with lactate), we required two
groups of 17 patients, aiming to investigate at least 32
episodes per group.
The specific design of this study led us to analyze the
results in different ways. Firstly, the efficacy of treatment
by mannitol or lactate was assessed by comparing the ICP
decrease at the fourth hour following acute infusion as
planned by the randomization (‘‘intention-to-treat analy-
sis’’: MAN vs. LAC). In addition, we also analyzed the
effect of the actual treatments administered on ICP
decrease by comparing the three groups: i.e., if successful,
either the initially randomized treatment (mannitol or
lactate) or the rescue therapy (mannitol/lactate) was used
when deemed necessary. Similarly, the 1-year neurological
outcomes were evaluated by both intention-to-treat anal-
ysis and by comparing the actual treatments administered.
When distribution was normal, statistical analysis was
performed when necessary by the following parametric
tests: univariate t test, two-way ANOVA for repeated
measures, followed by post-hoc analysis (unpaired stu-
dent’s t test), as indicated in Tables and Figures. When
distribution was not normal, non-parametric tests were
used: Mann–Whitney rank sum test, Kruskall-Wallis test,
and univariate sign test, also as indicated. Categorical
parameters were compared using chi-square or Fisher’s
exact test.
Results
Of the 132 patients assessed for eligibility, 96 were
ineligible as they did not meet the inclusion criteria or no
informed consent was obtained from their next-of-kin (see
appendix electronic material Figure I suppl.). One patient
died rapidly and another was excluded due to failed
SvJO
2
monitoring. Thirty-four patients were thus eligible
and randomized, with 17 in each group (MAN or LAC).
These two groups were subsequently divided according to
the actual treatment received: either as initially random-
ized or as crossover rescue treatment. Nine patients
received only mannitol, 12 received only lactate and 13
received both mannitol and lactate.
Initial clinical status and patient management
As shown in Table 1, the two randomized groups (MAN
and LAC) were comparable for age, gender, initial
Glasgow score and initial brain damage, as evaluated by
the Marshall score performed on the CT scan [32]. The
473
Page 3
average time to ICU admission was longer in the LAC
group in comparison to MAN: 195 (142–450) versus 105
(60–300) min, P = 0.059. Occurrence of unilateral
pupillary widening (25 vs. 24%) or central diabetes in-
sipidus (29 vs. 18%) was identical in the two groups as
well as prothrombin time (median 69 vs. 62%) and acti-
vated Kaolin time (median: 33 vs. 34 s) for LAC and
MAN respectively, NS. The characteristics of the treat-
ments applied to these patients during the episodes of
intracranial hypertension are also shown in Table 1.
During the period of data collection (4 h following
osmotherapy infusion), all patients received norepineph-
rine to maintain cerebral perfusion pressure in a same
manner. Tidal volume remained unchanged and end-tidal
CO
2
was maintained between 35 and 40 mmHg by
modifying the respiratory frequency. In the MAN group,
8 of the 17 required rescue therapy with lactate, while in
the LAC group, 5 of the 17 required rescue treatment with
mannitol. Fifty-eight episodes were treated in all patients
during the first 48 h of the study: 27 in MAN and 31 in
LAC. Of these, 11 required rescue treatment, leading to a
total of 69 treatments (30 MAN and 39 LAC). The per-
centage of episodes requiring rescue treatment was higher
in MAN compared to LAC (29.6 vs. 9.6%, P = 0.053).
Neurosedation as well as length of stay in ICU was
comparable in both groups. No difference regarding
patients’ characteristics, initial severity (prehospital GCS
and Marshall score), length of stay in the ICU or neuro-
logical outcome was found regarding the need or not for
rescue therapy (data not shown).
Effect of treatments on ICP and CPP
The effect of osmotherapy on ICP is shown in Fig. 1.
ICP expressed by the difference from baseline (delta)
decreased in the two groups following osmotherapy
(time effect, P \ 0.0001, Fig. 1a). However, significant
differences were observed among groups: LAC was
significantly lower than MAN (group effect P = 0.016).
Moreover, the interaction between time and group
effects was also significant (P = 0.0049), indicating a
more prolonged and more pronounced change: at
the fourth hour the decrease in ICP was -5.9 ± 1 versus
-3.2 ± 0.9 mmHg for LAC and MAN respectively,
P = 0.009. When considering the actual treatment
administered (lactate alone, mannitol or lactate/mannitol
when rescue therapy was necessary, Fig. 1b), we found
that the three groups were different (P = 0.032). Inter-
estingly, at the fourth hour, the effect of lactate
alone was significantly more pronounced compared to
both mannitol alone (P = 0.051) and lactate/mannitol
(P = 0.005), while mannitol versus lactate/mannitol
were not different (P = 0.67). When ICP is expressed as
absolute values (median ± 25–75th percentiles, Fig. 1c),
the decrease in the three groups following osmotherapy
was significant (P \ 0.0001), as were differences among
groups (P \ 0.001): lactate alone versus mannitol alone
(P = 0.0061), lactate alone versus lactate/mannitol
(P \ 0.0001) and mannitol alone versus lactate/mannitol
(P \ 0.0001). Hence, there was a more pronounced
decrease in ICP with lactate alone compared to the two
other treatments: mannitol alone and mannitol plus
sodium lactate.
As shown in Fig. 2, CPP increased in both groups
(time effect P \ 0.0001, Fig. 2a), and the difference
between the two groups was close to significant (group
effect P = 0.057). We found similar results when con-
sidering the actual treatments administered, i.e., when
comparing the three groups lactate alone, mannitol alone
and lactate/mannitol (time effect P \0.0001, group effect
P
= 0.18, Fig. 2b).
Table 1 Patient’s baseline characteristics and intracranial hypertensive episode treatments
Parameters MAN Group LAC Group P value
(n = 17) (n = 17)
Age (years)
a
33.8 (3.2) 37.6 (4.0) 0.460
Male, sex
b
11.0 (64.7) 13.0 (76.5) 0.871
Prehospital Glasgow Coma Scale score
c,d
6 (4–8) 4 (3.8–7) 0.438
First CT scan (Marshall Score)
b,e
II diffuse injury 3 (17.6) 3 (17.6) [0.999
III diffuse injury 11 (64.8) 10 (58.8)
IV diffuse injury 3 (17.6) 4 (23.6)
Number of patients with crossover treatments
b
8/17 (47.1%) 5/17 (29.4%) 0.353
Number of episodes with cross over treatments
b
8/27 (29.6%) 3/31 (9.6%) 0.053
Duration of neurosedation (h)
c
125.6 (92.5–180) 119.5 (102.5–189) 0.705
Length of stay in ICU (days)
c
16 (11–21) 14.5 (5–20) 0.540
Patients were randomized in two groups, MAN or LAC, according
to the treatment of episodes of intracranial hypertension. Values are
a
mean (SEM);
b
number (%);
c
median (25–75th percentiles)
d
Glasgow Coma Scale: scores conscious state using eye opening,
best motor and verbal response (range 3–15) by physicians at the
prehospital period before any neurosedation
e
Marshall Score classifies severity of brain injury using stan-
dardized CT criteria
Statistical analysis: (a) unpaired t test, (b) chi-square or Fisher’s
exact test, (c) Mann & Whitney’s test
474
Page 4
Urine output collected every hour (see Figure II sup-
pl.) peaked at the first hour in the mannitol group and at
the second hour in lactate group, however, no statistical
differences were observed.
Metabolic, oxygenation and hemodynamic
effects of osmotherapy
Basal metabolic (glucose, lactate, osmolality, sodium,
chloride, pH, PaCO
2
, PaO
2
, total CO
2
) parameters were
not different between the two treatments (Table 2).
Neither plasma glucose nor lactate was affected by
mannitol, while lactate infusion significantly increased
glucose (?3.8 ± 1.3%, P \ 0.01) and lactate (?48.6 ±
6.1%, P \ 0.001), the difference between the groups
being significant (P \ 0.0001 and P = 0.04 for lactate
and glucose respectively). Mannitol infusion was
responsible for a moderate but significant decrease in both
sodium and chloride, while after lactate infusion, only
chloride was significantly affected. Lactate infusion
moderately increased arterial pH (?0.5 ± 0.1%, P \
0.001). PaO
2
and PaCO
2
were not significantly
affected by the treatments, while total CO
2
increased
Time, min
Time, min
0
30 60
120 180 240
B
Time, min
-10
-8
-6
-4
-2
0
Intractanial pressure decrease
delta from TO, mmHg
Intractanial pressure decrease
delta from TO, mmHg
A
C
Osmotherapy
Osmotherapy
Osmotherapy
Intracranial pressure, mm Hg
20
25
30
35
Intent-to-treat
analysis
MAN
LAC
Mannitol+Lactate
Mannitol alone
Lactate alone
Actual treatment
administered
-10
-8
-6
-4
-2
0
24012030
0
60 180
0 30 60 120 180 240
Fig. 1 Intracranial pressure changes during the first 4 h of
treatment of hypertensive episodes by osmotherapy. Data are
expressed as delta from T0 (mean ± SEM) (a, b) and as absolute
values (median ± 25–75th percentiles) (c). a Changes in ICP
from baseline (delta from baseline, mm Hg) following the
treatments of episodes of intracranial hypertension (n = 58) were
divided into two groups according to the initial randomization
(intend-to-treat analysis). Filled circles lactate, n = 30; open
circles mannitol, n = 28. Inter-group comparison by ANOVA for
repeated measures: group effect P \0.016; time effect
P \ 0.0001; interaction time-group effect P = 0.0049. Post-hoc
intergroup analysis (student’s t test): 30 min P = 0.064; 60 min
P = 0.008; 120 min P = 0.006; 180 min P = 0.001; 240 min
P = 0.009. b Changes in ICP from baseline (delta from baseline,
mm Hg) following the treatments of episodes of intracranial
hypertension (n = 58) were divided into three groups according to
the actual treatment received (i.e. initial randomized treatment
followed or not by alternative crossover therapy: see text for
explanation). Filled squares lactate alone, n = 25; open squares
mannitol alone, n = 18; dashed squares mannitol/lactate, n = 15.
Comparison between the three groups was assessed by ANOVA
for repeated measures: group effect P = 0.032; time effect
P \ 0.0001; interaction time-group P
= 0.007. Post-hoc analysis
(unpaired student’s t test): mannitol alone versus lactate alone
180 min P = 0.004; 240 min P = 0.051; lactate alone versus
lactate/mannitol 60 min P = 0.029; 120 min P = 0.025; 180 min
P = 0.009; 240 min P = 0.005; mannitol alone versus mannitol/
lactate no significant difference at any time. c ICP evolution
(absolute values, mm Hg) following the treatments of episodes of
intracranial hypertension (n = 58) were divided into three groups
according to the actual treatment received (i.e. initial randomized
treatment followed or not by alternative crossover therapy: see
text for explanation). Filled squares lactate alone, n = 25; open
squares mannitol alone, n = 18; dashed squares mannitol/lactate,
n = 15. Comparison between the three groups was assessed by
Kruskall-Wallis test, intergroup comparison P = \0.0001: lactate
alone versus mannitol alone P = 0.0061; lactate alone versus
lactate/mannitol P \ 0.0001, mannitol alone versus lactate/man-
nitol P \ 0.0001
475
Page 5
following lactate administration (?5.1 ± 1.1%,
P \ 0.001). Plasma osmolality significantly rose follow-
ing mannitol (?3.06 ± 0.67 mosm/L, P \ 0.001), but
not lactate (?0.66 ± 0.95 mosm/L, P = 0.491) infusion,
the difference being significant (P = 0.046, (Table 2).
SvJO
2
significantly increased only after lactate adminis-
tration (?2.48 ± 0.5%, P \ 0.0001; Table 2). A positive
and significant (P \ 0.0001) arteriovenous difference in
glucose, which was not affected by osmotherapy, was
found after both treatments (data not shown), indicating
similar brain glucose consumption. Lactate arteriovenous
differences across the brain showed no significant effect
in either treatment.
Neurological status was assessed after 1 year of evo-
lution using the Glasgow Outcome, data are presented in
the electronic material supplement.
Lactate alone
Mannitol alone
B
60
70
80
0
Time, min
Time, min
Cerebral Perfusion Pressure, mmHg
A
Osmotherapy
Osmotherapy
Intent-to-treat
analysis
MAN
LAC
Mannitol+Lactate
Actual treatment
administered
0 30 60 120 180 240
0 30 60 120 180 240
Fig. 2 Cerebral perfusion pressure changes during the first 4 h of
treatment of hypertensive episodes by osmotherapy. Data are
expressed as mean ± SEM. a Cerebral perfusion pressure during
the treatments of intracranial hypertensive episodes. Episodes of
HICP were divided into two groups according to the initial
randomization (intend-to-treat analysis). Filled circles: lactate
n = 30; open circles: mannitol, n = 28. Inter-group comparison
by ANOVA for repeated measures: group effect P = 0.057; time
effect P \ 0.0001; interaction time-group effect P = 0.0001. b
Cerebral perfusion pressure during the treatments of intracranial
hypertensive episodes. Episodes of HICP were divided into three
groups according to the actual treatment received (i.e. initial
randomized treatment followed or not by alternative crossover
therapy: see text for explanation). Filled squares lactate alone,
n = 25; open squares mannitol alone, n = 18; dashed squares
mannitol/lactate, n = 15. Comparison between the three groups
was assessed by ANOVA for repeated measures: group effect
P = 0.18; time effect P = 0.001; interaction time-group P \
0.0001
Table 2 Biological and hemodynamic data before and after acute treatment of intracranial hypertensive episodes
Baseline (absolute values) Percentage of change following treatment
Mannitol Lactate P* Mannitol Lactate P*
Glucose (mmol/L) 7.4 (1.5) 7.4 (1.5) 0.97 98.9 (2.0) 103.8 (1.3)
b
0.04
Lactate (mmol/L) 2.1 (1.3) 1.8 (1.1) 0.25 100.4 (3.8) 148.6 (6.1)
c
\0.0001
Plasma osmolality (mosm/kg H
2
O) 298.8 (11.4) 298.6 (7.3) 0.93 101.0 (0.2)
c
100.2 (0.3) 0.04
Haemoglobin (mmol/L) 6.55 (0.19) 6.46 (0.13) 0.72 96.8 (0.8)
c
98.4 (0.7)
a
0.14
Haematocrit (%) 32.5 (0.9) 32.2 (0.9) 0.76 96.7 (0.8)
c
98.4 (0.8)
a
0.13
Na (mmol/L) 140.5 ± 0.4 142.5 ± 0.6 0.32 97.7 ± 0.8
a
101.4 ± 0.7
a
0.03
Cl (mmol/L) 105.5 ± 0.4 107.7 ± 0.6 0.25 98.5 ± 0.8
a
100.6 ± 0.8 0.12
pH 7.39 (0.07) 7.40 (0.06) 0.76 100.0 (0.1) 100.5 (0.1)
c
0.006
PaCO
2
(mmHg) 35.6 (0.8) 36.9 (0.9) 0.28 99.5 (1.6) 97.0 (2.0) 0.35
PaO
2
(mmHg) 144.6 (6.7) 139.3 (5.4) 0.54 101.5 (2.2) 99.0 (2.8) 0.49
Total CO
2
(mmol/L) 22.5 (0.5) 23.3 (0.4) 0.31 99.9 (0.9) 105.1 (1.1)
c
0.0005
SvJO
2
(%) 74.9 (1.7) 73.7 (1.5) 0.59 101.1 (1.2) 103.6 (0.8)
c
0.09
Mean arterial pressure (mmHg) 98.7 (1.6) 97.3 (1.9) 0.59 100.1 (1.1) 100.0 (1.5) 0.96
Cerebral perfusion pressure (mmHg) 67.9 (1.8) 66.0 (1.8) 0.46 108.2 (1.6)
c
109.9 (2.1)
c
0.51
Biological and hemodynamic parameters were assessed before and
immediately after each treatment of episodes of intracranial
hypertension by mannitol (n = 34) or lactate (n = 35). Data are
means ± SEM. Statistical analysis: *comparison between groups
by ANOVA; percentage of change due to treatment (intragroup
analysis): univariate t test from baseline (initial value = 100%):
a
P \ 0.05;
b
P \ 0.01;
c
P \ 0.001
476
Page 6
Discussion
This study aimed to investigate the efficacy and safety of
a specifically designed solution enriched with half-molar
sodium lactate in comparison with mannitol in the treat-
ment of episodes of intracranial hypertension in severe
TBI. Our purpose was to compare the efficacy of a new
treatment with the most standard recommended treatment;
therefore, mannitol was taken as a control since it remains
the reference osmotherapy treatment in the guidelines [4,
10, 11, 16, 17]. We report here that hyperosmolar lactate
solution is safe and more effective than mannitol in
achieving a prolonged decrease in intracranial pressure
during acute episodes of intracranial hypertension (study
endpoint). In this study we assumed independent out-
comes (ICP decrease) of all different episodes considered
(58), however considering the first episode only (i.e., 34
episodes, 17 in each group) lead to a similar conclusion,
without assuming independency between episodes (see
Table I suppl.). In addition, a better neurological status
after 1 year was noted in the LAC group as compared to
MAN (Fig. III suppl), but the sample size of this study
was not powered for this purpose.
Patients were similar for the various initial criteria,
which are important prognosis factors [2, 4, 32, 33]. Time
before admission to the ICU [34] was slightly longer in
the LAC group (P = 0.059). Failure to lower ICP was
observed in 19% of all treated episodes; however, this
occurred less often with lactate when compared to man-
nitol (P \ 0.051, Table 1).
Metabolic parameters were comparable before acute
infusion. Lactate infusion significantly increased plasma
glucose (P \ 0.05) and lactate (P \ 0.001). However, the
gluconeogenic effect of lactate is limited (3.8% or
0.22 mmol/L), and probably cannot be considered to be
harmful to the brain [35]. The increase in lactate con-
centration is moderate (0.9 mM), indicating an active
metabolism as already reported [36, 37].
No effect on gas exchange was observed in the two
groups. The modest alkalinizing effect of lactate infusion
[38] is negligible (less than 0.01 pH units) with no relevant
effect on cerebral perfusion [39]. The significant increase in
S
v
JO
2
following lactate infusion, in the absence of any
change in PaO
2
, indicates either a decrease in cerebral
oxygen consumption, or an increase in cerebral blood flow.
We failed to find any difference between lactate or mannitol
groups in the following parameters known to accompany a
decrease in brain oxygen consumption: identical patient
sedation, no difference in body temperature, comparable
brain glucose uptake (from AV difference) and lactate
consumption (no lactate release). Furthermore, CPP
increase was more pronounced after lactate. Lactate infu-
sion could be responsible for a decrease in cerebral vascular
resistance leading to increased cerebral blood flow as
already suggested in experimental studies [29, 30].
Increased plasma osmolality upon mannitol infusion
(1%, i.e., 3.06 mosm/kg, Table 2) is the expected con-
sequence of the osmotic load resulting from hyperosmolar
mannitol infusion (1160 mosm/kg). Interestingly, equiv-
alent hyperosmolar sodium lactate infusion did not affect
plasma osmolality (0.66 ± 0.95 mosm/kg, P = 0.491).
Although these solutions are equally hyperosmolar,
sodium lactate solution is less hypertonic since mono-
carboxylate carriers allow lactate to cross the cellular
plasma membrane [40]. However, despite being less
hypertonic than mannitol, lactate solution induces a
stronger effect on ICP. The lactate solution used in this
study contains metabolized (lactate) and non-metabolized
(inorganic) ions. Lactate is rapidly metabolized, but non-
organic ions are not, thus creating an imbalance between
positive and negative charges. A net anion efflux from
intracellular space must therefore compensate for the
excess of extracellular positive charges due to sodium in
order to maintain electroneutrality. Chloride, the principal
intracellular inorganic anion, is responsible for a sub-
stantial part of intracellular tonicity, hence the net efflux
of chloride is probably accompanied by a net flux of
water. This hypothesis fits with the reported data in
Table 2, showing an increase in sodium accompanied by
no change in chloride concentrations in the LAC group,
while both sodium and chloride decrease in the MAN
group. Recent data on Na
?
,K
?
and Cl
-
co-exchange
support a significant role of chloride balance on cell
volume regulation, especially in cerebral ischemia
reperfusion [41]. In the light of this, a change in cell
volume could result from the combination of increased
extracellular tonicity and decreased intracellular tonicity.
This hypothetical mechanism might explain why infusion
of the sodium lactate solution induces a stronger effect on
high ICP than mannitol, while changes in plasma osmo-
lality were hardly detectable. The imbalance between
intra- and extracellular tonicity due to mannitol disap-
pears after its excretion into the urine, and water can then
re-enter intracellular space. However, when exogenous
sodium and chloride are eliminated into the urine,
intracellular chloride loss persists, and there is no ther-
modynamic force to drive water back into cellular
compartments.
A defect in cellular energy status is a major cause of
cellular dysfunction leading to cellular swelling. Lactate
is a suitable source of energy for the brain, and evidence
from previous literature supports brain lactate metabolism
from either local [24, 42, 43] or systemic [24, 27, 28]
origins, thanks to monocarboxylate carriers in the BBB
[44]. Sodium lactate is probably working not only as a
hypertonic agent, but also as a metabolic fuel for the
brain.
This study has several methodological limitations: it is
a monocentric study with ethical constraints leading to the
proposal of an early rescue therapy when treatment was
477
Page 7
judged to be ineffective after 15 min. Because of the
specific metabolic effects of the two treatments (e.g., on
plasma lactate and pH), it was not possible to conduct a
double-blind study but only a prospective randomized
open-label study. However, all data were analyzed in a
blind manner including the 1-year neurological outcome
evaluation.
In conclusion, hyperosmolar sodium-lactate solution
appears to be an interesting alternative in the treatment of
episodes of cranial hypertension in TBI patients. This
solution is more effective on ICP than the reference
treatment mannitol. However, a further multicenter study
is warranted to confirm this finding.
Acknowledgments The study has been sponsored by Innogene
Kalbiotech Pte. Ltd. 24 Raffles Place 27-06 Clifford Center,
Singapore, 04862. The authors are most grateful to Dr. Rikrik Ilyas
for a constant support, to Professor Nino Stocchetti for helpful
comments and suggestions, to Professor Mervyn Singer for
stimulating discussions and careful review of the manuscript and to
Mr. Gareth Butt for the English corrections to this paper.
References
1. Bulger EM, Nathens AB, Rivara FP,
Moore M, MacKenzie EJ, Jurkovich GJ
(2002) Management of severe head
injury: institutional variations in care
and effect on outcome. Crit Care Med
30:1870–1876
2. Jiang JY, Gao GY, Li WP, Yu MK,
Zhu C (2002) Early indicators of
prognosis in 846 cases of severe
traumatic brain injury. J Neurotrauma
19:869–874
3. Stocchetti N, Penny KI, Dearden M,
Braakman R, Cohadon F, Iannotti F,
Lapierre F, Karimi A, Maas A Jr,
Murray GD, Ohman J, Persson L,
Servadei F, Teasdale GM, Trojanowski
T, Unterberg A (2001) Intensive care
management of head-injured patients in
Europe: a survey from the European
brain injury consortium. Intensive Care
Med 27:400–406
4. Stocchetti N, Rossi S, Buzzi F, Mattioli
C, Paparella A, Colombo A (1999)
Intracranial hypertension in head injury:
management and results. Intensive Care
Med 25:371–376
5. Cooper DJ, Myles PS, McDermott FT,
Murray LJ, Laidlaw J, Cooper G,
Tremayne AB, Bernard SS, Ponsford J
(2004) Prehospital hypertonic saline
resuscitation of patients with
hypotension and severe traumatic brain
injury: a randomized controlled trial.
Jama 291:1350–1357
6. Roberts I, Yates D, Sandercock P,
Farrell B, Wasserberg J, Lomas G,
Cottingham R, Svoboda P, Brayley N,
Mazairac G, Laloe V, Munoz-Sanchez
A, Arango M, Hartzenberg B, Khamis
H, Yutthakasemsunt S, Komolafe E,
Olldashi F, Yadav Y, Murillo-Cabezas
F, Shakur H, Edwards P (2004) Effect
of intravenous corticosteroids on death
within 14 days in 10008 adults with
clinically significant head injury
(MRC CRASH trial): randomised
placebo-controlled trial. Lancet
364:1321–1328
7. Clifton GL, Miller ER, Choi SC, Levin
HS, McCauley S, Smith KR Jr,
Muizelaar JP, Wagner FC Jr, Marion
DW, Luerssen TG, Chesnut RM,
Schwartz M (2001) Lack of effect of
induction of hypothermia after acute
brain injury. N Engl J Med
344:556–563
8. Polderman KH, Tjong Tjin Joe R,
Peerdeman SM, Vandertop WP, Girbes
AR (2002) Effects of therapeutic
hypothermia on intracranial pressure
and outcome in patients with severe
head injury. Intensive Care Med
28:1563–1573
9. Qiu W, Zhang Y, Sheng H, Zhang J,
Wang W, Liu W, Chen K, Zhou J, Xu Z
(2007) Effects of therapeutic mild
hypothermia on patients with severe
traumatic brain injury after craniotomy.
J Crit Care 22:229–235
10. Schierhout G, Roberts I (2000)
Mannitol for acute traumatic brain
injury. Cochrane Database Syst Rev
CD001049
11. Marik PE, Varon J, Trask T (2002)
Management of head trauma. Chest
122:699–711
12. Francony G, Fauvage B, Falcon D,
Canet C, Dilou H, Lavagne P, Jacquot
C, Payen JF (2008) Equimolar doses of
mannitol and hypertonic saline in the
treatment of increased intracranial
pressure. Crit Care Med 36(3):795–800
13. Schwartz ML, Tator CH, Rowed DW,
Reid SR, Meguro K, Andrews DF
(1984) The University of Toronto head
injury treatment study: a prospective,
randomized comparison of
pentobarbital and mannitol. Can J
Neurol Sci 11:434–440
14. Sorani MD, Manley GT (2008) Dose-
response relationship of mannitol and
intracranial pressure: a metaanalysis. J
Neurosurg 108:80–87
15. McManus ML, Soriano SG (1998)
Rebound swelling of astroglial cells
exposed to hypertonic mannitol.
Anesthesiology 88:1586–1591
16. Mendelow AD, Teasdale GM, Russell T,
Flood J, Patterson J, Murray GD (1985)
Effect of mannitol on cerebral blood flow
and cerebral perfusion pressure in human
head injury. J Neurosurg 63:43–48
17. Paczynski RP (1997) Osmotherapy.
Basic concepts and controversies. Crit
Care Clin 13:105–129
18. Berger S, Schurer L, Hartl R, Deisbock
T, Dautermann C, Murr R, Messmer K,
Baethmann A (1994) 7.2% NaCl/10%
dextran 60 versus 20% mannitol for
treatment of intracranial hypertension.
Acta Neurochir Suppl (Wien)
60:494–498
19. Doyle JA, Davis DP, Hoyt DB (2001)
The use of hypertonic saline in the
treatment of traumatic brain injury. J
Trauma 50:367–383
20. Qureshi AI, Suarez JI, Bhardwaj A,
Mirski M, Schnitzer MS, Hanley DF,
Ulatowski JA (1998) Use of hypertonic
(3%) saline/acetate infusion in the
treatment of cerebral edema: Effect on
intracranial pressure and lateral
displacement of the brain. Crit Care
Med 26:440–446
21. Battison C, Andrews PJ, Graham C,
Petty T (2005) Randomized, controlled
trial on the effect of a 20% mannitol
solution and a 7.5% saline/6% dextran
solution on increased intracranial
pressure after brain injury. Crit Care
Med 33:196–202 (discussion 257–198)
22. Schurr A (2002) Lactate, glucose and
energy metabolism in the ischemic
brain (Review). Int J Mol Med
10:131–136
23. Schurr A, Payne RS, Miller JJ, Rigor BM
(1997) Brain lactate is an obligatory
aerobic energy substrate for functional
recovery after hypoxia: further in vitro
validation. J Neurochem 69:423–426
24. Maran A, Cranston I, Lomas J,
Macdonald I, Amiel SA (1994)
Protection by lactate of cerebral
function during hypoglycaemia. Lancet
343:16–20
478
Page 8
25. King P, Kong MF, Parkin H,
MacDonald IA, Barber C, Tattersall RB
(1998) Intravenous lactate prevents
cerebral dysfunction during
hypoglycaemia in insulin-dependent
diabetes mellitus. Clin Sci (Lond)
94:157–163
26. Schurr A, Payne RS, Miller JJ, Tseng
MT (2001) Preischemic hyperglycemia-
aggravated damage: evidence that lactate
utilization is beneficial and glucose-
induced corticosterone release is
detrimental. J Neurosci Res 66:782–789
27. Rice AC, Zsoldos R, Chen T, Wilson
MS, Alessandri B, Hamm RJ, Bullock
MR (2002) Lactate administration
attenuates cognitive deficits following
traumatic brain injury. Brain Res
928:156–159
28. Holloway R, Zhou Z, Harvey HB,
Levasseur JE, Rice AC, Sun D, Hamm
RJ, Bullock MR (2007) Effect of lactate
therapy upon cognitive deficits after
traumatic brain injury in the rat. Acta
Neurochir (Wien) 149:919–927
(discussion 927)
29. Shackford SR, Schmoker JD, Zhuang J
(1994) The effect of hypertonic
resuscitation on pial arteriolar tone after
brain injury and shock. J Trauma
37:899–908
30. Shackford SR, Zhuang J, Schmoker J
(1992) Intravenous fluid tonicity: effect
on intracranial pressure, cerebral blood
flow, and cerebral oxygen delivery
in focal brain injury. J Neurosurg
76:91–98
31. Jennett B, Bond M (1975) Assessment
of outcome after severe brain damage.
Lancet 1:480–484
32. Marshall LF, Marshall SB, Klauber
MR, Van Berkum Clark M, Eisenberg
H, Jane JA, Luerssen TG, Marmarou A,
Foulkes MA (1992) The diagnosis of
head injury requires a classification
based on computed axial tomography. J
Neurotrauma 9 Suppl 1:S287–S292
33. Marmarou A (1994) Traumatic brain
edema: an overview. Acta Neurochir
Suppl (Wien) 60:421–424
34. Stocchetti N (2001) Risk prevention,
avoidable deaths and mortality-
morbidity reduction in head injury. Eur
J Emerg Med 8:215–219
35. Van den Berghe G, Schoonheydt K,
Becx P, Bruyninckx F, Wouters PJ
(2005) Insulin therapy protects the
central and peripheral nervous system
of intensive care patients. Neurology
64:1348–1353
36. Chiolero R, Tappy L, Gillet M, Revelly
JP, Roth H, Cayeux C, Schneiter P,
Leverve X (1999) Effect of major
hepatectomy on glucose and lactate
metabolism. Ann Surg 229:505–513
37. Mustafa I, Roth H, Hanafiah A, Hakim
T, Anwar M, Siregar E, Leverve XM
(2003) Effect of cardiopulmonary
bypass on lactate metabolism. Intensive
Care Med 29:1279–1285
38. Mustafa I, Leverve XM (2002)
Metabolic and hemodynamic effects
of hypertonic solutions: sodium-lactate
versus sodium chloride infusion
in postoperative patients. Shock
18:306–310
39. Stocchetti N, Maas AI, Chieregato A,
van der Plas AA (2005)
Hyperventilation in head injury: a
review. Chest 127:1812–1827
40. Halestrap AP, Price NT (1999) The
proton-linked monocarboxylate
transporter (MCT) family: structure,
function and regulation. Biochem J 343
Pt 2:281–299
41. Chen H, Sun D (2005) The role of
Na-K-Cl co-transporter in cerebral
ischemia. Neurol Res 27:280–286
42. Cater HL, Benham CD, Sundstrom LE
(2001) Neuroprotective role of
monocarboxylate transport during
glucose deprivation in slice cultures
of rat hippocampus. J Physiol
531:459–466
43. Schurr A (2006) Lactate: the ultimate
cerebral oxidative energy substrate? J
Cereb Blood Flow Metab 26:142–152
44. Pellerin L, Bergersen LH, Halestrap
AP, Pierre K (2005) Cellular and
subcellular distribution of
monocarboxylate transporters in
cultured brain cells and in the adult
brain. J Neurosci Res 79:55–64
479
Page 9
  • Source
    • "Both studies concluded that infused lactate was effectively metabolized after TBI (Bouzat et al. 2014; Carpenter et al. 2014). Exogenous lactate was found to dilate cerebral vasculature and increase cerebral blood flow (Gordon et al. 2008) and lactate infusion compared favorably to mannitol in reducing ICP after TBI (Ichai et al. 2009). However, the acceptance of this lactate augmentation intervention strategy is still being debated (Nordstrom and Nielsen 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms - diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.
    Full-text · Article · Oct 2014 · Journal of Bioenergetics
    • "Although equimolar infusion of 20% mannitol is as effective as 7.45% hypertonic saline (HSS) in decreasing ICP in patients with brain injury but in patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administration showed a significant increase in brain oxygenation and improved cerebral and systemic hemodynamics.[2428] Small trials have also investigated the effects of other hyperosmolar solutions including sodium bicarbonate and sodium lactate and these agents were found to have similar effects as mannitol or hypertonic saline.[29] "
    [Show abstract] [Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is a major global problem and affects approximately 10 million peoples annually; therefore has a substantial impact on the health-care system throughout the world. In this article, we have summarized various aspects of specific intensive care management in patients with TBI including the emerging evidence mainly after the Brain Trauma Foundation (BTF) 2007 and also highlighted the scope of the future therapies. This review has involved the relevant clinical trials and reviews (from 1 January 2007 to 31 March 2013), which specifically discussed about the topic. Though, BTF guideline based management strategies could provide standardized protocols for the management of patients with TBI and have some promising effects on mortality and morbidity; there is still need of inclusion of many suggestions based on various published after 2007. The main focus of majority of these trials remained to prevent or to treat the secondary brain injury. The future therapy will be directed to treat injured neurons and may benefit the outcome. There is also urgent need to develop some good prognostic indicators as well.
    No preview · Article · Mar 2014
  • Source
    • "Editorial [19] "
    Full-text · Article · Dec 2013 · Journal of Hepatology
Show more