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Effect of mannitol and hypertonic saline on
cerebral oxygenation in patients with severe
traumatic brain injury and refractory
intracranial hypertension
M Oddo, J M Levine, S Frangos, et al.
J Neurol Neurosurg Psychiatry 2009 80: 916-920 originally published online
March 16, 2009
doi: 10.1136/jnnp.2008.156596
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Research paper
Effect of mannitol and hypertonic saline on cerebral
oxygenation in patients with severe traumatic brain
injury and refractory intracranial hypertension
M Oddo,1 J M Levine,1,2,3 S Frangos,1 E Carrera,4 E Maloney-Wilensky,1 J L Pascual,5
W A Kofke,1,3 S A Mayer,4 P D LeRoux1
1
Department of Neurosurgery, ABSTRACT HTS improves systemic haemodynamics,8 9 cere-
University of Pennsylvania Background: The impact of osmotic therapies on brain bral blood flow (CBF)9–11 and may enhance cerebral
Medical Center, Philadelphia,
oxygen has not been extensively studied in humans. We microcirculation by reducing the adhesion of
Pennsylvania, USA;
2
Department of Neurology, examined the effects on brain tissue oxygen tension polymorphonuclear cells12 13 and by stimulating
University of Pennsylvania (PbtO2) of mannitol and hypertonic saline (HTS) in patients local release of nitric oxide.14
Medical Center, Philadelphia, with severe traumatic brain injury (TBI) and refractory Although ICP and cerebral perfusion pressure
Pennsylvania, USA; intracranial hypertension. (CPP) traditionally are the major targets of TBI
3
Department of Anesthesiology
and Critical Care, University of Methods: 12 consecutive patients with severe TBI who treatment, the interstitial partial pressure of
Pennsylvania Medical Center, underwent intracranial pressure (ICP) and PbtO2 mon- oxygen in brain tissue (PbtO2) is emerging as an
Philadelphia, Pennsylvania, USA; itoring were studied. Patients were treated with mannitol additional complementary therapeutic target.
4
Department of Neurology, (25%, 0.75 g/kg) for episodes of elevated ICP (.20 mm Specialised sensors placed directly into brain
Critical Care Division, Columbia
University Medical Center, New Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with parenchyma allow for continuous bedside assess-
York, New York, USA; mannitol. PbtO2, ICP, mean arterial pressure, cerebral ment of PbtO2 and for the quantification of
5
Department of Surgery, perfusion pressure (CPP), central venous pressure and secondary hypoxic events that occur after the
University of Pennsylvania cardiac output were monitored continuously. initial brain insult.15 Observational clinical studies
Medical Center, Philadelphia, demonstrate a relationship between reduced PbtO2
Pennsylvania, USA Results: 42 episodes of intracranial hypertension, treated
with mannitol (n = 28 boluses) or HTS (n = 14 boluses), and poor outcome16 17 and suggest that PbtO2
Correspondence to: were analysed. HTS treatment was associated with an targeted therapy may improve clinical outcomes.18
P D LeRoux, Department of increase in PbtO2 (from baseline 28.3 (13.8) mm Hg to It is therefore important to understand how
Neurosurgery, Clinical Research various treatments options impact on PbtO2.
Division, University of 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at
Pennsylvania Medical Center, 60 min and 41.4 (17.7) mm Hg at 120 min; all p,0.01) There has been limited study on the effect of
Philadelphia, Pennsylvania, USA; while mannitol did not affect PbtO2 (baseline 30.4 (11.4) different osmotic therapies on PbtO2 in brain
Peter.LeRoux@uphs.upenn.edu injured patients and the results vary. For example,
vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all
p.0.1). Compared with mannitol, HTS was associated in patients with TBI with elevated ICP, mannitol
This work was performed at the
Neurointensive Care Unit, with lower ICP and higher CPP and cardiac output. does not consistently improve PbtO2.12 19 In con-
University of Pennsylvania Conclusions: In patients with severe TBI and elevated trast, in patients with intracranial hypertension
Medical Center, Philadelphia, ICP refractory to previous mannitol treatment, 7.5% after subarachnoid haemorrhage, HTS may
Pennsylvania, USA. increase CBF20 21 and PbtO2.22 However, little is
hypertonic saline administered as second tier therapy is
Received 24 June 2008 associated with a significant increase in brain oxygena- known about the impact of HTS on PbtO2 in
Revised 17 February 2009 tion, and improved cerebral and systemic haemody- patients with severe TBI and intracranial hyper-
Accepted 26 February 2009 tension, and in particular those with elevated ICP
Published Online First
namics.
refractory to mannitol. In this study, we examined
16 March 2009
how mannitol and HTS, used to treat recurrent
Intracranial hypertension is common after severe episodes of elevated ICP, influenced brain oxygen
traumatic brain injury (TBI) and may adversely in patients with severe TBI.
affect outcome.1 2 Control of intracranial pressure
(ICP) is therefore a mainstay of treatment after
severe TBI. Osmotherapy is frequently used to CLINICAL MATERIAL AND METHODS
control ICP. Although no firm recommendations Patient population
exist, mannitol is more frequently used as a first Consecutive patients with severe TBI admitted to
tier therapy for elevated ICP while hypertonic the Hospital of the University of Pennsylvania, a
saline (HTS) is given as a secondline therapy in level I trauma centre, and who underwent PbtO2
patients unresponsive to mannitol therapy.3 The monitoring in the neurointensive care unit were
comparative effects of these two agents on cerebral retrospectively identified from a prospective obser-
physiology, rather than ICP alone, after severe TBI vational database (the Brain Oxygen Monitoring
are only beginning to be elucidated. While some Outcome study) over a 2 year period (2005–2006).
authors report that mannitol and HTS have a Severe TBI was defined by (1) a history of trauma,
similar effect, at least when given in equimolar (2) a post-resuscitation admission Glasgow Coma
doses,4 others have demonstrated that HTS may be Scale score (8 and (3) clinical and radiographic
more effective than mannitol in reducing elevated exclusion of alternate causes of coma. Patients who
ICP in patients with severe TBI.5 6 In addition to its received osmotherapy with both mannitol and
potent osmotic effect, HTS has beneficial effects HTS to treat refractory intracranial hypertension
on vascular tone,7 and in animal models of TBI, (defined as the occurrence of recurrent episodes of
916 J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596

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Research paper
Table 1 Patient clinical characteristics Foundation TBI guidelines.3 This included early evacuation of
space occupying mass lesions in the operating room. Each
Characteristic
patient was fully resuscitated according to Advanced Trauma
n 12 Life Support guidelines from the American College of Surgeons,
Age (years) 36 (16) intubated and mechanically ventilated with the head of the bed
Sex (women/men) 3/9 initially elevated ,20–30u. FiO2 and minute ventilation were
Injury type (n) adjusted to maintain SaO2 .93%, PaO2 between 90 and
Diffuse injury 6
100 mm Hg and PaCO2 between 34 and 38 mm Hg. Volume
Subdural haematoma 6
resuscitation was achieved with 0.9% normal saline and
Admission Glasgow Coma Scale (median (range)) 3 (3–8)
albumin for a target central venous pressure (CVP) of 6–
Time from admission to initiation of PbtO2 monitoring (hours) 8 (7)
10 cm H2O. After adequate fluid resuscitation, CPP was kept
Total duration of PbtO2 monitoring (days) 8 (3)
above 60 mmHg, using vasopressors if required. Vasopressors
Hospital length of stay (days) 20 (13)
Mortality (n (%)) 4/12 (33)
(mainly phenylephrine) were only used to ensure adequate CPP,
and patients who received vasopressors for cardio-circulatory
Data are expressed as mean (SD) unless otherwise indicated.
PbtO2, brain tissue oxygen pressure.
failure were excluded from the present study.
ICP .20 mm Hg for more than 10 min despite initial medical
Management of elevated ICP
management) were included in the analysis. Patients who had
A standard stair step approach was used to treat intracranial
bilateral fixed and dilated pupils at admission were excluded from
hypertension. Therapeutic targets were adjusted to maintain
the study. Our Institutional Review Board approved the study.
ICP ,20 mm Hg and CPP .60 mm Hg. Initial management
consisted of head of bed elevation, sedation (lorazepam),
Intracranial and systemic monitors analgesia (fentanyl), muscle paralysis (vecuronium) and inter-
ICP, brain temperature and PbtO2 were continuously monitored mittent cerebrospinal fluid drainage using an external ventri-
using commercially available products (Licox, Integra cular drain. Optimised moderate hyperventilation (PaCO2 30–
Neuroscience, Plainsboro, New Jersey, USA). Intracranial 35 mm Hg) was used selectively to control ICP provided PbtO2
monitors were inserted at the bedside in the neurointensive did not decrease during this intervention.
care unit through a burr hole into the frontal lobe and secured
with a triple lumen bolt. The monitors were placed into white
matter that appeared normal on head CT and on the side of Osmotherapy
maximal pathology. When there was no asymmetry in brain If ICP remained .20 mm Hg for more than 10 min despite the
pathology on CT, the probes were placed in the right frontal initial management, osmotherapy was started, provided that
region. If the patient had undergone a craniotomy, the probes serum osmolarity was ,320 mosmol and serum sodium
were placed on the same side as the injury if the craniotomy flap ,155 mmol/l. In all 12 patients, mannitol (25%, 0.75 g/kg,
permitted. Follow-up head CT scans were performed in all 412 mosmol/dose, infused over 20 min) was administered as
patients within 24 h of admission to confirm correct placement firstline treatment of intracranial hypertension. HTS (7.5%
of the various monitors (eg, not in a contusion or infarct). Probe solution, 250 ml, 641 mosmol/dose, infused over 30 min) was
function and stability was confirmed by an appropriate PbtO2 used as a secondline therapy to control ICP. The decision to
increase following an oxygen challenge (inspired O2 fraction infuse HTS was made at the discretion of the treating neuro-
(FiO2) 1.0 for 5 min). PbtO2 measurements were corrected for intensivist and based on each patient’s overall therapeutic
brain temperature fluctuations. To allow for probe equilibra- intensity. However, according to our management protocol,
tion, data from the first 6 h after PbtO2 monitor insertion were HTS could only be used if a patient had already received
discarded. mannitol for a previous episode of increased ICP or had a MAP
Each patient had an indwelling arterial (radial artery) (90 mm Hg. HTS was contraindicated if CVP was .
catheter. Heart rate, blood pressure (through the arterial line) 15 mm Hg, or the patient had chronic hyponatraemia, heart
and arterial oxygen saturation (SaO2) were recorded continu- failure or diabetes insipidus.
ously in all patients. CPP was calculated from the measured
parameters (CPP = MAP–ICP (corrected for ICP and arterial
catheter position)). Patients had a pulmonary artery catheter, Data collection and analysis
and central venous pressure and cardiac output (thermodilu- All physiological variables (ICP, brain temperature, MAP, CPP,
tion) were recorded. As part of routine care, FiO2, SaO2, CVP, SaO2 and PbtO2) were recorded continuously using a
respiratory rate and ventilator settings (eg, ventilator mode, bedside monitor (Component Monitoring System M1046-
tidal volume, minute ventilation and positive end expiratory 9090C; Hewlett Packard, Andover, Massachusetts, USA).
pressure) were recorded in the ICU flowsheet every 15 min. These variables and respiratory rate, FiO2, ventilator settings
Arterial blood gas analysis was usually performed at 08:00 and (ie, ventilatory mode, tidal volume, minute ventilation and
20:00 each day while the patient was ventilated and if there was positive end expiratory pressure) and cardiac output were
any significant cardiopulmonary change or at the discretion of recorded in the intensive care unit flowsheet every 30 min.
the neuro-intensivist. Arterial samples were analysed for Cardiac output was measured with the use of a pulmonary
haemoglobin, arterial oxygen (PaO2) and carbon dioxide artery catheter. Serum sodium and osmolarity before and after
(PaCO2) tension and pH. treatment were also measured. As the duration of ICP reduction
usually is maintained for 60–120 min after bolus administration
General patient management of both mannitol23 and HTS,7 24 ICP and other physiological
All patients were managed in the neurointensive care unit variables were averaged at 30, 60 and 120 min after each bolus
according to a local algorithm based on the Brain Trauma administration. Treatment baseline was defined as the average
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Research paper
Table 2 Physiological variables before and after a mannitol or
hypertonic saline bolus for elevated intracranial pressure
Hypertonic
Variable Mannitol saline p Value
ICP (mm Hg)
Baseline 29 (8) 27 (8) 0.40
30 min 21 (8) 17 (7) 0.15
60 min 23 (12) 15 (6) ,0.001
120 min 24 (9) 15 (5) ,0.001
MAP (mm Hg)
Baseline 87 (15) 90 (12) 0.52
30 min 85 (23) 93 (16) 0.18
60 min 84 (25) 89 (14) 0.26
120 min 88 (13) 90 (14) 0.27
CPP (mm Hg)
Figure 1 Line graph illustrating mean (SD) brain tissue oxygen pressure Baseline 60 (17) 63 (15) 0.56
(PbtO2) at baseline (time 0) and at 30, 60 and 120 min after hypertonic 30 min 71 (16) 78 (18) 0.32
saline and mannitol bolus administration. *p,0.05, **p,0.01 for 60 min 67 (20) 76 (16) 0.05
comparisons between the two treatments. 120 min 65 (19) 76 (17) 0.02
CVP (cm H2O)
Baseline 7 (3) 7 (4) 0.86
of all values obtained during the 120 min before a bolus was 30 min 6 (3) 8 (5) 0.21
administered. At each time point, means for each variable were 60 min 6 (2) 7 (4) 0.33
measured for each bolus of mannitol and HTS. 120 min 6 (3) 7 (4) 0.79
Cardiac output (l/min)
Baseline 6.7 (1.5) 6.4 (1.8) 0.76
Statistical analysis 30 min 6.3 (0.9) 7.5 (1.4) 0.003
As patients received a variable number of boluses of mannitol 60 min 6.6 (1.2) 7.8 (1.7) 0.007
and HTS, one grand average of treatment was calculated for 120 min 6.1 (1.0) 7.5 (1.4) 0.002
each individual patient. For each variable, differences between Data are expressed as mean (SD).
mannitol and HTS treatments at all time points were then CPP, cerebral perfusion pressure; CVP, central venous pressure; ICP, intracranial
analysed with ANOVA for repeated measures. The JMP starter pressure; MAP, mean arterial pressure.
software (SAS Institute Inc, Cary, North Carolina, USA) was
used for data analysis. For all analyses a p value ,0.05 was Effect of osmotherapy on other cerebral and systemic variables
considered to be statistically significant. Mean pretreatment values for ICP, MAP, CPP, CVP and cardiac
output were similar for mannitol and HTS treatments. Baseline
and post-osmotherapy PaO2/FiO2 ratio, respiratory rate and
RESULTS
ventilator settings (including FiO2) were similar in the two
Patient characteristics treatment groups. Arterial blood gas analysis was not performed
Twelve consecutive patients with severe TBI (nine men and during osmotherapy: however, SaO2, FiO2 and ventilator
three women, mean age 36 (16) years, median admission GCS settings were stable during all interventions.
score 3 (range 3–8)) were studied. Baseline clinical and Mannitol and HTS were both associated with a significant
demographic characteristics are shown in table 1. One-third of ICP reduction. However, at 60 and 120 min, HTS treatment
patients died. was associated with lower ICP and higher CPP than mannitol
(table 2). The decrease in ICP and PbtO2 increase did not
Effect of osmotherapy on PbtO2 demonstrate a significant correlation. In addition, HTS bolus
A total of 42 episodes of intracranial hypertension treated with administration was associated with an increase in cardiac
mannitol (n = 28 boluses) or HTS (n = 14 boluses) were output that was more significant than mannitol at all time
analysed. The median number of boluses analysed per patient points analysed. MAP and CVP did not differ significantly
was 2 (range 1–4) for mannitol and 1 (1–2) for HTS. The between treatment groups at each time point.
median time interval between mannitol and HTS administra- Baseline serum sodium and osmolarity were similar before
tion was 8.6 (interquartile range 4.3–16.7) h. Effect of HTS and mannitol or HTS administration. At the end of the study
mannitol on brain oxygen is shown in fig 1. After HTS, PbtO2 period, HTS treatment was associated with higher serum
increased from a mean pretreatment value of 28.3 sodium (141 (6) before vs 149 (6) mmol/l after; p,0.01).
(13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 Osmolarity did not differ significantly between the two
(17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min treatments. After HTS treatment, hypernatraemia (serum
(all p,0.01). In contrast, mannitol was associated with a non- sodium .155 mmol/l) was observed in three patients. No other
significant decrease in PbtO2 from the pretreatment value (30.4 complications (eg, pulmonary oedema, renal failure) associated
(11.4) mm Hg) at 30 min (28.7 (13.5) mm Hg), 60 min (28.4 with osmotherapy were observed.
(10.6) mm Hg) and 120 min (27.5 (9.9) mm Hg). Compared
with mannitol, HTS treatment was associated with higher DISCUSSION
levels of PbtO2 at all times analysed. In particular, brain tissue We analysed 12 consecutive patients who received osmotherapy
oxygen after HTS was significantly greater at 60 and 120 min with both mannitol (28 treatments) and HTS (14 treatments)
than after mannitol (see fig 1). for refractory intracranial hypertension after severe TBI. We
918 J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596

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Research paper
observed that: (1) HTS was associated with a significant mannitol.30 34–36 Therefore, whether HTS may be superior to
improvement in PbtO2; (2) HTS treatment was also associated mannitol for control of intracranial hypertension is still a
with both an effective reduction of ICP and a significant controversial issue. As we did not compare mannitol and HTS
improvement in cardiac output; and (3) compared with in a parallel or randomised fashion, and the treatments were not
mannitol, HTS had a more favourable effect on PbtO2, ICP, administered in equimolar doses, our study cannot provide a
CPP and cardiac output. definitive answer to this question. Rather, our results suggest
that HTS may have a more favourable effect on PbtO2 and
cerebral and systemic haemodynamics than mannitol when
Hypertonic saline and PbtO2
administered as a second tier therapy for elevated ICP refractory
The positive impact of HTS on PbtO2 was observed within
to mannitol in patients with severe TBI. Our data are also
30 min and was statistically significant at 60 and 120 min.
consistent with previous observations in patients with severe
Hypertonic saline solutions may improve PbtO2 by increasing
TBI that suggest that mannitol has a limited effect on PbtO212 19
CBF, through multiple complementary mechanisms involving
but this warrants further clinical investigation.
the cerebral macro- and/or microcirculation. Firstly, CBF may
increase as ICP decreases, thereby increasing CPP. Consistent
with this, the increase in PbtO2 was significant at 60 and Study limitations
120 min when the beneficial effect of HTS on ICP and CPP Our study has several potential limitations. First, HTS was
levels were most notable. In addition, as the PbtO2 probe is in administered after mannitol in all patients. Therefore, our data
white matter that appears ‘‘normal’’ on CT it is possible that only suggest that HTS improves PbtO2 and systemic haemo-
autoregulation is altered. However, we did not measure CBF or dynamics when administered as a secondline osmotherapy in
autoregulation and this will need future study. Another patients with severe TBI and recurrent episodes of intracranial
possibility is that HTS improved PbtO2 through a relative hypertension. In this context (ie, after mannitol), HTS had
augmentation of cardiac output which, in turn, may have more favourable effects on brain oxygen and ICP than the
caused an increase in oxygen delivery and CBF. The effect of previous mannitol treatment. Second, the observed physiologi-
HTS on cardiac output has previously been documented in non- cal changes after HTS administration may represent the
neurological25 and neurological critically ill patients.26 For cumulative effect of mannitol and HTS rather than HTS alone.
reasons that are poorly understood, intracranial hypertension However, pretreatment serum osmolarity and serum sodium
is associated with reduced systolic function.27 28 It is therefore were similar in the mannitol and HTS groups, and the time
plausible after severe TBI that HTS augments cardiac output interval between each treatment was relatively long (median
not only by directly increasing cardiac preload but also 8.6 h), suggesting that a cumulative effect is less likely. Third,
indirectly by lowering ICP. This hypothesis warrants further mannitol and hypertonic saline were not given at equimolar
study. A final possibility is that HTS improves PbtO2 by doses, and we cannot exclude the fact that the higher
improving flow in the cerebral microcirculation, by reducing osmolarity of HTS may, at least in part, explain some of the
serum viscosity, by improving endothelial function12 29 and/or observed benefits on brain oxygen. Additional studies are
through anti-inflammatory and antiapoptotic properties,30 all of needed to analyse whether mannitol and HTS may have
which improve CBF and brain oxygen delivery.11 20 21 31 Our comparable beneficial effects when administered in equimolar
findings are consistent with others in patients with acute brain doses.4 Fourth, data were obtained from only 12 patients and
injury22 and suggest that hypertonic saline solutions may have therefore the results should be considered preliminary.
beneficial effects on brain oxygenation in patients with severe However, a total of 42 episodes of elevated ICP were analysed
TBI and intracranial hypertension. and the effects of 28 boluses of mannitol and 14 boluses of HTS
were studied. Fifth, the retrospective nature of the analysis may
have introduced bias. However, patients were treated in a
Hypertonic saline and ICP
standardised fashion and the data were collected prospectively.
Although the potential beneficial effects of HTS on brain
Sixth, patients were examined at different time points after the
pathophysiology were first observed in 1919, mannitol is
initial injury, and variations in CBF and PbtO2 may therefore
frequently administered as firstline osmotherapy for intracranial
have occurred over time. Each patient however served as his/her
hypertension. However, in recent years, there has been
own internal control, and this may have partially reduced the
resurgent interest in the use of HTS. Recent small clinical series
potential influence of time. Seventh, given that MAP was
suggest that HTS is an effective agent to treat cerebral oedema
comparable between mannitol and HTS therapy, a possible
and elevated ICP.5 6 Our results are consistent with these
additional explanation for the observed HTS associated increase
findings.
in cardiac output may be a decrease in peripheral resistance or,
alternatively, a difference in vasopressor dose between mannitol
Comparison between HTS and mannitol and HTS. These data were not available in our dataset, and we
Few clinical studies have compared HTS with mannitol and are unable to more precisely address these issues. However, we
there is currently insufficient data to support the use of one over wish to point out that vasopressors were only used at low dose
the other. In experimental intracerebral haemorrhage, Qureshi to maintain adequate CPP and none of the patients included in
et al found that none of these treatments had a significant the study had low cardiac output (cardiac output ranged from
influence on CBF or cerebral metabolism.23 Recent clinical ,6 to 8 l/min) or circulatory shock requiring vasopressors.
studies in TBI patients showed that mannitol and HTS had Finally, we examined the effect of only a single dose of 7.5%
similar effects on elevated ICP and brain oxygen, at least when HTS and so could not observe any dose dependent effect to
given in parallel and in equimolar doses.4 In contrast with these confirm our findings.
clinical observations, other studies found HTS to be superior to Despite these study limitations, our findings suggest that
mannitol in reducing ICP in patients with severe TBI.5 6 32 33 hypertonic saline solutions may significantly improve brain
Furthermore, in animal models of intracranial hypertension, oxygen and systemic haemodynamics in patients with intra-
HTS also appears to provide better neuroprotection than cranial hypertension after severe TBI. Randomised clinical
J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596 919

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Research paper
studies are needed to confirm our findings and to examine 12. Hartl R, Bardt TF, Kiening KL, et al. Mannitol decreases ICP but does not improve
brain-tissue pO2 in severely head-injured patients with intracranial hypertension. Acta
whether hypertonic saline may be superior to mannitol for the Neurochir Suppl 1997;70:40–2.
treatment of elevated ICP when both treatments are given in 13. Chen Y, Hashiguchi N, Yip L, et al. Hypertonic saline enhances neutrophil elastase
equimolar doses and weight adapted. release through activation of P2 and A3 receptors. Am J Physiol Cell Physiol
2006;290:C1051–9.
14. Steenbergen JM, Bohlen HG. Sodium hyperosmolarity of intestinal lymph causes
CONCLUSIONS arteriolar vasodilation in part mediated by EDRF. Am J Physiol 1993;265:H323–8.
Our data suggest that osmotherapy with 7.5% hypertonic 15. Nortje J, Gupta AK. The role of tissue oxygen monitoring in patients with acute brain
injury. Br J Anaesth 2006;97:95–106.
saline, when given as a second tier therapy for elevated ICP, is 16. Valadka AB, Gopinath SP, Contant CF, et al. Relationship of brain tissue PO2 to
associated with a significant improvement in brain oxygen, CPP outcome after severe head injury. Crit Care Med 1998;26:1576–81.
and cardiac output in patients with severe TBI and intracranial 17. van den Brink WA, van Santbrink H, Steyerberg EW, et al. Brain oxygen tension in
hypertension refractory to previous mannitol administration. In severe head injury. Neurosurgery 2000;46:868–76.
18. Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with
this context, hypertonic saline also appears to have a more severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg
beneficial effect on cerebral and systemic haemodynamics than 2005;103:805–11.
mannitol. 19. Sakowitz OW, Stover JF, Sarrafzadeh AS, et al. Effects of mannitol bolus
administration on intracranial pressure, cerebral extracellular metabolites, and tissue
oxygenation in severely head-injured patients. J Trauma 2007;62:292–8.
Acknowledgements: The authors thank Professor Francois Feihl for the careful
¸ 20. Tseng MY, Al-Rawi PG, Pickard JD, et al. Effect of hypertonic saline on cerebral
review of statistical analysis. blood flow in poor-grade patients with subarachnoid hemorrhage. Stroke
Funding: Supported by Research Grants from the SICPA Foundation, Switzerland (to 2003;34:1389–96.
MO and EC), the Swiss National Science Foundation, Grant PBLAB-119620 (EC), the 21. Tseng MY, Al-Rawi PG, Czosnyka M, et al. Enhancement of cerebral blood flow using
Integra Foundation (PDL) and the Mary Elisabeth Groff Surgical and Medical Research systemic hypertonic saline therapy improves outcome in patients with poor-grade
Trust (PDL). spontaneous subarachnoid hemorrhage. J Neurosurg 2007;107:274–82.
22. Al-Rawi PG, Zygun D, Tseng MY, et al. Cerebral blood flow augmentation in patients
Competing interests: None. with severe subarachnoid haemorrhage. Acta Neurochir Suppl 2005;95:123–7.
Ethics approval: The study was approved by the Institutional Review Board, Hospital 23. Qureshi AI, Wilson DA, Traystman RJ. Treatment of elevated intracranial pressure in
of the University of Pennsylvania, Philadelphia, USA. experimental intracerebral hemorrhage: comparison between mannitol and hypertonic
saline. Neurosurgery 1999;44:1055–63.
24. Tyagi R, Donaldson K, Loftus CM, et al. Hypertonic saline: a clinical review.
REFERENCES Neurosurg Rev 2007;30:277–89.
1. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in 25. de Felippe J Jr, Timoner J, Velasco IT, et al. Treatment of refractory hypovolaemic
severe head injuries. Part I: the significance of intracranial pressure monitoring. shock by 7.5% sodium chloride injections. Lancet 1980;2:1002–4.
J Neurosurg 1979;50:20–5. 26. Bentsen G, Breivik H, Lundar T, et al. Hypertonic saline (7.2%) in 6% hydroxyethyl
2. Narayan RK, Greenberg RP, Miller JD, et al. Improved confidence of outcome starch reduces intracranial pressure and improves hemodynamics in a placebo-
prediction in severe head injury. A comparative analysis of the clinical examination, controlled study involving stable patients with subarachnoid hemorrhage. Crit Care
multimodality evoked potentials, CT scanning, and intracranial pressure. J Neurosurg Med 2006;34:2912–17.
1981;54:751–62. 27. Schmidt EA, Czosnyka Z, Momjian S, et al. Intracranial baroreflex yielding an early
3. The Brain Trauma Foundation. The American Association of Neurological cushing response in human. Acta Neurochir Suppl 2005;95:253–6.
Surgeons. The Joint Section on Neurotrauma and Critical Care. Critical pathway for 28. Schrader H, Hall C, Zwetnow NN. Effects of prolonged supratentorial mass
the treatment of established intracranial hypertension. J Neurotrauma 2000;17:537– expansion on regional blood flow and cardiovascular parameters during the Cushing
8. response. Acta Neurol Scand 1985;72:283–94.
4. Francony G, Fauvage B, Falcon D, et al. Equimolar doses of mannitol and hypertonic 29. Zausinger S, Thal SC, Kreimeier U, et al. Hypertonic fluid resuscitation from
saline in the treatment of increased intracranial pressure. Crit Care Med subarachnoid hemorrhage in rats. Neurosurgery 2004;55:679–86.
2008;36:795–800. 30. Soustiel JF, Vlodavsky E, Zaaroor M. Relative effects of mannitol and hypertonic
5. Vialet R, Albanese J, Thomachot L, et al. Isovolume hypertonic solutes (sodium saline on calpain activity, apoptosis and polymorphonuclear infiltration in traumatic
chloride or mannitol) in the treatment of refractory posttraumatic intracranial focal brain injury. Brain Res 2006 26;1101:136–44.
hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit 31. Dautermann C, Schurer L, Hartl R, et al. Treatment of hemorrhagic hypotension with
Care Med 2003;31:1683–7. hypertonic saline/dextran: effects on brain surface oxygen tension in experimentally
6. Battison C, Andrews PJ, Graham C, et al. Randomized, controlled trial on the effect traumatized brain. Adv Exp Med Biol 1992;317:731–6.
of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased 32. Harutjunyan L, Holz C, Rieger A, et al. Efficiency of 7.2% hypertonic saline
intracranial pressure after brain injury. Crit Care Med 2005;33:196–202. hydroxyethyl starch 200/0.5 versus mannitol 15% in the treatment of increased
7. Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral intracranial pressure in neurosurgical patients—a randomized clinical trial
edema and intracranial hypertension. Crit Care Med 2000;28:3301–13. (ISRCTN62699180). Crit Care 2005;9:R530–40.
8. Ducey JP, Mozingo DW, Lamiell JM, et al. A comparison of the cerebral and 33. Ware ML, Nemani VM, Meeker M, et al. Effects of 23.4% sodium chloride solution in
cardiovascular effects of complete resuscitation with isotonic and hypertonic saline, reducing intracranial pressure in patients with traumatic brain injury: a preliminary
hetastarch, and whole blood following hemorrhage. J Trauma 1989;29:1510–18. study. Neurosurgery 2005;57:727–36.
9. Walsh JC, Zhuang J, Shackford SR. A comparison of hypertonic to isotonic fluid in 34. Bermueller C, Thal SC, Plesnila N, et al. Hypertonic fluid resuscitation from
the resuscitation of brain injury and hemorrhagic shock. J Surg Res 1991;50:284–92. subarachnoid hemorrhage in rats: a comparison between small volume resuscitation
10. Prough DS, Whitley JM, Taylor CL, et al. Regional cerebral blood flow following and mannitol. J Neurol Sci 2006;241:73–82.
resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural 35. Toung TJ, Chen CH, Lin C, et al. Osmotherapy with hypertonic saline attenuates
mass. Anesthesiology 1991;75:319–27. water content in brain and extracerebral organs. Crit Care Med 2007;35:526–31.
11. Shackford SR, Zhuang J, Schmoker J. Intravenous fluid tonicity: effect on 36. Chen CH, Xue R, Zhang J, et al. Effect of osmotherapy with hypertonic saline on
intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain regional cerebral edema following experimental stroke: a study utilizing magnetic
injury. J Neurosurg 1992;76:91–8. resonance imaging. Neurocrit Care 2007;7:92–100.
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