Key-words:
Clinical outcome - hypertonic saline - traumatic brain injury
Introduction
Although osmotherapy along with other conventional treatment options, such as sedation,
analgesia, head elevation, neuromuscular paralysis, and ventriculostomy, are the first
line treatment in the management of patients with moderate-to-severe traumatic brain
injury (TBI).[[1]],[[2]],[[3]],[[4]],[[5]],[[6]],[[7]],[[8]],[[9]] Osmotherapy remains a controversial measure due to effects of osmotic agents being
complex as well as the relatively nonselective in nature. As they may cause alteration
in the volume of both damaged and undamaged brain parenchyma, and can exert widespread
effects on the systemic circulation, besides the dynamics of cerebrospinal fluid (CSF).[[10]]
Various osmotic agents such as glycerol, urea, sorbitol, mannitol, and hypertonic
saline have been formulated. They play an indispensable role in decreasing intracranial
pressure by establishing a strong trans endothelial osmotic gradient, thus causing
shrinkage through the water shifting outside the brain's tissue into the intravascular
compartment.[[11]],[[12]],[[13]] Urea is effective but with systemic side effects such as gastrointestinal complications
(nausea, vomiting, and diarrhea), hemoglobinuria, and even rebound intracranial hypertension.[[13]] Whereas, sorbitol and glycerol are associated with a significant increase in the
blood glucose level which could be harmful to the traumatized brain.[[13]] Mannitol is recommended by the European Brain Injury Consortium and Brain Trauma
Foundation, but it causes hypotension especially in the hypovolemic state, rebound
increase in intracranial pressure[[2]],[[13]],[[14]] along with renal toxicity due to increase in the serum osmolality[[15]],[[16]]
Weed and McKibben et al.,[[17]] 1919 first described the hypertonic saline therapy in the TBI. It has osmotic,
rheologic, and metabolic characteristics.[[18]] The osmotic property exists because of the sodium as it has a high reflection coefficient,
thus low permeability across the blood–brain barrier.[[18]],[[19]] The rheological effect is due to its property to reduce the blood viscosity by
alteration in the red blood cell deformity.[[12]],[[18]],[[20]],[[21]] This prompts compensatory vasoconstriction to maintain the cerebral blood flow
and thus reduces the cerebral blood volume and intracranial pressure.[[12]],[[22]] Although the data for pharmacokinetics of hypertonic saline are lacking, as per
Lazaridis et al.[[18]] it displays a similar onset as that of mannitol by effecting the intracranial pressure,
begins within minutes, peaks between 15 and 120 min, and lasts up to 4–6 h.[[23]]
In severe TBI, it is desirable to improve the hypovolemia and hypotension by adequate
resuscitation to prevent secondary brain damage.[[24]] Severe TBI patient with hypotension must have rapid active resuscitation with fluid,
taking in care to prevent the excessive hydrostatic capillary pressure and prevent
elevation of raised intracranial pressure. Therefore, lactated Ringers, which is slightly
hypotonic, is considered the fluid of choice[[25]] as a maintenance fluid for volume deficit, also keeps the intravenous line open
so as to administer medications.[[26]],[[27]] Hypertonic saline has advantages in patients with brain injury, as it is positive
inotropic and chronotropic and require less volume at lower capillary hydrostatic
pressure.[[28]],[[29]],[[30]]
The safety and efficacy of different variations in the dosage regimens of hypertonic
saline in TBI have not been established since available data are limited due to small
phase IIa-IIb randomized controlled trials (RCTs) or small case–control studies. Our
group did perform the first meta-analysis on the efficacy and safety of different
types of hypertonic saline in the management of patients with TBI.
Our study aims to evaluate whether hypertonic saline has any role in improving the
clinical outcome in comparison with the normal saline and lactated Ringers in TBI.
Our a priori hypothesis is that hypertonic saline plays an important role in improving
the clinical functional outcome and decreasing mortality in TBI by decreasing the
intracranial pressure. We hypothesize that hypertonic saline is safe and effective
and should be taken into account in the design of future RCTs.
Methods
Search strategy
We developed our research question: Does hypertonic saline (2%, 3%, or 7.5%) has any
role in improving the clinical outcome as compared to the normal saline/lactated Ringers
in TBI and based on that the following PICO question was developed:
Population
Patients with TBI due to motor vehicle injury, blows, fall, and penetrating head injury.
Intervention
Hypertonic solution (saline/acetate solution) with any dosage regimen (2%, 3%, or
7.5%).
Control
Normal saline/lactated Ringer's Solution.
Outcome
Good outcome and mortality at discharge or 6 months, number of interventions (frequency
of hyperventilation, sedation, mannitol, and CSF drainage) and length of stay in the
intensive care unit (ICU).
We applied stringent inclusion criteria. The following study's types were selected:
RCTs, case–control studies, prospective cohort study, and retrospective study with
two groups (intervention/control) and populations with TBI who were able to get hypertonic
solution. Retrospective (without groups), case series and case report studies were
excluded from our systematic review.
We used the following MeSH headings: Brain injury, traumatic or saline, hypertonic
or normal saline. We did not define any limitation in language. Articles published
between 1990 and the present were searched. Two reviewers MS and NF completed all
the review process.
The following databases were reviewed: The Cochrane Library, Medline, Embase, and
Pub Med. In addition, we reviewed the following gray literature: Unpublished abstracts
from Europeans and American Neurological conferences over the last 10 years to determine
whether there were any abstracts in the field of osmotherapy in TBI.
A total of 364 articles were retrieved based on the MeSH headings mentioned above.
Then, the titles of articles were reviewed, and the duplicates were deleted. The titles
and abstracts of the studies identified by the literature search were screened for
eligibility based on the inclusion criteria mentioned above. Manuscripts that met
the inclusion criteria were obtained illustrated in [[Figure 1]].
Figure 1: Database search
The reviewer was not blind to the author's name and institutions, journals of publication,
or study results.
Data extraction and management
Demographic information, detailed methods, intervention, and outcomes were abstracted
from the manuscripts chosen for the review and recorded on the special data form.
The data form included the following:
-
Methods, design, method of randomization, setting of the treatment, number of interventions,
mortality, and survival ratio
-
Population: Sample size, inclusion and exclusion criteria, age, and gender
-
Intervention: Type of hypertonic solution, dose of hypertonic solution
-
Control: Patients with normal saline or lactated Ringers
-
Outcome: Time of outcome, measurement, reported poor and good outcome, mortality and
survival ratio.
Outcome measures: Following outcomes were selected for our meta-analysis:
-
Functional Outcomes: Glasgow Coma Outcome Scale Extended (GOSE) 0–8: Outcomes were
dichotomized to good (5–8) or poor (1–4) at discharge or 6 months and 12 months, and
GCOS at discharge or 6 months good outcome (4–5) and unfavorable outcome (1–3)
-
Mortality defined as the number of deaths in a particular population per unit of time.
Assessment of risk of bias in included studies
To avoid publication bias, we reviewed the abstracts from the European and American
TBI meetings, looking at the unpublished trials, and contacted to experts to determine
if negative trials have been carried out and unpublished.
Measures of intervention effect
Intervention efficacy was determined by the good clinical outcome and relative mortality
risk ratio.
In order for the hypertonic saline to be effective in improving the clinical outcome,
we required the threshold of distribution between two groups to be clinically and
statistically significant (P < 0.05).
The risk ratio was determined for mortality in the pooled analysis whereas the Odds
Ratio (OR) was used for analysis of good outcome, subgroup mortality analysis, length
of stay in the ICU, and number of required interventions between two groups.
Subgroup analysis and investigation of heterogeneity
The following subgroup analysis was performed:
-
Subgroup analysis based on the mortality risk among types of hypertonic saline versus
normal saline/lactated Ringer's solution
-
Subgroup analysis based on the length of stay in ICU and number of interventions required
in intervention compared to the control group.
Statistical analysis
Statistical analyses were performed using Review Manager program version 5 that is
provided by the Cochrane Library. This software is used for performing meta-analysis
and presenting the results graphically as per Cochrane Reviews. The data from each
individual study were extracted and put in the review manager software to perform
a pooled meta-analysis.
First, the hypertonic saline, and good and poor outcomes, and mortality were computed
across the different crystalloid used in the different studies were analyzed. The
adjusted Wald method, which provides the best coverage for binomial confidence interval
(CI) when samples are <150, was used for computation of 95% CI. Statistical comparisons
between groups were performed using the Chi-square test and Fisher's exact test as
appropriate. The OR for experimental hypertonic Saline versus crystalloid associated
with good and poor outcome were calculated in all individual studies with available
data comparing the various outcomes among different studies. The OR from separate
studies were combined by the fixed-effects meta-analysis according to the Mantel–Haenszel
method, which is also valid for paired OR. Heterogeneity between studies was assessed
by the Breslow-Day Chi-square test and I2 statistic.[[31]] The I2 statistic describes the percentage of total variation across studies that
are attributable to heterogeneity rather than chance. Compared with the classical
Breslow-Day Chi-square test, its interpretation is more intuitive, and the value does
not depend on the number of studies. There is no simple categorization of values of
I2, although values >75% are usually considered as meaning high heterogeneity.
Results
Description of studies
A total of 364 articles were reviewed from the above-mentioned electronic literature.
Reviewing the grey literature did not add any abstracts. A total of 115 studies were
retrieved and analyzed. In total, 110 articles were excluded, and 5 articles were
added met the inclusion criteria, and included in our meta-analysis. The baseline
characteristics and the outcome of the RCTs, case–control, prospective cohort study,
and retrospective study are summarized in [[Table 1]], [[Table 2]], [[Table 3]], [[Table 4]].
Table 1: Baseline characteristics: Demographic variables
Table 2: Baseline characteristics: Outcome variables
Table 3: Different concentrations of hypertonic solutions
Table 4: Clinical outcomes and results
Risk of bias in the included studies
None of the prospective cohort trials followed adequate sequence generation (computer
generation), and few had the allocation of treatment concealed. Just one article has
double-blinded RCT. This is understandable in this type of prospective cohort study,
in which procedure is evaluated, and it could be difficult to blind the investigator
or the patient to procedure allocation. However, blindness could have been achieved
for functional outcome, and this was not the case in any of the studies except one.
No disclosures were made regarding the funding for these studies.
Effects of interventions
The pooled meta-analysis of all five studies (treatment arm 1107 and control arm 975)
revealed the following:
Five studies have reported the mortality rate in their results.[[32]],[[33]],[[34]],[[35]],[[36]] The RR of mortality at discharge or 6-month is 0.80; 95% CI: 0.64–0.99; P = 0.04.
Hence, the mortality rate is reduced with the hypertonic solutions as compared to
the crystalloid as shown in [[Figure 2]] Panel A.
Figure 2: Panel A: relative risk of mortality in hypertonic solutions versus crystalloids.
Panel B: Good Clinical Outcome in hypertonic solutions versus crystalloids in traumatic
brain injury Panel (a) and (b): Pooled meta-analysis
There is no statistically significant difference in the good clinical outcome at discharge
to 3 months between hypertonic solutions and crystalloids (normal saline and Ringer's
Lactate) (OR of favorable clinical outcome at discharge to 6-month: 0.01; 95% CI:
0.03–0.05; P = 0.65). Hence, there does not exist any comparative difference in the
clinical outcome between the hypertonic solutions and the control arm as indicated
in [[Figure 2]] Panel B.
Only two studies[[33]],[[36]] compared the hypertonic solution versus the normal saline. Bulger et al.[[36]] used two different types of hypertonic saline; 7.5% hypertonic saline and hypertonic
saline/acetate. There is no statistical significance difference in the mortality rate
between the two groups. The OR of mortality at discharge or 6 months; 0.83; 95% CI:
0.68–1.03; P = 0.09 [[[Figure 3]] Panel A].
Figure 3: Panel A: Subgroup analysis comparing relative risk of mortality in hypertonic solutions
versus the normal saline. Panel B: Relative risk of mortality in hypertonic saline
versus lactated Ringers
Regarding the mortality rate in comparison with the lactated Ringers, there is no
statistical significance difference in the mortality rate between the two groups.
OR of mortality rate in hypertonic solution versus lactated Ringers is 0.78; 95% CI:
0.48–1.26; P = 0.31 [[[Figure 3]] Panel B].
Four studies[[32]],[[33]],[[34]],[[36]] indicate the number of interventions during treatment. Interventions mean the use
of hyperventilation, sedation, mannitol, analgesia, and CSF drainage. The number of
interventions required with hypertonic saline is reduced significantly compared to
the normal saline. The OR of number of interventions is 0.53 95% CI: 0.48–0.59; P
< 0.00001 [[Figure 4]].
Figure 4: Subgroup analysis comparing number of interventions in hypertonic saline versus crystalloids.
Interventions means the use of hyperventilation, sedation, mannitol, analgesia, and
cerebrospinal fluid drainage
Two studies[[32]],[[33]] indicated that the stay in the ICU is reduced with the hypertonic solution compared
to the crystalloid. The OR of ICU stay is 0.46 95% CI: 0.21–1.01; P = 0.05 [[Figure 5]].
Figure 5: Subgroup analysis comparing the stay in intensive care unit in hypertonic saline
versus crystalloid group
Discussion
Our study is the first to evaluate whether hypertonic saline has any role in improving
the clinical outcome and mortality among patients with TBI. Our meta-analysis revealed
that hypertonic saline has no statistically significant difference in improving the
clinical outcome and reducing the mortality in patients with TBI. However, because
of the several limitations in the clinical studies (lack of adequate sequence generation,
blindness in randomized and clinical follow-up, and the small sample size in all of
the studies), future double-blinded RCT with large sample size is needed to prove
the concept of this novel intervention. In addition, more evidence is required regarding
different types of hypertonic saline correlating with decrease in the intracranial
pressure, thus improving the clinical and functional outcome.
Neuronal signals processing and transmission are greatly dependent on the brain ionic
and osmotic balance. Despite large fluctuations in the ionic and osmolality composition,
the brain is able to possess a well-developed osmoregulatory mechanism to maintain
the intracellular and extracellular ionic composition and volume within normal limits.[[37]] The interstitial fluid (ISF) also called as intracellular fluid compartment surrounds
cells of the nervous system. Blood–Brain Barrier separates it from plasma whereas
it is separated from the CSF by the ependymal cells lining the ventricles and from
the surface of the brain by pia mater. Both CSF and ISF appear to have a similar composition
that differs from the plasma significantly. K+, HCO3-, Ca2+, and glucose are higher
whereas Mg2+, Cl−, and H+ are lower than those in CSF and ISF.[[37]] As a result of increase in osmolality, there is shrinkage of the brain as cell
membranes are more permeable to water than electrolytes. “Idiogenic osmoles,” composed
of inorganic ions and organic solutes, are accumulated to restore the brain volume
to its normal level known as “Volume Regulatory Increase” in solutes.[[37]]
Acute hypernatremia, defined as the development of NA+>145 mmol/l in 24–48 h. It results
in the prompt reduction in the brain water content. However, the brain works as an
osmometer by rapidly accumulating the solutes to stabilize its brain volume.[[38]]
Acute (15–120 min) hypernatremia in rats showed the reduction in brain volume was
proportional to the increase in plasma osmolality and get stabilized within 15–30
min. However, after 30 and 120 min, the brain water loss was only 35% of the predicted.
In response to acute hyperosmotic stress, intracellular and extracellular water shift
leads to variations in the electrolytes balance especially total brain Na+, Cl− and
K+. Within 15–30 min after the elevation of plasma osmolality as a result of acute
hypernatremia, the brain loses water slowly and stabilizes at a new reduced volume.[[39]],[[40]]
Holliday et al.[[41]] 1968 in a study of rats revealed that 3 h of hypernatremia Na + >200 mmol/L leads
to decrease in the water content of the brain by 14% and 34% increase in Na+, 60%
increase in Cl-and no change in K+.
Our meta-analysis findings are in line with the previous findings.[[32]],[[33]],[[34]],[[35]],[[36]] In our meta-analysis, represents a further step in evaluating the efficacy of 7.5%
hypertonic saline in improving the outcome by decreasing the mortality. However, it
also indicates that there is no clinically significant difference between the hypertonic
saline and normal saline in reducing mortality. There are various kinds of hypertonic
solution with different dose regimens as shown in [[Table 3]].
The administration of mannitol increases the patient risk of renal toxicity and fluid
accumulation in the brain parenchyma leading to worsening of cerebral edema. Therefore,
Ware et al.[[42]] 2005 found that the 23.4% sodium chloride and mannitol when administered for reduction
in intracranial pressure have no significant difference between each other. However,
the increased intracranial pressure (ICP) reduction for hypertonic saline lasted for
96 min whereas that of mannitol lasted for 59 min. There were no complications associated
with hypertonic saline. Kerwin et al.[[43]] 2009 conducted a study on 22-patients with severe TBI and found that 23.4% of HTS
is more efficacious than mannitol in reducing ICP.
Suarez et al.[[44]] 1998 evaluated the efficacy of intravenous bolus administration of 23.4% saline
and found that there was a significant reduction in intracranial pressure and augmentation
in the cerebral perfusion pressure in patients with refractory intracranial pressure
in patients with intracranial disorders. Rockswold et al.[[45]] 2009 found that 23.4% of hypertonic saline decreases the intracranial presure by
mean of 8.3 mmHg (P < 0.0001) and there was improvement in brain tissue oxygenation
by 3.1 mmHg (P < 0.0001) whereas the cerebral perfusion pressure increased by mean
of 6 mmHg (P < 0.0001). The clinical outcome of the patient at 6 months' post-injury
showed that 48% of favorable outcome while mortality was 28%. Paredes-Andrade et al.[[46]] 2012 found that 23.4% hypertonic saline bolus was effective for the reduction of
intracranial pressure in patients with severe TBI despite the presence of high serum
and CSF osmolalities.
DeWitt et al.[[47]] evaluated the effect of resuscitation with 3.0% NaCl, 0.9% NaCl, and 10% hydroxyl
ethyl starch in cats subjected to fluid percussion injury and hemorrhagic hypotension.
There were no significant differences in ICP, cerebral oxygenation, or cerebral blood
flow at 60 and 120 min after the administration of fluid boluses. Weinstsabl et al.[[48]] found that in 10 patients with TBI the ICP was decreased, and HS improved cerebral
perfusion pressure in 7.5% hydroxyethyl starch. Fisher et al.[[49]] compared the efficacy of 3% saline and 0.9% saline infusions on elevated ICP in
pediatric patients with TBI. They found that mean ICP was lowered by a magnitude of
4 mm Hg for 2 h after infusion in the group that received 3% saline without changes
in central venous pressure or renal function.
In addition, more evidence is required regarding the use of various kinds of hypertonic
saline in patients with TBI and the role of different osmotherapies in improving the
prognosis of patients with TBI.
Our study has several limitations. First, there is the possibility of selection and
publication bias in our systematic review, since only two reviewers carried out this
part of the process and he is part of the largest trial in this systematic review.
He might, therefore, be more influenced by the positive trial results than by the
negative ones. However, we tried to limit such bias by doing the following steps:
A gray literature review, in which we reviewed the abstracts from several meetings
to capture any RCT that was presented as an abstract but not published because of
a negative result. Indeed, one abstract was found with a negative result, and it was
included in the meta-analysis (this abstract was available in the electronic research
record, however). Second, the lack of access to individual patient's data is one of
the limitations. Third, there were few trials using different types of hypertonic
solutions for the management of patients. Finally, our meta-analysis results cannot
be generalized to all forms of TBI since we restricted mostly to moderate and severe
TBI.
Conclusion
Our data point to a possible signal of reducing the financial burden by decreasing
the number of interventions and length of ICU stay. However, there does not exist
a significant difference in improving the clinical outcome and reducing mortality
in hypertonic solutions as compared to crystalloid in patients with TBI. Therefore,
it is needed to design an RCT with less bias, and large sample size, for future comparing
various concentrations of hypertonic solutions in patients with TBI.
